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2014 Basics of Lower Extremity Clinical and

COURSEBOOK Electrodiagnostic Evaluation


Polyneuropathy

Learn Connect Grow

61st Annual Meeting

Savannah, Georgia

Basics of Lower Extremity Clinical and


Electrodiagnostic Evaluation

Aiesha Ahmed, MD
Paul E. Barkhaus, MD
Kerry H. Levin, MD
Zachary Simmons, MD

AANEM 61st Annual Meeting


Savannah, Georgia

Copyright October 2014


American Association of Neuromuscular
& Electrodiagnostic Medicine
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Rochester, MN 55901
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Basics of Lower Extremity Clinical and


Electrodiagnostic Evaluation
Table of Contents
Program Committee & Course Objectives

Faculty 5
Lumbosacral Radiculopathies
Aiesha Ahmed, MD

Femoral Neuropathy, Obturator Neuropathy, and Lumbar Plexopathy


Paul E. Barkhaus, MD

13

Sacral Plexopathies and Sciatic Neuropathies


Zachary Simmons, MD

21

The Peroneal and Tibial Nerves


Kerry H. Levin, MD

29

CME Questions

41

No one involved in the planning of this CME activity had any relevant financial relationships to disclose.
Chair: Zachary Simmons, MD

The ideas and opinions expressed in this publication are solely those of the specific authors
and do not necessarily represent those of the AANEM.

Objectives
Objectives - Participants will acquire skills to (1) Arrive at a differential diagnosis for a patient with lower extremity pain, numbness, or weakness,
(2) design a plan for EDX evaluation of a patient with lower extremity pain, numbness, or weakness, (3) explain the proper placement of surface
electrodes for performance of lower extremity NCSs, and (4) interpret the results of an EDX evaluation of a patient with lower extremity pain,
numbness, or weakness.
Target Audience:
Neurologists, physical medicine and rehabilitation and other physicians interested in neuromuscular and electrodiagnostic medicine
Health care professionals involved in the diagnosis and management of patients with neuromuscular diseases
Researchers who are actively involved in the neuromuscular and/or electrodiagnostic research
Accreditation Statement - The AANEM is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide
continuing medical education (CME) for physicians.
CME Credit - The AANEM designates this live activity for a maximum of put in 3.25 AMA PRA Category 1 Credits. If purchased, the AANEM
designates this enduring material for a maximum of 5.75 AMA PRA Category 1 Credits. This educational event is approved as an Accredited Group
Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada. Physicians should claim on the credit commensurate with the extent of their
participation in the activity. CME for this course is available 10/2014 10/2017.
CEUs Credit - The AANEM has designated this live activity for a maximum of 3.25 AANEM CEUs. If purchased, the AANEM designates this
enduring material for a maximum of 5.75 CEUs.

2013-2014 Program Committee


Zachary Simmons, MD, Co-Chair
Hershey, PA

Elizabeth A. Giles, CNCT


Medina, TN

Vern C. Juel, MD
Durham, NC

Holli A. Horak, MD, Co-Chair


Tucson, AZ

Taylor B. Harrison, MD
Atlanta, GA

A. Arturo Leis, MD
Jackson, MS

Amanda Casey, CNCT


Jackson, TN

Robert W. Irwin, MD
Miami, FL

Samuel D. Nortman, MD
Denver, CO

Jasvinder P. Chawla, MBBS, MD, MBA


Darien, IL

Shawn Jorgensen, MD
Queensbury, NW

Katalin Scherer, MD
Tucson, AZ

Urvi G. Desai, MD
Charlotte, NC

2013-2014 AANEM President


Francis O. Walker, MD
Winston Salem, NC

Basics of Lower Extremity Clinical and


Electrodiagnostic Evaluation
Faculty

Aiesha Ahmed, MD

Kerry H. Levin, MD

Pennsylvania State University


Milton S. Hershey Medical Center
Hershey, PA

Department of Neurology
Neuromuscular Center
Cleveland Clinic
Cleveland, OH

Dr. Ahmed received her medical degree from Baquai Medical College
in Karachi, Pakistan, and an internship in internal medicine at St. Joseph
Hospital in Chicago. She completed her neurology residency from
the University of Illinois at Chicago, and a clinical neurophysiology
fellowship and neuromuscular medicine fellowship, both from Penn State
University. Dr. Ahmed is the program director of Clinical Neurophysiology
and Neuromuscular Medicine fellowships and an assistant professor of
neurology at Pennsylvania State University Hershey Medical Center. She
is certified by the American Board of Psychiatry and Neurology, and has
subspecialty certification in clinical neurophysiology, and neuromuscular
medicine. She is currently a GME Committee member for the American
Association of Neuromuscular & Electrodiagnostic Medicine.

