Sleep Medicine
FUNDAMENTALS of
Sleep Medicine
Richard B. Berry, MD
Professor of Medicine
University of Florida, Gainesville
Medical Director
University of Florida and Shands Sleep Disorder Center
Gainesville, Florida
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
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This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become
necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating
and using any information, methods, compounds, or experiments described herein. In using such
information or methods they should be mindful of their own safety and the safety of others, including
parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most
current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be
administered, to verify the recommended dose or formula, the method and duration of administration,
and contraindications. It is the responsibility of practitioners, relying on their own experience and
knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each
individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume
any liability for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.
The goal of this book is to provide the reader with a core of fundamental knowledge about
sleep medicine and polysomnography. I have tried to write the book so that a person
without training in sleep medicine can start reading chapter one and progress until the end
of the book. With the publication of the International Classification of Sleep Disorders,
Second Edition, and the American Academy of Sleep Medicine scoring manual, there is a
need for an up-to-date text using current terminology and diagnostic criteria. A single text
cannot hope to cover all aspects of sleep medicine and sleep physiology. Therefore, I have
tried to focus on information that I feel is the most clinically useful. The field of sleep
medicine is changing so rapidly that any text is out-of-date before it is even published.
To this end, there will be an associated website to allow for updates, corrections, review
questions, illustrative case studies, and some video clips of parasomnias.
My inspiration for writing this book has come in part from the satisfaction and appre-
ciation that I received from writing the text Sleep Medicine Pearls. Sleep Medicine Pearls
had short fundamentals chapters mixed with cases and was heavy on graphics and illustra-
tive sleep tracings. I have tried to amplify the fundamentals sections to provide what I hope
is a concise and useful introduction to the entire spectrum of sleep disorders. In particular,
I have tried to cover aspects of the technology of sleep monitoring and interpreting sleep
studies that many new to the sleep field find difficult. The challenging but enjoyable experi-
ence of teaching sleep fellows and residents about sleep medicine has also prompted me to
write a book covering the fundamentals both to serve as an introductory text and to assist
those physicians actively taking care of sleep patients.
Richard B. Berry, MD
vii
viii Chapter 21
Acknowledgments
I would like to express my gratitude for the support and encouragement of the University
of Florida sleep physicians, including Dr. Abby Wagner, co-director of the University of
Florida Sleep Medicine Fellowship, Dr. Stephan Eisenschenk, and Dr. Craig Foster. It is a
pleasure to work with such a dedicated and talented group of individuals. I would also like
to thank Dr. Klark Turpen for her assistance in editing the book chapters. The patience and
assistance of the Elsevier editorial staff is also greatly appreciated. Jessica Pritchard helped
assemble the chapters and many figures. Dolores Meloni, Senior Acquisitions Editor, was
instrumental in developing the concept for the book and provided critical support in the
planning stages. Julie Goolsby, Associate Acquisitions Editor, provided encouragement
during the final stages of book preparation. I am also grateful for the patience and diligence
of Berta Steiner of Bermedica Production, Ltd. during the production process.
viii
Chapter 1
TABLE 11 TABLE 12
Sleep Stage Nomenclature Electroencephalographic Electrode Nomenclature
R&K AASM LEFT RIGHT MIDLINE
Wake Stage W Stage W Frontopolar Fp1 Fp2 Fpz
NREM Stage 1 Stage N1 Frontal F3 F4 Fz
Stage 2 Stage N2
Central C3 C4 Cz
Stage 3 Stage N3
Stage 4 Occipital O1 O2 Oz
REM Stage REM Stage R Mastoid M1 M2
AASM = American Academy of Sleep Medicine ; NREM = nonrapid eye
2
movement; R&K = Rechtschaffen and Kales A1; REM = rapid eye movement;
stages 3 and 4 are combined into stage N3.
F3 Fz F4
20%
C3 Cz C4
M1 M2
20%
O1 O2
20% Oz
10%
Inion
10% 20%
10%
10% O2 10% Nasion
Inion Preauricular F4 F3
M2 Fpz
point
Fp2 Fp1
O1 Oz O2
Inion
TABLE 14
Alternative Electroencephalographic Derivations with Backup Derivations
ALTERNATIVE DERIVATIONS FZ FAILS CZ FAILS OZ FAILS C4 OR M1 FAILS
Fz-Cz Fpz-Cz Fpz-C3 Fz-Cz Fz-Cz
Cz-Oz Cz-Oz C3-Oz Cz-O1 Cz-Oz
C4-M1 C4-M1 C4-M1 C4-M1 C3-M2
TABLE 15
Characteristics of Alpha Rhythm and Sleep Spindles
ALPHA RHYTHM SLEEP SPINDLES
813 Hz. 1116 Hz (classically 1214 Hz).
Most prominent over the occipital areas. Duration 0.5 sec (0.51.5 sec).
Activity increased by eye closure. Maximal over central areas.
Activity suppressed by eye opening. One of the defining characteristics of stage N2.
Predominate EEG activity in drowsy, eyes closed stage W. Thalamocortical oscillations (reticular thalamic
Common in REM sleep (12 Hz slower than during stage W or N1). nucleus).
Can occur with arousals (brief awakenings). Can be seen in stage N3 sleep.
10% of persons do not produce alpha rhythm with eye closure. Drug spindles (benzodiazepines) may be slightly faster.
EEG = electroencephalographic; REM = rapid eye movement.
TABLE 16
Characteristics of K Complex and Slow Wave Activity
K COMPLEX SLOW WAVE ACTIVITY
High amplitudebiphasic deflection. Frequency 0.52 Hz and > 75 V peak to peak in the
A well-delineated negative sharp wave (upward) followed by a frontal derivations.
positive (downward) slow wave. Used to define stage N3 sleep.
Stands out from the lower voltage background. Stage N2 < 20% SWA (<6 sec).
Duration 0.5 sec. Stage N3 20% SWA (6 sec).
Characteristic of stage N2 sleep. SWA is usually transmitted to eye derivations.
Maximal over frontal areas (frontal > central > occipital).
K complexassociated arousal requires arousal to start no more
than 1 second after K complex termination.
SWA = slow wave activity.
TABLE 17
Characteristics of Vertex Sharp and Saw-Tooth Waves
VERTEX SHARP WAVES SAW-TOOTH WAVES
Sharply contoured waves Trains of triangular waves, often serrated
Duration < 0.5 sec 26 Hz waves
Maximal over the central region (derivations containing C3, C4, Cz) Maximal in amplitude in central derivations
and distinguishable from the background activity (higher amplitude). Often, but not always, preceding a burst of REMs
Occurs in stage N1 often near transition to stage N2 Characteristic of stage R but not required for
scoring stage R
REMs = rapid eye movements.
followed by a slow wave (Fig. 14). A burst of spindle activity complex. An arousal during sleep stages N1, N2, and N3 is
is often superimposed on a K complex. A K complex stands scored if there is an abrupt shift of EEG frequency including
out from the lower voltage background. K complex activity alpha, theta, and/or frequencies greater than 16 Hz (but not
is greatest in frontal derivations (also central > occipital). A spindles) that lasts at least 3 seconds, with at least 10 seconds
K complex is said to be associated with an arousal if the of stable sleep preceding the change. Arousals are discussed
arousal commences no more than 1 second after the K in more detail in Chapter 3.
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Chapter 1 Sleep Stages and Basic Sleep Monitoring 5
30 second
window
(as viewed)
1 sec
10 second
window
(as viewed)
1 sec
TABLE 18
Summary of Important Wave Form Characteristics
ALPHA SLEEP VERTEX SLOW WAVE SAW-TOOTH
RHYTHM SPINDLE K COMPLEX SHARP WAVE ACTIVITY WAVES
Frequency (Hz) 813 1116 N/A N/A 0.52 26
Amplitude/ Oscillation Spindle- High amplitude Sharp wave High-amplitude Triangular,
shape shaped (usually > 100 V) broad wave serrated
oscillation Stands out against >75 V peak to
EEG background peak
Biphasic-negative
sharp wave
followed by positive
component
Duration Variable 0.5 >0.5 sec <500 msec 0.52 sec Variable
Location of Occipital Central Frontal Central Frontal Central
highest (vertex)
amplitude
Associated Stage W Stage N2 Stage N2 Stage N1 Stage N2 Stage R
sleep stages/ Stage N1 Stage N3 Stage N3 Stage N3
events Stage R
Arousals
EEG = electroencephalogram; N/A = not applicable.
100 V
1 sec
V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
Alpha waves Sleep spindle K complex Vertex sharp Slow waves Saw-tooth waves
wave
FIGURE 14 Important EEG patterns for sleep staging. The grid lines are 1 second apart. V = position of the vertex sharp wave.
75 V
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin1-Chin2
FIGURE 15 A K complex associated with an arousal. An abrupt shift in EEG frequency immediately follows the K complex that lasts greater than 3 seconds. To be
considered associated with a K complex, an arousal must commence no later than 1 second after K complex termination.
a peak-to-peak amplitude of greater than 75 V in the meeting amplitude criteria) using the AASM scoring manual
frontal derivations (see Fig. 14). SWA has the greatest definition2 (frontal derivations) compared with the R&K
amplitude over frontal areas. In the R&K definitions, only definition (using central derivations).
central derivations were utilized. Because slow wave ampli- Vertex sharp waves (see Fig. 14) are narrow-duration
tude is higher over the frontal areas, a given epoch of EEG waves (<500 msec according to the AASM scoring manual2)
activity would potentially have greater SWA (longer duration prominent in derivations containing electrodes near the
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Chapter 1 Sleep Stages and Basic Sleep Monitoring 7
1 cm 1 cm 1 cm
LOC
E1 E2 E1
vertex (Cz, C3, C4). They are often seen near the transition E2
Look Look
between stage N1 and stage N2 sleep. Saw-tooth waves (see left right
Fig. 14) occur during REM sleep, although they are not
always present during this sleep stage. They are triangular
waves of 2 to 6 Hz of highest amplitude in the central deriva- E1
tions. The presence of saw-tooth waves is not required to
score stage R. However, the presence of saw-tooth waves is E1-M2
very helpful when they occur.
EOG MONITORING FOR SLEEP E2-M2
Recording of eye movements is possible because a potential
difference exists across the eyeball with the front/cornea E1 positive to M2, E1 negative to M2,
positive (+) and back/retina negative (). Eye movements are deflection down deflection up
detected by EOG recording of voltage changes associated E2 negative to M2, E2 positive to M2,
with eye movement. deflection up deflection down
The recommended EOG electrodes in the AASM scoring FIGURE 17 Schematic shows deflections in E1-M2 and E2-M2 from eye movements.
manual2 are illustrated in Figure 16. E1 and E2 refer to the
left and right eye electrodes, respectively. Previously eye
electrodes were named right outer canthus (ROC) and left In the recommended EOG derivations, eye movements
outer canthus (LOC). For comparison, the positions of the result in out-of-phase deflections. This is because eye move-
ROC and LOC electrodes are also shown. Please note that ments are conjugate, and when both eyes move laterally or
E1 is placed below the LOC and E2 is placed above the ROC, vertically, they both move toward one EOG electrode and
whereas LOC and ROC were placed lateral to the respective away from the other EOG electrode. The polarity of the eye
outer canthus. Because E1 is below and E2 above the eyes, electrodes determines the net voltage difference of the EOG
vertical as well as horizontal movement can be detected. derivations because the electrodes are much closer to the
Alternate eye electrode positions were also recommended eyes than M2. The schematic in Figure 17 illustrates eye
for use with alternate eye movement derivations (see movements and the resulting deflections (this assumes that
Fig. 16). The AASM scoring manual recommends the both eye derivation tracings have negative polarity upward
EOG derivations E1-M2 and E2-M2 (see Table 18). Note which is standard).
that both eye derivations use the right mastoid (M2) as the Note that when the alternate EOG derivations E1-Fpz and
reference electrode. Previous ROC and LOC derivations E2-Fpz are used, both E1 and E2 are 1 cm below and 1 cm lateral
varied between sleep centers, and these electrodes were ref- to the LOC and ROC, respectively. In this scheme, vertical
erenced either to the same mastoid or to the opposite eye movements result in in-phase deflections and lateral eye
mastoid. The AASM scoring manual also specified the alter- movements result in out-of-phase deflections (Fig. 18). The
native eye movement derivations (E1-Fpz and E2-Fpz). If these advantages of the alternative EOG derivations are that verti-
eye movement derivations are used, both E1 and E2 are cal deflections tend to produce larger deflections (blinks are
below and lateral to the LOC and ROC, respectively (see more prominent) and one can distinguish vertical (in-phase)
Fig. 16). from horizontal (out-of-phase) eye movements. In addition,
When the eyes move toward an electrode, a positive it is easy to remember that downward eye movements result
voltage is recorded (Fig. 17). Recall that in EEG recording, in downward deflections in the eye derivations and upward
by polarity convention, if an eye electrode is negative com- eye movements result in upward deflections. Alternatively,
pared with the reference electrode, the signal has an upward the recommended eye derivations make it easier to recognize
deflection. Thus, eye movement (cornea +) toward an elec- artifacts or EEG activity transmitted to the eye derivations
trode referenced to another electrode further away from the because these cause in-phase deflections while eye move-
eyes results in a downward deflection. ments cause out-of-phase deflections (Fig. 19).
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8 Chapter 1 Sleep Stages and Basic Sleep Monitoring
TABLE 110
Fpz Look Look Eye Movements Pattern Definitions
up down Eye blinks: Conjugate vertical eye movements at a
frequency of 0.52 Hz present in wakefulness with the
eyes open or closed.
E2 E1 Reading eye movements: Trains of conjugate eye
E1-Fpz movements consisting of a slow phase followed by a
rapid phase in the opposite direction as the subject reads.
Slow eye movements: Conjugate, fairly regular,
E2-Fpz sinusoidal eye movements with an initial deflection
lasting > 500 msec.
Rapid eye movements (REMs): Conjugate, irregular,
FIGURE 18 Schematic shows deflections in E1-Fpz and E2-Fpz due to horizontal and
sharply peaked eye movements with an initial deflection
vertical eye movements. Note that, using these derivations, vertical eye movements
usually lasting < 500 msec. Whereas rapid eye movements
result in in-phase deflections whereas lateral eye movements result in out-of-phase
are characteristic of stage R sleep, they may also be seen in
deflections. In addition, downward eye movements result in downward deflections.
wakefulness with eyes open (as patients look around the
room)
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.
F4-M1
C4-M1
O2-M1
E1-M1
E2-M2
Chin EMG
K complex REM
FIGURE 19 Using the recommended electro-oculographic (EOG) derivations, the K complex results in deflections that are in phase and the rapid eye
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movement (REM) results in out-of-phase deflections. The vertical lines are 1 second apart. EMG = electromyography.
Chapter 1 Sleep Stages and Basic Sleep Monitoring 9
100 V
1 sec
Reading eye
E1-M2
movements
E2-M2
E1-M2
Blinks
E2-M2
FIGURE 110 Eye movement patterns. The grid lines are 1 second apart.
but can occur with any of the SSRIs (see Chapter 4). Reading THREE ELECTRODES ARE RECOMMENDED
eye movements are due to a slow scan of the written page TO RECORD THE CHIN EMG
(left to right) followed by a rapid return to the left. This
results in a slowly increasing downward deflection in E2-M2
followed by a rapid upward deflection. In E1-M2, there is a
slow upward deflection followed by a rapid downward
deflection (see Fig. 110). Chin1
B
F4-M1
C4-M1
O2-M1
E1-M2
C
E2-M2
Chin EMG
A
FIGURE 112 A 30-second tracing shows a reduction in the chin EMG on transition to stage R sleep (A). Note saw-tooth waves (B) and REMs (C).
3. D. Sleep spindles have a frequency of 1116 Hz and rep- of Sleep and Associated Events: Rules, Terminology and Tech-
resent thalamocortical oscillations generated by the retic- nical Specifications, 1st ed. Westchester, IL: American Academy
of Sleep Medicine, 2007.
ular nucleus of the thalamus. Sleep spindles are most
3. International Federation of Societies for Electroencephalogra-
prominent in central derivations. phy and Clinical Neurophysiology: Ten twenty electrode
system. EEG Clin Neurophysiol 1958;10:371375.
4. B. SWA is characterized by a minimum amplitude peak 4. Williams RL, Karacan I, Hursch CJ: Electroencephalography of
to peak of > 75 V in the frontal derivations with a fre- Human Sleep: Clinical Applications. New York: John Wiley &
quency of 0.5 to 2 Hz. Sons, 1974.
5. West P, Kryger MH: Sleep and respiration: terminology and
5. A. In the recommended derivations, eye movements methodology. Clin Chest Med 1985;6:691712.
6. Caraskadon MA, Rechschaffen A: Monitoring and staging
cause out-of-phase deflections. Because the cornea is
human sleep. In Kryger MH, Roth T, Dement WC (eds): Prin-
positive with respect to the retina, a rightward gaze results ciples and Practice of Sleep Medicine. Philadelphia: Elsevier
in E2 being positive with respect to M2 (E2 is closer to the Saunders, 2005, pp. 13591377.
cornea) and this results in a downward deflection. With 7. DeGennaro L, Ferrara M: Sleep spindles: an overview. Sleep
a rightward gaze, E1 is negative with respect to M2 (upward Med Rev 2003;7:423440.
8. McCormick L, Nielsen T, Nicolas A, et al: Topographical dis-
deflection).
tribution of spindles and K complexes in normal subjects. Sleep
1997;20:939941.
6. A. SEMs can occur during wake (eyes closed drowsy 9. Silber MH, Ancoli-Israel S, Bonnet MH, et al: The visual
wake) or stage N1 and are sinusoidal out-of-phase scoring of sleep in adults. J Clin Sleep Med 2007;15:121131.
movements. 10. Schenck CH, Mahowlad MW, Kim SW, et al. Prominent eye
movements during NREM sleep and REM sleep behavior dis-
REFERENCES order associated with fluoxetine treatment of obsessive-
compulsive disorder. Sleep 1992;15:226235.
1. Rechtschaffen A, Kales A (eds): A Manual of Standardized 11. Armitage R, Trivedi M, Rush AJ: Fluoxetine and oculomotor
Terminology, Techniques and Scoring System for Sleep Stages activity during sleep in depressed patients. Neuropsychophar-
of Human Sleep. Los Angeles: Brain Information Service/Brain macology 1995;12:159165.
Research Institute, UCLA, 1968.
2. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring
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Chapter 2
It should be noted that a localized EEG transient (e.g., and abdomen), leg EMG inputs, and electrocardiographic
sharp wave) that is located midway between two electrodes (ECG) inputs.
will produce an equal signal in both sides of the differential In referential recording, multiple electrodes are recorded
AC amplifier that will cancel out (output approximately against a common electrical reference (often a single or two
zero). This cancellation effect will alter the overall EEG signal linked electrodes placed near the vertex). A display of any
amplitude less if electrodes are further apart. Thus, a greater derivation using two referentially recorded electrodes is then
distance between two electrode inputs will increase the obtained by digital subtraction [(electrode A reference)
amplitude of the recorded signal (less cancellation). This is (electrode B reference) = electrode A electrode B] either
one reason the recommended EEG derivations use contra- during live recording or during review (see Fig. 23). The
lateral mastoid references (C4-M1, not C4-M2). digital subtraction for display does NOT change the recorded
data. For example, if the sleep technologist failed to observe
REFERENTIAL AND BIPOLAR RECORDING that the electrode F4 went bad during the recording, the
reviewer can change the viewed frontal derivation to F3-M1
Most digital recording systems use a combintation of refer- or F3-M2 (the recommended alternative) (Fig. 24). For this
ential, true bipolar, and DC recording (Table 21).2 In true reason, both F3 and F4 are recorded (against the reference
bipolar recording, each amplifier records the difference electrode) even though only F4-M1 may be displayed in the
between two electrodes of interest (AB, CD). Before the default montage. Of note, if the reference electrode is faulty,
digital era, paper recording was performed using a selector all referential signals are affected (Fig. 25). In Figure 25,
panel and dedicated individual differential amplifiers. Using note that the true bipolar channels are not affected by a faulty
this approach, it is possible to change the electrodes (deriva- reference electrode. In most digital PSG systems, the EEG,
tion) that are recorded with a given amplifier (Fig. 23). EOG, mastoid, and chin EMG electrodes are recorded refer-
However, changing the derivation once the signal is recorded entially (see Table 21). DC recording is used for nasal pres-
(changing from AB to AD) is not possible. Today, selector sure, pulse oximetry, and other DC signals such as those
panels are rarely used in digital sleep recording. However,
true bipolar recording is still used for inputs that one would
not desire to change in reviewfor example, the two inputs TABLE 21
of the thermal flow sensor, respiratory effort bands (thorax Types of Recording
Referential EEG: F4, F3, C4, C3, O2, O1, M1, M2
recording EOG: E1, E2, M1, M2
IF G1 IS NEGATIVE TO G2,
DERIVATION G1-G2 THE DEFLECTION IS UPWARD Chin1, Chin2, Chin3
Reference
30 V
True bipolar ECG, thermal flow, thorax and
Differential amplifier 20 V
(two inputs abdominal sensors, right and left
each) anterior tibial EMG
G1
DC Nasal pressure, SpO2, positive airway
G2 0 pressure device (flow, leak, pressure),
end-tidal or transcutaneous PCO2
10 V
Ground ECG = electrocardiography; EEG = electroencephalography;
EMG = electromyography; EOG = electro-oculography; PCO2 = partial
FIGURE 21 Differential amplifier. The difference between the two inputs is amplified
pressure of carbon dioxide; SpO2 = pulse oximetry.
(for simplicity, the amplification factor = 1).
DETAILS
DIFFERENTIAL AMPLIFIER
80 V Common mode rejection Input 1
60 V
Input 1 Output
20 V
Output 1 Ground
0
Ground
Input 2
Input 2
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FIGURE 22 Common mode rejection by a differential amplifier (for simplicity, the amplification factor = 1).
Chapter 2 The Technology of Sleep Monitoring 15
BIPOLAR RECORDING REFERENTIAL RECORDING FIGURE 23 The difference between true bipolar
recording and referential recording. In referential
C4 C4-M1 C4
Amplifier 1
recording, each electrode is recorded against a common
C3 C3 reference. Specific derivations are then displayed by
C3-M2 Reference (Ref) digital subtraction (during acquisition or review).
M1 Amplifier 2 M1
M2 M2
Selector box
DISPLAY BIPOLAR VIEWS
F4-M1
F3-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 24 In the F4-M1, derivation 60-Hz artifact is present. The F4 electrode is at fault because other derivations containing M1 are not affected.
The displayed derivation is then changed to F3-M1, allowing an artifact-free frontal derivation to be viewed. Viewing a derivation using any two of the
referentially recorded electrodes is possible. The recommended derivation when the F4 electrode is faulty is actually F3-M2, but the use of F3-M1 is shown
for illustration. EMG = electromyography.
E1-M2
E2-M2
F4-M1
C4-M1
O2-M1
Chin1-Chin3
ECG
R, L legs
Airflow
Chest
Abdomen
SpO2
A B
FIGURE 25 A, The reference electrode is faulty. All referentially recorded electrodes show artifact. The true bipolar channels and DC
channels are not affected. In B, the reference electrode was repaired. SpO2 = pulse oximetry.
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16 Chapter 2 The Technology of Sleep Monitoring
000000000011
1250 000000000100
used, the signal can be very distorted and the addition of 000000000101
000000000110
frequencies lower than the original signal sampled may be
introduced (Fig. 26). For this reason, signals with a fre-
quency higher than half the sampling rate must be filtered Etc,
out because they can cause aliasing distortion.2,4,5 For Input at
example, if the sampling rate is 200 samples/sec, the ampli- A/D board
fied signal must be processed by a high frequency filter with Resolution 0.97 V per bit
a cutoff frequency of 100 Hz or lower before being sampled
(A/D converter). The required sampling rate depends on the FIGURE 27 Dynamic range and resolution of an analog-to-digital (A/D) converter.
frequency of the signal to be recorded. Slower varying signals
require a lower sampling rate. In Table 22, the sampling range. A typical A/D converter might have a dynamic range
rates recommended by the American Academy of Sleep for the amplified signal of 5 V (2.5 V). Commonly, a set
Medicine (AASM) scoring manual6 are illustrated. Some amplification is applied to all AC signals before A/D conver-
digital PSG systems have the ability to record different signals sion (e.g., a gain of 1250). If one assumes an amplification of
at different sampling rates. Ultimately, the computer program 1250, then the dynamic range (peak to peak) of an A/D
uses only a small portion of the data for the display because converter with an amplified voltage range of 5 V expressed
monitor resolution (in pixels per displayed time duration) is as the unamplified signal would be approximately 4000 V
usually much less than the sampling rate.5 (4000 V 1250 = 5,000,000 V = 5.0 V). If a 12-bit A/D
A/D conversion is also characterized by the dynamic converter is used, this would result in a resolution of 0.97 V/
range (the range of voltages accepted by the A/D converter) bit (4000 V/4096 digital values) (Fig. 27).
and the resolution. The dynamic range may be expressed as
the amplified or unamplified signal range. The resolution
Monitor Resolution
depends on the A/D converter as well as the dynamic range.
A 12-bit DC converter produces 212 = 4096 digital values An important limitation on the accuracy of signal recording
(bits) or a 16-bit converter = 65,536 values across the dynamic and display is introduced by the fact that the monitor
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Chapter 2 The Technology of Sleep Monitoring 17
Respiratory event
100%
95%
SpO2 90%
85%
80%
75%
Desaturation
Left
Right
Position Prone
Supine
Sitting
Wake
REM
Stage 1
2
3
Epoch
Time
FIGURE 28 An overview of the entire night of the recording shows respiratory events, pulse oximetry (SpO2), desaturation events, body position, and sleep stage
(hypnogram). REM = rapid eye movement.
resolution is usually much lower than the data sampling rate. an all-night condensed view with graphs of the hypnogram
Because the sampling rate used for most digital systems is (representation of sleep stages), arterial oxygen saturation
200 samples/sec or higher, the resolution of the monitor is (SpO2 tracing), continuous positive airway pressure (CPAP)
often the limiting factor in the accuracy of signal display. The levels, respiratory events, and body position (Fig. 28). This
minimum monitor resolution recommended by the AASM allows a useful overview of the entire recording. One can
scoring manual is 1600 1200. Assuming 1600 pixels hori- usually select a time point (double click) on a given position
zontally, the visual sampling rate for displays of a 30- or in the summary view and be taken to that time point in the
10-second window of data corresponds to a sampling rate of more detailed tracings.
approximately 50 and 150 samples/sec if the entire monitor
display consists of waveforms. Then according to the Nyquist FILTERS (LOW-FREQUENCY, HIGH-
theorem, frequencies of 25 or 75 Hz or greater would be
FREQUENCY, AND NOTCH FILTERS)
prone to aliasing. A monitor-induced aliasing distortion of
data can sometimes be noted if switching from a 30-second Any signal of interest can be contaminated by unwanted
to a 10-second view significantly changes the shape of the low- or high-frequency signals or 50- to 60-Hz artifact (from
activity being visualized.5 nearby AC power lines). Filters allow these components to
be diminished. For example, a low-frequency filter (high-
pass filter) attenuates the amplitude of low-frequency signals.
Time Window for Display
A high-frequency filter (low-pass filter) attenuates the ampli-
During traditional paper-ink recording for sleep, the paper tude of high-frequency signals.1 The amount of signal reduc-
speed was 10 mm/sec, which produced 30-second pages (30- tion due to a given analog or digital filter is given in decibels.
cm-wide paper). A faster speed was used for clinical EEG The amount of signal reduction in decibels (dB) is given by
(30 mm/sec). However, such a fast paper speed would the formula 20 log (voltage-out/voltage-in), where voltage-
produce a very large amount of paper for each sleep study. out and voltage-in are the amplitude of the signal entering
In digital recording, one can choose various time windows and leaving the filter, respectively. A signal reduction of 30%
during either acquisition or review. A 30-second window and 50% (voltage-out/voltage-in ratios of 0.7 and 0.5,
(equivalent to a paper speed of 10 mm/sec) is used for sleep respectively) corresponds to 3 dB and 6 dB reductions. Dif-
staging and for scoring arousals. Time windows of 60 to 240 ferent filter settings (e.g., 0.3, 1) are named by the cutoff
seconds may be used to view and score respiratory events frequency, which is the frequency of the signal that is reduced
and leg movements. Alternatively, viewing data in a by 3 or 6 dB depending on the terminology and the type of
10-second window (equivalent to 30 mm/sec) is the usual filter the manufacturer uses. Therefore, a filter setting of X
method for clinical EEG recording. This allows better visu- Hz means that the amplitude of a signal with a frequency
alization of very brief events (sharp waves and spikes) and of X is diminished by 30% or 50% depending on whether the
interictal or epileptiform activity. The 10-second window 3 dB or 6 dB cutoff frequency is used to name the filter.
can also be useful for measuring the frequency of a group of
oscillations or viewing the ECG result. The traditional ECG
Low-Frequency Filter
speed is 25 mm/sec, which is quite close to 30 mm/sec. Some
systems allow split screens with different time windows in A 1-Hz low-frequency filter (3 dB) attenuates a 1-Hz signal
each screen. All digital sleep monitoring systems also provide by 30% (or to 70% of the original signal). Similarly, a 6 dB
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18 Chapter 2 The Technology of Sleep Monitoring
filter would attenuate a 1-Hz signal by 50%. Signal strength circuits. In RC circuits, an increase in step voltage produces
of frequencies below 1 Hz would be attenuated even more an abrupt increase in voltage across the resistor, then an
(Figs. 29 and 210). It is important to realize that frequen- exponential fall in voltage to 1/e (0.37) of the maximum
cies slightly above the low-frequency filter setting of 1 Hz voltage in one time constant (TC). In a simple, low-frequency
will also be attenuated by a 1-Hz low-frequency filter, filter RC circuit, the frequency (fc) at which the output
although to a lesser degree. Figure 210 illustrates the effect voltage across the resistor is attenuated to 0.37% of the input
of various low-frequency filters (denoted by their 3 dB cutoff voltage is related to the TC by the formula fc = 1/(2/TC).
frequency) on low-frequency signals. A range of possible In RC circuits, the TC = RC, where R is the resistance and
low-frequency filter settings (off, 0.01, 0.03, 0.1, 0.3, 1, 3, and C the capacitance of the circuit. Even if digital filters are
10) is commonly provided. used, the relationship between the TC and the 3 dB fre-
Sometimes low-frequency filter settings are specified as a quency is given by Equation 21:
time constant rather than as a cutoff frequency (Fig. 211).
Traditional analog filters used resistance-capacitance (RC) TC = 1/(2 filter frequency ) Equation 21
Percent amplitude
3 less than 50%
the horizonal axis uses a logarithmic scale and 75 75
Filter setting of 1
the vertical axis is linear. 50 10 50 reduces signal with
frequency of 1 Hz
25 25 by 50%
Filter settings 1.0
0 0 Lower frequency
0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10
attenuated more
Signal frequency Signal frequency than 50%
LF 0.3
LF 1 70
LF 3 100 V
1 second
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Chapter 2 The Technology of Sleep Monitoring 19
Vin input
voltage LF = 0.3 Hz TC = 0.53
LF = 1 Hz TC = 0.16
Voltage 37%
across R
37% LF = 5 Hz TC = 0.03
TC
1 sec
30 Hz high filter FIGURE 212 The effects of a high-frequency filter. A 6 dB 30-Hz filter
0.3 Hz low filter Frequency slightly attenuates a 30-Hz signal by 50%. Signals less than 30 Hz are attenuated
lower than 30 Hz less (low pass). Signals with a frequency higher than 30 Hz are attenuated
100 attenuated slightly much more. The gray shows a frequency range that is attenuated less
Percent amplitude
For example, a 0.3-Hz low-frequency filter has a TC of Using the combination of a low-frequency and a high-
approximately 0.53 second. Of note, the actual TC after a frequency filter, a range of frequencies is amplified. Alterna-
step increase in voltage may vary depending on the high- tively, if digital filters are applied to raw digital data, a range
frequency filter setting as well. The lower the cutoff fre- of frequencies is displayed. The range of signal displayed or
quency, the longer the time constant (see Fig. 211). If amplified is called the bandwidth.
amplifiers are calibrated by step (square wave) voltage
change, the actual TC can be noted from the time it takes 60-Hz or Notch Filters
for the deflection to return to 0.37 of the maximum Most amplifiers (digital PSG systems) provide optional notch
deflection. filters to significantly attenuate a narrow range of frequency
associated with power line signal contamination (e.g., 50 or
60 Hz). The notch filter can be added or removed. If the
notch filter is turned on, it is applied to the signal in addition
High-Frequency Filters
to the low-frequency and high-frequency filters. The routine
A 35-Hz high-frequency filter attenuates a signal of 35 Hz use of a notch filter is usually not recommended. The sudden
by 50% (6 dB filter), and frequencies above 35 Hz would appearance of increased 60-Hz activity in a derivation is a
be attenuated more. In addition, frequencies slightly below clue that one or more electrodes is faulty. However, as previ-
the high-frequency filter setting will also be slightly attenu- ously mentioned, use of a high-frequency filter of 35 Hz
ated. Figure 212 illustrates the effects of a 6 dB 30 Hz (commonly used for EEG and EOG derivations) already
filter. A range of high-frequency filter settings is typically substantially attenuates a 60-Hz signal (much the same as
provided (off, 3, 15, 35, 70, and 100 Hz). Note that using a turning on the 60-Hz filter)
30-Hz high-frequency filter (see Fig. 212) significantly Turning on and off the 60-Hz (notch) filter can be useful
attenuates 60-Hz signals. Therefore, the addition of a 60-Hz in determining the degree of signal contamination by 60-Hz
notch filter adds little if a 30- to 35-Hz filter is already interference. If turning off the notch filter dramatically
being used. increases signal amplitude, this suggests considerable 60-Hz
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20 Chapter 2 The Technology of Sleep Monitoring
0.03
0.1
0.3
Nasal
pressure
Snore
Nasal
pressure
Snore
accessory box for DC channel inputs or dedicated input jacks derivations and processes the data with the selected digital
on the amplifier are also usually available. The amplifier is low-frequency and high-frequency filters. A display sensitiv-
then connected to the A/D converter. Today, the A/D con- ity is also chosen to determine the upper and lower limits
verter is often contained within the amplifier that sits at the of data to be displayed in the channel width (digital gain).
patients bedside. The digitized signal can then be sent over The changes in the display (specific derivations, digital
ethernet cables to the computer or sent in the wireless mode filters, digital gain) do not change the raw data that are
to a computer, which then records the digital data. This recorded by the computer. The entire process is summarized
arrangement avoids the difficulties that occur when an in Figure 216.
analog signal is sent over a long distance (60 Hz contamina-
tion or loss of signal strength). A schematic of a typical
Montages for Digital Recording
system is shown in Figure 216. A typical PSG amplifier
often has a fixed gain and default low- and high-frequency Digital systems allow the user to specify a number of user-
filter settings (e.g., 0.1 and 100 Hz). AC signals are recorded defined display montages with the ability to select the
over a wide frequency range (bandwidth). The A/D con- number of channels (traces) to be displayed, the derivations
verter samples the signal and raw digital data are stored in for each channel, the order in which the desired derivations
the computer. After the raw data are digitized and stored, are displayed (the inputs for each channel), as well as the
extensive manipulation is possible to produce the desired sensitivity (gain), low- and high-frequency filter settings,
signal display. During acquisition and review, the computer notch filter on or off, and the color of each tracing. A sample
program performs digital subtraction to display the desired montage (Table 24) is displayed in Figure 217. Typically,
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22 Chapter 2 The Technology of Sleep Monitoring
Amplifier
Computer
Fixed
program Data
gain Raw
Electrode A/D display
LF 0.1 data Digital sensitivity
box converter
HF 100 stored Digital filters C4-M1
C4 -Ref (LF, HF)
M1 -Ref
FIGURE 216 Schematic of a digital polysomnography (PSG) system. In many systems, the A/D converter is within the same
unit housing the amplifier(s). Modern digital PSG systems usually perform a fixed amplification with default low (LF) and high
(HF) filters permitting a wide frequency range to be amplified. The digitized data are stored on media (hard drive in the
computer). The PSG software then scales the raw data, applies the selected low-frequency and high-frequency filters, and
provides a display (either during acquisition or at review).
TABLE 24
Montage 1: Diagnostic Adult
CHANNEL INPUT SENSITIVITY (P-P) LF HF NOTCH
(TRACING) TYPE INPUT 1 INPUT 2 V UNLESS DC (HZ) (HZ) FILTER
1 Ref F4 M1 150 0.3 35 Off
2 Ref C4 M1 150 0.3 35 Off
3 Ref O2 M1 150 0.3 35 Off
4 Ref F3 M2 150 0.3 35 Off
5 Ref C3 M2 150 0.3 35 Off
6 Ref O1 M2 150 0.3 35 Off
7 Ref E1 M2 150 0.3 35 Off
8 Ref E2 M2 150 0.3 35 Off
9 Ref Chin1 Chin2 150 10 100 Off
10 BP ECG1 ECG2 1500 0.3 70 Off
11 DC Nasal pressure N/A 1 to +1 V
DC 100 Off
*
12 BP NOTFinput 1 Input 2 750 0.1 15 Off
*
13 BP Snoreinput 1 Input 2 750 10 100 Off
*
14 BP Thoraxinput 2 Input 2 1500 0.1 15 Off
*
15 BP Abdomeninput 1 Input 2 1500 0.1 15 Off
16 DC SpO2 DC 01 V DC N/A Off
17 BP RATinput 1 Input 2 150 10 100 Off
18 BP LATinput 1 Input 2 150 10 100 Off
*The sensitivity settings for bipolar channels depend on the output range for a particular device.
Varies with transducer type.
BP = dedicated bipolar inputs (input-1, input-2); ECG = electrocardiography; HF = high frequency filter setting; LAT = left anterior tibial; LF = low frequency filter
setting; N/A = not applicable; NOTF = nasal-oral thermal flow sensor; P-P = peak to peak; RAT = right anterior tibial; Ref = referential input; SpO2 = pulse oximetry.
one montage is adapted for a diagnostic study and another gain), low-frequency and high-frequency filters, channel
for a positive-pressure titration. During review or acquisi- width, and inversion of signal. Default settings for each
tion, each individual channel may be altered if so desired or channel can be specified, so they do not have to be individu-
an entirely different montage may be displayed. ally set for each recording. Figure 217 illustrates typical
channel controls. Recall that changes in channel settings do
not change the recorded (and digitally stored) data.
Channel Settings/Montages
In sleep recording using paper, the EEG was usually
Each channel (tracing) display can be changed by the viewer recorded at a sensitivity of 50 V/cm in adults. In children,
with respect to the inputs, sensitivity (sometimes called a lower sensitivity (100 V/cm) was used because of the very
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Chapter 2 The Technology of Sleep Monitoring 23
high amplitude EEG activity. The term gain rather than ultimate size of the channel width depends on the way the
sensitivity was also used. However, this implies an amplifica- computer program scales the signal for display. Some pro-
tion of signal. In digital recording, amplification actually grams have an option to allow signals either to overlap or to
occurs before the signal is digitized. The size of the display be cropped if they exceed the given channel width.
of a given signal is varied by the computer program that
scales the display based on the available channel width and Impedance Checking and Referential
the voltage limits or sensitivity. For example, if a channel
Display View
width of 100 pixels represents 100 V peak to peak, a signal
of 50-V peak to peak would vary between the 25th and the Traditionally, after electrodes were applied to the patients
75th pixel. The default digital displays for EEG often use 100 head, the impedance of each electrode was checked by plug-
or 150 V peak to peak per channel width (200 for children). ging the electrodes into an impedance box that allowed com-
Figure 218 shows two methods of adjusting the display parison of any electrode referred to the ground electrode or
(gain/voltage per division or peak-to-peak sensitivity). The a combination of all the other electrodes. Most digital
systems can measure impedance on line using a signal from
the amplifier. The values can then be stored with other digital
Channel 5 data for later review. The AASM scoring manual recom-
mends a maximum electrode impedance of 5 K (<10 K
Input 1 Input 2 Low freq filter High freq filter
is acceptable). Another useful method of looking at the
C4 M2 0.3 Hz 35 Hz
quality of each individual electrode is to display all of
the unfiltered referentially recorded electrode against the
Notch filter On Off common reference (rather than the digital subtraction of two
Trace width
100 Sensitivity referentially recorded electrodes). Figure 219 displays a ref-
erential view with all high-frequency filters set to 100 Hz.
100 V p-p Electrode impedance is also displayed. One can tell that F4,
Invert
Chin2, and Chin3 electrodes are faulty and should be
FIGURE 217 Example of typical controls for each display channel (tracing). Controls changed or fixed. As previously noted, if all tracings on the
allow selection of the derivation, low-frequency and high-frequency filters, notch filter referential view are bad, this suggests a problem with the
(on or off), and sensitivity. On most digital PSG systems, channel width and trace color reference electrode. However, a faulty reference electrode
can also be selected. p-p = peak to peak. does not affect the true bipolar channels (see Fig. 25).
1 second
One division
100 V/division
50 V/division
Channel width
FIGURE 218 Two methods of adjusting the sensitivity (digital gain) are shown. A 100-Hz peak-to-peak signal of 10 Hz is shown. The top panels
specify a voltage per division value. A larger channel width is needed to display a given signal if the actual division size remains constant when voltage per
division decreases. The bottom panel illustrates a method by which the peak-to-peak voltage of the entire channel width is specified. The actual
channel width will depend on the way the computer program scales the display.
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24 Chapter 2 The Technology of Sleep Monitoring
Impedance
O1-REF 6.4 K
O2-REF 6.3
C3-REF 5.6
C4-REF 2.5
E1-REF 3.5
E2-REF 4.4
M1-REF 4.8
M2-REF 4.3
Chin1-REF 3.8
Chin2-REF 19.2
Chin3-REF 10.3
F3-REF 6.7
F4-REF 30.2
FIGURE 219 A referential display with each electrode displayed against the common reference electrode. The electrode impedance is also displayed. One
can see that the Chin2, Chin3, and F4 electrodes should be replaced or repaired.
Reference
Patient
ground Circuit
ground Power
Chassis
ground Earth ground NH
Video-Audio PSG
sec). Simultaneous audio is also usually available and this is
Today, most digital systems allow for the simultaneous very useful for documenting teeth grinding (bruxism),
recording of video and audio signals. Ideally, the video talking during parasomnias, snoring, and other behaviors
should be synchronized with the recorded EEG and other during the recording.
signals. This will allow the reviewer to see patient movement
corresponding exactly to a given time point in the recorded
Grounds
PSG signals. For example, one could note facial twitching
during a particular EEG pattern. Video PSG is an important The terminology is confusing with three different grounds
development and allows the reviewer to confirm the patient being used in modern PSG recording (Fig. 220). These
position as well as document unusual behavior (e.g., para- include
somnias) during the night. Video files are often quite large
and are usually compressed (e.g., MPEG4). The size of the 1. The patient ground (iso-ground input on the electrode
file will depend on the quality of the video (10 or 25 frames/ box). This neutral electrode is usually connected to the
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Chapter 2 The Technology of Sleep Monitoring 25
forehead. It is used to balance the inputs of all the differ- C. Decreases the amplitude of a 0.1-Hz signal more than
ential amplifiers (essential for common mode rejection). a 0.3-Hz signal.
2. Chassis ground (container ground). Because a metal D. A and B.
chassis is rarely used today, this would be the amplifier E. A and C.
circuit ground (or the ground of the nonisolated portion
of the amplifier). 6. If a sampling rate of 400 samples/sec is used, what is the
3. Earth ground. In the three-wire power line (three-prong highest frequency cutoff for the high filter that can be
plug) AC input, the three wires are designated hot (H), used and still avoid significant aliasing distortion?
neutral (N), and earth ground. Most amplifiers use an A. 400 Hz.
isolated medical-grade power supply that outputs low- B. 200 Hz.
level DC voltage to power the amplifiers. C. 100 Hz.
In modern systems, the patient ground is never directly D. 50 Hz.
connected to the earth ground. A current-limiting device
7. Signals X, Y, and Z are recorded against a reference
or isolation device is always placed between the patient
(referential) and W1 and W2 are acquired by bipolar
ground and the earth ground. A common method is to use
recording (W1-W2) using digital PSG. Which of the
optical isolation in which the signal is transmitted by light
following is NOT true?
within a small element of the circuit. Figure 220 illustrates
one method in which part of the amplifier is isolated from A. The derivation X-Y can be displayed.
the chassis and earth grounds. B. The derivation W1-X can be displayed.
C. If all derivations containing X, Y, and Z show artifact,
CLINICAL REVIEW QUESTIONS the reference electrode is probably faulty.
1. What (low, high) filter settings are recommended for D. The filter settings of the displayed derivation W1-W2
PSG recording (display) of EEG and EOG derivations? can be changed.
A. 0.5, 70 Hz. 8. What is the minimum recommended sampling rate to
B. 0.3, 35 Hz. record the oximetry signal?
C. 0.5, 70 Hz. A. 50 samples/sec
D. 0.5, 35 Hz. B. 25 samples/sec.
C. 10 samples/sec.
2. What are the recommended (low, high) filter settings for
D. 100 samples/sec.
display of EMG?
A. 1 Hz, 70 Hz. 9. What is the recommended electrode impedance less
B. 0.3 Hz, 35 Hz. than?
C. 10 Hz, 100 Hz. A. 10 K.
D. 10 Hz, 70 Hz. B. 5 K.
C. 20 K.
3. What is the minimal recommended sampling rate for D. 1 K.
recording EEG, EOG, EMG, and ECG signals?
A. 100 samples/sec. 10. What are the recommended (low, high) filter settings for
display of the ECG?
B. 200 samples/sec.
A. 10, 100 Hz.
C. 400 samples/sec.
B. 0.3, 35 Hz.
D. 500 samples/sec.
C. 10, 70 Hz.
4. What is the minimal recommended sampling rate for D. 0.3, 70 Hz.
airflow, rib cage and abdominal movements, and NP?
11. Using a high filter of 35 Hz for the EEG and EOG display
A. 10 samples/sec. (recording) reduces 60-Hz activity in the displayed
B. 25 samples/sec. signal.
C. 100 samples/sec. A. True
D. 200 samples/sec. B. False
5. Which of the following is true about the effect of a low 12. What are the recommended (low, high) filter settings for
filter setting of 0.3 Hz? display of the thermal airflow or chest and abdominal
A. Has minimal effect on a 10-Hz signal. RIP signals?
B. Does not affect the amplitude of slow wave activity A. 0.3, 35 Hz.
(0.52 Hz). B. 0.1, 15 Hz.
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26 Chapter 2 The Technology of Sleep Monitoring
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Chapter 3
TABLE 31 TABLE 32
Comparison of R&K and the American Academy of Stage W Rules
Sleep Manual A. Score epochs as stage W when more than 50% of the
R&K* AASM SCORING MANUAL epoch has alpha rhythm over the occipital region.
1. EOG: Slow eye movements are characteristic of
Stage W Stage W eyes-closed stage W but are not required criteria for
Stages 1, 2, REM Stages N1, N2, R scoring stage W.
2. Chin EMG: The chin EMG amplitude is variable but is
Stages 3, 4 Stage N3
often higher than during sleep.
Central EEG derivations Frontal, central, and
B. Score epochs without visually discernible alpha
occipital derivations
rhythm (or portions of an epoch without alpha
3-minute rule for No time limit on stage N2 rhythm*) as stage W if any of the following are present:
continuation of stage 2 continuation 1. Eye blinks are present at a frequency of 0.52 Hz.
after an epoch with K 2. Reading eye movements are present.
complexes or sleep 3. Irregular conjugate REMs are present associated with
spindles normal or high chin muscle tone (in contrast, stage R
has low chin activity).
Movement arousal based on Arousal based on EEG (and
EMGan increase in the chin EMG for stage R) *Adaptation of AASM scoring manual stage W, rule B.
Notes:
EMG of any channel 1. Score stage W when the majority of an epoch has either alpha rhythm or
accompanied by a change eye movements consistent with wake as defined in B.
in pattern of any 2. Eye movement patterns (see Chapter 1).
additional channel A. Reading eye movements: trains of conjugate eye movements
consisting of a slow phase followed by a rapid phase in the opposite
Movement time when EEG No movement time direction as the subject reads.
and EOG obscured for Major body movement rules B. Blinks: conjugate vertical eye movements present in wakefulness with
eyes open or closed.
more than half the epoch C. REMs: conjugate irregular, sharply peaked eye movements with an
*Rechtschaffen A, Kales A (eds): A Manual of Standardized Terminology initial deflection lasting < 500 msec.
Techniques and Scoring System for Sleep Stages of Human Sleep. Los EMG = electromyogram; EOG = electro-oculogram; REMs = rapid eye
Angeles: Brain Information Service/Brain Research Institute, UCLA, 1968. movements.
Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Events: Rules, Terminology and Technical Specifications, 1st ed. Westchester, Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
IL: American Academy of Sleep Medicine, 2007. Westchester, IL: American Academy of Sleep Medicine, 2007.
EEG = electroencephalography; EMG = electromyography; EOG = electro-
oculography; REM = rapid eye movement.
100 V F -M
4 1
1 sec C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 31 Stage W. A 30-second epoch with eyes closed and then eyes open. More than 50% of the epoch has occipital alpha activity. EMG = electromyogram.
Epochs without visually discernible alpha rhythm (see Table chin EMG tone for REMs is because stage R (REM sleep) is
32, rule B) are scored as stage W if any of the following are characterized by REMs and low muscle tone.
present: Eye blinks of a frequency of 0.5 to 2 Hz, reading eye How should one score epochs that contain both portions
movements, or irregular conjugate REMs with normal or with alpha rhythm (but < 50% of the epoch) AND portions
high chin muscle tone. These eye movement patterns are with eye movements consistent with wake? The AASM
characteristic of stage W. The requirement of normal or high scoring manual did not specifically address this situation.
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Chapter 3 Sleep Staging in Adults 29
TABLE 34
Scoring Stage W and N1
EEG* EOG CHIN EMG
Alpha rhythm Stage W >50% of the epoch with alpha activity SEMs may be present Variable
on eye Eyes closed
closure Stage W Low-amplitude beta and alpha frequencies REMs Normal or high
Eyes open
Blinks Variable
Reading eye movements
Stage N1 >50% of epoch with alpha attenuation SEMs may be present Variable
and replacement with low-amplitude
mixed-frequency EEG
No alpha Stage W Low-amplitude beta and alpha frequencies REMs Normal or high
rhythm on
Eye blinks Variable
eye closure
Reading eye movements
SEMs absent
Stage N1 Vertex sharp wave Variable Variable
Slowing of 4 to 7 Hz, slowing of Variable Variable
frequency 1 Hz, compared to stage W
Low-amplitude beta and alpha frequencies SEMs appear Variable
Note: Bold text denotes essential features.
*The EEG is assumed not to contain sleep spindles or K complexes not associated with arousal.
EEG = electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; REMs = rapid eye movements; SEMs = slow eye movements.
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30 Chapter 3 Sleep Staging in Adults
100 V F -M
4 1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 32 Stage W. A 30-second epoch containing rapid eye movements (REMs), high chin electromyographic (EMG) activity, and some alpha activity. The majority of the
epoch contains either alpha activity or eye movements consistent with wakefulness.
100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 33 Stage W. A 30-second epoch is shown containing REMs, blinks, relatively high chin electromyographic (EMG) activity, and the absence of discernible alpha activity.
100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2 SEM
E2-M2
Chin EMG
FIGURE 34 Stage W with the eyes closed. A 30-second epoch is shown. Note that alpha rhythm is more prominent in the occipital derivation and present for more than 50% of
the epoch. Slow eye movements (SEMs) are present in this epoch. Although characteristic, they are not a criterion for scoring stage W or N1 in patients producing alpha rhythm
with eye closure. The chin electromyography (EMG) has a low amplitude, but this is variable. In some patients, the chin EMG activity is higher in stage W than during sleep.
(see Table 32, stage W rule B). The majority of the epoch eyes-closed stage W. Here, greater than 50% of the epoch has
contains either alpha rhythm or eye movements consistent prominent alpha activity. SEMs are also present and the
with wakefulness, and hence, the epoch is scored as stage W. EMG activity is relatively decreased. It should be noted that
In Figure 33, the chin EMG activity is relatively high, REMs SEMs can be seen during both eyes-closed stage W and stage
and blinks are present, and there is no discernible alpha N1. If patients produce alpha rhythm with eye closure, SEMs
activity. The epoch is scored as stage W using stage W rule are not part of the criteria to score stage W (although they
B (see Table 32). Figure 34 illustrates an example of are characteristic during eyes-closed stage W).
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Chapter 3 Sleep Staging in Adults 31
Stage N1 Stage N2
Low-amplitude mixed-frequency (LAMF) activity is defined Stage N2 is characterized by the presence of one or more
as a low-amplitude EEG pattern with predominantly 4- to nonarousal KCs (i.e., KCs NOT associated with an arousal)
7-Hz activity. Stage N1 is characterized by LAMF activity or one or more trains of SSs (Fig. 37). Arousal rules are
and the absence of sleep spindles (SSs) and K complexes discussed later in this chapter. During epochs of stage N2,
(KCs) not associated with arousal. SEMs may occur (see eye movements have usually ceased and the chin EMG is
Table 33). At the transition from stage N1 to stage N2, variable but usually at a level lower than that during wakeful-
vertex sharp waves may appear. In patients who produce ness. Recall that a KC is said to be associated with an arousal
alpha activity with eye closure (stage N1 rule A, see Table (KC+Ar) if the arousal commences no more than 1 second
33), the onset of stage N1 occurs when more than 50% of after the termination of the KC. Also note that the KC activ-
the epoch is marked by alpha attenuation (alpha activity in ity is seen in the recommended electro-oculographic (EOG)
< 50% of the epoch) and replacement with LAMF EEG (Fig. derivations (E1-M2 and E2-M2) as in-phase deflections in
35). In individuals who do not produce alpha activity with contrast to REMs (out-of-phase deflections). The rules for
eye closure (Fig. 36), the start of stage N1 occurs at the scoring stage N2 are listed in Table 35 and summarized in
earliest occurrence of SEMs, a slowing of the EEG by 1 Hz Table 36.
or more from that in stage W, or the presence of vertex sharp
waves (stage N1 rule B, see Table 33). Table 34 displays Start and Continuation of Stage N2
the characteristics of stage W and stage N1 for patients who According to the stage N2 rules (see Table 35, rule A), begin
do and do not produce alpha with eye closure. As noted in scoring stage N2 (see Fig. 37) when a KC (not associated
the AASM scoring manual, because SEMs may occur before with an arousal) or an SS occurs in the first half of the
alpha attenuation in subjects who have alpha activity with current epoch or the last half of the previous epoch. This
eye closure, the sleep onset may be scored somewhat earlier assumes that the epoch does not meet criteria for stage N3
in patients who do not produce alpha activity with eye (slow wave activity [SWA] present in 20% of the epoch,
closure. i.e., 6 sec). Recall that SWA is defined as EEG activity of
100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2
Chin1-Chin2
A
V
100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 35 A, Stage N1. A 30-second epoch in which no sleep spindles or K complexes are noted in the electroencephalogram (EEG). Less than 50% of the epoch has alpha rhythm.
The EEG shows alpha attenuation and low-amplitude mixed-frequency (47 Hz) activity for more than 50% of the epoch. Slow eye movements are present but not required. The
chin electromyogram (EMG) is often lower than stage W. B, Stage N1. A vertex sharp wave (V) is noted. No sleep spindles or K complexes are seen in the EEG. The chin EMG is relatively
high in this example.
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32 Chapter 3 Sleep Staging in Adults
Eyes closed
100 V
1 sec F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
A
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
B
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
C
FIGURE 36 Thirty-second epochs. A, Biocalibration at the start of recording. The patient was asked to close his eyes. No alpha rhythm was generated. B and C, Consecutive
30-second epochs. B, An epoch of stage W with REMs and high chin electromyographic (EMG) activity. C, Slow eye movements are present and the EEG frequency slows. Therefore,
epoch C is scored as an epoch of stage N1 sleep. The chin EMG also falls in C, but this is not a criterion used for scoring stage N1 sleep.
75 V
F4-M1
1 sec SS
C4-M1
O2-M1
E1-M2
E2-M2
KC
Chin1-Chin2
FIGURE 37 Stage N2: A 30-second epoch with sleep spindles (SS) and K complexes (KC). The dark horizontal bars at the top denote the presence of slow wave activity (>75 V
peak to peak, 0.52.0 Hz). The total duration of slow wave activity is less than 6 seconds. The dotted lines in F4-M1 are 75 V apart.
0.5 to 2 Hz with greater than 75-V peak-to-peak amplitude 3-min rule). If no new KCs or SSs were noted for more than
over the frontal areas. If the epoch in question contains 20% 3 minutes, the epochs following the epoch with the last KC
or more SWA, then stage N3 is scored (Fig. 38). Most digital or SS (during the 3-min period) were scored as stage 1 and
polysomnography (PSG) systems allow display of amplitude subsequent epochs were scored as N1 (unless there was new
grid lines, and placing lines at 37.5 V + 37.5 V in F4-M1 evidence for another sleep stage). In the AASM scoring
or F3-M2 allows one to easily note 75-V peak-to-peak activ- manual, there is no such time limitation. Stage N2 continues
ity (see Figs. 37 and 38). until there is a reason to score an end of a period of stage N2
In the R&K scoring manual, stage 2 continued without sleep (see Table 35, rule B). If an arousal occurs, a major
additional SSs or KCs for a maximum of 3 minutes (the body movement (MBM) followed by SEMs (signaling a
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Chapter 3 Sleep Staging in Adults 33
TABLE 35
Stage N2 Rules*
A. RULE DEFINING THE START OF N2 SLEEP
1. EEG: Begin scoring stage N2 (in the absence of evidence of N3, SWA < 6 sec) if one or both of the following occur during
the first half of the current epoch or the last half of the previous epoch:
a. One or more K complexes unassociated with arousals or
b. One or more trains of sleep spindles.
2. EEG: If the only K complexes present are associated with arousal, continue to score stage N1.
3. EOG: Usually no eye movements, slow eye movements have ended.
4. Chin EMG: Variable, usually less than wake.
Note: SWA = EEG activity 0.52 Hz with > 75 V peak-to-peak amplitude in the frontal areas. If SWA > 20% of the epoch (6 sec), score stage N3.
TABLE 36
Summary of Scoring Stage N2
START N2 CONTINUE N2 STOP N2
KC or SS in first half of EEG with LAMF without KC or SS. Transition to stage W, N3, or R.
current epoch or last half IF the epoch (or a group of epochs) is preceded Arousal.
of the previous epoch. by an epoch with a nonarousal KC or SS. Major body movement followed by an SEM.
EEG = electroencephalogram; KC = K complex not associated with arousal; LAMF = low-amplitude mixed-frequency; SEM = slow eye movement; SS = sleep spindle.
75 V F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 38 Stage N3 sleep (30-sec epoch). The dotted lines in F4-M1 are 75 V apart. The grid lines are 1 second apart. Slow wave activity is present in all 30 seconds of the epoch
(Table 37).
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34 Chapter 3 Sleep Staging in Adults
transition to stage N1), or the epoch meets criteria for stages End of Stage N2: Effects of Arousals
W, N3, or R, then stage N2 ends (see Table 35, rule C.1.a). Stage N2 ends following an arousal (see Table 35, rule
Figure 39 is a schematic illustrating the start of stage N2 C.1.b). Unless there is a transition to another sleep stage,
sleep. Epoch 101 has a KC not associated with an arousal in stage N1 is scored until there is evidence for resumption
the first half of the epoch and is scored stage N2. In epoch of stage N2 (see Table 35, rule A). Note if an arousal inter-
201, the KC begins in the second half of the epoch so stage rupts stage N2 in the second half of the epoch, the epoch is
N2 begins in epoch 202. Stage N2 continues in epochs 102 still scored as stage N2 because the majority of the epoch is
and 103 and 202 and 203 even though no SSs or KCs occur. stage N2. The effects of an arousal are illustrated in Figure
Note that a KC+Ar is NOT evidence that stage N2 has begun 310. An arousal occurs in epoch 201. Because the arousal
(Fig. 310, epoch 101). occurs in the last half of the epoch, the current epoch remains
as stage N2 but the next epoch is scored as stage N1. Stage N2
resumes only when there is evidence of a KC not associated
TABLE 37 with an arousal or SS (using rules for the start of stage N2).
Stage N3 Rules
A. Score stage N3 when 20% or more of an epoch consists End of Stage N2: Effect of MBM
of SWA, irrespective of age (20% of 30-sec epoch = 6 sec). A major body movement (MBM) is defined as movement
1. EEG: SWA 20% of the epoch (6 sec), sleep spindles and muscle artifact obscuring the EEG for more than half an
may be present in stage N3. epoch to the extent that the sleep stage cannot be deter-
2. EOG: Eye movements are not typically seen during mined. If stage N2 is interrupted by an MBM followed by an
stage N3 sleep. SEM and LAMF, stage N1 is scored until there is evidence
3. EMG: In stage N3, the chin EMG is of variable
to restart stage N2 (SS or KC not associated with an arousal)
amplitude, often lower than in stage N2 sleep and
(see Table 35, rule C.1.c). If the MBM is NOT followed by
sometimes as low as in stage R sleep.
an SEM, stage N2 does not end unless there is a transition
Definition: SWA = EEG activity 0.52 Hz with peak-to-peak amplitude > 75 V
measured over the frontal areas. to stage W, N3, or R (see Table 35, rule C.1.c). In Figure
Note: SWA may be seen in the EOG derivations. 311, an MBM interrupts stage N2 sleep. In Figure 311A,
EEG = electroencephalogram; EMG = electromyogram; the MBM is not followed by SEMs and stage N2 continues.
EOG = electro-oculogram; SWA = slow wave activity.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American The epoch with the MBM is scored using rules discussed
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and later. In Figure 311B, the MBM is followed by an SEM and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed. LAMF EEG activity and the epoch after the MBM is scored
Westchester, IL: American Academy of Sleep Medicine, 2007.
as stage N1. Stage N2 resumes only when there is new
Epoch Epoch
100 101 102 103 200 201 202 203
K complex Low amplitude Low amplitude K complex
mixed frequency mixed frequency
F4-M1 F4-M1
C4-M1 C4-M1
O2-M1 O2-M1
E1-M2 E1-M2
E2-M2 E2-M2
FIGURE 39 Schematic examples of the start and continuation of stage N2 sleep (stage N2 rules A and B; see Table 35). Score stage
N2 in epoch 101 as a nonarousalK complex is noted in the first half of the epoch. Stage N2 continues in epochs 102 and 103. In
epoch 201, the K complex occurs in the last half of the epoch, so stage N2 begins in epoch 202. The schematics assume the EEG activity
is low-voltage mixed-frequency unless otherwise depicted.
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Chapter 3 Sleep Staging in Adults 35
Epoch Epoch
100 101 102 103 200 201 202 203
K complex
associated with arousal
Arousal
F4-M1 F4-M1
C4-M1 C4-M1
O2-M1 O2-M1
E1-M2 E1-M2
E2-M2 E2-M2
FIGURE 310 Schematics illustrating the effects of a K complex associated with an arousal (epoch 101) (stage N2 rule A; see Table
35) and an arousal interrupting stage N2 sleep (stage N2 rule C.1.b; see Table 35). Epoch 202 is scored as stage N1.
Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage
N2 N2 N2 N2 N2 N1 N1 N2 N2 W N1
Major body movement
A B C
FIGURE 311 A major body movement (MBM) interrupts stage N2 (stage N2, rule C.1.c). A, If the epoch containing the MBM has no alpha and there are no slow eye movements
(SEMs) in the subsequent epoch, stage N2 continues (epochs 202 and 203). B, If SEMs and low-amplitude mixed-frequency (LAMF) activity follow the MBM, a transition to stage
N1 is scored (epoch 302). C, If the MBM epoch contains alpha, the epoch is scored as stage W (see MBM rules in Table 35, rule C.1.c). In this case, stage N2 ends. The next epoch
of sleep without K complexes or sleep spindles is scored as stage N1.
evidence for this sleep stage (a KC not associated with an epoch is scored based on the stage of the following epoch
arousal or an SS). (see Major Body Movements, later) (see Tables 313 and
As discussed in a subsequent section on MBM scoring, if 314, later in this chapter).
any alpha is present in the epoch (even < 15 sec) containing
the MBM, then the epoch is scored as stage W. In this case,
Stage N3
the period of stage N2 ends (see Fig. 311C). If the epoch
preceding or following an MBM is scored as stage W, the In stage N3, the amount of SWA (SWA = EEG activity
MBM epoch is scored as stage W. Otherwise, the MBM of 0.52 Hz and a peak-to-peak amplitude of > 75 V
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36 Chapter 3 Sleep Staging in Adults
SW
100 V
F4-M1
1 sec C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 312 Stage R. A 30-second epoch of definite (unambiguous) rapid eye movement (REM) sleep. Saw-tooth waves (SW) are not required to score stage R but are helpful.
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 313 Stage R. A 30-second epoch containing transient muscle activity (TMA) in the chin EMG.
measured over the frontal areas) is equal to or greater than sleep. Saw-tooth waves are often present in epochs of stage
20% of an epoch (6 sec). The SWA is also noted in the EOG R. They are 2- to 6-Hz triangular waves maximal over central
derivations but SEM or REMs are not present. The chin EMG regions (Fig. 312). During burst of REMs, transient muscle
is variable but typically less than during wake. The amount activity (TMA) is also often seen during stage R. TMA is
of stage N3 decreases in adult men but not women as age characterized by short irregular bursts of EMG activity
increases. This is primarily due to a decrease in EEG ampli- (<0.25 sec) in the chin derivations superimposed on low chin
tude (in the 0.22 Hz range) that occurs in men with aging. activity (Fig. 313). Saw-tooth waves and TMA are NOT part
In Figure 37, SWA is denoted by dark horizontal bars at the of the criteria for scoring stage R but are strongly supportive
top of the tracing and the total duration of SWA is less than that stage R is present. TMA may also occur in leg EMG
6 seconds. If SWA is 6 seconds, the epoch would be scored derivations often associated with bursts of REMs.
as stage N3. Figure 38 shows an epoch of stage N3. Nearly
all of the epoch meets SWA amplitude criteria. Definite REM Sleep (REM Rule A)
When epochs have all three characteristics of REM sleep
(Table 38, REM rule A), they are considered definite or
Stage R
unambiguous epochs of REM sleep (see Fig. 312). The EEG
The EEG activity in stage R resembles that of stage N1 and has low amplitude mixed frequency activity, REMs are
generally contains LAMF activity. However, alpha activity in present, and chin EMG tone is low. However, contiguous
stage R is usually more prominent than in stage N1 and epochs (before or after definite epochs of REM sleep) that
usually has a frequency 1 to 2 Hz lower than during wakeful- lack REMs but have a REM-like EEG with no sleep spin-
ness. The three components of stage R are (1) a low-amplitude dles or K complexes and low chin EMG activity are often
EEG without KCs or SSs, (2) REMs, and (3) low chin EMG scored as stage R, if they meet criteria specified in the stage
tone (activity). In the AASM scoring manual, low EMG tone R rules.
is defined as baseline EMG activity in the chin derivation no Stage REM typically follows epochs of stages N2 and, less
higher than in any other sleep stage and usually at the lowest commonly, stage W or stage N1. The AASM scoring manual
level of the entire recording. These three components of stage lists rules for transition from stage N2 to stage R (see later).
R may not all start or stop at the same time. In addition, The manual does not address transitions from stage W or
REMs are episodic and not all epochs of stage R have REMs. stage N1 to stage R. However, based on FAQ V7, stage R is
Therefore, special rules are needed for the start, continuation, not scored following stage W or N1 until an epoch of definite
and end of stage R as well as transitions from N2 to REM REM sleep is noted.
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Chapter 3 Sleep Staging in Adults 37
TABLE 38 TABLE 39
Stage R Rule A (Definite REM Sleep) Continuation and End of Stage R (REM Rules
B and C)
A. Score stage R sleep in epochs with all the following
phenomena (definite or unequivocal REM epochs): B. Continuation of stage R: Continue to score stage R
a. Low-amplitude mixed-frequency EEG. sleep, even in the absence of REMs, for epochs following
b. Low chin EMG tone (the baseline EMG activity in the one or more epochs of stage R as defined above
chin derivation is no higher than in any other sleep (unequivocal REM epochs), if
stage and usually at the lowest level of the entire a. EEG continues to show low-amplitude mixed-frequency
recording). activity without K complexes or sleep spindles.
c. REMs. b. Chin EMG: Tone remains low (at REM level).
Notes:
C. End of stage R.
1. Low chin EMG tone: The baseline EMG activity in the chin derivation is no
higher than in any other sleep stage and usually at the lowest level of the 1. Stop scoring stage R sleep when one or more of the
entire recording. following occur:
2. REMs: Conjugate, irregular, sharply peaked eye movements with an initial a. There is a transition to stage W or N3.
deflection usually lasting < 500 msec. b. An increase in chin EMG tone above the level of
3. Definite stage R (unequivocal stage R) = EEG without spindles or K
complexes, REMs, low chin EMG activity (at REM level).
stage R is seen and criteria for stage N1 are met.
EEG = electroencephalogram; EMG = electromyogram; REM = rapid eye c. An arousal occurs followed by low-amplitude
movement. mixed-frequency EEG and slow eye movements
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American (score as stage N1; if no slow eye movements and
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
chin EMG tone remains low, continue to score as
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007. stage R).
d. A major body movement followed by slow eye
movements and low-amplitude mixed-frequency
EEG without nonarousal-associated K complexes or
sleep spindles (score the epoch after the major
body movement as stage N1; if no slow eye
Continuation of REM Sleep (REM Rule B) movements and the EMG tone remains low,
REM rule B (Table 39) is illustrated in the schematic in continue to score as stage R; the epoch containing
Figure 314. Epochs following epochs of definite stage R the body movement is scored using major body
continue to be scored as stage R even if no REMs are present movement criteria).
so long as the chin EMG stays at the REM level and there e. One or more nonarousal-associated K complexes
or sleep spindles are present in the first half of the
are no KCs or SSs in the EEG. If the EMG increases above
epoch in the absence of REMs, even if chin EMG
the REM level for a majority of an epoch, stage R can no tone remains low (score as stage N2).
longer be scored (see Fig. 314, epoch 202).
EEG = electroencephalogram; EMG = electromyogram; REM = rapid eye
movement.
End of REM Sleep Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Stage R ends (see Table 39, REM rules C.l.a to C.1.e) when Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
there is a transition to stage W or N3, the chin EMG increases Westchester, IL: American Academy of Sleep Medicine, 2007.
above the REM level for the majority of the epoch, an arousal
occurs followed by an SEM(s), an MBM occurs followed by
SEMs, or there is a transition to stage N2 of sleep (appear-
ance of KCs or SSs in the first half of the epoch).
End of REM Sleep: Increase in Chin EMG Activity
End of REM Sleep: Transition to Stage W or N3 Stage R ends if there is an increase in chin EMG tone above
Stage R ends if there is a transition to stage W or stage N3 the level of stage R and criteria for stage N1 are met (see
(stage R rule C.1.a). Transitions from stage R to stage N3 are Table 39, rule C.1.b). In Figure 314, epoch 102 remains
very rare. However, awakenings out of REM sleep are stage R because the chin EMG does not increase until the
common. Patients may often return to sleep and subse- second half of the epoch. In epoch 202, the chin EMG
quently reenter stage R. The AASM scoring manual does not increases above the REM level and criteria for stage N1 are
directly address transitions from stage W to stage R. However, met (see Table 39, stage R rule C.1.b).
based on FAQ V7 concerning transition from N1 to stage R
(see later section), one would not resume scoring stage R End of REM Sleep: Arousal Followed by LAMF EEG
unless an epoch of definite stage R was present (REM-like and SEMs
EEG, REMs, and low chin EMG tone) even if a preceding Stage REM ends if there is an arousal followed by LAMF
epoch had a chin EMG at the REM level. In Figure 315, EEG and SEMs (score as stage N1). If the arousal is not fol-
stage R ends when there is a transition to stage W. Stage R lowed by SEMs and the chin EMG remains low, stage R
begins when there is an epoch of definite stage R (epoch continues (see Table 39, REM rule C.1.c). In Figure 316A,
304). an arousal interrupts stage R, but the epoch following the
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38 Chapter 3 Sleep Staging in Adults
Epoch Epoch
100 101 102 103 200 201 202 203
Low amplitude K complex Low amplitude
mixed frequency mixed frequency
F4-M1 F4-M1
C4-M1 C4-M1
O2-M1 O2-M1
REM REM
E1-M2 E1-M2
E2-M2 E2-M2
FIGURE 314 Schematics illustrate the continuation of REM sleep (stage R, rule B; see Table 39). Epochs 100 and 200 are definite
(unequivocal) stage R. Subsequent epochs are scored as stage R even in the absence of REMs if the EEG does not have K complexes or sleep
spindles and the chin EMG remains at the REM level. Epoch 102 is scored as stage R because the chin EMG activity remains low for the majority
of the epoch. The arrows show the time when the chin EMG is no longer at the REM level.
O2-M1
REM SEM
E1-M2
E2-M2
Chin EMG
arousal continues to be scored as stage R (even in the absence End of REM Sleep: MBM Followed by LAMF EEG
of REMs) because the chin EMG remains at the REM level and SEMs
for the majority of the epoch and there is no evidence of When REM sleep is interrupted by an MBM followed by
stage N1 (no SEM following the arousal) or stage N2 (EEG SEMs and LAMF EEG without nonarousal-associated KCs
with KCs or SSs). However, in Figure 316B, the arousal is or SSs, the epoch after the MBM is scored as stage N1 (see
followed by SEMs and stage N1 is scored. Table 39, REM rule C.1.d). If the MBM is not followed by
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Chapter 3 Sleep Staging in Adults 39
E2-M2 E2-M2
F4-M1 F4-M1
No alpha No alpha
C4-M1 C4-M1
O2-M1 O2-M1
REM REM
E1-M2 E1-M2
SEM
E2-M2 E2-M2
Low amplitude
mixed frequency
Chin EMG Chin EMG
SEMs and the EMG tone remains low, stage R continues. The signifying a change in sleep state. Stage R ends and the epoch
epoch containing the MBM is scored using MBM criteria is scored as stage N1. In this case, the MBM epoch (see MBM
(see Table 314). In Figure 317, stage R is interrupted by an rules) is scored based on the following epoch (stage N1).
MBM. In Figure 317A, the MBM epoch is not scored as
wake owing to the absence of alpha activity (see MBM rules) End of REM Sleep: Appearance of Nonarousal KCs or
and is not followed by an SEM. Therefore, stage R continues SSs in the EEG
and the MBM epoch is scored based on the following epoch If stage R is interrupted by one or more nonarousal-associated
(stage R). In Figure 317B, an SEM follows the MBM, KCs or SSs that are present in the first half of the epoch in
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40 Chapter 3 Sleep Staging in Adults
Epoch Epoch
100 101 102 103 200 201 202 203
Low amplitude K complex Low amplitude K complex
mixed frequency mixed frequency
F4-M1 F4-M1
C4-M1 C4-M1
O2-M1 O2-M1
REM REM
E1-M2 E1-M2
E2-M2 E2-M2
FIGURE 318 Schematic illustrates the end of stage R owing to transition to stage N2 (stage R, rule C.1.e; see Table 39). In epoch
202, the K complex appears only in the second half and the chin EMG is at the rapid eye movement (REM) level. Therefore, the next
epoch is scored as stage N2.
the absence of REMs is scored as stage N2 (even if chin EMG TABLE 310
tone remains low) (see Table 39, REM rule C.1.e). In Figure Transitions between Stage N2 and Stage R
318A, stage R ends when a KC not associated with an (REM Rule D)
arousal is present in the first half of the epoch. The start of
D. Score epochs of transition between stage N2 and stage
N2 follows the N2 rule (KC/SS located in the first half of R as follows:
the epoch 103). Epoch 103 is scored as stage N2. In contrast, 1. In epochs between definite N2 and definite stage R,
in Figure 318B, because the KC occurs in the second half score stage R (even in the absence of REMs) if:
of the epoch 202 and the chin EMG remains at the REM a. There is a distinct drop in the chin EMG to the
level, epoch 202 remains stage R but epoch 203 is scored as REM level in the first half of the epoch.
stage N2. b. There is absence of nonarousal-associated K
complexes and sleep spindles.
2. In epochs between definite stage N2 and definite
TRANSITIONS BETWEEN DEFINITE stage R, score stage N2 if all the following are met:
STAGE N2 AND STAGE R a. There is a distinct drop in the chin EMG to the
REM level in the first half of the epoch.
Intervening epochs between that last epoch of definite stage
b. There is the presence of nonarousal-associated K
N2 (KC or SS in the first half of the epoch or last half of the complexes and sleep spindles.
previous epoch) and definite stage R are scored according to c. Absence of REMs.
REM rule D (Table 310). 3. In epochs between definite N2 and definite stage R,
If epoch(s) preceding and contiguous with an epoch of score stage R even in the absence of REMs if:
definite stage R has (have) a chin EMG at the REM level and a. There is a low chin EMG activity (at the REM
no KCs or SSs in the EEG, such an epoch is (epochs are) level) for the entire epoch.
scored as stage R even in the absence of REMs (Fig. 319) b. There is absence of nonarousal-associated K
using stage R rule D1 (see Table 310). In Figure 319, epoch complexes and sleep spindles.
101 is scored as stage R because the chin EMG is at the REM EMG = electromyogram; REM = rapid eye movement.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
level for the majority of the epoch. Epoch 201 cannot be Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
scored as stage R because the chin EMG is above the REM Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
level for the majority of the epoch and is scored as N2. Westchester, IL: American Academy of Sleep Medicine, 2007.
If the chin EMG falls to the REM level in the first part of
the epoch but a KC or SS occurs in the epoch contiguous
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Chapter 3 Sleep Staging in Adults 41
E2-M2 E2-M2
E2-M2 E2-M2
with an epoch of definite stage R and no REMs are present, KC or SS. Epochs with mixtures of KCs and REMs are
the epoch is scored as N2 (Fig. 320A) using REM rule D2 discussed later. If the SS had been in the first half of epoch
(see Table 310). There are two important points to note. 202, the epoch would be scored as stage N2 by the stage
First, the rule does not require that the SS or KC be in the N2 rules.
first half of the epoch. The rationale is that without other In transitions between epochs of definite N2 with chin
evidence for a sleep stage transition, stage N2 sleep is present EMG at the REM level and definite stage R the intervening
up until the last KC/SS in the epoch preceding definite stage epochs are scored as stage R in the absence of nonarousal-
R. Second, no REMs are present in the epoch containing the associated KCs or SSs in the EEG (see Fig. 320B) using
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42 Chapter 3 Sleep Staging in Adults
REM rule D3. This of course assumes that the chin EMG After epoch 102, subsequent similar epochs are scored as
remains at the REM level. stage R because the chin EMG is at the REM level and the
During epochs in transition from stage N2 to stage R, the EEG remains without KCs or SSs (FAQ V6).
last epoch of definite stage N2 may not necessarily contain a
KC or SS (if the previous epoch contained a KC or SS in the EPOCHS WITH A MIXTURE OF SSs/KCs
last half). Figure 321 illustrates a case in which the last KC/
AND REMs
SS was in the last half of an epoch not scored as stage N2. In
this case, epoch 102 following the KC/SS is scored as stage In the first period of stage R sleep, epochs often contain a
N2 based on the N2 rules even if the chin EMG is at the REM mixture of sleep stages with SSs or KCs in an epoch that
level and no KCs or SSs are present. It is important to note would otherwise meet criteria for definite REM (low chin
that no REMs are present in epoch 101. Epochs with mix- EMG, presence of REMs). Such epochs with REMs are
tures of KCs and REMs are discussed in the next section. scored as stage R (Fig. 322 and Table 311). In Figure 322,
stage N2 and definite stage R. If the K complex in epoch 101 would have occurred
in the first half of epoch 101, the epoch would have been scored as stage N2 (in
the absence of REMs). In this case, epoch 102 would have been scored as stage R C4-M1
using the rules for transition from definite stage N2 to definite stage R. EMG =
electromyogram. O2-M1
REM
REM
E1-M2
E2-M2
Chin EMG
O2-M1
REM
E1-M2
E2-M2
Chin EMG
epochs 100 and 200 are scored as stage R. Epoch 101 is be scored similarly to rules for stage N2 to stage R transi-
scored as stage R by the REM continuation rule because it tions. However, according to an FAQ V7, stage R would be
contains no KC or SS. If epoch 100 had the KC in the second scored only once REMs are present (definite stage R) (Fig.
half of the epoch, it would still have been stage R. However, 323 and Table 312).
epoch 101 would be stage N2 by the stage N2 rules (KC or
SS in last half of previous epoch). Note that epoch 203 is EFFECTS OF AROUSALS AND MBMS:
scored as stage R by the continuation of REM rule and the
STAGE N2 VERSUS STAGE R RULES
fact that the KC is in the second half of the previous epoch.
Given the complexity of sleep staging, it is helpful to note
TRANSITIONS BETWEEN STAGE N1 AND that arousals are treated slightly differently in scoring stage
N2 and stage R. Stage N2 ends when an arousal occurs even
STAGE R (FAQ V7 AASM SCORING RULES)
in the absence of an SEM (see Fig. 310). Stage R ends fol-
The AASM scoring manual did not provide rules for the lowing an arousal only if the arousal is followed by an SEM
transition from stage N1 to stage R. (see Fig. 316). In both stage N2 and stage R, the stage is
One might assume that epochs intervening between defi- assumed to end only if an intervening MBM is followed by
nite stage N1 with low chin EMG and definite stage R would an SEM. This assumes that the MBM epoch contains no
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44 Chapter 3 Sleep Staging in Adults
F4-M1
No alpha No alpha No alpha
C4-M1
O2-M1
REMs
E1-M2
REMs
E2-M2
Chin EMG
Stage W Stage N1 Stage W Stage W Stage W Stage W Stage N1 Stage N1 Stage N2 Stage N2
FIGURE 324 Schematic of 30-second epochs illustrate scoring rules for major body movements (MBMs). EMG = electromyogram; LAMF = low-amplitude mixed-frequency;
REM = rapid eye movement.
alpha. If the epoch contains alpha, it is scored as stage W and the sleep stage cannot be determined (Table 314). The rules
either stage N2 or stage R end (transition to stage W) (Table for scoring epochs containing MBM are illustrated in Figure
313). 324. If any alpha is present in the MBM epoch, it is staged
as stage W. The MBM epoch is also scored as stage W if either
the epoch preceding or the one following the MBM epoch
MAJOR BODY MOVEMENTS
is scored as stage W. Finally, if the previous possibilities
An MBM is defined as movement and muscle artifact obscur- do not apply, the MBM epoch is scored the same as the
ing the EEG for more than half an epoch to the extent that following epoch.
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Chapter 3 Sleep Staging in Adults 45
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin1-Chin2
FIGURE 325 An arousal during nonrapid eye movement (NREM) sleep. A 30-second tracing is depicted. Note that the K complex was NOT included in criteria for the arousal.
In addition, an increase in the chin electromyogram (EMG), although present, is NOT required.
Arousal Rules
Figure 325 illustrates an arousal during NREM sleep. In
Arousals are transient phenomenon that may lead to wake- this example, the chin EMG also increases but this is not part
fulness or only briefly interrupt sleep. They are worth scoring of the criteria used to score an arousal. Note that there is a
because patients with frequent arousals may have daytime shift in EEG frequency greater than 3 seconds that does not
sleepiness even if the total sleep duration is normal. An include spindle activity. Also note that, although KCs may
arousal is scored during sleep stages N1, N2, and N3 (NREM be associated with arousals, the presence of a KC alone (no
sleep) if there is an abrupt shift of EEG frequency including 3-sec shift in EEG frequency) is not considered to indicate
alpha, theta, and/or frequencies greater than 16 Hz (but not an arousal even if it is associated with an increase in the chin
spindles) that lasts at least 3 seconds, with at least 10 seconds EMG. Figure 326 illustrates an arousal from stage R. Here
of stable sleep preceding the change (Tables 315 and 316). both the EEG and the chin EMG changes meet arousal cri-
An arousal is scored during REM sleep if there is a concur- teria. Figure 327 illustrates an epoch of stage R with a burst
rent increase in submental EMG lasting at least 1 second in of alpha activity that is not concurrent with the brief increase
addition to the EEG changes required for NREM arousals. in chin EMG activity and an arousal is not scored. Bursts of
Because alpha bursts during stage R are common, the addi- alpha are common during stage R. The alpha activity during
tional requirement of an increase in chin EMG was added. REM sleep is often about 1 Hz slower than during nonrapid
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46 Chapter 3 Sleep Staging in Adults
100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 326 Stage R with an arousal. A 30-second epoch is depicted. Note that the increase in chin electromyogram (EMG) is greater than 1 second (the criteria for arousal in
stage R is at least 1 sec).
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin1-Chin2
FIGURE 327 A 30-second epoch of Stage R is depicted. There is a burst of alpha activity after REMs. This is not an arousal. Note that the increase in EMG is less than 1 second
and not concurrent with the burst of alpha.
eye movement (NREM) sleep. The burst of chin EMG activ- 3. Artifacts, KCs, or delta waves are not scored as arousals
ity in Figure 327 is less than 1 second in duration and there unless accompanied by an EEG frequency shift, as defined
is no concurrent 3 seconds or longer abrupt shift in EEG previously.
frequency. 4. Intrusions of alpha activity less than 3 seconds in duration
Although the choice of a 3-second EEG change appears into NREM sleep at a rate greater than one burst per 10
arbitrary, studies have shown that reliability of scoring arous- seconds is not scored as an EEG arousal. Three seconds
als is better with a 3-second EEG change than with shorter of alpha sleep is not scored as an arousal unless a 10-second
durations of required EEG change.5 Although not specified episode of alpha-free sleep precedes.
in the recent AASM scoring manual, a previous American 5. Transitions from one stage of sleep to another are not
Sleep Disorders Association (AADA) task force produced a scored as arousals unless they meet the criteria indicated
number of additional recommendations for the scoring of previously.
arousals.6 A summary of the most important points follows:
2. Caraskadon MA, Rechschaffen A: Monitoring and staging 4. Silber MH, Ancoli-Israel S, Bonnet MH, et al: The visual scoring
human sleep. In Kryger MH, Roth T, Dement WC (eds): Prin- of sleep in adults. J Clin Sleep Med 2007;15:121131.
ciples and Practice of Sleep Medicine, 2nd ed. Philadelphia: WB 5. Bonnet MH, Doghramji K, Roehrs T, et al: The scoring of arous-
Saunders, 2005, pp. 13591377. als in sleep. Reliability, validity, and alternatives. J Clin Sleep
3. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Med 2007;3:133145.
Academy of Sleep Medicine: The AASM Manual for the Scoring 6. American Sleep Disorders AssociationThe Atlas Task Force:
of Sleep and Associated Events: Rules, Terminology and Techni- EEG arousals: scoring rules and examples. Sleep 1992;15:
cal Specifications, 1st ed. Westchester, IL: American Academy of 174184.
Sleep Medicine, 2007.
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Chapter 4
One advantage of a 5-Hz signal is that it is minimally changed the voltage sent by the device at each of the two calibration
by typical low- and high-frequency filter settings used in points. For example, when the low calibration voltage is sent
EEG derivations. the set low button is pushed. This action displays the actual
Calibration of DC signals (Fig. 43) is usually performed voltage in the voltage input 1 window (Fig. 4-3) and sends
using a two-point calibration method. This is performed by value to the computer for computation of the calibration
sending a lower and higher signal (usually 0 and 1 V or 1 factors. A similar procedure is performed when the high
and 1 V) and specifying the parameter values corresponding calibration voltage is sent. The computer then determines
to the two voltages. For example, a positive airway pressure and stores the calibration factors.
device and analog module outputs 0 V for 0 cm H2O pres-
sure and 1 V for 30 cm H2O. The device would be directed
Biocalibrations
to send 0 V to the digital system and 0 cm H2O pressure is
specified using the polysomnography (PSG) software. Then Biocalibration (Table 41 and Fig. 44) is an important part
1 V is sent and 30 cm H2O is specified. There is usually an of every PSG recording, but the value of the procedure is
option to type in the expected voltage or to actually measure often unrecognized. During the biocalibration, signals are
recorded while the patient performs maneuvers that verify
that the monitoring equipment, electrodes, and sensors are
working properly. The impedance of all EEG, EOG, and
EMG electrodes should be checked. For the reviewer, noting
50 V the patients EEG, EOG, and EMG pattern of eyes-open and
Sens
(V/mm) LF HF
1 cm
EEG 5 0.3 30 DC Input 1
Channel label
Chin EMG 10 10 30 cm H2O Units
CPAP pressure
FIGURE 41 Example of calibration using analog amplifiers and paper recording. A FIGURE 43 Schematic of computer screen used to calibrate DC signals. Most systems
square wave voltage signal of 50 V is sent by pushing a button on the amplifier system have an option to ask the system to measure the voltage input (Get low value) rather
and then releasing the button. The effects of the filters being used on the pen deflections than simply enter it. So voltage input 1 can be sent to the polysomnography (PSG)
can be seen (Chin EMG [electromyogram] channel). EEG = electroencephalogram; EMG system and the actual voltage measured (acquired). CPAP = continuous positive airway
= electromyogram; EOG = electro-oculogram; HF = high frequency; LF = low frequency. pressure.
500 V C4
510 V
Actual Ref C4-M1
M1
502 V
Ref
Cal1
500 V C4 500 500
510 V 510
After
Ref
calibration Cal2 C4-M1
M1
500 500
502 V 502
Ref
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Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep 51
TABLE 41
Biocalibration Procedure
COMMAND WHAT TO CHECK AND OBSERVE
While looking straight ahead, Quality of alpha production.
close your eyes Slow eye movements.
Open your eyes Attenuation of alpha.
EEG of wakefulness.
Pattern of eyes-open stage W.
REMs during wake.
Look right Integrity of eye electrodes.
Look left Pattern of the patients REMs and blinks.
Look up Ability to detect horizontal and vertical eye movements.
Look down
Blink eyes
Grit teeth Function of chin EMG.
Sensitivity should be adjusted so that some activity is present during relaxed wake.
Breathe in, breathe out Airflow sensors show airflow working properly, adjust sensitivity.
Proper polarity for all respiratory sensors. That is, during inspiration, all deflections are
upward or downward (depending on sleep center protocol).
Adjust sensitivity of chest and abdomen tracings.
Hold your breath Ability to detect apnea.
Wiggle your right toe Ability to detect leg movements.
Wiggle your left toe Adjust leg derivation sensitivity so movements can be easily seen in both legs.
EEG = electroencephalogram; EMG = electromyogram; REMs = rapid eye movements.
Eyes closed Eyes open Look up Look down Look left Look right Blink Grit teeth/chew
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
eyes-closed stage W can help with recognition of this sleep at the biocalibrations would also alert the physician that
stage during the recording and during scoring of sleep. It is stage R sleep would have an unusual appearance.
especially important to know whether the person being
recorded generates alpha activity with eye closure because
ARTIFACTS
this affects the scoring criteria for stage W and stage N1 (see
Chapter 3). Artifacts in the EEG, EOG, and EMG derivations due
Figure 45 shows a portion of the biocalibration proce- to inadequate electrode application or the effects of
dure in a patient with a prior left eye enucleation. Hopefully, patient movement and the environment are common in
technologists notes and patient history would have alerted polysomnography.14 It is essential that they be recognized
the reviewing physician to this situation. However, looking during recording to allow for intervention by the sleep
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52 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 45 Biocalibration in a patient with prior left eye enucleation. The deflections in the frontal derivations are noted because these electrodes are relatively
close to the eyes compared with other electrodes. The grid lines are 1 second apart. EMG = electromyogram.
TABLE 42 away from the skin (sudden loss of signal). The popping
Electrode Popping Artifact often tends to be regular and corresponds to body movement
Electrode popping artifact is a sudden, high-voltage during breathing. Electrode popping may also be caused by
deflection occurring at regular intervals, usually the patient lying on one mastoid electrode or pulling on the
coincident with respiration. wire connecting the electrode with the electrode box during
respiration. For example, if the wire runs under the patients
Electrode popping artifact is due to an electrode pulling
body or through chest or abdominal bands, patient move-
away from the skin or the drying of electrode gel or paste.
ment or respiration can pull on the electrode wire. Popping
Noting the affected derivations can identify the problem also can occur if the electrode gel dries out during the night.
electrode: At the time of recording, adding electrode gel or reapplica-
Several derivations with a common electrode. tion of the problem electrode may eliminate the problem.
One derivation with a unique electrode.
Postrecording, the artifact can frequently be handled by
Reapplication of the problem electrode, the addition of switching to an alternative derivation that does not use the
electrode paste, or change in the position of the electrode problem electrode. For example, if O2 is the problem, the
wire is indicated during recording. exploring occipital electrode is switched to O1. This is one
Review using a derivation not including the problem reason that redundant electrodes are routinely placed.
electrode will usually allow staging of sleep. In Figure 46, regular high-voltage deflections are noted
in all derivations containing M1. Therefore, the problem is
most likely in electrode M1. Video monitoring confirmed
that the patient was sleeping on the left side. After changing
technologist. Postrecording maneuvers to minimize the the reference electrode to M2 (using derivations F3-M2,
effects of some artifacts on sleep staging are often possible. C3-M2, O1-M2, E1-M2, and E2-M2), the problem was elimi-
nated. Displaying F4-M2, C4-M2, O2-M2 would also eliminate
the artifact. However, using an exploring electrode opposite
Electrode Popping
the reference is preferable because this produces a larger
Electrode popping is a common and severe artifact that voltage signal. In fact, F3-M2, C3-M2, and O1-M2 are the alter-
makes the staging of sleep very difficult (Table 42). It is nate derivations recommended by the American Academy
characterized by sudden, high-amplitude deflection (often of Sleep Medicine (AASM) scoring manual. If an electrode
with channel blocking) secondary to an electrode pulling in the standard derivation fails, use of corresponding
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F4-M1
C4-M1
O2-M1
Chapter 4
E1-M2
E2-M2
Chin
Airflow
FIGURE 46 Electrode popping artifact. The problem electrode is M1. The artifact is present only in derivations using the electrode M1, and M1 is the only electrode common to all affected derivations.
Biocalibration, Artifacts, and Common Variants of Sleep
53
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54 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep
electrode in the alternate derivation set for sleep monitoring derivation is significant, turning off the 60-cycle filter will
is recommended (see Chapter 1). significantly increase the amplitude of the artifact (if a high
filter of 100 Hz is used for the derivation). A 60-Hz artifact
can also be recognized on the usual 30-second view by a very
60-Cycle Artifact
dense uniform squared off or ropelike tracing that does not
A 60-cycle artifact in EEG, EOG, or EMG tracings is a vary. If 60-Hz artifact is due to a single electrode, it should
common problem in sleep study recording (Table 43). It is be replaced during recording. Using a different display deri-
caused by 60-Hz electrical activity from power lines con- vation after postrecording may solve the problem. In Figure
taminating the recorded signal. A 60-Hz artifact can be 47, prominent 60-Hz artifact is noted in the chin derivation
minimized by correct application of electrodes and proper and produces a band or ropelike tracing. Application of the
design of the sleep laboratory. EEG amplifiers are AC-coupled, 60-Hz filter dramatically reduced the amplitude consistent
which allows them to record low-voltage EEG activity while with a significant amount of 60-Hz artifact. The problem was
rejecting unwanted and sometimes higher-voltage AC or DC the chin2 electrode. When the derivation was changed, the
activity. Differential amplifiers can record low-voltage physi- artifact was eliminated even without the use of a 60-Hz filter.
ologic signals by amplifying the difference in voltage between The ideal intervention would have been replacement of the
two electrodes while rejecting the common-mode signal chin2 electrode.
consisting of higher-voltage, 60-Hz, background activity.
When recording the voltage difference between two elec-
Slow-Frequency (Sweat) Artifact
trodes, the background AC activity is rejected only if the
electrode impedances are low and fairly equal. Although Slow-frequency (sweat) artifact is characterized by a slowly
most AC amplifiers have notch filters to minimize 60-Hz undulating movement of the baseline of affected channels
activity, these filters may not prevent prominent 60-Hz activ- (Table 44 and Fig. 48). The movement may or may not be
ity when electrode impedances are very different (usually synchronous with the patients respiration. When in-phase
one defective electrode has very high impedance). The ideal with the patients respiration, the artifact also is called respi-
impedance of electrodes is below 5 K (acceptable <10 K). ratory artifact. Sweat artifact is believed to be secondary to
Electrode impedance should be checked by the sleep tech- the effects of perspiration. Sweat alters the electrode poten-
nician after electrode application before recording starts. tial, thereby producing an artifact that mimics delta waves
Routine use of 60-Hz notch filters makes recognition of and results in overscoring of stage N3. When the artifact is
60-Hz contamination more difficult and is not recom- not present in all channels, the artifact may be secondary to
mended. It should be appreciated that use of a 35-Hz high- pressure on an electrode (or pulling on the electrode). In this
frequency filter for EEG and EOG derivations significantly case, the artifact is usually coming from one or more elec-
attenuates 60-Hz activity. The effect of adding or removing trodes on the side on which the patient is lying. For example,
the notch filter is more prominent in chin and leg EMG if the patient is sleeping with the left side down, derivations
derivations that use a high-frequency filter of 100 Hz. containing M1 would be affected but not those containing
The sudden appearance of 60-Hz artifact usually means M2. If a single electrode is the problem, changing derivations
one electrode is faulty. In the days of paper PSG, the artifact to one that does not use the faulty electrode may be a solu-
caused a characteristic humming of the pens as they tion. If this does not work or if the problem involves all
oscillated at 60 cycles/sec. If a 60-Hz contamination of a derivations, other actions are necessary. Options include
reducing the room temperature, uncovering the patient,
and/or using a fan. As a last-ditch alternative, the setting of
TABLE 43
60-Hz Artifact
60-Hz artifact often produces a thick band or ropelike TABLE 44
appearance in the tracing.
Slow-Frequency (Sweat) Artifact
60-Hz contamination of the recorded signal may not be
A slowly undulating signal (sway) is typical of sweat
recognized if both a 35-Hz high-frequency filter and a
artifact.
60-Hz notch filter are used for display.
If sweat artifact is present in all derivations and the room
Recording with 60-Hz filter off will increase the ability to
or patient is warm, cooling of the patient should be
recognize the presence of 60-Hz signal contamination
attempted.
(usually a clue that an electrode needs replacement).
60-Hz artifact is more apparent with a high-frequency If sway is present only in derivations utilizing a given
filter of 100 Hz. mastoid electrode, the artifact may be due to movement
of the mastoid electrode during respiration.
If turning on and off the 60-Hz notch filter significantly
reduces (increases) signal amplitude, this is another clue Slow-frequency artifact may make scoring stage N3 very
that 60-Hz contamination is present in a given derivation. difficult.
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Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep 55
FIGURE 47 60-Hz artifact. A, The 60-Hz filter is off. Note the band
or ropelike appearance of the chin EMG. B, Turning on the 60-Hz
A 60 Hz filter OFF
notch filter dramatically reduced the amplitude consistent with the
presence of 60-Hz artifact. C, When chin2 was replaced with chin3,
F4-M1 the EMG amplitude decreased dramatically and the epoch containing
C4-M1 the 15-second fragment was scored as stage R (REM [rapid eye
movement] sleep). The impedance of the faulty chin2 electrode was
O2-M1 55 K (desired <5 K).
E1-M2
E2-M2
Chin1-Chin2
B 60 Hz filter ON
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin1-Chin3
C 60 Hz filter OFF
Chin1-Chin3
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 48 Slow-frequency (sweat) artifact is present in derivations containing both M1 and M2. Lowering the room temperature eliminated the problem.
TABLE 45 TABLE 46
Electrocardiogram Artifact Alpha Sleep Anomaly
ECG artifact can be easily recognized as sharp deflections Alpha sleep anomaly is characterized by the persistence
in the affected leads corresponding to the QRS complex of prominent alpha activity during NREM sleep (especially
in the ECG lead. stage N3 sleep).
Proper application of the mastoid electrodes and double The pattern has been associated with chronic pain
referencing (using an average of M1 and M2) can prevent syndromes or psychiatric disorders but can occur in
or minimize this artifact. normal individuals.
ECG = electrocardiogram. Alpha anomaly makes scoring stage N1 and sometimes
stage N2 sleep difficult.
Scoring stage N3 is less problematic.
EEG patterns. It can mimic spike activity. The artifact can be NREM = nonrapid eye movement.
minimized by placing the mastoid electrodes sufficiently
high (behind the ear) so that they are over bone instead of
neck tissue (fat). Either linking the two mastoid electrodes
physically by a jumper cable at the electrode box or using possible cause is simply movement of chin electrode wires
derivations in which the reference electrode is an average of with each inspiration. Nasal pressure monitoring is discussed
M1 and M2 can minimize ECG artifact. This is also some- in Chapter 7.
times called double-referencing. These techniques work
because, if the ECG voltage vector is toward one mastoid, it
Eye Movement Artifact
is away from the other. Hence, the ECG components of the
two signals tend to cancel each other out. In Figure 49, ECG Eye movements can be picked up in the frontal derivations
artifact is prominent in all derivations except one using an because F3 and F4 are fairly close to the eyes. In Figure 45,
average of M1 and M2 (F4-AVG). Two small dark circles in note the deflections in F4-M1 associated with eye movements.
E1-M2 mark the artifact. In the tracing shown, ECG artifact This is usually easily recognized by the apperance of frontal
is larger than desirable, but the record still can be scored. derivation deflections when deflections in the EOG deriva-
tions are seen.
Pulse Artifact
Ground Artifact
Pulse artifact is similar to ECG artifact except that, rather
than electrical interference, the artifact is due to movement If one of the two inputs to a differential amplifier (say G1 in
of an electrode caused by the pulsation of an underlying Fig. 21) is disconnected (electrode unattached), the ampli-
artery. Because the arterial pulse occurs after the QRS fier really records the difference between G2 and the ground
complex, the timing of the artifact is delayed after each QRS. electrode. Because the ground electrode is typically attached
Figure 410 shows the ECG (square) artifact and pulse arti- to the forehead near the eyes, one can see deflections associ-
fact (circles). ated with eye movements in channels in which they are
usually not visible (say, O2-M1). Usually, considerable 60-Hz
artifact would also be seen. However, if the display of the
Muscle Artifact
derivation uses a 35-Hz high-frequency filter, which attenu-
Muscle artifact in the EEG and EOG is due to increased ates a great deal of the 60-Hz signal contamination, this
muscle tone in the muscles underlying the EEG and EOG might be missed. Therefore, the appearance of eye move-
electrodes. Often, this will resolve as the patient relaxes and ments in unusual channels should trigger the technologist or
falls asleep (Fig. 411). reviewer to consider whether ground artifact is present.
F4-AVG
F4-M1
C4-M1
Chapter 4
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
FIGURE 49 Electrocardiogram (ECG) artifact is present in all derivations except for the top one using an average of M1 and M2 as the reference (F4-AVG). Black dots point out two deflections from the ECG artifact. EMG = electromyogram.
Biocalibration, Artifacts, and Common Variants of Sleep
57
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58 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep
F4-M1
ECG
1 sec
FIGURE 410 Pulse artifact (circles) follows the electrocardiogram (ECG) artifact in F4-M1
(squares) and the QRS in the ECG. The spike (narrow) deflection in the encephalogram (EEG)
corresponds to the QRS in the ECG. This is followed by a hump in the EEG associated with the
arterial pulse.
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 411 Muscle artifact. The patient was asked to grit his teeth then relax. Adding the 60-Hz filter makes little difference because the majority of signal activity is not due
to 60-Hz signal contamination.
impression of a background of diffuse higher-frequency symptoms of myalgia. It was present in 15% of normal sub-
activity. By changing to a 10-second window, one can count jects in undisturbed sleep.
the smaller wave forms in 1 second that are superimposed Roizenblatt and coworkers9 also studied patients with FM
on slower activity (alpha 813 Hz). off medications and normal controls. Alpha rhythm was
First described in 1973 by Hauri and Hawkings,6 alpha- noted during sleep in 70% of FM patients and 16% of normal
delta sleep was once thought to be a characteristic finding individuals. Three distinct patterns were noted: phasic alpha
associated with fibromyalgia (FM).7 However, alpha sleep is patternsepisodic alpha occurring simultaneously with
not seen in all patients with FM and can occur in patients delta activity (70% FM, 7% controls); tonic alpha continu-
with other psychiatric and chronic pain disorders. Mahow- ously present throughout NREM sleep (20% of FM and 9%
ald and Mahowald8 concluded that alpha sleep was not of controls); and low alpha pattern seen in 30% of FM
specific for FM and was not necessarily associated with patients and 84% of controls. The phasic pattern was
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Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep 59
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
Snore
Nasal
pressure
Nasal oral
therm flow
FIGURE 412 Snoring artifact is noted in the chin electromyogram (EMG). Note the evidence of snoring in the snore microphone and in the nasal pressure.
TABLE 47 TABLE 48
Drug Spindles Eye Movements Associated with Selective
Serotonin Reuptake Inhibitor Medications
Frequent and prominent sleep spindle activity is often
noted in patients taking benzodiazepine receptor Prominent slow and rapid eye movement activity may be
agonists. seen in stage N2 (and less commonly in stage N3) in
patients taking SSRI antidepressants.
Sleep spindle frequency is often at the higher end of the
sleep spindle range. The SSRI eye movements can be a mixture of slow and
The pattern may be a useful clue that a hypnotic more rapid eye movements.
medication was taken before the sleep study. SSRI = selective serotonin reuptake inhibitor.
associated with lower sleep efficiency, decreased slow wave vanish with the onset of stage N2. However, in patients
sleep, longer morning pain, and subjective feeling of super- taking selective serotonin reuptake inhibitors (SSRIs), a
ficial sleep. Further research is needed to confirm the mixture of slow and more rapid eye movements may persist
findings. into stage N2 or stage N3.13,14 Because this phenomenon was
first descibed with patients on fluoxetine, such eye move-
ments are often called Prozac eyes. Figure 415 shows a
Drug Spindles
tracing from a patient on fluoxetine (Table 48).
Patients who are taking benzodiazepine receptor agonists
(BZRAs) often have increased sleep spindle activity (Table Transient Muscle Activity during Rapid Eye
47 and Fig. 414).1012 Sleep spindle activity has a frequency
Movement Sleep
of 11 to 16 Hz. Drug spindles often have a frequency in the
higher end of the range. Benzodiazepines are associated with Stage R (REM [rapid eye movement] sleep) is characterized
a decrease in slow wave amplitude (less stage N3 sleep) and by low chin EMG tone; that is, the baseline chin EMG activ-
an increase in higher EEG frequencies.13 The nonbenzodiaz- ity in the chin derivation is no higher than in any other sleep
epine BZRAs (zolpidem, zaleplon, eszopiclone) tend to have stage and usually at the lowest level of the entire recording.
less effect on the amplitude of slow waves and, therefore, do However, transient bursts of EMG activity termed transient
not usually decrease the amount of stage N3 sleep. However, muscle activity (TMA; formerly called phasic activity),
they do increase EEG frequencies during sleep, including consisting of short irregular bursts of EMG activity (usually
sleep spindle activity. <0.25 sec), may be seen in the chin or anterior tibial EMG
derivations during stage R15,16 (Table 49). This activity is
Eye Movements Associated with Selective maximal in association with bursts of REMs (Fig. 416). In
normal individuals, twitching in muscles may occur but
Serotonin Reuptake Inhibitor Medications
usually no gross motor movements.
Slow eye movements are typically present during stage W TMA is termed excessive TMA in REM sleep when more
with the eyes closed and during stage N1. They typically than 50% of 10 sequential 3-second miniepochs contain such
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60
Chapter 4
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Biocalibration, Artifacts, and Common Variants of Sleep
Chin EMG
FIGURE 413 Alpha sleep. Prominent alpha activity is diffusely present in this 30-second epoch of stage N3 sleep. Note that the alpha activity is more prominent in the frontal and central derivations. A 1-second enlargement is shown.
EMG = electromyogram.
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1 second
F4-M1
C4-M1
Chapter 4
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 414 Prominent sleep spindle activity is noted in this 30-second tracing. A 1-second enlargement is shown. Unlike the diffuse alpha activity in Figure 413, the sleep spindles are noted in discrete bursts. EMG = electromyogram.
Biocalibration, Artifacts, and Common Variants of Sleep
61
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62 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep
100 V
1 sec F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 415 A 30-second tracing of a patient taking fluoxetine. Eye movements persist into stage N2 sleep. EMG = electromyogram.
100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2
Chin1-Chin2
FIGURE 416 Bursts of EMG activity are noted on the background of reduced tonic chin EMG activity. The transient muscle activity often occurs in association with bursts of eye
movements. Similar activity is not uncommon in normal individuals but is often more prominent in patients taking selective serotonin reuptake inhibitors.
FIGURE 417
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
1 sec
Answers
2. B. Cool the patient down. Sweat artifact is shown. The
1. A. The electrode M1 is faulty because only derivations first step is to cool the patient down with a fan, reducing
containing M1 have the artifact (electrode popping). The the room temperature, or removing covers. Using a
scoring rules state that if an electrode in the recommended higher setting for the low-frequency filter (either 0.5 or
derivations is faulty, then the alternative derivations 1 Hz) would remove much of the undulation but will also
(F3-M2, C3-M2, O1-M2) should be used (see Chapter 1). reduce the size of genuine slow waves, thus reducing the
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64 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep
amount of activity in the 0.5- to 2-Hz range meeting the rheumatic disease with particular reference to alpha-delta
amplitude criteria for slow wave activity. NREM sleep anomaly. Sleep Med 2000;1:195207.
9. Roizenblatt S, Moldofsky H, Benedito-Silva AA, Tufik S: Alpha
3. E. Both ECG and pulse artifact are noted. ECG artifact is sleep characteristics in fibromyalgia. Arthritis Rheum 2001;
44:222230.
visible in all of the derivations. Pulse artifact is best seen 10. Johnson LC, Hanson K, Bickford RG: Effect of flurazepam on
in F4-M1. Note the deflection follows the QRS and is sleep spindles and K complexes. Electroencephalogr Clin Neu-
usually broader than deflections due to ECG artifact. rophysiol 1976;40:6777.
11. Johnson LC, Spinweber CL, Seidel WF, et al: Sleep spindle and
delta changes during chronic use of a short acting and a long
REFERENCES acting benzodiazepine hypnotic. Electroencephalogr Clin Neu-
rophysiol 1983;55:662667.
1. Caraskadon MA, Rechschaffen A: Monitoring and staging 12. Obermeyer WH, Beneca RM: Effects of drugs on sleep. Neurol
human sleep. In Kryger MH, Roth T, Dement WC (eds): Prin- Clin 1996;14:827840.
ciples and Practice of Sleep Medicine, 4th ed. Philadelphia: WB 13. Schenck CH, Mahowald MW, Kim SW, et al: Prominent eye
Saunders, 2006, pp. 13591377. movements during NREM sleep and REM sleep behavior dis-
2. Harris CD, Dexter D: Recording artifacts. In Shepard JW (ed): order associated with fluoxetine treatment of obsessive-
Atlas of Sleep Medicine. Mount Kisco, NY: Futura, 1991, compulsive disorder. Sleep 1992;15:226235.
pp. 5051. 14. Armitage R, Trivedi M, Rush AJ: Fluoxetine and oculomotor
3. Butkov N. Clinical Polysomnography. Ashland, OR: Synapse activity during sleep in depressed patients. Neuropsychophar-
Media, 1996, pp. 344346. macology 1995;12:159165.
4. Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley 15. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
& Belfus, 2003, pp. 5873. Academy of Sleep Medicine: The AASM Manual for the Scoring
5. White DP: Pathogenesis of obstructive and central sleep apnea. of Sleep and Associated Events: Rules, Terminology and Tech-
Am J Respir Crit Care Med 2005;172:13631370. nical Specifications, 1st ed. Westchester, IL: American Academy
6. Hauri P, Hawkins DR: Alpha-delta sleep. Electroenceph Clin of Sleep Medicine, 2007.
Neurophysiol 1973;34:233237. 16. Silber MH, Ancoli-Israel S, Bonnet MH, et al: The visual
7. Moldofsky H, Scarisbrick P, England R, Smythe H: Musculosk- scoring of sleep in adults. J Clin Sleep Med 2007;15:121131.
eletal symptoms and non-REM sleep disturbance in patients 17. American Academy of Sleep Medicine: International Classifi-
with fibrositis syndrome and healthy subjects. Psychosom cation of Sleep Disorders, 2nd ed. Westchester, IL: AASM,
Med 1975;37:341351. 2005, pp. 148151.
8. Mahowald ML, Mahowald MW: Nighttime sleep and daytime 18. Winkelman JW, James L: Serotonergic antidepressants are asso-
functioning (sleepiness and fatigue) in less well defined chronic ciated with REM sleep without atonia. Sleep 2004;15:317321.
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Chapter 5
by long, dramatically flat EEG periods of 10 to 20 seconds 3. Low-voltage irregular (LVI): Continuous low-voltage
(Fig. 53). TD is seen at or before 30 weeks CA (see Fig. mixed-frequency with prominent delta and theta rhythms
52) and is the EEG pattern of QS in that age group. and little variation. Voltage (1435 V), theta rhythm
2. Trac alternant (TA): A discontinuous pattern (Figs. 54 predominates (see Fig. 54).
and 55) that characterizes the QS of newborns after 4. High-voltage slow (HVS) pattern: Continuous, irregular
about 30 weeks CA (see Fig. 52). Bursts of mixed activity mixed frequencies with higher voltages (50100 V) and
of 2 to 8 seconds are interspersed with periods of flatter more prominent delta frequencies (see Fig. 54).
EEG. The bursts are composed of high-voltage slow waves 5. Mixed pattern (M): Similar to LVI but with slightly higher
superimposed with rapid low-voltage sharp waves. There voltages and more delta activity. Mixture of HVS and low-
is a continuum between TD and TA, but in general, in voltage polyrhythmic activity (see Fig. 54).
TA, the high and low periods have fairly equal durations
and the bursts do not have full bilateral synchrony. In TD,
Premature Infants
the flat is very flat and the bursts are very high voltage
and have synchrony. In premature infants with a CA less than 30 weeks, QS
usually shows a pattern of TD.3,4 The pattern of TD is
characterized by electrical quiescence between bursts of
high-voltage activity. In contrast, TA is characterized by a
lesser reduction in amplitude between periods of higher-
amplitude activity. Another difference between TA and TD
is that delta brushes (fast waves of 1020 Hz) are superim-
Fp1 Fp2 posed on the delta waves in TD. As the infant matures, delta
brushes disappear and the TA pattern replaces TD. Finally,
F7 F8
Fz at term, the EEG of QS is characterized by an HVS pattern.
F3 F4
The EEG of AS in premature infants younger than 30 weeks
may also show TD but later is typically LVI or M. The
T7 C3 Cz C4 T8 EEG pattern of wake and sleep is similar and states are dis-
tinguished by sustained eye closure (sleep) and open eyes
(wake).
P3 Pz P6
P7 P8
Term Infants
O1 O2 Wakefulness is characterized by crying, open eyes, and
feeding. Non-nutritive sucking commonly continues during
sleep. Sleep is often defined by sustained eye closure. The
FIGURE 51 Electroencephalography (EEG) electrode positions. C = central; F = epochs during the transition from definite AS to QS are often
frontal; Fp = frontopolar; O = occipital; P = parietal; T = temporal. scored as indeterminant sleep.
TABLE 51
Characteristics of Sleep Stages in Term Infants3
WAKE ACTIVE SLEEP QUIET SLEEP INDETERMINANT
EEG LVI or mixed LVI TA or HVS Not meeting criteria
M, HVS rarely M rarely for QS or AS
Premature: TD
EOG Eyes open Eyes closed, horizontal REMs Eyes closed
Little or none
Chin Phasic Low tonic between movements High tonic
Breathing Irregular Irregular, some postsigh pauses Regular
Deep and slow
Body Calm or active Squirming, sucking, grimacing Few, peaceful
movements with eyes open Body: small digit or limb movements Sucking can occur
AS = active sleep; EEG = electroencephalogram; EOG = electromyography; HVS = high-voltage slow; LVI = low-voltage irregular; M = mixed; QS = quiet sleep;
REMs = rapid eye movements; TA = trac alternant; TD = trac discontinue.
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Chapter 5 Sleep Staging in Infants and Children 67
POST CONCEPTIONAL AGE IN WEEKS FIGURE 52 Appearance of different EEG patterns by conceptional age
24 26 28 30 32 34 36 38 40 42 44 46 48 50 in weeks. HVS = high-voltage slow; LVI = low-voltage irregular; M =
mixed; TA trac alternant; TD = trac discontinue. The dark bars refer to
Active sleep TD LVI or M discontinuous patterns. Examples of these patterns are illustrated in
Figures 53 to 56. From Libenson MH: Practical Approach to
Wakefulness TD LVI or M Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 321.
Delta brushes
Sharp transients
Sleep spindles
Vertex waves
Discontinuous Continuous
100 V
1 sec
LUE-RAE
ECG
Chin
Resp
Fp1-T7
T7-O1
Fp1-C3
C3-O1
Fp2-C4
C4-O2
Fp2-T8
T8-O2
T7-C3
C3-Cz
Cz-C4
C4-T8
FIGURE 53 Trac discontinue. Bursts of high-voltage activity alternate with long periods of flat EEG activity. ECG = electrocardiogram; LUE = left under eye electrode; RAE = right
above eye electrode. From Libenson MH: Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 307.
HVS
Trac alternant
(TA)
70 V
Resp
1 sec
Eyes
ECG
Fp1-F7
F7-T7
T7-P7
P7-O1
Fp1-F3
F3-C3
C3-P3
P3-O1
Fz-Cz
Cz-Pz
Fp2-F4
F4-C4
C4-P4
P4-O2
Fp2-F8
F8-T8
T8-P8
P8-O2
FIGURE 55 Trac alternant (TA; quiet sleep in a 1-mo-old). Note that the quiet portions are not as flat or as long as in trac discontinue (TD). Also, the higher-amplitude burst
portions are longer and less synchronous. ECG = electrocardiogram. From Libenson MH: Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 308.
norm. In contrast, the adult sleep cycle is 90 to 100 minutes, does not reach the adult value of 90 to 100 minutes until
REM occupies about 20% of sleep, and NREM sleep is noted adolescence.712
at sleep onset. As children mature, more typical adult EEG patterns
After about 3 months, the percentage of REM sleep starts begin to appear. The time of appearance is somewhat
to diminish and the intensity of body movements during AS variable, but the values in Table 52 are typical. Sleep
(REM) begin to decrease. The pattern of NREM at sleep architecture in children is discussed in more detail in
onset begins to emerge. However, the sleep cycle period Chapter 6.
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Chapter 5 Sleep Staging in Infants and Children 69
200 V
1 sec
Resp
Eyes
ECG
Chin
Fp1-F7
F7-T7
T7-P7
P7-O1
Fp1-F3
F3-C3
C3-P3
P3-O1
Fz-Cz
Cz-Pz
Fp2-F4
F4-C4
C4-P4
P4-O2
Fp2-F8
F8-T8
T8-P8
P8-O2
FIGURE 56 Active sleep. The EEG shows an LVI pattern. The respiration channel shows irregular respiration with a respiratory pause. The eye movement channel shows rapid eye
movements. ECG = electrocardiogram. Adapted from Libenson MH: Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 310.
70 V
1 sec Fp1-F7
F7-T7
T7-P7
P7-O1
Fp1-F3
F3-C3
C3-P3
P3-O1
Fz-Cz
Cz-Pz
Fp2-F4
F4-C4
C4-P4
P4-O2
Fp2-F8
F8-T8
T8-P8
P8-O2
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FIGURE 57 Quiet sleep showing an HVS EEG pattern in a term infant. From Libenson MH: Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 306.
70 Chapter 5 Sleep Staging in Infants and Children
Postterm means at least 40 weeks after conception Figure 58 presents an example of a 3-month-old infant
(2 mo postterm = 48 wk CA). For example, for an who had SWA but no definite sleep spindles or K complexes.
infant born at 36 weeks postconception, the scoring NREM sleep was scored either stage N3 (epochs meeting
rules apply 3 months after birth. criteria for stage N3) or stage N.
For children younger than 2 months postterm, the
AASM scoring manual refers the reader to the Pediatric Dominant Posterior Rhythm
Task Force review paper.1 The scoring rules of Anders, Dominant posterior rhythm (DPR) in both adults and chil-
Emde, and Parmelee can be used. dren is defined as the predominant rhythm seen over occipi-
There is no precise upper age limit for pediatric rules. tal derivations during eyes closed wakefulness that is
reactive. (Reactive = activity blocks or attenuates with eye
Terminology of Sleep Stages opening and appears with passive eye closure.)
A. The following terminology should be used when scoring The DPR in adults is often called alpha rhythm and
sleep in children 2 months postterm or older: consists of activity most prominent over occipital derivations
with an amplitude of less than 50 V and a frequency of
1. Stage W (wakefulness) 8.5 to 13 Hz; it is reactive to eye opening (decreased
2. Stage N1 (NREM 1) amplitude).
3. Stage N2 (NREM 2) Of note, 10% to 25% of adults have no or poorly defined
4. Stage N3 (NREM 3) alpha rhythm.
5. Stage N (NREM) The DPR in infants and children changes with age.
6. Stage R (REM) Table 53 shows the characteristic changes. A simple rule to
remember is greater than 8 by age 8, meaning that in
Scoring Sleep Stage normal awake children older than age 8, the DPR is greater
In the scoring of infant sleep, four possible scenarios are than 8 Hz (813 Hz).
described:
Additional Waveforms of Wakefulness
A. If all epochs of NREM sleep contain no recognizable 1. Posterior slow waves (PSWs) of youth: This waveform
sleep spindles, K complexes, or high-amplitude 0.5- to occurs in children between 8 and 14 years and has a fre-
2-Hz slow wave activity (SWA), score all epochs of quency of 2.5 to 4.5 Hz. PSW usually occurs at the same
NREM sleep as stage N (NREM). time as DPR with eyes closed wake and disappears with
B. If some epochs of NREM sleep contain sleep spindles drowsiness or transition to stage N1 sleep. Maximal inci-
or K complexes, score those as stage N2 (NREM 2). If dence is 8 to 14 years of age, rare younger than 2 years or
the remaining NREM epoch contains no SWA older than 211 (Fig. 59).
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Chapter 5 Sleep Staging in Infants and Children 71
200 V
1 sec F4-M1
C4-M1
O2-M1
E2-M2
E1-M2
Chin
A
F4-M1
C4-M1
O2-M1
E2-M2
E1-M2
Chin
FIGURE 58 This 3-month-old infant had no sleep spindles or K complexes but had slow wave activity (nonrapid eye movement N3 [NREM 3]) and epochs of rapid eye movement
(REM) sleep. This case shows stage N3 (A) and stage R (B).
TABLE 53
Dominant Posterior Rhythm Characteristics by Age
FREQUENCY % OF CHILDREN SHOWING AMPLITUDE
(HZ) THE PATTERN AT THIS AGE (V) WAVEFORM DISTRIBUTION
<34 mo Slow 100 Not used Irregular Occipital
34 mo 3.54.5 75 50100 Sinusoidal Occipital
56 mo 56 70 by 12 mo 50110 Sinusoidal Occipital
3 yr 7.59.5 82 Sinusoidal Occipital
69 yr 813 ~88 Average Sinusoidal Occipital
5060
>9 yr 813 90 Not used Sinusoidal Occipital
Memory tool: 4 Hz at 4 mo and 8 Hz at 8 yr.
P3-O1
A 50 V
1 sec
FIGURE 59 A, Posterior slow waves (PSWs) of youth in an occipital derivation. Alpha waves are superimposed on slow waves. B,
Underlying slow wave activity. PSW is present only with eyes closed and disappears with drowsiness and sleep. PSW is a pattern of
relaxed wakefulness.
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72 Chapter 5 Sleep Staging in Infants and Children
2. Blinks: Eye blinks in children, as in adults, are associated 1. Rhythmic anterior theta (RAT) activity consists of runs
with the eyeball turning upward (Bells phenomenon). In of moderate voltage, 5- to 7-Hz, activity largest over the
children, they cause occipital sharp waves that are mono- frontal regions. RAT activity is common in adolescents
phasic or biphasic (200400 msec) and less than 200 V and young adults during drowsiness and first appears
that follow eye blinks. around 5 years of age1,5 (Figs. 510 and 511).
3. Slow eye movements (SEMs) or REMs are defined the 2. Hypnagogic hypersynchrony (HH) is characterized by
same as in adults. bursts of very high amplitude 3- to 4.5-Hz sinusoidal
waves maximal in frontal and central derivations and
Pediatric Stage W Rules2 smallest in the occipital derivation (widely distributed)
A. DPR in children is the same as alpha in adults for scoring (see Fig. 510).
sleep and wake. 3. Low-amplitude mixed-frequency (LAMF): Low-
B. Score stage W when age-appropriate DPR or alpha occu- amplitude, predominantly 4- to 7-Hz activity.
pies more than 50% of the epoch over the occipital 4. Vertex sharp waves are sharply contoured waves with
region. duration less than 0.5 second maximal over the central
C. If there is no discernible reactive alpha or no age- region and distinguishable from background activity.
appropriate DPR, score stage W when either of these is 5. SEMs: Conjugate, reasonably regular, sinusoidal eye
present (Table 54): movements with initial deflection that last longer than
1. Eye blinks at a frequency of 0.5 to 2 Hz. 500 msec.
2. Reading eye movements.
3. Irregular conjugate REM associated with normal or Pediatric Stage N1 Rules2
high chin muscle tone. A. If alpha/DPR is generated, score stage N1 if the posterior
rhythm is attenuated or replaced by LAMF activity for
Waveforms for Scoring Pediatric Stage N12 more than 50% of the epoch (Fig. 512 and Table 56).
In staging N1, the presence or absence of certain waveforms B. If alpha/DPR is not generated, score stage N1 com-
is important (Table 55). mencing with the earliest of any of the following
phenomena:
1. Activity in range 4 to 7 Hz with slowing of back-
ground frequencies by 1 to 2 Hz or higher from stage
TABLE 5-4 W (e.g., 5 Hz and stage W had 7 Hz).
Pediatric Stage W Rules1,2 2. SEMs.
3. Vertex sharp wave.
A. If there is alpha rhythm or age-appropriate DPR
4. RAT activity.
1. Score wake if alpha/DPR is present for more than 50%
of the epoch.
5. HH.
6. Diffuse or occipital predominant high-amplitude
B. If there is no alpha or DPR, score wake when rhythmic 3- to 5-Hz activity.
1. Eye blinks are present.
2. Reading eye movements are present.
Pediatric Stage N2
3. There are rapid eye movements with normal or high
Score as per adult rules:
EMG tone.
Sleep spindles in children differ somewhat from those in
DPR = dominant posterior rhythm; EMG = electromyography.
adults. In infants, sleep spindles are often asynchronous until
TABLE 55
Waveforms Important for Scoring Pediatric Stage N11,2
FREQUENCY/DURATION DISTRIBUTION AMPLITUDE AGE OF ONSET
LAMF 47 Hz All regions Low
Vertex sharp <0.5 sec (usually Central, vertex Stands out from 23 mo (broad)
waves <200 msec) background 5 mo (adult-like)
RAT activity 57 Hz Frontal regions Not a criteria Starts around age 5 yr
generally low Common in children
and adolescents
Hypnagogic 34.5 Hz Frontal and Very large Appears around 3 mo
hypersynchrony central 75350 V Common 68 yr
Rare > 12 yr
LAMF = low-amplitude mixed-frequency; RAT = rhythmic anterior theta.
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Chapter 5 Sleep Staging in Infants and Children 73
200 V
1 sec
F4-M1
F3-M2
C4-M1
C3-M2
O2-M1
O1-M2
E1-M2
E2-M2
Chin
A B
FIGURE 510 A, Hypnagogic hypersynchrony (HH). High-voltage bursts, frequently 3 to 4 Hz, are prominent in frontal and central derivations.
B, Rhythmic anterior theta is faster than HH at 5 to 7 Hz and prominent in frontal derivations.
50 V
1 sec
F7-F3
F3-Fz
Fz-F4
F4-F8
A1-T3
T7-C3
C3-Cz
Cz-C4
C4-T8
T8-A2
P7-P3
P3-Pz
Pz-P4
P4-P8
Fz-Cz
Cz-Pz
FIGURE 511 Rhythmic anterior theta in a 12-year-old child during drowsiness (considered stage N1). From Neidermeyer E, Da Silva
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FL: Encephalography, Clinical Applications and Related Fields, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2005, p. 227.
74 Chapter 5 Sleep Staging in Infants and Children
1 sec
O2-M1
FIGURE 512 The dominant posterior rhythm slows from 4 to 4.5 Hz to 3 Hz in a 4-month-old during transition from stage W to stage N1.
P3-O1
Fp2-F4
F4-C4
100 V
1 sec
C4-P4
P4-O2
60 mo. HF 70 LF 1
200 V
1 sec SS
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 514 Stage N2 in a 5-year-old boy. Note the sleep spindle most prominent in the frontal derivation. In adults, sleep spindles are most prominent in central
derivations. There are also bursts of theta activity (hypnagogic hypersynchrony).
200 V
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 515 Stage N3 (30 second epoch). The patient is a 5-year-old boy. The horizontal amplitude lines in the derivation F4-M1 are 75 V apart. The dark bars
above F4-M1 show slow wave activity that exceeds 6 seconds in a 30-second epoch.
200 V
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 516 Stage N3 in a 5-month-old boy. The horizontal amplitude lines in F4-M1 are 75 V apart.
5. Posterior slow waves of youth occur in which sleep 5. D. Posterior slow waves of youth occur during eyes-
stage? closed wake and vanish with sleep onset.
A. Stage N3.
6. A. HH is important for staging N1 in children. The fre-
B. Stage N1. quency is usually 3 to 4.5 Hz and the waveform has a high
C. Stage N2. amplitude most prominent in frontal and central areas
D. Stage W. and smallest in occipital regions.
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Chapter 5 Sleep Staging in Infants and Children 77
7. B. Sleep spindles typically appear at 2 to 3 months of age. 5. Neidermeyer E, Da Silva FL: Encephalography, Clinical Appli-
cations and Related Fields, 5th ed. Philadelphia: Lippincott
8. C. Stage N1, N2, and N3 can typically be scored by 6 Williams & Wilkins, 2005, p. 227.
months of age (and sometimes sooner). 6. Tyner FS, Knott JR, Mayer WB: Fundamentals of EEG Technol-
ogy. New York: Raven, 1982, p. 243.
7. Kahn A, Dan B, Grosswasser J, et al: Normal sleep architecture
REFERENCES in infants and children. J Clin Neurophysiol 1996;13:184297.
1. Grigg-Damberger M, Gozal D, Marcus CL, et al: The visual 8. Seldon S: Polysomnography in infants and children. In Sheldon
scoring of sleep and arousal in infants and children. J Clin Sleep SH, Ferber R, Kryger MH (eds): Principles and Practice of
Med 2007;3:201240. Pediatric Sleep Medicine. Philadelphia: Elsevier Saunders,
2. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American 2005, pp. 4971.
Academy of Sleep Medicine: The AASM Manual for the Scoring 9. Iglowstein I, Jenni OG, Molinari L, Largo RH: Sleep duration
of Sleep and Associated Events: Rules, Terminology and Tech- from infancy to adolescense: reference values and generational
nical Specifications, 1st ed. Westchester, IL: American Academy trends. Pediatrics 2003;111:302307.
of Sleep Medicine, 2007. 10. Montgomery-Downs HE, OBrien LM, Gulliver TE, et al: Poly-
3. Anders T, Emde R, Parmelee A: A Manual of Standardized somnographic characteristics in normal preschool children.
Terminology, Techniques and Criteria for Scoring of Stages of Pediatrics 2006;117:741753.
Sleep and Wakefulness in Newborn Infants. Los Angeles: Brain 11. Mason TB, Teoh L, Calabro K, et al: Rapid eye movement latency
Information Service, UCLA, 1971. in children and adolescence. Pediatr Neurol 2008;39:162169.
4. Libenson MH: Practical Approach to Electroencephalography. 12. Beck SE, Marcus CL: Pediatric polysomnography. Sleep Med
Philadelphia: Elsevier Saunders, 2010, p. 321. Clin 2009;4:393406.
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Chapter 6
TABLE 61
Sleep Architecture Parameters
TRT (min) Time duration from lights out to lights on.
TRT = SL + WASO + TST
Lights out time (hr : min) Time of the start of the recording.
Lights on time (hr : min) Time of the end of the recording.
TRT (min) Time from lights off to lights on.
TST (min) Time spent in stages N1, N2, N3, and R.
SL (min) Time from lights out until the start of the first epoch of sleep (stages N1, N2, N3, or R).
Stage R latency (min) (REM latency) Time from start of first epoch of sleep until the start of the first epoch of stage R.
Sleep efficiency (%) = TST 100/TRT.
Stage W (min) All minutes of stage W during TRT.
WASO Stage W recorded after sleep onset until lights on time.
= stage W SL
Time in each sleep stage (min) Minutes of stages N1, N2, N3, R.
Time in each sleep stage as a % of TST Minutes of each sleep stage 100/TST.
Arousal (number) Total number of arousals.
ArI (#/hr) Total number of arousals 60/TST (min).
ArI = arousal index; REM = rapid eye movement; SL = sleep latency; TRT = total recording time; TST = total sleep time; WASO = wake after sleep onset.
After Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.
R
Stage N3 N1
Most stage N3 is during the first half of the night
N2
Delta power decreases with each NREM cycle
N3
Stage R A B C
Episodes of stage R are longer in the second part of 23 24 1 2 3 4 5 6 7 8
the night Time
REM density (number of eye movements per time
during REM sleep) is higher in later episodes of REM Hypnogram 2
sleep
NREM = nonrapid eye movement; REM = rapid eye movement. W
Sleep stage
R
N1
N2
between wake and the other stages of sleep. Stage N2 occu-
pies the greatest proportion of the TST and accounts for N3
A B
approximately 50% to 60% of sleep. Stage N3 occupies
approximately 15% to 20% of the TST and stage R approxi- 23 24 1 2 3 4 5 6 7 8
Time
mately 20% of the TST. The amplitude of the slow waves and
amount of stage N3 is greatest in the first sleep cycle (see Fig. FIGURE 61 Hypnograms. Hypnogram 1 is from a normal individual. Hypnogram 2 is
61). Using spectral analysis, one can compute the delta from a patient complaining of frequent nocturnal awakenings. The first rapid eye
power (the contribution of slow wave activity to the total movement (REM) period is missed and there is a long REM latency. There are frequent
electroencephalogram [EEG] activity) (Fig. 62). The delta awakenings during the night.
power is highest during the initial cycle of NREM sleep. The
episodes of stage R occur about every 90 to 120 minutes, and
they are of longer duration as the night progresses. The REM
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Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 81
TABLE 63
Stages in Sleep Architecture with Aging (2060 yr)
Delta power
TABLE 64
Change in Sleep Architecture with Age (Sleep Heart Health Study)*
AGE RANGE
QUARTILE 1 QUARTILE 2 QUARTILE 3 QUARTILE 4
STAGE SEX (3754 YR) (5560 YR) (6170 YR) (>70 YR)
Stage N1 Men 5.8 6.3 7.1 7.6
Women 4.6 5.0 5.0 4.9
Stage N2 Men 61.4 64.5 65.2 66.5
Women 58.5 56.2 57.3 57.1
Stage N3 Men 11.2 8.2 6.7 5.5
Women 14.2 17.0 16.7 17.2
Stage R Men 19.5 19.1 18.4 17.8
Women 20.9 20.2 19.3 18.8
*Stage as a % of TST in four age quartiles.
TST = total sleep time.
From Redline S, Kirchner L, Quan SF, et al: The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406418.
density is the number of eye movements per time. The REM is an increase in the sleep latency, WASO, and stages N1 and
density tends to be the highest in the later REM periods. In N2.5 One study found an increase in stages N1 and N2 in
fact, the initial REM period of the night is often difficult to men only.6 There is a decrease in stage N3 (men only) and a
score owing to infrequent REMs. The first REM period also small decrease in stage R. The REM latency decreases with
may have K complexes or sleep spindles in epochs with both age. Study of sleep architecture in older adults is complicated
low chin electromyogram (EMG) and REMs. According to by inclusion of individuals with medical or mental disorders
the AASM scoring manual, such epochs are scored as stage in some studies of the effect of aging on sleep architecture.
R1 (see Chapter 3). During the last half of the night, most Many early studies did not include a sufficient number of
sleep is composed of stage N2 and stage R with intervening women. Ohayon and coworkers5 performed a large meta-
stage W and stage N1. Figure 61A presents a normal hyp- analysis of sleep architecture and attempted to specify normal
nogram. Figure 61B shows a hypnogram with a longer sleep values with and without exclusion of patients with mental
latency, a long REM latency, two episodes of stage N3 sleep, diseases that could alter sleep architecture. Redline and col-
and more stage W. leagues6 have published another analysis of the effect of age
on sleep architecture (Sleep Heart Health Study). They
CHANGES IN SLEEP ARCHITECTURE WITH studied a large group of patients using standardized recording
and scoring techniques (Table 64). This study evaluated
AGING (ADULTS)
information from sleep studies of patients 37 years and older
Sleep architecture changes as adults grow older (Table 63).46 and divided the study group into four age quartiles. The sleep
In general, sleep becomes lighter and more fragmented. There studies were performed at home. Van Cauter and associates3
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82 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss
also published findings concerning the age-related changes in TST from childhood to adolescence and then a slower
in slow wave and REM sleep in healthy men. decrease from age 20 to 80 years. Sleep efficiency decreases
with age, especially after age 50.5
Sleep Latency and REM Latency
WASO and Stage N1 (as a Percentage of TST)
In the meta-analysis by Ohayon and coworkers,5 when
studies that included individuals with sleep and mental dis- In the meta-analysis by Ohayon and coworkers,5 WASO and
orders were excluded, sleep latency increased only minimally stage N1 (as %TST) increased from age 20 to 60 years
from ages 20 to 80 (~10 min) (Fig. 63). If patients with (Fig. 65). In the analysis of Redline and colleagues,6 the
mental and medical disorders were included, there was not amount of stage N1 increased over the four quartiles for men
a significant increase in sleep latency with age. This is con- but not for women (Fig. 66).
sistent with more reports of early morning awakening than
sleep onset problems in the healthy elderly. In general, a sleep
Stage N2 (as a Percentage of TST)
latency of 30 minutes or more is considered abnormal. In the
same meta-analysis, the REM latency decreased with age. In the meta-analysis of Ohayon and coworkers,5 the amount
of stage N2 increases with age (Fig. 67A). Redline and col-
leagues6 found stage N2 to increase with age in men but not
TST and Sleep Efficiency
in women (see Fig. 67B). This is consistent with the findings
TST decreases with age as does the sleep efficiency (TST of a decrease in stage N3 in men (see later). The amount of
100/TRT) (Fig. 64). There tends to be a more rapid decrease stage N2 was higher in men than in women when all age
groups were considered.
SLEEP LATENCY
50 Stage N3 (as a Percentage of TST)
45
In the large meta-analysis by Ohayon and coworkers,5 the
40 amount of stage N3 decreased with age (Fig. 68A). The
35
30
25
TOTAL SLEEP TIME
650
Total sleep time (minutes)
20 600
15 550
10 500
5 450
0 400
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Age 350
300
REM LATENCY 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
190 Age
170
SLEEP EFFICIENCY
100
150
95
(% total recording time)
130 90
Sleep efficiency
110 85
80
90
75
70 70
65
50
60
30 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Age
Age
FIGURE 64 Changes in total sleep time and sleep efficiency with age. Both total
FIGURE 63 The sleep latency increases and rapid eye movement (REM) latency sleep time and sleep efficiency decrease in older individuals. From Ohayon MM,
decreases with age. From Ohayon MM, Carskadon MA, Guilleminault C, Viteiello MV: Meta- Carskadon MA, Guilleminault C, Viteiello MV: Meta-analysis of quantitative sleep
analysis of quantitative sleep parameters from childhood to old age in healthy individuals: parameters from childhood to old age in healthy individuals: developing normative sleep
developing normative sleep values across the human lifespan. Sleep 2004;27:12551273. values across the human lifespan. Sleep 2004;27:12551273.
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Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 83
WASO STAGE N2
160 75
140 70
120 65
Stage N2 (%TST)
100
60
80
55
60
50
40
45
20
40
0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 35
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Age
A Age
STAGE N1
20.0 STAGE N2
18.0 70
16.0
14.0 Men
65
Stage N1 (%TST)
12.0
10.0
8.0
60
6.0
4.0
2.0 55
0.0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Women
Age 50
1 2 3 4
FIGURE 65 Wake after sleep onset (WASO) and stage N1 increase with age. From B Age quartiles
Ohayon MM, Carskadon MA, Guilleminault C, Viteiello MV: Meta-analysis of quantitative
sleep parameters from childhood to old age in healthy individuals: developing normative FIGURE 67 A, The relationship between the amount of stage N2 and age in the study
sleep values across the human lifespan. Sleep 2004;27:12551273. of Ohayon and coworkers.5 Stage N2 increased with age. B, Stage N2 increased with age
only in men in the study of Redline and colleagues.6 The age range for each quartile is
defined in Table 64.
STAGE N1
9 Stage R (as a Percentage of TST)
8 Ohayon and coworkers5 found a decrease in stage R between
Men
20 and 60 years of age (Fig. 69A). Most of the decrease in
Stage N1 (%TST)
STAGE N3 STAGE R
70 30
28
60
26
Stage N3 (%TST)
Stage R (%TST)
50 24
40 22
20
30 18
20 16
14
10
12
0 10
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
A Age A Age
20 Women 24
22
Women
15
Stage N3 (%TST)
20
Stage R (%TST)
18
10 Men
16
Men 14
5
12
0 10
1 2 3 4 1 2 3 4
B Age quartiles B Age quartiles
FIGURE 68 A, Stage N3 (%TST [total sleep time]) for men and women combined FIGURE 69 Stage R. A, The amount of stage R (%TST [total sleep time]) decreases
decreases in adults. B, Stage N3 (%TST) decreases with age only in men. The absolute with age. Most of the decrease comes between 20 and 30 years. B, There was a small
amount of stage N3 for the study group as a whole was greater in women than in men. decrease in rapid eye movement (REM) with age quartile. The age range for each
The age range for each quartile is defined in Table 64. A, From Ohayon MM, Carskadon quartile is defined in Table 64. In this study, only patients older than 37 years were
MA, Guilleminault C, Viteiello MV: Meta-analysis of quantitative sleep parameters from included. A, From Ohayon MM, Carskadon MA, Guilleminault C, Viteiello MV: Meta-
childhood to old age in healthy individuals: developing normative sleep values across the analysis of quantitative sleep parameters from childhood to old age in healthy individuals:
human lifespan. Sleep 2004;27:12551273. B, Data from Redline S, Kirchner L, Quan SF, developing normative sleep values across the human lifespan. Sleep 2004;27:12551273.
et al: The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. B, Data from Redline S, Kirchner L, Quan SF, et al: The effects of age, sex, ethnicity, and
Arch Intern Med 2004;164:406418. sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406418.
40
Given that most previous work on sleep architecture was
based on the scoring manual of Rechtschaffen and Kales
20 (R&K),10 normative values could be altered by the new AASM
scoring manual. Therefore, studies comparing sleep architec-
ture between R&K and the AASM scoring manual are needed.
0 Moser and colleagues11 found that the sleep latency, REM
16-25 26-35 36-50 51-60 61-70 71-83
latency, TST, and sleep efficiency were not affected (similar in
Age
AASM and R&K). The absolute duration of sleep stage and the
STAGE N1 N2 %TST in stage N1 increased and stage N2 decreased using
60 AASM criteria compared with those of R&K. Stage R also dif-
fered but was age-dependent, being slightly higher using
% of sleep period
Children
% of sleep period
40
The percentage of REM sleep decreases to approximately
30% at age 1 to 2 years and 20% to 25% at 3 to 5 years of age.
20 As children move toward adolescence (Table 67), there
tends to be a decrease in stage N3 sleep and stage R with an
increase in stage N2. TST decreases from early childhood to
0 adolescence from 14 hours at age 1 down to 9 hours in early
16-25 26-35 36-50 51-60 61-70 71-83
adolescence.16 Typical values for sleep parameters are listed
Age
in Tables 68 and 69.1719
FIGURE 611 Change in stage N3 and stage R (as a percentage of sleep period time)
with age in a group of normal men. Stage N3 decreased in the older age range as did AROUSALS
stage R after age 50. From Van Cauter E, Leprousl R, Plat L: Age-related changes in slow
wave sleep and REM sleep and relationship with growth hormone and cortisol levels in Chapter 3 presents the scoring criteria for arousals.2,20
Scoring of arousals is important because frequent arousals
healthy men. JAMA 2000;284:861868.
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86 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss
TABLE 66 TABLE 68
Normal Sleep Infants and Children Typical Sleep Architecture Values for Normal
INFANTS < 3 mo
Children Aged 118
Stage R (REM sleep, active sleep) at sleep onset. PARAMETER USUAL VALUES
Total sleep time 1618 hr. Sleep efficiency (%) 89%, large variability
Sleep episodes of 34 hr duration interrupted by feeding. Sleep latency (min) 23 min, large variability
Sleep cycles 45- to 60-min periodicity (90100 min in REM latency (min) 87155 (<10 yr)
adults). 136156 (>10 yr)
Entering sleep through NREM sleep instead of stage R. Stage N3 (%TST) 2932 (<10 yr)
2032 (>10 yr)
Sleep consolidates into major episodes with daytime
naps. Stage R (%TST) 1721 (can be higher in
younger children)
CHILDREN
REM = rapid eye movement; TST = total sleep time.
Sleep cycle period does not reach adult values until From Beck SE, Marcus CL: Pediatric polysomnography. Sleep Med Clin
2009;4:393406.
adolescence.
NREM = nonrapid eye movement; REM = rapid eye movement.
From Kahn A, Dan B, Grosswasser J, et al: Normal sleep architecture in infants
and children. J Clin Neurophysiol 1996;13:184197.
35
Current
TABLE 67 Mathur, 1995
Changes in Sleep Childhood to Adolescence 30
Boselli et al, 1998
FIGURE 612 Change in arousal index with age. The data are from references 2126.
result in nonrestorative sleep even in the absence of a decre- Current refers to data from reference 22. From Bonnet M, Arand DL: EEG arousal norms
ment in TST. The arousal index (ArI, number of arousals/ by age. J Clin Sleep Med 2007;3:271274.
hour of sleep) in normal individuals increases with age (Fig.
612).2125 Bonnet and Arand21 found the ArI in 51- to
60-year-old individuals and 61- to 70-year-old individuals to arousals alone can cause decrements in performance and
be 21.9 8.9/hr and 21.9 6.8/hr, respectively (mean mood as well as increases in subjective and objective sleepi-
standard deviation [SD]). Therefore, the 95% confidence ness. Consolidated episodes of sleep in excess of 10 minutes
limits may approach 35/hr in older age groups. Conversely, are needed for restorative sleep.26,27 When experimental sleep
an ArI of 25/hr would be high for a young adult. Figure 612 disturbance occurs more frequently than every 3 minutes
shows the data on the change in ArI with age from several (<3-min episodes of consolidated sleep), there is a sharp
studies. decrease in the sleep latency by the multiple sleep latency test
(MSLT)27 (Fig. 613). This would correspond to an ArI
greater than 20/hr. In sleep studies, some patients may have
SLEEP FRAGMENTATION
comparable ArIs but differ in the amount of preserved con-
Although in clinical practice, sleep fragmentation and solidated sleep. Table 610 lists the common clinical symp-
chronic partial sleep deprivation (chronic decreased TST) toms of sleep deprivation. Similar findings can occur with
commonly occur together, studies have shown that frequent severe sleep fragmentation.
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Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 87
60
2 yr 13.2 1.2
50
3 yr 12.5 1.1 40
7 nights
4 yr 11.8 1.0 30
in the amount of stage R (REM rebound). Withdrawal of in stage N3 at the expense of other sleep stages. On the second
REM-suppressant medications can also result in similar night, there may be an increase in REM sleep. Therefore, at
findings. Of note, other patients with OSA have a large least in most patients, stage N3 rebound wins out over stage
increase in stage N3 on first CPAP night. R rebound, at least during initial recovery sleep.
16 16
14 14
12 12
10 10
PVT lapses
PVT lapses
8 8
6 6
Daily sleep period
4 4
8 hr ( ),
2 2 4 hr ( )
6 hr ( ),
0 0 0 hr ( ) Sleep
deprivation
2 2
0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80
A Cumulative sleep debt (h) B Cumulative excess wakefulness (h)
FIGURE 615 Progressive impairment with greater sleep debt or cumulative excess wakefulness. For example, if a person needs
8 hours of sleep (16 hr of wake tolerated), then after 2 nights of 6 hours of sleep, the cumulative sleep debt is 4 hours or the excess
wake is 4 hours. In A, sleep deprivation causes much greater impairment expressed as sleep debt. B, When expressed as excess
wake, the values are similar to those from chronic sleep loss of equal accumulated wake. PVT = psychomotor vigilance test. From
Van Dongen HPA, Maislin G, Mullington JM, et al: The cumulative cost of additional wakefulness: dose-response effects of
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neurobehavioral function and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117126.
Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 89
REFERENCES
1. Kushida CA, Littner MR, Morgenthaler T, et al: Practice
parameters for the indications for polysomnography and
CLINICAL REVIEW QUESTIONS related procedures: an update for 2005. Sleep 2005;28:
499521.
1. Which of the following does NOT decrease with age? 2. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
A. TST. Academy of Sleep Medicine: The AASM Manual for the Scoring
B. Sleep stage N1 (men). of Sleep and Associated Events: Rules, Terminology and Tech-
nical Specifications, 1st ed. Westchester, IL: American Academy
C. Stage N3 (men). of Sleep Medicine, 2007.
D. Stage R. 3. Van Cauter E, Leproult R, Plat L: Age-related changes in slow
wave sleep and REM sleep and relationship with growth
E. REM latency. hormone and cortisol levels in healthy men. JAMA 2000;
284:861868.
2. Which of the following decreases with age? 4. Bliwise DL: Normal aging. In Kryger M, Roth T, Dement W
A. Sleep latency. (eds): Principles and Practice of Sleep Medicine. Philadelphia:
Elsevier, 2005, pp. 2438.
B. Sleep efficiency. 5. Ohayon MM, Carskadon MA, Guilleminault C, Viteiello MV:
C. ArI. Meta-analysis of quantitative sleep parameters from childhood
D. WASO. to old age in healthy individuals: developing normative sleep
values across the human lifespan. Sleep 2004;27:12551273.
3. Which of the following is true about infant sleep? 6. Redline S, Kirchner L, Quan SF, et al: The effects of age, sex,
ethnicity, and sleep-disordered breathing on sleep architecture.
A. Enter sleep via stage R (active sleep). Arch Intern Med 2004;164:406418.
B. Active sleep about 50% of TST. 7. Harding SM, Hawkins JW: Sleep and internal medicine. In
Carney P, Berry RB, Geyer J (eds): Clinical Sleep Medicine.
C. Typical sleep cycle duration is 90 minutes. Philadelphia: Lippincott Williams & Wilkins, 2005, pp.
D. A and B. 456470.
E. A and C. 8. Agnew HW Jr, Webb WB, Williams RL: The first night effect:
an EEG study of sleep. Psychophysiology 1966;2:263266.
9. Webb WB, Campbell S: The first night effect revisited with age
4. Which of the following increase the REM latency? as a variable. Waking Sleeping 1979;3:319324.
A. Depression. 10. Rechtschaffen A, Kales A (eds): A Manual of Standardized
B. Lithium. Terminology Techniques and Scoring System for Sleep Stages
of Human Subjects. Los Angeles: Brain Information Service/
C. Narcolepsy. Brain Research Institute, UCLA, 1968.
D. Withdrawal of tricyclic antidepressants. 11. Moser D, Anderer P, Gruber G, et al: Sleep classification
according to AASM and Rechtschaffen & Kales: effects of sleep
5. Sleep deprivation results in which of the following? scoring parameters. Sleep 2009;32:139149.
12. Danker-Hopfe H, Anderer P, Zeitlhofer J, et al: Interrater reli-
A. Increased leptin. ability for sleep scoring according to the Rechtschaffen & Kales
B. Increased ghrelin. and the new AASM standard. J Sleep Res 2009;18:7484.
C. Augmented response to immunization. 13. Novelli L, Ferri R, Bruni O: Sleep classification according to
AASM and Rechtschaffen and Kales: effects on sleep scoring
D. Stage R rebound before stage N3 rebound in recovery parameters of children and adolescents. J Sleep Res 2010;19:
sleep. 238247.
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90 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss
14. Kahn A, Dan B, Grosswasser J, et al: Normal sleep architecture 25. Boselli M, Parrino L, Smerieri A, et al: Effect of age on EEG
in infants and children. J Clin Neurophysiol 1996;13:184197. arousals in normal sleep. Sleep 1998;21:351357.
15. Seldon S: Polysomnography in infants and children: In Sheldon 26. Bonnet MH. Performance and sleepiness as a function of fre-
SH, Ferber R, Kryger MH (eds): Principles and Practice of quency and placement of sleep disruption. Psychophysiology
Pediatric Sleep Medicine. Philadelphia: Elsevier Saunders, 1986;23:263271.
2005, pp. 4971. 27. Bonnet MH, Arand DL: Clinical effects of sleep fragmentation
16. Iglowstein I, Jenni OG, Molinari L, Largo RH: Sleep duration versus sleep deprivation. Sleep Med Rev 2003;7:297310.
from infancy to adolescence: reference values and generational 28. Bonnet MH: Acute sleep deprivation. In Kryger MH, Roth T,
trends. Pediatrics 2003;111:302307. Dement WC (eds): Principles and Practice of Sleep Medicine,
17. Montgomery-Downs HE, OBrien LM, Gulliver TE, et al: Poly- 5th ed. St. Louis: Elsevier, 2011, pp 5465.
somnographic characteristics in normal preschool children. 29. Van Dongen HPA, Maislin G, Mullington JM, et al: The cumu-
Pediatrics 2006;117:741753. lative cost of additional wakefulness: dose-response effects of
18. Mason TB, Teoh L, Calabro K, et al: Rapid eye movement neurobehavioral function and sleep physiology from chronic
latency in children and adolescence. Pediatr Neurol 2008;39: sleep restriction and total sleep deprivation. Sleep 2003;26:
162169. 117126.
19. Beck SE, Marcus CL: Pediatric polysomnography. Sleep Med 30. Banks S; Dinges DF: Behavioral and physiological conse-
Clin 2009;4:393406. quences of sleep restriction. J Clin Sleep Med 2007;3:
20. Bonnet MH, Doghramji K, Roehrs T, et al: The scoring of 519528.
arousal in sleep; reliability, validity, and alternatives. J Clin 31. Donga E, van Dijk M, van Dijk JG, et al: A single night of partial
Sleep Med 2007;3:133145. sleep deprivation induces insulin resistance in multiple meta-
21. Bonnet M, Arand DL: EEG arousal norms by age. J Clin Sleep bolic pathways in healthy subjects. J Clin Endocrinol Metab
Med 2007;3:271274. 2010;95:29632968.
22. Wong TK, Galster P, Lau TS, et al: Reliability of scoring arousals 32. Van Cauter E, Spiegel K, Leproult R: Metabolic consequences
in normal children and children with obstructive sleep apnea of sleep and sleep loss. Sleep Med 2008;9(Suppl 1):S23S28.
syndrome. Sleep 2004;27:11391145. 33. Spiegel K, Tasali E, Penev P, Van Cauter E: Sleep curtailment
23. Mathur R, Douglas NJ: Frequency of EEG arousals from noc- in healthy young men is associated with decreased leptin levels,
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DaneshGroup.com
Chapter 7
Neurobiology of Sleep
and major associated neurotransmitters (neuromodulators)
Chapter Points are listed in Table 71.36
Serotonergic neurons in the DRN are active during The term neurotransmitter is currently applied to situa-
wake, less active during NREM, and even less active tions in which one presynaptic neuron directly influences
during REM sleep. another postsynaptic neuron. In neuromodulation, a given
Noradrenergic neurons in the LC are active during neurotransmitter regulates the activity of diverse popula-
wake, less active during NREM sleep, and inactive tions of neurons in the central nervous system. Examples of
during REM sleep. neurotransmitters that are also neuromodulators include
Histaminergic neurons in the TMN are active during acetylcholine (ACh), serotonin (5HT), dopamine (DA), and
wake and episodes of cataplexy. histamine (HA). Neurons are often characterized with
Cholinergic neurons in REM-on areas are active during respect to sleep by when they are most active.3 Some neurons
REM sleep. are active during wake, during rapid eye movement (REM)
Cholinergic neurons in wake/REM-on areas are active only (REM-on), during REM and wake (wake/REM-on),
during wake and REM sleep. during nonrapid eye movement (NREM) only (NREM-on),
Neurons in the VLPO are active during sleep and or during NREM and REM sleep (Fig. 71). Figure 72
inactive during wake. They contain GABA and galanin. shows sections through important brainstem areas involved
Hypocretin neurons in the lateral and posterior in the regulation of wake and sleep and identifies important
hypothalamus project to many areas of the brain brain regions.
important for the control of wake and sleep. They
stabilize transitions between wake and sleep.
Hypocretin neurons are absent (or very decreased) in MAJOR BRAIN AREAS IMPORTANT FOR
patients with narcolepsy with cataplexy. These patients SLEEP AND WAKE
also have low or undetectable cerebrospinal fluid
hypocretin-1. Hypothalamic Areas
The hypotonia of REM sleep is due to a combination of Lateral Hypothalamus
inhibition and dysfacilitation. Neurons in the lateral and posterior hypothalamus are the
The brainstem regions involved in hypotonia include sole source of the awake-promoting neuropeptides hypocre-
the subcoeruleus area (sublateral dorsal area), areas tin 1 (Hcrt1) and hypocretin 2 (Hcrt2), also known as Orexin
of the medulla and interneurons inhibiting the spinal A and Orexin B, respectively.7,8 Hcrt1 can attach to both
cord motor neurons (glycine and GABA). Hcrt1 and 2 receptors, whereas Hcrt2 attaches only to Hcrt2
receptors. Patients with narcolepsy with cataplexy have loss
of 90% or more of Hcrt-producing neurons and have low to
In 1930, von Economo published findings of an autopsy undetectable cerebrospinal fluid (CSF) levels of Hcrt1.9,10
study of the brains of patients dying from encephalitis lethar- One study of a few patients with narcolepsy without cataplexy
gica.1,2 Von Economo found that patients with damage to the found partial loss of Hcrt neurons.11 Canine narcolepsy is
posterior hypothalamus and rostral midbrain often had due to a mutation in the gene for the Hcrt2 receptor.
excessive sleepiness, whereas those with injury to the ante- Hcrt neurons send abundant excitatory projections to the
rior hypothalamus had unrelenting insomnia. Based on dorsal raphe (Hrct1 and Hcrt2 receptors) nucleus, the locus
these observations, he hypothesized that the anterior hypo- coeruleus (Hcrt1 receptors), and the tuberomammillary
thalamus contained neurons that promoted sleep, whereas nucleus (Hcrt2 receptors) (Fig. 73). These areas in turn
neurons near the hypothalamus-midbrain junction helped send inhibitory projections to Hcrt neurons. Hcrt neurons
promote wakefulness. Decades later, the importance of those have a strong excitatory effect on the cholinergic neurons of
areas of the brain for sleep and wake, respectively, has been the basal forebrain that contribute to cortical arousal but
increasingly understood. A number of major brain areas have no effect on GABAergic sleep-promoting neurons
involved in control of wake and sleep, their abbreviations, within the ventrolateral preoptic (VLPO) area.
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92 Chapter 7 Neurobiology of Sleep
TABLE 71
Brain Areas important for Sleep
AREA ABBREVIATION NEUROTRANSMITTER
Lateral dorsal tegmentum LDT Acetylcholine (ACh)
Pedunculopontine tegmentum PPT Acetylcholine (ACh)
Locus coeruleus LC Norepinephrine (NE)
Dorsal raphe nucleus DRN Serotonin (5HT)
Tuberomammillary nucleus TMN Histamine (HA)
Ventrolateral preoptic area VLPO Gamma-aminobutyric acid (GABA) Galanin
Lateral posterior hypothalamus LPH Hypocretin 1 and 2 (Orexin A, B)
EEG
EOG
LGN
EMG
10 s
Cortical and
thalamic
NREM-on
REM-
waking-on
PGO-on
REM-off
REM-on
FIGURE 71 Activity of different neurons during wake, nonrapid eye movement (NREM), and rapid eye movement (REM) sleep. EEG =
electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; LGN = lateral geniculate nucleus; PGO = ponto-geniculo-occipital.
From Rechtschaffen A, Siegel J: Sleep and dreaming. In Kandel E, Schwartz JH, Jessell TM (eds): Principles of Neural Science, 4th ed. New York:
McGraw-Hill, 2000, p. 940, Fig. 473.
As is discussed later, Hcrt appears to stabilize transitions sleep-inducing factors including adenosine and prostaglan-
between wake and sleep. Hcrt neurons are relatively inactive din D2. These neurons are sensitive to warmth, and heating
in quiet waking but are transiently activated during sensory this area of the brain increases their activity and decreases
stimulation. Mileykovskiy and coworkers12 found that Hcrt wake. A compact group of VLPO neurons (VLPO cluster)
cells are silent in slow wave sleep and tonic periods of projects to the tuberomammillary nucleus (TMN) and
REM sleep, with occasional burst discharge in phasic REM inhibits the neuronal activity of that area. A second group of
(Fig. 74). Hcrt cells discharge in active waking and have VLPO neurons is located dorsal and medial to the VLPO
moderate and approximately equal levels of activity during cluster neurons and the group is called the extended VLPO
grooming and eating and maximal activity during explor- (eVLPO) by some authors.14 The eVLPO neurons make up
atory behavior. The authors of this study concluded that Hcrt the majority of the projections to the dorsal raphe nucleus
cells are activated during emotional and sensorimotor condi- (DRN) and locus coeruleus (LC) as well as to the interneu-
tions similar to those that trigger cataplexy in narcoleptic rons of the lateral dorsal tegmental/pedunculopontine teg-
animals. mental (LDT/PPT) region.14 One study showed a subset of
neurons in the eVLPO were more active during REM than
Ventrolateral Preoptic Nucleus NREM.14 However, most VLPO neurons appear to be active
The VLPO is an area in the hypothalamus containing neurons during both NREM and REM. The neurons in the VLPO
active during sleep. Most sleep-active neurons in the VLPO contain the neurotransmitters/neuromodulators gamma-
are believed to be active during both NREM and REM sleep aminobutyric acid (GABA) and galanin. The VLPO neuro-
(Fig. 75).13 Many of the VLPO neurons are activated by nal projections to the DRN, LC, and TMN are inhibitory
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Chapter 7 Neurobiology of Sleep 93
A B C
SI
1
VLPO TM
D
a b c d e f
E F
PPT
DR LC
LDT
PnO
FIGURE 72 AF, Major brainstem areas important for sleep in the rat brain at various sections. Center, A lateral view of the brain shows locations of the
sections depicted (af). A, Ventrolateral preoptic area (VLPO). B, Substantia innominata (SI). C, Tuberomammillary nucleus (TM). D, Pedunculopontine
tegmentum (PPT) and dorsal raphe nucleus (DR). E, Lateral dorsal tegmentum (LDT). F, Locus coeruleus (LC) and pontine reticular nucleus, oral part
(PnO). The PnO in the rat is homologous to the medial pontine reticular formation in the cat. AF, From Baghdoyan HA, Lydic R: Neurotransmiters and
neuromodulators regulating sleep. In Bazi CW, Ballow BA, Sammaritan MR (eds): Sleep and Epilepsy: The Clinical Spectrum. Amsterdam: Elsevier Science, 2002,
pp. 1744.
10 **
Cortex **
**
Orexin
**
Firing rate (sp/sec)
**
**
BF 5
PPT *
TMN SN Raphe LDT
VTA LC
g
EM
EM
EM
rin
in
tin
ak
om
R
Ea
tw
o
pl
c
ro
e
Ex
ni
i
as
ui
G
To
Q
Ph
30
Spikes/sec
20
10
0
EMG
EEG
100 sec
FIGURE 75 Neurons of the ventrolateral preoptic (VLPO) are active during both nonrapid eye movement (NREM) and rapid eye movement
(REM) sleep. EEG = electroencephalogram; EMG = electromyogram. From Szymusiak R, Gvilla I, McGinty D: Hypothalamic control of sleep. Sleep
Med 2007;8:291301.
Brainstem Regions
(Fig. 76). The neurons in the VLPO receive inhibitory Dopamine Regions
projections from the DRN, LC and TMN. Destruction of Neurons producing dopamine (DA) are abundant in the SN
the VLPO impairs sleep. A group of sleep-active neurons and ventral tegmental area (VTA). Previously, studies sug-
in the median preoptic nucleus (MnPO) was described after gested that DA neurons do not change their firing rates
the identification of the VLPO.13 Similar to VLPO cells, a substantially across sleep stages.3 However, extracellular
subset of MnPO neurons expresses c-Fos and discharges DA levels are high in several brain regions during wakeful-
more rapidly during NREM and REM sleep. Interestingly, ness. Whereas the average rate of firing of the VTA neurons
unlike VLPO neurons, the MnPO cells also fire faster during does not change across states, they have burst firing during
prolonged wakefulness (which increases sleep pressure). wake that releases more DA. Recent work has identified DA
There is no evidence that lesions of the MnPO area impair cells in the ventral periaqueductal gray (vPAG) that are wake
sleep. active.18 The vPAG contains DA neurons that are active
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Chapter 7 Neurobiology of Sleep 95
(express Fos) during wakefulness but not sleep. DA neurons REM sleep but not wake or NREM sleep. Wake/REM-on
in the vPAG project to and receive input from cholinergic neurons are active during wake and REM sleep (Table 72
neurons in the LDT area, Orexin neurons, VLPO, and pre- and Fig. 78).19 Other cholinergic neurons in the basal fore-
frontal cortex. Loss of vPAG DA neurons promotes sleep. brain (BF) project to the cortex, hippocampus, and amyg-
DA agonists acting at D1, D2, and D3 receptors increase dala. The firing rate of these neurons is also high during wake
waking and decrease NREM and REM sleep. Exactly which and REM and low during NREM sleep.
DA neurons are important for maintenance of wakefulness
is not clear. DA blockers of D1 and D2 receptors can promote
sleep. In patients with low DA activity such as in Parkinsons
disease, low doses of DA agonists (pramipexole, ropinirole) TABLE 72
that bind D2/D3 autoreceptors on DA neurons can actually Activity of Brain Areas Important for Wake
cause sleepiness by reducing DA signaling. Amphetamines and Sleep
promote wakefulness by increasing DA signaling.
WAKE NREM REM
Reticular Formation EEG Fast, low Slow, high Fast, low
The reticular formation is a loose collection of neurons voltage voltage voltage
extending from the caudal medulla to the core of the mid-
LDT/PPT
brain. Sections above the mid pons produce coma or hyper-
somnolence. Wakefulness depends on the activity of the Wake-on Active Not active Active
ascending reticular activating system (ARAS). This system REM-on
projects to higher brain centers. One pathway ascends dor- REM-on Not active Not active Very active
sally to the thalamus, and the second ascends ventrally
TMN Active Reduced Absent
through the lateral hypothalamus and forebrain (Fig. 77).
DRN Active Less active Low activity
Dorsal RAS
Lateral Dorsal Tegmentum/Pedunculopontine Tegmentum. LC Active Less active Absent
Neurons in the LDT and PPT areas that are located in the VLPO* Not active Active Active
dorsal midbrain and pons make up the majority of the dorsal Hypocretin Maximally Not active Not active
RAS pathway through the pons and are cholinergic. Some of active
the neurons are active during wake and REM sleep (wake/
REM-on), whereas others are active mainly during REM Dopaminergic Activity previously thought not to be
neurons sleep state dependent.
sleep (REM-on).35 Acetylcholine (ACh) release in the thala-
vlPAG neurons active during wake
mus is high during wake and REM sleep. The cholinergic
*Some neurons in extended VLPO more active during REM than NREM sleep.
neurons from the LDT/PPT densely innervate the thalamus DRN = dorsal raphe nucleus; EEG = electroencephalogram; LC = locus
(especially the medial and intralaminar thalamic nuclei), coeruleus; LDT = lateral dorsal tegmentum; NREM = non-rapid eye
lateral hypothalamus, and midbrain. During wake and REM movement; PPT = pedunculopontine tegmentum; REM = rapid eye
movement; TMN = tuberomammilary nucleus; VLPO = ventrolateral preoptic
sleep, these cholinergic neurons depolarize thalamic relay area; vlPAG = ventrolateral periaqueductal gray.
neurons, thereby activating thalamocortical signaling and Adapted from Saper CB, Chou TC, Scammell TE: The sleep switch:
produce fast cortical rhythms. During NREM sleep, these hypothalamic control of sleep and wakefulness. Trends Neurosci
2001;24:726731.
neurons are inactive. REM-on neurons are active during
VENTRAL RAS DORSAL RAS FIGURE 77 Reticular activating system (RAS). The
ventral RAS includes neurons from the locus coeruleus,
dorsal raphe nuclei, tuberomammillary nucleus (TMN),
and lateral hypothalamus (LH). The dorsal RAS includes
Thalamus
projections from the lateral dorsal tegmental (LDT) and
pedunculopontine tegmental (PPT) areas.
Medulla
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96 Chapter 7 Neurobiology of Sleep
8 ORX LC
TMN
REM-on neurons DRN
Mean ( SEM) discharges/sec
More VLPO
More
active active
6 eVLPO ORX
LC
TMN
4 DRN VLPO
eVLPO
2 NREM Wake
Stimulatory
0 Inhibitory
A AW QW SWS REM REM
FIGURE 79 Nonrapid eye movement (NREM) flip-flop switch. During NREM, the
ventrolateral preoptic area (VLPO) inhibits hypocretin neurons as well as the locus
4
coeruleus (LC), tuberomammilary nucleus (TMN), dorsal raphe nucleus (DRN) areas
Wake/REM-on neurons
promoting sleep. During wake, the hypocretin neurons stimulate the LC, TMN, and DRN
Mean ( SEM) discharges/sec
areas, which are active and inhibit the VLPO neurons. eVLPO = extended ventrolateral
preoptic area; ORX = Orexin (hypocretin).
3
2
Basal Forebrain
Cholinergic neurons in the BF excite cortical pyramidal cells.
GABA BF neurons disinhibit cortical neurons. Lesions that
1 destroy BF ACh and GABA neurons increase delta power.
B AW QW SWS REM REM
FIGURE 78 Firing rate of rapid eye movement (REM)-on neurons and wake/REM-on CONTROL OF NREM SLEEP
neurons in the PPT/LPT area. AW = active wake; QW = quiet wake; REM+ = REM sleep
with eye movements; REM = REM sleep without eye movements; SEM = standard error During NREM sleep, the VLPO neurons are active and
of the mean; SWS = slow wave sleep. From Thakkar MM, Strecker RE, McCarley RW: inhibit the firing of neurons in the TMN, DRN, and LC (see
Behavioral state control through differential serotonergic inhibition in the mesopontine Table 72 and Fig. 75). The Orexin neurons do not inner-
cholinergic nuclei: a simultaneous unit recording and microdialysis study. J Neurosci vate the VLPO but stimulate the TMN, DRN, or LC more or
1998;18:54905497. less depending on the sleep state. Orexin neurons are active
during wake. This mutually inhibitory system functions as a
flip-flop switch transitioning between the two states (Fig.
79; see also Fig. 78).6
PPT-LDT
DR-LC
Glutamate
REM-on
PC
Glutamate
PC Glutamate
eVLPO Glutamate SLD
vIPAG
GABA
Orx LPT SLD
GABA
REM-on
REM-off Medulla
vIPAG ventrolateral SLD sublateral dorsal PC precoeruleus Interneuron
periaqueductal tegmentum
gray
Glycine, GABA
FIGURE 712 A flip-flop model for rapid eye movement (REM) sleep in which REM-off
and REM-on neurons mutually inhibit each other. The gamma-aminobutyric acid (GABA) Motor
neurons are inhibitory. DR = dorsal raphe; eVLPO = extended ventrolateral preoptic neuron
area; LDT = lateral dorsal tegmentum; LPT = lateral pontine tegmentum; ORX = Orexin FIGURE 713 Postulated mechanisms for rapid eye movement (REM) EEG
(hypocretin); PPT = pedunculopontine tegmentum. From Fuller PM, Saper CB, Lu J: The phenomenon and REM atonia in the flip-flop model of REM sleep. Glutaminergic
pontine REM switch: past and present. J Physiol 2007;584:735741. neurons of the precoerulus (PC) area project to the basal forebrain (BF). Glutaminergic
neurons of the sublateral dorsal nucleus (SLD; mesopontine tegmentum) project to
the medulla and spinal cord mediating hypotonia. GABA = gamma-aminobutyric
REM-off population then inhibits the REM-on population acid. Based on Fuller PM, Saper CB, Lu J: The pontine REM switch: past and present. J
(see Fig. 711, line b), terminating the REM episodes. The Physiol 2007;584:735741.
REM-off neurons have negative feedback (see Fig.
711, line c), and as the REM-off activity diminishes, the
REM-on population is released from inhibition and the to a region of the intermediate ventromedial medulla
activity increases until another REM episode occurs. This (IVMM) containing neurons that project to the spinal ventral
model provides an explanation for the cycles of NREM and horn. However, it is not known whether this projection is
REM sleep that occur during sleep. A more complicated excitatory or inhibitory nor is it known whether these pro-
model includes the influence of inhibitory neurons (GABA) jections are direct (i.e., spinal motor neuron) or indirect (i.e.,
in several brain areas.5 spinal interneuron). The interneurons hyperpolarize the
A different model of control of REM sleep by Lu and motorneurons with GABA and glycine. As noted previously,
Fuller and colleagues2022 concentrates on different nuclei as the atonia of skeletal muscles during REM sleep results not
the two parts of reciprocally interacting REM-on and only from the inhibition by GABA and glycine at the alpha
REM-off areas located in the mesopontine tegmentum (Fig. motor neurons but also from dysfacilitationloss of 5HT
712). GABAergic neurons in the REM-off and REM-on and NE stimulation on motorneurons from monoaminergic
areas mutually inhibit each other. In this REM sleep flip-flop nuclei.
circuit model, the REM-off GABAergic neurons in the ven- In this model, cholinergic and monoaminergic systems
trolateral periaqueductal gray (vlPAG) and LPT and REM-on may modulate REM sleep by acting on either the REM-off
GABAergic cells in the SLD tegmental area mutually inhibit or the REM-on groups or on both simultaneously (not
each other. The SLD in rats is equivalent to the subcoeruleus shown). However, the cholinergic and monoaminergic
area or perilocus coeruleus area in cats. The LDT/PPT and systems are located external to the REM flip-flop switch. Of
eVLPO provide inhibitory input to the REM-off neurons. note, this flip-flop model does not account for the periodicity
Hypocretin (Orexin) neurons provide stimulatory input to of alternation between NREM and REM sleep.5 In addition,
the REM-off neurons. neuronal activity in the brainstem on transitions from
In this model, REM-on glutamatergic neurons in the pre- NREM to REM is a gradual change. The important projec-
coeruleus (PC) and medial parabrachial (PB) areas project tions from cholinergic areas to the thalamus by REM-on cells
to the medial septumBF and activate the hippocampus are also not addressed.
(theta rhythm of REM sleep) and neocortex (Fig. 713).
REM-on glutamatergic neurons in the SLD project to
Effects of Medications
glycinergic/GABAergic interneurons in the spinal cord that,
in turn, project to anterior horn cell motor neurons inducing Given the previous models for NREM and REM sleep, one
muscle atonia. The SLD glutamatergic neurons also project can see that antihistamines in general cause sleepiness,
DaneshGroup.com
Chapter 7 Neurobiology of Sleep 99
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Chapter 8
Monitoring Respiration
Technology and Techniques
the AASM scoring manual)1 outlines rules for scoring
Chapter Points respiratory events. These are discussed in detail in Chapter
The recommended sensor to detect apnea is a 9. The AASM scoring manual1 recommends specific sensor
nasal-oral (oronasal) thermal device. types and techniques to be used for recording respiration
The recommended sensor to detect hypopnea is the during sleep (Table 81). The recommendations are based
NP signal (with or without square root linearization). on consensus and evidence from an accompanying system-
The NP signal is proportional to the flow squared. The atic review of the validity and reliability of scoring respira-
NP signal tends to underestimate low flow and tory events during sleep.2 This review serves as an update of
overestimate high flow. Flattening of the inspiratory a previous AASM consensus statement concerning the respi-
portion of the NP tracing is suggestive of airflow ratory definitions and the accuracy of monitoring techniques
limitation and high upper airway resistance. published in 1999.3
Although the most sensitive method to detect
respiratory effort is esophageal manometry, RIP is the
TECHNIQUES TO MEASURE AIRFLOW OR
recommended method used in most clinical studies.
The RIPsum is an estimate of tidal volume (more TIDAL VOLUME
accurate when calibrated). The techniques used to detect (measure) airflow during sleep
The relationship between the SpO2 and the studies are listed in Table 82. The pneumotachograph
corresponding PaO2 depends on many factors (PNT) is the most accurate method to measure airflow
affecting the position of the oxyhemoglobin saturation during sleep studies (Fig. 81).2,3 This device quantifies
curve (including PaCO2, temperature, and abnormal airflow by measurement of the pressure drop across a linear
hemoglobin). (constant) resistance (usually a wire screen)3. The relation-
A valid PETCO2 measurement assumes that the tracing ship between the pressure change, flow rate, and resistance
has an alveolar plateau. is given by the following equation:
SpO2 utilizes the absorption of two wavelengths of
light while co-oximetry utilizes four wavelengths and Pressure change = Flow Resistance Equation 81
can determine the true fraction of oxyhemoglobin The PNT is worn in a mask covering the nose and mouth.
when significant amounts of COHb or MetHb are Although the PNT is commonly used to measure airflow
present. during sleep research, this device is rarely used during clini-
cal sleep studies.
Thermal devices were the first to be used to monitor
The three major components of respiratory monitoring airflow during clinical sleep studies.2,3 These devices actually
during sleep include measurement/detection of airflow, detect changes in temperature induced by airflow (cooler
measurement/detection of respiratory effort, and measure- inspired air, warmer exhaled air). The changes in device tem-
ment of arterial oxygen saturation (SaO2). Ancillary moni- perature result in changes in voltage output (thermocouples)
toring may include detection of snoring and recording or resistance (thermistors). Thermal sensors are generally
surrogates of the arterial partial pressure of carbon dioxide adequate to detect an absence of airflow (apnea), but their
(PaCO2) including end-tidal partial pressure of carbon signal does not vary in proportion to airflow.4,5 Therefore,
dioxide (PETCO2) and transcutaneous partial pressure of thermal sensors are not an ideal means of detecting a reduc-
carbon dioxide (TcPCO2). The techniques employed for tion in airflow (hypopnea). Figure 82 compares thermal
respiratory monitoring are discussed in detail in this chapter. sensor estimates of minute ventilation with those using an
The criteria for defining important respiratory events are accurate measurement of tidal volume (the head out of the
presented in Chapter 9. The AASM Manual for the Scoring box plethysmograph).4 A wide scatter of points illustrates the
of Sleep and Associated Events (hereafter referred to as poor ability of thermal devices to track changes in tidal
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101
102 Chapter 8 Monitoring RespirationTechnology and Techniques
TABLE 81
American Academy of Sleep Medicine Recommended Sensors
ADULT PEDIATRIC
Airflow sensor to detect Recommended: Same as adult except alternative
apnea Nasal-oral thermal (oronasal) sensor sensors for apnea detection also
Alternative sensor (if recommended sensor signal include the end-tidal PCO2 signal and
is unreliable) summed calibrated respiratory
Nasal pressure (with or without square root inductance plethysmography signal
transformation of the signal)
Airflow sensor to detect Recommended: Recommended: same
hypopnea Nasal pressure (with or without square root Alternative sensors: Nasal-oral thermal
transformation of the signal) device
Alternative sensors (if recommended sensor signal
is unreliable)
Nasal-oral thermal device
Respiratory inductance plethysmography
(calibrated or uncalibrated)
Sensor to detect respiratory Recommended: Same except muscle EMG not
effort Esophageal pressure mentioned
Respiratory inductance plethysmography
(calibrated or uncalibrated)
Alternative:
Diaphragmatic or intercostal muscle EMG
Arterial oxygen saturation Recommended: Same
Pulse oximetry
Alveolar hypoventilation Insufficient evidence to recommend a sensor Acceptable:
(PaCO2) The following may be used if validated End-tidal PCO2 monitoring
End-tidal PCO2 monitoring Transcutaneous PCO2 monitoring
Transcutaneous PCO2 monitoring
EMG = electromyogram; PaCO2 = arterial partial pressure of carbon dioxide; PCO2 = partial pressure of carbon dioxide.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.
volume (and flow). Figure 83 compares thermistor and Because the cannula tips are inside the nares and the other
thermocouple signals in a nose model with a PNT as the gold side of the pressure transducer is open to the atmosphere,
standard (accurate measure of flow).5 Note that thermal the pressure being measured is actually the pressure drop
signals and PNT flow are equal at 1 L/sec (by design). across the resistance of the nasal inlet associated with nasal
However, as airflow decreases, the thermal signals overesti- airflow. The resistance of the nasal inlet is not a constant
mate flow. This figure illustrates that thermal sensors are not (nonlinear). The relationship of NP and flow is given by
ideal sensors to detect hypopneas (reductions in flow). The Equations 82 and 83.7,10
same study demonstrated that the thermal sensor signal
decreases when the nostrils are large or the thermal sensor NP = K1 (Flow )2 K1 = constant Equation 82
is further from the nares. Of note, thermal devices composed Flow = K2 NP. K2 = constant Equation 83
of polyvinylidine fluoride (PVDF) film may offer a better
estimate of flow6 (Fig. 84). Nasal-oral thermal sensors Because NP varies with the square of flow, the NP signal
usually have a portion of the device placed within or just tends to underestimate airflow at low flow rates and overes-
outside the nostrils with another portion over the mouth timate flow at high flows (Fig. 86). The NP signal is linear-
(detection of oral flow) (Fig. 85). A major advantage of ized by taking the square root (Equation 83) and when
thermal sensors is that they can detect both nasal and oral calibrated, it very closely approximates the flow from a PNT
airflow without the need for a cumbersome mask covering at least over a short period of time (see Fig. 86). However,
the face. in clinical practice, the NP signal rather than the square root
Measurement of nasal pressure (NP) provides an estimate of the signal is most often recorded as an estimate of nasal
of nasal airflow that is more accurate than one obtained with airflow. Even when linearized, the NP signal may not provide
most thermal sensors.712 NP is measured using a nasal an absolutely accurate estimate of total airflow over the entire
cannula connected to an accurate pressure transducer. night. Changes in cannula position, periods of partial oral
DaneshGroup.com
Chapter 8 Monitoring RespirationTechnology and Techniques 103
Thermistors (% of baseline)
PNT Pressure drop across PNT = Flow
Resistance 100
Flow = Pressure difference/Resistance
PNT usually placed in a mask covering the
nose and mouth
Nasal-oral Changes in temperature induced by airflow 50
thermal result in changes in resistance (thermistor)
device or voltage output (thermocouple)
Accurate for the presence or absence of
airflow 0
0 50 100 150
Can detect nasal and oral airflow
Signal not proportional to flow Plethysmograph signal (head out of box)
(% of baseline)
NP Measures pressure difference across the
nares FIGURE 82 Thermistor signals are not a good estimate of changes in minute
NP = K1 (Flow)2 (K1 and K2 are constants) ventilation (do not accurately track changes in flow or tidal volume). The dark line is the
Flow = K2 NP. line of identity. Reproduced from Berg S, Haight JSJ, Yap V, et al: Comparison of direct and
Flattening of the inspiratory flow contour indirect measurement of respiratory airflow: implications for hypopneas. Sleep
detects airflow limitation 1997;20:6064.
Oral breathing not well detected
RIP RIPsum is an estimate of tidal volume
Most accurate if calibrated
1.5
Time derivative of the RIPsum gives an
estimate of flow
NP = nasal pressure; PNT = pneumotachograph; RIP = respiratory inductance
Thermal flow (volts)
plethysmography.
1.0
PNEUMOTACHOGRAPH
Thermistor
Screen with resistance R 0.5
Thermocouple
Flow 0
0 0.5 1.0 1.5
P
P1 P2 Pneumotachograph flow (liters/sec)
FIGURE 83 Thermal devices overestimate the actual flow (underestimate the drop
in flow) as flow decreases. The straight line is the line of identity. Reproduced from Farr
Flow R, Montserrat JM, Rotger M, et al: Accuracy of thermistors and thermocouples as flow-
Pressure
transducer measuring devices for detecting hypopneas. Eur Respir J 1998;11:179182.
P P1 P2 P Flow R
MAXIMUM DEFLECTIONS
70 PNEUMOTACHOGRAPH
Line of identity
60
Flow
50
PVDF sensor
40 Regression
line NASAL PRONGS
30
Flow
20
10
LINEARIZED NASAL PRONGS
0
0 10 20 30 40 50 60 70
Pneumotachograph sensor (liters/minute) Flow
20
Difference AHI
60
2 SD
Bias
0 0
40 for NP
20 10
NP NP
NP NP
0 20
0 20 40 60 80 0 20 40 60 80
AHI flowmeter (h1) Mean AHI
A flowmeter PNT B nasal pressure & flowmeter (h1)
FIGURE 87 A, The relationship of AHI (apnea + hypopnea index) values detected by PNT (pneumotachograph; flowmeter), nasal pressure (NP), and
linearized NP (square root of NP). The linearized NP detects slightly fewer and the NP slightly more events than the PNT. B, A Bland-Altman plot
shows the differences in the NP AHI and the flowmeter AHI plotted against the mean of the two values for each subject. The mean difference in AHI
values (bias) and the spread of the differences (limits of agreement = 2 standard deviations [SD]) for the NP AHI values are also shown. A plot of
differences in the linearized NP and PNT AHI values is also shown (bias and limits of agreement not shown). A and B, Reproduced from Thurnheer R,
Xie X, Bloch KE: Accuracy of nasal cannula pressure recordings for assessment of ventilation during sleep. Am J Respir Crit Care Med 2001;146:19141919.
0 5 10 15 20 25
Time (sec)
No flow limitation
Inspiratory flow
Inspiratory flow
Inspiratory flow
Driving pressure Driving pressure Driving pressure
A B C
FIGURE 88 Changes in nasal pressure (cannula flow) and pressure recorded below the site of upper airway narrowing (glottic refers to supraglottic
pressure) during a reduction in airflow. At A, the flow is rounded, whereas at C, the flattened airflow contour is associated with an increase in pressure
drop across the upper airway and airflow limitation. AC, Reproduced from Hosslet J, Normal RG, Ayapa I, Rapoport DM: Detection of flow limitation
with a nasal cannula/pressure transducer system. Am J Respir Crit Care Med 1988;157:14811467.
Snore
17 sec
Nasal
pressure
Nasal-oral
thermal sensor
Chest
Abdomen
SpO2
FIGURE 89 The nasal pressure signal shows an absence of airflow, whereas the nasal-oral thermal sensor shows continued airflow. This pattern of airflow is due to oral breathing.
Nasal-oral thermal sensors are the recommended device for detecting apnea. SpO2 = pulse oximetry.
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Chapter 8 Monitoring RespirationTechnology and Techniques 107
AB (abdomen)
RC
AB
with chest and abdomen moving in opposite directions (see in esophageal pressure are estimates of changes in pleural
Fig. 811). If a RIPsum signal is not available, one can detect pressure that occur during respiration (negative intratho-
hypopnea by a reduction in the RC and AB RIP signals. RIP racic pressure during inspiration). Esophageal pressure
is discussed further in the respiratory effort section. In the monitoring can detect rather feeble respiratory efforts even
previously discussed study of Thurnheer and coworkers,11 when RC and AB movements are minimal. In addition, the
detection of apnea-hypopnea by the calibrated RIPsum and size of the pressure deflections provides an estimate of the
the time derivative of the RIPsum were compared with the magnitude of respiratory effort. As discussed in Chapter 9,
PNT (flowmeter) signal (see Table 83). The AHI values detection of respiratory effortrelated arousals (RERAs)
obtained from the RIPsum and time derivative of the RIPsum is most accurately performed with esophageal pressure
signals showed good agreement with AHI values from the manometry. Measurement of esophageal pressure can be
PNT signal. performed using air-filled balloons, fluid-filled catheters, or
catheters with pressure transducers on their tips.13 The tech-
nique does require special equipment and expertise and is
MEASURING RESPIRATORY EFFORT
routinely performed in only a few sleep centers. In Figure
Determination of respiratory effort is essential to classify 812, note that RC and AB effort belts (here RIP) fail to
apneas as obstructive (continued respiratory effort), central detect the presence of the progressive increase in inspiratory
(absent effort), or mixed (central followed by obstructive effort documented by increasing esophageal pressure excur-
portions). The commonly used methods of detecting respira- sions during an OSA. Some research sleep studies measure
tory effort are listed in Table 84. The most sensitive and supraglottic pressure instead of esophageal pressure using a
accurate method of detecting respiratory effort is by mea- transducer tip placed just below the tongue base. This allows
surement of esophageal pressure13,1315 (Fig. 812). Changes measurement of the pressure drop across the upper airway.
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108 Chapter 8 Monitoring RespirationTechnology and Techniques
TABLE 84 Because this site is below the area of upper airway closure or
Measurement of Respiratory Effort narrowing in obstructive respiratory events, supraglottic
pressure can also be used to detect respiratory effort.
METHOD SENSORS COMMENTS
Until recently, the most common method for detecting
Esophageal Esophageal Signal proportional to respiratory effort in clinical sleep studies utilized piezoelec-
pressure balloon changes in pleural tric (PE) sensors connected to bands around the RC and AB.
deflections Transducer- pressure Changes in the tension on the PE transducer as the RC and
tipped Sensitive for
AB expand and contract produce a voltage that can be mea-
catheter detection of
Fluid-filled inspiratory effort
sured. The signal from these devices depends on the degree
catheter Relatively invasive of tension on the transducer. The PE belts are adequate for
detection of respiratory effort in most patients but do not
Intercostal/ Bipolar ECG artifact a really quantify the changes in RC or AB volume. Although
diaphragm recording problem
relatively inexpensive compared with RIP effort belts, the PE
EMG activity using surface Obtaining a good
effort belts may provide misleading information (false
electrodes signal may be
difficult in some absence of respiratory effort), especially if not properly posi-
patients tioned and tensioned.
RIP belts provide a more accurate method of detecting
Chest and Piezoelectric Relatively inexpensive
changes in RC and AB motion during respiration than PE
abdominal belts Signals may not
belts.3,14,15 The inductance of coils in bands around the RC
movement accurately reflect
changes in chest and AB changes during respiration as the RC and AB expand
and abdominal and contract. The band inductance varies proportionately to
volume during the cross-sectional area the band encircles. An oscillator is
respiration applied to each circuit and changes in inductance are con-
verted into a voltage output. The RIP bands consist of wires
Chest and RIP belts Inductance varies
abdominal with cross-sectional
attached to a cloth band in a zig-zag pattern. This produces
movement area subtended by a larger change in inductance for a given change in band
the belt circumference.
Can quantify changes Recall that if the RIP signals are calibrated, the RIPsum
in volume when signal = a RC + b AB is an estimate of tidal volume. Here,
RIP signals are the constants a and b are determined during a calibration
calibrated procedure. The accuracy of the RIPsum signal can deterio-
ECG = electrocardiogram; EMG = electromyogram; RIP = respiratory rate if body position changes or the positions of the bands
impedance plethysmography. change during sleep. Stats and associates15 studied patients
Airflow
Chest
1 sec
Abdomen
Esophageal
pressure
40 cm H2O
FIGURE 812 Esophageal pressure deflections increase during an obstructive apnea that might at first glance appear to be central
apnea (absent inspiratory effort). In this patient, the chest and abdomen effort belt signals showed minimal deflections during
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obstructive apnea. The situation was corrected by increasing the gain of the signals while scoring respiratory events.
Chapter 8 Monitoring RespirationTechnology and Techniques 109
with sleep apnea using both calibrated RIP belts and esopha- The AASM scoring manual1 recommends use of esopha-
geal pressure monitoring. In only 9% of patients were geal manometry or calibrated or uncalibrated RIP belts for
obstructive apneas sometimes misclassified as central apneas detection of respiratory effort during sleep studies in adults
by the RIP belts. In these instances, esophageal pressure and children (see Table 81). The measurement of respira-
deflections were present when there was no detectable tory muscle EMG is listed as an alternative method of detect-
change in the RIP belt signals. Thus, RIP effort belts are not ing respiratory effort in adults.
100% sensitive for detecting respiratory effort. However, if
the bands are properly positioned and tensioned (sized),
MEASURING SaO2
they will detect respiratory effort (if present) in most patients.
The vast majority of sleep centers do not perform RIP belt Continuous measurement of the arterial partial pressure of
calibration. It should be noted that the deflections of uncali- oxygen (PaO2) during sleep studies is not feasible. Spot
brated RIP bands do not always accurately reflect the mag- checks of arterial blood gases (ABGs) are only rarely per-
nitude of inspiratory effort or always show paradox (see Figs. formed during sleep studies and many facilities do not have
810 and 811) during obstructive apnea and hypopnea. the capability to process arterial blood samples. Instead of
Chest-abdominal paradoxical motion is discussed in detail PaO2, SaO2 is estimated during sleep studies by continuous
in Chapter 9. recording of pulse oximetry (SpO2), typically with finger or
Respiratory effort can also be measured by recording the ear probes. The relationship of SaO2 and the PaO2 is given
respiratory muscle electromyogram (EMG) signal using by the oxyhemoglobin (O2Hb) saturation curve (Fig. 814A).
bipolar surface electrodes.1618 The common sites include the The curve is also called the oxyhemoglobin dissociation
intercostal muscles and the diaphragm (Fig. 813). Surface curve in some texts. The relationship between the SaO2 and
diaphragm EMG recording utilizes two electrodes about 2 the PaO2 is affected by temperature, hydrogen ion concentra-
cm apart horizontally in the seventh and eighth intercostal tion, PCO2, and 2,3-diphosphoglycerate (2,3-DPG) concen-
spaces in the right anterior axillary line. The right side of the tration. An abnormal hemoglobin19 (e.g., hemoglobin S in
body is used to reduce electrocardiogram (ECG) artifact. Fig. 814B) or changes in acid-base status can influence the
Intercostal EMG recording often uses the right parasternal relationship of the SaO2 and the PaO2 in the blood. The P50
area (second and third intercostal spaces in the midaxillary is the PaO2 at which hemoglobin is 50% saturated. Normally,
line). Inspiratory EMG activity is noted in the intercostal the P50 is approximately 26 mm Hg. A higher P50 implies a
muscles and the diaphragm during nonrapid eye move- shift to the right, lower oxygen affinity, and a higher PaO2
ment (NREM) sleep. During rapid eye movement (REM) for a given SaO2.
sleep, the intercostal activity is inhibited but diaphragmatic The total hemoglobin concentration (Hbt) is the sum of
activity persists, although often diminished in amplitude concentrations of oxygenated hemoglobin (O2Hb), deoxy-
during bursts of eye movements. genated or reduced hemoglobin (RHB), carboxyhemoglobin
R intercostal
EMG
NO therm
Nasal
pressure
CHEST
ABDOMEN
SpO2
Inspiratory
EMG activity ECG artifact removed
Raw signal
FIGURE 813 An obstructive apnea with respiratory effort monitored by both chest and abdominal respiratory inductance plethysmography (RIP) bands and
right intercostal electromyogram (EMG). The right intercostal EMG signal shows bursts coincident with inspiratory effort (and movement of chest and abdomen).
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A blow up of one EMG burst is shown at the bottom of the figure in a raw form and with the electrocardiogram (ECG) artifact minimized. SpO2 = pulse oximetry.
110 Chapter 8 Monitoring RespirationTechnology and Techniques
80
70 Right shift
If COHb or MetHb are present in significant amounts,
60 increase in one can define a fractional saturation based on Equation 87.
temperature This shows that the fractional hemoglobin oxygen saturation
50 H
2-3 DPG
of oxygenated hemoglobin (FO2Hb) depends on the concen-
40
PCO2 trations of COHb and MetHb as well as RHb. An accurate
30 oxygen-carrying capacity can be computed using Equation
20 85 with SaO2 replaced by FO2Hb. FO2Hb is sometimes
10 referred to as the fractional saturation. Using equations
0
similar to Equation 87, fractional concentrations can be
0 10 20 30 40 50 60 70 80 90 100 defined for carboxyhemoglobin (FCOHb), methemoglobin
A PaO2 (mmHg) (FMetHb), and reduced hemoglobin (RHb) as the concen-
tration of each entity divided by the total hemoglobin times
100.
Hb A
100
FO2 Hb ( % ) = O2 Hb 100 (O2 Hb + RHb + COHb + MetHb)
90 Hb S
= O2 Hb 100 Hbt
80
Equation 87
Oxygen saturation (%)
70
60 One should note that the SaO2 value supplied by some
50 clinical laboratories is determined by a measured PaO2 and
40 the use of a table or computer program to provide a value
for the SaO2. Accurate measurement of SaO2 and FO2Hb
30
depends on the clinical laboratory using a co-oximeter. This
20
instrument uses absorption of 4 wavelengths of light to
10 determine the concentrations of oxygenated and deoxygen-
0 ated hemoglobin as well as COHb and MetHb. Thus, COHb
0 10 20 30 40 50 60 70 80 90 100
and MetHb can affect the relationship between PaO2 and
B PaO2 (mmHg)
SaO2 (position of the oxyhemoglobin saturation curve) and
FIGURE 814 A, The oxyhemoglobin saturation curve. Changes in body temperature, the relationship between the SaO2 and the FO2Hb.
hydrogen ion concentration, partial pressure of carbon dioxide (PCO2) and the In the sleep center, the major purpose of SpO2 is not to
concentration of 2-3-diphosphoglycerate (2-3 DPG) can shift the curve. B, The determine the oxygen-carrying capacity of the blood
oxyhemoglobin saturation curve for normal hemoglobin (HbA) and sickle hemoglobin (depends on FO2Hb) but to infer changes in PaO2 due to
(HbS). PaO2 = arterial partial pressure of oxygen. respiratory events. The oxyhemoglobin saturation curve
describes the relationship between O2Hb and the free hemo-
globin (O2Hb + RHb, Hb available for oxygen binding). In
(COHb) and methhemoglobin (metHb) (Equation 84). this sense, the ability of the SpO2 to allow correct inference
COHb and MetHb do not bind oxygen but shift the oxyhe- about the PaO2 depends on the accuracy with which SpO2
moglobin saturation curve to the left.20,21 In addition, they reflects the SaO2 (rather than the FO2Hb) and the position of
affect the fraction of hemoglobin available for binding to the oxyhemoglobin saturation curve. As discussed later,
oxygen. The ability of carbon monoxide to bind Hb is about COHb and MetHb also affect the performance of the
240 times that of oxygen. 2-wavelength oximeters commonly used in clinical settings.
The SaO2 as defined in Equation 85 is often called the
functional saturation. The arterial oxygen content of the
PULSE OXIMETRY
blood (CaO2) is determined largely by the SaO2 (Equation
86). Here CaO2 is in mLO2/mL, Hb is in g/100mL, 1.34 is Pulse oximeters22 provide an estimate of the SaO2 by deter-
the mLO2/g of fully saturated Hb. mining the absorption of two wavelengths of light (660 nm
[red] and 940 nm [infrared]) by capillary blood. This deter-
Hbt = O2Hb + RHb + COHb + MetHb Equation 84
mines the relative amount of the O2Hb and RHb. The absorp-
where O2Hb = concentration of oxygenated hemoglobin, tion of radiation at 660 nm is much greater with RHb than
RHb = concentration of reduced hemoglobin, COHb = con- with O2Hb, while O2Hb absorbs more radiation at 940 nm
centration of carboxyhemoglobin, MetHb = concentration (Fig. 815A). The ability of SpO2 to determine the SaO2 is
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Chapter 8 Monitoring RespirationTechnology and Techniques 111
Hemoglobin extinction curves elevated by about 1% compared with the FO2Hb. Fortu-
10 660 nm 940 nm nately, the SpO2 is closer to the SaO2 as determined by Equa-
tion 85 than the FO2Hb. For example, a typical set of values
would be: FO2Hb = 87%, FRHb = 9%, FCOHb = 4%, SpO2
Extinction coefficient
SpO2
82% 85%
75%
80
70
90
SpO2 (%)
80
70
0 60 120 180 240
Time (s)
applied to assess the severity of desaturation, including com- is especially important in light of the definitions of hypopnea
puting the number of desaturations, the average minimum that depend on an associated desaturation.
SpO2 during desaturations, the time below 80%, 85%, 90%, The AASM scoring manual1 recommends a maximum
as well as the mean SaO2 and the minimum saturation during averaging time of 3 seconds at a heart rate of 80 bpm. In
NREM and REM sleep. The time with an SpO2 88% is also patients with a slow heart rate, a slightly longer averaging
commonly determined. time (at least a 3-beat average) may be needed.
Oximeters may vary considerably in the number of desat-
urations they detect and their ability to discard movement
MEASUREMENT OF PaCO2 DURING SLEEP
artifact. As illustrated in Figure 817, using long averaging
times may dramatically decrease the detection of desatura- Documentation of hypoventilation during sleep requires
tions.25,26 Here, the results of identical oximeters monitoring measurement (or estimate) of the PaCO2. The AASM scoring
the same patient are shown. The averaging time of one of the manual1 defines sleep-related hypoventilation in adults as an
oximeters is increased and there are obvious large differences increase in the PaCO2 during sleep 10 mm Hg compared
in the results. The ability of oximeters to detect desaturations with an awake supine value. However, continuous ABG
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Chapter 8 Monitoring RespirationTechnology and Techniques 113
monitoring during polysomnography to determine the The two common methods of capnography are main-
PaCO2 is not practical. An ABG sample sometimes is per- stream and side stream. In the mainstream method, the
formed at the start or the end of the study. The sample can sensor is located directly in the path of exhaled gas. In the
be used to validate a surrogate measure of PaCO2 such as side stream method, gas is continually suctioned through a
PETCO2 or TcPCO2. If an ABG sample is taken just at awak- tube to a more remote sensor (in the instrument at bedside).
ening, it may be used to infer hypoventilation. In children, In the side stream approach, nasal cannulas are used to
an arterialized capillary blood gas is often performed rather suction exhaled gas from the nares (Fig. 819). When no
than an arterial sample. The AASM scoring manual1 defines CO2 is exhaled (during inspiration or apnea), the nasal
hypoventilation in children based on a PaCO2 greater than cannula suctions room air (PCO2 = 0). In the side stream
50 mm Hg for 25% of total sleep time. method, there is a delay in exhaled gas reaching the sensor
so the CO2 tracing is delayed compared with the exhaled
airflow (see Fig. 819).
PETCO2
The exhaled CO2 tracing is sometimes used to indicate
Capnography27,28 consists of the continuous measurement apnea (absence of exhaled PCO2). However, this is not rec-
of the fraction of CO2 in exhaled gas. This is usually per- ommended for two reasons. First, gas sampled by the nasal
formed using an infrared sensor and, less commonly, a mass cannula may not detect mouth breathing, and second, small
spectrophotometer. The PCO2 is determined by multiplica- expiratory puffs rich in CO2 may still produce deflections in
tion of the fraction of CO2 by (Patm47 mm Hg). Here, the the exhaled CO2 trace29 (Fig. 820).
Patm is the atmospheric pressure (760 mm Hg at sea level) Capnography is used much more frequently during pedi-
and 47 mm Hg is the partial pressure of H2O in exhaled gas atric than in adult sleep studies.13,30 Children may have long
at body temperature. A schematic tracing of exhaled PCO2 periods of obstructive hypovenilation (see Chapter 9) due to
versus time is shown in Figure 818. During initial exhala- high upper airway resistance (airflow limitation without dis-
tion, the dead space (PCO2 = 0) reaches the sensor (phase crete apneas or hypopneas). Other than a mild decrease in the
1), then a mixture of dead space and alveolar gas (phase 2), SpO2, the significance of these events would be underesti-
and finally, alveolar gas (phase 3). The alveolar plateau occurs mated except for the demonstration of an increase in PETCO2.
because the PCO2 in the air from the different alveoli differs
slightly. The differences are larger (slope of alveolar plateau
TcPCO2 MONITORING
steeper) in patients with lung disease. The PETCO2 is an esti-
mate of the mean alveolar PCO2 (and, therefore, an estimate Measurement of TcPCO230,31 depends on the fact that heating
of the PaCO2). Of note, there is a gradient between the of capillaries in the skin causes increased capillary blood flow
PaCO2 and the PETCO2 (PaCO2PETCO2) with the PaCO2 and makes the skin permeable to the diffusion of CO2. The
being typically 2 to 5 mm Hg higher than the PETCO2 in CO2 in the capillaries diffuses through the skin and is mea-
normal individuals. In lung disease, the gradient can be sured by an electrode at the skin surface. The measured value
much larger. In general, the PETCO2 is a valid estimate of is corrected for the fact that heat increases the skin CO2
PaCO2 only if an alveolar plateau is present. production as the measured value exceeds the PaCO2 mea-
sured at 37C. Typically, TcCO2 electrodes are calibrated with
a reference gas. A thermostat controls the heating of the
CAPNOGRAPHY - Exhaled CO2 Versus Time membrane-skin interface. It is usually recommended that
the probe of most TcPCO2 monitoring devices be moved
End-tidal PCO2 every 3 to 4 hours to avoid skin irritation/damage.
III The response time of newer TcPCO2 units has improved,
but in general, the measured PCO2 may not increase rapidly
enough to correlate with short respiratory events. However,
II
TcPCO2 can be a good instrument for documenting trends in
0 I 0
the PCO2 during the night. Figure 821 shows trends in the
SpO2 and TcPCO2. Decreases in the SpO2 occur in association
with increases in the TcPCO2 during episodes of REM sleep.
Expiration Inspiration
ACCURACY OF PETCO2 AND TcPCO2
Phases of exhaled PCO2
The limitations of both methods for estimating the PaCO2
0 Inspiration
should be considered by the clinician when interpreting the
I Dead space (no CO2 exhaled)
data. This is especially true if measured values are not con-
II Mixture of dead space and alveolar gas
sistent with what is occurring clinically with the patient. The
III Alveolar plateau measurement of PETCO2 and TcPCO2 was not found to be
FIGURE 818 A schematic tracing of exhaled partial pressure of carbon dioxide (PCO2). accurate for determining changes in PaCO2 during sleep by
Sanders and coworkers.32 PETCO2 was especially inaccurate
The end-tidal PCO2 is an estimate of the arterial PCO2.
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114 Chapter 8 Monitoring RespirationTechnology and Techniques
Gas suctioned
Nasal Sensor Side stream method
cannula
Inspiration
Airflow
(nasal press)
Exhaled CO2
CO2 tracing is delayed relative to exhaled airflow with the side stream method
FIGURE 819 The CO2 tracing is delayed relative to exhaled airflow in the side stream method.
Exhaled CO2
Inspiration
Pneumotachograph
0
Expiration
Thermal airflow
at nose and mouth
FIGURE 820 The exhaled CO2 tracing shows continued deflections during inspiratory apnea due to small exhaled puffs of air rich
in CO2. Reproduced from Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 90.
during simultaneous administration of supplemental oxygen during sleep. However, it was stated that PETCO2 or TcPCO2
or during positive airway pressure treatment. Of note, may be acceptable if validated and calibrated. In the pediatric
exhaled gas was sampled from a mask rather than using a rules, it states that acceptable methods for assessing alveolar
nasal cannula. Another investigation found reasonable hypoventilation are either transcutaneous or end-tidal PCO2
agreement between the PETCO2 and the TcPCO2 during monitoring.1
pediatric polysomnography.30 Storre and colleagues31 found Concerning PETCO2 monitoring, the clinician should
reasonable agreement between PaCO2 and TcPCO2 values review the exhaled CO2 tracings to determine whether an
during noninvasive positive airway pressure titration. The alveolar plateau is present. If an alveolar plateau is not
best agreement was between a given PaCO2 value and the present, the PETCO2 value may not be an accurate estimate
corresponding TcPCO2 value about 2 minutes later. of PaCO2. Other problems for exhaled PCO2 monitoring
The AASM scoring manual1 in the respiratory scoring include oral breathing and occlusion of the nasal cannula
rules for adults states that there was insufficient evidence to with secretions. If tidal volumes are very small, a true alveo-
recommend a specific method for detecting hypoventilation lar sample may never reach the sensor. If only a mixture of
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Chapter 8 Monitoring RespirationTechnology and Techniques 115
80
70
60
TcPCO2 (mm Hg)
40
20
1 hour
Snore
Chest
Abdomen
SpO2 94%
dead space (PCO2 = 0) and alveolar gas is sampled, the measurement/detection of snoring during sleep. When
PETCO2 value will likely be much lower than the PaCO2. snoring is present, upper airway narrowing of some degree
Concerning TcPCO2 measurement, the actual tracings can be inferred. There is evidence that vibration of different
should also be carefully reviewed. If an abrupt change (offset) areas of the upper airway causes different sounds. However,
in the TcPCO2 tracing is noted, this suggests a measurement the utility of this information remains to be determined.
artifact is present. Most TcPCO2 devices require calibration Snore sensors are usually microphones or PE transducers
at the start of monitoring. Poor application of the sensor or that are usually applied to the neck near the trachea. Micro-
dislodgment of the sensor during sleep can cause a measure- phones can also be attached to the upper chest area or the
ment artifact. There is some advantage to the simultaneous face. Snoring can also be seen in the NP signal as a rapid
use of both PETCO2 and TcPCO2 if tolerated. If the values oscillation9,13 in the pressure tracing if an appropriate high-
show reasonable agreement during periods of stable breath- frequency filter setting (100 Hz) is used and the transducer
ing, this increases confidence in their validity. Of course, the is sufficiently sensitive. Of note, some NP transducers have
goal standard to validate the accuracy of their measurements a choice of output of a filtered or an unfiltered signal. The
is a simultaneous ABG measurement. unfiltered signal must be used to detect snoring. The AASM
scoring manual1 does not provide guidance on use of snoring
sensors and the signal is not part of the scoring criteria for
SNORING SENSORS
respiratory events in adults. Snoring is mentioned in scoring
Snoring is a sound produced by vibration of upper airway of RERAs in children. Figure 822 illustrates an example of
structures. Although snoring sensors are widely used, there snoring. Snoring is visualized in both the snore sensor
is little published evidence to demonstrate the utility of applied to the neck and the NP signal.
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116 Chapter 8 Monitoring RespirationTechnology and Techniques
50
40 3. B. The PETCO2 provides an estimate of the PaCO2 when
30 a plateau is present. There is a gradient between the
20 PETCO2 and the PaCO2. Usually, the PaCO2 is 2 to
10 5 mm Hg above the end-tidal value. The exhaled PCO2 is
0 the mixture of gas from many alveoli. (Rarely, the PETCO2
Time (sec)
is greater than the PaCO2 due to late emptying of alveoli
FIGURE 823 with very high PaCO2 values).
16. Bennett JR, Dunroy HMA, Corfield DR, et al: Respiratory 25. Davila DG, Richards KC, Marshall BL, et al: Oximeter perfor-
muscle activity during REM sleep in patients with diaphragm mance: the influence of acquisition parameters. Chest 2002;
paralysis. Neurology 2004;61:134137. 122:16541660.
17. White JES, Drinnan MJ, Smithson AJ, et al: Respiratory muscle 26. Jasani R, Sanders MH, Strollo PJ: Diagnostic studies for apnea/
activity and oxygenation during sleep in patients with muscle hypopnea. In Johnson JT, Gluckman JL, Sanders MH (eds):
weakness. Eur Respir J 1995;8:808814. Management of Obstructive Sleep Apnea. London: Martin
18. Stoohs RA, Blum HC, Knaack L, et al: Comparison of pleural Dunitz, 2002, p. 68.
pressure and transcutaneous diaphragmatic electromyogram 27. Gravenstein JS, Paulus DA: Clinical perspectives. In Graven-
in obstructive sleep apnea syndrome. Sleep 2005;28:321329. stein JS, Jaffe MB, Paulus DA (eds): Capnography. Cambridge,
19. Wagner MH, Berry RB: A patient with sickle disease and a UK: Cambridge University Press, 2004, pp. 312.
low baseline sleeping oxygen saturation. J Clin Sleep Med 28. DMello J, Butani M: Capnography. Indian J Anaesthesiol
2007;3:313315. 2002;46:269278.
20. Toffaletti J, Zijlstra W: Misconceptions in reporting oxygen 29. Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley
saturation. Anesth Analg 2007;105:S5S9. & Belfus, 2003, p. 90.
21. Roughton FJW, Darling RC: The effect of carbon monoxide on 30. Kirk VG, Batuyong ED, Bohn SG: Transcutaneous carbon
the oxyhemoglobin dissociation curve. Am J Physiol 1944; dioxide monitoring and capnography during pediatric poly-
141:1731. somnography. Sleep 2006;29:16011608.
22. Tremper KK, Barker SJ: Pulse oximetry. Anesthesiology 31. Storre JH, Steurer B, Kabitz HJ, et al: Transcutaneous PCO2
1989;70:98108. monitoring during initiation of noninvasive ventilation. Chest
23. Barker SJ, Tremper KK: The effects of carbon monoxide inhala- 2007;132:18101816.
tion of pulse oximetry and transcutaneous PO2. Anesthesiol- 32. Sanders MH, Kern NB, Costantino JP, et al: Accuracy of end-
ogy 1987;66:677679. tidal and transcutaneous PCO2 monitoring during sleep. Chest
24. Barker SJ, Tremper KK, Hyatt J: Effects of methemoglobin on 1994;106:472483.
pulse oximetry and mixed venous oximetry. Anesthesiology
1989;7:112117.
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Chapter 9
Monitoring RespirationEvent
Definitions and Examples
of hypopnea (reductions in airflow) have resulted in a float-
Chapter Points ing metric.1 Early studies of patients with obstructive sleep
An oronasal thermal sensor is recommended for apnea apnea (OSA) focused on obstructive apnea,2 hence, the name
identification. The nasal pressure signal is of the syndrome. However, it soon became obvious that
recommended for hypopnea identification. An event reductions in airflow (hypopnea) also had clinical signifi-
with absent nasal pressure excursions but persistent cance. The importance of hypopnea, defined as a reduction
oronasal sensor excursions >10% of baseline would in airflow associated with a 4% or greater desaturation, was
not be scored as an apnea. emphasized by Block and coworkers.3 Gould and colleagues4
In adults, an event may be an RERA or a hypopnea noted that some patients fit the clinical picture of OSA but
based on which hypopnea definition is being used. the majority of their respiratory events were hypopneas
Hypoventilation in adults is defined as an increase in rather than apneas. They defined hypopnea as a 50% reduc-
the PaCO2 of 10 mm Hg or greater from an awake tion in respiratory inductance plethysmography (RIP) belt
supine value. deflections lasting greater than 10 seconds and proposed the
Hypoventilation in children is defined as a PCO2 greater term the sleep hypopnea syndrome. Others have used the
than 50 mm Hg for 25% or more of the total sleep time term the obstructive sleep apnea hypopnea syndrome. A
by either PETCO2 monitoring or TcPCO2 monitoring. landmark paper on the incidence of obstructive sleep apnea
Obstructive apneas and hypopnea in children are (Wisconsin cohort study) defined hypopnea as a discernible
defined based on two missed breaths rather than an reduction in the amplitude of calibrated RIP plus an arterial
absolute time duration. oxygen desaturation of 4% or more.5 The Sleep Heart Health
Respiratory rules for children are used for patients Study,6 a large multicenter population-based investigation,
younger than 18 years. Adult respiratory scoring rules defined hypopneas as a decrease in airflow or thoracoab-
may be used for children aged 13 years or older. dominal excursion of at least 30% of baseline for 10 seconds
In children, central apneas have absent inspiratory or more accompanied by a 4% or more decrease in oxygen
effort throughout the entire duration of the event saturation.5 Airflow was monitored with an oronasal thermal
and one of the following is met: sensor and respiratory effort with RIP belts. Using this defi-
1. The event lasts 20 seconds or longer. nition of hypopnea, the study found associations between an
2. The event lasts 2 breaths (or the duration of 2 increase in the AHI and cardiovascular morbidity.
breaths as determined by the baseline breathing The widespread use of nasal pressure (NP) monitoring
pattern) AND is associated with an arousal, an allowed recognition of more subtle and more frequent
awakening, or a 3% or greater desaturation. changes in airflow during sleep than was possible with
thermal devices.7 It was also recognized that reductions in
airflow from obstructive events not associated with desatura-
RESPIRATORY EVENTS IN ADULTS tions could be associated with consequences such as arousal
from sleep and sleep fragmentation (upper airway resistance
History of Respiratory Event Definitions
syndrome).8 Therefore, definitions of hypopnea based on
To understand the origins of the current respiratory event flow and arousal were proposed. In order to standardize
definitions, a historical perspective is helpful. The apnea- definitions of respiratory events, a consensus statement was
hypopnea index (AHI) is the number of apneas and hypop- published in 1992 (Chicago criteria).9 Criteria for an
neas per hour of sleep. This metric is often used to make the obstructive apnea/hypopnea event (OAHE) was presented
diagnosis of sleep apnea and to grade the severity. Defini- with no differentiation between obstructive apnea and
tions of apnea have been relatively standard (typically absent hypopnea because both events have similar pathophysiol-
or nearly absent airflow for 10 sec), but varying definitions ogy. An OAHE was defined as a 50% or greater reduction
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119
120 Chapter 9 Monitoring RespirationEvent Definitions and Examples
TABLE 92
Adult Respiratory Event Rules
Apnea Score apnea when all of the following are met:
Oronasal thermal sensor (or alternative) drops by 90% of baseline.
Duration 10 sec.
At least 90% of events duration must meet apnea amplitude reduction criteria.
Classification
1. Obstructive: continued or increased inspiratory effort for duration of apnea.
2. Mixed
Initially absent inspiratory effort in the first portion of the event.
Resumption of inspiratory effort during second portion of event.
3. Central: Absent inspiratory effort for duration of apnea.
(Desaturation NOT needed to score an apnea.)
Hypopnea recommended All criteria must be met:
NP excursions (or alternative sensor) drop by 30% of baseline amplitude.
Duration 10 sec.
At least 90% of duration must meet hypopnea amplitude criteria.
4% arterial oxygen desaturation from pre-event baseline.
Hypopnea alternative All criteria must be met:
NP excursions (or alternative sensor) drop by 50% of baseline amplitude.
Duration 10 sec.
At least 90% of duration must meet hypopnea amplitude criteria.
3% arterial oxygen desaturation from pre-event baseline
OR arousal.
RERA A sequence of breaths lasting at least 10 sec.
Increasing respiratory effort or flattening of the NP waveform.
Followed by an arousal from sleep.
Does not meet criteria for an apnea or hypopnea.
Hypoventilation* Increase in PaCO2 or validated surrogate 10 mm Hg above a supine awake value.
*For adults, hypoventilation is based on the PaCO2. No other sensor was recommended for documentation of hypoventilation. It was stated that PETCO2 or TcPCO2
may be used as surrogate measures of PaCO2 if there is demonstration of reliability and validity.
NP = nasal pressure; PaCO2 = arterial partial pressure of carbon dioxide; PETCO2 = end-tidal carbon dioxide pressure; RERA = respiratory effortrelated arousal;
TcPCO2 = transcutaneous carbon dioxide pressure.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.
The term respiratory disturbance index17 (RDI) is used by sensor for hypopnea detection is NP with or without a square
some sleep centers and publications. In many sleep centers, root transformation. If the NP signal is inadequate, either the
the terms RDI and AHI mean the same thing. However, the oronasal thermal signal or the RIP signal (calibrated or
2005 AASM practice parameters for indications for polysom- uncalibrated) may be used. Whether the RIP sum signal or
nography (PSG) defined the RDI as equal to the AHI + RERA both chest and abdomen RIP signals are to be used was not
index. Here, the RERA index is the number of RERAs/hr of specified. The sensors recommended for detecting respira-
sleep. The 1992 Consensus statement of the AASM recom- tory effort include esophageal manometry or RIP (calibrated
mended making a diagnosis of OSA based on the number of or uncalibrated). An alternative sensor for detection of respi-
apneas/hypopneas obstructive events + RERAs/hr of sleep ratory effort is diaphragmatic/intercostals EMG. The sensor
and also presented severity criteria based on this metric.9 for detection of arterial oxygen desaturation is pulse oxim-
However, the term RDI was not specifically used. Of note, etry. It is recommended that oximeters use a maximal aver-
the term RDI was not defined in the AASM scoring manual. aging time of 3 seconds at a heart rate of 80 bpm or greater.
It is important to note the definition of RDI when reading At lower heart rates, most oximeters choose the averaging
sleep study reports or publications concerning sleep apnea. time based on heart rate and average at least 3 pulses. The
recommended sensor for detection of an RERA (see later) is
esophageal manometry. Flattening in the NP signal or RIP
Recommended Respiratory Sensors in Adults14
are alternative sensors that may be used.
The sensors and methods for respiratory monitoring are dis-
cussed in detail in Chapter 8. The recommended sensor for
Definition of Apnea (AASM Scoring Manual)14
apnea detection is a thermal flow sensor at the nose and
mouth (oronasal thermal sensor). If the thermal signal is Sensor: The recommended sensor for apnea detection is a
inadequate, the NP signal may be used. The recommended thermal flow sensor at the nose and mouth.
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122 Chapter 9 Monitoring RespirationEvent Definitions and Examples
Apnea Scoring Rules in Adults (AASM 2. The duration of this drop occurs for a period of at least
10 seconds.
Scoring Manual)14
3. There is a 4% or greater desaturation from the pre-event
Apnea Rule: Score an apnea when all of the following criteria baseline.
are met: 4. At least 90% of the events duration must meet the
amplitude reduction of criteria.
1. There is a drop in the peak thermal sensor excursion by
90% of baseline.
This recommended hypopnea definition is essentially the
2. The duration of the event lasts at least 10 seconds.
definition recommended by the 2001 AASM Clinical Prac-
3. At least 90% of the events duration meets the amplitude
tice Parameter13 and later accepted by CMS. As discussed
reduction criteria for apnea.
previously, evidence for the use of this definition includes
the fact that a similar definition was used in the Wisconsin
Apnea Types
Cohort Study and the Sleep Heart Health Study and that an
1. Score a respiratory event as an OBSTRUCTIVE apnea if
increased AHI based on this hypopnea definition was associ-
it meets apnea criteria and is associated with continued
ated with an increased risk of cardiovascular morbidity in
or increased inspiratory effort throughout the entire
those studies. In addition, as previously mentioned, defini-
period of absent airflow.
tions of hypopnea using changes in SaO2 tend to have high
2. Score a respiratory event as a CENTRAL apnea if it meets
interscorer reliability. The respiratory event illustrated in
apnea criteria and is associated with absent inspiratory
Figure 94 meets the recommended criteria for a hypopnea
effort throughout the entire period of absent airflow.
because the NP signal excursions are essentially zero for over
3. Score a respiratory event as a MIXED apnea if it meets
10 seconds and the event is associated with an SaO2 of 4%
apnea criteria and is associated with absent inspiratory
or greater.
effort in the initial part of the event, followed by resump-
tion of inspiratory effort in the second part of the event.
Hypopnea (Alternative)
Figure 91 presents examples of obstructive, central, and Score a hypopnea if all of the following criteria are met:
mixed apneas using esophageal pressure to detect respiratory
1. The NP signal excursions (or those of the alternative
effort. Figure 92 presents examples of the corresponding
hypopnea sensor) drop by 50% of baseline.
events using chest and abdominal RIP belts.
2. The duration of this drop occurs for a period of at least
The nasal-oral thermal sensor and not the NP signal is
10 seconds.
used to score apnea. Absent NP signal excursions do not
3. There is a 3% desaturation from the pre-event baseline
meet criteria for scoring apnea if nasal-oral thermal sensor
or the event is associated with an arousal.
excursions are still present and do not meet criteria for
4. At least 90% of the events duration must meet the ampli-
scoring an apnea. In the event shown in Figure 93, NP
tude reduction of criteria for hypopnea.
excursions are absent for greater than 10 seconds. However,
the event is not scored as an apnea because the thermal The alternative definition of hypopnea is similar to the
signal is not decreased by 90% of baseline. The combination 1999 AASM Task Force Consensus definition of an obstruc-
of absent NP excursions and persistent nasal-oral thermal tive apnea/hypopnea event. The use of 3% rather than 4% is
sensor excursion is likely due to oral breathing. Also note based on the fact that reanalysis of some of the large studies
that the apnea criteria do NOT depend on the presence of using a 3% desaturationbased instead of a 4% desaturation
either arterial oxygen saturation (SaO2) or arousal. The based hypopnea definition found similar results.9 The defini-
AASM scoring manual states that if the oronasal thermal tion recognizes that some reduction in airflow events are not
signal is not functioning, one then uses the NP signal to associated with a drop in the SaO2 of 4% or greater but are
score apnea. Although not specifically recommended by the associated with arousal. Frequent respiratory arousals in the
AASM scoring manual, one could also use the RIPsum absence of significant desaturation can result in fragmented
signal. sleep and daytime sleepiness. However, interscorer reliability
of scoring hypopneas with a definition based on either desat-
uration or arousals is slightly lower than with the scoring of
Hypopnea Scoring Rules in Adults14
events associated only with desaturations (see Table 91).
In the AASM scoring manual, two hypopnea definitions are
presented (a recommended hypopnea definition and an
Event Duration Rules14
alternate hypopnea definition).
A. Event duration (apnea or hypopnea) is measured from
Hypopnea (Recommended) the nadir preceding the first breath that is clearly reduced
Score a hypopnea if all of the following criteria are met: to the beginning of the first breath that approximates
the baseline breathing amplitude (Fig. 95).
1. The NP signal excursions (or those of the alternative B. When the baseline amplitude cannot be easily deter-
hypopnea sensor) drop by 30% of baseline. mined (underlying breathing variability is large), events
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Chapter 9 Monitoring RespirationEvent Definitions and Examples 123
Obstructive apnea
Airflow
Esoph
pressure
Central apnea
Mixed apnea
FIGURE 91 Examples of obstructive, central, and mixed apnea. Airflow was recorded using a pneumotachograph in a mask over the nose and mouth and
respiratory effort by esophageal pressure monitoring. The frequent small deflections in the esophageal pressure are cardiac artifact.
Nasal
pressure
26 sec
NO airflow
Chest
OA
Abdomen
SpO2
98%
91%
Nasal
pressure
28 sec
NO airflow
Chest CA
Abdomen
SpO2
98%
91%
Nasal
pressure
28 sec
NO airflow
Chest MA
Abdomen
SpO2
98%
91%
FIGURE 92 Obstructive apnea (OA), central apnea (CA), and mixed apnea (MA) events are illustrated. NO airflow = the nasal-oral thermal
airflow sensor signal; chest and abdomen = RIP belt signals; SpO2 = pulse oximetry.
Snore
17 sec
Nasal pressure
Nasal-oral
thermal sensor
Chest
Abdomen
SpO2
FIGURE 93 This event is not scored as an apnea because excursions in the nasal-oral thermal sensor do not meet criteria for apnea. The lack of deflections in
the nasal pressure signal is likely due to oral breathing during the event. The event would meet criteria for hypopnea using either the recommended or the alternate
American Academy of Sleep Medicine (AASM) criteria. SpO2 = pulse oximetry.
44 sec
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
A
B
SpO2
98% 92%
FIGURE 94 An event meeting the recommended definition of hypopnea. The amplitude of the nasal pressure signal drops by more than 30% of baseline for
well over 9 contiguous seconds and the event duration is longer than 10 seconds. In addition, the event is associated with a greater than 4% desaturation. Note
the paradox in the chest and abdomen tracings at A during the event but not at B after the event. SpO2 = pulse oximetry. The vertical lines are 30 seconds apart.
obstructive respiratory events, it is the magnitude of the This implies a decrease in arousability (high arousal thresh-
inspiratory effort (magnitude of esophageal pressure excur- old) in these groups.
sion) and the threshold for arousal that determine whether Because esophageal pressure monitoring is infrequently
arousal occurs.18 During experimental mask occlusion in used, RERA detection is usually based on flattening of the
normal subjects, arousal usually occurs when esophageal NP signal (flow limitation arousal).14,19 After arousal, there
pressure deflections (negative pressure) reaches 20 to 30 cm is usually a sudden change in the NP contour from flat to
H2O. However, snorers and patients with OSA may not round (see Fig. 97). Ayappa and colleagues19 compared
arouse until esophageal pressures reach 40 to 80 cm H2O. arousal associated with flow limitation (FLA) and arousal
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126 Chapter 9 Monitoring RespirationEvent Definitions and Examples
Nasal pressure
Nasal-oral
thermal sensor
Apnea or hypopnea duration is measured from the nadir preceding the first breath that is clearly
reduced to the beginning of the first breath that approximates the baseline breathing amplitude
FIGURE 95 Event duration rules. Note that the oronasal thermal sensor is used to define the apnea duration and the nasal pressure signal the hypopnea duration.
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore 19 sec
NP
Airflow
Chest
Abdomen
SpO2
96%
1 sec
FIGURE 96 Respiratory effortrelated arousal (RERA). Flattening of nasal pressure for more than 10 seconds followed by an arousal. There is no
desaturation so it would not qualify as a hypopnea (by the recommended definition). The drop in flow is not 50% of baseline so the event would not qualify
as a hypopnea (alternative definition). ECG = electrocardiogram; NP = nasal pressure; SpO2 = pulse oximetry.
associated with increased respiratory effort by esophageal manometry) were noted without flow limitation. Thus,
manometry (RERAs). The FLA index and RERA index were although flow limitation (NP flattening) and high respiratory
highly correlated (Fig. 98). However, a few FLA events effort most often occur together, this is not invariably true.
were noted with flow limitation but without an increase Fortunately, the majority of RERAs will be detected with NP
in respiratory effort. Some RERAs (esophageal pressure monitoring.
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Chapter 9 Monitoring RespirationEvent Definitions and Examples 127
F4-M1
C4-M1
O2-M1
E1-M1
E2-M2
Chin
ECG
28 sec
Nasal pressure
Nasal-oral
thermal flow
Esophageal
pressure
Chest
Abdomen
SpO2
96% 95%
FIGURE 97 RERA. The event demonstrates increasing respiratory effort by esophageal pressure (slanted line) and flattening of the nasal pressure signal for longer
than 10 seconds followed by an arousal. After the event termination, there is a decrease in esophageal pressure excursions and the nasal pressure contour becomes
round. The event is not associated with a desaturation and is not a hypopnea by the recommended hypopnea scoring rule. The event also is not associated with a 50%
drop in the nasal pressure excursions. Therefore, the event is not a hypopnea using the alternative hypopnea scoring rule. ECG = electrocardiogram; SpO2 = pulse
oximetry.
Hypopnea or RERA? ratory event termination can occur slightly before, concur-
Of note, if the recommended definition of hypopnea is used, rent with, or after event termination.20
some obstructive events that would otherwise meet criteria
for the alternate definition of hypopnea would be scored as
Scoring Apneas and Hypopneas during Wake
RERAs. Such an event would be associated with an arousal
but not 4% or greater desaturation and have NP flattening In some cases, apneas and hypopneas may begin during an
for 10 seconds or longer with drop in the excursions of the epoch scored as sleep but end in an epoch scored as wake (or
NP signal by 50% or more from baseline (Fig. 99). Note that vice versa). Scoring manual FAQ R10 states If any portion
part of the RERA definition is that the event does not meet of either the apnea or hypopnea occurs during an epoch
criteria for a hypopnea. that is scored as sleep, then the corresponding respiratory
event can be scored and included in the computation of
the AHI. However, if the apnea or hypopnea occurs entirely
Relationship of Arousal and Respiratory Event
during an epoch scored as wake, it should not be scored or
The AASM scoring manual did not specify a maximum time counted toward the apnea-hypopnea index because of the
interval from respiratory event termination until arousal ini- difficulty of defining a denominator in that situation.
tiation for the arousal to be considered respiratory. FAQ R19
states The scoring manual does not specify the time require-
Classification of Hypopneas
ment linking arousals and respiratory event. When arousals
do occur with respiratory events, they usually occur within The AASM scoring manual recommends that hypopneas
5 seconds of airway opening. Arousals associated with respi- not be classified (obstructive, central, or mixed) without a
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128 Chapter 9 Monitoring RespirationEvent Definitions and Examples
y
of airflow (PNT or NP) would also be needed. The AASM
tit
en
scoring manual did not provide definitions for hypopnea
Id
types. However, a possible scheme for defining types of
20 hypopneas is presented in Table 93 and Figure 910. One
can define an obstructive hypopnea as one due to an increase
in upper airway resistance (usually with increased respira-
tory effort). A central hypopnea would be due to a reduction
in respiratory effort with a proportionate decrease in airflow.
10
A mixed hypopnea would be characterized by both increased
upper airway resistance (NP flattening and airflow limita-
tion) and decreased respiratory effort (decreased esophageal
pressure excursions). In the absence of esophageal pressure
Asymptomatic monitoring, the shape of the NP tracing (or PNT) can
EDS/snoring provide some clues (see Table 93). The presence of a flat-
0 tened NP tracing, snoring, or chest-abdominal paradox sug-
0 10 20 30 gests airflow limitation (increased upper airway resistance),
Flow limitation events with arousal whereas a rounded shape without snoring is consistent with
by nasal cannula (events/hr) a lack of airflow limitation. Even with sophisticated monitor-
FIGURE 98 Flow limitation arousals and respiratory effortrelated arousals (RERAs) ing equipment, it may be difficult to precisely classify some
by esophageal monitoring (events/hour) were highly correlated, although not hypopneas.
identical. Reproduced from Ayappa I, Norman RG, Krieger AC, et al: Non-invasive
detection of respiratory effortrelated arousals (RERAs) by a nasal cannula/pressure
transducer system. Sleep 2000;23:763771. Chest-Abdominal Paradox
During normal inspiration, the rib cage expands and
the diaphragm contracts, moving the abdominal contents
F4-M1
C4-M1
O2-M1
E1-M1
E2-M2
Chin
ECG
20 sec
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
SpO2
92 92 93 93 93 93 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95
FIGURE 99 RERA if the recommended hypopnea definition is used or hypopnea if the alternative hypopnea definition is used. Note that the 20 second arrow
is the duration of the 50% drop in NP excursions. However, the event duration as defined by the event duration rules would be longer (nadir preceding first breath
that is clearly reduced to the beginning of the first breath that approximates baseline breathing). The event duration would begin one breath earlier and end one
breath later than the 20 second line. ECG = electrocardiogram; SpO2 = pulse oximetry.
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Chapter 9 Monitoring RespirationEvent Definitions and Examples 129
TABLE 93
Idealized Findings in Hypopnea
PNT/NP CHEST/ABDOMEN ESOPHAGEAL PRESSURE UPPER AIRWAY
TYPE AMPLITUDE/SHAPE DEFLECTIONS DEFLECTIONS RESISTANCE SNORE
Central Decreased amplitude Decreased Decreased Normal None
Round shape No paradox
Obstructive Decreased amplitude Variable Increased Increased Present
Flattened shape Paradox common Airflow limitation
Mixed Decreased amplitude Decreased Decreased Increased May be present
Flattened shape Paradox common Airflow limitation
NP = nasal pressure; PNT = pneumotachogram.
Central hypopnea
Airflow
(PNT)
Esophageal
pressure
Obstructive hypopnea
Airflow
(PTN)
Esophageal
pressure
Mixed hypopnea
Airflow
(PTN)
Esophageal
pressure
FIGURE 910 Examples of central, obstructive, and mixed hypopneas with an accurate measure of airflow (pneumotachograph [PNT]) and esophageal
pressure monitoring. In central and mixed hypopnea, the esophageal excursions decrease (up arrows). In mixed hypopnea, airflow limitation is present
(flattened airflow), and in central hypopnea, the airflow contour is round. In obstructive hypopnea, the esophageal pressure excursions are increased (black
circles) for at least part of the event.
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130 Chapter 9 Monitoring RespirationEvent Definitions and Examples
Snore
Nasal pressure
Nasal-oral
thermal flow
Chest
no P
P
Abdomen
96%
SpO2
88%
30 sec
FIGURE 911 An obstructive hypopnea with paradox (P) in chest and abdominal movement during the respiratory event but not during less obstructed breathing
(no P). SpO2 = pulse oximetry.
downward; the abdomen also moves outward. During chest- of chest and abdominal bands (position and tightness) is
abdomen paradox, the chest moves outward and the crucial to avoid significant errors in event classification.
abdomen inward or vice versa. Paradox is most helpful at Computer software often adjusts sensitivity with an
identifying high upper airway resistance when it is present autogain to avoid large breaths being off-scale. However,
during the obstructive event and NOT present during unob- this may decrease the gain so that small efforts are not rec-
structed breathing (Fig. 911; see also Fig. 94). ognized. In Figure 913, with an increase in the gain (size)
Conditions in which paradox may occur21: of chest and abdominal tracings, the event is clearly not a
central apnea.
1. Loss of diaphragm tone/weakness: The abdomen is sucked
Regarding central apneas, it is worth noting that the
inward as the rib cage expands during inspiration.
upper airway can actually close during a central apnea.24 This
2. Loss of accessory muscle tone: Destabilizes the rib cage
should not be surprising, considering the obstructive portion
so it may be sucked inward when the diaphragm contracts
of mixed apneas. Some have proposed that the observation
(abdomen expands).
of cardiac oscillations in airflow tracings allows one to con-
3. Partial upper airway obstruction: High pleural pressures
clude that the upper airway is open (Fig. 914).25 However,
can overcome mechanisms maintaining rigidity of
a study by Morrell and associates26 found that during
thoraxparts are sucked inward. This is common in chil-
ventilator-induced central apneas in dogs, cardiac oscilla-
dren with more pliable chest walls.
tions could be present in the flow tracings even if the airway
4. Complete upper airway obstruction: The total volume of
was noted to be closed by direct visualization. The appear-
respiratory system does not changewhen the abdomen
ance of cardiac oscillations in the airflow tracings is rarely
expands (diaphragm contracts) the chest volume must
noted in obstructive apnea. Therefore, the presence of cardiac
decrease.
oscillations in the flow may be a clue that a central apnea is
present but one may not be able to infer that the upper
airway is indeed open.
False Classification of Apneas as Central
As discussed in Chapter 8, even with RIP, an obstructive
Hypoventilation in Adults14
apnea (by esophageal pressure manometry) may appear to
be a central apnea.22,23 In Figure 912, the RIP rib cage and Hypoventilation during wakefulness is usually defined as an
abdominal band tracings are nearly flat but persistent respi- arterial partial pressure of carbon dioxide (PaCO2) equal to
ratory effort is definitely noted in the esophageal pressure or greater than 45 mm Hg. During sleep, there may be
tracing. Although misclassification of a few events is unlikely periods of time in which the SpO2 is reduced without associ-
to have major clinical consequences, proper adjustment ated events that meet criteria for apnea or hypopnea. Such
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Chapter 9 Monitoring RespirationEvent Definitions and Examples 131
100
O2 Sat %
75
Contraction
50
PESOPH
10cm H2O
Sum (VT)
50 mL
5s
RC
Inspiration Expiration
ABD
FIGURE 912 An obstructive apnea appears to be a central apnea based on the rib cage (RC) and abdominal (ABD) respiratory inductance plethysmography
(RIP) tracings. The true nature of the event is shown by the persistent esophageal pressure (PESOPH) deflections. Data from Tobin MJ, Cohen MA, Sackner MA:
Breathing abnormalities during sleep. Arch Intern Med 1983;143:12211228.
Normal chest and abdomen gain High chest and abdomen gain
Nasal pressure
Nasal oral
thermal flow
Chest
Abdomen
SpO2
97 96 96 94 94 95 97 98 98 98 98 98 97 97 96 96 96 96 96 95 94 92 97 96 96 94 94 95 97 98 98 98 98 98 97 97 96 96 96 96 96 95 94
FIGURE 913 Left, The event may at first appear to be a central apnea. However, with an increase in gain in the chest and abdomen tracings, the obstructive nature of the event
is apparent. Right, The many small fluctuations in the chest and abdomen tracings are due to cardiac oscillations that are readily apparent only at the high gain. SpO2 = pulse
oximetry.
periods of arterial oxygen desaturation are sometimes not sufficient to document hypoventilation. It is observed
termed hypoventilation. However, this is presumptive that finding an increase in the PaCO2 obtained immediately
without direct measurement of PaCO2 or a surrogate. The upon awakening is suggestive of sleep hypoventilation. The
AASM scoring manual provides criteria for hypoventilation manual concluded that sufficient evidence was not available
during sleep and discourages use of the term hypoventila- to recommend a sensor to document hypoventilation. The
tion without documentation of an elevated PaCO2. manual also states that both end-tidal carbon dioxide pres-
sure (PETCO2) and transcutaneous carbon dioxide pressure
Hypoventilation Rule (AASM Scoring Manual14) (TcPCO2) may be used as surrogate measures of PaCO2 if
Score hypoventilation during sleep if there is a 10 mm Hg demonstrated to be reliable and valid.
increase in PaCO2 during sleep in comparison with an awake Continuous arterial blood gas monitoring during PSG
supine value. is not practical (or well tolerated) and arterial blood gas
The AASM scoring manual also notes that persistent testing is most often performed at the start (to validate a
oxygen desaturation in the absence of apnea or hypopnea is surrogate measure of PCO2) or on awakening often at study
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132 Chapter 9 Monitoring RespirationEvent Definitions and Examples
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
SpO2
FIGURE 914 A central apnea is seen with cardiac oscillations in the chest and airflow channels. The oscillations are also seen in the nasal pressure signal. There
is controversy about whether this means that the upper airway is open or closed. As discussed previously, the upper airway can close during central apnea.
SpO2 = pulse oximetry.
termination (to provide evidence for hypoventilation during CSB is characterized by central apnea or hypopnea at the
sleep). In children, an arterialized capillary blood gas rather nadir of respiratory effort (Fig. 916) as well as an interven-
than an arterial sample is often performed. ing pattern of crescendo-decrescendo ventilation (flow or
The most common approaches to documenting hypoven- tidal volume) between apneas/hypopneas. CSB is most com-
tilation during sleep monitoring include measurement of monly noted in patients with systolic congestive heart failure
PETCO2 or TcPCO2. These methods are discussed in Chapter (CHF) but can occur after stroke or with diastolic heart
8. Figure 915 presents a tracing from a patient with a neu- failure. When CSB is associated with systolic CHF, a few
romuscular disorder. The awake PETCO2 was 43 mm Hg, but other characteristic PSG findings are of interest. First, the
during sleep, the PETCO2 reached the mid 70s. As discussed cycle time (time from the onset of one apnea to the next
in Chapter 8, a PETCO2 tracing should show an alveolar apnea) is usually approximately 50 to 60 seconds with long
plateau to be accepted as an accurate estimate of the PaCO2. ventilatory phases (crescendo-decrescendo) between the
In Figure 915, many of the breaths are not associated with central apneas.27 If associated arousals are present, they are
a good alveolar plateau. The last 2 breaths illustrate a desired often at the zenith of respiratory effort. In addition, due to
alveolar plateau. It should also be noted that the PaCO2 low cardiac output, there is a long circulation time and the
typically exceeds the PETCO2 by 4 to 6 mm Hg in normal nadir in desaturation is delayed relative to the event termina-
individuals. The difference can be increased in patients with tion. Figure 917 presents a schematic showing the differ-
lung disease. ences between central apnea in primary (idiopathic) central
apnea and CSB.
Cheyne-Stokes Breathing Rule14
Respiratory Parameters Reported
Score Cheyne-Stokes breathing (CSB) if there are at least
in PSG (Adults)14,17
three consecutive cycles of cyclic crescendo and decrescendo
change in breathing amplitude and at least one of the The following is a list of respiratory parameters that are rec-
following: ommended for presentation in a PSG report. Of note, the
RDI was not defined in the AASM scoring manual but is
1. Five or more central apneas or hypopneas per hour of added for completeness. Not all sleep centers report an RDI.
sleep. Two definitions of the RDI in common use are presented
2. The cyclic crescendo and decrescendo change in breath- here. The sleep study report should specify the RDI definition
ing amplitude has a duration of at least 10 consecutive (if reported) and the definition of hypopnea (recommended
minutes. or alternative) that was used for scoring the sleep study.
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Chapter 9 Monitoring RespirationEvent Definitions and Examples 133
Nasal pressure
Airflow
Chest
Abdomen
SpO2
96 96 96 96 96 96 96 96 96 95 95 95
PETCO2
52 53 58 58 56 64 65 68 68 74 73 76
PCO2
FIGURE 915 Documentation of an increased partial pressure of carbon dioxide (PCO2) during sleep. Note the alveolar plateaus (black circles). PCO2 = exhaled
PCO2 waveform tracing; PETCO2 = most recent end-tidal reading; SpO2 = pulse oximetry.
60 sec
30 sec
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
95%
SpO2
82%
FIGURE 916 Cheyne-Stokes respiration with a crescendo-decrescendo pattern of respiration with central apneas at the nadir of effort. Note the nadir in the
pulse oximetry (SpO2) is very delayed following the end of the apneas. Top left corner, A tracing of Cheyne-Stokes breathing with a hypopnea at the nadir.
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134 Chapter 9 Monitoring RespirationEvent Definitions and Examples
Airflow
DS
SpO2
Idiopathic CSA
Cycle Length
Airflow
DS
SpO2
1. AH = number of apneas + number of hypopneas. respiration in children are very similar to those for monitor-
2. Number of obstructive, central, and mixed apneas. ing adults (Table 94). In children, it is very common for
3. Number of hypopneas. some respiratory sensors to fail during monitoring. For
4. AHI = number of apneas and hypopneas per hour of example, sensors might be pulled off by the child or the NP
sleep cannula may be dislodged or occluded with secretions.
TABLE 94
Pediatric Respiratory Rules
Obstructive apnea Duration at least 2 missed breaths or equivalent duration.
>90% fall in signal for 90% of event duration.
Continued or increased inspiratory effort.
Event duration is from the end of last normal breath to the beginning of first breath achieving
baseline amplitude.
Mixed apnea Duration at least 2 breaths or equivalent duration.
>90% fall in signal for 90% of event duration.
Absent inspiratory effort in the initial portion of the event, followed by resumption of inspiratory
effort before the end of the event.
Central apnea Absent inspiratory effort.
Duration 20 sec.
OR
duration at least 2 missed breaths AND associated with arousal, awakening, or 3% desaturation.
Hypopnea NP signal falls by 50% from baseline.
Duration at least 2 missed breaths (or equivalent duration).
Fall lasts 90% of the event duration.
Arousal, awakening, or 3% desaturation occurs.
RERA All of the following in NP:
a. Discernible but <50% fall in signal.
b. Flattening of NP.
c. The event accompanied by snoring, noisy breathing, elevation in the end-tidal PCO2 or
transcutaneous PCO2, or increased WOB.
d. Duration at least 2 breath cycles.
All of the following when using esophageal pressure:
a. Progressive increase in respiratory effort.
b. Snoring, noisy breathing, increased end-tidal or transcutaneous PCO2, increased WOB.
c. Duration at least 2 breath cycles.
Hypoventilation 25% of the total sleep time with a PCO2 > 50 mm Hg. (PETCO2 or TcPCO2 are acceptable.)
Periodic breathing There are >3 episodes of central apnea lasting >3 sec separated by no more than 20 sec of normal
breathing.
NP = nasal pressure; PCO2 = partial pressure of carbon dioxide; PETCO2 = end-tidal carbon dioxide pressure; RERA = respiratory effortrelated arousal;
TcPCO2 = transcutaneous carbon dioxide pressure; WOB = work of breathing.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.
Snore
Nasal pressure
8 sec
Nasal-oral
thermal flow
Chest
Abdomen
98%
SpO2
93%
FIGURE 918 A short obstructive apnea in a 7-year-old child. There is a fall in the nasal-oral thermal flow of greater than 90% and continued inspiratory efforts
are noted. Even though the event duration is short, it was followed by an arterial oxygen desaturation. Of note, a desaturation is NOT necessary to score an obstructive
apnea. SpO2 = pulse oximetry.
Nasal pressure
Nasal-oral
thermal flow 11 sec
Chest
Abdomen
SpO2
94 94 95 94 94 94 95 95 96 96 97 98 98 99 99 99
16 sec
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
SpO2
98 98 98 98 98 98 98 98 98 98 97 95 94 94 93 91 91
FIGURE 919 A respiratory event in a 6-year-old child. The upper central event would not be scored as a central apnea because the duration is less than 20 seconds
and there is no associated arousal or desaturation. The bottom central event would be scored as a central apnea because it is longer than 2 missed breath cycles
and is associated with an arterial oxygen desaturation. SpO2 = pulse oximetry.
Snore
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
SpO2
93%
Exhaled 50
PCO2 0
FIGURE 920 Obstructive hypoventilation. The end-tidal partial pressure of carbon dioxide (PCO2) is greater than 50 mm Hg and there is evidence of snoring
and flattening of the nasal pressure. A very mild drop in the pulse oximetry (SpO2) is noted.
Nasal pressure
CO2
Chest
Abdomen
SpO2
98 92 98 95 93 96 98
10 sec
FIGURE 921 Periodic breathing in a newborn infant (43 wk conceptual age). Note the lag in the end-tidal PCO2 tracing (CO2) compared with the nasal pressure
tracing. SpO2 = pulse oximetry.
6. AHI during supine and nonsupine sleep. A. PaCO2 50 mm Hg for 10% of total sleep time.
7. AHI NREM and AHI REM. B. PaCO2 > 50 mm Hg for 25% of total sleep time.
8. OD = number of arterial oxygen desaturations. C. PaCO2 50 mm Hg for 25% of total sleep time.
9. ODI = (OD 60)/TST (min).
D. PaCO2 < 55 mm Hg for 25% of total sleep time.
10. # RERA = number of RERAs.
11. RERA index = number of RERAs 60/TST (min). 4. At what age and above can adult scoring rules be used at
12. RDI the discretion of the clinician?
Definition #1 RDI = AHI
A. 12 years.
Definition #2 RDI = AHI + RERA index
13. Time with PETCO2 or TcPCO2 greater than 50 mm Hg B. 13 years.
(as total minutes or as % TST). C. 14 years.
D. 16 years.
CLINICAL REVIEW QUESTIONS 5. According to the AASM scoring manual, score periodic
1. Hypoventilation during wakefulness for adults is defined breathing in children if:
as a PaCO2 45 mm Hg. Hypoventilation during sleep is A. >3 episodes, central apnea lasting >3 seconds,
defined as: separated by no more than 20 seconds.
A. PaCO2 5 mm Hg above an awake supine value. B. >3 episodes, central apnea lasting >3 seconds,
B. PaCO2 10 mm Hg above an awake supine value. separated by no more than 10 seconds.
C. PETCO2 5 mm Hg above the wake value. C. >3 episodes, central apnea lasting >2 seconds,
separated by no more than 20 seconds.
D. PETCO2 10 mm Hg above the wake value.
D. >3 episodes, central apnea lasting >5 seconds,
2. In the table, which group (A, B, C, or D) is correct for separate by no more than 20 seconds.
recommended and alternate definitions of hypopnea in
adults and hypopnea in children? NP = nasal pressure Answers
excursions.
1. B. The AASM scoring manual defines hypoventilation
CHANGE IN NP based on the arterial PaCO2 of 10 mm Hg above the
FROM BASELINE DESATURATION waking value. The PETCO2 or TcPCO2 can be used to
A. Adult hypopnea Drop of 30% 4% define hypoventilation only when it has been validated as
(recommended) an estimate of the patients ventilation.
Adult hypopnea Drop of 30% 4% (or arousal) 2. D
(alternate)
Child hypopnea Drop of 50% 3% (or arousal) 3. B
B. Adult hypopnea Drop of 30% 4% 4. B
(recommended)
Adult hypopnea Drop of 50% 3% (or arousal)
5. A
(alternate)
Child hypopnea Drop of 30% 3% (or arousal)
REFERENCES
1. Redline S, Sander M: Hypopnea, a floating metric: implications
C. Adult hypopnea Drop of 30% 4%
for prevalence, morbidity estimates, and case finding. Sleep
(recommended) 1997;20:12091217.
Adult hypopnea Drop of 50% 3% (or arousal) 2. Guilleminault C: State of the art: sleep and control of breathing.
(alternate) Chest 1978;73:293299.
3. Block AJ, Boysen PG, Wynne JW, et al: Sleep apnea, hypopnea,
Child hypopnea Drop of 30% 3% (or arousal) and oxygen desaturation in normal subjects: a strong male
predominance. N Engl J Med 1979;330:513517.
D. Adult hypopnea Drop of 30% 4% 4. Gould GA, Whyte KF, Rhind GB, et al: The sleep hypopnea
(recommended) syndrome. Am Rev Respir Dis 1988;137:895898.
Adult hypopnea Drop of 50% 3% (or arousal) 5. Young T, Palta M, Dempsey J, et al: The occurrence of sleep-
(alternate) disorders breathing among middle-aged adults. N Engl J Med
1993;28:12301235.
Child hypopnea Drop of 50% 3% (or arousal) 6. Neito FJ, Young TB, Lind BK, et al: Association of sleep disor-
ders breathing, sleep apnea, and hypertension in a large com-
munity based study. JAMA 2000;283:18291836.
7. Norman RG, Ahmed M, Walsben JA, Rapoport DM: Detection
3. In children, hypoventilation is defined by which of the of respiratory events during NPSG: nasal cannula/pressure
following?
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sensor versus thermistor. Sleep 1997;20:11751184.
140 Chapter 9 Monitoring RespirationEvent Definitions and Examples
8. Guilleminault C, Stoohs R, Clerk A, et al: A cause of excessive 19. Ayappa I, Norman RG, Krieger AC, et al: Non-invasive
daytime sleepiness: the upper airway resistance syndrome. detection of respiratory effortrelated arousals (RERAs) by a
Chest 1993;104:781787. nasal cannula/pressure transducer system. Sleep 2000;23:
9. American Academy of Sleep Medicine Task Force: Sleep- 763771.
related breathing disorders in adults: recommendation for syn- 20. Younes M: Role of arousals in the pathogenesis of obstructive
drome definition and measurement techniques in clinical sleep apnea. Am J Respir Crit Care Med 2004;169:623633.
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10. Whitney CW, Gottleib DJ, Redline S, et al: Reliability of scoring sleep. In Principles and Practice of Sleep Medicine, 3rd ed.
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1998;21:749757. 22. Staats BA, Bonekat HW, Harris CD, Offord KP: Chest wall
11. Redline S, Kapur VK, Sanders MH, et al: Effects of varying motion in sleep apnea. Am Rev Respir Dis 1984;130:5963.
approaches for identifying respiratory disturbances on sleep 23. Tobin MJ, Cohen MA, Sackner MA: Breathing abnormalities
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369374. 24. Badr SM, Toiber F, Skatrud JB, Dempsey J: Pharyngeal
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definitions of hypopnea. Am J Respir Crit Care Med 1999; 25. Ayappa I, Norman RG, Rapoport DM: Cardiogenic oscillations
159:4348. on the airflow signal during continuous positive airway pres-
13. Meoli AL, Casey KR, Clark RW: Clinical practice review com- sure as a marker of central apnea. Chest 1999;116:660666.
mittee-AASM. Hypopnea in sleep disordered breathing in 26. Morrell MJ, Badr MS, Harms CA, Dempsey JA: The assessment
adults. Sleep 2001;24:469470. of upper airway patency during apnea using cardiac oscillation
14. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American in the airflow signal. Sleep 1995;18:651668.
Academy of Sleep Medicine: The AASM Manual for the Scoring 27. Hall MJ, Xie A, Rutherford R, et al: Cycle length of periodic
of Sleep and Associated Events: Rules, Terminology and Tech- breathing in patients with and without heart failure. Am J
nical Specifications, 1st ed. Westchester, IL: American Academy Respir Crit Care Med 1996;154:376381.
of Sleep Medicine, 2007. 28. Grigg-Damberger M, Gozal D, Marcus CL, et al: The visual
15. Redline S, Budhiraja R, Kapur V, et al: The scoring of respira- scoring of sleep and arousal in infants and children: develop-
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2007;3:169200. tive methods. J Clin Sleep Med 2007;3:201-240.
16. Ruehland WR, Rochford PO, ODonoghue FJ, et al: The new 29. Rosen C, DAndrea L, Haddad G: Adult criteria for obstructive
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Chapter 10
Computation of the PAO 2 and the A-a gradient equation (Equation 101) using the known PaCO2. The A-a
PAO2 = FIO2 ( PB PH2O ) PaCO2 /R gradient (Equation 103) in such patients is normal. Lung
disease severe enough to cause an increased PaCO2 is always
R = VCO
2 /VO2 ( assumed to be 0.8 ) associated with an increased A-a gradient.
VCO
2 = CO2 elimination VO2 = O2 uptake
Box 101 presents examples of use of the alveolar gas
Equation 101 equation (Equation 101). In a patient with amyotrophic
lateral sclerosis (ALS; Example 1), an arterial blood gas
Breathing room air, Equation 101 becomes Equation 102. reveals a PaO2 of 60 and PaCO2 of 65 mm Hg. The computed
The A-a gradient (Equation 103) is the difference between A-a gradient is 8.7 mm Hg (normal). Hypoxemia is due to
the ideal PAO2 and the actual (measured) PaO2. Equation hypoventilation. In Example 2, a patient with chronic
104 gives the predicted A-a gradient (usually <25 mm Hg). obstructive pulmonary disease has evidence of both hypox-
emia and hypercapnia and the A-a gradient is increased. The
(room air ) PAO2 = 0.21(760 47 ) PaCO2 /0.8 mismatch and hypoventila-
hypoxemia is due to both V Q
= 150 PaCO2 /0.8 tion. In patients with hypoventilation of unclear etiology,
Equation 102 calculating an A-a gradient can provide an important clue as
A-a gradient = PAO2 PaO2 Equation 103 to whether the hypoventilation is due to lung disease or due
totally to hypoventilation. A normal A-a gradient in a patient
Predicted estimate of normal A-a gradient = 4 + age (yr )/4 with hypoventilation would suggest a disorder of ventilatory
For example, for a 48-year-old, A-a gradient = 16 control or muscle weakness.
Equation 104
OXYGEN TRANSPORT AND SATURATION
The major causes of hypoxemia are listed in Table 101.
Causes of hypoxemia include a low FIO2, a low PB (high The majority of the oxygen-carrying capacity of the blood is
altitude), hypoventilation (increased PaCO2), and incom- due to oxygen bound to hemoglobin (Hb) with a small frac-
plete oxygenation of the blood by the lung (ventilation- tion of dissolved oxygen (Equation 105).1 When fully satu-
mismatch or shunt). In V Q
perfusion [ V Q] mismatch, rated, a gram of Hb carries about 1.34 mL/dL of oxygen
some alveoli are underventilated for their blood flow (low (1 dL = 100 mL).
and blood is incompletely oxygenated. This can be
V Q) Oxygen content of arterial blood (CaO2 [mL O2/100 mL])
overcome by increasing the FIO2, thereby increasing the
CaO2 = 1.34 mL/g Hb ( g/100 mL ) SaO2 + 0.003 PaO2
effective oxygen flow to underventilated alveoli. If shunt is
Equation 105
causing hypoxemia, blood completely bypasses the alveoli.
The deoxygenated blood mixes with oxygenated blood to
give a lower than ideal PaO2. Raising the FIO2 has no effect
on shunted blood. Most patients with lung disease also have
defects in CO2 excretion. This may not result in alveolar BOX 101
hypoventilation because the patient may compensate by Examples of Computation of the Alveolar Partial
increasing the minute ventilation (discussed later). Pressure of Oxygen and the A-a Gradient
Hypoxemia can occur simply as a consequence of
EXAMPLE 1: HYPOVENTILATION DUE TO AMYOTROPHIC
hypoventilation. For example, a patient with normal lungs
LATERAL SCLEROSIS (NORMAL A-a GRADIENT)
may have an increased PaCO2 due to muscle weakness or
abnormal ventilatory control. In this case, the PaO2 is fairly Laboratory: PaO2 = 60 mm Hg and PaCO2 = 65 mm Hg
close to the ideal (PAO2) computed from the alveolar gas (breathing room air)
SHIFT TO LEFT
Temperature
PaCO2
Hydrogen ion HIGHER PaO2 WITH RIGHT SHIFT
concentration
100 2,3-DPG 100
Shift to right
60 60
Temperature
PaCO2
40 Hydrogen ion 40
concentration
20 2,3 DPG 20
0 0
0 20 40 60 80 100 0 20 40 60 80 100
PaO2 (mm Hg) PaO2 (mm Hg)
Oxyhemoglobin dissociation curve Oxyhemoglobin dissociation curve
FIGURE 101 Left, The shift in the oxygen hemoglobin dissociation curve left or right depends on the illustrated factors.
Right, A shift to the right increases the arterial partial pressure of oxygen (PaO2) for a given arterial oxygen saturation (SaO2).
2,3-DPG = 2,3-diphosphoglycerate; PaCO2 = arterial partial pressure of carbon dioxide.
Extinction coefficient
70
SpO2 (%)
1 R Hb 60
50
40
30
O2Hb 20
.1
10
FIGURE 103 A, Hemoglobin extinction curves for reduced hemoglobin (R Hb), oxyhemoglobin (O2Hb), and carboxyhemoglobin
(COHb) at different wavelengths of light. Note that the y axis is a log scale. B, Empirical curve of the ratio of absorption of radiation
(R) at wavelengths of 660 and 940 nm. AC = pulse added absorption; DC = steady state or background absorbance; SpO2 = pulse
oximetry. A and B, Adapted from Temper KK, Barker SJ: Pulse oximetry. Anesthesiology 1989;70:98108.
However, determining the oxygen-carrying capacity of Hb is the SaO2, not the FO2Hb. That is, the oxyhemoglobin satura-
complicated by the fact that both carboxyhemoglobin tion curve expresses the ratio of oxygenated Hb to the total
(COHb) and methemoglobin (MetHb) are forms of circulat- Hb available for oxygen binding. Neither COHb nor MetHb
ing Hb that do not bind oxygen. Carboxyhemoglobin occurs binds oxygen. However, the position of the oxyhemoglobin
when carbon monoxide (CO) binds to Hb. Smokers have saturation curve is shifted to the left by the presence of
increased carboxyhemoglobin. MetHb occurs when the COHb or MetHb.4,7
normal ferrous state (Fe2+) of the iron moiety in Hb is oxi- The previous four fractions of Hb can be accurately mea-
dized to the ferric stage (Fe3+). Significant methemoglobin- sured by co-oximeters that measure the absorption of 4 or
emia can occur after exposure to certain medications but is more wavelengths of electromagnetic radiation by blood.1,5
uncommon in the sleep center. The sum of the fractional This is possible because the four forms of Hb differ in their
concentrations of O2Hb, RHb, COHb, and MetHb equal absorption for the different wavelengths of radiation. In con-
100% (Equation 107). The true fraction of hemoglobin trast, pulse oximetry3 uses only two wavelengths: 660 nm
bound to oxygen (FO2Hb) is given by Equation 108 and (red) and 940 nm (infrared) to measure the O2Hb and RHb.
depends on the fraction (%) of carboxyhemoglobin (FCOHb) The absorption of radiation at 660 nm is much greater with
and methemoglobin (FMetHb) as well as the fraction of RHb than O2Hb, whereas O2Hb absorbs more radiation at
reduced hemoglobin (FRHb).46 940 nm (Fig. 103A). SpO2 is based on the empirical obser-
vation that the ratio (R) of absorbance at the 2 wavelengths
FO2 Hb + FRHb + FCOHb + FMetHb = 100%
is related to the oxygen saturation (see Fig. 103B). This
Equation 107
relationship (calibration curve) is calculated experimentally
or by determining R at varying oxygen saturations. To specifi-
FO2 Hb = O2 Hb 100/ ( O2 Hb + RHb + COHb + MetHb ) cally determine the absorbance of arterial blood, the AC
(pulse added absorbance) at each wavelength is divided by
FO2 Hb = O2 Hb 100/Hbt the DC (background absorbance) to account for the effect of
Equation 108 the absorption of the radiation by venous blood and tissue.
where O2Hb, RHb, COHb, and MetHb are the concentra- COHb has about the same absorbance at 660 as O2Hb and,
tions of the types of Hb and equal the total Hb concentration if present, increases the measured SpO2 value. In normal
(Hbt). For example, if the FO2Hb = 85%, FCOHb = 8%, individuals, FCOHb is 2% or less but can be 8% or more in
FmetHb = 1%, then the FRHb is 6%. Using these numbers cigarette smokers. Patients with SCD often have FCOHb
and Equation 103, the SaO2 equals 85 100/(85 + 6) or values of 4% or more due to production of CO from chronic
93%, which is considerably higher than FO2Hb of 85%. The hemolysis. Based on a canine experiment,3 it has been esti-
FO2Hb and the amount of Hb are the main determinants of mated that a pulse oximeter sees COHb as 90% O2Hb and
the bloods oxygen-carrying capacity. When significant 10% RHb. For example, from the values FO2Hb = 85%,
COHb or MetHb is present, Equation 105 should have SaO2 COHb = 4%, MetHb = 0%, RHb = 11%, one can estimate the
replaced by FO2Hb. The difference between the SaO2 and the SpO2 as 88.6% (85 + 0.9 4). This is essentially the same as
FO2Hb (in %) at normal PO2 values is approximately equal the SaO2 computed from Equation 102 for these values.
to the sum of FCOHb and FMetHb.4 The FO2Hb is some- Thus, the SpO2 is a much better estimate of the SaO2 than
times called the fractional saturation and the SaO2 the func- the FO2Hb is. In patients who are heavy smokers, it is impor-
tional or effective saturation. Of note, the PaO2 depends on tant to remember that the SpO2 may overestimate the FO2Hb.
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Chapter 10 Sleep and Respiratory Physiology 145
TABLE 103
Different Patterns of Breathing with Changing Dead Space and Tidal Volume
ALVEOLAR
VD VT RR MV VENTILATION PACO2
VD/V T (ML) (ML) (BPM) (L/MIN) (L/MIN) (MM HG)
A Normal 0.3 200 600 10 6.0 4.0 40
B Low V T, same MV 0.5 200 400 15 6.0 3.0 53
C High VD 0.42 300 700 10 7.8 4.0 40
D High VD, low V T 0.75 300 500 20 10.0 4.0 40
Notes:
B. Low V T; even with higher RR and similar MV, the alveolar ventilation is decreased.
C. High VD is compensated by an increase in V T; with a higher MV, a normal alveolar ventilation is obtained.
D. High VD, low V T results require much higher MV to achieve a normal alveolar ventilation.
PaCO2 = K VCO 2 / (RR VT )(1 VD /VT )
Assume K VCO
2 = 160
K = constant = 0.863; MV = minute ventilation; PaCO2 = arterial partial pressure of carbon dioxide; RR = respiratory rate; VCO 2 = carbon dioxide production;
VD = dead space; V T = tidal volume.
60
PaCO2 2-8 mm Hg
PaO2 3-10 mm Hg
SaO2 1-2% 40
FIGURE 104 Changes in ventilation and gas exchange with normal sleep. The loss of
wakefulness stimuli and reduced ventilatory drive + increased upper airway resistance 20
result in a reduction in minute ventilation. Although the metabolic rate and CO2
excretion are lower, the net effect is a mild increase in the arterial partial pressure of 0
carbon dioxide (PaCO2) and decrease in the arterial pressure of oxygen (PaO2). SaO2 = 20 40 60 80 100
arterial oxygen saturation. From Mohsenin V: Sleep in chronic obstructive pulmonary PaO2 (mm Hg)
disease: sleep and respiration. Semin Respir Crit Care Med 2005;26:109115. Oxygen-hemoglobin saturation curve
FIGURE 105 The same drop in arterial partial pressure of oxygen (PaO2) causes a
greater drop in the arterial oxygen saturation (SaO2) if the starting point is on the steeper
slope of the oxygen-hemoglobin saturation curve.
110 110
100 100
Percent
Percent
90 90
80 80
FIGURE 106 The fall in minute ventilation with sleep is due to a fall in tidal volume (VT) with no significant change
in respiratory rate (RR). REM = rapid eye movement; St. 2 = stage N2; St. 3-4 = stage 3-4 (stage N3); W = wake. From
Krieger J: Respiratory physiology: breathing in normal subjects. In Kryger MH, Roth T, Dements WC (eds): Principles and
Practice of Sleep Medicine. Philadelphia: Elsevier, 2005, pp. 232255.
partial pressure of oxygen (PETO2) are determined on a system compliance is not an ideal method to test the neural
breath-by-breath basis (assumed to be alveolar values) and drive to breathe. The mouth occlusion pressure (P0.1)the
plotted against the ventilation at that time on a breath-by- mouth pressure measured 0.1 second after the start of inspi-
breath basis. A line is then drawn to fit the points. The HCVR ration (unexpected airway occlusion)can be used instead
is measured under hyperoxic conditions (minimizing the of ventilation as a better index of drive. Pressures at 0.1
effect of peripheral chemoreceptors) and the HOVR is mea- second are before voluntary changes in pressure can occur.
sured under eucapnic conditions (PaCO2 kept constant by Because there is no flow during occlusion, the P0.1 is not
removal of some of the CO2 from the system).16,17 The slope affected by airway resistance. However, maintaining ade-
of the HCVR is a measure of sensitivity to hypercapnia (Fig. quate ventilation with a high airway resistance may require
107A). However, the position of the curvethat is, set point a compensatory increase in ventilatory drive (increased
or base pointis also important. The slope of the HOVR (see P0.1). The P0.1 response to hypercapnia or hypoxemia is
Fig. 107B) is not constant and analysis is more complex. determined during rebreathing with intermittent airway
However, if expressed as ventilation versus the SaO2 (SpO2 occlusion (measurement of P0.1). The P0.1 values are plotted
is measured), the slope is linear (see Fig. 107C). versus PCO2, PO2, or SaO2 depending on the test.
If a person has a normal ventilatory control center but During sleep, the HCVR and HOVR are reduced during
abnormal lungs, high airway resistance, or abnormal tho- NREM compared with wake and decreased in REM sleep
racic cage, the slope of the ventilatory response to CO2 will compared with NREM sleep (Fig. 108).10,11 Figure 109
be lower (see Fig. 107A). Thus, measuring ventilation in a shows the breath-by-breath values of the ventilatory response
patient with a high airway resistance or low respiratory to PaCO2 in an obstructive sleep apnea (OSA) patient before
Minute ventilation (L/min)
40 50 60 40 60 80 100 60 80 100
A PACO2 (mmHg) B PAO2 (mmHg) C SaO2 (mmHg)
FIGURE 107 Schematic representation of the hypercapnic ventilatory response (A) and the hypoxic ventilatory response (B and
C). If the hypercapnic response is performed with a resistive load, the slope is lower. This illustrates that this testing depends not
simply on the ventilatory control centers but also on the resistance and compliance of the respiratory center. PACO2 = alveolar partial
pressure of carbon dioxide (estimated from end-tidal values during the rebreathing test); PAO2 = alveolar partial pressure of oxygen
(estimated from end-tidal values during the rebreathing test); SAO2 = arterial oxygen saturation (actually SpO2 from oximetry).
20 P < .05
ke
15
ke
a
a
Aw
P < .05 4
Aw
3/
Ventilation (L/min)
Ventilation (L/min)
2 P < .05
4
3/
e
t ag e 2 P < .05
10 S ag 10
St
M REM
RE
5
0
30 40 50 100 90 80
A End-tidal PCO2 (mmHg) B Oxygen saturation (%)
FIGURE 108 A, The hypercapnic ventilatory response is reduced during nonrapid eye movement (NREM) sleep compared with
wake and decreased in rapid eye movement (REM) sleep compared with NREM sleep. PCO2 = partial pressure of carbon dioxide. B,
The hypoxic ventilatory response is also decreased during NREM compared with wake and REM compared with NREM. A and B, From
Douglas NJ, White DP, Weil JV, et al: Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 1982;126:286289.
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148 Chapter 10 Sleep and Respiratory Physiology
ACID-BASE PHYSIOLOGY
40
Some basic information regarding acid-base physiology can
be useful in evaluating patients with sleep-related breathing
Control
disorders. The relationship of the pH (log [H+]) to the
serum HCO3 and PaCO2 is given by the logarithmic version
of the Henderson-Hasselbalch equation (Equation 1012). A
nonlogarithmic form of the Henderson-Hasselbalch equa-
20 tion relates the [H+] to the ratio of the PaCO2 and HCO3
55 65 75 (Equation 1013).21
Alveolar CO2 tension (mmHg)
pH = 6.10 + log ( HCO3 /0.03 PaCO2 ) pH = log[H + ]
FIGURE 109 The hypercapnic ventilatory response before and after continuous
Equation 1012
positive airway pressure (CPAP) treatment. The slope did not change but the curve
shifted to the left. Alveolar CO2 = estimated PACO2 from end-tidal sample of exhaled gas
PaCO2 [H ] in nanomoles/L = 10 moles/L
+ 9
during rebreathing test. From Berthon-Jones M, Sullivan CE: Time course of change in [H + ] = 24
ventilatory response to CO2 with long-term CPAP therapy for obstructive sleep apnea. Am [HCO3 ] HCO3 in mEq/L
Rev Respir Dis 1987;135:144147. Equation 1013
If a change in PaCO2 occurs, the body attempts to compen-
sate by changing the HCO3 in the same direction, thereby
Metabolic alkalosis minimizing the change in the PaCO2toHCO3 ratio (Fig.
Metabolic acidosis Normal
1011). However, compensation is never complete (pH
Slight Marked
Marked
Slight
remains below or above 7.4). Of note, at a pH of 7.40, the
A B C E [H+] is 40 nanomoles/L. In order to use the nonlogarithmic
D
form of the Henderson-Hasselbalch equation (Equation
30 1013), one can use the fact that around a pH of 7.40, when
Ventilation (L/min)
ACID BASE CHANGES FIGURE 1011 The major acid-base changes. For primary
respiratory changes, there is renal compensation, and for
Goal keep the PCO2 /HCO3 ratio unchanged
metabolic changes, there is respiratory compensation. PCO2 =
Primary Compensation partial pressure of carbon dioxide.
BOX 103 capacity (FVC), and the FEV1/FVC ratio. OVD is associated
Patterns of Pulmonary Function Abnormality with a reduced FEV1/FVC ratio, whereas the ratio is normal
or increased in RVD (see Table 105). OVD processes are
OVD associated with reductions in airflow, hence, a reduced FEV1.
A reduction in flow rates often with an increase in absolute In very mild disease, the FEV1 may be normal but the FEV1/
lung volumes (increase RV > TLC) FVC reduced. The RVD pattern of spirometry is character-
1. Asthma ized by a normal FEV1/FVC ratio and a reduced FVC.
2. Chronic bronchitis Bronchodilator testing is performed by administering
3. Emphysema inhaled bronchodilator to a patient who has not used a bron-
RVD chodilator before the study. American Thoracic Society cri-
teria21 for a significant bronchodilator response include an
A reduction in the total lung capacity with or without a
increase in the FEV1 or FVC by 12% AND an absolute increase
reduction in other lung volumes
of at least 200 mL. A large improvement of 15% to 40% is
1. Intrinsic RVDdue to parenchymal lung disease (e.g.,
interstitial lung disease) suggestive of asthma. However, asthmatics may not have an
2. Extrinsic RVDdue to chest wall, pleural disease, or acute bronchodilator response but may improve with chronic
muscle weakness bronchodilator therapy. Patients with COPD typically have
OVD = obstructive ventilatory dysfunction; RVD = restrictive ventilatory
no response (predominant emphysema) or a modest response
dysfunction. of 10% to 15% (predominant chronic bronchitis).
FIGURE 1012 A, Lung volume nomenclature. ERV = expiratory OVD Normal RVD
reserve volume; FRC = functional residual capacity; IC = inspiratory
capacity; RV = residual volume; TLC = total lung capacity; VC =
TLC
vital capacity; Vt = tidal volume. B, Changes in lung volumes with TLC
disease. In obstructive ventilatory dysfunction (OVD), the VC can be
decreased due to an increase in the RV that exceeds any increase VC
in the TLC. In restrictive ventilatory dysfunction (RVD), by definition,
there is a decrease in the TLC and the VC decreases due to a VC IC
VC
decrease in the total capacity that exceeds any decrease in the RV.
Vt
FRC
VC
ERV
RV
RV
0
A B
3
Mild OVD
Volume
1
Inspiration Lung volume here is TLC
0
0 1 2 3 4 5 Time
Time (seconds)
FIGURE 1013 Left, Spirometry records exhaled volume versus time. Right, Typical patterns of obstructive ventilatory dysfunction (OVD) and
restrictive ventilatory dysfunction (RVD) are noted. OVD is characterized by a reduced forced expiratory volume in 1 secondtoforced vital capacity
(FEV1/FVC) ratio. Either OVD or RVD can result in a reduced vital capacitybut with different alternations in the total lung capacity (TLC) and residual
volume (RV) (see Fig. 1012).
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Chapter 10 Sleep and Respiratory Physiology 151
Lung volume testing by helium dilution or body plethys- pulmonary blood volume, and the Hb. CO diffuses across
mography is used to determine the FRC. The patient then the alveoli and binds to Hb. The diffusing capacity must be
performs a slow VC maneuver and the inspiratory capacity corrected for anemia if this is present. Destruction of the
(IC) and ERV are determined (see Fig. 1012A). Then the effective surface area for diffusion occurs with emphysema
TLC and RV are computed (TLC = FRC + IC and RV = FRC or parenchymal lung disorders causing RVD. Pulmonary
ERV). Note that the VC equals the difference between the vascular diseases that reduce the pulmonary blood volume
TLC and the RV. Changes in either the TLC, the RV, or both can reduce the diffusing capacity. Table 105 presents a
can decrease the VC. summary of pulmonary function findings and normal
By definition, RVD is associated with a reduced TLC. ranges. Of note, the pattern of near normal spirometry and
Ideally, a spirometric diagnosis of RVD should always be a decreased diffusing capacity can occur with emphysema,
confirmed by documenting a reduced TLC. In OVD, the interstitial lung disease, pulmonary vascular disease, or
TLC is normal or increased. The RV in OVD is usually anemia. Some patients with emphysema have minimal
increased (airtrapping) more than the TLC, and this can abnormalities in airflow but a reduced diffusing capacity.
result in a decrease in the VC. In RVD, the TLC is decreased Some patients with early manifestations of disorders of the
more than the RV, and this results in a decrease in the VC lung causing RVD can have a reduction in the diffusing
(see Fig. 1012B). capacity while the FVC and TLC are still normal.22 The situ-
The FRC is the resting end-expiratory volume and is the ation is especially common in lung disease due to medica-
volume at which the outward recoil of the chest wall is bal- tions (e.g., amiodarone, chemotherapy agents). In pulmonary
anced by the inward lung elastic recoil. The inspiratory activ-
ity (diaphragm, intercostals, sternocleidomastoid) is required
to reach TLC and expiratory muscle activity is required
(abdominal muscles) to reach RV. In OVD, the RV is the first TABLE 104
lung volume to be significantly affected (due to airtrapping). Clinical Use of the Diffusing Capacity
In advanced OVD, the RV is increased much more than the DIFFUSING
FRC and TLC. In severe OVD, the FRC and TLC can also DIFFUSING CAPACITY
be increased. CAPACITY NORMAL REDUCED
The DLCO is a noninvasive method to assess the ability
OVD Asthma Emphysema
of the lung to transfer gas (Table 104). As might be expected,
Chronic bronchitis COPD with
obstructive diseases that affect the alveoli (emphysema) are COPDpredominant emphysema
associated with a reduced DLCO. OVD due to asthma or chronic bronchitis
chronic bronchitis is usually associated with a relatively
normal DLCO. Disorders causing RVD that affect the lung RVD Extrinsic RVD Intrinsic RVD
parenchyma (alveolar filling or interstitial lung disease) are Normal or Anemia
associated with a reduced DLCO. Of note, early in these near- Emphysema
disorders, the DLCO may be reduced even though the FVC normal Interstitial lung
and TLC are still in the normal range. In extrinsic RVD spirometry disease
(respiratory muscle weakness or chest wall/pleural disor- Pulmonary
vascular disease
ders), the DLCO is relatively normal because the alveoli are
not directly affected by the disorder. The diffusing capacity COPD = chronic obstructive pulmonary disease; OVD = obstructive
ventilatory dysfunction; RVD = respiratory ventilatory dysfunction.
depends on the effective surface area for gas transfer, the
TABLE 105
Patterns of Pulmonary Function
NORMAL OVD INTRINSIC RVD EXTRINSIC RVD
FEV1 80120% of predicted Decreased Decreased Decreased
FVC 80120% of predicted Normal to decreased Decreased Decreased
FEV1/FVC >0.70 Decreased Normal Normal
TLC 80120% of predicted Normal to increased Decreased Decreased
DLCO 7580% of predicted Normalasthma, bronchitis Decreased Normal to mildly
(corrected for hemoglobin) Reducedsignificant emphysema decreased
Note: Mixed OVD + RVD = decreased FEV1/FVC ratio and reduced TLC.
DLCO = diffusing capacity for carbon monoxide; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; OVD = obstructive ventilatory dysfunction;
RVD = restrictive ventilatory dysfunction; TLC = total lung capacity.
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152 Chapter 10 Sleep and Respiratory Physiology
vascular disease (e.g., scleroderma), reduction in the diffus- Typically, muscle weakness affects both the inspiratory
ing capacity can occur in association with minimal changes muscles (diaphragm and intercostal muscles) and the expira-
in spirometry. A mixed pattern of OVD and RVD can occur tory muscles (abdominal muscles) at the same time. This
and is characterized by a reduced FEV1/FVC ratio in combi- results in a pattern of low TLC, high RV, and low VC. Note
nation with a reduced TLC (normal or increased in OVD). that at FRC, no muscle force is needed. One might predict
Severity criteria for OVD and RVD are somewhat arbi- that patients with muscle weakness would have a normal
trary,2226 but some commonly used criteria are listed in FRC. However, owing to chronic changes in the chest wall
Appendix 101. and lungs in patients with chronic neuromuscular disorders,
the FRC is usually decreased. Most individuals with a normal
chest wall and lungs can reach TLC with pleural pressures of
OBESITY
20 to 30 cm H2O. If the chest wall and lungs are normal,
Because a significant percentage of patients with OSA have significant muscle weakness must occur before the lung
obesity, it is useful to understand the typical pulmonary volumes and the VC change.
function findings in this condition (Fig. 1014). In obesity,
the FRC is either reduced or reduced in relation to the
RV. Therefore, in simple obesity, the most common pulmo-
nary function finding is a reduced ERV. Usually, the TLC CHANGES WITH SIMPLE OBESITY AND THE OBESITY
and RV are normal, as is the VC. In contrast, the obesity HYPOVENTILATION SYNDROME (OHS)
hypoventilation syndrome may be associated with reduc-
Obesity
tions in the TLC and VC (see Fig. 1014). The finding of a
Simple hypoventilation
reduced TLC in a patient with severe obesity and OSA obesity syndrome
could be a clue that the obesity hypoventilation syndrome TLC
might be present.
MUSCLE STRENGTH
Muscle Forces FRC
FIGURE 1015 Summary of the muscle forces needed at the different RESPIRATORY SYSTEM STATIC FORCES
lung volumes. At total lung capacity (TLC), inspiratory muscles are
needed to overcome inward lung elastic recoil and inward recoil of the
chest wall (CW). At residual volume (RV), expiratory muscles (along Lung
with lung recoil) are needed to balance the outward recoil of the chest Inspiratory
muscles
wall. At functional residual capacity (FRC), no muscle forces are needed. CW
TLC
At FRC
CW
Chest wall Lung
FRC recoil recoil
Lung
RV
CW
0
Lung
Expiratory
muscles
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Chapter 10 Sleep and Respiratory Physiology 153
8. Chronic metabolic alkalosis is associated with which of 9. What column (A, B, or C) lists the correct expected PO2
the following phenomenon? values for the SaO2 values?
A. Increased PaCO2, shift in hypercapnic ventilatory A B C
response line to the right. SaO2 = 60% PO2 40 30 30
B. Decreased PaCO2, shift in hypercapnic ventilatory SaO2 = 75% PO2 60 40 40
response curve to the left.
SaO2 = 90% PO 2 75 60 80
C. Increased PaCO2, shift in hypercapnic ventilatory
response line to the left.
D. Decreased PaCO2, shift in hypercapnic ventilatory
response line to the right.
10. The following pulmonary function test results are most consistent with:
A. RVD intrinsic.
B. RVD extrinsic.
C. OVD-predominant asthmatic bronchitis.
D. OVD-predominant emphysema.
13. Hudgel DW, Devadda P: Decrease in functional residual capac- 23. Miller WF, Scacci R, Gast LR (eds): Laboratory Evaluation
ity during sleep in normal humans. J Appl Physiol 1984;57; of Pulmonary Function. Philadelphia: JB Lippincott, 1987,
13191322. pp. 106109.
14. Muller NLP, Francis W, Gurwitz D, et al: Mechanism of hemo- 24. Crapo RO: Pulmonary function testing. N Engl J Med 1994;
globin desaturation during rapid eye movement sleep in normal 331:25.
subjects and in patients with cystic fibrosis. Am Rev Respir Dis 25. Pellegrino R, Viegi G, Brusasco V, et al: Interpretative strategies
1980;121:463469. for lung function tests. Eur Respir J 2005:26:948968.
15. Caruana-Montaldo B, Gleeson K, Zwillich CW: The control of 26. Rabe KF, Hurd S, Anzueto A, et al: Global Initiative for Chronic
breathing in clinical practice. Chest 2000;117:205225. Obstructive Lung Disease. Global strategy for the diagnosis,
16. Rebuck A, Slutsky AS: Measurement of ventilatory responses management, and prevention of chronic obstructive pulmo-
to hypercapnia and hypoxia. In Hornbein TF (ed): Regulation nary disease: GOLD executive summary. Am J Respir Crit Care
of Breathing. New York: Marcel Dekker, 1981, pp. 745772. Med 2007;176:532555.
17. Berger JA: Control of breathing. In Murray JF, Nadel JA (eds): 27. ATS/ERS statement of respiratory muscle testing. Am J Respir
Textbook of Respiratory Medicine, 3rd ed. Philadelphia: WB Crit Care Med 2002:166:518624.
Saunders, 2000, pp. 179196. 28. American College of Chest Physicians: Clinical indications for
18. Berthon-Jones M, Sullivan CE: Time course of change in noninvasive positive pressure ventilation in chronic respiratory
ventilatory response to CO2 with long-term CPAP therapy failure due to restrictive lung disease, COPD, and nocturnal
for obstructive sleep apnea. Am Rev Respir Dis 1987;135: hypoventilation. Chest 1999;116:521534.
144147. 29. De Troyer A, Borenstein S, Cordier R: Analysis of lung volume
19. Oren A, Whipp BJ, Wasserman K: Effects of chronic acid-base restriction in patients with respiratory muscle weakness.
changes on the rebreathing hypercapnic ventilatory response in Thorax 1980;35:867873.
man. Respiration 1991;58:181185. 30. Lechtzin N, Wiener CM, Shade DM, et al: Spirometry in the
20. Javaheri S, Shore NS, Burton R, et al: Compensatory hypoven- supine position improves the detection of diaphragmatic weak-
tilation in metabolic alkalosis. Chest 1982;81:296301. ness in patients with amyotrophic lateral sclerosis. Chest
21. Effros R, Widell JL: Acid-base balance. In Murray JF, Nadel JA 2001;121:436442.
(eds): Textbook of Respiratory Medicine, 3rd ed. Philadelphia:
WB Saunders, 2000, pp. 155178
22. American Thoracic Society: Lung function testing: selection of
reference values and interpretative strategies. Am Rev Respir
Dis 1991;144:12021218.
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Appendix 10-1
RVD
TLC or VC > 70% to <80% Mild
TLC or VC 6070% predicted Moderate
TLC or VC < 50% predicted Severe
DLCO
DLCO 6080% Mild
DLCO 40% to <60% Moderate
DLCO < 40% predicted Severe
Notes:
1. Severity criteria are arbitrary, the above are fairly simple to use.
2. Most severity scales for OVD use postbronchodilator FEV1.
3. The global initiative for lung disease (GOLD) criteria for COPD severity differ: < 0.70; mild, FEV1 > 80% of predicted; moderate, FEV1 5080% of
predicted; severe, FEV1 3050% of predicted; very severe, FEV1 < 30% of predicted or FEV1 < 50% of predicted and severe symptoms.
4. RVD severity criteria for intrinsic RVD usually are commonly based on the worst classification for the TLC and DLCO. A TLC moderate but DLCO
severe would be considered severe or FEV1 < 50% of predicted and severe symptoms.
COPD = chronic obstructive pulmonary disease; DLCO = diffusing capacity for carbon monoxide; FEV1 = forced expiratory volume in 1 second; OVD =
DaneshGroup.com
obstructive ventilatory dysfunction; RVD = restrictive ventilatory dysfunction; TLC = total lung capacity; VC = vital capacity.
157
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Chapter 11
segment) but can be slightly up-sloping. The ST segment can leads V1 (fourth intercostal space to the right of the sternum),
be changed by ischemia (ST depression), acute myocardial V2 (fourth intercostal space to the left of the sternum), V4
infarction (ST elevation), or pericarditis (ST elevation). (fifth intercostal space on the midclavicular line), V3 (mid-
The standard ECG uses 12 leads. In standard ECG record- point on a straight line between V2 and V4), V5 (lateral to V4
ing, electrodes are placed on the right and left arms (RA, LA) and on the anterior axillary line), and V6 (lateral to V5 on the
and left leg (LL). A ground is placed on the right leg (RL). midaxillary line) are depicted in Figure 116. Each precor-
Leads I, II, and III are then recorded as (I LA+/RA, II LL+/ dial lead is recorded against linked left arm, left leg, and right
RA, III LL+/LA) (Fig. 114). These leads plus an addi- arm electrodes, with the right leg as ground.
tional three frontal plane leads (aVF, aVR, aVL) are depicted
in Figure 115. In the standard ECG, transverse plane elec-
ECG RECORDING DURING POLYSOMNOGRAPHY
trodes are also recorded (precordial leads). The precordial
In most sleep centers, a single ECG lead is recorded during
sleep monitoring. Monitoring of a single ECG lead is most
useful for determining the cardiac rhythm and the heart rate.
QRS
Determination of the QRS axis requires multiple frontal
R
plane electrodes. In addition, accurate determination of ST
changes requires both frontal and precordial electrodes. The
QRS duration in a single lead may not reflect the widest value
P wave T wave U wave if part of the QRS is isoelectric in that particular lead. Mul-
tiple precordial leads are also needed for differentiation of
R
ST R R
interval
R
S S
R R
PR
interval QRS
interval
QS Q S
QT interval Q
FIGURE 111 Nomenclature of components of the QRS complex. From Wagner GS FIGURE 112 Nomenclature of the QRS complex. Adapted from Wagner GS (ed):
(ed): Marriotts Practical Electrocardiography, 9th ed. Philadelphia: Williams & Wilkins, Marriotts Practical Electrocardiography, 9th ed. Philadelphia: Williams & Wilkins, 1994,
1994, pp. 1113. pp. 1113.
FIGURE 113 Long QT. The vertical gray lines are 1-second apart and the black bar marks the QT interval which is 0.55 second. The
RR interval is approximately 1 second, so that the QTc = 0.55 (prolonged). The patient was taking risperidone, which can prolong the
QT interval. The patient also appears to have ST elevation and a wide QRS. A 12 lead ECG is needed to assess the significance of these
findings. The patient was asymptomatic.
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Chapter 11 Cardiac Monitoring during Polysomnography 161
I
III
II
A B
FIGURE 114 A, The three leads I, II, and III. B, The three leads are moved so that they V1 V6
intersect at the heart. Lead II is in a heart basetoapex direction.
V5
V4
ECG FRONTAL PLANE LEADS
V2 V3
90
120 60
FIGURE 116 Placement of the precordial leads V1 to V6. Adapted from Drew BJ, Califf
RM Funk M, et al: Practice standards for electrocardiographic monitoring in hospital
180 I 0 settings. Circulation 2004;110:27212746.
150 30
III II
120 60
aVF
90
I
Eithoven triangle
II
III
A B
FIGURE 117 A, Standard ECG lead II. B, Modified lead II recommended for sleep
FIGURE 115 Electrocardiogram (ECG) frontal plane leads. recording by the American Academy of Sleep Medicine (AASM) scoring manual. From
Iber C, Ancoli-Isreal S, Chesson A, Quan SF for the American Academy of Sleep Medicine:
The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and
Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine,
the causes of wide-complex tachycardia (WCT). Some sleep
2007, p. 39.
centers record three or more cardiac electrodes. The Ameri-
can Academy of Sleep Medicine (AASM) scoring manual2,3
recommends use of a modified lead II with the negative torso the main purpose is detecting the cardiac rhythm, a precise
electrode placed parallel with the right leg and below the location is not essential.
right shoulder and the positive electrode parallel to the left In the standard and modified lead II, the P wave, R wave,
leg (hip) on the lower left chest rib cage around the sixth to and T wave are upright (Fig. 118). Examples of abnormal
seventh intercostal spaces (Fig. 117). The exact intercostal P wave, ST elevation, and a peaked T wave are also shown
level was not specified in the AASM scoring manual. Because in this figure. A digital polysomnography (PSG) recording
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162 Chapter 11 Cardiac Monitoring during Polysomnography
Lead II
Abnormal P wave
ST elevation
Peaked T wave
1 sec
inspiration
ECG
Airflow
FIGURE 119 An example of sinus arrhythmia in a 5-year-old boy. The heart rate varies with the respiratory cycle. The heart rate increases with inspiration and
decreases with expiration. The average heart rate is approximately 100 bpm. The electrocardiogram (ECG) was recording during a period of low arterial oxygen
saturation.
viewed in a 10-second window corresponds to a traditional beats per minute. If the rhythm is irregular, a longer interval
ink pen recording at a paper speed of 30 mm/sec. The tradi- of 20 to 30 seconds should be used for a more accurate esti-
tional ECG paper speed used for recording was 25 mm/sec. mate of the average heart rate.
Therefore, a 10-second PSG window provides a view similar
to a standard ECG and is useful to observe the details of the SINUS RHYTHM AND NORMATIVE DATA
ECG tracing. Most PSG software also has tools allowing
FOR HEART RATE
measurement of durations and intervals of interest. The
AASM scoring manual recommends that the ECG signal be Normal sinus rhythm is associated with an upright P wave,
acquired with a sampling rate of 500/sec (a sampling rate of R wave, and T wave in lead II. Each P wave is followed by a
200/sec is acceptable). The recommended low- and high- QRS complex with a relatively constant PR interval. If there
frequency filter settings for display of the signal are 0.3 and is significant variability in heart rate with respiration, this is
70 Hz, respectively. often called a sinus arrhythmia (Fig. 119). In a sinus arrhyth-
A simple way to estimate heart rate is to count the number mia, the heart rate increases with inspiration and decreases
of QRS complexes in 10 seconds and then multiply by 6 for during expiration. Traditionally, sinus bradycardia is defined
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Chapter 11 Cardiac Monitoring during Polysomnography 163
as a heart rate less than 60 bpm and tachycardia greater than TABLE 111
100 bpm. However, the heart rate normally decreases during Cardiac Scoring Rules (AASM)
sleep. The lowest heart rate in normal adults is usually during
Score sinus tachycardia during sleep for a sustained heart
nonrapid eye movement (NREM) sleep when there is an rate > 90 bpm for adults.
increase in parasympathetic tone and a decrease in sympa-
thetic tone. A review of the evidence that formed the basis Score sinus bradycardia during sleep for a sustained heart
for the AASM cardiac scoring rules by Caples and cowork- rate < 40/min for ages 6 through adult.
ers2 reports unpublished data from the Sleep Heart Health Score asystole for cardiac pauses greater than 3 seconds
Study cohort of 2067 adult individuals. The individuals in for ages 6 years through adult.
the analysis had an apnea-hypopnea index (AHI) lower than Score wide-complex tachycardia for a rhythm lasting a
5/hr and were not taking cardiac or antihypertensive medi- minimum of 3 consecutive beats at a rate > 100/min with
cations. The 95% confidence interval based on mean 2 a QRS duration 120 msec (0.12 sec).
standard deviations (SD) for heart rate during sleep found a
Score narrow-complex tachycardia for a rhythm lasting a
minimum normative value of 43 bpm in men and 47.5 bpm
minimum of 3 consecutive beats at a rate > 100/min with
in women. The maximum normative values for heart rate a QRS duration < 120 msec (0.12 sec).
were 80.8 bpm for men and 84.7 bpm for women. Based on
this information, the new AASM cardiac scoring rules define Score atrial fibrillation if there is an irregularly irregular
sinus bradycardia during sleep as a sustained heart rate ventricular rhythm associated with replacement of
consistent P waves by rapid oscillations that vary in size,
less than 40 bpm for adults and children 6 years and older
shape, and timing.
(Table 111). Here, sustained means longer than 30 seconds
Note: The term sustained was defined in an FAQ from the AASM Scoring
in duration.4 It should be noted that normal individuals, Manual committee to be > 30 sec. Sustained wide-complex tachycardia and
especially endurance-conditioned athletes, often exhibit sustained narrow-complex tachycardia are present for > 30 sec.
heart rates less than 40 bpm during sleep. The AASM cardiac AASM = American Academy of Sleep Medicine; FAQ = frequently asked
question.
scoring rules also define sinus tachycardia during sleep in Adapted from Anonymous: Scoring Manual FAQs. Available at http://
adults as a sustained heart rate greater than 90 bpm (see www.aasmnet.org/Resources/PDF/FAQScoringManual.pdf
Table 111). From Iber C, Chesson A, Ancoli-Israel S, et al: The Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Defining normal heart rate limits is more complex in Westchester, IL: American Academy of Sleep Medicine, 2007.
children in whom the heart rate is faster than in adults. The
heart rate in normal children during wakefulness undergoes
a large decrease with age57 (Table 112). Scant information
TABLE 112
Normal Heart Rate during Wakefulness in Children
AGE MINIMUM MAXIMUM MEAN 2ND98TH PERCENTILE NO. OF SUBJECTS
<1 day 88 168 123 93154 189
12 days 57 170 123 91159 179
36 days 87 166 129 91166 181
13 wk 96 188 148 107182 119
12 mo 114 204 149 121179 112
35 mo 101 188 141 106186 109
611 mo 100 176 134 109169 138
12 yr 68 165 119 89151 191
34 yr 68 145 108 73137 210
57 yr 60 139 100 65133 226
811 yr 51 145 91 62130 233
1215 yr 51 133 85 60119 247
Adapted from Davignon A, Rautaharju P, Boiselle E, et al: Normal ECG standards for infants and children. Pediatr Cardiol 1979;1:133152.
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164 Chapter 11 Cardiac Monitoring during Polysomnography
is available for normative heart rates in children during sleep. left anterior and right posterior fascicles. The Purkinje fibers
As in adults, one would expect a lower heart rate in sleep then transmit the signal to myocardial cells. Purkinje cells
than during wakefulness. The Cleveland Childrens Sleep and have both pacemaking capability and the ability to rapidly
Health Study6 (CCHS) in a group of children aged 8 to 11 conduct electrical impulses. Impulses conducted via the
years (AHI < 5/hr) reported the mean 2 SD heart rate normal pathway produce a narrow QRS complex and coor-
during sleep was 73 10 bpm overall, 70 9 bpm in boys, dinated right and left ventricular contraction. Impulses orig-
and 75 9 bpm in girls. These values represented a 20% inating in the AV node or His bundle (together termed the
reduction from waking values. A 95% lower confidence limit AV junction) usually have a rate of 40 bpm and result in a
of 51 bpm in boys and 57 bpm in girls was found. The cor- normal QRS duration. Impulses beginning below the separa-
responding upper limits for boys and girls were 89 bpm and tion of the common bundle result in wide QRS complexes.
94 bpm, respectively. A recent study analyzed data from the Of note, if an impulse reaches the normal AV junction
CCHS study and the Tucson Childrens Assessment of Sleep during a relatively refractory period, it may be conducted
Apnea (TUCASA) study.7 The study concluded that sleeping with a wide QRS (aberrant conduction). If an impulse arrives
heart rates in children are lower than wake and decrease at the AV junction very early during a refractory period, it
significantly with age. African American ethnicity, female may not be conducted at all. This phenomenon does not
sex, and obesity were associated with faster heart rates. The represent heart block but is simply a reflection that the AV
AASM scoring manual did not provide rules for scoring the node does have a refractory period that depends on a number
heart rate in children because of the age dependence and of factors including the heart rate.
scant data. In summary, normally electrical impulses begin in the SA
node, traverse the AV node, and are transmitted out to the
ventricles by the Purkinje system via the left and right
CONDUCTION SYSTEM
bundles. When the P wave is not present or is not conducted,
A brief review of the cardiac conduction system (Fig. 1110) slower pacemakers in the heart may function to continue
is useful for understanding the terminology of premature regular ventricular rhythm. Rhythms from pacemakers in
beats and block. The electrical impulse during normal sinus junctional areas (AV node and His bundle) usually have a
rhythm starts with an impulse from the sinoatrial (SA) node narrow QRS complex with a rate approximately 40 to 60 bpm
located high in the right atrium near the entry of the superior (junctional or nodal rhythm). If the rhythm originates from
vena cava. The SA node is the major cardiac pacemaker a pacemaker in the ventricles, the QRS is wide and the rate
because the cells there have the highest intrinsic rate. The is slow (idioventricular rhythm). If the sinus node activity
impulse is conducted through atrial muscle without special slows sufficiently, one of the other pacemakers may cause
fibers until it reaches the atrioventricular (AV) node located ventricular capture (so-called escape rhythms). The junc-
at the bottom of the right atrium near the interatrial septum. tional and idioventricular rates can increase above the typical
The next part of the specialized conducting system is the values in some circumstances. The terms accelerated junc-
bundle of His (common bundle). The bundle splits into a tional rhythm and accelerated idioventricular rhythm (AVIR)
right bundle and a left bundle. The left bundle then splits into are used to describe these rhythms.
Bundle branch block (BBB) is due to dysfunction of either
the right or the left bundles (RBBB or LBBB) and results in
a wide QRS. The type of BBB is best identified using a 12-lead
Sinoatrial (SA) node ECG. RBBB and LBBB produce characteristic patterns in
leads I, V1, and V6. The pattern in lead II is variable. The
other cause of a widened QRS commonly encountered in
Atria sleep centers is a ventricular pacemaker with the lead in the
right ventricle. This gives a pattern of an LBBB because the
right ventricle depolarized slightly before the left.
Atrioventricular (AV) node
BRADYCARDIA AND AV BLOCK DURING SLEEP
His bundle (common bundle)
The common causes of a slow heart rate during sleep are
Left bundle
listed in Table 113. A slow heart rate during sleep (sustained
Left anterior
heart rate < 40 bpm) can be a normal variant, associated with
fascicle the effects of medications, high parasympathetic tone, or
associated with disease of the conduction system (SA node,
AV node). Cyclic increases and decreases in heart rate are
Left posterior commonly associated with untreated obstructive sleep apnea
fascicle (OSA). This phenomenon is often called tachycardia-
Right bundle
bradycardia cycles. However, in many patients, the lower
heart rate is typically greater than 40 bpm and the high heart
FIGURE 1110 The normal cardiac conduction system.
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Chapter 11 Cardiac Monitoring during Polysomnography 165
TABLE 113 rate may not exceed 90 bpm. The heart rate typically acceler-
Causes of a Slow Heart Rate ates at apnea termination owing to withdrawal of vagal tone
and an increase in sympathetic activity. The slowing of the
Sinus bradycardia
heart rate at event onset is thought to be due to vagal tone.
Sinus pauses (>3 sec) Typically, the heart rate slows, then speeds up toward the end
Sinus node disorder (sick sinus syndrome) of the obstructive events with a sudden increase in heart rate
at apnea termination. Some PSG computer programs provide
AV block
a moving time average heart rate based on the ECG. Others
Medications simply record a heart rate output of the oximeter, which is a
Increased parasympathetic (vagal) tone moving time average (Fig. 1111).
AV = atrioventricular.
Sinus Pause/Asystole
The AASM scoring manual recommends scoring asystole if
a sinus pause is greater than 3 seconds in duration for ages
6 years through adult4 (Fig. 1112; see also Table 111). The
ECG
Heart Rate
85 85 83 81 80 80 80 80 80 80 79 76 72 71 71 71 69 67 66 66 71 81 88 94 96 95 93 91 88
Snore
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
SpO2 91 91 91 91 91 91 91 91 90 90 90 90 90 90 89 89 88 86 85 84 83 81 79 78 77 78 79 81 87
1 sec
FIGURE 1111 The heart rate during an obstructive apnea. The heart rate signal is the output of the oximeter (a moving time average) that tends to lag behind
the actual change in heart rate. Changes in the heart rate can be noted by changes in the RR interval, which widen at apnea onset then narrow at apnea termination.
ECG = electrocardiogram; SpO2 = pulse oximetry.
100 V
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E1-M2
Chin EMG
ECG
3.6 sec
FIGURE 1112 Three sinus pauses in a 30-second tracing. The second pause is longer than 3 seconds and should be reported as asystole according to the AASM Cardiac
Scoring Rules. ECG = electrocardiogram; EMG = electromyogram.
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166 Chapter 11 Cardiac Monitoring during Polysomnography
review paper providing evidence for scoring rules quotes PR interval is usually 0.12 to 0.20 second. A prolonged
normative data in young healthy subjects2 that found sinus PR interval was found in between 0.5% and 2% of healthy
pauses to be longer in males (range 1.202.06 sec) than in middle-aged males.
females (1.081.92 sec). In trained athletes, up to 37% had 2. Second-degree AV block is defined when one or more
sinus pauses between 2 and 3 seconds. A study of a cohort (but not all) of atrial impulses fail to reach the ventricle
of 40- to 79-year-old individuals found the longest pause because of abnormal conduction.
during sleep to be 2 seconds.8 For this reason, sinus pauses a. Mobitz type I (Wenckebach): A pattern of AV block in
of 3 seconds or longer are scored as asystole. which there are varying PR intervals. Usually, there is
Of note, a common cause of apparent sinus pause is a progressive prolongation of the PR interval until a P
nonconducted premature atrial impulse. This is discussed in wave is not conducted (Fig. 1114). This is typical of
the section on Premature Beats (PBs). a block in the AV node, which is capable of variations
in conduction time. This type of second-degree AV
block is generally thought to be benign.
AV Block
b. Mobitz type II: A pattern of AV block in which the PR
AV block is classified into three types1 based on ECG char- intervals are nearly constant (Fig. 1115). It is often
acteristics that correlate with the location of the abnormality seen in the setting of BBB.
in the conducting system or the influences of changes in 3. Third-degree AV block (complete AV block): None of
autonomic tone. the atrial impulses are conducted to the ventricles
(Fig. 1116). One can often see both P waves and QRS
1. First-degree AV block is defined as a prolongation of PR complexes, but they have no fixed relationship (AV
interval longer than 0.20 second (Fig. 1113). The normal dissociation).
10 second
window
0.4 sec
30 second
window
FIGURE 1113 First-degree atrioventricular (AV) block. Top, A 10-second window shows a prolonged PR interval. Bottom, A 30-second window.
One can see the difficulty in noting the abnormality unless viewed in a 10-second window.
30 second
window
1 sec
10 second
window
A B C
1 sec
FIGURE 1114 Second-degree AV block type I (Wenckebach) viewed in 30-second and 10-second windows. Arrow shows nonconducted P wave. A, Note
that the PR interval at B is longer than at A. At C, P wave without a QRS.
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Chapter 11 Cardiac Monitoring during Polysomnography 167
30 second
window
1 sec
10 second
window
0.3 sec
1 sec
FIGURE 1115 Second-degree AV block, Mobitz II. The PR interval is constant but some P waves (up arrows) are not conducted (no associated QRS).
1 sec
FIGURE 1116 Third-degree AV block. The down arrows show P waves with a PP interval that is fairly constant. The P waves have
no fixed relationship to the QRS (AV dissociation). Because the QRS is narrow, this means the pacemaker is in the AV junctionso-
called junctional rhythm. Here, the junction rate is slow at approximately 33 bpm.
Aberrant Conduction
When cardiac tissue responds to a stimulus, the reaction is FIGURE 1117 A schematic example of atrial fibrillation with irregular RR intervals
followed by a refractory period (dormant interval) during and normal QRS duration. The fifth beat has a wide QRS duration due to aberrant
conduction. The immediate cycle is short and the preceding cycle is long. These factors
which it cannot respond to a similar stimulus. The refractory
predispose to aberrant conduction.
period of cardiac conducting paths is proportional to the
length of the preceding cycle (RR interval). Thus, a long
preceding cycle in combination with a short immediate cycle reach the left and right fascicles at the same time. In the third
predisposes to the cardiac conduction system being in a case, a critical rate occurs above which part of the ventricular
refractory state. A wide QRS can occur even if the beat origi- conducting system is refractory. A preceding long RR inter-
nates in a supraventricular location (SA node or AV junc- val and a short current RR interval increases the chance of
tion). This occurs for three reasons1: (1) a refractory right or aberrant conduction. Figure 1117 shows an example of a
left bundle fascicle, (2) anomalous supraventricular activa- beat with aberrant conduction when the preceding cycle is
tion, or (3) a paradoxical critical rate.1 In the first case, the long and the current cycle is short.
impulse transverses the bundle of His but finds either the
right or the left bundle refractory. In the second case,
Premature Beats
the impulse bypasses the AV node, arises in the AV node in
an eccentric location, or is abnormally conducted due to PBs are QRS complexes not originating in the SA node that
diseased junctional fibers such that the impulse does not occur earlier than the next expected sinus beat. These can
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168 Chapter 11 Cardiac Monitoring during Polysomnography
occur as a single PB, a pair of PBs (couplet of PBs), three PBs Ventricular premature beats (VPBs) invariably are associ-
(by convention, nonsinus tachycardia > 100 bpm). The PBs ated with a wide QRS (usually > 0.16 sec) and are not pre-
can also follow every normal beat (bigeminy), every second ceded by an abnormal P wave. There is usually a compensatory
sinus beat (trigeminy), or every third sinus beat (quadri- pause following the VPB with the next P wave occurring
geminy) (Table 114). about two PP intervals after the last normal P wave (Fig.
The characteristics of PBs are listed in Table 115. Supra- 1120). VPBs originate in a ventricular focus and can be
ventricular premature beats (SVPBs) are either atrial prema- conducted retrograde via the AV node to the atria. The ret-
ture beats (APBs), or junctional premature beats (JPBs). rograde P wave can be seen deforming the VPBs or following
Although exceptions occur, SVPBs usually have a narrow the beat. When all VPBs have the same morphology, they are
QRS complex and the QRS morphology resembles that of said to be unifocal (unimorphic or monomorphic). If VPBs
the normal sinus beats. In the case of APBs, there is usually originate from multiple ventricular areas, they are usually of
a visible abnormal P wave (sometimes called P) (Fig. 1118). different morphology (polymorphic VPBs).
The abnormal P wave may be negative in lead II or have a
different morphology than the sinus P waves. The APBs are
TACHYCARDIAS DURING SLEEP
also known as PACs (premature atrial complexes). The P
wave can be hidden in the preceding T wave. SVPBs usually The scoring criteria for narrow-complex tachycardia (NCT)
reset the SA node and the next sinus beat occurs less than and WCT are listed in Table 111. In both cases, there must
two PP intervals after the last normal P wave (Fig. 1119). If be 3 or more beats with rate greater than 100 bpm. Note
the SVPB is aberrantly conducted, the QRS can be wide. that this differs from sinus tachycardia during sleep, which
must have a sustained (>30 sec) rate of greater than
90 bpm. The common causes of tachycardias seen during
TABLE 114 sleep studies are shown in Table 116. Tachycardias are
Premature Beat Terminology divided into NCT and WCT. With a single ECG lead, it is
not possible to determine whether a WCT originates from a
1 beat A PB ventricular focus rather than a supraventricular focus with
2 beats A pair or couplet aberrant conduction. Therefore, the AASM scoring manual
3 beats Nonsustained rhythm
recommends scoring a WCT rather than a ventricular tachy-
(nonsustained tachycardia if cardia (VT). However, most WCTs are VT.
rate > 100 bpm)
>30 sec Sustained rhythm Narrow-Complex Tachycardia
PB follows every normal Bigeminy NCT is characterized by a QRS duration shorter than 0.12
sinus beat second, with 3 or more beats and a heart rate greater than
PB follows every second Trigeminy 100 bpm (Fig. 1121). The major types of narrow complex
normal beat tachycardias are listed in Table 116. The term paroxysmal
supraventricular tachycardia (PSVT) is used to describe a
PB follows every third Quadrigeminy
normal beat
diverse group of rhythms characterized by regular rhythm
and narrow QRS, when the morphology does not otherwise
PB = premature beat.
allow identification of atrial fibrillation (Afib) or atrial flutter.
TABLE 115
Characteristics of Premature Beats
SVPBS VPBS ALSO KNOWN AS PVCS
QRS complex Normal duration (usually), resembles sinus beats Wide QRS
Wide QRS can occur (aberrant conduction)
Source of rhythm Atria: APB Ventricles
Junctional (AV node + His)
Compensatory pause No (usually): SA node discharged (reset) Compensatory pause: sinus node not reset
P wave Atrial: P wave premature and abnormal Usually none
Junctional: none Retrograde P wave can occur
Exceptions APB: P wave can be obscured in preceding T wave May appear < 0.12 sec in a given lead if
part of wave is isoelectric in that lead
APB = atrial premature beat; AV = atrioventricular; PVCs = premature ventricular complexes; SA = sinoatrial; SVPB = supraventricular premature beat; VPBs =
ventricular premature beats.
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Chapter 11 Cardiac Monitoring during Polysomnography 169
30 second
window
10 second
window
10 second
window
FIGURE 1118 Atrial premature beats (APBs) are shown with dark lines that are over the abnormal P wave. Note that the QRS intervals are normal in
duration and have the same morphology as the QRS in the sinus beats.
2 PP interval
Sinus rhythm
2 PP interval Compensatory
pause
PVB with
compensatory
pause
No
2 PP interval Compensatory
pause
APB without
compensatory
pause
PP interval
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170 Chapter 11 Cardiac Monitoring during Polysomnography
30 second
window
Couplet
30 second
window
Quadrigeminy
2 pp intervals
10 second
window
FIGURE 1120 Tracings of PVBs illustrate a couplet, quadrigeminy, and the compensatory pause.
TABLE 116
Common Tachycardias during Sleep
The etiology of PSVT could be a rapidly firing ectopic focus
SINUS TACHYCARDIA DURING SLEEP in the atria or nodal area or via re-entrant mechanisms in
Rate > 90 sec for 30 sec. the AV nodal areas. AV re-entrant tachycardia is due to an
NARROW-COMPLEX TACHYCARDIA
accessory path outside the AV node (Wolff-Parkinson-
White), and AV nodal re-entrant tachycardia is due to a
3 consecutive beats, rate > 100 bpm, QRS duration
conduction loop through the nodal area. The reader is
< 0.12 sec
referred to reference 1 for further reading on this topic.
PSVT: usually regular, rate 120240 bpm PSVT has regular RR intervals, and Afib has irregular RR
Ectopic atrial tachycardia intervals. Atrial flutter can have regular or irregular RR inter-
Ectopic nodal tachycardia vals. Both Afib and atrial flutter, which are discussed later,
AV nodal re-entrant tachycardia, AV re-entrant can result in a ventricular rate greater than 100 bpm and
tachycardia
narrow QRS complexes. When a burst of NCT is short, it is
Afib: irregular atrial activity, ventricular activity irregular, often not possible to differentiate between PSVT and Afib.
rate variable
Aflutter: flutter waves 280300 bpm, ventricular response Afib and Atrial Flutter
is variable (2/1 block ventricular rate 150, 4/1 block
ventricular rate 70) Afib and atrial flutter can present as either NCT or WCT in
the sleep center. However, patients may also exhibit a ven-
MAT: irregular RR intervals, with three or more P wave
morphologies (atrial rate 100250 bpm) tricular rate less than 100 bpm due to the effects of medica-
tions on the AV node or intrinsic AV node disease. In the
WIDE-COMPLEX TACHYCARDIA case of Afib with an average ventricular response less than
3 beats, rate > 100 bpm, QRS duration > 0.12 sec 100 bpm, the rhythm is called Afib with a controlled ventricu-
Ventricular tachycardia: usually regular lar rate. If the average heart rate exceeds 100 bpm, the
rhythm is termed Afib with a rapid ventricular response (Afib
PSVT usually regular with RVR). The hallmark of Afib is that it is an irregular
SVT with aberrant conduction: usually regular rhythm (Fig. 1122). This occurs due to irregular conduction
Afib with aberrant conduction: regular, irregular via the AV node. In atrial flutter, the saw-toothshaped
flutter waves (called F waves) usually have a frequency of 250
Aflutter with aberrant conduction: often irregular to 300 bpm and are often discernible (Fig. 1123). The ven-
Afib = atrial fibrillation; Aflutter = atrial flutter; AV = atrioventricular; MAT = tricular rate can be regular (fixed AV block) or irregular
multifocal atrial tachycardia; PSVT = paroxysmal supraventricular tachycardia.
(variable AV conduction). An NCT of 150 bpm should
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Chapter 11 Cardiac Monitoring during Polysomnography 171
100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
4 sec
FIGURE 1121 Narrow-complex tachycardia in a 30-second window. ECG = electrocardiogram; EMG = electromyogram.
30 second
window
10 second
window
FIGURE 1122 Atrial fibrillation. Absence of P waves and irregularly irregular RR intervals. The average rate is approximately 64 bpm. This is an example
of atrial fibrillation with a controlled ventricular response. Therefore, although abnormal, this would not qualify for narrow-complex tachycardia.
1 sec
30 second
window
0.85 sec
0.20 sec
10 second
window
FIGURE 1123 Atrial flutter. The saw-toothlike flutter waves are noted. They have a frequency of approximately 60/0.20 sec = 300/min. Note that owing
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to variable block, the ventricular response is variable. For the RR interval of 0.85 sec, the rate is 70 bpm (4/1 block).
172 Chapter 11 Cardiac Monitoring during Polysomnography
1 sec
FIGURE 1124 Nonsustained wide-complex tachycardia (WCT). The WCT is most likely ventricular tachycardia based on probability.