Paul E. Barkhaus, MD
Medical College of Wisconsin
Milwaukee, WI
Dr. Barkhaus received his medical degree from Wayne State University
in Detroit, MI. He completed electromyography (EMG) fellowships at
the University of Minnesota and Duke University, as well as a fellowship
in clinical neuromuscular diseases at the University of Arizona. He is
a professor of neurology and physical medicine & rehabilitation at the
Medical College of Wisconsin. He is also head of the Neuromuscular
Disease and Autonomic Section in the Department of Neurology and
director of the ALS Program. He has numerous publications on quantitative
EMG, motor nerve conductions, motor unit estimation as well as multimedia educational materials.

Dr. Levin received his medical degree from Johns Hopkins University
School of Medicine. He completed his neurology residency at University
of Chicago Hospitals and an electromyography (EMG) fellowship at Mayo
Clinic in Rochester, MN. He is currently the chairman of the Department
of Neurology and the director of the Neuromuscular Center at Cleveland
Clinic. He also serves as a neurology director for the American Board of
Psychiatry and Neurology.

Zachary Simmons, MD
Pennsylvania State University
Milton S. Hershey Medical Center
Hershey, PA
Dr. Simmons received his medical degree from the University of Florida,
and then trained in neurology at the University of Iowa and in neuromuscular
diseases and electromyography at the University of Michigan. He now
serves as professor of neurology at Pennsylvania State Hershey Medical
Center, where he is the director of the Neuromuscular Program and the
EMG Laboratory. He founded and directs the Hershey Medical Center ALS
Clinic. Active research programs under his supervision include studies of
quality of life, the development of evidence-based practice protocols, the
use of brain-computer interfaces, and genomics of ALS. Dr. Simmons has
served on the American Association of Neuromuscular & Electrodiagnostic
Medicine Training Program, Workshop, and Program Committees, and has
been chair of the American Board of Electrodiagnostic Medicine (ABEM)
Maintenance of Certification Committee. He is currently co-chair of the
Program Committee and serves on the AANEM Board of Directors. Dr.
Simmons is an ABEM Diplomat.

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Lumbosacral Radiculopathies
Aiesha Ahmed, MD
Assistant Professor of Neurology
Penn State College of Medicine
Milton S. Hershey Medical Center
Hershey, Pennsylvania

INTRODUCTION
Lumbosacral radiculopathy is one of the diagnoses commonly
referred to an electromyography (EMG) laboratory. The
electrodiagnostic (EDX) testing conducted there complements
magnetic resonance imaging with its ability not only to localize
the lesion but also to functionally assess the nerve.

ANATOMY
The lumbar spine consists of five vertebral bodies (L1-5). The
sacrum comprises five fused vertebral levels (S1-5), followed by
the coccyx. These two regions are described as the lumbosacral
spine. Directly beneath each vertebra is a pair of neural foramina
with the same number designation. Neural foramina are
bounded superiorly and inferiorly by pedicles, anteriorly by the
intervertebral disc and vertebral body, and posteriorly by facet
joints. Through each neural foramen passes the same numbered
spinal nerve root, recurrent meningeal nerves, and radicular
blood vessels. On each side, there are five lumbar, five sacral,
and one coccygeal spinal nerve roots.
The spinal cord ends as the conus medullaris at or around L1
where all lumbar and sacral spinal nerve roots originate. A dorsal
root from the posterolateral aspect of the spinal cord and a ventral
root from the anterolateral aspect of the cord join in the spinal
canal to form the spinal nerve root. The roots then form the cauda
equina, until they exit at their respective neural foramina. Thus,
the lumbosacral nerve roots exit the spinal canal at a lower level
than where they arise. Cell bodies of the motor nerve fibers are
located in the ventral horns of the spinal cord, while those of the
sensory nerve fibers are in a dorsal root ganglion at each lumbar
and sacral level. Dorsal root ganglia (DRG) tend to be located
within the neural foramina, and they are therefore not within

the lumbar canal. However, at the low lumbar and sacral levels,
DRG often are situated proximal to the neural foramina within
the intraspinal canal. The DRG are attached to the vertebral body
on the transverse process.
Distal to the neural foramen, the nerve root divides into the
dorsal and ventral primary rami. The small dorsal primary
ramus supplies motor innervation to the paraspinal muscles
and cutaneous innervation to the skin of the trunk and back.
The large ventral primary ramus supplies motor and sensory
innervation to the legs and trunk. However, there is variability to
the dermatomal and myotomal distribution of innervation. There
is overlap in areas supplied by dorsal rami making it difficult to
evaluate individual paraspinal muscles.1,2