From a single ECG lead, differentiating supraventricular tachycardia with aberrant conduction (SVTAC) from ventricular tachycardia
(VT) is not possible.
always trigger the suspicion of atrial flutter with 2/1 block. For nonsustained ventricular tachycardia (NSVT), the
In this circumstance, the flutter waves may be hidden by the clinical setting and condition of the patient dictate the
preceding T wave. A sinus tachycardia with a heart rate of actions. A symptomatic patient would require EMS activa-
150 bpm in the absence of an extreme situation such as tion (outpatient setting) or transfer to the emergency depart-
hypotension or exercise is unlikely. The ventricular response ment or evaluation of the patient by an in-house on-call
to atrial flutter may also be approximately 70 bpm (4/1 physician. An asymptomatic patient would usually require
block). Sometimes, the AV block can be variable resulting in notification of the primary physician or physician on call for
an atrial flutter with irregular RR intervals (see Fig. 1123). the sleep center. In order to be accredited by the AASM, a
Multifocal atrial tachycardia (MAT), also known as multi- sleep center must have clearly specified written procedures
focal atrial rhythm if the rate is less than 100 bpm, is char- for handling cardiac emergencies. In some sleep centers, it is
acterized by at least three different P wave morphologies and a policy to wake the patient up if recurrent NSVT is noted
has an irregular PP and RR interval. MAT is often seen in to check for symptoms.9
association with an exacerbation of chronic obstructive pul- Patients with NSVT require a cardiac evaluation if this
monary disease (therefore, it is uncommon in the sleep has not been recently performed. NSVT in patients with
center). Atrial fibrillation and MAT are the two rhythms structural heart disease has a poor prognosis without inter-
characteristically associated with irregular RR intervals. vention. A typical evaluation includes echocardiography
(evaluation for cardiomyopathy and valvular heart disease),
Holter monitoring, and stress testing to rule out coronary
Wide-Complex Tachycardia
artery disease.9
WCT is characterized by a QRS of 0.12 sec or greater (Fig.
1124; see also Table 116). The two causes are VT (or
ADVERSE EVENTS DURING PSG
Vtach) originating in the ventricles or supraventricular
tachycardia with aberrant conduction (SVTAC) originating An investigation by Mehra and Strohl10 collected informa-
from the atria or junctional areas. Even with multiple ECG tion from 16,084 sleep studies and found that the incidence
leads, differentiating VT from SVTAC is difficult. The lead of serious adverse events during nocturnal PSG was very low
V1 has been used in emergency settings and intensive care at 0.35% and the incidence of death within 2 weeks of an
units to help distinguish VT from SVTAC. However, this is adverse event was 0.006%. A total of 56 events were noted.
beyond the scope of the sleep disorders center. At least three These included 1 death due to VT in a patient with coronary
wide complexes are the minimum to score WCT. Sustained artery disease, 28 events noted during the study (due to
WCT is usually defined as longer than 30 seconds and non- arrhythmias), and another 28 events noted after the study by
sustained WCT as less than 30 seconds. VT accounts for up the scoring technologist (complex ventricular arrhythmias).
to 80% of cases of WCT in unselected populations. It accounts In the latter cases, the referring physician was notified of the
for 95% of cases in patients with previous myocardial infarc- problem. Of the 28 nonfatal events noted during the sleep
tion. Sustained WCT in the sleep center should be consid- study, only 1 patient reported chest pain and shortness of
ered VT until proved otherwise. breath.
If sustained WCT occurs in the sleep center in an out-of-
hospital setting, the emergency medical services (EMS)
PACEMAKERS AND WIDE-COMPLEX QRS
should be called (911) and emergency equipment including
an automated external defibrillator (AED) should be brought A detailed discussion of ECG patterns from BBBs and pace-
to the bedside. If the patient is asleep, she or he should be makers is beyond the scope of this chapter. However, an
gently awakened and assessed for chest pain or shortness of example is presented here to emphasize a few points. The
breath. If the sleep center is within the hospital, an emer- sudden appearance of wide complexes on the ECG can cause
gency code is usually called for rapid response. panic in the sleep center. Sometimes, the fact that the rate is
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Chapter 11 Cardiac Monitoring during Polysomnography 173
FIGURE 1125 Atrial fibrillation with ventricular pacer activity. A 10-second window is shown. Although only the pacer spikes of
the last 3 wide beats are visualized, all the wide beats have the same morphology and are all paced beats. Note that the 3-beat run
of paced beats follows a long pause in ventricular activity (pacemaker activated when rate dipped below a cutoff). The dark upright
bars mark the pacer spikes. These were not well visualized until the 60-Hz filter was turned off and 100 Hz was used for the high filter.
FIGURE 1126 A dual-chamber pacemaker. On the left, the atrial pacer spikes are noted with a narrow QRS showing normal
conduction of the atrial impulse to the ventricles. The longer vertical black line marks an atrial pacer spike. On the right, both atrial
and ventricular pacer spikes are noted and the QRS is wide. The atrial impulse is not conducted normally and the ventricular pacer is
activated, leading to a wide QRS. The small vertical black lines mark pacer spikes.
less than 100 (often 60 or 70) is missed in the excitement. initial upward deflection followed by a wider downward
However, in the prestudy evaluation, it is always helpful deflection. However, accurate diagnosis of a BBB requires a
if the sleep technologist asks the patient whether he or she 12-lead ECG. One can simply comment in the sleep study
has a pacemaker. As mentioned previously, a ventricular report that a wide QRS appeared to be present.
pacemaker with the pacing lead in the right ventricle will
produce wide-paced beats with an LBBB morphology. Pacer
spikes are often difficult to see. Using a high-frequency filter REFERENCES
of 100 Hz rather than the AASM-recommended high- 1. Wagner GS (ed): Marriotts Practical Electrocardiography, 9th
frequency filter setting of 70 Hz AND turning off the 60-Hz ed. Philadelphia: Williams & Wilkins, 1994.
filter may help in visualizing pacer spikes. 2. Caples SM, Rosen CLK, Shen WK, et al: The scoring of cardiac
events during sleep. J Clin Sleep Med 2007;3:147154.
Figure 1125 shows a single-chamber ventricular pace- 3. Iber C, Ancoli-Isreal S, Chesson A, Quan SF for the American
maker in a patient in Afib with AV nodal dysfunction. When Academy of Sleep Medicine: The AASM Manual for the Scoring
the ventricular rate falls below a cutoff value, the ventricular of Sleep and Associated Events: Rules, Terminology and Tech-
pacer fires producing a wide-complex QRS. Figure 1126 nical Specification, 1st ed. Westchester, IL: American Academy
shows a tracing with a patient with a dual-chamber pacer of Sleep Medicine, 2007.
4. Anonymous: Scoring Manual FAQs. Available at http://
(one atrial and one ventricular lead). On the left portion of www.aasmnet.org/Resources/PDF/FAQScoringManual.pdf
the tracing, only the atrial pacer lead is activated. On the 5. Davignon A, Rautaharju P, Boiselle E, et al: Normal ECG
right, both atrial and ventricular leads are pacing. This pro- standards for infants and children. Pediatr Cardiol 1979;1:
duces a wide QRS. 133152.
If all beats have a wide QRS and the patient does not have 6. Rosen CL, Quan SF, Xue W, et al: Pediatric heart rate data during
sleep from ethnically diverse cohorts. Sleep 2006;29:8889.
a pacemaker, the patient likely has a BBB. From lead II alone, 7. Archbold KH, Johnson NL, Goodwin JL, et al: Normative heart
one cannot accurately tell whether an LBBB or an RBBB is rate parameters during sleep for children aged 6 to 11 years.
present. In precordial lead V1 (see Fig. 116), an RBBB J Clin Sleep Med 2010;6:4750.
usually is manifested by a QRS with an M or rSR pattern 8. Bjerregaard P: Mean 24 hour heart rate and pauses in healthy
(small initial upward deflection, downward deflection, larger subjects 4079 years of age. Eur Heart J 1983;4:4451.
9. Gamaldo C, Sala RE, Collop NA: Complex arrhythmia during
upward deflection). LBBB in V1 is usually manifested by a a sleep studywhat to do? J Clin Sleep Med 2009;5:171173.
QS or rS pattern. The QS pattern is a single wide down- 10. Mehra R, Strohl KP: Incidence of serious adverse events during
ward deflection (see Fig. 112). The rS pattern has a small
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nocturnal polysomnography. Sleep 2004;27:13791383.
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Chapter 12
TABLE 121
Sleep-Related Movement Disorders (ICSD-2)
Restless legs syndrome
Periodic limb movement disorder Stress
loop Extensor
Sleep-related leg cramps RAT1 digitorum
LAT1
Sleep-related bruxism RAT2 LAT2
The current criteria for determining a significant LM to define a PLM series is 4 consecutive LMs. The time from
event are listed in Table 122. In the new criteria, a signifi- onset of one LM to the onset of the next LM is 5 to 90
cant LM has a duration from 0.5 to 10 seconds with a seconds. LMs on different legs separated by less than 5
minimum amplitude 8 V above the resting leg EMG. The seconds between LM onsets are counted as a single LM.
time of onset is the time at which the amplitude increased to Figure 123 presents a 90-second segment of left and right
8 V above baseline resting activity, and the end of the LM anterior tibial EMG tracings.
(offset) is defined as the START of a period lasting at least
0.5 second during which the EMG does not exceed 2 V LMs ASSOCIATED WITH RESPIRATORY
above resting EMG (Fig. 122). Use of voltage criteria based
EVENTS ARE NOT SCORED
on an absolute increase in microvolts above the resting base-
line requires a stable resting EMG for the relaxed anterior An LM should not be scored if it occurs during a period
tibialis muscle. The absolute signal should be no greater than from 0.5 second before an apnea or hypopnea to 0.5 second
10 V between negative and positive deflections (5 V). after an apnea or hypopnea (LMs associated with respira-
The AASM scoring manual also provides rules for defin- tory events are not scored).3 The scoring rules did not provide
ing a PLM series (Table 123), that is, criteria for identifying information about scoring LMs associated with respiratory
a LM as a PLM. The minimum number of consecutive LMs
TABLE 123
TABLE 122 Rules Defining a Periodic Leg Movement Series*
Rules Defining a Significant Leg Movement Event 1. The minimum number of consecutive LM events to
1. Minimum duration of an LM event is 0.5 sec. define a PLM series is 4 LMs.
2. Maximum duration of an LM event is 10 sec. 2. The minimum period length between LMs (defined as
the time between onsets of consecutive LMs) to include
3. The minimum amplitude of an LM event is an 8-V them as part of a PLM series is 5 sec.
increase in EMG voltage above resting EMG.
3. The maximum period length between LMs (defined as
4. The timing of the onset of an LM event is defined as the the time between onsets of consecutive LMs) to include
point at which there is an 8-V increase in EMG above them as part of a PLM series is 90 sec.
resting EMG.
4. LMs on two different legs separated by < 5 sec between
5. The timing of the ending of an LM event is defined as movement onsets are counted as a single LM.
the START of a period lasting at least 0.5 sec during
*Criteria for LMs to be considered PLMs.
which the EMG does not exceed 2 V above resting EMG. Note: It is understood that PLMS means that the LMs occur during sleep.
EMG = electromyogram; LM = leg movement. LM = leg movement; PLM = periodic leg movement.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL: Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142. American Academy of Sleep Medicine, 2007, pp. 4142.
Inter-LM interval
LM duration
Offset threshold
2 V above
resting baseline
0 V
Resting baseline
(should be 5 V)
FIGURE 122 Criteria for onset and offset of leg movements (LMs). The time of onset is the time at which the amplitude increased to
8 V above the baseline resting activity. The end of the LM (offset) is defined as the START of a period lasting at least 0.5 second during
which the EMG does not exceed 2 V above the resting EMG. Adapted from Zucconi M, Ferri R, Allen R, et al: The official World Association
of Sleep Medicine (WASM) Standards for Recording and Scoring Periodic Leg Movements in Sleep (PLMS) and Wakefulness (PLMW) developed
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in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med 2006;7:175183.
178 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep
1 sec
7.8 sec
LAT 10 V
RAT 50 V
A B C D
FIGURE 123 A 90-second tracing of the left anterior tibilais (LAT) and right anterior tibialis (RAT) EMGs. The broken lines in the LAT
tracing are +10 V amplitude lines. The dark bars are durations in seconds. According to the scoring rules, a total of 5 periodic limb
movements (PLMs) are shown. In group A, there is 1 PLM. In group B, there is 1 PLM. In group C, there is 1 PLM because limb
movements (LMs) whose onset is separated by less than 5 seconds are considered as 1 LM. In group D, there are 2 PLMs.
Nasal pressure
NO therm
Chest
Abdomen
SpO2
LAT
RAT
90 seconds
FIGURE 124 The LMs are not counted as part of a PLM series because they occur in association with respiratory events. LAT = left anterior tibialis; NO = nasal-oral
thermal flow; RAT = right anterior tibialis; SpO2 = pulse oximetry.
effortrelated arousals (RERAs). However, some clinicians sleep index (PLMSI), which is the number of PLMs per hour
would extend the previous rule to RERAs. It is not uncom- of sleep. The number of PLMs associated with arousal and
mon for LMs to be noted at apnea termination even if an the periodic limb movement in sleep arousal index (PLMSAI)
associated cortical arousal is not present. In Figure 124, the should also be reported.
leg EMG bursts associated with respiratory events are not
PLMSI = 60 number of PLMs/TST (min )
scored as LMs or PLMs.
PLMSAI = 60 number of PLMs with arousal/TST (min )
ASSOCIATION OF AROUSALS WITH PLM
PERIODIC LIMB MOVEMENTS IN WAKE
According to the AASM scoring manual, an arousal and
PLM should be considered associated with each other (Fig. The AASM scoring manual did not recommend criteria for
125) when there is less than 0.5 second between the END scoring periodic limb movements during wake (PLMW). The
of one event and the ONSET of the other event, regardless WASM in collaboration with the IRLSSG6 published recom-
of which is first. This recommendation differs from previous mendations for PLMW. The criteria for PLMW events is the
criteria, which required the arousal to follow the onset of the same as for PLMS events except that the patient is awake (Fig.
PLM by not more than 3 seconds. 126). The PLMW index is defined as the number of PLMW
events divided by wake time (hr) from lights out to lights on
while the patient is in bed. That is, time when the patient is
PERIODIC LIMB MOVEMENTS IN SLEEP
out of bed or sitting on the side of the bed is not included. Of
Of note, the term PLMS implies that PLMs occur during note, frequent PLMW events are highly suggestive of the RLS.
sleep. The AASM scoring manual3 recommends reporting If PLMW events are noted, the patient history should be
the number of PLMS and the periodic limb movement in reviewed to determine if RLS symptoms are reported.
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Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep 179
100 V
F4-M1
1 sec C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
CFLOW
Chest
Abdomen
LAT
RAT
SpO2
94 94 93 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 94 94 94 94 94 94 94 94
FIGURE 125 A LM (part of a PLM series) is associated with an arousal. Note that the LM on the LAT tracing and the LM on the RAT tracing are counted as a single
LM. CFLOW = positive airway pressure device flow signal; ECG = electrocardiogram; LAT = left anterior tibialis; RAT = right anterior tibialis; SpO2 = pulse oximetry.
50 V
1 sec F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
Flow
Chest
Abdomen
RAT
LAT
SpO2
96 96 96 96 96 96 95
FIGURE 126 PLMs in wake. A 60-second tracing with the patient in stage W during the start of a continuous positive airway pressure (CPAP) titration. Flow = machine
flow (CFLOW). PLMs in wake are noted. The patient reported severe symptoms of the restless legs syndrome. ECG = electrocardiogram; EMG = electromyogram; LAT =
left anterior tibialis; RAT = right anterior tibialis; SpO2 = pulse oximetry.
PLMSI less than 5/hr normal, 5 to 25 mild, 25 to less than TABLE 124
50/hr moderate, and greater than 50/hr severe. A PLMSAI Periodic Leg Movement Disorder Diagnostic
greater than 25/hr was identified as severe. It has been rec- Criteria (ICSD-2)*
ognized that most patients with PLMS in the absence of the
A. PLMs presentLMs meet criteria to be PLMs
RLS are usually asymptomatic. Approximately 80% to 90% i. 0.510 sec in duration.
of patients with RLS will have PLMs on a given sleep study.9 ii. Amplitude > 8 V above baseline.
The PLMD (clinical sleep disturbance or daytime fatigue due iii. In a sequence of four or more movements.
to PLMS without RLS) is thought to be rare. The new AASM iv. Onsets of consecutive LMs 5 and 90 sec.
scoring manual does not provide a scheme for grading sever-
B. PLM index > 15/hr adults and > 5/hr in children (in most
ity of the PLM index. The ICSD-2 requires a PLM index of cases).
15/hr in adults and 5/hr in children as criteria for the diag-
nosis of the PLMD (Table 124).1 C. There is a clinical sleep disturbance or complaint of
daytime fatigue.
D. The PLMs and clinical sleep disturbance are not better
OTHER LMS DURING SLEEP
explained by another current sleep disorder or medical,
In the following sections, other identifiable LM patterns are neurologic, or psychiatric disorder.
discussed, including ALMA, HFT, and EFM. To date, the Notes:
presence of these patterns does not appear to be associated 1. A diagnosis of RLS excludes PLMD.
2. If PLMs are present without a sleep complaint, they can simply be noted
with clinically significant disorder. However, ALMA and as a PSG finding.
HFT are fairly common and are sometimes confused with 3. If only the bed partners sleep is disturbed, this is not sufficient to make a
PLMs. diagnosis of PLMD.
*Updated according to the AASM scoring manual.
Of note, PLMS during REM sleep (stage R) is uncommon AASM = American Academy of Sleep Medicine; LMs = leg movements;
except in patients with the RBD. PLMs should not be con- PLMD = periodic leg movement disorder; PLMs = periodic leg movements;
fused with transient muscle activity in the leg EMG that can PSG = polysomnography; RLS = restless leg syndrome.
Data from American Academy of Sleep Medicine: ICSD-2 International
occur during stage R. Transient muscle activity is discussed Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
in a later section. Westchester, IL: American Academy of Sleep Medicine, 2005; and Iber C,
Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep
Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
ALTERNATING LEG MUSCLE ACTIVATION Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.
ALMA7,1012 is characterized by EMG bursts that alternate
between the legs (Fig. 127). Because there have been no
reported clinical consequences of this pattern, it is believed
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Nasal pressure
No airflow
Chest
Abdomen
SpO2
96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 97 97 97 97 97 97 97 97 97 97 97 97 97 97
LAT
RAT
100 V
FIGURE 127 Alternating leg movement activity (ALMA). A 30-second tracing shows EMG bursts alternating between the legs. ECG = electrocardiogram; LAT =
left anterior tibialis; RAT = right anterior tibialis; SpO2 = pulse oximetry.
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Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep 181
EXCESSIVE FRAGMENTARY MYOCLONUS 3. The maximum frequency of the EMG bursts of HFT is
4 Hz (0.25 sec between onset of bursts).
EFM7,11,13,14 (Fig. 129) is defined by a characteristic EMG EMG = electromyogram; HFT = hypnagogic foot tremor.
pattern in the leg tracings consisting of very brief EMG From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
bursts (<150 msec). It is thought to be a benign phenome- of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
non. It most cases, no movements are visible, or if present, American Academy of Sleep Medicine, 2007, pp. 4142.
they are much like the small twitchlike movements of the
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
ECG
Nasal pressure
No therm
Chest
Abdomen
SpO2 98 98 98 98 98 98 98 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97
LAT
RAT
100 V
100 uv
FIGURE 128 A 30-second tracing of hypnagogic foot tremor (HFT) during stage W. ECG = electrocardiogram; LAT = left anterior tibialis; RAT = right anterior
tibialis; SpO2 = pulse oximetry.
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182 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep
TABLE 127
Comparison of Periodic Leg Movements, Alternate Leg Movement Activity, and Hypnagogic Foot
Tremor Events
LMS, PLMS ALMA HFT
EMG burst duration 0.510 sec 100500 msec 2501000 msec
Number of bursts in a series 4 4 4
Minimum frequency (1/sec) 0.01 0.5 0.3
Maximum frequency (1/sec) 0.2 3 4
Minimum time between onsets (sec) 5 0.33 0.25
Maximum time between onsets (sec) 90 2.0 3.3
Sleep present Yes Not required Not required
ALMA = alternating leg movement activity; EMG = electromyogram; HFT = hypnagogic foot tremor; LMs = leg movements; PLMs = periodic leg movements.
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Nasal pressure
Airflow
Chest
Abdomen
RAT
LAT
SpO2
95 95 94 94 94 94 94 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93
93%
FIGURE 129 Excessive fragmentary myoclonus (EFM). A 30-second epoch with fragmentary myoclonus during nonrapid eye movement (NREM) sleep. In this
patient, 30 minutes of similar activity were noted meeting criteria for EFM. ECG = electrocardiogram; LAT = left anterior tibialis; RAT = right anterior tibialis;
SpO2 = pulse oximetry.
fingers and toes seen intermittently during REM sleep in TABLE 128
normal individuals. To qualify for EFM, the EMG pattern Scoring Criteria for Excessive
often seen during REM sleep must also be seen during non Fragmentary Myoclonus
rapid eye movement (NREM) sleep (Table 128). These rules define EFM:
1. The usual maximum EMG burst duration seen in EFM
events is 150 msec.
BRUXISM 2. At least 20 minutes of NREM sleep with EFM must be
Bruxism is a grinding or clinching of the teeth1,3,7 (Fig. 12 recorded.
10). It is associated with characteristic rhythmic muscle arti- 3. At least 5 EMG potentials/min must be recorded.
fact in the EEG (rhythmic EMG activity of the scalp muscle Note: Twitchlike movements in fingers, toes, and corner of mouth may be
underlying the EEG electrodes) and chin EMG activity. seen but no gross movements.
During sleep, jaw contractions are either tonic (jaw clinch- EFM = excessive fragmentary myoclonus; EMG = electromyogram; NREM =
nonrapid eye movement.
ing) or phasic (intermittent bursts of activity) termed rhyth- From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
mic masticatory muscle activity (RMMA). Of note, a diagnosis of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
of bruxism consists of more than detection of RMMAthere Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.
must be audible tooth grinding (Table 129).
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Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep 183
100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 1210 An episode of bruxism. The sound of tooth grinding was heard during the episode. EMG = electromyogram.
100 V
1 sec F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
Snore
Nasal pressure
Nasal-oral
thermal flow A
Chest
Abdomen
RAT
LAT
SpO2
99 99 99 99 99 99 99 99 99 99 99 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98
FIGURE 1211 Head banging, a form of rhythmic movement (RM) disorder. A 60-second tracing of a 5-year-old child. The RMs are seen as rhythmic activity in
multiple tracingsespecially prominent here in the leg tracings and E1-M2. This is stage W with RM stopping at point A. ECG = electrocardiogram; EMG =
electromyogram; LAT = left anterior tibialis; RAT = right anterior tibialis; SpO2 = pulse oximetry.
(Fig. 1211). The scoring manual recommends that bipolar TABLE 1214
surface electrodes be placed to record large muscle group Rapid Eye Movement Sleep Behavior Disorder
involvement. However, time-synchronized video PSG is nec- (ICSD-2)
essary to make the diagnosis of RMD. For most patients, no A. Presence of REM sleep without atonia: the EMG finding
treatment for SRRMD is needed. In others with violent of excessive amounts of sustained or intermittent
movements, bed padding may be necessary. The disorder can elevation of submental EMG tone or excessive phasic
persist into childhood and adulthood. In some studies, an submental or (upper or lower) limb EMG twitching.
association between RMD and attention deficit hyperactivity
B. At least one of the following is present:
disorder has been found in school-age children.16 i. Sleep-related injurious, potentially injurious, or
disruptive behavior by history.
RBD: SCORING PSG FEATURES ii. Abnormal REM sleep behavior documented during
PSG monitoring.
The RBD requires PSG evidence of REM sleep without atonia
C. Absence of EEG epileptiform activity during REM sleep
and either video PSG showing dream-enacting behavior or
unless RBD can be clearly distinguished from any
a compatible clinical history of episodes of dream-enacting concurrent REM sleep-related seizure disorder.
behavior (Table 1214).1,3,7,18 The sustained muscle activity of
the chin EMG or transient muscle activity of the chin or leg D. The sleep disturbance is not better explained by another
EMG is interrupted by episodes of dream-enacting behavior. sleep disorder, medical or neurologic disorder, mental
disorder, or substance use disorder.
The AASM scoring manual presents a system for defining
EMG = electromyogram; ICSD = International Classification of Sleep Disorders,
excessive sustained chin EMG activity or excessive transient
2nd ed; PSG = polysomnography; RBD = rapid eye movement sleep behavior
muscle activity in the chin or leg EMG derivations1,1821 disorder; REM = rapid eye movement.
(Table 1215). Figure 1212 is a 30-second tracing with From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
periods of sustained chin EMG activity as well as excessive
Westchester, IL: American Academy of Sleep Medicine, 2005.
transient muscle activity in the leg EMG. Sustained chin
EMG activity is defined as an epoch of REM sleep with at
least 50% of the epoch having a chin amplitude greater than
the minimum amplitude in NREM sleep. Excessive transient epoch of stage R (REM) with typical low-amplitude chin
muscle activity in the leg EMG is defined as an epoch having EMG activity but excessive transient muscle activity in the
at least 5 of the 10 sequential 3-second miniepochs contain- leg EMG derivations.
ing bursts of transient muscle activity. Excessive transient In frequently asked questions (FAQ) M1 (http://
muscle activity bursts are 0.1 to 5.0 seconds in duration www.aasmnet.org/Resources/PDF/FAQsScoringManual.
and at least four times as high in amplitude as the back- pdf), the following question was asked: In scoring the PSG
ground EMG activity. Figure 1213 presents a 30-second features of RBD, how many epochs of REM sleep must show
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186 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep
TABLE 1215
Scoring Rules for the Polysomnography Features* Associated with the Rapid Eye Movement Sleep
Behavior Disorder
RULES
1. The PSG characteristics of RBD are characterized by either or both of the following features:
a. Sustained muscle activity in REM sleep in the chin EMG.
b. Excessive transient muscle activity during REM in the chin or limb EMG.
DEFINITIONS
Sustained muscle activity in REM sleep is defined as an epoch of REM sleep with at least 50% of the duration of the epoch
having a chin EMG amplitude greater than the minimum amplitude in NREM.
Excessive transient muscle activity in REM sleep: In a 30-second epoch of REM sleep divided into 10 sequential 3-sec
miniepochs, at least five (50%) of the miniepochs contain bursts of transient muscle activity. In RBD, excessive transient
muscle activity bursts are 0.15.0 sec in duration and at least four times as high in amplitude as the background EMG activity.
*Note: PSG features ALONE are not sufficient to diagnose RBD.
EMG = electromyogram; NREM = nonrapid eye movement; PSG = polysomnography; RBD = rapid eye movement sleep behavior disorder; REM = rapid eye
movement.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specification, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007, pp. 4142.
100 V
F4-M1
1 sec C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
RAT
LAT
FIGURE 1212 A 30-second tracing of stage R with transient muscle activity seen in the right anterior tibialis (RAT) and left anterior tibialis (LAT). Sustained muscle
activity in the chin electromyogram (EMG) is noted in the last two thirds of the epoch. The RAT and LAT activity also meets criteria for excessive transient muscle
activity. ECG = electrocardiogram.
100 V
F4-M1
1 sec C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
RAT
LAT
FIGURE 1213 Another 30-second epoch in the same patient presented in Figure 1212. Here, the chin electromyogram (EMG) is typical of stage R but the right
DaneshGroup.com
anterior tibialis (RAT) and left anterior tibialis (LAT) show excessive transient muscle activity. ECG = electrocardiogram.
Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep 187
either sustained or excessive transient muscle activity for C. The minimum and maximum frequency of move-
REM sleep as a whole to be considered compatible with ments must be 13 Hz.
RBD? The answer was the manual has deliberately not spec-
ified this as there are little normative data. Clinicians are
encouraged to read the relevant section of the supporting Answers
paper7 to help them decide how to address this issue in their 1. C. The diagnosis of RLS is based on clinical history but
own laboratories. Certainly, a relatively large number of frequent LMs during wake (as during a prolonged sleep
epochs with sustained or excessive transient EMG activity latency) are suggestive of the diagnosis.
would be suggestive of RBD. Conversely, fewer epochs with
intense EMG activity associated with characteristic body 2. D.
movements would also be suggestive of a diagnosis of RBD.
In summary, patients with RBD can have characteristic find- 3. B.
ings in the chin EMG, limb EMGs (e.g., RAT and LAT), or
both. Clinical correlation is needed. The RBD is discussed in 4. C.
more detail in Chapter 28. 5. C.
13. Broughton R, Tolentino MA, Krelina M: Excessive fragmentary 18. Lapierre O, Montplaisir J: Polysomnographic features of REM
myoclonus in NREM sleep: a report of 38 cases. Electroen- sleep behavior disorder: development of a scoring method.
cephalogr Clin Neurophysiol 1985;6:123133. Neurology 1992;43:13711374.
14. Vetrugno R, Piazzi G, Provini F, et al: Excessive fragmentary 19. Consens F, Chervin RD, Koeppe RA, et al: Validation of poly-
hypnic myoclonus: clinical and neurophysiological findings. somnographic score for REM sleep behavior disorder. Sleep
Sleep Med 2001;3:7376. 2005;28:993997.
15. Hoban TF: Rhythmic movement disorder in children. CNS 20. Sforza E, Krieger J, Petiau C: REM sleep behavior: clinical and
Spectr 2003;8:135138. physiopathological findings. Sleep Med Rev 1997;1:5769.
16. Stepanova I, Nevsimalova S, Hanusova J: Rhythmic movement 21. Eisensehr I, Lindeiner H, Jager M, Noachtar S: REM sleep
disorder in sleep persisting into childhood and adulthood. behavior disorder in sleep-disordered patients with versus
Sleep 2005;28:851857. without Parkinsons disease: is there a need for polysomnogra-
17. Kohyama J, Matsukura F, Kimura K, Tachibana N: Rhythmic phy? J Neurol Sci 2001;186:711.
movement disorder: polysomnographic study and summary of
reported cases. Brain Dev 2002;24:3338.
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Chapter 13
Polysomnography,
Portable Monitoring,
and Actigraphy
circumstances such as severe desaturation or arrhythmia nocturnal complaints. Table 134 is a summary of the cir-
thought due to OSA, and (3) at least 3 hours remain for the cumstances in which PSG is not indicated.
PSG titration.1,2,11,12 If the PSG titration does not last at least
3 hours or is not adequate, a repeat PSG titration is indicated. Approach to the Sleepy Patient
PSG PAP titration techniques and PAP treatment are dis-
on PAP Treatment
cussed in Chapter 19. Of note, financial constraints may
require use of less stringent split study criteria. If a patient with OSA continues to have daytime sleepiness
PSG is NOT recommended in patients on CPAP treat- on adequate PAP treatment (documented adequate adher-
ment who are doing well. If the patient is being treated on ence and adequate control of respiratory events), there are
CPAP and is NOT doing well, a repeat PSG study on CPAP two options. As discussed in Chapter 18 on medical treat-
is indicated.2 However, before this expensive procedure, ment of OSA, an alerting agent such as modafinil may be
it is essential to document adequate objective adherence and added.13 If there is a suspicion of narcolepsy in addition to
to optimize treatment and the mask interface. PSG is also OSA, a nocturnal PSG on PAP treatment (documenting
indicated if a patient on CPAP gains more than 10% of adequate treatment) followed by an MSLT on PAP can be
body weight to determine whether the pressure is adequate. performed (see Chapters 14 and 24). If unambiguous cata-
However, a repeat PSG titration may not be clinically plexy is present, the patient likely has narcolepsy and the
indicated. MSLT is simply confirmatory. It is essential that adequate
PAP treatment for OSA be confirmed before expensive
testing. This includes documentation of adequate objective
PSG Indications: Nonrespiratory Disorders
adherence. Many PAP devices also have the ability to
PSG Indicated (see Tables 133 and 134) record residual AHI. A high residual AHI would be an indi-
A PSG preceding an MSLT is indicated for evaluation of cation for an adjustment in pressure (empirical increase) or
suspected narcolepsy or to help differentiate narcolepsy a PSG PAP titration.1,2 The PAP device estimate of residual
from idiopathic hypersomnia.13 PSG is indicated for evalu- AHI is not always accurate, but a high value has a reasonable
ation of suspected periodic limb movement disorder but positive predictive value that the residual AHI is indeed
NOT the restless legs syndrome (RLS; a clinical diagnosis). elevated.14 A surprising number of patients (up to 15%) on
A PSG with extended (and bilateral) electroencephalogram chronic PAP treatment are not adequately treated (AHI >
(EEG) derivations and video monitoring is indicated to eval- 10/hr).15,16
uate (1) nocturnal behavior possibly due to seizures, (2)
atypical parasomnia behavior (frequent episodes each night, Approach to Reading the PSG
stereotypic behavior, or behavior unusual for age), (3) noc- Before the PSG is read, a review of the clinical history with
turnal behavior/parasomnia that has resulted in injury to the special attention to symptoms of sleep apnea, narcolepsy,
patient or others (or has the potential to do so), (4) presumed RLS, and medications is very useful. The amount of chronic
parasomnia or nocturnal seizure disorder that does not alcohol intake and the medications actually taken before the
respond to conventional treatment, or (5) if there are legal/ sleep study should be noted. The presence of underlying lung
forensic implications of nocturnal behavior.2 The practice disease may help explain a low awake arterial oxygen satura-
parameters recommend looking at events in a 10-second tion (SaO2) or low baseline sleeping SaO2. A clinical history
window to observe for seizure activity and consultation of pacemaker insertion or known atrial fibrillation is also
with a physician with expertise in reading clinical EEGs very helpful in providing a useful interpretation of ECG
if necessary. findings. If a PAP titration is planned for a patient currently
using CPAP, the current treatment pressure level should be
PSG NOT Indicated (see Tables 133 and 134) noted. During the reading of the PSG, a return to the clinical
PSG is not indicated for evaluation of insomnia (unless OSA history may be helpful (Table 135).
is suspected) or unless insomnia does not respond to usual All digital PSG systems have a view that shows graphical
treatment. PSG is not indicated for diagnosis of depression summary information of the entire night (Fig. 131 and
or insomnia with depression.2,4 The practice parameters for Table 136). It is often useful to look at the big picture before
use of PSG4 in evaluation of insomnia state PSG is indicated going through the data in smaller time windows. The bio-
when initial diagnosis is uncertain, treatment fails (behav- calibrations are often helpful in noting the appearance of
ioral or pharmacologic), or precipitous arousals occur with eyes-open wake in a given patient and whether the patient
violent or injurious behavior (Guideline). produces an alpha rhythm with eye closure (see Chapters 3
Although the PSG finding of a short rapid eye movement and 4).
(REM) latency is common in depression, this finding is not
sufficiently sensitive or specific to warrant a PSG in evaluat- PORTABLE MONITORING (HOME SLEEP
ing patients with suspected depression. A PSG is NOT indi- TESTING, OUT OF CENTER SLEEP TESTING)
cated for (1) typical uncomplicated and noninjurious
parasomnias when the diagnosis is clearly delineated or PM, also called home sleep testing (HST) or out of center
(2) patients with known seizure disorders who have no sleep testing (OCST), has been the subject of intense interest
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Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 193
TABLE 135
Historical Elements to Review Based on Polysomnography Findings
EEG/EOG/EMG
Long sleep latency?history of insomnia
Short REM latency?history of symptoms of narcolepsy, cataplexy, or depression
Alpha sleep?chronic pain syndrome or psychiatric disorders
Persistent eye movements during stage N2?SSRI medication
Increased spindle activity?benzodiazepines (regular medication or special medication before sleep study)
Transient muscle activity (chin EMG) activity during stage R?SSRI treatment, history of dream enactment
Arousals from stage N3 with body movement?history of NREM parasomnia
Body movement and speech during REM sleep?history suggestive of RBD
RESPIRATION
Low awake SaO2?presence of lung disease
Low sleeping baseline SaO2?presence of lung disease
Cheyne-Stokes breathing?history of congestive heart failure
Ataxic breathing, low respiratory rate?history of potent opiates
Delay in SaO2 nadir after respiratory events?decreased cardiac output
LEG MONITORING
Frequent LMs during wake?symptoms of RLS
High PLM indexcan be seen associated with OSA, PAP titration, RLS
Increased transient muscle activity during REM sleep?SSRI medications, history of dream enactment
ECG
Tachycardia in sleep (>90 bpm)?anxiety, stimulants
Bradycardia in sleep (<40 bpm)?beta blocker, ?known cardiac disorder
Atrial fibrillation?previously documented
Pacemaker?if wide complex QRS with normal rate (e.g., 6080)
? = consult history for relevant items.
ECG = electrocardiogram; EEG = electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; LMs = limb movements; NREM = nonrapid eye
movement; PAP = positive airway pressure; PLM = periodic limb movement; RBD = rapid eye movement sleep behavior disorder; REM = rapid eye movement;
RLS = restless legs syndrome; SaO2 = arterial oxygen saturation; SSRI = selective serotonin reuptake inhibitor.
recently.17,18 The tests are not always performed in the home; per hour of monitoring time. Therefore, the index deter-
hence, the terms HST or PM are not ideal but are used in mined by PM (no EEG) would be an RDI using the CMS
much of the literature on this subject. The term PM is used definition. CMS also refers to PM as HST.
in this chapter. In the past, PM has been used to diagnose
OSA in settings in which access to PSG is limited or delayed.
Developments in the Use of PM
The traditional classification of monitoring devices for the
diagnosis of sleep apnea was originated by Ferber and col- Important developments in the history of PM are listed in
leagues (Table 137).1921 This classification was used for the Table 139. AASM practice parameters in 1994,20 1997,1 and
Tri-Society PM evidence review,22 executive summary,23 and 20052 specified a limited role for attended PM. However,
practice parameters for the PM.7 The original classification unattended PM was widely used in locales in which access
used level I, II, III, and IV to refer to different classes of to PSG was very limited. On the basis of a Tri-Society evi-
monitoring but currently the terminology is type 1, 2, 3, and dence review for the use of PM,22 practice parameters pub-
4. The Centers for Medicare and Medicaid Services (CMS) lished in 20037 stated that certain type 3 PM devices used in
has a different classification for monitoring (Table 138).9 the attended setting could be used to rule in or rule out
The CMS terminology defines the respiratory disturbance OSA.7 Before 2008, the National Carrier Determination
index (RDI) as the total number of apneas and hypopneas (NCD) 240.4 on CPAP treatment specified a diagnosis of
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194 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
100%
95%
SpO2 90%
85%
80%
75%
A B C
70%
Left
Right
Position
Prone
Supine
Respiratory event
Desaturation
Wake
Stage REM
1
2
3
Epoch 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960
22:17:44 23 00 01 02 03 04 05 06 06:43:15
Time
FIGURE 131 Summary view shows three periods of significant arterial oxygen desaturations (A, B, and C) during rapid eye movement (REM) sleep. In addition, the
summary view shows that no supine REM sleep was recorded. SpO2 = pulse oximetry.
TABLE 137
Classification of Portable Monitoring*
TYPE 4: CONTINUOUS
TYPE 3: MODIFIED SINGLE OR DUAL
TYPE 1: ATTENDED TYPE 2: PORTABLE SLEEP APNEA BIOPARAMETER
PSG UNATTENDED PSG TESTING RECORDING
Measures Minimum of seven Minimum of seven Minimum of four, including Minimum of one
(channels) channels including channels including ventilation (at least two oxygen saturation,
ECG, EEG, EOG, chin EEG, EOG, chin channels of respiratory flow, or chest
EMG, airflow, EMG, heart rate or movement or respiratory movement
respiratory effort, ECG, airflow, movement and airflow),
oxygen saturation respiratory effort, heart rate or ECG, and
oxygen saturation oxygen saturation
Body position Documented or Possible Possible No
objectively measured
Leg movement EMG or motion sensor Optional Optional No
desirable but optional
Personnel Possible No No No
interventions
*Levels I, II, III, and IV monitoring are now termed types 1, 2, 3, and 4.
ECG = electrocardiogram; EEG = electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; PSG = polysomnography.
From Ferber R, Millman R, Coppola M, et al: ASDA standards of practice: portable recording in the assessment of obstructive sleep apnea. Sleep 1994;17:378392.
TABLE 138
Centers for Medicare and Medicaid Services Classification of Portable Monitoring
HCPCS CODE TYPE SETTING MONITORING
G0398 2 Unattended Minimum of seven channels including EEG, EOG, EMG,
ECG/heart rate, oxygen saturation, anterior tibial EMG
G0399 3 Unattended Minimum of four channels and must record ventilation,
oximetry, and ECG or heart rate
G0400 4 Unattended Minimum of three channels, and one must be airflow
Unattended Minimum of three channels including peripheral arterial
tonometry, actigraphy, and oximetry
2011 Codes for PM Studies
95800 Sleep study, unattended, simultaneous recording; heart rate, oxygen saturation, respiratory analysis (e.g., by airflow or peripheral arterial tone), and sleep
time;
95801 Sleep study, unattended, simultaneous recording; minimum of heart rate, oxygen saturation, and respiratory analysis (e.g., by airflow or peripheral arterial
tone);
95806 Sleep study, simultaneous recording of ventilation, respiratory effort, ECG or heart rate, and oxygen saturation, unattended by a technologist.
Note: Some durable medical equipment (DMAC) providers still use G codes. The entire area is in flux. The reader should consult the CMS website or their local DMAC
provider for the latest information.
ECG = electrocardiogram; EEG = electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; HCPCS = Healthcare Common Procedure Coding System.
are problematic. In either case, even if the same type of the devices are actually used. The different nightsdifferent
sensors are used and the same number of events are identi- locations approach mimics real world conditions. However,
fied, the two devices would still give different AHI values as if the different nights approach is used to compare PSG and
monitoring time (PM) would exceed total sleep time (PSG). PM, the AHI values could differ simply due to night-to-night
For example, if both methods detect 70 apneas and hypop- variability in the AHI.
neas, dividing by 5 hours of total sleep time (TST; AHI = 14/ In general for milder OSA, the amounts of REM and
hr) will give a higher index than dividing by 7 hours of supine sleep are the major determinants of the AHI. These
monitoring time (AHI = 10/hr). It is also possible that the patients have elevated AHI mainly in the supine position or
oximeters used in different systems could differ in their during REM sleep. Table 1311 presents the effect of differ-
ability to detect desaturations. Comparing PM and PSG AHI ent proportions of REM and supine sleep on the overall AHI
values during simultaneous recording reduces the effects of (assuming certain AHI values in different conditions). In
night-to-night variability. However, this does not mimic how milder OSA patients, night-to-night differences in the
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196 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
TABLE 139
History of Recent Developments in Portable Monitoring (Home Sleep Testing)
1994 Practice Parameter for Type 2 or type 3 PM is an acceptable alternative to PSG in the following circumstances:
Portable Monitoring20 1. Patients with severe clinical symptoms of OSA and when initiation of treatment is
urgent and PSG is not readily available.
2. Patient unable to be studied in sleep laboratory.
3. Diagnosis already established by PSG and treatment initiated and the purpose is
to evaluate response to treatment.
Tri-Society (ACCP, ATS, AASM) 2003 Attended type 3 studies may be used to rule in or rule out OSA provided certain
Evidence Review (Chest)22 limitations are met. These include manually scoring the records, using the device in
Executive Summary23 patients without significant co-morbid conditions, not using type 3 devices for PAP
(Am J Respir Crit Care Med) titrations or split-night studies, and symptomatic patients who have a negative type
PM Practice Parameters (Sleep)24 3 study should have a PSG.
Type 2, type 4 studies not recommended.
2004 CMS Decision Insufficient evidence to recommend unattended type 2, 3, 4 PM.
2005 AASM Practice Parameters Attended cardiorespiratory study (type 3) is an acceptable alternative to PSG if:
for PSG and Related Procedures2 High pretest probability of OSA.
A negative type 3 study with patients with high pretest probability of OSA is
followed by a PSG.
Here, type 3 is defined as airflow, effort, oximetry, and ECG or heart rate.
Attended cardiopulmonary study acceptable:
Preoperative for planned surgery for snoring or OSA.
After surgery for OSAmoderate to severe.
To document effectiveness of an OA.
After surgical or dental treatment of OSA and symptoms return.
Attended cardiorespiratory study NOT recommended for PAP titration.
AASM Portable Monitoring Task Clinical Guidelines for Unattended Monitoring 20076
Force 20062007
CMS 240.4 Final decision Unattended HST permitted
200820099,10 Type 3 (four channels with ventilation, oximetry, ECG or heart rate, and SpO2).
Type 4 (three channels, one airflow)
PAT type: three channels including PAT, actigraphy, SpO2.
Local Carrier Determinations Restrictions on who can perform and interpret HST.
May require monitoring of airflow.
Set Fee schedule.
Most have followed AASM Clinical Guidelines for unattended monitoring.
AASM = American Academy of Sleep Medicine; ACCP = American College of Chest Physicians; ATS = American Thoracic Society; CMS = Centers for Medicare Services;
ECG = electrocardiogram; HST = home sleep testing; OA = oral appliance; OSA = obstructive sleep apnea; PAP = positive airway pressure; PAT = peripheral arterial
tonometry; PM = portable monitoring; PSG = polysomnography; SpO2 = pulse oximetry.
TABLE 1310
proportions of REM and supine sleep are a significant source
Reasons for Difference in Apnea-Hypopnea Index of night-to-night variability. A study by Smith and associ-
by Polysomnography versus Portable Monitoring ates25 found that patients tend to sleep more in the supine
PM AHI > PSG AHI PSG AHI > PM AHI position in the sleep center. During this study, PSG and PM
Respiratory events Monitoring time > TST (i.e.,
were simultaneously recorded in the sleep center and PM
scored when patient 10/5 < 10/2). was also performed on a separate night at home (Table 13
actually awake. Less supine time at home. 12). Differences in the AHI during simultaneous monitoring
Ethanol intake? PM sensors dislodged were likely due to the effect of using monitoring time versus
More sleep/more REM during the night. TST to compute the AHI. During PM monitoring at home,
sleep at home. Different sensors. less supine sleep also contributed to differences in the AHI.
Night-to-night variability. Different scoring (hypopnea To compensate for night-to-night variability, many PM
Variability in human with arousals only with PSG). devices now have the ability to monitor multiple nights. One
scoring. Night-to-night variability. study suggested that night-to-night variability in the home
Variability in human scoring. might be less than in the sleep center (Fig. 132).26
AHI = apnea-hypopnea index; PM = portable monitoring; PSG = A Bland-Altman plot27 is a commonly used method
polysomnography; REM = rapid eye movement; TST = total sleep time.
to display agreement between two measuring devices. The
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Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 197
TABLE 1311
Effects of Different Proportions of Supine and Rapid Eye Movement Sleep on the Total
Apnea-Hypopnea Index
SUPINE NONSUPINE SUPINE NONSUPINE
NREM NREM REM REM
Assumed AHI (#/hr) in different conditions 5 2 30 10
PROPORTIONS OF DIFFERENT CONDITIONS OVERALL SUPINE NONSUPINE SUPINE NONSUPINE
OF FOUR NIGHTS AND THE RESULTING AHI AHI NREM (%TST) NREM (%TST) REM (%TST) REM (%TST)
Night 1 6.8 40 40 10 10
Night 2 4.2 20 60 0 20
Night 3 3.3 30 65 0 5
Night 4 9.7 70 10 20 0
Note: The AHI was highest on night 4 because the amount of supine REM sleep (as %TST) was the highest on that night.
AHI = apnea-hypopnea index; NREM = nonrapid eye movement; REM = rapid eye movement; TST = total sleep time.
90 90
r 0.56, P .001 r 0.65, P .0001
80 80
70 70
PSG overall AHI - retest
PSG
60
50
40
30
AHI PSG - AHI PM
1.96 SD
20
22.6
10
Mean
0
0.7
10
20 1.96 SD
24.0
30
FIGURE 133 A Bland-Altman plot of pairs of apnea-hypopnea index (AHI) values (device 1, device 2). The difference (AHI PSG AHI PM) is
plotted on the y axis against the average on the x axis [(device 1 + device 2)/2]. The confidence limits are + 1.96 standard deviations (SDs). The
mean difference (bias) is near zero. There tended to be more scatter at the higher AHI values. PM = portable monitoring; PSG = polysomnography.
From Santos-Silva R, Truksians V, Truksina E, et al: Validation of a portable monitoring system for the diagnosis of obstructive sleep apnea syndrome.
Sleep 2009;32;629636.
TABLE 1313 sensors that are used for PSG (the recommendation), then
Indications for Use of Unattended PM and PSG should have similar ability to detect central
Portable Monitoring apnea, Cheyne-Stokes breathing, or hypoventilation (mani-
fested by a low SaO2 without discrete events).29 The counter-
PM must be combined with a comprehensive sleep
evaluation. argument is that such patients will likely need a PSG PAP
titration. In this case, a split-sleep study may be more cost
Patient has a high pretest probability of moderate to effective than PM followed by a PSG titration. PM also would
severe OSA. miss arrhythmias because pulse rate obtained from the
No co-morbid medical conditions that may degrade PM oximeter rather than an ECG tracing is usually recorded. The
accuracy AASM PMGs state that PM may be used in the unattended
Severe pulmonary disease. setting and can be used to document the effectiveness of
Neuromuscular disease. non-PAP treatment IF PM guidelines are followed. Examples
Congestive heart failure. would include a study with the patient wearing an OA (after
No clinical suspicion of other sleep disorders suitable adjustment) or after previous upper airway surgery.
CSA.
Narcolepsy. Recommended PM Methodology
PLMD. The PMGs8 recommend monitoring at a minimum airflow,
Parasomnias. respiratory effort, and SaO2 (Table 1314). The recom-
Circadian rhythm sleep disorders. mended sensors for PM are the same as those recommended
Not for screening asymptomatic populations. for PSG in the AASM scoring manual.29 Note that CMS uses
Patients who cannot have PSG due to immobility, safety,
the metric RDI rather than AHI for PM [(apneas + hypop-
or critical illness. neas)/monitoring time]. RDI usually means AHI + RERA
index. Adequately trained personnel should either place the
Unattended PM may be used to monitor response to monitoring equipment on the patient or train them on the
non-PAP treatments for sleep apnea (oral appliances,
application of the sensors. This is essential to avoid a high
surgery, weight loss).
percentage of technically inadequate studies. The PM data
Unattended PM in patients home is permitted when all must be viewed in the raw form, and if automated scoring is
guidelines are followed. used, it must be edited for accuracy. A physician must look
CSA = central sleep apnea; OSA = obstructive sleep apnea; PAP = positive at the raw data as well as the data summary before making
airway pressure; PLMD = periodic limb movement disorder; PM = portable
monitoring; PSG = polysomnography.
an interpretation. It was recommended that PSG be inter-
preted by a BC/BE sleep physician or a physician associated
with an accredited sleep center.
For quality assurance, standard operating procedures for
disorders (e.g., narcolepsy) requiring PSG should also be the PM process must exist. To verify adequate scoring, inter-
excluded. A minimum of airflow, respiratory effort, and rater reliability on scoring of PM studies should be per-
oxygen saturation must be measured (type 3 PM). The same formed on a routine basis and documented. If PM is
sensors and respiratory definitions recommended for PSG in inadequate technically or if the study results are negative in
the AASM scoring manual should be used if possible. The a patient with a high pretest probability of having OSA, an
raw data must be reviewed and the PSG interpreted by a attended PSG should be performed. The reader may wish to
qualified sleep physician. A follow-up visit with the patient review the AASM accreditation standards for OOC sleep
to discuss results is indicated. If a PM study is negative or testing on the website (www.aasmnet.org).
technically inadequate, a PSG should be ordered to avoid a
false-negative PM result. The following sections discuss rec-
Types of PM Devices
ommended patient selection and methodology for PM.
Numerous devices are available for PM (Fig. 134). Devices
Patient Selection for PM having more sensors provide more information but are more
Ideally, each patient should be seen by a BC/BE sleep physi- difficult for patients to place. It is always a trade off between
cian before PM testing. If this is not possible, an evaluation information and complexity of sensor application. Tracings
can be performed with questionnaires before or at the time from a typical PM device (type 3) are shown in Figures 135
of testing. Review of the medical record to exclude patients and 136. Figure 135 shows a tracing from a device that
with co-morbidities that degrade PM accuracy is also impor- monitors airflow using both an oronasal thermal device and
tant. In the PMGs, these include patients with severe pulmo- nasal pressure. Respiratory effort is monitored by chest and
nary disease, neuromuscular disease, or congestive heart abdominal respiratory inductance plethysmography (RIP)
failure (CHF). The rationale is that such patients may exhibit bands. An oximetry channel and derived heart rate are also
hypoventilation without discrete respiratory events or recorded as well as body position. Figure 136 shows a
Cheyne-Stokes breathing (common in severe systolic CHF). tracing from a different PM device that monitors airflow by
However, one can argue that if PM devices use the same nasal pressure (with or without oronasal thermistor) and
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200 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
TABLE 1314
Recommended Portable Monitoring Methodology
Parameters to be monitored Monitor at least three parameters: airflow, effort, and oximetry.
Sensors Same sensors as for PSG
Airflow (ideally two sensors)
Apneaoronasal thermal device.
Hypopneanasal pressure.
Respiratory effortRIP
Pulse oximetry with adequate averaging time and motion artifact rejection.
Personnel and setting PM should be performed by AASM accredited sleep center
Policy and procedures.
Quality assurance program.
Interscorer reliability program.
Experienced sleep technician/technologist either places sensor or directly educates the
patient on sensor application.
Device Display of raw data is available for manual scoring and editing.
Scoring criteria according to AASM scoring manual.
PSG should be performed when PM is technically inadequate or fails to establish diagnosis
of OSA in patients with high pretest probability.
BC/BE SP or physician on Review of raw data by BC/BE SP and interpretation.
staff of AASM accredited
sleep center
Follow-up If PM study is technically inadequate or fails to establish a diagnosis of OSA in a patient
with a high pretest probability, a diagnostic PSG should be performed.
Follow-up visit with MD or trained health care provider after PM testing to discuss results of
test with the patient and plan treatment.
AASM = American Academy of Sleep Medicine; BC/BE SP = Board-certified/Board-eligible sleep physician; OSA = obstructive sleep apnea; PM = portable monitoring;
PSG = polysomnography; RIP = respiratory inductance plethysmography.
A B C D
FIGURE 134 PM devices. A, Embletta (Embla). B, WatchPAT 100 (Itamar). C, Stardust II (Philips-Respironics). D, ARES (Advanced Brain Monitoring).
effort by two RIP belts. The device also records SaO2, body a backup (Fig. 137). The downside is that the two RIP bands
position by a position sensor in the device, and actigraphy are more difficult to place than a single effort band. Dispos-
to enable elimination of periods of wake/artifact from the able band material is available for the RIP bands.
final index time (the monitoring time used for AHI calcula-
tion). One useful feature is that the device provides XFlow, Peripheral Arterial Tonometry
which is an estimate of total flow derived by differentiating Unique PM devices that detect respiratory events by record-
the sum of the chest and abdominal RIP bands. If the airflow ing changes in sympathetic tone (rather than airflow) using
sensors fail (become dislodged), the XFlow signal provides peripheral arterial tonometry (PAT) are also available.30,31
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Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 201
40
20
N Press Flw Pres 0
20
40
60
24
16
NO flow Flw Ther 8
0
8
16
2
Chest Tho 0
2
3
Abdomen Abd
2
1
0
1
2
80
40
Snore Snore 0
40
80
98
94
95 97 98 98 97 97 96 94
90
91 94 92 92 92 93
SpO2 SpO2 86
87 86 86 88 87
82
78 86
130
90
Pulse Puls Rate 50
10 74 73 65 64 66 66 66 66 66 67 67 68 68 70 72 73 69 66 65 65
30
S S S S S S S S S S S S S S S S S S S S S S S S S S S SS S S S S S S S S S S S S S S S S S S S S S S S S S S S S SS S
Body Pos
Body position
210 211 211 212
10 20 30 40 50 60
1 min.
FIGURE 135 A 60-second tracing shows an obstructive hypopnea recorded with a type 3 PM device (PDX by Philips-Respironics). An oronasal thermal device (NO flow)
and nasal pressure (N Press), chest and abdominal respiratory inductance plethysmography (RIP) bands, snoring, oximetry, pulse rate (from the oximeter), and body position
(S = supine) are recorded. SpO2 = pulse oximetry.
Nasal flow
Apnea central (12.90s) Apnea central (15.20s)
200
100
Nasal pressure 0
(flow)
100
200
mL/s
Thermistor
3
Oronasal thermal 2
1
device
0
1
2
3
mV
Resp.Mo...
192V/cm
Desaturation (21.33s) [8] Desaturation (18.33s) [7]
98
98
98
97
97
97
97
97
96
96
98
96
96
96
96
96
96
98
98
97
97
97
95
95
95
95
95
95
100
94
94
94
94
94
94
93
93
93
92
92
92
92
SpO2 - %
91
91
91
91
SpO2
90
90
90
89
89
90
80
70
60
175
150
125
Pulse - bpm
100
Pulse
66
65
62
60
60
59
61
61
61
60
58
58
59
59
57
59
57
75
58
55
55
55
55
55
55
55
52
53
53
57
53
54
54
54
54
53
51
53
53
54
53
51
53
51
49
50
51
49
49
49
49
50
25
FIGURE 136 Tracing from a type 3 PM device (Embletta by Embla) shows nasal pressure, oronasal thermal flow, chest and abdominal respiratory inductance plethysmography
(RIP) channels, oximetry (SpO2), and pulse. Body position and actigraphy were also recorded but are not shown. The illustrated event is a central apnea of the Cheyne-Stokes
type. This was an unexpected finding. The patient had no history of known congestive heart failure but did report nocturnal dyspnea.
apply the devices themselves had 33% inadequate studies. Integration of PM into the Overall Patient
This study used a five-channel device recording oronasal
Care Algorithm
airflow, wrist actigraphy, body position, and SaO2. In our
experience, patients have difficulty applying some types of Diagnosis of OSA using PM is only the first part of the process
oximeter probes as well as chest and abdominal belts. Other if the study is positive. It is expected that in populations with
common problems include dislodgment of either the nasal a high probability of OSA, a high percentage of PM tests will
cannula or the oximeter probe as well as pulling leads out of be positive. If PAP is chosen for treatment, there are several
the PM device during body movement. Patients can be alternative pathways to proceed (Table 1317).3335 The stan-
trained to apply tape at strategic points to reduce these dard approach would be to perform a PSG PAP titration and
events. The selection of the device to be used must take into subsequent PAP treatment. Patients could also use an auto-
account how the setup will be delivered. PAP (autotitrating, autoadjusting, positive airway pressure
It is also useful to have patients complete a brief sleep [APAP]) device at home for 3 days or more and information
diary to record their estimate of how long they slept and if obtained could be used to select a pressure for chronic CPAP
the night of sleep was fairly typical. An occasional patient treatment.33,35 APAP devices automatically provide the lowest
will sleep very poorly with the device attached. If minimal effective pressure during the night. Commonly, the 90th or
sleep is recorded, a false-negative study is likely. Devices 95th percentile pressure is chosen for treatment with a fixed
that can record more than one night provide another moni- pressure (CPAP). The use of APAP devices is discussed in
toring night opportunity and may also reduce the influence Chapter 19. A third possible approach is starting CPAP at a
of night-to-night variability. pressure derived using prediction equations with subsequent
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Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 203
XFlow
XFlow (335V/s/cm)
Thorax (221V/cm)
Thorax
Abdomen (146V/cm)
Abdomen
SpO2 (15.9%/cm)
94%
SpO2
80%
FIGURE 137 In this tracing from an Embletta, the nasal flow channel is inadequate (likely nasal cannula dislodged or occluded) but the derived XFlow
(derivative of thorax and abdomen RIP bands) provides a reasonable estimate of flow. SpO2 = pulse oximetry.
FIGURE 138 Peripheral arterial tonometry (PAT) detection of a respiratory event. The PAT signal falls (increased sympathetic tone) associated with an increase then a
decrease in pulse and an arterial oxygen desaturation. SaO2 = arterial oxygen saturation.
TABLE 1316
TABLE 1315 Method of Device Setup and Return
Practical Considerations in Portable Monitoring
SLEEP CENTER SETUP
Choice of Device
Advantages
More complex PM devices provide backup sensors and
Controlled environment
more informationbut are more difficult to place.
Technologist can place device
Multiple-night recording ability may reduce night-to-night
Disadvantages
variability effects.
Travel cost for patients (two round trips unless device
An automatic scoring program that is accurate and easily mailed back)
editable is essential given low reimbursement for IN-HOME SETUP
technical component.
Technologist Travels to Home
Ease of device setup is essentialif patient is to self-apply
device. Advantages
Lower % technically inadequate studies (compared with
Efficient device use requires ability to patient sensors at home)
Clean device and reprogram easily.
Rapid device turnaround requires a systematic Disadvantages
approach. Travel costs
Technologist safety issues
Methods of dealing with device damage or loss
Mail Device to Patient
Patient signing responsibility contract.
Warranty options. Requires simple device
PM = portable monitoring. Higher percentage of failed studies
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Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 205
TABLE 1317
ACTIGRAPHY
Positive Airway Pressure Treatment after Portable
Monitoring Diagnosis of Obstructive Sleep Apnea Actigraphy utilizes a portable device (the actigraph) usually
worn on the wrist that records movement over an extended
PSG PAP titration followed by CPAP treatment
period of time (Fig. 1310). Sleep-wake patterns are esti-
Autotitration followed by CPAP treatment mated from the pattern of movement. Software is available
CPAP on empirically determined pressure to estimate TST and wake time from the data. The estimates
Adjustment on basis of residual snoring/apnea of TST and wake time are more accurate in normal individu-
Adjustment on basis of bed partner observations als than in patients with sleep disorders. However, the sleep-
Adjustment based on pulse oximetry wake pattern of actigraph data is extremely valuable in
Adjustment based on device estimate of residual AHI documenting patterns of sleep and wake. AASM practice
Treatment with APAP device parameters have been published in 2005 and most recently
APAP = autotitrating, autoadjusting positive airway pressure;
in 2007.36,37 The temporary Healthcare Common Procedure
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; Coding System (HCPCS) code for actigraphy was 0089T. In
PAP = positive airway pressure; PSG = polysomnography (see Chapter 19). 2009, actigraphy received a current procedural terminology
(CPT) code. The new code is 95803actigraphy testing,
recording, analysis, interpretation, and report (minimum of
72 hr14 consecutive days of recording). Medical practices
often set fees for actigraphy in the $250 to $300 range.
Clinical
evaluation
OSA likely and uncomplicated Other sleep Complications OSA less likely
Disorders suspected Very high BMI
Narcolepsy, PLMD, (likely to need high PAP)
RBD OHS
Mod-severe COPD
PM Neuromusc Ds
On 24 hour oxygen
Potent narcotics
CHF (if CSB, may need ASV)
Clinic
No
CPAP
treatment PAP
treatment
FIGURE 139 Systematic approach to using combination of polysomnography (PSG) and portable monitoring (PM) to evaluate patients. AHI = apnea-hypopnea index; APAP =
autoadjusting, autotitrating positive airway pressure; ASV = adaptive servo-ventilation, a treatment for CSA or CSB; BMI = body mass index; CHF = congestive heart failure; COPD =
chronic obstructive pulmonary disease; CPAP = continuous positive airway pressure; CSA = central sleep apnea; CSB = Cheyne-Stokes breathing; MSLT = multiple sleep latency test;
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OSA = obstructive sleep apnea; PAP = positive airway pressure; PLMD = periodic limb movement disorder; RBD = rapid eye movement sleep behavior disorder.
206 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
Actogram:
12:00 PM 8:00 PM 12:00 AM 6:00 AM 12:00 PM
Friday
9/4/2009
(Day 1)
Saturday
9/5/2009
(Day 2)
Sunday
9/6/2009
(Day 3)
Monday
9/7/2009
(Day 4)
Tuesday
9/8/2009
(Day 5)
Wednesday
9/9/2009
(Day 6)
Thursday
9/10/2009
(Day 7)
FIGURE 1310 Actigraphy. The dark black represents the amount of activity (when present = wake). The light blue represents periods of low activity identified as sleep.
The light gray represents ambient light detection. This patient had irregular bedtimes.
However, at this writing, actigraphy is still not reimbursed phase syndrome (ASPS), delayed sleep phase syndrome
by most insurance plans or Medicare. Studies of actigraphy (DSPS), and shift work disorder. In addition, there is some
have usually compared the results with that of PSG or sleep evidence to support the use of actigraphy in the evaluation
logs. However, actigraphy does not measure sleep (EEG) or of patients suspected of jet lag disorder and non24-hour
the subjective experience of sleep (sleep logs). sleep-wake syndrome (including that associated with blind-
ness). Actigraphy is also useful for documenting the response
to treatment in circadian disorders.
Indications
When PSG is not available, actigraphy is indicated to
The indications for actigraphy are listed in Table 1318. estimate TST in patients with OSA.37 In patients with insom-
Actigraphy provides a fairly accurate estimate of sleep pat- nia and hypersomnia, there is evidence to support the use
terns in normal, healthy adult populations and in patients of actigraphy in the characterization of circadian rhythms
suspected of certain sleep disorders. Actigraphy is indicated and sleep patterns/disturbances. In assessing response to
to assist in the evaluation of patients with advanced sleep therapy, actigraphy has proved useful as an outcome measure
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Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 207
Log/PSG
Log/PSG
2 2
Act/PSG
1 Act/PSG Log/PSG 1
Act/PSG
Act/PSG
0 0
TST Wake Sleep latency TST Wake Sleep latency
A B
FIGURE 1311 A, A plot of the ratios of actigraphic/polysomnography (Act/PSG) and sleep log/PSG estimates of total sleep time (TST), wake, and sleep latency from the
data of a study by Vallires and Morin in patients with insomnia. Both Act and sleep logs slightly underestimated the TST but overestimated wake time. Sleep logs
overestimated sleep latency and Act underestimated sleep latency (laying in bed still but awake). B, A plot of Act/PSG ratios (all three bars) for TST, wake, and sleep latency
from a study of older insomniacs by Sivertsen and coworkers. Act slightly overestimated TST but underestimated wake and sleep latency. A, Data from Vallires A, Morin
CM: Actigraphy in assessment of insomnia. Sleep 2003;26:902906; B, data from Sivertsen B, Omvki S, Havik OE, et al: A comparison of actigraphy and polysomnography in
older adults: treatment of chronic primary insomnia. Sleep 2006;29:13531358.
actigraphy and sleep logs with PSG (Fig. 1311A). Both 2. A 40-year-old man was referred to the sleep center with
actigraphy and sleep logs underestimated TST and overesti- a long history of loud snoring, witnessed apnea, and
mated wake time. Actigraphy underestimated the sleep daytime sleepiness. The physical examination shows a
latency whereas sleep logs overestimated the sleep latency. BMI of 31 kg/m2, and a very long, swollen uvula. His
They found actigraphy to be more sensitive at detecting neck is 18 inches in circumference. The patient is other-
treatment effects than sleep logs. In contrast, Sivertsen wise healthy. Which of the following would you do next?
and coworkers42 found different results in a group of older A. PM (type 3 airflow, effort, SaO2, heart rate).
adults treated for primary insomnia (expected to have B. Attended PSG.
more wake time). Actigraphy slightly overestimated TST
C. Nocturnal oximetry.
and underestimated wake (see Fig. 1311B). In this study,
actigraphy provided a better estimate of TST than of wake D. Treatment with APAP.
time. E. Refer him for an OA or surgery to treat primary
snoring.
CLINICAL REVIEW QUESTIONS 3. A 40-year-old man was referred to the sleep center
with a history of loud snoring that bothers his wife. The
1. A 45-year-old man referred to the sleep laboratory with patient denies daytime sleepiness. His wife has never
a long history of snoring, witnessed apnea, and daytime noted breathing pauses. The patient has been evaluated
sleepiness. The physical examination shows a body mass by an ear-nose-throat (ENT) physician who recom-
index (BMI) of 31 kg/m2, very crowded upper airway, mends upper airway surgery for snoring. On exami-
and neck circumference of 17 inches. An unattended nation, he has a long uvula but a minimally crowded
PM (type 3) sleep study found an AHI of 3.5 events/hr upper airway. His neck circumference is 15 inches and
with the lowest SaO2 being 89%. The patient reports he his BMI is 22 kg/m2. Which of the following do you
did not sleep that well (worried about pulling out wires recommend?
from PM device). Which of the following would you do A. Proceed to have the upper airway surgery.
next?
B. Schedule for a PSG.
A. Repeat PM (type 3).
C. Schedule for oximetry (type 4 PM).
B. Attended PSG.
D. Schedule an unattended type 3 PM study.
C. Tell the patient that he doesnt have OSA.
D. Refer him for an OA or upper airway surgery to treat 4. You are asked to follow a 50-year-old woman who was
primary snoring. diagnosed with OSA about 2 years ago at another sleep
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Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 209
center. She was placed on CPAP at 8 H2O. Her initial has extreme muscle weakness. Physical examination
symptoms of snoring and daytime sleepiness have shows diffuse muscle atrophy and weakness, obesity.
resolved, and she reports using her CPAP nightly. She is Arterial blood gases on room air show arterial partial
otherwise healthy. There has been no change in her pressure of oxygen (PaO2) = 65 mm Hg, SaO2 = 92%,
weight (BMI = 31 kg/m2), her menopause status (post- arterial partial pressure of carbon dioxide (PaCO2) =
menopausal), or medications (for hypertension). Which 46 mm Hg. Which of the following do you recommend?
of the following do you recommend? A. Empirical nocturnal low-flow O2.
A. Clinical follow-up in 1 year or sooner if symptoms B. Nocturnal SpO2 arterial oxygen saturation
recur. monitoring.
B. Verify CPAP compliance objectively from machine C. PSG.
information. D. Hypnotic.
C. Order a PSG on CPAP.
D. Order a diagnostic PSG to see if CPAP is still 9. A 45-year-old woman has complaints of poor sleep
needed. with frequent nocturnal arousals. Her husband says
that she kicks her legs at night. Only mild snoring
5. A 35-year-old man with OSA had palatal surgery per- and no witnessed apneas are reported. The patient
formed 3 months ago for OSA (preoperative AHI was DENIES symptoms of the RLS. Which of the following
25/hr). He reports that his snoring is much improved is recommended?
and that his daytime sleepiness is better as well. Physical A. PSG.
examination shows a well-healed palatal scar. Which of B. Unattended type 3 PM study.
the following do you recommend?
C. Sleep diary for 2 weeks.
A. PSG.
D. Empirical treatment with a hypnotic.
B. Nocturnal oximetry.
E. Actigraphy
C. Clinical follow-up only.
D. PSG if symptoms return. 10. A 60-year-old woman is complaining of severe difficulty
initiating and maintaining sleep. This has not improved
6. A 55-year-old man was recently diagnosed with CHF. with several hypnotics and cognitive behavioral therapy
He has been treated with a beta blocker, angiotensin- for insomnia. Her husband reports mild snoring and no
converting enzyme inhibitor, and diuretic, but continues breathing pauses. She has coronary artery disease and
to have nocturnal dyspnea and frequent awakenings. He has recently undergone an angioplasty with two stents.
reports only mild snoring that is unchanged. On physi- The patient also has a long history of hypertension and
cal examination, he has minimal upper airway crowding diabetes mellitus. Her medications include clopidogrel
but has basilar crackles and 1+ pedal edema. Which of and aspirin. Physical examination shows moderate
the following do you recommend? obesity and a slightly crowded oropharynx. Which of
A. Increased diuretic dose. the following do you recommend?
B. PSG. A. Ask the patient whether she snores and/or has
C. Trial of a hypnotic to consolidate sleep. daytime sleepiness.
D. Unattended type 3 PM. B. PSG.
C. SpO2.
7. A 75-year-old man recently had a left-sided cerebrovas- D. Actigraphy.
cular accident and now has mild right hemiparesis. Per
E. Cognitive behavioral therapy.
spouse, there is no snoring or witnessed apnea. He com-
plains of insomnia and frequent nocturnal arousals. 11. A PM test is performed for insomnia and the results are
Physical examination is notable for the hemiparesis and listed here. The patient reports loud snoring but no
moderate obesity. Which of the following do you daytime sleepiness. What do you recommend?
recommend?
Monitoring time: 7 hr.
A. SpO2.
AHI (based on monitoring time) = 3/hr.
B. PSG.
Events: 13 obstructive apneas, 8 hypopneas.
C. Unattended cardiorespiratory sleep study (level 3).
Desaturations: 70, with oxygen desaturation index
D. Cognitive behavior therapy for insomnia. (ODI) of 10/hr, lowest SpO2 = 83%.
E. Empirical trial of a hypnotic. A. PSG.
8. A 16-year-old boy with Duchennes muscular dystrophy B. Evaluate raw tracings.
complains of frequent episodes of nocturnal dyspnea C. Treatment for snoring.
and frequent awakenings. He is wheelchair-bound and D. Inform the patient that OSA is not present.
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210 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
11. B. There is an inconsistency between the ODI of 10/hr 15. Baltzan MA, Kassissia I, Elkholi O, et al: Prevalence of persis-
and the AHI of 3/hr. The technical adequacy of the tent sleep apnea in patients treated with continuous positive
airway pressure. Sleep 2006;29:557563.
oximetry and flow tracings should be determined. In
16. Pittman SD, Pillar G, Berry RB, et al: Follow-up assessment of
many cases, the ODI is more accurate than the AHI. The CPAP efficacy in patients with obstructive sleep apnea using an
other explanation for the above findings is that the auto- ambulatory device based on peripheral arterial tonometry.
mated scoring did not pick up respiratory events where Sleep Breath 2006;10:123131.
a desaturation is present. Scoring may need to be manu- 17. Chediak AD: Why CMS approved home sleep testing for CPAP
coverage. J Clin Sleep Med 2008;4:1618.
ally edited. Whereas a PSG could be indicated, the first
18. Collop NA: Portable monitoring for the diagnosis of obstruc-
issue is to determine whether the PM study already per- tive sleep apnea. Curr Opin Pulm Med 2008;14:525529.
formed can provide an accurate estimate of breathing 19. Ferber R, Millman R, Coppola M, et al: ASDA standards of
abnormalities. practice: portable recording in the assessment of obstructive
sleep apnea. Sleep 1994;17:378392.
20. American Sleep Disorders Association: ASDA Standards of
Practice. Practice parameters for the use of portable recording
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36. Littner MR, Kushida DA, Anderson WM, et al: Standards of 39. Penzel T, Kesper K, Pinnow I, et al: Peripheral arterial tonom-
Practice Committee of the American Academy of Sleep Medi- etry, oximetry and actigraphy for ambulatory recording of sleep
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of sleep and circadian rhythms: an update for 2002. Sleep 40. Elbaz M, Roue GM, Lofaso F, Quera Salva MA: Utility of actig-
2003;26:337341. raphy in the diagnosis of obstructive sleep apnea. Sleep
37. Morgenthaler T, Alessi C, Friedman L, et al: Practice parame- 2002;25:527531.
ters for the use of actigraphy in the assessment of sleep and 41. Vallires A, Morin CM: Actigraphy in assessment of insomnia.
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38. Hedner J, Pillar G, Pittman SD, et al: A novel adaptive wrist 42. Sivertsen B, Omvki S, Havik OE, et al: A comparison of actig-
actigraphy algorithm for sleep-wake assessment in sleep apnea raphy and polysomnography in older adults: treatment of
patients. Sleep 2004;27:15601566. chronic primary insomnia. Sleep 2006;29:13531358.
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Appendix 13-1
4.1.3.1 Polysomnography is routinely indicated for the 3. When clinical response is insufficient or when sym-
diagnosis of sleep-related breathing disorders (SRBDs). ptoms return despite a good initial response to treat-
(Standard) ment with CPAP. In these circumstances, testing
4.1.3.2 Polysomnography is indicated for positive should be devised with consideration that a concur-
airway pressure (PAP) titration in patients with SRBDs. rent sleep disorder may be present (e.g., OSA and
(Standard) narcolepsy).
4.1.3.3 A preoperative clinical evaluation that includes
polysomnography or an attended cardiorespiratory (type 3) 4.1.3.6 Follow-up polysomnography or a cardiorespira-
sleep study is routinely indicated to evaluate for the presence tory (type 3) sleep study is NOT routinely indicated in
of obstructive sleep apnea (OSA) in patients before they patients treated with CPAP whose symptoms continue to be
undergo upper airway surgery for snoring or OSA. resolved with CPAP treatment. (Option)
(Standard) 4.1.3.7 A multiple sleep latency test is not routinely indi-
4.1.3.4 Follow-up polysomnography or an attended car- cated for most patients with SRBDs. A subjective assessment
diorespiratory (type 3) sleep study is routinely indicated for of excessive daytime sleepiness should be obtained routinely.
the assessment of treatment results in the following circum- When an objective measure of daytime sleepiness is also
stances: (Standard) required, previously published practice parameters should
be consulted. (Standard)
1. After good clinical response to oral appliance treat- 4.1.3.8 Patients with systolic or diastolic heart failure
ment in patients with moderate to severe OSA.* should undergo polysomnography if they have nocturnal
2. After upper airway surgery in patients with moderate symptoms suggestive of SRBDs (disturbed sleep, nocturnal
to severe OSA, to ensure therapeutic benefit. dyspnea, snoring) or if they remain symptomatic despite
3. After surgical or dental treatment of patients with optimal medical management of congestive heart failure
SRBDs whose symptoms return despite a good initial (CHF). (Standard)
response to treatment. 4.1.3.9 Patients with coronary artery disease should be
evaluated for symptoms and signs of sleep apnea. If there is
4.1.3.5 Follow-up polysomnography is routinely indi- suspicion of sleep apnea, the patients should undergo a
cated for the assessment of treatment results in the following sleep study. (Guideline)
circumstances: (Standard) 4.1.3.10 Patients with history of stroke or transient isch-
emic attacks should be evaluated for symptoms and signs of
1. After substantial weight loss (e.g., 10% of body weight) sleep apnea. If there is suspicion of sleep apnea, the patients
has occurred in patients on continuous positive airway should undergo a sleep study. (Option)
pressure (CPAP) for treatment of SRBDs to ascertain 4.1.3.11 Patients referred for evaluation of significant
whether CPAP is still needed at the previously titrated tachyarrhythmias or bradyarrhythmias should be ques-
pressure. tioned about symptoms of sleep apnea. A sleep study is
2. After substantial weight gain (e.g., 10% of body weight) indicated if questioning results in a reasonable suspicion
has occurred in patients previously treated with CPAP that OSA or central sleep apnea (CSA) is present.
successfully, who are again symptomatic despite the (Guideline)
continued use of CPAP, to ascertain whether pressure
adjustments are needed. Polysomnography in Other Medical Disorders
4.2.3.1 For patients with neuromuscular disorders and
6
*Amended in Practice Parameters for Oral Appliance treatment to sleep-related symptoms, polysomnography is routinely
indicated to evaluate symptoms of sleep disorders that are
include mild, moderate, and severe OSA.
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213
214 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
not adequately diagnosed by obtaining a sleep history, assess- 4.4.4.2 Interpretation of polysomnography with video
ing sleep hygiene, and reviewing sleep diaries. (Standard) and extended EEG montage requires skills in both sleep
4.2.3.2 Polysomnography is not indicated to diagnose medicine and seizure recognition. Polysomnographers and
chronic lung disease. (Standard) electroencephalographers who are not experienced or
trained in recognizing and interpreting both polysomno-
Alternate Tools graphic and EEG abnormalities should seek appropriate con-
sultation or should refer patients to a center where this
4.2.5.1 Nocturnal oximetry may be helpful or sufficient in expertise is available. (Option)
assessing a disorder in which the only or principal clinical 4.4.4.3 A paper speed of at least 15 mm/sec and preferably
issue is the level of hypoxemia and when determining sleep 30 mm/sec is recommended to enhance the recognition of
stages or assessing sleep apnea is not necessary. (Standard) seizure activity. In digital EEG recordings, the sampling rate
must be adequate to identify brief paroxysmal discharges.
4.3 Narcolepsy (Option)
4.3.3.1 Polysomnography and a multiple sleep latency test 4.5 Restless Legs Syndrome and Periodic Limb
performed on the day after the polysomnographic evaluation
Movement Disorder
are routinely indicated in the evaluation of suspected narco-
lepsy. (Standard) 4.5.3.1 Polysomnography is indicated when a diagnosis of
periodic limb movement disorder is considered because of
4.4 Parasomnias and Seizure Disorders complaints by the patient or an observer of repetitive limb
movements during sleep and frequent awakenings, frag-
4.4.1.1 A clinical history of any parasomnia must describe mented sleep, difficulty maintaining sleep, or excessive
and characterize the behaviors in detail with special empha- daytime sleepiness. (Standard)
sis on age of onset, time of night, frequency, regularity, and 4.5.3.2 Polysomnography is not routinely indicated to
duration of episodes. (Standard) diagnose or treat restless legs syndrome, except where uncer-
4.4.1.2 Common, uncomplicated, noninjurious parasom- tainty exists in the diagnosis. (Standard)
nias, such as typical disorders of arousal, nightmares, enure- 4.5.4.1 The minimum channels required for the evalua-
sis, sleeptalking, and bruxism, can usually be diagnosed by tion of periodic limb movements and related arousals include
clinical evaluation alone. (Standard) EEG, EOG, chin EMG, and left and right anterior tibialis
4.4.1.3 A clinical history, neurologic examination, and a surface EMG. Respiratory effort, airflow, and oximetry
routine electroencephalogram (EEG) obtained while the should be used simultaneously if sleep apnea or upper-
patient is awake and asleep are often sufficient to establish airway resistance syndrome is suspected to allow a distinc-
the diagnosis and permit the appropriate treatment of a tion to be made between inherent periodic limb movements
sleep-related seizure disorder. The need for a routine EEG and those limb movements associated with respiratory
should be based on clinical judgment and the likelihood that events. (Standard)
the patient has a sleep-related seizure disorder. (Option) 4.5.4.2 Intraindividual night-to-night variability exists in
4.4.3.5 Polysomnography may be indicated when the pre- patients with periodic limb movement sleep disorder, and a
sumed parasomnia or sleep-related seizure disorder does not single study might not be adequate to establish this diagno-
respond to conventional therapy. (Option) sis. (Option)
4.4.3.6 Polysomnography is not routinely indicated in
cases of typical, uncomplicated, and noninjurious parasom- 4.6 Depression with Insomnia
nias when the diagnosis is clearly delineated. (Option)
4.4.3.7 Polysomnography is not routinely indicated for 4.6.3.1 Neither a polysomnogram nor a multiple sleep latency
patients with a seizure disorder who have no specific com- test is routinely indicated in establishing the diagnosis of
plaints consistent with a sleep disorder. (Option) depression. (Standard)
4.4.4.1 The minimum channels required for the diagnosis
of parasomnia or sleep-related seizure disorder include 4.7 Circadian Rhythm Sleep Disorders
sleep-scoring channels (EEG, electro-oculogram [EOG],
chin electromyogram [EMG]); EEG using an expanded bilat- 4.7.3.1 Polysomnography is not routinely indicated for the
eral montage; and EMG for body movements (anterior tibi- diagnosis of circadian rhythm sleep disorders. (Standard)
alis or extensor digitorum). Audiovisual recording and
documented technologist observations during the period of
study are also essential. (Option)
From Kushida CA, Littner MR, Morgenthaler T, Alessi CA: Practice parameters for the indications for polysomnography and related procedures: an
update for 2005. Sleep 2005;28:499521.
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Appendix 13-2
1.1 Portable monitoring (PM) for the diagnosis of obstruc- 2.2 The sensor to detect apnea is an oronasal thermal
tive sleep apnea (OSA) should be performed only in con- sensor and to detect hypopnea is a nasal pressure transducer.
junction with a comprehensive sleep evaluation. Clinical Ideally, PMs should use both sensor types.
sleep evaluations using PM must be supervised by a practi- 2.3 Ideally, the sensor for identification of respiratory
tioner with Board certification in Sleep Medicine or an indi- effort is either calibrated or uncalibrated inductance
vidual who fulfills the eligibility criteria for the Sleep plethysmography.
Medicine Certification Examination. In the absence of a 2.4 The sensor for the detection of blood oxygen is pulse
comprehensive sleep evaluation, there is no indication for oximeter with appropriate signal averaging time and accom-
the use of PM. modation for motion artifact.
1.2 Provided that the recommendations of 1.1 have been
satisfied, PM may be used as an alternative to polysomnog-
raphy (PSG) for the diagnosis of OSA in patients with a high 3. Methodology for Portable Monitoring
pretest probability of moderate to severe OSA. PM should
NOT be used in patient groups described in 1.2.1, 1.2.2, and 3.1 PM testing should be performed under the auspices of
1.2.3 (those with co-morbidities, other sleep disorders, or for an American Academy of Sleep Medicine (AASM)accred-
screening). ited comprehensive Sleep Medicine Program with policies
1.2.1 PM is not appropriate for the diagnosis of OSA in and procedures for sensor application, scoring, and interpre-
patients with significant co-morbid medical conditions that tation of PM. A quality/performance improvement program
may degrade the accuracy of PM, including, but not limited for PM including interscorer reliability must be in place to
to, moderate to severe pulmonary disease, neuromuscular ensure accuracy and reliability.
disease, or congestive heart failure (CHF). 3.2 An experienced sleep technician, sleep technologist,
1.2.2 PM is not appropriate for the diagnostic evaluation or appropriately trained health care practitioner must
of OSA in patients suspected of having other sleep disorders, perform the application of PM sensors or directly educate
including central sleep apnea, periodic limb movement dis- the patient in correct application of sensors.
order (PLMD), insomnia, parasomnias, circadian rhythm 3.3 PM devices must allow for the display of raw data
disorders, or narcolepsy. for manual scoring or editing of automated scoring by
1.2.3 PM is not appropriate for general screening of a trained and qualified sleep technician/technologist.
asymptomatic populations. Evaluation of PM data must include review of the raw
1.3 PM may be indicated for the diagnosis of OSA in data by a Board-certified sleep specialist or an individual
patients for whom in-laboratory PSG is not possible by who fulfils the eligibility criteria for sleep medicine
virtue of immobility, safety, or critical illness. certification.
1.4 PM may be indicated to monitor the response to 3.4 Scoring criteria should be consistent with current
noncontinuous positive airway pressure (CPAP) treatments published AASM standards for scoring apneas and
for OSA, including oral appliances, upper airway surgery, hypopneas.
and weight loss. 3.5 Due to the known rate of false-negative PM tests,
2.1 At a minimum, the PMs must record airflow, respira- in-laboratory polysomnography (PSG) should be performed
tory effort, and blood oxygenation. The type of biosensors in cases where PM is technically inadequate or fails to estab-
used to monitor these parameters for in-laboratory PSG are lish the diagnosis of OSA in patients with a high pretest
recommended for use in PMs. probability.
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216 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
3.6 A follow-up visit with a physician or other appropri- 3.7 Unattended PM can be used with the parameters
ately trained and supervised health care provider should be above in the patients home.
performed on all patients undergoing PM to discuss the
results of the test.
From Collop NA, Anderson WM, Boehlecke B, et al: Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep
DaneshGroup.com
apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3:737747.
Appendix 13-3
Local Carrier Determinations for indicative of OSA if performed attended in a sleep laboratory
Polysomnography and Sleep Testing facility. Type 1 devices are capable of recordings of all of the
physiologic parameters and signals defined for PSG. The
(L29949)Excerpts
recording is furnished in a sleep laboratory facility in which
Prior to ordering the tests, the patient must have a face-to- a technologist is physically present to supervise the record-
face clinical evaluation by a physician. The evaluation must ing during sleep time and has the ability to intervene if
include: needed. Minimal requirements include recording of electro-
encephalogram (EEG), electro-oculogram (EOG), chin elec-
1. A sleep history and physical examination including, tromyogram (EMG), anterior tibialis EMG, electrocardiogram
but not limited to, snoring, daytime sleepiness, (ECG), airflow, respiratory effort, and oxygen saturation.
observed apneas, choking or gasping during sleep, Body position must be documented or objectively measured.
morning headaches; and Trained personnel must be in constant attendance and able
2. Epworth sleepiness scale; and to intervene.
3. Physical examination that documents body mass A type 2 sleep testing device is covered when used to aid
index, neck circumference, and a focused cardiopul- the diagnosis of OSA in beneficiaries who have clinical signs
monary and upper airway evaluation. and symptoms indicative of OSA if performed unattended
in or out of a sleep laboratory facility or attended in a sleep
Accreditation laboratory facility. Type 2 devices are portable devices that
may measure the same channels as type 1 testing, except that
All centers billing sleep studies must maintain proper a heart-rate monitor can replace the ECG. This device has a
certification/accreditation documentation on file that indi- minimum of seven channels (e.g., EEG, EOG, EMG, ECG-
cates it is accredited by the American Academy of Sleep heart rate, airflow, respiratory effort, and oxygen saturation
Medicine (AASM) or that it is accredited as a sleep labora- this type of device monitors sleep staging). A sleep technician
tory by the Joint Commission. is not necessarily in constant attendance in type 2 studies but
is needed for preparation.
Physician Training/Certification A type 3 sleep testing device is covered when used to aid
the diagnosis of OSA in beneficiaries who have clinical signs
All sleep tests must be reviewed and the tests must be inter- and symptoms indicative of OSA if performed unattended
preted by either: in or out of a sleep laboratory facility or attended in a sleep
laboratory facility. Type 3 devices monitor and record a
1. A Diplomate of the American Board of Sleep Medicine minimum of four channels and must record ventilation or
(ABSM) OR airflow, heart rate or ECG, and oxygen saturation. A sleep
2. A Diplomate in Sleep Medicine by a member board of technician is not necessarily in constant attendance in type
the American Board of Medical Specialties (ABMS) OR 3 studies but is needed for preparation.
3. An active physician staff member of an AASM- A type 4 sleep testing device measuring three or more
accredited sleep center or sleep laboratory OR channels, one of which is airflow, is covered when used to
4. An active physician staff member of a Joint aid the diagnosis of OSA in beneficiaries who have signs and
Commissionaccredited sleep laboratory. symptoms indicative of OSA if performed unattended in or
out of a sleep laboratory facility or attended in a sleep labora-
tory facility. Type 4 devices must include airflow as one of
Home Sleep Testing the required three channels. Other measurements may
include oximetry and heart rate. A sleep technician is not
Type 1 PSG is covered when used to aid the diagnosis of necessarily in constant attendance in type 4 studies but is
OSA in beneficiaries who have clinical signs and symptoms needed for preparation.
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218 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
PAT. A sleep testing device measuring three or more indicative of OSA if performed unattended in or out of a
channels that include actigraphy, oximetry, and peripheral sleep laboratory facility or attended in a sleep laboratory
arterial tone is covered when used to aid the diagnosis facility. A sleep technician is not necessarily in constant
of OSA in beneficiaries who have signs and symptoms attendance in such studies but is needed in preparation.
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Chapter 14
Chapter Points (see also Box 146) 3 consecutive epochs of stage N1, or after a single
The ESS measures self-rated average sleep propensity epoch of any other sleep stage (N2, N3, or R). The sleep
(chance of dozing) over eight common situations. The latency is defined as the time from lights out until the
scale ranges from 0 to 24 with 10 or less being first epoch of any stage of sleep.
considered normal.
The MSLT objectively measures the tendency to fall
asleep (MSL) and the propensity to have SOREMPs. Excessive daytime sleepiness (EDS) is defined as sleepiness
The MSLT consists of five naps spaced every 2 hours that occurs in a situation when an individual would usually
beginning about 1.5 to 3 hours after the wake-up time. be expected to be awake and alert. EDS is said to affect at
The MSLT should be preceded by a PSG to detect least 5% of the general population. Causes of EDS include
causes of sleepiness such as sleep apnea and to verify sleep deprivation/inadequate sleep, a number of sleep disor-
adequate sleep before the MSLT. MSLT findings are not ders (obstructive sleep apnea [OSA], narcolepsy, and idio-
considered reliable if less than 360 minutes of sleep is pathic hypersomnia), sleep disturbance from medical
recorded. conditions, and medication side effects. The periodic limb
The MSLT diagnostic criteria for narcolepsy include an movement disorder can be associated with EDS but is a fairly
MSL of 8 minutes or less and 2 or more SOREMPs. uncommon disorder. Depression and mood disorders are
However, a negative MSLT does NOT rule out narcolepsy common but are more likely to be associated with insomnia
because the sensitivity of the MSLT for diagnosing complaints than with EDS. However, up to 15% of depressed
narcolepsy is only approximately 70% to 80%. patients may complain of daytime sleepiness. The degree of
The MSLT diagnostic criteria for idiopathic sleepiness can be assessed by subjective and objective mea-
hypersomnia include an MSL of less than 8 minutes sures of sleepiness.
and 0 to 1 SOREMPs in five naps.
Up to 6% of untreated patients with OSA will have an SUBJECTIVE MEASURES
MSLT meeting criteria for narcolepsy.
If narcolepsy in addition to OSA is suspected, patients Questionnaires such as the Stanford Sleepiness Scale or the
should have a PSG on CPAP to document good Epworth Sleepiness Scale (ESS)1,2 are measures of self-rated
treatment and adequate sleep and a subsequent MSLT symptoms of sleepiness. The Stanford Sleepiness Scale (Table
on CPAP. This assumes that OSA has been well treated 141) measures subjective feelings of sleepiness (fogginess,
with CPAP for a period of time (e.g., documented CPAP beginning to lose interest in staying awake). A score above
adherence). 3 is considered sleepy. In contrast, the ESS measures self-
Medications that may affect MSLT sleep latency rated average sleep propensity (chance of dozing) over eight
(stimulants, sedatives) or the number of SOREMPs common situations that almost everyone encounters. The
(REM-suppressant medications) should be withdrawn propensity to fall asleep is rated as 0, 1, 2, or 3 where 0 cor-
for 10 days to 2 weeks preceding testing if possible. responds to never and 3 to a high chance of dozing (Table
The MWT objectively quantifies a patients ability to 142). The maximum score is 24 and normal is assumed to
remain awake in a situation predisposing to sleep be 10 or less. ESS scores of 16 or greater are associated with
(dimly lighted room, sitting on a bed). The 40 minute severe sleepiness.
MWT is recommended. Each MWT nap is terminated The ESS correlates roughly with the severity of OSA
after 40 minutes if no sleep has been recorded; after (apnea-hypopnea index [AHI]) (Table 143)2,3 and improves
(lower score) after continuous positive airway pressure
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220 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness
TABLE 142
Epworth Sleepiness Scale
SITUATION: USUAL WAY OF LIFE CHANCE OF DOZING
10
IN RECENT TIMES SCORE 0, 1, 2, 3*
Mean Epworth Sleepiness Scale
24 BOX 141
Indications for Use of the Multiple Sleep
Latency Test
18
MSLT INDICATED
Confirmation of suspected narcolepsy (Standard).
Suspected idiopathic hypersomnia (Option)to help
ESS
12
differentiate idiopathic hypersomnia from narcolepsy.
MSLT NOT INDICATED (STANDARD)
6 Routine evaluation of patients with OSA.
Change in sleepiness in OSA after CPAP treatment.
Evaluation of sleepiness in medical or neurologic
0 conditions (other than narcolepsy).
0 5 10 15 Evaluation of sleepiness in insomnia.
Sleep latency (min)
REPEAT MSLT INDICATED (STANDARD)
FIGURE 142 Scatter plot of Epworth Sleepiness Scale (ESS) score versus mean sleep
Initial MSLT affected by extraneous/unusual conditions.
latency on the multiple sleep latency test (MSLT) in 522 drug-free patients with
Appropriate study conditions not present during initial
narcolepsy. The line represents a quadratic fit. From Sangal RB, Mitler MM, Sangal JM:
testing.
Subjective sleepiness ratings (Epworth Sleepiness Scale) do not reflect the same parameter
of sleepiness as objective sleepiness (maintenance of wakefulness test) in patients with Ambiguous or uninterpretable findings.
narcolepsy. Clin Neurophysiol 1999;110:21312135. Clinical suspicion of narcolepsy not confirmed by an
earlier MSLT.
AASM Levels of recommendation: Standard > Guideline > Option.
AASM = American Academy of Sleep Medicine; CPAP = continuous positive
airway pressure; MSLT = multiple sleep latency test; OSA = obstructive sleep
apnea.
From Littner MR, Kushida C, Wise M, et al: Practice parameters for clinical use
modest correlation between the sleep latencies as deter- of the multiple sleep latency test and the maintenance of wakefulness test.
mined by the MSLT and MWT. Of interest, the correlation Sleep 2005;28:113121.
between the MSLT and the MWT latencies (r = 0.52, P <
.001) was stronger than correlations between the ESS and the
MWT or the MSLT latencies (r = 0.29, P < .001 and r =
0.27, P < .001, respectively).6
parameters concerning the use of the MSLT10 and prior
guidelines published by this organization.8,9
OBJECTIVE MEASURES A standard-level recommendation states the MSLT is a
validated objective measure of the ability or tendency to fall
Multiple Sleep Latency Test
asleep. As mentioned previously, the sleep latency is the
The MSLT712 is used to support a diagnosis of narcolepsy parameter that reflects the degree of daytime sleepiness. The
and/or quantify the degree of daytime sleepiness. The MSL MSLT is indicated for evaluation of patients with suspected
(lights out to sleep onset) is a measure of the degree of narcolepsy or idiopathic hypersomnia, but NOT for evalua-
daytime sleepiness. The sleep latency is the time from lights tion of OSA patients before or after treatment, or to quantify
out to the beginning of the first epoch of any stage of sleep. sleepiness in patients with insomnia, medical, or neurologic
The test is terminated if no sleep occurs within 20 minutes disorders (other than narcolepsy). The practice parameters
of lights out (maximum sleep latency is 20 min). After sleep also outlined conditions under which a repeat MSLT is indi-
onset, the MSLT continues for 15 minutes of clock time. If cated. These include a prior MSLT with unusual conditions
rapid eye movement (REM) sleep occurs within this time or if the initial MSLT was negative in a patient with a strong
period, a sleep-onset rapid eye movement period (SOREMP) clinical suspicion of narcolepsy (see Box 141).
is said to have occurred. The MSLT criteria used to support
a diagnosis of narcolepsy are an MSL of 8 minutes or less MSLT Protocol
and 2 or more SOREMPs.13 Many factors can alter the find- A standardized MSLT protocol performed by an experienced
ings of the MSLT and considerable clinical judgment is sleep technologist (Boxes 142 and 143) is required to
needed to avoid an error in interpretation. The MSLT may obtain accurate testing results. A four-nap MSLT is not reli-
be used in the research setting as an objective measure of able for the diagnosis of narcolepsy unless 2 SOREMPs have
daytime sleepiness of a given population of interest or to occurred after four naps. Even then, a five-nap MSLT is sug-
assess a response to treatment. The clinical indications for gested because the physician reading the study may disagree
the use of the MSLT (Box 141) are outlined by the current with the technologists assessment of SOREMPs. A technolo-
American Academy of Sleep Medicine (AASM) practice gist experienced in performing the MSLT is essential.811 The
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222 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness
have an MSL greater than 5 minutes and 16% of normal is medically practical. Abrupt withdrawal before the study
controls have an MSL below 5 minutes.11,13 should also be avoided.
BOX 144 16
Factors Known to Affect the MSL 15
Age.
14
Sleep latency (minutes)
8
10 20 30 40 50 60 70 80
16 Age (yr)
15
14
FIGURE 144 Effects of age on the mean sleep latency (MSL) during the MSLT in
13 normal individuals. The MSL increases with age. A linear regression is shown. From
Sleep latency (minutes)
12 Arand D, Bonnet M, Hurwitz T, et al: A review by the MSLT and MWT Task Force of the
11 Control
Standards of Practice Committee of the AASM. The clinical use of the MSLT and MWT. Sleep
10 2005;28:123144.
9
8
7
6
5
4
Narcolepsy BOX 145
3
2
1 Causes of Sleep-Onset Rapid Eye Movement
0 Periods
00
00
00
00
00
Narcolepsy
0:
4:
6:
8:
12
-1
-1
-1
-1
0-
Untreated OSA
10
30
30
30
:3
:
:
09
11
13
15
17
TABLE 146
Multiple Sleep Latency Test Findings in Patients Evaluated for Daytime Sleepiness
NARCOLEPSY WITH NARCOLEPSY WITHOUT SLEEP-RELATED BREATHING
CATAPLEXY CATAPLEXY* DISORDER
N 106 64 1251
MSL < 5 min 87% 81% 39%
MSL < 8 min 93% 97% 63%
2 SOREMPs 74% 91% 7%
2 SOREMPs + 67% 75% 4%
MSL < 5 min
2 SOREMPs + 71% 91% 6%
MSL < 8 min
SOREMP on PSG 33% 24% 1%
*Diagnosis made in patients with narcolepsy without cataplexy by repeat MSLT (if necessary).
MSL = mean sleep latency; MSLT = multiple sleep latency test; PSG = nocturnal polysomnography; SOREMPs = sleep-onset rapid eye movement periods.
From Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620629.
Stage W
LO = lights out; W = wake.
TABLE 1412
Nap 5
Epoch 30 31 32 33 34 35 36 37 38 39
Tables 148 to 1412). In the tables, the lights out time (LO)
is assumed to be at the end of the epoch listed. The epochs Stage LO W W W W 2 W 1 2 3
are 30 seconds in duration. The light gray shading marks the Epoch 40 41 42 43 44 45 46 47 48 49
sleep latency, and the dark gray the REM latency.
Stage W 1 2 3 R R W 1 2 2
Nap 1 In nap 1, the sleep latency is 1.5 minutes (start of Epoch 50 51 52 53 54 55 56 57 58 59
epoch 34start of epoch 31) and the REM latency is 10 Stage 2 R R R 1 2 3 W 1 1
epochs or 5 minutes (start of epoch 44start of epoch 34).
Epoch 60 61 62 63 64 65 66 67 68
The MSLT continues for 15 minutes of clock time after sleep
onset to start of epoch 64 (start of epoch 34 + 30 epochs = Stage 1 W W W W
to start of epoch 64) (Table 148). LO = lights out; R = rapid eye movement; W = wake.
TABLE 1413
Example of a Multiple Sleep Latency Test Report
REM
NAPS LIGHTS OUT LIGHTS ON SLEEP LATENCY (MIN) REM (YES OR NO) LATENCY (MIN)
1 8:10 am 8:24:30 am 1.5 1 5.0
2 10:05 am 10:25 am 20.0 0 N/A
3 12:05 pm 12:21 pm 1.0 0 N/A
4 2:06 pm 2:22:30 pm 1.5 1 3.0
5 4:08 pm 4:15 pm 2.0 1 4.5
Mean: 5.2 SOREMPs: 3
N/A = not applicable; REM = rapid eye movement; SOREMP = sleep-onset rapid eye movement period.
100 V
EPOCH 10
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
EPOCH 11
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 145 Two 30-second epochs of sleep during an MSLT. Lights out was at the end of epoch 9. Epochs 10 and 11 are stage W.
epoch 31 = 4 epochs). The first epoch of stage R is epoch 44. LO is assumed to have occurred at the end of epoch 9.
Therefore, the REM latency is 9 epochs or 4.5 minutes. The Because epoch 12 is the first epoch of sleep (stage N1), the
MSLT continues for 30 epochs after sleep onset until the start sleep latency is 1 minute. The REM latency is determined by
of epoch 65 (start of epoch 35 + 30 = start of epoch 65) (Table the time from the start of epoch 12 to the start of REM sleep.
1412). The first epoch of REM sleep is epoch 15. Therefore, the
A summary of the data from these naps appears in Table REM latency is 3 epochs or 1.5 minutes.
1413.
The typical MSLT report summarizes the reason for per-
Maintenance of Wakefulness Test
forming the test, pertinent findings on the preceding PSG,
associated findings from the sleep diary and urine drug The MWT was designed to test the patients ability to stay
screen, and a interpretation of the MSLT findings. The time awake.10,11,18 The recent AASM practice parameters10 regard-
of the start of each nap should also be specified along with ing the MWT state:
any unusual circumstances or deviations from the standard
protocol. 1. The MWT is a validated objective measure of the ability
to stay awake for a defined time. (Standard)
Clinical Example #2 Thirty-second epochs during an MSLT 2. The MWT is used in association with clinical history to
(epoch numbers 1015) are shown in Figures 145 to 147. assess the ability to maintain wakefulness. (Standard)
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228 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness
100 V
EPOCH 12
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
EPOCH 13
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 146 The next two 30-second epochs of the MSLT starting in Figure 145. Epochs 12 and 13 are stage N1. Epoch 12 is sleep onset.
100 V
EPOCH 14
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
EPOCH 15
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 147 Continuation of the MSLT starting in Figure 145. Epoch 14 is stage N2 and epoch 15 is stage R.
3. The MWT 40-minute protocol is recommended when stay awake as reflected by the MSL.11,1820 The study is
the sleep clinician requires objective data to assess believed to assess different information than can be
an individuals ability to remain awake. (Option) attained with the MSLT.21 For example, some patients
with a short MSLT sleep latency may have a normal
Although the MWT has been used in both the MWT sleep latency. In research, the MWT is often used
20-minute and the 40-minute versions,1820 the longer test to document the effects of treatment from alerting
was recommended by the AASM practice parameters. agents.22 The AASM practice parameters for the use of
The MWT has been used to assess the effects of sleep the MWT list specific indications as summarized in the
disturbance and treatment on the ability of patients to following paragraph.10
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Chapter 14 Subjective and Objective Measures of Daytime Sleepiness 229
1. The MWT 40-minute protocol may be used to assess an Four trials at 2-hr intervals.
individuals ability to remain awake when his or her ability MWT begins 1.53 hr after the patients usual wakeup
to remain awake constitutes a public or personal safety time (0900 or 1000 hr).
issue. (Option)
Performance of a PSG is not requiredneed decided by
2. The MWT may be indicated in patients with excessive clinician based on clinical circumstances.
sleepiness to assess response to treatment. (Guideline)
Sleep log not requiredneed decided by clinician based
MWT Protocol on clinical circumstances.
The MWT protocol recommended by the AASM practice ROOM CONDITIONS
parameters10 is outlined in Table 1414. The 40-minute nap Light source positioned behind the subjects head such
protocol is recommended. A four-nap protocol is standard. that it is just out of his or her field of vision and should
Note that the sleep latency is defined as the time from LO deliver an illuminance of 0.100.13 lux at the corneal level
to the start of any epoch of sleep. The requirement of a (a 7.5-W night light can be used, placed 1 ft off the floor
preceding PSG is left up to the clinician. In contrast to the and 3 ft laterally removed from the subjects head).
MSLT, during the MWT, the patient sits upright in bed (head Room temperature for patient comfort.
and shoulders comfortably supported) and the instruction
before LO is Please sit still and remain awake for as long as Subject seated in bed, the back and head supported by a
possible. Look directly ahead of you, and do not look directly bedrest (bolster pillow) such that the neck is not
uncomfortably flexed or extended.
at the light. Of note, it is essential that the testing individual
be observed and not allowed to use extreme measures OTHER CONSIDERATIONS
(hitting, moving in bed) to maintain alertness. Drug screening may be indicated. If ordered, it is usually
Each MWT nap lasts a maximum of 40 minutes after LO. performed on the morning of MWT (timing can be
The nap is terminated if no sleep has occurred in 40 changed by clinician).
minutes or if three consecutive epochs of stage N1 are
Conventional recording montage for MWT includes
noted or any single epoch of other stages of sleep. A low- frontal, central, occipital EEG as well as right and left EOGs,
intensity light is present behind the patients head just out of chin EMG, ECG.
the visual field (usually a nightlight). The MWT definitions
and recommended information to be included in the MWT MWT NAP PROTOCOL
report are listed in Table 1415. The patient should be asked if she or he needs to go to
the bathroom.
MWT Normative Data Biocalibration instructions: (1) Lie quietly with your eyes
Normative data for the MWT from a systematic review of open for 30 sec, (2) close both eyes for 30 sec, (3) without
MWT studies are displayed in Table 1416. Using the moving your head, look to the right, then left, then right,
40-minute MWT, 59% of patients were able to stay awake for then left, right, and then left, (4) blink eyes slowly for five
40 minutes on each nap. The 95% lower confidence limit was times, (5) clinch or grit your teeth tightly together.
8 minutes (97.5% had MSL > 8 min). Conversely, these data Light breakfast is recommended at least 1 hr before the
do little to set a standard for individuals in whom alertness first trial.
is essential for personal and public safety. Certainly, staying
awake for all trials is an appropriate expectation for individu- A light lunch is recommended immediately after
termination of the second/noon trial.
als requiring the highest level of safety. Therefore, whereas a
MSL less than 8 minutes is abnormal, an MSL of 8 to 40 Instructions: Please sit still and remain awake for as
minutes is of uncertain significance. A normal MWT long as possible. Look directly ahead of you, and do
finding is no guarantee of what will happen in the work not look directly at the light.
environment. The ability to maintain alertness (different Trials are ended after 40 min if no sleep occurs, or after
than the ability to maintain wakefulness) may depend on unequivocal sleep, defined as three consecutive epochs of
adherence to treatment, prior total sleep time, medication stage 1 sleep or one epoch of any other sleep stage.
side effects, and circadian factors. Of note, the sleep latency Patients are not allowed to use extraordinary measures to
on the MWT increases with age similar to the sleep latency stay awake such as singing or slapping the face.
on the MSLT.11 ECG = electrocardiogram; EEG = electroencephalogram;
EMG = electromyogram; EOG = electro-oculogram; MWT = maintenance of
Relationship between the MSLT and the MWT wakefulness test; PSG = polysomnography.
From Littner MR, Kushida C, Wise M, et al: Practice parameters for clinical use
Some of the differences in MSLT and MWT protocols are of the multiple sleep latency test and the maintenance of wakefulness test.
outlined in Table 1417. When Sangal and associates21 Sleep 2005;28:113121.
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230 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness
TABLE 1418
0
Very sleepy Sleepy Alert Controls
(019 min) (2033 min) (3440 min)
20
FIGURE 149 The mean number of inappropriate line crossings (ILCs) in four groups
of patients divided by the MWT sleep latency. The very sleepy and sleepy groups had
15 significantly more ILCs than the alert and control groups (*P < .05). From Philip P,
Sagaspe P, Taillard J, et al. Maintenance of wakefulness test, obstructive sleep apnea
MSLT mean
Potential airplane pilots must undergo an aeromedical makes the MSLT interpretation problematic if fewer than 2
examination (AME) by a Federal Aviation Administration SOREMPs are noted. Conversely, discontinuation of antide-
(FAA)designated medical examiner in order to receive a pressant medication must be done cautiously. Weaning the
medical certificate. If there is evidence of OSA, the patient antidepressant is recommended rather than abrupt discon-
must be evaluated. If OSA is present, the disorder must be tinuation. Close patient follow-up and coordination of care
adequately treated and a waiver is then needed to allow a with the physician who prescribed the medication. In some
patient with OSA to obtain a medical certificate and fly patients with severe depression, the risks may outweigh the
(Appendix 141). At the discretion of the examiner, an potential benefits. If patients have significant OSA, this dis-
MWT may be requested. However, the criterion for what order must be effectively treated (objective CPAP adherence
constitutes an acceptable MSL is not specified. documented) before a MSLT evaluation to diagnose narco-
lepsy. Finally, a negative MSLT result does not rule out
Limitations of MSLT and MWT Key points concerning the MSLT narcolepsy and a significant proportion of patients with
and MWT and the limitations of the tests are outlined in narcolepsy and cataplexy may have a negative study on any
Box 146. Many factors can alter the MSL on the MSLT given day.12
including prior sleep deprivation and medications. Evalua-
tion of shift workers or patients with a delayed circadian
CLINICAL REVIEW QUESTIONS
phase is problematic. The MSL by MSLT and the MSL by
MWT do not separate groups of normal individuals from 1. Which of the following are the MSLT diagnostic criteria
groups with sleep disorders causing EDS. Considerable for narcolepsy?
overlap in the MSL values occurs. If a patient is taking an A. MSL < 5 minutes and 2 or more SOREMPs in five
antidepressant that is known to suppress REM sleep, this naps.
B. MSL < 8 minutes and 2 or more SOREMPs in five
naps.
BOX 146
C. MSL 8 minutes and 2 or more SOREMPs in five
Key Points and Limitations of Multiple Sleep naps.
Latency Test and Maintenance of Wakefulness Test
D. MSL < 10 minutes and 2 or more SOREMPs in five
1. Proper interpretation of an MSLT requires analysis of the naps.
preceding nocturnal sleep study, a careful medication
history, and knowledge of the sleep habits (diary) for at 2. After the first epoch of sleep occurs, how many minutes
least 1 wk preceding the MSLT. are recorded before the MSLT is terminated (beginning
2. Previous sleep deprivation (sleep restriction) can affect with the start of the first epoch of sleep)?
the MSL.
A. 15 minutes of clock time.
3. No validated normal MSLT findings exist outside of the
usual testing hours of 0800 to 1800. Therefore, B. 15 minutes of sleep.
evaluation of shift workers or patients with a delayed C. Until the first epoch of unequivocal REM sleep.
circadian phase is problematic. D. 20 minutes of clock time.
4. Due to large standard deviations, MSLs determined by
the MSLT and MWT do not separate normal populations 3. After lights out, how many minutes of continuous wake
from those with sleep disorders such as narcolepsy. are allowed before an MSLT nap is terminated (maximum
5. MSLT diagnostic criteria are not validated for patients sleep latency)?
younger than 8 years of age. A. 15 minutes.
6. Antidepressants are widely used but are highly
problematic for MSLT.
B. 20 minutes.
7. As a diagnostic test for narcolepsy, the MSLT is specific if C. 10 minutes.
OSA and other causes of SOREMPs are ruled out. D. 40 minutes.
However, a significant percentage of false-negative
MSLTs can occur (sensitivity ~70%). 4. Which of the following is true concerning the MWT?
8. A small but clinically significant proportion of untreated A. A 20-minute test is recommended.
OSA patients can have 2 or more SOREMPs on the MSLT. B. A PSG must precede testing.
Therefore, if OSA is present, this should be adequately
treated before the MSLT can be used to support a C. A 40-minute test is recommended.
diagnosis of narcolepsy. D. The patient is supine during testing.
9. MWT results cannot be assumed to necessarily reflect a
patients ability to maintain alertness during real-life 5. Which of the following are true about the recommended
conditions. MSLT protocol?
MSL = mean sleep latency; MSLT = multiple sleep latency test; A. PSG (required), patient out of bed between naps and
MWT = maintenance of wakefulness test; OSA = obstructive sleep apnea; observed to prevent sleep (required).
SOREMPs = sleep-onset rapid eye movement periods.
B. Sleep diary for 1 to 2 weeks before MSLT (required).
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Chapter 14 Subjective and Objective Measures of Daytime Sleepiness 233
C. Urine drug screen (required). showed moderate to severe OSA. After treatment with
D. Stop cigarette smoking 30 minutes before a nap CPAP, the patient remained somewhat sleepy and began
(optional). taking modafinil (alerting agent). To receive medical
clearance for a pilots license, a PSG (to document ade-
6. About what percentage of normal individuals will have quate CPAP) with a subsequent MWT was ordered. The
an MSL 8 minutes? PSG found an AHI of 3/hr on CPAP treatment. The
A. 10%. patient took his usual modafinil before the MWT and
B. 20%. the MSL on four naps was 40 minutes. What do you
recommend?
C. 30%.
A. Medical clearance (assuming continued treatment
D. 40%.
adherence).
7. An 18-year-old male is evaluated for daytime sleepiness. B. Denial of medical clearance.
He falls asleep in morning classes routinely but denies C. Increase modafinil dose and repeat MWT.
cataplexy (emotionally induced muscle weakness). The D. Objective download of CPAP use.
patients normal sleep period is from midnight (or later
on weekends) until approximately 6 am (weekdays) and 11. All of the following concerning the MWT protocol are
10 to 11 am on weekends. An MSLT is performed with true EXCEPT:
naps at 8 am, 10 am, 12 noon, 2 pm, and 4 pm. The A. The patient is seated upright in bed.
results include an MSL of 8 minutes and 2 SOREMPs (9 B. A preceding PSG is not required.
am and 11 am naps). The patient was off from school for
C. The MWT is stopped after 3 consecutive epochs of
1 week before the sleep study. What is the most likely
stage N1 or any single epoch of any other stage of
diagnosis?
sleep (N2, N3, R).
A. Narcolepsy without cataplexy.
D. Four naps lasting up to 40 minutes is recommended
B. Idiopathic hypersomnia. (40-min protocol).
C. Insufficient sleep syndrome. E. The study is stopped after the first epoch of any stage
D. Insufficient sleep syndrome and delayed sleep of sleep.
phase.
history consistent with cataplexy and, therefore, likely of wakefulness test) in patients with narcolepsy. Clin Neuro-
has narcolepsy with cataplexy. If cataplexy is present in a physiol 1999;110:21312135.
7. Richardson GS, Carskadon MA, Flagg W: Excessive daytime
patient with a normal neurologic examination, the MSLT
sleepiness in man: multiple sleep latency measurements in nar-
is considered confirmatory (see Chapter 24). Drug abuse coleptic and control subjects. Electroencephalogr Clin Neuro-
is an important consideration. On questioning, the physiol 1978;45:621627.
patient admitted to exposure to second-hand marijuana 8. Carskadon MA: Guidelines for the multiple sleep latency test.
smoke from her boyfriend. For this reason, she declined Sleep 1986;9:519524.
9. Standards of Practice Committee, American Sleep Disorders
a urine drug screen. The patient did have mildly insuf-
Association: The clinical use of the multiple sleep latency test.
ficient sleep, but this is not uncommon in students. Sleep 1992;15:268276.
10. Littner MR, Kushida C, Wise M, et al: Practice parameters for
9. B. About 6% of patients with untreated OSA will have clinical use of the multiple sleep latency test and the mainte-
an MSLT meeting criteria for narcolepsy. Sleep apnea nance of wakefulness test. Sleep 2005;28:113121.
should be treated before an MSLT is performed. If 11. Arand D, Bonnet M, Hurwitz T, et al: A review by the MSLT
daytime sleepiness persists on adequate treatment and and MWT Task Force of the Standards of Practice Committee
of the AASM. The clinical use of the MSLT and MWT. Sleep
narcolepsy is suspected, a PSG on treatment (or after
2005;28:123144.
surgical treatment) followed by an MSLT can be used to 12. Aldrich MS, Chervin RD, Malow BA: Value of the multiple
support a diagnosis of narcolepsy (the patient has both sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep
OSA and narcolepsy). Note that if the patient had 1997;20:620629.
unequivocal cataplexy, then the correct answer is C 13. American Academy of Sleep Medicine: International Classifi-
cation of Sleep Disorders, 2nd ed. Diagnostic and Coding
(both OSA and narcolepsy are present).
Manual. Westchester, IL: American Academy of Sleep Medi-
cine, 2005, pp. 8190.
10. A and D? The use of an MWT to clear a patient for duty
14. Janjua T, Samp T, Cramer-Bornemann MC, et al: Clinical
where alertness is essential is an area of controversy. A caveat: prior sleep deprivation can affect the MSLT for days.
normal MWT does not ensure the patient will perform Sleep Med 2003;4:6972.
safely (i.e., adhere to treatment and obtain adequate 15. Chervin RD, Aldrich MS: Sleep onset REM periods during
sleep). The required sleep latency cutoff is poorly multiple sleep latency tests in patients evaluated for sleep
apnea. Am J Respir Crit Care Med 2000;161:426431.
defined. The use of a patients usual stimulant medica-
16. Carskadon M: The second decade. In Gulleminault C (ed):
tion before the MWT seems reasonable but is not Sleeping and Waking DisordersIndications and Techniques.
included in the MWT practice parameters. In this case, Boston: Butterworths, 1982, pp. 99125.
the patient maintained wakefulness during the entire 17. Carskadon MA, Wolfson AR, Acebo C, et al: Adolescent sleep
test. A CPAP download showed excellent adherence. A patterns, circadian timing, and sleepiness at a transition to early
school days. Sleep 1998;21:871881.
recommendation for medical clearance was reported
18. Doghramji K, Mitler MM, Sangal RB, et al: A normative study
with the stipulation that the patient demonstrate contin- of the maintenance of wakefulness test (MWT). Electroen-
ued adherence to treatment. cephalogr Clin Neurophysiol 1997;103:554562.
19. Poceta JS, Timms RM, Jeong D, et al: Maintenance of wakeful-
11. E. Although the sleep latency is defined as the time ness test in obstructive sleep apnea syndrome. Chest
from lights out to the first epoch of any stage of sleep, 1992;101:893902.
the study is terminated after 3 consecutive epochs of 20. Marshall NS, Barnes M, Travier N, et al: Continuous positive
airway pressure reduced daytime sleepiness in mild to moder-
stage N1 or a single epoch of any other stage of sleep
ate obstructive sleep apnea: a meta-analysis. Thorax 2006;61:
(N2, N3, R). 430434.
21. Sangal RB, Thomas L, Mitler MM: Maintenance of wakefulness
REFERENCES test and multiple sleep latency test: measurements of different
abilities in patients with sleep disorders. Chest 1992;101:
1. Johns MW: A new method for measuring daytime sleepiness: 898902.
The Epworth Sleepiness Scale. Sleep 1991;14:540545. 22. Sangal RB, Thomas L, Mitler M: Disorders of excessive sleepi-
2. Johns MW: Sleepiness in different situations measured by the ness: treatment improves the ability to stay awake but does not
Epworth Sleepiness Scale. Sleep 1994;17:703710. reduce sleepiness. Chest 1992;102:699703.
3. Gottlieb DJ, Whitney CW, Bonekat WH, et al: Relation of 23. Randomized Trial of modafinil as a treatment for the excessive
sleepiness to respiratory disturbance index. Am J Respir Crit daytime somnolence of narcolepsy: US Modafinil in Narcolepsy
Care Med 1999;159:502507. Multicenter Study Group. Neurology 2000;54:11661175.
4. Patel SR, White DP, Malhotra A, et al: Continuous positive 24. George CFP, Boudreau AC, Smiley A: Comparison of simu-
airway pressure therapy in a diverse population with obstruc- lated driving performance in narcolepsy and sleep apnea
tive sleep apnea. Arch Intern Med 2003;163:565571. patients. Sleep 1996;19:711717.
5. Benbadis SR, Mascha E, Perry MC, et al: Association between 25. Sagaspe P, Taillard J, Chaumet G, et al: Maintenance of wakeful-
the Epworth Sleepiness Scale and the multiple sleep latency test ness test as a predictor of driving performance in patients with
in a clinical population. Ann Intern Med 1999;130:289292. untreated obstructive sleep apnea. Sleep 2007;30:327330.
6. Sangal RB, Mitler MM, Sangal JM: Subjective sleepiness 26. Philip P, Sagaspe P, Taillard J, et al: Maintenance of wakefulness
ratings (Epworth Sleepiness Scale) do not reflect the same test, obstructive sleep apnea syndrome and driving risk. Ann
parameter of sleepiness as objective sleepiness (maintenance Neurol 2008;64:410416.
DaneshGroup.com
Appendix 14-1
Examiners may re-issue an airman medical certificate under There is any question concerning the adequacy of
the provisions of an Authorization, if the applicant provides therapy;
the following: The applicant appears to be non-compliant with
therapy;
An Authorization granted by the FAA; and The MWT demonstrates sleep deficiency; or
A current report (performed within last 90 days) The applicant has developed some associated illness,
from the treating physician that references the present such as right-sided heart failure.
treatment, whether this has eliminated any symptoms,
and with specific comments regarding daytime Authorization for Special Issuance of a Medical Certificate
sleepiness. (Authorization), valid for a specified period, may be granted
If there is any question about response to or compliance to a person who does not meet the established medical stan-
with treatment, then a Maintenance of Wakefulness dards if the person shows to the satisfaction of the Federal
Test (MWT) will be required. Air Surgeon that the duties authorized by the class of medical
certificate applied for can be performed without endangering
The Aeromedical Examiner must defer to the Aerospace public safety during the period in which the Authorization
Medical Certification Division (AMCD) or Region if: would be in force.
Available at http://flightphysical.com/AASI/AASI-Sleep-Apnea.htm
DaneshGroup.com
DaneshGroup.com
Chapter 15
a prevalence of sleep-disordered breathing (SDB) defined as in the risk of developing moderate to severe OSA. Other
an AHI of 5/hr or greater (with hypopneas based on a defini- studies have documented a decrease in the AHI with weight
tion of discernible change in airflow and 4% desaturation) loss.22,23 Whether the type of obesity or areas of excess fat
to be 9% in women and 24% in men.14 The sleep apnea syn- (neck vs. abdomen) are important is currently under inves-
drome, defined as the presence of both SDB and self-reported tigation. Davies and colleagues21 found that neck circumfer-
sleepiness, was present in 2% of women and 4% of men. ence correlated with AHI better than general obesity.
Bixler and associates15 found a 17% and 7% prevalence of an Prediction models for OSA have used neck circumference as
AHI greater than 5/hr in and 15/hr in men, respectively. a predictor.24 However, a recent study found neck circumfer-
Higher prevalence rates may be present in referral or clinical ence to correlate best with AHI in women whereas abdomi-
populations. It is estimated that in Western countries, up to nal girth correlated better in men.25
5% of the population have an undiagnosed OSA syndrome
(elevated AHI and symptoms).16 Another publication in Male Sex
1997 presented data that 93% of women and 82% of men In the Wisconsin cohort study by Young and associates,14,16
with moderate to severe OSA were undiagnosed.17 There is men had about twice the incidence of the OSA syndrome
also evidence that OSA severity can progress with time. compared with women (4% vs. 2%) (AHI 5/hr + symp-
Analysis of 8-year follow-up of 282 participants of the Wis- toms). Bixler and coworkers26 found the prevalence of OSA
consin cohort study showed a mean increase in the AHI defined as an AHI greater than 10/hr + symptoms to be 3.9%
from 2.6 events/hr to 5.1.16 In obese individuals with a body in men and 1.2% in women (P = .0006). Analysis of the Sleep
mass index (BMI) over 30, the mean AHI increased from Heart Health data also showed the risk of OSA in men was
4.8/hr to 10.1/hr. However, not all studies of untreated greater (odds ratio 1.5).27 Further discussion of the effect of
patients with OSA have also shown progression in AHI gender on the pathophysiology of OSA is contained in
severity. Chapter 16.
Age
Risk Factors
The prevalence of OSA appears to be higher in the elderly
A number of population-based studies have documented than in middle-aged populations. The prevalence of a chronic
several risk factors for the presence of OSA (Table 151).16 nonfatal disease would increase as cases accumulate even if
Of these, the most consistent findings have been the presence the incidence (new cases/yr) was constant or declining.
of obesity and male gender.16,18 Ancoli-Israel and colleagues28 studied 427 community-
dwelling elderly age 65 years or older using limited channel
Obesity ambulatory monitoring. A prevalence of OSA, defined as an
An association between AHI and obesity has been docu- AHI greater than 10/hr, was found to be 62%. Here, hypop-
mented in many studies.1621 Peppard and coworkers19 fol- neas were based on changes in flow (based on two channels
lowed the effects of weight change on AHI. A 10% weight of respiratory inductance plethysmography) independent of
gain predicted an approximate 32% increase in the AHI. A changes in the SaO2 (no oximetry). This is a prevalence of
10% weight loss predicted a 26% reduction in the AHI. A about three times that in middle-aged populations. There is
10% increase in weight was associated with a sixfold increase evidence from the Sleep Heart Health Study that the SDB
prevalence increases from age 40 to around 60.27 After that,
the prevalence appears to plateau (Fig. 151). In older adults,
the AHI may be less correlated with excessive sleepiness and
TABLE 151 increased cardiovascular risk. Enright and coworkers29
Risk Factors for Obstructive Sleep Apnea studied a large group of subjects over age 65 with question-
naires and echocardiography, ultrasound of the carotids, and
RISK FACTOR EVIDENCE
an electrocardiogram. Snoring was very common but, inter-
Obesitypresent in roughly 70% +++ estingly, reported snoring seemed to decrease after age 75.
of OSA Loud snoring, observed apneas, and daytime sleepiness were
Male sex +++ not associated with hypertension or the prevalence of car-
diovascular disease. Conversely, decreased snoring reports
Aging ++
could be secondary to a lower frequency of having a bed
Postmenopausal state ++ partner or hearing deficits in the elderly. It is possible that
Black race + (some studies) the presence of OSA in the elderly population has different
implications.30
Alcohol ++
Smoking + Postmenopausal Status
OSA = obstructive sleep apnea. Conventional wisdom is that postmenopausal women have
Adapted from Malhotra A, White DP: Obstructive sleep apnea. Lancet a greater incidence of OSA than premenopausal women.
2002;360:237245.
However, the confounders of increased age and often
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240 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
15
10
0
35 45 55 65 75 85
Age, yr
increased BMI in the postmenopausal group complicate the Heavy smokers were at the greatest risk. Of interest, former
analysis. An analysis of the Wisconsin cohort study of the smokers did not have an increased risk. Therefore, smoking
risk of having an AHI greater than 15 (adjusted for age and cessation should be considered in all patients with OSA.
body habitus) found an odds ratio of 3.5 for greater risk in
postmenopausal compared with premenopausal women.31 Alcohol Intake
Another frequently quoted study found a greater risk but Most studies of acute ingestion of alcohol in patients with
included men in the control group.26 The Sleep Heart Health snoring or OSA have found an increase in the AHI.38,39
Study analysis of women older than 50 years found that the Alcohol does suppress REM sleep and, in this sense, could
prevalence of an AHI greater than 15/hr in women on reduce the longer events associated with REM sleep during
hormone replacement therapy (HRT) was approximately the early part of the night. However, more severe desatura-
half that of the nonusers.32 There was a higher prevalence of tions and presumably longer events do occur in some patients
SDB in non-HRT users even when other factors such as age in the early portion of the night if bedtime alcohol is con-
and BMI were considered. The risk was especially high in the sumed.38 Block and associates40 found effects of alcohol on
50- to 59-year-old group. Thus, it appears that postmeno- breathing in normal men but not women. Stradling and
pausal women are at increased risk of developing OSA if they coworkers20 found alcohol consumption to be associated
are not on HRT treatment. with the presence of OSA in a group of middle-aged men.
However, definite epidemiologic evidence for a worsening of
Ethnicity OSA with chronic alcohol consumptions is lacking. It seems
One study found that OSA is more common in African likely that consumption of alcohol (or abstinence from
American than in white populations.33 However, this finding alcohol) could significantly change the AHI in individual
was not present in another study that controlled for differ- patients. Alcohol could also prolong respiratory events. In a
ences in age and BMI.27 An investigation by Redline and study of the effect of alcohol on the arousal response to mask
associates34 found an increase in the risk of having OSA occlusion in normal subjects, ethanol ingestion delayed the
greater in African Americans than in whites only for those time to arousal during nonrapid eye movement (NREM)
younger than age 25 years. Ip and coworkers35 found a similar sleep.41 Most occlusions were preformed in the early part of
prevalence of OSA in a Chinese population as in whites. The the night when the alcohol level would have been higher.
fact that OSA is common in Asian areas where obesity is Considering the very common use of alcohol, relatively little
much less common has led to the hypothesis that craniofa- is known about its effects on breathing during sleep.
cial characteristics of the Asian population might predispose
to OSA.36 Whereas increasing BMI was still associated with Hypothyroidism
an increased prevalence of OSA in the study of Chinese Hypothyroidism has been thought to be associated with
patients, the association was not as strong as that typically sleep apnea.4244 However, there are no large cohort studies
seen in white populations. The lack of obesity in Asian evaluating the prevalence of sleep apnea in hypothyroid sub-
patients should certainly not discourage evaluation for pos- jects versus euthyroid patients. Pelttari and coworkers43
sible sleep apnea. examined 26 patients with hypothyroidism and 188 euthy-
roid control subjects, finding that 50% of hypothyroid
Smoking patients and 29% of control subjects had significant respira-
Analysis of data for the Wisconsin sleep cohort data by tory events. If hypothyroidism is found in a patient with
Wetter and colleagues37 found that current cigarette smokers OSA, continued effective treatment is indicated until restora-
are at a greater risk for sleep apnea than never smokers. tion of the euthyroid condition.44 Even then, one would need
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Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 241
a sleep study to demonstrate that treatment of OSA was not TABLE 152
needed. Whereas some physicians order thyroid function Recommendations for Evaluation of General
tests on all OSA patients, this is not cost effective. Winkel- Medical Patients and Populations at High Risk for
man and colleagues45 reviewed the results of 255 consecutive Obstructive Sleep Apnea
patients suspected of having OSA in whom thyroid function
ROUTINE COMPREHENSIVE
studies were ordered. Hypothyroidism was present in only
HIGH-RISK QUESTIONS SLEEP
1.6% of patients and the frequency did not differ between
PATIENTS FOR AND EXAMINATION
those documented to have OSA and those who did not.
OSA OBSERVATIONS QUESTIONS
Thyroid testing is recommended only for high-risk groups
(women > 60 yr) and if there are clinical signs or symptoms Obesity Obesity? Witnessed apneas?
suggesting possible hypothyroidism.46 Postmenopausal (BMI > 30) Retrognathia? Snoring?
Congestive heart Daytime Gasping/choking
women with OSA or OSA patients without predisposing
failure sleepiness? at night?
OSA risk factors might warrant thyroid studies. The reason
Atrial fibrillation Snoring? Nonrefreshing
hypothyroidism exacerbates OSA is unclear and possibly Refractory Breathing sleep?
multifactorial. Upper airway muscle myopathy, narrowing of hypertension pauses? Total sleep
the upper airway by mucoprotein deposition in the tongue Type 2 diabetes Hypertension? amount?
(macroglossia), and abnormalities in ventilatory control are Nocturnal Sleep
possible mechanisms. arrhythmias fragmentation?
CVA Nocturia?
Acromegaly Pulmonary Morning
Growth hormone excess resulting in acromegaly is also asso- hypertension headaches?
ciated with sleep apnea. Grunstein and associates46 noted High-risk driving Decreased
populations concentration?
that 60% of unselected patients with acromegaly had sleep
Preoperative for Memory loss?
apnea. Weiss and coworkers47 found that 75% of a group
bariatric Decreased libido?
with acromegaly had OSA. Independent predictors of OSA surgery Irritability?
included increased activity of acromegaly (higher growth
BMI = body mass index; CVA = cerebrovascular accident; OSA = obstructive
hormone), older age, and an increased neck circumference. sleep apnea.
Potential pathophysiologic mechanisms of the association From Epstein LJ, Kristo D, Strollo PJ, et al: Clinical guideline for the evaluation,
between acromegaly and OSA include macroglossia and management and long-term care of obstructive sleep apnea in adults. J Clin
Sleep Med 2009;5:263276.
increased muscle mass of the upper airway. Patients with
acromegaly may have central as well as obstructive apnea.46
Therefore, alterations in ventilatory control may also play a
role. Patients with acromegaly without sleep apnea may also BOX 152
have daytime sleepiness as a direct manifestation of growth Common Symptoms and Manifestations of
hormone excess. The daytime sleepiness may improve after Obstructive Sleep Apnea
effective treatment of the acromegaly.48
Symptoms Nocturnal Behavior
Excessive daytime Loud habitual snoring
DIAGNOSIS OF OSA Choking, gasping during
sleepiness
Recent clinical guidelines for the evaluation, management, Nonrestorative sleep sleep
and long-term care of OSA in adults recommended that Frequent awakenings Breathing pauses/witnessed
high-risk populations for OSA be questioned in detail con- Morning headaches apnea
Dry mouth in the morning Body movements,
cerning symptoms of OSA.49 However, certain basic sleep
Personality change restlessness in bed
questions were recommended for all patients as part of a
Intellectual changes
general history and physical examination (Table 152). The Erectile dysfunction
comprehensive sleep examination questions the patient con- Nocturia
cerning the typical manifestations of OSA. A number of
populations with a high prevalence of OSA have been identi-
fied including patients with refractory hypertension, conges-
tive heart failure, and recent or past cerebrovascular accident or nonrestorative sleep (Box 152). Patients may also report
or transient ischemic attack (see Table 152). a progression of symptoms with recent weight gain or nasal
congestion. The Epworth Sleepiness Scale (ESS), a subjective
estimate of the propensity to doze off in eight situations, is
OSA Symptoms and Key Historical Points
often (but not invariably) increased (see Chapter 14). The
The patient or bed partner frequently reports excessive range of the scale is 0 to 24 with greater than 10 indicating
daytime sleepiness, loud habitual snoring, gasping/choking excessive daytime sleepiness.50 Data in Table 153 taken
or witnessed apnea, personality change, morning headache, from one of the first descriptions of the ESS show that the
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242 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
TABLE 153
10
Epworth Sleepiness Scale Scores in Mild,
score increases with severity of OSA (the AHI), but there was BOX 153
a wide range of scores at any AHI range.50 Other studies have Obstructive Sleep Apnea Physical Examination
confirmed that the correlation between the AHI and subjec- Key Elements in Patients Suspected of Having
tive or objective sleepiness, although statistically significant, Obstructive Sleep Apnea
is low (correlation coefficient in the range of 0.40.5).51,52 The
wide variability in symptoms is likely due in part to different Increased BMI*
individual susceptibility to sleep fragmentation or other Presence of nasal obstruction
factors contributing to symptoms of daytime sleepiness Increased Mallampati or modified Mallampati score*
such as medications or reduced sleep time. A number of High-arched palate (narrow airway)
population-based studies have found that a substantial per- Retrognathia
centage of patients with OSA do not report daytime sleepi- Increased neck circumference (>17 inches in men, >16
ness, and the absence of sleepiness should not discourage a inches in women)
further evaluation. However, patients with more severe OSA Evidence of right heart failure (JVD, pedal edema)
do have, on average, greater daytime sleepiness (Fig. 152). *Independent predictor of the presence of OSA.
BMI = body mass index; JVD = jugular venous distention; OSA = obstructive
It is important to remember that two patients with the same sleep apnea.
AHI can have vastly different degrees of daytime sleepiness From Nuckton TJ, Glidden DV, Brownder WS, Claman DM: Physical
or arterial oxygen desaturation. Severe desaturation, even in examination: Mallampati score as an independent predictor of obstructive
sleep apnea. Sleep 2006;29:903908.
the absence of daytime sleepiness, could put the patient at
risk for a number of adverse cardiovascular consequences of
sleep apnea.
A number of investigations have studied the effect of undergoing a positive airway pressure (PAP) titration (see
gender on presenting symptoms of OSA.5355 In general, men Chapter 21).
and women report many of the same symptoms. However,
women may report more insomnia and less witnessed apnea.
Physical Examination
Women with OSA are also more likely to complain of depres-
sion, morning headache, awakenings, and fatigue.55 It is The physical examination of patients with suspected OSA
important to remember that patients with central sleep should target abnormalities known to be associated with the
apnea may present with many of the same symptoms as syndrome (Box 153). These include measurement of BMI
OSA. Historical elements that may alert the clinician to and systemic blood pressure as well as careful examination of
possible central apnea include congestive heart failure or the nose, ears, and oropharynx.5658 Observation of the oro-
the use of potent narcotics. Patients with congestive heart pharynx usually reveals a crowded upper airway and exami-
failure can have either OSA, Cheyne-Stokes breathing, or a nation of the patients face in profile may reveal retrognathia
combination of OSA and central sleep apnea. Patients with (Figs. 153 and 154). Measurement of neck circumference
narcotics often have central apneas at baseline or when and observation of signs of right heart failure may also be
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Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 243
FIGURE 153 Mallampati and modified Mallampati airway classification. In the Mallampati maneuver, patients are instructed not to emit sounds but to
open the mouth as wide as possible and protrude the tongue as far as possible. In the modified Mallampati, the patient is instructed to open the mouth
as wide as possible without emitting sounds. Mallampati reproduced from Friedman M, Tanyeri H, La Rosa M, et al: Clinical predictors of obstructive sleep
apnea. Laryngoscope 1999;109:19011907; and modified Mallampati reproduced with permission from Nuckton TJ, Glidden DV, Brownder WS, Claman DM:
Physical examination: Mallampati score as an independent predictor of obstructive sleep apnea. Sleep 2006;29:903908.
FIGURE 154 A patient with severe retrognathia on the left and orthognathia
(normal) on the right. From Friedman M, Tanyeri H, La Rosa M, et al: Clinical predictors
of obstructive sleep apnea. Laryngoscope 1999;109:19011907.
revealing. A neck size greater than 17 inches in men and 16 MMP, tonsil size, and BMI were reliable predictors of OSA.
inches in women suggests the possibility of OSA. However, Zonato and colleagues57 found a significant correlation
a smaller neck circumference does not rule out OSA. between the AHI and the MMP and BMI. Although retrog-
The Mallampati (MP) score of the upper airway was nathia (see Fig. 154) was not correlated with AHI, this
developed to predict the risk of difficult endotracheal intuba- abnormality was more frequent in patients with severe OSA
tion (see Fig. 153). The patients oropharynx is examined as compared with snorers. Nuckton and associates58 analyzed
with tongue protruded. The modified Mallampati score over 30 variables reflecting airway anatomy, body habitus,
(MMP), also called the Friedman score,56 is similar but the symptoms, and medical history and found the MMP and MP
patient simply opens the mouth without saying ah or to be independent predictors of the presence and severity of
tongue protrusion. Friedman and coworkers56 found that the OSA. The variables associated with an increased risk of OSA
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244 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
in their study included increased neck circumference, wit- off while driving a vehicle, and category 3 concerns the
nessed apnea, and hypertension. presence of hypertension. After questionnaire completion,
patients were studied by PM. The Berlin Questionnaire iden-
tified patients with an AHI 5/hr (based on assignment to
Laboratory Testing in OSA
the high-risk group) with a sensitivity of 0.86 and a specific-
Laboratory testing in patients with OSA is usually not indi- ity of 0.77. The STOP-BANG (snoring, tired, observed apnea,
cated apart from routine health maintenance unless a par- [blood] pressure, body mass index, age, neck circumference,
ticular problem such as hypothyroidism is suspected. In gender) Questionnaire is a screening tool (Appendix 152)
patients with severe nocturnal hypoxemia, polycythemia that has been used for preoperative evaluation to detect sleep
(increased hematocrit) may be present. An unexplained apnea. A study of 2467 patients found sensitivities of 84%,
elevation in the serum CO2 (composed primarily of HCO3) 92%, and 100% for AHI cutoffs of greater than 5/hr, greater
on electrolyte testing is suggestive of chronic compensation than 15/hr, and greater than 30/hr.63,64
for hypercapnia (in the absence of evidence of causes of
metabolic alkalosis).59,60 Pulmonary function testing, chest
Diagnostic Testing for Suspected Sleep Apnea
radiography, and arterial blood gas testing are indicated
in patients with a low awake SaO2 or suspected hypo- Attended PSG is the gold standard to determine whether
ventilation to eliminate pulmonary causes of impaired gas OSA is present and to classify the severity.65 Figure 155
exchange.60 presents an obstructive apnea during REM sleep. Box 154
lists the classic PSG findings in patients with OSA. The
abnormality in the sleep architecture varies with severity.
Prediction of the Presence of OSA
Patients with severe OSA usually have a high arousal index,
A number of clinical indices and questionnaires have been increased wake after sleep onset (WASO) and stage N1 sleep,
developed to predict the presence of OSA based on symp- and decreases in stage N3 or stage R sleep. A typical classi-
toms, signs, and measurements. Although they have some fication of OSA severity based on the AHI (or RDI in some
success, they are neither satisfactorily sensitive nor specific sleep centers) is 5 to fewer than 15/hr mild, 15 to 30 moder-
enough to be a substitute for objective documentation of the ate, and greater than 30/hr severe OSA. Whereas the AHI
presence of OSA by a sleep study. An adaptation of a predic- (RDI) is the most widely used index for classification of
tion rule developed by Flemons and coworkers24,61 used an severity, it is also important to characterize the severity of
adjusted neck circumference (Table 154) to classify patients arterial oxygen desaturation. A widely accepted standard for
as low, moderate, or high probability. The population in the characterization of the severity of desaturation does not
which the prediction value was developed was predomi- exist. It is common to present the number of desaturations
nantly male, hypopneas were defined as a reduction in (usually defined as a drop in the SaO2 > 4%), the lowest SaO2,
airflow associated with a 3% or greater desaturation, and the the average SaO2 at desaturation, and the time below various
presence of OSA was defined by an AHI greater than 10/hr. saturations. For example, a commonly used metric is the
Netzer and colleagues62 studied the utility of the Berlin time at or below an SaO2 of 88%.
Questionnaire (Appendix 151) to predict whether patients PSG can diagnose OSA either with an entire night of
were high or low risk for having OSA. The questionnaire monitoring or by the initial diagnostic portion of a split
consists of three categories: category 1 concerns snoring and (partial-night) study. The second part of the study is used as
witnessed apnea, category 2 concerns being sleepy/tired/ a PAP titration. CMS formerly required a minimum of 2
fatigued more than three or four times a week or nodding hours of sleep (not monitoring) during the diagnostic
portion to qualify a patient for reimbursement of CPAP
treatment. Currently, if less than 2 hours of monitoring is
performed, the number of events to qualify the patient
TABLE 154
should be the same as if 2 hours of sleep had been recorded.
Prediction of Obstructive Sleep Apnea For example, if an AHI of 15/hr qualifies a patient for CPAP
(symptoms not required) a total number of apneas and
NC = measure neck circumference (cm) hypopneas must equal 30 or more10 (Box 155).
A. If hypertension present, +4 Because the AHI is often higher in the supine position66,67
and during REM sleep,6870 presentation of the AHI for those
B. If habitual snoring present, +3
conditions in the sleep study report may be useful. The diag-
C. If gasping or choking present, +3 nosis of postural OSA is usually made when the AHI-supine
Adjusted neck circumference = NC + A + B + C is greater than twice the AHI-nonsupine.
Some clinicians define REM-associated OSA as a normal
<43 cm (17 inches) low probability AHI during NREM sleep associated with an elevated AHI
4348 cm (1719 inches) moderate probability
during REM sleep. Other clinicians use the term to denote
>48 cm (19 inches) high probability
patients with an AHI-REM/AHI-NREM greater than 2.
From Flemons WW: Obstructive sleep apnea. N Engl J Med 2002;347:498504.
There is also an interaction between body position and sleep
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Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 245
Arousal
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin REMs
EMG
L,R,leg
EMG
ECG
Airflow 22 sec
RC Apnea
AB
Paradoxical
motion
Vsum
100%
SpO2
91%
74%
FIGURE 155 An obstructive apnea during rapid eye movement (REM) sleep. The longest respiratory event duration and most severe arterial oxygen desaturation are usually
during REM sleep (especially supine REM sleep). Note the slowing of the heart rate at the start of the apnea and speeding at apnea termination. Here Vsum is the sum of
rib cage (RC) and abdominal (AB) respiratory inductance plethysmograph bands. ECG = electrocardiogram; EMG = electromyogram; SpO2 = pulse oximetry.
stage. The AHI tends to be higher during supine than during one should carefully consider other causes of daytime sleepi-
nonsupine REM sleep.69 Patients with a mild to moderate ness (narcolepsy, insufficient sleep). Conversely, if a patient
overall AHI are more likely to have REM-related OSA. An is completely asymptomatic with an overall AHI of 15/hr or
occasional patient with REM-related OSA may exhibit very less, conservative therapy may suffice.
severe arterial oxygen desaturation and long apneas during Cyclic variation in heart rate is typically noted during the
REM sleep but a relatively normal AHI-NREM. A study by repeated episodes of obstructive events.74,75 The heart rate
Kass and coworkers70 identified a group of patients with slows at the start of the events and increases at event termi-
overall AHI less than 10/hr but AHI-REM greater than 15/ nation (Fig. 156). Often, the heart rate remains between 60
hr who had objective evidence of daytime sleepiness. Other and 100 bpm. A standard part of most PSG reports is to
studies have not demonstrated a relationship between the present the maximum and minimum heart rate along with
AHI-REM and sleepiness.71,72 A recent large population- notations of abnormalities (premature ventricular contrac-
based analysis of the Sleep Heart Health Study cohort found tions, atrial fibrillation, sinus pauses).
a relationship between the AHI-NREM but not the AHI-REM There are many formats for summarizing respiratory
and daytime sleepiness.73 However, treatment decisions in an event results of PSG in OSA patients. However, given the
individual patient with REM-related OSA should be indi- importance of REM sleep and supine sleep, the AHI is often
vidualized. In patients with milder OSA, there can be con- presented for those situations (Table 155). Note that the
siderable night-to-night variability in the AHI. The best patient in Table 155 has a much higher AHI during supine
advice is to treat the patient not the AHI. If a patient with and REM sleep. It is also important to present the amount of
REM-related OSA is symptomatic and the overall AHI is 5/ supine sleep (% of total sleep time supine) during the record-
hr or greater, it is reasonable to offer treatment. However, ing period. The longest respiratory events and most severe
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246 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
ECG
Heart
rate
Snore
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
SpO2
1 sec
FIGURE 156 The heart rate during an obstructive apnea. The heart rate signal is the output of the oximeter (a moving time average) that tends to lag behind the actual change
in heart rate. Changes in the heart rate can be noted by changes in the RR interval, which widens at apnea onset then narrows at apnea termination. ECG = electrocardiogram;
SpO2 = pulse oximetry.
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Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 247
TABLE 155
Typical Presentation of Respiratory Events
TOTAL
TST (min) 360
NREM (min) 290
REM sleep (min) 70
% supine 16
TOTAL SUPINE NONSUPINE NREM REM
TST in condition 360 60 300 290 70
OA (#) 24 14 10 4 20
MA (#) 5 5 0 0 5
CA (#) 2 1 1 1 1
Hypopnea (#) 24 19 5 20 4
Total (#) 55 39 16 25 30
AHI (#/hr) 9.2 39.0 3.2 5.2 25.7
AHI = apnea-hypopnea index; CA = central apnea; MA = mixed apnea; NREM = nonrapid eye movement; OA = obstructive apnea; REM = rapid eye movement;
TST = total sleep time.
SpO2
82% 85%
75%
severity. In addition, patients with heavy snoring are at risk arousals as well as desaturation), most RERAs will be classi-
for developing OSA as they age or if significant weight gain fied as hypopneas.86,87
occurs.
Although not every snorer needs a sleep study, evaluation
Obesity Hypoventilation Syndrome
is recommended if the patient has a moderate to high likeli-
hood of having OSA, is symptomatic, or if a surgical inter- Most patients with the OSA do not have daytime hypoventila-
vention is being considered. A PSG is also needed before an tion. Two groups of OSA patients who do present with
oral appliance is made for snoring to rule out significant hypoventilation include those with OHS and the overlap
OSA.65 If significant sleep apnea is present, this may syndrome (a combination of chronic obstructive pulmonary
change the treatment approach. If upper airway surgery or disease [COPD] and OSA). Those obese patients (BMI >
an oral appliance is used for treatment, a sleep study post- 30 kg/m2) with daytime hypoventilation (partial pressure of
operatively or with the oral appliance in place is needed to carbon dioxide [PCO2] 45 mm Hg) that is not secondary
document treatment efficacy. Some surgical interventions to lung disease or muscle weakness are said to have OHS (Box
such as laser-assisted uvuloplasty (LAUP) are indicated for 158).8892 These patients were previously referred to as pick-
treatment of snoring but not OSA.81 Surgical treatments for wickian. It is important to recognize whether a patient has
snoring and OSA are discussed in detail in Chapter 18. Of OHS as well as OSA because this group has a high incidence
note, if the patient has unsuspected moderate to severe OSA, of complications if not properly treated. Nowbar and col-
then PAP is the treatment of choice.12,49 leagues90 studied the outcomes of obese patients admitted to
The treatment options for simple snoring are similar to a medical service. Of those who had hypoventilation, the
those for mild OSA. These include weight loss, the side 18-month mortality was 23% compared with 9% in the group
sleep position, treatment of nasal congestion, upper airway with equivalent obesity but no hypoventilation. Of interest,
surgery, an oral appliance, and avoidance of alcohol. only 6% of the hypoventilation group received treatment for
Although nasal CPAP is effective for snoring, this treatment the hypoventilation!
is usually reserved for patients with OSA.82 Chapter 20 pro-
vides an overview of treatments for snoring and OSA. Diagnosis of OHS
The definitive diagnosis of hypoventilation requires an arte-
rial blood gas while awake with a PCO2 of 45 mm Hg or
Upper Airway Resistance Syndrome
greater. However, an arterial blood gas is rarely performed
Guilleminault and coworkers83 identified a group of patients on a morbidly obese patient with severe OSA unless they
who exhibited subjective and objective (multiple sleep have daytime hypoxemia or present with respiratory failure.
latency test [MSLT]) daytime sleepiness but did not have an Fortunately, an elevated serum HCO3 (primarily HCO3) is a
AHI of 5/hr or greater (thermal devices measured airflow). very useful clue that a patient with OSA should be tested for
The group was defined by having a respiratory arousal index
greater than 10/hr using esophageal pressure monitoring.
BOX 158
The respiratory arousal events were not associated with
desaturation or a change in thermal devicedetected airflow. Obesity Hyperventilation Syndrome
The symptom of sleepiness responded to CPAP treatment. Daytime PCO2 > 45 + BMI > 30 kg/m2 + no lung disease
The mean arousal index of the group was 33/hr (range 16 Suspect OHS if HCO3 > 27 mEq/L (especially without
52) and the mean maximally negative esophageal pressure reason for metabolic alkalosis)
nadir was 37 cm H2O. There has been controversy as to High mortality if untreated
whether the upper airway resistance syndrome (UARS) is a 8090% of OHS patients have OSA
distinct entity or simply a milder form of OSA.84,85 The Severe nocturnal desaturation
ICSD-2 does not contain a separate diagnostic category for 100% sleep-related hypoventilation (worsening of
UARS. daytime hypercapnia)
As discussed in Chapter 8, esophageal manometry and Cor pulmonalecommon
nasal pressure monitoring each identify many (but not all) Treatment
of the same events. However, it is possible that use of esopha- CPAPdaytime PCO2 may improve, the addition of
geal pressure monitoring would identify a few patients oxygen may be needed
missed by nasal pressure monitoring. For example, a patient BPAPrecommended for moderate to severe
arousing easily might develop relatively high inspiratory hypercapnia or persistent low SaO2 on CPAP
effort (esophageal pressure excursions) before airflow BPAP + oxygen
changed significantly. If PSG is performed using nasal pres- Tracheostomy + oxygenrepeated respiratory failure
sure and if an RDI of 5/hr or greater (RDI = apneas + hypop- and nonadherence to PAP
neas + RERAs/hr of sleep) is used to define OSA, then most BMI = body mass index; BPAP = bilevel positive airway pressure; CPAP =
patients who would meet criteria for UARS as defined previ- continuous positive airway pressure; OHS = obesity hyperventilation
syndrome; OSA = obstructive sleep apnea; PAP = positive airway pressure;
ously would also be diagnosed as having OSA. Furthermore, PCO2 = partial pressure of carbon dioxide.
if the alternative definition of hypopnea is used (considers
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250 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
hypoventilation. The serum CO2 is included on routine meta- 10 mm Hg in the morning compared with the afternoon
bolic or electrolyte laboratory panels. The elevated HCO3 in were excluded. An equivalent reduction in daytime PCO2
OHS patients represents renal compensation for chronic was noted at 3 months in patients randomized to CPAP or
respiratory acidosis (elevated arterial partial pressure of BPAP. Adherence to the treatment modalities was also not
carbon dioxide [PaCO2]). However, an elevated HCO3 could significantly different. In the BPAP group, the mean inspira-
also be due to metabolic alkalosis. Mokhlesi and associates59 tory positive airway pressure (IPAP) and expiratory positive
found that 20% of 410 patients referred to a sleep center to airway pressure (EPAP) levels used were 16 and 10 cm H2O,
rule out OSA had OHS. In this study, only 3% of OHS patients respectively, and the spontaneous mode of BPAP was
had an HCO3 less than 27 mEq/L but 50% of patients with employed. A few patients in both groups required supple-
an HCO3 of 27 or greater had OHS. The authors concluded mental oxygen in addition to PAP. As noted, the most severe
that patients with both OSA and an HCO3 greater than OHS patients were excluded from this study and were treated
27 mEq/L should undergo arterial blood gas testing. Other with noninvasive positive-pressure ventilation (NPPV;
clues that OHS may be present include a borderline awake BPAP) outside of the study protocol.
SaO2 (9092%) or evidence of significant cor pulmonale. OHS patients may require high levels of EPAP to prevent
Patients with the OHS are a heterogeneous group.89 The obstructive apnea and this tends to limit the available range
causes of hypoventilation include nocturnal upper airway of pressure support unless very high IPAP levels are used. In
obstruction (OSA), decreased respiratory system compli- a study of the effect of NPPV in OHS patients by Berger and
ance from obesity, and intrinsic or acquired abnormalities in colleagues,89 EPAP values up to 14 cm H2O and IPAP values
ventilatory drive.91 Patients with OHS have very increased up to 25 cm H2O were needed. The mean IPAP and EPAP
levels of leptin. This is a protein produced mainly by adipose values were 18 and 8 cm H2O, respectively. OHS patients
tissue that is a ventilatory stimulant and interacts with the may present with acute respiratory failure.96,97 The treatment
hypothalamus to inhibit eating. OHS patients are believed of choice is PAP (usually BPAP and oxygen). Very severe
to have leptin resistance or perhaps central leptin defi- patients may require temporary endotracheal intubation and
ciency.92 Most OHS patients will have OSA (8090%) and mechanical ventilation. Tracheostomy can be life-saving in
severe arterial oxygen desaturation.88,92 However, up to 20% patients noncompliant with PAP treatment who have
of OHS patients have an AHI of 5/hr or less but exhibit both repeated bouts of hypercapnic respiratory failure.
daytime hypercapnia and severe sleep-related hypoventila- For stable chronic OHS patients, treatment with PAP may
tion and arterial oxygen desaturation. One study character- reduce the daytime PCO2 as well as reduce apnea and hypop-
ized the patients on the basis of their response to PAP nea and nocturnal desaturation. Berthon-Jones and Sulli-
treatment.89 Some OHS patients could be adequately treated van98 showed chronic CPAP treatment of OSA patients with
with CPAP alone. Opening the upper airway with CPAP daytime hypoventilation resulted in a leftward shift in the
during sleep restored adequate oxygenation. Others still had ventilatory response to carbon dioxide (ventilation plotted
hypoventilation despite the absence of apnea or hypopnea. vs. PCO2) during the day without a change in slope (Fig.
Some with persistent airflow limitation responded to higher 158). The PCO2 set point is lowered and there is higher
levels of CPAP (decreasing the upper airway resistance). Pre- ventilation at any given PCO2. A study by Mokhlesi and
sumably, they could not compensate for a high upper airway associates99 found that the amount of improvement in the
resistance even if apnea and hypopnea were not present. daytime PCO2 is critically dependent on adherence. There
Some patients required the addition of supplemental oxygen was considerable variability but the PCO2 dropped by about
along with CPAP.92,93 Another group of patients required 3 mm Hg for every hour of nightly adherence and reached
either nasal bilevel positive airway pressure (BPAP) or a plateau with longer than 4.5 hours of use.
mechanical ventilation with or without oxygen. The group In summary, the treatment of OHS patients may require
of OHS patients who manifest hypoventilation without sig- CPAP or BPAP with or without the need for supplemental
nificant OSA are likely to have abnormal ventilatory control oxygen. Although CPAP is often sufficient for some patients,
or very decreased respiratory system compliance due to most clinicians would use BPAP if the hypoventilation is
massive obesity. The relative importance of OSA, abnormal moderate to severe. Adequate treatment can improve daytime
ventilatory control, and decreased respiratory system com- as well as nocturnal gas exchange and prevent apneas and
pliance varies between individuals with OHS. Of note, hypopneas. It is of interest that a fair number of OHS patients
patients with severe OHS who are not treated or do not do not complain of significant daytime sleepiness. OHS
comply with treatment have a high mortality.90,94 patients may present with acute on chronic respiratory
failure. Moderate to severe OHS patients have a poor prog-
Treatment of OHS nosis if they do not receive appropriate treatment or are not
Piper and coworkers95 performed a randomized trial that adherent to treatment.
compared CPAP and BPAP for treatment of patients with
OHS. Patients with significant residual desaturation (SaO2 <
Overlap Syndrome
80% for > 10 min) on a level of CPAP that eliminated
obstructive events, an acute rise in PCO2 greater than 10 mm Patients with the OSA and COPD may have daytime
Hg during REM sleep, or an increase in PCO2 greater than hypoventilation and severe nocturnal oxygen desaturation.