CLINICAL FEATURES
The clinical presentation of radiculopathy includes pain and
paresthesia radiating in the distribution of the nerve root often
associated with paraspinal muscle spasm. Motor dysfunction
can also be present. Each nerve root supplies cutaneous
sensation to a specific skin region known as dermatome as well
as motor innervation to certain muscles known as myotomes.
Due to overlapping of dermatomes, as mentioned above, the
sensory loss if present is usually poorly defined. Similarly, due
to overlapping of myotomes, there is usually weakness but
not complete paralysis of a muscle. The deep tendon reflexes
may be depressed in radiculopathy depending upon the root
innervation to the muscle tendon under examination. In lower
extremities, the knee jerk may be depressed in the setting of
L3 or L4 root lesions. Similarly, the ankle jerk may be reduced
with the lesion of S1 nerve root.2
7

LUMBOSACRAL RADICULOPATHIES

ETIOLOGY

Tibial Motor Nerve Conduction Study

The most common etiology of lumbosacral radiculopathy is nerve


root compression caused by a disc herniation or spondylosis.
Congenital abnormalities such as congenital narrowing of the
canal can be factor upon which spondylosis may result. Other
developmental abnormalities include tethered cord or and spina
bifida. These may lead to radicular dysfunction due to injuries
resulting from traction of the root.3

Using standard disc electrodes, G1 is placed over the abductor


hallucis brevis muscle which is found 1 cm proximal and 1
cm inferior to the navicular prominence. The G2 electrode is
placed over the metatarsalphalangeal joint of the big toe. The
tibial nerve is stimulated at two sites. The distal stimulation site
is above and posterior to the medial malleolus, 8 cm from the
G1 electrode, and the proximal stimulation site is at the midposterior knee over the popliteal pulse. It is important to note
that the compound muscle action potential (CMAP) amplitude at
the popliteal fossa stimulation site is often lower and may drop
by up to 50%. Therefore caution must be used when identifying
a conduction block on tibial motor NCSs between the ankle and
popliteal fossa. A side-to-side comparison would help in such
instances (Fig. 1).

Additional etiologies include infection, inflammation, neoplasm,


and vascular disease. Of note, root infarction may occur from
either large vessel or small vessel disease and is seen commonly
in diabetics whose microvasculature is affected.2

DIFFERENTIAL DIAGNOSIS
The differential diagnosis for those presenting with pain and
radiating paresthesia would include plexopathy as well as
entrapment neuropathy. Due to the possibility of referred pain, it is
possible for distal entrapment neuropathy to cause pain proximally.
However, pain with back movement can help clinical;y distinguish
between focal neuropathy and radiculopathy. The differential also
includes orthopedic injury or disease in the back which would
result in muscle spasm and pain. The EDX assessment can help
accurately establish the diagnosis.2

ELECTRODIAGNOSTIC EVALUATION
The diagnosis of radiculopathy is established largely on the results
of the needle EMG examination since nerve conduction studies
(NCSs) are normal in patients with radiculopathies. However,
Preston and Shapiro recommend a NCS protocol for patients
with a suspected radiculopathy (Table 1).2 As with all NCSs,
limb temperatures should be maintained within the reference
range (greater than 32C) and documented in the report.
Table 1. Recommended nerve conduction study protocol for a
suspected radiculopathy2

LOWER LIMB
Motor nerve conduction studies
Peroneal and tibial motor studies (bilaterally, if responses
are borderline or abnormal on the symptomatic side)
Sensory nerve conduction studies
At least one sensory study in the distribution of the
suspected radiculopathy (e.g., saphenous-L4, superficial
peroneal-L5, and sural-S1)
Late responses
Peroneal and tibial F responses (bilaterally, if responses are
borderline or abnormal on the symptomatic side)
H reflex to soleus, bilaterally

Figure 1. Electrode placement for a tibial motor nerve conduction study


for a suspected lumbosacral radiculopathy.

Peroneal Motor Nerve Conduction Study


Using standard disc electrodes, G1 is placed over the extensor
digitorum brevis muscle located in the dorsal lateral foot. The
G2 electrode is placed distally over the metatarsalphalangeal
joint of the little toe. The peroneal nerve is stimulated at three
sites: (1) at the anterior ankle, 9 cm proximal to the G1 electrode,
lateral to the tibialis anterior tendon; (2) below the fibular head,
which is one to two finger breadths inferior to the fibular head in
the lateral calf; and (3) at the lateral popliteal fossa, adjacent to
the external hamstring tendons, at a distance of 10-12 cm from
the below-fibular site (Fig. 2).

Figure 2. Electrode placement for a peroneal motor nerve conduction


study for a suspected lumbosacral radiculopathy.

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Late Responses
The F response and the H reflex are used routinely to study
proximal nerve segments.

F Response
The F response is a late motor response occurring after the
CMAP. In the lower extremity, when peroneal and tibial nerves
are stimulated at the ankle, the F response latency is usually
45-56 ms. The F response circuitry, which is both afferent and
efferent, is pure motor. It is derived by an antidromic traveling
up the nerve to the anterior horn cell and an orthodromic
traveling back down the nerve past the stimulation site to the
muscle. The F response is the CMAP, representing 1-5% of
the muscle fibers. Each F response varies slightly in latency,
morphology, and amplitude depending upon the population of
anterior horn cells activated. The shortest latency represents
the largest and fastest motor fibers.
In order to obtain an F response the gain should be increased to
200 V since the F response amplitude is low. The sweep speed
should be increased to 5-10 ms. Supramaximal stimulation is
used. Due to variation in latency, at least 10 F responses should
be obtained. The minimal F wave latency is the most useful
measurement. Although F responses generally are used to assess
proximal nerve segments, in actuality they check the entire
nerve. Therefore, the distal motor latency, conduction velocity,
and height of the patient should be considered prior to accepting
a prolonged F response as indicative of a proximal nerve lesion.
F responses can be elicited from all motor nerves so the setup is
the same as for a routine motor NCS.

The H reflex with the shortest latency is the preferred


measurement. Comparison to the contralateral side is useful
for unilateral lesions. An abnormal result would be a difference
greater than 1.5 ms. As the H reflex is an electrical correlate of the
S1 angle reflex, any lesion that may depress the ankle jerk (e.g.,
polyneuropathy, S1 nerve root lesion, and sciatic neuropathy)
will prolong the H reflex (Fig. 3).

Figure 3. Electrode placement for an H reflex study for a suspected


lumbosacral radiculopathy.

Superficial Peroneal Sensory Nerve


Conduction Study
Using standard disc electrodes, G1 is placed between the tibialis
anterior tendon and the lateral malleolus. The G2 electrode is
placed 3-4 cm distally. The stimulation site is at a distance of 14
cm on the lateral calf (Fig. 4).

H Reflex

The H reflex includes the Ia muscle spindles as sensory


afferents and motor neurons and their axons as the efferents.
With low submaximal stimulation of increased duration (1 ms),
selective activation of the Ia fibers is achieved. The gain must
be increased to 200-500 V and the sweep speed increased to
10 ms. Usually, the H reflex is elicited from the tibial nerve in
the popliteal fossa, recording over the gastroc-soleus muscle.
The typical latency is approximately 30 ms.2
To conduct the examination, the G1 electrode is placed over
the soleus. The G2 electrode is placed on the Achilles tendon.
The tibial nerve is stimulated in the popliteal fossa with the
cathode placed proximally. The H reflex appears at a latency
of 25-34 ms. With a continued increase in stimulus intensity, a
direct motor (M) response appears which grows in size while
the H reflex decreases in size with a continued increase in
stimulus intensity. At supramaximal stimulation, the H reflex
disappears. The M response appears because with an increase
in stimulus intensity not only the Ia afferents but also the motor
axons are stimulated and the orthodromically-traveling motor
action potentials create the M potential. However, the motor
action potentials also travel antidromically toward the spinal
cord and collide with the orthodromically-traveling H reflex
potential, resulting in a decrease in the size of the H reflex.
At supramaximal stimulation, there is a greater collision
proximally of the descending H reflex, making it disappear,
while allowing for the M potential to get larger.2

Figure 4. Electrode placement for a superficial peroneal sensory nerve


conduction study for a suspected lumbosacral radiculopathy.

LUMBOSACRAL RADICULOPATHIES

Sural Sensory Nerve Conduction Study


Using standard disc electrodes, G1 is placed posterior to the
lateral malleolus. The G2 electrode is placed 3-4 cm distally.
The stimulation site is 14 cm proximally at posterior lateral
calf (Fig. 5).