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Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 251
60 TABLE 156
90 days Differences Between Children and Adults with
Obstructive Sleep Apnea
CHILDREN ADULTS
CLINICAL FINDINGS
Minute ventilation (L/min)
Diagnosis
The ICSD-2 criteria13 for the diagnosis of pediatric OSA are
listed in Box 159. The criteria emphasize parental observa-
tions as well as PSG findings. In pediatric sleep monitoring, with an OAHI of 2 to 5/hr. An AHI of 10/hr is considered
any scoreable obstructive apnea of a duration equal to two moderate to severe in children. Most apnea in pediatric
respiratory cycles is considered abnormal. Many pediatric patients occurs during REM sleep. However, the most
sleep reports separate the central from obstructive apnea- common pattern in pediatric sleep monitoring is obstruc-
hypopnea index (OAHI). The values of the obstructive apnea tive hypoventilation (Fig. 159). This pattern consists of
index (OAI; obstructive apneas/hr of sleep) or OAHI needed long periods of airflow limitation, increased inspiratory
to diagnose pediatric OSA remains somewhat controversial. effort, increased end-tidal partial pressure of carbon dioxide
Table 157 presents normative values from two publications. (PETCO2), and variable amounts of arterial oxygen desatura-
Most clinicians make the diagnosis of pediatric OSA based tion. Traditional monitoring (thermistor flow) often demon-
on an obstructive apnea index (OAI) greater than 1/hr or an strates few changes except for an elevation in PETCO2 and
OAHI greater than 1 to 2/hr. However, the decision to treat perhaps no or mild drops in the SaO2. Paradoxical motion
a given patient depends on symptoms. No widely accepted of the chest and abdomen may be noted (chest moving
severity ranges are available, but many centers treat patients inward during inspiration). Nasal pressure monitoring shows
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Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 253
TABLE 157 airflow limitation (flattening) and reduced but stable flow.
Normative Respiratory Values for Children Ages This common pattern is the reason that PETCO2 is an integral
1 to 18 part of most pediatric sleep studies. The AASM scoring
manual states that sleep-related hypoventilation in children
BECK AND
should be scored when the PCO2 > 50 mm Hg for 25% of
VALUE MARCUS* ULIEL ET AL
the total sleep time using transcutaneous or end-tidal mea-
Obstructive AHI 1.4 surement of the PCO2.9 However, a PSG study of normal
(#/hr) children by Uliel and coworkers115 recommended that
Obstructive AI 0 1 PETCO2 greater than 45 mm Hg for longer than 10% of total
(#/hr) (any obstructive sleep time be considered abnormal.
apnea is Although the major cause of OSA in children is adeno-
considered tonsillar hypertrophy, tonsil size does not correlate with find-
abnormal) ings on sleep studies. One child with large tonsils may be
Central apnea 0.4 0.9 without symptoms while another with modest tonsil enlarge-
index (#/hr) ment may have significant symptoms. Other upper airway
Time with SaO2 0% TST < SaO2 0% TST < SaO2
characteristics are likely responsible. With the obesity epi-
< 89 or 90% of 90% of 89% demic in children, obesity is becoming a major risk factor
(%TST) for OSA in children. Indeed, very obese children may present
with symptoms similar to those of adults (daytime
SaO2 nadir 91% 89
sleepiness).
Baseline sleeping
Tonsillectomy and adenoidectomy (TNA) is considered
SaO2 > 92%
the treatment of choice in patients with pediatric sleep apnea
Time PETCO2 <25% (even if obese). A PSG is recommended before TNA to avoid
50 mm Hg unnecessary surgery and to triage patients to appropriate
Time PETCO2 > <10% postsurgical care. Patients with a high AHI, extremes of body
45 mm Hg weight, severe oxygen desaturation, cor pulmonale, daytime
Periodic limb 4.3
hypoventilation, young age, and congenital craniofacial
movement abnormalities are at an increased risk for postoperative com-
index (#/hr) plications. In high-risk patients, TNA should be performed
AHI = apnea-hypopnea index; AI = apnea index; PETCO2 = end-tidal carbon
in the hospital with appropriate postoperative monitor-
dioxide pressure; SaO2 = arterial oxygen saturation; TST = total sleep time. ing.105,116 The efficacy of TNA is much lower than expected
*Beck SE, Marcus SL: Pediatric polysomnography. Sleep Med Clin and a postoperative PSG is recommended.117,118 Even if TNA
2009;4:393406.
Snore
Nasal
pressure
NO therm
Chest
Abdomen
SpO2
93%
Exhaled 50
PCO2 0
FIGURE 159 Obstructive hypoventilation in a pediatric patient with OSA. The end-tidal partial pressure of carbon dioxide (PCO2) is greater than 50 mm Hg and
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there is evidence of flattening of the nasal pressure (airflow limitation). A very mild drop in the pulse oximetry (SpO2) is noted.
254 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
discussed in more detail in Chapter 20. Patients with 7. Which of the following combinations has the highest
significant residual OSA following TNA can be treated probability of having OSA?
with weight loss, CPAP, or other surgical procedures. A. Snoring, no witnessed apnea, hypertension.
B. Snoring, daytime sleepiness, no witnessed apnea.
CLINICAL REVIEW QUESTIONS C. Snoring, witnessed apnea, hypertension.
D. No snoring, no witnessed apnea, daytime sleepiness.
1. Of the following, what is the best documented risk factor
for OSA?
A. Cigarette smoking. Answers
B. Alcohol consumption.
1. D. Obesity is the best documented risk factor of those
C. Postmenopausal status. listed.
D. Obesity.
2. D. Approximately 20% of OHS patients do not have OSA
2. Which of the following is NOT always true about patients but simply have daytime hypoventilation that worsens
with the OHS? during sleep.
A. Daytime PCO2 45 mm Hg.
3. D. Daytime sleepiness is not a major complaint of pedi-
B. BMI > 30 kg/m2.
atric OSA patients. However, sleepiness may not be rec-
C. Worsening PCO2 and PO2 with sleep. ognized. Obese pediatric OSA patients are more likely to
D. AHI 5/hr. report sleepiness.
3. Which of the following symptoms is less typical of pedi- 4. D. This option most completely describes the criteria for
atric patients with OSA? adult OSA.
A. Diaphoresis and labored breathing during sleep.
B. Hyperactivity or behavioral problems. 5. A. This describes a patient with a high probability of
moderate to severe OSA who does not have co-morbid
C. Adenotonsillar hypertrophy of variable severity.
medical disorder such as congestive heart failure or a
D. Daytime sleepiness. neuromuscular disorder. Patient C may well have sleep
apnea but is not considered to have a high probability of
4. Which of the following is the ICSD-2 criterion for diag-
having OSA based on lack of witnessed apnea.
nosis of OSA in adults?
A. (Apneas + hypopneas + RERAs)/hr = 5/hr. 6. B. This answer describes the findings of the Wisconsin
B. (Apneas + hypopneas + RERAs)/hr = 15/hr. study by Young and associates. The prevalence likely
C. (Apneas + hypopneas + RERAs)/hr = 5/hr + varies with the population being studied and the preva-
symptoms lence may well be increasing owing to the obesity
D. (Apneas + hypopneas + RERAs)/hr = 5/hr + symp- epidemic.
toms OR (Apneas + hypopneas + RERAs)/hr 15/hr. 7. C. Snoring, witnessed apnea, and hypertension were
5. Which of the following group of symptoms in a patient found to be major risk factors for the presence of OSA.
would indicate a good candidate for portable Although daytime sleepiness is a cardinal symptom of
monitoring? OSA, many OSA patients do not report sleepiness.
A. Snoring, witnessed apnea, daytime sleepiness,
hypertension. REFERENCES
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Appendix 15-1
Berlin Questionnaire
259
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Appendix 15-2
1. Snoring 6. Age
Do you snore loudly (louder than talking or loud enough to Age older than 50 yr old? Yes No
be heard through closed doors)? Yes No
7. Neck circumference
2. Tired Neck circumference > 40 cm? Yes No
Do you often feel tired, fatigued, or sleepy during daytime?
8. Gender
Yes No
Gender male? Yes No
3. Observed
High risk of OSA: Answering yes to three or more items.
Has anyone observed you stop breathing during your sleep?
Low risk of OSA: Answering yes to less than three items.
Yes No
4. Blood pressure
Do you have or are you being treated for high blood pres-
sure? Yes No
5. BMI
BMI > 35 kg/m2? Yes No
Pathophysiology of Obstructive
Sleep Apnea
during general anesthesia in normal individuals with those during inspiration is commonly caused by narrowing of a
of OSA patients found that the upper airways of OSA patients hypotonic upper airway in response to the increasingly nega-
are narrower and more collapsible.13 tive intraluminal pressure developed during inspiration.14,15
Airflow through the pharynx shows various degrees of In Figure 162, the first three breaths do not show airflow
airflow limitation during sleep. Inspiratory flow limitation is limitation and airflow has a round shape. The fourth breath,
defined by an increase in the pressure drop across the which occurs after sleep onset, demonstrates airflow limita-
upper airway (more negative supraglottic and intrathoracic tion with a constant flow during the time when the inspira-
pressure) without a corresponding increase in flow rate tory pressure (supraglottic pressure) as reflected by
(Fig. 161). This alinearity in the pressure-flow relationship esophageal pressure is becoming more negative (increased
pressure difference across the upper airway).
The pharynx is not rigid and pharyngeal resistance is not
TABLE 161 constant. The nonrigid portions of the pharynx tend to
Factors Determining Upper Airway Patency become increasingly narrow with more negative inspiratory
OPEN UPPER AIRWAY CLOSED UPPER AIRWAY pressure. The collapsibility of the upper airway and tendency
for closure can be defined by the pharyngeal passive closing
PASSIVE FACTORS
pressure (PCRIT).16,17 The PCRIT values for normal people,
Larger, stiffer upper Smaller, more compliant snorers, patients with obstructive hypopneas, and patients
airway (PCRIT 0 or negative) upper airway (positive PCRIT ) with obstructive apnea are plotted in Figure 163.14 As upper
Large bony enclosure Small bony enclosure airway dysfunction increases (normal snorers apnea),
Less soft tissue (thinner More soft tissue the PCRIT is progressively more positive. During sleep, a posi-
lateral pharyngeal walls) Lower lung volume
tive pressure is needed to keep the airway open (PCRIT > 0)
Higher lung volume Supine posture
in patients with sleep apnea. In normal patients, the airway
Lateral decubitus posture
does not collapse unless a negative mask pressure is applied.
UPPER AIRWAY MUSCLE FACTORS The PCRIT is determined by applying various positive or
High upper airway muscle Low upper airway muscle negative mask pressures (Pmask) and determining the inspi-
activity activity ratory flow rate. In patients with OSA, flow decreases as
Large upper airway Low upper airway muscle mask pressure decreases from a more positive pressure (Fig.
muscle response to response to negative upper 164). The mask pressure at which flow is zero is PCRIT. The
negative pressure airway pressure inverse of the slope is the effective resistance ( pressure/
VENTILATORY CONTROL STABILITY flow) and is called the upstream resistance (Rus). The equa-
tion relating flow ( V max), mask pressure, and PCRIT
STABLE VENTILATORY DRIVE FLUCTUATING VENTILATORY
DRIVE V max = (Pmask PCRIT )/ R us
Low loop gain High loop gain Pus = Pmask in Starling resistor model
Low controller gain High controller gain
Equation 161
Low plant gain High plant gain
High arousal threshold Low arousal threshold
The relationship between flow and mask pressure can be
PCRIT = passive closing pressure of the upper airway.
modeled using a Starling resistor (Fig. 165) using Pus
P 5
Supraglottic
pressure Airflow
Greater pressure
difference across
Nose P 0 Lungs Inspiration the upper airway
0
Upper at B versus A with
airway Pressure 5 no increase in flow
A cm H2O
10
P 10
A B
B
FIGURE 161 A higher pressure (P) difference across the upper airway (more negative supraglottic pressure) at B compared with
A does not increase airflow. This is an example of airflow limitation. The effective resistance has increased with more negative
supraglottic pressure.
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Chapter 16 Pathophysiology of Obstructive Sleep Apnea 265
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
ECG
EMGgg
Airflow limitation
Flow
MTA-EMGgg
FIGURE 162 With sleep onset, there is a fall in genioglossus activity and inspiratory effort and flow. This results in airflow limitation
(flat flow). Note the phasic (inspiratory) increase in genioglossus activity during stable breathing preceding sleep. ECG =
electrocardiogram; EMGgg = genioglossus electromyogram; MTA-EMGgg = rectified moving time average of EMGgg. Adapted from
Berry RB: OSAHS definitions, epidemiology, and consequences. In Carney P, Berry RB, Geyer JD (eds): Clinical Sleep Disorders, 1st ed.
Philadelphia: Lippincott Williams & Wilkins, p. 261.
(upstream pressure) = Pmask. This consists of a collapsible muscles of the respiratory pump. This allows for a stable
segment between rigid tubes.16 As long as the intraluminal upper airway during inspiratory flow. The inspiratory activ-
pressure within any point of the collapsible segment is less ity of the GG muscle is affected by (1) negative intraluminal
than PCRIT, the relationship in Figure 164 will hold. Creating pressure via effects on upper airway mechanoreceptors in
more negative pressure downstream from the collapsible the laryngeal area, (2) central pattern generators in the
segment will not increase flow. When the intraluminal pres- brainstem, and (3) influences of sleep state (wakefulness
sure along the entire collapsible segment is less than the stimulus).16 The activity of the phasic upper airway muscles
PCRIT, no flow occurs. (GG) but not the tonic palatal muscles relates closely to
During wakefulness, upper airway muscle activity main- pharyngeal pressure. The activity of tonic upper airway
tains an open upper airway even if the airway is anatomically muscles appears to be more sleep statedependent (wake
narrow. Some upper airway muscles such as the genioglossus > nonrapid eye movement [NREM] > rapid eye movement
(GG; tongue protruder) and palatoglossus show increased [REM]).18,20
activity with inspiration (phasic activity) (see Fig. 162), The effects of negative upper airway pressure on the GG
whereas others such as the tensor velli palatini (a muscle of are mediated through a reflex neural pathway. The pathway
the palate) show tonic (constant) activity.1820 Activation of starts with upper airway mechanoreceptors and travels
phasic upper airway muscles is triggered slightly before the through the superior laryngeal nerve to sensory brainstem
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266 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
0
1
Slope
PCRIT (cm H2O)
. Rus
4 Vmax
8
12
16
15 9
Collapsible segment
Pin
Pus Pcrit 10 Pds Pcrit
Pout
A C . Pus Pcrit
Vmax
Rus
Condition #1 Condition #3
R
nuclei (nucleus of the solitary tract [NTS]). Neurons in the measured. The etiology of the effect of posture is not clear.
NTS then stimulate hypoglossal motoneurons in the brain- With sleep onset, the loss of the wakefulness stimulus on
stem that innervate the GG via the hypoglossal nerve. upper airway muscles causes a decrement in their activity.
Greater upper airway inspiratory muscle activity occurs This may be mediated in part by a loss of serotonergic or
with more negative upper airway pressure. Hypoxia and noradrenergic excitatory modulation of upper airway motor
hypercapnia could potentially modulate (increase) upper neuron activity.5
airway muscle activity via effects on the central pattern gen- At the onset of NREM sleep, the activity of both phasic
erators or indirectly by augmenting ventilatory drive/ and tonic upper airway muscles decreases18,19,22,23 and upper
inspiratory effort, generating more negative upper airway airway resistance increases24 (see Fig. 162). With stable
pressure (higher suction pressure). Pillar and coworkers21 sleep, the activity of the GG may actually return to waking
administered exogeneous CO2 to normal individuals during or higher than wakefulness levels as upper airway pressure
NREM sleep and found no significant augmentation of GG becomes increasingly negative25 (Fig. 166). If upper airway
activity. The epiglottic negative pressure was not significantly activity is favorable or upper airway muscle activity has
different between baseline and CO2 inhalation. Thus, hyper- compensatory effectiveness, stable ventilation will be main-
capnia was not associated with more negative upper airway tained. Compensatory effectiveness requires a sufficient
pressure or an increase in GG activity. This study was per- increase in upper airway muscle activity (stimulated by
formed with subjects in the lateral sleep position. In contrast, hypercapnia and negative upper airway pressure) and that
during monitoring in the supine position, Lo and colleagues8 the increase in muscle activity is effective in maintaining
did find that exogenous CO2 administration augmented GG upper airway patency.26
activity. The administration of continuous positive airway Patients with OSA tend to have higher than normal awake
pressure (CPAP) did not change the slope of the GG response basal GG activity.2729 The higher activity is believed to be
to hypercapnia. However, upper airway pressure was not compensation for an intrinsically narrow or more collapsible
FIGURE 166 Tracings from a patient with periods of both obstructive apnea and stable ventilation during sleep. During stable
stage N2 sleep without apneas (Stable S2), high genioglossus activity (B) is noted associated with more negative epiglottic pressure
(PEPI) (D). Note that the genioglossus activity is higher than during wakefulness. During slow wave sleep (SWS; stage N3), the
genioglossus activity is higher than stage N2 and PEPI is more negative. The inspiratory activity of the moving time average of the
genioglossus (GG mta) is higher at B than at A because epiglottic pressure (PEPI) is more negative at D than at C. ABD = abdominal
band; Cyclical S2 = stage N2 with repeated obstructive apneas; RC = chest band; SaO2 = arterial oxygen saturation; VT = tidal
volume. From Jordan AS, White DP, Lo YL, et al: Airway dilator muscle activity and lung volume during stable breathing in obstructive
sleep apnea. Sleep 2009;32:361368.
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268 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
upper airway. Most patients with OSA also have a greater During upper airway obstruction, phasic GG activity
than normal fall in GG activity with sleep onset.29 A reflex increases proportionately to esophageal pressure deflections
activation of the GG muscle to a sudden brief pulse of nega- (reflecting increased respiratory drive) (see Figs. 166 and
tive pressure can be demonstrated.30 The response of the GG 167).9,37,38 Stimulation of chemoreceptors by hypoxia and
and palatal muscles to negative pressure is reduced during hypercapnia increase inspiratory drive and esophageal pres-
sleep.3032 During wake, patients with OSA have a greater sure deflections increase. At apnea termination, both GG
response in GG activity to a sudden negative pressure pulse and palatal muscles are preferentially augmented and the
than normal subjects.33 The greater response to negative upper airway opens.9,37,38 Although it was once assumed that
pressure and higher basal GG activity allow the upper airway increasing GG activity during obstructive apnea or hypop-
to remain open during wakefulness. In contrast, the response nea was driven entirely by hypoxia and hypercapnia, a study
of the palatal muscles to negative pressure may be impaired of the effect of upper airway local anesthesia suggests that
in OSA patients.34 Despite evidence for higher basal upper mechanoreceptor stimulation (from increasingly negative
airway muscle activity during wakefulness, the upper airways pressure below the site of obstruction) plays an important
of OSA patients are still more collapsible than those of role in the augmentation of GG activity.37 In Figure 168, the
normal persons.35 With sleep onset, the wakeful stimulus to top panels (Pre-lidocaine) show a progressive increase in GG
GG activity is no longer present and upper airway muscle activity during apnea. After topical lidocaine anesthesia of
activity falls in normal individuals and patients with OSA. the upper airway, the GG activity is markedly diminished.
However, as noted previously, OSA patients have a greater This implies that mechanoreceptor stimulation from increas-
than normal fall in upper airway muscle activity.29 Owing to ingly negative pressure below the site of obstruction results
unfavorable anatomy, the residual upper airway activity is in augmentation of GG activity.
not sufficient to maintain an open upper airway. In Figures Traditionally, a concept of a balance between negative
166 and 167, a fall in GG activity as the patient returns inspiratory pressure tending to collapse the airway and
to sleep is associated with an obstructive apnea. Posture upper airway muscle dilating forces was assumed to deter-
also has important effects on airway patency,36 and some mine the state of the airway. However, more recently, the
patients with OSA have apnea or hypopnea only in the concept of passive collapse at sleep onset (including return
supine position. to sleep after termination of respiratory events) has gained
Arousal Arousal
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
ECG
EMGgg
16 seconds
Airflow
MTA-EMGgg
Esophageal
pressure
SaO2
91%
FIGURE 167 After the arousal, genioglossus activity decreases as the patient returns to sleep and is associated with an obstructive apnea. During
the obstructive apnea, the moving time average of the genioglossus muscle (MTA-EMGgg) progressively increases and esophageal pressure swings
also progressively increase. However, the airway does not open until there is a large increase in genioglossus activity associated with an arousal.
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ECG = electrocardiogram; EMGgg = electromyogram of the genioglossus muscle; SaO2 = arterial oxygen saturation.
Chapter 16 Pathophysiology of Obstructive Sleep Apnea 269
Post lidocaine
*
88 cmH2O
60 cmH2O
5 sec
favor. In fact, at sleep onset, the ventilatory drive decreases The upper airways of patients with OSA have greater lung
and supraglottic pressure may initially decrease (less nega- volume dependence than normal individuals.41 The lung
tive) in some patients (although resistance increases). Upper volume dependence of the upper airway may be mediated
airway closure has also been documented during central via passive distending forces due to a downward tension
apnea in which there is no inspiration or negative collapsing on upper airway structures during inspiration (tracheal
forces.39 Therefore, suction pressure during obstruction may tug).43 Another way of thinking of the tracheal tug is a
help keep the airway closed but is not necessary for the onset decrease in extramural pressure surrounding the airway.
of airway occlusion. Cyclic variations in ventilatory drive can Any fall in end-expiratory volume (functional residual
induce obstructive or central apneas at the nadir in drive.40 capacity [FRC]) would then reduce upper airway size. FRC
Thus, even if ventilatory drive to the respiratory pump is known to decrease during sleep,44 and this would tend
muscles decreases, the simultaneous reduction of neural to predispose to airway closure. Morrell and coworkers45
drive to the upper airway muscles can result in airway nar- demonstrated a progressive fall in end-expiratory retro-
rowing or collapse. palatal cross-sectional area as well as end-expiratory lung
volume in the breaths leading up to obstructive apnea.
Heinzer and colleagues46 found that an increase in lung
LUNG VOLUME EFFECTS
volume (induced by extrathoracic pressure) resulted
Upper airway size also has a dependence on lung volume in a lower level of CPAP required to prevent airflow
with decreasing airway size as lung volume decreases.41,42 limitation.
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270 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
Esophageal
pressure
Pes min
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Chapter 16 Pathophysiology of Obstructive Sleep Apnea 271
have obstructive events only during REM sleep or the apnea- individuals did not find a significant change in ventilation
hypopnea index (AHI) is much higher during REM sleep. between early and late REM sleep periods because an increase
However, the reason for the susceptibility for apnea during in respiratory rate compensated for fall in VT.54 However,
REM sleep remains unclear. During REM sleep, ventilation patients with OSA or lung disease are more susceptible to
is irregular even in normal persons. REM sleep without the phasic changes of REM sleep and VT falls with either no
phasic eye movements is called tonic REM and with eye change in respiratory rate or a change insufficient to main-
movements phasic REM. There tends to be more respira- tain ventilation.55 During REM sleep, there is generalized
tory irregularity during periods of bursts of eye movements muscle hypotonia and the muscles of respiration other than
(phasic REM)53,54 (Fig. 1610). During phasic REM, there are the diaphragm are less active.55 Although the diaphragm is
often periods of reduced airflow, tidal volume (VT), and not affected by the generalized tonic muscle hypotonia of
respiratory effort. The eye movement bursts are markers of REM sleep, periodic decrements in diaphragmatic activity
brainstem phasic REM activity that affects respiration. (inspiratory effort) do occur and are often associated with
Because periods of REM sleep are longest and the REM bursts of eye movements (Fig. 1611).55 The decrements in
density (number of eye movements per time) highest during diaphragmatic activity are associated with reduced VT. Upper
the early morning hours, it is not surprising that this is the airway muscles are also affected during REM sleep. In normal
time of the greatest changes in ventilation during sleep in persons during REM sleep, GG tonic activity is reduced
patients with lung disease and OSA.53,55 One study in normal but phasic activity can still be detected if intramuscular
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
Airflow
(nasal press)
Esophageal
pressure
20 cm H2O
FIGURE 1610 A period of reduced airflow associated with decreased inspiratory effort as reflected by esophageal pressure
deflections during REM sleep (stage R). The reduced airflow occurs during a prolonged burst of eye movements. Note that the airflow
profile is flat during inspiration, suggesting the presence of airflow limitation. EMG = electromyogram.
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272 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
EOG
EEG
0.3 L/sec
Airflow
500cc
Tidal volume
Genioglossus
EMG
Integrated
genioglossus
EMG
FIGURE 1612 Reduction in genioglossus activity during bursts of eye movements in REM sleep (stage R). EEG = electro-
encephalogram; EMG = electromyogram; EOG = electro-oculogram. From Wiegand L, Zwillich CW, Wiegand D, White DP: Changes in
upper airway muscle activation and ventilation during phasic REM sleep in normal men. J Appl Physiol 1991;71:488497.
electromyogram (EMG) electrodes are used (Fig. 1612). patients with OSA had more REM-induced changes in upper
During bursts of eye movements, diaphragmatic and GG airway muscle activity than normal subjects. Therefore, the
phasic activity are often decreased.56 normal REM-associated changes in respiratory physiology
As noted previously, many patients have obstructive may have greater impact on patients with susceptible upper
apnea only during REM sleep (REM-related OSA). However, airway anatomy. More investigations in this area of inquiry
two studies found no greater collapsibility (PCRIT) of the are needed.
upper airway during REM than during NREM sleep.36,57 This
variance with clinical experience could be due to REM-
GENDER AND OSA
associated manifestations that do not affect the PCRIT mea-
surement. These might include changes in lung volume A number of investigations have sought to determine the
during prolonged reductions in ventilation or impairment pathophysiology of the higher incidence of OSA in men
of the ability of the airway to compensate for increasing than in women. Men have longer upper airways and this is
resistance. Jordan and coworkers58 studied OSA patients believed to predispose them to pharyngeal collapse.60 Of
who could maintain upper airway patency during some note, postmenopausal women have longer upper airways
periods of NREM sleep. Stable breathing during stage N2 than premenopausal women.61 One study found that men
was compared with cyclic REM sleep (with apneas). The also have more fat around their upper airway than women.62
end-expiratory lung volume and peak GG EMG did not There have been no clear gender differences in loop gain,
differ. During REM sleep, the relationship between the nega- upper airway collapsibility (PCRIT), or pharyngeal muscle
tive epiglottic pressure (PEPI) and the phasic GG activity also activation.6365 Pillar and associates65 found that men deve-
did not differ from stage N2 sleep. However, PEPI was much loped more hypopnea due to resistive loading. Because no
less negative and the tonic GG activity was lower during difference in upper airway muscle activation was noted, the
REM sleep (Fig. 1613). Perhaps lower GG tonic activity increased tendency for male upper airway narrowing was
during REM sleep makes the upper airway susceptible to believed to be due to anatomic factors. There have been
closure especially at end-exhalation when the upper airway efforts to determine whether a difference in ventilatory
size is the smallest. Eckert and associates59 did not find that control between men and women could explain the higher
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Chapter 16 Pathophysiology of Obstructive Sleep Apnea 273
FIGURE 1613 Comparing rapid eye movement (REM) sleep with obstructive apneas with breathing during stable stage N2
sleep (S2). The tonic (expiratory) genioglossus (GG) EMG is much lower (*) and the epiglottic pressure (PEPI) is much less negative (**).
ABD = abdominal band; mta = moving time average; RC = chest band; SaO2 = arterial oxygen saturation; VT = tidal volume. From
Jordan AS, White DP, Lo YL, et al: Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep
2009;32:361368.
prevalence of OSA in men. Loop gain is not different between BOX 161
men and women.63 As previously noted, the apneic threshold Respiratory Arousal Mechanisms
is the sleeping PaCO2 at which ventilation is no longer trig- The arousal stimulus during obstructive apnea and
gered (see Chapter 21). Men have a smaller difference hypopnea appears to be proportional to the magnitude
between their sleeping PaCO2 and their apneic threshold, of inspiratory effort (esophageal pressure excursions).
predisposing them to central apnea or hyponea after periods Hypercapnia, hypoxemia, and negative pressure stimuli
of hyperventilation.66,67 In summary, no clear explanation for during obstructive respiratory events result in increasing
the gender difference in the prevalence of OSA has been respiratory effort. However, arousal occurs when the level
found. Anatomic differences (longer upper airway length) or of effort reaches an arousal threshold.
increased upper airway susceptibility to resistive loading The arousal threshold to respiratory stimuli during NREM
or falling ventilatory drive in men may be possible sleep is increased in patients with OSA compared with
normal individuals (higher inspiratory effort is needed to
explanations.
trigger arousal).
A higher arousal threshold may predispose to longer
MECHANISMS OF APNEA TERMINATION respiratory events, but a low arousal threshold may
AND AROUSAL contribute to ventilatory instability.
Obstructive apneas and hypopneas are longer during
Obstructive apnea or hypopnea termination is often associ- REM than during NREM sleep. In contrast, normal
ated with cortical arousals. The relationship between these individuals arouse from experimental mask occlusion
two phenomena is still the subject of investigation (Box more rapidly in REM than in NREM sleep.
161). During obstructive apnea or hypopnea during NREM The mechanisms responsible for obstructive event
sleep, upper airway muscle activity increases proportional to termination and respiratory arousal have similar time
inspiratory effort. Studies by Reemers and coworkers9 sug- courses but may be independent parallel processes. In
some studies, 2040% of obstructive event terminations
gested that airway opening does not occur until there is
are not associated with cortical arousal.
a preferential increase in upper airway muscle activity
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274 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
(compared with the diaphragm) (see Figs. 166 and 167). hypoxia or hypercapnia seems to trigger arousal.70,72,73 Thus,
The preferential increase in upper airway muscle activity the level of effort is an index of the combined arousal stimu-
was believed to be due to associated arousal. One problem lus. Studies have suggested that information from upper
with this concept is that not all event terminations are asso- airway mechanoreceptors may contribute to the arousal
ciated with cortical arousal (e.g., 6080% of event termina- stimulus.76,77 In NREM sleep, arousal appears to occur when
tions are associated with arousal). Sometimes, obstructive inspiratory effort reaches an arousal threshold. Normal
event termination is associated with signs of cortical activa- subjects tend to arouse during mask occlusion when suction
tion, although the electroencephalogram (EEG) changes pressure reaches 20 to 40 cm H2O. In contrast, many
may not always meet American Academy of Sleep Medicine patients with OSA arouse only after esophageal pressure
(AASM) criteria.68 For example, a delta burst may be seen at reaches 60 to 80 cm H2O.70,73,78 The increased arousal
apnea termination. OMalley and coworkers69 suggested that threshold in OSA patients is probably due in part to chronic
by using frontal electrodes, one could detect arousal in the sleep deprivation or hypoxemia. Withdrawal of CPAP for
majority of events. Even when cortical arousal cannot be even three nights has been shown to increase the arousal
detected, some have hypothesized a state change at the level threshold in OSA.78 However, chronic CPAP treatment does
of the brainstem.70 These are sometimes referred to as sub- not restore the arousal threshold to normal. Patients with
cortical or autonomic arousals because changes in sympa- OSA could have an intrinsically increased respiratory arousal
thetic tone, heart rate, or blood pressure can occasionally be threshold. Another possible explanation for an elevated
detected in the absence of cortical changes meeting criteria arousal threshold is damage to mechanoreceptors from years
for arousal. of snoring or to chemoreceptors from repetitive nightly
Younes71 has challenged the concept that arousal is an stimulation. Support for this idea comes from studies
essential component of upper airway opening. His work showing that upper airway sensation is impaired in patients
found that arousal may precede, coincide with, follow, or with OSA.79 A study of respiratory-related evoked potentials
not occur with upper airway opening. Thus, in this view, (RREPs) in patients with mild OSA suggested that there is a
arousal may be associated with event termination, but what sleep-specific blunted cortical response to inspiratory occlu-
opens the airway is a sufficient augmentation of upper sion.80 At least in these milder patients, there was no evi-
airway muscle activity by chemical and mechanical stimuli. dence of impaired mechanoreceptor function because the
Thus, Younes hypothesizes that airway opening and arousal RREP was normal during wakefulness. One study found that
are two separate independent phenomena that occur in par- the prolongation in event duration that occurs overnight in
allel with similar time courses during obstructive respira- patients with OSA is secondary to a blunting of the cortical
tory events. Upper airway muscle activity is progressively response as the level of inspiratory effort at apnea termina-
augmented until an upper airway opening threshold is tion increased during the night.81 Another study found that
reached and the airway opens. Likewise, during obstructive the within-night variation in the arousal threshold followed
events, the arousal stimulus (proportional to the level of the cycles of NREM sleep82 with a higher arousal threshold
inspiratory effort70,72,73) increases until the arousal threshold associated with higher EEG delta power (deeper sleep).
is reached and arousal occurs. If augmentation of upper Sforza and colleagues83 studied the within-night changes in
airway muscle activity is brisk, the required degree of the arousal threshold associated with respiratory events and
muscle augmentation is not excessive, and the arousal found that the arousal threshold tended to peak during the
threshold is high, the airway could reopen without arousal first 3 hours of sleep, plateau, and then decrease slightly in
(the patient remains asleep). Evidence for this concept is the last hour of sleep. They did find a mild increase in apnea
that most patients with OSA have some periods of the night duration over the night. The authors concluded that their
without events and, thus, are able to maintain upper airway findings showed the arousal threshold was not dependent on
patency without arousal. However, this concept does not sleep fragmentation (which should have continued to worsen
explain event termination during REM sleep when upper during the entire night) and might reflect circadian or
airway muscles do not necessarily augment during the event homeostatic rhythms. Another explanation is that greater
(see Fig. 1613). In addition, whereas phasic upper airway delta power (sleep depth) occurs in the early part of the
muscles augment with increasing inspiratory drive (and night82 and greater sleep depth delayed arousal.
more negative upper airway pressure), tonic upper airway It is worth noting that the apnea duration (time to arousal)
muscles do not. Tonic muscles increase their activity with a depends on both the arousal threshold and the rate of
state change (arousal). Thus, arousal may play a role in ter- increase in inspiratory effort (respiratory response to
mination of some obstructive events. Even if arousal is not arousal).70 For example, the addition of supplemental oxygen
essential to upper airway opening, repeated arousals are results in longer apneas (reduction in rate of augmentation
thought to contribute to daytime sleepiness (along with the in inspiratory effort) but event termination occurs at similar
associated hypoxemia).74,75 levels of esophageal pressure (similar arousal threshold).70 If
The mechanisms that contribute to respiratory arousal are one believes that airway opening is independent of arousal,
also of interest and still incompletely understood. Whereas a similar scheme can still be invoked with the determinants
hypercapnia and hypoxia drive the increase in respiratory of event duration being the rate of upper airway muscle
effort, the level of effort rather than individual values of augmentation and the airway opening threshold.
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Chapter 16 Pathophysiology of Obstructive Sleep Apnea 275
In REM sleep, the arousal mechanisms are less well BOX 162
understood. Esophageal pressure deflections do not show a Factors Associated with More Severe Arterial
steady increase (see Fig. 1613). However, normal subjects Oxygen Desaturation
arouse more quickly from mask occlusion during REM sleep
than during NREM sleep.70,84 In contrast, patients with OSA Higher BMI
have the longest apneas and most severe desaturation during More effect during REM than NREM sleep.
REM sleep.85 More effect supine > lateral sleep.
The reasons for the delayed arousal (longer event dura- More effect men > women.
tion) during REM sleep in OSA patients are not known. The Lower baseline awake supine PaO2 or SaO2
slower and erratic augmentation of respiratory drive that Lower ERV (FRC RV).
occurs during REM sleep could delay arousal and event ter- Low FRCobesity.
mination even if the arousal threshold is similar to that of High RVobstructive airways disease (COPD).
NREM sleep.86 Conversely, there could be an increase in the Longer event duration.
arousal threshold during REM compared with NREM sleep Greater change in V T (hypopnea).
in some OSA patients with chronic REM sleep fragmenta- Short ventilatory period between apnea.
tion. Certainly, some OSA patients exhibit a tremendous REM sleep versus NREM sleep (REM events are also
longer).
increase in eye movements during REM sleep on the first
Supine versus lateral position.
night on CPAP. This may be evidence of prior REM sleep
fragmentation or deprivation. Prior sleep disturbance could BMI = body mass index; COPD = chronic obstructive pulmonary disease;
ERV = expiratory reserve volume; FRC = functional residual capacity;
increase the arousal threshold. Zavodny and coworkers87 NREM = nonrapid eye movement; PaO2 = arterial partial pressure of
found evidence that sleep fragmentation from acoustic oxygen; REM = rapid eye movement; RV = residual volume; SaO2 = arterial
stimuli impaired the arousability to resistive loading in stage oxygen saturation; V T = tidal volume.
80
UPPER AIRWAY SENSATION
60
There is evidence that upper airway sensation is impaired in
patients with OSA.79 This could be due to years of trauma
from snoring. It is unclear whether damage to upper airway 40
mechanoreceptors could be playing a role in the pathogen-
esis of OSA in some patients. 20
FIGURE 1615 A total night view shows the hypnogram with rapid eye movement (REM) sleep shown by horizontal bars. The patient had almost no events except
during REM sleep, but during REM sleep, the desaturation was significant. SaO2 = arterial oxygen saturation.
oxygen desaturation during respiratory events. The ERV is than in nonsmokers. Another study found that obstructive
the difference between the functional residual capacity (FRC; events in the supine position tended to be longer, were asso-
end-expiratory volume) and the residual volume (RV). A ciated with more severe desaturation, and were more likely
small ERV is usually due to a low FRC, a high RV, or both. to be associated with an arousal at event termination.92
In obesity, the FRC is reduced. A lower FRC is associated As previously mentioned, REM sleep is associated with
with lower oxygen stores before a respiratory event. Tidal more severe desaturation than NREM sleep.85,93 Oksenberg
breathing at low lung volumes results in substantial small and coworkers also found that supine REM sleep is associ-
airway closure (below the closing volume). This increases the ated with more severe arterial oxygen desaturation than non-
amount of ventilation-perfusion mismatch (no ventilation supine REM sleep. This was not due to longer event
reaches some alveoli). A high RV is usually due to airtrap- duration.93 Thus, one would expect the most severe arterial
ping associated with obstructive airways disease. The pres- oxygen desaturation to usually occur during supine REM
ence of obstructive airway disease also causes more sleep.
ventilation-perfusion mismatch (see Chapter 10). Low
oxygen stores at the start of apnea and ventilation-perfusion CLINICAL REVIEW QUESTIONS
mismatch both contribute to a more rapid and more severe
drop in the SaO2 during apnea or reduced ventilation 1. Which of the following factors may help explain the
(hypopnea). greater prevalence of OSA in men than in women?
Clinically, the groups of OSA patients with severe desatu- A. Longer upper airway length in men.
ration include patients with a low PaO2 for any reason (severe B. Higher PCRIT (more positive) in men.
obesity, daytime hypoventilation, and chronic obstructive C. Less pharyngeal muscle activation.
pulmonary disease [COPD]). In fact, some patients can have
D. Higher loop gain in men than in women.
significant desaturation after events as short as 10 to 15
seconds. The severity of desaturation also depends on sleep 2. Breathing through the nose rather than the mouth causes
stage. As noted previously, in most OSA patients, the longest more negative supraglottic airway pressure during inspi-
apneas and most severe desaturations occur in REM sleep ration (e.g., 6 cm H2O with nasal breathing, 2 cm H2O
(Fig. 1615).85 Some studies also have suggested that at with oral breathing). Which route of breathing is associ-
equivalent apnea length, the severity of desaturation is ated with greater phasic activity of the GG muscle?
worsened in obstructive compared with central apnea.90 A A. Oral breathing route.
recent large study of the Wisconsin cohort found that a
B. Nasal breathing route.
higher BMI was associated with oxygen desaturation severity
independent of age, gender, sleeping position, baseline SaO2, 3. Which of the following would NOT predispose to upper
and event duration.91 A higher body mass index (BMI) had airway narrowing or closure?
a greater effect on desaturation in REM than in NREM sleep.
A. Falling ventilatory drive.
In addition, a fall in VT had a greater effect on arterial oxygen
desaturation when the BMI was higher. The predicted change B. Higher FRC.
in the SaO2 was also higher in the supine position than in C. Less negative upper airway pressure.
the lateral position, in men than in women, and in smokers D. Higher PCRIT.
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Chapter 16 Pathophysiology of Obstructive Sleep Apnea 277
4. Higher BMI is associated with worse arterial oxygen 6. Horner RL: Motor control of pharyngeal musculature and
desaturation in OSA patients. implications for the pathogenesis of obstructive sleep apnea.
Sleep 1996;19:827853.
Which of the following is true about the effect of BMI on 7. Badr MS: Pathophysiology of upper airway obstruction during
sleep. Clin Chest Med 1998;19:2132.
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A. REM > NREM. response to CO2 stimulation during NREM sleep. Sleep 2006;
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patients with sleep disordered breathing. Am Rev Respir Dis
A. Higher PCRIT.
1993;148:13851400.
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C. Lower tonic upper airway muscle activity. upper airway anatomic risk factors for obstructive sleep apnea
with volumetric magnetic resonance imaging. Am J Respir Crit
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12. Leiter JC: Upper airway shape: is it important in the pathogen-
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related to which of the following? 1996;153:894898.
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Chapter 17
Consequences of Obstructive
Sleep Apnea and the Benefits
of Treatment
Chapter Points pulmonary hypertension is usually of a mild nature
The nocturnal consequences of OSA vary with severity. (unless other factors are present).
Possible changes include episodic hypercapnia, Untreated OSA is associated with nocturnal
hypoxia, negative intrathoracic pressure, increases in arrhythmia, although the incidence is low. In some
pulmonary and systemic pressure, cyclic slowing then cases, effective treatment will improve arrhythmias.
speeding of heart rate, and surges of sympathetic tone Untreated OSA is associated with an increased
at event termination. Most studies show that the incidence of recurrence of Afib after cardioversion.
cardiovascular consequences are most closely related Observational studies suggest that untreated OSA is
to the severity of hypoxemia. associated with a higher risk of adverse outcomes in
Patients with untreated OSA often have elevated patients with CAD.
post-awakening AM blood pressure, high daytime Untreated OSA is associated with a higher incidence of
sympathetic tone, and decreased heart rate variability. stroke. In stroke patients, CPAP treatment of OSA can
The best evidence of increased mortality in untreated reduce mortality.
OSA is for men, with moderate to severe OSA, with an Untreated OSA can worsen nocturia and CPAP
approximate age range of 60 years (4070 in other treatment can improve this manifestation.
studies). Pediatric OSA has significant neurobehavioral
Observational studies suggest that OSA patients consequences that can be improved with treatment.
effectively treated with CPAP have normal survival, all
other factors being equal.
The severity of daytime sleepiness increases with
higher AHI but there is substantial variability. Other This chapter reviews the consequences of untreated obstruc-
PSG indices such as the arousal index do not have tive sleep apnea (OSA) and the benefits of treatment. Many
significantly higher correlations with subjective or of the studies discussed are cross-sectional population-based
objective sleepiness than the AHI. investigations looking for associations between the preva-
OSA patients are at increased risk for motor vehicle lence of a cardiovascular consequence (e.g., hypertension) at
accidents (especially if there is a history of sleepiness a given time with the severity/presence of OSA (various
at the wheel). Effective CPAP treatment can reduce the levels of apnea-hypopnea index [AHI]). Prevalence is the
risk of motor vehicle accidents. amount of disease in a given population. Others follow a
Patients with OSA may fail to have a fall in blood population over a period of time and determine the amount
pressure with sleep (nondippers). Clinical cohorts with of new cases (incidence of a given disease). These studies
hypertension or resistant hypertension have a high determine the risk of developing consequences at various
prevalence of OSA. Although investigations differ, levels of AHI. The results of population-based studies may
effective CPAP treatment likely is associated with a also vary depending on the group to be evaluated. It is always
small decrease in 24-hour blood pressure. worth noting that investigations of clinic-based versus
OSA in the absence of lung disease or diastolic asymptomatic individuals randomly selected may well be
dysfunction is associated with daytime pulmonary different.
hypertension in 20% to 40% of patients. The Considering the effects of continuous positive airway
pressure (CPAP) treatment on consequences of untreated
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281
282 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
OSA, it is important to understand that observational studies across the left ventricle walls and increases the effective after-
are less convincing than randomized controlled trials. There load. The cycles of increased sympathetic tone6 (Fig. 172)
is always the concern that patients who adhered to CPAP increase systemic vascular resistance. Arousal at apnea ter-
treatment are somehow more compliant with other medical mination is associated with a large increase in sympathetic
therapy as well and, therefore, more likely to have better tone and decreased vagal tone with the result that blood
outcomes. A study by Platt and colleagues1 found CPAP pressure and heart rate increase. High sympathetic tone is
users were more adherent in taking lipid-lowering medica- still present during wakefulness (see Fig. 172) and associ-
tions. However, another study by Villar and coworkers2 ated with impaired vagally mediated heart rate variability.
found that patients adherent or nonadherent to CPAP did Intermittent hypoxia causes oxygen free radical production
not differ in their adherence to medication. Both of these and activates inflammatory pathways that can predispose to
studies relied on prescriptions filled or patient report, so atherosclerosis and thrombosis.
actual medication use could differ. There are a number of
ethical and experimental considerations to designing a study
MORTALITY
to prove a benefit of CPAP treatment on cardiovascular out-
comes. With the widespread knowledge of CPAP, it is diffi- In patients with OSA, frequent coexisting conditions such as
cult to design a study with effective blinding and a satisfactory hypertension and obesity make analysis of the impact of
control treatment (e.g., subtherapeutic CPAP).3 OSA on survival difficult. It is unlikely that a randomized
long-term trial of treatment of OSA versus observation is
now possible for ethical reasons. Most of the information we
PATHOPHYSIOLOGY
have about mortality and OSA is from retrospective studies
During normal nonrapid eye movement (NREM) sleep, or prospective observational studies. Some of the studies are
there is a decrease in metabolic rate, sympathetic nerve from clinical cohorts that would be expected to have a
activity, blood pressure, and heart rate, whereas vagal tone higher prevalence of disease, but such studies are subject to
increases compared with wakefulness.4,5 OSA changes this referral bias. Other studies are from large population-based
normal pattern considerably46 (Fig. 171). Cycles of hypoxia cohorts that are free of referral bias but have a relatively low
and CO2 retention elicit changes in sympathetic and para- number of patients with severe OSA. Some studies have ana-
sympathetic activity. Hypoxia and hypercapnia increase ven- lyzed all-cause mortality and others looked at cardiovascular
tilatory drive and obstructed inspiratory efforts create mortality.
negative intrathoracic pressure (sometimes reaching 80 cm An early retrospective study by He and associates7 showed
H2O). The negative pressure increases venous return to the a decreased survival in untreated patients with an apnea
right side of the heart (increased right ventricular [RV] index (AI) greater than 20/hr. Patients with an AI greater
preload) and the hypoxia causes pulmonary vasoconstric- than 20/hr who were treated with tracheostomy or CPAP did
tion (increased RV afterload). The right ventricle may dilate not have a decreased survival. The causes of death in the
and the septum bulge into the left ventricle, impairing left patients were not documented. Lavie and coworkers8
ventricular (LV) filling and decreasing stroke volume. Nega- reviewed the results on 1620 patients diagnosed with OSA
tive intrathoracic pressure increases the transmural pressure between 1976 and 1988. Fifty-seven patients had died by
HR BP Hypertension
Atherosclerosis
Myocardial ischemia LV wall tension
LV hypertrophy and failure Cardiac O2 demand
Cardiac arrhythmias
Cerebrovascular disease
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Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 283
AWAKE CPAP-REM
SNA
AWAKE
Normal OSA RESP
150 150
100 100
BP 50 50
0 0
OSA-REM
SNA
A B
FIGURE 172 A, Recordings of sympathetic nerve activity (SNA) during wakefulness in patients with obstructive sleep apnea (OSA) and matched controls show high levels of
SNA in awake patients with sleep apnea. B, Recording of arterial blood pressure (BP) and SNA in the same subject awake, during rapid eye movement (REM) sleep with obstructive
apnea (OSA-REM), and during REM sleep on continuous positive airway pressure (CPAP-REM). A and B, From Somers VK, Dyken ME, Clary MP, Abboud FM: Sympathetic neural
mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:18971904.
1990 with 53% of the deaths due to respiratory and cardio- OSA patients. Young and associates15 published results from
vascular causes. Excess mortality was noted in men of 30 to the Wisconsin Sleep Cohort and found that severe OSA
50 years of age with OSA but not in patients older than 70 patients had an increased risk of all-cause mortality. The
years of age. Lavie and colleagues9 later published results of results of this study were adjusted for gender. Punjabi and
a sleep clinic cohort (19912000) consisting of 14,589 coworkers16 published results on a large population cohort
patients and found that the hazard of mortality was higher from the Sleep Heart Health Study. There was an increase in
in male patients with moderate and severe OSA compared mortality for the severe OSA patients who were male and
with the general population. The results were significant for aged 40 to 70 years. In this study, statistical corrections for
patients younger than 50 years of age. Another analysis of a the effects of age, BMI, and gender (when appropriate) were
similar cohort sought to determine the factors associated performed.
with mortality in OSA patients.10 The study found that the Summarizing the results, there is strong evidence for an
risk of mortality in patients with OSA was increased by the increased mortality in untreated middle-aged male patients
presence of co-morbidities. For patients younger than 62 with severe OSA (Table 171). Indeed, two clinic-based
years, increased mortality was associated with the presence population studies included only or predominantly men.
of heart failure or diabetes mellitus. For OSA patients older Conversely, the Wisconsin Cohort data did not show a sex
than 62 years, predicators of increased mortality included difference in the increased mortality associated with severe
chronic obstructive pulmonary disease, congestive heart OSA. However, relatively few patients had severe OSA in this
failure, and diabetes mellitus.10 Older patients (age > 65 study. It seems likely that women with untreated severe OSA
years) with mild to moderate OSA appear to be resistant to also have increased mortality, but the evidence for this
the adverse effects of OSA on mortality.11 increased mortality is not as strong as that for men. There is
Marshall and associates12 found an increase in all-cause also the controversy about whether patients who are not
mortality associated with moderate to severe OSA in a sleepy have an increased risk of cardiovascular morbidity.
population-based study. Marin and coworkers13 studied a Evidence from the Sleep Heart Health Study16 found that
clinic population of men and found an increase of fatal and adverse outcomes correlated more with measures of oxygen-
nonfatal cardiovascular events for severe OSA compared ation than with sleepiness (or impaired sleep), suggesting
with normal individuals, snorers, patients with mild OSA, that intermittent hypoxemia rather than indices of sleep
and patients with OSA on CPAP treatment (Fig. 173). Yaggi fragmentation is associated with increased mortality. Con-
and colleagues14 published data on another cohort referred versely, the Wisconsin-based cohort15 found an increase in
to a sleep clinic and found an increased mortality in severe cardiovascular mortality with severe OSA that was present
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284 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
Mild OSAH
fatal CVS events (%)
10
30
30 29
5
26 25
24
0 20 21
0 36 72 108 144 20
A 16
10 12
9
35
Controls
Snorers
0
30
non-fatal CVS events (%)
Mild OSAH Severe 5:59 a.m. 11:59 a.m. 5:59 p.m. 11:59 p.m.
25 Severe OSAH OSA
OSAH with CPAP Time of day
20
FIGURE 174 Day-night pattern of sudden death from cardiac causes in 78 persons
15 with and 34 persons without obstructive sleep apnea (OSA) and in the general
10
population. For OSA patients, the most common time of sudden death is during the sleep
period. In normal individuals without OSA, the most common time of sudden death is
5 in the morning. From Gami AS, Howard DE, Olson EJ, Somers VK: Day-night pattern of
sudden death in obstructive sleep apnea. N Engl J Med 2005;352:12061214.
0
0 36 72 108 144
B Months
FIGURE 173 Cumulative incidence of fatal (A) and nonfatal (B) cardiovascular events variable. Chronic sleep deprivation and/or fragmentation
(CVS) in controls, snorers, and patients with mild or severe obstructive sleep apnea from respiratory events is believed to be the major cause of
(OSA). The patients with OSA treatment with continuous positive airway pressure (CPAP) sleepiness, although hypoxemia may also play a role. Normal
are also shown. Patients with severe OSA had increased cumulative adverse events. individuals subjected to experimental sleep fragmentation
OSAH = obstructive sleep apnea-hypopnea. A and B, From Marin JM, Carrizo S, Vicente without hypoxemia develop subjective and objective daytime
E, Agusti AGN: Long term cardiovascular outcomes in men with obstructive sleep apnea- sleepiness.18,19 Attempts at finding abnormalities demon-
hypopnea with or without treatment with continuous positive airway pressure: an strated on polysomnography that correlate highly with sub-
observational study. Lancet 2005;365:10461053. jective or objective sleepiness have not been very successful.
Johns20 found the Epworth Sleepiness Scale (subjective sleep-
irrespective of symptoms of sleepiness. The controversy con- iness) to correlate with the respiratory distress index (RDI)
tinues, but it seems likely that the severity of oxygen desatu- in a group of 165 patients with OSA (r = 0.439) and slightly
ration due to OSA is the major factor associated with less with the minimum arterial oxygen saturation (SaO2; r =
increased cardiovascular morbidity. 0.404). Guilleminault and associates21 found no polysom-
The time of sudden death appears to be different for nographic variable to be significantly correlated with sleepi-
patients with OSA. Gami and colleagues17 found that for ness as assessed by the multiple sleep latency test (MSLT).
patients with OSA, the relative risk of sudden death from Roehrs and coworkers19 analyzed data from 466 patients
cardiac causes from midnight to 6 AM was 2.57 (95% confi- using multiple regression analysis and found daytime sleepi-
dence interval 1.873.52) compared with other times during ness as assessed by the MSLT had a slightly higher correlation
the day. People with OSA have a peak in sudden death from with the respiratory arousal index (r = 0.36) than indices of
cardiac causes during the sleeping hours, which contrasts hypoxemia (r = 0.34). Cheshire and colleagues found the
strikingly with the nadir of sudden death from cardiac causes arousal index to correlate with impaired cognitive function
during this period in people without OSA and in the general testing but not objective daytime sleepiness.22 Bennett and
population. In patients without sleep apnea, the risk of associates23 found that the AHI, cortical arousal index
sudden death was greatest in the morning hours after awak- (central and frontal electroencephalogram [EEG]), sleep dis-
ening (Fig. 174).17 turbance based on a neural network model, and a body
movement index correlated with objective daytime sleepi-
EXCESSIVE DAYTIME SLEEPINESS AND ness. The correlation between excessive sleepiness and the
indices of sleep disturbance was only slightly higher than the
NEUROCOGNITIVE DYSFUNCTION
correlation between sleepiness and the AHI. The body move-
Excessive daytime sleepiness is a cardinal manifestation of ment index (based on video recording rather than EEG) and
OSA. However, the severity of this symptom is extremely the neural network had the highest correlation coefficients.
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Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 285
TABLE 171
Increased Mortality and Obstructive Sleep Apnea
AUTHOR SELECTION PARTICIPANTS FINDINGS
Punjabi, 200916 Sleep Heart Health 6441 patients Severe OSA AHI > 30/hr associated with
Population-based Cohort Average f/u 8.2 yr increased mortality only in men
Severe OSA N = 341 4070 yr old.
Measures of sleep-related hypoxemia
but not sleep fragmentation were
associated with increased mortality.
Marin, 200513 Snorers, OSA, and MEN ONLY Men with severe OSA AHI > 30/hr had
Clinical cohort matched control 264 healthy men increased incidence of fatal (MI, CVA)
sleep clinic population 337 simple snorers and nonfatal adverse cardiovascular
recruited 403 untreated mild to events (MI, CVA, CABPG, coronary
moderate OSA angiography) compared with control
235 severe OSA untreated group, mild OSA group, and CPAP
372 OSA treated with CPAP group.
Odds ratio fatal CVE 2.87
Odds ratio nonfatal CVE 3.17
Severe group treated with CPAP did not
have increased risk compared with
normal men.
Yaggi, 200514 Patients referred to sleep 1022 patients (77% male) OSA (AHI > 5/hr) was associated with
Clinical cohort clinic 697 had OSA increased risk of death from any
PSG for diagnosis cause.
Adjustments for age, sex,
race, smoking status,
BMI, DM, Afib, HTN
Lavie, 20059 Patients referred to sleep N = 14,589 RDI > 30/hr males had higher mortality
Clinical cohort clinic 372 deaths after median but only in males aged < 50 yr.
f/u of 4.6 yr
Young, 200815 18-yr mortality f/u N = 1522 All-cause mortality higher in severe OSA
Population-based PSG at baseline Severe OSA N = 63 (AHI > 30/hr) vs. no OSA even when
Adjustments for age, CPAP-treated patients eliminated.
gender, BMI, DM, The results were not changed based on
cholesterol, mean BP the presence or absence of sleepiness.
Marshall, 200812 Prospective observational 397 participants moderate Moderate to severe OSA (AHI > 15/hr)
(Busselton Health Home sleep testing to severe OSA N = 18 had greater risk of all-cause mortality
Study) 14-yr f/u 380 free from MI and CVA compared with no OSA.
Population-based Adjustments for age, at baseline Mild OSA had no increased risk.
gender, BMI, DM, 18 AHI > 15/hr
cholesterol, mean BP 77 AHI 5 to <15/hr
285 no OSA
Afib = atrial fibrillation; AHI = apnea-hypopnea index; BMI = body mass index; BP = blood pressure; CABPG = coronary artery bypass grafting; CPAP = continuous
positive airway pressure; CVA = cerebrovascular accident; CVE = complex ventricular event; DM = diabetes mellitus; f/u = follow-up; HTN = hypertension; OSA =
obstructive sleep apnea; PSG = polysomnography; RDI = respiratory distress index.
Routine EEG analysis based on sleep staging or EEG the Sleep Heart Health Study show an increase in sleepiness
arousals may not be sensitive enough to detect all the adverse with higher AHI, but the relationship is weak.27 There is also
effects of respiratory disturbance. For example, noncortical evidence from several studies that hypoxemia may be a
arousals from respiratory events or other causes may result factor associated with impaired cognition in patients with
in daytime sleepiness.24 It may also be possible that long OSA.28 For many patients, a number of factors other than
periods of airflow limitation with high respiratory effort OSA contribute to daytime sleepiness including insufficient
without discrete arousal could be associated with symptoms. sleep and medication side effects. There is also considerable
This pattern commonly occurs in children with OSA who individual variability in the ability to tolerate sleep fragmen-
develop behavioral changes and impaired school perfor- tation. Therefore, it should not be surprising that there is
mance without frequent discrete arousals.25,26 Findings from only a modest correlation between the AHI and subjective
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286 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
or objective measures. Of note, studies of heart failure not generalize to the real world in which sleep deprivation
patients with OSA often show a large proportion do not and other factors are operative. There have been promising
complain of daytime sleepiness.29 It should also be noted that attempts at developing protocols using driving simulators,35,36
effective treatment of sleepy OSA patients (e.g., CPAP) does but results in a simulator may not correlate with driving
not always abolish daytime sleepiness. performance. A study of untreated OSA patients36 found an
MWT mean sleep latency (MSL) less than 19 minutes was
associated with impairment on a driving simulator. The same
AUTOMOBILE ACCIDENTS AND SLEEP APNEA
group extended this work by testing patients with OSA
The true increase in risk of patients with OSA having an during actual 90-minute driving sessions on the road with a
automobile accident is difficult to determine. However, pub- driving instructor intervening if necessary (the test car had
lished studies have found a two to three times greater risk in two steering wheels).37 Inappropriate line crossing was deter-
untreated patients with OSA.3032 Clearly, not all patients mined by video recording. Two groups very sleepy with a
with sleep apnea are at high risk of having an auto accident. MWT MSL less than 19 minutes and sleepy with a MSL 20
It appears that the presence of sleep apnea plus a history of to 33 minutes had significantly more line crossings than
a previous accident (or frequent falling asleep at the wheel) controls and patients with mild sleepiness (MWT MSL
identifies a group of patients with especially high risk. The 3440 min).
decision of whether to report a patient with OSA to a motor Studies have shown improved performance on driver
vehicle licensing agency is a difficult one. A balance between simulators after CPAP treatment of OSA.38 In addition,
patient confidentiality and protection of the public is studies have also shown that the risk of traffic accidents does
required. A committee of the American Thoracic Society has appear to be reduced with nasal CPAP therapy (if patients
issued the following recommendations33: In those jurisdic- are compliant).39,40 The evidence for a reduction in motor
tions in which conditions such as excessive daytime sleepi- vehicle accidents with effective OSA treatment was recently
ness caused by sleep apnea may be construed as reportable summarized by Tregear and coworkers40 in a systematic
events, we recommend reporting to licensing bureaus if: (a) review with meta-analysis.
the patient has excessive daytime sleepiness, sleep apnea, and
a history of a motor vehicle accident or equivalent level of
ARTERIAL HYPERTENSION
clinical concern; and (b) one of the following circumstances
exists: (i) the patients condition is untreatable or is not ame- Normal persons and many patients with hypertension but
nable to expeditious treatment (within 2 months of diagno- without sleep apnea have a nocturnal fall in blood pressure.
sis) or (ii) the patient is not willing to accept treatment or is However, 20% to 40% of patients with OSA fail to have the
unwilling to restrict driving until effective treatment has normal nocturnal fall in systemic blood pressure (nondip-
been instituted. The committee also noted that it is the phy- pers).41 During obstructive apnea, blood pressure tends to
sicians responsibility to notify every patient with sleep apnea rise slightly and then to rise abruptly at apnea termination
that driving when sleepy is unsafe. Some form of written (Fig. 175) secondary to arousal from sleep and restoration
documentation that the patient understands this warning is of breathing associated with sympathetic activation and
prudent. A statement concerning sleep apnea and commer- parasympathetic withdrawal.
cial motor vehicle operators by a joint task force of the Amer- There is continued controversy about whether OSA can
ican College of Chest Physicians, the American College of cause daytime (diurnal) as well as nocturnal hypertension.
Occupational and Environmental Medicine, and the National Animal models of simulated OSA suggest that it can.42
Sleep Foundation34 provides guidance concerning the evalu- Several studies have found that OSA is very common in adult
ation, treatment, and return to work of drivers with sus- populations with hypertension (>30%).43 This association
pected or known OSA. does not prove causality because patients with hypertension
It is concerning that large financial tort settlements have and OSA share common, potentially causative, factors such
been brought successfully against some physicians for failure as obesity. Carlson and coworkers44 found that age, obesity,
to report a person with a medical condition who was subse- and sleep apnea were independent and additive risk factors
quently involved in a serious traffic accident. Each state has for the presence of hypertension. The Sleep Heart Health
its own laws, and local medical societies have guidelines. Study, a large population-based investigation, found an
However, in the end, the decision rests with the judgment of increased risk of having self-reported hypertension when
the treating physician. In some states, reporting is done to a OSA was present (Table 172).45
health agency rather than directly to the motor vehicle A prospective study of the Wisconsin cohort found an
licensing agency. Note that reporting does not always result increase in AHI predicted the development of hypertension
in the loss of the patients license. in the following 4 years (increased incidence) after adjusting
To date, there is no objective test that can quantify a for confounding factors such as obesity, age, and smoking
patients degree of driving impairment. The use of the main- (Table 173).46 In contrast to these findings, a recent analysis
tenance of wakefulness test (MWT) and MSLT were dis- of the Sleep Heart Health data found that there was no rela-
cussed in Chapter 14. The MWT is the appropriate test to tionship between the AHI and the risk of incident hyperten-
assess the ability to stay awake. However, MWT results may sion (risk of developing hypertension in the next 5 yr) when
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Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 287
20 sec
Airflow
TABLE 172
Cardiovascular Disease and Obstructive Sleep Apnea Sleep Heart Health StudyRisk of Self Reported
Cardiovascular Disease (Prevalence)
QUARTILE
I II III IV P
AHI (#/hr) 01.3 1.44.4 4.511.0 >11.0
CAD* 1.0 0.92 (0.711.20) 1.20 (0.931.54) 1.27 (0.991.62) .004
CHF* 1.0 1.13 (0.542.39) 1.95 (0.993.83) 2.38 (1.224.62) .002
Stroke* 1.0 1.15 (0.721.83) 1.42 (0.912.21) 1.58 (1.022.46) .03
APNEA-HYPOPNEA INDEX CATEGORY
AHI (#/hr) <1.5 1.54.9 514.9 1529.9 30
HTN 1.0 1.07 (0.911.26) 1.20 (1.011.42) 1.25 (1.01.56) 1.37 (1.031.83) .005
CAD = coronary artery disease; CHF = congestive heart failure; HTN = hypertension.
Values are risk (95% confidence interval).
*Data from Shahar E, Whitney CW, Redline S, et al: Sleep-disordered breathing and cardiovascular disease. Am J Respir Crit Care Med 2001;163:1925.
Data from Nieto FJ, Young TB, Lind BK, et al: Association of sleep disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA
2000;283:18291836.
TABLE 173 hypertension. The risk is most significant with severe OSA
Risk of Incident Hypertension in Obstructive Sleep and is confounded by the presence of obesity.
Apnea (Wisconsin CohortPopulation-Based)* Even if sleep apnea does not cause daytime hypertension,
it may well worsen the physiologic impact of the disorder or
QUARTILE
impair treatment efficacy. For example, Verdeechia and
I II III IV P coworkers48 found that hypertensive patients who failed to
AHI (#/hr) 0 0.14.9 5.014.9 >15 have a 10% nocturnal fall in blood pressure had greater LV
hypertrophy. Studies have also documented an increase in
Relative risk 1.0 1.42 2.03 2.89 .002
mortality among nondippers.49 Studies of populations with
(CI) 1.131.78 1.293.17 1.465.64
resistant hypertension have found a high prevalence of
*Based on laboratory measure of blood pressure at baseline versus follow-up
in 4 years (incident HTN).
OSA.50 Therefore, the possibility of the presence of OSA
CI = confidence interval; HTN = hypertension. should be considered in all patients with resistant hyperten-
From Peppard PE, Young T, Palta M, Skatrud J: Prospective study of the sion. One study found that CPAP treatment was helpful in
association between sleep-disordered breathing and hypertension. N Engl J
Med 2000;342:13781384.
patients with resistant hypertension who had OSA.51
If sleep apnea is effectively treated, does hypertension
improve? This question has been approached by a number
of studies that have determined the effect of nasal CPAP on
the risk was adjusted for obesity.47 There was a trend for a nocturnal and daytime blood pressure in patients with OSA.
relationship when the AHI was greater than 30/hr. One Becker and colleagues52 found that effective treatment of
problem with the Sleep Heart Health Study is that the popu- sleep apnea with nasal CPAP for 9 weeks or more lowered
lation contained relatively few patients with severe OSA. In both nocturnal and daytime blood pressure by approxi-
summary, patients with OSA are likely at risk of developing mately 10 mm Hg using a placebo-controlled (sham CPAP)
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288 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
FIGURE 176 A, Time course of mean arterial blood pressure (MAP) 140
before (dark black circles) and on treatment (gray circles) with therapeutic Baseline
Effective nCPAP Baseline
nasal continuous positive airway pressure (nCPAP). On average, 7.2 hours
were recorded during the night. B, Time course of MAP before (closed 120
circles) and on treatment (open circles) with subtherapeutic nCPAP. Note
MAP (mmHg)
the decreased blood pressure on CPAP but not subtherapeutic CPAP. From
Becker HF, Jerrentrup A, Ploch T, et al: Effect of nasal continuous positive 100
airway pressure treatment on blood pressure in patients with obstructive
sleep apnea. Circulation 2003;107:6873.
80
CPAP
60
3:15 pm 7:15 pm 11:15 pm 3:15 am 7:15 am 11:15 am
A
140
Baseline
Subtherapeutic nCPAP
120
MAP (mmHg)
100
80
60
3:15 pm 7:15 pm 11:15 pm 3:15 am 7:15 am 11:15 am
B
study design (Fig. 176). Other investigations have shown pulmonary pressures usually return to normal. Pulmonary
smaller53,54 or no effects on daytime blood pressure.55,56 These hypertension is often defined as a mean pulmonary artery
conflicting results may reflect inadequate CPAP treatment pressure greater than 25 mm Hg. The term pulmonary arte-
(poor adherence), too short a treatment interval, or less rial hypertension is reserved for disorders of the pulmonary
severe sleep apnea populations. arteries that result in pulmonary hypertension. Of note, dia-
A meta-analysis of 12 randomized trials of the effect of stolic dysfunction (high pulmonary venous pressures and LV
CPAP on blood pressure found that CPAP did significantly end-diastolic pressure) also results in increased pulmonary
reduce 24-hour blood pressure by about 2 mm Hg. Results arterial pressure. It has been said that OSA patients with
were greatest in patients with more severe OSA and better normal daytime blood gases usually have normal or only
use of CPAP.57 Of note, ambulatory blood pressure monitor- mildly increased daytime pulmonary pressures.60,61 The pres-
ing can cause awakenings and change what it is trying to ence of coexistent chronic obstructive pulmonary disease
measure.58 The study of Becker and colleagues52 used beat- (COPD) or LV diastolic dysfunction does appear to increase
to-beat blood pressure with a finger probe rather than a the prevalence and severity of daytime pulmonary hyperten-
periodically inflating cuff. In general, most hypertensive sion. However, the presence of COPD is not obligatory.61,62
patients with sleep apnea will still continue to require anti- Some OSA patients may have an increased vascular response
hypertensive medications when treated with CPAP. However, to nocturnal episode acidosis and hypoxemia. In the absence
24-hour control of blood pressure may improve on CPAP of lung disease or elevated LV end-diastolic pressure, the
treatment. incidence of pulmonary hypertension in OSA patients has
been estimated to be 20% to 40%.60 Sajkov and associates62
described a group of patients without OSA with mean pul-
PULMONARY HYPERTENSION
monary pressures up to 26 mm Hg (their normal <20 mm
Both hypoxemia and acidosis cause constriction of the pul- Hg) and pulmonary systolic pressures up to 40 mm Hg. The
monary arteries. Hence, it is not surprising that episodes of affected group seemed to have a greater increase in pulmo-
pulmonary hypertension occur during obstructive apnea in nary pressures in response to an increase in cardiac output
patients with OSA (Fig. 177).59,60 For patients with normal or hypoxemia. The authors hypothesized that remodeling of
daytime arterial partial pressure of oxygen (PaO2), the the pulmonary vascular bed (possibly due to OSA) was
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Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 289
100
SaO2 %
SpO2
50 10 s
60
P < 0.0001 ARRHYTHMIAS
In normal individuals, the heart rate is lower during NREM
50
sleep than during wakefulness. This is thought to be due to
parasympathetic predominance during sleep.5 In patients
40
with OSA, the heart rate varies in cycles: slowing with apnea
PASP (mmHg)
Chest
Abdomen
SaO2
80%
arrest from 2.5 to 13 seconds was noted in 11%. A prospec- associates77 found that patients with untreated OSA had a
tive study of 45 recently diagnosed OSA patients used Holter higher recurrence of Afib after cardioversion than patients
monitoring for 18 hours after diagnosis and again after 2 to without a polysomnographic diagnosis of sleep apnea.
3 days of CPAP.72 Only 8 of the 45 had significant rhythm Appropriate treatment with CPAP in OSA was associated
disturbances including ventricular tachycardia, atrial fibril- with a lower recurrence of Afib. Mehra and coworkers78
lation (Afib), supraventricular tachycardia, and second- or evaluated a cohort of older men and found that sleep-
third-degree heart block. In 7 of these 8 patients, CPAP disordered breathing was associated with Afib and complex
resulted in the abolition of rhythm disturbances. ventricular events (CVEs). The prevalence of CVE was asso-
The parasympathetic predominance during apnea in ciated with OSA and hypoxemia whereas Afib was associated
some patients may have little significance, except in cases of with central sleep apnea (CSA). An evaluation of the Sleep
significant bradycardia or heart block. One study docu- Heart Health cohort found that, although the rate of arrhyth-
mented a reversal of atrioventricular conduction block on mias was low, the relative risk of Afib or nonsustained ven-
CPAP treatment.73 The periods of tachycardia and elevated tricular tachycardia was much higher following respiratory
blood pressure postapnea increase myocardial oxygen events.79 In Figure 1710, a patient with OSA changes from
demand at the same time that hypoxemia exists, predispos- sinus rhythm to Afib after apnea termination. Ryan and
ing to ischemia and possibly tachyarrhythmias. In normal coworkers80 performed a randomized, controlled trial of
individuals, sleep usually is a time of reduced tachyarrhyth- CPAP in heart failure patients to determine whether ven-
mias and ischemia. Patients with OSA may not enjoy the tricular premature beats (VPBs) would decrease. The study
same protection. PVCs are not uncommon in patients with found that CPAP did reduce VPB frequency (58% reduction)
OSA. However, in some patients, the PVC frequency is actu- during sleep. The urinary norepinephrine concentration also
ally lower during sleep. Shepard and associates74 found no decreased. No changes were noted in the control group.80
correlation between the SaO2 at desaturation and PVC fre-
quency during sleep unless the SaO2 was less than 60%.
CORONARY ARTERY DISEASE
Heart rate variability has been used as a tool to study the
balance of parasympathetic and sympathetic tone in patients The Sleep Heart Health Study of a large prospective cohort
with OSA. During wakefulness, OSA patients show less heart of patients found evidence of a slight increase in risk of
rate variability than normal individuals. This is thought sec- having self-reported coronary artery disease (CAD) at even
ondary to an increase in sympathetic tone that is still present low levels of sleep apnea (prevalence) (see Table 172).81
during the day. After successful treatment with CPAP, the Peker and colleagues82 found an increase in mortality in
heart rate variability may increase suggesting a drop in sym- patients with CAD who had untreated OSA. Gottlieb and
pathetic activity. Khoo and coworkers75 found that CPAP associates83 evaluated the Sleep Heart Health cohort data and
treatment of OSA improved vagal heart rate control and that found an increased risk of incident CAD was associated with
the degree of improvement varied directly with the amount the presence of OSA in men younger than 70 years of age.
of CPAP adherence. The association was strongest for severe OSA. Milleron and
Gami and colleagues76 found that the risk of developing coworkers84 found CPAP treatment of patients with OSA and
Afib was more associated with obesity and the degree of CAD improved event-free survival (Fig. 1711). The end
arterial oxygen desaturation than the AHI. Untreated point was a composite of cardiovascular death, acute coro-
OSA appears to worsen arrhythmia control. Kanagala and nary syndrome, hospitalization for CHF, or need for
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Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 291
A
ECG
NP
NO airflow
Chest
Abdomen
SpO2
96%
85%
FIGURE 1710 A patient with sleep apnea in sinus rhythm develops atrial fibrillation after termination of an obstructive apnea. A blow-up of area A is
shown in the lower left corner. NO airflow = nasal oral thermal flow; NP = nasal pressure; SpO2 = pulse oximetry. The tracing is 60 seconds in duration.
TABLE 174
1 Effect of Obstructive Sleep Apnea on Factors
Contributing to Atherosclerosis and Thrombosis
0.8
IMPROVED
Event-free survival
FIGURE 1711 Patients with coronary artery disease (CAD) and OSA. Those treated VEGFLavie, 200287 Yes87
with CPAP had improved survival compared with untreated patients. From Milleron O, Reactive oxygen species Yes88
Pillire R, Foucher A, et al: Benefits of obstructive sleep apnoea treatment in coronary Dyugovskaya, 200288
artery disease: a long-term follow-up study. Eur Heart J 2004;25:728734.
Superoxide releaseSchulz, 200089 Yes89
Elevated C-reactive protein9193 Yes93
coronary revascularization. The control group was patients
Elevated IL-691 Yes91
who declined CPAP (not a randomized trial). The mean
follow-up was 86 months. Elevated TNF-alpha, IL-894 Yes94
CPAP = continuous positive airway pressure; IL = interleukin; OSA =
obstructive sleep apnea; TNF-alpha = tumor necrosis factor-alpha; VEGF =
ATHEROSCLEROSIS AND THROMBOSIS vascular endothelial growth factor.
necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) showed that CPAP improved the ejection fraction in
are elevated in untreated OSA but decrease with CPAP treat- CSB-CSA patients,108,109 and one study suggested that there
ment.95 TNF-alpha can also cause daytime sleepiness. In this may be a survival advantage if patients with CHF and
study, higher TNF-alpha levels were associated with higher CSB-CSA were treated with CPAP.109 However, a large ran-
Epworth Sleepiness Scale scores and worsened arterial domized trial of CPAP versus standard care in patients with
oxygen desaturation. Other studies found a reduction in CSB-CSA was unable to show a survival benefit.110 However,
leptin96 (a hormone secreted by adipose tissue) and a reduc- only roughly 50% of the patients in this study responded to
tion in visceral fat97 on CPAP treatment. Increased visceral CPAP. An analysis of the subgroup that responded to CPAP
fat is associated with an increased risk of cardiac disease. Of did have a survival advantage (a post-hoc analysis).111 The
note, not all studies have found an association between OSA reasons CPAP treatment improves CSA102 are unclear but
and leptin that is independent of the degree of obesity. In could include beneficial effects on hemodynamics (decreased
some studies, increased leptin levels were associated with the afterload), reduction in pulmonary wedge pressure (may
degree of obesity rather than with the AHI.98 Endothelial reduce ventilatory drive), or induction of mild increases in
function is impaired (specifically NO-dependent flow- PCO2. The latter two possibilities might stabilize ventilatory
mediated dilatation) in patients with OSA, and studies control (see Chaper 21). Adaptive servoventilation (ASV)
suggest improvement after CPAP.99 has been more successful than CPAP in acutely reducing the
In studies comparing OSA patients with normal subjects, AHI in patients with CSB-CSA and benefits in cardiac func-
using an appropriate control group is essential. For example, tion have been shown.112115 However, no study has shown
it is often difficult to match groups for obesity. Trials of the that ASV treatment improves survival.
effects of CPAP do not require a normal control group.
However, many of the previously discussed studies of effects
CEREBROVASCULAR ACCIDENTS AND OSA
of CPAP on inflammatory changes in OSA patients were not
randomized, controlled trials. Therefore, the results need to A number of studies have shown a high prevalence of sleep-
be confirmed by controlled trials. For example, a recent ran- disordered breathing in patients soon after a cerebrovascular
domized, controlled trial of CPAP found no change in several accident (CVA).116,117 Although the predominant form of
inflammatory mediators following 4 weeks of CPAP.100 sleep-disordered breathing is OSA, CSA with CSB can also
Another study found decreases in C-reactive protein after occur.11,118 The CSB-CSA is believed to occur early in the
CPAP treatment only in those patients with good CPAP post-CVA period and then usually resolves. In contrast, OSA
compliance and with elevated C-reactive protein levels at seems to persist after a CVA. However, the temporal relation-
baseline.93 Therefore, results may vary depending on the ship between OSA and stroke is not well defined. It is not
characteristics of the patients at baseline and the compliance known whether brain damage from CVA causes sleep apnea
with CPAP treatment. or if sleep apnea preceded the stroke. If so, is the presence of
sleep apnea an independent risk factor for the development
of a CVA? The Sleep Heart Health Study showed an increased
CONGESTIVE HEART FAILURE
risk of having a self-reported CVA (prevalence) if OSA is
The Sleep Heart Health study found that the presence of OSA present (see Table 172).81 In a recently published study,
increases the risk of having CHF (see Table 172).81 Con- Redline and associates119 evaluated the Sleep Heart Health
versely, studies have suggested that sleep-disordered breath- data and found an increased risk for incident ischemic
ing is common in patients with CHF.101,102 One should not stroke in men with mild to moderate OSA. In this study, data
assume that complaints of disturbed nocturnal sleep are were adjusted for a number of confounders that complicated
simply secondary to heart failure. Sin and colleagues103 ret- the analysis including obesity. If there is a causal role for OSA
rospectively evaluated a group of patients with significant LV in stroke, what are the mechanisms? As noted previously,
failure referred to the sleep laboratory and found that risk OSA may predispose to atherosclerosis, hypertension, and
factors for OSA included an increased BMI for men and early morning hemoconcentration. These factors increase
increased age for women. In patients with CHF and OSA, the risk of stroke. During sleep apnea, there are increases in
negative intrathoracic pressure, hypoxemia, and increased intracranial pressure (ICP)120 and decreases in cerebral blood
sympathetic tone associated with the apneas are believed to flow.121 There is an increase in ICP with each apneic event
negatively affect ventricular function.5,103 Treatment of OSA and the rise tends to be correlated with the length of apnea.
with nasal CPAP in patients with CHF has been found to The increase in ICP is thought to be secondary to increases
improve the ejection fraction and symptoms in a number of in central venous pressure, systemic pressure, and cerebral
studies.104106 This appears to occur because of a reduction in vasodilatation from increases in PaCO2 during respiratory
sympathetic tone and a decrease in ventricular afterload.103 events. Because cerebral perfusion is proportional to the
However, all studies have not shown a significant benefit.107 mean arterial pressure (MAP) ICP, increases in ICP may
To date, no study has confirmed a reduction in mortality reduce perfusion pressure even if MAP also rises. Studies of
with CPAP treatment. cerebral blood flow velocity using Doppler monitoring have
Patients with CHF may manifest Cheyne-Stokes breath- shown that flow velocity increases in early apnea, then has
ing (CSB) type of CSA (see Chapter 21). Short-term studies approximately a 25% fall below baseline at end apnea.121
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Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 293
There is some evidence that the presence of OSA in events/night) in OSA patients. The percentage of PN was
patients who have suffered a CVA is a bad prognostic sign 47.8% and age, arousal index, AHI, and measures of oxygen-
regardless of whether OSA precedes or follows the CVA. ation were predictors of the presence of PN. Some of the
Good and coworkers122 found that the Barthel index (a mul- reported effect of CPAP treatment could be due to better
tifaced scale measuring mobility and activities of daily living sleep. However, studies have shown a reduced sodium excre-
that is used to assess patients after stroke) was significantly tion in OSA patients treated with CPAP. Krieger and col-
lower in patients with OSA and CVA compared with those leagues132 found that OSA patients had greater urinary flows
with no evidence of OSA after CVA. The presence of OSA and greater urinary sodium excretion compared with con-
was determined at discharge and the Barthel index was lower trols. Nasal CPAP resulted in a reduction in urinary flow and
at 3 and 12 months in the OSA-CVA group. Martinez-Garcia sodium and chloride excretion. A second study by the same
and colleagues123 found that CPAP treatment reduced the group found evidence of increased guanosine 35-cyclic
mortality after ischemic stroke in patients with concomitant monophosphate excretion in untreated OSA patients, which
OSA. However, adherence to CPAP in patients with a recent reflects atrial natriuretic peptide (ANP) release. The authors
CVA tends to be low. hypothesized that atrial stretch during sleep apnea induced
release of ANP, which caused increased sodium excretion.133
Umlauf and associates134 also found increased nocturia and
ERECTILE DYSFUNCTION
elevated urinary ANP when the AHI was greater than or
An association between erectile dysfunction and sleep dis- equal to 15/hr. Fitzgerald and coworkers135 found that CPAP
orders appears to exist in survey studies relying on self- decreased nocturia in OSA patients.
report and in small case series.124 Hormonal, neural, and
endothelial mechanisms have been implicated in linking
CONSEQUENCES OF CHILDHOOD OSA
sleep disorders with erectile dysfunction. Treatment of sleep
disorders, specifically sleep apnea with CPAP, has been Many of the important consequences of untreated pediatric
shown to improve patient erectile function.125 OSA are listed in Table 175.136 They are divided into neu-
robehavioral, metabolic, and cardiovascular groups.
DIABETES
Obesity is a major confounding factor in the analysis of the
association between diabetes mellitus (DM) and OSA
TABLE 175
because both are worsened with increased BMI. Studies have
Sequelae of Pediatric Obstructive Sleep Apnea
found that obese and nonobese patients have abnormal
glucose metabolism related to OSA. Punjabi and Beamer126 NEUROCOGNITIVE
found that independent of adiposity, sleep-disordered Decreased quality of life
breathing was associated with impairment of insulin sensi- Aggressive behavior
tivity, glucose effectiveness, and pancreatic beta cell func- Poor school performance
tion. Harsch and associates127 found that CPAP rapidly Depression
improved insulin sensitivity, although the greatest results Attention deficit
were in nonobese patients. Babu and coworkers128 found that Hyperactivity
in diabetic OSA patients with a hemoglobin A1c greater than Moodiness
7%, CPAP treatment reduced the A1c. Lam and colleagues129 METABOLIC
compared sham CPAP and effective CPAP in patients with
Elevated C-reactive protein
OSA and found that 1 week of CPAP improved insulin sen- Insulin resistance
sitivity in nondiabetic males, and the improvement was Hypercholesterolemia
maintained for 12 weeks of treatment in those with moderate Elevated transaminases
obesity. Conversely, West and associates130 were not able to Decreased insulin-like growth factor
show an improvement in insulin resistance with CPAP treat- Decreased/altered growth hormone secretion
ment. Although these studies do suggest that OSA indepen- Increased leptin
dent of obesity impairs glucose metabolism, the effect may CARDIOVASCULAR
be more pronounced in nonobese patients. The impact of
treatment of OSA on long-term diabetes and the diabetic Autonomic dysfunction
Systemic hypertension
complications remains to be determined.
Absent blood pressure dipping during sleep
Left ventricular dysfunction
NOCTURIA Pulmonary hypertension
It has been a common clinical observation that many patients Abnormal heart rate variability
with OSA who start CPAP treatment report fewer awaken- Elevated vascular endothelial growth factor
ings to urinate. Hajduk and coworkers131 found a high inci- From Katz E, Ambrosio CM: Pediatric obstructive sleep apnea. Clin Chest Med
2010;31:221.
dence of pathologic nocturia (PN; defined as 2 urination
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294 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
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Chapter 18
TABLE 181
Treatment Alternatives for Obstructive Sleep Apnea (Adults)46
SNORING MILD MODERATE SEVERE
Primary Treat nasal congestion Oral appliance PAP PAP
or
Lateral positioning Upper airway surgery
Secondary Oral appliance PAP (if symptomatic) Oral appliance Upper airway surgery
or or or
Upper airway surgery Upper airway surgery Oral appliance
Adjunctive Weight loss Weight loss Weight loss Weight loss
Lateral positioning Lateral positioning Lateral positioning
PAP = positive airway pressure.
TABLE 182
ConsiderationWhom to Treat?
SYMPTOMATIC ASYMPTOMATIC ASYMPTOMATIC
AHI No significant medical morbidities Significant medical morbidities
Mild Treat Observation or conservative treatment ? Treat
Moderate Treat Treat Treat
Severe Treat Treat Treat
Conservative treatment: weight loss, side sleep position, treat nasal congestion, avoid alcohol.
AHI = apnea-hypopnea index.
medical treatment of nasal congestion, the side (lateral) PAP, the dictum when in doubt, pressurize the snout
sleeping position, and avoidance of alcohol. If medical treat- should be considered.26 If PAP is not an acceptable option,
ment does not improve nasal congestion, nasal surgery may the choice between upper airway surgery or an OA to treat
address this problem, although improvement in snoring is mild OSA often depends upon financial considerations and
variable.18,19 OAs or upper airway surgery involving the patient preference. At the present time, many insurance
palate may improve snoring in many patients.6,2025 The sur- plans will not pay for OA treatment for sleep apnea. However,
gical procedures commonly used for snoring include OA treatment is now reimbursed by Medicare if certain con-
laser-assisted uvulopalatoplasty (LAUP), radiofrequency ditions are met (see Chapter 20). Reimbursement by insur-
palatoplasty, and uvulopalatopharyngoplasty (UPPP).2123 ance or Medicare requires that patients with mild OSA be
The Pillar procedure involves insertion of Teflon strips into symptomatic.
the palate. The success of this procedure is variable, and
sometimes additional strip insertion is needed.22 A con-
Moderate OSA
trolled study comparing the Pillar procedure with a sham
surgery found modest improvement in snoring without a For moderate OSA, the treatment of choice is some form of
significant improvement in the AHI.23 The LAUP procedure PAP.1,2,5 For moderate OSA, OA treatment and upper airway
is not recommended for treatment of sleep apnea.24 The surgery are less reliable than PAP at reducing the AHI to less
recently published American Academy of Sleep Medicine than 10/hr. However, they may be more acceptable to some
(AASM) practice parameters for surgical treatment of OSA4 patients and more effective if patients do not have reason-
state palatal implants may be effective in some patients with able PAP adherence.1,5,20,21 Upper airway surgery obviates the
mild OSA who cannot tolerate or are unwilling to adhere to need for treatment adherence. Treatment adherence is still
PAP therapy, or in whom oral appliances have been consid- an issue with OA treatment, and currently, there is no
ered and found ineffective or undesirable. However, the method to objectively monitor adherence to OA treatment.
evidence to support this recommendation is not very con- A recent AASM task force review concluded that OA was
vincing and it is not clear that palatal implants are any more about 50% effective for moderate OSA (defined as a treat-
effective for sleep apnea than the LAUP procedure. ment AHI < 10/hr).20 A meta-analysis of surgery in OSA
patients concluded that palatal surgery with or without
genioglossus advancement was approximately 30% effective,
Mild OSA
using a strict outcome measure of reduction in the AHI to
For mild OSA, one may again begin with conservative mea- less than 10/hr.25 Therefore, for moderate OSA, PAP is the
sures in (especially in asymptomatic patients) including most reliably efficacious treatment. It is very effective if
treatment of nasal congestion, weight loss, or the lateral adherence is adequate. Most clinicians would recommend a
sleeping position. Weight loss takes time, and if the patient trial of PAP therapy for patients with moderate OSA. If this
is symptomatic, weight loss should be considered a second- treatment is not acceptable or the patient is not adherent to
ary (adjunctive) treatment.3 Both OAs and upper airway PAP treatment, upper airway surgery or an OA would be
surgery are reasonably effective for mild OSA.4,5,2025 PAP is alternatives.
very efficacious at reducing the AHI,1,2,6 but acceptance and The AASM practice parameters for the surgical treatment
adherence are typically lower than with more severe OSA. of OSA4 state Uvulopalatopharyngoplasty (UPPP) as a sole
PAP treatment is not indicated in mild OSA if patients are procedure, with or without tonsillectomy, does not reliably
asymptomatic and have no co-morbid cardiovascular dis- normalize the AHI when treating moderate to severe OSA.
orders.2 In symptomatic patients with mild OSA, some Therefore, patients with severe OSA should initially be
patients may prefer a trial of PAP rather than an OA or upper offered PAP therapy, while those with moderate OSA should
airway surgery. PAP treatment is safe and it is often difficult initially be offered either PAP therapy or oral appliances.
to predict who will benefit. If the patient is motivated to try However, economics or patient preference may favor surgery
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302 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
over OA treatment in some settings. If patients with moder- for ultimate recommendations, involving the patient and
ate OSA pursue weight loss with bariatric surgery, an effec- spouse in decision making is essential to improve treatment
tive immediate treatment for OSA is indicated because outcomes. Drowsy driving counseling should be performed
weight loss takes time. and documented. Many patients have co-morbid conditions
such as depression, insomnia, restless legs syndrome (RLS),
or chronic pain that will make compliance with PAP or other
Severe OSA
treatments more difficult. These should be evaluated and
For severe OSA, PAP is the treatment of choice because of treated.
its effectiveness and safety.1,2,6 Unfortunately, acceptance and
adherence can be as low as 50% depending on the definition
FOLLOW-UP AND OUTCOMES ASSESSMENT
of adherence. The maxillary mandibular advancement
(MMA) operation can result in acceptable residual AHIs in Following treatment initiation, careful follow-up is essential
many patients with severe OSA.4,21 A recent meta-analysis because OSA is a chronic disease. Table 185 lists some
found that up to 90% of patients undergoing MMA had
improvement in symptoms and a postoperative AHI less
than 20/hr (only 30% had a reduction in AHI to < 10/hr)25 TABLE 184
(Table 183). Some surgeons perform MMA only after other Patient Education and Co-morbid Disorders
surgical procedures have failed. However, in very obese
PATIENT EDUCATION
patients with retrognathia, performing MMA as the first sur-
gical procedure is recommended by some clinicians. Trache- Testing resultsdiscuss with the patient without
ostomy is effective when life-threatening OSA and respiratory excessive medical jargon, answer questions
failure are present and the patient is not compliant with PAP Pathophysiology of OSA
treatment.4 Surgical treatment options are discussed in more
Consequences of untreated OSA
detail in Chapter 20. If neither PAP nor surgery is an accept-
able treatment option, some patients with severe OSA will Treatment optionspros and cons
have significant improvement in the AHI with OA treat- Drowsy driving counseling
ment. Although the AHI is usually not reduced below 10/hr,
one could argue that a drop from 80/hr to 20/hr is worth- EVALUATION AND TREATMENT OF CO-MORBID DISORDERS
while, especially if there is symptomatic improvement and RLS
an improvement in oxygenation. Depression
Insomnia
PATIENT EDUCATION BEFORE TREATMENT
Insufficient sleep
Following polysomnography (PSG) or portable monitoring
Chronic pain
(home sleep testing, limited-channel sleep testing), the phy-
sician ordering the study should discuss the findings and the Narcolepsy
consequences of untreated sleep apnea with the patient OSA = obstructive sleep apnea; RLS = restless legs syndrome.
(Table 184).1 The factors that can exacerbate OSA, includ-
ing weight gain, insufficient sleep, medications, and alcohol
consumption, should also be addressed. The available treat-
TABLE 185
ment options and the pros and cons of each option should
Assessments for Treatment Follow-up
be discussed. Whereas most patients look to the physician
ASSESSMENTS
TABLE 186
American Academy of Sleep Medicine Practice Parameter Recommendations for Medical Treatment of
Obstructive Sleep Apnea
WEIGHT REDUCTION
Successful dietary weight loss may improve the AHI in obese OSA patients. (Guideline)
Dietary weight loss should be combined with primary treatment of OSA. (Option)
Bariatric surgery may be adjunctive in treatment of OSA in obese patients. (Option)
POSITIONAL THERAPIES
Positional therapy, consisting of a method that keeps the patient in a nonsupine position, is an effective secondary therapy or
can be a supplement to primary therapies for OSA in patients who have a low AHI in the nonsupine versus the supine
position. (Guideline)
OXYGEN SUPPLEMENTATION
Oxygen supplementation is not recommended as a primary treatment for OSA. (Option)
NASAL CORTICOSTEROIDS
Topical nasal corticosteroids may improve the AHI in patients with OSA and concurrent rhinitis and, thus, may be a useful
adjunct to primary therapies for OSA. (Guideline)
MODAFINIL, ARMODAFINIL
Modafinil is recommended for treatment of residual excessive sleepiness in OSA patients who have sleepiness despite
effective PAP treatment and who are lacking any other identifiable cause for their sleepiness. (Standard)
OTHER TREATMENTS (NOT RECOMMENDED)
Protriptyline, SSRIs, aminophylline, estrogen preparations with or without progesterone, and short-acting decongestants.
AHI = apnea-hypopnea index; OSA = obstructive sleep apnea; PAP = positive airway pressure; SSRIs = selective serotonin reuptake inhibitors.
Weight Loss
80 90 100 110 120
Obesity is a major risk factor for the development of OSA. Body weight (kg)
In some studies, approximately 70% of patients with OSA
were obese (body weight > 120% of predicted). In the Wis- FIGURE 181 Decrease in apnea-hypopnea index (AHI) with weight loss. The y axis is
consin cohort study, for every standard deviation increase in a logarithmic scale. The weight loss was due to medication. From Browman CP, Sampson
MG, Yolles SF, et al: Obstructive sleep apnea and body weight. Chest 1984;85:435436.
the body mass index (BMI), there was a fourfold increase in
the prevalence of OSA.28 A BMI of 25.0 to 29.9 kg/m2 is
considered overweight, greater than 30 is obesity, and greater Figure 181 illustrates the AHI versus weight of a patient
than 40 is severe obesity. Many studies have documented undergoing weight loss.29 Even patients with mild obesity
that weight loss of modest proportions (510%) can produce (110115% of ideal body weight) can benefit from weight
significant improvement in sleep apnea2934 as well as decrease reduction.30 Peppard and colleagues34 followed the effects of
upper airway collapsibility.35 weight change on AHI. A 10% weight gain predicted an
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304 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
approximate 32% increase in the AHI. A 10% weight loss TABLE 187
predicted a 26% reduction in the AHI. A 10% increase in Selected Studies of Weight Loss in Obstructive
weight was associated with a sixfold increase in the risk of Sleep Apnea
developing moderate to severe OSA. WEIGHT REDUCTION AT 1 YR IN MILD OSA WITH VERY
The effectiveness in reducing the AHI with weight loss LOW CALORIE DIET*
varies among patients. This may be due to the fact that a
given amount of weight loss may have more effect on upper CONTROL INTERVENTION
body obesity or upper airway anatomy in one individual Weight (kg) 92.3 101.2
than in another. One study found that neck fat was the best
AHI (#/hr) 9.3 10.0
predictor of a high AHI in women whereas central obesity
was a better predictor in men.36 Weight loss may also be less AHI supine 21.3 20.1
effective in reducing the AHI if skeletal abnormalities play a Change in AHI 0.3 4.0
more prominent role in the pathogenesis of OSA in a given
Change in weight (kg) 2.4 10.7
patient. The level of nasal CPAP required to maintain upper
airway patency may decrease after weight reduction. Lettieri EFFECTS OF A VERY LOW ENERGY DIET (9 WK)
of weight loss. Johansson and coworkers31 (Table 187) BASELINE WEIGHT LOSS
studied the effects of a very low energy diet on OSA in
patients on CPAP (intervention vs. control group) with Weight (kg) 106 96.9
moderate to severe OSA. At 9 weeks, the intervention group Apnea index 55 29.2
had lost weight (18.8 kg) with a drop in AHI of 23/hr. AHI = apnea-hypopnea index; OSA = obstructive sleep apnea.
Tuomilehtol and colleagues32 reported on use of lifestyle *Adapted from Tuomilehto HPI, Seppa JM, Partine MM, et al: Lifestyle
intervention with weight reduction: first-line treatment in mild obstructive
intervention and weight reduction in mild OSA. Although
sleep apnea. Am J Respir Crit Care Med 2009;179:320327.
both the weight and the AHI decreases were small, a signifi-
From Johansson K, Neovius M, Lagerros YT, et al. Effect of a very low energy
cant number of the intervention group dropped their AHI diet on moderate and severe sleep apnea in obese men: a randomised
controlled trial. BMJ 2009;339:b4609.
below 5/hr. In the AHEAD (Action for Health in Diabetes)
From Smith PL, Gold AR, Meyers DA, et al: Weight loss in mildly to
study, weight loss also resulted in a drop in the AHI.33 moderately obese patients with obstructive sleep apnea. Ann Intern Med
Grunstein and associates38 reported on a 2-year reduction in 1985;103:850855.
sleep apnea symptoms following surgically induced weight
loss. Another study of the effect of the weight reduction with
subitramine found a reduction of 7.9 kg was associated with of OSA after previous weight loss without concomitant
a 30% reduction in the AHI (change in AHI 16/hr).39 weight gain. This illustrates the need for continued clinical
Today, bariatric surgery is performed as a treatment for follow-up. Sampol and associates44 followed 24 patients
morbid obesity.40,41 However, it could be considered as an cured by weight loss for a mean of 94 months. Six of the
adjunctive treatment for OSA. The most common bariatric 13 patients who maintained weight loss had recurrence of
operation is a Roux-en-Y procedure, although other surgery OSA (AHI = 40.5/hr).
such as laparoscopic gastric banding may be tried for less The AASM practice parameters for use of medical treat-
obese patients. The mortality of the Roux-en-Y procedure is ments for OSA recommended that weight loss be combined
less than 2%.40,41 Greenburg and coworkers42 performed a with a primary treatment for OSA3 (see Table 186). This
meta-analysis of bariatric surgery and the effects on OSA in recommendation is based on the fact that weight loss takes
morbidly obese patients. Twelve studies including 342 time, results vary between patients, and OSA can recur even
patients were analyzed. The mean BMI was reduced by if initially improved by weight loss. It was stated that bariat-
17.9 kg/m2 (baseline 55.3 kg/m2) and the AHI was reduced ric surgery may be adjunctive in treatment of OSA in obese
from 54.7 to 15.8/hr. The authors concluded that bariatric patients. This recommendation falls short of recommenda-
surgery does result in both dramatic weight loss and improve- tion of bariatric surgery as a primary treatment for OSA
ment of the AHI, but not always to normal levels. Many treatment given the variable improvement in the AHI.
patients will still likely require treatment of OSA (CPAP and Patients with OSA undergoing bariatric surgery should be
others). In another series of 24 consecutive patients under- treated with an effective treatment (usually CPAP) in the
going bariatric surgery, only 4% were cured of OSA.40 Pillar postoperative period and during weight loss. If a sleep study
and colleagues43 reported on a patient who had recurrence after significant weight loss documents a cure, stopping
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Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments 305
primary treatment could be considered. If significant OSA is individuals. However, other studies have found OSA patients
still present, a lower level of CPAP may be effective.37 If to have an upper airway with narrower lateral dimensions
CPAP or other treatment for OSA is stopped, patients should (see Fig. 182B).48,49 Changes in airway shape or size with
be followed closely for signs and symptoms of recurrence changes in posture could be due to an effect of gravity on the
(Table 188). tissue surrounding the upper airway or to posterior move-
ment of the tongue. Reductions in lung volume in the supine
position may also reduce upper airway size. A limitation of
Posture and Positional Treatment
many studies of the upper airway in OSA patients is that the
Many patients with OSA have a significant worsening of patients were evaluated either awake or under anesthesia.
apnea in the supine position.45 Some but not all studies have Neither of these circumstances may accurately represent
found an increase in upper airway size in the lateral position. what happens during sleep.
Walsh and coworkers,46 using optical coherence tomography Neill and associates50 found that elevation of the head by
in awake normal subjects and patients with sleep apnea, 30 improved airway stability (compared with the supine
found airway size not to change (supine to lateral) but airway position) in OSA patients as measured by airway occlusion
shape was more circular (Fig. 182A). A circular shape may during sleep. In this study, lateral sleep positioning had less
be more resistant to closure. In contrast, Isono and col- of a stabilizing effect compared with elevation of the head.
leagues47 found a larger airway in the lateral position in This suggests that sleeping with the head elevated may reduce
anesthetized normal subjects. Walsh and coworkers46 did not the AHI more in some patients than sleeping in the lateral
find a difference in shape between OSA patients and normal position. In the same study, CPAP was also progressively
elevated until apneas and hypopneas were abolished. The
mean effective pressure was 10.4 cm H2O in the supine posi-
tion, 5.3 cm H2O with the head-elevated position, and 5.5 cm
TABLE 188
H2O in the lateral position.
Weight Loss Treatment for Obstructive
A considerable number of patients with a significant
Sleep Apnea
overall AHI will have minimal sleep apnea in the lateral
Weight loss is considered a secondary or adjunctive position. In fact, many of these patients have chronically
treatment. favored this position at home. In one study, approximately
Modest weight loss can be helpful (10% weight loss is 55% of a large group of patients with sleep apnea had posi-
associated with a 26% reduction in the AHI). tional sleep apnea, defined as an AHI at least two times
Recurrence of OSA can occur after previous weight loss
higher in the supine than in the nonsupine position.45
despite maintenance of lower weight.
Because the amount of supine sleep can dramatically affect
the overall AHI, one must always note the amount of
Bariatric surgery rarely cures patients of OSA but may supine sleep when interpreting a sleep study or comparing
reduce the required level of CPAP. the results of different sleep studies.
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; Avoiding the supine posture has been proposed as a treat-
OSA = obstructive sleep apnea.
ment for sleep apnea. To maintain the lateral posture during
A L A A
A PA P L R L R
L PA L
P P
P L
BE BE Normal OSA
Gravity
A B
FIGURE 182 A, Schematic of changes in upper airway shape. In the lateral position the pharyngeal airway (PA) has a rounder
shape. A = anterior; BE = bony enclosure; L = lateral; P = posterior. B, Schematic of upper airway shape found in normal and
obstructive sleep apnea (OSA) patients with the supine position in other studies. R = right. A, From Walsh JH, Leigh MS, Paduch A,
et al: Effect of body posture on pharyngeal shape and size in adults with and without obstructive sleep apnea. Sleep 2008;31:15431549.
B, From Schwab RJ, Gefter WB, Hoffman EA, Pack AI: Dynamic upper airway imaging during awake respiration in normal subjects and
patients with sleep disordered breathing. Am Rev Respir Dis 1993;148:1385.
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306 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
A B
FIGURE 183 A, and B, A lateral positioning device. The ZZsoma Positional Sleeper. From Permut I, Diaz-Abad M, Eissam C, et al: Comparison of positional
therapy to CPAP in patients with positional obstructive sleep apnea. J Clin Sleep Med 2010;6:238243.
sleep, a number of night shirts or straps with foam balls or TABLE 189
cushions are available that prevent comfortable supine Treatment of Nasal Congestion/Rhinitis3
sleep51,52 (Fig. 183). Another approach was training with Short-acting nasal decongestants are not recommended
an auditory alarm when patients turn supine.53 Jokic and for treatment of OSA. (Option)
coworkers52 performed a randomized cross-over trial of
Topical nasal corticosteroids may improve the AHI in
position therapy and CPAP in a group of patients with posi-
patients with OSA and concurrent rhinitis and, thus, be
tional OSA. The positional device consisted of a backpack
useful adjuncts to primary therapies for OSA. (Guideline)
with a foam ball (10 5.5 inches). Positional treatment was
AHI = apnea-hypopnea index; OSA = obstructive sleep apnea.
slightly less effective than CPAP but there was no difference
in improvement in the ESS, sleep architecture, or subjective
sleep quality. There have been no long-term studies of posi-
tional therapy. Permut and colleagues51 found positional CPAP device are methods to document the efficacy of this
treatment (see Fig. 183) to be as effective as CPAP as approach.
assessed by one night of PSG in a group of patients with mild
and positional OSA. McEvoy and associates54 also found a
Medical Therapies to Improve Nasal Patency
lower AHI, better oxygen saturation, and better sleep quality
in the seated sleeping posture (60) compared with the The AASM practice parameters for medical treatment3 did
supine position. Skinner and coworkers55 studied the effect not recommend use of short-acting nasal decongestants
of a shoulder-head elevation pillow in mild to moderate (Table 189). The major consideration is the development of
OSA. In 7 of 14 patients, the AHI dropped to less than 10/ rhinitis medicamentosa.59 A study by Kiely and associates,60
hr. In contrast with CPAP, the AHI was less than 5/hr in all using a placebo-controlled, randomized, cross-over design,
patients. There seems little doubt that positional treatment found a modest reduction in the AHI in a group of apneic
would work in a number of patients with positional OSA. snorers with intranasal fluticasone but no reduction in
However, a recent study found poor adherence to the tennis snoring noise in nonapneic snorers. There was no improve-
ball technique.56 Studies of long-term outcomes with more ment in objective sleep quality. Of interest, the improvement
comfortable positioner devices are needed. in the AHI was correlated with a reduction in the nasal
An increase in the required CPAP pressure to maintain resistance. A treatment effect is likely only if intranasal ste-
upper airway patency is commonly required in the supine roids improve nasal resistance, and this change may not
compared with the lateral body position.57,58 Oksenberg and occur in all patients.
colleagues57 documented about a 3-cm H2O difference
between supine and nonsupine postures. As noted previ-
Supplemental Oxygen
ously, Neill and associates50 noted a significantly lower PAP
was needed in the lateral position or with the head elevated. Supplemental oxygen can improve nocturnal oxygenation in
In pressure-intolerant patients undergoing CPAP treatment, patients with OSA. In a study by Smith and coworkers,61
one approach might be to lower the pressure to one effective nocturnal supplemental oxygen did not improve objective
in the lateral position and encourage patients to sleep in that daytime sleepiness but did improve nocturnal oxygenation
position (or use a device to discourage supine sleep), at least in a group of patients with OSA. In general, oxygen does not
during an adaptation period. Nocturnal oximetry at home significantly reduce the AHI or improve daytime
and/or observation of the residual AHI recorded on the sleepiness.6163 Caution is advised in hypercapnic OSA
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Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments 307
OXYGEN SATURATION DURING REPETITIVE FIGURE 184 Effects of supplemental oxygen on oxygen
OBSTRUCTIVE APNEAS desaturation during repetitive obstructive apneas. Supplemental
oxygen at 4 L/min did not completely eliminate events (which
REM sleep NREM sleep
appear slightly longer during rapid eye movement [REM] sleep).
100
NREM = nonrapid eye movement. From Alford NJ, Fletcher EC,
Nickeson D: Acute oxygen in patients with sleep apnea and COPD. Chest
1986;89:3038.
80
Room air
60
O2 saturation
80
Nasal O2 at 4 L/min
60
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
Time in minutes
patients, because some may develop worsening hypercapnia, movement disorder, idiopathic hypersomnia, depression).
especially on high flow rates of oxygen.65 In some studies, Other sleep disorders should be ruled out if clinically indi-
acute administration of oxygen caused prolongation of cated. Of note, although some might assume 6 to 7 hours of
apneas.6265 Supplemental oxygen tends to convert central nightly CPAP adherence to be good adherence, in patients
and mixed apneas to obstructive apneas.66 Loredo and col- with continued daytime sleepiness, the first step would be an
leagues67 compared oxygen with CPAP treatment in OSA. attempt at sleep extension. This includes using CPAP during
CPAP improved sleep quality but supplemental oxygen naps. Another option would be an empirically small increase
improved only nocturnal oxygenation. It should also be in CPAP pressure. Adequacy of pressure should also be doc-
noted that supplemental oxygen often improves but does not umented because a surprisingly high percentage of patients
normalize nocturnal oxygen saturation in patients with remain inadequately treated.71 Many PAP devices today give
severe drops in the arterial oxygen saturation65 (Fig. 184). an estimate of the residual AHI. Finally, one might consider
Norman and associates68 compared supplemental oxygen a repeat PAP titration if there is any suspicion that the
with CPAP with respect to changes in blood pressure in a current level of CPAP is not effective.
group of patients with OSA. CPAP reduced daytime and
nighttime blood pressure whereas supplemental oxygen had
Modafinil, Armodafinil, and Stimulants
no effect. Supplemental oxygen did improve nocturnal oxy-
genation. In summary, supplemental nocturnal oxygen is not If daytime sleepiness persists on optimized CPAP treatment
the treatment of choice for OSA, but individual patients may and there is no identifiable additional sleep disorder/cause
benefit from this treatment if all other treatment options fail. of sleepiness, treatment with an alerting agent (modafinil
The AASM practice parameters for medical treatment of [Provigil] or armodafinil [Nuvigil]) is indicated.3 These med-
OSA state that supplemental oxygen is not indicated for ications have been shown to improve daytime alertness (sub-
treatment of OSA.3 jective and objective) using randomized, placebo-controlled
studies in OSA patients with residual sleepiness despite ade-
quate PAP treatment.69,70,7276 Figure 185 illustrates improve-
Persistent Daytime Sleepiness on CPAP
ment in the ESS in patients taking modafinil compared with
A substantial number of patients with OSA continue to have placebo. Figure 186 displays results documenting an
daytime sleepiness despite adequate PAP treatment.69,70 In improvement in objective daytime sleepiness (longer sleep
such patients, the first steps are to document adequate objec- latency) with modafinil compared with placebo. The side
tive PAP adherence, document effective treatment, and to try effects of modafinil and use of this medication are discussed
sleep extension if indicated. Other causes of persistent in more detail in Chapter 24. Headache is the most common
daytime sleepiness despite PAP treatment include medica- side effect of modafinil. The Stevens-Johnson syndrome is a
tions and other sleep disorders (narcolepsy, periodic limb very rare but severe complication of modafinil treatment.
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308 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
12
10.1
* circumstance.
9.6 Armodafinil (Nu-vigil) is the R enantiomer of modafinil
and has a longer half-life than the L enantiomer. The dose of
8 armodafinil is 150 to 250 mg daily. One would expect
armodafinil to be as effective for daytime sleepiness as
modafinil, but fewer studies have been published.78,79
4 Armodafinil has also been shown to be effective in treatment
of wakefulness in CPAP-adherent patients with OSA with
co-morbid depression.78 This is an important issue because
0 a significant proportion of patients with OSA do suffer from
N 80 77 49 53 80 75 depression.
Baseline Week 1 Week 4 Unfortunately, the addition of modafinil has minimal or
CPAP Placebo CPAP Modafinil modest benefits in a significant number of OSA patients who
are still sleepy on PAP treatment. Kingshott and colleagues70
FIGURE 185 Modafinil decreased the Epworth Sleepiness Scale (ESS) compared with
found no improvement in ESS or multiple sleep latency test
placebo at week 1 and week 4. *P = .001 placebo versus modafinil. Modafinil decreased
the ESS compared with placebo. CPAP = continuous positive airway pressure; SEM =
(MSLT) with modafinil but did find an improvement in the
standard error of the mean. From Pack AI, Black JE, Schwartz JR, Matheson JK: Modafinil MWT sleep latency. Although stimulants are not U.S. Food
as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care and Drug Administration (FDA) or AASM practice param-
Med 2001;164:16751681. eter approved for treatment of persistent sleepiness, there are
individual OSA patients with persistent daytime sleepiness
despite adequate PAP treatment who will respond better
10 * to stimulants (methylphenidate, amphetamine) than to
8.6 modafinil. Treatment with stimulants in addition to PAP
Mean sleep latency (SEM) (min)
7.5 7.4 7.2 could be tried if patients continue to have disabling sleepi-
8
ness despite other measures. If clinically indicated, the pos-
sibility of coexistent narcolepsy should be ruled out. (This
6 situation is discussed in Chapter 24). Performing an over-
night sleep study on CPAP followed by an MSLT on CPAP
4
can help document coexistent narcolepsy. If the MSLT is
positive for narcolepsy, stimulants could certainly be used if
modafinil was not effective. If the MSLT is negative or not
2 possible (current treatment with an antidepressant), one
could still try the addition of a stimulant to PAP treatment
0 as a last resort (an off-label treatment).
Baseline Week 4
CPAP Placebo CPAP Modafinil Overview of Treatment of Pediatric OSA
FIGURE 186 Mean multiple sleep latency test (MSLT) sleep latency at baseline and
Pediatric OSA is diagnosed if the apnea index >1/hr or the
after treatment with nasal continuous positive airway pressure (nCPAP) and modafinil
obstructive AHI (OAHI) >12/hr. OAHI values of 1 to <5,
or nCPAP plus placebo. *P = .021. Modafinil increased the sleep latency. SEM = standard
error of the mean. From Pack AI, Black JE, Schwartz JR, Matheson JK: Modafinil as adjunct 510, and >10/hr are considered to characterize mild, mod-
therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med erate, and severe pediatric OSA.80 These classifications are
2001;164:16751681. arbitrary and fail to account for different susceptibility in
children to sleep disruption or hypoxemia. Patients with an
OAHI <5/hr are treated based on the presence of significant
During treatment of OSA patients with modafinil, it is essen- symptoms. The treatment of choice for most patients with
tial to document continued adequate adherence to PAP pediatric OSA is tonsillectomy and adenoidectomy (TNA)
treatment. In one study evaluating the addition of modafinil (see Chapter 21). Even if patients are obese or the AHI is
to CPAP treatment, poorer CPAP use was noted with elevated to the severe range, TNA is usually recommended
modafinil than with placebo.70 The usual modafinil dose is unless minimal tonsillar and adenoidal tissues are present.
200 to 400 mg in the morning. Some patients will benefit PSG after surgical healing is recommended in all patients by
from a split dose if they have an increase in sleepiness in the some clinicians. Certainly, patients with residual symptoms
late afternoon (modafinil 200 mg q AM and 100200 mg q 2 on a pre-treatment OAHI in the moderate to severe range
PM). Patients with OSA who are adherent to PAP treatment should be studied. If a significant residual OAHI is present
will sometimes not be able to use CPAP for various reasons after TNA, possible treatments include weight loss, positive
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Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments 309
airway pressure (see Chapter 20), dental procedures such as A. Sleep extension and, if not successful, modafinil.
rapid maxillary expansion (see Chapter 21), or medications B. PSG on CPAP followed by MSLT.
to reduce adenoidal and tonsillar inflammation. C. Addition of methylphenidate.
D. A repeat PAP PSG titration.
Medications for Pediatric OSA
5. A 30-year-old man with a BMI of 19 denies sleepiness but
Leukotrienes and their receptors are increased in adenoton- is a very loud snorer. This is worse when he drinks alcohol
sillar tissue and exhaled condensates of children with or has worsening of nasal congestion. A sleep study
OSA.81,82 The combination of nasal inhaled steroid and the revealed an overall AHI of 15/hr. He has declined CPAP
leukotriene inhibitors (montelukast) was found to have or uvuloplasty and cannot afford an OA. An overnight
benefit in a study of patients with residual sleepiness after summary of the sleep study is shown in Figure 187.
tonsillectomy and adenoidectomy.83 What treatment do you recommend?
A. Pillar procedure (palatal implants).
CLINICAL REVIEW QUESTIONS B. Supplemental oxygen.
1. A 40-year-old man without daytime sleepiness undergoes C. Nasal corticosteroid and positional therapy.
a PSG. The AHI = 50/hr with a low arterial oxygen satura- D. Mirtazapine.
tion (SaO2) of 80%. On physical examination, a very long
uvula and a mild tonsillar enlargement is present. Which
Answers
treatment do you recommend?
A. UPPP. 1. B. The treatment of choice for severe OSA is CPAP (or
B. CPAP. other PAP treatment) even if some potentially surgically
C. OA. correctable anatomic changes are present.
D. MMA.
2. E. Protriptyline and supplemental oxygen are not recom-
mended treatments for OSA. Weight loss with either a
2. A 50-year-old woman with a BMI of 35, AHI of 40/hr
dietary or a surgical intervention takes time and is con-
cannot tolerate CPAP. She does not want surgery. What
sidered a secondary treatment. Although an OA is not the
do you recommend?
treatment of choice for severe OSA, it can be effective in
A. Bariatric surgery. a significant proportion of patients. If severe arterial
B. Nocturnal oxygen. oxygen desaturation is present and no other treatments
C. Structured medical weight loss (diet modification). are acceptable, one might use supplemental oxygen,
D. Protriptyline. although the benefit of oxygen treatment for OSA is
E. OA. unproven. A sleep study on OA treatment should be per-
formed to document efficacy.
3. A 35-year-old woman with previously documented OSA
stopped CPAP of 10 cm H2O after weight loss of 50 pounds 3. A. A PSG is indicated to determine whether significant
following bariatric surgery was documented to reduce the OSA has returned. This can occur after bariatric surgery
AHI to less than 5/hr (study performed without CPAP). even if weight loss has been maintained. Restarting CPAP
Over the last 6 months, daytime sleepiness has returned, is not indicated without documentation of the need for
although snoring is described only as mild. The patients treatment and lower pressure may be effective. If a PSG
body weight has not changed since the last sleep study. documents significant OSA, a PSG PAP titration can be
What do you recommend? performed to determine an effective pressure level at the
new lower weight.
A. PSG.
B. Thyroid function studies. 4. A. Of the answers presented, this is the best option. An
C. Modafinil. MSLT is often of limited value if a patient is taking a
D. CPAP of 10 cm H2O selective serotonin reuptake inhibitor. Methylphenidate is
not FDA approved for treatment of residual daytime
4. A 40-year-old man has persistent severe daytime sleepi- sleepiness on CPAP treatment. A repeat PSG CPAP titra-
ness (ESS 15/24) despite good adherence to CPAP of tion is not unreasonable, but a recent study showed good
10 cm H2O (average nightly use of 6 hr). A recent sleep control at the current treatment pressure.
study showed an AHI of 2/hr on CPAP of 10 cm H2O
during supine REM sleep. The patients wife reports no 5. C. The figure reveals postural OSA with few respiratory
snoring or apnea on treatment. He is taking fluoxetine for events in nonsupine positions. Nasal corticosteroids and
depression and denies symptoms of cataplexy. What do positional therapy are the best answer, although the long-
you recommend? term effectiveness of positional therapy is unproved.
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310 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
Wake
REM
Stage 1
2
3
95%
SpO2
90%
85%
Respiratory
event
Left
Right
Position Prone
Supine
FIGURE 187 Overnight summary of the sleep study. REM = rapid eye movement; SpO2 = pulse oximetry.
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pressuretreated obstructive sleep apnea/hypopnea syndrome.
Sleep 2005;28:464471.
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Chapter 19
A
B
TABLE 191
Modes of Positive Airway Pressure Devices
CPAP Continuous pressure during inhalation and exhalation.
BPAP (S mode) IPAP.
EPAP.
IPAP EPAP = PS.
BPAP may be better tolerated in patients complaining of difficulty exhaling on CPAP.
Flexible PAP, expiratory pressure Pressure falls in early exhalation.
relief (Cflex, EPR) Returns to set pressure at end-exhalation.
APAP autotitrating, Titrates between maximum and minimum pressure limits to prevent apnea,
autoadjusting PAP (autoCPAP) hypopnea, airflow flattening, and airway vibration (snoring).
Auto-BPAP Titrates IPAP and EPAP between EPAPmin and IPAPmax with PSmin = 3 and PSmax set
by the clinician. PSmax constrained by IPAPmax.
BPAP with backup rate (NPPV) BPAP modes
ST.
T.
ASV PS varies to stabilize breathing.
EPAP set to eliminate airway obstruction.
Backup rate AVAILABLE (see Table 192).
APAP = autoadjusting positive airway pressure; ASV = adaptive servoventilation; BPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure;
EPAP = expiratory positive airway pressure; EPR = expiratory pressure relief; IPAP = inspiratory positive airway pressure; NPPV = noninvasive positive pressure
ventilation; PAP = positive airway pressure; PS = pressure support; S mode = spontaneous mode; ST = spontaneous timed mode; T = timed mode.
airway structures during lung expansion (tracheal tug).12 respiratory arousals. In some patients, PAP treatment can
Whereas CPAP maintains a positive intraluminal pressure also increase the amount of stage N3 and stage R (rapid eye
during both inspiration and expiration, one study using only movement [REM] sleep). An occasional patient with very
expiratory positive airway pressure (EPAP) showed a reduc- severe apnea will have a large REM or stage N3 sleep rebound
tion in respiratory events.13Another study was not able to on the first night of PAP treatment. This is most commonly
reproduce a beneficial effect of EPAP.14 This could be due to seen when an entire night of polysomnography (PSG) is
differences in study design or the method of delivery of available for PAP titration. The most difficult problem with
EPAP (threshold valve vs. expiratory resistance). PAP treatment is that adherence is suboptimal in a large
percentage of patients.6 Many of the benefits of PAP treat-
ment are discussed in Chapter 17.
EFFECTIVENESS
Numerous studies have shown that PAP can bring the apnea-
MODES OF PAP
hypopnea index (AHI) down to below 5 to 10/hr in the
majority of patients.2 The virtual elimination of apnea and A number of modes of delivering PAP exist (Table 191).
hypopnea improves arterial oxygen saturation and decreases CPAP delivers a predetermined constant pressure during
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Chapter 19 Positive Airway Pressure Treatment 315
I Inspiration E Exhalation FIGURE 192 Modes of positive airway pressure used to treat
obstructive sleep apnea (OSA). BPAP = bilevel positive airway
pressure; CPAP = continuous positive airway pressure.
Airway pressure (cm H2O)
I E I I I
10
E E
0
CPAP 10 BPAP 15/5 CPAP 10 with
expiratory
pressure relief
both inspiration and exhalation (Fig. 192). Bilevel positive IPAP time is usually set at 1.2 to 1.6 seconds depending
airway pressure (BPAP) delivers separately adjustable higher on the backup rate.
inspiratory positive airway pressure (IPAP) and lower EPAP Autoadjusting (autotitrating) positive airway pressure
(see Fig. 192).15 Of note, in unselected patients, BPAP treat- (autoCPAP, autoPAP, APAP) devices were developed with
ment does not result in higher rates of adherence than two potential uses: (1) autotitrating PAP to select an effective
CPAP.16 A Cochrane database analysis of six studies and 285 level of CPAP without the need for an attended titration and
participants found no significant difference in usage with (2) autoadjusting PAP for chronic treatment with the advan-
BPAP compared with CPAP.17 However, some patients failing tage of delivering the lowest effective pressure in any
CPAP will tolerate BPAP.18,19 This is especially true of patients circumstance.2326 Chronic treatment with APAP would also
having difficulty exhaling or with complaints of bloating. The eliminate the requirement for a CPAP titration. When APAP
IPAP-EPAP differential (pressure support [PS]) is useful for was first developed, improvement in PAP adherence was a
augmenting ventilation in patients with OSA and concomi- goal. Although there are conflicting data, one meta-analysis
tant hypoventilation. These groups include the obesity showed that APAP does not improve adherence compared
hypoventilation syndrome (OHS) and the overlap syn- with CPAP.27 A more recent larger meta-analysis of 30 studies
drome (OSA + chronic obstructive pulmonary disease and 1136 participants found a statistically significant differ-
[COPD]). Some patients with the OHS or the overlap syn- ence in machine usage of 0.21 hour (12 min), which is not
drome can be adequately treated with CPAP alone.20,21 clinically significant.17 However, individual patients may tol-
However, other patients in this group require BPAP, espe- erate APAP better than CPAP.
cially if significant hypoventilation is present. The APAP algorithms vary between different devices, but
BPAP is also used for noninvasive positive pressure ven- in most instances, the pressure changes in response to varia-
tilation (NPPV) in chronic alveolar hypoventilation syn- tions in airflow magnitude (apnea or hypopnea), airflow
dromes.22 In patients with OSA and OHS, BPAP is usually limitation (flattening of the airflow contour), snoring (vibra-
used in the spontaneous (S) mode. In this mode, the patient tion), and/or airway impedance.23 The pressure changes
cycles the device from EPAP to IPAP and sets the respiratory gradually between the preset lower and upper pressure limits
rate. BPAP is also available with a backup rate (spontaneous- (Pmax, Pmin) to avoid inducing arousal. If none of the mon-
time [ST] mode) or a set respiratory rate (timed [T] mode). itored variables is detected, the device slowly lowers the pres-
These modes are used to provide NPPV to patients who sure to a minimum effective setting. The pressure varies
unreliably cycle the device between IPAP and EPAP due to during the night in response to changes in body position or
muscle weakness or abnormal central ventilatory control sleep stage that may alter the pressure required to maintain
(central apnea). In the ST mode, the device will provide a an open upper airway (Fig. 194). The average pressure is
machine-triggered breath with the specified IPAPtime typically only 2 to 3 cm H2O lower than the fixed pressure
(inspiratory time) if no spontaneous breath occurs within a that would be effective during the entire night but can be up
time window. For example, if the backup rate is 12 breaths/ to 6 cm H2O lower.28 Of note, different brands of devices may
min, there is a 5-second window following the start of respond very differently to changes in airflow.29 High air leak
the last breath. If no spontaneous breath occurs during the (mask or mouth leak), which simulates physiologic events,
time window, the machine will deliver a machine-triggered and inability to differentiate between central and obstructive
breath (Fig. 193). In the T mode, the device delivers IPAP/ apnea by these devices can result in errors in APAP titra-
EPAP cycles with a set IPAPtime at a specified respiratory tion.23,30 The APAP devices have no method of determining
rate. For example, with a rate of 20, the cycle time is 3 whether inspiratory effort is present during an apnea. In the
seconds. If IPAPtime = 1 sec, then EPAP time = 2 sec. The past, some autotitration algorithms would not titrate above
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316 Chapter 19 Positive Airway Pressure Treatment
A B C D
Flow
5 sec
5 sec
20
Pressure 5
1.8 sec
1.2 sec
Leak
1000 ml
Tidal
volume
0
FIGURE 193 Tracings of flow, pressure, leak, and tidal volume signals provided by the positive airway pressure device while a
patient is breathing on BPAP spontaneous timed (ST) mode with a backup rate of 12 breaths/min. Breaths A and C are patient-
initiated and breaths B and D are machine-cycled breaths. If the device does not cycle from expiratory positive airway pressure
(EPAP) to inspiratory positive airway pressure (IPAP) within a 5-second window, a machine breath (IPAPcycle) for the chosen
inspiratory time (IPAPtime) occurs (breath B). The particular noninvasive positive airway pressure (NPPV) device illustrated supplies
a negative-pressure spike signifying a machine-triggered breath. Note the shorter inspiratory time in breath B compared with
breath A. Although the peak flow rates are similar, the tidal volume differs between breaths A and B due to a different IPAPtime.
This illustrates the utility of recording tidal volume as well as flow.
CPAP
Obstructive
Flow
apnea
CPAP
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Chapter 19 Positive Airway Pressure Treatment 317
can occur with some central apneas.31 Thus, using this Adaptive servoventilation (ASV)3338 is a variant of BPAP
approach, some apneas classified as obstructive could that was developed to treat Cheyne-Stokes central apnea in
actually be closed airway central apneas. The use of APAP patients with congestive heart failure.33,37,38 Both ASV and
devices for autotitration is discussed in more detail in later BPAP devices with a backup rate are approved for use with
sections. patients with central apnea and complex sleep apnea
An autoBPAP device is also available (Fig. 196). The (CompSA; central apnea that persists or appears during a
physician sets the minimum EPAP, and the minimum and PAP titration). ASV devices attempt to stabilize ventilation
maximum pressure support (IPAP-EPAP), as well as the in patients with ventilatory instability such as Cheyne-Stokes
maximum IPAP. The minimum PS is 3 cm H2O by default. breathing (CSB),33,37,38 narcotic-induced central apnea,36 and
The machine then adjusts both the EPAP and the IPAP to CompSA of unknown etiology.34,35 During an ASV titration,
maintain an open airway. The advantages of autoBPAP over a level of EPAP is chosen to keep the upper airway open
other PAP modes remain to be demonstrated. A recent study (preventing obstructive apnea) and the IPAP-EPAP differ-
found autoBPAP to be useful as rescue therapy in patients ence (PS) automatically adapts between minimum and
not compliant to CPAP treatment in spite of the usual inter- maximum levels to stabilize ventilation (Fig. 197).
ventions.32 Thus, autoBPAP could potentially be useful in ASV devices from two manufacturers are available in the
very pressure-intolerant patients who find BPAP alone unac- United States (Table 192). They both adjust pressures with
ceptable or in patients for whom an effective bilevel pressure a goal of stabilizing ventilation. The ResMed device (VPAP
is not known. Adapt SV) uses a goal of providing 90% of the recent average
30
Max IPAP setting
20
10
Min EPAP setting
0
0 1 2 3 4 5 6 7
Time (hrs)
FIGURE 196 An overnight pressure-versus-time tracing is shown for a patient using autobilevel positive airway
pressure (PAP) with a minimum expiratory positive airway pressure (EPAP) of 6 cm H2O and a maximum inspiratory
airway pressure (IPAP) of 25 cm H2O. The 90th percentile IPAP and EPAP pressures were 19.2 cm H2O and 16.2 cm H2O,
respectively. The average IPAP and EPAP values were 14.6 cm H2O and 11.8 cm H2O, respectively. From Kakkar RK, Berry
RB: Positive airway pressure treatment for obstructive sleep apnea. Chest 2007;132:10571072.
Inspiration
Cflow
Chest
ABD
SpO2
96 95 98 97 95 96 96
Cpress
20
10
0
Lateral position, ASV adapting
FIGURE 197 The adaptive servoventilation (ASV) device responds to variation in flow by increasing pressure support (PS) when flow and ventilation are
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low and decreasing PS when flow is high. ABD = abdomen; Cflow = flow signal from the PAP device; Cpress = delivered pressure; SpO2 = pulse oximetry.
318 Chapter 19 Positive Airway Pressure Treatment
TABLE 192
Adaptive Servoventilation Devices
BRAND NAME RESMED ADAPT SV PHILIPS-RESPIRONICS AUTO BIPAP SV ADVANCED
Target 90% of previous average ventilation 90% of average peak flow (moving time window)
(moving time window)
EPAP EPP titrated manually EPAP automatically adjusted between EPAPmin and
To prevent upper airway obstruction EPAPmax
IPAP Max available 25 cm H2O Max pressure up to 30 cm H2O
Varies to deliver optimal PS IPAP varies to deliver PS between PSmin (can be 0)
Limits: PSmin to PSmax depending on to PSmax
EPP and maximum machine pressure PSmax constrained by maximum pressure and
PSmin 3 cm H2O current level of EPAP
Backup rate Automatic Auto rate
Approximately 15 breaths/min Fixed rate
Inspiratory time Automatic Automatic in auto rate mode
Set in manual rate mode (default 1.5 sec)
Recommended EPP = 4 cm H2O EPAPmin = 4 cm H2O
initial settings PSmin 3 cm H2O EPAPmax = 15 cm H2O
PSmax 10 cm H2O PSmin = 0
PSmax = 20
Max pressure = 25 cm H2O
Rate: auto
If rate set, use IPAPtime (I-time) = 1.5 sec
BiPAP = bilevel positive airway pressure; EPAP = expiratory positive airway pressure; EPP = EPAP; IPAP = inspiratory positive airway pressure; PS = pressure support;
SV = servoventilation.
ventilation (moving time window). With low tidal volume, advanced, can automatically titrate EPAP with algorithms
the PS increases, and with high tidal volume, the PS decreases. similar to the one used for APAP devices to overcome any
An automatic backup rate triggers an IPAP/EPAP cycle if obstructive component of breathing. The clinician specifies
central apnea is present (default 15 breaths/min). The tech- EPAPmin and EPAPmax and the device titrates EPAP
nologist can only adjust the EPAP (termed EPP for this between those settings. The initial EPAPmin = 4 cm H2O
brand of ASV). The PS is constrained by PSmax (10 cm unless it is known or suspected that CPAP higher than 10 cm
H2O is recommended) and the maximum IPAP is con- H2O is needed to maintain an open upper airway. In that
strained by maximum pressure of 25 cm H2O. case, EPAPmin of 6 to 8 cm H2O is used. For example, a
The Philips-Respironics device (BiPAP Auto SV) targets previous titration showed that CPAP of 12 cm H2O was
90% of the previous average peak flow (moving time average) needed during REM sleep.
and has a within-breath adjustment capability. The IPAP Of note, patients with CSB-central apnea and CompSA
increases to provide PS between the limits of PSmin and (including patients on narcotics) can also be treated with
PSmax as needed to augment flow. The EPAP is adjusted to BPAP in the ST mode. One study comparing BPAP-ST with
maintain an open upper airway. The BiPAP Auto SV pro- ASV in patients with central apnea and CompSA found ASV
vides CPAP = EPAP if ventilation is stable and if PSmin = 0 to result in only a slightly lower AHI than BPAP-ST.34
(default setting). The backup rate can be set at a fixed rate However, stabilizing ventilation with BPAP-ST in this situa-
(or rate = 0) but usually the autorate is used. The autorate tion often requires a high backup rate (with a high propor-
provides a background rate of 8 to 10 breaths/min or higher tion of machine-triggered breaths). Higher PS is usually
depending on previous percentage of patient-triggered needed to deliver a machine-triggered breath because the
breaths. The rate is increased based on current cycle time and patient does not assist with inspiration. It is preferable to
EPAPtime (time since start of the EPAP cycle). If a fixed have the patient trigger the majority of breaths because
backup rate is specified, an IPAPtime (or inspiratory time timing and effective ventilation are usually better. Thus, ASV
[Ti]) must also be specified. The Ti is usually 1.2 to 1.6 sec is generally preferable because, if ventilation is stabilized, a
(recommended 1.5 sec). However, in the autorate mode, the majority of the breaths will be patient-triggered. However,
device automatically selects a Ti. If a fixed backup rate is there are individual patients who may respond better to
used, the manufacturer suggests starting at 2 breaths/min BPAP-ST.
below the spontaneous rate (minimum 810). The latest An important concept when using ASV is that of
version of the BiPAP Auto SV device, called BiPAP Auto SV closed airway central apnea. As noted previously, during
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Chapter 19 Positive Airway Pressure Treatment 319
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Cflow
D
Chest
ABD
SpO2
Cpress CPAP for stable flow IPAP incr for low flow Machine triggered breaths
A B C
20
10
0
ASV IPAPmax = 20 EPAP = 10 180 second window 120 V
PSmin = 0
FIGURE 198 A patient with Cheyne-Stokes breathing on a BPAP Auto SV device. A, Continuous positive airway pressure (CPAP) is delivered as pressure support
(PS) equals PSmin (here = 0) and flow is high. B, PS increases as flow is low. C, Machine-triggered breaths during a central apnea. D, The machine-triggered PS
was not effective due to a closed upper airway. An increase in expiratory positive airway pressure (EPAP) is needed. ABD = abdomen; ASV = adaptive servoventilation;
Cpress = delivered pressure; ECG = electrocardiogram; IPAP = inspiratory positive airway pressure; SpO2 = pulse oximetry. From Brown LK: Adaptive servo-
ventilation for sleep apnea: technology, titration protocols, and treatment efficacy. Sleep Med Clin 2010;5:433.
central apnea, the upper airway may close.31 For example, automatically varying the PS to deliver a targeted tidal
during a mixed apnea, the airway has closed during the volume if the condition of the patient changes. For example,
central portion. If a closed airway central apnea occurs, the if respiratory muscle strength declined and the tidal volume
machine-triggered PS will not effectively deliver flow (or decreased, the device would deliver higher PS to return the
tidal volume). In this case, higher EPAP is needed (Fig. 19 delivered tidal volume to the targeted level. VT-BPAP can be
8). ASV was not specifically designed for patients with noc- used in the S, ST, or T mode. Relatively few studies on
turnal hypoventilation. However, some patients with VT-BPAP devices have been published. To date, only one
CompSA due to narcotics have both hypoventilation and VT-BPAP device is available in the United States (Average
instability in breathing. A higher PSmin (4 cm H2O) may Volume Assured Pressure Support [AVAPS], Philips-
be needed if the arterial oxygen saturation (SaO2) remains Respironics). Storre and colleagues39 compared BPAP and
low but breathing is regular. Another situation in which AVAPS (both in the ST mode) using a randomized, cross-
PSmin greater than 0 is useful is the pressure-intolerant over trial in patients with OHS. AVAPS resulted in a slightly
patient. Rather than using EPAP of 16, one could use an higher ventilation and lower arterial partial pressure of
EPAP of 14 and a PSmin of 4. Thus, the device would deliver carbon dioxide (PaCO2) without any better sleep quality or
a basal pressure of 18/14 cm H2O with higher IPAP as needed quality of life measures compared with BPAP-ST. Using the
to stabilize ventilation. This example also illustrates that if a same device, Ambrogio and associates40 studied an assort-
patient requires high EPAP, quite high IPAP values may be ment of patients with chronic alveolar hypoventilation who
needed to deliver an adequate PS. were stable on BPAP support. A validation night preceded
the study nights to ensure the BPAP settings were adequate
and to provide guidance for the AVAPS settings. Patients
VOLUME-TARGETED BPAP
then were studied on BPAP or AVAPS in random order. On
Recently, volume-targeted bilevel positive airway pressure AVAPS, the minute ventilation was greater than on BPAP but
(VT-BPAP) has been developed in which the IPAP-EPAP sleep quality was comparable between the two NPPV modes.
difference is automatically adjusted to deliver a target tidal Using a different VT-BPAP device, Janssens and coworkers41
volume.3942 VT-BPAP has the potential advantage of monitored patients with the OHS using either BPAP or
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320 Chapter 19 Positive Airway Pressure Treatment
VT-BPAP for one night each in random order. Sleep quality COMFORT MEASURES
was worse but nocturnal transcutaneous partial pressure of
Ramp
carbon dioxide (TcPCO2) was slightly lower on VT-BPAP. It
is possible that patients might have exhibited better sleep Most PAP devices, with the exception of certain APAP
quality after a longer period of adaptation to the VT-BPAP. devices, allow the patient to trigger the ramp option. In the
Jaye and colleagues42 compared BPAP-ST with an autotitrat- ramp option, the pressure starts at a preset levelusually a
ing bilevel ventilator (autoVPAP) in patients with stable low level of CPAPand then slowly increases to the treat-
neuromuscular and chest wall disease with nocturnal ment pressure (CPAP) over the set ramp time. Some APAP
hypoventilation and found autoVPAP to produce compara- devices have a settling time at a low pressure before the
ble control of nocturnal oxygenation without compromising device starts autoadjusting pressure. The ramp option is
sleep quality. The mean nocturnal TcPCO2 was higher with appealing and can be used during midnight awakenings to
autoVPAP, although the difference was unlikely to be clini- help patients return to sleep. However, no study has shown
cally significant. AutoVPAP (ResMed, Poway, CA) is not that the ramp option increased adherence.
currently available in the United States. These studies suggest
VT-BPAP can be effective, but the role of VT-BPAP in the
Flexible Pressure
NPPV treatment of patients with chronic alveolar hypoven-
tilation syndromes remains to be determined. Two manufacturers of PAP devices have developed flexible
When VT-BPAP is used, the purpose of a PSG PAP titra- PAP in an attempt to improve patient comfort and adher-
tion is to select a level of EPAP that eliminates obstructive ence. Some PAP devices manufactured by Philips-Respironics
events (obstructive apnea and hypopnea) and document that provide several comfort options (Cflex, Cflex+, and Aflex)
the device does deliver adequate tidal volumes. According to (Fig. 199). ResMed devices offer expiratory pressure relief
the manufacturers recommendations, a target tidal volume (EPR). However, there are no convincing data that any of
of 8 cc/kg (based on ideal body weight) is selected. Initial these options improve adherence in unselected patients. In
settings are EPAP = 4 cm H2O, IPAPmin = EPAP + 4 cm Cflex, expiratory pressure drops at the start of exhalation but
H2O, and IPAPmax = 25 to 30 cm H2O. If VT-BPAP is used returns to the set CPAP at end-exhalation. The amount of
in the ST or T mode, the backup rate and Ti must also be drop (Cflex 1, 2, 3) is determined by a proprietary algorithm.
specified. A default Ti (IPAPtime) of 1.5 seconds is recom- In general, there is a greater pressure drop for greater flow
mended by the manufacturer. during exhalation. Cflex is available on APAP devices as well
A (1,2,3)
Flow
Aflex
1
2 Pressure
difference
Pressure
3
B
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Chapter 19 Positive Airway Pressure Treatment 321
as CPAP. Cflex+ adds a smoothing of the transition from introduced. One study suggested that use of humidity is
inhalation to exhalation. Aflex is a form of APAP that pro- associated with an increase in risk of infectious complica-
vides a 2 cm H2O lower end-expiratory pressure than the tions53 that can be reduced with use of a filter.54 There is an
inspiratory pressure (in addition to the features of Cflex+). occasional patient with recurrent sinus infections who seems
For both BPAP and autoBPAP devices, a form of expiratory to do better without humidificationbut the etiology of this
pressure relief is available (Biflex). The technology provides improvement is unclear.
a smoothing of transition from IPAP to EPAP as well as Studies determining whether HH improves either accep-
expiratory pressure relief during the EPAP cycle (Biflex 1, tance of CPAP after titration or long-term adherence to
2, 3). CPAP treatment have found conflicting results. Massie and
ResMed devices provide EPR and drop the pressure associates55 studied patients who received either HH or cool
during the start of exhalation pressure by 1, 2, or 3 cm H2O humidity for 3 weeks (random order), a 2-week washout
(EPR 1, 2, 3). The EPR can be used full time or only during period of no humidity, and 3 weeks of the alternative humid-
the ramp period. EPR is not available with ResMed APAP ity. Patients on HH had about 1 2 hour greater objective
devices. adherence than those on no humidity (Table 193). However,
An initial study found that flexible PAP improved adher- several other studies have not found an improvement in
ence by about 1 2 hour using a cross-over design.43 A number adherence5661 with the use of HH for PAP treatment. Other
of subsequent studies in patients on CPAP4448 or APAP49
have not found an increase in adherence. The mode can still
be useful for individual patients who find CPAP difficult to
tolerate. Conversely, some patients actually prefer CPAP to TABLE 193
flexible PAP. Effect of Humidity on Outcomes
COLD
Humidification HEATED PASSOVER NO
HUMIDITY HUMIDITY HUMIDITY
Today, most PAP devices come with the option of an inte-
grated heated humidification system. They can be used in the Usage (hr/night) 5.52 2.1* 5.15 1.9 4.93 2.2
cool humidity mode if desired. Heated humidity (HH) can Epworth 6.2 3.8 7.2 4.8 6.7 3.9
deliver a greater level of moisture than cool humidification Sleepiness
and may be especially useful in patients with mouth leak or Scale
nasal congestion. Mouth leak can cause a dramatic fall in Feeling on 74 15.9 68.9 23.4 62.0 23.4
relative humidity50 (Fig. 1910) and a loss of humidity from awakening
the upper airway/CPAP system, thus drying the nasal or oral
Satisfaction 73.9 19.1 72.9 22.6 62.3 27.6
mucosa. Drying of the nasal mucosa increases nasal resis- with CPAP
tance and this is minimized by use of HH.51,52 HH is more
effective than cool at delivering moisture. The level of humid- Adverse side 4.9 3.3 6.2 3.8 6.5 4.9
ity can be adjusted by the patient to meet variable needs. An effects score
occasional patient will prefer cool humidity (heat turned off) *P < .008.
P < .05. Heated humidity versus no humidity.
or no humidity at all. Adequate cleaning of the humidifier
P < .05. Cool humidity versus no humidity.54
chamber and hoses does require extra patient effort. A Data from Massie CA, Hart RW: Clinical outcomes related to interface type in
number of technologic advances for adjusting humidity to patients with obstructive sleep apnea/hypopnea syndrome who are using
continuous positive airway pressure. Chest 2003;123:11121118.
prevent rain-out in the tubing and mask have recently been
FIGURE 1910 This tracing shows a fall in the relative humidity at the
nasal mask during mouth leaks (leak detected by an oral thermistor).
100 Heated humidification minimized but did not eliminate the fall in relative
humidity. CPAP = continuous positive airway pressure. From Martins de
Araujo MT, Vieira SB, Vasquez EC, Fleury B: Heated humidification or face mask
Relative humidity (%)
Leaks
to prevent upper airway dryness during continuous positive airway pressure
therapy. Chest 2000;117:142147.
50
Leaks
0
Nasal CPAP Nasal CPAP + Humidification
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322 Chapter 19 Positive Airway Pressure Treatment
investigations could not document a benefit from the pro- have severe nasal congestion or open their mouths during
phylactic use of HH for titration. A criticism of these PAP treatment, oronasal (full face masks)64,65 and oral inter-
studies is that patients with baseline nasal congestion or faces66,67 are available. Oronasal masks have to seal over a
dryness were not targeted. It seems reasonable to use humid- large area, and this makes finding a good fit very difficult in
ity in patients with complaints of nasal congestion or mouth some patients. In edentulous patients, oronasal masks may
breathing at baseline. Certainly, in some patients, use of HH also compress the soft tissues. Patients tend to overtighten
is crucial, and in others, it may improve satisfaction. Rain- masks, and this can cause damage to the nasal bridge or
out in the tubing and the mask is a significant problem for actually impair the ability of the mask to seal. Often, a trial
some patients. Lowering the CPAP unit to a level below the of several masks is needed to find one that patients can use
bed (water flows back into the humidifier chamber by comfortably. This is a challenge because insurance providers
gravity), reducing the humidity setting, or using a tube typically will pay for only one mask every 3 to 6 months. This
insulator may help. New technology recently available is one situation in which trying several different types of
adjusts the humidifier setting based on room temperature mask in the sleep center before the titration can be very
and relative humidity. However, it is not clear that this tech- useful. Adequate care and replacement of masks are also
nology will improve adherence. In the practice parameters essential to maximize their ability to seal. If the patient gets
for PAP treatment (Appendix 191), use of HH is recom- up to use the bathroom during the night, we encourage
mended to improve CPAP utilization.3 In the clinical guide- disconnection of the hose from mask rather than taking off
lines for titration, having HH available for titration was the mask. Masks that are removed in the middle of the night
recommended.62 are often not replaced.
option provided that both the parents and the patient accept TABLE 194
this treatment. The exact AHI cutoff is not well defined, but Factors Predicting Good or Worse Adherence
many pediatricians consider a residual greater than 5/hr as
WORSE
indicating significant OSA in children and an indication for
GOOD ADHERENCE ADHERENCE NO EFFECT
CPAP treatment. Those less symptomatic patients with an
AHI between 1 and 5 are in a gray zone and treatment must More sleepy Spouse referred Level of
be individualized. Starting CPAP in children often requires Higher AHI Not sleepy pressure
Greater perception High nasal Pressure
periods of adaptation to a mask before a titration can be
of benefit resistance technology
attempted.62,70 Other options include weight loss, dental pro-
Good early Poor early minimal if
cedures, or intranasal steroids and leukotriene modifier adherence adherence any effect
therapy.71
AHI = apnea-hypopnea index.
ADHERENCEDEFINITIONS
AND MEASUREMENT
Despite the excellent efficacy of PAP devices for reducing the patients), different definitions of adherence, different length
AHI, the actual effectiveness is much lower. For example, if of follow-up, and different algorithms of initiating PAP treat-
CPAP reduces the AHI from 40 to 5/hr but is used only 50% ment and following patients. One of the largest studies of
of nights, the mean AHI has only been reduced to 25/hr. long-term adherence with nasal CPAP reported only 68% of
Monitoring PAP adherence at one time involved looking at patients were still using CPAP at 5 years.73 Ppin and col-
the run time meter on devices. Then the devices began to leagues74 found 79% of patients using CPAP for longer than
record both blower hours and time at pressure (actual use). 4 hours on 70% of nights at 3 months. Sin and coworkers75
Today, PAP machines have both internal memory and followed patients with an AHI greater than 20/hr and found
removal memory (smart cards, memory sticks, or disks). greater than 85% were using the device longer than 3.5 hr/
The removable media can store extensive information on night at 6 months. Kohler and associates76 found that 81% of
adherence and patterns of use. The recorded device informa- patients were using CPAP at 5 years.
tion can be assessed by direct machine interrogation (inter-
nal memory) or transferring of information on removable Factors Influencing Adherence and Importance
media to a computer. Some devices when attached to a
of Early Adherence
modem can send information to a central location and phy-
sicians can obtain ongoing data on a patient. Other devices Several studies have addressed the factors associated with
can communicate with a central location using wireless good versus poor PAP adherence (Table 194). In general,
technology. The data obtained from PAP devices often the factors identified to date explain relatively little of the
includes useful information on leak as well as an estimate of large variance in CPAP acceptance and adherence.73,74,76,77
the residual AHI. Detailed daily information can show The level of pressure does not seem to be important. Finding
important patterns, for example, consistent mask removal at an acceptable interface is often the biggest challenge in
5 AM. As discussed later, it has been shown that the pattern getting patients to adhere to PAP treatment. However, there
of use is established early and that objective adherence is no evidence for the superiority of any type of interface.
(not patient report) is essential to guide treatment. Data Although a great deal of effort is spent in intervening for side
via modem or wireless communication can provide infor- effects, the presence or absence of side effects does not seem
mation during the critical first weeks of use without requir- to be a major determinant of PAP use.77 Patients may be
ing the patient to come to a clinic or a durable medical willing to tolerate side effects if there is a significant improve-
equipment office. ment in pretreatment symptoms. Factors favoring better
Adherence rates are defined in many ways. Most devices adherence include symptomatic daytime sleepiness, good
compute the percentage of days used, the average use all days response in sleepiness to treatment, and to a lesser extent
(averaging in 0s for days not used), average nightly use (days disease severity (AHI). In one study a high arterial oxygen
used), and the percentage of nights used 4 hours. An early desaturation index predicted good adherence.76 Poor prog-
paper reporting measurement of objective adherence by nostic factors include spouse referral and high nasal resis-
Kribbs and coworkers72 defined regular users as those who tance.75,78 Whether CPAP treatment follows a split night
used CPAP at least 4 hr/day on at least 70% of nights. In their (diagnostic/PAP titration) or separate diagnostic and PAP
study, only 46% of patients met this criterion. titration studies does not seem to affect PAP adherence.
Early adherence is a good predictor of long term PAP use.
In a study of 32 patients followed for 9 weeks, the nightly
PAP Adherence in Large Studies
duration of use differed between compliant and noncompli-
There has been a tremendous variability in the reported rates ant patients by the fourth night of use.79 Budhiraja and col-
of PAP adherence. This is due to a number of factors includ- leagues80 found that long-term adherence to CPAP can be
ing different populations (moderate to severe OSA vs. all predicted as early as 3 days after CPAP initiation.
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324 Chapter 19 Positive Airway Pressure Treatment
70 TABLE 195
60 Methods to Improve Positive Airway Pressure
% with normal values
Adherence
50
Education about OSA and PAP by staff, video, printed
40
information
30
Involvement of significant other/spouse
20
Subsequent mask and headgear adjustment or change as
10 needed
FOSQ ESS MSLT
0 PAP help line
2 >2<4 4,<5 5<6 6<7 7
Hours of nightly CPAP use Unsolicited telephone follow-up
FIGURE 1912 Cumulative proportion of participants obtaining normal threshold Early interventions for side effects and concerns
values on the Epworth Sleepiness Scale (ESS), multiple sleep latency test (MSLT), and
Functional Outcomes of Sleep Questionnaire (FOSQ). CPAP = continuous positive airway Objective monitoring of adherence
pressure. From Weaver TE, Maislin G, Dinges DF, et al: Relationship between hours of Early and regular clinic visits
CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep OSA = obstructive sleep apnea; PAP = positive airway pressure.
2007;30:711719.
TABLE 196
Interventions for Common Positive Airway Pressure Treatment Side Effects
POSITIVE PRESSURE SIDE EFFECTS INTERVENTIONS
MASK SIDE EFFECTS
Air leaks Proper mask fitting
Conjunctivitis Proper mask application (education)
Discomfort Different brand/type of mask
Noise
Skin breakdown Avoid overtighteningintervene as above for leaks
Alternate between different mask types
Nasal prongs/pillows
Tape barrier for skin protection
Mouth leaks Treat nasal congestion if present (see below)
Mouth dryness Chin strap
Heated humidity
Full face (oronasal) mask
Consider BPAP, flexible PAP, lower pressure, APAP
Mask claustrophobia Nasal pillows/prongs interface
Desensitization
Unintentional mask removal Low-pressure alarm
Consider increase in pressure
NASAL SYMPTOMS
Congestion/obstruction Nasal steroid inhaler
Antihistamines (if allergic component)
Nasal saline
Humidification (heated)
Full face (oronasal) mask
Nighttime topical decongestants (oxymetazoline) as a last resort
Epistaxis Nasal saline
Pain Humidification (heated)
Rhinorrhea Nasal ipratropium bromide
OTHER PROBLEMS
Pressure intolerance Ramp
Flexible PAP
BPAP
APAP
Lower prescription pressure temporarilyaccept higher AHI
Lower pressure + adjunctive measures (elevated head of bed, side sleeping position,
weight loss)
Aerophagia/bloating BPAP, flexible PAP, reduce pressure
AHI = apnea-hypopnea index; APAP = autoadjusting positive airway pressure; BPAP = bilevel positive airway pressure; PAP = positive airway pressure.
However, one study found that moderate alcohol consump- longer-acting medication is needed to improve CPAP adher-
tion near bedtime did not impair the efficacy of CPAP.90 ence. Although routine use of a hypnotic cannot currently
Another study found that zolpidem, a commonly used hyp- be recommended, at least temporary use of a hypnotic
notic, did not impair efficacy of a given level of CPAP.91 should be considered if insomnia is a major obstacle to
Conversely, it has been hypothesized that using a hypnotic CPAP use.
might improve adherence to PAP in some patients. A study
by Bradshaw and colleagues92 using zolpidem did not find an
CPAP/BPAP TITRATION FOR OSA
improvement. In contrast, Lettieri and associates93,94 found
improvement during CPAP titration (sleep quality) and A PSG is the standard method PAP for titration and is
long-term adherence with eszopiclone (a hypnotic with a usually accomplished either as the second part of a split
longer duration of action that zolpidem). It is possible that a study or during an entire night after a previous diagnostic
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326 Chapter 19 Positive Airway Pressure Treatment
study. The American Academy of Sleep Medicine (AASM) on low pressure (CPAP practice). If a split study has been
practice parameters for the use of PSG provide guidance ordered, these events should take place before any
about when a split study is acceptable.95 A split study is rec- diagnostic monitoring begins. A number of interfaces
ommended only if the AHI is greater than 40/hr and 2 should be available (nasal, oronasal, oral, pillows) including
hours of monitoring have occurred. In addition, 3 hours of masks in sizes suitable for children if a child is being studied.
PAP titration is the minimum acceptable duration. If an HH should be available as well as a source of supplemental
adequate titration is not obtained, a repeat PSG titration is oxygen.
indicated. Of note, these recommendations for a split study
are based on limited data and some sleep centers have more
Pediatric Considerations
lenient criteria for use of a split study. CMS guidelines for
qualifying a patient for PAP formerly required at least 2 PAP titrations in children require some extra considerations.
hours of recorded sleep in the diagnostic portion of a split Children are often given a mask to play with and try on
study. This requirement has been dropped. If less than 2 during the day for a week before scheduled studies. The
hours of sleep are recorded, the minimum number of apneas child should be desensitized to the mask during the day by
and hypopneas must equal the number that would have wearing it for increasing periods of time while engaging in
been required if 2 hours of sleep had been recorded68 (see a fun activity (e.g., watching a favorite video). Split-night
also Appendix 192). For example, to meet a cutoff of an studies are not recommended for children. If the child
AHI of 15/hr, a total of 30 apneas and hypopneas must be without previous mask desensitization undergoes a split-
recorded. Recently, Clinical Guidelines for the Titration of night study, you may frighten the child and this will make
BPAP and CPAP for Obstructive Sleep Apnea were written subsequent CPAP use unlikely. Pediatric size masks should
by a task force of the AASM and approved by the board be available. Durable medical equipment providers and sleep
of directors.62 Excerpts from the titration guidelines are technologists skilled and willing to provide care for pediatric-
discussed later. The reader is referred to this informative age patients should be utilized.62,96 Studies have shown that
document. structured behavioral interventions help with compliance
(graduated exposure, positive reinforcement, dealing with
escape and avoidance behavior, and praising distracting
General Titration Considerations
activities that allow the child to wear a mask).70,97,98
A number of general recommendations for PAP titration are
listed in Table 197. Before PAP titration, the patient should
Monitoring during Positive-Pressure Titration
be educated about OSA, PAP treatment, and the PAP titra-
tion process.3,62 They should be given mask interface options. Most positive-pressure devices used in the sleep disorders
They should try on one or more interfaces while breathing center provide several analog or digital outputs that can be
TABLE 197
Positive Airway Pressure Titration (Equipment, Patient Preparation, and General Recommendations)
All potential PAP candidates (PAP PAP education.
titration and potential split titration) Mask fitting, try several interfaces.
Acclimatization period with low pressure.
Monitoring Airflow monitored from machine flow signal.
RERAs identified by flattening of the machine flow signal associated with arousal.
Leak, machine pressure recorded if possible.
Interfaces Nasal, full face (oronasal), nasal pillows, oral should be available.
Interfaces in pediatric sizes if children are studied.
High leakone higher than expected Mask adjustment, refit, change.
for a given interface and pressure
Heated humidity available Used for nasal congestion or dryness
Treatment emergent central apneas Let the patient settle downif they reach stage N3, central apneas may stop.
Try lowering CPAP or IPAP.
Do not switch from CPAP to BPAP as a response to central apneas unless a backup
rate is used.
Repeat PAP titration Less than 3 hours during PAP titration of split study.
Good or acceptable titration results NOT obtained.
BPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; IPAP = inspiratory positive airway pressure; PAP = positive airway pressure;
RERAs = respiratory effortrelated arousals.
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Chapter 19 Positive Airway Pressure Treatment 327
TABLE 198
Monitoring during Positive Airway Pressure or Noninvasive Positive Pressure Ventilation Titration
PARAMETER SENSOR REASON
Airflow PAP/NPPV device output (accurate internal flow Detection of apnea, hypopnea, and RERAs.
sensor).
Leak Leak estimate by PAP or NPPV device from accurate Total leak = intentional + unintentional leak
flow measurement. (some device output an estimate of
unintentional leak rather than total leak).