Figure 5. Electrode placement for a sural sensory nerve conduction


study for a suspected lumbosacral radiculopathy.

pattern of abnormality that is beyond the distribution of any


one nerve. Table 2 describes the needle EMG protocol of
Preston and Shapiro. One key point is to ensure that distal and
proximal muscles innervated by the same myotome should
be sampled to exclude a distal-to-proximal gradient as seen
in polyneuropathies. As the paraspinals are innervated by the
dorsal rami of the spinal nerves, they should be always tested
as well. However, in half of radiculopathies, they may not be
affected. The earliest change would be in recruitment which
will be decreased. It is followed by fibrillation potentials and
positive sharp waves which appear at days 10-14 in paraspinal
muscles followed in 2-3 weeks by similar changes in proximal
muscles. It can take up to 4 weeks to see these changes in distal
lower extremity muscles of the myotome. With reinnervation,
the motor unit action potentials become large in amplitude and
duration along with polyphasia. Therefore, the needle EMG
can approximate the time course of a radiculopathy.
However, there are limitations of EDX studies in the setting of
a radiculopathy. Examples include difficulty in localizing to a
single root, normal findings in an acute lesion, normal results
in paraspinals, and denervation potentials which may persist in
paraspinals post spine surgery, to name a few.2

EXPECTED ELECTRODIAGNOSTIC FINDINGS


The Lumbosacral Radiculopathy Task Force was charged by the
Depending on pathophysiology and severity, in demyelinating
American Association of Neuromuscular and Electrodiagnostic
lesions routine motor NCSs may be normal. The only possible
Medicine (AANEM) to systematically review the available
abnormality that can be observed would be in the F responses
literature to evaluate the utility of EDX studies in the diagnosis
as they assess conduction both distally and proximally. In the
of lumbosacral radiculopathies. The published conclusions from
setting of normal distal NCSs, abnormal F responses suggest a
2010 are listed in Table 3.4
proximal lesion in the plexus or roots.
Therefore, in L5-S1 radiculopathies, the Table 2. Recommended needle electromyography protocol for a suspected lumbosacral radiculopathy2
tibial and peroneal F responses may be Examine the relevant myotome first, with sampling of two muscles in each of the
prolonged. Similarly, the H reflex may following areas: (A) paraspinals, (B) proximal, (C) distal extremity.
be prolonged in an S1 radiculopathy; In the post spinal surgery setting, fibrillation potentials may not have any diagnostic
however, it cannot differentiate between significance in paraspinal muscles so they may not be useful for sampling.
plexopathy and radiculopathy. In
addition, other conditions that depress If abnormalities are found: Examine adjacent If findings are equivocal: Compare with
muscles on the contralateral side.
the ankle jerk (e.g., sciatic neuropathy myotomes to look for widespread lesion.
and polyneuropathy) can also cause a
delayed H reflex.
In the setting of axonal loss, a
decreased CMAP amplitude with mild
abnormalities in distal latencies and
conduction velocities will be seen.
Because the sensory nerve action
potential (SNAP) remains normal in
lesions proximal to the DRG, the lesions
of nerve roots are associated with normal
SNAPs as compared to plexopathies and
neuropathies where the SNAPs will be
abnormal. Therefore, a normal SNAP
in a patient with the same distribution
as their sensory symptoms suggests a
lesion proximal to the DRG.
The needle EMG approach is to
sample distal, proximal, and paraspinal
muscles in order to prove a myotomal
10

Table 3. AANEM Lumbosacral Radiculopathy Task Force recommendations4

1. In patients with suspected lumbosacral radiculopathy, the following EDX studies


probably aid the clinical diagnosis:
A. Peripheral limb needle EMG (Class II evidence, Level B recommendation).
B. Paraspinal mapping with needle EMG in lumbar radiculopathy
(Class II evidence, Level B recommendation).
C. H reflex in S1 radiculopathy (Class II and III evidence, Level C recommendation).
2. Evidence suggests a low sensitivity of peroneal and posterior tibial F waves
(Class II and III evidence, Level C recommendation).
3. There is inadequate evidence to reach a conclusion on the utility of the following
EDX studies:
A. Dermatomal/segmental somatosensory evoked potential examination of the L5
or S1 dermatomes (Class III evidence, Level C recommendation).
B. Paraspinal mapping with needle EMG in sacral radiculopathy
(one small Class II study, Level U).
C. Motor evoked potential with root stimulation in making an independent diagnosis
of lumbosacral radiculopathy (Class III evidence, Level U).
EDX=electrodiagnostic EMG=electromyography

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Based on the limitations noted above and the weight of the


task forces recommendations, the diagnosis of a lumbosacral
radiculopathy is made clinically, and it is based upon certain
symptoms and examination findings. Evaluation requires a
careful neurologic examination. Additional neuroimaging and
EDX studies can be useful aids in making the correct diagnosis.

MANAGEMENT
While acute lumbosacral radiculopathy is often extremely
painful, the likelihood of spontaneous improvement is thought
to be high when the cause is disc herniation or lumbar spinal
stenosis due to degenerative arthritis. Although a trial of
208 patients with acute L5 and/or S1 radiculopathy found no
significant difference in outcome at 4 weeks for those assigned
to nonsteroidal antiinflammatory drug (NSAID) treatment
or to placebo, symptomatic treatment does include NSAIDs,
muscle relaxants, and physical therapy.5 Epidural glucocorticoid
injections may provide modest transient benefit towards pain
relief. However, they provide no benefit beyond 3 months.6
For patients with persistent (at least 6 weeks duration) lumbar
radicular symptoms, who are also good surgical candidates,
either open discectomy or microdiscectomy can be considered.7

REFERENCES
1. Hay MC. Anatomy of the lumbar spine. Med J Aust
1976;1:874.
2. Preston DC, Shapiro BE. Electromyography and
neuromuscular disorders: clinical-electrophysiologic
correlations, 2nd ed. Philadelphia: Elsevier, ButterworthHeinemann; 2005.
3. Ljunggren AE. Natural history and clinical role of the
herniated disc. In: Wiesel SW, Weinstein JN, Herkowitz H,
et al, eds. The lumbar spine, 2nd ed, Vol 1. Philadelphia:
WB Saunders; 1996. p 473.
4. Cho C, Ferrante MA, Levin KH, Harmon RL, SoYT.
Utility of electrodiagnostic testing in evaluating patients
with lumbosacral radiculopathy: an evidence-based review.
Muscle Nerve 2010;42(2):276-282.
5. Weber H, Holme I, Amlie E. The natural course of acute
sciatica with nerve root symptoms in a double-blind
placebo-controlled trial evaluating the effect of piroxicam.
Spine (Phila Pa 1976) 1993;18:1433.
6. Pinto RZ, Maher CG, Ferreira ML, et al. Epidural
corticosteroid injections in the management of sciatica:
a systematic review and meta-analysis. Ann Intern Med
2012;157:865.
7. Chou R, Loeser JD, Owens DK, et al. Interventional
therapies, surgery, and interdisciplinary rehabilitation
for low back pain: an evidence-based clinical practice
guideline from the American Pain Society. Spine (Phila Pa
1976) 2009;34:1066.

11

12

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Femoral Neuropathy, Obturator Neuropathy,


and Lumbar Plexopathy
Paul E. Barkhaus, MD
Professor of Neurology and Physical Medicine & Rehabilitation
Medical College of Wisconsin
Milwaukee, Wisconsin

INTRODUCTION
The goal of this discussion is to provide a basic understanding
of the anatomy, electrodiagnostic (EDX) testing, and
pathophysiology of the lumbar plexus (LP) and the femoral
(FN) and obturator nerves (ON). The lateral cutaneous nerve of
the thigh (LCNT, also known as the lateral femoral cutaneous
nerve) will also be discussed. Following the section on anatomy,
common lesions and clinical problems of these structures will
be discussed. The last section will cover EDX testing. (During
the live course, case studies will be presented to demonstrate
the pathophysiology and EDX testing in assessing lesions of this
region.) As in any presentation to an audience of mixed levels
of experience, the author hopes that while those with minimal
experience will obtain the most, those with greater experience
will also find this a helpful review, including perhaps a snippet
or two of new information.

In some individuals the L3 root is the lowest in the LP and may,


instead of L4, send fibers to the lumbosacral trunk. In such cases
(or when it contributes fibers with L4 to the lumbosacral trunk),
the LP is defined as high or prefixed. Conversely and more
commonly, L5 is divided between the LP and sacral plexus. In
the latter situation the LP is described as low or postfixed.26,28

ANATOMY

CLINICAL EVALUATION AND TESTING

The LP and its derivative nerves arise from the rostral portion
of the lumbosacral plexus. As opposed to the exposed brachial
plexus that is surrounded mainly by soft tissue, the lumbosacral
plexus is more protected within the retroperitoneum and pelvis.
The LP is mainly derived from the ventral (anterior) rami of the
L1, L2, and L3 roots. There is some contribution to the LP from
the ventral rami of the T12 root and the majority of the L4 root.