Snoring Piezoelectric sensor or microphone. Detection of snoring.
Pressure External pressure transducer or NPPV device signal Documentation of amount and pattern of
(internal pressure sensor). pressure delivery.
Chest and abdominal Respiratory inductance plethysmography. Differentiating central and obstructive
movement events, detection of paradox.
NPPV
Tidal volume NPPV device output (from integration of flow signal). Estimate of tidal volume.
Respiratory muscle Bipolar monitoring: use surface electrodes over the Absence or reduction in respiratory muscle
EMG diaphragm or intercostal muscles. EMG suggests adequate respiratory
muscle rest has been achieved.
PETCO2 Side stream via nasal cannula in nares under the Breath-by-breath estimate of PaCO2.
mask.
TcPCO2 Transcutaneous sensor. Estimate of trends in PaCO2.
EMG = electromyogram; NPPV = noninvasive positive pressure ventilation; PAP = positive airway pressure; PaCO2 = arterial partial pressure of carbon dioxide;
PETCO2 = end-tidal carbon dioxide pressure; RERAs = respiratory effortrelated arousals; TcPCO2 = transcutaneous carbon dioxide pressure.
Flow Flow FIGURE 1913 Total flow increases with pressure but
Total flow CPAP flow Leak Total flow CPAP flow Leak is separated into a variable component (continuous
Inspiration
recorded (Table 198).62 The total flow delivered by the orifice system consisting of small holes to provide an inten-
machine is measured by an accurate flow sensor in the PAP tional leak that washes out exhaled CO2 from the mask and
device. Use of a thermal device under the mask to monitor prevents rebreathing. This intentional leak increases with the
flow is not recommended. The total flow is then divided by amount of pressure and varies between different masks (Fig.
the device into two components (Equation 191) that are 1914). The unintentional leak is due to mask or mouth leak
supplied for monitoring: (1) the PAP flow (also known as (in the case of a nasal mask). Leak is seen by the machine as
CPAP flow, Cflow, or machine flow), which varies with inspi- bias or constant baseline inspiratory flow onto which the
ration and expiration, and (2) the leak (bias flow), which is variations in patient flow is superimposed. The leak signal
a fairly constant portion due to system leak (Fig. 1913). The provided by some devices is the total leak whereas others
CPAP flow signal is used to score respiratory events (apneas, provide an estimate of unintentional leak by subtracting the
hypopneas, or respiratory eventrelated arousals [RERAs]). expected leak given the mask and pressure (mask type must
The same respiratory scoring rules defined by the AASM be specified). Absolute values are less useful than relative
scoring manual are utilized with the exception that there is increases in leak.
one flow signal rather than the usual two (oronasal thermal
Total flow = PAP flow + Leak Equation 191
flow and nasal pressure).99 The total leak is due to the inten-
tional leak (to prevent rebreathing) and unintentional leak Leak = Intentional leak +
Equation 192
(Equation 192). All CPAP mask interfaces have a built-in Unintentional leak
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328 Chapter 19 Positive Airway Pressure Treatment
60
A The PAP flow signal provides not only an estimate of the
B magnitude of flow but also information from the inspiratory
50
flow contour. High upper airway resistance is manifested by
Leak rate (lpm)
C
40 a flattened profile100 (Fig. 1915). The normal profile is a
30 rounded one. Figure 1916 shows that the CPAP flow signal
is flat at a pressure of 7 cm H2O and snoring is present. These
20
findings suggest significant upper airway narrowing is still
10 present. An increase in CPAP results in a round signal shape
0 and cessation of snoring.
5 10 15 20 25 30 35 40 CPAP flow signals are usually either filtered or insuffi-
Pressure (cm H2O) ciently sampled to show snoring. Snoring can be detected by
FIGURE 1914 Intentional leak increases with pressure and depends on the mask
a snoring sensor placed on the neck or from pressure vibra-
type (A, B, or C). Information is available with each mask. tions in mask pressure. Nearly all sleep center PAP units will
also provide a signal of the machine pressure. This is the
pressure at the machine outlet and can differ slightly from
the set pressure (value entered by technologist). The actual
13
consistent with airflow limitation. Here, a
drop in continuous positive airway pressure 12
(CPAP; arrow) results in change of flow signal 11
and increased pressure gradient across the
10
upper airway (increased resistance). From
Condos R, Norman RG, Krishnasamy I, et al: 50
Total flow (l/min)
4
2
0
2
4
6 Resistance 12 Resistance 29
0 5 10 15 20 25 30
Time (seconds)
CPAP 8 cm H2O
CPAP flow
Snore
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Chapter 19 Positive Airway Pressure Treatment 329
mask pressure may be somewhat lower during inhalation a nasal mask and chin strap when there is a transition to
and sometimes slightly higher during exhalation. Mask pres- REM sleep. Because there was no change in pressure or body
sure can also be directly measured by connecting the mask movement, this suggests that mouth leak was present (con-
to a pressure transducer. Actual mask pressure can then be firmed by video monitoring). Observation using video
recorded. (zooming in) can show an open mouth or fluttering of the
PAP units also provide a leak signal that can be monitored lips during mouth leak. If the flow signal becomes truncated
and recorded. Recording of the leak signal is useful for the during expiration, this means that part or all of flow during
physician reviewing a PAP titration. The trend in the leak is exhalation is not sensed by the machine flow sensor (no flow
more useful than the absolute number. If the patient has not returning to the hose/device system) consistent with an expi-
moved and leak suddenly increases, this could be a hint that ratory leak from either the mask or the mouth. If the patient
mouth leak is occurring (assuming the patient is wearing a is wearing a nasal mask (which has not moved), the sudden
nasal mask). Sometimes, an increase in leak can occur with appearance of truncated expiratory flow (often associated
the onset of REM sleep. Relaxation in the facial musculature with vibration in the snoring sensor) is suggestive of expira-
can sometimes produce mask or mouth leaks. In Figure tory mouth leak (Fig. 1918). The technician does not neces-
1917, there is a sudden increase in leak in a patient wearing sarily have to intervene unless mouth leak is arousing the
C4-M1
O2-M1
E1-M2
E2-M1
Stage N2 Stage R
Chin
Mouth open
Cflow
SaO2
94%
60
CPAP 18
Leak
CPAP
12 cm H2O
FIGURE 1917 A 120-second tracing shows flow from the continuous positive airway pressure device (Cflow), leak, and the delivered pressure at the device outlet
(CPAP). The patient was wearing a nasal mask and chin strap. At the transition to stage R, a large increase in leak was noted. The patient was not noted to move but
video observation showed that one corner of his mouth had opened slightly. Note that the increase in leak signal lags behind the obvious change in flow that occurs
a few seconds earlier. Stage R is associated with muscle hypotonia. SaO2 = arterial oxygen saturation.
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330 Chapter 19 Positive Airway Pressure Treatment
Epoch 600
Snore
CPAP
flow
Epoch 602
Snore
CPAP
flow
Expiratory
vibration
FIGURE 1918 A change in expiratory flow combined with expiratory snoring is suggestive of an expiratory leak. Compare the truncated
expiratory flow in epoch 602 with the normal expiratory flow in epoch 602. This is due to expiratory mask or mouth leak (if a nasal mask is
being used). This patient was using a nasal mask and subtle lip fluttering was noted on video. The expiratory flow is truncated because part
of the expiratory flow does not pass into the tubing (escapes from the system) and is not sensed by the device flow sensor. Inspiration is
upward. CPAP = continuous positive airway pressure; REM = rapid eye movement.
patient or preventing PAP from maintaining a patent diluted. A downside is that this can cause problems with the
airway. If mouth leak is a problem, either using a chin strap mask seal. Another option is to record is the TcPCO2. These
or an oronasal mask or lowering the pressure could be surrogate measures of PCO2 are useful only if calibrated and
considered. validated (ideally with an arterial or capillary blood gas).22,99
As mentioned in Chapter 8, a PETCO2 tracing should show a
plateau.
Additional Monitoring for NPPV Titration
For NPPV titration, it is useful to record the tidal volume
Titration Protocol
signal from the PAP device that is derived from integration
of the flow signal (see Fig. 193).22 Tidal volume depends The recommended PAP titration protocol for adults and
both on flow and inspiratory time. Therefore, monitoring the children is shown in Tables 199 and 1910.62 CPAP is
flow signal alone may not provide an accurate estimate of usually started at 4 to 5 cm H2O and then increased for
ventilation. Some sleep centers that perform NPPV in obstructive apneas, hypopneas, RERAs, and snoring. Usually,
patients with neuromuscular disorders also record an inter- as pressure is increased, the apneas hypopneas RERAs
costal electromyogram (EMG) or surface diaphragmatic snoring resolve in that order.105 CPAP is increased in
EMG with techniques similar to those for leg EMG. If the adults after two obstructive apneas, three hypopneas, or five
signal decreases, tidal volume increases and respiratory rate RERAs and no more often than every 5 minutes. When
decreases; these changes suggest that adequate respiratory titrating BPAP, starting pressures of 8/4 cm H2O are typically
muscle rest is being delivered by the current level of PS (Fig. used. Both IPAP and EPAP are increased together for
1919).101,102 In addition, some sleep centers record either the obstructive apnea. For obstructive hypopneas, RERAs, and
end-tidal partial carbon dioxide pressure (PETCO2) or snoring, the IPAP alone is increased. The clinical guidelines
TcPCO2.103,104 However, the exhaled gas sampled for the suggest that the IPAP-EPAP difference should be at least 4
PETCO2 measurement can be diluted by NPPV flow. A but not greater than 10 cm H2O. Note that, when NPPV
common method is to use a small nasal cannula under the titration is discussed later, a wider IPAP-EPAP difference
mask that suctions exhaled air at the nares before it can be can be used. In general, if the IPAP-EPAP difference widens,
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Chapter 19 Positive Airway Pressure Treatment 331
Flow
Chest
8/4 cm H2O
Abdomen
Rate 18
Intercostal
EMG
Flow
Chest
15/5 cm H2O
Abdomen
Rate 12
Intercostal
EMG
FIGURE 1919 A patient with neuromuscular disease underwent an NPPV titration. When the level of pressure support was increased,
there was a decrease in the respiratory rate and in the intercostal electromyogram (EMG). From Berry RB: Initiating NPPV treatment with
patients with chronic hypoventilation. Sleep Med Clin 2010;5:485505.
TABLE 199
Continuous Positive Airway Pressure Titration Guidelines62
ADULTS AND CHILDREN > 12 YR CHILDREN < 12 YR
Beginning pressure (cm H2O; minimum) 4 4
Maximum pressure (cm H2O) 20 15
Increase CPAP in at least 1 cm H2O increments Increase pressure for: Increase pressure for:
no more frequently than every 5 min 2 obstructive apneas 1 obstructive apnea
3 hypopneas 1 hypopnea
5 RERAs 3 RERAs
3 min loud snoring 1 min loud snoring
Switch to BPAP Intolerant to CPAP
Events still present on CPAP of 15 cm H2O (option)
Snoring guidelines state that pressure may be increased.
BPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; RERAs = respiratory effortrelated arousals.
an increase in EPAP is often needed to maintain upper use BPAP 18/14 cm H2O. Another approach is to use EPAP
airway patency. Higher PAP is needed for the supine posi- = CPAP, and IPAP = EPAP + 4 cm H2O and titrate pressure
tion and during REM sleep.106,107 For this reason, an effec- upward if needed. Of note, in pressure-intolerant patients,
tive pressure during supine REM sleep should be determined sleep in the lateral position or with the head elevated can be
if possible during the titration.62 Note that the recommended tried to reduce the required level of pressure.108 If mouth leak
maximum CPAP and number of events triggering pressure is a problem, a chin strap can be tried followed by an orona-
changes are lower in children. sal mask. In patients with allergic rhinitis or nasal conges-
If the patient awakens and complains of excessive pres- tion, use of HH from the start of the study is suggested.
sure, pressure should be lowered. If this does not work, a Although studies have not shown a benefit from using pro-
switch from CPAP to BPAP or use of flexible PAP may be phylactic HH in all patients, many sleep centers find it to
tried. When switching from CPAP to BPAP, one approach is be very useful. Once the nose is congested, this problem is
to use IPAP 2 cm H2O higher than CPAP and EPAP 2 cm not easily reversed. If there is excessive mask leak, a readjust-
H2O lower. Thus, with a change from CPAP of 16, one would ment of the mask, change in mask size, or change in mask
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332 Chapter 19 Positive Airway Pressure Treatment
TABLE 1910
Bilevel Positive Airway Pressure Titration Guidelines62
ADULTS CHILDREN < 12 YR
Beginning pressure (cm H2O) 8/4 8/4
IPAP/EPAP
Maximum IPAP (cm H2O) 30 20
Minimum PS (cm H2O) 4 4
Maximum PS (cm H2O) 10 10
Increase BOTH IPAP AND EPAP in at least 1 cm H2O Increase pressure for: Increase pressure for:
increments no more frequently than every 5 min 2 obstructive apneas 1 obstructive apnea
Increase IPAP in at least 1 cm H2O increments no Increase pressure for: Increase pressure for:
more frequently than every 5 min 3 hypopneas 1 hypopnea
5 RERAs 3 RERAs
3 min loud snoring 1 min loud snoring
Snoring guidelines state that pressure may be increased.
EPAP = expiratory positive airway pressure; IPAP = inspiratory positive airway pressure; PS = pressure support = IPAP EPAP; RERAs = respiratory effortrelated
arousals.
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
PAP
flow
Chest
Abdomen
SpO2 94%
81%
FIGURE 1920 A patient on continuous positive airway pressure (CPAP) of 15 cm H2O has persistent arterial oxygen desaturation without discrete events. The
options are to add supplemental oxygen, try an increase in CPAP, or switch to bilevel positive airway pressure (BPAP). A switch to BPAP was effective in this patient.
EMG = electromyogram; PAP = positive airway pressure; SpO2 = pulse oximetry.
50
4 Lpm backup rate when obstructive events have disappeared.
45 Patient with CompSA have predominantly obstructive or
40 mixed apneas during the diagnostic sleep study (or diagnos-
FIO2 (%)
35
2 Lpm tic portion of a split study) occurring at 5/hr or greater. The
30
CMS definition of CompSA requires that greater than 50%
of the residual respiratory events on PAP are central apneas
25 0 Lpm or central hypopneas, the central AHI is 5/hr or greater, and
20
the total AHI is 5 or greater (Appendix 19-3). Patients with
15 a combination of OSA and CSB may manifest CSB-central
0 4 12 20
CPAP (cm H2O) apneas when CPAP eliminates obstructive events. These
patients meet the definition of CompSA. Other patients
FIGURE 1921 Approximate change in effective fractional concentration of oxygen in taking potent opiates develop central apneas on CPAP (treat-
inspired gas (FiO2) with supplemental oxygen and various continuous positive airway ment emergent central apneas) or central apneas persist
pressure (CPAP) levels in a model system. Plotted from data from Yoder EA, Klann K, on CPAP. Other patients may manifest CompSA without
Strohl KP: Inspired oxygen concentrations during positive pressure therapy. Sleep Breath
an obvious cause (idiopathic CompSA). The treatment of
2004;8:15.
CompSA is discussed in detail in Chapter 21.
Patients with Cheyne-Stokes central apnea or idiopathic
CompSA tend to have high ventilatory drives or difficulty
required supplemental oxygen flow will likely be much maintaining sleep. Central apnea occurs because the PaCO2
higher (assuming the same fractional concentration of drops below the apneic threshold. The approach to CompSA
oxygen on CPAP treatment is still required). and PAP titration protocol for handling central apneas varies
between sleep centers.111113 One approach is to increase
CPAP only until the obstructive apneas and hypopneas are
Complex Sleep Apnea
eliminated. CPAP is increased further only if RERAs are
CompSA is defined as a form of central apnea specifically believed to be causing central apneas (after the arousals).
identified by the persistence or emergence of central apneas Many patients will stabilize if they enter stage N3 sleep
or hypopneas upon exposure to CPAP or a BPAP without a (i.e., patience rather than increasing the CPAP). A small
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334 Chapter 19 Positive Airway Pressure Treatment
PB CA 1.5
CA OA 1.9
OA H 2.4
H FL 0.0
FL
VS VS 102.9
RE RE 2.8
AHI 5.8
0 1 2 3 4 5 6 7 8
Min in large leak
Total leak (LPM) Normal mask fit Large leak Total leak
0.0 min
% of night in
100
Large leak
50 0%
Average leak 43.0
0 1 2 3 4 5 6 7 8
FIGURE 1922 Sample PAP device download on a patient using continuous positive airway pressure (CPAP) of 12 cm H2O. The
residual apnea-hypopnea index (AHI) is 5.8 (adequate) but snoring is very prominent in the second half of the night. Leak is not
increased. On the basis of this information CPAP was increased to 13 cm H2O. Large leak is defined as a leak greater than twice the
intentional leak from interfaces at that pressure. CA = clear airway apnea; FL = flow limitation; H = hypopnea; OA = obstructive airway
apnea; PB = periodic breathing; RE = respiratory effortrelated arousal; VS = vibratory snore.
the adherence data, most PAP machines give information on setting has been used, the function of the humidifier should
leak and residual AHI. Some can give detailed information be checked, the possibility of mouth leak considered (if the
about residual events including clear airway events (central patient has a nasal mask), or the fit of the mask should be
apneas). Three studies found a surprisingly high proportion evaluated. If a mouth leak is suspected, one could try a full
of patients well treated with CPAP who had elevated AHI face mask or chin strap. The patients bed partner often pro-
values on their current treatment pressures.122124 A high vides important clues as to persistent snoring or apnea,
residual AHI found on CPAP machine download would pulling the mask off during the night, noisy mask, or mouth
suggest that the current pressure was inadequate (unless the leak. Most clinicians have the patient fill out an Epworth
events were central apneas) or that an inadequate mask seal Sleepiness Scale each visit; this is used along with questions
significantly reduced the delivered pressure. Some CPAP and about the quality of sleep to assess effectiveness of CPAP
APAP devices present the residual AHI, AHI, hypopnea treatment. In patients with significant insomnia, use of a
index (HI), and a snoring index. If the residual apnea index hypnotic could be considered once sleep hygiene and medi-
exceeds the HI, this is a clue that central apnea may be cation side effects are optimized.
present. Recall that as pressure increased, first obstructive
apnea then hypopnea resolve. However, false elevations of
NPPV Titration and Treatment
the AHI can occur. Recently, CPAP and APAP devices can
separate apneas into obstructive apneas and clear airway The titration of NPPV focuses on providing ventilatory
apneas. In Figure 1922, a sample report from a patient on support in addition to maintaining an open airway.22,124
CPAP shows a reasonable residual AHI and no evidence of Patients with neuromuscular disorders, thoracic cage disor-
excessive leak. However, there is evidence of considerable ders, or disorders of inadequate ventilatory control may not
snoring and slightly higher pressure is indicated. A high be obese and may not require as high an EPAP as patients
residual AHI in a patient with congestive heart failure or with OSA or OHS.22,125,126 IPAP and EPAP are titrated as per
potent narcotic use would suggest the possibility of central the protocol discussed previously to eliminate obstructive
apneas. High leak would suggest need for better interface fit. events. However, the goal is to provide adequate PS without
The interface could be adjusted or changed to a different size using excessive pressure. Therefore, BPAP of 16/4 or 20/5 cm
or interface type. We have found it very useful to pressurize H2O might be typical pressures. The ST mode is used for
the mask in the office before the patient leaves to check the treatment of all patients with central ventilatory control
seal. If extreme dryness is present and a reasonable humidity disorders and is also recommended for patients with
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Chapter 19 Positive Airway Pressure Treatment 337
neuromuscular disorders and thoracic cage disorders. These Chapter 21. The nocturnal PaCO2 goal is a value equal to or
patients may not reliably cycle the BPAP device from EPAP less than the daytime PaCO2. However, sufficient PS may not
to IPAP. The ST mode is also needed if central apneas are be tolerated initially. NPPV can be started on an outpatient
noted during the NPPV titration. The backup rate is usually basis at low pressure (BPAP 8/4) and increased as tolerated
set 1 to 2 breaths below the sleeping spontaneous breathing based on patient symptoms and oximetry, daytime PETCO2
rate (810 breaths/min minimum). The cycle time in seconds measurements, or daytime arterial blood gas measure-
is equal to 60 divided by the respiratory rate in breaths per ments.128 However, an NPPV PSG titration is recommended
minute. The Ti is chosen between 30% and 40% of the cycle and allows a treatment to be chosen (IPAP, EPAP, backup
time. When expressed as a fraction of the cycle time, this is rate) that will eliminate obstructive apnea/hypopnea and
also known as the %IPAP time. deliver optimal PS. Some patients will also require the addi-
tion of supplemental oxygen. Close follow-up is needed
Example: If the respiratory rate = 15, because the given level of pressure support may prove inad-
cycle time = 60/15 = 4 sec. equate if respiratory muscles weaken.
If the %IPAP time is 30%, the Ti would be 1.2 sec. Titration using VT-BPAP is performed to determine an
effective EPAP. The ST mode is commonly used. The device
In general, patients with airflow obstruction (COPD) are will automatically adjust PS to provide a desired tidal volume.
best treated with 30% %IPAP time and those with restrictive If pressure intolerance is a problem, a lower tidal volume
disorders may do better with 40% %IPAP time. One manu- target with a higher respiratory rate (spontaneous or
facturer recommends using 1.5 seconds as the default inspi- machine-triggered) may be better tolerated.
ratory time for BPAP-ST. The rise time is the time from start
of the IPAP cycle until IPAP pressure is reached. It is typi-
NPPV Titration Protocol
cally around 200 msec (200600 msec) but can be varied for
patient comfort. Before the titration, the patient should be educated about
the process and be able to try different interfaces with
low pressure. Monitoring during a NPPV titration uses
Goals of NPPV Titration and Treatment
methods similar to those for a PAP titration.22,125 A BPAP
The goals of the NPPV treatment vary between patients22,125,126 device with capability to function in the ST or T mode is
but generally include (1) improving sleep quality and pre- needed. Most NPPV devices provide an analog output of
venting nocturnal dyspnea, (2) preventing nocturnal tidal volume that can be recorded. As shown in Figure 193,
hypoventilation (or worsening of hypoventilation during monitoring and recording tidal volume in addition to flow
sleep if daytime hypoventilation is present), and (3) provid- is useful because tidal volume depends on both flow and
ing respiratory muscle rest. For patients with daytime Ti. A Best Clinical Practices NPPV titration protocol has
hypoventilation, use of NPPV can improve the quality of recently been published by the AASM and is a useful guide
life and delay or prevent the progression of respiratory to NPPV titration.22 Some of the titration recommendations
failure.125,126 The indications for NPPV127 are discussed in are listed in Table 1914. Generally, a starting pressure
TABLE 1914
Recommendations for Adjustment of Pressure Support during Noninvasive Positive Pressure
Ventilation Titration
DURATION
PRESSURE CHANGE TRIGGER BETWEEN CHANGES GOAL
IPAP/EPAP increased Eliminate apnea, hypopnea RERA 5 min Prevent apnea, hypopnea, RERAs,
(see Table 1910) snoring.
PS increased 12 cm H2O Low tidal volume (<68 cc/kg IBW) 5 min Adequate tidal volume.
PS increased 12 cm H2O PaCO2 > 10 mm Hg above goal 10 min Adequate ventilation and PaCO2
PS increased 12 cm H2O Respiratory muscle rest not 10 min Adequate respiratory muscle rest.
achieved Reduction of respiratory rate with
higher tidal volumes and/or reduction
in inspiratory respiratory EMG activity.
PS increased 12 cm H2O SaO2 < 90% with tidal volume < 5 min Adequate oxygenation.
8 cc/kg (assumes discrete apnea,
hypopnea, RERAs not present)
EMG = electromyogram; EPAP = expiratory positive airway pressure; IBW = ideal body weight; IPAP = inspiratory positive airway pressure; PaCO2 = arterial carbon
dioxide pressure; PS = pressure support; RERA = respiratory effortrelated arousal; SaO2 = arterial oxygen saturation.
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338 Chapter 19 Positive Airway Pressure Treatment
BPAP of 8/4 cm H2O is used. The IPAP and EPAP are both Apnea-hypopnea index Hypopnea index (HI)
increased if obstructive apneas are noted. IPAP is increased (AHI)
for obstructive hypopneas. Otherwise, the IPAP is adjusted Adherence (all nights) 7.5/hr
to deliver adequate PS. The adequacy of PS can be assessed AHI 4.0/hr Apnea index 0.5/hr
by monitoring the delivered tidal volume (goal 68 mL/kg HI 3.5/hr
ideal body weight) and the SaO2. If the sleep center has the
Large leak 10 min
ability to monitor PETCO2 or TcPCO2, these measurements
can help guide the titration (if devices are calibrated and Average tidal volume 400 mL
validated). Monitoring of PETCO2 requires using a nasal Average rate 20
cannula under the mask to avoid dilution of the sampled Patient-triggered breaths 99%
gas. If there is continued arterial oxygen desaturation, PS A. Continue present treatment.
can be increased to reach a slightly higher tidal volume B. BPAP 12/4 cm H2O.
goal. If further increases in ventilation are desired but the
C. BPAP 10/6 cm H2O.
patient does not tolerate high PS, use of a higher backup
rate can be tried. D. Increase backup rate to 18 breaths/min.
As PS is increased, the finding of a higher tidal
volume and lower respiratory rate is compatible with a 3. Which of the following is most likely to be an effective
level of support providing respiratory muscle rest. However, treatment for a patient with the OHS (BMI = 40 kg/m2),
use of surface EMG recordings of respiratory muscle activ- neck circumference (NC) of 19 inches, and daytime PCO2
ity can also be useful. A reduction in respiratory muscle of 60 mm Hg?
EMG activity as PS increases would be evidence that a A. BPAP 19/16 cm H2O.
level of support was providing muscle rest. Supplemental B. BPAP 22/14 cm H2O.
oxygen can be added if desaturation persists despite opti- C. BPAP 16/8 cm H2O.
mization of NPPV. The same considerations for supple- D. BPAP 16/6 cm H2O.
mental oxygen apply as for CPAP/BPAP titrations for sleep
apnea.
4. A patient treated with CPAP of 12 cm H2O complains of
severe bloating. Pressure is reduced to 10 cm H2O but
bloating continues and the patients wife notes mild
Reimbursement for NPPV Devices snoring. What do you recommend?
NPPV devices are called RADs (respiratory-assist devices) A. CPAP 8 cm H2O.
and these are of two types: E0470 (BPAP) and E0471 (BPAP- B. APAP range 416 cm H2O.
ST). RADs have specific criteria for reimbursement depend- C. BPAP 12/8 cm H2O.
ing on the type of patient (see Appendix 193). The different
D. BPAP 10/6 cm H2O.
categories include neuromuscular disease/chest wall disor-
ders, hypoventilation, central apnea/CompSA, and COPD. A
5. A patient with severe COPD requiring supplemental
summary of the major CMS criteria is listed in Appendix
oxygen at 2 L/min during the day is found to have severe
193. The criteria may vary with the local carrier determina-
OSA with an AHI of 40/hr. BPAP of 16/12 cm H2O is the
tion and/or private health providers.
optimal treatment pressure. The patient is started on the
combination of BPAP and oxygen. Which of the follow-
ing is likely true about the required oxygen flow on BPAP
CLINICAL REVIEW QUESTIONS treatment?
1. Which of the following is most predictive of good PAP A. 2.5 L/min should be adequate.
adherence? B. Higher BPAP would require higher supplemental
A. Epworth Sleepiness Scale 16. oxygen flow.
B. Treatment prescription CPAP = 8 cm H2O vs. 16 cm C. The required supplemental oxygen flow would
H2O. increase with high mouth leak.
C. Spouse referral. D. A and B.
D. Entire night for PAP titration. E. B and C.
2. A patient with amyotrophic lateral sclerosis (ALS) who 6. A patient with OSA undergoes an attended PAP titra-
weighs 70 kg is started on empirical BPAP-ST with pres- tion. The CPAP treatment table follows. What pressure
sure of 8/4 cm H2O and a backup rate of 12 breaths/min. do you recommend? (CA = central apnea; H = hypo-
The patient reports improved sleep and his wife notes no pnea; MA = mixed apnea; OA = obstructive apnea;
snoring. On the basis of the following 6-week download TST = total sleep time). Assume all sleep is in the supine
what do you recommend? position.
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Chapter 19 Positive Airway Pressure Treatment 339
REM AHI in the 2 cm H2O range. This may not provide enough
CPAP TST SLEEP AHI REM OA MA CA H pressure reduction but would not be an unreasonable
7 30 0 20 0 10 0 0 0 approach.
8 30 10 10 30 0 0 0 5 5. E. The patient likely requires fairly high BPAP and,
9 30 20 4 6 0 0 0 2 therefore, 2.5 L/min will likely not be adequate given
10 30 10 10 0 0 0 5 0 that 2 L/min provides a daytime SaO2 of only 94%. The
11 30 10 20 0 0 0 10 0 required supplemental oxygen flow increases with
A. 7. increasing levels of PAP due to the higher delivered flow
rate. The supplemental oxygen flow can be adjusted
B. 8.
during a PSG PAP titration. However, checking nocturnal
C. 9. oximetry on treatment is suggested to determine oxygen
D. 10. requirements in the home setting.
E. 11.
6. C. On CPAP of 9 cm H2O, the AHI = 4/hr and supine
Answers REM sleep was recorded. Higher pressure was associated
with central apneas.
1. A. Patients with daytime sleepiness are more likely to
experience a symptomatic benefit and adhere to PAP
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Appendix 19-1
CPAP/BPAP Recommendations*
pressure is needed and the patient experiences difficulty
4.1.1 Treatment with CPAP must be based on a prior diag- exhaling against a fixed pressure or coexisting central
nosis of OSA established using an acceptable method. hypoventilation is present. (Guideline)
(Standard) 4.5.2 BPAP may be useful in treating some forms of
4.1.2 CPAP is indicated for the treatment of moderate to restrictive lung disease or hypoventilation syndromes associ-
severe OSA. (Standard) ated with daytime hypercapnia. (Option)
4.1.3 CPAP is recommended for the treatment of mild
OSA. (Option)
APAP Recommendations
4.1.4 CPAP is indicated for improving self-reported sleep-
iness in patients with OSA. (Standard) 3.1. APAP is not recommended to diagnose OSA.
4.1.5 CPAP is recommended for improving quality of life (Standard)
in patients with OSA. (Option) 3.2. Patients with CHF, significant lung disease such as
4.2.1 Full-night, attended polysomnography performed COPD, patients expected to have nocturnal arterial oxyhe-
in the laboratory is the preferred approach for titration to moglobin desaturation due to conditions other than OSA
determine optimal PAP; however, split-night, diagnostic- (e.g., obesity hypoventilation syndrome), patients who do
titration studies are usually adequate. (Guideline) not snore (either naturally or as a result of palate surgery),
4.3.1 CPAP usage should be objectively monitored to help and patients who have central sleep apnea syndromes are not
ensure utilization. (Standard) currently candidates for APAP titration or treatment.
4.3.2 Close follow-up for PAP usage and problems in (Standard)
patients with OSA by appropriately trained health care pro- 3.3. APAP devices are not currently recommended for
viders is indicated to establish effective utilization patterns split-night titration. (Standard)
and remediate problems, if needed. This is especially impor- 3.4. Certain APAP devices may be used during attended
tant during the first few weeks of PAP use. (Standard) titration with polysomnography to identify a single pressure
4.3.3 The addition of heated humidification is indicated for use with standard CPAP for treatment of moderate to
to improve CPAP utilization. (Standard) severe OSA. (Guideline)
4.3.4 The addition of a systematic educational program is 3.5. Certain APAP devices may be initiated and used in
indicated to improve PAP utilization. (Standard) the self-adjusting mode for unattended treatment of patients
4.4.1 After initial CPAP setup, long-term follow-up for with moderate to severe OSA without significant
CPAP-treated patients with OSA by appropriately trained co-morbidities (CHF, COPD, central sleep apnea syndromes,
health care providers is indicated yearly and as needed to or hypoventilation syndromes). (Option)
troubleshoot PAP mask, machine, or usage problems. 3.6. Certain APAP devices may be used in an unattended
(Option) way to determine a fixed CPAP treatment pressure for
4.4.2 CPAP and BPAP therapy are safe; side effects patients with moderate to severe OSA without significant
and adverse events are mainly minor and reversible. co-morbidities (CHF, COPD, central sleep apnea syndromes,
(Standard) or hypoventilation syndromes). (Option)
4.5.1 While the literature mainly supports CPAP therapy,
BPAP is an optional therapy in some cases in which high
From Morgenthaler TI, Aurora RN, Brown T, et al: Standards of Practice
*From Kushida CA, Littner MR, Hirshkowitz M, et al: Practice Committee of the AASM: Practice parameters for the use of autotitrating
parameters for the use of continuous and bilevel positive airway pressure continuous positive airway pressure devices for titrating pressures and
devices to treat adult patients with sleep related breathing disorders. Sleep treating adult patients with obstructive sleep apnea syndrome: an update
2006;29:375380.
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for 2007. Sleep 2008;31:141147.
343
344 Chapter 19 Positive Airway Pressure Treatment
3.7. Patients being treated with fixed CPAP on the basis 3.8. A re-evaluation and, if necessary, a standard attended
of APAP titration or being treated with APAP must have CPAP titration should be performed if symptoms do not
close clinical follow-up to determine treatment effectiveness resolve or if the APAP treatment otherwise appears to lack
and safety. This is especially important during the first few efficacy. (Standard)
weeks of PAP use. (Standard)
APAP = autotitrating positive airway pressure; BPAP = bilevel positive airway pressure; CHF = congestive heart failure; COPD = chronic obstructive
DaneshGroup.com
airway pressure; CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea; PAP = positive airway pressure.
Appendix 19-2
The details of local carrier determinations can vary by region A Type I sleep test is the continuous and simultane-
and are frequently updated. ous monitoring and recording of various physiological
Excerpts from the Local Carrier Determination (LCD) for and pathophysiological parameters of sleep with physi-
Positive Airway Pressure (PAP) devices for the treatment of cian review, interpretation, and report. It is facility-based
Obstructive Sleep Apnea (L11518) CIGNA-DMAC. and must include sleep staging, which is defined to
include a 14 lead electroencephalogram (EEG), electro-
oculogram (EOG), submental electromyogram (EMG)
Initial Coverage
and electrocardiogram (ECG). It must also include at
A single level continuous positive airway pressure (CPAP) least the following additional parameters of sleep: airflow,
device (E0601) is covered for the treatment of obstructive respiratory effort, and oxygen saturation by oximetry. It
sleep apnea (OSA) if criteria AC are met: may be performed either as a whole night study for diag-
nosis only or as a split night study to diagnose and ini-
A. The patient has a face-to-face clinical evaluation by the tially evaluate treatment.
treating physician prior to the sleep test to assess the An HST is performed unattended in the beneficiarys
patient for OSA. home using a portable monitoring device. A portable moni-
B. The patient has a Medicare-covered sleep test that meets toring device for conducting an HST must meet one of the
either of the following criteria (1 or 2): following criteria:
1. The apnea-hypopnea index (AHI) or Respiratory Dis-
turbance Index (RDI)* is greater than or equal to 15 Type II deviceMonitors and records a minimum of
events per hour with a minimum of 30 events; or seven (7) channels: EEG, EOG, EMG, ECG/heart rate,
2. The AHI or RDI is greater than or equal to 5 and less airflow, respiratory movement/effort and oxygen satu-
than or equal to 14 events per hour with a minimum ration; or
of 10 events and documentation of: Type III deviceMonitors and records a minimum
a. Excessive daytime sleepiness, impaired cognition, of four (4) channels: respiratory movement/effort,
mood disorders, or insomnia; or airflow, ECG/heart rate and oxygen saturation; or
b. Hypertension, ischemic heart disease, or history of Type IV deviceMonitors and records a minimum of
stroke. three (3) channels, one of which is airflow that allows
C. The patient and/or their caregiver have received instruc- direct calculation of an AHI or RDI; or
tion from the supplier of the CPAP device and accesso- OtherDevices that monitor and record a minimum of
ries in the proper use and care of the equipment. three (3) channels that include actigraphy, oximetry,
and peripheral arterial tone that allow calculation of
If a claim for a CPAP (E0601) is submitted and all of the an AHI or RDI.
criteria above have not been met, it will be denied as not
medically necessary. Continued Coverage beyond the First 3 Months
Sleep Tests of Therapy
Coverage of a PAP device for the treatment of OSA is limited Continued coverage of a PAP device (E0470 or E0601)
to claims where the diagnosis of OSA is based upon a beyond the first three months of therapy requires that no
Medicare-covered sleep test (Type I, II, III, IV, Other). A sooner than the 31st day but no later than the 91st day after
Medicare-covered sleep test must be either a polysomno- initiating therapy, the treating physician must
gram performed in a facility-based laboratory (Type I study)
or a home sleep test (HST) (Types II, III, IV, or Other). The 1. Face-to-face a clinical re-evaluation by the treating
test must be ordered by the beneficiarys treating physician physician with documentation that the symptoms of
and conducted by an entity that qualifies as a Medicare pro- OSA have improved; and
vider of sleep tests and is in compliance with all applicable 2. Objective evidence of adherence to use of the PAP
state regulatory requirements. device, reviewed by the treating physician
If the above criteria are not met, continued coverage of a 1. Face-to-face clinical re-evaluation by the treating phy-
PAP device and related accessories will be denied as not sician to determine the etiology of the failure to
medically necessary. respond to PAP therapy; and
Beneficiaries who fail the initial 12-week trial are eligible 2. Repeat sleep test in a facility-based setting (Type 1
to re-qualify for a PAP device but must have both: study).
Available at http://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?ContrNum=18003&ContrTypeId=10&LCDId=11518&ver=55&Date
=01%2f01%2f2011&DocID=L11518&bc=iAAAABAAQAAA&
DaneshGroup.com
Appendix 19-3
Device terminology: E0470 = BPAP no backup rate; E0471 medical record should document relevant symptoms and
= BPAP with backup rate usage of the device up to that time. Failure of the patient to
be consistently using the device for an average of 4 hours per
24-hour period by the time of re-evaluation would represent
Requirements for Initial Coverage for 3 Months
noncompliant utilization for the intended purpose and
A. Restrictive thoracic and neuromuscular disorders (Table expectations of benefit. This would constitute reason for
1915) Medicare to deny continued coverage as not medically nec-
B. Hypoventilation syndrome (Table 1916) essary. A signed and dated statement by the treating physi-
C. Central apnea/CompSA (Table 1917) cian no sooner than 61 days after initiating device use,
D. Severe COPD (Table 1918) declaring that the patient is compliantly using the device (an
average of 4 hours per 24-hour period) and that the patient
is benefiting from its use, must be obtained by the supplier
Coverage beyond 3 Months
of the device before continued coverage beyond 3 months.
Coverage beyond 3 months requires a physician evaluation
no sooner than the 61st day after starting the RAD. The
TABLE 1915
Medicare Guidelines for Reimbursement for Respiratory Assist Device Restrictive Thoracic and
Neuromuscular Disorders
Criterion A: There is documentation in the patients medical record of a neuromuscular disease (ALS) or severe thoracic cage
abnormality
AND
Criterion B1: PaCO2 45 mmHg while awake and breathing patients prescribed FIO2.
AND Criterion B2 OR B3
Criterion B2: Sleep oximetry shows SaO2 88% for at least 5 min of nocturnal recording time while breathing prescribed FIO2
(2 hr minimum recording time).
OR
Criterion B3 (NMD only): Maximal inspiratory pressure < 60 cm H2O or FVC < 50% predicted.
AND
Criterion C: COPD does not contribute significantly to the patients pulmonary limitation.
Either E0470 or E0471 (backup rate) will be covered for first 3 mo of treatment.
ALS = amyotrophic lateral sclerosis; COPD = chronic obstructive pulmonary disease; FIO2 = fractional concentration of oxygen in inspired gas; FVC = forced vital
capacity; NMD = neuromuscular disease; PaCO2 = arterial partial pressure of carbon dioxide; SaO2 = arterial oxygen saturation.
BPAP = bilevel positive airway pressure; COPD = chronic obstructive pulmonary disease; CompSA = complex sleep apnea; RAD = respiratory-assist
device.
Available at http://www.cms.gov/mcd/viewlcd.asp?lcd_id=5023&lcd_version=56&show=all
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347
348 Chapter 19 Positive Airway Pressure Treatment
TABLE 1916
Medicare Guidelines for Reimbursement for Respiratory Assist Device Hypoventilation Syndrome
HYPOVENTILATION SYNDROME (E0470 DEVICE, BPAP WITHOUT A BACKUP RATE)
An E0470 will be covered for first 3 mo of treatment if Criteria A and B and either C or D is met.
Criterion A: Arterial blood gas PaCO2 45 mm Hg while awake and breathing patients prescribed FIO2.
AND
Criterion B: Spirometry shows an FEV1/FVC 70% and FEV1 50% of predicted.
AND either Criterion C or D
Criterion C: An arterial blood gas PaCO2, done during sleep or immediately on awakening, and breathing the patients
prescribed FIO2, show the beneficiarys PaCO2 worsened 7 mm Hg compared with original result in Criterion A.
Criterion D: A facility-based PSG demonstrates oxygen saturation < 88% for 5 min of nocturnal recording time (minimal
recording time of 2 hr) that is not caused by obstructive upper airway events.
HYPOVENTILATION SYNDROME (E0471 DEVICE, BPAP WITH A BACKUP RATE)
An E0471 will be covered for first 3 mo of treatment if criterion A and B and either C or D is met.
Criterion A: A covered E0470 device is being used
AND
Criterion B: Spirometry shows an FEV1/FVC 70% and FEV1 50% of predicted.
AND either Criterion C or D
Criterion C: An arterial blood gas PaCO2, done while awake, and breathing the patients prescribed FIO2, show the beneficiarys
PaCO2 worsened 7 mm Hg compared with the arterial blood gas result used to qualify the patient for the E0470 device.
Criterion D: A facility-based PSG demonstrates SaO2 < 88% for 5 min of nocturnal recording time (minimal recording time of
2 hr) that is not caused by obstructive upper airway events (AHI < 5/hr) while using an E0470 device.
AHI = apnea-hypopnea index; BPAP = bilevel positive airway pressure; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; PaCO2 = arterial
partial pressure of carbon dioxide; PSG = polysomnography; SaO2 = arterial oxygen saturation.
TABLE 1917
Medicare Guidelines for Reimbursement for Respiratory-Assist Device Central Apnea and Complex Sleep
Apnea (E0470 or E0471)
Before initiating therapy, a complete facility-based attended PSG must be performed documenting the following criteria:
Criterion A: Diagnosis of central sleep apnea or complex sleep apnea.
AND
Criterion B: Significant improvement of the sleep-associated hypoventilation with the use of E0470 or E0471 device on settings
that will be prescribed for initial use at home, while breathing the patients usual prescribed FIO2.
Central sleep apnea is defined as
1. AHI > 5/hr.
2. Central apnea/hypopnea > 50% of the total apneas and hypopneas.
3. Central apneas or hypopneas 5/hr.
4. Symptoms of excessive sleepiness or disturbed sleep.
Complex sleep apnea is a form of central apnea specifically identified by the persistence or emergence of central apneas or
hypopneas upon exposure to CPAP or an E0470 when obstructive events have disappeared. These patients have
predominantly obstructive or mixed apneas during the diagnostic sleep study occurring at 5/hr. With use of a CPAP or
E0470, they show a pattern of apneas and hypopneas that meet the definition of central sleep apnea described previously.
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; FIO2 = fractional concentration of oxygen in inspired gas; PSG = polysomnography.
TABLE 1918
Medicare Guidelines for Reimbursement for Respiratory-Assist Device Severe Chronic Obstructive
Pulmonary Disease (E0470*)
Criterion A: An arterial blood gas PaCO2 52 mm Hg, done while awake and breathing the patients prescribed FIO2.
AND
Criterion B: Sleep oximetry demonstrates oxygen saturations < 88% for at least 5 min nocturnal recording time, done while
breathing oxygen at 2 L/min or the patients prescribed FIO2 (whichever is higher), 2-hr minimum recording time.
AND
Criterion C: Before initiating therapy, OSA (and treatment with CPAP) has been considered and ruled out.
If all above criteria are met, an E0470 with be covered for the first 3 mo of therapy.
*E0470 = BPAP with no backup rate.
CPAP = continuous positive airway pressure; FIO2 = fractional concentration of oxygen in inspired gas; OSA = obstructive sleep apnea; PaCO2 = arterial partial pressure
of carbon dioxide. DaneshGroup.com
Chapter 20
Herbst appliance
Before
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Herbst appliance
Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 351
FIGURE 204 Versions of the Thornton anterior positioner (TAP) oral appliance, which consists of two separate arches connected
by an advancing mechanism. Left two panels, The adjustment apparatus extends outward from the maxillary arch. This is turned
to change the amount of protrusion of the mandible by moving the hook which pulls the bar forward. Right, TAP-3 appliance; key
is used to advance the mandibular arch.
the temporomandibular joint (TMJ), evidence or history of jaw positioned anteriorly during sleep. Moderate to severe
bruxism, quality of dental occlusion, the presence of signifi- bruxism is also a contraindication in most cases. Bruxism
cant periodontal disease, overall dental health, and protru- during sleep can actually damage some types of OAs.
sive ability. Cephalometrics or dental radiographs may be However, bruxism in some patients improves with adequate
indicated.10 The patients occlusion type should be noted. treatment of OSA. An experienced dental practitioner should
Three classes (types) of skeletal occlusions are illustrated in evaluate patients with bruxism for suitability for an OA. A
Figure 205. One might expect that patients with mandibu- history of bruxism may also alter the choice of the type of
lar deficiency (retrognathia) would benefit the most from an OA used. Of note, edentulous patients can be treated with a
OA but the amount of improvement is somewhat unpredict- TRD/TSD.
able. The location of airway occlusion during sleep might
also be expected to predict the response to OA treatment.
Mechanism of Action of OAs
Patients with occlusion mainly in the retroglossal area rather
than the retropalatal area might be expected to improve the OAs are believed to work by increasing upper airway size.
most with a MRA. However, in one study, some patients with TRDs/TSDs move the tongue forward. MRAs move the
upper airway occlusion mainly in the velopharynx also tongue and mandible forward, increasing the posterior air-
improved with MRA treatment.11 space. By stabilizing the mandibular position, MRAs resist
the downward rotation of the mandible with sleep and the
accompanying retrusion of the mandible. They may also
Exclusions and Contraindications
tense palatal muscles. Some studies have found an increase
Patients must have a minimal amount of healthy teeth for an in upper airway muscle tone with an MRA in place.12 As
MRA. A minimum of 6 to 10 teeth in each arch is needed.1,5 noted previously, patients with airway closure mainly in the
However, treatment with dental implants can permit future velopharynx may also respond to OA treatment. In agree-
MRA treatment in patients with insufficient dentition at the ment with this finding, a study of the effect of an MRA on
time of evaluation. Patients must be able to open the jaw upper airway size during wakefulness using fiberoptic endos-
adequately for OA insertion and must have the ability to copy found the most significant increase in airway size was
voluntarily protrude the mandible. Moderate to severe TMJ at the velopharynx.13 Another study of videofluoroscopy
disease or inadequate protrusive ability are contraindica- during sleep found increases in both the retroglossal and the
tions. Mild TMJ dysfunction may actually improve with the retropalatal airway size during sleep with an MRA in place.14
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352 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
120 20
Time below 90% oxygen saturation (%)
110
Apnea hypopnea index (events/hour)
100
90 15
80
70
60 10
50
40
30 5
20
10
0 0
TABLE 202 expensive. OAs are now viewed by the U.S. Food and Drug
Attributes of an Ideal Oral Appliance Administration (FDA) as class 2 medical devices and, as
such, must adhere to more detailed standards with special
ATTRIBUTE COMMENT
controls.19 A short list of commonly used devices is pre-
Adjustable Allows for modification if dental work is sented in Table 203. A more extensive list is available in
needed. Reference 5. A list of FDA-approved devices can be found at
Titratable Ability to modify vertical opening or http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/
advancement of mandible. pmn.cfm
Full tooth Makes certain upper and lower teeth are
coverage fully engaged to prevent tooth Titration/Adjustment of OAs
movement.
After OAs are fabricated, they are usually adjusted by the
Posterior The upper and lower components dentist taking care of the patient for fit and comfort. Patients
support should have contact in the posterior
are then instructed to slowly increase mandibular protrusion
area for stabilization of TMJ.
until symptoms improve (cessation of snoring and improve-
Mandibular Allows free movement of mandible ment in sleep quality) or until either the maximum protru-
mobility during sleepbeneficial in patients sion is reached or further advances are not tolerated. In one
with bruxism. study, patients were studied during polysomnography (PSG)
Adequate lip Improves nasal breathing, prevents and a remotely controlled mandibular appliance was
seal drying of teeth. advanced until respiratory events were controlled or until
Adequate Prevents collapse of tongue into further advances were not tolerated.20 The results of the PSG
tongue space oropharyngeal airway. OA titration were highly predictive of the effectiveness of
TMJ = temporomandibular joint.
chronic OA treatment with a permanent device. In another
Adapted from Bailey DR, Hoekema A: Oral appliance therapy in sleep study, patients were allowed to adjust their devices at home.21
medicine. Sleep Med Clin 2010;5:9198. During a PSG if persistent events were noted, further adjust-
ment during the PSG was performed by protocol (increased
protrusion in 1-mm increments). Of the patients completing
come out during the night. However, the TSD (see Fig. 201) the protocol, 55% were successfully treated (AHI < 10/hr)
may be an affordable alternative for some patients. Purchase after home titration. A total of 64.9% of patients were suc-
of a TSD requires a prescription from a doctor or dentist cessfully treated overall. Thus, some patients will likely
(approximate price range is $125$180). need further adjustments either during or after a PSG
Some ideal attributes for an MRA are listed in Table 202. documenting the efficacy of OA treatment.
The ideal device has coverage of both arches and is adjustable
(protrusion can be changed). A recent study compared a
Adherence to OA Treatment
custom-made and thermoplastic OA for the treatment of
mild OSA. The custom-made device was more effective.18 Studies of adherence to OA treatment have almost always
However, custom-made devices are typically much more relied on patient report. There is a single report of the use
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354 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
TABLE 203
Selected Oral Appliances
DEVICE TELEPHONE NUMBER WEBSITE
Tongue retaining device 800-828-7626
Tongue stabilizing device 800-854-7256 (United States) http://www.glidewelldental.com
Glidewell Dental is the authorized U.S. dealer.
TAP 866-AMI-SNOR http://www.TAPINTOSLEEP.COM
SUAD Herbst 888-447-6673
Klearway 800-828-7626 http://www.klearway.com
OASYS 888-866-2727 http://www.oasyssleep.com
FDA = U.S. Food and Drug Administration; OASYS = oral/nasal airway system; TAP = Thornton anterior positioner.
After Bailey DR, Hoekema A: Oral appliance therapy in sleep medicine. Sleep Med Clin 2010;5:9198.
See complete list on FDA website: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm
TABLE 204
Comparison of Oral Appliance and Continuous Positive Airway Pressure
TOTAL
NO. AHI ESS RX SUCCESS
CRITERION
AUTHOR N BASELINE CPAP MRA BASELINE CPAP MRA CPAP MRA (AHI#/hr)
Barnes, 104 21.3 12.8 4.8 4.7 14.0 10.1 10.2 4.7 9.2 3.8 9.2 3.7 Not stated 49% <10
200427
Clark, 23 33.9 14.3 11.2 3.9 19.9 12.8 52% 19% <10
199628
Engleman, 51 31 26 86 15 16 14 4 85 12 5 66% 47% <10
200229
Ferguson, 24 26.8 11.9 4.2 2.2 13.6 14.5 10.7 3.4 5.1 3.3 4.7 2.6 70% 55% <10 + SI
199725
Ferguson, 25 24.5 8.8 3.6 1.7 9.7 7.3 62% 48% <10 + SI
199626
Randerath, 20 17.5 7.7 3.2 2.9 13.8 11.1 100% 30% <10
200230
Tan, 24 22.2 9.6 31. 2.8 8.0 10.9 13.4 4.6 8.1 4.1 9.2 1 Not stated 67% <10
200231
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; ESS = Epworth Sleepiness Scale; MRA = mandibular repositioning appliance;
SI = symptoms improved.
From Ferguson KA, Cartwright R, Rogers R, et al: Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 2006;29:244262.
of a temperature-sensitive embedded monitor to objectively were discomfort (44%), little or no effect (34%), and the
determine OA use.13 OA adherence rates tend to decrease patient changing to CPAP treatment (23%).24 In two cross-
with the duration of use. One study reported 60% adherence over studies of CPAP, adherence to OA was equal to or better
at 1 year and 48% at 2 years.22 Another study reported adher- than to CPAP.25,26
ence dropped from 82% to 62% over 4 years.23 The reasons
for discontinuing OA included side effects, complications,
Effectiveness Compared with Other Treatments
and lack of efficacy. In a questionnaire study of OA patients
5 years after starting treatment, 64% of respondents were A number of studies have compared OSA and CPAP (Table
using the OA. Of these, 93% were using the OA more than 204).2531 They show that OAs are not as effective as CPAP
4 nights/wk. Of those stopping OA treatment, the causes but are effective in a significant proportion of patients
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Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 355
60 70
50 60
Apnea/hypopnea index
Apnea/hypopnea index
50
40
40
30
30
20
20
10 10
0 0
Pre-nCPAP nCPAP Pre-AMP AMP
FIGURE 208 The AHI as determined by home monitoring before and after treatment with nasal continuous positive airway pressure (nCPAP;
left) and an anterior mandibular positioner (AMP; right). The AHI was significantly reduced (P < .05) by both devices, although the
posttreatment AHI was lower with nCPAP. From Ferguson KA, Ono T, Lowe AA, et al: A short-term controlled trial of an adjustable oral appliance
for the treatment of mild to moderate obstructive sleep apnoea. Thorax 1997;52:362368.
(1967%) (Fig. 208).1 In some studies listed in Table 204, BOX 201
a significant proportion of patients preferred the OA to OA Treatment Guidelines
CPAP. In some studies, improvement in daytime sleepiness
was similar with both OA and CPAP treatment even if the 1. Initial diagnosis: Presence or absence of OSA must be
determined before OA treatment.
AHI was higher with OA than with CPAP. In the study by
2. Appliance fitting: OA treatment should be managed by
Barnes and colleagues27 using a cross-over design, 28% pre-
dental practitioners with training in sleep medicine and
ferred CPAP, 41% preferred the OA, and 31% preferred
sleep-related breathing disorders.
placebo (a tablet). In a study by Ferguson and associates,25
3. Cephalometrics are not always needed, but if used,
the compliance to an OA and CPAP were similar but patient qualified professionals should perform and evaluate.
satisfaction was better with an OA. 4. Primary snoringGoal of OA is to reduce snoring to a
subjectively acceptable level.
OA Treatment Guidelines 5. OSAGoals of treatment are resolution of clinical signs
and symptoms of OSA, and normalization of the AHI and
The AASM practice parameters for the OA treatment of arterial oxygen saturation.
patients with snoring and OSA2 are listed in Appendix 201. 6. OAs are indicated for treatment of primary snoring in
The guidelines are summarized in Boxes 201 and 202. The patients who do not respond to or are not appropriate
presence or absence of OSA must be determined before OA candidates for weight loss or sleep position change.
treatment. It is important to determine whether OSA or 7. OA treatment is indicated for mild to moderate OSA
snoring is being treated. If OSA is present, the severity has a. OA is not as efficacious as CPAP but is preferred by
implications for treatment selection and the probability of some patients.
success with OA. The OA should be fitted by a qualified b. OA is indicated with CPAP failures.
dental professional. The treatment goals for snoring are to c. OA treatment is indicated when there is failure of
reduce noise to an acceptable level. For OSA, treatment goals weight loss or side sleep position treatments for
are to reduce the AHI, improve oxygenation, and improve mild OSA.
sleep quality. OAs are indicated for primary snoring that 8. OAs are not indicated for initial treatment of severe
OSA. Upper airway surgery may also supersede use of
does not respond to simple measures such as weight loss,
OA in patients for whom surgery is predicted to be
lateral position, and treatment of nasal congestion. OAs are
highly effective.
also indicated for mild to moderate OSA. It is acknowledged
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure;
that CPAP may be more effective. CPAP rather than OA OA = oral appliance; OSA = obstructive sleep apnea.
should be the first treatment for severe OSA. If CPAP is not
accepted, upper airway surgery or an OA should be consid-
ered. Upper airway surgery may also supersede use of OA in Adjustment of OA is usually preformed over days to
patients for whom surgery is predicted to be highly effective. weeks with progressive protrusion until obvious apnea and
In patients with severe OSA who decline CPAP or surgery, snoring have ceased or the limit of the device or patient
a trial of OA may be reasonable. Another indication for OA tolerance is reached. A study can then be performed to assess
would be patients who had failed surgery and do not want efficacy. As noted in a later section, documentation of effi-
CPAP or further surgery. cacy with some type of sleep study is indicated for any level
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356 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
result in discontinuation of appliance use. More severe OSA in adults and practice parameters have been published
and continuous side effects included TMJ pain, myofas- by the AASM (Appendix 203).40,41
cial pain, tongue pain (tongue devices only), gagging (soft
palate lifter mostly), tooth pain, gum pain, dry mouth,
Evaluation for Possible Surgical Treatment
and salivation.1 Occasionally, these phenomena prevent
continued use of the appliance. Several studies have found The typical evaluation of patients with snoring or OSA for
long-term changes in dental occlusion but the results vary possible upper airway surgery includes fiberoptic examina-
between studies. The changes are relatively mild in most tion of the nose, pharynx, and hypopharynx.42 Fiberoptic
patients. One study found occlusal changes after a mean pharyngoscopy while the patient performs a Mller maneu-
treatment duration of about 30 months.33 The anteropos- ver (inspiration with the nose occluded) is performed to help
terior position of the molars and the inclination of upper identify the most prominent site of collapse (retropalatal or
and lower incisors changed with MRA treatment. No retroglossal/hypopharyngeal area). A limitation of this tech-
skeletal changes in mandibular position were noted. nique, which is typically performed during wakefulness and
often in an upright posture, is that the results may not cor-
respond to what happens during supine sleep. Lateral cepha-
Combinations of OA with Other Treatments
lometric radiographs are also standard and can help visualize
Use of OSA in patients with persistent sleep apnea after bony abnormalities and the posterior airspace. On cephalo-
uvulopalatopharyngoplasty (UPPP) was reported by Millman metrics, OSA patients tend to have long soft palates, small
and coworkers34 in 18 patients. The post UPPP AHI was posterior air spaces (<10 mm behind the tongue), mandibu-
37.2/hr and the arterial oxygen saturation (SaO2) nadir was lar deficiency, and a long distance to the hyoid. The AASM
84%. With OA treatment, the AHI fell to 15.3/hr and the practice parameters for surgical treatment of OSA
SaO2 nadir was 87.9%. With the addition of a Herbst device, mandate that all patients scheduled for surgery to correct
10 of the patients had a fall in the AHI to less than 10/hr. snoring or OSA should undergo PSG for diagnosis and to
assess severity.39,41
Effects of OA Treatment on Consequences of OSA
Indications for Surgical Treatment
There have been few studies of the effects of OA treatment
of OSA on the cardiovascular consequences of OSA. Gotso- The AASM practice parameters for surgical treatment of
poulos and colleagues35 found that OAs reduced blood pres- OSA have recently been updated40,41 (see Appendix 203).
sure in a randomized, controlled trial. Another study found The practice parameters state that the presence and severity
an improvement (normalization) of heart rate variability of OSA must be determined before initiating surgical therapy.
after 3 months of OA treatment.36 More studies of the impact The patient should be advised about the success of surgical
of OAs are expected in the future. procedures and side effects as well as the success rate of
alternative treatments. The practice parameters state that
PAP should first be offered to patients with severe OSA and
SURGICAL TREATMENTS FOR OSA either PAP or an OA for patients with moderate OSA.41 For
Tracheostomy was the first treatment available for OSA.37 those requiring the stepped procedure approach, patients
Since that time, a number of surgical options have become should be informed that multiple surgical procedures may
available (Box 204).3841 These are more acceptable than be needed.39
tracheostomy but none is more effective. Recently, a system-
atic review of surgical treatment options for treatment of
Surgical Options
BOX 204 A number of surgical options are available (see Box 204).3848
Each is briefly discussed and then an overall approach is
Surgical Options presented.
BYPASSES ALL OBSTRUCTION
Tracheostomy
Tracheostomy
This procedure bypasses all obstructions and is uniformly
SELECTIVELY IMPROVES UPPER AIRWAY OBSTRUCTION effective at preventing upper airway obstruction.3741 Some
Nasal reconstruction patients will still require supplemental oxygen, and some
UPPP and LAUP patients with the obesity hypoventilation syndrome may con-
Genioglossus advancement tinue to hypoventilate during sleep or require oxygen for
Hyoid advancement persistent nocturnal desaturation. The main use of tracheos-
MMA tomy is for patients who have life-threatening OSA (often the
Temperature-controlled RF tongue base reduction obesity hypoventilation syndrome with recurrent hypercap-
LAUP = laser-assisted uvuloplasty; MMA = maxillomandibular nic respiratory failure) and are poorly adherent to PAP treat-
advancement; RF = radiofrequency; UPPP = uvulopalatopharyngoplasty.
ment. Another use is as a temporary measure while patients
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358 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
recover from other upper airway surgery. Tracheostomy is resection of the inferior turbinates.50 A review of the role of
cosmetically unacceptable to most patients. The indications the nose in the pathogenesis of OSA and snoring found no
used in one large series included (1) disabling sleepiness with published evidence to support the use of nasal surgery (cor-
severe consequences, (2) cardiac arrhythmias with sleep rection of septal deviation or external valve collapse) as a
apnea, (3) cor pulmonale, (4) AHI > 40/hr, (5) frequent treatment of OSA.51 Thus, whereas nasal surgery can improve
desaturations below 40%, and (6) no improvement after other the quality of life for some patients, it is considered as an
therapy.37 Recent AASM practice parameters state that tra- adjunctive rather than a primary treatment for OSA.
cheostomy has been found to be an effective single interven-
tion.41 However, this operation should be considered only Palatal Implants
when other options do not exist, have failed, are refused, or The Pillar procedure involves insertion of Teflon strips into
when this operation is deemed necessary by clinical urgency. the palate and can be done in the office or outpatient surgery
Tracheostomy has significant complications in patients with center. The purpose of the strips is to stiffen the palate
OSA.37,43 For example, anesthesia and intubation tend to be (reduced snoring). The success is variable and sometimes
more difficult in patients with large necks and narrow upper additional strip insertion is needed.40,5456 A randomized,
airways. Postoperative complications include stoma infection/ placebo-controlled study (sham implant procedure as
granulation tissue, accidental decannulation, obstruction of control) of palatal implants (PIs) in mild OSA found that the
the tube when the head is turned or hyperextended, recurrent AHI in both placebo and PI groups actually increased!53
purulent bronchitis, and psychosocial difficulties (depres- Although the increase in the AHI was significantly less with
sion).3739,43 Noncuffed, size 6 French tubes usually suffice. A PI compared with control, this can hardly be seen as docu-
longer-than-usual tracheostomy tube may be needed for very mentation of PI effectiveness. Snoring was slightly but sig-
obese patients with thick necks. The end of the tracheostomy nificantly improved more with PI than with control. Although
tube typically is plugged during the day and, because of its the evidence that palatal implant surgery is effective in
small size, air flows around it between the lungs and the patients with OSA is very marginal, recent practice param-
upper airway. If resistance to flow around the tube is a eters stated Palatal implants may be effective in some
problem, a fenestrated tube (hole at bend of the superior end patients with mild OSA who cannot tolerate or are unwilling
of the tube) may be used. During sleep, the tracheostomy to adhere to PAP therapy, or in whom oral appliances have
tube is unplugged to bypass the upper airway obstruction. been considered and found ineffective or undesirable
However, one must not forget that very obese patients can (Option).41 Thus, PIs may be effective in some patients with
still occlude the tracheostomy opening with triple chins. mild OSA but results are variable at best.
A B C
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Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 359
2001.54 Recent practice parameters for surgical treatment of can occur during the recovery period in patients with
OSA state LAUP is not routinely recommended as a treat- severe OSA. These problems often can be managed with
ment for obstructive sleep apnea syndrome (Standard).41 nasal CPAP.
However, the major problem with UPPP is less-than-
Radiofrequency Ablation perfect efficacy as a treatment for OSA.40,41,61 UPPP does not
Radiofrequency has been used in the upper airway with and address airway narrowing behind the tongue or in the hypo-
without temperature control of the probe tip. RFA has been pharynx; therefore, it is not universally effective in prevent-
used for treatment of the soft palate, base of the tongue, and ing sleep apnea. UPPP is generally reasonably effective in
treatment of multiple levels.40,46,47,56 Somnoplasty (a variant decreasing the incidence or loudness of snoring (vibration
of RFA) is a method of palatoplasty for treatment of snoring, of the soft palate). In general, 40% to 50% of all patients
appears to be well tolerated (possibly less pain), but is no undergoing UPPP have about a 50% decrease in their AHI,
more effective than traditional UPPP.40,56 It can be performed to less than 20/hr, or about a 30% chance of a postoperative
as an outpatient procedure. Repeated treatments may be AHI dropping below 10/hr.38,40,60,61 The results will, of course,
needed. Several other procedures that utilize cautery or depend on the presurgery AHI and the locations of upper
injection of sclerotic agents to stiffen the palate have also airway obstruction. Frequently, the number of apneas
been used.46 The recent practice parameters for surgical decreases and the number of hypopneas increases after
treatment of OSA state RFA can be considered as a treat- UPPP. Of interest, one study of UPPP failures found the site
ment in patients with mild to moderate OSA who cannot of upper airway obstruction to still occur at the retropalatal
tolerate or who are unwilling to adhere to PAP, or in whom area.62 Sasse and associates63 reported on a group of patients
oral appliances have been considered and have been found in whom the AHI was actually higher after UPPP. Another
ineffective or undesirable (Option). RFA of the palate is not study reported that a significant number of initial responders
more effective than traditional UPPP.
BOX 205
Uvulopalatopharyngoplasty
UPPP is an operation that removes residual tonsillar tissue, Complications from Uvulopalatopharyngoplasty
the uvula, a portion of the soft palate, and redundant tissue IMMEDIATE
from the pharyngeal area (Fig. 2010).4648,57 Its disadvantages
Paincan be severe
include the need for general anesthesia and considerable Velopharyngeal incompetence (fluid out the nose during
postoperative pain. The most frequent complication (Box swallowing)
205) is velopharyngeal insufficiency, which is manifested as Voice change
some degree of nasal reflux when drinking fluids.5860 This Globus sensationmucus in the back of the throat
usually resolves within a month of surgery. Other potential Worsening of apnea in the postoperative period
complications include voice change, postoperative bleeding, DELAYED
nasopharyngeal stenosis (secondary to scarring), or a persis-
tent globus sensation. A few cases of severe postsurgical Return of snoring
Worsening of OSA
bleeding or upper airway obstruction requiring reintubation
Nasopharyngeal stenosis
have been reported. It is prudent to admit patients to the
Increased probability of mouth leak during CPAP treatment
intensive care unit after surgery for close observation if sig-
CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea.
nificant OSA is present. Significant apnea and desaturation
A B C
FIGURE 2010 Technique of uvulopalatopharyngoplasty. A, Redundant soft palate and tonsillar pillar mucosa
are outlined. B, Tonsils, tonsil pillar mucosa, and posterior soft palate are excised. The extent of the soft palate
excision is determined by placing traction on the uvula and noting the position of the mucosal crease. C, Mucosal
flaps of the lateral pharyngeal wall and nasal palatal muscle are advanced to the anterior pillar and/or mucosa of
the soft palate. The wound is closed with 3-0 polyglactin braided suture. AC, From Li KK, Powell NB, Riley RW:
Surgical management of OSA. In Lee-Chiong TL, Sateia MJ, Carskadon MA (eds): Sleep Medicine. Philadelphia: Hanley
& Belfus, 2002, p. 439, reproduced with permission.
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360 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
to UPPP may later relapse, especially if there is weight gain.64 long-term evaluation of relative UPPP efficacy compared
Thus, patients treated with UPPP should be restudied if with CPAP.
symptoms or signs of sleep apnea return.
Recent practice parameters for surgical treatment of OSA Uvulopalatal Flap
state UPPP as a sole procedure, with or without tonsillec- This surgery is a modification of the UPPP and, instead of
tomy, does not reliably normalize the AHI when treating removing the uvula and soft palate, the uvula is retracted and
moderate to severe OSA. Therefore, patients with severe tucked superiorly under the soft palate. The pharyngeal
OSA should initially be offered positive airway pressure pillars are sutured back and tonsils are removed in this pro-
therapy, while those with moderate OSA should initially be cedure as well. The advantages are less postoperative pain
offered either PAP therapy or oral appliances (Option).41 and perhaps less nasopharyngeal reflux. The results are
Several methods have been studied to determine whether similar to UPPP. The procedure cannot be done if the palate
UPPP responders can be identified preoperatively. These is very long or bulky.45,47
methods include cephalometric radiographs, computed axial
tomography, fluoroscopy, fiberoptic endoscopy of the upper Genioglossus Advancement/Hyoid Advancement
airway during Mller maneuvers (precipitating airway col- In the genioglossus advancement (GA) (Fig. 2011), the
lapse), and upper airway pressure monitoring during attachment of the genioglossus at the genoid tubercle of the
sleep.42,62,64 In some of these methods, the patient is upright, mandible is advanced by making a limited rectangular man-
and in most, the patient is awake. Therefore, it is not surpris- dibular osteotomy to include the genial tubercle (site of
ing that predictions of what happens during sleep are less attachment of genioglossus and geniohyoid on the mandi-
than perfect. In general, patients with obstruction only in the ble).38,40,44,45,48 The rectangular piece of bone with muscular
retropalatal area are the most likely to respond to UPPP. attachments is advanced and rotated to prevent retraction of
However, no method can predict with certainty which the piece of bone back into the mandible. A screw is then
patients will benefit from this surgery. As previously noted, placed for stabilization.
a few studies have determined that the site of upper airway When initially introduced, the second component of the
obstruction in UPPP failures is the retropalatal area. Pre- surgery, hyoid advancement (HA) (Fig. 2012) was called
sumably, postsurgical changes secondary to either palatal hyoid myotomy with suspension. The original surgery con-
edema or scarring are to blame.62 sisted of release of the hyoid from its inferior muscular
UPPP is considered less effective than nasal CPAP because attachments and suspension from the anterior mandible
it is less likely to eliminate apnea and normalize sleep. with suture or ligament. Today, the hyoid is often attached
However, when nasal CPAP is refused or not tolerated, UPPP to the superior border of the thyroid cartilage. This modifica-
can be a treatment alternativeespecially in mild to moder- tion has increased the response rate to approximately 80%.
ate apnea. With disease of this severity, there usually is a Some surgeons perform only the GA at the first surgery with
reasonable chance of obtaining a postoperative AHI less than the HA performed only if needed at a subsequent operation.
15/hr. If UPPP fails, there is always the option of trying nasal The GAHA does not require any change in dental occlusion.
CPAP. However, one study suggested that when nasal CPAP Complications of GAHA include transient anesthesia of
is used after UPPP, air leak via the mouth may be more the lower anterior teeth (all) and, rarely, tooth injury. Indica-
likely.65 Of interest, a retrospective study of a Veterans tions for GAHA include a small posterior airspace by
Administration (VA) population found better survival in lateral cephalometrics (<10 mm), an increased mandible-to-
patients after UPPP than treatment with CPAP.66 The study thyroid distance (>20 mm) by cephalometrics, mandibular
was not adjusted for OSA severity or for the amount of CPAP deficiency, tongue base prominence on nasopharyngoscopy,
use. However, it does point out the need for prospective or macroglossia.44
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Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 361
The recent AASM practice parameters for surgical treat- BOX 206
ment of OSA did not provide a specific statement about the Indications for Maxillomandibular Advancement
GA or HA procedures. The practice parameters state mul-
tilevel or stepwise surgery (MLS), as a combined procedure FIRST SURGICAL OPTION
or stepwise operations, is acceptable in patients with narrow- Severe OSA (especially with minimally redundant palate)
ing of multiple sites in the upper airway, particularly if they Retrognathia or facial skeletal deficiency
have failed UPPP as a sole treatment (Option).41 Morbid obesity
Adequate health to undergo surgery
Maxillomandibular Advancement SECOND SURGERY
Maxillomandibular advancement (MMA) is a complex
Failed previous surgical procedures
upper airway surgery, but excluding tracheostomy, this pro-
OSA = obstructive sleep apnea.
cedure has the best record of success as a treatment for OSA
(Fig. 2013). The maxilla and mandible are advanced
together and both upper and lower teeth are moved to main-
tain adequate occlusion.44,45,48,67 The procedure increases the institutions, MMA is performed only after UPPP and GAHA.
retrolingual and, to a small extent, the retropalatal segments For patients with severe OSA and/or mandibular deficiency,
of the upper airway. The maxilla is moved by a Le Fort I MMA can also be offered as the initial surgery. If the palate
osteotomy and the mandible by a sagittal split osteotomy. is long, doing a UPPP at the same time as the MMA is also
Numbness of the chin and cheek areas is an expected com- an option.
plication that resolves in 6 to 12 months in most patients. The MMA enlarges the pharyngeal and hypopharyngeal
The indications for MMA are listed in Box 206. In some areas by moving the skeletal framework and tensions the
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362 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
suprahyoid and velopharyngeal musculature. Whereas used as an adjunctive measure with other procedures. After
patients with retrognathia may be especially good candi- the first procedure, subsequent procedures are often done in
dates, this procedure does not require that patients have this an outpatient surgery center.
problem.
Tongue Base Suspension Suture A suspension suture is looped
MMA Procedure The maxillary procedure is a Le Fort I oste- from an anchor screw on the inner surface of the mandible
otomy above the apices of the upper teeth. The maxilla is to the base of the tongue. The suture is tensioned, bringing
advanced 10 to 12 mm and stabilized with plates. The man- the tongue forward. The procedure can be performed in less
dibular procedure involves a sagittal split osteotomy. The than 1 2 hour and has few side effects (infection, injury to
medial and lateral cortex of the mandible is separated at the tooth roots, and detachment of screw). The success rates are
ramus region with care to preserve the inferior alveolar variable.69 The procedure is often performed with a UPPP or
nerve. The dentated mandibular segment is then advanced another procedure.
to align with the maxilla and rigid fixation is performed with
screws or plates.
Overall Surgical Approach
Outcomes of MMA Response rates up to 90% have been The overall surgical approach depends on OSA severity,
publisheddepending on the definition of surgical success. upper airway anatomy, prior treatment failures, and patient
Li and coworkers67 reported 95% cure rate defined as an preference. Box 207 presents a summary of recommenda-
AHI < 20/hr and at least a 50% reduction. In a group of tions from recent surgical practice parameters. One approach
patients who responded to MMA (36 of 40 studied), the AHI to treatment is to classify patients as type 1 to 3. Obstruction
dropped from 69.6/hr preoperatively to 7.7/hr postopera- can be classified as type 1 to 3 based on the predominant
tively. A recent meta-analysis found MMA to reduce the AHI level of upper airway obstruction.44,46 A type 1 obstruction is
to less than 20/hr in 80% to 90%.61 This procedure is usually at the retropalatal area. Type 3 obstruction is at the hypo-
offered only at large tertiary hospitals by experienced maxil- pharyngeal area (behind the tongue or lower), and type 2 is
lofacial surgeons. The recent AASM practice parameters for a combined obstruction (palate + hypopharynx). Type 1
surgical treatment of OSA state MMA is indicated for surgi- patients are considered favorable candidates for palatal
cal treatment of severe OSA in patients who cannot tolerate
or are unwilling to adhere to positive airway pressure therapy,
or in whom oral appliances, which are often more appropri- BOX 207
ate in mild and moderate OSA patients, have been consid-
ered and found ineffective or undesirable (Option).41 The Surgical Practice Parameter Recommendations
reason for the grade of Option rather than a higher grade of PROCEDURE INDICATIONS/CONDITIONS
Guideline is that the published studies were considered low Tracheostomy Other options do not exist or have failed.
quality of evidence because they were small and not con- Clinical urgency (e.g., repeated bouts of
trolled. Other than tracheostomy, the procedure is most hypercapnic respiratory failure).
likely to significantly improve the AHI in patients with
MMA Severe OSA.
severe OSA, although the AHI is often not normalized. Of
Unwilling or unable to tolerate PAP.
note, there are individual patients with severe OSA in whom
OA considered and undesirable or
OA treatment may be equally effective. ineffective.
(Failure)
Phase II
MMA
to them.
FIGURE 2016 Occlusal sequence of treatment with rapid maxillary expansion from crowding in the upper central incisors (top)
to a wide space (bottom). Note how the palatal vault has changed. From Pirelli P, Saponara M, Guilleminault C: Rapid maxillary
expansion in children with obstructive sleep apnea syndrome. Sleep 2004;27:764.
2. An 11-year-old male has a history of snoring and daytime 5. Of the following factors, which is predictive of a good
sleepiness. On physical examination, he is obese (BMI = response to an OA?
30) and has 4+ enlarged tonsils. A sleep study shows an A. Higher BMI.
AHI of 20/hr with all events being obstructive apneas or B. Mild retrognathia.
hypopneas. What treatment do you recommend? C. Presence of postural OSA.
A. TNA. D. Rapid eye movementrelated OSA.
B. CPAP.
C. Weight loss. 6. A 40-year-old woman has loud snoring and mild OSA
(AHI 10/hr). She also has nasal congestion with septal
D. UPPP.
deviation and hypertrophy of the inferior turbinates. She
3. A 40-year-old man with loud snoring but no witnessed has good dentition and no TMJ problems. Her orophar-
apnea or daytime sleepiness is considering the palatal ynx is a Mallampati 2, and she has a long uvula. Which
implant surgery for snoring. He is seeking a second of the following treatment options do you recommend?
opinion. What do you recommend? A. LAUP.
A. PSG; if OSA is present, PI surgery not indicated. B. Nasal surgery.
B. Proceed with palatal surgery but obtain postproce- C. OA.
dure PSG. D. OA or UPPP
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366 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
7. A 40-year-old man has severe daytime sleepiness and an 7. C. In patients with severe OSA in whom PAP treatment
AHI of 40/hr with moderate arterial oxygen desaturation. has failed (or not tolerated), the treatment options include
The patients only medical problems are obesity and OA and MMA. Given the severity of symptoms and
hypertension. Multiple attempts at PAP treatment have desaturation, MMA is indicated. OA can be effective in
been unsuccessful. Which treatment alternatives do you some patients with severe OSA. If the patient declines
recommend? surgery or is not a good surgical candidate, then OA treat-
A. UPPP. ment may be the best option.
B. UPPP + GAHA.
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28. Clark GT, Blumenfeld I, Yoffe N, et al: A crossover study com- ous positive airway pressure: a randomized, double-blind,
paring the efficacy of continuous positive airway pressure with placebo-controlled clinical pilot trial. Laryngoscope 2001;
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obstructive sleep apnea. Chest 1996;109:14771483. 50. Koutsourelakis I, Georgoulopoulos G, Perraki E, et al: Ran-
29. Engleman HM, McDonald JP, Graham D, et al: Randomized domized trial of nasal surgery for fixed nasal obstruction in
crossover trial of two treatments for sleep apnea/hypopnea obstructive sleep apnea. Eur Respir J 2008;31:110117.
syndrome: continuous positive airway pressure and mandibu- 51. Kohler M, Bloch KE, Stradling JR: The role of the nose in the
lar repositioning splint. Am J Respir Crit Care Med 2002;166: pathogenesis of obstructive sleep apnea and snoring. Eur
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30. Randerath WJ, Heise M, Hinz R, Ruehle KH: An individually 52. Friedman M, Schalch P, Lin HC, et al: Palatal implants for the
adjustable oral appliance vs continuous positive airway pres- treatment of snoring and obstructive sleep apnea/hypopnea
sure in mild to moderate obstructive sleep apnea. Chest syndrome. Otolaryngol Head Neck Surg 2008;138:209216.
2002:122:569575. 53. Steward DL, Huntley TC, Woodson BT, Surdulescu V: Palate
31. Tan YK, LEstrange PR, Luo YK, et al: Mandibular advance- implants for obstructive sleep apnea: multi-institution, ran-
ment splints and continuous positive airway pressure in domized, placebo-controlled study. Otolaryngol Head Neck
patients with obstructive sleep apnea: a randomized cross-over Surg 2008;139:506510.
trial. Eur J Orthod 2002;24:239249. 54. Littner M, Kushida CA, Hartse K, et al: Practice parameters
32. Collop NA, McDowell W, Boehlecke B, et al: Clinical guidelines for the use of laser-assisted uvulopalatoplasty. Sleep 2001;
for the use of unattended portable monitors in the diagnosis of 245:603619.
obstructive sleep apnea in adult patients. J Clin Sleep Med 55. Ryan CF, Love LL: Unpredictable results of laser assisted uvu-
2007:3:737747. lopalatoplasty in the treatment of obstructive sleep apnea.
33. Rose E, Statts R, Virchow C, Jonas IE: Occlusal and skeletal Thorax 2000;55:399404.
effects of an oral appliance in treatment of obstructive sleep 56. Powell NB, Riley RW, Troell RJ, et al: Radiofrequency volumet-
apnea. Chest 2002;122:871877. ric tissue reduction of the palate in subjects with sleep-
34. Millman RP, Rosenberg CL, Carlisle CC, et al: The efficacy of disordered breathing. Chest 1998;113:11631174.
oral appliances in the treatment of persistent sleep apnea after 57. Fujita S, Conway W, Zorick F, Roth T: Surgical correction
uvulopalatopharyngoplasty. Chest 1998;113:992996. of anatomic abnormalities in obstructive sleep apnea. Uvulo-
35. Gotsopoulos H, Kelly JJ, Cistulli PA: Oral appliance therapy palatopharyngoplasty. Otolaryngol Head Neck Surg 1981;
reduces blood pressure in obstructive sleep apnea: a random- 89:923934.
ized, controlled trial. Sleep 2004;27:934941. 58. Larsson LH, Carlsson-Norlander B, Svanborg E: Four year
36. Coruzzi P, Gualerzi M, Bernkopf E, et al: Effects of an oral follow-up after uvulopalatopharyngoplasty in 50 unselected
appliance on autonomic cardiac modulation in obstructive patients with obstructive sleep apnea syndrome. Laryngoscope
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60. Franklin KA, Anttla H, Axelsson S, et al: Effects and side-effects 72. American Academy of Pediatrics: Clinical practice guideline.
of surgery for snoring and OSA: a systematic review. Sleep Diagnosis and management of childhood obstructive sleep
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61. Elshaug AG, Moss JR, Southcott A, et al: Redefining success in 73. American Thoracic Society: Standards and indications for car-
airway surgery for obstructive sleep apnea: a meta-analysis and diopulmonary sleep studies in children. Am J Respir Crit Care
synthesis of the evidence. Sleep 2007;30:461467. Med 1996;153:866878.
62. Hudgel DW, Harasick T, Katz RL, et al: Uvulopalatopharyngo- 74. Guilleminault C, Huang YS, Glamann C, Chan A: Adenotonsil-
plasty in obstructive apnea: value of preoperative localization lectomy and obstructive sleep apnea in children: a prospective
of site of upper airway narrowing during sleep. Am Rev Respir survey. Otolaryngol Head Neck Surg 2007;136:169175.
Dis 1991;143:942946. 75. Tauman R, Gulliver TE, Krishna J, et al: Persistence of obstruc-
63. Sasse SA, Mahutte CK, Dickel M, Berry RB: The characteristics tive sleep apnea syndrome in children after adenotonsillec-
of five patients with obstructive sleep apnea whose apnea- tomy. J Pediatr 2006;121:803808.
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Sleep Breath 2002;6:7784. and adenoidectomy in the treatment of pediatric obstructive
64. Launois SH, Feroah TR, Campbell WN, et al: Site of pharyngeal sleep apnea/hypopnea syndrome: a meta-analysis. Otolaryngol
narrowing predicts outcome of surgery for obstructive sleep Head Neck Surg 2006;134:979984.
apnea. Am Rev Respir Dis 1993;147:182189. 77. Friedman M, Wilson M, Chang HW: Updated systematic
65. Mortimore IL, Bradley PA, Murray JAM, Douglas NJ: Uvulo- review of tonsillectomy and adenoidectomy for treatment of
palatoplasty may compromise nasal CPAP therapy in sleep pediatric obstructive sleep apnea/hypopnea syndrome. Otolar-
apnea syndrome. Am J Respir Crit Care Med 1996;154: yngol Head Neck Surg 2009;140:800808.
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66. Weaver EM, Maynard C, Yueth B: Survival of veterans with respiratory compromise in children with obstructive sleep
sleep apnea: continuous positive airway pressure versus surgery. apnea syndrome: can it be anticipated? Pediatrics 1994;93:
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67. Li KK, Powell NB, Riley RW, et al: Long term results of 79. Pirelli P, Saponara M, Guilleminault C: Rapid maxillary expan-
maxillomandibular advancement surgery. Sleep Breath 2000; sion in children with obstructive sleep apnea syndrome. Sleep
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68. Li K, Powell NB, Riley RW, Guilleminault C: Temperature con- 80. Cistulli PA, Palmisano RG, Poole MD: Treatment of obstructive
trolled radiofrequency tongue base reduction for sleep disor- sleep apnea syndrome by rapid maxillary expansion. Sleep
dered breathing: long term outcomes. Otolaryngol Head Neck 1998;21:831835.
Surg 2002;127:230234. 81. Villa MP, Malagola C, Pagani J, et al: Rapid maxillary expansion
69. Miller FR, Watson D, Malis D: Role of tongue base suspension in children with obstructive sleep apnea syndrome: 12-month
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surgical management of obstructive sleep apnea. Otolaryngol 82. Cohen SR, Simms C, Burstein F: Mandibular distraction osteo-
Head Neck Surg 2002;126:392398. genesis in the treatment of upper airway obstruction in chil-
70. Hoban TF: Polysomnography should be required both before dren with craniofacial deformities. Plast Reconstr Surg 1998;
and after adenotonsillectomy for childhood sleep disordered 101:312318.
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71. Friedman N: Polysomnography should not be required before
and after adenotonsillectomy for childhood sleep disordered
breathing. J Clin Sleep Med 2007;3:678680.
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Appendix 20-1
clinician. The purpose of follow-up is to assess the patient patient care. An objective re-evaluation of respiration during
for signs and symptoms of worsening OSA. Close commu- sleep is indicated if signs or symptoms of OSA worsen or
nication with the dental specialist is most conducive to good recur. (Option)
CPAP = continuous positive airway pressure; OA = oral appliance; OSA = obstructive sleep apnea.
From Kushida CA, Morgenthaler TI, Littner MR, et al: American Academy of Sleep Medicine. Practice parameters for the treatment of snoring and
obstructive sleep apnea with oral appliances: an update for 2005. Sleep 2006;29:240243.
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Appendix 20-2
A custom-fabricated mandibular advancement oral appli- C. The device is ordered by the treating physician following
ance (E0486) used to treat obstructive sleep apnea (OSA) is review of the report of the sleep test. (The physician who
covered if criteria AD are met. provides the order for the oral appliance could be differ-
ent from the one who performed the clinical evaluation
A. The patient has a face-to-face clinical evaluation by the in criterion A.)
treating physician prior to the sleep test to assess the D. The device is provided and billed for by a licensed dentist
patient for OSA testing. (DDS or DMD).
B. The patient has a Medicare-covered sleep test that meets
one of the following criteria (13): If all of these criteria (AD) are not met, the custom-
1. The apnea-hypopnea index (AHI) or respiratory dis- fabricated oral appliance (E0486) will be denied as not rea-
turbance index (RDI) 15 events/hr with a minimum sonable and necessary.
of 30 events; or Custom-fabricated appliances that achieve their effect
2. The AHI or RDI 5 and 14 events/hr with a through positioning of the tongue (E1399) will be denied as
minimum of 10 events and documentation of not reasonable and necessary. There is insufficient evidence
a. Excessive daytime sleepiness, impaired cognition, to show that these items are effective therapy for OSA.
mood disorders, or insomnia; or A prefabricated OA (E0485) will be denied as not reason-
b. Hypertension, ischemic heart disease, or history of able and necessary. There is insufficient evidence to show
stroke, or that these items are effective therapy for OSA.
3. If the AHI > 30 or the RDI > 30 and meets either of Custom-fabricated mandibular advancement devices that
the following (a or b): do not meet the requirements in the Coding Guidelines
a. The patient is not able to tolerate a positive airway section of the Related Policy Article (E1399) will be denied
pressure (PAP) device, or as not reasonable and necessary.
b. The treating physician determines that the use of a
PAP device is contraindicated.
Note: Here AHI = apnea + hypopnea index (hypopnea = 30% drop in flow + 4% desaturation).
RDI is determined by a type 3 or type 4 home sleep test (RDI = apneas + hypopneas/hour of monitoring time).
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Available at Noridian https://www.noridianmedicare.com/dme/coverage/docs/lcds/current_lcds/oral_appliances.htm%3f
371
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Appendix 20-3
4.1 Diagnosis
with moderate OSA should initially be offered either PAP
4.1.1 The presence and severity of OSA must be determined therapy or oral appliances. (Option)
before initiating surgical therapy. (Standard) 4.3.4 Multilevel or stepwise surgery. Use of MLS, as a
4.1.2 The patient should be advised about potential surgi- combined procedure or stepwise operations, is acceptable in
cal success rates and complications, availability of alternative patients with narrowing of multiple sites in the upper airway,
treatment options such as nasal PAP and oral appliances, and particularly if they have failed UPPP as a sole treatment.
the levels of effectiveness and success rates of these alterna- (Option)
tive treatments. (Standard) 4.3.5 Laser-assisted uvulopalatoplasy: LAUP is not rou-
4.2 Treatment objective: The desired outcomes of treat- tinely recommended as a treatment for OSA syndrome.
ment include resolution of the clinical signs and symptoms (Standard)
of OSA and the normalization of sleep quality, the AHI, and 4.3.6 Radiofrequency ablation: RFA can be considered as
oxyhemoglobin levels. (Standard) a treatment in patients with mild to moderate OSA who
cannot tolerate or who are unwilling to adhere to PAP, or in
whom oral appliances have been considered and have been
4.3 Surgical Procedures
found ineffective or undesirable.
4.3.1 Tracheostomy: Tracheostomy has been shown to be an 4.3.7 Palatal implants: Palatal implants may be effective in
effective single intervention to treat OSA. This operation some patients with mild OSA who cannot tolerate or are
should be considered only when other options do not exist, unwilling to adhere to PAP therapy, or in whom oral appli-
have failed, are refused, or when this operation is deemed ances have been considered and found ineffective or unde-
necessary by clinical urgency. (Option) sirable. (Option)
4.3.2 Maxillomandibular advancement: MMA is indi-
cated for surgical treatment of severe OSA in patients who
5.0 Follow-up
cannot tolerate or are unwilling to adhere to PAP therapy, or
in whom oral appliances, which are often more appropriate Postoperatively after an appropriate period of healing,
in mild and moderate OSA patients, have been considered patients should undergo follow-up evaluation including an
and found ineffective or undesirable. (Option) objective measure of the presence and severity of sleep-
4.3.3 Uvulopalatopharyngoplasty as a single surgical pro- disordered breathing and oxygen saturation, as well as clini-
cedure: UPPP as a sole procedure, with or without tonsil- cal assessment for residual symptoms. In addition, patients
lectomy, does not reliably normalize the AHI when treating should be followed over time to detect recurrent of disease.
moderate to severe OSA. Therefore, patients with severe (Standard)
OSA should initially be offered PAP therapy, while those
AHI = apnea-hypopnea index; LAUP = laser-assisted uvuloplasty; MMA = maxillomandibular advancement; MLS = multilevel or stepwise surgery;
OSA = obstructive sleep apnea; PAP = positive airway pressure; RFA = radiofrequency ablation; UPPP = uvulopalatopharyngoplasty.
From Aurora RN, Casey KR, Kristo D, et al: Practice parameters for the surgical modifications of the upper airway for obstructive sleep apnea in adults.
Sleep 2010;33:14081413.
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373
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Chapter 21
E1-M2
E2-M2
Chin EMG
Airflow
(nasal
pressure)
Chest
Abdomen
Cflow
Chest
Abdomen
SpO2
180 seconds
FIGURE 212 Cheyne-Stokes breathing with central hypopnea at the nadir of ventilatory effort. This patient had obstructive and mixed apneas during the
diagnostic portion of a sleep study. When placed on continuous positive airway pressure (CPAP), the underlying ventilatory instability was uncovered. Here,
Cflow is the signal from the accurate flow transducer in the positive airway pressure (PAP) device. SpO2 = pulse oximetry.
Central apnea in adults is defined as a cessation in airflow CSA have accounted for less than 5% to 15% of patients with
of 10 seconds or longer that is associated with an absence sleep apnea evaluated at most sleep centers. However, two
of respiratory effort.4 During diagnostic studies oronasal factors have increased the number of CSA patients being
thermal sensor signal is used to detect apnea. During a posi- evaluated. First, there has been an increased recognition of
tive airway pressure (PAP) titration the PAP flow signal is sleep-disordered breathing in congestive heart failure (CHF)
used. The diagnosis of a CSA syndrome requires that the and a substantial number of patients with systolic heart
majority of apneic events be central in nature. The exact failure have Cheyne-Stokes breathing central sleep apnea
proportion of central events required is not clear, with (CSB-CSA) (Fig. 212). Second, recently, there has been
various authors diagnosing the CSA syndromes when 50% more aggressive use of opiates to control pain. As discussed
to 80% of the events are central. Traditionally, patients with in this chapter, many patients develop central apnea as a
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Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 377
Esophageal
pressure b b
Mixed Hypopnea
Airflow
(PTN)
Esophageal
pressure
PTN pneumotachograph
result of the use of potent narcotics. Central apnea may occur BOX 211
either at baseline or once patients are exposed to PAP treat- Central Sleep Apnea Syndromes
ment. Thus, sleep centers can expect to see more patients
1. Primary central sleep apnea
with CSA.
2. Cheyne-Stokes breathing pattern
Many patients who exhibit central apneas also exhibit
3. High-altitude periodic breathing
central hypopneas (see Fig. 212). The challenges in defining
4. Central sleep apnea due to drug or substance
central hypopnea were discussed in earlier chapters. The
5. Primary sleep apnea of infancy
American Academy of Sleep Medicine (AASM) scoring
From American Academy of Sleep Medicine: ICSD-2 International
manual discourages identification of central hypopnea unless Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
an accurate method to quantify respiratory effort is being Westchester, IL: American Academy of Sleep Medicine, 2005.
used (esophageal pressure or respiratory inductance plethys-
mography).4 In general, central hypopneas are characterized
by a proportionate decrease in both airflow and respiratory
effort (Fig. 213).5 Usually, there is no snoring or chest-
abdominal paradox and the nasal pressure or PAP device 211).6 Primary CSA is termed idiopathic central sleep apnea
flow signal is fairly rounded (minimal or no signs of airflow (ICSA) in this chapter, in keeping with much of the literature.
limitation). Primary CSA, CSB-CSA, and high-altitude periodic breath-
ing (HAPB) are hypocapnic forms of CSA. Patients with
these syndromes have a normal or low PaCO2 during wake-
CLASSIFICATION OF CSA SYNDROMES
fulness. During sleep, these patients do not develop hyper-
There is a number of classifications of CSA and the hypoven- capnia. In contrast, patients with CSA due to drug or
tilation syndrome but none of these classifications is entirely substance and primary sleep apnea of infancy have normal
satisfactory.1,6 The International Classification of Sleep Dis- or increased daytime PaCO2 and may develop or have
orders, 2nd edition (ICSD-2) lists five CSA syndromes (Box worsening hypercapnia during sleep. The ICSD-2 lists five
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378 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
30 seconds
Airflow
Chest
Abdomen
SaO2
88%
FIGURE 214 A mixed apnea. Note the crescendo-decrescendo pattern of ventilatory effort. When the patient was placed on CPAP, the mixed apneas were
converted to central apneas of the Cheyne-Stokes type. Another hint that the patient has congestive heart failure is the delay in the arterial oxygen saturation
(SaO2) nadir. The 88% occurs before the termination of the event pictured. In fact, this desaturation is not due to the event pictured but to the previous event.
Airflow = nasal pressure. From Malhotra A, Berry RB, White DP: Central sleep apnea. In Carney P, Berry RB, Geyer JW (eds): Clinical Sleep Medicine. Philadelphia:
Lippincott Williams & Wilkins, 2005, p. 341.
with tracheostomy (elimination of obstruction), patients the disease course, some patients with chronic hypoventi-
were found to have residual central apneas that tended to lation syndromes will have an increased PaCO2 only
resolve with chronic treatment.8 The term CompSA is also during sleep. They may present with complaints of disturbed
sometimes used to include patients with narcotic-associated sleep or nocturnal dyspnea, morning headaches, daytime
sleep-disordered breathing who have persistent or emergent sleepiness, or insomnia. Later in the disease course, these
central apneas on PAP. Patients with this condition usually may present with hypercapnic respiratory failure and cor
have high normal or mildly increased PaCO2 during wake- pulmonale.
fulness. In this chapter, this group is discussed under the
hypercapnic CSA group. It is also not uncommon for patients PATHOPHYSIOLOGY OF CSA
with CHF to have a combination of obstructive or mixed
Effects of Normal Physiologic Changes
apnea and CSB-CSA (Fig. 214).10 In some of these patients,
application of PAP will eliminate obstruction but frequent In normal individuals, there is a 2 to 8 mm Hg rise in PaCO2
central apneas of the Cheyne-Stokes type may persist or during nonrapid eye movement (NREM) sleep. This is
emerge. For this reason, the term CompSA is sometimes thought due to loss of the wakefulness drive, reduction of the
applied. These patients are discussed with the nonhypercap- hypercapnic and hypoxic ventilatory drives, and increased
nic CSA disorders. Patients with CompSA without an upper airway resistance (Table 211).11 The wakefulness
obvious etiology (no narcotics or heart failure) are termed drive is a poorly understood generalized augmentation of
idiopathic CompSA for lack of a better terminology. These ventilation associated with the wakefulness state. During
patients have an instability in ventilatory control either at NREM sleep, ventilation is totally under metabolic control
baseline or due to PAP treatment. Because they have normal (chemoreceptors). Ventilatory control centers respond to
or low daytime PaCO2, they are discussed in the hypocapnic information from the peripheral chemoreceptors including
CSA sections. the carotid body (arterial partial pressure of oxygen [PaO2]
The hypercapnic CSA syndromes associated with and PaCO2) and medullary chemoreceptors (H+ due to
hypoventilation include those with a defect in ventilatory changes in PaCO2).11 During rapid eye movement (REM)
control (congenital central alveolar hypoventilation, acquired sleep, ventilation is irregular and nonmetabolic factors also
central alveolar hypoventilation, CSA due to medication/ affect ventilation. The hypercapnic and hypoxic ventilatory
substance), patients with the OHS, thoracic cage disorders, drives are lower during REM than during NREM sleep. In
and neuromuscular disorders. The hypercapnic CSA group addition, during REM sleep, there is generalized skeletal
can be divided into a wont breathe group (can reduce their muscle hypotonia.1113 The contribution of accessory muscles
PaCO2 with voluntary increases in ventilation) and a cant of ventilation is either reduced or absent and ventilation
breathe group due to an abnormal thoracic cage or neuro- depends entirely on the diaphragm. The loss of accessory
muscular weakness. This classification is not entirely satis- inspiratory muscles can compromise the ability to maintain
factory because patients with OHS have various combinations adequate ventilation, especially in patients with muscle
of OSA, abnormal ventilatory control, and respiratory pump weakness or a high work of breathing. During the phasic
abnormality (mass loading due to obesity). Of note, early in changes of REM sleep (associated with bursts of eye
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380 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
TABLE 211
Effect of Sleep on Ventilatory Control
WAKE NREM REM
Wakefulness drive Present Absent Absent
+
Central chemoreceptors (H , PCO2) Intact Reduced Very reduced
+
Peripheral chemoreceptors (PO2, PCO2 [H ]) Intact Reduced Very reduced
Apneic threshold Not present Present N/A
Behavioral and other nonventilatory Present Absent Periods of reduced tidal volume during phasic REM
control center influences sleep often associated with bursts of eye movements
N/A = not applicable; NREM = non-rapid eye movement; PCO2 = partial pressure of carbon dioxide; PO2 = partial pressure of oxygen; REM = rapid eye movement.
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
Airflow
(nasal pressure)
Esophageal 20 cm H2O
pressure
FIGURE 215 Respiration during rapid eye movement (REM) sleep. Periods of diminished diaphragmatic activity (reflected in decreased
esophageal pressure excursions) and tidal volume associated with the phasic changes of REM sleep (associated with bursts of eye
movements). EMG = electromyogram. From Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 31.
Decreased Recovery
PETCO2
50
PETCO2 mmHg
40
30
20
10
0
10 sec
Tidal volume
0.8
0.6
(liters)
0.4
0.2
0
Recovery
Prehyperventilation Hyperventilation
FIGURE 216 Determination of the apneic threshold (AT). The subject undergoes positive-pressure ventilation until the end-tidal partial pressure of
carbon dioxide (PETCO2) drops and the ventilator is turned off. If PETCO2 is below the AT, central apnea ensues. From Skatrud JB, Dempsey JA: Interaction of
sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983;55:813822.
5
Apneic Threshold
During wakefulness, hypocapnia does not cause cessation of 0
breathing due to the presence of the wakefulness stimulus to
breathing. During NREM sleep, ventilation depends com- Spontaneous eupnea
pletely on metabolic control. If the PaCO2 falls below a char-
acteristic value (AT) for each individual, a central apnea 32 34 36 38 40 42 44 46
occurs14,15 (Fig. 216). Ventilation does not resume until the PETCO2, mmHg
PaCO2 climbs above (and actually slightly higher than) the
FIGURE 217 The results of determination of the apneic threshold (AT) in an individual
AT. The AT can be experimentally determined by serial runs who spontaneously increases the end-tidal partial pressure of carbon dioxide (PETCO2)
of hyperventilation with positive-pressure ventilation that from slightly above 40 mm Hg when awake to 44 mm Hg during sleep (spontaneous
progressively drop the PaCO2 to various levels below the eupnea shown by arrow). The AT varied but was usually at or slightly below the awake
eucapnic PaCO2 level during sleep. The positive-pressure arterial carbon dioxide pressure (PaCO2) value. PETCO2 values from 38 mm Hg to slightly
ventilation is terminated suddenly, and if the PaCO2 has above 40 mm Hg resulted in central apnea (apnea duration > 0 sec). Note that there
dropped below the AT, a central apnea occurs. For example, was some variability with one trial resulting in a PETCO2 of 38 mm Hg that did not result
suppose the spontaneous sleeping PaCO2 is 42 mm Hg, then in central apnea. From Skatrud JB, Dempsey JA: Interaction of sleep state and chemical
trials could progressively induce PaCO2 values of 41, 40, 39, stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983;55:813822.
38, 37, and so on. The level at which a central apnea occurs
when the positive-pressure device is turned off is the AT. As
noted previously, the sleeping PaCO2 is normally about 2 to Of note, it is the difference between the sleeping PaCO2
8 mm Hg above waking value. The typical AT is usually at and the AT rather than the position of the AT that is the
or 1 to 2 mm Hg lower than the waking PaCO2. In Figure critical determinant of the propensity to develop central
217, during normoxia, an individual end-tidal partial pres- apnea. The smaller the PaCO2-AT difference the more likely
sure of carbon dioxide (PETCO2) increases with sleep from CSA is to occur. Figure 218 shows awake and sleeping
40 to 44 mm Hg. Hyperventilation trials with positive- PaCO2 values for CHF patients with and without periodic
pressure ventilation resulted in central apnea (apnea dura- breathing. Those with periodic breathing have a small differ-
tion > 0 sec) in a range of PETCO2 values from about 38 to ence between the sleeping PaCO2 and the AT. This is because
42 mm Hg. the PaCO2 increased relatively little with transition from
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382 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
PETCO2, mmHg
CO2 in patients with congestive heart failure. Am Respir Crit Care Med
2002;165:12451250.
35
30
25
Awake Sleep Apnea Awake Sleep Apnea
eupnea eupnea threshold eupnea eupnea threshold
CHF CHF
periodic breathing
wake to sleep but the AT did not show a corresponding Controller gain
decrease.19
VE
Studies have shown that the PaCO2-AT difference can
vary with changes in ventilatory drive.20 Specifically, the PCO2 Response
PaCO2-AT difference increases with the induction of meta-
Circulatory delay (VE)R
bolic acidosis (acetazolamide) and decreases with metabolic VE
alkalosis. This is somewhat counterintuitive because one Plant gain
PCO2
might expect that further increases in ventilatory drive due
PCO2
to metabolic acidosis would increase the propensity for
central apnea. In contrast to metabolic acidosis, hypocapnic
hypoxia decreases the PaCO2-AT difference. Thus, hypox- VE
emia can increase the likelihood of central apnea. A detailed Disturbance
description of the factors that affect the PaCO2-AT difference
is found in references 15 and 20. (VE)D
0
20 25 30 35 40 45 50 55
A PCO2 (torr)
Disturbance Response
Disturbance
A: LG 0.5
Response
VT
Response Response
Disturbance
Disturbance Disturbance
B: LG 1
VT
B
TABLE 213
Differences in Respiration between Patients with Idiopathic Central Sleep Apnea and Cheyne-Stokes
Breathing
CENTRAL APNEA CYCLE VENTILATORY DELAY IN
DURATION (SEC) LENGTH (SEC) PHASE (BETWEEN APNEAS) (SEC) SaO2 NADIR (SEC)
ICSA 20.9 37.3 16.7 10.3
CSB-CSA (CHF) 22.3 59.0 36.7 24.3
CHF = congestive heart failure; CSA = central sleep apnea; CSB = Cheyne-Stokes breathing; ICSA = idiopathic central sleep apnea; SaO2 = arterial oxygen saturation.
From Hall MJ, Xie A, Rutherford R, Bradley TD: Cycle length of periodic breathing with and without heart failure. Am J Respir Crit Care Med 1996;154:376381.
central apneas typically are 20 to 40 seconds in duration. In to a long circulation time. The patterns of ventilation
ICSA, there is typically a short ventilatory phase of 2 to 4 in treatment-emergent CSA (nonhypercapnic, non-CSB
breaths between central apneas, and arousals tend to occur CompSA) resembles that of ICSA.
at apnea termination (Fig. 2111). Patients with CSB have a
longer ventilatory phase between consecutive apneas, and
Idiopathic CSA (Primary CSA)
the ventilatory phase has a characteristic crescendo-
decrescendo morphology. Hall and colleagues23 compared These patients have central apneas of unknown etiology.
cycle length between patients with ICSA and CSB-CSA due CHF, neurologic disorders, or medications suppressing ven-
to heart failure (Table 213). The apnea durations were tilation are not present. The prevalence varies but is thought
similar but cycle length was longer in CSB-CSA due to a to be 5% to 10% of patients being studied in sleep centers.
long ventilatory phase. The CSA-CSB patients also had a Patients may present with symptoms similar to those of
longer delay in the arterial oxygen saturation (SaO2) nadir. patients with OSA. These may include daytime sleepiness or
The lower the cardiac output, the longer the ventilatory insomnia, snoring, witnessed breathing pauses, and dis-
phase and the delay in SaO2 nadir. This is believed due turbed sleep. They tend to be thinner than patients with OSA
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384 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
Airflow
Airflow
CSA-CSB often has arousal at the zenith of ventilatory effort and the nadir in the SaO2 is delayed
A A
Airflow Airflow
B B
SaO2 SaO2
A position of arousal
B delay in saturation nadir
FIGURE 2111 Schematic illustrations of the difference between idiopathic central sleep apnea (CSA) and Cheyne-Stokes breathing
(CSB) central apnea associated with heart failure. The ventilatory phase is longer in CSB-CSA, arousal occurs at the zenith of ventilation,
and the nadir in the arterial oxygen saturation (SaO2) is delayed.
BOX 215
CSB WITH CSA
Possible Treatments for Idiopathic Central
Sleep Apnea CSB occurs most commonly in patients with left ventricular
systolic dysfunction3638 but also can occur in patients with
CPAP diastolic CHF or neurologic disorders.39,40 The neurologic
Hypnotics
disorders associated with CSB include a prior cerebrovascu-
Respiratory stimulants (acetazolamide)
lar accident (CVA) and neurodegenerative disorders. CSB
Oxygen therapy??
may be present in up to 30% of patients in the first few days
CPAP = continuous positive airway pressure.
after stroke.39,41 Central apnea tends to resolve and is less
commonly seen in studies of patients studied several months
after stroke. OSA is the predominant form of sleep apnea
individualized (Box 215). Various respiratory stimulants present in patients after CVA. Of interest, a recent study sug-
have been tried as treatments for idiopathic CSA, with vari- gested that a significant proportion of CSB-CSA in stroke
able amounts of success.2729 The best evidence is for use of patients was due to occult cardiovascular disease.42 CSA-CSB
acetazolamide (Diamox), which is a carbonic anhydrase has also recently been reported in patients with heart failure
inhibitor. Acetazolamide induces a metabolic acidosis and with normal systolic function (diastolic heart failure).40
reduces the pH even if the PaCO2 also decreases slightly. CSB-CSA due to systolic CHF is probably the most
DeBacker and associates27 studied the effects of acetazol- common cause of CSA seen today. Javaheri and colleagues36
amide 250 mg 1 hour before sleep after 1 month of treatment found occult sleep-disordered breathing in 45% of a group
in ICSA patients. The apnea-hypopnea index (AHI) was with stable heart failure and an ejection fraction less than
reduced by about 50% and symptoms improved, although 45% and CSA was common in the affected individuals. Mac-
sleep efficiency was not significantly better.27 Donald and associates37 studied a group of patients in stable
Another treatment approach is to decrease arousals and CHF with maximal modern medical management and found
promote stage N3 sleep where ventilation is more stable and 61% to have some form of sleep-disordered breathing (31%
the PaCO2 likely slightly higher. Hypnotics including central apnea and 30% OSA). Oldenberg and coworkers38
triazolam and zolpidem have been tried.3032 A recent trial studied 700 patients with CHF and found similar results. It
of zolpidem 10 mg in ICSA was reported by Quadri and should be noted that many patients in these studies had
coworkers.31 The central AHI decreased from 30 to 13.5/hr various amounts of both central and obstructive apneas.
and subjective sleepiness as measured by the Epworth Sleepi- Defining what percentage of events qualified the patient for
ness Scale improved (from 13 to 8). However, in some the central apnea group was somewhat arbitrary. In addition,
patients, obstructive events increased with hypnotic treat- patients can vary in the percentage of central events over-
ment. Of note, hypnotics are relatively contraindicated in night43 or from night to night.44 In any case, the prevalence
hypercapnic CSA. of CSB-CSA is very high in patients with significant systolic
As noted previously, CPAP also appears to be effective heart failure.
treatment in some patients with ICSA.21,25 The mechanisms Patients with CSA-CSB may complain of the typical
by which CPAP works are unknown. Four possibilities are symptoms of sleep apnea including disturbed sleep or
that nasal CPAP minimizes overshoots in PaCO2 after daytime sleepiness. However, in most studies, the majority
arousal, slightly increases the sleeping PaCO2 in patients who of patients do not complain of subjective excessive daytime
are hypocapnic at baseline, prevents high upper airway resis- sleepiness. Thus, a high index of suspicion is needed to
tance from inducing arousals, or prevents significant nega- suspect the presence of CSB. Nocturnal sleep complaints are
tive upper airway pressure (which may trigger reflex central often assumed to be secondary to CHF rather than to
apnea). Patients who snore or have central apnea mainly in co-morbid sleep apnea. Despite the lack of subjective sleepi-
the supine position might be assumed to be the best candi- ness complaints in CSB-CSA patients, studies have docu-
dates for CPAP treatment. Of note, one case report found mented improvement in sleep quality and objective daytime
that CPAP helped but bilevel positive airway pressure (BPAP) sleepiness with successful treatment.45
worsened CSA.33 BPAP may destabilize the system by aug-
menting ventilation. No study evaluating the effect of adap-
Polysomnography in CSB-CSA
tive servo-ventilation (ASV), a mode designed to stabilize
ventilation, in ICSA has been published but a trial of that The crescendo-decrescendo morphology of CSB-CSA has
treatment might be reasonable. Supplemental oxygen has previously been discussed (see Figs. 212, 214, and 2111).
been shown to improve CSA in patients with CSB.34,35 Another characteristic to appreciate is the long delay in the
However, an evaluation of supplemental oxygen in ICSA nadir in the SaO2 tracing after event termination due to a
patients has not been published. Supplemental oxygen might prolonged circulation time (low cardiac output) (Fig. 2112).
work by decreasing ventilatory instability by blunting the The distinctive pattern of CSB may not be recognized during
hypercapnic ventilatory response. The hypercapnic ventila- a diagnostic study in a patient who has both OSA and
tory response is increased by hypoxia and decreased underlying CSB.10 However, during a subsequent PAP
by hyperoxia. titration, pure CSB-CSA may emerge when upper airway
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386 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
Nasal
pressure
Oronasal
thermal airflow
Chest
Abdomen
SpO2
91 96 94 91 96
30 sec 46 sec
FIGURE 2112 Cheyne-Stokes breathing with central apnea in a patient with systolic heart failure central apnea. Note the long delay in the nadir in the pulse oximetry (SpO2). The
tracing is 180 seconds and the vertical lines denote 30-second epochs.
obstruction is eliminated (Fig. 2113). The possibility of had a lower daytime PaCO2.47 Other studies have found
underlying CSB should be considered if mixed apneas during lower ejection fractions in patients with CSB.37 A study by
the diagnostic study have a long central component or if the Sin and colleagues50 of 450 men and women with CHF iden-
nadir in the SaO2 following obstructive event termination is tified risk factors for the presence of OSA and CSA. Risk
delayed. If central hypopneas rather than central apneas are factors for CSA included male sex, atrial fibrillation, age
present, this may also make CSB more difficult to recognize. older than 60, and hypocapnia (PaCO2 < 38 mm Hg) during
As noted previously, central hypopneas rather than apneas wakefulness. Risk factors for OSA included a high body mass
can occur at the nadirs in ventilatory effort (see Fig. 212). index (BMI) in men and an increase in age in women. The
The typical CSB cycle time is relatively long at 60 to 90 presence of CSB-CSA also has prognostic implications.
seconds and may be missed if a short time window is used Studies have suggested that the presence of CSA in
to monitor sleep during a PAP titration. Figure 2113 also patients with CHF is associated with a worse prognosis
illustrates the typical cessation of CSB-CSA when a patient (Fig. 2115).51,52
transitions from NREM to REM sleep.
Treatment of CSB-CSA
Pathophysiology of CSB-CSA
CSB-CSA in patients with CHF may improve with improved
The factors contributing to CSB include high ventilatory medical treatment of heart failure.53 Transplantation may
drive (high sympathetic tone, pulmonary congestion), long also cure CSB-CSA.54 A number of treatments have been
circulation time, and a small difference between the sleeping tried including aminophylline,55 acetazolamide,56 hypnot-
PaCO2 and the AT. Patients with CSB have low daytime ics,57 oxygen,34,35,58,59 and PAP52,60,61 (Box 216). Neither ami-
PaCO2 compared with CHF patients without CSB46,47 due to nophylline (can increase arrhythmias) nor acetazolamide
increased ventilatory drive. High drive is thought to be due has been widely used. One study found temazepam reduced
to increased sympathetic tone and pulmonary congestion the arousal index without worsening oxygenation but the
stimulation of lung J receptors. In one study of patients with amount of CSB was not improved.57 In contrast, a number
CHF, the higher the pulmonary capillary wedge pressure, the of studies of 1 to 3 months duration have documented
lower the awake PaCO2 (Fig. 2114A).48 In another study, improvement with CPAP in a substantial number of patients
the higher the pulmonary capillary wedge pressure, the showing an improvement in sleep quality and ejection frac-
higher the AHI (see Fig. 2114B).49 As noted previously, tion and reduced sympathetic activity.52,60,61 Titration of
CHF patients with CSB also have a small difference between CPAP in CSB-CSA patients differs from that in OSA
the sleeping PaCO2 and the AT.19 patients. On a given titration night, a pressure that eliminates
One might expect CHF patients with CSA to have lower CSA cannot usually be found. Typically, pressure is increased
cardiac output or ejection fraction compared with those that until obstructive events are eliminated and then increased
do not have periodic breathing. However, one study compar- to 8 to 10 cm H2O (if pressure is not already above that
ing groups with CHF with and without CSB found the two level). In some studies of CPAP treatment for CSB-CSA,
groups had similar ejection fractions but the CSB patients CPAP was started on an outpatient basis and increased
DaneshGroup.com
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Cflow
Chapter 21
CPAP 10 cmH2O
Chest
Abdomen
SpO2
FIGURE 2113 Note the presence of CSB-CSA on continuous positive airway pressure (CPAP). Also note the sudden cessation of CSB-CSA on transition to rapid eye movement (REM) sleep. Cflow = flow signal from the CPAP
device; ECG = electrocardiogram; SpO2 = pulse oximetry.
Central Sleep Apnea and Hypoventilation Syndromes
387
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388 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
44 100
42 Non-CSR-CSA
40
PaCO2 mmHg
60
CSR-CSA
38
40
36
20 P .032
34
0
0 6 12 18 24 30 36 42 48 54 60
32
12 14 16 18 20 22 24 26 28 30 Time from randomization (months)
A PCWP (mmHg) FIGURE 2115 Transplant-free survival in CHF patients with CSR-CSA was significantly
worse than in those with Cheyne-Stokes respiration (CSR)-CSA independent of the use
70 of CPAP. From Sin DD, Fitzgerald F, Parker JD, et al: Risk factors for central and obstructive
r 0.47 sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care
60 P .006 Med 1999;160:64.
Apnea-hypopnea index (no/hr)
50
40 BOX 216
80
60 40
Events/hr
40
20
20 CPAP-CSA-suppressed (5 events)
Control (26 events)
CPAP-CSA-unsuppressed (13 events)
0
A 0 3 6 12 18 24 30 36 42 48 54 60 0
Control Oxygen CPAP Bilevel ASV
vs Control P < .001 P < .001 P < .001 P < .001
Baseline
3 mo vs ASV P < .001 P < .001 P < .001 P = .02
P = .984
40 FIGURE 2117 Effectiveness in reducing the central apnea index by oxygen,
P < .001 P = .006 continuous positive airway pressure (CPAP), bilevel positive airway pressure (BPAP) with
35 P = .409 P < .001 P = .678 a backup rate, and adaptive servoventilation (ASV). ASV was the most successful at
lowering the central apnea index. The figure shows box plots: horizontal bar (median);
30
thick vertical bars (interquartile range); thin bars (range excluding outliers); dots
LVEF (%)
0
most insurance carriers. Conversely, if a patient has pre-
Control CPAP-CSA- CPAP-CSA- dominantly CSB-CSA on the diagnostic study, one may
B suppressed unsuppressed proceed directly with an ASV titration unless reimburse-
FIGURE 2116 Results from an analysis of the data from the Canadian Continuous ment issues mandate an initial trial of CPAP. The Centers for
Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Medicare and Medicaid Services (http://www.cms.gov/mcd/
(CANPAP) study. A, The patients who responded to continuous positive airway pressure viewlcd.asp?lcd_id=5023&lcd_version=56&show=all) and
(CPAP; *) had better survival than the controls or the nonresponders. CSA = central sleep many insurance carriers no longer require an attempt at
apnea. B, The responders had an improvement in the left ventricular ejection fraction CPAP if a patient meets criteria for CSA on the diagnostic
(LVEF). A and B, From Naughton M, Bernard D, Tam A, et al: Role of hyperventilation in study. A PSG must demonstrate the effectiveness of BPAP-ST
the pathogenesis of central sleep apnea in patients with congestive heart failure. Am Rev or ASV for treatment of CSA.
Respir Dis 1993;148:330338.
CMS criteria for CSA include:
1. AHI 5/hr,
low levels typical of CPAP titrations in OSA patients. Another 2. Central apneas/hypopneas > 50% of the total apneas
study found BPAP-ST to improve breathing in CSB-CSA and hypopneas, and
patients.66 A number of studies have documented that ASV 3. Central apneas/hypopneas 5/hr, and
is well tolerated and effective in CSB-CSA patients.45,67,68 In 4. Symptoms of excessive daytime sleepiness or disrupted
general, sleep quality improves with ASV treatment and sleep.
some studies have shown an improvement in ejection frac-
tion.67 Details of the use of ASV are discussed in Chapter 19. Of note, some clinicians would still order a titration with
At the present time, a randomized trial of ASV is in progress CPAP (at least during the initial part of the titration). Failure
to determine whether this treatment can improve mortality of CPAP would then trigger an ASV titration during the rest
in patients with CHF and CSB-CSA. of the study. A problem with this approach is that there may
If a patient with CHF has predominantly OSA on a diag- be insufficient time for an optimal ASV titration.
nostic study, then a CPAP titration is certainly indicated. If In summary, while the best treatment for patients with
underlying CSB is suspected in a patient with predominantly CSB-CSA remains controversial, most clinicians would use
obstructive events, a CPAP titration would still be indicated ASV unless a patient has a satisfactory response to CPAP.
because a study must demonstrate that the patient has Of note, BPAP without a backup rate is unlikely to be effec-
CompSA (emergence of frequent central apneas on CPAP) tive if CPAP is not effective. Attempts to optimize treatment
before a device with a backup rate (ASV) is reimbursed by of CHF are an essential component of treatment in patients
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390 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
with CSB-CSA associated with heart failure. In fact, opti- reported on 100 patients with a retrospective analysis; 13
mization of medical treatment of CHF should be the first subjects (13%) had CSA-CPAP. Risk factors included male
treatment intervention in patients with CSB-CSA due to sex, cardiac disease, and CSA on baseline PSG.74 In a referral
heart failure. sleep clinic setting, Morganthaler and colleagues7 found that
15% of 223 consecutive patients referred for a sleep study
had CompSA.
COMPLEX SLEEP APNEA
Thus, the incidence of CompSA will depend on the clini-
CompSA has been defined in many ways7,68,69 but the CMS cal setting and whether patients taking opioids and those
definition is one of the most widely used. CompSA is defined with CSB are included. The published studies suggest that
as a form of CSA identified by the persistence or emergence CSA will resolve in a large proportion of patients with
of central sleep apneas or hypopneas upon exposure to chronic CPAP treatment or with ASV treatment if indi-
CPAP or BPAP without a backup rate when obstructive cated.70,74 However, if patients with CompSA do not have
events have disappeared. These patients have predominantly improvement in control of sleep apnea, they tend to have
obstructive or mixed apneas during the diagnostic portion poor sleep quality and are at risk for poor adherence. In one
of the study occurring 5/hr or more. With use of CPAP or study, patients with CompSA had more mask issues and
BPAP without a backup rate, they show a pattern of apneas more complaints of removal of the mask.74
and hypopneas that meets the definition of CSA (see previ-
ous section).
Polysomnography
CompSA includes patients with no obvious cause for
treatment-emergent central apneas (idiopathic) as well as CompSA patients have primarily obstructive or mixed
some patients with a combination of OSA and CSB-CSA or apneas and obstructive hypopneas during the diagnostic
medication-induced central sleep apnea. However, these last study (or diagnostic portion of a split study). A small number
two groups are discussed in separate sections due to their of central apneas may also occur. During the PAP titration,
unique features. This section discusses mainly the idio- the AHI remains elevated due to persistence or emergence
pathic CompSA group, which is composed of patients who of central apneas or hypopneas. Because central hypopneas
develop treatment-emergent CSA without an obvious cause. are not well defined, this can be a problem in identifying
these patients. Often, CPAP is titrated to very high pressures
in an attempt to control respiratory events. Of interest, CPAP
Pathophysiology
may be more effective in CompSA patients during REM
Patients with CompSA are thought to have an instability in sleep or in the lateral body position. Often an effective level
ventilatory control or a sleep state instability.69 The underly- of CPAP appears to have been found, only to have the patient
ing instability is believed to be exacerbated by CPAP or change to the supine position with a subsequent return of
BPAP. CPAP or BPAP could result in a lower sleeping PaCO2 frequent central apneas. Figures 2118 and 2119 show trac-
by decreasing upper airway resistance. CompSA patients ings on CPAP of a typical CompSA patient. In REM sleep,
probably also have low ATs and difficulty reaching stable respiration on CPAP is relatively stable on CPAP of 10 cm
sleep. Some studies show a male predominance.70,71 H2O (see Fig. 2118, top panel). In stage N2, periodic breath-
ing with central apneas and hypopneas developed on the
same level of CPAP (see Fig. 2118, bottom panel). Subse-
Incidence and Natural History
quently, the pressure was raised to 12 cm H2O without
The incidence of CompSA varies between studies.7,7074 Java- benefit. After repeated arousals, the patient attained stage N3
heri and colleagues72 published a large retrospective analysis and respiration on CPAP of 12 cm H2O stabilized (see Fig.
of 1286 patients with a diagnosis of OSA who underwent a 2119, top panel). However, after a subsequent arousal, the
CPAP titration and 6.5% of the patients had treatment- periodic breathing returned (see Fig. 2119, bottom panel).
emergent CSA. These patients had the most severe OSA and These tracings emphasize that patients with idiopathic
had a central apnea index (CAI) of 5/hr or greater at baseline. CompSA often are better controlled during REM sleep and,
Of the 84 patients with CompSA, 42 returned for a second if they can attain stage N3, respiration may stabilize.
titration. In 33 patients (78%), CSA was eliminated by CPAP.
Of note, most patients in this study had diagnostic and titra-
Treatment of CompSA
tion sleep studies on separate nights (no split studies). In
split studies, rapid titration could predispose to CompSA. The best treatment for CompSA remains controversial. In
Dernaika and associates73 reported on a population of 116 the absence of CSB-CSA or opioids, it appears that a signifi-
patients who met criteria for a split-night study. Twenty- cant portion will improve with chronic CPAP alone.72,73 The
three (19.8%) had CSA during a CPAP titration. Fourteen of only problem with watchful waiting is that if the AHI remains
these patients underwent chronic CPAP treatment. Repeat high, sleep quality will be impaired and adherence may
PSG with CPAP was performed an average of 9 weeks decrease. Therefore, it is prudent to assess patients soon after
after treatment. Objective adherence was documented. CSA starting CPAP. Many CPAP devices provide the ability to
resolved in 12 of the 14 (92%). Lehman and coworkers74 estimate residual events. It is also important to remember
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Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 391
100 V F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
CFLOW
Chest
Abdomen
CPAP 10 stage R supine epoch 428
SpO2
Cpres
30 sec
100 V F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
CFLOW
Chest
Abdomen
SpO2
Cpres
CPAP 10 stage N2 supine epoch 446
FIGURE 2118 A patient with complex sleep apnea (CompSA). Top, The patient is in stage R on continuous positive airway pressure (CPAP) of 10 cm H2O with stable breathing.
Cflow = flow from PAP device; Cpres = pressure from PAP device; ECG = electrocardiogram; SpO2 = pulse oximetry. Bottom, A few epochs later in stage N1 or N2 on the same pressure,
recurrent central apneas are noted.
that the patient is being treated, not the AHI. Therefore, if a to provide a reasonable amount of pressure support (IPAP-
patient reports good sleep and objective adherence is good, EPAP). As discussed in Chapter 19, an ASV device that
intervention may not be necessary if the residual AHI automatically adjusts the EPAP during the night (between
remains mildly elevated (510/hr). If patients do not improve EPAPmin and EPAPmax) is now available from one manu-
or if the residual AHI is high, most clinicians would order a facturer. This option could be useful in a pressure-intolerant
titration with ASV. Studies have documented that ASV is patient or in one in whom the ASV titration does not docu-
effective in the majority of CompSA patients.75,76 A higher ment an effective EPAP setting.
minimal amount of pressure support may be needed if there
is significant nocturnal hypoventilation. Another option
HIGH-ALTITUDE PERIODIC BREATHING
would be treatment with BPAP-ST (backup rate) if ASV is
not effective. In one study comparing BPAP-ST with ASV, The ICSD-2 diagnostic criteria for HAPB are listed in Box
both reduced the central apnea index, although ASV was 217. Periodic breathing is actually a normal adaptation to
slightly more effective.75 ASV may be able to treat CompSA high altitude. Some individuals develop mainly central
patients using lower average pressures and a decreased hypopnea whereas others have frank central apnea.77 As in
number of machine-triggered breaths compared with BPAP- all hypocapnic CSA syndromes, the disorder is worse in
ST. The main adjustment required during ASV titration is NREM than in REM sleep.
titration of expiratory positive airway pressure (EPAP). In HAPB occurs in nearly everyone at 7600 m and is associ-
general, the EPAP will need to be at or close to the level of ated with fragmented sleep (decreased stage N3) from arous-
CPAP needed to prevent obstructive apnea. This is often the als. There are repeated cycling periods of hyperpnea and
pressure that was effective during supine REM sleep. apnea/hypopnea (periodic breathing). Patients complain of
However, if high EPAP is needed, this means that a fairly poor sleep quality or suffocation. There is no association
high inspiratory positive airway pressure (IPAP) is required between HAPB and the other altitude syndromes including
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392 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
F4-M1
100 V C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
Cflow
Chest
Abdomen
CPAP 12 supine epoch 495
SpO2
Cpres
100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
Cflow
Chest
Abdomen
SpO2
CPAP 12 supine epoch 515
Cpres
FIGURE 2119 Top, The same patient in Figure 2118 attained stage N3 sleep and respiration stabilized on the same continuous positive airway pressure (CPAP) of 12 cm H2O.
Cflow = flow signal from the CPAP device; Cpres = delivered pressure by the CPAP device; ECG = electrocardiogram; SpO2 = pulse oximetry. Bottom, After an arousal, the pattern of
periodic breathing returned on the same level of CPAP.
can, with voluntary effort, lower their PaCO2 values. The Evaluation of Patients with Suspected
hypercapnic CSA syndromes are classified in the ICSD-2
Hypoventilation
under the hypoventilation syndromes. The hypoventilation
syndromes included in the ICSD-2 are listed in Box 212. The diagnosis of hypoventilation (daytime or nocturnal)
Detailed diagnostic criteria are listed in Appendix 211. The should be considered in all patients with the disorders listed
ICSD-2 classification of hypoventilation syndromes is not in Box 213 or Figure 2120 who complain of nocturnal
completely satisfactory because the OHS is probably better symptoms including insomnia, dyspnea, disturbed sleep, or
classified with OSA syndromes rather than with neuromus- frequent awakenings. However, lack of symptoms does not
cular disorders and disorders of the thoracic cage. In addi- rule out hypoventilation. The development of right heart
tion, some causes of central hypoventilation (brain tumor) failure should also trigger suspicion but is often a late sign
are neither idiopathic nor congenital. (Fig. 2121). A reduced daytime SaO2 (92%) or an elevated
serum HCO3 (possible compensation for chronic respiratory
Mechanisms of Hypercapnic CSA acidosis) should also increase suspicion of hypoventilation.78
In patients with normal lungs (normal alveolar-arterial [A-a]
and/or Hypoventilation
gradient), significant hypoventilation can be present and the
The mechanisms of CSA and/or hypoventilation in the group SaO2 remains in the low-normal range (Box 218). An arte-
of patients with hypercapnic CSA include alterations in che- rial blood gas with a PaCO2 of 45 mm Hg or greater during
moreceptors, central ventilatory control centers, central the day is the most definite method to diagnose daytime
nervous system (CNS) respiratory pattern generators, lesions hypoventilation. Depending on the clinical setting, a careful
of CNS or spinal cord motor pathways (trauma, tumor), neurologic examination, pulmonary function testing, chest
motor neuron disease (ALS), dysfunction of motor nerves, radiography, CNS imaging (ventilatory control dysfunction
neuromuscular junction disorders (myasthenia gravis), suspected), genetic testing (if congenital central hypoventila-
myopathies (muscular dystrophy), or disorders of the tho- tion syndrome [CCHS] is a possibility), and PSG may be
racic cage (Fig. 2120). useful.78 Early in the disease course, some patients have only
NREM
Arousal Wakefulness
from sleep drive
Chemo-sensors
Medulla
Ventilatory Sedatives, narcotics,
Idiopathic central hypoventilation CO2 (H)
pattern alkalosis
brain tumor, CVA
generators Carotid body
(PO2, PCO2)
Polio Upper
motor neuron
Lower
ALS, polio, phrenic nerve injury motor neuron
Myasthenia gravis Neuromuscular
junction
Myopathy Muscle
Lungs/
Kyphoscoliosis
chest wall
Ventilation
PCO2, PO2
FIGURE 2120 Summary of mechanisms of hypercapnic central sleep apnea and/or hypoventilation during sleep. ALS =
amyotrophic lateral sclerosis; CVA = cerebrovascular accident; NREM = nonrapid eye movement; PCO2 = partial pressure of carbon
dioxide; PO2 = partial pressure of oxygen. From Malhotra A, Berry RB, White DP: Central sleep apnea. In Carney P, Berry RB, Geyer JW
(eds): Clinical Sleep Medicine. Philadelphia: Lippincott Williams & Wilkins, 2005, p. 338.
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394 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
Daytime symptoms
FIGURE 2121 The severity of symptoms of alveolar hypoventilation are related to the degree of alveolar hypoventilation.
As hypoventilation increases in severity, symptoms increase from only abnormalities during sleep to daytime symptoms and
finally to symptoms of overt respiratory failure. In patients with reduced cardiopulmonary reserve from co-morbid conditions,
this relationship is shifted upward and to the left as shown by the dashed line. From American College of Chest Physicians:
Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD,
and nocturnal hypoventilationa consensus conference report. Chest 1999;116:530.
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Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 395
Snore
NP
Airflow
Chest
Abdomen
SaO2 90 90 90 89 90 90 90 91 92 91 92 93 93 94
PETCO2 54 54 56 54 56 54 55 54 54 53 56 56 57 53
Exhaled PCO2
disease (20%) usually presenting with constipation, esopha- CCHS are heterozygous for polyalanine repeat expansion
geal dysmotility presenting with feeding difficulty, tumors of mutations in exon 3 of PHOX2b. The expansion results in
neural crest origin (6%) such as neuroblastoma or ganglio- lengthening the normal 20-repeat polyalanine tract to 2533
neuroma, decreased heart rate variability, decreased heart repeats. Longer expansions are associated with more severe
rate response to exercise, decreased papillary light response, phenotypes. Most mutations occur de novo, but in families
intermittent profuse sweating, and dysregulation of body with CCHS, it is inherited as an autosomal dominant trait.
temperature with decreased baseline body temperature.78,82,83 Treatment includes lifelong ventilatory support for all
CCHS patients are at risk for adverse outcomes from respira- patients during sleep. Some patients will require ventilatory
tory infections because they may not exhibit a fever or com- support while awake as well. Ventilatory support for severe
plain of dyspnea even if severely hypoxemic. cases is usually provided by a volume-cycled ventilator via
The diagnosis of CCHS should be considered if apneic a tracheostomy. In older and milder patients, noninvasive
or cyanotic spells are noted in infants, especially if associ- mask ventilation may suffice.79,83,87 Diaphragmatic pacing has
ated with sleep. The most severe cases occur in patients who also been used during the day. Diaphragmatic pacing at
do not breathe adequately during wakefulness after birth night requires the presence of a tracheostomy, because
and require immediate ventilatory support. In others, the obstructive events usually occur when the upper airway
abnormalities are noted when the infants sleep. Milder cases muscles do not contract in synchrony with the diaphragm.
may present later with signs of cor pulmonale or hypoxic Infants in CCHS must be closely monitored because they
damage to CNS structures. Some cases may not present are at risk for hypoventilation or apnea at sleep onset. These
until late childhood and a few present in adulthood.84,85 The children are also at increased risk during chest infections
diagnosis of CCHS depends on exclusion of other causes owing to their abnormal temperature control, lack of per-
of hypoventilation such as brainstem malformation, inborn ception of dyspnea, and nonappearance of respiratory dis-
errors of metabolism, myopathy, diaphragmatic paralysis, tress. Noninvasive positive-pressure ventilation (NPPV)
lung or respiratory pump abnormalities. PSG with PETCO2 with BPAP with a backup rate has been successfully used
monitoring usually reveals high PETCO2 and low tidal in infants when parents have refused tracheostomy.88,89
volume (Fig. 2123).82 Appropriate alarms are essential. Older children may be
A suspected diagnosis is confirmed by genetic testing for transitioned to NPPV if their symptoms are milder and
mutations in the PHOX2b gene.79,82,86,87 Most persons with they are adherent to treatment.
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396 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
Nasal
pressure
Chest
Abdomen
SpO2
96 97 80 75
PETCO2
36 42 65 57
FIGURE 2123 Thirty-second tracings during wakefulness (left) and NREM sleep (right) in a patient with congenital central
hypoventilation syndrome. Right central and occipital electroencephalographic (C4-M1, O2-M1) and right and left electro-oculographic
derivations (E1-M2, E2-M2) as well as a chin electromyogram (EMG) tracing are shown. During sleep, there is a dramatic reduction in tidal
volume, increase in end-tidal partial pressure of carbon dioxide PETCO2, and decrease in pulse oximetry (SpO2). ECG = electrocardiogram.
From Wagner MH, Berry RB: A full term infant with cyanotic episodes. Congenital central hypoventilation syndrome. J Clin Sleep Med
2007;3:425426.
Other Neural Disorders Causing snoring, breathing pauses, headaches, neck pain, ataxia, ocu-
lomotor disturbances, scoliosis, and lower cranial nerve
Central Hypoventilation
palsies. Although CM I can present in infancy and child-
CSA and hypoventilation due to abnormalities in the control hood, the most common presentation is in young adulthood
of ventilation have been noted in a wide variety of disorders between 20 and 40 years. Sleep apnea is believed due to
but most are relatively uncommon. These include idiopathic pressure on the medullary structures controlling ventilation
central hypoventilation, neurodegenerative disorders with and upper airway muscles. Surgical decompression (poste-
autonomic dysfunction90 such as multiple system atrophy, rior fossa decompression, duraplasty, and cervical laminec-
paraneoplastic encephalitis,91 and tumors of the medulla.92,93 tomy) often improves the degree of sleep apnea, although
CSA and OSA can occur late in the course in patients with significant apnea can be present in the postoperative period.
prior polio infection (postpolio syndrome).94 The Chiari syn- There have been reports of patients treated for obstructive
drome is discussed in the next section. hydrocephalus with shunts who experienced an acute wors-
ening of sleep apnea as the only manifestation of shunt
Chiaris Malformation failure.
Sleep-related breathing disorders are common in both chil-
dren and adults with Chiaris malformation (CM).95,96 With CSA Due to Medication (Opiate/Narcotic-Induced CSA)
the increased use of magnetic resonance imaging (MRI), The opiate-induced sleep-related breathing disorder
cases are often detected before symptoms begin. CM type I (OSRBD) is increasingly common with more aggressive
is defined as herniation of the cerebellar tonsils through the treatment of chronic pain with potent narcotics including
foramen magnum. CM II includes caudal displacement of morphine, fentanyl, and methadone, often in very high
the vermis and is usually associated with myelodysplasia and doses. Affected patients may manifest obstructive apneas
meningomyelocele. In CM I, obstructive apneas, central often of long duration, ataxic breathing, low sleeping respira-
apneas, or a combination can occur. Nocturnal hypoventila- tory rates, and central apneas either intermittent or in the
tion without discrete apneas can also occur. A minority of form of periodic breathing.97,98 They also tend to have either
CM I patients have daytime hypercapnia, but the disorder is persistent or treatment-emergent central apneas on CPAP (a
included in this section because central apnea is believed to form of CompSA). The etiology of the disorder is believed
be secondary to alterations in brainstem control of respira- to be depression of central drive by opiate medications.
tion. Presenting symptoms of CM include worsening of Although opiate-induced CSA is placed in the hypercapnic
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Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 397
CSA group, patients often have either normal or only mildly 2125). Individual patients may have long obstructive apneas
increased daytime PaCO2 values (4550 mm Hg). However, during REM sleep or mixed apneas with a long central com-
patients with OSRBD more often exhibit significant worsen- ponent. Patients may also exhibit relatively few central
ing of hypoventilation during sleep. The many breathing apneas until placed on CPAP (Fig. 2126). As in CSB-CSA,
abnormalities noted in OSRBDs are listed in Box 219. An patients with opiates are often more effectively treated with
unusual characteristic noted during sleep studies is the ataxic CPAP during REM sleep (Fig. 2127).
breathing patternvariation in tidal volume and respiratory
rate (Fig. 2124). Some patients actually have central apneas Treatment
during stage N3 sleep (uncommon in other types of central Some patients will improve with a reduction in narcotic
sleep apnea) and others have a low respiratory rate during dose,2 but this is rarely acceptable to the patient. Other
sleep (see Fig. 2124) or periodic breathing with repetitive patients with mainly obstructive events may respond to
central apneas that are typically short in duration (Fig. CPAP. However, central apneas either persist or emerge on
CPAP in a significant number of patients (see Figs. 2125
and 2126). There is a single case report of use of acetazol-
amide99 as an adjunct to CPAP treatment in patients with
BOX 219
narcotic-induced CompSA. Treatment with either BPAP
Important Facts about Opiates and Sleep-Related with a backup rate or ASV can be successful in narcotic-
Breathing Disorders induced CompSA.100102 Relatively few studies using ASV in
Ataxic breathingvariation in respiratory rate and tidal patients with opiate-induced CSA have been published. One
volume. study found ASV less effective but the EPAP probably was
Slow respiratory rate during sleep. not adequately increased to eliminate obstruction.101 When
Intermittent central apneas (even during stage N3) or using ASV, it is essential to increase EPAP sufficiently to
periodic breathing with central apneas. prevent upper airway closure.100,102 Javaheri and associates102
Long obstructive apneas. found ASV to be an effective treatment for both central and
Relatively few arousals, amount of stage N3 can be obstructive apnea in narcotic-induced CompSA.
increased.
In some patients, NREM AHI REM AHI.
Treatment-emergent central apneas are common even if
Primary Sleep Apnea of Infancy
diagnostic study shows mainly obstructive events. This syndrome was formerly termed primary sleep apnea of
AHI = apnea-hypopnea index; NREM = nonrapid eye movement; REM = the newborn. As the name implies, this syndrome is char-
rapid eye movement.
acterized by CSA due to an immature respiratory control
F4-M1 F4-M1
C4-M1 C4-M1
O2-M1 O2-M1
E1-M2
E2-M2 E1-M2
Chin E2-M2
ECG Chin EMG
Snore
ECG
Nasal
pressure Snore
Oronasal
airflow Nasal
pressure
Chest
Chest
Abdomen
Abdomen
SpO2 SaO2
94%
30 sec 30 seconds
FIGURE 2124 Left, Low respiratory rate in a patient on methadone (67 breaths/min). A 60-second tracing is shown. Right, Variation in flow amplitude and rate (ataxic
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breathing) in another patient on methadone. ECG = electrocardiogram; EMG = electromyogram; SaO2 = arterial oxygen saturation; SpO2 = pulse oximetry.
398 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
100 V F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Nasal
pressure
No airflow
Chest
Abdomen
SpO2
FIGURE 2125 Periodic breathing during a diagnostic study in a patient on a fentanyl patch. Repeated central apneas are noted without any arousals. Respiratory events without
arousals is common in opiate-induced central sleep apnea. ECG = electrocardiogram; SpO2 = pulse oximetry.
100 V F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
HR
ECG
Snore
CFLOW
Chest
Abdomen
SpO2
Cpres
FIGURE 2126 Periodic breathing with central apneas on CPAP of 10 cm H2O during NREM sleep. The patient was taking methadone. Cflow = flow signal from the CPAP device;
Cpres = pressure from PAP device; ECG = electrocardiogram; HR = heart rate; SpO2 = pulse oximetry.
system.6,103 Periodic breathing is a normal finding in pre- hypoventilation. Causes include thoracoplasty, fibrothorax,
mature infants but is deemed pathologic only if the duration kyphoscoliosis, and ankylosing spondylitis.6,105 In general,
of apnea is greater than 20 seconds or if the events are associ- isolated nocturnal hypoventilation precedes daytime
ated with desaturation or other physiologic compromise. The hypoventilation. These disorders result in extrinsic restric-
disorder may be treated with caffeine or low-dose theophyl- tive ventilatory dysfunction78 (Fig. 2128). In patients with
line104 (Box 2110). chest wall disease, the total lung capacity is decreased and
the functional residual capacity is either normal to increased
(ankylosing spondylitis) or decreased (kyphoscoliosis).78 The
Restrictive Thoracic Cage Disorders
chest wall has decreased compliance, so there is an increased
Disorders causing restriction of the thoracic cage due to work of breathing. Patients tend to take rapid shallow breaths.
disease of the spine, chest wall, or pleura can result in The severity of impairment may be roughly gauged by the
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Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 399
F4-M1
100 V C4-M1
O2-M1
E1-M2
E2-M2
Chin
HR
ECG
Snore
Cflow
Chest
Abdomen
SpO2
Cpres
30 sec
FIGURE 2127 Good control of respiratory events with CPAP of 10 cm H2O during REM sleep in the patient with methadone-induced central apnea during NREM sleep shown in
Figure 21-26. Cflow = flow signal from the CPAP device; ECG = electrocardiogram; HR = heart rate; SpO2 = pulse oximetry.
84
other studies reported improvement in quality of life with
NPPV. Patients with bulbar involvement may have more dif-
78
ficulty tolerating NPPV and mask ventilation. These patients
may also have a greater risk of aspiration than those without
72
upper airway dysfunction.
66
0 10 20 40 50 60 70 80
CLINICAL REVIEW QUESTIONS
FVC (% predicted)
1. All of the following are true about CCHS EXCEPT
FIGURE 2131 The mean arterial oxygen saturation (SpO2) determined by nocturnal
oximetry is plotted against the forced vital capacity (FVC; % predicted) for a group of A. It is associated with Hirschsprungs disease.
patients with ALS. Note that many patients with an FVC greater than 50% of predicted B. It is due to mutations in the PHOX2b gene.
had substantial nocturnal desaturation (and presumably nocturnal hypoventilation). C. Hypoventilation is manifested by low tidal volume.
From Morgan RS, McNally S, Alexander M, et al: Use of sniff nasal inspiratory force to
predict survival in amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2005;171:101. D. Patients develop dyspnea when hypoxic.
E. Patients may require 24-hour ventilatory support
from birth.
5. Which of the following is likely present in a patient with 2. A. A small PaCO2-AT gradient predisposes to hypocap-
CSB-CSA associated with heart failure? nic CSA.
A. High wedge pressure (left ventricular end-diastolic
pressure). 3. B. A longer ventilatory phase between events is associ-
B. Low hypercapnic ventilatory response. ated with a longer circulation time, lower cardiac output,
and a longer delay in the SaO2 nadir. The ventilatory
C. Daytime PaCO2 = 44 mm Hg.
phase = cycle length apnea duration = A (20 sec), B
D. Normal left atrial size. (50 sec), C (25 sec), D (30 sec).
6. A 50-year-old man undergoes a split sleep study. The
4. E. CSB may improve with improvement in cardiac func-
results are shown below. The central apneas were not of
tion. CPAP was not effective at reducing the AHI. The
the Cheyne-Stokes type. What do you recommend?
patient may receive some benefit from CPAP, which did
DIAGNOSTIC TITRATION eliminate OSA, but the residual AHI due to central apnea
Total sleep time (min) 120 150 is quite high. ASV can often reduce the AHI to less than
REM sleep (min) 10 40 5/hr. Whereas ASV is more effective at acutely reducing
AHI (#/hr) 50 22 the AHI, no direct long-term comparisons have been per-
Obstructive apneas (no.) 40 15 formed with CPAP treatment of patients with CSB-CSA.
However, short-term studies of ASV do report improve-
Central apneas (no.) 5 30
ment in symptoms and some report improvement in
Mixed apneas (no.) 5 0 cardiac function.
Hypopneas (no.) 40 10
5. A. Patients with CSB-CSA are more likely to have a large
REM AHI
left atrium, atrial fibrillation, a low daytime PCO2, and an
CPAP TST SLEEP AHI REM OA MA CA H
elevated wedge pressure.
6 15 0 40 0 10 0 0 0
7 15 0 40 0 5 0 0 5 6. B. The patient has treatment-emergent CSA. CPAP of
8 30 10 10 30 0 0 0 5 9 cm H2O was effective at eliminating obstructive events.
9 30 20 0 0 0 0 0 0 Higher pressure was associated with central apneas. In
10 30 10 10 0 0 0 5 0 other patients, treatment-emergent central apneas may
occur on pressures needed to prevent obstructive apneas
11 30 10 40 0 0 0 20 0
during REM sleep. The treatment-emergent central
A. CPAP of 8 cm H2O. apneas may resolve with chronic CPAP treatment (espe-
B. CPAP of 9 cm H2O. cially if the patient does not have CSB or is taking potent
C. CPAP of 10 cm H2O. narcotics).
D. ASV titration.
E. BPAP-ST titration. 7. D. The patient may have nocturnal hypoventilation, and
NPPV rather than supplemental oxygen is indicated for
7. A patient with a progressive neuromuscular disorder treatment of nocturnal hypoventilation. Some clinicians
reports mild snoring and has a daytime PaCO2 of would begin empirical BPAP 8/4 cm H2O with upward
42 mm Hg. However, nocturnal oximetry reveals an titration as indicated. However, a diagnostic PSG is indi-
SaO2 88% for 15 min. The FVC is 60% of predicted and cated to determine if OSA, nocturnal hypoventilation, or
the maximum inspiratory force is 70 cm H2O. What do both are present. If the nocturnal arterial oxygen desatu-
you recommend? ration is due to OSA alone, one might consider treatment
A. Nocturnal supplemental oxygen. with CPAP. However, given the likely need for NPPV in
the future, treatment with BPAP rather than CPAP is
B. Diagnostic PSG and PSG for titration with CPAP.
probably the best answer. A titration with NPPV (BPAP-
C. Diagnostic PSG and PSG for titration with BPAP. ST) can eliminate OSA events and treat nocturnal
D. Diagnostic PSG and PSG for titration with hypoventilation as well as provide respiratory muscle
BPAP-ST. rest. BPAP with a backup rate is recommended for
E. Empirical treatment with BPAP-ST 8/4 cm H2O and patients with neuromuscular disorders because they may
backup rate of 12 breaths/min. not trigger IPAP/EPAP cycles due to weak muscles (espe-
cially during REM sleep). A backup rate will also provide
Answers intervention for central apneas. Of note, a saw-tooth
pattern in the oximetry tracings used to screen a neuro-
1. D. Patients with CCHS do not experience dyspnea when muscular disorder patient for abnormal nocturnal gas
hypoxemic and are at risk from death due to respiratory exchange would suggest that sleep apnea is present (dis-
infections. crete events).
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Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 403
21. Issa FG, Sullivan CE: Reversal of central sleep apnea using
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Appendix 211
1. Sleep-Related Nonobstructive Alveolar Hypoventilation, A. Lower airways obstructive disease is present (as
Idiopathic evidenced by a forced expiratory volume exhaled
A. Polysomnographic monitoring demonstrates episodes in one second/forced vital capacity ratio less
of shallow breathing longer than 10 seconds in dura- than 70% on pulmonary function testing) and is
tion associated with arterial oxygen desaturation and believed to be the primary cause of hypoxemia.
frequent arousals from sleep associated with the B. Polysomnography or sleeping arterial blood
breathing disturbances or brady-tachycardia. gas determination shows at least one of the
Note: Although symptoms are not mandatory to make following:
this diagnosis, patients often report excessive daytime i. An SpO2, during sleep of less than 90% for
sleepiness, frequent arousals and awakenings during more than 5 minutes with a nadir of at least
sleep, or insomnia complaints. 85%.
B. No primary lung diseases, skeletal malformations, or ii. More than 30% of total sleep time with an
peripheral neuromuscular disorders that affect venti- SpO2 of less than 90%.
lation are present. iii. Sleeping arterial blood gas with PaCO2 that
C. The disorder is not better explained by another is abnormally high or disproportionately in-
current sleep disorder, medical or neurologic disor- creased relative to levels during wakefulness.
der, mental disorder, medication use, or substance C. The disorder is not better explained by another
use disorder. current sleep disorder, another medical or neuro-
Key features: No obvious cause such as a medical dis- logic disorder, medication use, or substance use
order or structural problems with the lung or chest disorder.
wall. These patients do not have a congenital form of II. Sleep-Related Hypoxemia Due to Pulmonary Paren-
alveolar hypoventilation. However, late-onset con- chymal or Vascular Pathology
genital central hypoventilation has been described. A. Lung parenchymal disease or pulmonary vascular
2. Congenital Central Alveolar Hypoventilation Syndrome disease is present and believed to be the primary
A. The patient exhibits shallow breathing, or cyanosis cause of hypoxemia.
and apnea, of perinatal onset during sleep. B. Polysomnography or sleeping arterial blood
Note: In severely affected infants, consequences of gas determination shows at least one of the
hypoxia, including pulmonary hypertension and cor following:
pulmonale, may also be present. i. An SpO2 during sleep of less than 90% for
B. Hypoventilation is worse during sleep than during more than 5 minutes with a nadir of at least
wakefulness. 85%.
C. The rebreathing ventilatory response to hypoxia and ii. More than 30% of total sleep time at an SpO2
hypercapnia is absent or diminished. of less than 90.
D. Polysomnographic monitoring during sleep demon- iii. Sleeping arterial blood gas with PaCO2 that
strates severe hypercapnia and hypoxia predominantly is abnormally high or disproportionately
without apnea. increased relative to levels during wakeful-
E. The disorder is not explained by another current sleep ness.
disorder, medical or neurologic disorder, medication C. The disorder is not better explained by another
use, or substance use disorder. current sleep disorder, another medical or neuro-
3. Sleep-Related Hypoventilation Due to Medical logic disorder, medication use, or substance use
Condition disorder.
I. Sleep-Related Hypoventilaton/Hypoxemia Due to III. Sleep-Related Hypoventilation/Hypoxemia Due to
Lower Airways Obstruction Neuromuscular and Chest Wall Disorders
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407
408 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
A. A neuromuscular or chest wall disorder is present iii. Sleeping arterial blood gas with PaCO2 that
and believed to be the primary cause of is abnormally high or disproportionately in-
hypoventilation/hypoxemia. creased relative to levels during wakefulness.
B. Polysomnography or sleeping arterial blood gas C. The disorder is not better explained by another
determination shows at least one of the following: current sleep disorder, another medical or neuro-
i. An SpO2 during sleep of less than 90% for logic disorder, medication use, or substance use
more than 5 minutes with a nadir of at least disorder.
85%. Examples: Obesity hypoventilation syndrome,
ii. More than 30% of the total sleep time at an neuromuscular disease, kyphoscoliosis.
SpO2 of less than 90%.
FEV1/FVC ratio. For convenience, the lower limit of normal patients. For example, using 90% of predicted as the lower
for the FEV1 is assumed to be 80% of predicted and the lower limit of normal for the FEV1/FVC ratio may be more sensitive
limit of normal for the FEV1/FVC ratio is assumed to be 0.70. for identification of OVD. Patients with OVD have normal
However, using a slightly higher value of the FEV1/FVC ratio or increased lung volumes (residual volume [RV], function
for the lower limit of normal is appropriate in younger residual capacity [FRC], and total lung capacity [TLC]) (Fig.
222). The first lung volume to be affected is the RV. Most
Lung volume here is RV
patients with OVD have an elevated RV due to airtrapping
from small airway narrowing and closure. With more severe
6 disease, the FRC and then the TLC may also be increased
(hyperinflation). However, the relative increase in the RV is
5 Expiration
greater than any increase in the FRC or TLC. In moderate
FEV1 FVC to severe OVD, the increase in RV is large enough (compared
4
Volume (liters)
FIGURE 222 Lung volumes including total lung capacity (TLC), Moderate
functional residual capacity (FRC), and residual volume (RV). In to severe
TLC Normal Mild
obstructive ventilatory dysfunction (OVD), the RV increases more than OVD
TLC OVD
the FRC and TLC. In moderate to severe OVD, the RV increase may be
enough to decrease the vital capacity (VC). ERV = expiratory reserve VC IC
volume; IC = inspiratory capacity; Vt = tidal volume. VC
Vt
FRC VC
VC
ERV
RV
0
RV
RV residual volume
FRC function residual capacity
TLC total lung capacity
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Chapter 22 Sleep and Obstructive Lung Disease 411
TABLE 221
Spectrum of Obstructive Ventilatory Dysfunction
DIFFUSING BRONCHODILATOR AIRTRAPPING AND
DIAGNOSIS CAPACITY RESPONSE HYPERINFLATION
Asthma Reversible airflow obstruction Normal Yes >12% often 25% May be present
(physiologic diagnosis)
Chronic bronchitis Productive sputum for 3 mo for 2 Normal Sometimes 1015% Air trapping (high
consecutive yr (clinical diagnosis) RV)
Emphysema Destruction of gas-exchanging units Decreased Rarely Yes
and enlargement of terminal
airspaces (pathologic diagnosis)
Mixed chronic bronchitis Combination Decreased None or small Yes
and emphysema (COPD)
In OVD the increase in RV > increase in FRC > increase in TLC.
Air trapping manifested by an increased RV and hyperinflation manifested by an increased FRC and TLC.
COPD = chronic obstructive pulmonary disease; FRC = functional residual capacity; OVD = obstructive ventilatory dysfunction; RV = residual volume; TLC = total lung
capacity.
TABLE 222
GOLD Criteria for Chronic Obstructive Pulmonary Disease Severity
STAGE DESCRIPTION FINDINGS (BASED ON POSTBRONCHODILATOR FEV1)
0 At risk Risk factors and chronic symptoms but normal spirometry
I Mild FEV1/FVC 70%
FEV1 at least 80% of predicted value
May have symptoms
II Moderate FEV1/FVC 70%
FEV1 50% to < 80% of predicted value
May have chronic symptoms
III Severe FEV1/FVC 70%
FEV1 30% to < 50% of predicted value
May have chronic symptoms
IV Very severe FEV1/FVC 70%
FEV1 < 30% of predicted value
or
FEV1 < 50% of predicted value + chronic respiratory failure
Respiratory failure: PaO2 < 60 mm Hg with or without PaCO2 > 50 mm Hg
while breathing room air at sea level
FEV1 = postbronchodilator forced expiratory volume in 1 second; FVC = forced vital capacity; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial
partial pressure of oxygen.
From Rabe KF, Hurd S, Anzueto A, et al: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of
chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532555.
90 100
90
80 A
80
Arterial oxygen saturation (%)
70 70
60
60
SpO2
50
50 40
15 minutes
30
40
20
30 10
0
20
FIGURE 224 A portion of overnight oximetry in a patient with both snoring and
10 moderate COPD. The baseline is reduced during sleep but the saw-tooth pattern is
suggestive of obstructive sleep apnea. A = period of REM sleep. From Berry RB: Sleep
0 Medicine Pearls 2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 227.
11 12 1 2 3 4 5 6 7
PM AM
Time of night
FIGURE 223 Nocturnal oximetry in a patient with severe chronic obstructive BOX 221
pulmonary disease (COPD). The awake arterial oxygen saturation (SaO2) is mildly Major Mechanisms of Nocturnal Oxygen
reduced at 92% but falls to the low 80s with sleep. Further severe falls in the SaO2 occur Desaturation in Chronic Obstructive
during rapid eye movement (REM) sleep (dark bars). Note that the worst period of Pulmonary Disease
desaturation was noted in the early morning hours. From Berry RB: Sleep Medicine
Pearls, 2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 216. Hypoventilationbelieved by most to be the most
important factor
Decreased chemosensitivity (REM < NREM < wake)
Reliance on accessory respiratory muscles and loss of
individual indicates very severe disease. Daytime hypercap- this assistance during REM atonia
nia is usually associated with an FEV1 of 30% to 40% of Increased upper airway resistance
predicted or less. Patients with the overlap syndrome (COPD Lower alveolar ventilation per minute ventilation (high
+ obstructive sleep apnea [OSA]) can develop hypercapnia dead spacetotidal volume ratiodue to high dead
with higher FEV1 values. space and low tidal volume)
Ventilation-perfusion mismatching (drop in PaO2 exceeds
the increase in PaCO2)
Sleep in COPD
High closing volume and decreases in FRCespecially
Sleep in patients with COPD is often impaired in both dura- during REM-associated hypopnea
tion and quality.57 Many patients also have significant Coexisting sleep apnea (1215%)especially blue
hypercapnia and hypoxemia at night. Ten percent to 15% of bloaters
patients may also have concomitant OSA that worsens noc- Low awake SaO2starting position on the steep portion
turnal gas exchange (overlap syndrome). The typical pattern of the oxygen-hemoglobin saturation curve (larger fall in
of nocturnal oxygen desaturation (NOD) in a patient with SaO2 for a given fall in PaO2)
COPD is shown in Figure 223. The baseline sleeping arte- FRC = functional residual capacity; NREM = nonrapid eye movement;
PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial partial
rial oxygen saturation (SaO2) falls 2% to 4% from the awake pressure of oxygen; REM = rapid eye movement; SaO2 = arterial oxygen
baseline with minor fluctuations until much larger drops are saturation.
noted during rapid eye movement (REM; stage R) sleep. In
contrast, a typical oximetry of a patient with the overlap
syndrome is shown in Figure 224. There is a low baseline
sleeping SaO2 and a saw-tooth pattern consistent with mechanisms of nocturnal arterial oxygen desaturation are
repeated discrete events. Whereas central sleep apnea could listed in Box 221. The relative importance of hypoventila-
cause a saw-tooth pattern, this is most likely to represent mismatch is still
tion and ventilation-perfusion ( V/Q)
OSA. debated.
increases slightly (Fig. 225). Recall that PaCO2 = constant in normal individuals (see Fig. 227).8,10 During REM sleep,
(CO2 production)/(alveolar ventilation); see Chapter 10. there is typically a decrease in chest wall movement,9 likely
The fall in ventilation is due to a loss of the wakefulness due to chest wall hypotonia. These REM-associated physio-
stimulus to breathe, decreased ventilatory responses (che- logic changes result in a slight increase in PaCO2 and
mosensitivity) to hypoxia and hypercapnia, and increased decreases in PaO2 during REM compared with NREM sleep.
upper airway resistance.5,7 The increase in PaCO2 results in The slight fall in PaO2 results in minimal changes in the SaO2
a mild decrease in the PaO2. However, because the awake due to the position of the oxygen-hemoglobin saturation
PaO2 value is on the flat portion of the oxygen-hemoglobin curve (see Fig. 226).
saturation curve (Fig. 226), minimal drops in the SaO2 are
noted (e.g., from 97% to 95%). The FRC may decrease slightly Sleep-Related Changes in Respiration in COPD
from wake to NREM sleep (Fig. 227).8,9 Koo and colleagues11 studied 15 patients with severe COPD
During REM sleep in normal individuals, ventilation is (FEV1 of 0.96 L) with a mean daytime PaO2 greater than
irregular and periods of reduced tidal volume occur, often
during bursts of REMs. Skeletal muscle hypotonia reduces 10 mmHg decrease in PO2
the contribution from the accessory respiratory muscles and causes a greater desaturation
respiration depends on the diaphragm.8,9 Two studies did not starting on the steeper part of
the curve
find a lower FRC during REM compared with NREM sleep
100
Upper 40
Ventilation Chemosensitivity
airway
resistance 0.5-1.5 LPM 20-50%
20
*P .05
* *P .05 *P .05
3.5 3.5 3.5 *
*
*
FRC (liters)
FRC (liters)
FRC (liters)
FIGURE 227 (Left) In normal subjects the FRC is lower during sleep but the FRC does not differ between stages 2, 34, and REM (N2, N3, and R). (Middle) In asthma the FRC
decreases from wake to stage N2N3 and then further decreases during REM sleep. (Right) FRC during wake and stages N2 and N3 is higher in asthmatics compared to normal
individuals. In this study the FRC during REM sleep was similar in asthmatics and normal individuals. FRC = functional residual capacity; REM = rapid eye movement. Adapted from
DaneshGroup.com
Ballard RD, Irvin CG, Martin RJ, et al: Influence of sleep on lung volume in asthmatic patients and normal subjects. J Appl Physiol 1990;68:20342041.
414 Chapter 22 Sleep and Obstructive Lung Disease
60 mm Hg and found a mean decrease in PaO2 of 13.5 mm Hg COPD exhibit REM-related hypoventilation and NOD,
and a mean increase in PaCO2 of 8.3 mm Hg during REM despite having a daytime PaO2 above 60 mm Hg.12
sleep (Fig. 228). Although patients with daytime hypercap-
nia or a low awake PaO2 or SaO2 are more likely to have NonRapid Eye Movement During supine wakefulness, patients
worse gas exchange during sleep, up to 25% of patients with with COPD often start with low-normal or slightly decreased
SaO2 values. Therefore, even the normal fall in PaO2 with
80 sleep will cause a greater decrease in the SaO2. Koo and col-
leagues11 documented a fall in PaO2 of approximately
8 mm Hg from wake to NREM sleep and an increase in
Mean 1 SD
PaCO2 of about 5 mm Hg. In patients with COPD, the onset
of NREM sleep is associated with mild falls in the SaO2 (4
Partial pressure arterial O2 and CO2 (mmHg)
Rapid Eye Movement During REM sleep, there are more pro-
PaCO2 found periods of arterial oxygen desaturation compared with
50 NREM sleep in patients with COPD. These episodes of desat-
uration are characterized by long periods of irregular breath-
ing and reduced tidal volume (Figs. 229 and 2210). In
contrast to obstructive hypopnea in OSA patients, the onset
and termination of these nonapneic periods of REM desatu-
40
ration are less well defined. As noted previously, it is believed
Awake 2 3 REM that REM-associated hypotonia reduces the contribution for
Stages of sleep the intercostal muscles so that ventilation depends on the
diaphragm. Hyperinflation in patients with COPD reduces
FIGURE 228 Changes in arterial partial pressure of carbon dioxide (PaCO2) and
the effectiveness of the diaphragm. During the periods of
arterial partial pressure of oxygen (PaO2) during sleep in a group of patients with severe
COPD. Here stages 2, 3, and REM represent stages N2, N3, and R. REM = rapid eye
REM-associated diaphragmatic inhibition (often during
movement; SD = standard deviation. From Koo KW, Sax DS, Snider GL: Arterial blood bursts of eye movements),1315 the tidal volume and minute
gases and pH during sleep in chronic obstructive pulmonary disease. Am J Med ventilation often decrease dramatically (see Figs. 229 and
1975;58:663670.
Wake
Sleep stage
1
2
3
REM
REM
100
O2 saturation %
90
80
70
60
50
Tidal volume
500 cc
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time in minutes
FIGURE 229 An episode of hypopneic breathing during rapid eye movement (REM) sleep in a patient with COPD. The episode lasted over 10 minutes. From Fletcher EC, Gray BA,
Levin DC: Nonapneic mechanisms of arterial oxygen desaturation during rapid-eye-movement sleep. J Appl Physiol 1983;54:632639.
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Chapter 22 Sleep and Obstructive Lung Disease 415
1.4 20 FIGURE 2210 Fall in tidal volume during a period of rapid eye
movement (REM)associated hypoventilation. Note that there is no
Respiratory rate
1.2 overall significant change in the respiratory rate. NREM = nonrapid eye
movement. From Becker HF, Piper AJ, Flynn WE, et al: Breathing during
15
1.0 sleep in patients with nocturnal desaturation. Am J Respir Crit Care Med
Tidal volume
0.4
5
0.2
NREM REM NREM
0 0
0 20 40 60 80
Breaths
*
Total volume 0.5 L
10 cm
Esophageal pressure
H2O
Normal COPD hypopneic breathing during REM sleep are still debated. The
analysis is complicated by the nonsteady-state condition of
transient hypopneic breathing.
FRC
FRC Time of Night and Circadian Variation in Lung Function
CV REM episodes in the early morning have greatest REM
CV
density and the greatest variation in ventilation even in
normal individuals.19 These REM periods also are typically
longer. In the early morning hours, there is greater lower
Awake REM Awake REM
airway resistance due to circadian changes in bronchomotor
supine supine supine (hypopneic tone that are exaggerated in many patients with COPD.5,6
breathing Ballard and colleagues18 found an increase in upper airway
supine) resistance but not lower airway resistance during the night
FIGURE 2213 In patients with chronic obstructive pulmonary disease (COPD), the in a group of patients with emphysema. Conversely, lower
closing volume (CV) is nearer the functional residual capacity (FRC) than in normal airway resistance does increase in asthmatics20 and likely in
individuals. The fall in FRC associated with hypopneic breathing during rapid eye some COPD patients with a significant component of airway
movement (REM) sleep results in tidal breathing below the CV. This worsens ventilation- disease. These factors help explain why the most severe and
perfusion mismatch. Note that, in this figure, the FRC for COPD during hypopneic longest REM-associated desaturation typically occurs in
breathing in REM sleep is shown as approximately equal to that of a normal individual the early morning hours.
during REM sleep. The actual FRC in COPD patients may depend on other factors such as
obesity and vary between individuals.
COPD Types and Respiration during Sleep
Several studies have tried to find factors predicting more
severe desaturation during sleep in COPD. As might be
expected, a lower awake PaO2 and higher PaCO2 predict
hypoxemia. Hudgel and coworkers14 concluded that hypoven- more dramatic changes in gas exchange during sleep. One
mismatch, causes REM-
tilation, and to a lesser extent V/Q study compared blue bloaters and pink puffers and found the
associated desaturation. Fletcher and associates15 found an former were more likely to desaturate during sleep (Table
increase in venous admixture during REM hypopnea epi- 223).21 Analysis of the Sleep Heart Health data suggested
sodes and concluded that V/Q mismatch was a significant that the odds of having desaturation more than 5% of total
cause of hypoxemia. The relative roles of hypoventilation and sleep time was minimally increased until the FEV1/FVC ratio
mismatch in inducing nocturnal desaturation during was less than 60% (Table 224).22 A plot of awake SaO2 versus
V/Q
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Chapter 22 Sleep and Obstructive Lung Disease 417
40 40
20 20
0 0
60 70 80 90 100 60 70 80 90 100
Mean SaO2 awake (%) Mean SaO2 awake (%)
minimum sleeping value is shown in Figure 2214. Patients oxygen found no difference in quality of life, subjective sleep-
with lower awake SaO2 or PaO2 values tend to have lower iness, or subjective sleep quality in COPD patients who had
values at night.23 However, there is considerable variability NOD compared with those who did not.24 It is likely that
and oximetry or polysomnography (PSG) is needed to reli- other factors such as cough, nocturnal dyspnea, and medica-
ably exclude NOD. tion side effects have greater effect than transient hypoxemia
on sleep quality. In many patients, the NOD is less than 15
Sleep Quality in COPD minutes and confined to the last few REM periods of the
Sleep quality is impaired with reductions in total sleep time, night.
stage N3 sleep, and REM sleep. In contrast, the wake after
sleep onset (WASO) and stage N1 sleep are increased as is Treatment of Sleep-Related Hypoxemia in COPD
the total arousal index. Patients often complain of insomnia Studies have shown that long-term oxygen therapy (LTOT)
but can also complain of daytime sleepiness if OSA is also will improve survival in patients with COPD with daytime
present. A study of NOD in COPD patients not on 24-hour hypoxemia.2527 The standard indication for 24-hour
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418 Chapter 22 Sleep and Obstructive Lung Disease
100
Room air
SaO2
80
SaO2 (%)
40
REM
10 min
Oxygen SaO2
100
SaO2 (%)
TcPCO2
TcPCO2 (mm Hg)
80
REM
FIGURE 2215 Top, The arterial oxygen saturation (SaO2) and transcutaneous partial pressure of carbon dioxide (TcPCO2) during the
night with an impressive drop in the SaO2 during rapid eye movement (REM) sleep associated with a mild increase in the TcPCO2. The
TcPCO2 is approximately 70 mm Hg during NREM sleep. Bottom, The same patient on supplemental oxygen with a TcPCO2 now
approximately 80 mm Hg. There is improved SaO2, although the TcPCO2 increases during REM sleep. From Goldstein RS, Ramcharan V,
Bowes G, et al: Effect of supplemental nocturnal oxygen on gas exchange in patients with severe obstructive lung disease. N Engl J Med
1984;310:425429.
and SaO2 during NREM sleep.35 Martin and associates36 Hypnotics in COPD Patients Hypnotics have been used with
found that inhaled ipratropium bromide (a short-acting some caution in patients with COPD. In general, in nonhy-
anticholinergic) given by nebulizer improved subjective percapnic patients, clinically significant worsening of gas
sleep quality, NOD, and the amount of REM sleep. This study exchange does not occur with benzodiazepine receptor ago-
used 4 nights of sleep monitoring, allowing patients to nists.41 Girault and coworkers42 studied 10 patients with
acclimate to the monitoring equipment. McNicholas and severe COPD before and after 10 days of zolpidem 10 mg
coworkers37 found that tiotropium (a long-acting inhaled and could find no worsening in performance or gas exchange.
anticholinergic) given either in the morning or in the evening Of interest, the only objective improvement in sleep was an
improved the SaO2 during REM sleep compared with placebo increase in stage N2. Subjective sleep quality was also
but did not improve sleep quality. Ryan and colleagues38 improved (not placebo-controlled). Another study found no
found that salmeterol, a long-acting inhaled beta agonist, detrimental effects from temazepam 10 mg.43 Steens and col-
improved nocturnal oxygenation without impairing sleep leagues44 studied the effects of zolpidem and triazolam in
quality. Donahue and associates39 compared fluticasone mild to moderate COPD. Total sleep time was increased as
propionate/salmeterol with ipratropium bromide/albuterol well as sleep efficiency without an adverse effect on gas
during an 8-week period. The former treatment combination exchange. This was a randomized, double-blind, placebo-
was more effective at reducing nocturnal and sleep symp- controlled study. A double-blind, placebo-controlled cross-
toms. The use of inhaled corticosteroids in patients with over study of patients with moderate to severe COPD
COPD remains somewhat controversial and the controversy evaluated the effects of 8 mg of ramelteon, a melatonin
was reviewed by Sin and Man.40 The use of inhaled cortico- agonist with no respiratory depressant properties. This study
steroids does not improve mortality but, in some studies, found no worsening of nocturnal gas exchange.45 However,
improved the quality of life, reduced exacerbations, and there was an improvement in total sleep time, sleep effi-
improved lung function when added to a long-acting bron- ciency, and the latency to persistent sleep on ramelteon com-
chodilator. Based on the previously mentioned studies, most pared to placebo. This medication has a short duration of
clinicians would use a long-acting beta agonist or anticho- action and is generally used for sleep-onset insomnia.
linergic in patients with significant COPD who complain of However, the duration of action may vary between individu-
nocturnal dyspnea, cough, or poor sleep quality. Inhaled als. In summary, the benzodiazepine receptor agonists are
corticosteroids are also a reasonable addition especially if the probably safe in nonhypercapnic nonhypoxemic patients.
patient has repeated COPD exacerbations, a significant com- However, caution is still required. Ramelteon is a safe hyp-
ponent of bronchospasm, or do not respond to other notic that may be effective in some patients with COPD.
treatments. Many clinicians use sedating antidepressants as hypnotics
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420 Chapter 22 Sleep and Obstructive Lung Disease
(e.g., trazodone), believing that this is safer. However, the BOX 223
utility of the use of sedating antidepressants to improve sleep Overlap Syndrome
quality in COPD patients has never been documented.
Combination of OSA and COPD.
Nocturnal Noninvasive Positive-Pressure Ventilation For patients Prevalence of OSA in COPD is the same as the general
population.
with COPD who present with hypercapnic respiratory
Predisposes OSA patients to more severe arterial oxygen
failure, noninvasive positive-pressure ventilation (NPPV)
desaturation.
has proved to be an effective treatment, often avoiding the
Hypercapnia may occur in OLS at FEV1 values greater than
need for intubation and mechanical ventilation. The results
typically associated with hypercapnia in patients with
for long-term use are much less clear. Those COPD patients COPD without OSA.
most likely to benefit are individuals with substantial daytime Optimal treatment of OLS
CO2 retention and NOD who are highly motivated. A con- PAP (CPAP or BPAP), BPAP may be better tolerated.
sensus conference recommended the following indications Supplemental oxygen if needed (low awake or
for NPPV in patients with COPD46: baseline sleeping SaO2).
Bronchodilator treatment and smoking cessation.
1. Symptoms criteria (e.g., fatigue, dyspnea, or morning Nocturnal supplemental oxygen alone is not adequate
headache), treatment, may be associated with significant
2. Physiologic criteria daytime PaCO2 > 55 or 5054 mm Hg hypercapnia during sleep and worse outcomes.
with NOD, or OLS patients who adhere to CPAP (in addition to oxygen
3. PaCO2 5054 mm Hg with recurrent hospitalization if needed) have a better outcome.*
related to episodes of hypercapnic respiratory failure. OLS patients have an increased risk of death and
hospitalization due to severe COPD exacerbations.
Patients with severe swallowing dysfunction or those who Treatment with CPAP may improve survival of OLS
cannot protect their airway are not candidates for NPPV. patients and decrease hospitalizations.
*From Machado MCL, Vollmer WM, Togeiro SM, et al: CPAP and survival in
moderate to severe obstructive sleep apnea syndrome and hypoxemic COPD.
Overlap Syndrome Eur Respir J 2010;35:132137.
From Marin JM, Soriano JB, Carrizo SJ, et al: Outcomes in patients with
The overlap syndrome (OLS) consists of patients with both chronic obstructive pulmonary disease and obstructive sleep apnea. Am J
OSA and COPD (Box 223). One study found that OSA is Respir Crit Care Med 2010;182:325331.
BPAP = bilevel positive airway pressure; COPD = chronic obstructive
no more frequent in COPD patients than in the general pulmonary disease; CPAP = continuous positive airway pressure; FEV1 =
population.22 That is, the prevalence of OSA in COPD forced expiratory volume in 1 second; OLS = overlap syndrome; OSA =
patients is the same as in the general population. However, obstructive sleep apnea; PAP = positive airway pressure; SaO2 = arterial
oxygen saturation.
because both are common, the combination is also fairly
common. The two groups of OSA patients with daytime
hypercapnia include patients with the obesity hypoventila- 90 mm Hg. Therefore, use of supplemental oxygen in patients
tion syndrome and some patients with OLS.4749 Patients with OLS and significant daytime hypercapnia may worsen
with OLS tend to have severe NOD even if they do not have nocturnal hypercapnia. Fletcher and associates50 followed
daytime hypercapnia. Patients with COPD usually become patients with chronic lung disease and OSA including a
hypercapnic when the FEV1 is around 1.0 liters (or 40% of group treated with oxygen but no effective treatment for
predicted). OLS patients can be hypercapnic with milder sleep apnea. They found that patients who did not have ade-
reductions in the FEV1 (Table 22-6, Study #2). However, OLS quate treatment for OSA had no improvement in their pul-
patients can also maintain a normal daytime PCO2 even monary hemodynamics whereas those who had effective
when their FEV1 is quite reduced (Table 22-6, Study #1). In treatment improved. A recent observational study of patients
clinical practice, one often treats patients with a combination with OSA and hypoxemic COPD receiving LTOT found that
of COPD, OSA, and severe obesity who have significant those who accepted continuous positive airway pressure
hypoventilation. It is difficult to know how to label them (CPAP; in addition to oxygen) and adhered to treatment had
because they likely have components of both OHS and OLS. a better survival than those who did not.51 Another study by
Marin and coworkers52 of patients with OLS found an
Treatment of OLS increased risk of death and hospitalization due to COPD
Treatment of patients with OLS with supplemental oxygen exacerbations. CPAP treatment was associated with improved
alone can result in significant increases in nocturnal PaCO2. survival and decreased hospitalizations. The treatment of
In Figure 2216, on room air, there is a saw-tooth pattern in patients with OLS includes treatment of their COPD and
the SaO2 tracing. As mentioned previously, this is a clue that CPAP or bilevel positive airway pressure (BPAP) with sup-
OSA as well as COPD is present. On the bottom, the patient plemental oxygen if needed. If significant CO2 retention is
is on supplemental oxygen and the transcutaneous partial present, most clinicians would use BPAP. Some patients with
pressure of carbon dioxide (TcPCO2) has climbed from COPD have difficulty exhaling on CPAP and may be more
approximately 60 mm Hg (top tracing) to just below adherent to treatment with BPAP.
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Chapter 22 Sleep and Obstructive Lung Disease 421
TABLE 226
Eucapnic and Hypercapnic Patients with Overlap
Syndrome Healthy
3-5%
STUDY #1 STUDY #1 STUDY #2
Peak flow
OLS OLS OLS
Baseline
EUCAPNIC HYPERCAPNIC HYPERCAPNIC
(N = 14) (N = 14) (N = 7)
FEV1 (liters) 1.01 1.12 2.03 (61%
Nocturnal
pred) 15-20% asthma
FEV1/FVC 0.44 0.47 0.61
4 PM 4 AM
PaO2 71 60 52 Time
(mm Hg)
FIGURE 2217 Both healthy individuals (solid line) and subjects with nocturnal
PaCO2 40 50 51
asthma (dotted line) have circadian alterations in lung function with nadirs occurring at
(mm Hg)
approximately 4 AM. The circadian variation in lung function is increased in subjects with
NREM AHI AHI 40 51 57 (AHI NREM nocturnal asthma and might exceed 20% over the course of the 24-hour period. From
+ REM) Sutherland ER: Nocturnal asthma. J Allergy Clin Immunol 2005;116:11791186.
Lowest SaO2 85 77 no data
AHI = apnea-hypopnea index; FEV1 = forced expiratory volume in 1 second; BOX 224
FVC = forced vital capacity; NREM = non-rapid eye movement; OLS = overlap
syndrome; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial Manifestations of Nocturnal Asthma
partial pressure of oxygen; REM = rapid eye movement; SaO2 = arterial
oxygen saturation. Morning drop in FEV1 > 15% (often 1550%)
Study #1 Chan CS, Grunstein RR, Bye PT, et al: Obstructive sleep apnea with Increased circadian variation in FEV1
severe chronic airflow limitation. Am Rev Respir Dis 1989;140:12741278. Decreased response to bronchodilators during early AM
Study #2 Bradley TD, Rutherford R, Lue F, et al: Role of diffuse airway
Increased bronchial hyperresponsiveness to methacholine
obstruction in the hypercapnia of obstructive sleep apnea. Am Rev Respir Dis
1986;134:920924. Nocturnal awakenings with symptoms of asthma
FEV1 = forced expiratory volume in 1 second.
ASTHMA
Nocturnal asthma is usually defined as occurring in patients increasing airway inflammation, and a decreased response
with a 15% or greater drop in the peak flow (or FEV1) to inhaled bronchodilators.5457 Some of the manifestations
between bedtime and morning awakening.53,54 Even normal of nocturnal asthma are listed in Box 224.
persons have a circadian variation in lung function with Important considerations for the diagnosis and treatment
the best function around 4 PM and the worst at 4 AM. of nocturnal asthma are listed in Box 225.
However, the variation is much greater in patients with
asthma. Asthmatic patients can experience a 20% to 50%
Epidemiology
drop in the FEV1 from bedtime until morning (morning
dippers) (Fig. 2217). The overnight drop in lung func- The largest study of the prevalence of nocturnal asthma was
tion is also associated with airway hyperresponsiveness, reported by Turner-Warwick in 198858 and surveyed 7729
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422 Chapter 22 Sleep and Obstructive Lung Disease
50 50
Asthma Normal
Rla (cm H2O/L/sec)
30 30
20 20
10 10
0 0
0000 0100 0200 0300 0400 0500 0600 0000 0100 0200 0300 0400 0500 0600
A Time B Time
Supine, sleep Supine, awake
Rla lower airway resistance
FIGURE 2218 A, In asthmatics, lower airway resistance (Rla) increased overnight during supine wake and sleep. However, during sleep, the change was greater.
B, In normal subjects, there was minimal change overnight and no difference between wake and sleep. A and B, From Ballard RD, Saathoff MC, Patel DK, et al: Effect
of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol 1989;67:243249.
10
from having patients use allergen-impermeable bed covers.
15 It still seems prudent to minimize exposure to allergens if
20 possible.
investigators concluded the GER is unlikely to be a major asthma and demonstrated that administration of the once-
factor in uncontrolled asthma. However, this group of daily preparation at 7 PM resulted in a higher serum theoph-
patients did not have GER symptoms. Treatment of patients ylline concentration at night than did an equivalent dose of
with asthma and GER could be considered (for GER alone) the twice-daily preparation given at 7 PM and 7 AM. The 7 AM
but may also help asthma in individual patients. However, FEV1 was higher in subjects who received the once-daily
there is no evidence that treatment of GER in patients with preparation. The dosing of oral78 or inhaled steroids79 at 3 to
intractable asthma without symptomatic GER is of benefit. 4 PM appears to have a greater effect on nocturnal asthma. A
double-blind, placebo-controlled study evaluated the effects
OSA/Obesity of a 50-mg oral dose of prednisone given at 8:00 AM, 3:00 PM,
If OSA is present in patients with asthma, treatment with or 8:00 PM on overnight spirometry, blood eosinophil counts,
nasal CPAP can improve the asthma. Chan and associates75 and BAL cytology in seven individuals who had asthma.79 A
treated patients with both OSA and asthma and found that single prednisone dose at 3:00 PM resulted in a reduction in
the peak expiratory flow rate improved in the morning and the overnight percentage decrease in FEV1 and improvement
night after 2 weeks of treatment. In another study, weight in the FEV1 measured at 4:00 AM. In contrast, neither the 8:00
loss in a group of obese asthmatics improved pulmonary AM nor the 8:00 PM prednisone dose resulted in overnight
function.76 spirometric improvement. After the 3:00 PM prednisone
dose, blood eosinophil counts were also significantly reduced
at both 8:00 PM and 4:00 AM. These findings have not altered
Diagnosis of Nocturnal Asthma
the usual clinical practice of administering oral steroids in
The easiest way to diagnose severe nocturnal worsening of the morning.
asthma is to have the patient record peak flow measurements
at bedtime and upon awakening. Although there is not a
Treatment of Nocturnal Asthma
widely accepted criteria, a fall in the peak flow of greater than
15% (evening to awakening) supports the diagnosis of noc- Important treatment considerations for nocturnal asthma
turnal asthma. are listed in Box 225, and general asthma guidelines (Step
treatment) are listed in Table 227. Reducing the burden of
allergen exposure by keeping the bedroom free of dust may
Chronotherapy
help. The foundation of treatment of chronic persistent
Chronotherapy is the design of treatment to respond to cir- asthma is inhaled corticosteroids. Weersink and colleagues80
cadian changes in disease. If theophylline is used, dosing so studied a group with nocturnal asthma and patients were
that the peak level will occur in the early morning may treated with inhaled fluticasone, salmeterol (a long-acting
improve effectiveness. Martin and coworkers77 compared beta agonist [LABA]), or the combination. The three treat-
twice-daily sustained-release theophylline versus once-daily ments all reduced the circadian variation in peak flow
sustained-release theophylline in subjects with nocturnal to less than 10% (Fig. 2220), improved the bronchial
TABLE 227
Guidelines for Asthma Management
INTERMITTENT
ASTHMA PERSISTENT ASTHMA
STEP 6
STEP 5 Preferred:
High-dose ICS +
STEP 4 Preferred:
LABA + oral
High-dose ICS + LABA
STEP 3 Preferred: corticosteroid
And
Medium-dose ICS And
STEP 2 Preferred: Consider omalizumab
+ LABA Consider omalizumab
Low-dose ICS + LABA for patients who
STEP 1 Preferred: Alternatives: for patients who
Or have allergies
Low-dose ICS Medium-dose ICS have allergies
Preferred: Medium-dose
Alternatives: + either LTRA,
SABA prn ICS
Cromolyn, LTRA, theophylline, or
Alternatives:
nedcromil, or zileuton
ICS + either LTRA,
theophylline
theophylline, or
zileuton
ICS = inhaled corticosteroid; LABA = long-acting beta agonist; LTRA = leukotriene receptor antagonist; SABA = short-acting beta agonist.
Adapted from Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood InstituteNational Asthma
Education and Prevention Program. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf
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Chapter 22 Sleep and Obstructive Lung Disease 425
Salmeterol Fluticasone Salmeterol fluticasone FIGURE 2220 Effects of three treatment regimens on the
60 variability in peak expiratory flow (PEF) over the night. All three
were effective. From Weersink EJM, Douma RR, Postma DS, et al:
55 Fluticasone propionate, salmeterol xinafoate, and their
combination in the treatment of nocturnal asthma. Am J Respir
50
Circadian variation in PEF (median, range)
40
35
30
25
20
15
10
hyperresponsiveness to methacholine both day and night, noted previously, if theophylline is used, the dosing should
and improved cognitive performance during daytime testing. be altered so levels are relatively high at night. Because of the
Thus, the usual practice is to start with inhaled steroids and need to follow theophylline levels and adjust the dose to both
add a long-acting inhaled beta agonist if symptoms persist obtain optimal treatment and avoid serious toxicity, long-
(see Table 22-7). acting beta agonists are favored by most clinicians. If there
Both inhaled long-acting beta agonists and sustained- are symptoms of nocturnal GER, treatment with a proton
action theophylline preparations have been effective in treat- pump inhibitor may improve asthma in some patients. The
ment of nocturnal asthma.77,8184 Selby and associates82 found evening proton pump inhibitor should be given before the
only a slight advantage for salmeterol compared with the- evening meal rather than at bedtime. If sleep apnea is present,
ophylline in sleep quality (fewer arousals). The falls in treatment with CPAP may improve asthma in some patients.75
morning flow rates were similar but awakenings were less
frequent on salmeterol. Weigand and coworkers83 found sal-
CLINICAL REVIEW QUESTIONS
meterol to be more effective than theophylline at preventing
the morning drop in flow rates. The drugs did not differ in 1. A 50-year-old man with moderate COPD has a room air
PSG findings, but patients perceived better sleep with salme- blood gas showing a PaO2 of 60 mm Hg. He undergoes
terol than with theophylline. In any case, the long-acting nocturnal oximetry that reveals 200 minutes with an SaO2
beta agonists require less attention to dosing than theophyl- less than 88%. There are long periods in which the average
line. Whereas asthmatics generally have a greater response SaO2 is around 85%. A saw-tooth pattern is seen in about
to beta agonists than anticholinergic medications, vagal tone half of the tracing. The patient reports snoring but no
is increased at night. Therefore, one might expect that daytime sleepiness. What do you recommend?
inhaled anticholinergics might be helpful. There is evidence A. Treatment with supplemental oxygen at 2 L/min.
that the addition of an inhaled anticholinergic to standard B. Treatment with supplemental oxygen at 2 L/min and
treatment may be helpful in some patients with moderate to repeat the oximetry.
severe asthma.84A recent study85 documented the effective-
C. PSG.
ness of the addition of tiotropium (long-acting anticholiner-
gic) to patients still not well controlled with an inhaled D. Addition of an inhaled long-acting beta agonist and
steroid. This approach may provide an alternative to long- repeat the oximetry.
acting beta agonists or an additional treatment if the combi- 2. Which of the following is (are) mechanisms of nonapneic
nation of inhaled steroids and a long-acting beta agonist is (hypopneic) NOD during REM sleep?
unable to control nocturnal symptoms.
A. Low baseline SaO2.
Although theophylline could have stimulatory effects and
impair sleep, this possible side effect is probably outweighed B. Intercostal muscle hypotonia.
by benefit from bronchodilator effects in some patients. As C. Hypoventilation.
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426 Chapter 22 Sleep and Obstructive Lung Disease
mismatch.
D. V/Q 4. E. Worse nocturnal SaO2 is predicted by a lower daytime
E. All of the above. SaO2/PaO2, hypercapnia, and the blue bloater clinical
type.
3. Which of the following is thought to play a role in the
morning fall in the FEV1 in asthma patients? 5. D.
A. High cortisol levels at night. 6. C. The patient has nocturnal asthma evidenced by a 22%
B. High circulating catecholamines. fall in the peak flow as well as symptoms. The treatment
C. Increased inflammatory cells in the lung. of choice is inhaled corticosteroids. If this is not effective,
the addition of a long-acting beta agonist is the next step.
D. Low parasympathetic tone.
However, the patient may improve with inhaled cortico-
4. Which of the following are predictive of significant arte- steroids alone.
rial oxygen desaturation during sleep in a patient with
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esophageal reflux in asthma patients with reflux symptoms. Am 82. Selby C, Engleman HM, Fitzpatrick MF, et al: Inhaled salme-
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outcomes. Am J Med 1996;100:395405. line. Sleep and efficacy outcomes in patients with nocturnal
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Chapter 23
20
TABLE 231
Different Leg Movement Conditions
RLS PLMS PLMD
Diagnosis History PSG PSG + History
Prevalence Common Very common Rare
Asymptomatic individuals
Narcolepsy
REM sleep behavior disorder
OSA
Associated findings 80% have PLMS Usually asymptomatic or Must exclude other
symptoms are not due to PLMS causes of insomnia or
A minority of patients have RLS daytime sleepiness
Relationship with other leg A diagnosis of RLS excludes a A PSG finding not a disorder Not diagnosed if RLS is
movement conditions diagnosis of PLMD present
OSA = obstructive sleep disorder; PLMD = periodic limb movement disorder; PLMS = periodic limb movement in sleep; PSG = polysomnography; REM = rapid eye
movement; RLS = restless leg syndrome.
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Chapter 23 The RLS, PLMS, and the PLMD 431
TABLE 232
Characteristics of Restless Legs Syndrome Mimics
URGE TO ABNORMAL WORSE IN THE IMPROVED BY NEUROLEPTIC
MOVE SENSATIONS EVENING/NIGHT MOVEMENT NEUROLOGIC STUDIES USE
RLS Yes Usually Always Temporary Neurologic examination No
improvement usually normal, EMG
often normal
Hypnic jerk No No Sleep onset Single whole body Normal No
jerk
Neuropathy No Yes, can be Sometimes No Decreased sensation, No
painful abnormal EMG/nerve
conduction
Positional Yes Usually Usually Change in position Variable No
discomfort not movement
Neuroleptic Inner No Not usually Not usually Variable YES
akathisia restlessness
Leg cramps No Pain localized Sometimes Stretching not Normal No
to muscle movement
Claudication No Pain Not usually Walking may Decreased pulses No
worsen
Painful toes, No Pain, burning Not usually No Abnormal EMG, MRI may No
moving leg show lumbosacral
syndrome nerve compression
EMG = electromyogram; MRI = magnetic resonance imaging; RLS = restless legs syndrome.
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Chapter 23 The RLS, PLMS, and the PLMD 433
TABLE 233
Genetic Linkages and Associations in Restless Legs Syndrome
LINKAGES
AUTHOR POPULATION CHROMOSOME MODEL
22
RLS-1Desautels, 2001 French Canadian 12q Dominant
RLS-2Bonati, 200323 Italian 14q Dominant
RLS-3Chen, 200424 United States 9p Dominant
25 26
RLS-4Levchenko, 2006, 2009 French Canadian 20p Dominant
27
RLS-5Pichler, 2006 Italian 2q Dominant
ASSOCIATIONS
AUTHOR POPULATION CHROMOSOME GENE
28
Winkelmann, 2007 French Canadian/ 2p MEIS1, exon 9
European 6p BTBD9, intron 5
15q MAP2K5, LBXCOR1
Stefannson, 200729 Icelandic/US 6p BTBD9
30
Winklemann, 2007 European 12q BTBDR, intron 5
Adapted from Hening WA, Buchfuhrer MJ, Lee HB: Clinical Management of Restless Legs Syndrome. West Islip, NY: Professional Communications, 2008, pp. 5657.
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Chapter 23 The RLS, PLMS, and the PLMD 435
20 TABLE 234
Any frequency
Frequency 1 /week Manifestation of Restless Legs Syndrome in
16 Restless Legs Syndrome Sufferers (N = 551)
Sufferer group
Prevalance (%)
Sleep efficiency 82.2 80.1 72.7 .01 B. The child meets all adult criteria for RLS but does NOT
(%) relate a description in his or her own words that is
consistent with leg discomfort.
PLMSI (#/hr) 10.6 24.7 33.2 <.05
AND
PLMWI 29.1 25.8 31.0 NS
C. The child has at least two of the following three
*Patients were rated as mild, moderate, or severe based on frequency and
findings:
severity of RLS complaints, severity of sleep-onset insomnia, and frequency
and duration of nocturnal awakenings. i. Sleep disturbance for age.
NS = not significant; PLMSI = periodic limb movements in sleep index; ii. A biologic parent or sibling with definite RLS.
PLMWI = periodic limb movements during wake index.
iii. A PSG documented PLM index of 5/hr (5/hr of
From Montplasir J, Boucher S, Poirer G, et al: Clinical, polysomnographic,
and genetic characteristics of restless legs syndrome: a study of 133 patients sleep)
diagnosed with new standard criteria. Mov Disord 1997;12:6165. PLM = periodic limb movement; PSG = polysomnography; RLS = restless legs
syndrome.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
RLS in Children
RLS can be difficult to diagnose in children.6,13,4043 Some
complain of typical RLS symptoms while others complain of
growing pains or simply have difficulty sitting still. The the maximum duration of PLM events was extended from 5
ICSD-2 diagnostic criteria for RLS in children are shown in to 10 seconds and voltage amplitude criteria were used to
Box 239. These criteria are based on the NIH workshop on define a significant LM. Similar scoring criteria for PLMS
RLS, which listed criteria for probable and possible RLS for were published in the AASM scoring manual.47 The AASM
research purposes.13 The Peds REST study found criteria for manual did not provide criteria for scoring PLMW. As
definite RLS in 1.9% of children aged 8 to 11 years and 2% reviewed in Chapter 12, for LMs to be counted as part of a
in adolescents age 12 to 17 years.40 Of note, PLMS is less PLM series (to be PLMs), they must be 0.5 to 10 seconds in
common in children and a PLMSI of 5/hr or greater is con- duration and have an amplitude greater than 8 V above the
sidered abnormal. Some children with attention deficit resting baseline anterior tibial electromyogram (EMG) level.
hyperactivity disorder (ADHD) have PLMS and possible The time of onset of successive LMs must be between 5 and
RLS and vice versa.44 The relationship of RLS and ADHD 90 seconds. If two leg EMG bursts are separated by less than
remains to be determined. 5 seconds from onset to onset, they are considered a single
LM if they occur on the same or different legs. LMs must
occur in groups of four or more to be considered PLMs (part
PERIODIC LIMB MOVEMENTS IN SLEEP
of a PLM sequence). An LM is not scored as a PLM if it
In the earlier descriptions of PLMS, the phenomenon was occurs during a period starting 0.5 second before the start
referred to as nocturnal myoclonus, but this terminology of the apnea/hypopnea to 0.5 second after an apnea and
is no longer used. As discussed in detail in Chapter 12, the hypopnea. How to handle PLMs associated with RERAs was
limb movements (LMs) composing PLMS are characterized not mentioned, but many clinicians would consider these as
by the rhythmic repetitive stereotypic dorsiflexion/extension associated with respiratory events.
of the big toe, dorsiflexion at the ankle, and sometimes
flexion at the knee and hip joints. Individual LMs that meet
PLMSI and PSG Findings
criteria for PLMS are referred to as PLMs. Criteria for iden-
tifying LMs qualifying as PLMs were first proposed by The PLMSI is the number of PLM events per hour of sleep.
Coleman3 and later revised by a task force of the American The ICSD, first edition,48 listed the following grading of the
Academy of Sleep Medicine (AASM) in 1993.45 A revised severity of PLMs: PLMSI < 5 normal, 524 mild, 2549
scoring system was published in 2006 by the World Associa- moderate, and 50/hr severe. However, these cutoffs are
tion of Sleep Medicine in association with the IRLSSG.46 entirely arbitrary and are not based on any outcome
Criteria for scoring PLMs during both sleep (PLMS) and data. Given the high prevalence of PLMS in asymptomatic
wake (PLMW) were published. The major change was that individuals, there is unlikely to be a value separating
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438 Chapter 23 The RLS, PLMS, and the PLMD
TABLE 237
Medications Used to Treat the Restless Leg Syndrome
DOSE USUAL HALF-LIFE (HR)/
FORMS INITIAL EFFECTIVE MAX DOSE TIME TO ONSET OF ELIMINATION
(MG) DOSE (MG) DOSE (MG) (24 HR) ACTION (H, R)
DOPAMINE PRECURSORS
CD/LD 25/100 1 1 tablet
2 100200 of 200 LD hs 30 min 1.53 H
(Sinemet) of 25/100 LD
CD/LD CR 25/100 1 1 tablet
2 100200 of 200 LD hs 120 min 68 H
(Sinemet CR) 50/200 of 25/100 LD
DOPAMINE AGONISTS
Pramipexole 0.125 0.125 0.250.75 1.5 mg 120 min 812 R
(Mirapex) 0.25 23 hr max effect
Ropinirole 0.25 0.25 0.52.0 4.0 mg 60120 min 6H
(Requip) 0.5 2 or 3 divided 13 hr max effect
doses
OPIOIDS
Propoxyphene 100 100 100 100 mg q4h 1560 min, peak level 46 H, R
napsylate 32, 65 65 65 600/24 hr 22.5 hr
(Darvon) 65 mg q4h
Propoxyphene HCl 390/24 hr
HC/APAP (Lortab, 5, 7.5, 5 515 HC 2030 mg/day 1.3 hr peak level 34
Vicoden) 10/325 in 2 or 3 (hydrocodone)
5, 7.5, divided doses
10/500
Oxycodone 5, 10, 15 5 515 530 q4h 1015 min, peak level 36 H, R
3060 min
Methadone 5, 10 2.55 515 15 3060 min 859 H
Tramadol 50 50 50100 50100 q4h 1 hr, peak level 23 hr 67 H
400 mg/24 hr
BENZODIAZEPINE RECEPTOR AGONISTS
Clonazepam 0.5 0.25 0.251.0 2 mg 60120 min peak 1939 H
(Klonopin) level
Temazepam 15, 30 30 (15 1530 30 mg 4560 min, peak level 89 H
(Restoril) elderly) 90120 min
Zolpidem 5, 10 10 (5 elderly) 510 10 mg 30 min, peak level 2.53 H
Zolpidem-CR 6.25, 12.5 12.5 (6.25 6.2512.5 12.5 mg 90 min
(Ambien CR) elderly)
Eszopiclone 1, 2, 3 2 (1 elderly) 23 3 mg <30 min, peak level 6H
(Lunesta) 60 min
Zalpelon (Sonata) 5, 10, 20 10 1020 20 mg 1530 min, peak level 12 H
3090 min
ANTICONVULSANTS
Gabapentin 100, 300 300 6001800 2400 mg Peak level 24 hr 57 R
(Neurontin) 200300 Slow upward titration
after HD recommended
APAP = acetaminophen; CD = carbidopa; CR = controlled release; H = hepatic metabolism; HC = hydrocodone; HD = hemodialysis; LD = l-dopa; R = renal metabolism.
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442 Chapter 23 The RLS, PLMS, and the PLMD
TABLE 238
Benzodiazepine Receptor Agonists and Periodic Limb Movement in Sleep/Periodic Limb Movement Disorder
MEDICATION/ DECREASED IMPROVED
STUDY STUDY DESIGN DISORDER PLMSI SLEEP IMPROVED SYMPTOMS
Clonazepam and Case series PLMS No Sleep efficiency improved Improved
temazepam subjective sleep
Mitler, 198688 quality but not
alertness
Clonazepam Placebo-controlled PLMS Yes Sleep latency decreased N/A
Peled, 198789 Sleep efficiency improved
Triazolam Double-blind, PLMS with sleep No Sleep efficiency increased Objective daytime
Bonnet, 199090 placebo-controlled fragmentation Total sleep time increased alertness
cross-over improved
Triazolam Cross-over, placebo- PLMS No Decreased PLM arousal Less daytime
Doghramji, 199191 controlled index sleepiness MSLT
Clonazepam Placebo-controlled, PLMD and RLS No Yes Improved
Saletu, 200192 single-blind with subjective sleep
cross-over with quality
clonazepam given
first
MSLT = multiple sleep latency test; N/A = not applicable; PLM = periodic limb movement; PLMD = periodic limb movement disorder; PLMS = periodic limb
movement in sleep; PLMSI = periodic limb movement in sleep index; RLS = restless leg syndrome.
(zolpidem, zaleplon, eszopiclone) can be used for treatment occur. LD/CD in the short-acting form is active within 1 2
of RLS or PLMD.70,8892 Clonazepam, a potent and long- hour and, therefore, is a good choice for treatment with
acting BZRA, has been the most studied88,89,92 (Table 238). intermittent RLS (that may not be predictable). A DA will be
The BZRAs work mainly by reducing the sleep latency, effective, although the time to onset is delayed for 1 to 3
increasing sleep efficiency, and reducing the arousals due to hours. Ropinirole may have a more rapid effect than prami-
PLMS. Most studies have NOT found a decrease in the pexole. Other choices are low-potency opiates such as pro-
PLMSI. Unfortunately, clonazepam can cause profound poxyphene or codeine. Sedative-hypnotics may also be
morning grogginess due to its long half-life. The BZRAs with effective.
a short duration of action (triazolam,90,91 zaleplon, or zolpi-
dem) or an intermediate duration of action (zolpidem-CR, Daily RLS
eszopiclone, temazepam) are likely to be as effective and Daily RLS of moderate severity requires a different approach
better tolerated. In patients with early morning awakening, from milder disease. Although LD/CD may be effective, it is
a change from the shorter-acting to the medium-duration associated with augmentation in 80% of the cases. In addi-
medications may be helpful. This class of medications should tion, due to the short duration of action, patients may have
be used with caution in patients with OSA or severe lung rebound (return of symptoms in the middle of the night or
disease. Side effects include hallucinations, sleep-related morning). The options are taking an additional short-acting
eating disorder, confusion, falls, morning grogginess, and LD/CD in the middle of the night or using a continuous-
unpleasant taste (eszopiclone). release LD/CD preparation. The longer-acting preparation
has a slow onset. One of the nonergotamine DAs (ropini-
role or pramipexole) is considered the treatment of choice
RLS Treatment Algorithm
for daily/moderate to severe RLS.70
In choosing treatment, it is useful to classify the patient using The initial dose should be low (0.125 pramipexole 0.25
the approach of Silber and coworkers70 into the following ropinirole) and given 2 hours before symptom onset. The
groups: (1) mild/intermittent RLS symptoms, (2) daily RLS dose can be slowly increased every 3 to 5 days. The usual
symptoms, and (3) refractory RLS symptoms (Table 239). effective dose ranges are 0.25 to 0.75 mg for pramipexole and
The mild/intermittent group may be treated with conserva- 0.5 to 1.5 mg for ropinirole (higher doses have been used by
tive measures such as avoiding precipitating medications some clinicians). If a given DA is not effective, the other
(sedating antihistamines) and substances (alcohol, caffeine), should be tried because some patients respond better to
warm baths, and iron supplementation if there are low iron either pramipexole or ropinirole. If the clinical response is
stores. If a RLS medication is used, it should be rapidly acting inadequate or side effects prevent the use of the DA, a low- to
because the patient can often not predict that symptoms will moderate-potency opiate, gabapentin, or a sedative-hypnotic
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Chapter 23 The RLS, PLMS, and the PLMD 445
TABLE 239
Treatment Algorithm for Restless Leg Syndrome
Mild/intermittent RLS Nonpharmacologic Abstain from caffeine, nicotine, alcohol.
Iron replacement.
Discontinue drugs (find alternate) that may worsen or cause RLS.
Alerting activities.
Pharmacologic Levodopa/carbidoparapid onset.
DAslow onset (2 hr).
Low-potency opiates/opioid agonist (propoxyphene, tramadol).
Sedative-hypnotic BZRA.
Daily RLS First choice DA Ropinirole or pramipexole
If side effects or not
effective, change to the
other DA.
If side effects on both DAs,
use second or third choice.
Second choice Opiateslow to high potency Low potency:
propoxyphene, tramadol.
High potency:
hydrocodone/APAP,
oxycodone, methadone.
Use DA if unsuccessful.
Third choice (unless pain Gabapentin Gabapentin may be first
or history of addiction) Sedative-hypnotic choice in patients with
painful sensations.
Use DA if unsuccessful.
Refractory RLS If DA is initially effective Split DA dose Ropinirole (0.251.5 mg)
but augmentation Change to another DA Pramipexole (0.1250.75 mg)
RLS treated with DA then develops.
1. Inadequate initial response Moderate to severe Change to high-potency Oxycodone (515 mg),
2. Response inadequate with augmentation or DA opiate methadone (510 mg).
time not tolerated
3. Intolerable side effects
4. Augmentation Moderate to severe Change to gabapentin Start gabapentin 300600 mg,
augmentation or DA lower in elderly, or renal
not tolerated failure.
Pain prominent May require 13001800 mg
Addiction concerns
Inadequate initial Add BZRA, opioid, or Multiagent treatment may
response gabapentin to DA avoid use of high doses of a
DA only partially effective single agent.
at moderate dose or
highest tolerated dose.
APAP = acetaminophen; BZRA = benzodiazepine receptor agonist; DA = dopamine agonist; RLS = restless legs syndrome.
should be tried. If side effects are noted at higher doses of become inadequate over time, (3) intolerable side effects
a DA, one might also combine a lower dose of DA with have occurred, or (4) augmentation is present. The approach
another class of medications. If the RLS is associated with to augmentation has already been discussed. Treatment
pain, some physicians recommend starting with gabapentin approaches to refractory/severe RLS include (1) switch to
instead of a DA. another DA, (2) add an opioid, gabapentin, or BZRA, (3)
change from a DA to gabapentin, or (4) change to a high-
Refractory/Severe RLS potency opioid. Because of the difficulty in treating severe
Refractory RLS is defined as (1) inadequate initial response augmentation, it is best to avoid very high doses of DAs if
despite adequate dose (and timing of dose), (2) response has possible.
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446 Chapter 23 The RLS, PLMS, and the PLMD
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apnea with continuous positive airway pressure. Sleep 2003; 82. Kaplan PW, Allen RP, Bucholz DW, Walters JK: A double-blind,
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of restless leg syndrome: a follow-up study. Eur J Neurol 2000; 89. Peled R, Lavie P: Double-blind evaluation of clonazepam on
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with restless legs syndrome. Sleep 2004;27:907914. 91. Doghramji K, Browman CP, Gaddy JR, et al: Triazolam dimin-
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less legs syndrome: a case-control study. Sleep 2010;33:8187.
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Chapter 24
BOX 241
History
Hypersomnias of Central Origin
The key symptoms of narcolepsy were described by West-
1. Narcolepsy with cataplexy phal in 1877.8 The term narcolepsy, meaning to seize with
2. Narcolepsy without cataplexy drowsiness, was coined by Gelinau.8 Aidie termed the loss
3. Narcolepsy due to medical condition of muscle tone as cataplexy in the early 20th century.9 Yoss
4. Narcolepsy unspecified and Daly10 described the classic tetrad of daytime sleepi-
5. Idiopathic hypersomnia with long sleep time ness, cataplexy, hypnagogic hallucinations, and sleep paraly-
6. Idiopathic hypersomnia without long sleep time sis (SP). In 1960, Vogel11 reported that sleep-onset REM
7. Recurrent hypersomnia periods were associated with narcolepsy. Initially, the asso-
8. Behaviorally induced insufficient sleep ciation of narcolepsy with the human leukocyte antigen
9. Hypersomnia due to medical condition (HLA) DR2 antigen was described in Japanese patients.12
10. Hypersomnia due to drug or substance Later, the HLA DQB1*602 was found to be strongly associ-
11. Hypersomnia not due to substance or known ated with narcolepsy in white and African American popu-
physiologic condition (including hypersomnia due to
lations.13 In 1998, two groups simultaneously reported the
mental disorder) (nonorganic hypersomnia [NOS])
existence of hypocretin (Orexin) peptides present in the
12. Physiologic (organic) hypersomnia, unspecified
lateral and posterior hypothalamus.5,6 Cleavage of a single
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
precursor protein produces the peptides hypocretin-1
American Academy of Sleep Medicine, 2005. (Orexin A) and hypocretin-2 (Orexin B). In 2000, the asso-
ciation of narcolepsy with cataplexy and low or undetect-
able levels of CSF Hcrt1 was described.7
TABLE 241
Features of Narcolepsy
FEATURES OF SPECIFIC FOR
NARCOLEPSY COMMENTS NARCOLEPSY?
CLASSIC TETRAD SYMPTOMS
EDS Continuous daytime sleepiness, with exacerbations (sleep attacks). No
Usually first symptom.
Present in virtually 100% of narcolepsy patients.
Cataplexy Muscle weakness triggered by emotion. Yes
Most common triggers: hearing or telling a joke.
Onset usually occurs within a few years of the onset of sleepiness.
Duration: Seconds to minutes.
Consciousness preserved at least at beginning of episodes.
Present in 6070% of patients with narcolepsy.
Hypnagogic (at sleep onset) Vivid dreamlike images that occur at sleep-wake transitions. No
or hypnapompic (on Duration: Several minutes.
awakening) hallucinations Can be associated with SP.
Sleep paralysis A partial or complete paralysis of the skeletal muscles that occurs at sleep No
onset or sleep offset.
Can be associated with HPH > HH. The patient is awake but cant move.
Can be associated with dyspnea, although the diaphragm is not affected.
Duration: A few seconds to several minutes.
OTHER MANIFESTATIONS OF NARCOLEPSY
Disturbed nocturnal sleep Increased stage N1. No
Frequent awakenings.
2030% have short nocturnal REM latency (<15 min).
PLMS is common.
Automatic behavior Semipurposeful activity with amnesia. No
REM sleep behavior disorder Dream enactmentoften violent, REM without atonia. No
EDS = excessive daytime sleepiness; HH = hypnagogic hallucinations; HPH = hypnopompic hallucinations; PLMS = periodic limb movements during sleep;
REM = rapid eye movement; SP = sleep paralysis.
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Chapter 24 Hypersomnias of Central Origin 453
TABLE 242
Narcolepsy Facts
INCIDENCE OF NARCOLEPSY 1/2000
RISK FOR DEVELOPING Excitatory
Inhibitory
FAMILIAL RELATIONSHIP NARCOLEPSY
Identical twin has narcolepsy 2531% of other twin has
with cataplexy. narcolepsy.
First-degree relative has 12% (1040 higher risk). SLD Glu Glu
narcolepsy. SOM
Glu Interneurons
Motor neurons
HLA ANTIGEN PREVALENCE HLA DQB1*0602 POSITIVE
GABA/Gly
General population. 1238%. B
N+C. 90% (10% negative).
FIGURE 241 A, Orexin (Hypocretin) neurons in the hypothalamus project widely to
NC. 4060%. many brain areas responsible for maintenance of wakefulness including the
tuberomammillary nucleus (TMN), dorsal raphe, and locus coeruleus (LC). B, Possible
HYPOCRETIN CSF HYPOCRETIN-1
pathways mediating atonia of REM sleep. Neurons in the atonia areas of the pons, the
N+C Absent or low 90100%. sublateral dorsal nucleus (SLD), project directly to interneurons in the spinal cord that
Normal in up to 10%. inhibit motor neurons. An indirect pathway via the supraolivary medulla (SOM) is also
illustrated. Other pathways are also likely important. The atonia neurons are
NC 90% normal levels.
glutaminergic and the inhibitory spinal cord interneurons secrete glycine (Gly) and
510% reduced levels
gamma-aminobutyric acid (GABA). Glu = glucose. A, Adapted from Scammell TE: The
(most + for DQB1*0602).
neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154166.
CSF = cerebrospinal fluid; HLA = human leukocyte antigen; N+C = narcolepsy
B, Vetrivelan R, Fuller PM, Tong Q, Lu J: Medullary circuitry regulating rapid eye movement
with cataplexy; NC = narcolepsy without cataplexy.
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sleep and motor atonia. J Neurosci 2009;29:93619369.
454 Chapter 24 Hypersomnias of Central Origin
the activity of brain areas active during wakefulness (tuber- wakefulness. It is not clear whether low CSF histamine is a
omammillary nucleus [TMN]histamine, locus coeruleus cause or an effect of EDS in these patients. Recall that Hcrt
norepinephrine [NE], and dorsal rapheserotonin).1823 neurons stimulate histaminergic neurons in the TMN.
Their activity is believed to stabilize the sleep-wake system However, CSF histamine was low even in patients without
to prevent abrupt transitions between sleep and wake- Hcrt ligand deficiency (NC and IH). Therefore, other
fulness. Histaminergic neurons are located exclusively in defects beside Hcrt deficiency must be involved in producing
the TMN of the posterior hypothalamus and project to low CSF histamine levels.
various brain regions associated with regulation of sleep-
wake cycles. Activity of these histaminergic neurons is
believed to help promote wakefulness. Hcrt neurons project NC Group
to the TMN and stimulate the TMN neurons via Hcrt2 The pathophysiology of NC is not well understood. A
receptors. small percentage (510%) of NC patients have a reduced
CSF Hcrt (most are positive for HLA DQB1*0602). NC
patients negative for the HLA DQB1*0602 almost always
have normal CSF Hcrt1 levels.7,25,26 The etiology of NC
Pathophysiology of Narcolepsy
is currently unknown but may represent a dysfunction of
N+C Group the Hcrt system without total loss of Hcrt-producing
As noted previously, canine N+C is usually secondary to a cells. Thannickal and coworkers39 examined the brain of
defect in the receptor for Hcrt2. Human N+C is associated one patient with NC and found a 33% reduction in hypo-
with absent or very low CSF levels of Hcrt1 (90100% of cretin cells (compared to normals) with maximal loss in
patients).15,2426 Brains of patients with N+C have reduced the posterior hypothalamus. Thus, partial loss of Hcrt
staining for Hcrt in the hypothalamus.27,28 N+C is associated neurons and other alterations in the Hcrt system without a
with a loss of approximately 90% of Hcrt neurons. Melanin- reduction in CSF Hcrt could be the etiology of NC. As
concentrating hormone neurons, which are intermixed with noted previously, CSF histamine is low in NC patients.37,38
Hcrt cells in the normal brain, were not reduced in number, This may be a marker of hypersomnia, or reduced hista-
indicating that cell loss is relatively specific for Hcrt neurons. mine secretion could be part of the pathogenesis of the
It is believed that hypothalamic Hcrt cells are destroyed disorder.
before disease onset. Mutations in Hcrt genes do not appear
to be the cause of most human narcolepsy.29 Of note, up to
10% of patients with N+C have normal CSF Hcrt1 levels.25,26 Mechanisms of Cataplexy
Thus, other abnormalities of the Hcrt system or other mech- The mechanisms inducing cataplexy are still under
anisms must be the cause of the syndrome in these patients. investigation.4042 The atonia of REM sleep is thought to be
The cause of the loss of Hcrt cells in patients with N+C is due to inhibition of the spinal alpha motor neurons of the
unknown. Because of the association of narcolepsy with anterior horn cells by glycine and gamma-aminobutyric acid
HLA antigens, an autoimmune mechanism has been hypoth- (GABA) secreted by spinal interneurons (see Fig. 241B).
esized but has been difficult to document.30 Elevated anti- The interneurons are activated directly by projections from
streptococcal antibodies were found in one study of patients areas in the pons responsible for atonia or via an intermedi-
with recent narcolepsy onset.31 Another study found that ate relay area in the ventral medulla. Glutamate is believed
narcolepsy is also associated with a polymorphism in the to activate the spinal interneurons. The atonia neurons of the
T-cell receptor alpha gene.32 Recently, several studies have pontine reticular formation are located ventral to the locus
found that some patients with narcolepsy have elevated levels coeruleus and are often called the subcoeruleus (SubC) or
of antibodies against a protein known as Tribbles homolog 2 sublaterodorsal nucleus (SLD). The neurons are believed to
(TRIB2).3335 In one study, antibodies were found in about be glutaminergic. During REM sleep, there also appears to
25% of patients with N+C but in only 3.5% in patients with be inhibition of pathways normally promoting alpha motor
NC or 4.5% in normal controls.35 The presence of TRIB2 neuron activity.
antibodies was associated with a short duration since disease Cataplexy and the atonia of REM sleep may share some
onset (recent onset of narcolepsy). TRIB2 is produced in common pathways, but there are important differences. John
Hcrt neurons, providing some of the firmest evidence yet for and colleagues41 reported that histaminergic neurons in the
an autoimmune cause of narcolepsy. However, whether the ventral posterior lateral hypothalamus remain active during
Tribbles antibodies cause Hcrt damage, occur secondary to cataplexy as opposed to REM sleep (Fig. 242). Because his-
damage of the Hcrt neurons, or are simply an associated tamine is associated with wakefulness, this may at least par-
phenomenon secondary to another cause of Hcrt neuron tially explain why patients remain conscious during cataplexy
injury is unknown.36 but not REM sleep. The other important difference between
Two investigations have documented low CSF histamine REM-associated atonia and cataplexy is the triggering emo-
in patients with narcolepsy (with and without cataplexy) and tional stimulus for cataplexy. Neural pathways involving the
idiopathic hypersomnia (IH).37,38 As noted previously, hista- amygdala are thought to be important for the emotional
mine secretion is believed important for maintaining induction of cataplexy.
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Chapter 24 Hypersomnias of Central Origin 455
8 1.6 1.6
4 0.8 0.8
2 0.4 0.4
0 0 0
AW QW NREM REM CAT AW QW NREM REM CAT AW QW NREM REM CAT
Posterior hypothalamus Dorsal raphe Locus coeruleus
(REM-off neurons) (REM-off neurons) (REM-off neurons)
(histamine) (serotonin) (noradrenergic)
FIGURE 242 Posterior hypothalamic (histaminergic) neurons remained active during cataplexy (CAT) whereas dorsal raphe (serotonergic) reduced discharge and
locus coeruleus neurons (noradrenergic) nearly ceased discharge. Note the difference between rapid eye movement (REM) and cataplexy for posterior hypothalamic
neurons and dorsal raphe neurons. AW = active wake; NREM = nonrapid eye movement; QW = quiet wake. From John J, Wu MF, Boehmer LN, Siegel JM: Cataplexy-
active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 2004;42:619634.
REM sleep
W
Sleep stage
R
Normal
N1
N2
NS
1800 2000 2200 2400 0200 0400 0600 0800 1000 1200 1400 1600
Time of day
REM sleep
W
Sleep stage
Narcolepsy
R
N1
N2
NS
1800 2000 2200 2400 0200 0400 0600 0800 1000 1200 1400 1600
Time of day
Normal and narcoleptic 24-h PSG recordings
FIGURE 243 Hypnogram of a normal individual and a patient with narcolepsy. Sleep and rapid eye movement (REM) periods were noted
throughout the day in the patient with narcolepsy. PSG = polysomnography. From Rogers AE, Aldrich MS, Caruso CC: Patterns of sleep and
wakefulness in treated narcolepsy subjects. Sleep 1994;17:590597.
Manifestations of Narcolepsy
inappropriate situations. Napping is usually restorative but
Similarities and differences between N+C, NC, and IH are provides only temporary relief. It has been said that falling
outlined in Table 24-3. IH is discussed in detail in a later asleep while standing or eating is especially suggestive of
section. narcolepsy. Even though patients may sleep at every hour of
the day, the total sleep time over a 24-hour period is normal
Excessive Daytime Sleepiness (N+C and NC) or only slightly increased.44,45 Rogers and associates44 per-
The EDS of narcolepsy can occur as discrete sleep attacks formed 24-hour polysomnography (PSG) in a group of nar-
or as constant sleepiness with intermittent worsening. Unre- colepsy patients who were well controlled. Of 25 subjects
lenting EDS is usually the first and most prominent symptom with narcolepsy, 10 had no daytime sleep but the other 14
of narcolepsy.14,43 Sleepiness may occur throughout the averaged 2.7 naps and 76.2 minutes of sleep during the day
day, regardless of the amount or quality of prior nighttime (compared with 4.8 min for controls).44 The two groups did
sleep. Sleep episodes may occur at work and social events, not differ in the total amount of sleep or the total amount of
while eating, talking, and driving, and in other similarly REM sleep in 24 hours. Figure 243 compares the 24-hour
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456 Chapter 24 Hypersomnias of Central Origin
TABLE 243
Features of Narcolepsy Syndromes versus Idiopathic Hypersomnia
N+C NC IH
SYMPTOMS
Daytime sleepiness Yes Yes Yes
Hypnagogic hallucinations (%) 7086 1560 40
Sleep paralysis (%) 5070 2560 4050
POLYSOMNOGRAPHY
Sleep latency Short Short Variable
Nocturnal REM latency < 15 min 33%
24%
Normal REM latency
Disturbed nighttime sleep Yes Yes No
Sleep efficiency (%)* 81 91 93
Stage N1 sleep Increased Mildly increased Normal
24-hr total sleep time Normal to slight Normal to slight Very increased in patients with
increase increase IH with long sleep time
MSLT
Mean sleep latency (min) 2.7 3.5 6.2 3.0
Sleep-onset REM periods (N) 2 2 01
(33.7 SOREMPs) (23.3 SOREMPs)
DQB1*0602 (% positive) 90100 4060 52
CSF hypocretin-1 Undetectable in 9095% Normal in 90% Normal
10% normal Reduced in 510%
Neuropathology Marked reduction in Unknown Unknown
hypocretin neurons
Body mass index Increased in 515% Normal Normal
*Sleep efficiency = total sleep time/total recording time.
From Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620629.
From Arand D, Bonnet M, Hurwitz T, et al: A review by the MSLT and MWT Task Force of the Standards of Practice Committee of the AASM. The clinical use of the
MSLT and MWT. Sleep 2005;28:123147.
From Scammel TE: The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154166.
CSF = cerebrospinal fluid; IH = idiopathic hypersomnia; MSLT = multiple sleep latency test; N+C = narcolepsy with cataplexy; NC = narcolepsy without cataplexy;
REM = rapid eye movement; SOREMPs = sleep-onset rapid eye movement periods.
Adapted from Scammel TE: The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154166, with permission.
hypnograms of a patient with narcolepsy and a normal fair degree of insight that they are hallucinatory in nature,
subject. The hypnogram shows sleep episodes scattered but often consider them no less frightening. The duration is
throughout the day, and some of the daytime sleep episodes usually less than 10 minutes, and the frequency is quite vari-
contain REM sleep. able. Visual imagery is the predominant feature for many
In a study comparing narcoleptics and normal subjects patients, sometimes with intense colors. A commonly
using 24-hour ambulatory monitoring, Broughton and described vision is that of an animal or stranger in the room.
coworkers45 found no increase in the total amount of sleep Auditory or vestibular hallucinations (sensation of falling)
in 24 hours. However, narcoleptics had more daytime and may also occur. The percentage of narcolepsy patients report-
less nighttime sleep than normal persons. ing sleep-related hallucinations varies from 20% to 70%
depending on whether data are obtained from questionnaire
Sleep-Related Hallucinations (N+C and NC) or physician interview.24 A questionnaire study by Aldrich4
The sleep-related hallucinations of narcolepsy that occur at found the proportion of N+C patients reporting sleep-related
nocturnal sleep onset are called hypnagogic hallucinations hallucinations was higher than in the NC or IH groups.
(HGHs) and those on awakening are termed hypnopompic Sleep-related hallucinations (especially HPH) can be associ-
hallucinations (HPHs). The hallucinations are typically ated with SP (discussed in the next section) and can also
bizarre and may be frightening. Patients sometimes have a occur in normal individuals.
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Chapter 24 Hypersomnias of Central Origin 457
Sleep Paralysis (N+C and NC) relatively specific to narcolepsy.14,50 Isolated cataplexy or
SP is partial or complete paralysis during the onset of sleep cataplexy with sleepiness (secondary narcolepsy) can occur
or upon awakening. Patients are awake and conscious during in a few rare neurologic disorders associated with mental
the attack. There is no emotional precipitant. The episodes retardation and obvious neurologic deficits. These are dis-
may last longer than a typical cataplectic attack. People who cussed in a later section. In a patient with daytime sleepiness
experience SP sometimes experience hallucinations simulta- and a normal neurologic examination, cataplexy is virtually
neously. Studies have found that up to 50% to 80% of patients diagnostic of narcolepsy.
with N+C report SP, with a lower percentage in the NC Cataplexy is characterized by the sudden, temporary loss
group.4,43 of bilateral muscle tone with preserved consciousness trig-
Adequate ventilation is maintained during SP because gered by strong emotions such as laughter, anger, or sur-
diaphragmatic function is spared. However, some patients prise.43,50 After cataplexy episodes, patients have total recall
have a sensation of dyspnea. SP is often very frightening of the entire event. If the episodes last longer than a few
owing to the inability to move, speak, or communicate minutes, the patient may transition into REM sleep and
during the episode. SP is also reported in patients with sleep experience HHs. A systematic survey of symptoms of muscle
apnea and occasionally in normal subjects especially after weakness associated with emotion in a large group of patients
periods of sleep deprivation. A syndrome of isolated recur- with daytime sleepiness found that weakness during joking
rent SP (narcolepsy not present) exists and can be very (telling or hearing a joke), laughter, and anger were the
problematic for affected individuals. most specific for cataplexy associated with narcolepsy.43,50
Involvement of the legs also seemed to be more specific for
Disturbed Nocturnal Sleep and Other Symptoms: narcolepsy.
N+C, NC When loss of muscle strength during cataplexy is severe,
Although HH/HPH, SP, and daytime sleepiness are the almost all of the voluntary muscles in the body are affected,
classic narcolepsy symptoms, patients often report other leading to complete collapse. The muscles of the eyes are not
associated symptoms that can be significant (see Table 241). affected during cataplexy; individuals can move their eyes
Narcolepsy patients often experience disturbed nighttime during a cataplectic episode. Diaphragmatic activity is also
sleep with tossing and turning in bed, leg jerks, nightmares, not impaired. In one study, the legs and knees were most
and frequent awakenings. The amount of stage N1 sleep is frequently affected during cataplexy.50 In milder cases of
increased. In general, N+C patients have more disturbed cataplexy, the loss in muscle strength can be quite subtle,
sleep than NC patients.14 Automatic behavior is present involving only a few muscle groups or occurring unilater-
in up to 50% of patients. Automatic behavior is defined as ally. For example, ptosis, difficulty speaking, or partial neck
performing a seemingly purposeful task with no clear muscle weakness may occur (head nodding). In some
memory of having performed the activity. For example, patients, partial attacks are more frequent than complete
patients report driving a car and not remembering the trip. attacks. Loss of muscle function may not be evident, and the
They may find themselves doing activities that make no sense patient may experience only a vague feeling of weakness.
like putting salt in iced tea. These episodes typically involve Patients may fall to the ground, and injuries do occur.
activities that are habitual or not demanding of skill. However, most people are able to find support at the onset
Inattentiveness related to drowsiness may occur. Aldrich4 of an attack. The attacks do start abruptly but usually take
reported that the proportions of patients reporting automatic several seconds to reach their maximum intensity. Episodes
behavior were similar in groups of N+C and NC patients. of cataplexy usually last from seconds to minutes; rarely does
Patients with narcolepsy may also have the rapid eye move- an attack last longer than 2 minutes. Clinical signs during an
ment sleep behavior disorder (RBD).46 In this disorder, attack are the loss of muscle tone and loss of deep tendon
skeletal muscle atonia is absent during REM sleep and reflexes including a loss or decrease in the H reflex. During
dreams may be acted out. Because the Hcrt system has affects an attack of cataplexy, there are cardiovascular changes con-
on appetite, it is not surprising that some patients with N+C sisting of increased blood pressure and decreased heart rate.
have an increased body-mass index.4,47 Obstructive sleep The phenomenon of virtually continuous attacks of cataplexy
apnea (OSA) is also not uncommon.48 If cataplexy is not (status catapleticus) can occur after sudden withdrawal of
present in a patient with OSA, narcolepsy may be suspected medications that suppress cataplexy.
only if daytime sleepiness persists after adequate treatment
of the sleep apnea. Periodic leg movements in sleep (PLMS) DIAGNOSTIC TESTING FOR NARCOLEPSY
are also common in narcolepsy.49 PLMS may be present
History
during REM sleep, a feature uncommon in most patients
with PLMS. Patients with daytime sleepiness are invariably questioned
about SP, HH/HPHs, and the severity and nature of the
daytime sleepiness. However, none of these historical ele-
CATAPLEXY: N+C
ments is specific for narcolepsy and they can occur in sleep
As the name implies, cataplexy is an essential criterion for apnea and other causes of daytime sleepiness including IH4
the diagnosis of N+C. Cataplexy is the only symptom (Table 244). A history of cataplexy is the most important
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458 Chapter 24 Hypersomnias of Central Origin
Narcolepsy 3.1 2.9 min. MSL <5 min 87% 81% 39%
Idiopathic hypersomnia 6.2 3.0 min. MSL <8 min 93% 97% 63%
30% of the normal population has an MSL <8 min. 2 SOREMPs + MSL <5 min 67% 75% 4%
REQUIREMENTS FOR VALID MSLT 2 SOREMPs + MSL <8 min 71% 91% 6%
Previous PSG excluded causes of abnormal MSLT, SOREMPs on PSG 33% 24% 1%
TST >360 min. *Diagnosis made in patients with NC by repeat MSLT if initial test
negative.
Free of drugs that influence sleep for 15 days (at least 5 MSL = mean sleep latency; N+C = narcolepsy with cataplexy;
times the drug half-life). NC = narcolepsy without cataplexy; PSG = polysomnography;
SOREMPs = sleep-onset rapid eye movement periods; SRBD = sleep-related
Standardized sleep schedule for at least 7 days breathing disorder.
documented by actigraphy or sleep diary. Adapted from Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep
latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620629.
MSLs = mean sleep latencies; MSLT = multiple sleep latency test;
PSG = polysomnography; SOREMPs = sleep-onset rapid eye movement
periods; TST = total sleep time.
Data from references 1, 54, and 55.
latency less than 8 minutes with two SOREMPs on an useful for ruling in narcolepsy (for either N+C or NC). The
MSLT.53,56 A few patients with narcolepsy will occasionally HLA DQB1*602 is found in 12% to 38% of the general popu-
have a mean sleep latency above 10 minutes. However, the lation. Therefore, a positive result does not rule in N+C.
mean sleep latency is less than 5 minutes in the vast majority Conversely, a negative test for presence of DQB1*0602 is not
of patients with narcolepsy (Fig. 244). The mean sleep useful because up to 10% of N+C patients and 40% to 60%
latency in patients with SRBDs tends to be higher than in of NC patients are negative for the antigen.1,2,13,57
narcolepsy, although overlap does occur.
Unfortunately, the MSLT is not very sensitive or com- CSF Hcrt Levels
pletely specific for the diagnosis of narcolepsy. Aldrich and Hcrt1 levels of the CSF can be assayed at a few centers. In
colleagues53 reviewed MSLT findings in patients evaluated patients with N+C, over 90% have very low or undetectable
for daytime sleepiness (see Table 245). A diagnosis of nar- Hcrt1 levels. In one study of patients with many neurologic
colepsy in patients without cataplexy required a repeat MSLT diseases, only patients with N+C and a few patients with
in some cases. In patients with N+C, a single MSLT was Guillain-Barr had undetectable Hcrt levels.58,59 Patients with
positive only about 70% of the time. Hence, a negative MSLT a number of neurologic diseases had levels that were lower
does not rule out the diagnosis of narcolepsy. In patients than normal but still detectable. As noted previously, patients
ultimately believed to have only an SRBD, approximately 6% with NC usually have normal levels of CSF Hcrt1. However,
had a positive MSLT53,56 (see Table 245). about 10% of NC patients have low CSF Hcrt1. Most of
It is recommended that sleep apnea be treated adequately these NC patients with low CSF Hcrt1 are positive for the
before an MSLT is performed to evaluate for narcolepsy. HLA DBQ1*602.5860
Thus, successful treatment with continuous positive airway
pressure (CPAP) should be accomplished for several weeks. Diagnostic Criteria and Important Findings for
Then, the patient should undergo a repeat PSG on CPAP
N+C and NC Forms of Narcolepsy
(documenting adequate treatment and sleep) and a subse-
quent MSLT. If good control of sleep apnea is demonstrated Narcolepsy with Cataplexy (N+C) The ICSD-2 diagnostic crite-
during the night study but the MSLT meets criteria for nar- ria for N+C1 are listed in Box 242. EDS for at least 3 months
colepsy, one can make a diagnosis of narcolepsy. This assumes
adequate adherence to CPAP has been documented. In this
setting, most clinicians perform the MSLT with the subjects
BOX 242
wearing CPAP.
Narcolepsy with CataplexyDiagnostic Criteria
HLA Typing A. The patient has a complaint of excessive daytime
Although a high percentage of patients with N+C are posi- sleepiness occurring almost daily for at least 3 months.
tive for the HLA DQB1*602 antigen, this test is not very B. A definite history of cataplexy defined as sudden and
transient episodes of loss of muscle tone triggered by
emotions is present.
Cataplexy = episodes must be triggered by strong
140
emotionmost reliably laughing or jokingand must be
120
bilateral and brief (<2 min). Consciousness must be
preserved (at least in the beginning)
100 Strong evidence = observed cataplexy with loss of DTRs.
Number of studies
is required along with cataplexy. When possible, the diagno- BOX 243
sis should be confirmed by an MSLT (sleep latency 8 min Narcolepsy without CataplexyDiagnostic Criteria
and two or more SOREMPs). A low CSF Hcrt1 level is con-
sidered confirmatory even in the absence of an MSLT A. Complaint of excessive daytime sleepiness almost daily
for at least 3 months.
meeting diagnostic criteria. Other sleep disorders causing
B. Typical cataplexy is not present.
the abnormal MSLT should be excluded.
C. Nocturnal PSG followed by MSLT findings:
MSLT less than or equal to 8 min.
N+C Manifestations Whereas only daytime sleepiness and
Two or more SOREMPs (MSLT)
cataplexy are required to make the diagnosis of N+C, other
Sufficient nocturnal sleep (at least 6 hr).
manifestations such as sleep-related hallucinations, SP, and
D. Hypersomnia is not better explained by another sleep
automatic behavior are often present (see Table 241). Only
disorder, medical or neurologic disorder, medication, or
10% to 15% of patients have the classic symptom tetrad of
substance use disorder.
daytime sleepiness, cataplexy, HGH/HPHs, and SP. Patients
MSLT = multiple sleep latency test; PSG = polysomnography;
with N+C tend to have a higher frequency of SP, HHs, and SOREMPs = sleep-onset rapid eye movement periods.
more severe sleepiness than NC patients. During PSG, sleep From American Academy of Sleep Medicine: International Classification of
is more disturbed in N+C patients than in NC patients. On Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
the MSLT, N+C patients tend to have more SOREMPs.
Although 90% of N+C patients are positive for DQBQ1*602,
this is not useful diagnostically.
Onset of N+C The manifestations of N+C generally begin be present. Compared with patients with N+C, a lower per-
between the ages of 15 and 30 years.43 However, this form of centage of patients with NC report SP or HH (see Table
narcolepsy can present in the pediatric age group or in 243).2
patients older than 60 years. EDS alone or in combination
with HHs and/or SP is the presenting symptom in approxi- Polysomnography (NC) NC patients have a short nocturnal
mately 90% of patients.43 Cataplexy may develop several sleep latency and 20% to 30% have a short nocturnal
years after symptoms begin. However, most patients with REM latency.53 The amount of stage N1 sleep is increased.
N+C develop cataplexy within 3 to 5 years of the onset of NC patients tend to have less disturbed sleep than N+C
daytime sleepiness.14,43 Rarely, cataplexy can precede daytime patients.
sleepiness.
MSLT Findings (NC) The findings are similar to those of N+C
Polysomnography Typical findings include a short sleep patients. However, there may be a slightly longer mean sleep
latency and approximately 20% to 30% have a short noc- latency and fewer SOREMPs. Patients with NC tend to have
turnal REM latency.53 Of interest, in one study, the pres- milder sleepiness and fewer numbers of naps with sleep-
ence of sleep-onset REM during the nocturnal sleep study onset REM sleep compared with N+C patients. Unfortu-
had a high positive predictive value for the presence of nately, as discussed previously, an MSLT meeting criteria for
narcolepsy.53 There tends to be an increase in stage N1 the diagnosis of narcolepsy is not completely sensitive or
sleep. specific. If clinically indicated, repeat testing could be needed.
This is in contrast to patients in whom definitive cataplexy
Multiple Sleep Latency Test Approximately 70% of patients with is present. A diagnosis of N+C can be made even if the MSLT
N+C will have a MSLT meeting criteria for narcolepsy. The does not meet criteria if daytime sleepiness and unequivocal
mean sleep latency tends to be slightly less in N+C than in cataplexy are present.
NC patients and SOREMPs are slightly more frequent than
in patients with NC (see Table 243).
TREATMENT OF NARCOLEPSY
Other Studies in N+C The treatment of narcolepsy is usually broken into two com-
1. Absent to low Hcrt1 in the CSF fluid (90100%). ponents: (1) treatment of EDS and (2) treatment of cataplexy,
2. Absence of Hcrt-staining cells in the hypothalamus. SP, and HGH/HPHs.6164
3. Ninety percent are positive for DQBQ1*602 antigen.
Treatment of EDS
Narcolepsy without Cataplexy (NC)
The ICSD-2 diagnostic criteria for NC are listed in Box The treatment of daytime sleepiness includes conservative
243. Daytime sleepiness must be present for at least 3 measures (adequate sleep time, good sleep hygiene, sched-
months but typical cataplexy is NOT present. An MSLT uled daily naps65), stimulant medications, alerting medica-
shows a mean sleep latency of 8 minutes or less and two or tions, and sodium oxybate (Table 246). Adequate control of
more SOREMPs. The other manifestations of narcolepsy daytime sleepiness can be attained in about 60% to 80% of
including SP, HHs, and automatic behavior may or may not patients. The stimulant medications used to treat the daytime
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Chapter 24 Hypersomnias of Central Origin 461
TABLE 246
Medications Used to Treat Excessive Daytime Sleepiness
MEDICATION MAXIMUM
(FDA PREGNANCY BRAND DOSE HALF-LIFE SELECTED SIDE
CATEGORY) NAME DOSE (DAILY) (hr) EFFECTS
Methylphenidate* Ritalin 1030 mg bid or 1020 mg 100 mg 24 Nervousness,
(C) tid (5, 10, 20 mg tabs) tremulousness,
headache
Methylphenidate SR Metadate 1020 mg SR qAM (10, 20 mg
and others tabs) + 10 to 20 mg
Concerta short-acting in afternoon
1836 mg SR qAM (18, 27, 36,
54 mg tabs) + 10 to 20 mg
short-acting in afternoon
Dextroamphetamine* Dexedrine 560 mg qd 60 mg 1030 Nervousness,
(C) Dextrostat 530 mg bid tremulousness,
and others (5, 10 mg tabs) headache
Amphetamine/ Adderall (5, 7.5, 12.5, 15 mg tabs)
dextroamphetamine
Dextroamphetamine SR 10 mg SR qAM
SR 5, 10, 15 mg tabs
+10 to 20 mg short-acting in
afternoon
Amphetamine/ Adderall XR 5, 10, 15, 20, 25, 30 mg
dextroamphetamine capsules
XR
Methamphetamine* Desoxyn 5 to 60 mg qd (5, 10 mg 60 mg 1234 Nervousness,
(C) tabs) tremulousness,
headache
Lisdexamfetamine Vyvanse 20, 30, 40, 50, 60 mg 70 mg 1213 Nervousness,
dimesylate* (duration of tremulousness,
(C) action) headache
Modafinil Provigil 200 or 400 mg qd (100, 400 mg 914 Headache, drug
(C) 200 mg tabs) interactions,
nervousness
Armodafinil Nuvigil 150250 mg daily 250 mg 1014 Headache, drug
(C) 150, 250 mg tabs interactions,
nervousness
Sodium oxybate Xyrem 4.59 g/night in 2 divided 9g 13 Sedation, enuresis,
(B) doses respiratory suppression
Selegiline Eldepryl 2040 mg 40 mg 914 Nausea, dizziness,
(C) confusion, dry mouth,
requires low-tyramine
diet, drug interactions
FDA approved for treatment of EDS in narcolepsy: modafinil, armodafinil, dextroamphetamine, methylphenidate, sodium
oxybate.
Black box warnings:
Stimulants: Abuse potential.
Sodium oxybate: Abuse potential, should not be used with alcohol or other CNS depressants.
*Schedule II medication (no refills, no telephone prescriptions).
Schedule IV medication.
CNS = central nervous system; EDS = excessive daytime sleepiness; FDA = U.S. Food and Drug Administration; SR = sustained release.
B and C: Pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in
pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to
the fetus in any trimester. Pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-
controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
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462 Chapter 24 Hypersomnias of Central Origin
sleepiness of narcolepsy include amphetamine (racemic), dextroamphetamine, and the highest postdrug values were
dextroamphetamine, methamphetamine, and methylpheni- for methylphenidate (although baseline values were the
date. Dextroamphetamine and methylphenidate are U.S. highest for this medication). No medication came close to
Food and Drug Administration (FDA) approved for treat- normalizing objective sleepiness.
ment of narcolepsy. A mixture of amphetamine and
dextroamphetamine (~25% L-amphetamine and 75% Stimulant Medications
D-amphetamine) is also available (Adderall). Some patients The stimulant medications increase dopamine transmission
respond best to a mixture, although D-amphetamine may by presynaptic mechanisms. The medications inhibit the
cause less anxiety. Methamphetamine is effective but has a reuptake of dopamine (DA) and, to a lesser extent, NE and
high abuse potential. The FDA does not list narcolepsy as an serotonin by the dopamine transporter (DAT).6770 The
indication for methamphetamine. The stimulant medica- action of amphetamines on DAT causes a reverse efflux of
tions are indirect sympathomimetic stimulants (increase the DA through the site as well as blocking reuptake. The
synaptic availability of dopamine and norepinepherine). amphetamines also inhibit cytoplasmic vesicular storage of
Modafinil and its R enantiomer armodafinil are two DA by the vesicular monoamine transporter (VMAT2). In
alerting medications that are FDA approved for treatment contrast, methylphenidate has no effect on DA storage. The
of daytime sleepiness in narcolepsy. There are no studies overall action of the stimulant medications is to increase the
directly comparing the efficacy of stimulant and alerting synaptic levels of DA.
medications. However, the relative objective improvement The peak action of dextroamphetamine, methamphet-
in the sleep latency after medication on the MSLT or main- amine, and methylphenidate is 1 to 3 hours from ingestion,
tenance of wakefulness test (MWT) has been compared so the medications should be taken at least 1 hour before the
by computing the pre- and postdrug sleep latency values time of desired effectiveness. If a sleep attack has begun
as a percentage of normal for the test66 (Fig. 245). Because before medication is taken, a nap may be the best treatment
the predrug values differ between the studies, the change in some patients. Also note that methylphenidate has a much
from baseline of drug is the main effect of interest. The shorter half-life than dextroamphetamine and methamphet-
relative improvements in objective sleepiness are displayed amine (see Table 246) and must be taken several times a
by normalizing the pretreatment (gray bars) and post- day (bid to tid). Sustained-action forms of the amphetamines
treatment (green bars) values of the sleep latency on the and methylphenidate are available. Of note, stimulant medi-
MWT or MSLT as a percentage of the published normal cations may have a mild beneficial effect on cataplexy but
values for the MSLT (13.4 min) or the MWT (18.9 min). modafinil has no effect on cataplexy.
The largest changes were for methamphetamine and The side effects of the stimulant medications include ner-
vousness, headache, loss of appetite, palpitations, irritability,
and tremor. All of these medications are schedule II drugs
100 (requiring monthly prescriptions). There are several poten-
Baseline
90 Treatment tial problems with the use of stimulant medications.66,67 First,
Sleep latency (% of normal)
Modafinil
Methamphetamine
Methylphenidate
morning with short-acting forms in the afternoon or evening. a schedule II medication. As noted previously, there are no
In some patients, a small dose of short-acting methylpheni- head-to-head studies comparing effectiveness of modafinil
date must also be added in the morning to help patients and stimulant medications. However, when compared for
more rapidly achieve alertness for early morning activity. the ability to normalize the sleep latency, stimulant medica-
There are individual patients who will tolerate the slower tions appear slightly more effective.66 Thus, although
onset of sustained-action medications while they find the modafinil is considered the drug of choice for daytime
shorter-acting medications intolerable (jittery or nervous). sleepiness in patients with narcolepsy, some patients will
The American Academy of Sleep Medicine (AASM) Practice respond better to a stimulant.
Parameters for Treatment of Narcolepsy and Other Hyper- The mechanism of action of modafinil is not known,67,8284
somnias of Central Origin61 stated combinations of long- but the drug likely targets the DA reuptake system. The alert-
and short-acting stimulants may be indicated and effective ing effect of modafinil is not specific to patients with narco-
for some patients (Option). Lisdexamfetamine dimesylate lepsy. Modafinil does not bind the receptors or uptake sites
(Vyvanse) is a once-daily medication approved for treating of NE, GABA, adenosine, or benzodiazepines. It does weakly
attention deficit hyperactivity disorder (ADHD) for ages 6 bind to the DAT.82 Modafinil does enhance the activity of
to 17 and adults. It is a prodrug that is converted to dextro- many brain sites associated with wakefulness including the
amphetamine in the gastrointestinal tract. This medication tuberomammillary nucleus and Hcrt cells of the periforni-
has also been used off label to treat narcolepsy (see Table cal area.83 However, modafinil does not require the Hcrt
246). system to be effective. Modafinil can reduce the extracellular
GABA concentrations.84 Because GABA is an inhibitory
Modafinil and Armodafinil neurotransmitter, this could disinhibit a number of wake-
Modafinil and armodafinil (R entaniomer of modafinil) are promoting sites such as the tuberomammillary neurons
nonamphetamine wakefulness-promoting medications that (TMNs). Another possibility is that modafinil may increase
are schedule IV medications (refills and telephone orders dopaminergic signaling. All the brain regions activated by
allowed). They are considered to have less abuse potential modafinil receive dopaminergic innervation.85 Wisor and
than the stimulant medications. Modafinil is considered to coworkers70 found that modafinil does not improve wakeful-
be the first-line medication for treatment of EDS associated ness in mice lacking the DAT. As noted previously, modafinil
with narcolepsy.61,67,73 Randomized, placebo-controlled trials does bind weakly to the DAT. A study by Gallopin and col-
have documented the effectiveness of modafinil in patients leagues85 found that modafinil blocks reuptake of NE by
with narcolepsy.7375 noradrenergic terminals that interface with sleep-promoting
The elimination half-life of modafinil is 9 to 14 hours, neurons of the ventrolateral preoptic nucleus (VLPO).
permitting once-daily administration for most patients. Higher NE at the VLPO would be wake-promoting because
Modafinil is usually administered once daily in the morning NE inhibits the activity of the VLPO. The mechanism by
(200400 mg). However, some patients taking modafinil in which modafinil blocks reuptake is unclear because modafinil
the morning may experience poor control of daytime sleepi- does not bind to NE receptors. After numerous investiga-
ness in the afternoon or early evening. They may respond to tions, the mechanism by which modafinil works is still
split dosing (200 mg in AM, 200 mg at 12 PM).76,77 Although unknown.86 In summary, modafinil may promote NE and
the maximum recommended daily dose of modafinil is dopaminergic transmission of wake-promoting centers.
400 mg, higher doses have been used. There are some Continued research in this area will likely help design more
patients in whom adequate control of sleepiness may require effective treatments for narcolepsy.
a slightly higher dose than 400 mg (400 mg in the AM and The most common side effects of modafinil include head-
200 mg in the early afternoon).76,77 ache, nausea, and nervousness. Headache can be minimized
The L enantiomer of modafinil has a shorter half-life by a slow increase in dose. A few cases of severe skin rash
(34 hr) than the R enantiomer (1014 hr). Modafinil (Stevens-Johnson syndrome) have been reported in patients
(racemic, containing both L and R enantiomers) has a similar taking modafinil (very low prevalence). Modafinil is metab-
terminal half-life as armodafinil. Within a few hours after olized in the liver by the cytochrome P-450 (CYP450) system.
taking modafinil the only enantiomer left in the blood is Hence, a number of drug interactions are possible. The main
armodafinil.7880 If the same doses of modafinil and interaction of significance is that certain oral contraceptives
armodafinil are given in the morning, the afternoon blood may be less effective after modafinil is started. Female
levels of armodafinil are considerably higher. For this reason, patients of reproductive age taking oral contraceptives
a morning dose of armodafinil (150250 mg) may control should use additional (or alternative) methods of contracep-
afternoon sleepiness better than modafinil. A double-blind tion. Unlike the indirect sympathomimetics, withdrawal of
study by Harsh and associates81 documented the efficacy and modafinil does not result in a rebound of REM and slow
safety of armodafinil. wave sleep. Patients can be switched from stimulants to
There is no evidence that tolerance develops to modafinil modafinil without a washout period. However, because stim-
or that the drug impairs sleep quality (if taken in the ulant medications have some anticataplectic action, patients
morning). It has a number of advantages including once- changed from methylphenidate to modafinil may require the
daily dosing, low abuse potential, and the fact that it is not addition of specific medications for cataplexy.87
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464 Chapter 24 Hypersomnias of Central Origin
14
12
*
10
8 Normal
range
6
Stable
modafinil
dose
14
MWT sleep latency (min)
13 Modafinil-sodium oxybate
12 (Placebo modafinil)-sodium oxybate
11
10 Modafinil-(Placebo sodium oxybate)
9
8
7 (Placebo modafinil)-(placebo sodium oxybate)
6
Visit 2 Visit 3 Visit 4 Visit 5
Sodium oxybate
increased to 9 grams
FIGURE 247 A combination of modafinil and sodium oxybate may be more effective than sodium oxybate alone in some patients.
After visit 4, one group was changed to placebo-modafinil, one group to placebo-sodium oxybate, one group to both placebo-
modafinil and placebo-sodium oxybate; one group continued on active medications. Both modafinil and sodium oxybate resulted in
a higher sleep latency compared with placebo-placebo. At visit 4, the highest latency was in the group with both active medications.
However, there was less benefit from the addition of modafinil at visit 5 after the dose of sodium oxybate was increased to 9 g. MWT
= maintenance of wakefulness test. From Black J, Houghton WC: Sodium oxybate improves excessive daytime sleepiness in narcolepsy.
Sleep 2006;29:939946.
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Chapter 24 Hypersomnias of Central Origin 465
SOXB may be needed to improve daytime sleepiness as anticataplectic activity in addition to its alerting ability.
compared with cataplexy.92,93 The benefits on EDS may take Patients who experience intolerable side effects with other
a few months for maximum effect. The FDA approved SOXB agents may benefit from this medication as long as they are
for treatment of both daytime sleepiness and cataplexy. willing to adhere to a low-tyramine diet.
SOXB is the only medication FDA approved for cataplexy. Improving nocturnal sleep and treatment of concurrent
The mechanism of action of SOXB with respect to reducing sleep disorders is also important for improving daytime
daytime sleepiness is unknown. Studies have shown that the sleepiness. Benzodiazepine receptor agonists may improve
medication reduces nocturnal awakenings and increases sleep quality in some patients. If the restless legs syndrome/
stage N3 sleep and consolidates REM periods.94 Some have PLMS are significantly impairing sleep, specific treatment for
hypothesized that sleep consolidation improves daytime these problems may be helpful. The combination of narco-
sleepiness. lepsy and OSA is commonly encountered. Adequate treat-
SOXB (Xyrem) is available as a liquid (500 mg/mL) and, ment of OSA with nasal CPAP or other therapies is essential.
because of a short half-life, must be taken at bedtime and Good sleep hygiene with a regular sleep schedule and ade-
repeated 2.5 to 4 hours later. The drugs effect is so rapid that quate sleep is essential for narcolepsy patients. Some find
after ingesting each dose of the medication, patients should short scheduled naps to also be beneficial.
lie down and remain in bed. SOXB taken on an empty
stomach reaches peak concentrations in 0.5 to 1.5 hours and Choosing Treatment for Daytime Sleepiness
has a half-life of 40 to 60 minutes. Each dose of medication The AASM has recently published practice parameters
is diluted with 60 mL of water in the child-resistant dosing regarding the treatment of narcolepsy and central hypersom-
cups. Both doses should be prepared before going to bed. nias61 (Table 247). For daytime sleepiness, both modafinil
The dose in the middle of the night should be taken while and SOXB received Standard recommendations. Due to
the patient is sitting in bed. It is very important to note that convenience and tolerability, most physicians would start
food can reduce the bioavailability of SOXB. SOXB is treatment with modafinil or armodafinil. If modafinil (or
started at 4.5 g/night taken in divided doses (2.25 g taken at armodafinil) is not sufficiently effective, one option is to
bedtime and repeated 2.54 hr [usually ~3 hr] later). The switch to a stimulant medication. A combination of short-
dose is then increased in 1.5-g/night increments each week acting and long-acting methylphenidate may be better toler-
until a maximum of 9 g/night is reached. One might aim for ated in some patients (methylphenidate 20 mg SR qAM and
lower doses in smaller patients. If side effects are intolerable, 1020 mg short-acting in early afternoon). Another option
the dose can be decreased temporarily and then a trial at an for patients not responding to modafinil is to move directly
increased dose can be tried later. Nausea, dizziness, and to SOXB (especially if cataplexy is significant). In some
enuresis are the most common side effects. SOXB is associ- studies, SOXB restored subjective sleepiness to the normal
ated with a high sodium load and this can be a significant range. However, SOXB is an expensive medication and
concern in patients with congestive heart failure. The simul- requires that the patient reliably follow instructions. In any
taneous use of SOXB and alcohol or other CNS depressants case, if both modafinil and stimulants are not effective, one
is contraindicated. could prescribe SOXB. Often, modafinil (or stimulant medi-
A study of 4 consecutive nights of SOXB in patients with cation) is continued as the dose of SOXB is increased. If
mild to moderate OSA not on CPAP found no significant treatment of both daytime sleepiness and cataplexy is needed,
worsening in the apnea-hypopnea index (AHI) and mean SOXB would be especially useful. Some patients do not toler-
arterial oxygen saturation (SaO2).95 In this study, stage N3 ate alternative medications for cataplexy, and in this group,
increased but the number of central apneas also increased SOXB is also a good option.
and a few patients did experience significant oxygen desatu-
ration. Thus, although not an absolute contraindication,
Treatment of Cataplexy, HGH/HPHs, and SP
SOXB should be used with caution in patients with OSA. If
SOXB is used in patients with very severe OSA, adequate In some patients with N+C, the episodes of cataplexy are so
treatment of OSA (CPAP) is essential. It may be prudent to uncommon or mild that treatment is not needed. In others,
perform nocturnal oximetry when SOXB treatment is started they constitute an important problem for patients. The medi-
or the dose is increased. cations that are useful for the treatment of cataplexy also
suppress the other associated symptoms of narcolepsy
Other Interventions for Daytime Sleepiness including SP and HGH/HPHs (Table 248). It should be
Another treatment alternative that can be tried in patients recalled that these phenomenon can occur in normal indi-
not tolerating stimulants is the irreversible monoamine viduals and do not require treatment unless recurrent and
oxidase (MAO) type B inhibitor selegiline. At doses of 10 to clinically significant. The classic medications useful in treat-
40 mg/day, this drug has been shown to improve narcoleptic ing cataplexy have a common property of suppressing REM
symptoms.96 Unfortunately, at doses over 20 mg/day, it loses sleep. In the canine form of narcolepsy, drugs increasing NE
its MAO B inhibitor selectivity and a low-tyramine diet are the most efficacious.97
is indicated to avoid the risk of hypertensive reactions. Sege- The tricyclic antidepressants (TCAs) were the first group
line is metabolized to amphetamine. The drug also has used to treat cataplexy. The first agent used was imipramine,
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466 Chapter 24 Hypersomnias of Central Origin
TABLE 248
Medications Used for Treatment of Cataplexy, Hypnagogic Hallucinations, and Sleep Paralysis
DRUG (BRAND MAXIMUM HALF-LIFE
NAME) DOSE DOSE (DAILY) (hr) SELECTED SIDE EFFECTS
TRICYCLIC ANTIDEPRESSANTS
Protriptyline 510 mg bid or tid 30 mg 6789 Dry mouth, urinary hesitancy,
(Vivactil) (5-, 10-, 20-mg tabs) constipation
Clomipramine Start 50 mg qhs 250 mg 32 Dry mouth, sweating,
(Anafranil) (75125 mg) drowsiness
Imipramine Start 50 mg qhs 300 mg 620 Dry mouth, constipation,
(Tofranil) (75125 mg) drowsiness
SSRIS
Fluoxetine Start 20 mg qAM 80 mg 48216 Headache, dry mouth, sexual
(Prozac) (2060 mg) dysfunction
NSRIS
Venlafaxine Start 37.5 mg bid 375 mg 37 Nausea, dry mouth, headache,
(Effexor) (75100 mg bid) blood pressure elevation,
insomnia, nervousness,
XL form 225 mg (XL)
withdrawal syndrome
Start 37.5 mg qAM
wean slowly
75150 mg qAM
SNRIS
Atmoxetine 40 mg qAM 3 days then 100 mg 5.2 Nausea, dry mouth, headache,
(Strattera) 40 mg bid or 80 mg qAM blood pressure elevation,
(10, 18, 25, 40, 60, 80 mg tabs) insomnia, nervousness
OTHER MEDICATIONS
Selegiline (Eldepryl) 2040 mg 40 mg 914 Nausea, dizziness, confusion,
dry mouth
Sodium oxybate* Starting dose 2.25 mg qhs 9 g daily in divided 0.51 Nausea, headache, confusion,
(Xyrem) repeated in 2.54 hr (see text) doses enuresis, sleepwalking
*FDA approved for treatment of cataplexy.
FDA = U.S. Food and Drug Administration; NSRIs = nonselective serotonin reuptake inhibitors; SNRIs = selective norepinephrine reuptake inhibitors; SSRIs = selective
serotonin reuptake inhibitors.
Cataplexy can be confused with syncope (except the child is BOX 244
awake) or seizure-like activity. In children with narcolepsy, Narcolepsy Due to Medical Condition
cataplexy can sometimes be the first symptom and often the
first prominent symptom.104 If cataplexy is the first symptom, A. Complaint of daytime sleepiness occurring almost daily
for at least 3 months.
an evaluation of narcolepsy due to medical condition (sec-
B. One of the following is observed:
ondary narcolepsy) is indicated (including CNS imaging and
i. A definite history of cataplexy, defined as sudden
genetic testing). In one study, 43% of children had falls as
and transient episode of loss of muscle tone (muscle
part of their attacks.104 During cataplexy, knees, head, and
weakness) triggered by emotion, is present.
jaw were the most often involved. Eyelids, arms, and trunk
ii. If cataplexy is not present or is very atypical,
were less often involved. More rarely, blurred vision, slurred PSG monitoring performed over the patients
speech, or irregular breathing was noted. A cataplectic habitual sleep period followed by an MSLT must
facies was reported characterized by partially closed eyelids demonstrate a mean sleep latency on the MSLT of
and jaw weakness (open mouth). In some episodes of child- <8 min with two or more SOREMPs despite sufficient
hood cataplexy, a clear-cut emotional trigger may not be nocturnal sleep prior to the MSLT (minimum of
noted. The development of obesity in children associated 360 min).
with the onset of narcolepsy is common (up to 25%) and iii. Hypocretin-1 levels in the CSF <110 pg/mL (or 30%
nocturnal eating syndrome can be present. As discussed in of the normal control values), provided the patient is
Chapter 14, children tend to have long sleep latencies on the not comatose.
MSLT. For example, the mean sleep latency on the MSLT in C. A significant underlying medical or neurologic disorder
one study of normal prepubertal children was 19 16 accounts for the daytime sleepiness.
minutes (in adults, 10.4 4.3).106 Therefore, use of sleep D. The hypersomnia is not better explained by another
sleep disorder, mental disorder, medications use, or
latency criteria of 8 minutes or less may be problematic.
substance use disorder.
Some clinicians consider a mean sleep latency less than 12
CSF = cerebrospinal fluid; MSLT = multiple sleep latency test;
minutes as consistent with daytime sleepiness in children. PSG = polysomnography; SOREMPs = sleep-onset rapid eye movement
Conversely, a study by Serra and colleagues104 found that periods.
most of their children diagnosed with N+C had a mean sleep From American Academy of Sleep Medicine: International Classification
of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
latency of 5.3 minutes with a range of 1 to 13 minutes on the American Academy of Sleep Medicine, 2005.
MSLT. A repeat MSLT may be needed because lack of
SOREMPs does not rule out the diagnosis. A lumbar punc-
ture for CSF sampling (Hcrt1) could be considered if
possible/ambiguous cataplexy is present. The AASM Practice
BOX 245
Parameters for Treatment of Narcolepsy and Other Hyper-
somnias of Central Origin stated that methylphenidate or Medical Disorders Causing Narcolepsy Due to
modafinil in children 6 to 15 appears to be relatively safe in Medical Condition
the treatment of hypersomnias of central origin (Option).61 NARCOLEPSY WITH CATAPLEXY
The practice parameters made no recommendation in this
age group regarding cataplexy. Fluoxetine, venlafaxine, and Tumors, sarcoidosis, arteriovenous malformations affecting
the hypothalamus
SOXB have been used in children.104,105 A study of Israeli
children with narcolepsy reported successful use of modafinil Multiple sclerosis plaques impairing the hypothalamus
and SOXB for sleepiness.105 Paraneoplastic syndrome anti-Ma2 antibodies
Neimann-Pick type C disease
NARCOLEPSY DUE TO MEDICAL CONDITION Possibly Coffin-Lowry syndrome
Narcolepsy Due to Medical Condition (NDMC) is a group NARCOLEPSY WITHOUT CATAPLEXY
of disorders also known as secondary or symptomatic nar-
Head trauma
colepsy.1,107109 The patient must report or manifest daytime
sleepiness. The disorder must be associated with a medical Myotonic dystrophy
disorder known to cause narcolepsy and the combination of Prader-Willi syndrome (rarely with cataplexy)
either cataplexy or an MSLT meeting diagnostic criteria for
Parkinsons disease
narcolepsy must be present. The ICSD-2 criteria for NDMC
are listed in Box 244. A low level of CSF Hcrt1 is also Multisystem atrophy
acceptable evidence of NDMC. From American Academy of Sleep Medicine: International Classification of
Medical disorders commonly causing narcolepsy are Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
listed in Box 245. Note that if hypersomnia is thought sec-
ondary to one of the listed medical conditions but criteria
for narcolepsy are not met, the diagnosis is Hypersomnia
Due to Medical Condition (HDMC).
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Chapter 24 Hypersomnias of Central Origin 469
Patients with idiopathic narcolepsy usually have a normal without cataplexy, patients with PWS can have cataplexy114
neurologic examination and no definite pathology on brain (accurate history is often difficult to obtain in these patients).
imaging. Patients with NDMC often have specific brain Nevsimalova and associates115 found reduced levels of CSF
pathology.107109 Damage to the hypothalamus due to sar- Hcrt1 levels in four patients with PWS. However, none had
coidosis, tumors,110 arteriovenous malformations, or cere- cataplexy. Fronczek and coworkers116 found no difference in
brovascular accidents can cause NDMC. Other reported the total number of Hcrt-containing neurons in seven PWS
associations of cerebral disease and narcolepsy include mul- patients compared with age-matched controls. If sleepiness
tiple sclerosis and Niemann-Pick disease type C.111 Daytime is present in PWS but criteria for narcolepsy are not met and
sleepiness following closed head injury is a well-known syn- sleepiness is NOT felt to be due to sleep apnea, a diagnosis
drome.112 However, most patients with daytime sleepiness of HDMC is appropriate.
following head trauma do not have narcolepsy. Postencepha-
litic narcolepsy was common in the 1920s, but no similar Myotonic Dystrophy
epidemic has been recently described. Myotonic dystrophy type 1 (MD1) is an autosomal dominant
inherited disorder characterized by myotonia and muscle
Disorders Associated with NDMC, Isolated weakness. The incidence is estimated to be about 1/10,000,
so it is a much more rare disorder than narcolepsy. Myotonia
Cataplexy, or HDMC
is defined as repetitive muscle depolarization resulting in
Cataplexy can rarely occur with syndromes other than muscle stiffness and impaired relaxation. The muscles
idiopathic narcolepsy. In some cases, a diagnosis of NDMC usually involved include facial, masseter, levator palpebra,
can be made. In others, it may be difficult to determine forearm, hand, pretibial, and sternocleidomastoid. Pharyn-
whether daytime sleepiness is present (e.g., in the setting of geal and laryngeal and muscles of respiration including the
significant mental retardation). The term isolated cataplexy diaphragm can be involved. Dysfunction of the hypotha-
implies the presence of cataplexy without daytime sleepiness. lamic region can result in daytime sleepiness or daytime
Cataplexy has been reported in the Prader-Willi syndrome sleepiness with SOREMPs (NDMC).1,107109,124 Involvement
(PWS),113116 Niemann-Pick disease type C,111,117,118 Coffin- of upper airway muscles can result in sleep apnea. Some
Lowry syndrome,119,120 Norries disease,121,122 and Moebius patients have abnormal ventilatory control and hypoventila-
syndrome.123 These patients have variable mental retarda- tion. Involvement of the cardiac condition system can occur.
tion and/or obvious neurologic deficits in contrast to the There are differences in presentation depending on the age
patient with idiopathic narcolepsy. of onset. Congenital MD is apparent at birth and often
severe. Juvenile MD is characterized by symptoms that
Genetic Disorders Causing NDMC or Isolated Cataplexy appear between birth and adolescence. Adult-onset MD
Prader-Willi Syndrome PWS is a genetic disorder usually asso- usually appears in individuals aged 20 to 40 and tends to be
ciated with a deletion of the long arm of chromosome 15 and slowly progressive. Late-onset MD occurs after age 40 and
is characterized by hyperphagia, obesity, hypogonadotrophic has mild symptoms.
hypogonadism, behavioral disorders, and sleep disorders.113116 Daytime sleepiness is a common complaint and can be
Abnormal growth hormone secretion results in short stature, due to MD (hypersomnia due to medical condition), MD
reduced muscle mass, and low bone density (scoliosis is as a cause of secondary narcolepsy (NDMC), or OSA.
common). The characteristic appearance of PWS includes a Thus, several mechanisms can cause daytime sleepiness in
high narrow forehead, almond-shaped eyes, turned-down patients with MD.
lips, a prominent nasal bridge, and small hands and feet. On physical examination, findings include a narrow face,
Intelligence is variable but usually ranges from low normal premature frontal balding, distal weakness, and myotonia.
to mild to moderately decreased. Patients with PWS may MD patients have decreased strength on hand grip but then
have daytime sleepiness from a number of etiologies are slow to relax (distal myopathy with myotonia). There is
including sleep apnea, narcolepsy, or the PWS itself. PWS wasting of hand and forearm muscles. PSG can reveal OSA,
patients may manifest obstructive apnea, central apnea, and PSG + MSLT can meet criteria for narcolepsy or simply
hypoventilation, or a mixture of these disorders. EDS is document EDS without SOREMPs.
reported commonly in persons with PWS, may begin early The AASM Practice Parameter on the Treatment of Nar-
in life, and has been correlated with daytime behavioral colepsy and Other Hypersomnias of Central Origin61 stated
issues. In fact, EDS has been reported independent of noc- methylphenidate and modafinil may be effective treatment
turnal sleep problems (sleep apnea), suggesting it is a primary for MD (Optionthe lowest recommendation level) (see
feature of PWS. Some sleepy persons with PWS meet the Table 247). Two studies found modafinil to be effective,124,125
diagnostic criteria for narcolepsy and PWS is considered a but a more recent small study did not show a benefit.126
cause of NDMC.1 Abnormal sleep architecture has been
reported in persons with PWS including reduced REM Rare Genetic Disorders Causing NDMC
latency and SOREMPs. These findings can be present in PWS or Isolated Cataplexy
patients without significant sleep-related breathing prob- Niemann-Pick type C disease is a rare autosomal recessive
lems. Although PWS is felt to most commonly cause NDMC disorder characterized by lysosomal accumulation of
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470 Chapter 24 Hypersomnias of Central Origin
Autonomic Dysfunction Some patients with IH+LST report Diagnostic Approach CNS imaging is suggested if there is any
symptoms including headaches (often migraine-like in suspicion of a CNS lesion. The differential diagnosis includes
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Chapter 24 Hypersomnias of Central Origin 471
head trauma and sleepiness associated with a psychiatric Prevalence Unknown; recent studies suggest that there is 1
disorder or structural CNS lesion. A sleep diary or clinical IH patient for every 10 patients with narcolepsy. Males and
history should eliminate the possibility of the insufficient females are equally affected.
sleep syndrome.
Onset Usually before age 25.
Treatment Amphetamines, methylphenidate, and moda-
finil61,128,130 have all been used with variable success for treat- Polysomnography Total sleep time greater than 6 hours but
ment of daytime sleepiness (see Table 247). The AASM less than 10 hours. Normal distribution of the sleep stages.
Practice Parameters for Treatment of Narcolepsy and Other The sleep efficiency is greater than 85%. The nocturnal REM
Hypersomnias of Central Origin state that modafinil may latency is normal.
be effective for treatment of idiopathic hypersomnia
(Option).61 Amphetamine, methamphetamine, and methyl- Multiple Sleep Latency Test Mean sleep latency (<8 min) and
phenidate were also listed as treatments for IH (Option). no or one SOREMP.
IH without Long Sleep Time (IHLST) CSF Hcrt1 Levels CSF Hcrt1 levels are normal in IH patients.
IH without long sleep time (IHLST) patients have similar One study found CSF histamine to be low.38
symptoms as IH+LST except that the nocturnal sleep time
is between 6 and 10 hours. The ICSD-2 criteria are listed in Diagnostic Approach CNS imaging is suggested if there is any
Box 247. The disorder has also been called idiopathic CNS suspicion of a CNS lesion. Psychiatric consultation may also
hypersomnia. Comparison of patients with narcolepsy and be considered. The differential diagnosis includes head
IH are also illustrated in Table 243. trauma and sleepiness associated with a psychiatric disorder
or structural CNS lesion, the chronic fatigue syndrome,
Manifestations Constant and severe daytime sleepiness is behaviorally induced insufficient sleep, and NC. The PSG
reported with unrefreshing naps and a normal to slightly should rule out sleep apnea. A sleep diary or clinical history
prolonged nocturnal sleep episode (610 hr). Patients may should eliminate the possibility of the insufficient sleep
report difficulty awakening in the morning or after naps. SP syndrome.
and HHs may be present. However, cataplexy is absent.
Treatment Same as for IH+LST.
Autonomic Dysfunction Some patients with IHLST report
symptoms including headaches (often migraine in nature), Recurrent Hypersomnia (Including Kleine-Levin
orthostatic hypotension with symptoms of peripheral vascu-
Syndrome and Menstrual-Related Hypersomnia)
lar dysfunction (Raynauds phenomenonvascular con-
striction on exposure to cold). Kleine-Levin Syndrome
Recurrent episodes of hypersomnia are noted and are clearly
associated with behavioral abnormalities.1,131 These may
BOX 247 include binge eating, hypersexuality, abnormal behaviors
Idiopathic Hypersomnia without Long Sleep that exhibit irritability and aggression as well as cognitive
TimeDiagnostic Criteria abnormalities such as a feel of unreality, confusion, and hal-
lucinations (Box 248). Episodes occur 1 to 10 times per year
A. The patient has a complaint of excessive daytime
and last a few days to several weeks. Kleine-Levin syndrome
sleepiness occurring almost daily for at least 3 months.
(KLS) is rare with just over 200 cases reported. The
B. The patient has normal nocturnal sleep (>6 hr but
<10 hr), documented by interview, actigraphy, or sleep
logs. BOX 248
C. Nocturnal PSG has excluded other causes of daytime
Recurrent Hypersomnia (Including Kleine-Levin
sleepiness.
Syndrome and Menstrual-Related Hypersomnia)
D. PSG demonstrates a major sleep period that is normal in
duration. A. The patient experiences recurrent episodes of excessive
E. An MSLT following the overnight PSG demonstrates a sleepiness of 2 days to 4 weeks in duration.
mean sleep latency of less than 8 minutes with fewer B. Episodes recur at least once a year.
than two SOREMPs. C. The patient has normal alertness, cognitive function,
(MSL in idiopathic hypersomnia has been shown to be and behavior between attacks.
6.2 + 3.0 min). D. Hypersomnia is not better explained by another sleep
F. Hypersomnia is not better explained by another sleep disorder, medical or neurologic disorder, medication, or
disorder, medical or neurological disorder, medication, substance use disorder.
or substance use disorder. From American Academy of Sleep Medicine: International Classification of
MSL = mean sleep latency; MSLT = multiple sleep latency test; PSG = Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
polysomnography; SOREMPs = sleep-onset rapid eye movement periods. American Academy of Sleep Medicine, 2005.
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472 Chapter 24 Hypersomnias of Central Origin
disease itself.133 The RBD is very common and may precede BOX 2413
Parkinsons disease onset. The Hcrt levels in the CSF are
Common Medications Associated with
normal but reduced in the lateral ventricles. Recently, one
Daytime Sleepiness
study found a reduction in Hcrt cells in the hypothalamus of
patients with Parkinsons disease.134 Benzodiazepines
Hypnotics (especially with long half-life)
Treatment of Hypersomnia Due to Medical Condition The AASM Dopamine agonists
Practice Parameters for Treatment of Narcolepsy and Hyper- Antidepressants
somnia of Central Origin (see Table 247) stated that Sedating (usually > frequent sedation [trazodone,
modafinil may be effective for treatment of excessive daytime doxepin, mirtazapine])
sleepiness in Parkinsons disease (Option), MD (Option), Nonsedating (usually <15%)lower percentage
and multiple sclerosis (Guideline).62 It was also stated that associated with sedationincluding citalopram,
fluoxetine, paroxetine, sertraline
methylphenidate may be indicated for treatment of EDS due
Narcotics
to MD (Option). If modafinil is not effective in Parkinsons
Antihypertensives: Clonidine, methyldopa
disease or multiple sclerosis, treatment with methylpheni-
Antihistamines (first generation)
date could also be tried.
Antiepileptics
Dilantin, carbamazepine, phenobarbital, lamotrigine,
Hypersomnia Due to Drug or Substance gabapentin, valproic acid, topiramate
This diagnosis is reserved for patients with excessive sleep or
daytime sleepiness believed to be due to substance use (Box
2412). There is often a historical report of symptoms begin- insufficient sleep syndrome, or chronic fatigue. Medications
ning with the starting of a particular medication. A sleep can also result in worsening of symptoms of another sleep
study is not needed unless there is the suspicion of another disorder.
sleep disorder. An MSLT may be needed if narcolepsy is
suspected. A urine drug screen may help make the diagnosis Hypersomnia Not Due to Substance or Known
of substance abuse. The diagnosis is confirmed when symp-
Physiologic Condition
toms improve after discontinuation of the substance. A list
of common medications associated with daytime sleepi- Nonorganic HypersomniaHypersomnia Associated
ness135 is listed in Box 2413. One must also remember that with Mental Disorders
medications causing insomnia can indirectly result in The name of this category is somewhat confusing but most
daytime sleepiness. disorders of daytime sleepiness classified here are associated
The differential diagnosis of hypersomnia due to drug or with mental disorders (Box 2414). Women are more
medication includes sleep apnea, behaviorally induced commonly affected than men. Sleep is often said to be
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474 Chapter 24 Hypersomnias of Central Origin
BOX 2414 SOREMPs that do not meet criteria for other disorders are
Hypersomnia Not Due to Substance or Known classified here.
Physiologic Condition: Nonorganic
HypersomniaHypersomnia Associated CLINICAL REVIEW QUESTIONS
with Mental Disorders: Diagnostic Criteria
and Pathologic Subtypes 1. A patient is being evaluated for severe daytime sleepi-
ness (Epworth Sleepiness Scale 20/24). He reports sleep-
DIAGNOSTIC CRITERIA ing about 7 hours per night. The patient reports neck
A. The patient has a complaint of excessive daytime muscle weakness (head nods) when he hears or tells a
sleepiness or excessive sleep. joke. He undergoes a PSG followed by an MSLT. The
B. The complaint is temporally associated with a PSG is fairly normal without evidence of sleep apnea.
psychiatric diagnosis. On the MSLT, the mean sleep latency is 4 minutes but
C. Polysomnography monitoring demonstrates both of the only one of five naps has REM sleep. What is the
following: diagnosis?
i. Reduced sleep efficiency and increased frequency
A. Narcolepsy without cataplexy.
and duration of awakenings.
ii. Variable, often normal, mean sleep latencies on the B. Idiopathic hypersomnia with long sleep time.
MSLT. C. Idiopathic hypersomnia without long sleep time.
D. The hypersomnia is not better explained by another D. Narcolepsy with cataplexy.
sleep disorder, medical or neurologic disorder, mental
disorder, or substance use disorder. 2. Which of the following is an effective (and FDA-
PATHOLOGIC SUBTYPES approved) treatment for both daytime sleepiness and
cataplexy?
1. Hypersomnia associated with a major depressive
A. Sodium oxybate (SOXB).
episode.
2. Hypersomnia as a conversion disorder or an B. Fluoxetine.
undifferentiated somatoform disorder. C. Modafinil.
3. Hypersomnia associated with seasonal affective disorder. D. Methylphenidate.
MSLT = multiple sleep latency test.
From American Academy of Sleep Medicine: International Classification of 3. A patient with daytime sleepiness denies cataplexy. He
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
normally sleeps about 8 hours per night. The nocturnal
American Academy of Sleep Medicine, 2005.
PSG shows a sleep latency of 5 minutes and a REM
latency of 10 minutes. The total sleep time is normal and
nonrestorative. The disorder class represents 5% to 7% of there is no evidence of sleep apnea, but the periodic limb
patients seen with complaints of EDS.1,136 movement index is 20/hr. The MSLT shows a mean sleep
latency of 3 minutes and REM sleep on one of five naps.
Hypersomnia Associated with a Major Depressive Episode Depres- What is the likely diagnosis?
sion is more often associated with complaints of insomnia. A. Narcolepsy without cataplexy.
However, hypersomnia is frequently associated with atypical B. Idiopathic hypersomnia with long sleep time.
depression (mood reactivityability to improve with posi- C. Idiopathic hypersomnia without long sleep time.
tive events, overeating) and bipolar type II disorder (major
D. PLMD.
recurrent depression episodes with hypomania episodes).
Long hours are spent in bed. However, the sleep latency on 4. CSF Hcrt1 is low or undetectable in what percentage of
MSLT is usually normal.137 patients with N+C?
A. 100%.
Hypersomnia Associated with Seasonal Affective Disorder Daytime
B. 9095%.
fatigue, loss of concentration, increased appetite for carbo-
hydrates, and weight gain have been reported with seasonal C. 85%.
affective disorder (SAD). D. 70%.
Hypersomnia as a Conversion Disorder or an Undifferentiated 5. A 20-year-old male with N+C is being treated with
Somatoform Disorder Pseudocataplexy and pseudonarcolepsy modafinil 400 mg daily. Daytime sleepiness has improved
have been reported. but is still a problem from 4 to 7 PM. Which of the fol-
lowing would NOT be a reasonable intervention?
A. Change to modafinil 200 mg qAM, 200 mg in early
Physiologic (Organic Hypersomnia), Unspecified afternoon.
Daily sleepiness for at least 3 months with an MSLT showing B. Change to modafinil 300 mg qAM, 100 mg in early
sleep latency less than 8 minutes and fewer than two afternoon.
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Chapter 24 Hypersomnias of Central Origin 475
C. Change to armodafinil 250 mg qAM. 11. A patient with Prader-Willi syndrome (PWS) is being
D. Change to methylphenidate 2030 mg in the AM. evaluated with daytime sleepiness. He denies cataplexy.
A PSG shows an AHI of 3/hr. An MSLT shows a sleep
6. An 18-year-old man is evaluated for three episodes of latency of 3 minutes and one SOREMP. Which of the
daytime sleepiness each lasting about 6 weeks that have following is the most likely diagnosis?
occurred over the last 8 months. The patient does not A. Narcolepsy Due to Medical Condition (NDMC).
have periods of depression. Which of the following is B. OSA.
NOT true about the patients disorder? C. Hypersomnia Due to Medical Condition.
A. Lithium has been reported to be effective is small D. Idiopathic hypersomnia without long sleep time.
case series (delay or preventing recurrences).
B. Hypersexuality can occur during the periods of 12. If one member of a pair of identical twins has narco-
excessive sleepiness. lepsy, in what percentage of twin pairs is the other twin
C. Reports of derealization and cognitive impairment likely to have or develop narcolepsy?
are common. A. 10%.
D. Increased amount of daily sleepusually 15 hours B. 30%.
or greater. C. 50%.
E. No precipitating event is usually reported. D. 75%.
7. A 40-year-old patient with narcolepsy has disabling 13. A patient is diagnosed with narcolepsy. What percent-
daytime sleepiness despite taking modafinil 400 mg age of his first-degree relatives are likely to have or
daily (Epworth Sleepiness Score 16/24). Cataplexy is not develop narcolepsy?
reported. What is the first intervention that you
A. 12%.
recommend?
B. 5%.
A. Increase modafinil to 600 mg daily.
C. 10%.
B. Change to methylphenidate 20 mg bid.
D. 25%.
C. Begin SOXB.
D. Schedule naps. 14. Which of the following is NOT true about modafinil?
A. Headache is the most common side effect.
8. What duration of nocturnal sleep separates patients
with IH+LST from those with IHLST? B. Modafinil can alter the metabolism of oral
contraceptives.
A. Sleep duration >8 hr.
C. If modafinil is given in the morning, it can still
B. Sleep duration >10 hr.
disturb nocturnal sleep
C. Sleep duration >12 hr.
D. Modafinil is very rarely associated with a life-
D. Sleep duration >14 hr. threatening rash.
value. PLMS is common in patients with narcolepsy (see 13. A. 12% of the first-degree relatives are at risk for
Chapter 23). narcolepsy.
4. B. About 9095% of patients with N+C have a low or 14. C. Modafinil does not disturb nocturnal sleep if given
undetectable CSF Hcrt1. However, 510% of patients in the morning. Women of reproductive age should
with N+C do not have a reduced CSF Hcrt. always be informed that the effectiveness of oral contra-
ceptives may be impaired by modafinil.
5. D. Patients taking modafinil in the morning sometimes
have problems with alertness in the late afternoon and
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Chapter 25
Insomnia
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482 Chapter 25 Insomnia
BOX 251
TECHNIQUE EVIDENCE BRIEF SUMMARY Diagnostic Criteria for Insomnia
Biofeedback Guideline Reduce somatic A. A complaint of difficulty initiating sleep, difficulty
tension. maintaining sleep, or waking up too early, or sleep that
Paradoxical Guideline Passively remain is chronically nonrestorative or of poor quality. In
intention awake and avoid children, the sleep difficulty is often reported by the
any effort (intention) caretaker and may consist of observed bedtime
to fall asleep. resistance or inability to sleep independently.
B. The above sleep difficulty occurs despite adequate
Sleep No Improved sleep
opportunity and circumstances for sleep.
hygiene recommendation scheduling, used
education bed only for sleep. C. At least one of the following forms of daytime
impairment related to the night sleep difficulty is
reported by the patient.
Options for treatment of insomnia in a patient with
i. Fatigue or malaise.
depression include using (1) a sedating antidepressant
ii. Attention, concentration, or memory impairment.
at a dose effective for depression, (2) an effective
iii. Social or vocational dysfunction or poor school
antidepressant + a low dose of a sedating performance.
antidepressant, (3) an effective antidepressant + a iv. Mood disturbance or irritability.
BZRA. In patients with a history of alcohol or drug v. Daytime sleepiness.
dependence, use of a BZRA should be avoided. vi. Motivation, energy, or initiative reduction.
In patients with benign prostatic hypertrophy, vii. Proneness to error/accidents at work or while
medications with anticholinergic side effects should driving.
be avoided. viii. Tension, headaches, or gastrointestinal symptoms in
response to sleep loss.
ix. Concerns or worries about sleep.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
The International Classification of Sleep Disorders, second Westchester, IL: American Academy of Sleep Medicine, 2005.
edition (ICSD-2)1 lists diagnostic criteria for insomnia (Box
251) that include requirements for an insomnia sleep com-
plaint, adequate opportunity/sleep, and some form of
daytime impairment related to the sleep difficulty. The sleep
PREVALENCE OF INSOMNIA AND RISK FACTORS
complaints associated with insomnia include difficulty initi-
ating sleep (sleep-onset insomnia), difficulty maintaining It has been estimated that insomnia complaints occur on at
sleep (sleep-maintenance insomnia), waking up too early, least a few nights per year in 33% to 50% of the adult popula-
or sleep that is chronically nonrestorative or poor in quality. tion. Insomnia complaints plus symptoms of impairment
A diagnosis of insomnia requires that patients must report due to insomnia occur in 10% to 15% of the population.
at least one of these insomnia complaints. However, it is not Specific insomnia disorders occur in 5% to 10%.25 A number
uncommon for individual patients to report all of them. of risk factors for the development of insomnia have been
There must be adequate opportunity and circumstances for identified, including older age, female gender, co-morbid
sleep to occur. A diagnosis of insomnia also requires evi- problems (depression and other psychiatric disorders, sub-
dence of daytime impairment related to the sleep problem. stance abuse), shift work, unemployment, and lower socio-
Patients suffering from insomnia may report a wide variety economic status. Some studies suggest that single, divorced,
of complaints (see Box 251) including fatigue or malaise, and separated patients have greater insomnia rates than
problems with attention or concentration, memory impair- married patients. The most common cause of insomnia in
ment, social or vocational dysfunction, and poor school per- patients evaluated by a physician is insomnia due to or asso-
formance. Other symptoms associated with insomnia include ciated with depression. Insomnia occurs in the majority of
mood disturbance or irritability; daytime sleepiness; reduc- patients (80%) with major depressive or chronic pain disor-
tion in motivation or initiative; proneness to error/accidents ders. Persistent insomnia symptoms increase the likeli-
at work or while driving; tension headaches or gastrointesti- hood of developing a major depression within a 1-year
nal symptoms in response to sleep loss; and concerns or period by a factor of four.3 In addition, up to one third of
worries about sleep.1 In children, the sleep difficulty is often all cases of insomnia are associated with a mental disorder.
reported by the caretaker and may consist of observed
bedtime resistance or inability to sleep independently.
INSOMNIA SUBTYPES
Although the minimum duration of insomnia complaints is
not specified in the definition of insomnia (see Box 251), The ICSD-2 classification lists a number of distinct sleep
the diagnostic criteria for several individual insomnia types disorders associated with insomnia (Box 252). The three
does specify a minimum duration of 1 month.1 most common insomnia disorders include adjustment
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Chapter 25 Insomnia 483
TABLE 251
Major Characteristics of Insomnia Types in International Classification of Sleep Disorders, 2nd Edition
INSOMNIA TYPES ESSENTIAL FEATURES CLINICAL CLUES
Adjustment Temporally associated with identifiable stressor. Recent psychological, psychosocial,
Duration less than 3 months. environmental, or physical stressor.
Expected to resolve.
Psychophysiologic Duration at least 1 month. Better sleep in novel environment
Anxiety about sleep. (away from home)
Heightened arousal when in bed. Can fall asleep outside bedroom or
Conditioned sleep-preventing associations (bedroom when not trying to sleep
as stimulus for wake not sleep).
Paradoxical Duration at least 1 month. Objective sleep duration much
Extreme and physiologically improbable complaints: greater than reported.
I never sleep. No or rare naps.
Despite report of little sleep, relatively minor daytime
impairment.
Idiopathic Onset in infancy or childhood. Lifelong insomnia without
No identifiable precipitant. remissions.
No period of sustained remission. Insidious onset.
Associated with a mental Insomnia present for at least 1 month. Insomnia waxes and wanes with
disorder Mental disorder has been diagnosed. mental disorder.
Temporally associated with mental disorder (can
precede by a few days of weeks).
Inadequate sleep hygiene Improper sleep scheduling. Variable bedtime and wake times.
Use of products that disturb sleep near bedtime. Napping.
Stimulating activities near bedtime.
Use of the bed for nonsleep activities.
Behavioral insomnia of Falling asleep is an extended process. Nighttime awakenings require
childhood Sleep-onset associations demanding. caregiver for return to sleep.
sleep association type In absence of associated factors, sleep onset delayed.
Behavioral insomnia of Difficulty initiating or maintaining sleep Caregiver demonstrates
childhood Refusal to go to bed or return to bed after awakening. insufficient limit setting to
limit-setting type Caregiver demonstrates insufficient limit setting to establish appropriate behavior.
establish appropriate behavior.
Adapted from Schutte-Rodin S, Broch L, Buysee D, et al: Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med
2008;4:487504.
bed, extreme hot or cold temperature). Activities near as discussed in a following section. Daytime function should
bedtime, including working late on the computer, drinking be discussed with emphasis on possible consequences of
caffeinated beverages or alcohol in the evening, or exercise insomnia. Reports of daytime fatigue or impaired cognition
near bedtime, may impair the ability to sleep. The mental and mood are more common than true daytime sleepiness.
status at bedtime should be explored. Often, patients began True daytime sleepiness should trigger suspicion for addi-
worrying about their stresses and problems when retiring for tional sleep problems such as sleep apnea, narcolepsy, or
the night. The presence or absence of nocturnal symptoms depression. Daytime activities that may affect sleep such as
including snoring, gasping during sleep, symptoms of the the amount of caffeine, alcohol, exercise, sunlight exposure,
restless legs syndrome, and body movements should be and napping should be detailed. A general medical and psy-
evaluated. chiatric history is important to identify mental or medical
The sleep-wake schedule should be determined by report conditions that may affect sleep. A detailed medication
including variability of bedtime and rise time as well as the history including over-the-counter medications and sub-
frequency and duration of naps. Factors that worsen or stances of abuse is extremely important.
improve sleep should be detailed. For example, some patients A physical examination and a general medical history
with psychophysiologic insomnia report sleeping better in a including appropriate laboratory (if not recently performed)
novel environment (reverse first-night effect).11 Patient should rule out obvious medical causes of insomnia. Exami-
recall can be supplemented by sleep logs and/or actigraphy nation of the upper airway showing a high Mallampati score
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Chapter 25 Insomnia 485
TABLE 252
Questionnaires to Evaluate Patients with Insomnia
Epworth Sleepiness Scale Propensity to fall asleep in eight situations (0 never, 1 slight, 2 moderate, 3 high chance)
with a total score 0 to 24. Normal 10.
Beck Depression Inventory BDI-I or BDI-II is a 21-item self-report inventory used to measure depression.
BDI-I scores: Minimal or no depression BDI < 10, moderate to severe depression BDI 19.
BDI-II scores: Minimal or no depression BDI < 14, moderate to severe depression BDI 20.
Pittsburgh Sleep Quality Index A 24-item self-report measure of sleep qualities (poor sleep: global score > 5).
Dysfunctional Beliefs and Attitudes DBAS is a self-rating of 30 statements that is used to assess negative cognitions about
about Sleep Questionnaire sleep. Shorter version of the DBAS-16 also exists (see Appendix 251).
BDI = Beck Depression Inventory; DBAS = Dysfunctional Beliefs and Attitudes about Sleep.
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486 Chapter 25 Insomnia
SLEEP DIARY
FIGURE 251 A typical sleep log. From the answers, one can determine the time in bed (TIB), the sleep latency, and the total sleep time. The wake after sleep onset = TIB sleep
latency total sleep time.
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Chapter 25 Insomnia 487
PM Midnight AM Noon PM
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6
Sun X Mon
Mon X Tues
Tues X Wed
Wed X Thurs
Thurs X Fri
Fri X Sat
Sat X Sun
Sun X Mon
Mon X Tues
FIGURE 252 A sleep log (diary) shows inadequate sleep hygiene with variable bedtimes and wake times as well as
napping. Note that on Sunday and Wednesday, the sleep latency was prolonged. Once asleep, the patient had no middle of the
night awakenings.
BOX 255
TABLE 253
Some Typical Sleep Log Patterns Selected Recommendations for the Use of
Actigraphy According to American Academy of
Delayed sleep Late bedtime or long sleep latency, Sleep Medicine Practice Parameters (2007 Update)
phase few awakenings, normal sleep
duration on weekends or 1. Actigraphy is a valid method to determine sleep
nonwork/nonschool days. patterns in normal healthy population (Standard) and
in certain sleep disorders. (Option-Guideline)
Inadequate sleep Irregular wake and rise times, naps.
2. Actigraphy is indicated to assist in evaluation of patients
hygiene
with suspected advanced sleep phase syndrome,
Psychophysiologic Long sleep latency, decreased total delayed sleep phase syndrome, and shift work
insomnia sleep time, frequent awakenings. disorder (Guideline); and circadian rhythm disorders,
Variability in sleep quality. including jet lag, and non24-hr sleep/wake CRSD.
(Option)
Paradoxical Nights of minimal or no sleep are
3. When PSG is not available, actigraphy is indicated to
insomnia reported followed by no or few
estimate TST in patients with OSA. (Standard)
naps the next day.
4. Actigraphy is indicated as a method to characterize
circadian rhythm patterns of sleep disorders in
individuals with insomnia including insomnia with
Actigraphy depression. (Option)
Actigraphy involves use of a portable device (often resem- 5. Actigraphy is indicated as a way to determine circadian
bling a watch and typically worn on the wrist) that collects pattern and estimate average daily sleep time in
movement information (activity) over an extended period of individuals complaining of hypersomnia. (Option)
time (Fig. 253). The absence of movement is assumed to be 6. Actigraphy is useful as an outcome measure in
a surrogate of sleep.2129 The use of actigraphy is included in evaluating the response to treatment for circadian
rhythm disorders. (Guideline)
the ICSD-2 diagnostic criteria for several CRSDs, paradoxi-
7. Actigraphy is useful for evaluation of the response to
cal insomnia, and behaviorally induced insufficient sleep
treatment for patients with insomnia, including insomnia
syndrome.1 Practice parameters for use of actigraphy have associated with depression. (Guideline)
been published by the American Academy of Sleep Medicine
CRSD = circadian rhythm sleep disorder; OSA = obstructive sleep apnea;
(AASM).23,29 Some of the recommendations are listed in PSG = polysomnography; TST = total sleep time.
Box 255. Note that, although actigraphy was said to be From Morgenthaler T, Alessi C, Friedman L, et al. Practice parameters for the
indicated for determining the circadian patterns of patients use of actigraphy in the assessment of sleep and sleep disorders: an update
for 2007. Sleep 2007;30:519529.
with insomnia, the practice parameters did not state that
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488 Chapter 25 Insomnia
Normal
100
Activity 50
12 14 16 18 20 22 24 02 04 06 08 10 12
Wake Sleep
12 14 16 18 20 22 24 02 04 06 08 10 12
In bed
12 14 16 18 20 22 24 02 04 06 08 10 12
Disturbed sleep
100
Activity 50
12 14 16 18 20 22 24 02 04 06 08 10 12
Wake Sleep
12 14 16 18 20 22 24 02 04 06 08 10 12
In bed
12 14 16 18 20 22 24 02 04 06 08 10 12
FIGURE 253 Examples of actigraphy in a normal subject and a patient with disturbed sleep. Top, Normal subject. Measures of activity,
actigraphic estimates of wake and sleep, and sleep log reported time in bed are displayed. Bottom, A patient with disturbed sleep. Note
persistent activity during the sleep period. In the wake sleep data, periods identified as wake (thin line) are above periods of sleep (thicker
line). Adapted from Crdoba J, Cabrera J, Lataif L, et al: High prevalence of sleep disturbance in cirrhosis. Hepatology 1998;27:339345.
actigraphy was indicated as a routine evaluation of patients provide the capability of recording the amount of ambient
with insomnia. light. This is useful in patients with CRSDs in whom light
Actigraphy does not measure sleep as defined by electro- exposure may either exacerbate or improve the underlying
encephalogram (EEG)/electro-oculogram (EOG)/chin elec- disorder. Some actigraphy devices also have event markers
tromyogram (EMG) criteria or the subjective experience of that the patient can press when getting in bed, trying to sleep,
sleep (as measured by sleep logs and questionnaires). There- or after awakening in the morning.
fore, it is not surprising that estimates of TST, wake time, and Sleep logs and actigraphy provide complementary
the sleep latency from sleep logs and actigraphy may differ information. In a study of patients with insomnia undergo-
from polysomnography (PSG) findings. Algorithms have ing treatment, Vallires and Morin24 compared findings from
been developed to estimate TST and WASO from the activity actigraphy and sleep logs with PSG (Fig. 254A). Both actig-
data. Modern actigraphic software allows the clinician to raphy and sleep logs underestimated TST and overestimated
mark periods of possible sleep (rest periods). The software wake time. Actigraphy underestimated the sleep latency and
then provides automatic estimates of periods of sleep and sleep logs overestimated the sleep latency. These authors
wake. These can be edited if desired. However, there are found actigraphy to be more sensitive at detecting treatment
limitations to the accuracy of these estimates. Actigraphic effects than sleep logs. In contrast, Sivertsen and coworkers25
estimates of sleep duration, WASO, and sleep latency are found different results in a group of older adults treated for
more accurate in normal individuals than in patients with primary insomnia (expected to have more wake time).
insomnia. Periods of low activity in which patients lay quietly Actigraphy slightly overestimated TST and underestimated
in bed but are awake may be scored as sleep by actigraphy wake (see Fig. 254B). In this study, actigraphy provided a
software. When performing actigraphy, it is essential to better estimate of TST than of wake time.
require patients to complete a sleep log (e.g., lights off, lights
on, out of bed, actigraph off for shower; TST; sleep latency).
Polysomnography
This information enables a correct interpretation of acti-
graphic tracings. For example, total absence of movement PSG is not indicated for the routine assessment of insom-
usually indicates that the actigraph has been removed nia.9,10 However, if there is a suspicion for sleep apnea, peri-
(shower, swimming), but here patient logs are essential to odic limb movement disorder, or a parasomnia, a PSG may
verify device removal. If the actigraphic estimate of TST be useful. The 2003 AASM practice parameters for the role
far exceeds patient estimates, this would suggest paradoxi- of PSG in insomnia stated polysomnography is indicated
cal insomnia. Many modern wrist actigraph devices also when the initial diagnosis (insomnia) is uncertain, treatment
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Chapter 25 Insomnia 489
Log/PSG
Act/PSG Log/PSG
2 2
Act/PSG
Act/PSG Log/PSG
1 1
Act/PSG
0 0
TST Wake Sleep TST Wake Sleep
A latency B latency
FIGURE 254 A, A plot of the ratios of actigraphic (Act)/PSG (polysomnography) and sleep log (Log)/PSG estimates of total
sleep time (TST), wake, and sleep latency from the data of a study by Vallries and Morin in patients with insomnia. Both
actigraphy and sleep logs slightly underestimated the total sleep time but overestimated wake time. Sleep logs overestimated
sleep latency while actigraphy underestimated sleep latency (laying in bed still but awake). B, A plot of data from a study of
older insomnias by Sivertsen and coworkers. Actigraphy slightly overestimated TST but underestimated wake and sleep latency.
A, From Vallires A, Morin CM: Actigraphy in the assessment of insomnia. Sleep 2003;26:902906. B, Sivertsen B, Omvik S, Havik
OE, et al: A comparison of actigraphy and polysomnography in older adults treated for chronic primary insomnia. Sleep
2006;29:13531358.
paradoxical insomnia often report being aware of the envi- insomnia, a more severe abnormality of sleep is usually
ronment for the entire night or ruminating on problems, reported and the disorder does not start at an early age.
they tend to have less prominent sleep-preventing asso-
ciations compared with patients with psychophysiologic Treatment
insomnia. CBTI, pharmacotherapy, or both are options. No large
studies of treatment outcomes have been published.
Treatment
CBT of insomnia (CBTI), pharmacotherapy, or both are
Insomnia Due to a Mental Disorder
recommended.
Insomnia due to mental disorder (IDMD) is the most
common form of insomnia seen by sleep physicians (Box
Idiopathic Insomnia
2511). Many times, patients have fixated on the insomnia
Idiopathic insomnia is also called childhood-onset insomnia. problems while ignoring (denying) or minimizing their
The patient usually recalls the insidious onset of the insom- other symptoms of depression.
nia problems in childhood. The history is one of lifelong
insomnia problems (Box 2510). Key Features
The insomnia is viewed as a consequence of the mental dis-
Key Features order (e.g., depression) and shares the course of the disorder
Patients with idiopathic insomnia report this problem since (waxing and waning together). However, insomnia can actu-
childhood with no periods of significant remission. There is ally precede the development of depression in some patients.
no identifiable cause or precipitating factor. The onset is Of note, insomnia complaints are very common in mood
often insidious. disorders and are often considered secondary (co-morbid)
to the mood disorder. A separate diagnosis of insomnia due
Epidemiology to mental disorder (IDMD) is made only if the insomnia is
Idiopathic insomnia occurs in less than 10% of patients with significant enough to warrant special attention. Common
insomnia. Idiopathic insomnia is a rare disorder occurring mental disorders associated with IDMD include major
in only approximately 0.7% of adolescents.1 depression, bipolar disorder, and anxiety disorder. In anxiety
disorders, prominent sleep-onset insomnia is usually present.
Objective Findings In depressive disorders, especially in older patients, the
Polysomnography PSG findings include a long sleep latency, sleep disturbance is characterized by prominent sleep-
increased WASO, reduced TST, and low sleep efficiency. maintenance insomnia and early morning awakening.
These findings are not specific for idiopathic insomnia. Younger patients with depression may experience more
prominent sleep-onset insomnia.
Sleep Log Findings from a sleep log are typically consistent
with the patients complaints. Epidemiology
IDMD is the most common cause of insomnia in
Differential Diagnosis patients presenting to sleep disorder centers complaining
Whereas idiopathic insomnia has an insidious onset in
childhood, psychophysiologic insomnia starts in adulthood
and the time of onset can often be defined. In paradoxical BOX 2511
Insomnia Due to Mental Disorder
BOX 2510
Diagnostic Criteria
TABLE 254
Techniques Used for Behavioral Treatment of Insomnia of Childhood
TECHNIQUE DESCRIPTION RATIONALE
Unmodified extinction Involves parents putting the child to bed at a designated Reduce undesired behaviors (e.g.,
bedtime and then ignoring the child until morning crying, screaming) by eliminating
(parents continue to monitor for safety issues). parental attention (reinforcer).
Graduated extinction Involves parents ignoring bedtime crying and tantrums for Enable a child to develop self-
predetermined periods before briefly checking on the soothing skills and be able to
child. A progressive (graduated) checking schedule (e.g., fall asleep independently
5 min, then 10 min) or fixed checking schedule (e.g., without undesirable sleep
every 5 min) may be used. associations.
Scheduled awakenings Involves parents preemptively awakening their child, prior Prevents nightly reinforcement for
to a typical spontaneous awakening, and providing the undesirable behaviors involved
usual responses (e.g., feeding, rocking, soothing) as if with waking.
child had awakened spontaneously.
Positive routines Parents develop set bedtime routines characterized by Removes negative stimuli
enjoyable and quiet activities to establish a behavioral associated with bedtime.
chain leading up to sleep onset.
Delayed (faded) bedtime Temporarily delaying the bedtime to more closely coincide Reduced arousal at bedtime
with the childs natural sleep-onset time, the fading
(bedtime) is moved earlier as the child gains success
falling asleep quietly.
Response cost Response cost involves removing the child from bed for A type of stimulus control for child:
prescribed brief periods of time if the child does not fall the bedroom is a place for sleep
asleep within a prescribed time. not crying/attention seeking.
Parental education and Involves parent education to prevent the occurrence of the Preventing problems before they
prevention development of sleep problems. Behavioral interventions occur.
are incorporated into these parent education programs.
Adapted from Mindell JA, Kuhn B, Lewin DS, et al: Behavioral treatment of bedtime problems and night wakings in infants and young children. An American
Academy of Sleep Medicine Review. Sleep 2006;29:12631276.
extinction with parental presence involves the parent staying Key Features
in the childs bedroom but not talking with the child, rocking Patients must have ongoing use of a drug or substance asso-
the child, or other behaviors. ciated with symptoms of insomnia. The insomnia can also
occur on withdrawal from the agent. In recovering alcohol-
Graduated Extinction Parents are instructed to ignore bedtime ics, sleep disturbance may persist for many months after
crying and tantrums for specified periods according to a the start of abstinence (Box 2516).
fixed schedule of progressively longer intervals and to avoid
reinforcing protest behavior. For example, suppose a child Epidemiology
typically starts crying when placed in the crib. On subse- Insomnia complaints due to medications or substances are
quent nights, bedtime crying is ignored for 10, then 20, then very common. Caffeine is a widely used stimulant that may
30, and 60 minutes or more on successive nights. affect sleep for hours after ingestion. The half-life of caffeine
For these techniques to be effective, parents must be moti- varies from 3 to 7 hours and is longer at higher doses.35
vated and consistent. It is important that the caregivers Alcohol may aid sleep onset but tends to cause frequent
choose an approach that they are comfortable with and then awakenings in the second part of the night.36
apply it every night.
Causes
A large number of medications can be associated with
Insomnia Due to Drug or Substance
insomnia (Table 255).37 Nonsedating antidepressants, anti-
Insomnia due to drug or substance implies that the insomnia convulsants, beta blockers, bronchodilators, and stimulants/
complaints are associated with the use of or withdrawal from alerting agents can all be associated with insomnia. Medica-
a medication or substance. Some patients may often be able tions that cause nightmares may also result in insomnia.
to relate the onset of sleep problems with the start of a new
medication. In others, the onset is more insidious and may Beta Blockers Because beta blockers are frequently used to
not be noticed. treat patients with cardiovascular disease, it is important for
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496 Chapter 25 Insomnia
sleep physicians to know that they can cause nightmares Efavirenz (Sustiva)
and/or sleep disturbance. Beta blockers can reduce noctur- Adapted from Schweitzer PK: Drugs that disturb sleep and wakefulness. In
Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep
nal melatonin secretion. However, the mechanism by which
Medicine, 4th ed. Philadelphia: Elsevier Saunders, 2005, pp. 495518.
beta blockers disturb sleep is not known. Beta blockers that
have high lipid solubility (easily penetrate blood brain
barriere.g., propanolol) and affect norepinephrine are con-
sidered more likely to be associated with nightmares.
However, nightmares have also been noted with beta block- withdrawal because alcohol suppresses REM sleep. In some
ers with less lipid solubility. Beta blockers with high lipid patients during acute alcohol withdrawal, sleep consists of
solubility include metoprolol, propanolol, and timolol. repeated REM episodes interposed on wakefulness.38
Atenolol is an example of a beta blocker with lower lipid
solubility. Abstinent Alcoholic In abstinent alcoholics (recovering alco-
holics), sleep disturbance can persist for a long period of
Effects of Alcohol Alcohol is commonly used as a sleep aid and time with reduced stage N3 and increased wakefulness
patients often do not connect their sleep problems with (WASO). In one study of patients admitted to alcohol recov-
alcohol consumption because most sleep disturbances ery, an increase in REM sleep (REM sleep as % of TST) and
occur hours after the last drink. an increased REM density (REMs per time in REM sleep)
on admission predicted those who relapsed within 3
Patients without Alcoholism Bedtime alcohol may shorten the months.38 Another study found longer sleep latency, shorter
latency to sleep, at least on the first few nights of consump- REM latency, and decreased stage 4 (stage N3) predicted
tion. However, bedtime alcohol consumption tends to frag- relapse.39
ment sleep in the later half of the night. Alcohol also increases
the REM latency. Of interest, one study found that late after- Treatment
noon (happy hour) alcohol consumption approximately The treatment for insomnia due to drug or substance is to
6 hours before bedtime increased wakefulness during the withdraw the offending agent. If a withdrawal syndrome is
second half of sleep.36 possible, gradual weaning is indicated. If withdrawal of a
substance of abuse is planned, this often requires admission
Active Alcoholism Sleep disturbances associated with active to a rehabilitation or mental facility and close medical super-
alcoholism include increased sleep latency, frequent awaken- vision. If chronic insomnia is present in the recovering alco-
ing, and decreased subjective sleep quality. Abrupt with- holic or patient recovering from other drug addiction,
drawal of alcohol can trigger profound insomnia and marked the use of BZRAs is not recommended for treatment. Typi-
sleep fragmentation. A decrease stage N3 is also typically cally, sedating antidepressants and behavioral treatments are
noted. An increase in REM sleep may also occur with acute utilized.
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Chapter 25 Insomnia 497
Relaxation Therapy (Standard) The term relaxation therapy time in bed is gradually increased. When using this tech-
(RT) is a generic term that encompasses any number of nique, the patient should be cautioned about sleepiness to
techniques.43,44 Progressive muscle relaxation (PMR) prevent accidents or other mishaps.
focuses on somatic arousal and was developed by Edmund
Jacobsen. Thus, the technique is often called Jacobsen PMR. Paradoxical Intention (Guideline) Instructing the patient to pas-
In this technique, the patient systematically goes through sively remain awake and avoid any effort (intention) to fall
the parts of the body initially tensing muscles, maintaining asleep. The goal is to eliminate performance anxiety.
muscle tension, then relaxing the muscles. The patient is
asked to concentrate on the sensations associated with Biofeedback (Guideline) Biofeedback trains the patient to
tensing and then relaxation. Guided imagery relaxation control some physiologic variable through visible or auditory
focuses on cognitive arousal and uses techniques of visual- feedback. The goal is to reduce somatic arousal.
izing a relaxing setting or activity. RT is useful in patients
who report or display elevated levels of arousal. The tech- Multicomponent Therapy (Without Cognitive Therapy) (Guide-
nique can be helpful with both sleep-onset and sleep- line) This form of treatment uses multiple behavioral tech-
maintenance insomnia. niques (e.g., SCT, SRT, RT) without cognitive therapy (Table
257).
Stimulus Control Therapy (Standard) This is a specific type of
CBT that is based on the idea that arousal occurs as a con- Evidence for Behavioral Treatment
ditioned response to the stimulus of the sleep (bedroom) CBTI for periods of 4 to 8 weeks has been proven effective
environment.43,45 This technique is among the most effective by randomized, controlled trials comparing CBT with stan-
behavioral treatments. The standard instructions are listed in dard care or pharmacotherapy. In contrast to pharmaco-
Box 2518. The goal of stimulus control therapy (SCT) is to therapy, the benefits persist when treatment is stopped.
extinguish the negative association between the bed and Jacobs and colleagues47 compared CBT, pharmacotherapy
undesirable outcomes such as wakefulness, frustration, and (zolpidem 10 mg nightly 28 days then 5 mg nightly for 7
worry. These associations become conditioned as a result of days, then 5 mg every other day for 7 days), combined
prolonged efforts to fall asleep and time in bed awake. SCT therapy (zolpidem + CBT), or placebo over 6 weeks of active
will replace these negative associations with positive associa- treatment and another 2 weeks of either drug washout or
tions between the bed and sleep. consolidation of CBT (no treatment sessions). The main
outcome was the sleep-onset latency assessed by diary. The
Sleep Restriction Therapy (Guideline) Sleep restriction therapy greatest improvement was with CBT and there was no
(SRT; Box 2519) limits the time in bed to the TST as derived advantage to combined treatment. In addition, at follow-up,
from sleep logs.46 The goal is to improve sleep continuity, benefits of CBT were maintained (Fig. 255). Edinger and
enhancing sleep drive with sleep restriction. Sleep will associates48 compared CBT with RT and quasidesensitization
become more consolidated when long periods in bed and (placebo). The CBT group had a 54% reduction in WASO
napping are prohibited. As sleep continuity improves, the compared with 16% with relaxation and 12% with placebo.
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Chapter 25 Insomnia 499
60
Midtreatment Smith and coworkers49 compared the effect sizes of CBT and
pharmacotherapy with respect to sleep latency, TST, and
Changes in sleep latency, %
After treatment
50
WASO and found CBT to be equal or better. Figure 256
40 illustrates the time course of improvement in TST with
temazepam and CBT from a study by Morin and colleagues.50
30 The major point is that, unlike pharmacotherapy, improve-
20
ment with CBT continues after the active treatment period.
In summary, CBT is effective for measures of sleep-onset
10 insomnia, sleep-maintenance insomnia, and nonrestor-
ative sleep. There is currently no evidence that adding
0
CBT Combination Pharmacotherapy Placebo hypnotics (combined treatment) has any advantage.
therapy
Treatment condition CBT in Hypnotic-Dependent Patients and
FIGURE 255 Percent changes (decreases) in the sleep latency with the four treatment in Co-morbid Insomnia
conditions. Combination therapy included a combination of cognitive behavioral Although studies to date have not documented an advantage
therapy (CBT) and pharmacotherapy. CBT was more effective than pharmacotherapy of combining CBT and hypnotics, CBT can be used in
(P = .03) and placebo (P = .02). Combination therapy was more effective than patients already on hypnotics with the possible goal of
pharmacotherapy (P = .02) or placebo (P = .001). Combination therapy and CBT therapy weaning the hypnotics.
did not differ. From Jacobs GD, Pace-Schott EF, Stickgold R, Otto MW: Cognitive behavior Several studies have documented the efficacy of CBT in
therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct patients on hypnotics.5153 Using structured programs, hyp-
comparison. Arch Intern Med 2004;164:18881896.
notic tapering and withdrawal is facilitated by combining the
process with CBTI.5153 In one study comparing supervised
benzodiazepine (BZ) withdrawal, CBT alone, or supervised
TEMAZEPAM (TEM) VS. CBT IN THE TREATMENT FIGURE 256 Total sleep time (TST) in groups treated with temazepam
OF PRIMARY INSOMNIA (TEM) and cognitive behavioral treatment (CBT). Note that after 8 weeks of
TST
treatment with TEM, the benefits decreased (drug stopped after 8 wk).
395 However, the CBT group continued to show improvement. From Riemann
CBT D, Perlis ML: The treatments of chronic insomnia: a review of benzodiazepine
385
receptor agonists and psychological and behavioral therapies. Sleep Med Rev
375
2009;13:205214, data from Morin CM, Colecchi C, Stone J, et al: Behavioral
365 and pharmacological therapies for late life insomnia: a randomized controlled
355 trial. JAMA 1999;281:991999.
TEM
345
335
325
315
Baseline 8 weeks of Follow up Follow up Follow up
therapy (3 months) (12 months) (24 months)
TABLE 257
Evidence Levels Concerning Behavioral Techniques for Treatment of Insomnia
EFFECTIVE (STANDARD) EFFECTIVE (GUIDELINE) NO RECOMMENDATION
Cognitive-behavioral treatment (with Paradoxical intention Improved sleep hygiene
or without relaxation therapy)
Stimulus control therapy Biofeedback
Relaxation therapy Sleep restriction
Multicomponent therapy (combinations of
SCT, RT, and SRT without cognitive therapy)
RT = relaxation therapy; SCT = stimulus control therapy; SRT = sleep restriction therapy.
From Morgenthaler T, Kramer M, Alessi C, et al: Practice parameters for the psychological and behavioral treatment of insomnia: an update. Sleep 2006;29:14151419.