The clinicians task is to define potential lesions, usually by


negative findings such as weakness, sensory loss, and reduced or
absent muscle (myotatic) stretch reflexes. This requires a detailed
knowledge of how to test the muscles and assess for sensory loss.
A focused examination is essential and it is important to exclude
subtle involvement of other regions (e.g., ipsilateral higher and
lower roots, or a contralateral limb).

One may conceptually consider the LP as being composed of two


main parts. There is an upper lumbar, predominantly sensory,
group of three nerves: the ilioinguinal, iliohypogastric, and
genitofemoral. These are uncommonly involved clinically and
are not generally amenable to standard EDX testing. The second
part of the LP comprises the two main sensorimotor branches
(FN and ON) plus a large sensory branch (LCNT). Tables 1 and
2 summarize these principle nerves of the LP. See Figure.

13

FEMORAL NEUROPATHY, OBTURATOR NEUROPATHY, AND LUMBAR PLEXOPATHY


Table 1. Upper lumbar/predominant sensory branches of the the femoral plexus26,28

Nerve
Iliohypogastric

Ilioinguinal

Genitofemoral

Root(s)
Anatomic course
L1 (minor T12) Arises at the lateral border of the psoas major, then between the kidney and quadratus
lumborum; perforates posterior transverse abdominis. Between the latter muscle and internal
oblique it divides into an anterior and lateral cutaneous branch. The nerve is primarily cutaneous
and has communications with the subcostal and ilioinguinal nerves. The lateral branch supplies
sensation to the anterior buttock which may present as an isolated lesion. The anterior branch
supplies cutaneous sensation in a band going medially to the anterior superior iliac spine,
inguinal ligament, medial upper thigh (adjacent to the genitals), and symphysis pubis.
L1 (minor T12) Smaller than the iliohypogastric nerve and may in some cases be a branch of it. Arises
along the lateral border of the psoas major, with or just caudal to the iliohypogastric nerve,
coursing obliquely across the quadratus lumborum and proximal iliacus. It then perforates
the transverse abdominis at the anterior iliac crest (may communicate with iliohypogastric
nerve). It penetrates the internal oblique (contributing some twigs to it), then courses with
the spermatic cord in the inguinal canal and follows it through the superficial inguinal ring.
Supplies cutaneous sensation to the skin overlying the inguinal canal and the superior medial
scrotum in males or mons pubis/labia majora in females.
L1, L2
Courses anteroinferior through the psoas major as a single nerve or may divide into its two
branches very proximally. Then descends on its surface under the peritoneum, dividing
proximal to the inguinal ligament into its genital and femoral branches. The genital branch
goes through the inguinal canal supplying the cremaster muscle and some twigs to the
scrotum. The femoral branch passes behind the inguinal ligament, enters the femoral sheath
lateral to the femoral artery, supplying cutaneous sensation to the proximal femoral triangle.