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500 Chapter 25 Insomnia
withdrawal and CBT, all groups significantly reduced BZ use. and one gamma subunit. In addition, the alpha, beta, and
However, more patients were BZ free in the combined group gamma subunits have isoforms (e.g., 1, 2, 3, ). The
and both groups with CBT had better improvements in sub- GABA binding site is located between alpha and beta sub-
jective sleep quality.51 The utility of CBT is not confined to units and the BZ receptor site is located between alpha and
primary insomnia. CBT has also proved effective in second- gamma subunits (see Fig. 257). The most common GBC
ary (co-morbid) insomnia due to mental or medical disor- receptor configuration is denoted as 1, 2, 2 (understood
ders.53 Whereas it is appropriate to optimize treatment of the to mean two 1, two 2, and one 2 subunits) also known as
underlying co-morbid disorder, physicians should remem- a BZ type 1 receptor. The GBC also has receptors for barbi-
ber that CBT as well as hypnotics may improve insomnia turates, certain inhaled anesthetics, and alcohol.
complaints. GABAA receptors composed of different alpha subtypes
are located in different locations of the central nervous
system and mediate different effects (see Box 2519). GABAA
Pharmacologic Treatment of Insomnia
receptors composed of 1 subunits mediate sedation (hyp-
GABABZChloride Ionophore Complex notic effect), amnesia, and anticonvulsant effects. GABAA
GABA is the major inhibitory neurotransmitter in the central receptors associated with 2 and 3 subunits mediate anxio-
nervous system. There are two major GABA receptor sub- lytic and myorelaxant effects.
types GABAA and GABAB. The GABAA receptor is associated BZs tend to have high affinity for all these subtypes. The
with a chloride (Cl) channel ionophore located in cell mem- new nonbenzodiazepine BZRAs (zolpidem, zaleplon, eszopi-
branes. Ionophores are molecular complexes located in cel- clone), also known as the Z hypnotics, have preferential
lular lipid membranes that allow transport/passage of binding to GABAA receptors containing certain subunits.
compounds across the membrane. The GABAA receptor is Zolpidem and zaleplon selectively bind GABAA receptors
the binding site for several drugs other than GABA including containing 1 subunits and are often called selective BZRAs
agonists (muscimol, gaboxadol) and antagonists (bicucul- (Table 258). However, the preferential binding is only rela-
line). The GABAA receptor complex also contains a receptor tive, and at higher doses, GABAA receptors containing 1, 2,
for BZs and related compounds, hence, the complex is and 3 are bound. Eszopiclone has receptor binding more
usually referred to as the GABAbenzodiazepinechloride like traditional BZs but has many of the same advantages of
ionophore complex (GBC).5456 When GABA binds the the other Z hypnotics. Eszopiclone does bind 1 subunits
GABAA receptor on the complex, this allows passage of chlo- with higher affinity than 3 but also binds 2 subunit recep-
ride ions through the membrane, resulting in hyperpolariza- tors with only slightly lower affinity than 1 subunits.56 The
tion and reduced neuronal activity. When BZs and certain clinical importance of selective binding for the clinical effects
nonbenzodiazepine medications bind the BZ receptor on the
GBC, the configuration of the GABA receptor changes to
TABLE 258
enhance the ability of GABA binding to open the associ-
Relative Binding of Benzodiazepine
ated chloride channel (increased frequency). The medica-
Receptor Subtypes
tions are, therefore, sometimes called GABAA receptor
modulators. Medications (including nonbenzodiazepines) ALPHA 1 ALPHA 2 ALPHA 3 ALPHA 5
that bind the BZ receptor and enhance the ability for GABA Zaleplon 17 2 2 1
to open the chloride channel are called benzodiazepine
receptor agonists (BZRAs). Zolpidem 21 1 1 Negligible
The GBC is composed of five protein subunits surround- Eszopiclone 8 5 1 8
ing the chloride channel (Fig. 257). The subunits compos- 1 = the lowest affinity of a given drug for any receptor.
ing the GBC have different structure and are denoted as Adapted from Nutt DJ, Stahl SM: Searching for perfect sleep: the continuing
evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol
alpha, beta, gamma, epsilon, and rho (see Box 2519).54,55
2010;14:16011612; Epub 2009;November 26.
The receptor complex is composed of two alpha, two beta,
1 2
Membrane
GABAA
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Chapter 25 Insomnia 501
TABLE 259
GABAA Receptor Alpha Subunits and Associated Actions
PROPORTION OF
ACTION GABA RECEPTORS LOCATION
1 Sedative, amnestic, 60% All brain regions
anticonvulsant Cortex, hippocampus
2 Anxiolytic, myorelaxant 1520% Cortex, hippocampus, amygdala, forebrain, hypothalamus
3 Anxiolytic, myorelaxant 1015% Cerebral cortex, thalamus (reticular nucleus)
4, 6 Insensitive to BZ Dentate gyrus
5 High affinity for BZ Cerebral cortex, hippocampus
Low affinity for zolpidem
BZ tolerance
BZ = benzodiazepine; GABA = gamma-aminobutyric acid.
shorter than eszopiclone. Zolpidem may not increase TST in withdrawal.58 Triazolam causes rebound insomnia and is no
some patients, and for this reason, zolpidem CR (continuous longer recommended as a first-line hypnotic. Significant
release) was developed. Zolpidem CR is a coated two-layer rebound insomnia has NOT been noted in most studies of
tablet with one layer that releases the drug content immedi- zaleplon, zolpidem, and eszopiclone.58,59,62 However, with-
ately and another layer that slowly releases additional drug drawal side effects and rebound insomnia can potentially
beyond three hours after administration. Zolpidem CR, occur with all BZRAs and slow withdrawal is recommended
eszopiclone, and temazepam have intermediate durations of if possible.
action (Table 2512) and may be more effective for sleep-
maintenance insomnia than medications with a shorter General Considerations for BZRA Hypnotic Use BZRA hypnotics
duration of action. However, patients are quite variable in are well studied and the medications listed in Table 2512
their response to the different hypnotics, and some patients are FDA approved for treatment of insomnia unless other-
with sleep-maintenance insomnia will respond to generic wise noted. It is especially important to note the duration of
zolpidem. action. The hypnotics are grouped into nonbenzodiazepines
The BZRAs have a number of effects on sleep (see Table and BZs. At this time, the only nonbenzodiazepine available
2511). A decrease in sleep latency is common to all medica- in the United States in generic form is zolpidem. The brand
tions. Those with an intermediate or longer duration of name Z hypnotics are in general quite expensive. Some
action also can increase TST and decrease WASO. BZRAs general considerations for using hypnotics and choosing a
can increase sleep spindle activity and higher EEG frequen- specific hypnotic medication are listed in Table 2513.
cies. The BZs reduce stage N3 sleep with no or a mild reduc- Ideally, hypnotics should be used on a short term or inter-
tion in REM sleep. The major effect on stage N3 sleep is via mittent basis at the lowest effective dose. A lower dose and
a reduction in slow wave amplitude. As mentioned previ- more caution is indicated in the elderly or in patients with
ously, the nonbenzodiazepine BZRAs (Z hypnotics) result in impaired hepatic function because most BZRAs undergo
no or minimal decrease in the amount of stage N3 because hepatic metabolism.7,56 Until 2005, the FDA labeling stated
they do not substantially reduce the amplitude of slow waves. that the hypnotic medications were indicated for short-term
The clinical importance of less reduction in stage N3 sleep is use. Since 2005, the duration of action has not been specified.
still unclear. New studies have documented effectiveness of some medica-
The BZRAs have a number of side effects (see Table 2510) tions for 6 months or longer6366 (Table 2514). Clinical
including anterograde amnesia (decreased ability to learn and experience also has noted continued long-term effectiveness
retain new information), ataxia (fall risk), as well as residual (at least by patient report) in a number of BZRA hypnotics.
sedation during the day. Of note, eszopiclone is associated The effect of eszopiclone on sleep latency for a 12-month
with an unpleasant (often metallic) taste in a significant period (blinded and open-label portions) is illustrated in
number of patients (25%).62,63 BZRAs can also be associated Figure 258.
with nausea in some patients. They are not recommended for
use in nursing women or in pregnant women. In 2007, the
U.S. Food and Drug Administration (FDA) required packag- 75
PBO-ESZ
ing information on the BZRA hypnotics to include a warning ESZ-ESZ
regarding several specific potential adverse effects. The new 60
information states that BZRAs have been associated with
Minutes (median)
zolpidem designed to improve sleep maintenance. Funda Clin Pharmacol 2006;20:397403. DaneshGroup.com
*Time when drug concentration reaches 50% of maximum = 4.6 hours. Weinling E, McDougall S, Andre F, et al: Pharmacokinetic profile of a new modified release formulation of
BZRA = benzodiazepine receptor agonist; FDA = U.S. Food and Drug Administration. SMI = sleep-maintenance insomnia; SOI = sleep-onset insomnia.
504 Chapter 25 Insomnia
TABLE 2514
Studies Documenting Long-term Effectiveness of Benzodiazepine Receptor Agonists
TYPE OF STUDY
BRZA STUDY FOCUS (LENGTH) COMMENTS STUDY
Eszopiclone Adults RCT-DB-PC Efficacy maintained for 6 mo including sleep latency Krystal,
3 mg Chronic insomnia 6 mo and ability to function during the day 200363
Eszopiclone Adults 12 mo total (6-mo 6 mo DB placebo (no benefit) changed to open-label Roth,
3 mg Chronic insomnia open-label eszopiclone showed benefit over the last 6 mo 200564
extension) DB eszopiclone benefits were sustained over 12 mo
Eszopiclone Older adults primary RCT-DB-PC Efficacy maintained Ancoli-
2 mg and co-morbid 12-wk treatment No rebound Israel,
insomnia 2-wk withdrawal (SB) 201065
Zolpidem-ER Chronic primary RCT-DB-PC 37 nights/wk efficacy maintained Krystal,
12.5 mg insomnia 24 wk (6 mo) Sleep onset and sleep maintenance improved 200866
Next day concentration improved
Morning sleepiness improved
DB = double-blind; PC = placebo-controlled; RCT = randomized, controlled trial; SB = single-blind.
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Chapter 25 Insomnia 505
symptoms may occur after long-term use. Clonazepam is a rhythms. Ramelteon is about 17 times more potent at the
potent BZRA with a very long half-life and is commonly MT1/MT2 receptors than melatonin. Studies have shown an
associated with morning grogginess. However, individual absence of next-day residual effects, withdrawal, or rebound
patients may respond well to this medication and not report effects. The medication lacks abuse potential. Randomized,
morning sedation. Starting with the lowest possible dose and placebo-controlled studies have demonstrated efficacy of
having patients plan on a long sleep period is prudent. An ramelteon with most effects being on sleep latency. The med-
occasional rare patient requires up to 2 mg of clonazepam ication has a short half-life. One study by Mayer and col-
for sleep-maintenance insomnia. leagues71 demonstrated that 8 mg of ramelteon 30 minutes
Several studies have compared continuous versus inter- before bedtime reduced subjective sleep latency over a
mittent use of hypnotics and found intermittent hypnotic 6-month trial. Ramelteon also decreased latency to persis-
administration was effective. Walsh and associates67 com- tent sleep by PSG over the trial. TST was increased only at
pared zolpidem 10 mg (more than 3 but no more than 5 week 1. Side effects of ramelteon include headache, nausea,
nights per week on as-needed basis) versus placebo and dizziness, somnolence, nightmares, hallucinations, and
found significant benefits. Hajak and coworkers68 compared uncommonly suicidal ideation. Arthralgia and myalgia can
nightly zolpidem, placebo twice weekly, and zolpidem 5 also occur. Because ramelteon has no dependence potential,
nights per week and found both zolpidem regimens were it may be a good choice for patients with alcohol or drug
effective compared with placebo. dependency. Ramelteon undergoes hepatic metabolism and
should be avoided in patients with severe liver disease. Use
Ramelteon (Rozerem)A Melatonin Receptor Agonist of ramelteon is contraindicated in patients taking luvox-
Ramelteon is the first melatonin receptor agonist approved amine, because this antidepressant significantly increases the
in the United States for treatment of insomnia.6972 It is an levels of ramelteon in the blood.7
MT1/MT2 receptor agonist. The effects at MT1 are thought
to inhibit neuronal firing of the suprachiasmatic nucleus Sedating Antidepressants and Antipsychotics
(SCN), effectively turning off the alerting signal and allowing Sedating antidepressants used in doses lower than required
sleep to occur. In contrast, MT2 receptor effects are thought for antidepressant effects are widely used as hypnotics
to mediate melatonins phase shifting effects on circadian (Table 2515). Until recently, relatively little evidence has
TABLE 2515
Sedating Antidepressants and Antipsychotics Used Off-Label As Hypnotics (Not FDA Approved
As Hypnotics Except for Silenor)
NAME GENERIC DOSE HYPNOTIC
(BRAND NAME) FORMS DOSE COMMENTS NOTABLE SIDE EFFECTS
Trazodone 50, 100 mg 25100 mg qhs Less anticholinergic side Priapism
effects than TCAs Postural hypotension
T1/2 9 (314) hr
Mirtazapine 15, 30 mg 7.515 mg qhs T1/2 2040 hr Weight gain
(Remeron) Higher doses less sedating
TCAs
Amitryptyline 10, 25, 1025 mg qhs T1/2 1026 hr metabolite Dry mouth, constipation
(Elavil) 50 mg active (nortriptyline) QT prolongation
Doxepin 10, 25, 50 110 mg (elixir) T1/2 68 hr Dry mouth, constipation
(Sinequan) 10 mg/mL 25 mg qhs
Doxepin 3, 6 mg 6 mg qhs T1/2 68 hr FDA approved for sleep-maintenance insomnia
(Silenor) 3 mg qhs Cimetidine increases drug levelsmax dose of
elderly doxepin should not exceed 3 mg if cimetidine
co-administered
Sertraline can also increase levels of doxepin
SEDATING ANTIPSYCHOTIC MEDICATIONS
Quetiapine 25, 50, 100 12.550 mg T1/2 6 hr Weight gain, headache, dizziness
(Seroquel) qhs Intermediate-acting Neuroleptic syndrome
Tardive dyskinesia
Long QT
Lens change
FDA = U.S. Food and Drug Administration; TCAs = tricyclic antidepressants.
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506 Chapter 25 Insomnia
demonstrated their effectiveness as hypnotics in patients respond to or tolerate other medications. The usual dose is
without depression. Trazodone is a sedating antidepressant 300 to 900 mg at bedtime. Side effects include dizziness,
with minimal anticholinergic activity that is frequently used ataxia, and less commonly, leukopenia. Gabapentin could
as a hypnotic. The evidence for its efficacy as a hypnotic in potentially be useful in patients with insomnia associated
patients without depression is very modest.73,74 However, with pain. The use of melatonin has been analyzed with a
some patients seem to benefit from the medication. It is a meta-analysis and appears to have a small effect on sleep
reasonable hypnotic in co-morbid depression,75,76 in patients latency with little effect on WASO or TST.79 One problem
with significant sleep apnea, or in patients with a history of with both ramelteon and melatonin as hypnotics is that the
medication dependence. Its main side effects are priapism endogenous melatonin levels are already elevated during the
and postural hypotension. The usual dose is 25 to 100 mg dark hours. The hypnotic dose is 3 to 5 mg. There is some
qhs. Mirtazapine (Remeron) is used in low doses as a hyp- evidence that valerian extracts have some benefit as a hyp-
notic.77 Of interest, lower doses (7.5 mg and 15 mg) are notic.80 Antihistamines (diphenhydramine and doxylamine)
sometimes more sedating than higher doses. The major side are the primary ingredients in over-the-counter sleep aids.
effect is weight gain. Mirtazapine antagonizes alpha 2 recep- There is some limited evidence for their efficacy.80 The main
tors and serotonin (5HT2) receptors. Its sedation is believed problem is that they have considerable anticholinergic activ-
due to its antihistamine activity. Doxepin (Sinequan, Silenor) ity (urinary retention) and can cause daytime sedation.7
and amitriptyline (Elavil) are sedating tricyclic antidepres-
sants that have been used in low doses as hypnotics. They Pharmacotherapy for Co-morbid Insomnia
have significant anticholinergic side effects (dry mouth, con- of Psychiatric Disorders or in Patients
stipation, urinary retention). It is important to recall that with Dependence Issues
tricyclic antidepressants are very dangerous in overdose. Patients with anxiety or major depressive disorders fre-
Recently, doxepin has been evaluated with randomized, con- quently have prominent co-morbid insomnia. In such
trolled trials for its utility as a hypnotic in low doses (1, 3, patients, one might choose to use (1) a sedating antidepres-
6 mg). Lower doses avoid significant anticholinergic side sant at antidepressant doses (e.g., mirtazapine 3045 mg
effects.78 In these studies, the major significant effect was a qhs), (2) the combination of an effective nonsedating anti-
decrease in WASO. The mechanism of hypnotic action of depressant (at antidepressant doses) and a sedating antide-
doxepin is antagonism of histamine (H1) receptors. A prepa- pressant at low doses, or (3) the combination of an effective
ration of doxepin (Silenor) available as 3-mg and 6-mg nonsedating antidepressant + BZRA hypnotic. Fava and
tablets has recently been approved by the FDA for treatment associates81 studied a group of patients with both major
of sleep-maintenance insomnia. This is the only sedating depressive disorder and insomnia. The combination of
antidepressant FDA approved for treatment of insomnia. fluoxetine (FLX) and placebo was compared with FLX +
Silenor is fairly expensive. An alternative is to use a low dose 3 mg of eszopiclone. Co-administration of eszopiclone
of generic doxepin (10 mg or 5 mg using the elixir). Medica- resulted in improved subjective sleep latency, WASO, and
tions with substantial anticholinergic activity can cause TST compared with FLX alone. Whereas this result was not
urinary retention in patients with benign prostatic hypertro- unexpected, a surprising finding was that there was also
phy. Use of even low-dose doxepin in patients with severe greater improvement in depression at 4 and 8 weeks with
urinary retention should be avoided. the combination of FLX and eszopiclone. A similar trial
Quetiapine (Seroquel) is a second-generation antipsy- with zolpidem found improvement in sleep but no evidence
chotic medication that antagonizes histamine, dopamine D2, of greater improvement in depression.82 It is possible eszopi-
and 5HT2 receptors. At low doses, the medications main clone has beneficial antidepressant effects not present with
effect is as an antihistamine. Quetiapine is indicated for treat- zolpidem. Indeed, eszopiclone does have greater binding
ment of schizophrenia and bipolar disorder. Side effects affinity for BZ receptors associated with 2 subunits that
include QT prolongation, weight gain, extrapyramidal symp- have an effect on mood. However, a definite benefit of eszop-
toms, headache, lens changes/cataracts, and decreased white iclone over zolpidem remains to be documented by studies
blood cell count. Even at low doses, quetiapine has been asso- comparing the drugs in a head-to-head comparison in
ciated with significant weight gain. Due to its side effects, this depressed patients. In another study, the use of zolpidem
medication is usually not used in patients without significant when added to escitalopram (Lexapro) did improve sleep
psychiatric disorders unless other treatments have failed. but not anxiety in a group of patients with generalized
anxiety disorder.83 In summary, BZRAs can be used effec-
Other Medications Used for Insomnia tively in combination with antidepressants in patients with
Other sedating medications have been used for insomnia. depression or anxiety associated with prominent insomnia
Gabapentin (an anticonvulsant structural analog of GABA) complaints. In patients with a history of past or current
is used for chronic pain and the restless legs syndrome. The alcohol or BZ dependence, the use of BZRAs is problem-
half-life of gabapentin is approximately 5 to 9 hours, and it atic. For these patients, use of ramelteon (no abuse poten-
is excreted by the kidneys unchanged. Due to the sedative tial) or a sedating antidepressant may be the best treatment
properties of gabapentin, the medication can be used as a option. However, studies documenting effectiveness of this
hypnotic treatment alternative in patients who do not approach are lacking.
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Chapter 25 Insomnia 507
Improved Continue
Insomnia
hypnotic indicated
Duration of
action too long Use shorter
acting BZRA
AM grogginess
FIGURE 259 Clinical pathway for hypnotic treatment of insomnia. BZRA = benzodiazepine receptor agonist; SMI = sleep-maintenance insomnia; SOI = sleep-
onset insomnia. Adapted from Schutte-Rodin S, Broch L, Buysee D, et al: Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin
Sleep Med 2008;4:487504.
A. Zaleplon. D. Eszopiclone.
B. Eszopiclone. E. Ramelteon.
C. Flurazepam.
7. A 45-year-old woman complains of not sleeping at all
D. Ramelteon.
for 2 to 3 nights each week. Other nights, it takes over
2. Which of the following behavioral techniques has the an hour to fall asleep and the TST is never over 4 hours.
least evidence of its efficacy? The patient rarely takes naps but feels terrible the next
A. SCT. day when she does not sleep the night before. The patient
describes laying in bed all night thinking about her
B. RT.
work. She kept a sleep log and was studied with actigra-
C. SRT. phy. One night no sleep was reported but the actigraph
D. Sleep hygiene education. estimated about 5 hours of sleep. What is the most likely
E. Multimodality therapy diagnosis?
A. Idiopathic insomnia.
3. A 60-year-old obese man has a history of alcohol depen-
B. Psychophysiologic insomnia.
dence, insomnia, and benign prostatic hypertrophy.
What is the most appropriate medication for treatment C. Paradoxical insomnia.
of his insomnia? D. Insomnia associated with a mood disorder.
A. Doxepin 25 mg. 8. What of the following is NOT true about the GABAA
B. Amitriptyline 25 mg. receptor complex?
C. Zolpidem 10 mg. A. It contains a chloride ionophore.
D. Trazodone 50 mg. B. It is composed of five protein subunits.
E. Diphenhydramine 25 mg. C. Binding of a BZRA opens the chloride pore.
4. A 30-year-old woman reports problems with insomnia D. The complex is usually composed of two alpha, two
since childhood. There have been no periods of remis- beta, and one gamma subunits.
sion. She denies sleeping better in novel environments.
9. Which of the following medications is associated with
During the last few months, her mood and sleep com-
an unpleasant taste?
plaints have worsened. What is the most likely
diagnosis? A. Zolpidem.
A. Psychophysiologic insomnia. B. Eszopiclone.
B. Idiopathic insomnia. C. Ramelteon.
C. Paradoxical insomnia. D. Trazodone.
D. IDMD. 10. Which of the following statements about CBTI is not
true?
5. A 30-year-old man complains of episodes of waking up
at 3 AM and not being able to return to sleep. These epi- A. It consists of cognitive therapy and one or more of
these behavioral treatments (SCT, SRT) with or
sodes occur about every 2 weeks but are not predictable.
without RT.
What do you prescribe?
B. It continues to show benefits after the treatment
A. Zolpidem.
period.
B. Zaleplon.
C. It is more effective if combined with hypnotic
C. Eszopiclone. treatment.
D. Temazepam. D. It is effective for both primary and secondary
6. A 50-year-old woman is taking a hypnotic for insomnia. insomnia.
Recently, she has been sleepwalking and eating during 11. A 5-year-old boy often awakens during the night and
sleep. Some episodes she can remember but other times will not return to sleep without at least 1 2 hour of paren-
she is surprised to find evidence of food consumption tal presence and attention. Which diagnosis best
when she awakens in the morning. Although the behav- describes the problem?
ior could occur with almost any hypnotic, which of the
A. Childhood behavioral insomnialimit-setting type.
following BZRAs has been most often associated with
the behavior. B. Childhood behavioral insomniasleep-association
type.
A. Zaleplon.
B. Temazepam. 12. A 50-year-old man with both sleep-onset and
C. Zolpidem. sleep-maintenance insomnia is started on 12.5 mg of
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Chapter 25 Insomnia 509
PM Midnight AM Noon PM
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6
Sun Mon
Mon Tues
Tues Wed
Wed Thurs
Thurs Fri
Fri Sat
Sat Sun
FIGURE 2510
zolpidem CR. He tolerated the medication and falls 3. D. Trazodone. Doxepin (at 25 mg), amitriptyline, and
asleep quickly but awakens at 4 AM. Which of the follow- diphenhydramine all have significant anticholinergic
ing is the most appropriate next step? activity and could cause urinary retention. Use of zolpi-
A. Eszopiclone. dem is relatively contraindicated in a patient with
B. Trazodone. current or prior substance dependence. Trazodone has
minimal anticholinergic activity. Recently, low-dose
C. Quetiapine.
doxepin (1, 3, and 6 mg) has been used and this might
D. Ramelteon. be another alternative. In patients with drug depen-
E. Zaleplon. dence, BZRAs should be avoided if possible.
13. Which of the following is NOT true about adjustment 4. B. Idiopathic insomnia is characteristically present
insomnia? since childhood without periods of remission. Psycho-
A. Duration must be less than 3 months. physiologic and paradoxical insomnia are not present
B. It is associated with an identifiable stressor. since childhood. IDMD would be a reasonable possibil-
ity but the patient had significant insomnia many years
C. It is expected to resolve spontaneously in most
before her mood worsened.
cases.
D. Duration must be less than 1 month. 5. B. Zaleplon is the only medication on the list with a
very short half-life. It is most appropriate for rescue
14. A patient complains of sleep-onset and sleep- medication for middle of the night awakening. It should
maintenance insomnia. A sleep log is shown in Figure not be used if there are not at least 3 to 4 more hours of
2510. Which of the behavioral techniques would be possible sleep. If the patient could predict which nights
most applicable to this patient? were associated with middle of the night awakening, use
A. RT. of a longer-acting medication at bedtime might also be
B. SCT. appropriate.
C. Sleep hygiene education. 6. C. Zolpidem is the BZRA most associated with sleep-
D. SRT. walking, sleep violence, and the sleep-related eating dis-
order. However, all BZRAs could be associated with
these problems.
Answers
7. C. Paradoxical insomnia is associated with extreme
1. B. A BZRA with a longer duration of action is needed. reduction in reported sleep times but relatively little
Zaleplon and ramelteon are short acting. Flurazepam is daytime impairment relative to the reported sleep loss.
very long acting and often associated with daytime The subjective amount of sleep loss always far exceeds
sedation. objective determination (PSG or actigraph)
2. D. There is no evidence that sleep hygiene education 8. C. BZRA binding alone is not sufficient to open the
alone is effective treatment for insomnia. pore. Rather, BZRA binding enhances the ability of
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510 Chapter 25 Insomnia
GABA binding to open the pore. BZRAs are GABAA Practice parameters for using polysomnography to evaluate
receptor modulators (enhancers). insomnia: an update for 2002. Sleep 2003;26:754760.
11. Agnew HW, Webb WB, Williams RL: The first night effect: an
9. B. EEG study. Psychophysiology 1966;2:263266.
12. Nuckton TJ, Glidden DV, Browner WS, Claman DM: Physical
examination: Mallampati as an independent predictor of
10. C. Studies have not shown advantage to combining
obstructive sleep apnea. Sleep 2006;29:903908.
hypnotic treatment with CBTI. 13. Johns MW: Sleepiness in different situations measured by the
Epworth Sleepiness Scale. Sleep 1994;17:703710.
11. B. 14. Buysee DJ, Reynolds CF, Monk TH, et al: Quantification of
subjective sleep quality in healthy elderly men and women
12. A. Patients may respond differently to different BZRAs. using the Pittsburgh Sleep Quality Index (PSQI). Sleep 1991;
Because zolpidem CR was tolerated, using another 14:331338.
intermediate-acting BZRA is a reasonable next step. 15. Buysse DJ, Reynolds CF, Monk TH, et al: The Pittsburgh Sleep
Quality Index: a new instrument for psychiatric practice and
Eszopiclone (has a longer duration of action than zolpi-
research. Psychiatry Res 1989;28:193213.
dem CR in some patients) or temazepam are options. 16. Beck AT, Steer RA, Brown GK: Manual for the Beck Depression
Trazodone might work but there is less evidence for Inventory, 2nd ed. (BDI-II). San Antonio, TX: The Psychologi-
efficacy than other BZRAs. The addition of trazodone to cal Association, 1996.
zolpidem CR is another option. Quetiapine is an anti- 17. Beck AT, Ward CH, Mendelson M, et al: An inventory for
measuring depression. Arch Gen Psychiatry 1961;4:561571.
psychotic with many side effects. Ramelteon and
18. Carney CE, Ulmer C, Edinger JD, et al: Assessing depression
zaleplon would not be appropriate for sleep-maintenance symptoms in those with insomnia: an examination of the Beck
insomnia. Depression Inventory, 2nd ed (BDI-II). J Psychiatr Res 2009;
43:576582.
13. A. The duration must be less than 3 months. Adjust- 19. Morin CM: Dysfunctional beliefs and attitudes about sleep.
ment insomnia is associated with an identifiable stressor Preliminary scale development and description. Behav Ther
and would meet the definition of insomnia only if 1994;Summer:163164.
20. Morin CM, Vallires A, Ivers H: Dysfunctional beliefs and atti-
present for at least 1 month. tudes about sleep (DBAS): validation of a brief version (DBAS-
16). Sleep 2007;30:15471554.
14. D. Although all the above behavioral treatments could 21. Hauri PJ, Wisbey J: Wrist actigraphy in insomnia. Sleep
potentially be helpful, SRT is the one most suggested by 1992;15:293301.
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almost 12 hours most days. By shortening the time in in the study of sleep and circadian rhythms. Sleep 2003;
26:342392.
bed, hopefully the sleep efficiency will increase.
23. Littner M, Kushida CA, McDowell Anderson W, et al: Practice
parameters for the role of actigraphy in the study of sleep
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512 Chapter 25 Insomnia
74. Walsh J, Erman M, Erwin CW, et al: Subjective hypnotic effi- 80. Morin CM, Koetter U, Bastien C, et al: Valerian-hops combina-
cacy of trazodone and zolpidem in DSMIII-R primary insom- tion and diphenhydramine for treating insomnia: a randomized
nia. Hum Psychopharmacol 1998;13:191198. placebo controlled clinical trial. Sleep 2005;28:14651471.
75. Kaynak H, Kaynak D, Gzkirmizi E, et al: The effects of tra- 81. Fava M, McCall V, Krystal A, et al: Eszopiclone co-administered
zodone on sleep in patients treated with stimulant antidepres- with fluoxetine in patients with insomnia coexisting with major
sants. Sleep Med 2004;5:1520. depressive disorder. Biol Psychiatry 2006;59:10521060.
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antidepressant associated insomnia. Am J Psychiatry 1993;151: release 12.5 mg co-administered with escitalopram, improves
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77. Winkour A, DeMartins NA, McNally DP, et al: Comparative depressive disorder improved insomnia symptoms and next
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Appendix 25-1
From Morin CM; Vallires A; Ivers H: Dysfunctional Beliefs and Attitudes about Sleep (DBAS): validation of a brief version (DBAS-16). Sleep
2007;30:15471554.
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514 Chapter 25 Insomnia
Name: Date:
Several statements reflecting peoples beliefs and attitudes about sleep are listed below. Please
indicate to what extent you personally agree or disagree with each statement. There is no right
or wrong answer. For each statement, circle the number that corresponds to your own personal
belief. Please respond to all items even though some may not apply directly to your own
situation.
Strongly Strongly
disagree agree
0 1 2 3 4 5 6 7 8 9 10
1. I need 8 hours of sleep to feel refreshed and function well during the day.
0 1 2 3 4 5 6 7 8 9 10
2. When I dont get proper amount of sleep on a given night, I need to catch up on the next day
by napping or on the next night by sleeping longer.
0 1 2 3 4 5 6 7 8 9 10
3. I am concerned that chronic insomnia may have serious consequences on my physical health.
0 1 2 3 4 5 6 7 8 9 10
4. I am worried that I may lose control over my abilities to sleep.
0 1 2 3 4 5 6 7 8 9 10
5. After a poor nights sleep, I know that it will interfere with my daily activities on the next day.
0 1 2 3 4 5 6 7 8 9 10
6. In order to be alert and function well during the day, I believe I would be better off taking a
sleeping pill rather than having a poor nights sleep.
0 1 2 3 4 5 6 7 8 9 10
7. When I feel irritable, depressed, or anxious during the day, it is mostly because I did not sleep
well the night before.
0 1 2 3 4 5 6 7 8 9 10
8. When I sleep poorly on one night, I know it will disturb my sleep schedule for the whole week.
0 1 2 3 4 5 6 7 8 9 10
9. Without an adequate nights sleep, I can hardly function the next day.
0 1 2 3 4 5 6 7 8 9 10
10. I cant ever predict whether Ill have a good or poor nights sleep.
0 1 2 3 4 5 6 7 8 9 10
11. I have little ability to manage the negative consequences of disturbed sleep.
0 1 2 3 4 5 6 7 8 9 10
12. When I feel tired, have no energy, or just seem not to function well during the day, it is
generally because I did not sleep well the night before.
0 1 2 3 4 5 6 7 8 9 10
13. I believe insomnia is essentially the result of a chemical imbalance.
0 1 2 3 4 5 6 7 8 9 10
14. I feel insomnia is ruining my ability to enjoy life and prevents me from doing what I want.
0 1 2 3 4 5 6 7 8 9 10
15. Medication is probably the only solution to sleeplessness.
0 1 2 3 4 5 6 7 8 9 10
16. I avoid or cancel obligations (social, family) after a poor nights sleep.
0 1 2 3 4 5 6 7 8 9 10
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Chapter 26
Circadian Rhythm
Sleep Disorders
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515
516 Chapter 26 Circadian Rhythm Sleep Disorders
TABLE 261
Sleep load Wake Sleep-Wake Regulation
Nighttime First part Homeostatic drive is high
sleep of night (from awake all day).
Circadian alerting signal is
low.
Second Homeostatic drive is lower.
part of Circadian alerting signal is
night low.
Alerting Sleep
signal Daytime First part Homeostatic drive is low
wakefulness of day (due to prior sleep).
Circadian drive is increasing.
9AM 3PM 9PM 3AM 9AM Second Homeostatic drive is high
part of and increasing (prior wake).
FIGURE 263 Opponent model of sleep. The sleep load (down arrows) increases
day Circadian alerting signal is
proportional to the amount of prior wake and decreases with sleep onset. It is opposed
high (compensation).
by the alerting signal from the SCN (up arrows). The alerting signal increases to a
maximum just before sleep onset to help maintain wakefulness (the forbidden sleep
period) but then decreases during the sleep period so that sleep can occur. The solid line
is the wake-sleep propensity. Note a small dip in the afternoon. Adapted from Edgar
DM, Dement WC, Fuller CA: Effect of SCN lesions on sleep in the squirrel monkey: evidence BOX 262
for opponent processes in sleep-wake regulation. J Neuorsci 1993;13:10651079. Markers of Circadian Phase
CBTmin occurs 23 hr before awakening from
unconstrained sleep (45 AM)
DLMO occurs ~23 hr before typical sleep onset
a reduced signal at night. The other major influence on sleep
CBTmin = DLMO + 7 (i.e., CBTmin occurs about 7 hr later
propensity is the amount of accumulated wakefulness (time than DLMO)
since the last sleep). This homeostatic process (sleep load)
CBTmin = core body temperature minimum; DLMO = dim light melatonin
builds during wakefulness and then falls during sleep. As the onset.
pressure for sleep builds, the circadian signal increases to
help maintain alertness despite a growing sleep debt but then
decreases so that sleep can occur (Fig. 263). The two-
process model considers the interaction of process S (homeo-
MARKERS OF CIRCADIAN PHASE
static sleep drive) and process C (circadian rhythms, driven
in large part by the SCN). The opponent model of sleep2,9 The minimum of the core body temperature (CBTmin) and
(SCN-alerting signal vs. sleep load) is illustrated in Figure the dim light melatonin onset (DLMO) are two useful
263. Alertness peaks during the early evening hours. There markers of the position of an individuals circadian rhythms
is a midday decrease in alertness around 2 to 4 PM and the with respect to the external environment (i.e., time of day)
lowest alertness is 4 to 6 AM. The interaction of the opponent (Box 262). The CBTmin occurs about 2 hours before spon-
processes (homeostatic sleep load and circadian alerting taneous awakening from nocturnal sleep (45 AM in most
signal) allows humans to be alert during the day and to sleep individuals) (Fig. 264).1012 The reduction in core body tem-
at night (Table 261). The secretion of melatonin at night perature during the sleep period corresponds to the eleva-
exerts an inhibitory influence on the SCN that helps main- tion in plasma melatonin. The wakefulness in sleep episode
tain sleep by reducing the alerting signal. is an estimate of the wake propensity and is maximum in the
The pathways by which the alerting signal of the SCN evening before the sleep period and falls during sleep.
regulates sleep-wake are complex.2,5 One of the major path- The DLMO occurs about 2 to 3 hours before typical
ways is as follows. Neurons in the SCN project to neurons in bedtime.1015 One can estimate the timing of the CBTmin as
the ventral subparaventricular zone (vSPZ). This area is DLMO + 7 hours (see Box 262). The DLMO is determined
immediately dorsal to the SCN. Neurons in the vSPZ then by interval measurement of salivary or plasma melatonin
project to the dorsal medial hypothalamus (DMH). Gluta- performed in dim light (5 lux; because light inhibits melato-
minergic neurons in the DMH project to the lateral hypo- nin secretion) in the evening. A rise in melatonin levels
thalamus neurons producing hypocretin (stabilizing detects the DLMO time (Fig. 265). The melatonin mid-
wake-to-sleep transitions). In addition, DMH neurons using point can also be used as a circadian marker and occurs
GABA as an inhibitory neurotransmitter project to the ven- about 2 hours before CBTmin. When the circadian rhythm
trolateral preoptic area (VLPO), a sleep-promoting area. of the body (CBTmin or DLMO) moves to a later clock time,
These pathways mediate some of the effect of the SCN- this is said to represent a phase delay in circadian rhythms
alerting signal by inhibiting sleep-promoting areas and stim- and to an early time phase advance. The relationship between
ulating areas stabilizing transitions from wake to sleep. the timing of sleep and the circadian phase (as estimated by
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Chapter 26 Circadian Rhythm Sleep Disorders 519
30
(minutes)
zone) just before the sleep period but falls with the onset of
20 melatonin secretion. From Duffy JF, Dijk DJ, Klerman EB, Czeisler
10 CA: Later endogenous circadian temperature nadir relative to
an earlier wake time in older people. Am J Physiol 1998;
0
2 275:R1478R1487.
(mean Z-score)
(difference from mean) melatonin
1
Plasma
1
Body temperature
0.4
(degrees F)
0.0
0.4
360 240 120 0 120 240 360
Circadian phase of core body temperature
(degrees)
21 70
Normal 60
50
18 40
30
20
Melatonin (pg/ml)
15
DSPD 10
0 0
MEL (pg/ml)
12 5
10
9 10
15
Day
20
6
25
10
3 30
6A 6P 6A 6P
t
ht
gh
gh
g
n
n
ni
ni
ni
0
oo
oo
id
id
id
N
N
M
M
19:00
20:00
21:00
22:00
23:00
24:00
01:00
02:00
03:00
04:00
FIGURE 266 Melatonin secretion is shown for a patient whose DLMO (large circles)
occurs progressively later (free-running type of circadian rhythm sleep disorder).
FIGURE 265 Salivary melatonin (MEL) for a normal individual and one with delayed Reproduced from Sack RK, Brandes RW, Kendall AR, Lewy AJ: Entrainment of free-running
sleep phase disorder (DSPD). The dim light melatonin onset (DLMO) is taken as the time circadian rhythms by melatonin in blind people. N Engl J Med 2000;343:10701077.
at which melatonin reaches 3 pg/mL. This is around 23:00 in the normal individual but
is delayed to around 02:30 in the morning in an individual with DSPD. From Wyatt JK,
Stepanski EJ, Kirkby J: Circadian phase in delayed sleep phase syndrome: predictors and
temporal stability across multiple assessments. Sleep 2006;29:10751080. Use of the core body temperature as a marker of circadian
rhythms is complicated by the fact that eating, activity, and
sleep can affect the timing of CBTmin. In research settings,
a circadian marker) can be quantified by the time interval a constant routine protocol is utilized in which the subject is
(phase angle) between the two rhythms. In Figure 266, the kept awake at bedrest and fed equally distributed small meals
progressive delay in the DLMO is evidence of a progressive for at least 24 hours. An alternative to the constant routine
delay in circadian rhythm in a patient with the circadian protocol is to use mathematical adjustments to the tempera-
rhythm sleep disorderfree-running type (CRSD-FRT), ture rhythm. The DLMO can be affected (masked) by posture
also called the free-running disorder (FRD).14 and drugs such as beta blockers and caffeine. One can
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520 Chapter 26 Circadian Rhythm Sleep Disorders
12 16 20 24 4 8 12 12 16 20 24 4 8 12
Time of day Time of day
Light
Body temperature (C) Phase delay
37.6
37.0
36.4
12 16 20 24 4 8 12 12 16 20 24 4 8 12
Time of day Time of day
4 100
60
1
0 40
1
20
2
3 0
0.1 1 10 100 1000 10000 0.1 1 10 100 1000 10000
A Illuminance (lux) B Illuminance (lux)
FIGURE 268 The amount of phase shifting of melatonin and melatonin suppression against illuminance. The relationship was determined by
a subject kept in a controlled environment with dim light except for the light stimulus being tested. From Zeitzer JM, Dijk DJ, Kronauer RE, et al:
Sensitivity of human circadian pacemaker to nocturnal light: melatonin resetting and suppression. J Physiol 2000;526:695702.
1000 2
CBTmin
Bright light (BL) 1
Phase shift (hours)
Light intensity (lux)
1
0 75 150 225 300 375 0
15 min
1000 1
Intermittent (IBL)
1 2
bright light
0 75 150 225 300 375 3
Control (VDL) 4
1 (very dim light)
0 75 150 225 300 375 0 23 100
Time (minutes) Relative duration of bright
light exposure (%)
FIGURE 269 Intermittent exposure to bright light induces almost as much shift in the core body temperature minimum (CBTmin) as continuous bright
light, although the duration of light exposure was about 23% of the time of continuous exposure. 0% light exposure = baseline; 23% light exposure =
intermittent light exposure; 100% = continuous light exposure. Adapted from Gronifer C, Wright KP, Kronauer RE, et al: Efficacy of a single sequence of
intermittent bright light pulses for delaying circadian phase in humans. Am J Physiol Endocrinol Metab 2004:287:E174E181.
a therapeutic response to light therapy. However, a recent amount of phase shift versus the timing of the light stimulus
study showed no benefit of light enriched with blue light (constant stimulus intensity). By convention, the positive
compared with white light.21 It is possible that new light vertical axis represents phase advances and the negative axis
boxes with light-emitting diode (LED) emission of mono- phase delays. For light, the magnitude of phase shifting
chromatic blue light could be more effective. Intermittent as depends on the proximity to the CBTmin (Fig. 2610). In
well as continuous light is also effective at resetting the cir- most studies, the maximum phase shift occurs approximately
cadian pacemaker22,23 (Fig. 269). This fact has clinical impli- 3 to 4 hours before (phase delay) or after (phase advance) the
cations for delivery light treatment when a patient cannot sit CBTmin (Fig. 2611). Light in the middle of the day has
in front of a light box for long periods of time. minimal phase shifting effects.
Of note, the published PRCs for light vary somewhat
depending on the methodology used to determine the PRC.
Phase-Response Curve for Light
For example, the PRC can be obtained by studying entrained
The relationship between the timing of light exposure and the subjects on a constant routine protocol or non-entrained
amount of phase shift is best presented using a phase response subjects with a free-running routine. Typically, shifts in the
curve (PRC). The curves are constructed by plotting the DLMO are determined for different timing of light pulses.
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522 Chapter 26 Circadian Rhythm Sleep Disorders
Advance
Phase Shifting with Melatonin and
Light A Hypnotic Effects
3 Light A - large phase advance PRC approximately opposite to light PRC (12 hr out of
Amount of phase shift (hr)
1
Melatonin CBTmin Light FIGURE 2612 Phase response curves (PRCs) for light and
3 3 melatonin (3 mg). The position of DLMO and the core body
Light PRC temperature minimum (CBTmin) are shown. The rectangle
Melatonin PRC
2 DLMO 2 represents a period of 7.5 hours of sleep. The PRC curves of light
Advance
0 0
1 1
Hypothesized
Delay
dead zone
2 2
3 3
12 15 18 21 0 3 6 9 12
Clock time
9 6 3 0 3 6 9 12 15
Hours before and after the dim light melatonin onset (DLMO)
time of melatonin or bright light
HUMAN PHASE REPONSES CURVES TO DIFFERENT FIGURE 2613 PRCs for different doses of exogenous
DOSES OF MELATONIN melatonin. Note that for the higher dose of melatonin,
3 3 the maximal effect was noted at an earlier time
3 mg
DLMO compared with the DLMO. The rectangle illustrates a
Phase shift with 3.0 mg melatonin (h)
Phase shift with 0.5 mg melatonin (h)
CBTmin
2 typical sleep period with core body temperature
Advance
Advance
0 0
1
Delay
Delay
0.5
2
1.0 3
12 15 18 21 0 3 6 9 12
Clock time
9 6 3 0 3 6 9 12 15
Hours before and after the dim light melatonin onset (DLMO)
time of taking melatonin pill
between the DLMO and the CBTmin (endogenous melato- melatonin administration is often not used in the early
nin already high). The cross-over point for melatonin (tran- morning because any hypnotic effects would not be well
sition from phase advance to phase delay) is during the night tolerated outside of a research setting. An exception is when
but may not precisely coincide with CBTmin. In addition, morning sleep is desired by a person working a night shift.
the shape of the melatonin PRC appears to depend on the
dose of melatonin studied and the method of determination Summary of Effects of Light and Melatonin
of the PRC (Fig. 2613). Note that the timing of the maximum A summary of the effects of bright light and melatonin is
phase delay induced by melatonin is several hours after the presented in Figure 2614 with illustrations of the use of
CBTmin. Thus, taking melatonin 1 or 2 hours after spontane- these interventions in two circadian rhythm sleep disorders
ous awakening causes the most phase delay. However, (CRSDs). Bright light in the evening causes a phase delay and
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524 Chapter 26 Circadian Rhythm Sleep Disorders
in the early morning a phase advance. Melatonin in the early autoregulatory feedback loops on transcription (DNA to
evening causes a phase advance and in the early morning a mRNA) and translation (mRNA to proteins) that drive the
phase delay. A simple description of the effects of light and cycling pattern. The feedback is provided by the protein
melatonin is that bright light pushes and melatonin pulls translational products that can either stimulate or repress
the circadian rhythms. In this figure, it is assumed that the further gene transcription. A brief description of a few of the
CBTmin lies within the initial sleep period of the advanced many molecular mechanisms responsible for the 24-hour
sleep phase disorder (ASPD) and the delayed sleep phase cycle in transcription, translation, and posttranscriptional
disorder (DSPD) patients. protein metabolism that drives the rhythmic cycle of the
circadian clock genes follows (Fig. 2615 and Table 263).
By convention, small letters refer to genes and capital letters
GENOMICS OF CRSD
refer to protein translational products. For example, tran-
The intrinsic 24-hour rhythm in the SCN neurons is due to scription and translation of clock results in production of the
the interactions of a number of genes.27,28 These genes form protein CLOCK. The human forms of genes are denoted
with a preceding h (e.g., hper2).
Proteins CLOCK and BMAL1 (synthesized from clock
and Bmal1 genes) diffuse into the cytoplasm and associate
6P Midnight 6A Noon
as heterodimers (CLOCK:BMAL1). These heterodimers
then return to the nucleus and bind the Ebox region of genes
Normal Per1, Per2, Cry1, and Cry2 and promote transcription of
these genes. Ebox is a DNA sequence that usually lies
S ASPD M upstream of a gene in a promoter region. The translational
products PER and CRY proteins are negative regulators that
M DSPD S
turn off their own synthesis. The heterodimer PER:CRY and
homodimer CRY:CRY diffuse back into the nucleus, inhibit-
ing transcription of the associated genes. That is, PER:CRY
S Light pushes M Melatonin pulls and CRY:CRY repress the CLOCK:BMAL1-driven transcrip-
tion of Pers and Crys. The synthesis of PER and CRY is under
FIGURE 2614 Summary of effect of light and melatonin on the circadian phase. In
the influence of CLOCK:BMAL1 and can occur only when
patients with the advanced sleep phase disorder (ASPD), melatonin in the late night/
early morning phase delays, and in patients with the delayed sleep phase syndrome the level of intranuclear PER and CRY is low enough (after
(DSPD), melatonin in the early evening phase advances. For light, the effects are degradation of these proteins). A number of other processes
opposite with early evening light phase delaying and early morning light phase alter these molecular events because PER and CRY can be
advancing. Adapted from Barion A, Zee PC: A clinical approach to circadian rhythm sleep phosphorylated by several enzymes including casein kinase
disorders. Sleep Med 2007;8:566577. 1 epsilon (CK1), resulting in the ultimate degradation of the
C
B
Clock Clock
C B
Bmal1 Bmal1 PER CRY
C B Nucleus C B
E Pers PER CRY
E Pers
C B C B
E Crys E Crys
Cytoplasm
CLOCK: BMAL1 heterodimer binds PER and CRY heterodimers and CRY
to Ebox enhancer resulting in increased homodimers suppress CLOCK and BMAL1
transcription of Pers and Crys genes driven transcription of Pers and Crys
FIGURE 2615 A schematic of molecular mechanism controlling the circadian clock. Some proteins are inducers of gene transcription,
and others inhibit transcription. Adapted from Vitaterna MH, Pinto LH, Turek FW: Molecular genetic basis for mammalian circadian
rhythms. In Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: Elsevier Saunders, 2005,
pp. 335350.
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Chapter 26 Circadian Rhythm Sleep Disorders 525
PM Midnight AM Noon PM
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6
Sun X Mon
Mon X Tues
Tues X Wed
Wed X Thurs
Thurs X Fri
Fri X Sat
Sat X Sun
Sun X Mon
Mon X Tues
FIGURE 2617 A sleep log from a patient with DSPD. Note the stable delay in sleep-onset time despite attempts to fall
asleep earlier on some nights. On the weekends, sleep continues until the late morning. Note that once the patient is asleep,
few awakenings are noted.
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528 Chapter 26 Circadian Rhythm Sleep Disorders
Thu/Fri
Fri/Sat
Sat/Sun
Sun/Mon
Mon/Tue
Tue/Wed
Wed/Thu
Thur/Fri
FIGURE 2618 An actigraph recording of sleep-wake activity, recorded using wrist activity monitoring, from an individual with DSPD. The individual goes to sleep around 5
to 6 AM and wakes between 12 and 1 PM each day. Note that all actigraphy data are double-plotted. A period of 48 consecutive hours is shown on each line. The last 24 hours
(second half) of each line is then repeated as the first 24 hours (first half) of the following line (00:00 is midnight). From Barion A, Zee PC: A clinical approach to circadian rhythm
sleep disorders. Sleep Med 2007;8:566577.
Advanced Sleep Phase Disorder Note: In addition, an advance in the timing of other
circadian rhythms, such as the nadir of the core body
The ASPD is thought to be quite rare if diagnostic criteria temperature rhythm, or DLMO, is useful for confirmation of
are strictly followed. Advanced related sleep complaints, par- the advanced sleep phase.
ticularly early awakening, are more common. Often, patients D. The sleep disturbance is not better explained by another
are able to stay awake but are unable to stay asleep. As a current sleep disorder, medical or neurologic disorder,
consequence, classic ASPD is fairly rare but early morning mental disorder, medication use, or substance use
awakening is much more common. ASPD is associated with disorder.
aging, and nonaging ASPD is rare. Early morning awakening DLMO = dim light melatonin onset.
can also be noted in depression. From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Epidemiology
The prevalence of ASPD is not well documented but believed
to be about 1% in middle-aged populations and increases
with age. Men and women are equally affected.
Sleep Logs and Actigraphy
Pathophysiology Patients with ASPD demonstrate a stable advance in sleep
Familial ASPD has been described with a mutation in the period with sleep onset 6 PM to 9 PM and awakenings from
circadian clock gene hPer2.45,46 However, other familial cases 2 AM to 5 AM (Fig. 2619).
do not show this pattern. Causes of ASPD include a short
endogenous circadian period or a dominant phase advance Core Body Temperature, Dim Light Melatonin Onset
region to light. In elderly patients who take early morning Circadian phase makers in ASPD patients demonstrate
walks, this behavior tends to phase advance. advanced timing (Table 266).
Diagnosis Treatment
The ICSD-2 criteria (Box 268) require that the sleep period Chronotherapy (sleep schedule) can be used with a progres-
be advanced with respect to the desired sleep time and sive phase advance around the clock until the desired bedtime
wakeup times. The use of a sleep log or actigraphy for at least is reached.48 For most patients, this is not practical. The most
7 days is required to document a stable advance in the common treatment is bright light in the evening from 7 to 9
normal sleep period. These patients complain of not being PM (Table 267 and Boxes 269 and 2610). In one study,
able to stay awake in the evening for desired activities and 4000 lux was administered for 11 consecutive days then
then early morning awakening.47 The differential diagnosis twice weekly for a 3-month period (maintenance).49 Unfor-
includes poor sleep hygiene (evening or afternoon naps), tunately, patients have difficulty complying with this treat-
caffeine abuse, alcohol, and depression (can cause early ment plan. The AASM practice parameters mention evening
morning awakening). light as an Option for ASPD (see Table 267).31 Another
important form of light therapy is to AVOID early morning
Morningness-Eveningness Questionnaire light, which tends to cause a phase advance. Although early
Patients with ASPD when completing the MEQ (Horne- morning melatonin would be a potential treatment (phase
Ostberg questionnaire)32 record answers consistent with delay), this is not practical and may not be safe if individuals
morning type. have to function in the morning. Melatonin has sedative
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530 Chapter 26 Circadian Rhythm Sleep Disorders
Tues X Wed
Wed X Thurs
Thurs X Fri
Fri X Sat
Sat X Sun
BOX 269
Treatment of Advanced Sleep Phase Disorder
Day 1 Day 2
Sleep schedule (chronotherapy)progressive phase
advance.
Light
Day 2 Day 3
Bright evening light 79 PM.
Avoid light after temperature minimum (early morning
light).
Day 3 Day 4
Melatonin
Early AM melatonin potentially effective but sedative
effects make this impractical for most patients. Consider
Day 4 Day 5
a low dose to attempt to minimize sedative effects.
BOX 2610
Day 5 Day 6
Circadian Rhythm Sleep DisorderIrregular
Sleep-Wake TypeDiagnostic Criteria 24 12 24 12 24
A. There is a chronic complaint of insomnia, excessive
sleepiness, or both.
FIGURE 2620 Actigraphy shows an irregular pattern of wake and sleep in a nursing
B. Sleep logs or actigraphy monitoring (including sleep home patient with dementia. Note that much of the sleep occurred during the day.
diaries) for at least 7 days demonstrates multiple At least three episodes of sleep were noted during each 24 hours. This is a double plot.
irregular sleep bouts (at least three) during a Each line is 48 hours. The last 24 hours on one line is repeated as the first 24 hours on
24-hour period. the next line.
C. Total sleep time per 24 hours is essentially normal for
age.
D. The sleep disturbance is not better explained by another demonstrates multiple sleep periods (at least three) within
current sleep disorder, medical or neurologic disorder, 24 hours with approximately a normal total amount of sleep
mental disorder, medication use, or substance use for age. For most patients with ISWR, the sleep log is prob-
disorder. lematic and this is one setting in which actigraphy is espe-
From American Academy of Sleep Medicine: ICSD-2 International cially helpful. Some actigraph devices also record light
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
exposure, and decreased light exposure may be a predispos-
Westchester, IL: American Academy of Sleep Medicine, 2005.
ing factor for ISWR.
FIGURE 2621 Actigram shows progressive delay in sleep offset (blue line) with a parallel delay in sleep onset. This is characteristic of the CRSD free-running type.
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Reproduced with permission from Barion A, Zee PC: A clinical approach to circadian rhythm sleep disorders. Sleep Med 2007;8:566577.
Chapter 26 Circadian Rhythm Sleep Disorders 533
Day
60 decreased 4 every 2 weeks
2
80
1
100 0.5
120
End of
140 treatment
0
160
180
200
0 12 24 12 24 12
Hour
Antidromic Entrainment However, napping can improve alertness for special demands
Travel over six time zones may result in phase shifting in the (e.g., giving a talk). Napping removes photic stimuli so
opposite direction of the direction of travel (i.e., adapting this can delay adaptation if napping occurs at a time when
the wrong way), so-called antidromic re-entrainment. light exposure would shift circadian rhythms in the correct
For example, eastern flight requires a phase advance to accli- direction.
mate to the new time zone. However, after an eastward flight
across nine time zones, the travelers CBTmin normally at 5 Eastward Flights The patient is phase delayed (a phase advance
AM in the old time zone would occur at 2 PM in the new time is required) (Fig. 2623). One method is to phase advance 1
zone. Thus, morning light in the new time zone would cause hour per day with bright light in the morning before travel
phase delay because light exposure occurs before CBTmin. begins (Fig. 2624).60,61 At the new destination, morning
Of note, some experts recommend that all flights that cross light should be sought (as long as it is after CBTmin). Evening
more than 8 to 10 time zones be treated as if they were west- light should be avoided on arrival at the new destination (to
ward travel (interventions target progressive phase delay). avoid phase delay). Melatonin before CBTmin might be
useful if the hypnotic effects would not interfere with wakeful
Symptoms Associated with Jet Lag CRSD activities. Hypnotics can help with sleep but do not neces-
Symptoms associated with jet lag may include (1) daytime sarily help with alertness the next day.62 Even if the indi-
tiredness or impaired daytime alertness, (2) inability to get vidual gets adequate sleep, decreased circadian alertness will
to sleep at night (eastward flight), and (3) early awakening occur at time of CBTmin. Stimulants (caffeine) may be
(westward flight). Other symptoms may include disorienta-
tion; gastrointestinal problems (poor appetite), inappro-
TABLE 2610
priate timing of defecation (gut lag), excessive urination,
Jet Lag Facts
menstrual abnormalities (flight crew), inappropriate meta-
bolic responses (insulin and other hormones); and heart Typical internal 92 min/day delay on westward flights.
disease. Symptoms may be worsened by stresses of airplane clock resetting 57 min/day advance on eastward
travel itself or use of caffeine or alcohol. flights.
Eastern travel Difficulty falling asleepsleep-onset
Treatment of Jet Lag insomnia.
A number of treatments for jet lag have been recommended May not notice sleep difficulty the
depending on the direction of travel (Tables 2610 to 2612). first night in new time zone if sleep
Websites are available that allow the traveler to enter current deprived (because sleep during
and future locations and a prescription is generated for inter- flight may have been poor).
ventions to minimize jet lag. One difficulty with providing Sleep fragmented, decreased REM
and stage N3 sleep.
recommendations is in estimating the current CBTmin and
also that entrainment in the new destination may depend on Western travel Less persistent symptoms.
societal demands in the new time zone that preclude follow- First night: sleep quality good early
ing the prescription. in sleep period (deprivation).
General sleep hygiene measures include a dark, quiet Increased REM early in sleep period
as new bedtime falls nearer to prior
sleep environment with earplugs or eye shades if needed. If
REM period.
the plane flight is long, sleeping on the flight during appro-
Early awakenings
priate hours (destination nighttime) may be helpful. In
REM = rapid eye movement.
general, daytime naps should be avoided at the destination.
New York FIGURE 2623 Schematic of a flight from New York to Paris (6 time
Noon 6P Midnight 6A Noon zones eastward). Sleep times are shown as rectangles and the CBTmin
as blue triangles. On arrival, light is avoided (D) before CBTmin to
Paris prevent phase delay and sunlight exposure is used after CBTmin to
6P Midnight 6A Noon 6P produce a phase advance. Melatonin is taken at bedtime. The
6 time zones eastward circadian phase advances until the CBTmin is within the sleep period
(rectangle). However, this process takes several days. For simplicity,
Flight D D S S S S timing of melatonin is kept constant.
M S S S S
M SS S S
M S SS S
M SS SS
M SS S
TABLE 2611
Recommendations for Jet Lag
EASTWARD TRAVEL WESTWARD TRAVEL
Internal rhythm is phase delayed. Internal rhythm is phase advanced.
Adaptationphase advance. Adaptationphase delay.
BEFORE TRAVEL
Try to reset body clock to Shift sleep 12 hr earlier before trip Shift sleep 12 hr later before trip (bright
minimize necessary change. (bright light in AM). light in PM).
DURING TRAVEL
During flight. Sleep if possibleespecially on long Sleep if possibleespecially on long
flightsto avoid sleep loss. flightsto avoid sleep loss.
Sleep during time corresponding to night Sleep during time corresponding to night
in the destination if possible. in the destination if possible.
Drink adequate H2O, avoid alcohol. Drink adequate H2O, avoid alcohol.
ON ARRIVAL
Anticipated changes in sleep. Difficulty falling asleep. Difficulty staying asleep.
Difficulty waking up. Early awakening.
Appropriate light exposure. Seek morning light. Seek evening light.
If crossing more than eight For the first 2 days after arrival, avoid For 23 days, avoid bright light in the late
time zones, avoid light bright light for the first 23 hr after evening (at dusk); starting on the third
when it may inhibit dawn; starting on the third day, seek day, seek exposure to bright light in the
adaptation. exposure to bright light in the morning. evening.
Melatonin. Take 0.53 mg at local bedtime nightly Take 0.5 mg during the second half of the
until you adjust (phase advance). night (after CBTmin to phase delay).
Hypnotics. Consider taking at bedtime for a few days. Consider taking at bedtime for a few days.
Caffeine. Drink judiciously, avoid after midday. Drink judiciously, avoid after midday.
CBTmin = core body temperature minimum.
Adapted from Sack RL: Jet lag. N Engl J Med 2010;362:440447.
FIGURE 2624 The patient illustrated in Figure 2623 attempts New York
to reduce the time required for adaptation by use of a preflight Noon 6P Midnight 6A Noon
phase advance to minimize jet lag on arrival. There are fewer days
until the CBTmin (blue triangles) is within the desired sleep period
Baseline Pre-flight advance
(rectangles).
BL
Paris BL
6P Midnight 6A Noon 6P
6 time zones eastward
Flight D SSSS
M S SSS
M SS S S
M S SS S
helpful to maintain alertness during the day in the new delay before travel begins (go to bed later, get up later) using
locale. A recent study found that 150 mg of armodafinil (R evening bright light for 1 to 3 hours. Light should be avoided
isomer of modafinil) increased wakefulness after eastward in the morning in the new destination (if it occurs soon after
travel through six time zones.63 CBTmin) to prevent phase advance. Exposure to light in the
evening (if before CBTmin) may be helpful (phase delay).
Westward Flights The patient is phase advanced relative to Melatonin at bedtime in the destination if taken before
local time (a phase delay is required). One could try to phase CBTmin may have hypnotic action but induces phase shift
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Chapter 26 Circadian Rhythm Sleep Disorders 537
200
Better 1 2 3 4 5
FIGURE 2625 Change in psychomotor vigilance task (PVT) over five consecutive simulated night shifts in groups non-entrained,
partially entrained, and completely re-entrained. The non-entrained group had a worsening in the PVT over five nights (increased
response time). The other two groups did not have a deterioration over the five night shifts. The time of core body temperature
minimum (CBTmin) is illustrated for each group at baseline and after five nights. The CBTmin shifted to within daytime sleep in the
two groups with better function. Subjects were given different combinations of bright light versus dim light during the simulated
night shift, dark glasses or normal sunglasses in the morning, and melatonin or placebo before sleep time. Adapted from Crowley SJ,
Tseng CU, Fogg LF, Eastman CI: Complete or partial re-entrainment improves performance, alertness, and mood during shift-work. Sleep
2004;27:10771087.
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Chapter 26 Circadian Rhythm Sleep Disorders 539
A Work Sleep
Rotating Shifts
There is greater sleep loss with rapidly rotating shifts than L Sleep
with slowly rotating shifts (slow = 3-wk periods). Clockwise L Sleep
rotation is better tolerated than counterclockwise due to
L Sleep
natural tendency to phase delay.
L Sleep
C
that affect the timing or duration of sleep.
B. An underlying medical or neurologic disorder
predominantly accounts for the circadian sleep disorder. 37.0
C. Sleep log or actigraphy monitoring (with sleep diaries)
for at least 7 days demonstrates disturbed or low-
amplitude circadian rhythmicity.
D. The sleep disturbance is not better explained by another 36.4
current sleep disorder, medical or neurologic disorder,
mental disorder, medication use, or substance use
12 16 20 24 4 8 12
disorder.
Time of day
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. FIGURE 2627 What should the timing of light be for maximum phase advance
Westchester, IL: American Academy of Sleep Medicine, 2005.
(A, B, C, D, E)?
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Chapter 26 Circadian Rhythm Sleep Disorders 541
5. Point mutation in which gene has been associated with C. Measured with the subject in dim light.
ASPD? D. Typical threshold values are 3 pg/mL for salivary
A. Clock. and 10 pg/mL for plasma melatonin.
B. Time.
12. A patient with the delayed sleep phase syndrome has a
C. hPer2. typical wake time on the weekends of 1 PM. He typically
D. Alarm. has to awaken at 8:30 AM to make a 10:00 AM class. He
starts treatment with light by walking to class to get
6. What intervention would be most helpful in a patient bright light exposure (~910 AM). Unfortunately, using
with ASPD? this regimen, he is unable to fall asleep any earlier. What
A. Evening light. do you recommend for initial treatment?
B. Morning light. A. Wear dark glasses on walk to 10 AM class, get bright
C. Evening melatonin. light exposure after 12 noon.
D. Morning melatonin. B. Wake up at 8 AM, light box for 1 hour, light exposure
on walk to 10 AM class.
7. What set of interventions would be most helpful for a
C. Wear dark glasses on walk to 10AM class, bright light
night shift worker (Table 2614)?
exposure after 3 PM.
8. A blind patient is found to have the non24-hour circa- D. Continue present light exposure, add melatonin 5
dian rhythm disorder. His desired bedtime is 11 PM. hours before habitual sleep time.
What treatment do you recommend?
A. Melatonin 5.0 mg at 8 AM. Answers
B. Melatonin 5.0 mg at 10 PM.
1. D. This patient has the DSPD. It is important to use
C. Melatonin 0.5 mg at 7 PM. bright light treatment after the CBTmin. The timing of
D. Melatonin 0.5 mg at 10 PM. the CBTmin is not known but can be estimated from the
spontaneous wake time. In normal subjects, the CBTmin
9. A businessman travels 5 hours eastward. What time
occurs about 2 hours before wake time. It may be some-
should light be avoided in the new time zone?
what earlier in patients with DSPD. With a normal wake
A. 6 AM9 AM. time of 11:00 AM, one could estimate a CBTmin around
B. 11 AM2 PM. 9 AM or slightly earlier. Of interest, the patient is exposed
C. 2 PM6 PM. to light on his way to work (67 AM). This may be on the
phase advanced side of his temperature minimum and
10. A patient with the DSPD has a habitual sleep time of 3 worsen the problem. He should wear dark glasses on the
AM and wake time of 11 AM on the weekends. When way to work in the morning.
should melatonin be administered?
A. 3 AM. 2. C. 24.2 hours.
B. 2 AM. 3. D. The maximum phase advance for bright light occurs
C. 12 midnight. about 34 hours after the CBTmin. C is at the CBTmin,
D. 9 PM. the transition between the phase delay and the phase
advance regions. Light at A and B would phase delay.
11. Which of the following is not true about DLMO? Light at E would have less phase advancing effect.
A. Occurs 23 hours before habitual bedtime. 4. B. The major photosensors are the retinal ganglion cells
B. Occurs 1 hour before habitual bedtime. containing melanopsin.
5. C. Mutation of hPer2 gene has been associated with
TABLE 2614
familial ASPD.
Interventions for Night Shift Worker
6. A. Evening light will cause phase delay. Morning mela-
A Bright light Dark glasses Nap before
start of shift drive home night shift tonin will also cause a phase delay, but the hypnotic
effects are undesirable for most patients.
B Bright light Dark glasses Nap before
end of shift drive home night shift 7. A. Bright light at the start of the shift, dark glasses on the
C Bright light Delay bedtime Nap before
way home, going to bed on arrival at home, and a nap
start of shift until 11 AM night shift before the shift are suggested interventions. Light at the
end of the shift, on the way home, or during the first hours
D Bright light Delay bedtime Nap before at home could phase advance. A phase delay so that
end of shift until 11 AM night shift
CBTmin is within the daytime sleep period is desirable.
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542 Chapter 26 Circadian Rhythm Sleep Disorders
8. D. Melatonin given 1 hour before the desired bedtime 10. Duffy JF, Dijk DJ, Klerman EB, Czeisler CA: Later endogenous
is recommended. Although 5 mg may work, some circadian temperature nadir relative to an earlier wake time in
older people. Am J Physiol 1998;275:R1478R1487.
patients will fail to entrain on 5 mg but entrain on a
11. Fahey CD, Zee PC: Circadian rhythm sleep disorder and pho-
lower dose. However, the AASM practice parameters totherapy. Psychiatr Clin North Am 2006;29:9891007.
did not recommend a specific time or dose. 12. Czeisler CA, Buxton OM, Khalsa SBS: The human circadian
timing system and sleep-wake regulation. In Kryger MH,
9. A. If the baseline CBTmin is assumed to be 4 AM, this Roth T, Dement WC (eds): Principles and Practice of Sleep
corresponds to 9 AM in the new time zone. The patient Medicine, 4th ed. Philadelphia: Elsevier Saunders, 2005,
must phase advance for adaptation. Light for several pp. 375394.
13. Wyatt JK, Stepanski EJ, Kirkby J: Circadian phase in delayed
hours before the CBTmin induces the most significant sleep phase syndrome: predictors and temporal stability across
phase delay. Light exposure should be avoided before 9 multiple assessments. Sleep 2006;29:10751080.
AM and pursued from 11 AM to 2 PM to induce the 14. Sack RK, Brandes RW, Kendall AR, Lewy AJ: Entrainment of
maximum phase advancing effect. Light from 6 to 9 AM free-running circadian rhythms by melatonin in blind people.
may cause phase delay. Light at 2 to 6 PM is so far away N Engl J Med 2000;343;10701077.
15. Khalsa SBS, Jewett ME, Cajocen C, Czeisler CA: A phase
from the CBTmin that it has minimal effect. response curve to single bright light pulses in human subjects.
J Physiol 2003;549:945952.
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light therapy. J Clin Sleep Med 2009;5:155163.
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circadian pacemaker to nocturnal light: melatonin resetting
before typical wake time on weekends). Bright light
and suppression. J Physiol 2000;526:695702.
exposure before 11 AM causes an unwanted phase delay. 20. Lockley SW, Brainard GC, Czeisler CA: High sensitivity of the
The best option is to minimize light exposure before 11 human circadian melatonin rhythm to resetting by short wave
AM and then seek bright light exposure for 12 hours length light. J Clin Endocrinol Metab 2003;88:45024505.
after 12 noon (after CBTmin for phase advance). Bright 21. Smith MR, Eastman CR: Phase delaying the human circadian
clock with blue-enriched polychromatic light. Chronobiol Int
light exposure at 3 PM will be less effective than light
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exposure closer to the CBTmin. Melatonin 5 hours 22. Rimmer DW, Boivin DB, Shanahan TL, et al: Dynamic
before the habitual bedtime may help, but the most resetting of the human circadian pacemaker by intermittent
important intervention is use of the correct exposure to bright light. Am J Physiol Regul Integr Comp Physiol 2000;
light. 279:R1574R1579.
23. Gronifer C, Wright KP, Kronauer RE, et al: Efficacy of a single
sequence of intermittent bright light pulses for delaying circa-
dian phase in humans. Am J Physiol Endocrinol Metab 2004;
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Chapter 27
Clinical Electroencephalography
and Nocturnal Epilepsy
Chapter Points montage and visualization of waveforms in a
Nocturnal epilepsy can be difficult to differentiate from 10-second window is recommended.
parasomnias because some patients have seizures only The focal seizures of FLE are more likely to occur at
at night, scalp EEG findings may not be visible during night than during the day. The focal seizures of TLE are
seizures, bizarre movements can occur during partial more likely to occur during the day than during the
seizures, consciousness can be maintained, and night. FLE events during the day are more likely to
minimal postictal confusion may be present in some generalize. TLE events during the night are more likely
cases. to generalize compared with those occurring during
NFLE manifests as three syndromes: paroxysmal the day.
arousals (mimics confusional arousals), nocturnal Because mastoid electrodes are fairly near the
paroxysmal dystonia (dystonic posturing), and episodic temporal lobes, interictal activity associated with TLE
wandering (mimics sleepwalking). The paroxysmal can often be easily seen in standard PSG montages.
arousals and nocturnal paroxysmal dystonia episodes For example, a left temporal spike may be visible in
tend to be brief. derivations containing M1. The spike will be more
Factors favoring NFLE over a parasomnia include prominent in C4-M1 than in C3-M2 even though the
multiple episodes per night, stereotypical spike is on the left.
manifestations, onset out of stage N2 versus N3, and Changing to a 10-second window is essential to
certain behaviors (e.g., cycling, fencing, pelvic accurately identify interictal activity because spikes
thrusting) as well as immediate alertness after the may be difficult to see in the 30-second window. It is
episode. useful to examine paroxysmal changes in EEG tracings
In roughly 50% of the cases of NFLE, there is no in a 10-second window to avoid incorrectly assuming
abnormality in the scalp EEG during the seizure (other that ictal activity is an artifact.
than artifact due to body movement).
The partial seizures of TLE are typically complex
partial seizures (consciousness is impaired during ELECTROENCEPHALOGRAPHIC MONITORING
the seizure). The partial seizures of FLE may be either
complex or simple (no impairment of consciousness). The international 10-20 system1,2 for electrode placement for
Seizures from the supplemental motor area may electroencephalographic (EEG) monitoring is illustrated in
occur with intact responsiveness and no postictal Figure 271. Each electrode is represented by a letter that
confusion. Classic manifestations of seizures from represents the underlying area or lobe of the brain (Fp =
the supplementary motor area include fencing with frontopolar; F = frontal; P = parietal; O = occipital; T = tem-
head turned away from the outstretched arm, poral) (Fig. 272) and numerical subscripts representing
kicking, laughing, or pelvic thrusting. Unlike position. The odd subscripts are on the left and the even on
psychogenic activity, there is an abrupt onset and the right, and the z subscripts refer to electrodes in the
offset. midline.1,2 The left and right auricular (earlobe) electrodes
Video PSG is essential for evaluation of patients with are A1 and A2. In sleep monitoring, these are actually placed
possible nocturnal epilepsy. A substantial number of on the mastoids and termed M1 and M2.3 Figure 271 illus-
patients with NFLE will not have either ictal or trates the new electrode nomenclature1 in which T7, T8, P7,
interictal EEG findings and the type of body and P8 have replaced T3, T4, T5, and T6. In the new nomen-
movements (seminology) can be very helpful in clature, all electrodes in a given sagittal plane have the same
arriving at a correct diagnosis. Using an extended EEG subscript (F7, T7, P7) and most electrodes in the same coronal
plane have the same letter (P7, P3, Pz, P4, P8). However, many
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546 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
F7 F3 F4 F8 F7 F3 F4 F8
FZ FZ
A1 A2 A1 A2
T7 C3 CZ C4 T8 T3 C3 CZ C4 T4
P3 PZ P4 P3 PZ P4
P7 P8 T5 T6
O1 O2 O1 O2
New Old
FIGURE 271 Electrode nomenclature (new and old terminology). T3 and T4 are replaced by T7 and T8 and T5 and T6 are replaced by P7 and P8.
Supplementary Mesial
motor area Central Mesial frontal
fissure frontal lobe
Cz Su
p fr
ont
al g
Fz Cingulate gyrus yru
tex
s
cor
F3 Pz Corpus callosum
C3
tor
Fornix
Mo
FIGURE 272 Schematic views of the brain illustrate areas of interest for epilepsy and electroencephalography (EEG) monitoring. The central fissure is also known as the Rolandic
fissure.
Cz Cz
20%
20% Fz
Pz 20% C3 C4
C3 Fz Pz
F4 20% F4 F3
20% P4 P3 P4
20%
Fpz F8 Fp2 Fp1 F7
Fp1
Oz F8 10% P7 O1 O2 P8
O2 P8 T8
10% 10% Nasion
Inion Preauricular
A1
point
FIGURE 273 The 1020 system of electrode placement. All electrodes are placed either 10% or 20% of the distance between two standard landmarks.
EEG laboratories still use the old electrode nomenclature as BIPOLAR MONITORING AND
does the majority of the published literature on epilepsy. Of
STANDARD MONTAGES
note, the 10-20 electrode position2 refers to the fact that elec-
trodes are positioned at 10% or 20% of the distance between A derivation is the voltage difference between electrodes: for
landmarks such as nasion, inion, or the preauricular points example, Fp1-F3 is the voltage difference between electrodes
(Fig. 273). Fp1 and F3. By electroencephalography (EEG) convention, if
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Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 547
Fp1 is more negative than F3, the deflection is up.4,5 A set of electrodes with the ipsilateral auricular electrodes A1 and A2
derivations is called a montage. Montages are designed with (see Table 272). Different laboratories may display the elec-
a particular purpose in mind. Standard montages for sleep trodes in a given montage in different sequences. In modern
monitoring were illustrated in Chapter 1. Tables 271 and digital EEG recording, all electrodes are usually recorded
272 show standard clinical EEG montages.6 Bipolar longi- against a common reference. Then any two electrodes may
tudinal montages (Fig. 274; see also Table 271) sequen- be compared by digitally subtracting the signals (F7-ref)
tially compare two adjacent electrodes in chains covering the (P7-ref) = F7-P7. Thus, one can change the display montage
head in an anteroposterior (AP) direction (double banana). while recording or later during study review. Digital record-
In the most frequently used variant (LB-18.1), the chains ing also allows one to visualize multiple time scales. The
start at the left temporal area and then progressively move polysomnography (PSG) window to stage sleep is 30 seconds
toward the right. Bipolar transverse montages compare two but the clinical EEG window is 10 seconds. The 10-second
electrodes in chains in the transverse directions (Fig. 275; time window allows detection of brief, sharply contoured
see also Table 272). Referential montages compare waveforms that may signify seizure activity.
Longitudinal Biopolar
7 10 13 5 2 9 11 18 15
3 17 17 3 7
13
P3 Pz P4 P3 Pz P4 P3 Pz P4
P7 P8 P7 P8 P7 P8
8 14 6 10 12 16
4 O1 O2
18 14 O1 O2 18 4 O1 O2 8
LB-18.1
FIGURE 274 Longitudinal bipolar montage chains. LB-18.1, LB-18.2, and LB-18.3 are three methods of arranging the derivations for display.
Transverse bipolar
2 1
1 Fp1 Fp2 3 Fp1 Fp2
F7 F8 F7 2 3 4 5 F8
4 F3 Fz F4 F3 Fz F4
5 6 7
17
A1 A2
T7 C3 Cz C4 T8 T7 C3 Cz C4 T8 11
8 9 10 11 6 7 8 9 10
18
12 13 14 15
P3 Pz P4 P3 Pz P4
P7 P8 P7 13 14 P8
12 15
16 O1 O2
18 O1 O2
17 16
TB-18.1 TB-18.2
FIGURE 275 Transverse bipolar montages.
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548 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
TABLE 271
Longitudinal Bipolar (AP Bipolar) 18-Channel Double Banana
LB-18.1 LB-18.2 LB-18.3
Fp1-F7 Left temporal Fz-Cz Vertex Fp1-F7 Left temporal
F7-T7 Cz-Pz F7-T7
T7-P7 T7-P7
P7-O1 P7-O1
Fp1-F3 Left parasagittal Fp1-F3 Left parasagittal Fp2-F8 Right temporal
F3-C3 F3-C3 F8-T8
C3-P3 C3-P3 T8-P8
P3-O1 P3-O1 P8-O2
Fz-Cz Vertex Fp2-F4 Right parasagittal Fp1-F3 Left parasagittal
Cz-Pz F4-C4 F3-C3
C4-P4 C3-P3
P4-O2 P3-O1
Fp2-F4 Right parasagittal Fp1-F7 Left temporal Fp2-F4 Right parasagittal
F4-C4 F7-T7 F4-C4
C4-P4 T7-P7 C4-P4
P4-O2 P7-O1 P4-O2
Fp2-F8 Right temporal Fp2-F8 Right temporal Fz-Cz Vertex
F8-T8 F8-T8 Cz-Pz
T8-P8 T8-P8
P8-O2 P8-O2
From American Clinical Neurophysiology Society: Guideline 6: a proposal for standard montages to be used in clinical EEG. J Clin Neurophysiol 2006;23:111117.
If the capacity to add a few electrodes to traditional sleep a slow wave. The term epileptiform activity literally means
monitoring exists, one can increase the ability to detect epi- EEG activity resembling that found in patients with epi-
leptiform activity. For example, one could add two electrodes lepsy. This is a somewhat circular definition. Interictal
(T7, T8). The derivations F3-T7, T7-O1, F4-T8, and T8-O2 would activity is defined as abnormal EEG activity that occurs
add coverage over much of the frontal and temporal areas. between seizures. Epileptiform activity includes spikes, spike
These areas are the predominant foci of seizures occurring and waves, and polyspike complexes. Abnormal sharp waves
mainly during sleep. Other clinicians have utilized the addi- are also considered epileptiform or interictal activity. Of
tion of Fz, Cz, F7, and F8 to the usual PSG electrodes.7 The course, sharp waves can be normal (e.g., vertex sharp waves).
addition of synchronized digital video monitoring to noctur- Artifacts can sometimes mimic spikes or spikes and waves.
nal EEG or PSG recording greatly enhances the ability of the In general, true spike and wave complexes have a field (Box
clinician to diagnose nocturnal events.8 As is discussed later, 271). That is, true spike and wave activity should be seen
many nocturnal seizure disorders are not associated with in derivations containing several contiguous electrodes.
scalp EEG findings and the patients actions during the If a spike and wave is seen only in a single derivation, the
seizure (seminology) may be very helpful in determining activity is usually be an artifact.
whether an episode is likely a parasomnia or nocturnal Because seizures do not always appear during a given
epilepsy.8 recording (see Box 271), the physician reading an EEG or
PSG searches for spikes and/or abnormal sharp waves that
may represent the interictal footprint of possible seizure
WAVEFORM AND SEIZURE TERMINOLOGY
activity. However, it should be noted that not all patients with
The terminology and identification of epileptic seizures and spikes have seizures and not all patients with seizures have
interictal activity is challenging for physicians without exten- detectable interictal activity. Spikes represent abnormal
sive training in EEG (Table 273). A transient is any isolated brain activity that is seen as an area of negativity at the scalp.
wave or complex that stands out compared with background Spikes can be localized (negativity at the scalp over one area
activity. A spike is defined as a transient with a pointed peak of the brain) or appear diffusely. Focal seizures usually,
and a duration of 20 to 70 msec (Fig. 276). On a 30-second though not invariably, begin at the same location as the
page, spikes look like a single vertical line. A sharp wave is interictal spikes. The classic spike is followed by a slow wave.
a transient with a deflection of 70 to 200 msec. Although most common postictally, spike and sharp waves
A spike and wave complex is a spike followed by a slow will occur sporadically at any time and may have a slight
wave (usually wide and often higher amplitude). Polyspike increase preictally. Using the usual 30-second time window,
complexes often consist of multiple spikes superimposed on it may be difficult to appreciate spikes. A switch to a 10-second
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Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 549
T7-C3 C3-Cz P3-A1 F3-A1 A single EEG will show epileptiform abnormalities in
about 50% of adult patients with epilepsy.
C3-Cz Cz-C4 Fz-A1 P4-A2 F4-A2
Diagnostic yield increased to 70% with repeated
Cz-C4 C4-T8 Pz-A1 O1-A1 C3-A1 recordings and/or sleep EEGs.
A normal EEG does NOT rule out epilepsy.
C4-T8 T8-A2 O2-A2 C4-A2
An abnormal EEG (epileptiform activity) does NOT rule in
Fp2-A2 P3-A1 epilepsy.
P7-P3 P7-P3 F4-A2 F7-A1 P4-A2 ECG = electrocardiogram; EEG = electroencephalography.
FIGURE 276 Sharp waves, spikes, spike and wave, polyspikes, 10 sec page 30 sec page
and polyspike and wave. EEG = electroencephalography; PSG = (30 mm/sec) (10 mm/sec)
polysomnography. EEG speed PSG speed
Sharp waves
Spikes
1 second
Polyspikes
Polyspike
and wave
1 second
Nasion Nasion
Seizure
Seizure focus
Fp1 Fp2 Fp1 - F7 Fp1 Fp2 Fp2 - F8
focus
F7 F3 Fz F4 F8 F7 F3 Fz F4 F8
F7 - T7 F8 - T8
Left T7 C3 Cz C4 T8 Right Left T7 C3 Cz C4 T8 Right
P7 P3 P8 T7 - P 7 P7 P3 P8 T8 - P 8
Pz P4 S Pz P4
W
O1 O2 P7 - O1 O1 O2 P8 - O2
A Inion B Inion
FIGURE 277 Examples of phase reversal. A, A spike (s; negative) originates at electrode position T7 and a bipolar chain through the area shows phase reversal.
w = wave. B, Spike originated in between electrodes. The bipolar pair spanning the location show low amplitude due to cancellation effects but bipolar pairs on either
side show phase reversal.
F7 F3 Fz F4 F8
F8 - T8 F8 - Ref
Left T7 C3 Cz C4 T8 Right
T8 - P8 T8 - Ref
P7 P3 Pz P4 P8
O1 O2 P8 - O2 P8 - Ref
Inion
spike. In Figure 278, a spike focus is located between F8 and electrodes are referenced to the opposite mastoid.3 Therefore,
T8. On the bipolar montage, this results in the electrical a spike located near F4 will result in greater deflection in F4-
activity being nearly equal in the two electrodes, resulting in M1 compared with C4-M1 or O2-M1. It is also important to
minimal activity in F8-T8 but a phase reversal in adjacent recall that the mastoid electrodes may actually be closer to
bipolar pairs. However, in referential recording, the spike spikes in the temporal area than the F4, C4, and O2 electrodes.
results in larger and nearly equal activity in F8 and T8 with For example, a left temporal focus of activity may be nearer
less activity in adjacent electrodes. In the usual PSG montage, M1 than F3, C3, and O1. Thus, C4-M1 will actually show more
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Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 551
Up
Fp2 Fp1 Fp1 - F7
F8 F7 F7 - T7
Cornea retina
Fp1 compared to F7 Fp2 - F8
F7 compared to T7 F8 - T8
F3
Fp2 compared to F8
Fp1 T7
F8 compared to T8
F7
Down
Fp2 Fp1 Fp1 - F7
F8 F7 F7 - T7
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FIGURE 2710 Effect of vertical eye movements on bipolar derivations containing electrodes near the eyes.
552 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
Right
Fp2 Fp1 Fp1 - F7
F8 F7
F7 - T7
Cornea retina
Fp1 compared to F7 Fp2 - F8
F7 compared to T7 F8 - T8
F3
T7 Fp2 compared to F8
Fp1
F7 F8 compared to T8
Left
Fp2 Fp1 Fp1-F7
F8 F7 F7 F7-T7
Fp2-F8
Fp1 compared to F7
F7 compared to T7 F8-T8
Fp2 compared to F8
F8 compared to T8
FIGURE 2711 Effect of lateral eye movements on bipolar derivations containing electrodes near the eyes.
Fp1-F7 Fp1-F7
F7-T7 F7-T7
T7-P7 T7-P7
P7-O1 P7-O1
Fp2-F8 Fp2-F8
F8-T8 F8-T8
T8-P8 T8-P8
P8-O2 P8-O2
Fp1-F3 Fp1-F3
F3-C3 F3-C3
C3-P3 C3-P3
P3-O1 P3-O1
Fp2-F4 Fp2-F4
F4-C4 F4-C4
C4-P4 C4-P4
P4-O2 P4-O2
Fz-Cz Fz-Cz
Cz-Pz Cz-Pz
ECG ECG
FIGURE 2712 Effect of eye closure and opening on the alpha rhythm (dominant posterior rhythm). The rhythm is increased with eye closure or visual inattention and attenuated
by eye opening and most prominent in derivations containing O1 and O2. Recall that with eye closure, the eyes turn upward under the eyelids (Bells phenomenon). ECG =
electrocardiogram.
movements appear much wider in the 10-second window be downward deflections (O1 is positive compared with M2).
than in a 30-second time window. In Figure 2715, the POSTS show phase reversal across O1.
The fact that the POSTS are in fact positive in the occipital
Positive Occipital Sharp Transients of area is documented by the fact that the deflections are up in
C3-O1 and downward in O1-M1.
Sleep and Lambda and Mu Rhythms
Lambda waves have similar morphology and location as
Positive occipital sharp transients of sleep (POSTS) are POSTS but lambda waves are noted during wakefulness.
sharp waves that can occur normally in nonrapid eye move- Lambda waves are low-voltage triangular waves that appear
ment (NREM) sleep. They are most prominent in occipital in the occipital areas. They may be surface positive or nega-
derivations and are positive. Therefore, in O1-M2, they would tive (POSTS are surface positive) (Fig. 2716).
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Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 553
50 V
1 sec
Fp1-F7 Fp1-F3
F7-T7 F3-C3
T7-P7 C3-P3
P7-O1 P3-O1
Fp1-F3 Fp2-F4
F3-C3 F4-C4
C3-P3 C4-P4
P3-O1 P4-O2
Fz-Cz Fp1-F7
Cz-Pz F7-T7
V V SS T7-P7
Fp2-F4 P7-O1
F4-C4 K
C4-P4 Fp1-F8
P4-O2 F8-T8
T8-P8
Fp2-F8 P8-O2
F8-T8
T8-P8 T7-C3
P8-O2 C3-CZ
sec CZ-C4 P
C4-T8
A B C
FIGURE 2713 Waveforms of sleep using a clinical EEG montage (longitudinal bipolar) and a 10-second window. Vertex sharp waves (V; A), sleep spindles (SS; B), and a K
complex (K; C) are shown. Note phase reversal across Cz in the vertex sharp waves (A) and for K complex in C as denoted by P.
F3-C3
C3-O1
F4-C4
C4-O2
F3-T3
T3-O1
F4-T4
T4-O2
F3-F4
M1-T3
T3-C3
C3-C4
C4-T4
T4-M2
O1-O2
E1-M2
E2-M2
Chin
100 V 1 sec
FIGURE 2714 Stage R using a clinical EEG montage (combination of longitudinal and transverse bipolar) and a 10-second window. The underlined activity is a saw-tooth wave
(theta activity prominent in central derivations). Note also that alpha activity is common during stage R and usually 12 Hz slower. Alpha activity is seen in the occipital derivations
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at the same time as the saw-tooth waves. However, note that the alpha bursts stop before the saw-tooth activity ends. Note older electrode terminology (T3, T4 instead of T7, T8).
554 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
100 V
F4-M1 F4-M1
C4-M1 C4-M1
O2-M1 O2-M1
E1-M2 E1-M2
E2-M2 E2-M2
Chin Chin
A B
C3-O1
O1-M1
FIGURE 2715 Positive occipital sharp transients of sleep (POSTS) as seen in typical PSG montage in a 30-second (A) and a 10-second window (B). C, Bipolar derivations containing
the occipital electrode show that there is a phase reversal at O1 and that the waves are positive (downward deflection in O1-M1). The vertical lines are 1 second apart.
1 sec
lambda
Fp1-F3
F3-C3
C3-P3
P3-O1
Fz-Cz
Cz-Pz
FIGURE 2716 Lambda waves are noted in the P3-O1 derivation and marked by dots under the waves. Adapted from Libenson MH: Practical Approach to Electroencephalography.
Philadelphia: Elsevier Saunders, 2010, p. 270.
Ictal (seizure) activity may be manifested by rhythmic activ- Shape Archiform Sinusoidal
ity of many types. By definition, to be considered ictal, a Comblike
given burst of activity must be associated with an abnormal-
ity of movement or mentation. Whereas the spike and wave
activity is the most familiar waveform associated with ictal activity. In Figure 2719, a portion of a tracing visualized in
activity (Fig. 2718), the pattern of repetitive sharp waves of a 10-second window shows a spike and wave complex (SW)
various frequencies is also common.4,5 On traditional sleep followed by rhythmic activity of 8 to 9 Hz (R). The rhythmic
monitoring montages, ictal activity can even be mistaken for activity is differentiated from normal alpha rhythm by being
muscle artifact or normal alpha (813 Hz) and beta (>13 Hz) more prominent in the eye derivations than in the occipital
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Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 555
Cz-Pz
Fp2-F4
F4-C4
C4-P4
P4-O2
FIGURE 2717 An example of mu rhythm (archiform comb like pattern with phase reversal at C4). The vertical lines are 1 second apart. From Libenson MH:
Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 272.
F7-T
T-P7
P7-O1
Fp2-F8
F8-T8
T8-P8
P8-O2
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
R
E2-M2
sw
1 sec
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556 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
derivations. This is, in fact, a portion of a frontal seizure In Box 272, the partial epilepsies are divided into simple
manifested by oral automatisms and loss of responsiveness. partial (consciousness not impaired), complex partial (con-
One might suspect the frontal nature because the activity is sciousness impaired), and focal seizures (simple or partial
higher amplitude in the eye leads (near the frontal lobes). A complex) that evolve into generalized seizures. The simple
complete EEG montage documented a right frontal location partial seizures are divided into those with (1) motor symp-
(note in Fig. 2719, slightly higher amplitude in E2-M1 than toms, (2) somatosensory symptoms, (3) autonomic symp-
in E1-M2). toms, and (4) psychic symptoms or signs. The complex
As previously mentioned, ictal activity may not be seen partial seizures are divided based on whether or not impaired
in scalp EEG monitoring. Video recording is absolutely consciousness is apparent at the start of the seizure.
essential because the pattern of movements (seminology) is Primary generalized seizures are ones in which initial
very important for helping differentiate nonepileptic move- manifestations involve both hemispheres usually with loss of
ments (parasomnias) from epileptic movements. The type of consciousness (or impairment), bilateral motor activity, or
movement and the focal or generalized distribution may both. As noted previously, generalized epilepsy is associated
help define the type of seizure and/or focus in partial or with a diffuse origin of the seizure activity and is always
partial complex seizures. High-resolution magnetic reso- associated with impairment (usually loss of consciousness).
nance imaging (MRI) or invasive EEG monitoring may also Generalized epilepsy is divided into nonconvulsive (absence
identify the epileptic location in the brain. or petit mal) epilepsy and convulsive.
Ictal activity can be mistaken for a recording artifact and Nonconvulsive epilepsy is divided into typical (3/sec
vice versa. Some useful characteristics of true ictal activity spike and wave activity) and atypical with slower frequency
are noted in Box 271. True ictal activity evolves (i.e., changes complexes. Nonconvulsive generalized epilepsy starts in
in frequency, amplitude, and distribution) during the childhood and may resolve by late adolescence to adulthood.
episode. There is often EEG slowing after an ictal episode. Typical absence (petit mal) epilepsy (AE) is associated with
Synchronized video is very useful to determine whether impairment of consciousness (staring blankly) without loss
there are behavioral correlates (e.g., movements) temporally of muscle tone or posture. Attacks are triggered by hyper-
associated with ictal activity. ventilation and photic stimuli. Atypical AE is associated with
spike and wave complexes of less than 3/sec frequency and
CLASSIFICATION OF SEIZURES may be associated with combinations of impaired conscious-
ness and motor or autonomic changes. Patients with atypical
AND TERMINOLOGY
nonconvulsive epilepsy may develop convulsive generalized
A seizure is defined as an episode of disturbance of mental, seizures later in life.
motor, sensory, or autonomic activity caused by a paroxys- Convulsive generalized epilepsy is divided into myo-
mal cerebral neuronal malfunction. Epilepsy is defined as a clonic, tonic, clonic, tonic-clonic, and atonic seizures.
disorder of recurrent seizures. The disorder is called symp- Myoclonic seizures are characterized by brief muscle jerking
tomatic if there is an identifiable lesion or idiopathic if a (muscle contraction then relaxationoften involving the
discrete structural abnormality is not found. The term idio- shoulder muscles). An example of this type is juvenile myo-
pathic is misleading because many seizure disorders classi- clonic epilepsy (JME). Tonic seizures are associated with
fied as idiopathic have a genetic basis and some have a muscle tensing. Clonic seizures manifest with repeated
known mechanism. jerking (repeated contraction and relaxation). Generalized
The most commonly used classification of seizures is tonic-clonic (GTC) seizures (grand mal) are characterized
based on their manifestations9 (Box 272). Seizure disorders by initial tonic activity followed by clonic activity. Atonic
are divided into partial (focal) seizures that are due to the seizures are characterized by a sudden loss of muscle tone
initial involvement of a localized group of neurons limited (drop attacks).
to one hemisphere. If consciousness is not impaired, the Unclassified seizures are ones in which the origin (focal
disorder is termed a simple partial seizure (SPS). If con- or general) has not been determined.
sciousness is impaired, the disorder is a complex partial
seizure (CPS). An aura is an SPS manifested by sensations
Nocturnal Epilepsy
preceding a seizure and is, in fact, a manifestation of focal
epilepsy. Automatisms are repetitive movements that may Seizure disorders are part of the differential diagnosis of
be purposeful but serve no obvious purpose in the actual nocturnal spellsparticularly episodes of abnormal motor
situation. The postictal state is the state following ictal activity occurring during sleep or soon after awakening.
activity often associated with impaired sensorium or confu- Depending on the type of patients studied, as many as 10%
sion. Simple partial seizures may not show an EEG abnor- to 40% of seizures occur exclusively or mainly during
mality with scalp EEG recording. Complex partial seizures sleep. The lack of daytime seizure activity and the fact that
usually do exhibit some abnormality. Partial seizures may automatisms or episodes of changed sensorium during sleep
show secondary generalization (see Fig. 2718), resulting may not be noted by a bed partner or remembered by the
in the ictal activity associated with generalized convulsive patient make simple partial or partial complex seizures dif-
seizures. ficult to diagnose. Some seizures such as those associated
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Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 557
BOX 272
Classification of Seizures
1. PARTIAL (FOCAL, LOCAL) SEIZURES c. Dysamnesic (dj vu).
d. Affective (fear).
A. Simple partial seizuzres (consciousness not impaired)
e. Illusions.
i. Motor symptoms
f. Hallucinations.
a. Focal motor without marchsustained tonic,
intermittent clonic, or a sequence of tonic-clonic B. Complex partial (with impairment of consciousness)
movements. i. Simple partial onset followed by impairment of
b. Focal motor with march (Jacksonian)move- consciousness
ments progressively involve adjacent parts of one ii. Impairment of consciouness at onset
side of the body. a. Impairment of consciousness only.
c. Versiveturning of head or body, usually in a dire- b. Automatisms.
tion away from the side of the seizure discharge. C. Partial seizures (simple or complex) evolving to
d. Posturalinvoluntary changes in body posture. generalized seizures.
e. Aphasicexpressive or receptive, global loss of 2. GENERALIZED SEIZURES
language.
f. Phonatory (vocalization or arrest of speech). A. Nonconvulsive (absence)petit mal
ii. Somatosensory or special sensory symptoms i. Typical (3/sec spike and slow wave on EEG)
a. Somatosensory. ii. Atypical (<3/sec spike and slow wave complexes
on EEG)
b. Visualhallucinations.
B. Convulsive
c. Auditoryhallucinations of simple or complex
sounds. i. Myoclonic seizuresbrief jerks
d. Olfactoryhallucination of odors, often precedes ii. Clonic seizures
complex partial seizures. iii. Tonic seizurestensing of muscles
e. Gustatoryhallucination of taste. iv. Tonic-clonic seizures (grand mal)
f. Vertiginoustransient vertigo. v. Atonic (drop attacks)
iii. Autonomic symptoms or signs: epigastric, pallor, 3. UNCLASSIFIED SEIZURE
sweating
iv. Psychic symptoms or signs (usually occur with
impairment of consciousness and classified as
complex partial)
a. Dysphasic.
b. Cognitive.
EEG = encephalogram.
Adapted from Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsies and
epileptic syndromes. Epilepsia 1981;22:389399.
with nocturnal frontal lobe epilepsy (NFLE) can occur types of focal nocturnal epilepsy are frontal lobe epilepsy
without loss of consciousness or postictal confusion and (FLE) and temporal lobe epilepsy (TLE). Herman and
may be incorrectly assumed to be a parasomnia. The inci- coworkers12 studied patients with partial epilepsy undergo-
dence of nocturnal seizures has two peaksone about 2 ing long-term video-EEG monitoring and found that FLE
hours after bedtime and another between 4 and 5 AM (Table seizures were significantly more common during sleep than
275).10,11 Daytime seizures are most prevalent in the first wake.10,11 In contrast, TLE seizures were more common
hour after awakening. In general, all manifestations of noc- during wake. Figure 2720 illustrates the percentage of
turnal seizure disorders are much more common in NREM each seizure type that occurs during wake and sleep. Some
and rare during rapid eye movement (REM) sleep. Prior patients with FLE have seizures only during sleep. TLE
sleep deprivation activates seizures; therefore, patients often is less likely to occur during sleep than during wake.
undergo clinical EEG monitoring in a sleep-deprived state However, because TLE is much more common than FLE,
to increase the likelihood of recording seizure activity. Epi- TLE is the most common type of nocturnal seizure. TLE
lepsy syndromes commonly associated with nocturnal sei- seizures at night are more likely to generalize than TLE
zures are listed in Table 276. seizures during the day. In contrast, FLE seizures during
the day are more likely to generalize than those during
Focal Nocturnal Epilepsy the night.
Nocturnal simple partial seizures result in focal motor,
General Characteristics
sensory, autonomic, or psychic manifestations without a
Focal seizure disorders are often associated with interictal change of consciousness. Complex partial seizures usually
discharges or seizure activity in NREM sleep. The major arise from the mesial or lateral part of the temporal lobe or
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558 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
70
50
60
% seizures
50 40
40 30
30
20
20
10 10
0 0
FLE TLE (all) MTLE NTLE OLE FLE TLE (all) MTLE NTLE OLE
FIGURE 2720 Left, The percentage of different seizure types occurring while awake and asleep. Note that frontal lobe epilepsy (FLE) occurs more
often during sleep than awake. Some patients with FLE may have seizures only at night. Temporal lobe epilepsy (TLE) is more likely to occur during awake
than sleep. Right, The percentage of focal epilepsy that generalized during awake and asleep. TLE occurring during sleep is more likely to generalize. FLE
occurring during awake is more likely to generalize. From Herman ST, Walczak TS, Bazil CW: Distribution of partial seizures during the sleep-wake cycle:
differences by seizure onset site. Neurology 2001;56:1456.
adjacent parts of the frontal lobe. The symptoms consist of sensation such as a visual or olfactory disturbance that pre-
changes in the content of consciousness that reduce the cedes the start of the event.
patients ability to interact with the surroundings. They can There have been efforts to identify characteristics allow-
occur with only a change in consciousness or can include ing differentiation between FLE and TLE. Unfortunately,
automatisms. For example, lip smacking is a common there is considerable overlap. FLE is more likely to be associ-
automatism. Patients with complex partial seizures may have ated with dystonic posturing (fencing) and TLE more likely
no recollection of the events or only partial memory of the to be associated with interictal or ictal activity visualized on
seizure. Patients may remember an aura, a subjective the scalp EEG.
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Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 559
FIGURE 2721 Spikes (S) are noted in a standard PSG montage in all
derivations containing M1. These spikes are from a left temporal focus
(near M1). ECG = electrocardiogram.
F4-M1
C4-M1
O2-M1
S
E1-M2
E2-M2
ECG
50 V
1 sec
1 sec 1 sec
Fp1-F7
F7-T7
T7-P7
P7-O1
Fp2-F8
F8-T8
T8-P8
P8-O2
FIGURE 2722 Bipolar recording from the patient in Figure 2721 shows ictal activity of approximately 8 Hz in the left frontotemporal derivations. This confirms
the suspected left-sided focus noted in Figure 2721. The low amplitude in F7-T7 suggests that the focus is equidistant from both electrodes (see Fig. 278).
TABLE 277
Manifestations of Nocturnal Frontal Lobe Epilepsy
PA NPD ENW
Frequency. Multiple times per night Multiple times per night Multiple times (13/night).
(mean 2). (mean 3).
Duration of episodes. Short 2040 sec. More prolonged (2598 sec). 31180 sec.
Patients sit up, look Arm and leg movements. Jump out of bed.
around, confused, Cycling. Wander.
often with loud Kicking. Vocalize.
scream. Dystonic posture (fencing). Violent behavior.
Pelvic thrusting.
Vocalization.
Violence can occur.
Can communicate at end of 100%. 44% can communicate at 100%.
seizure. end of episode.
Can communicate during 12/27. 10/59 during episode. None.
seizure.
Stereotypical or varied. Stereotyped. Stereotyped. Stereotyped, agitated
somnambulism.
Daytime seizures. No. 57% (49% secondarily 13%.
generalized seizures).
Brain structural abnormality. 0%. 24%. 5%.
NPD = nocturnal paroxysmal dystonia; ENW = episodic nocturnal wandering; PA = paroxysmal arousal.
Adapted from Provini F, Plazzi G, Tinuper P, et al: Nocturnal frontal lobe epilepsy. Brain 1999;122:10171031.
with symptoms similar to sleepwalking and sleep terrors. midline, is a type of FLE that typically involves unilateral or
Patients may jump out of bed, wander, vocalize, and show asymmetrical bilateral tonic posturing and may be associ-
violent behavior during sleep. Classically, treatment with ated with facial grimacing, vocalization, or speech arrest
older anticonvulsants (in particular, carbamazepine) or (Fig. 2723). SMA seizures may be preceded by a somato-
newer anticonvulsants such as levetiracetam at bedtime is sensory aura.1315 Complex automatisms such as kicking,
generally effective. However, some patients are refractory to laughing, or pelvic thrusting may be present with respon-
antiepileptic medications. It is important to note that a sig- siveness often preserved. A classic manifestation of SMA
nificant proportion of patients with NFLE do have seizures epilepsy is the fencing posture with the head turned toward
during wakefulness, generalization to tonic-clonic seizures, an outstretched arm (head turns away from side of seizure
and a demonstrable brain abnormality. focus). Because consciousness is often well preserved and
postictal confusion minimal, these episodes are some-
times thought to be psychogenic. However, unlike psycho-
Familial NFLE
genic movements, SMA epilepsy episodes are typically brief
The original description was an autosomal dominant noc- and stereotypical.
turnal frontal lobe epilepsy (ADNFLE) associated with a
missense mutation of the neuronal nicotinic acetylcholine
Parasomnia Versus NFLE
receptor (nAChR) alpha 4 subunit. Other mutations of the
nAChR gene system have been found and there is genetic Information contrasting NFLE and NREM parasomnias
heterogeneity in families with ADNFLE. Four known loci are listed in Table 278. In general, NFLE is associated
are 20q13.2, 15q24, 1q21, and 8p12.3-q12.3. Motor seizures with greater frequency (episodes per month) and is more
are frequent (nearly every night), often violent, occur in likely to consist of multiple episodes in a given night.
clusters, and are brief (<1 min). The age of onset is variable The manifestations of NREM parasomnias also vary from
(2 mo56 yr). Ninety percent of patients present by age 20 night to night whereas NFLE seizures have very stereo-
years. typical manifestations. They can be bizarre but they always
consist of the same activity. EEG is not that helpful in
many cases because approximately 40% to 50% of NFLE
Supplemental Motor Area Epilepsy
patients have no interictal or ictal EEG findings (apart
Focal seizures arising from the supplementary motor area from movement and muscle artifact associated with the
(SMA), a region anterior to the motor cortex in the spells).
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562 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
F7-F3
F3-Fz
Fz-F4
F4-F8
T3-C3
C3-Cz
Cz-C4
C4-T4
FIGURE 2723 A nocturnal attack due to frontal lobe epilepsy from the supplemental motor area. Ictal EEG recording of a nocturnal
episode of frontal lobe epilepsy. The ictal EEG shows electrodecremental pattern associated with rhythmic low-amplitude 20- to 24-Hz
fast activity localized in the right midfrontal region (horizontal arrow) that evolved into activity of slower frequency and higher
amplitude as the clinical seizure began. HFF = high-frequency filter; TC = time constant. From Tachiban N, Shinde A, Ikeda A, et al:
Supplementary motor area seizure resembling sleep disorder. Sleep 1996;19:813.
50 V
1 sec
Fp1-F3
F3-C3
C3-P3
P3-O1
Fp2-F4
F4-C4
C4-P4
P4-O2
FIGURE 2724 An example of EEG tracing with interictal activity in a patient with benign epilepsy of childhood with centrotemporal
spikes (BECTS). Note the spikes prominent in the frontocentral derivations on the left. There is a phase reversal at C3. From Chokroverty
S, Quinto C: Sleep and epilepsy. In Chokroverty S (ed): Sleep Disorders Medicine. Boston: Butterworth Heinemann, 1999, p. 711.
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 2725 Three-Hz spike and wave complexes in a patient with absence epilepsy.
higher frequency has been found in patients with refractory was noted in 28% of CPAP patients and 15% in the sham
epilepsy. Therefore, a high index of suspicion is indicated group (P = .40). Further large studies are needed, but cer-
when patients with epilepsy report disturbed sleep and tainly in individual patients, effective treatment of OSA may
snoring. A randomized, pilot-controlled study of continu- improve seizure control. The etiology of the benefit of CPAP
ous positive airway pressure (CPAP vs. sham) in a group of treatment is not clear. It is known that prior sleep deprivation
patients with medically refractory epilepsy and coexistent or disturbance can worsen seizure control. Therefore,
OSA found a trend for improvement in nocturnal seizures improvements in sleep with CPAP treatment may be one
frequency.23 A 50% or greater reduction in seizure frequency mechanism by which seizure control is improved.
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Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 565
Fp1-F7
100 V
F7-T7
T7-P7
P7-O1
Fp2-F8
F8-T8
T8-P8
P8-O2
Fp1-F3
F3-C3
C3-P3
P3-O1
Fp2-F4
F4-C4
C4-P4
P4-O2
Fz-Cz
Cz-Pz
1 sec
FIGURE 2726 A tracing from a patient with slow spike and wave activity and the Lennox-Gastaut syndrome. From Foldvary-Schaefer N,
Grigg-Damberger M: Sleep and epilepsy. Sleep Med Clin 2008;3:450.
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Philadelphia: Saunders Elsevier, 2010.
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C. They occur during wake.
7. Foldvary N, Caruso AC, Mascha E, et al: Identifying montages
D. They are sharp wave. that best detect electrographic seizure activity during polysom-
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A. They are 8 to 13 Hz. monitoring nocturnal events. In Lee-Chiong TL, Sateia MJ,
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Academy of Sleep Medicine: The AASM Manual for Scoring of 2008;71:572577.
Sleep and Associated Events: Rules, Terminology and Technical
Specifications, 1st ed. Westchester, IL: American Academy of
Sleep Medicine, 2007.
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Chapter 28
Parasomnias
F4-M1 100 V
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 281 A 30-second epoch shows a confusional arousal from stage N3 in a 45-year-old adult. There was no evidence of change in airflow before the episode. Note the
absence of any change in the electroencephalogram (EEG) or electromyogram (EMG) derivations before the arousal. The patient abruptly sat up and looked around, appearing
confused.
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570 Chapter 28 Parasomnias
Schenck and coworkers6 found evidence of prior or cur- Evidence for an altered state of consciousness includes dif-
rent psychopathology in only about 48% of adults with ficulty in arousing the person, mental confusion when awak-
sleepwalking/sleep terrors who underwent PSG monitoring ened from an episode, amnesia (complete or partial) for the
for sleep-related injury. Therefore, the adult sleepwalking episode, and abnormal behaviors. Abnormal behaviors
patients were equally as likely not to have psychopathology include routine behaviors that occur at inappropriate times,
as to have this problem. In addition, there was typically no inappropriate or nonsensical behaviors, and dangerous or
association between sleepwalking/sleep terrors and any con- potentially dangerous behaviors.
current psychopathology with respect to onset, clinical
course, or treatment response.12 However, because mental Differential Diagnosis of Sleepwalking
illness and medication used to treat mental illness can The differential diagnosis of sleepwalking is discussed with
disturb sleep, sleepwalking could well occur or re-emerge in confusional arousal and sleep terrors in a later section.
patients with active mental illness.
Sleep-Related Sexual Behavior
PSG in Sleepwalking and Sleep-Related Violence
Although PSG is rarely performed to evaluate cases of sleep- The main complications of sleepwalking are social embar-
walking, the classic finding is a sudden arousal occurring in rassment and danger of self-injury or injury to others.
stage N3 sleep (Fig. 282). During the prolonged arousal, Violent behavior (self-mutilation or homicide) and sexual
there usually is tachycardia and often persistence of slow assault (sleep sex) have been reported in association with
wave EEG activitydespite the presence of high-frequency sleepwalking episodes. Sleep-related sexual behavior or
EEG activity and an increase in EMG amplitude. Analysis of sex-somnia14,15 is a parasomnia in which sexual behavior
a large group of patients with sleepwalking and sleep terrors occurs with limited awareness during the act, relative unre-
found that there was no prearousal buildup of delta activ- sponsiveness to the external environment, and amnesia for
ity, increase in heart rate, or prearousal increase in chin the event. The behaviors range from sexual vocalizations to
EMG. Postarousal, the EEG showed three patterns: (1) intercourse. These actions may include behaviors very atypi-
diffuse rhythmic (synchronized) delta activity, (2) diffuse cal for the individual (e.g., anal intercourse). In contrast to
delta and theta activity, and (3) prominent alpha and beta typical sleepwalking, these events can exceed 30 minutes.
activity.13 The heart rate is often noted to increase at the onset Sleep-related violence occurs in a state consistent with
of the event. sleepwalking/sleep terrors and is associated with an emotion
of fear or anger. The violent behavior may be directed at
Diagnosis of Sleepwalking individuals in close proximity or those who confront the
Diagnostic criteria for sleepwalking are listed in Box 283 individual during the parasomnia.16,17 The patient may either
and do not require PSG findings. The ICSD-2 major criteria awaken or go back to sleep but typically has amnesia for the
for a diagnosis of sleepwalking1 include (A) ambulation event. The violence is often atypical for the individual. Most
during sleep and (B) evidence of persistent sleep, altered cases of sleep-related violence occur in middle-aged men
consciousness, or impaired judgment during ambulation. with a history of prior sleepwalking.
100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 282 A 60-second tracing shows an episode of sleepwalking that occurred out of stage N3 in a 5-year-old boy. Note the persistence of slow wave activity during the
arousal and subsequent body movements. The patient abruptly aroused, sat up, and left the bed.
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572 Chapter 28 Parasomnias
Sleep Disorders and the Law with benzodiazepines was NOT effective in those without
Automatisms are defined as involuntary behavior over sleep-related breathing problems.11 A recent systematic
which an individual has no control. The behavior may be out review of sleepwalking treatments found that no large con-
of character and the individual may have no recall for the trolled studies of treatment for sleepwalking have been
events. The sleep automatisms likely to result in injurious reported.18
behavior include NREM parasomnias, sleep-related disso-
ciative disorders (SRDDs; discussed in a later section), and
Sleep Terrors
sleep-related epilepsy. An important legal question for con-
sideration is the presence or absence of criminal intent. Sleep terrors, also called night terrors or pavor nocturnus,
When criminal action is taken against the violent sleep- consist of sudden arousal, usually from stage N3 sleep,
walker, sleep medicine physicians may be called as expert accompanied by a blood-curdling scream or cry and mani-
witnesses.16,17 There are guidelines for expert witness qualifi- festations of severe fear (behavioral and autonomic) (Boxes
cations and testimony.17 In addition, criteria have been pro- 287 and 288). The affected individual typically is confused,
posed to assist in determination of the putative role of an diaphoretic, and tachycardic, and he or she frequently sits up
underlying sleep disorder17 (Box 286). in bed. It is difficult or impossible to communicate with a
Treatment of Sleepwalking
The treatment of sleepwalking includes environmental pre- BOX 287
cautions (e.g., closed doors and windows, sleeping on the Sleep TerrorsDiagnostic Criteria
first level) and avoidance of precipitating causes such as A. Sudden episode of terror occurs during sleep, usually
sleep deprivation as well as reassurance. If the episodes are initiated by a cry or loud scream that is accompanied by
determined to require medication, benzodiazepines, TCAs, autonomic nervous system activation and behavioral
or selective serotonin reuptake inhibitors (SSRIs) may be manifestations of intense fear.
tried. Clonazepam 0.5 to 2.0 mg qhs or temazepam 30 mg B. At least one of the following is present:
qhs are commonly prescribed. Medications should be given i. Difficulty in arousing the person.
early enough before bedtime so that sleepwalking in the ii. Mental confusion when awakened from episode.
first slow wave cycle is prevented. In one study of patients iii. Amnesia (complete or partial) for the episode.
with self-injurious behavior, bedtime clonazepam was suc- iv. Dangerous or potentially dangerous behaviors.
cessful in controlling sleep terrors/sleepwalking in greater C. The disturbance is not better explained by another sleep
than 80% of cases.6 However, not all studies have found disorder, medical or neurologic disorder, mental
clonazepam to be this effective. Another study of treatment disorder, medication use, or substance use disorder.
of patients with sleepwalking found that those with any From American Academy of Sleep Medicine: ICSD-2 International
degree of sleep apnea had fewer sleepwalking episodes if Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
sleep apnea was effectively treated.11 Conversely, treatment
BOX 286
Guidelines for Determination of the Putative Role BOX 288
of a Sleep Disorder in a Violent Act Sleep Terror Facts
1. A reason to suspect a sleep disorder exists (history, PSG In children, sleep terrors occur out of stage N3 in the first
findings). part of night.
2. Duration of episodes is brief (min)can be much longer. In adults, sleep terrors can occur from stage N2 sleep.
3. Behavior is abrupt, immediate, impulsive, without Patients may manifest both sleep terrors and
apparent motivation, no premeditation. sleepwalking.
4. Victim is someone who happened to be present. In contrast to confusional arousals, patients with sleep
5. Immediately upon return of consciousnesshorror at terrors have profound autonomic hyperactivity and
event, no attempt to escape or conceal act. manifestations of fear.
6. Some degree of amnesia for event. Unlike RBD or nightmares, patients with sleep terrors do
7. In case of sleepwalking, the act must: not relate dream mentation associated with the event,
a. Occur upon awakening, usually at least 1 hour after The persistence of sleep terrors into adulthood,
sleep onset. re-emergence of sleep terrors in adulthood, or onset of
b. Occur on attempt to awaken the patient. sleep terrors in adulthood is not necessarily evidence that
c. Be potentiated by alcohol ingestion, sedative/ psychopathology is present.
hypnotic administration, or prior sleep deprivation. Sleep terrors have been described in adults during nasal
PSG = polysomnography.
CPAP treatment of OSA.
Adapted from Mahowald MW, Schenck CH: Parasomnias: sleep walking and CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea;
the law. Sleep Med Rev 2000;4:321339. RBD = rapid eye movement sleep behavior disorder.
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Chapter 28 Parasomnias 573
person having a sleep terror, and total amnesia for the event fear. In addition, evidence of an altered state of conscious-
is usual. Patients may sleepwalk during episodes of sleep ness including difficulty in arousing the person, mental con-
terrors. Thus, many consider sleepwalking and sleep terrors fusion after awakening, and partial or complete amnesia for
to be one syndrome with a spectrum of manifestations. the event is required.
TABLE 281
Comparison of the Characteristics of NonRapid Eye Movement Parasomnias
CONFUSIONAL AROUSAL SLEEPWALKING SLEEP TERRORS
Onset Stage N3 children Same Same
Stage N2, N3 adults
Autonomic hyperactivity No No Prominent
Loud scream No No Yes
Confusion during episode Yes Yes Yes
Amnesia (partial or complete) Yes Yes Yes
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574 Chapter 28 Parasomnias
evaluation, about 60% of cases of chronic RBD are idiopathic BOX 2811
(see Box 2810). Causes of chronic RBD include multiple Scoring Rules for the Electromyogram Activity
sclerosis, subarachnoid hemorrhage, dementia, ischemic Associated with the Rapid Eye Movement Sleep
cerebrovascular disease, and brainstem neoplasms.2426 RBD Behavior Disorder
can be associated with a number of neurologic disorders
including narcolepsy and alpha synucleopathies including RULES
Parkinsons disorder, Lewy body dementia, and multiple 1. The PSG findings of RBD are characterized by either or
system atrophy.24,25 In one study, almost 40% of patients with both of the following features:
idiopathic RBD later developed Parkinsons syndrome, a. Sustained muscle activity in REM sleep in the chin
although the mean time from onset of RBD to onset of Par- EMG.
kinsons disease was approximately 12 years.27 There is a strong b. Excessive transient muscle activity during REM in the
male predominance in RBD. The acute onset of RBD in a chin or limb EMG.
middle-aged woman with other neurologic complaints should DEFINITIONS
raise the possibility of multiple sclerosis. Drug-induced or
Sustained muscle activity in REM sleep is defined as an
drug-exacerbated cases of RBD have been reported (see Box epoch of REM sleep with at least 50% of the duration of the
2810) with the use of monoamine oxidase inhibitors (e.g., epoch having a chin EMG amplitude greater than the
phenelzine), TCAs (e.g., imipramine), SSRIs (e.g., fluoxetine), minimum amplitude in NREM.
selective serotonin norepinephrine reuptake inhibitors (ven-
Excessive transient muscle activity in REM sleep: In a
lafaxine), and other antidepressants (mirtazapine).26 There
30-second epoch of REM sleep divided into 10 sequential
can also be a sudden exacerbation of RBD when the dose of 3-second miniepochs, at least 5 (50%) of the miniepochs
medications associated with RBD is increased. contain bursts of transient muscle activity. In RBD, excessive
Pseudo-RBD A group of patients with a history of dream- transient muscle activity bursts are 0.1 to 5.0 seconds in
duration and at least four times as high in amplitude as the
enactment behavior and daytime sleepiness was found to
background EMG activity.
have OSA on PSG but no evidence of REM sleep without
EMG = electromyogram; NREM = nonrapid eye movement;
atonia.29 Treatment with CPAP eliminated the behaviors. It PSG = polysomnography; RBD = rapid eye movement sleep behavior
is possible that increased pressure for REM sleep (prior REM disorder; REM = rapid eye movement.
sleep fragmenation) overwhelms normal REM atonia pro- Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
cesses in these cases. Of note, patients with both true RBD Associated Events: Rules, Terminology and Technical Specification, 1st ed.
and OSA may also exhibit fewer RBD episodes when ade- Westchester, IL: American Academy of Sleep Medicine, 2007.
quately treated with CPAP.
PSG in RBD Video PSG including both leg and arm EMG is
recommended. A given PSG study may or may not reveal an can also be mistaken for periodic limb movement in sleep
episode of abnormal behavior/body movements, because (PLMS) activity. However, TMA usually contains many more
most patients do not have nightly attacks. For this reason, brief spikes of activity. Of interest, during RBD body move-
some sleep centers perform multiple sleep studies if the diag- ments, video monitoring of the face will often show closed
nosis remains unclear. However, even if abnormal behavior eyes but obvious movements of the eyes under the eyelids
is not documented by a given PSG, evidence of REM sleep consistent with REMs. In contrast, during confusional
without atonia (tonic or phasic EMG abnormality during arousals or sleepwalking, the eyes are typically open with a
REM sleep) is usually present. The American Academy of blank stare and dilated pupils (affected individual is still
Sleep Medicine (AASM) scoring manual30 provides criteria minimally responsive).
for scoring the EMG activity associated with RBD (Box 28 Whereas the AASM scoring manual provides criteria to
11). In the chin EMG, sustained muscle activity may be determine whether a given epoch has sufficient activity in
noted. Excessive phasic activity (TMA) may be noted in the the chin and limb EMGs during REM sleep to be classified
chin EMG, limb EMGs (anterior tibial, extensor digitorum), as abnormal or excessive (see Box 2811), the number of
or both (see Chapter 12). TMA in the leg EMG derivations such epochs (as a percentage of the total amount of REM
can also be seen without evidence of sustained muscle activ- sleep) that should be considered to be abnormal was not
ity in the chin EMG (Figs. 283 and 284). specified. In fact, it is really not possible to define what is
When the chin EMG derivation is abnormal, identifica- abnormal given the night-to-night variability in manifesta-
tion of REM sleep (vs. stage W) may be challenging. Epochs tions of RBD. Some evidence of REM without atonia can be
could potentially be scored as stage W (REMs + increased seen in patients taking SSRIs who have no history of dream
chin EMG). Clues that abnormal REM sleep is present enactment. As is discussed in the next section, a diagnosis
include the presence of saw-tooth waves in the EEG, exces- of RBD requires more than REM sleep without atonia.
sive TMA in the chin and/or limb EMGs, and alterations in
airflow associated with bursts of eye movements. The heart Diagnosis of RBD
rate also may remain constant despite the sudden appearance The ICSD-2 criteria for RBD are listed in Box 289. The
of increased EMG tone (as opposed to an awakening). TMA major points are demonstration of REM sleep without
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576 Chapter 28 Parasomnias
100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
CPAP flow
Chest
Abdomen
SpO2
RAT
LAT
FIGURE 283 A 30-second epoch of rapid eye movement (REM) sleep shows both sustained and phasic chin electromyogram (EMG) activity during REM sleep (REM sleep without
atonia) and increased transient muscle activity (phasic) in the right anterior tibial (RAT) and left anterior tibial (LAT) EMG derivations. CPAP = continuous positive airway pressure;
ECG = electrocardiogram; SpO2 = pulse oximetry.
100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
RAT
LAT
A B C
FIGURE 284 A 30-second epoch during stage R (REM) sleep. At A, the chin EMG is not increased but transient muscle activity is noted in the leg EMG derivations. At B, the chin
shows sustained and increased phasic EMG activity but there is no increased EMG activity in the legs. At C, both chin and leg EMG activity is increased. At B and C, the patient was
moving arms and legs and talking. ECG = electrocardiogram; LAT = left anterior EMG; RAT = right anterior tibial EMG.
atonia (sustained chin EMG activity) or increased TMA occurs most commonly out of NREM sleep but can rarely
during REM sleep (chin, limbs, or both), abnormal dream- occur out of REM sleep (NREM > wake > REM). A
enacting behavior documented by history or video PSG, detailed neurologic evaluation of patients suspected of
and absence of epileptiform activity during REM sleep having RBD is indicated with attention to symptoms and
(unless RBD can be clearly distinguished from any concur- signs of associated neurologic disorders such as Parkinsons
rent REM sleep-related seizure disorder). Seizure disor- disease (see Box 2810). A magnetic resonance imaging
ders can present with manifestations virtually identical (MRI) study of the brain (to rule out structural causes) and
to those of RBD. Therefore, making a diagnosis of RBD a full clinical EEG (preferably during sleep) are usually
without PSG monitoring is not recommended. Absence of performed especially if manifestations are atypical or
REM without atonia and/or body movements out of NREM patients do not respond to therapy. Important facts about
sleep would be inconsistent with RBD. Nocturnal epilepsy RBD are listed in Box 2812.
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Chapter 28 Parasomnias 577
BOX 2815 are required. One would probably not classify the rare
Nightmare DisorderDiagnostic Criteria occurrence of a nightmare as a disorder given the high per-
centage of normal individuals experiencing an occasional
A. Recurrent episodes of awakenings from sleep with recall nightmare.
of intensely disturbing dream mentation, usually
involving fear or anxiety, but also anger, sadness,
Differential Diagnosis
disgust, and other dysphoric emotions.
The differential diagnosis of nightmare disorder includes
B. Full alertness or awakening, with little confusion or
disorientation; recall of sleep mentation is immediate sleep terrors, RBD, sleep paralysis, SRDDs (to be discussed
and clear. in a later section), and nocturnal panic attacks. Nocturnal
C. At least one of the following associated features is present: panic attacks occur during or immediately after nocturnal
i. Delayed return to sleep after the episode. awakenings from NREM sleep. Some patients report that
ii. Occurrence of episodes in the latter half of the disturbing dreams preceded the attacks but most do not have
habitual sleep period. dream recall.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Treatment of Nightmare Disorder
Westchester, IL: American Academy of Sleep Medicine, 2005. If a medication is temporally associated with nightmares, a
trial of medication discontinuation or change is prudent.
BOX 2816
Cognitive behavioral treatments have been used to treat
nightmares with some success. One behavioral technique
Medications Commonly Associated called imagery rehearsal therapy has proved successful in
with Nightmares several studies.42,43 Patients are asked to rewrite their previ-
Beta blockerspropranolol, atenolol ous dreams with a positive outcome. In the past, use of
Cholinergic agonistsdonepezil medications for nightmares had limited success. Recently,
Antibioticslevaquin several small studies report success with the alpha 1 blocker
Antiviral agentsamantadine, gancyclovir prazosin. Note that when prazosin is started, the drug
Antiretroviralefavirenz (Sustiva) should be initiated with a dose of 1 mg at bedtime to avoid
Dopamine agonistsropinirole, pramipexole severe first-dose hypotension (often orthostatic hypoten-
Antidepressantsfluoxetine, paroxetine sion). The drug can then be titrated upward slowly over
Benzodiazepine receptor agonists (zolpidem) several nights. A parallel placebo-controlled study in trau-
Melatonin agonistramelteon matic nightmares in PTSD associated with combat showed
Ethanol withdrawalREM rebound improvements in sleep and reduction in nightmares. A rela-
REM = rapid eye movement. tively high dose (mean 13 mg) was reached over a protracted
period of upward titration.44 Another study using a cross-
over design and a dose of 2 to 6 mg at bedtime also found
experiences that usually occur during REM sleep and often benefit in civilian trauma PTSD.45 One study also reported
result in an awakening (Box 2815). Nightmares can follow success in reducing disturbing nightmares using topiramate
acute trauma (acute stress disorder [ASD]) or occur 1 month in PTSD patients.46 However, neither prazosin or topiramate
or more after trauma (PTSD). The dreams of PTSD can are FDA approved for treatment of nightmares in PTSD.
occur out of NREM stages N2 or N3, during REM sleep, and Prazosin must be used with caution to avoid hypotension.
at sleep onset. A number of medications can also be associ-
ated with nightmares41 (Box 2816). OTHER PARASOMNIAS
Sleep-Related Dissociative Disorders
Epidemiology of Nightmare Disorder
Fifty percent to 80% of adults report one or more night- The ICSD-21 states sleep-related dissociative disorders
mares.1 Ten percent to 50% of children age 3 to 5 experience (SRDD) emerge throughout the sleep period during well-
nightmares severe enough to disturb their parents. Night- established EEG wakefulness, either at transition from
mares within 3 months of trauma are present in up to 80% wakefulness to sleep or within several minutes after awaken-
patients with PTSD.1 ing from stage N1, N2, or R (Box 2817). An important
distinction from other parasomnias is that whereas typi-
PSG Recordings in Nightmare Disorder cal parasomnias tend to emerge almost simultaneously
Few PSG studies of nightmares exist, but typically, acceler- with arousal, the SRDDs emerge from well-established
ated heart rate and respiratory rate precede awakening from wakefulness.
REM sleep with report of a nightmare. The Diagnostic and Statistical Manual of Mental Disor-
ders, 4th edition (DSM-IV), states that a dissociative disor-
Diagnosis of Nightmare Disorder der is characterized by a disruption in the usually integrated
The ICSD-2 diagnostic criteria for the nightmare disorder functions of consciousness, memory, identity, or perception
are listed in Box 2815. Note that recurrent episodes of the environment.47 An SRDD would include dissociative
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580 Chapter 28 Parasomnias
LOC
ROC
Fz-Cz
Cz-Oz
C4-A1
Arm EMG
ECG
Nasal P
SpO2
Sum (A)
Inspiration
RC
(B)
Abd
HR
FIGURE 285 A 120-second tracing during REM sleep shows a deep inhalation (A) followed by a prolonged exhalation (B) associated with monotonous sound generation
(groaning). Note that in the Sum, rib cage (RC), and abdominal (Abd) tracings, the direction of inspiration is downward and exhalation upward. The absence of nasal pressure
excursions is due to exhalation through the mouth during groaning. ECG = electrocardiogram; EMG = electromyogram; HR = heart rate; LOC = left outer canthus; Nasal P = nasal
pressure; ROC = right outer canthus; SpO2 = pulse oximetry. Reproduced from Ramar K, Olson EJ, Morgenthaler TI: Catathrenia. Sleep Med 2008;9:457459.
Epidemiology
Sleep-Related Eating Disorders
HGH events have a prevalence of 25% to 35% and HPH
events have a prevalence of 7% to 13%. Both HGHs and Sleep-related eating disorders (SREDs) are manifested by
HPHs are more common in younger patients. SRHs can eating and drinking during the main sleep period (Boxes
occur in association with sleep paralysis. 2825 and 2826). The behavior must be associated with one
or more of several manifestations including eating peculiar
Factors Precipitating SRH food items, associated with insomnia due to sleep distur-
Precipitating factors include current drug use, mood disor- bance from the eating episodes, sleep-related injury, danger-
der, anxiety, and past alcohol use. ous behaviors in pursuit of food, morning anorexia, or
adverse consequences of binge eating. In the past, SRED was
Associations with SRHs differentiated from nocturnal eating syndrome (NES) by the
1. HGHs and HPHs are common, can occur in normal sub- level of alertness during the episodes and the degree of
jects, and are common in patients with narcolepsy or recall.1,4,6567 However, there is considerable overlap between
idiopathic hypersomnia. SRED and NES. In the current ICSD-2 diagnostic criteria for
2. CNVHs are rare and can occur in idiopathic form. There SRED, altered awareness and lack of recall are NOT required.1
may be an association with a neurologic disorder: narco- In SRED, the degree of alertness and recall for the
lepsy, Parkinsons disease, dementia with Lewy bodies, eating behavior are variable. Some patients cannot be
visual loss (Charles Bonnet hallucinations), midbrain and brought to full consciousness during the eating events and
diencephalic pathology (peduncular hallucinosis), and
the use of beta blocker medications.
BOX 2825
have no recall of the event. Others are relatively alert during cigarette smoking cessation, and cessation of alcohol or other
the episode and have considerable recall of the event the next drugs of abuse.1,66
morning. The amount of alertness can even vary between
episodes on a given night. A sensation of hunger is usually PSG in SRED
missing and patients may eat in an out of control manner.1 PSG may show multiple arousals from stage N3 with behav-
Patients often eat peculiar, nonedible, or even dangerous ior typical of confusional arousal (with or without attempted
substances. These may include frozen food, coffee grounds, eating behavior). Sometimes, OSA or PLMS is also noted.
and cat food. Of interest, alcoholic beverages are rarely con-
sumed. High-calorie foods are often chosen. There may be SRED Complications
multiple episodes of eating during a single night. Complications include weight gain or injury due to prepara-
tion of food (cookinge.g., burns, opening cans, cutting
Demographics food with a knife).
SRED is much more common in females than in males.
Females make up 66% to 83% of affected individuals in Diagnosis
most series. The prevalence is higher in patients with other The ICSD-2 diagnostic criteria are listed in Box 2825.
eating disorders. Typical age of onset of SRED is 20 to 30 Observations by a significant other, finding evidence of noc-
years. turnal eating behavior (e.g., open food packages, dirty
plates), videotaping, and self-report (in patients with some
Pathophysiology recall) have been used to make a diagnosis.
The cause of SRED is unknown but more than 50% of
patients have another parasomnia and the strong female Differential Diagnosis
predominance is typical of eating disorders. Other possible etiologies of this behavior include NES, recur-
rent hypersomnia (Kleine-Levin syndromehyperphagia,
Causes of SRED and Association with Other hypersomnia). Whereas NES is said to be characterized by
Sleep Disorders full alertness (Table 282), there is considerable overlap
The causes and associations of SRED are listed in Box 2827. between SRED and NES. Some clinicians consider them to
An idiopathic form does exist when no obvious cause or be two eating disorders at the opposite ends of the spectrum
association is identified. SRED is most commonly associated of awareness.
with sleepwalking but can occur with PLMD, restless leg
syndrome, OSA, and circadian rhythm disorders (irregular Treatment
sleep phase). Medication-induced SRED has been reported If SRED is medication associated (zolpidem), the medication
with BZRAs,66,67 including zolpidem and triazolam, and psy- should be withdrawn. Patients may not have the behavior
chotropic medications (lithium). Zolpidem is by far the with another medication in the same class (e.g., switch from
medication most commonly associated with the SRED. zolpidem to eszopiclone). Sometimes, medication-induced
Zolpidem-associated SRED is especially common if patients SRED will continue, at least temporarily, even with discon-
take higher than the recommended dose (e.g., zolpidem tinuation of the offending medication. Topiramate appears
20 mg). Patients also report triggering of episodes by stress, to be the best-documented treatment, although sertraline,
carbidopa/levodopa, and pramipexole have been used
successfully.6872 In one study, the mean dose of topiramate
was 218 mg, although patients may note an improvement at
BOX 2827 a 100-mg dose.70 The side effects of topiramate include
weight loss, paresthesias, renal calculi, cognitive dysfunc-
Causes of Sleep-Related Eating Disorder
tion, and orthostasis. In one series, up to 41% of patients
1. Idiopathicless common than #2 discontinued the medication because of side effects. If SRED
2. Associated with another sleep disorder is associated with sleepwalking, clonazepam has sometimes
a. Sleepwalkingmost common association been effective.
b. Obstructive sleep apnea
c. PLMD, RLS Parasomnia, Unspecified
d. Circadian rhythm sleep disorders (esp. irregular
sleep-wake type) This diagnosis is used on a temporary basis when the para-
3. Associated with medication somnia is believed to be secondary to a psychiatric diagnosis
a. BZRAs: zolpidem, triazolam but before this diagnosis can be made with certainty.
b. Psychotropic medications (lithium, olanzapine,
risperidone) Parasomnia Due to Drug or Substance
c. Anticholinergic medications This category can be used when a temporal association
BZRAs = benzodiazepine receptor agonists; PLMD = periodic limb movement between starting a medication and the onset of a parasomnia
disorder; RLS = restless legs syndrome.
can be documented.
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586 Chapter 28 Parasomnias
TABLE 282
Traditional Characteristics of Sleep-Related Eating Disorder and Nocturnal Eating Syndrome
SLEEP-RELATED EATING DISORDER NOCTURNAL EATING SYNDROME
State of consciousness Partial to full arousal state Fully awake during compulsive eating.
Timing of onset Onset out of sleep period Eating between evening meal and onset of
nocturnal sleep
or
Eating during complete awakenings from sleep.
Food Unusual foods or toxic substances Absence of bizarre or atypical foods.
Preference for high-caloric foods
Foods NOT typically preferred during daytime
(e.g., raw food, cat food, frozen food)
Recall Partial or complete amnesia Complete recall.
State in AM Morning anorexia and abdominal distention Morning anorexia can occur, bulimia can occur.
Associated disorders Associated with sleepwalking Associated with eating and psychiatric disorders.
OSA, PLMS
Gender Female 6080% Female < 60%.
Note that in the ICSD-2 diagnostic criteria, there is no requirement for amnesia or an impaired state of consciousness for diagnosis of the sleep-related eating disorder.
ICSD-2 = International Classification of Sleep Disorders, 2nd ed.; OSA = obstructive sleep apnea; PLMS = periodic limb movement during sleep.
TABLE 283
Differential Diagnosis of Unusual Behavior Associated with Sleep
GROUP DIAGNOSIS USUAL SLEEP STAGE
Normal sleep phenomenon Sleep starts (hypnic jerks) Sleep onset
Apparently normal variants
Nightmares (REM anxiety attacks) REM >> NREM
Hypnogogic foot tremor Wake or arousal from NREM
Alternating leg movement activity Wake or arousal from NREM
Sleep talking (somniloquy) NREM and REM
Sleep-related movement disorders Periodic limb movements in sleep NREM > REM
Bruxism Any sleep stage, N2 most common
Rhythmic movement disorder Stage W, NREM, REM
Parasomnias Confusional arousal NREM
Sleepwalking (somnambulism) NREM
Sleep terrors NREM
REM sleep behavior disorder REM
Recurrent sleep paralysis REM-wake transition
Nightmare disorders REM >> NREM
Overlap parasomnia NREM and REM
Sleep-related dissociative disorder Occurs from established wake
Enuresis NREM and REM
Catathrenia (sleep-related groaning) REM >> NREM
Psychiatric disorders Panic attacks From wake after arousal from NREM
Posttraumatic stress disorder REM and NREM
Seizure disorders Nocturnal seizures NREM > Wake > REM
NREM = nonrapid eye movement; REM = rapid eye movement.
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588 Chapter 28 Parasomnias
TABLE 284
Common Features Associated with Nocturnal Events
NREM PARASOMNIA REM
CONFUSIONAL AROUSALS, BEHAVIOR
SLEEPWALKING, SLEEP TERRORS DISORDER NIGHTMARES SEIZURE
Time of night Childrenearly Late Late > early Any
Adultsearly or late
Sleep stage at start ChildrenStage N3 REM REM NREM > Wake > REM
AdultsStages N2, N3
Screams Yes in sleep terrors Can occur, Rare, talking Rare
No in confusional arousals, talking, yelling more
sleepwalking more common common
Autonomic activation Extreme in sleep terrors Mild Mild Mild
Walking Yessleepwalking Rare No Can occur
Noconfusional arousals, sleep Walking (nocturnal
terrors wandering)
Stereotypical behavior
Confusion after episode Usual No Rare Usual
on awakening
Age Childcommon Adult > 50 yr Any age Adult
Adultless common Male
Episodes also in wake No No No Usual
CNS lesion No Can occur No Common
CNS = central nervous system; NREM = nonrapid eye movement; REM = rapid eye movement.
Paroxysmal arousals typically present during NREM sleep CLINICAL REVIEW QUESTIONS
consisting of a stereotypical series of movements lasting 2 to
20 seconds in which the individuals raise their head, sit up, 1. Which of the following is NOT true about sleepwalking
and look around confused with a frightened expression then in adults?
scream. NPD is characterized by nocturnal coarse move- A. Approximately 60% to 70% have a history of sleep-
ments associated with tonic spasms that often occur multiple walking in childhood.
times per night. The episodes can be violent or be associated B. It can be precipitated by sleep deprivation.
with vocalization. Patients often move the arms and legs with C. Approximately 50% of patients with adult-onset
cycling or kicking movements and sometimes adopt a dys- sleepwalking have psychopathology.
tonic posture of the limbs. ENWs may present with symp- D. It always occurs out of stage N3.
toms similar to sleepwalking and sleep terrors. Patients may
jump out of bed, wander, vocalize, and show violent behavior
2. Which of the following disorders is NOT commonly
during sleep. Treatment with older anticonvulsants such as
associated with RBD?
carbamazepine or newer anticonvulsants such as levetirace-
tam at bedtime is effective. A. Narcolepsy.
Among psychiatric disorders, panic attacks can present B. Parkinsons disease.
as nocturnal spells. Panic attacks occur from wakefulness C. Dementia with Lewy bodies.
after arousal from sleep.20 The individual is alert and D. Alzheimers disease.
the severity builds with intense fear, tachycardia, dyspnea, E. Multiple system atrophy.
chest pain, or flushing. Whereas nocturnal panic attacks
usually occur in patients with known daytime attacks, a
3. Which of the following medications are associated with
few patients may have panic attacks only at night. PTSD
RBD?
patients also may complain of terrifying dreams and may
awaken with episodes similar to sleep terrors.34 They are A. Fluoxetine.
usually not confused on awakening and may have vivid B. Venlafaxine.
dream recall. C. Mirtazapine.
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Chapter 28 Parasomnias 589
D. TCAs. E. A and B.
E. All of the above. F. C and D.
4. Which of the following is true about RBD? 10. Which of the following patterns is NOT considered
A. It typically occurs in the first half of the night. compatible with RBD?
B. Women > men. A. Chin EMGsustained tonic activity during REM
C. It responds to clonazepam in approximately 80% of sleep.
patients. B. Chin EMGTMA (phasic) during REM sleep.
D. It responds to 0.3 to 0.5 mg of melatonin. C. Leg EMGsustained tonic activity.
E. Dream recall is always present. D. Leg EMGTMA (phasic).
E. Chin EMGsustained tonic activity and TMA
5. What characteristic(s) are true about nocturnal panic
during REM sleep.
attacks?
A. They are associated with autonomic hyperactivity, 11. Which of the following describes catathrenia?
tachycardia. A. Deep inspiration, prolonged expiratory groan, slow
B. The patient is alert during a panic attack. breathing rate.
C. The patient has amnesia for the event. B. Long inspiratory groan, slow breathing rate.
D. B and C. C. NREM > REM sleep.
E. A and B. D. Women > men.
E. Patient complains of disturbed sleep.
6. Which of the following factors favor nocturnal epilepsy
over a parasomnia? 12. A child was previously dry until age 8 when he began to
A. Confusion following the event. have frequent nocturnal enuretic episodes. He also was
B. Stereotypical behavior. noted to snore loudly and to have difficulty concentrat-
C. Several episodes per night. ing in classes. Which of the following are true?
D. Amnesia for the event. A. The patient has secondary enuresis.
E. B and C. B. One of his parents likely had enuresis.
F. A and B. C. OSA should be considered.
D. A and B.
7. Which of the following is true concerning the SRED?
E. A and C.
A. Patients are not alert during events.
B. Amnesia for SRED events is always present.
Answers
C. Prevalence of SRED: men > women.
D. Zolpidem is the medication most often associated 1. D. Sleepwalking in adults can occur out of stages N1
with SRED. and N2 as well as N3.
E. Normal foods are eaten.
2. D. Although RBD can occur with patients with
8. Which of the following characterize events associated Alzheimers disease, it is not typical of that disorder.
with the exploding head syndrome?
A. They are painless. 3. E. All of the above.
B. Men > women. 4. C. RBD responds to clonazepam in about 80% of cases,
C. They occur out of NREM sleep. although many patients experience side effects. Melato-
D. They are not associated with fright. nin, often in doses up to 12 mg may also be effective.
RBD is typically a disorder of men older than 50 years
9. In which of the following situations would a diagnosis of age. Because this parasomnia occurs out of REM
of RBD be indicated? sleep, the usual timing is the second part of the night.
A. REM sleep without atonia, history of dream
enactment. 5. E. Unlike NREM parasomnias, during panic attacks,
B. REM without atonia, body movements on video patients are alert and do not have amnesia for the event.
PSG during REM sleep. Panic attacks may occur out of NREM sleep and be
associated with autonomic hyperactivity and intense
C. REM without atonia, no body movements during
fear.
PSG, no history of dream-enacting behavior.
D. No evidence of REM with atonia, violent movements 6. E. Stereotypical behaviors (same manifestations with
out of REM sleep. every episode) and several episodes per night are more
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590 Chapter 28 Parasomnias
common with nocturnal epilepsy. Confusion after the 6. Schenck CH, Milner DM, Hurwitz TD, et al: A polysomno-
event and amnesia can occur with both NREM para- graphic and clinical report of sleep related injury in 100 adult
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7. Crisp AH: The sleepwalking/night terrors syndrome in adults.
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with SRED. Alertness during event and recall of the NREM parasomnias in adults: clinical and forensic implica-
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Chapter 29
MOOD EPISODES
WITH MINIMUM TIME
CRITERIA (DSM-IV) MOOD DISORDERS
Bipolar 2 disorder
FIGURE 291 Schematic of episodes (showing minimum durations) and examples of mood disorders (elevations about and below
baseline represent elevated or depressed mood). Adapted from Priviter MR, Lness JM: Psychiatry Mentor, 2nd ed. Philadelphia: FA Davis,
2008, p. 121.
TABLE 292 tends to increase REM sleep.38 It can cause severe hepatotox-
Factors to Consider in Choosing an Antidepressant icity and is rarely used today. Mirtazapine also has been
reported to be associated with no or only mild reduction in
Previous medication history
Use a medication with a previous good response (unless the amount of REM sleep. The monoamine oxidase inhibi-
side effects) tors (MAOIs) are less commonly used but are the most
Avoid a medication if previous negative response or powerful suppressors of REM sleep. In general, sedating
negative response to two or more in subclass antidepressants have a beneficial effect on sleep efficiency
Choose best fit for depression subtype whereas nonsedating antidepressants tend to decrease sleep
Ability to treat co-morbid psychiatric or medical disorder efficiency. Of note, if patients respond to an antidepres-
Patient preference sant, their subjective estimate of their sleep quality may
Side effect profile improve even if objective sleep quality by PSG does not.
Cost issues A study comparing fluoxetine and nefazodone showed sub-
jective improvements in sleep quality with both medications
blocks histamine, central alpha 2 receptors, and 5HT2 and but only patients on the sedating nefazodone had objective
5HT3 serotonin receptors. In low doses (7.515 mg), mir- improvements in sleep.38
tazapine is more sedating compared with higher doses. The
typical effective antidepressant dose is 30 to 45 mg. Mir- Pharmacotherapy for Co-morbid Insomnia of Psychiatric
tazapine, like bupropion, is less likely to cause sexual side Disorders Patients with an MDD frequently have prominent
effects but can cause significant weight gain. Mirtazapine co-morbid insomnia. In such patients, one might choose to
may help patients with anxiety. Blockade of 5HT2 receptors use (1) a sedating antidepressant at antidepressant doses
may improve sleep quality. (e.g., mirtazapine 3045 mg qhs), (2) the combination of an
An approach for choosing an antidepressant for treatment effective nonsedating antidepressant (at antidepressant
of depression is listed in Table 292. If the patient has promi- doses) and a sedating antidepressant at low doses, (3) the
nent melancholic or atypical features, one might consider combination of an effective nonsedating antidepressant and
different medications. If the patient does not respond to an a benzodiazepine receptor agonist [BZRA] hypnotic), or (4)
effective dose of the initial medication, either trial of another the combination of an antidepressant and a sedating atypical
medication or the addition of another agent (augmentation) antipsychotic (quetiapine). Sedating antidepressants and
could be considered. Note that the serotonin syndrome antipsychotics commonly used for their hypnotic effect are
(agitation, tachycardia, hyperthermia) can rarely occur when listed in Table 294. For information on BZRA hypnotics,
two medications blocking serotonin re-uptake are used see Chapter 25.
together. The syndrome is most common with use of an SSRI Several sedating antidepressants are used in lower than
+ MAOI (contraindicated). Do not start an SSRI until a antidepressant doses for their sedating properties. Doxepin
MAOI has been stopped for 21 days. Do not start a MAOI is a sedating antidepressant but has anticholinergic side
unless an SSRI has been stopped for up to five weeks (depend- effects. It has been used in low doses (25 mg) as a hypnotic.
ing on SSRI half-life). It has recently been approved by the FDA for sleep mainte-
A detailed discussion of the use of second-generation nance in very low doses (3, 6 mg Silenor). Silenor is much
antipsychotics (SGAs)3436 (e.g., quetiapine, aripiprazole) or more expensive than generic doxepin. Trazodone is used in
alerting agents (modafinil)37 for augmentation of treatment low doses (50 mg) as a hypnotic but rarely in higher doses
of depression is beyond the scope of this chapter. However, as an antidepressant. Trazodone can be used in combination
the reader should be aware that such medications are being with an SSRI to reduce antidepressant-associated insomnia.39
used for this purpose. Aripiprazole (Abilify) is FDA approved Trazodone can rarely cause priapism but has minimal anti-
for adjunctive therapy of major depression. This medication cholinergic side effects compared with sedating TCAs.
tends to cause less metabolic side effects (weight gain) than Because of the lack of anticholinergic side effects and avail-
other SGAs. Quetiapine (Seroquel) is approved as both an ability of generic medication, trazodone is widely used as a
adjunctive and a single agent treatment for depression.35,36 hypnotic. As discussed in Chapter 25, the evidence for its
hypnotic efficacy in patients who are not depressed is limited.
Effects of Antidepressants on Sleep A discussion of the effects The utility of using the combination of an antidepressant
of antidepressants on sleep (Table 293) is complicated by and a BZRA has recently been studied using placebo-
the fact that the results can vary depending on whether controlled trials. Fava and coworkers40 studied a group of
normal or depressed individuals are studied. The acute and patients with both MDD and insomnia. The combination of
chronic effects may also vary.27,28 The literature is somewhat FLX and placebo was compared with FLX + 3 mg of eszopi-
conflicting on the effects of a few medications. In general, clone. Co-administration of eszopiclone resulted in improved
antidepressants increase the REM latency and decrease the subjective sleep latency, wake after sleep onset (WASO), and
amount of REM sleep. Bupropion is one of the few medica- total sleep time compared with FLX alone. Although this
tions that can actually increase the amount of REM sleep, result was not unexpected, a surprising finding was that
although it increases the REM latency (at least in depressed there was also greater improvement in depression at 8 weeks
patients). Nefazodone is a sedating antidepressant that also with the combination of FLX and eszopiclone (Fig. 292). A
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Chapter 29 Psychiatry and Sleep 601
TABLE 293
Effects of Antidepressants on Sleep
CONTINUITY STAGE N3 REM REM LATENCY SEDATION
TCAs
Amitriptyline ++++
Doxepin ++++
Imipramine ++
Nortriptyline ++
Desipramine +
Clomipramine
MAOIs
Phenelzine
SSRIs
Fluoxetine
Paroxetine +
Sertraline +
Citalopram +
Escitalopram +
SNRIs
Venlafaxine ++
Desvenlafaxine Same
Duloxetine Same
ATYPICAL
Bupropion
Trazodone ++++
Mirtazapine 3+ (low doses)
Up arrows = increased; down arrows = decreased; horizontal arrows = no or minimal change; plus signs (14) = increasing amount of sedation; MAOIs = monoamine
oxidase inhibitors; REM = rapid eye movement; SNRIs = selective norepinephrine reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic
antidepressants.
42
P = .14
40 36 40
33
30
30 30 P = .29
22
20 20 19
10 10
0 0
Week 4 Week 8 Week 4 Week 8
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602 Chapter 29 Psychiatry and Sleep
TABLE 294
Antidepressants and Atypical Antipsychotics Used for Sleep
NAME GENERIC DOSE HYPNOTIC
(BRAND NAME) FORMS DOSE COMMENTS NOTABLE SIDE EFFECTS
Trazodone 50, 100 mg 25100 mg qhs Less anticholinergic side Priapism (1/8000 males)
effects than TCAs Postural hypotension
T 9 (314) hr
Mirtazapine 15, 30 mg 7.515 mg qhs T 2040 hr Weight gain
(Remeron) Higher doses possibly less sedating
TCAs
Amitryptyline 10, 25, 50 mg 1025 mg qhs T 1026 hr metabolite Dry mouth, constipation
(Elavil) active (nortriptyline) QT prolongation
Doxepin 10, 25, 50 110 mg (elixir) T 68 hr Dry mouth, constipation
(Sinequan) 10 mg/mL 25 mg qhs
Doxepin 3, 6 mg 6 mg qhs T 68 hr FDA approved for sleep-maintenance
(Silenor) 3 mg qhs elderly insomnia
Cimetidine increases drug levelsmax dose
of doxepin should not exceed 3 mg
Sertraline can also increase levels of doxepin
SEDATING ANTIPSYCHOTIC MEDICATIONS
Quetiapine 25, 50, 100 12.550 mg qhs T 6 hr Headache, dizziness
(Seroquel) Intermediate acting Neuroleptic syndrome
Tardive dyskinesia
Long QT
Lens change
FDA = U.S. Food and Drug Administration; TCAs = tricyclic antidepressants.
similar trial with zolpidem found improvement in sleep but BOX 2912
no evidence of greater improvement in depression.41 Dysthmic Disorder
In patients with a history of past or current alcohol or
A. Depressed mood for most of the day, for more days than
benzodiazepine dependence, the use of BZRAs is prob-
not, as indicated either by subjective account or
lematic. For these patients, use of ramelteon (a melatonin observation by others, for at least 2 years.
receptor agonist with no abuse potential) or a sedating anti- B. Presence while depressed of two or more of the
depressant may be the best treatment option. Ramelteon is following:
approved only for sleep-onset insomnia and is not useful to i. Poor appetite or overeating.
improve sleep maintenance. It should NOT be used with the ii. Insomnia or hypersomnia.
SSRI luvoxamine, which causes increased melatonin levels. iii. Low energy or fatigue.
Quetiapine (Seroquel) is an SGA medication that antago- iv. Low self-esteem.
nizes histamine, dopamine D2, and serotonin 5HT2 recep- v. Poor concentration or difficulty making decision.
tors. At low doses, the medications main effect is as an vi. Feelings of hopelessness.
antihistamine. Therefore, it can be used in low doses as a C. During the 2-year period of the disturbance, the person
hypnotic. Quetiapine is indicated for treatment of schizo- has never been without the symptoms in criterion A or
phrenia and bipolar disorder. As noted previously, quetiap- B for more than 2 months at a time.
ine has been used as a second medication (augmentation) in D. No major depressive episodes have been present the
treatment-resistant depression35 or as a single antidepressant first 2 years of the disturbance.
medication.36 Side effects of quetiapine include QT prolonga- E. There has never been a manic episode, mixed episode,
tion, weight gain, extrapyramidal symptoms, headache, lens or hypomanic episode and criteria have never been
changes/cataracts, and decreased white blood cell count. met for cyclothymic disorder.
Even at low doses, quetiapine has been associated with sig- Adapted from American Psychiatric Association: Diagnostic and Statistical
nificant weight gain. Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
Dysthymic Disorder
Dysthymic disorder (Box 2912) is manifested by a
depressed mood for most of the day, for more days than
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Chapter 29 Psychiatry and Sleep 603
not for at least 2 years. During depressed mood and two or hypomania is one of degree of severity. Patients with mania
more of the following are present2: are severely impaired and are often hospitalized. Their
actions often cause financial or physical harm to themselves
1. Poor appetite or overeating. or others.
2. Insomnia or hypersomnia.
3. Low energy or fatigue. In summary:
4. Low self-esteem. 1. BP-I diagnosis requires:
5. Poor concentration or difficulty making decisions. A. A current (or recent) hypomanic episode, ME, mixed
6. Feelings of hopelessness. episode, or MDE.
B. If the current episode is hypomanic or an MDE, there
The diagnosis of dysthymic disorder is NOT made if must be history of a prior mixed episode or ME.
there has been an MDE during the 2-year period qualifying Note that, unlike diagnostic criteria for BP-II, the pres-
for dysthymic disorder. In addition, an ME, a hypomanic ence of at least one MDE is not required.
episode, or a mixed episode cannot have occurred 2. BP-II diagnosis requires at least one hypomanic episode,
previously. one or more depressive episodes, and no history of current
(or prior) MEs or mixed episodes.
Cyclothymic Disorder The diagnostic criteria for cyclothymic
disorder (Box 2913) require that the patient have numerous Bipolar Depression
periods of both hypomania and depressive symptoms for 2 The depression of BP disorders is problematic for several
years that do not meet criteria for MDEs.2 The periods of reasons. First, treatment of depression in BP-I patients can
depressive or hypomanic symptoms can disturb sleep. send the patient into mania unless they are on a mood sta-
bilizer. Second, there is a great risk of suicide during the
depressive phasea lifetime risk of suicide attempts up to
Bipolar Disorders
25%! Third, only a few medications are actually FDA
The bipolar disorders include bipolar I (BP-I) and bipolar II approved for bipolar depression. Some bipolar patients
(BP-II)2 (Box 2914). The major difference between these present with complaints of depression and may be misdiag-
disorders is that the up period in BP-II is hypomania and nosed as MDD (unipolar depression) rather than bipolar
the patient has never had an ME or mixed episode. A BP-I depression. It is important to question patients carefully
patient can have hypomania or most recently be depressed about prior symptoms consistent with mania or hypomania.
BUT the diagnosis of BP-I requires a current or previous There are no pathognomonic characteristics of BP-I depres-
mixed episode or ME. The difference between mania and sion compared with unipolar depression. Table 295 present
characteristics that are more probable in each category.42
BOX 2913
Sleep in Bipolar Disorder
Diagnostic Criteria for Cyclothymic Disorder In BP-I, there is usually severe insomnia and a reduced need
A. For at least 2 years, the presence of numerous periods for sleep during MEs or hypomanic episodes. BP-II patients
with hypomanic symptoms and numerous periods of
depressive symptoms that do not meet criteria for major
depressive episodes. For children and adolescents, the BOX 2914
duration must be at least 1 year. Bipolar Disorders
B. During the above 2-year period, the person has not
been without the symptoms of criterion A for more than BIPOLAR I DISORDER (AT LEAST ONE MANIC OR
2 months at a time. MIXED EPISODE)
C. No major depressive episode, manic episode, or mixed A. Currently (or recently) hypomanic, manic, mixed, or
episode has been present during the first 2 years of the major depressive episode.
disturbance. B. If current episode is hypomanic or major depressive
D. The symptoms in criterion A are not better accounted episode, there has previously been at least one manic or
for by schizoaffective disorder and are not mixed episode.
superimposed on schizophreniform disorder, delusional
BIPOLAR II DISORDER (AT LEAST ONE HYPOMANIC
disorder, or psychotic disorder not otherwise classified.
EPISODE, NO MANIC, NO MIXED)
E. Symptoms are not due to physical effects of a substance
or a general medical condition. A. Presence (or history) of one or more major depressive
F. The symptoms cause clinical significant disorder or episodes.
impairment in social, occupation, or other important B. Presence (or history) of at least one hypomanic episode.
areas. C. There has never been a manic or mixed episode.
Adapted from American Psychiatric Association: Diagnostic and Statistical Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000. Association, 2000.
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604 Chapter 29 Psychiatry and Sleep
TABLE 296
U.S. Food and Drug AdministrationApproved Medications for Bipolar Disorder
GENERIC TRADE MANIA MIXED MAINTENANCE DEPRESSION
Valproic acid/valproate Depakote X X NFA NFA
Carbamazepam ER Equetro X X
Lamotrigine Lamictal X (BP-I) NFA
Lithium X X X NFA
Aripiprazole Abilify X X X
Ziprasidone Geodon X X X
Risperidone Risperdal X X
Quetiapine XR Seroquel X X X* X (BP-I and BP-II)
Olanzapine Zyprexia X X X
Olanzapine + fluoxetine Symbyax X (BP-I)
*Approved for maintenance as adjunctive treatment with lithium or divalproex.
Approved for combination with lithium or valproic acid.
BP-I, BP-II = bipolar I and II; FDA = U.S. Food and Drug Administration; NFA = not FDA approved for this indication but often used.
(2030 mg/kg/day on a tid schedule). In less urgent cases, ziprasidone (Geodone) are the only antipsychotic medica-
the medication is started at 250 mg with a meal on day 1, tions currently approved for maintenance. Aripiprazole is a
then increased to 250 mg tid for 3 to 6 days. Mania typically partial dopamine D2 agonist and serotonin 5HT1A agonist
begins improving 1 to 4 days after drug levels exceed 50 g/ as well as an antagonist at 5HT2A receptors. Ziprasidone
mL. Side effects of divalproex include nausea, vomiting, dys- antagonizes dopamine D2 receptors and serotonin 5HT2
pepsia, and diarrhea. When titrated up rapidly, divalproex receptors. Of note, even with maintenance treatment relapse
can also cause sedation. Rare but very severe side effects of mania or depression may occur in up to 30 to 40% of
include hepatoxicity, leukopenia, thrombocytopenia, and BP-I patients in the first year and up to 75% over five years.
pancreatitis. Drug levels can be obtained before the morning
dose with a therapeutic range of 50 to 125 g/mL (com- Bipolar Depression Treatment of bipolar depression is often
monly felt > 75 needed for mania). Both lithium and dival- challenging.47 Few medications are actually FDA approved
proex have been associated with an increased risk of birth for treatment of bipolar depression. Quetiapine XR or a com-
defects. Of note, lithium increases stage N3 sleep and bination of olanzapine and FLX (Symbyax) are the only
decreases REM sleep. medications FDA approved for bipolar depression. One
problem with the olanzapine/FLX combination is that FLX
Mixed Episode The treatment of a mixed episode is similar to has a very long half-life. If mania occurs, the residual effects
the treatment of mania. can be problematic.
Studies have NOT documented an advantage of the
Maintenance Treatment The goal of maintenance treatment is addition of a standard antidepressant to a mood stabilizer
to prevent relapse of mania and depressive episodes. The in treatment of bipolar depression.48 The addition of an
cumulative rate of relapse after an episode of mania in the antidepressant can worsen anxiety, increase mood insta-
absence of maintenance treatment is 50% at 12 months bility, or trigger a switch to mania. However, individual
and nearly 90% at 60 months. Lithium and lamotrigene are patients may benefit from the long-term combination of a
the two mood stabilizers that are FDA approved for mainte- mood stabilizer and an antidepressant. If an antidepressant
nance treatment. Divalproex is not FDA approved for main- is used, the activating ones like venlafaxine or duloxetine are
tenance treatment but is also widely used for this application. more likely to cause switches (mania). Bupropion or a non-
Lithium has the advantage of also preventing bipolar depres- fluoxetine SSRI are used by many clinicians.
sion and reducing suicide risk. It appears to have an advan- Although not FDA approved for bipolar depression, most
tage over divalproex in these respects. Lamotrigine (Lamictal) treatment algorithms (Fig. 293) use a mood stabilizer
may be used as a mood stabilizer for maintenance. Lamotrig- (lithium or divalproex) as the initial step. Lithium is gener-
ine also has antidepressant effects and, therefore, is useful for ally more effective for bipolar depression than divalproex.
maintenance. This medication requires a slow upward titra- Many clinicians would next add lamotrigine, which has anti-
tion (over 6 wk) to avoid a significant skin rash. It can be depressant activity. If this was not successful, quetiapine or
associated with the Stevens-Johnson syndrome. Lamotrigine the olanzapine/FLX combination could be added. If this does
is NOT approved for acute mania. Aripiprazole (Abilify) and not work, antidepressants are then often added.
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606 Chapter 29 Psychiatry and Sleep
Response
CONT
Partial response
or nonresponse
Response
CONT
Partial response
or nonresponse
Response
CONT
Partial response
or nonresponse
FIGURE 293 The first three stages of a five-stage algorithm for treatment of bipolar depression (Bipolar Disorder ICurrently Depressed). Stage 1 consists
of an antimanic medication (lithium or divalproex) and lamotrigine. Stage 2 consists of either quetiapine or the olanzapine + fluoxetine combination used
alone. *There is overlap with the medications in Stage 1. The stage 1 medications are gradually withdrawn. QTP or OFC used alone after taper of stage 1
medications (if taper possible). Stage 3 means a combination of a medication used in stage 2 and one or more medications used in stage 1. For example:
Lithium + lamotrigine + quetiapine. From Texas Implementation of Medication Algorithm for Bipolar Disorders. Austin: Texas Department of State Health
Services, 2005.
could be having a panic attack and not being able to escape Sleep and Panic Disorder A nocturnal panic attack is in the
and being embarrassed. Agoraphobia without panic attack is differential diagnosis of parasomnias including night terrors.
a separate disorder. Patients with this disorder have agora- The majority of patients with panic disorder have at least
phobia, but it is not tied to apprehension about a panic attack one nocturnal panic attack. About one third of patients with
but to apprehension about being in a strange place or being panic disorder have recurrent nocturnal panic attacks. Of
out in the open or near crowds (social anxiety) (Boxes 2917 those panic disorder patients with nocturnal panic attacks,
and 2918). up to two thirds report insomnia often associated with fear
of returning to sleep.49 The symptom of dyspnea appears to
be more common in nocturnal panic attacks. The attacks
BOX 2916 occur from nonrapid eye movement (NREM) sleep, com-
Criteria for Panic Attack monly at the transition from stage N2 to stage N3 sleep. In
most patients, sleep architecture is normal (normal REM
A. A discrete period of intense fear or discomfort in which
latency and sleep efficiency). However, some patients may
four (or more) of the following symptoms developed
develop sleep phobiaand this can be associated with find-
abruptly and reached a peak within 10 minutes:
ings consistent with insomnia (Box 2919).
i. Palpitation, pounding heart, or accelerated heart
rate
Differential Diagnosis of Panic Attack The differential diagnosis
ii. Sweating
iii. Trembling or shaking of panic attacks includes night terrors, nightmares, posttrau-
iv. Sensation of shortness of breath or smothering matic stress disorder (PTSD), and REM behavior disorder.
v. Feeling of choking
vi. Chest pain or distress
vii. Nausea or abdominal discomfort
BOX 2918
viii. Feeling dizzy, unsteady, lightheaded, or faint
ix. Derealization (feelings of unreality) or Sleep and Panic Disorder
depersonalization (being detached from oneself ) Most patients with nocturnal panic attacks also have
x. Fear of losing control or going crazy daytime panic attacks.
xi. Fear of dying Majority of patients with panic disorder have at least one
xii. Paresthesias (numbness of tingling sensation) nocturnal panic attack.
xiii. Chills or hot flashes One third or more of patients have recurrent nocturnal
Adapted from American Psychiatric Association: Diagnostic and Statistical panic attacks.
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Usually during NREM sleep at transition to stage N3.
Association, 2000.
Two thirds of patients with panic disorder report
sleep-onset and sleep-maintenance insomnia (fear of
returning to sleep).
BOX 2917 In contrast to a NREM parasomnia, the patient is awake.
Criteria for Diagnosis of Panic Disorder In contrast to nightmares, there is no dream recall.
If SSRIs are started, they should be started at low doses to
A. Both (i) and (ii) are present avoid exacerbation of nocturnal panic.
i. Recurrent unexpected panic attacks. NREM = nonrapid eye movement; SSRIs = selective serotonin reuptake
ii. At least one of the attacks has been followed by 1 inhibitors.
month (or more) of the following:
a. Persistent concern about having additional attacks.
b. Worry about the implications of the attack or its
consequences (e.g., losing control, having a heart BOX 2919
attack, going crazy). Differential Diagnosis of Nocturnal Panic Attacks
c. A significant change in behavior related to the
1. Medical disorder (hyperthyroidism, pheochromocytoma)
attacks.
2. Paroxysmal nocturnal dyspnea (CHF)
B. The panic attacks are not due to the direct physiologic
effects of a substance (e.g., a drug of abuse, medication) 3. Arousal from OSA
or a general medical condition (e.g., hyperthyroidism). 4. Arousal for GERD
C. The panic attacks are not better accounted for by 5. Nocturnal laryngospasm
another mental disorder (e.g., social phobia, specific 6. NREM parasomnianight terrors
phobias, obsessive-compulsive disorder, PSTD, or 7. PTSD
separation anxiety disorder). 8. RBD
PTSD = posttraumatic stress disorder. CHF = congestive heart failure; GERD = gastroesophageal reflux disease;
Adapted from American Psychiatric Association: Diagnostic and Statistical NREM = nonrapid eye movement; OSA = obstructive sleep apnea;
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric PTSD = posttraumatic stress disorder; RBD = rapid eye movement sleep
Association, 2000. behavior disorder.
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608 Chapter 29 Psychiatry and Sleep
Night terrors usually begin in childhood and during the BOX 2920
episodes the individual is not well aware of his or her sur- Generalized Affective Disorder
roundings and does not remember the episodes in the Diagnostic Criteria
morning. In panic attacks, the patient is awake and aware of
his or her surroundings. In nightmares, the patient usually A. Excessive anxiety and worry (apprehensive expectation),
occurring more days than not for at least 6 months,
is aware of a frightening dream. In contrast, patients with
about a number of events or activities (such as work or
panic attacks remember the episode, but typically do not
school performance).
report a terrifying dream. In nocturnal laryngospasm, the
B. The person finds it difficult to control the worry.
patient wakes up choking with near-total cessation for
C. The anxiety and worry are associated with three (or
airflow from 5 to 43 seconds with stridor. more) of the following six symptoms (with at least one
symptom present for more days than not for the past 6
Treatment of Panic Disorder The treatment of panic attacks months):
includes behavioral psychotherapy or relaxation techniques i. Restlessness or feeling keyed up or on edge.
and pharmacotherapy.49,50 Although benzodiazepines (e.g., ii. Being easily fatigued.
alprazolam, clonazepam) were the classic treatments for iii. Difficulty concentrating or mind going blank.
panic disorder, the long-term treatment of the panic disorder iv. Irritability.
is an antidepressant. Both SSRIs (e.g., paroxetine, sertraline) v. Muscle tension.
and TCAs (e.g., imipramine) must be started at very low vi. Sleep disturbance (difficulty falling or staying asleep
doses or the panic attack initially may be exacerbated. For or restless unsatisfying sleep).
example, paroxetine is started at 10 mg daily or imipramine D. The focus of anxiety and worry is NOT confined to
at 10 to 25 mg daily. The doses are slowly increased to 20 to features of an axis I disorder (i.e., another major
40 mg for paroxetine or 100 to 200 mg for imipramine, as psychiatric disorder: e.g., worry about having a panic
tolerated. Because improvements may take 4 to 6 weeks or attack, being embarrassed in public with social phobia,
longer, many physicians add benzodiazepines during the being contaminated in obsessive compulsive disorder).
early course of therapy. Alprazolam (Xanax) has a short half- Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
life and many psychiatrists prefer to use clonazepam, which Association, 2000.
has a long duration of action. This is especially true for
patients requiring antianxiety treatment during the day.
Unfortunately, clonazepam (long duration of action) can be
quite sedating in some patients. Alprazolam is available in
an extended action preparation (Xanax XR), which prevents the addition of zolpidem had improved insomnia (subjective
the need for repeated dosing. total sleep time) and next day symptoms (but not anxiety
symptoms). Note that zolpidem is a BZRA hypnotic without
antianxiety activity. Medications such as clonazepam and
Generalized Anxiety Disorder
lorazepam could be used for sleep in GAD patients for both
Generalized anxiety disorder (GAD) is characterized by their hypnotic and their antianxiety effects. Alprazolam is
excessive anxiety and worry (apprehensive expectation), another alternative, although it may have less hypnotic activ-
occurring more days than not for a period of at least 6 ity because it tends to be less sedating. Note that clonazepam,
months, about a number of events or activities (Box 2920). lorazepam, and alprazolam are not FDA approved for use as
The individual finds it difficult to control the worry. The hypnotics.
anxiety and worry are with three (or more) of the following
six symptoms (with at least one symptom present for more Differential Diagnosis of Sleep Problems with GAD In psychophys-
days than not for the past 6 mo)2,51: (1) restlessness or feeling iologic insomnia, patients are anxious about their sleep but
keyed up or on edge, (2) being easily fatigued, (3) difficulty not to the degree as in GAD, and in psychophysiologic
concentrating or mind going blank, (4) irritability, (5) muscle insomnia, the anxiety is focused on sleep. Other anxiety
tension, or (6) sleep disturbance (difficulty falling or staying disorders such as phobia, or anxiety about medical condi-
asleep or restless unsatisfying sleep). tions, or substance use anxiety should be considered.
BOX 2921
Posttraumatic Stress DisorderDiagnostic Criteria
A. The person has been exposed to a traumatic event in v. Physiologic reactivity on exposure to internal or
which both of the following were present: external cues that symbolize or resemble an aspect of
i. The person experienced, witnessed, or was confronted the traumatic event.
with an event or events that involved actual or C. Persistent avoidance of stimuli associated with the trauma
threatened death or serious injury, or a threat to the and numbing of general responsiveness (not present
physical integrity of self or others. before the trauma), as indicated by three (or more) of the
ii. The persons response involved intense fear, following:
helplessness, or horror. i. Efforts to avoid thoughts, feelings, or conversation
Note: In children, this may be expressed instead by associated with the trauma.
disorganized or agitated behavior. ii. Efforts to avoid activities, places, or people that arouse
B. The traumatic event is persistently re-experienced in one recollection of the trauma.
(or more) of the following ways: iii. Inability to recall important aspects of the trauma.
i. Recurrent and intrusive distressing recollections iv. Markedly diminished interest or participation in
of the event, including images, thoughts, or significant activities.
perceptions. v. Feeling of detachment or estrangement from others.
Note: In young children, repetitive play may occur in vi. Restrict range of affect (e.g., inability to have loving
which themes or aspects of the trauma are expressed. feelings).
ii. Recurrent distressing dreams of the event. vii. Sense of foreshortened future (e.g., does not expect to
Note: In children, there may be frightening dreams have a career, marriage, children, or a normal lifespan).
without recognizable content. D. Persistent symptoms of increased arousal (not present
iii. Acting or feeling as if the traumatic event were before the trauma) as indicated by two or more of the
recurring (includes a sense of reliving the experience, following:
illusions, hallucinations, and dissociative flashback i. Difficulty falling or staying asleep.
episodes, including those that occur on awakening or ii. Irritability or outbursts of anger.
when intoxicated).
iii. Difficulty concentrating.
Note: In young children, trauma-specific reenactment
iv. Hypervigilance.
may occur.
v. Excessive startle response.
iv. Intense psychological distress at exposure to internal
E. Duration of the disturbance (symptoms in criteria B, C,
or external cues that symbolize or resemble an aspect
and D) is more than 1 month.
of the traumatic event.
Adapted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 2000.
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610 Chapter 29 Psychiatry and Sleep
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32. Gursky JT, Krahn LE: The effects of antidepressants on sleep: 48. Sachs GS, Nierenberg AA, Calabrese JR, et al: Effectiveness of
a review. Harvard Rev Psychiatry 2000;8:298306. adjunctive antidepressant treatment for bipolar depression.
33. Dubovsky SL, Dubovsky AN: Psychopharmacology for neu- N Engl J Med 2007;356:17111722.
rologists. Semin Neurol 2009;29:200219. 49. Mellman TA, Ude TW: Patients with frequent sleep panic:
34. Chen J, Gao K, Kemp DE: Second-generation antipsychotics in clinical findings and response to medication treatment. J Clin
major depressive disorder: update and clinical perspective. Psychiatry 1990;51:513516.
Curr Opin Psychiatry 2011;24:1017. 50. Moroze G, Rosenbaum JF: Efficacy, safety, and gradual discon-
35. Anderson IM, Sarsfield A, Haddad PM: Efficacy, safety and tinuation of clonazepam in panic disorder: a placebo-controlled,
tolerability of quetiapine augmentation in treatment resistant multicenter study using optimized doses. J Clin Psychiatry
depression: an open-label, pilot study. J Affect Disord 2009; 1999;60:604612.
117:116119. 51. Fricchione G: Generalized anxiety disorders. N Engl J Med
36. Bortnick B, El-Khalili N, Banov M, et al: Efficacy and tolerabi- 2004;351:675682.
lity of extended release quetiapine fumarate (quetiapine 52. Fava M, Asnis GM, Shrivastava R, et al: Zolpidem extended-
XR) monotherapy in major depressive disorder: a placebo- release improves sleep and next-day symptoms in comorbid
controlled, randomized study. J Affect Disord 2011;128: insomnia and generalized anxiety disorder. J Clin Psychophar-
8394. macol 2009;29:222230.
37. Abolfazli R, Hosseini M, Ghanizadeh A, et al: Double-blind 53. Stein DJ: Algorithms for primary care: an evidence-based
randomized parallel-group clinical trial of efficacy of the com- approach to the pharmacotherapy of depression and anxiety
bination fluoxetine plus modafinil versus fluoxetine plus disorders. Prim Psychiatry 2004;11:5578.
placebo in the treatment of major depression. Depress Anxiety 54. Ross RJ, Ball WA, Dinges DR, et al: Rapid eye movement sleep
2011;28:297302. disturbance in posttraumatic stress disorder. Biol Psychiatry
38. Gillin JC, Rapaport M, Erman MK, et al: A comparison of 1994;35:195202.
nefazodone and fluoxetine on mood and on objective, subjec- 55. Mellman TA, Nolan B, Hedding J, et al: A polysomnographic
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J Clin Psychiatry 1997;58:186192. men, and non-ill controls. Sleep 1997;20:4651.
39. Nierenberg AA, Adler LA, Peselow E, et al: Trazodone for 56. Brown TM, Boudewyns PA: Periodic limb movements of sleep
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40. Fava M, McCall V, Krystal A, et al: Eszopiclone co-administered 57. Davis LL, English BA, Ambrose SM, et al: Pharmacotherapy for
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41. Fava M, Asnis GM, Shrivastava RK, et al: Improved insomnia 58. Davidson JR, Rothbaum BO, van der Kolk BA, et al: Multi-
symptoms and sleep-related next-day functioning in patients center, double-blind comparison of sertraline and placebo in
with comorbid major depressive disorder and insomnia follow- the treatment of posttraumatic stress disorder. Arch Gen Psy-
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talopram treatment: a randomized controlled trial. J Clin 59. Kim Y, Asukai N, Konishi T, et al: Clinical evaluation of par-
Psychiatry Epub ahead of print 2010;December 28. oxetine in post-traumatic stress disorder (PTSD): 52-week,
42. Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RMA: non-comparative open-label study for clinical use experience.
Diagnostic guidelines for bipolar depression: a probabilistic Psychiatry Clin Neurosci 2008;62:646652.
approach. Bipolar Disord 2008;10:144152. 60. Robert S, Hamner MB, Ulmer HG, et al: Open-label trial of
43. McGuffin P, Rijsdijk F, Andrew M, et al: The heritability of escitalopram in the treatment of posttraumatic stress disorder.
bipolar affective disorder and the genetic relationship to uni- J Clin Psychiatry 2006;67:15221526.
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44. Suppes T, Dennehy EB, Hirschfeld RM, et al, Texas Consensus therapy for chronic nightmares in sexual assault survivors with
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der: The Texas implementation of medication algorithms: 62. Raskind MA, Peskind ER, Hoff DJ, et al: A parallel group
update to the algorithms for treatment of bipolar I disorder. placebo-controlled study of prazosin for trauma nightmares
J Clin Psychiatry 2005;66:870886. and sleep disturbance in combat veterans with post-traumatic
45. Fountoulakis KN: An update of evidence-based treatment of stress disorder. Biol Psychiatry 2007;61:928934.
bipolar depression: where do we stand? Curr Opin Psychiatry 63. Taylor FB, Martin P, Thompson C, et al: Prazosin effects on
2010;23:1924. objective sleep measures and clinical symptoms in civilian
46. Hilty DM, Leamon MH, Lim RF, et al: Diagnosis and treatment trauma PTSD: a placebo-controlled study. Biol Psychiatry
of bipolar disorder in the primary care setting: a concise review. 2008;63:629632.
Prim Psychiatry 2006;13:7785. 64. Berlant JL: Prospective open-label study of add-on and mono-
47. Nivoli AM, Colom F, Murru A, et al: New treatment guidelines therapy topiramate in civilians with chronic nonhallucinatory
for acute bipolar depression: a systematic review. J Affect posttraumatic stress disorder. BMC Psychiatry 2004;4:24.
Disord 2011;129:1426; Epub 2010;June 8.
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Appendix 29-1
PHQ-9 is adapted from PrimeMD today, developed by Dr. RL Spitzer, JBW Williams, K Kroenke, and colleagues, with an education grant from Pfizer,
Inc. Use of the PHQ-9 may only be made in accordance with the terms of use available at http://www.pfizer.com
Copyright 1999 Pfizer, Inc.
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Chapter 30
hormone (g/L)
Plasma growth
wakefulness (nocturnal hours: white bar), and 8 hours of
daytime sleep (light blue bar). Subjects were young healthy
10
men. The shaded area corresponds to normal 24-hour
conditions. The vertical bar at each time point represents the
standard error of the mean (SEM). The temporal organization 5
of GH secretion is mainly regulated by the homeostatic
control of sleep such that shifted sleep is associated with a 0
18 22 02 06 10 14 18 22 02 06 10 14 18 22
shift in the secretion of GH. Adapted from Van Cauter E,
Spiegel K: Circadian and sleep control of hormones. In Turek FW, Nocturnal sleep
Zee PC (eds): Regulation of Sleep and Circadian Rhythms. New Nocturnal sleep deprivation
York: Marcel Dekker, 1999, p. 399, with permission. Daytime sleep
MEN WOMEN
14 14
12 12
Plasma GH (g/L)
Plasma GH (g/L)
10 10
8 8
6 6
4 4
2 2
0 0
11 15 19 23 03 07 11 11 15 19 23 03 07 11
FIGURE 302 Growth hormone (GH) secretion in a group of young men (left) and women (right). The plots are mean values. The dark blue bar is the sleep
period. Men have most of their GH secretion during sleep, but in women, bursts during the day are more common. From Van Cauter E, Plat L, Copinschi G:
Interrelations between sleep and the somatotropic axis. Sleep 1998;21:553566.
160 800
120 600
80 400
40 200
0 0
10 20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 80 90
Age (years) Age (years)
FIGURE 303 Patterns of the amount of slow wave sleep (stage N3, formerly stages III + IV) and nocturnal GH secretion throughout aging, obtained in 102 healthy
nonobese men, ages 18 to 83 years, who were grouped according to age bracket (mean SEM for each age bracket). GH decreases with age in parallel to the amount of
slow wave sleep. Data from Van Cauter E, Plat L, Copinschi G: Interrelations between sleep and the somatotropic axis. Sleep 1998;21:553566.
The adrenals secrete cortisol under the control of pituitary Adrenocorticotropic Hormone (ACTH) and Cortisol
adrenocorticotropic hormone (ACTH). There is strong cir- Under circadian control (peak around 7 AM).
cadian control of ACTH secretion (and cortisol). The Nadir shortly after the typical time of sleep onset (does
plasma levels of cortisol and ACTH peak in the early morning not depend on sleep).
and decline during the day (Box 302 and Fig. 304). The Peak levels in the early morning then decline over the
nadir of cortisol and ACTH levels is during the first part of day.
sleep. The levels start to climb a few hours before waking. The overall shape of the corticotropic profile is not
During shifted sleep, the cortisol rhythm remains tied to markedly affected by the absence of sleep or by sleep at
clock time. There is a weak sleep-related component. The an unusual time of day.
presence of sleep causes inhibition and maintains low levels During sleep deprivation, the nocturnal cortisol is higher
early in the sleep period (Fig. 305). Awakening at the end (amplitude of oscillation reducedi.e., early night not as
low, early AM not as high).
of sleep is associated with a burst of cortisol secretion.
20
22 02
10
0 22 02
18 22 02 06 1 18 22 02 06 10 14 18 22
When sleep is absent
Nocturnal sleep rise in cortisol starts
Nocturnal sleep deprivation earlier - sleep inhibitory
Daytime sleep
FIGURE 305 When sleep is present, it is inhibitory on cortisol secretion. When sleep is absent, the start of the rise in cortisol is earlier. The vertical bar shows the
time of onset in the upswing in cortisol secretion. An enlargement of the areas is shown to the right. Adapted from Van Cauter E, Spiegel K: Circadian and sleep
control of hormones. In Turek FW, Zee PC (eds): Regulation of Sleep and Circadian Rhythms. New York: Marcel Dekker, 1999, p. 399.
Mean evening
25 cortisol level (g/dL)
7
Plasma cortisol (g/dL)
20 6
ns
15 5
4
10 3
2
5
1
0 0
18 22 02 06 10 14 18 22 02 Day 1 Day 2
Clock time
25
7
Plasma cortisol (g/dL)
20 P 0.003
6
15 5
4
10 3
2
5
1
0 0
18 22 02 06 10 14 18 22 02 Day 1 Day 2
Clock time
FIGURE 306 During sleep deprivation, the nocturnal cortisol is greater. Mean profiles of plasma cortisol for two groups of
healthy young subjects during a 32-hour period with normal sleep (upper panel) and sleep deprivation (lower panel). The
dark bar represents the sleep period. The shaded areas represent cortisol secretion between 18:00 and 23:00 on Day 1 and Day
2 (before and after the night shown). The mean of these areas determines the mean evening cortisol level (bar graphs). In the
top panel, the mean of the two shaded areas is virtually identical (bar graph to the right of the upper panel). In the
bottom panel, sleep deprivation results in an increase in the mean evening cortisol level (bar graph to the right of
the bottom panel). Thus, sleep deprivation results in a higher nocturnal cortisol and higher late evening cortisol levels. From
Van Cauter E: Endocrine physiology. In Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine. Philadelphia:
Elsevier, 2005, p. 270.
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Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders 619
1
18 22 02 06 10 14 18 22 02 06 10 14 18 22
Nocturnal sleep
Nocturnal sleep deprivation
Daytime sleep
FIGURE 307 Mean 24-hour profiles of levels of plasma thyroid-stimulating hormone (TSH) during a 53-hour
period including 8 hours of nocturnal sleep (dark blue bar), 28 hours of continuous wake (white bar), and 8
hours of daytime sleep (light blue bar). Subjects were young healthy men. The shaded area corresponds to
normal 24-hour conditions. The vertical bar at each time point represents the SEM. The nocturnal elevation of
plasma TSH remains synchronized to clock time even when sleep is shifted. The effect of nocturnal sleep is an
inhibition of TSH secretion that is relieved by sleep deprivation, resulting in an augmentation of the nocturnal
TSH rise. The inhibitory effects of sleep on TSH secretion depend on the time of day. Daytime sleep does not
significantly alter (inhibit) TSH levels, which are already low at that time of day because of circadian
influences. Adapted from Van Cauter E, Spiegel K: Circadian and sleep control of hormones. In Turek FW, Zee PC
(eds): Regulation of Sleep and Circadian Rhythms. New York: Marcel Dekker, 1999, p. 399, with permission.
Plasma prolactin
200
(% of mean)
(nocturnal hours: white bar), and 8 hours of daytime sleep
(light blue bar). Subjects were young healthy men. The
150
shaded area corresponds to normal 24-hour conditions.
The vertical bar at each time point represents the SEM. The
temporal pattern of PRL secretion is mainly regulated by 100
sleep so that shifted sleep is associated with a shift in the
secretion of PRL. Adapted from Van Cauter E, Spiegel K: 50
18 22 02 06 10 14 18 22 02 06 10 14 18 22
Circadian and sleep control of hormones. In Van Cauter E,
Spiegel K (eds): Circadian and Sleep Control of Hormones. In Nocturnal sleep
Turek FW, Zee PC (eds): Regulation of Sleep and Circadian Nocturnal sleep deprivation
Rhythms. New York: Marcel Dekker, 1999, p. 399. Daytime sleep
that nocturnal sleep times were not very reduced or that nights). The study found decreased glucose tolerance in the
variable degrees of obesity were present in the populations sleep-debt condition compared with the fully rested condi-
studied. tion. Evening cortisol concentrations were raised and activ-
ity of the sympathetic nervous system was increased in the
sleep-debt condition.
OBESITY AND SLEEP DURATION
Gottlieb and associates23 analyzed a subsample of the
Numerous cross-sectional population studies have tried to population from the Sleep Heart Health Study (1486 sub-
determine whether obesity is associated with sleep loss.14 jects; 722 men and 764 women).
Two longitudinal studies are mentioned. Analysis of data The usual sleep time was obtained by self-report. Statisti-
from the first National Health and Nutrition Examination cal adjustments made for numerous covariates including age,
Survey (NHANES I) indicated that subjects between the ages gender, race, apnea-hypopnea index (AHI), and waist girth.
of 32 and 49 years with self-reported sleep durations at base- Lower sleep time was associated with impaired glucose toler-
line of less than 7 hours had higher average body mass ance and diabetes mellitus based on serum glucose measure-
indices (BMIs) and were more likely to be obese than sub- ments (fasting and 2-hr).
jects with sleep durations of 7 hours.19 A second longitudinal Chapter 17 discusses the evidence that OSA is associated
study analyzed the association between sleep and BMI over with impaired glucose tolerance and an increased risk of
a 13-year period and reported that the odds ratio for sleep developing diabetes. The major confounder is the presence
duration predicting obesity was 0.50, which means that of obesity. A cross-sectional analysis of the Sleep Heart
every extra hour increase of sleep duration was associated Health data24 was performed (2588 participants aged 52
with a 50% reduction in risk of obesity.20 In humans, part of 96 yr; 46% men) on individuals without known diabetes.
the tendency for weight gain after sleep loss is that sleep loss Sleep-disordered breathing (SDB) was defined as a respira-
may reduce energy expenditure. In rodents, leptin increases tory disturbance index of 10 events/hr or greater. Impaired
energy expenditure and ghrelin decreases expenditure. In fasting glucose (IFG), impaired glucose tolerance (IGT),
rodents, sleep loss experiments involve constant movement occult diabetes, and body weight were classified according
or other activity and rodents do not gain weight even to recent accepted guidelines. Participants with and without
with increased food intake. The importance of leptin and SDB were compared on prevalence and odds ratios for mea-
ghrelin on energy expenditure in humans remains to be sures of impaired glucose metabolism (IGM) after adjust-
documented. ing for age, sex, race, BMI, and waist circumference. SDB was
observed in 209 non-overweight and 1036 overweight/obese
participants. SDB groups had significantly higher adjusted
SLEEP AND GLUCOSE TOLERANCE
prevalence and adjusted odds ratios of IFG, IFG plus IGT,
Sleep has important effects on glucose metabolism, suggest- and occult diabetes. The adjusted odds ratio for all subjects
ing that sleep disturbances may adversely affect glucose tol- was 1.3 for IFG, 1.2 for IGT, 1.4 for IFG plus IGT, and 1.7
erance. In a study by Scheen and coworkers,21 subjects for occult diabetes. SDB was associated with occult diabetes,
received a constant glucose infusion during (1) nocturnal IFG, and IFG plus IGT after adjusting for age, sex, race, BMI,
sleep, (2) nocturnal sleep deprivation, and (3) daytime and waist circumference. The magnitude of these associa-
recovery sleep. The investigators analyzed plasma glucose tions was similar in non-overweight and overweight partici-
levels, insulin secretion rates (ISRs), and plasma GH and pants. The consistency of associations across all measures of
cortisol levels. Plasma glucose and ISR markedly increased IGM and body habitus groups and the significant association
during early nocturnal sleep and returned to presleep levels between SDB and IFG plus IGT (a risk factor for rapid pro-
during late sleep. These changes in glucose and ISR appeared gression to diabetes, cardiovascular disease, and mortality)
to reflect the predominance of slow wave activity (stage N3) suggest the importance of SDB as a risk factor for clinically
in early sleep and of REM and wake stages in late sleep. important levels of metabolic dysfunction. Chapter 17 dis-
Major differences in glucose and ISR profiles were observed cusses some studies showing that continuous positive airway
during sleep deprivation as glucose and ISR remained essen- pressure (CPAP) may improve glucose control in some
tially stable during the first part of the night and then patients with both obstructive sleep apnea (OSA) and dia-
decreased significantly, despite the persistence of bedrest and betes. At least in some studies, CPAP treatment has more
constant glucose infusion. significant effects in patients who are not obese.
During daytime recovery sleep, slow wave activity (stage
N3) was increased, glucose levels peaked earlier during noc-
turnal sleep, and the decreases of glucose and ISR in late SLEEP AND GASTROINTESTINAL PHYSIOLOGY
sleep were reduced by one half. Thus, sleep has important AND DISORDERS
effects on brain and tissue glucose utilization, suggesting that
Gastric and Intestinal Function
sleep disturbances may adversely affect glucose tolerance.
Spiegel and colleagues22 studied 11 healthy volunteers using There is a peak in acid secretion occurring between 10 PM
a protocol of experimental sleep restriction (4 hr/night 6 and 2 AM. Basal waking acid secretion is minimal unless
nights) followed by a recovery period (12 hr/night 6 stimulated by food. The peak in acid secretion is under
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Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders 623
Arousal
L-EOG
R-EOG
C4-A1
O2-A1
Chin EMG
Flow
Chest
Abdomen
pH distal
8
6
4
2
0
FIGURE 3010 An episode of gastroesophageal reflux (GER) follows an arousal. Note that the pH drops below 4.
EMG = electromyogram; EOG = electro-oculogram. From Berry RB, Harding SM: Sleep and medical disorders. Med Clin North
Am 2004;88:679703.
incidence of complaints of nocturnal reflux in patients with experimental evidence suggests that GER can worsen airway
Barretts esophagus.31 Symptoms of nocturnal GER include function with or without aspiration into the lungs. Jack
multiple awakenings, substernal burning or chest discom- and colleagues33 monitored both tracheal and esophageal
fort, indigestion, and heartburn. Other symptoms include a pH in four nocturnal asthmatics with GER. There were
sour or bitter taste in the mouth, regurgitation, coughing, 37 episodes of esophageal reflux of which 5 episodes were
and choking. associated with a fall in tracheal pH. Tracheal acid episodes
were associated with prolonged reflux episodes, nocturnal
pH Monitoring awakenings, and bronchospasm during the night. Aspira-
Esophageal pH testing (see Box 307) is used to diagnose tion, however, may not be required to trigger changes in
GER and has a sensitivity and specificity of approximately bronchial tone. Afferent vagal fibers are present in the lower
90%.32 It can be performed as an ambulatory study or inte- esophagus and could trigger changes in bronchial tone
grated with polysomnography (sleep monitoring) for temp- when stimulated by gastric contents. Cuttitta and associ-
oral correlation of sleep-related events such as arousals. ates34 evaluated spontaneous reflux episodes and airway
Esophageal pH testing is performed by placing a pH probe in patency during the night in seven asthmatics with GER.
the distal esophagus (5 cm above the LES). Many laboratories Multiple stepwise linear regression analysis revealed that
utilize dual pH probes, in which a proximal pH probe is also the most important predictor of change in lower respira-
placed at the upper esophageal sphincter or in the pharynx. tory resistance was the duration of esophageal acid expo-
A GER episode is defined by the presence of material that has sure. Both long and short GER episodes (those < 5 min
a pH less than 4. Figure 3010 shows a GER event after an and those > 5 min) were associated with higher respiratory
arousal from sleep. ACT, defined as the time with a pH less resistance compared with baseline. These data collectively
than 4, is often computed as absolute time or as a percentage suggest that esophageal acid is able to elicit nocturnal
of monitoring time or sleep time. A normal ACT is often bronchoconstriction. Given these findings, an important
assumed to be less than 4%. GER episodes should be sus- question is whether or not treatment of nocturnal GER
pected on routine polysomnography if there is an arousal can improve asthma. Some uncontrolled studies have shown
followed by a prolonged period of increased chin electro- a benefit in asthma with aggressive treatment of GER.35
myogram (manifestation of swallowing) (see Fig. 3010). A large parallel-group, randomized, double-blind study of
esomperazole for treatment of poorly controlled asthma
Nocturnal Asthma and GER (patient did not complain of GER) found no difference
Recently, there has been considerable interest in the rela- in episodes of asthma excerbations.36 GER was found in
tionship between nocturnal GER and asthma. Some 40% of patients using pH monitoring (asymptomatic). No
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Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders 625
Reflux Events
toms. Treatment of patients with asthma and symptomatic
GER could be considered (for GER alone) but may also 75
help asthma in individual patients.
48.4 36.8
50
GER and OSA
Given the negative intrathoracic pressure during obstructive
25
apnea and the frequent arousals from sleep, one would
8.6 11
suspect that nocturnal GER is common in patients with
OSA. Green and coworkers37 prospectively examined 331 0
Before CPAP After CPAP
OSA patients. Significant nighttime GER was found in 62%
of subjects before OSA treatment. Patients compliant with FIGURE 3011 Continuous positive airway pressure (CPAP) reduced the reflux events
CPAP had a 48% improvement in their nocturnal GER in the supine position in patients with obstructive sleep apnea (OSA) and GER. From
Tawk M, Goodrich S, Kinasewitz G, Orr W: The effect of 1 week of continuous positive airway
symptoms. There was no change in nighttime reflux symp-
pressure treatment in obstructive sleep apnea patients with concomitant gastroesophageal
toms if patients did not use CPAP. Furthermore, there was reflux. Chest 2006;130:10031008.
a strong correlation between higher levels of CPAP and
improvement in nocturnal GER symptom scores (higher
pressure levels associated with more improvement). This
study shows that nocturnal reflux is common in OSA patients and sodas. Medications that promote reflux should be
and that nasal CPAP decreases the frequency of nocturnal avoided, including calcium channel blockers, theophylline,
GER symptoms. Of note, the fact that nocturnal GER is prostaglandins, and bisphosphonates. Smoking significantly
common in OSA patients and that CPAP reduces GER does decreases LES pressure, so all patients should be encouraged
not necessarily prove that OSA causes GER. In some studies, to stop smoking. Patients should lose weight if they are obese
episodes of GER were not correlated with apneic events.38 and sleep in loose-fitting clothing. Positional therapy can
CPAP by increasing the pressure gradient between the thorax also be used. Sleeping with the head of the bed elevated 6
and the stomach may also reduce GER independent of the inches with a full-length wedge or placing blocks under the
effects of CPAP on OSA. Tawk and colleagues39 studied a head of the bed may be useful. The right lateral decubitus
group of OSA patients (AHI > 20/hr) and a 24-hour ACT of position worsens GER, whereas the left lateral decubitus
at least 6%. They performed 24-hour pH monitoring before posture seems to be the best sleep position for sleep-
and after 1 week of CPAP. The final monitoring was per- related GER.42
formed with the subjects wearing CPAP at night. The ACT Medications to treat sleep-related GER include antacids
fell as did the number of reflux episodes (Fig. 3011). Eighty- for acute symptom control, H2 receptor antagonists, proton
one percent of subjects had ACT reduced to normal range pump inhibitors, and prokinetic agents.43 H2 receptor antag-
(<4%). onists provide heartburn relief in 60% of patients and can be
given before sleep onset. Proton pump inhibitors provide
Sleep-Related Laryngospasm superior gastric acid suppression. One study found that
GER may also have a role in sleep-related laryngospasm 40 mg of omeprazole with dinner, or omeprazole, 20 mg,
(SRL). Episodes of SRL consist of the patient abruptly awak- before breakfast and with dinner, resulted in better gastric
ening with an intense feeling of suffocation often accompa- acid suppression than giving 40 mg before breakfast only.44
nied with stridor and choking sensations.40 Other features Of note, proton pump inhibitors should be given before
include intense anxiety, rapid heart rate, sensation of impend- the evening meal rather than before bedtime to treat noc-
ing death, and residual hoarseness. The differential diagnosis turnal GER. Some data suggest there may be nocturnal acid
for SRL includes OSA, epilepsy, sleep choking syndrome, breakthrough despite proton pump inhibitor therapy.45
sleep terrors, vocal cord dysfunction, and other upper airway Whether nocturnal gastric acid breakthrough is clinically
pathologies. Thurnheer and associates41 noted that 9 of 10 important in GER is not known. Metoclopramide is the only
patients with SRL had GER documented by esophageal prokinetic agent available in the United States and has a high
pH testing. Six patients responded to antireflux therapy, prevalence (2050%) of central nervous system side effects.
showing that GER may be associated with SRL. Prokinetic agents can be used concomitantly with gastric
acidsuppressive agents. Antireflux surgery, primarily fun-
Treatment of Nocturnal GER doplication (both open and laparoscopic methods), is suc-
Patients should not eat for at least 2 hours before bedtime cessful in 80% to 90% of patients. Long-term results, however,
and avoid foods that promote GER, including high-fat foods, show that many surgically treated patients use antireflux
caffeine, chocolate, mint, alcohol, tomato products, citrus, medications regularly.46
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626 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
TABLE 302
Treatments for Fibromyalgia
Cognitive behavioral treatment
Exercise
Anticonvulsants
Pregabalin* (Lyrica)
Gabapentin (Neurontin)
Muscle relaxants
Baclofen
Cyclobenzaprine
Antidepressants
TCAs
Amitriptyline (2550 mg qhs)
SSRIs (if associated depression)
SNRIs
Venlafaxine (Effexor)
Duloxetine* (Cymbalta)
Milnacipran* (Savella)
*FDA approved for treatment of fibromyalgia.
FDA = U.S. Food and Drug Administration; SNRI = selective norepinephrine
reuptake inhibitor; SSRIs = selective serotonin reuptake inhibitors; TCAs =
tricyclic antidepressants.
FIGURE 3012 Location of tender points used to diagnose fibromyalgia. From Wolfe decreased stage N3 and REM sleep, and increased arousals.48
F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 criteria for the An interesting EEG pattern (alpha sleep or alpha-NREM
classification of fibromyalgia: report of the multi-center criteria committee. Arthritis
anomaly) was first described in FS patients by Roizenberg
Rheum 1990;33:160172.
and coworkers53 and Branco and colleagues.54 This is charac-
terized by prominent alpha activity (813 Hz) persisting into
NREM sleep (alpha intrusion). Alpha activity is normally
SLEEP AND RHEUMATOLOGY present during relaxed wake and after brief awakenings
Fibromyalgia Syndrome (arousals) but is normally virtually absent during stages N2
and N3 except as associated with arousals. Alpha intrusion
Manifestations of Fibromyalgia into stage N3 (slow wave or delta sleep) is called alpha-delta
Fibromyalgia syndrome (FS) is defined by the American sleep. Since that time, it has been recognized that the alpha-
College of Rheumatology as the presence of widespread NREM sleep anomaly is not specific for FS and is not present
musculoskeletal pain for at least 3 months, which is bilateral in all patients with FS. Other groups in which the alpha-
above and below the waist, including axial pain and the pres- NREM sleep anomaly can be found include patients with
ence of 11 of 18 tender points47 (Fig. 3012). FS should be chronic pain syndromes, depression, and diverse causes of
considered a syndrome rather than a disease process. Fibro- nonrestorative sleep. Indeed, alpha sleep has been seen in
myalgia affects about 3% of the population aged 30 to 50 up to 15% of normal subjects.55 In a variant of alpha sleep
years and 70% to 90% of patients are women.48 Depression (phasic alpha activity), alpha intrusion is seen mainly during
is common in the disorder. The pathophysiology of FS is very stage N3 rather than being present diffusely in NREM sleep.
complex.4952 A possible mechanism is thought to be central In one study, phasic alpha activity seemed to be present in FS
sensitization of nociceptive neurons in the dorsal horn of the patients with prominent sleep disturbance, subjective feeling
spinal cord with activation of N-methyl-D-aspartate recep- of superficial sleep, and more pain and stiffness.53 Chapter 4
tors. This central sensitization results in generalized height- contains sleep tracings illustrating the alpha anomaly.
ened pain sensitivity caused by pathologic nociceptive
processing within the central nervous system. There is a Treatment of FS
threefold increase in substance P and a decrease in serotonin Treatments for FS include antidepressants, anticonvulsants
levels in the cerebrospinal fluid.52 (to treat pain), hypnotics, muscle relaxers, cognitive therapy,
exercise, biofeedback, and hypnosis.56,57 Patients should
Sleep in FS incorporate good sleep hygiene habits. Furthermore, screen-
Sleep complaints are common and include nonrestorative ing for primary sleep disorders is also indicated. Of note, FS
sleep, fragmented sleep, and insomnia. Poor sleep seems to patients have a higher prevalence of restless legs syndrome
worsen pain symptoms in 67% of the patients.48 Sleep studies than controls.58 Some FS patients have clinical improvement
in FS patients have shown decreased total sleep time, with low doses of antidepressants, whereas others require the
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Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders 627
Aldosterone (ng/dL)
20
10
3
PRA (ng/mL/h)
18 22 2 6 10 14 18 18 22 2 6 10 14 18
Clock time Clock time
FIGURE 3013 Mean 24-hour profiles of plasma renin activity (PRA) and aldosterone in eight normal young men during
normal nocturnal sleep and acute sleep deprivation. The vertical bar at each time point represents the SEM. Sleep deprivation
blunts the nocturnal increase in PRA and aldosterone. From Charloux A, Gronfier C, Chapotot F, et al: Sleep deprivation blunts
the nighttime increase in aldosterone release in humans. J Sleep Res 2001;10:29, with permission.
usual doses needed for an antidepressant effect. Tradition- SLEEP AND RENAL
ally, low doses of tricyclic antidepressants (both serotonin
Renin-Aldosterone and Sleep
and norepinephrine reuptake inhibitors) such as amitrypti-
line 25 to 50 mg qhs were used for FS.59 The selective sero- Water and sodium homeostasis depends on coordination of
tonin reuptake inhibitors (SSRIs) have not been very effective a number of factors including several hormones. Arginine
as treatment for FS unless depression was present. Two med- vasopressin (AVP) is secreted by the posterior pituitary and
ications selectively blocking reuptake of both serotonin and is also known as antidiuretic hormone (ADH). AVP is
norepinephrine (SNRIs) are U.S. Food and Drug Adminis- secreted in bursts but is independent of sleep stage. AVP
tration (FDA) approved for treatment of FS. These medica- results in reabsorption of water from the collecting duct of
tions are duloxetine (Cymbalta) and milnacipran (Savella)57 the kidney. Renin is secreted by the juxtaglomerular cells of
(Table 302). Venlafaxine (Effexor, also an SNRI) has also the kidney and aldosterone secreted by the adrenal cortex.
been used but is not FDA approved for FS. The SNRIs appear Renin hydrolyzes angiotensinogen (produced by the liver) to
to work in both depressed and nondepressed patients with produce angiotensin I. Angiotensin I is metabolized by lung
FS.6063 Pregabalin (Lyrica) is an anticonvulsant that has also endothelial cells containing angiotensin-converting enzyme
been FDA approved for FS. Gabapentin is another anticon- (ACE) to angiotensin II. Angiotensin II is a potent vasocon-
vulsant that has been used for chronic pain syndromes strictor and also stimulates the adrenal to produce aldoste-
including FS (not FDA approved for FS). Both pregabalin rone. Aldosterone causes absorption of sodium and water
and gabapentin have been shown to have benefit in FS and excretion of potassium. Atrial natriuretic peptide (ANP)
patients.64,65 Muscle relaxants such as cyclobenzaprine have is secreted by the atrial myocytes in response to stretch and
also been used.66 Studies have shown benefit from treatment other influences. ANP causes an increase in the renal excre-
of FS with sodium oxybate.67,68 tion of sodium and is a mechanism to respond to fluid over-
Sodium oxybate is believed to work in FS by improving load. ANP is elevated in untreated sleep apnea (negative
sleep quality. Sodium oxybate is currently FDA approved for intrathoracic pressure swings stretch the atria), resulting in
treatment of narcolepsy (cataplexy and daytime sleepiness). nocturia. Patients with untreated OSA have nocturnal natri-
An application was made to the FDA for an indication for uresis. Urine volume and electrolyte secretion is normally
the use of sodium oxybate as a treatment for FS. However, lower at night. In particular, REM sleep is associated with
this application was rejected in part because the large FS decreased urine flow and increased osmolality.
population and the potential for abuse of medication (date Plasma renin activity (PRA) and aldosterone levels are
rape drug). elevated during sleep.6972 This effect is mainly related to
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628 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
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Chapter 31
Physical Examination Impaired voluntary vertical gaze espe- Parkinsonism = tremor, rigidity, bradykinesia, and postural
instability
cially in downward direction is an early finding.
Disorders with parkinsonism
Epidemiology in PSP Patients with PSP have a mean age of 63 PDalso known as idiopathic parkinsonism
and the mean survival from symptoms is 9 years. PD+disorders with parkinsonism + other
manifestations
Histology Tau-positive neurofibrillary tangles are present in PSP
multiple subcortical nuclei including the locus coeruleus. CBD
There is relative preservation of the hippocampus and cortex. DLBD
MSA
Sleep in PSP PSP patients have severe sleep-maintenance Medication side effects (dopamine blockers)
insomnia (worse than PD). Sleep complaints in PSP include Wilsons disease (hereditary copper accumulation)
an increased sleep latency, increased arousals, increased presents in younger patients with parkinsonism features,
awakening frequency, decreased REM sleep, and increased diagnosis by slit lamp examination showing Kayser-
REM latency.14,15 Fleischer rings
CBD = corticobasal degeneration; DLBD = diffuse Lewy body dementia;
MSA = multiple system atrophy; PD = Parkinsons disease; PSP = progressive
Polysomnography in PSP Polysomnography (PSG) reveals
supranuclear palsy.
absence of vertical eye movements during REM sleep. Hori-
zontal movements are present but are slower.
of DLBD also present much earlier in the course of the
disease than the dementia associated with PD. However,
Corticobasal Degeneration
there is overlap between PD and DLBD. The PD+ disorders
CBD is a neurodegenerative disorder characterized by pro- tend to progress more quickly than PD. The typically anti-
gressive asymmetrical rigidity, apraxia, and other findings Parkinsons medications are either less effective or completely
reflecting cortical and basal ganglia dysfunction.1,2 Tau- ineffective in PD+ disorders. PD+ patients are also very
positive astrocytic threads and oligodendral coiled bodies sensitive to dopamine blockers.
are noted. Apraxia is characterized by loss of the ability to
execute or carry out learned purposeful movements, despite Differential Diagnosis of Parkinsonism
having the desire and the physical ability to perform the 1. Essential tremorresponds to beta blocker, worse on
movements. It is a disorder of motor planning, which may intention, improved with alcohol.
be acquired or developmental but may not be caused by 2. Wilsons diseasea disorder of hereditary copper accu-
incoordination. mulation. The typical presentation is a young person who
has parkinsonian features. Diagnosis is by performing a
slit lamp examination for Kayser-Fleischer rings.
Frontotemporal Dementia
FTD is a type of cortical dementia resembling AD.1,2 It is
Parkinsons Disease
characterized by insidious onset, early loss of insight, social
decline, emotional blunting, relative preservation of percep- PD is also called primary parkinsonism or idiopathic PD. The
tion and memory, perseverance, and echolalia. Computed term idiopathic means no secondary systemic cause. The
tomography (CT) or magnetic resonance imaging (MRI) etiology of PD is partially understood and, in this sense, is
shows frontal or anterior temporal atrophy. not truly idiopathic. PD is a chronic neurodegenerative
disorder associated with a loss of dopaminergic neurons
(substantia nigra and other sites). It is characterized by bra-
Parkinsonism Syndromes (PD, PD+)
dykinesia (slowing of physical movement), akinesia (loss of
The term parkinsonism is used to refer to a group of mani- physical movement), rigidity, resting tremor, postural insta-
festations including tremor, rigidity, bradykinesia, and pos- bility, and a good response to levodopa (LD; Box 317).16,17
tural instability. Parkinsonism is found in both PD and The disorder often starts unilaterally. Movements are slow
Parkinson Plus (PD+) disorders (Box 316).16,17 The PD+ and reduced facial expressiveness is noted (masklike facies)
disorders include those characterized by parkinsonism and with infrequent blinking and a monotonous voice. Gait is
other manifestations. The PD+ disorders include PSP, DLBD, slow and shuffling with small steps. The tremor in PD is a
and MSA. Of note, the brains of PD patients do have Lewy resting tremormaximal when limb is at rest and disappear-
bodies (LBs), but in DLBD, the distribution of LBs is more ing with voluntary movement and sleep. Secondary symp-
dense and more diverse. DLBD patients have more promi- toms may include cognitive dysfunction and subtle language
nent dementia than noted in patients with PD. The dementia problems.
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Chapter 31 Sleep and Neurologic Disorders 635
BOX 317 improve markedly. Off times refers to periods of time when
Parkinsons Disease Manifestations symptoms return. Wearing off time refers to times when
symptoms are under less control. Dyskinesias, manifested
Resting tremor (pill rolling). by sudden jerky or uncontrolled movements of the limbs and
Gabellar reflex (sensitive but not specific)breakdown of neck, are side effects of LD/CD treatment. Dystonias con-
frontal lobe inhibition.
sisting of abnormal posture or cramps of the extremities or
Masklike facies.
trunk can occur.
Small handwriting (micrographia).
Dopamine agonists (DAs) are less likely to cause dyskine-
Walking without arm swinging.
sia but have some dose-dependent side effects of their own.
Flexed forward posture when walking with small shuffling
In low doses, DAs tend to cause sleepiness or promote sleep.
steps.
Ropinirole or pramipexole have dopamine D2/D3 receptor
RBD in 2030%often precedes PD manifestations
activity and can stimulate autoreceptors to decrease dopa-
sometimes by 10 years.
mine release. In high doses, DAs can cause insomnia, fre-
Insomnia in 50%.
quent awakenings, and a reduction in the amount of stage
OSA.
N3. Another serious side effect of DA treatment of PD
OSA = obstructive sleep apnea; PD = Parkinsons disease; RBD = rapid eye
movement sleep behavior disorder. patients is the often unpredictable sudden onset of severe
daytime sleepiness.
Catechol-O-methyl transferase (COMT) inhibitors have
Nonmotor manifestations of PD include sleep disorders, also been used as adjunctive medications in PD. This enzyme
dementia, orthostatic hypotension, oily skin, and seborrheic is involved in degrading neurotransmitters including dopa-
dermatitis. The sleep disorders in PD can occur secondary mine. The COMT inhibitors available include entacapone
to medication side effects but are also a primary manifesta- (Comtan) and tolcapone (Tasmar). Entacapone is only
tion of PD. PD patients have a sixfold increased risk of peripherally active, whereas tolcapone is active in both the
dementia. Physical findings in PD include resting pill rolling peripheral and the central nervous system. Tolcapone can be
tremor, gabellar tap (tap of forehead elicits continued blink- hepatotoxic, whereas entacapone is not. These medications
ing [a frontal lob sign]), and cogwheel rigidity (joint stiffness can permit LD to last longer or maintain higher levels of
and increased muscle tone). Imaging of the central nervous effectiveness.
system (MRI, CT scan) is typically normal. The neuropathol- Anticholinergic agents are typically used in younger
ogy of PD includes the presence of LBs. A major component patients without cognitive impairment in whom tremor is
of LB is alpha synuclein. Secondary parkinsonism can occur the major feature. The concept behind the use of these agents
secondary to drugs such as dopamine blockers (phenothi- is that PD has upset the cholinergic-dopaminergic balance
azines and butyrophenones) or head trauma. in the basal ganglia due to loss of dopaminergic neurons.
Anticholinergic drugs restore the balance. The anticholin-
Differential Diagnosis of PD ergic drugs do not work for other PD manifestations. LD
1. Essential tremorResponds to beta blocker, worse on can also help tremor. The two anticholinergic drugs most
intention, improved with alcohol. commonly used include trihexyphenidyl (Artane) and ben-
2. PD+ disordersIf cognitive dysfunction occurs early in zotropine (Cogentin). Trihexyphenidyl is started at 0.5 to
the disease course of a patient with parkinsonism, DLBD 1 mg bid and gradually increased to 2 mg tid as tolerated.
would be suspected. If early postural instability + supra- Benzotropine is used in doses of 0.5 to 2 mg bid.
nuclear gaze palsy is prominent early, the PSP should be Side effects of these medications including memory impair-
suspected. If autonomic dysfunction is prominent early ment and hallucinations limit their use. The anticholinergic
(erectile dysfunction or syncope), MSA should be side effects include dry mouth, constipation, and urinary
suspected. retention. Of note, LD improves tremor as well as rigidity
3. CBDIf CT or MRI shows prominent asymmetry with and can be used to treat tremor in patients not tolerating
patchy changes and cortical deficits (apraxia) are promi- anticholinergic medications.
nent, CBD should be suspected. Amantadine is an antiviral agent that can improve rigid-
ity, akinesia, or tremor in approximately two thirds of
Treatment of PD A detailed discussion of the treatment of PD patients. The mechanism of action is unknown. The usual
is beyond the scope of this chapter. A very comprehensive dose of amantadine is 100 to 200 mg one to three times daily.
and useful discussion of PD is recommended.18 A number of The dose should be lower in patients with renal failure. The
different medications have been used to treat PD (Table starting dose of amantadine is 100 mg daily with slow
313). The usual treatment of PD is with levodopa/carbidopa increases as tolerated. Side effects include confusion, hallu-
(LD/CD). CD prevents peripheral metabolism of LD to cinations, insomnia, and nightmares.
dopamine, thus reducing side effects and allowing for more Selegiline (Deprenyl, Eldepryl), a selective monoamine
LD to reach the central nervous system. Patients may respond oxidase B (MAO-B) inhibitor, is approved for use in PD
to LD/CD but have a number of reported problems. On patients as an adjunct to LD because it modestly increases
times refers to periods of time when symptoms go away or the percent of on time in advanced PD patients. When used
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636 Chapter 31 Sleep and Neurologic Disorders
TABLE 313
Medications Used to Treat Parkinsons Disease
Dopamine precursor Very effective for akinetic symptoms or tremor.
LD/CD Start 12 of 25/100 tid, titrate up to 25/100 tid.
10/100, 25/100, 25/100
SR LD/CD Poorly and slowly absorbed, 30% higher dose needed for same effect.
(25/100, 50/200 ER) Very low dose of SR can cause nausea owing to inadequate CD.
DAS Less likely than LD to cause dyskinesias.
Ropinirole (Requip) Can cause sudden episodes of severe sleepiness.
Pramipexole (Mirapex) Dopamine dysregulation syndrome.
Some recommend using DAs in younger patients as neuroprotective.
COMT Inhibitors These medications prolong the effect of LD and can allow a reduction in dose.
Tolcapone (Tasmar) COMT inhibition reduces the peripheral methylation of LD or dopamine, which increases
Entacapone (Comtan) the plasma half-life of LD; thus, prolongs action of LD.
Entacaponeperipheral inhibition of COMT.
Tolcaponeperipheral and central inhibition of COMT.
Tolcaponedeaths from hepatotoxicity.
Amantadine Antiviral.
May improve rigidity, akinesia, and tremor.
Monotherapy or combined with LD.
Trihexyphenidyl (Artane) For younger patients with predominant tremor.
Benzotropine (Cogentin) Side effects include cognitive impairment and typical anticholinergic side effects (dry
mouth, urinary retention, constipation).
MAOI (segiline) MAO-B inhibitor
Modest benefit; can be used with LD to reduce motor fluctuations.
CD = carbidopa; COMT = catechol-O-methyl transferase; DAs = dopamine agonists; ER = extended-release; LD = levodopa; MAO = monoamine oxidase;
MAOI = monoamine oxidase inhibitor; SR = sustained release.
alone at 5 mg bid, it is well tolerated. When used with LD, it of alpha activity during drowsiness even before the onset of
can increase dopaminergic side effects. Some clinicians use stage N1 or N2. Tremor is rare during stage N3. However, in
selegiline at a lower dose in combination with LD to decrease some patients, motor manifestations persist during sleep.
motor fluctuations. Other clinicians use selegiline as a puta- Examples of motor findings associated with sleep include
tive neuroprotective therapy. repeated eye blinking at onset of sleep, blepharospasm at the
There is controversy about which dopaminergic medica- onset of REM sleep, and prolonged tonic contractions of
tion is most appropriate for initiation of treatment of PD. limb extensor or flexor muscles during nonrapid eye move-
The most common approach is to start with LD/CD if symp- ment (NREM) sleep. Because of rigidity, patients with PD
toms are significant. LD/CD is particularly effective for have difficulty changing body position during the night.
rigidity. However, patients taking LD/CD can develop dys- Early morning akinesia and painful off dystonia can be prob-
kinesias. This tends to happen if patients have been on the lematic. LD/CD has a short duration of action. The DAs have
medication for years or if high doses are used. If a patient on a longer duration of action and may be useful in patients
LD/CD develops dyskinesias, she or he can be switched to a with motor manifestations during sleep.
DA. Conversely, some clinics recommend starting a DA as
initial dopaminergic treatment. It is possible that DAs have DAYTIME SLEEPINESSIN PD Excessive daytime sleepiness (EDS)
a neuroprotective effect not present with LD/CD. not due to OSA or medications is a well-known phenome-
non in PD. Sleep attacks were once thought due to side
Sleep-Related Manifestations of PD Patients with PD have a effects from DAs. Most recent studies suggest medications
number of sleep-related manifestations and disturbances used to treat PD may worsen EDS but that the underlying
(Table 314).19,20 Treating the nocturnal manifestations of disease process is the most common cause of EDS in PD.
PD can be challenging. Studies have reported 50% loss of hypocretin neurons in
patients with PD.21 Treatment of EDS not due to OSA in PD
SLEEP DISTURBANCE DUE TO MOTOR MANIFESTATIONS Patients with PD patients includes modafinil, bupropion, and traditional stim-
have motor symptoms including tremor that are worse ulants. Fatigue can also be a major complaint. The American
during wakefulness (Fig. 311) and usually decrease or are Academy of Sleep Medicine (AASM) practice parameters for
abolished with sleep. The tremor often stops with the onset treatment of central hypersomnia22 state that modafinil may
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Chapter 31 Sleep and Neurologic Disorders 637
TABLE 314
Sleep Disturbance in Parkinsons Disease
PATHOPHYSIOLOGY MANIFESTATION TREATMENT
Changes in cholinergic and Impaired wake-sleep control Cautious use of sedating antidepressants
monoaminergic systems Decreased REM sleep and hypnotics
Bradykinesia and rigidity Decreased body shifts during sleep Sustained-release LD/CD or DAs
discomfort and increased awakenings
Impaired ability to use the bathroom
Tremor Arousals Sustained release CD/LD or DAs
Insomnia
Drug-induced dyskinesia Jerks, arousals Decrease evening LD/CD or DAs
Abnormal motor control of respiratory OSA (BMI often normal) CPAP
and upper airway muscles
RBD Disturbed REM sleep Clonazepam
Injury to self or bed partner Melatonin
RBD ?Dopamine agonists
May precede other findings by years
Prevalence 1530%
PLMS, RLS Arousals, difficult sleep onset Dopamine agonists
Depression and anxiety Insomnia Cautious use of hypnotics and
Difficulty with sleep onset antidepressants
Early AM awakening
Dementia Nocturnal confusional episodes Quetiapine
Aricept
BMI = body mass index; CD = carbidopa; CPAP = continuous positive airway pressure; DAs = dopamine agonists; LD = levodopa; OSA = obstructive sleep apnea;
PLMS = periodic limb movements during sleep; RBD = rapid eye movement sleep behavior disorder; REM = rapid eye movement; RLS = restless legs syndrome.
Adapted from Comella CL: Sleep disorders in Parkinsons disease. Curr Treat Options Neurol 2008;10:215221.
be an effective treatment of daytime sleepiness in PD. can be the earliest manifestation, occurring many years
However, the evidence from studies of the effects of modafinil before other PD symptoms and signs. In general, treatment
in PD is somewhat conflicting. A study by Ondo and col- options for RBD in PD are similar to those for idiopathic
leagues23 found no significant improvement in the Epworth RBD. DAs have been reported to be effective treatment of
Sleepiness Scale (ESS; subjective sleepiness). A study by Hogl RBD in some patients.
and associates24 found an improvement in the ESS but Nocturnal hallucinations can occur in PD and disturb
no increase in the sleep latency on the maintenance of wake- sleep. A recent study compared sleep between groups of PD
fulness test (MWT). An uncontrolled study by Nieves and patients with and without visual hallucinations. Whereas
Lang25 found improvement in the ESS with modafinil in PD both groups slept poorly, the group with visual hallucina-
patients. Another study investigated whether modafinil tions had much poorer sleep.28
would improve fatigue in PD. Using a double-blind, placebo- Drug-induced psychosis is a major problem in PD. It can
controlled design, Lou and coworkers26 noted no improve- occur in up to 22% and is a major cause of placing patients
ment in fatigue symptoms, no improvement in ESS, and in a chronic care facility. Treatments have included reducing
some improvement in finger tapping. In summary, even the dose of anti-Parkinsons medication, adding a neurolep-
though the evidence is less than totally convincing, a trial of tic drug, or discontinuing PD treatment for a period of time.
modafinil is indicated if daytime sleepiness is a significant Low-dose clozapine was found effective even if anti-
problem for a patient with PD. Of course, the possibility of Parkinsons medications were still taken and did not worsen
OSA should be eliminated. As noted previously, treatment tremor. In this study, doses of 6.25 to 50 mg were used (far
with DAs can be associated with sudden attacks of severe lower than the 300900 mg used for schizophrenia). The
daytime sleepiness. One case report found that the addition drug can cause leukopenia.29 Quetiapine has also been effec-
of modafinil to DA therapy reduced the severity of this DA tive for drug-induced psychosis but can cause problems with
side effect.27 glucose control and oversedation.30
NOCTURNAL BEHAVIOR: RBD, NOCTURNAL HALLUCINATIONS, NOCTURNAL Dementia in PD A study found modest benefit from donepezil
PSYCHOSIS RBD occurs in 20% to 40% of patients with PD. It and the drug did not cause worsening of PD.31 Another study
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638 Chapter 31 Sleep and Neurologic Disorders
1234
E1-M2
E2-M2
F3-M2
F4-M1
1 sec
C3-M2
C4-M1
O1-M2
O2-M1
EMG1-EMG2
R Leg1 - R Leg2
L Leg1 - L Leg2
Nasal pressure
Chest
Abdomen
96 96 96 96 96 96 96 96 96 96 96 96 96 96 96
SpO2
ECG1-ECG2
FIGURE 311 A 30-second tracing during wakefulness in a patient with Parkinsons disease shows a classic 4-Hz tremor noted in the chin electromyogram (EMG).
RLeg1-RLeg2 and LLeg1-LLeg2 are the right and left anterior tibial EMG derivations. ECG = electrocardiogram; SpO2 = pulse oximetry.
has reported some benefit from memantine in patients with and transient loss of consciousness. The RBD can have an
PD with dementia or DLBD.32 onset years before the other manifestations of DLBD
(similar to PD).
Diffuse Lewy Body Dementia
VISUAL HALLUCINATIONS The most common reported hallucina-
DLBD is also known as dementia with Lewy bodies (DLB), tion is of people or animals. The patient may misinterpret
Lewy body dementia, or diffuse Lewy body disease. DLBD what he or she sees. For example, the patient may open a
is a type of dementia characterized anatomically by the drawer full of socks but see snakes.
presence of Lewy bodies, clumps of alpha synuclein and
ubiquitine proteins in neurons. In this disorder, loss of cho- SENSITIVITY TO DA BLOCKERS An important characteristic of
linergic neurons results in cognitive dysfunction and loss DLBD is exquisite sensitivity to dopamine blockers. When
of dopamine neurons results in parkinsonism (Box 318). given dopamine blockers, patients with DLBD can develop
If dementia occurs more than 1 year after other symptoms life-threatening rigidity or malignant neuroleptic syndrome.
in PD, the disorder is called PD with dementia. If dementia Anticholinergic drugs such as benadryl or hytrin can worsen
occurs within the first year of parkinsonism, the diagnosis dementia.
is DLBD. DLBD tends to progress much more rapidly
than PD. DEMENTIA VARIANT A variant of DLB and RBD but without par-
kinsonism or hallucinations has been reported. This disorder
Manifestations of DLBD The major manifestations of DLBD33 may be a variant of DLBD.34
include (1) fluctuating cognition with great variation in
attention and alertness from day to day and hour to hour, (2)
Multiple System Atrophy
recurrent visual hallucination (75% of patients with DLBD),
(3) motor features of parkinsonism (tremor less common in MSA is a neurodegenerative disorder characterized by a
DLBD than in PD), (4) RBD (5075%), and (5) problems combination of parkinsonism, dysautonomia, cerebellar dys-
with orthostasis, including repeated falls, syncope (fainting), function, and features of pyramidal tract dysfunction (Box
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Chapter 31 Sleep and Neurologic Disorders 639
319).35 Some patients have more prominent dysfunction in recent consensus conference35 recommended new MSA ter-
one category. MSA is sometimes divided into three separate minology and the term Shy-Drager was not used in this
conditions (Table 315). These include (1) striatonigral classification, although it is widely used in the literature.
degeneration, (2) olivopontocerebellar degeneration, and (3)
progressive autonomic failure (Shy-Drager syndrome). A Symptoms
1. Autonomic dysfunction (erectile dysfunction, bladder
controlurgency, incomplete emptying, constipation,
BOX 318 abnormal breathing during sleep, orthostatic
Diffuse Lewy Body Dementia hypotension).
2. Parkinsonism = rigidity tremor, bradykinesia, and pos-
Fluctuating cognition and alertness. tural instability. The tremor of MSA is irregular and
Visual hallucinations in 70%. usually not a pill rolling tremor as seen in PD.
Orthostasis and frequent falls. 3. Gait ataxia (poor coordination/unsteady walking) may be
Motor manifestations of parkinsonism (rigidity, tremor a presenting symptom. Ataxia of speech (cerebellar dys-
less common than in PD).
arthria) is also common and manifested by slow and
Onset of dementia within 1 year of symptoms of
slurred speech and sudden uncontrolled alterations in
parkinsonism.
loudness of voice.
RBD is very common (5080%).
Life-threatening rigidity with dopamine blockers. Epidemiology of MSA The typical age of onset of MSA is 50
PD = Parkinsons disease; RBD = rapid eye movement sleep behavior to 60 years. The disease course is fairly rapid with onset to
disorder.
death in about 9 years. The disorder progresses more rapidly
than PD.
TABLE 315
Classifications of Multiple System Atrophy
1996 CONSESNUS 2007 CONSENSUS
CHARACTERISTICS CONFERENCE CONFERENCE
Striatonigral degeneration Predominantly Parkinsons type symptoms MSA-P MSA-P
Sporadic OPCA Progressive ataxia of gait, limbs, and MSA-C MSA-C
speech (cerebellar dysarthria)
Shy-Drager syndrome Characterized by parkinsonism + MSA-A No longer used
pronounced failure of the autonomic
nervous system
MSA = multiple system atrophy; OPCA = sporadic olivopontocerebellar atrophy.
From Gillman S, Wenning P, Low PA, et al: Second consensus statement of the diagnosis of multiple system atrophy. Neurology 2008;71:670676.
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640 Chapter 31 Sleep and Neurologic Disorders
sleep. A normal laryngeal examination during wakeful- Positron Emission Tomography Scan
ness does not rule out the problem.36 The presence of Positron emission tomography (PET) reveals nearly absent
stridor is associated with a poor prognosis (compared with or very low activity of the thalamus.
MSA patients without stridor) and has traditionally been
managed by tracheostomy. Recently, CPAP has been used Summary
to assist with stridor at night.36,37 Patients with MSA often FFI should be considered in any patient with prominent
have OSA as well as worsening stridor during sleep. The sleep-wake disturbance and dementia. Treatment is
etiology of stridor is controversial but is likely due to over- supportive.
activity of the vocal cord adductors (close vocal cords) and
underactivity of vocal cord abductors (posterior cricoaryte-
Sleep Disturbances in Stroke
noid muscles [PCAs]). A neuropathy of the recurrent laryn-
geal nerves that innervate the PCA muscles may be involved. Important points concerning stroke and sleep are listed in
The syndrome of stridor in many patients is a dystonia rather Box 3111. SDB occurs in 50% to 70% of stroke patients
than vocal cord paralysis. In others, there is complete vocal (defined by apnea-hypopnea index [AHI] > 10/hr).4246
cord immobility. Sudden death has been reported in MSA Central sleep apnea including CSB can be noted, especially
patients with stridor even though treated with tracheostomy soon after stroke, but tends to decrease with time. CSB in
or CPAP.37,38 some chronic stroke patients is associated with heart
failure.45,46 Other patients with stroke and central sleep apnea
Central Apnea and Cheyne-Stokes Breathing Central apnea, have occult heart failure.47 OSA is the most common
nocturnal hypoventilation, and Cheyne-Stokes breathing
(CSB) have been reported in MSA, especially in patients with BOX 3110
prominent autonomic features.39
Fatal Familial InsomniaDiagnostic Criteria
Treatment of MSA The treatment of MSA is mostly support- A. Complaint of insomnia is initially present and becomes
ive. There is usually no or only a short initial response to LD. progressively more severe.
Patients with stridor can be treated with CPAP or tracheos- B. Progressive autonomic hyperactivity with pyrexia,
tomy (although sudden death can still occur at night). hypersalivation, hyperhydrosis, cardiac and respiratory
dysfunction, tremor-like muscle activity.
C. Polysomnographic monitoring demonstrates
Other Neurodegenerative Disorders i. Loss of sleep spindles.
Fatal Familial Insomnia ii. Loss of slow wave sleep.
Fatal familial insomnia (FFI) is a familial autosomal domi- iii. Dissociated REM sleep.
nant prion disorder associated with the D178N mutation D. The disorder is not better explained by another sleep
and methionine-methionine genotype at codon 129 in the disorder, medical or neurologic disorder, mental
disorder, medication use, or substance use disorder.
prion protein gene on chromosome 20.40,41 Of note, the
D178N mutation and valine-valine genotype at codon 129 OR
are associated with familial Creutzfeldt-Jakob disease (CJD). E. A missense GAC to AAC mutation at codon 17 of the
PRNP gene (d178N) co-segregating with the methionine
Topography of Degeneration polymorphism at codon 129 of the PRNP on the
Methionine-methionine genotype at codon 129 produces mutated allele is found (this mutation is absent in
dorsomedial and anteroventral thalamic dysfunction, sporadic fatal familial insomnia).
whereas the valine-valine genotype of CJD is associated with REM = rapid eye movement.
Adapted from International Classification of Sleep Disorders, 2nd ed.
more general cortical involvement.
Westchester, IL: American Academy of Sleep Medicine, 2005.
FFI Manifestations
FFI manifestations include insomnia, dementia, ataxia, dys- BOX 3111
arthria, dysautonomia, hallucinations, and hypersomno-
Stroke and Sleep Apnea
lence. The duration from onset to death varies from a few
months to 4 years. OSA > CSA are common in patients after CVA.
If OSA is present, adequate treatment may improve
Diagnosis outcome.
The International Classification of Sleep Disorders, 2nd CPAP treatment is often challenging, especially in
edition (ICSD-2), diagnostic criteria for FFI are listed in Box nonsleepy patients.
3110. The PSG in FFI reveals severe disruption of the sleep- Incidence of stroke increased in men with mild to
wake cycle, loss of sleep spindles, reduction in stage N3 and moderate OSA.
stage R, as well as reduced sleep efficiency. REM sleep CSA = central sleep apnea; CVA = cerebrovascular accident; OSA =
obstructive sleep apnea.
without atonia can occur.
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Chapter 31 Sleep and Neurologic Disorders 641
35. Gillman S, Wenning P, Low PA, et al: Second consensus state- 46. Hermann DM, Siccoli M, Kirov P, et al: Central periodic
ment of the diagnosis of multiple system atrophy. Neurology breathing during sleep in ischemic stroke. Stroke 2007;38:
2008;71:670676. 10821084.
36. Iranzo A: Management of sleep-disordered breathing in mul- 47. Nopmaneejumruslers C, Kaneko Y, Hajek V, et al: Cheyne-
tiple system atrophy. Sleep Med 2005;6:297300. Stokes respiration in stroke: relationship to hypocapnia and
37. Kuniar TJ, Morgenthaler TI, Prakash UBS, et al: Effects of occult cardiac dysfunction. Am J Respir Crit Care Med
continuous positive airway pressure on stridor in multiple 2005;171:10481052.
system atrophysleep laryngoscopy. J Clin Sleep Med 2009; 48. Shahar E, Whitney CW, Redline S, et al: Sleep-disordered
5:6567. breathing and cardiovascular disease: cross-sectional results of
38. Silber MH, Levine S: Stridor and death in multiple system the Sleep Heart Health Study. Am J Respir Crit Care Med
atrophy. Mov Disord 2000;15;699714. 2001;163:1925.
39. Sadaoka T, Kakitsub N, Fujiwara Y, et al: Sleep-related breath- 49. Redline S, Yenokyan G, Gottlieb DJ, et al: Obstructive sleep
ing disorders in patients with multiple system atrophy and apnea-hypopnea and incident stroke: the Sleep Heart Health
vocal fold palsy. Sleep 1996;19:479484. study. Am J Respir Crit Care Med 2010;182:269277.
40. Lugaresi E, Tobler I, Montagna P, et al: Fatal familial insomnia 50. Sugita Y, Susami I, Yoshio T, et al: Marked episodic elevation
and dysautonomia with selective degeneration of thalamic of cerebral spinal fluid pressure during nocturnal sleep in
nuclei. N Engl J Med 1986;315:9971003. patients with sleep apnea hypersomnia syndrome. Electroen-
41. Montagna P, Gambetti P, Cortelli P, Lugaresi E: Familial and cephalogr Clin Neurophysiol 1985;60:214219.
sporadic fatal insomnia. Lancet Neurol 2003;2:167176. 51. Balfors EM: Impairment of cerebral perfusion during obstruc-
42. Hermann DM, Bassetti CL: Sleep-related breathing and sleep tive sleep apneas. Am J Respir Crit Care Med 1994;150:
wake disturbances in ischemic stroke. Neurology 2009;73: 15871591.
13131322. 52. Good DC, Henkle JQ, Gelber D, et al: Sleep disordered breath-
43. Turkington P, Bamfor J, Wanklyn P, et al: Prevalence and pre- ing and poor functional outcome after stroke. Stroke 1996;
dictors of upper airway obstruction in the first 24 hours after 27:252259.
acute stroke. Stroke 2002;33:20372041. 53. Martinez-Garcia MA, Soler-Cataluna JJ, Ejarque-Martinez L, et
44. Para O, Arboix A, Bechichi S, et al: Time course of sleep-related al: Continuous positive airway pressure treatment reduces
breathing disorders in first-ever stroke or transient ischemic mortality in patients with ischemic stroke and obstructive sleep
attack. Am J Respir Crit Care Med 2000;161:375380. apnea: a five-year follow-up. Am J Respir Crit Care Med
45. Siccoli MM, Valko PO, Hermann DM, Bassetti CL: Central 2008;180:3641.
periodic breathing during sleep in 74 patients with acute isch- 54. Lee SJ, Kim JS, Song IU, et al: Post-stroke restless legs syndrome
emic strokeneurogenic and cardiogenic factors. J Neurol and lesion location. Anatomical considerations. Mov Disord
2008;255:16871692. 2008;24:7784.
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NMDA = N-methyl-d-aspartate.
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Glossary endogenous circadian rhythm and exogenous factors (clock time, soci-
etal demands) that affects timing or duration of sleep.
A Confusional arousals A parasomnia characterized by confusion after
AASM American Academy of Sleep Medicine. a spontaneous or forced arousal from sleep. Confusional arousals
AASM scoring manual The AASM Manual for the Scoring of Sleep and tend to occur out of stage N3 sleep. In contrast to sleep terrors, there is
Associated Events. Iber C, Ancoli-Israel S, Chesson AL, Quan SF. West- no autonomic hyperactivity, signs of fear, or blood-curdling scream.
chester, IL, American Academy of Sleep Medicine, 2007. Continuous positive airway pressure (CPAP) Maintenance of positive
Adaptive servoventilation A mode of positive airway pressure that varies airway pressure during inspiration and expiration.
pressure support (IPAP-EPAP) to stabilize ventilation (or flow). ASV is Core body temperature minimum (CBTmin) Minimum core body tem-
used for Cheyne-Stokes breathing or complex sleep apnea. perature occurs about 2 hours before habitual wake time, a marker of
Advanced sleep phase syndrome (ASPS) Characterized by early sleep circadian phase.
onset and early wake time relative to societal (clock) norms in the CPAP flow The flow signal from the positive airway pressure device uti-
external world. lized in polysomnography (also known as PAP flow).
Alpha activity EEG activity of 813 Hz (see Alpha rhythm).
Alpha-delta sleep Prominent alpha activity occurring during stage N3 D
sleep. Delayed sleep phase syndrome (DSPS) Characterized by delayed sleep
Alpha rhythm 8- to 13-Hz activity recorded over the occipital region onset and final wake-time relative to societal (clock) norms in the exter-
during eye closure and attenuated with eye opening. nal world.
Alpha sleep Prominent alpha activity occurring during NREM sleep. Delta activity EEG activity at less than 4 Hz. In human sleep staging, slow
Apnea Absence of air flow (90% reduction) at the nose and mouth for 10 wave activity (SWA) is defined as a frequency 0.5 to 2 Hz with greater
seconds or longer (using oronasal thermal sensor or CPAP flow). than 75 V peak-to-peak amplitude (see Slow wave activity).
Apnea-hypopnea index (AHI) The number of apneas and hypopneas per Derivation A set of two electrodes and the voltage difference between them
hour of sleep. (e.g., C4-M1).
Arousal In NREM sleep, an arousal is an abrupt shift in EEG frequency Desaturation Fall in arterial oxygen saturation from baseline, usually a 4%
including alpha, theta, and/or frequencies greater than 16 Hz (but not or greater decrease.
spindles) that lasts at least 3 seconds with at least 10 seconds of stable Dim light melatonin onset (DLMO) The time that serum melatonin starts
sleep preceding the change. Scoring of an arousal during REM sleep to increase above daytime levels under dim light conditions. The DLMO
requires a concurrent increase in the submental EMG that lasts at least occurs about 2 to 3 hours before habitual bedtime or 7 hours before
1 second. CBTmin and is a marker of circadian timing (see Chapter 26).
ASDA American Sleep Disorders Association, now called the American Diurnal Pertaining to daytime.
Academy of Sleep Medicine.
AutoCPAP (APAP) Autoadjusting or autotitrating CPAP units that deliver E
the lowest required pressure at any time needed to maintain upper E1, E2 Left and right electrode positions to recorded eye movements. The
airway patency. recommended derivations are E1-M2 and E2-M2. E1 is 1 cm below the
Automatisms Involuntary or unconscious movements often described as left outer canthus and E2 is 1 cm above the right outer canthus (see
purposeless. They may mimic purposeful behaviors but are of no Chapter 1).
benefit. Early morning awakening Final awakening earlier than expected; charac-
teristic of depression, sleep-maintenance insomnia, or the advanced
B sleep phase syndrome.
Beta activity EEG activity greater than 13 Hz. Electroencephalogram (EEG) Recording of brain electrical activity.
Bilevel positive airway pressure (BPAP) Method of ventilation allowing Electromyogram (EMG) Recording of the electrical activity of a muscle.
separately adjustable pressure levels in inspiration (inspiratory positive In routine sleep monitoring, surface electrodes monitor EMG activity
airway pressure [IPAP]) and expiration (expiratory positive airway pres- in the chin area (three electrodes) and the right and left anterior tibialis
sure [EPAP]). muscle (see Chapters 1 and 7).
Biocalibration Recording of voluntary maneuvers during wakefulness at Electro-oculogram (EOG) Recording of the electrical activity generated
the beginning of polysomnography to determine if the EEG, EOG, chin during eye movements. In some texts the term is spelled without a
and leg EMG, ECG, airflow, respiratory effort, and oximetry signals are hyphen (electrooculogram).
adequate. Electrodes of sensors are replaced or repositioned if necessary. EPAP Expiratory positive airway pressure.
Biocalibrations are useful to determine if alpha rhythm is produced with Epoch A period of time usually corresponding to 30 seconds (one page of
eye closure and to note the appearance of eyes open wakefulness. recording at a paper speed of 10 mm/sec).
Bruxism Clinching or grinding of the teeth (see Chapter 12 for scoring Epworth Sleepiness Scale (ESS) A score from 0 to 24 of the propensity to
rules). fall asleep in eight normal situations (see Chapter 14). Normal is 10 or
less, and 24 is the maximal ESS score (the most sleepy).
C
C3, C4 Central EEG electrode on the right (left) side of the head. F
Capnogram Tracing of exhaled PCO2 versus time. The plateau of the delec- F3, F4 Frontal electrodes over the right and left frontocentral portions of
tion from each exhalation is the end-tidal PCO2 (an estimate of the the brain.
arterial PCO2). FEV1/FVC Ratio of the forced expiratory volume in 1 second to the forced
Cataplexy Sudden loss of muscle tone (especially antigravity muscles) at vital capacity. Reduced in obstructive airway disease. In this text, normal
moments of high emotion (e.g., surprise, laughter, fear) with preserva- is 0.70 and 90% of predicted.
tion of consciousness, characteristic of narcolepsy. Forced expiratory volume in 1 second (FEV1) The volume of air in
Central apnea Apnea associated with an absence of respiratory effort. liters exhaled in the first 1 second of a maximal forced vital capacity
Cheyne-Stokes breathing Crescendo-decrescendo pattern of breathing maneuver. In this text, normal is assumed to be 80% to 120% of
with central apneas or hypopneas at the nadir. predicted.
Chronic obstructive pulmonary disease (COPD) Chronic bronchitis, Forced vital capacity (FVC) Volume of air in liters exhaled from maximal
emphysema, or a mixture. inhalation (total lung capacity) to residual volume (maximal exhalation)
Circadian rhythm sleep disorder (CRSD) Pattern of sleep disturbance due during a forced maneuver. In this text, normal is assumed to be 80% to
to alterations of the circadian timing system or misalignment between 120% of predicted.
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647
648 Glossary
H Multiple sleep latency test (MSLT) Test to determine the mean sleep
Hypnagogic An event occurring on transition from wake to sleep. latency during daytime naps as an objective measure of daytime sleepi-
Hypnagogic hallucination Vivid imagery at sleep onset; a feature of nar- ness and the presence of REM sleep without 15 minutes of sleep onset
colepsy in which REM periods occur at sleep onset (see Chapter 24). (sleep-onset REM periods). A diagnosis of narcolepsy requires 2 or
Hypnic jerk (sleep start) Brief total body jerk at sleep onset. more SOREMPs (see Chapter 14).
Hypnogram A graphical overview of the cyclic nature of sleep (see
Chapter 6). N
Hypnopompic An event occurring on transition from sleep to Nasal pressure Used to detect airflow = K flow2, where K is a constant
wakefulness. (see Chapter 7).
Hypnopompic hallucination Vivid imagery at the transition from sleep to Nonrapid eye movement (NREM) sleep Sleep stages N1, N2, N3.
wake (see Chapter 24).
Hypocretins Two peptides, Hcrt 1 and Hcrt 2 (also known as orexins A O
and B), that are secreted by lateral posterior hypothalamic neurons. O1, O2 Occipital EEG electrode on the left and right side of the head.
Hypocretins project to many brain areas involved with the control of Obesity-hypoventilation syndrome (OHS) Daytime hypoventilation
sleep and wake. CSF hypocretin 1 is absent or very low in 90% to 95% (hypercapnia) not secondary to lung disease in an obese patient, usually
of patients with narcolepsy + cataplexy (see Chapters 7 and 24). accompanied by severe obstructive sleep apnea.
Hypopnea Reduction in air flow for 10 seconds or longer. Definitions vary Obstructive apnea Apnea with persistent respiratory effort.
(see Chapter 9). Obstructive sleep apnea syndrome (OSAS) Syndrome characterized by
obstructive and mixed apnea and hypopneas. In adults, the diagnostic
I criteria include an AHI of 5/hr or greater with symptoms or 15/hr with
ICSD-1, ICSD-2 International Classification of Sleep Disorders, 1st and or without symptoms.
2nd editions. Overlap syndrome Obstructive sleep apnea plus chronic obstructive
Interictal Refers to transient focal or generalized discharges between pulmonary disease (OSA + COPD).
seizure events.
K P
Paradoxical insomnia The patient shows a consistent mismatch
K complex A well-delineated large-amplitude biphasic complex consisting
between objective findings from PSG or actigraphy and subjective
of a negative sharp wave (upward deflection) followed by a positive
sleep estimates derived from either sleep report or sleep diary (see
component (downward) standing out from the background EEG, with
Chapter 25).
a total duration of 0.5 seconds or longer, usually maximal in the frontal
Parasomnia A condition associated with or occurring from sleep. Disor-
derivations.
ders of arousal or partial arousal. Examples include sleepwalking, night
K complex with arousal An arousal is associated with a K complex when
terrors, and REM sleep behavior disorder (see Chapter 28).
it commences no more than 1 second after termination of the K complex.
Periodic limb (leg) movementarousal index (PLM-arousal index)
L Number of PLMs associated with arousal per hour of sleep.
Laser-assisted uvuloplasty (LAUP) Palatoplasty performed with a laser. Periodic limb movement disorder (PLMD) A disorder of sleep distur-
Left outer canthus (LOC) Outer corner of the left eye (formerly left eye bance resulting in a sleep complaint (insomnia or, less often, excessive
electrode placed slightly lateral and below the LOC). daytime sleepiness) secondary to PLMS when other causes have been
Low-amplitude mixed frequency activity (LAMF) Low amplitude, pre- ruled out. A diagnosis of RLS excluds a diagnosis of PLMD. A diagnosis
dominantly 4 to 7 Hz activity. of PLMD requires a PLMS index greater than 5/hr in children or 15/hr
Low chin EMG tone (REM level) Baseline chin EMG activity in the chin in adults. However, the normal range of the PLMS index is not well
derivation no higher than in any other sleep stage and usually the lowest defined and can be higher than 15/hr in normal elderly individuals (see
level of the entire recording (see Chapter 3). Chapter 23).
Periodic limb (leg) movement in sleep (PLMS) Leg movements charac-
M terized by foot flexion, big toe extension, and partial flexion at hip
M1, M2 Left and right mastoid electrodes (formerly A1 and A2). Frontal, and knee. To be considered part of a PLMS series (e.g., a PLM separately
central, occipital, E1, and E2 electrodes are referred to the mastoid elec- by 5 and 90 seconds from onset to onset of consecutive movements),
trodes (see Chapter 1). a leg movement must be 0.5 to 10 seconds in duration and must occur
Maintenance of wakefulness test (MWT) Test to determine the ability to in a group (sequence) of four or more movements (see Chapters 12
stay awake (see Chapter 14). and 23).
Major body movement (MBM) Movement and muscle artifact obscuring Periodic limb (leg) movement in sleep index (PLMS index or PLMSI)
the EEG for more than half of the epoch to the extent that the sleep stage Number of movements per hour of sleep.
cannot be determined (see Chapter 3 for scoring rules for epochs with Phase response curve (PRC) A curve characterizing the magnitude and
a MBM). direction of the shift of the internal clock (circadian rhythm) induced
Mean sleep latency (MSL) The mean of sleep latencies recorded during by light (or exogenous melatonin) as a function of the timing of light
naps over the course of a multiple sleep latency test or a maintenance relative to the baseline circadian rhythm (relative to the nadir in body
of wakefulness test. temperature).
Mixed apnea Apnea composed of an initial central part followed by an Phasic REM sleep REM sleep in which rapid eye movements are present.
obstructive component. Polysomnography The detailed monitoring of sleep.
Montage The particular arrangement of a number of derivations that are Popping artifact High-voltage artifact caused by temporary disconnection
displayed simultaneously in a polysomnogram. of electrodes from the skin (see Chapter 4).
Movement arousal Defined in the R&K scoring manual as an increase in Psychophysiologic insomnia Conditioned sleep difficulty falling asleep in
the chin EMG accompanied by a change in pattern on any additional bed at the desired time (the bedroom is a stimulus for arousal), height-
channel. For EEG channels, qualifying changes include a decrease in ened arousal and difficulty relaxing in bed, excessive focus on sleep, and
amplitude, paroxysmal high-voltage activity, or an increase in alpha ability to sleep better away from home.
activity. Not used in the AASM scoring manual.
Movement time (MT) The total duration of epochs in which the sleep stage R
is indeterminant owing to movement artifact in the EEG. Not used in R&K The sleep staging criteria of Rechtschaffen and Kales, published in A
the AASM scoring manual (see Major body movement).
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Manual of Standardized Terminology Techniques and Scoring System
Glossary 649
for Sleep Stages of Human Sleep. Los Angeles: UCLA, Brain Information derivations, characteristic of stage N2 (can also occur in stage N3) (see
Service/Brain Research Institute, 1968. Chapters 1 and 3).
Rapid eye movement density Number of eye movements per time in REM Sleep stages Stage N1 (formerly stage 1), stage N2 (formerly stage 2), stage
sleep. Normally highest during the last REM peiods of the night. N3 (formerly stage 3 + stage 4), and stage R (formerly stage REM) (see
Rapid eye movement sleep Stage R (see Chapters 3 and 5 for scoring Chapters 3 and 5 for scoring criteria).
rules). Sleep starts (hypnic jerk) Brief whole body jerk at sleep onset.
Rapid eye movement sleep behavior disorder (RBD) A parasomnia Sleep state misperception (see Paradoxical insomnia).
occurring from REM sleep associated with REM without atonia and Sleep terrors A parasomnia characterized by sudden awakening from
dream enactment often with body movements and violent behavior (see NREM sleep (usually stage N3 in children, but any stage of NREM sleep
Chapter 28). in adults) with a cry or scream, confusion, and autonomic hyperactivity.
Rapid eye movements (REMs) Conjugate, irregular, sharply peaked eye Sleepwalking (somnambulism) Characterized by a partial awakening
movements with an initial deflection lasting less than 500 msec. REMs from NREM sleep (classically from stage N3 in children, but also N1
can be seen during eyes open wake or stage R. and N2 in adults) with complex movements including walking.
Recording time; time in bed (TIB) Total time of sleep monitoring from Slow rolling eye movement or slow eye movements (SEMs) Smooth,
lights out to lights on. undulating eye movements occurring during drowsy wakefulness and
REM latency Time from sleep onset to the start of stage R. stage N1 sleep.
Respiratory arousal index (RAI) Arousals secondary to an apnea or Slow wave activity (SWA) Waves of frequency 0.5 to 2 Hz with a peak-to-
hypopnea, and in some sleep laboratoies, respiratory effortrelated peak amplitude greater than 75 V. The amount of SWA determines
arousals. whether stage N2 or N3 is present. Score stage N3 when SWA is 20% or
Respiratory disturbance index (RDI) Definitions vary, RDI = AHI, RDI higher.
= AHI + RERA index, RDI = apneas + hypopneas/monitoring time Slow waves (delta waves) EEG waves with a frequency of 1 to 4 Hz (see
(Centers for Medicare and Medicaid Services definition used for home Slow wave activity).
sleep testing). The RDI was not defined in the AASM scoring manual SOREMPs Sleep-onset rapid eye movement periods. Stage R begins 15
OR in the ICSD-2. minutes or less (clock time) after sleep onset.
Respiratory effortrelated arousal (RERA) An event characterized by an Spike An EEG transient with a pointed peak and a duration of 20 to
arousal following a period of increased respiratory effort lasting 10 70 msec.
seconds or longer that does not qualify as an obstructive apnea or Suprachiasmatic nucleus (SCN) Major circadian pacemaker in humans
hypopnea. Increased respiratory effort is detected by increased esopha- (see Chapter 27).
geal pressure deflections or flattening of the nasal pressure signal (see Sweat artifact Slow undulations in EEG and EOG tracings secondary to
Chapter 8). sweat (see Chapter 4).
Respiratory inductance plethysmography (RIP) A method of detecting
chest and abdominal movement secondary to changes in the inductance T
(a component of impedance) of bands around those regions. Used to Ten-twenty system An international standard for the placement of EEG
detect respiratory effort (see Chapters 7 and 8). electrodes in which spacing of electrodes is 10% or 20% of the distance
Restless legs syndrome (RLS) Syndrome marked by URGE: urge to move between landmarks on the head (see Chapters 1 and 27).
legs, rest makes symptoms worse, gets better with movement (partial Theta activity EEG activity at 4 to 7 Hz.
temporary improvement), and worse in the evening. The urge to move Three-minute rule An R&K scoring rule for determining how long stage
is often associated with uncomfortable sensation in the legs that can be N2 could continue without a sleep spindle or K complex. Not used in
temporarily relieved by movement. the AASM scoring manual.
Right outer canthus (ROC) Right outer corner of the eye. The ROC elec- Time in bed (TIB) Recording time total monitoring time, from lights out
trode is placed lateral to the ROC and slightly above the eye. The ROC to lights on.
terminology and electrode placement has been replaced by the E2 elec- Tonic REM sleep REM sleep in which rapid eye movements are absent.
trode (AASM scoring manual). Total sleep time (TST) Total minutes of stages N1, N2, N3, and R.
Transient muscle activity (TMA) Short irregular bursts of EMG activity
S usually with a duration less than 0.25 seconds superimposed on low
Saw-tooth waves Trains of sharply contoured or triangular, often serrated, EMG tone during stage R. The activity may be seen in the chin or ante-
2- to 6-Hz waves maximal over the central regions, characteristically rior tibial EMG derivations. Formerly called phasic activity.
seen during stage R, often before a burst of eye movements.
Sharp wave Duration 70 to 200 msec. U
Sleep architecture The relative amounts of the different sleep stages com- Upper airway resistance syndrome (UARS) Syndrome characterized by
posing sleep and timing of sleep cycles (see Chapter 6). daytime sleepiness secondary to frequent arousals related to increased
Sleep efficiency Usually defined as total sleep time 100/time in bed. respiratory effort during periods of high upper airway resistance (nar-
Sleep hygiene Conditions and practices that promote continuous and rowing) without an abnormal amount of frank apnea or hypopnea. Most
effective sleep. authorities believe it is simply a mild form of OSA.
Sleep latency Time from lights out (statistic of monitoring period) to the Uvulopalatopharyngoplasty (UPPP) An upper airway surgery for sleep
first epoch of any stage of sleep. apnea and snoring. The uvula, a portion of the soft palate, and excess
Sleep-maintenance insomnia Difficulty maintaining sleep; frequent pharyngeal tissues are removed.
awakenings.
Sleep-onset insomnia Difficulty falling asleep (usually sleep latency > V
30 min). Vertex sharp wave A negative sharp wave (upward deflection) with highest
Sleep paralysis Inability to move while still awake at sleep onset (hypnago- amplitude in derivations containing electrodes near the vertex (e.g., Cz)
gic) or at the end of a sleep period (hypnopompic). Sleep paralysis can characteristic of stage N1 (typically near transition to stage N2). Accord-
occur in normal individuals but is one of the symptoms of narcolepsy. ing to the AASM scoring manual, vertex sharp waves have a duration
Episodes of sleep paralysis may be associated with hallucinations. less than 500 msec (usually sharp waves are defined as <200 msec).
Sleep period time (SPT) Time from sleep onset until the final awakening.
Not used in the AASM scoring manual. W
Sleep spindle EEG activity of 11 to 16 Hz (most commonly 1214 Hz) Wake after sleep onset (WASO) Wake after sleep onset during the time in
with a duration of 0.5 second or greater, usually maximal in central
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bed (wake from sleep onset to lights on).
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Index
Note: Page numbers followed by f refer to figures; page numbers followed by t refer to tables; page numbers followed by b refer to boxes.
Autoadjusting positive airway pressure devices, Cannula flow, 106f Cheyne-Stokes breathing with central sleep
315, 316f Capnography, 113, 113f apnea, 385390
Autobilevel positive airway pressure, 317, 317f Carbamazepine (Tegretol), 604605 pathophysiology of, 386, 388f, 400t
Automatisms, 556 Cardiac monitoring during polysomnography polysomongraphy in, 385386, 386f387f
Automobile accidents, obstructive sleep apnea aberrant conduction, 167 treatment of, 386390, 388b, 389f
and, 286 adverse events during polysomongraphy, Chiaris malformation, 396
Autonomic arousals, 273274 172 Children. See also Pediatric obstructive sleep
Autotitration technique, 335, 335t afib and atrial flutter, 170172 apnea; Pediatric respiratory events;
AV block, 166167 Pediatric rules for scoring sleep; Sleep
B bradycardia and AV block during sleep, architecture
Bariatric surgery, 304 164168 multiple sleep latency tests in, 225, 225t
Basal forebrain, 96 conduction system and, 164 normal heart rate during wakefulness, 163t
Beck Depression Inventory, 485486 ECG recording, 160162 normal sleep and, 85, 86t
Behavioral insomnia of childhood, 493495, narrow-complex tachycardia, 168170 sleep duration by age, 86, 87t
494b pacemakers and wide-complex QRS, Chin EMG monitoring, 9, 9f10f, 37
graduated extinction and, 495 172173 Chronic bronchitis, 411t
key features of, 494 premature beats, 167168 Chronic obstructive pulmonary disease
modified extinction and, 494495 sinus pause/asystole, 165166 (COPD), 142, 149, 411420
treatment of, 494495, 495t sinus rhythm and normative data for heart abnormal nocturnal gas exchange and, 412,
unmodified extinction and, 494 rate, 162164 413f
Behaviorally induced insufficient sleep tachycardias during sleep, 168172 bronchodilators and, 418419
syndrome, 472, 472b wide-complex tachycardia, 172 functional residual capacity and, 413f
Bells phenomenon, 551, 551f552f Cardiovascular disease, obstructive sleep apnea GOLD criteria for, 411t
Benign epilepsy of childhood with and, 286288, 287t hypnotics and, 419420
centrotemporal spikes, 562 Cataplexy, 457 major mechanisms of, 412b
Benzodiazepine receptor agonists, 500505, isolated cataplexy in medical and neurologic nocturnal noninvasive positive-pressure
500t, 600602 disorders, 469470 ventilation and, 420
effects and side effects of, 482b, 501502, mechanisms of, 454 nocturnal oximetry in, 412f
501t medications used to treat, 467t non-rapid eye movement and, 414
general considerations for, 502, 503t preserved consciousness and, 457 nonapneic desaturation and, 415416, 415f
medication choice and, 504505, 504t treatment of, 465466, 466t normal individuals and, 412413
restless legs syndrome and, 441t Catathrenia, 581583, 582b overlap syndrome, 420
Berlin questionnaire, 259 diagnosis of, 582, 582f rapid eye movement and, 414415,
Beta blockers, insomnia and, 495496 differential diagnosis of, 582 414f415f
Bilevel positive airway pressure epidemiology of, 581 respiration during sleep and, 416417, 417f,
obstructive sleep apnea and, 325334 polysomongraphy and, 581582 417t
titration guidelines, 332t treatment of, 583 sleep quality in, 412420
Biocalibrations, 5051, 51f52f, 51t Catechol-O-methyl transferase inhibitors, 635 sleep-related changes in respiration and,
Biofeedback, insomnia and, 498 Central derivations, 554 413416, 414f
Bipolar depression, 603, 604t, 606f Central hypopnea, 127128, 129f supplemental oxygen and, 417420, 418b,
Bipolar disorders, 603605, 603b Central sleep apnea, 122, 123f124f, 130, 136 418t
acute mania, 604605 apneic threshold and, 381382, 381f time of night and circadian variation of lung
approved medications for, 605t with cardiac oscillations, 132f function, 416
bipolar depression, 603, 604t, 605 Cheyne-Stokes breathing and, 385390 treatment of sleep-related hypoxemia in,
genetics and, 604 Chiaris malformation and, 396 417420
maintenance treatments and, 605 complex sleep apnea, 390391 Chronic partial sleep deprivation, 88, 88f, 89t
mixed episodes, 605 due to medication, 396397, 397b, 397f398f Chronotherapy, nocturnal asthma and, 424
sleep and, 603604, 604t hypercapnic, 392401 Circadian clock genes, 524525, 525t
treatment of, 604605, 604b hypocapnic, 382385 Circadian phase markers, 518520, 518b, 519f
Bipolar electroencephalogram recordings, 65, idiopathic, 383385 Circadian rhythm shifting, 520524
66f loop gain and, 382, 382f383f phase-response curve for light, 521522,
Bipolar longitudinal montages, 546548, mechanisms inducing, 380t 522f
547f, 548t multiple system atrophy and, 640 phase shifting by exogenous melatonin,
Bipolar recording, 1417, 14t, 15f neural disorders causing hypoventilation 522524, 522t
Bland-Altman plot, 196197, 198f and, 396397 phase shifting by light, 520521, 520b,
Body-mass index, narcolepsy and, 457 neuromuscular weakness and, 400401, 401f 520f521f
Bradycardia, 164168 normal physiologic changes and, 379380, Circadian rhythm sleep disorders (CRSD)
Bradytachycardia, 289 380t advanced sleep phase disorder, 529530
Brain areas important for sleep, 9196, 92t pathophysiology of, 379382 circadian phase markers, 518520, 518b
activities of, 95t primary sleep apnea of infancy, 397398, circadian physiology facts, 517b
brainstem regions, 9496 399b circadian rhythm shifting, 520524
hypothalamic areas, 9194 restrictive thoracic disorders and, 398400, delayed sleep phase disorder, 526529
Brainstem regions, 91, 93f, 9496 399f due to drug or substance, 540
basal forebrain, 96 syndrome classification, 377379, 377b378b due to medical conditions, 540
dopamine regions, 9495 upper airway and posture effects and, 382 free-running type, 532537
reticular formation, 9596 ventilatory control and, 380382 general diagnostic criteria for, 525b
Bronchodilator testing, 150 Cerebrovascular accidents genomics of, 524525
Bronchodilators, chronic obstructive obstructive sleep apnea and, 292293 irregular sleep-wake type, 530532
pulmonary disease and, 418419 sleep disturbances and, 640641, 640b jet lag type, 533534
Bruxism, 182184, 183f, 183t Channel settings/montages, 2223, 23f melatonin and, 516517
Bundle branch block, 164 Chest-abdominal paradox, 128130, 130f morningness-eveningness questionnaire and,
Bupropion, 599600, 601t Cheyne-Stokes breathing, 132, 133f134f, 526
318319, 319f polysomnography and, 214
C idiopathic central sleep apnea and, 382383, shift-work type, 537540
C-Flex, 320321, 320f 383t, 384f suprachiasmatic nucleus and sleep-wake
Calibrations, 4950 multiple system atrophy and, 640 DaneshGroup.com
cycle, 517518
Index 653
Circadian variation of lung function Diffuse Lewy body dementia, 638, 639b Electroencephalography (EEG) (Continued)
asthma and, 421, 421f dementia variant and, 638 electroencephalographic patterns, 37
chronic obstructive pulmonary disease and, dopamine blocker sensitivity and, 638 newborn infants and, 6566, 66t, 68f
416 manifestations of, 638 patterns by conceptual age, 67f
Claudication, restless legs syndrome and, 433 visual hallucinations and, 638 Electroencephalography and nocturnal
Clonic seizures, 556 Diffusing capacity for carbon dioxide, 151152, epilepsy. See also Nocturnal epilepsy
Closed airway central apnea, 318319 151t bipolar monitoring and standard montages,
Co-morbid insomnia, 499500, 506 Digital gain adjustment, 2223, 23f 546548, 547f
Coffin-Lowry syndrome, 470 Digital polysomnography (PSG) systems, electroencephalographic monitoring,
Cognitive therapy, insomnia and, 497 2025, 22f. See also Polysomnography 545546
Comfort measures, positive airway pressure channel settings/montages, 2223 eye movements and Bells phenomenon, 551,
and, 320322 grounds, 2425 551f552f
Complex nocturnal visual hallucinations, impedance checking and, 23 ictal activity, 554556, 555f
583584, 584b montages for digital recording, 2122 localization in referential and PSG montages,
Complex partial seizure, 556 referential display view and, 23 549551, 550f
Complex sleep apnea, 390391 video-audio PSG, 24 normal sleep waveforms in the 10-second
incidence and natural history of, 390 Dissociative disorder not otherwise specified, window, 551554
pathophysiology of, 390 580 phase reversal and, 549, 550f
polysomnography and, 390, 391f Dissociative fugue state, 580 positive occipital sharp transients of sleep
treatment of, 390391 Dissociative identity disorder, 580 and lambda and mu rhythms,
Conduction system, cardiac, 164, 164f Disturbed nocturnal sleep, narcolepsy and, 457 552554
Confusional arousals, 568569, 569b Divalproex (Depakote), 604605 posterior rhythm, 551552, 552f
diagnosis of, 569 Dominant posterior rhythm, 70, 71t, 551552, waveform and seizure terminology, 548549,
differential diagnosis of, 569 552f 549t
polysomnographic findings during, 569, 569f Dopamine agonists, 635 Emphysema, 411t
precipitating and predisposing factors, 569 Dopamine dysregulation syndrome, 440442 End of REM sleep, 37, 37t
prevalence of, 568 Dopamine regions, 9495 Enuresis. See Sleep enuresis
treatment of, 569 Dopaminergic medications Epileptiform activity, 548
variants of, 569 periodic limb movement disorder and, Episodic nocturnal wanderings, 560561
Congestive heart failure, obstructive sleep 440443 Epworth Sleepiness Scale, 219221, 220f221f,
apnea and, 292 restless legs syndrome and, 440443, 441t 220t, 241, 242f, 242t, 485
Continuation of REM sleep, 37, 37t, 38f side effects from, 442b Erectile dysfunction, obstructive sleep apnea
Continuous positive airway pressure, Dorsal raphe nucleus, 96 and, 293
obstructive sleep apnea and, 325334 Dorsal reticular activating system, 95 Esophageal pressure deflections, 107108,
Conversion disorder, hypersomnia associated Downward deflection, 7 108f
with, 474 Doxepin, 505506, 505t, 600 Eszopiclone, 600602, 601f
Convulsive epilepsy, 556 Drug or substance, parasomnia due to, 585 Ethnicity, obstructive sleep apnea and, 240
Coronary artery disease, obstructive sleep Drug or substance-related insomnia, 495, 496b Event duration rules, 122123, 126f
apnea and, 290291, 291f abstinent alcoholic and, 496 Excessive daytime sleepiness, 219, 460465,
Cortical arousals, obstructive sleep apnea and, active alcoholism and, 496 461t. See also Daytime sleepiness;
273275 alcohol effects and, 496 Narcolepsy
Corticobasal degeneration, 634 beta blockers and, 495496 choosing treatment for, 465
Corticotropic axis, 617, 617b causes of, 495496 modafinil and armodafinil and, 463
Cortisol, 617, 617b epidemiology of, 495 obstructive sleep apnea and, 284286
Cyclothymic disorder, 603, 603b key features and, 495 selegiline and, 465
medications and substances known to cause, sodium oxylate and, 464465
D 496t stimulant medications and, 462463
Daytime sleepiness treatment and, 496 Excessive fragmentary myoclonus, 181182,
common medications associated with, 473b Drug spindles, 59, 59t, 61f 182f, 182t
maintenance of wakefulness test and, Dual-chamber pacemakers, 173f Exploding head syndrome, 583, 583b
227232 Duloxetine (Cymbalta), 599600 Eye blinks, 8t, 72
multiple sleep latency test and, 221227 Dysfunctional Beliefs and Attitudes about Sleep Eye movement
objective measures of, 221232 (DBAS) Questionnaire, 486 artifacts and, 56
subjective measures of, 219221 Dysfunctional Beliefs and Attitudes about Sleep electrode positions and, 7, 7f
DC signal calibration, 50, 50f Worksheet, 513 patterns and, 89, 8t, 9f
Dead space, breathing patterns and, 145, 145t Dysrhythmic disorder, 602603, 602b selective serotonin reuptake inhibitor
Definite REM sleep, 36, 37t medications and, 59, 59t, 62f
Delayed sleep phase disorder, 526529, 526b E toward an electrode, 7
epidemiology of, 526527 Eating disorders, sleep-related, 584585, 584b Eyes-closed stage W, 27
evaluation and treatment recommendations, Electrical quiescence, 66 Eyes-open stage W, 27
527t Electro-oculographic derivations, 5t
pathophysiology of, 527 Electro-oculographic monitoring, 79 F
sleep logs and actigraphy and, 527528, Electrocardiogram artifact, 5556, 56t, 57f Familial nocturnal frontal lobe epilepsy,
527f528f Electrocardiographic recording during 561
treatment of, 528529, 528t polysomnography, 160162, 161f Fatal familial insomnia, 640, 640b
Dementias. See Neurodegenerative disorders Electrode nomenclature, 546f Fee-running type CRSD, 532537, 533b
Dependence issues, insomnia and, 506 Electrode popping artifact, 5254, 52t, 53f epidemiology of, 532533
Depression. See also Major depressive disorder; Electrode positions using 10-20 system, 12, pathophysiology of, 533
Major depressive episode 2f3f sleep logs and actigraphy and, 532f, 533
bipolar, 603, 604t Electroencephalography (EEG) treatment of, 533, 533b, 533t
hypersomnia associated with, 474 age of onset and, 70t Fibromyalgia syndrome, 626627
with insomnia, 214 electroencephalographic derivations, 23, 3t manifestations of, 626
Desaturation, obstructive sleep apnea and, electroencephalographic electrode sleep and, 626
276 nomenclature, 2t tender points and, 626f
Diabetes, obstructive sleep apnea and, 293 electroencephalographic electrode treatment of, 626627, 626t
Differential amplifiers, 13, 14f placement, 17 DaneshGroup.com
Firing rate, neuronal, 95, 96f
654 Index
First coast services durable medical area Head banging, 186f Hypopnea, 102104, 104f105f, 119, 120t
contractor, 217218 Head trauma, recurrent hypersomnia and, 472 classification of, 127128
accreditation and, 217 Heart rate, obstructive sleep apneas and, 245, event duration criteria and, 123
home sleep testing and, 217218 246f idealized findings in, 129t
local carrier determinations and, 217 Hemoglobin extinction curves, 104f, 110111, respiratory effort-related arousal and, 127
physical training/certification and, 217 111f, 144 scoring during wake, 127
First-night effect, 84 Henderson-Hasselbalch equation, 149b scoring rules in adults, 122
Flexible pressure, positive airway pressure and, Herbst appliance, 350f Hypopneic breathing, chronic obstructive
320321, 320f High-altitude periodic breathing, 391392 pulmonary disease and, 415416,
Flip-flop model for rapid eye movement sleep, diagnostic criteria and, 392b 415f416f
98, 98f pathophysiology of, 392 Hypothalamic areas, 9194
Flow limitation arousals, 128f treatment of, 392 lateral hypothalamus, 9192
Fluoxetine, 600602, 601f High-frequency filters, 1920, 19f tuberomammilary nucleus, 94
Focal nocturnal epilepsy, 557558 High-voltage slow (HVS) pattern, 6566 ventrolateral preoptic nucleus, 9294, 94f
Fractional saturation measurement, 110 Home sleep testing. See Portable monitoring Hypothyroidism, obstructive sleep apnea and,
Frontal derivations, electroencephalographic, Homeostatic process, sleep-wake cycle and, 518 240241
56, 6f Hormone secretion control, 620621, 620t Hypoventilation, 141142, 142b
Frontotemporal dementia, 634 Humidification, positive airway pressure alveolar hyperventilation severity, 393394,
Functional residual capacity, 151 treatment and, 321322, 321f, 321t 394f
Functional saturation measurement, 109110, Hyoid advancement, 360361, 361f central congenital hypoventilation syndrome,
110f Hypercapnic central sleep apnea 394395
central congenital hypoventilation syndrome, Chiaris malformation and, 396
G 394395 evaluation of, 393394
GABA-benzodiazepine-chloride ionophore mechanisms of, 393, 393f muscular dystrophy and, 393394, 395f
complex, 500505 patient evaluation with suspected neural disorders causing, 396397
Gabapentin, 506 hypoventilation, 393394, 394b, 394f neuromuscular diseases and, 394b, 401
Gastric and intestinal function, 622623 Hypercapnic ventilatory response, 146148, neuromuscular weakness and, 400401
Gastroesophageal reflux, 623625, 623b 147f148f restrictive thoracic disorders and, 398400
nocturnal asthma and, 423424, 624625 Hypersomnia rule for adults, 131132
nocturnal gastroesophageal reflux, 623624 actigraphy and, 207 rule for children, 137
normal gastroesophageal physiology and, as an undifferentiated somatoform disorder, sleep-related syndromes diagnostic criteria,
623 474 407408
obstructive apnea and, 625 associated with major depressive episode, syndromes, 377379, 378b
pH monitoring and, 623b, 624 474 during wakefulness, 130132
sleep-related laryngospasm and, 625 associated with mental disorders, 472b473b, Hypoxemia, 141142, 142t, 417420
treatment of, 625 473474
Gender, obstructive sleep apnea and, 272273 associated with seasonal affective disorder, I
General seizures, 556 474 Ictal activity, 554556, 555f
Generalized anxiety disorder, 608609, 608b as a conversion disorder, 474 Ictal effects on sleep, 563
differential diagnosis and, 608 due to drug or substance, 471, 473b Idiopathic central sleep apnea, 383385
sleep in, 608609 due to medical conditions, 472473 pathophysiology of, 384
treatment of, 608609 idiopathic hypersomnia, 470474 polysomnography and, 384
Generalized epilepsy syndromes with nocturnal nonorganic hypersomnia, 473474 treatment of, 384385, 385b
seizures, 562563 not due to substance or known physiologic Idiopathic hypersomnia, 470474, 470b
absence epilepsy, 563 condition, 473474 with long sleep time, 470471, 470b471b
benign epilepsy of childhood with physiological (organic hypersomnia), narcolepsy features vs., 456t
centrotemporal spikes, 562 unspecified, 474 treatment of, 466t
epilepsy with GTC seizures on awakening, recurrent hypersomnia, 471473 without long sleep time, 471
562 Hypersomnias of central origin Idiopathic insomnia, 492, 492b
generalized epilepsy syndromes, 562 cataplexy, 457 Imagery rehearsal therapy, 579, 610
generalized seizures during or after sleep, diagnostic testing for narcolepsy, 457460 Impedance checking, digital polysomnography
562563 narcolepsy due to medical condition, and, 23
juvenile myoclonic epilepsy, 562563 468470 In-phase deflections, 7, 8f
Lennox-Gastaut syndrome, 563 narcolepsy syndromes, 451457 Inadequate sleep hygiene, 493, 493b
Genioglossus activity, 263269, 268f269f treatment of narcolepsy, 460468 Indeterminant sleep in newborns, 65
Genioglossus advancement, 360361, 360f treatment parameters and, 466t Infant sleep staging
Genomic of circadian rhythm sleep disorders, Hypnagogic foot tremor, 181, 181f, 181t182t bipolar electroencephalogram recording, 65,
524525, 524f, 525t Hypnagogic hallucinations, 456, 467t, 583584, 66f
Ghrelin, 621622, 621b 584b newborns, 6566
Glottic pressure, 106f Hypnagogic hypersynchrony, 72, 73f premature infant and infants younger than
Glucose tolerance, 622 Hypnic jerks 48 weeks, 6568
Glutamate, 516 parasomnias and, 586, 586b premature infants, 66
Gonadal axis, 621 restless legs syndrome and, 432 scoring sleep in infants older than 40 weeks
Groaning. See Catathrenia Hypnogram with rapid eye movement sleep, and children, 7074
Ground artifact, 56 276f sleep architecture, 6768
Grounds, polysomnography, 2425 Hypnograms, 79, 80f term infants, 6667
Growth hormone, 615616, 616b Hypnopompic hallucinations, 583584, 584b Infants normal sleep, 85. See also Sleep
age-related changes in, 616, 617f Hypnotic-dependent patients, cognitive- architecture
growth hormone releasing hormone effects, behavioral therapy and, 499500 Insomnia
616 Hypnotics, chronic obstructive pulmonary actigraphy and, 207208, 487488
sleep-related burst and, 616 disease and, 419420 adjustment insomnia (acute insomnia),
twenty-four hour profile and, 615616, 616f Hypocapnic central sleep apnea 489490
idiopathic CSA, 383385 behavioral insomnia of childhood,
H ventilation patterns and, 382383, 383t, 384f 493495
Hallucinations, 583584, 584b ventilatory control in, 380382 biofeedback and, 498
Hamilton Depression Scale, 594 Hypomanic episode, 596597, 596b597b DaneshGroup.com
co-morbid insomnia, 499500, 506
Index 655
Multiple sleep latency test (Continued) Narrow-complex tachycardias, 168170, 171f Nocturnal epilepsy (Continued)
report example, 227t Nasal congestion treatment, 306, 306t localization in referential and PSG montages,
sleep apnea and, 231t Nasal masks, 322, 322f 549551
sleep-onset rapid eye movement periods and, Nasal obstruction, 358 nocturnal frontal lobe epilepsy, 559562,
224, 224b Nasal-oral thermal sensor, 102, 104f, 106f 561t
timetable and, 223t Nasal pressure monitoring, 119120 nocturnal frontal lobe epilepsy syndromes,
two 30-second epochs of sleep during, 227f Nasal pressure sensors, 102, 104f 560561
values in normal populations and patients, Nasal pressure techniques, 101107 normal sleep waveforms in the 10-second
223224 Neocortical temporal lobe epilepsy, 559 window, 551554
Multiple system atrophy, 638640, 639b Neurocognitive dysfunction, obstructive sleep obstructive sleep apnea and, 563564
central apnea and, 640 apnea and, 284286 parasomnia vs. nocturnal frontal lobe
Cheyne-Stokes breathing, 640 Neurodegenerative disorders, 631641, 632b epilepsy, 561, 563t
classifications of, 639t Alzheimers disease, 632633 phase reversal and, 549
diagnosis of, 639 corticobasal degeneration, 634 seizure classifications, 556558
epidemiology of, 639 dementias, 632 temporal lobe epilepsy, 559
pathology of, 639 diffuse Lewy body dementia, 638, 639b timing of nocturnal seizures and sleep
symptoms of, 639640 fatal familial insomnia, 640, 640b effects, 558t
treatment of, 640 frontotemporal dementia, 634 waveform and seizure terminology, 548549
vocal cord palsy and stridor in, 639640 multiple system atrophy, 638640, 639b Nocturnal hypoventilation, 141
Muscle artifact, 56, 58f Parkinsonian syndromes, 634, 634b Nocturnal leg cramps, restless legs syndrome
Muscle forces, lung volumes and, 152153, progressive supranuclear palsy, 633634, and, 433
152f 633b Nocturnal paroxysmal dystonia, 587
Myoclonic seizures, 556 stroke, 640641, 640b Nocturnal wandering, 587
Myoclonus, propriospinal, 587, 587b synucleopathies, 631632 Non-rapid eye movement (NREM)
Myotonic dystrophy, 469 Neuroleptic akathisia, restless legs syndrome parasomnias, 568573, 573t. See also
and, 432433 Parasomnias
N Neuromuscular disorders, polysomnography Non-rapid eye movement (NREM) sleep
Narcolepsy. See also Cataplexy; Excessive and, 213214 chronic obstructive pulmonary disease and,
daytime sleepiness Neuromuscular weakness, central sleep apnea 414
cataplexy mechanisms and, 454 and, 400401, 401f control of, 96, 96f
cataplexy treatment, 465466, 466t Neuron activity, 91, 92f Nonapneic desaturation, chronic obstructive
children and, 467468 Neuropathy, restless legs syndrome and, 432 pulmonary disease and, 415416,
diagnostic criteria and important findings Newborn sleep stages, 6566, 66t 415f416f
for, 459460 Niemann-Pick type C disease, 469470 Nonconvulsive epilepsy, 556
diagnostic testing for, 457460 Night shift work, 538539, 538f539f, 539b Noninvasive positive pressure ventilation
disturbed nocturnal sleep and, 457 Night terrors. See Sleep terrors (NPPV), 315, 330, 331f
epidemiology of, 453 Nightmare disorder, 578579, 579b chronic obstructive pulmonary disease and,
excessive daytime sleepiness and, 455456, Nightmares, posttraumatic stress disorder and, 420
460465 610 device reimbursement and, 338
features of, 452t Nocturia, obstructive sleep apnea and, 293 goals and, 337
future treatments for, 466467 Nocturnal asthma, 421425 titration and treatment, 336337
genetics and, 453 airway inflammation and, 422 titration protocol and, 337338, 337t
Hcrt levels and, 459 allergens in bedroom and, 423 Nonorganic hypersomnia, 473474
Hcrt neurons and, 453454 characteristics of, 411t Nonrespiratory physiology
history and, 452, 457458 chronotherapy and, 424 corticotropic axis, 617
HLA typing and, 453, 459 circadian alterations in lung function and, endocrine physiology and sleep, 615
hypnagogic hallucinations and, 456 421, 421f fibromyalgia syndrome, 626627
idiopathic hypersomnia vs., 456t diagnosis and treatment of, 422, 422b, 424 gastric and intestinal function, 622623
manifestations of, 455457 epidemiology and, 421422 gastroesophageal reflux and sleep, 623625
multiple sleep latency test and, 225, 225t, etiology of, 422, 422b glucose tolerance, 622
458459 factors worsening, 423424 gonadal axis, 621
N-C group and, 454 gastroesophageal reflux and, 423424 growth hormone, 615616
narcolepsy facts, 453t gastrointestinal reflux and, 624625 leptin and ghrelin, 621622
narcolepsy syndromes, 451457 manifestations of, 421b obesity and sleep duration, 622
narcolepsy with cataplexy (N+C), 454, melatonin and, 422423, 423f prolactin secretion, 619621
459460, 459b obesity and, 424 renin and aldosterone, 627628
narcolepsy without cataplexy (N-C), 460, treatment of, 424425, 424t, 425f thyroid axis, 617619
460b Nocturnal eating disorder, 586t. See also Nonrespiratory sleep disorders,
pathophysiology of, 454 Sleep-related eating disorder polysomnography and, 191t, 192
polysomnography and, 214, 458459 Nocturnal epilepsy. See also Nonselective serotonin reuptake inhibitors, 467t
sleep paralysis and, 457 Electroencephalography and nocturnal Nonsupine rapid eye movement sleep, 195196,
treatment of, 460468 epilepsy; Generalized epilepsy syndromes 196t197t
Narcolepsy due to medical condition (NDMC), with nocturnal seizures Norries disease, 470
468470, 468b antiepileptic drugs and sleep, 563 Notch filters, 1920, 20f
Coffin-Lowry syndrome, 470 bipolar monitoring and standard montages,
genetic disorders and, 469 546548 O
idiopathic hypersomnia, 470474, 470b classification of, 556557 Obesity
isolated cataplexy in medical and neurologic electroencephalographic monitoring and, hypoventilation syndrome, 237238,
disorders, 469470 545546 249250, 249b, 314
Kleine-Levin syndrome, 471472 epilepsy syndromes associated with sleep, lung volume changes and, 152, 152f
menstrual-related hypersomnia, 472 558t nocturnal asthma and, 424
myotonic dystrophy, 469 frontal lobe epilepsy, 559562, 561t obstructive sleep apnea and, 239, 303305,
Niemann-Pick type C disease, 469470 generalized epilepsy syndromes with 303f, 304t305t
Norries disease, 470 nocturnal seizures, 562563 sleep duration and, 622
rare genetic disorders and, 469470 ictal activity and, 554556 Obstructive apnea, gastroesophageal reflux and,
recurrent hypersomnia, 471473 ictal effects on sleep, 563 DaneshGroup.com
625
Index 657
Obstructive apnea/hypopnea event (OAHE), Obstructive sleep apnea (Continued) Oral appliances (Continued)
119120 palatal implants and, 358 Medicaid and Medicare and, 356
Obstructive hypopnea, 127128, 129f pathogenesis of upper airway obstruction, patient evaluation and, 350351
Obstructive hypoventilation syndrome, 138 263269 practical parameters for, 369370
Obstructive lung disease pathophysiology of, 282, 282f selected appliances, 354t
asthma, 421425 patient education before treatment, 302, 302t side effects and complications and, 356357,
chronic obstructive pulmonary disease, pediatric, 251254 356b
411420 pediatric medications and, 309 titration/adjustment of, 353
obstructive ventilatory dysfunction, 409411 pediatric surgery and, 363364 treatment adherence and, 353354
Obstructive sleep apnea, 122, 123f124f, 131f, persistent daytime sleepiness and, 307 treatment guidelines and, 355356, 355b
135. See also Oral appliances; Positive physical examination and, 242244, 242b Orexin (hypocretin) enzymes, 91, 93f
airway pressure treatment polysomnography and, 190192, 246b Organic hyperosmia, unspecified, 474
acromegaly and, 241 portable monitoring and, 205t, 247248 Orthognathia, 243f
actigraphy and, 207 posture and positional treatment and, Out-of-phase deflections, 7, 8f
age and, 239 305306 Overlap syndrome, 250251, 314, 420, 420b,
alcohol intake and, 240 practice parameters for surgical treatment of, 421t
apnea termination and arousal, 273275 373 Oxygen. See Supplemental oxygen
arrhythmias and, 289290 prediction of presence of, 244, 244t Oxygen hemoglobin dissociation curve, 143,
arterial hypertension and, 286288 premenopausal status and, 239240 143f
arterial oxygen desaturation and, 245247, prevalence and progression of, 238239, 240f Oxygen transport and saturation, 142145
247b, 248f, 275276 primary (simple) snoring, 248249 Oxyhemoglobin saturation curve, 109, 110f
atherosclerosis and, 291292 pulmonary hypertension and, 288289
automobile accidents and, 286 radiofrequency ablation and, 359 P
cerebrovascular accidents and, 292293 rapid eye movement sleep and, 244245, P wave, 159
childhood consequences of, 293294 245f Pacemakers
common symptoms and manifestations of, respiratory events and, 245247, 247t dual-chamber, 173f
241t risk factors and, 239241, 239t wide-complex QRS and, 172173
congestive heart failure and, 292 severe apnea treatment, 302 PaCO2 determinants, 145, 145t
coronary artery disease and, 290291 smoking and, 240 PaCO2 during sleep, 112113
day-night pattern of sudden death and, 284, snoring and, 300301 Painful legs-moving toes (PLMT) syndrome,
284f snoring variants and, 248251 433
diabetes and, 293 stage R effects and, 270272 Palatal implants, 358
diagnosis and, 241248 stepped surgical approach and, 363f Panic attacks, 588, 606, 607b
diagnostic criteria and, 238 stroke and, 640641, 640b Panic disorder, 606608
epidemiology of, 238241 supplemental oxygen and, 306307, 307f diagnosis criteria for, 607b
epilepsy and, 563564 surgical evaluation and, 357 differential diagnosis and, 607608, 607b
Epworth Sleepiness Scale and, 219221, 220f, surgical indications and, 357 sleep and, 607, 607b
220t surgical options and, 357362, 357b treatment of, 608
erectile dysfunction and, 293 surgical practice parameter Paradoxical insomnia (sleep state
ethnicity and, 240 recommendations, 362b misperception), 491492, 498
evaluation recommendations for, 241t surgical success rates and, 363, 363t differential diagnosis and, 491492
excessive daytime sleepiness and, 284286 surgical treatments for, 357364 incidence of, 491, 491b
follow-up and outcomes assessment, suspected sleep apnea and, 244247 key features of, 491
302303, 302t sympathetic nerve activity and, 282, 283f objective findings and, 491
gender and, 272273 thrombosis and, 291292 treatment of, 492
genioglossus advancement and, 360361, tongue procedures and, 362 Paralysis, sleep, 578, 578b
360f tracheostomy and, 357358 Parasomnias
heart rate and, 165f, 245, 246f treatment categories and, 300, 301t classification of, 568b
history and definitions and, 237238 treatment selection and, 300302, 300t common features associated with nocturnal
hyoid advancement and, 360361, 361f upper airway resistance syndrome, 249 events, 588t
hypothyroidism and, 240241 upper airway sensation and, 275 confusional arousals, 568569
international classification, 238b uvulopalatal flap and, 360 differential diagnosis of, 587588, 587t
key historical points and, 241242 uvulopalatopharyngoplasty and, 359360, due to drug or substance, 585
laboratory testing and, 244 359b, 359f due to medical condition, 586
laser-assisted uvuloplasty and, 358359, 358f ventilatory control and, 270 exploding head syndrome, 583
lung volume effects, 269 weight loss and, 303305, 303f, 304t305t hypnic jerks and, 586
male sex and, 239 Obstructive sleep apnea hypopnea syndrome nightmare disorder, 578579, 579b
Mallampati score and, 243244, 243f (OSAHS), 237238 NREM parasomnias, 568573
maxillomandibular advancement and, Obstructive ventilatory dysfunction, 149, parasomnia overlap disorder, 577
361362, 361b, 361f 409411, 410f, 411t polysomnography and, 214
mean arterial blood pressure and, 287288, Opiate/narcotic-induced central sleep apnea, propriospinal myoclonus and, 587
288f 396397, 397b, 397f398f recurrent isolated sleep paralysis, 578
medical treatment and, 303309, 303t Opiates, restless legs syndrome and, 441t, 443 REM sleep behavior disorder, 574578
mild apnea treatment, 299, 301 Opioids, restless legs syndrome and, 441t, 443 sleep enuresis, 580581
modafinil, armodafinil, and stimulants and, Opponent model of sleep, 518f sleep-related dissociative disorders, 579586
307308 Opposite mastoid electrode, 23 sleep-related eating disorders, 584585
moderate apnea treatment, 301302 Oral appliances, 350357 sleep-related groanings, 581583
mortality and, 282284, 285t combination with other treatments, 357 sleep-related hallucinations, 583584
nasal obstruction and, 358 comparison with continuos positive airway sleep talking and, 586
nasal patency and, 306 pressure, 354t sleepwalking, 569572, 570b
neurocognitive dysfunction and, 284286 devices, 352353 unspecified, 585
nocturia and, 293 effectiveness of, 352, 354355 usually associated with REM sleep, 574579
obesity and, 239 exclusions and contraindications and, 351 vs. nocturnal frontal lobe epilepsy, 561, 563t
obesity hypoventilation syndrome, 249250 follow-up and, 356, 356b Parkinsonian disease
oral appliances and, 350357 local coverage determination and, 371 differential diagnosis of, 635
overlap syndrome, 250251 mechanisms of actions and, 351 DaneshGroup.com
treatment of, 635636
658 Index
Parkinsonian syndromes, 634, 634b Periodic limb movements in sleep, 437439. Portable monitoring, 192203
Parkinsons disease, 634638, 635b See also Limb movement monitoring accuracy and, 194197
daytime sleepiness in, 636637 arousal index and, 438439 apnea-hypopnea index and, 196t
dementia in, 637638 arousals and, 178, 179f, 438 classification of, 195t
drug-induced psychosis and, 637 benzodiazepine receptor agonists and, clinical guidelines for, 215216
medications used in, 636t 443444, 444t clinical use of, 197199
nocturnal hallucinations and, 637 clinical significance of, 179180 developments in use of, 193194
recurrent hypersomnia and, 472473 common syndromes and disorders and, 439, device choice and, 204t
sleep disturbances due to motor 439t device types, 199201, 200f
manifestations, 636 comparisons of, 182t history of recent developments in, 196t
sleep-related manifestations of, 636637, diagnostic criteria and, 180t indications for attended, 197
637t differential diagnosis and, 438 indications for unattended, 198199
Paroxysmal arousals, 560561 index, 431432 integration into overall patient care, 202203
Patient Health Questionnaire (PHQ), 594, 613 narcolepsy and, 457 method of device setup and return, 204t
Pavor nocturnus. See Sleep terrors PLMSI and PSG findings and, 437438 methodology for, 200t, 215216
Pediatric narcolepsy, 467468 Peripheral arterial tonometry, 200201, 204f obstructive sleep apnea and, 205t, 247248
Pediatric obstructive sleep apnea, 251254 Persistent daytime sleepiness, obstructive sleep patient selection for, 199
cardiovascular consequences of, 294 apnea and, 307 peripheral arterial tonometry, 200201
consequences of, 293294 PETCO2 measurement, 113115 practical considerations and, 201202
diagnosis of, 252254 Pharyngeal passive closing pressure, 264, 266f recommended methodology and, 199
epidemiology of, 252 Phase-response curve for light, 521522, 522f using polysomnography and, 203
international classification and, 252b Phase reversal, 549, 550f Positional discomfort, restless leg syndrome
medications for, 309 Phase shifting by light, 520521, 520b, and, 432
metabolic and inflammatory consequences 520f521f Positional treatment, obstructive sleep apnea
of, 294 Philips-Respironics device, 318 and, 305306, 306f
neurobehavioral consequences and, 294 Physiologic findings, primary insomnia and, 489 Positive airway pressure adherence, 323325
normative respiratory values and, 253t Piezoelectric (PE) sensors, 108 acceptable levels of, 324, 324f
obstructive hypoventilation and, 253f Pittsburgh Sleep Quality Index (PSQI), 485 early adherence importance, 323
rapid maxillary expansion and, 364 Plasma renin activity, 627628, 627f factors predicting, 323, 323t
sequelae of, 293t Plethysmograph, 101102, 103f hypnotics, alcohol, and CPAP, 324325
tonsillectomy and adenoidectomy and, Pneumotachograph, 101, 103f105f, 105t interventions to improve, 324, 324t
253254, 363364, 364b, 364f Polysomnography, 189192. See also Cardiac in large studies, 323
Pediatric patients, positive airway pressure and, monitoring during polysomnography; side effects interventions and, 325t
326 Digital polysomnography systems Positive airway pressure titration,
Pediatric periodic breathing rule, 138, 138f AASM practice parameters for, 213214 polysomnography and, 190t, 191192
Pediatric respiratory events, 134139 adult respiratory parameters and, 132134 Positive airway pressure treatment
ages which scoring rules should be used, adverse events during, 172 adaptive servo-ventilation titration protocol,
134 apnea-hypopnea index and, 196t 334
apnea rules, 135136 bruxism and, 183184 additional monitoring for NPPV titration,
hypopnea rule, 136 catathrenia and, 581582 330, 331f
hypoventilation rule for, 137 children respiratory parameters and, 138139 adherence and, 323325
obstructive hypoventilation and, 137f, 138 circadian sleep disorders and, 214 alternative methods of starting, 334338
pediatric respiratory rules, 135t circumstances not indicated for, 191t autotitration technique, 335, 335t
periodic breathing rule, 138, 138f combined with portable monitoring, 182f comfort measures and, 320322
polysomongraphy reported parameters, complex sleep apnea and, 390, 391f CompSA and, 333334
138139 confusional arousals and, 569, 569f CPAP/BPAP for obstructive sleep apnea,
recommended sensors and, 135 CSB-CSA and, 385386, 386f387f 325334
respiratory effort-related arousal rules, depression with insomnia and, 214 effectiveness and, 314
136137 ECG recording during, 160162, 161f flexible pressure and, 320321
Pediatric restless legs syndrome, 437, 437b historical elements to review based on, 193t follow-up and, 335336
Pediatric rules for scoring sleep (AASM), insomnia and, 488489, 489b general titration considerations and, 326,
7074. See also Children respiratory event narcolepsy and, 214, 458459 326t
scoring neuromuscular disorders and, 213214 humidification and, 321322
additional waveforms of wakefulness, nightmare disorder and, 579 interfaces and, 322
7072 nonrespiratory sleep disorders and, 191t, 192 local carrier determination and, 345346
ages for which rules apply, 70 obstructive sleep apnea and, 246b mechanism of action and, 313314
arousal rules, 74 parasomnias and, 214 Medicare criteria for reimbursement and, 347
dominant posterior rhythm, 70 periodic limb movement disorder and, 214 modes of, 314319, 314t, 315f
pediatric stage N1 waveforms, 72, 72t positive airway pressure titration and, 190t, monitoring during, 326330, 327t
pediatric stage W rules, 72, 72t 191192 NPPV titration and treatment, 336337
scoring sleep stage, 70 rapid eye movement sleep behavior disorder NPPV titration protocol, 337338, 337t
sleep stage terminology, 70 and, 185187, 185t186t, 575, 576f obstructive sleep apnea and, 205t
stage N1 rules, 72, 74t restless legs syndrome and, 214, 436, 437t patient selection for alternative titrations,
stage N2 rules, 7274, 75f rhythmic movement disorders and, 184185 335
stage N3 rules, 74, 75f76f, 75t seizure disorders and, 214 pediatric considerations and, 326
stage R, 74, 75t sleep enuresis and, 581 practice parameters and, 343344
Pedunculopontine tegmentum, 95 sleep-related breathing disorders and, ramp option and, 320
Periodic limb movement disorder (PLMD), 190192, 190t reimbursement for NPPV devices and, 338
439440 sleep-related eating disorders and, 585 sample device download and, 336f
diagnostic criteria and, 439b sleep terrors and, 572573 supplemental oxygen and, 332333, 332t
dopaminergic medications and, 440443 sleepwalking and, 571, 571f titration adequacy and, 334
nonpharmacologic treatments and, 440 sleepy patient and, 192 titration protocol, 330332, 331t
objective findings and, 439440 special elements to note during treatment indications and, 322323
polysomnography and, 214 interpretation, 194t volume-targeted, 319320
prevalence and manifestations of, 439 Polyvinylidene fluoride thermal sensor, Positive occipital sharp transients of sleep,
treatment of, 440445 101102, 104f DaneshGroup.com
552554, 554f
Index 659
Posterior rhythm, 551552, 552f Rapid eye movement (REM) sleep (Continued) Respiratory physiology (Continued)
Posterior slow waves (PSW) of youth, 7072, pattern definition, 8t maximum inspiratory pressure, 153
71f reciprocal interaction model, 9798, 97f muscle forces and, 152153, 152f
Postictal state, 556 transition to stage W or N3, 37, 38f muscle strength and, 152
Postmenopausal status, obstructive sleep apnea without atonia, 577 normal changes in ventilation during sleep,
and, 239240 Rapid maxillary expansion, 364, 365f 145146, 146f
Posttraumatic stress disorder, 609610, 609b Reading eye movements, 8t obesity and, 152, 152f
associated features, 609 Rechtschaffen and Kales manual, 27, 28t, 85 oxygen transport and saturation, 142145
differential diagnosis and, 610 Reciprocal interaction model of rapid eye PaCO2 determinants, 145, 145t
nightmares in, 610 movement sleep, 9798, 97f pulmonary function testing, 149152, 150f
treatment of, 610 Recommended EOG derivations, 7, 8f ventilatory control tests, 146148, 147f148f
Posture, obstructive sleep apnea and, 305306, Recovery from sleep loss, 88 Respiratory-related evoked potentials (RREP),
305f Recurrent hypersomnia, 471473, 471b 274
Premature beats, 167168, 168t, 169f behaviorally induced insufficient sleep Respiratory sensor recommendations in adults,
Premature infant sleep stages, 66 syndrome, 472 121
Primary sleep apnea of infancy, 397398, 399b head trauma and, 472 Respiratory volume dysfunction, 151
Primary (simple) snoring, 248249 hypersomnia due to medical condition, Restless legs syndrome, 430437
Progressive supranuclear palsy, 633634, 633b 472473 abnormal sensations in, 431b
Prolactin secretion, 619621, 620b, 620f Kleine-Levin syndrome, 471472 anticonvulsant medications and, 443
Propriospinal myoclonus, 587, 587b menstrual-related hypersomnia, 472 augmentation and, 442443, 442b
Prostaglandin D2, 9294 Parkinsons disease and, 472473 causes of, 433, 433b
Prozac eyes, 59, 59t treatment, 466t children and, 437, 437b
Psychiatry and sleep. See Anxiety disorders; Recurrent isolated sleep paralysis, 578, 578b claudication and, 433
Mood disorders Referential display view, digital clinical features of, 434, 434b
Psychophysiologic insomnia, 490491 polysomnography and, 23, 24f differential diagnosis of, 432433, 432t, 433b
incidence of, 490 Referential montages, 546548 dopaminergic medications and, 440443
key features of, 490, 490b Referential recording, 1417, 14t, 15f essential diagnostic criteria and, 431, 431b
objective findings and, 490491 Relaxation therapy, insomnia and, 498 familial patterns and genetics and, 434, 434t
Pulmonary function patterns, 150b, 151t REM sleep behavior disorder, 185187, hypnic jerks and, 432
Pulmonary hypertension, obstructive sleep 185t186t, 457, 574578 medical evaluation in, 435436, 436b
apnea and, 288289, 289f classifications and causes of, 574575, 574b medications used to treat, 441t
Pulse artifact, 56, 58f diagnosis of, 575576 neuroleptic akathisia and, 432433
Pulse oximetry, 110112, 112f differential diagnosis of, 577 neuropathy and, 432
epidemiology of, 574 nocturnal leg cramps and, 433
Q parasomnia overlap disorder, 577 nonpharmacologic treatments and, 440
Q wave, 159 pathophysiology of, 574 onset and clinical course of, 435
QRS complex, 159, 160f polysomnography in, 575, 576f opioids/opiates and, 443
QS wave, 159 pseudo-RBD, 575 painful legs-moving toes syndrome and, 433
QT duration, 159 REM sleep without atonia, 577 pathophysiology of, 434
QT interval, 159 scoring rules for electromyogram activity, polysomnography and, 214, 436, 437t
Questionnaires, insomnia and, 485486, 485t 575b positional discomfort and, 432
Quetiapine, 505506, 505t, 602 status dissociatus, 577 prevalence of, 434435, 435f
Quiet sleep in newborns, 65, 69f treatment of, 577578, 577b sedative hypnotics and, 443444
variants of, 577 sleep disturbance associated with, 435
R Renin activity, 627628, 627f study group rating scale and, 436b
R wave, 159 Resistance-capacitance (RC) circuits, 18 supportive clinical features and, 431432,
Radiofrequency ablation, 359 Respiration during rapid eye movement sleep, 432b
Radiofrequency palatoplasty, 300301 379380, 380f treatment algorithm and, 444445, 445t
Ramelteon, 505, 602 Respiration monitoring. See also Adult treatment of, 440445
Ramp option, positive airway pressure and, 320 respiratory events; Children respiratory Restrictive thoracic disorders, central sleep
Rapid eye movement (REM) sleep. See also events apnea and, 398400, 399f
Parasomnias; REM sleep behavior airflow and tidal volume measurement, Restrictive ventilatory dysfunction, 149
disorder; Stage R 101107 Reticular activating system, 9596, 95f
adenosine and, 99 PaCO2 during sleep, 112113 Reticular formation, 9596
arousal followed by LAMF EEG and SEMs, PETCO2, 113115 Reticular nucleus, 3
3738, 39f pulse oximetry, 110112, 112f Retinohypothalamic tract, 516, 516f
chronic obstructive pulmonary disease and, respiratory events in adults, 119134 Retrognathia, 243f
414415, 414f415f SaO2 measurement, 109110, 110f Rhinitis, 306, 306t
continuation of, 37, 37t, 38f snoring sensors, 115, 115f Rhythmic anterior theta, 72, 73f
control of, 4243 TcPCO2 monitoring, 113115 Rhythmic masticatory muscle activity, 182
definite, 36, 37t Respiratory disturbance index (RDI), 121, 238 Rhythmic movement disorders, 184185
end of, 37, 37t Respiratory effort measurement, 107109, 108t classification of, 184t
epochs with mixture of, 4243, 43t Respiratory effort-related arousal (RERA), head banging and, 186f
features of, 9699 107108, 119120, 122, 124127, 126f, polysomongraphy and, 184185, 184t
first-night effect and, 84 128f, 136137 prevalence of, 184t
flip-flop model for, 98, 98f Respiratory events, obstructive sleep apnea Rotating work shifts, 539
gender differences and, 84 and, 245247, 247t Roux-en-Y procedure, 304
increase in chin EMG activity and, 37 Respiratory impedance plethysmography, RR interval, 159
latency and, 8384, 84t 108109
latency decrease with age, 82, 82f Respiratory inductance plethysmography, S
MBM followed by LAMF EEG and SEMs, 105107, 107f S wave, 159
3839, 39f Respiratory muscle electromyogram, 109, 109f Sampling rate, 16, 16t
medications effects on, 9899 Respiratory physiology SaO2 measurement, 109110, 110f
obstructive sleep apnea and, 244245, 245f acid-base physiology, 148, 149f Saw-tooth waves, 4t5t, 67
parasomnias usually associated with, arterial blood gases, 141142 Scoring sleep in infants older than 40 weeks
574579, 574b maximum expiratory pressure, 153 DaneshGroup.com
and children, 7074
660 Index
Seasonal affective disorder, hypersomnia Sleep monitoring basics Spirometry, 149150, 150f
associated with, 474 electro-oculographic monitoring, 79 ST interval, 159160
Sedating antidepressants and antipsychotics, electroencephalographic electrode Stage N1, 29t, 31, 31f, 43
insomnia and, 505506, 505t placement, 17 age-related changes and, 82, 83f
Sedating antipsychotic medications, 602t Sleep monitoring technology pediatric scoring rules, 72, 74t
Sedative hypnotics, restless legs syndrome and, amplifier filter settings for digital sleep pediatric waveforms, 72, 72t
443444 recordings, 20, 20t Stage N2, 3135, 4344
Seizure classification, 556558, 557b digital PSG system overview, 2025 age-related changes and, 82, 83f
Seizure disorders, polysomnography and, 214 filters (low-frequency, high-frequency, and effect of arousals and, 34
Selective serotonin reuptake inhibitors (SSRIs), notch filters), 1720 effect of major body movement and, 3435,
59, 59t, 466, 599, 601t referential and bipolar recording, 1417, 14t 35f
Selegiline, 465, 635636 Sleep-onset rapid eye movement sleep pediatric scoring rules, 7274, 75f
Sensor recommendations, 102t (SOREM), 224, 224b, 458 rules for, 33t
Severe obstructive sleep apnea, 302 Sleep paralysis, 457, 467t, 578, 578b start and continuation of, 3134, 32f, 34f
Severity criteria for pulmonary function Sleep-related breathing disorders, summary of scoring, 33t
testing, 157 polysomnography and, 190192, 190t Stage N3, 34t, 3536
Sexual behavior, sleep-related, 571 Sleep-related dissociative disorders, 579580, age-related changes and, 8283, 84f
Sharp waves, EEG patterns and, 3 580b pediatric scoring rules, 74, 75f76f, 75t
Shift-work type CRSD, 537540, 537b Sleep-related eating disorders, 584585, Stage R, 3640, 36f, 4344
circadian markers and, 538 584b585b, 586t age-related changes and, 83, 84f
epidemiology of, 537 Sleep-related hallucinations, 583584, 584b with arousal, 46f
evaluation and treatment of, 538t, 539540 Sleep-related hypoventilation, 137 arousal followed by LAMF EEG and SEMs,
night shift work and, 538539, 538f539f, 539b Sleep-related laryngospasm, gastroesophageal 3738, 39f
pathophysiology of, 537 reflux and, 625 continuation of REM sleep, 37, 37t
risk factors and, 537 Sleep-related movement disorders, 176t definite REM sleep, 36, 37t
rotating shifts and, 539 Sleep-related rhythmic movement disorder, end of REM sleep, 37, 37t
sleep logs and diaries and, 538 184185 increase in chin EMG activity and, 37
Sickle hemoglobin, 143, 143f Sleep-related sexual behavior (sex-somnia), 571 MBM followed by LAMF EEG and SEMs,
Silenor, 600 Sleep-related violence, 571 3839, 39f
Simple partial seizure, 556 Sleep restriction therapy, insomnia and, 498, obstructive sleep apnea and, 270272, 271f,
Sinus arrhythmia, 162163, 162f 498b 273f
Sinus bradycardia, 162163 Sleep spindles, 3, 4t5t, 5f, 4243, 43t, 74f pediatric scoring rules, 74, 75t
Sinus pauses, 165166, 165f Sleep stage nomenclature, 2t thirty-second epoch of, 46f
Sinus rhythm, heart rate data and, 162164 Sleep terrors, 572573, 572b transient muscle activity during, 59, 59t,
Sinus tachycardia, 162163 diagnosis of, 573 62f
Sixty-cycle artifact, 54, 54t, 55f epidemiology of, 573 transition to stage W or N3, 37, 38f
Sixty-Hz filters, 1920, 20f facts on, 572b Stage W (wake), 2730, 28f, 28t29t, 30f, 72,
Sleep apnea, 231t polysomnographic findings associated with, 72t
Sleep architecture 573 Stanford Sleepiness Scale, 219, 220t
adult normal sleep, 7981 precipitating and predisposing factors, 573 Starling resistor, 264265, 266f
arousals, 8586, 86f treatment of, 573 Status dissociatus, 577
changes with aging, 8183, 81t Sleep-wake cycle, 516518, 517f. See also Stimulant medications, excessive daytime
facts, 80t Circadian rhythm sleep disorders sleepiness and, 462463
infants and children, 85, 86t Sleep-wake regulation, 518t Stimulus control therapy, insomnia and, 498
parameters, 80t Sleepwalking, 569572, 570b STOP-BANG scoring model, 261
REM latency alternations, 8384 diagnosis of, 571 Stridor, 639640
scoring system comparisons and, 85 differential diagnosis of, 571 Stroke, sleep disturbances in, 640641, 640b
sleep fragmentation, 8688 epidemiology and familial pattern of, 570 Subcortical arousals, 273274
sleep latency and REM latency, 82, 82f facts on, 570b Suggested Immobilization Test (SIT), 179
stage N2, 82, 83f familial, precipitating, and predisposing Sundowning, 633b
stage N3, 8283, 84f factors, 570571 Supine rapid eye movement sleep, 195196,
stage R, 83, 84f polysomnographic findings in, 571, 571f 196t197t
TST and sleep efficiency, 82, 82f predisposing factors for, 570b Supplemental motor area epilepsy, 561
WASO and stage N1, 82, 83f sleep disorders and the law, 572, 572b Supplemental oxygen
Sleep deprivation sleep-related sexual behavior, 571 chronic obstructive pulmonary disease and,
chronic partial, 88, 88f, 89t sleep-related violence, 571 417420, 418b, 418t
selective, 8788 treatment of, 572 obstructive sleep apnea and, 306307, 307f
total, 87, 87f, 87t Slow eye movements, 8t positive airway pressure treatment and,
Sleep efficiency, age-related changes, 82, 82f Slow-frequency (sweat) artifact, 5455, 54t, 55f 332333, 332t
Sleep enuresis, 580581, 580b Slow heart rate during sleep, 164165, 165t Suprachiasmatic nucleus, sleep-wake cycle and,
polysomongraphy in, 581 Slow wave activity, 36, 4t5t, 549 516518, 517f
primary enuresis, 581 Smoking, obstructive sleep apnea and, 240 Synucleopathies, 631632
secondary enuresis, 581 Snoring
treatment for, 581, 581b obstructive sleep apnea and, 248251, T
Sleep fragmentation, 8688 300301 Tachycardia-bradycardia cycles, 164165
chronic partial sleep deprivation, 88, 88f, 89t polysomnography and, 190192 Tachycardias during sleep, 168172
recovery from sleep loss, 88 sensors, 115, 115f Afib and atrial flutter, 170172
selective sleep deprivation, 8788 Snoring/respiratory chin EMG artifact, 56, 59f common tachycardias, 170t
total sleep deprivation, 87, 87f, 87t Sodium oxylate, 464465, 464f narrow-complex tachycardias, 168170
Sleep hygiene, 497 Somatoform disorder, hypersomnia associated wide-complex tachycardia, 172
Sleep latency, 79, 82, 82f with, 474 TcPCO2 monitoring, 113115
Sleep logs, 486, 486f487f, 487t Somatostatin, 617619 Temazepam, 498499, 499f
advanced sleep phase disorder and, 529, 530f Somnambulism. See Sleepwalking Temporal lobe epilepsy, 559
delayed sleep phase disorder and, 527528, Somniloquy, 586 10-20 electrode position, 546f
527f Spike and wave complex, 548 Term infants sleep stages, 6667
irregular sleep-wake rhythm and, 531 Spikes, EEG patterns and, 3 DaneshGroup.com
Testosterone levels, morning, 621, 621f
Index 661
Thermal devices, airflow monitoring and, Trac discontinue (TD), 6566, 67f Uvulopalatopharyngoplasty, 300301, 359360,
101102, 103f Tracheostomy, 357358 359b, 359f
Thirty-second epochs, 31, 32f, 42f Transient muscle activity during REM sleep,
Thornton anterior positioner, 351f 59, 59t, 62f V
Three-dB filters, 18f Transitions between definite stage N2 and stage Valproic acid (Depakene), 604605
Thrombosis, obstructive sleep apnea and, R, 4042, 40t, 41f Ventilation changes during sleep, 145146, 146f
291292, 291t Transverse bipolar montages, 546548, 547f, Ventilatory control, obstructive sleep apnea
Thyroid axis, 617619, 619b 549t and, 270
Thyroid hormone levels, 619 Trazodone, 505506, 505t, 600, 601t602t Ventilatory control tests, 146148, 147f148f
Thyroid-stimulating hormone secretion, 619, Tricyclic antidepressants (TCAs) Ventral reticular activating system, 96
619b cataplexy and, 465466, 467t Ventricular premature beats, 168, 169f
Thyrotropin-releasing hormone (TRH), depression and, 599 Ventrolateral preoptic nucleus, 9294, 94f
617619 effects on sleep, 601t602t Vertex sharp waves, 4t5t, 67, 72
Tidal volume, 105107, 145, 145t Tuberomammilary nucleus, 94 Video-audio polysomnography, 24
Tidal volume measurement techniques, Violence, sleep-related, 571
101107 U Vocal cord palsy, 639640
Time window for display, 17 U wave, 159 Voltage differences, EEG patterns and, 3
Titration considerations, positive airway Unattended portable monitoring indications, Volume-targeted bilevel positive airway
pressure and, 326, 326t 198199, 199t pressure, 319320
Tongue procedures, 362 Unclassified seizures, 556
Tongue retaining device, 350f Upper airway muscle activity, 263269 W
Tongue sustaining device, 350f Upper airway patency, 263269, 263t Wake after sleep onset (WASO), 79, 82, 83f
Tonic-clonic seizures, 556 Upper airway sensation, obstructive sleep Waveform examples, 162f
Tonic seizures, 556 apnea and, 275 Weight loss, obstructive sleep apnea and,
Tonsillectomy, 363364, 364b, 364f Upper airway surgery, 302, 302t 303305, 303f, 304t305t
Tonsillectomy and adenoidectomy, 253254 Upper respiratory resistance syndrome, Wide-complex QRS, 172173
Total recording time (TRT), 79 249 Wide-complex tachycardia, 160161, 172, 172f
Total sleep time, age-related changes, 82, Upstream resistance, 264
82f Upward deflection, EEG patterns and, 3 Z
Trac alternant (TA), 6566, 68f Uvulopalatal flap, 360 ZZsoma positional sleeper, 306f
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