Table 2. Lower major branches of the femoral plexus26,28

Nerve
Root(s)
Lateral cutaneous L2, L3
nerve of the thigh

Obturator nerve

L2, L3, L4

Femoral nerve

L2, L3, L4

Lumbosacral
trunk

L4, L5

FN=femoral nerve
LP=lumbar plexus

14

Anatomic course
Emerges from the lateral border of the psoas major, obliquely crossing the iliacus, coursing
towards the anterior superior iliac spine, then behind or through the inguinal ligament at a
variable distance medial the anterior superior iliac spine (usually about 1 cm). Anatomic
variations in its course may occur in about 25%.10 Divides into an anterior and posterior
branch. The anterior branch supplies cutaneous sensation to the anterior and lateral thigh as far
distal as the knee; the posterior branch to lateral thigh from the greater trochanter to mid thigh.
Usually the L3 branch is largest, L2 smallest. Courses inferiorly through the psoas major,
emerges on its medial border at the pelvic brim. Courses inferior and anterior along the pelvic
wall through the obturator foramen, entering the thigh. The anterior branch courses between
the obturator externus/adductor brevis and the pectineus/adductor longus. Some sensory
fibers combine with the medial cutaneous nerve of the thigh and saphenous nerve to form the
subsartorial plexus that supplies sensation to the proximal medial thigh. The posterior branch
pierces the obturator externus, supplies this muscle, adductor magnus, sometimes adductor
brevis, and an articular branch to the knee joint. A smaller accessory ON may be present (830%), arising from L3, L4. Has similar course to the ON, branches supply the pectineus and
hip joint. May join the anterior branch of the ON.
Largest branch of the LP. Descends through the psoas major and exits at the lower lateral
border between the psoas and iliacus muscles, deep to the iliac fascia. In the abdomen
gives off branches to the iliacus and pectineus. The FN enters the thigh from behind the
inguinal ligament. The anterior division of the FN gives off branches to the sartorius, then
the intermediate and medial cutaneous branches to the thigh. The [osterior division forms
the saphenous nerve, motor branches to the quadriceps femoris, and articular branches to the
knee. The saphenous nerve is the distal branch of the FN. It supplies sensory branches to the
anteromedial knee, medial distal leg, ankle, and arch of the foot.
L4 primarily supplies the LP, but a small portion joins with L5 to form the lumbosacral trunk
that contributes a significant number of axons that help form the sacral plexus. Because L4
is split between the two plexuses, it is also known as the nervus furcalis. This will not be
discussed further as it becomes part of the sacral plexus.

LCNT=lateral cutaneous nerve of the thigh


ON=obturator nerve

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Motor Testing
Clinical assessment of strength may help localize lesions to one
of the major motor branches of the LP (i.e., FN or ON). If both
are involved that implies a higher lesion of the LP or a lumbar
radiculopathy. Note that the psoas minor receives multiple root
innervations from the LP and S1 and S2. As it does not cross the
hip joint it is not considered a true lower extremity muscle and
is present in only about 40% of individuals. It is not clinically
significant for evaluations of the LP. The rectus femoris, vastus
lateralis, vastus medialis, and vastus intermedius collectively
form the quadriceps femoris muscle group. These muscles and
how they are clinically tested are summarized in Table 3.17

Sensory Testing
Trying to determine the boundaries of a peripheral nerves
distribution in a lesion may be either very obvious or very
frustrating. The first clinical rule is to remember that lesions are
not necessarily all or none and that partial lesions or variations
in anatomy may in turn produce apparent atypical sensory
deficits.10,14 Of the various sensory modalities, sharp touch (this
authors preferred term to pain sensation) and light touch
would be the preferred modalities to test given the types and
patterns of lesions discussed here. Position sense and vibratory
perception would be less useful. Assessing temperature sensation
may be useful, but it requires much more time to do correctly.

Figure. Lumbar Plexus (from Wikipedia)

Table 3. Muscles of lumbar plexus with their roots and testing positions17

Major root supply in bold.


Muscle
Root*/ nerve
Psoas major
L1, L2, L3, L4

Iliacus

L1, L2, L3, L4 / FN

Rectus femoris

L2, L3, L4 / FN

Vastus lateralis
Vastus intermedius
Vastus medialis

Action
Primary hip joint flexor with
assistance in hip joint lateral
rotation and abduction
Primary hip joint flexor with
assistance in hip joint lateral
rotation and abduction
Knee joint extensor and hip
joint flexor
Knee joint extensor

Testing position
These two muscles cannot be clinically
separated functionally. Patient supine, hip
flexion against resistance in a position of slight
lateral rotation and abduction.

Patient supine. Hip in flexion, abduction, and


lateral rotation with the knee flexed against
resistance. Pitfall: If the foot is placed on the
opposite leg (similar to Patrick sign) then the
adductors are maintaining their position.
Patient in lateral decubitus position; examiner
holds patients upper leg in abduction while
patient adducts dependent leg (up) without
rotation, flexion, or extension of hip or tilt of
pelvis.

Sartorius

L2, L3, L4 / FN

Hip joint flexor, abductor, and


lateral rotator

Pectineus
Adductor brevis
Adductor longus
Gracilis

L2, L3, L4 / FN and ON


L2, L3, L4 / ON
L2, L3, L4 / ON
L2, L3, L4 / ON

Adductor magnus

L2, L3, L4, L5, S1 / ON


and sciatic nerve

Hip joint adductor and flexor


Hip joint adductor and flexor
Hip joint adductor and flexor
Hip joint adductor; flexes and
medially rotates knee
Hip joint adductor; may or
may not assist in hip flexion or
extension

FN=femoral nerve

Patient seated with the leg flexed at the knee at


the table edge; examiner places their hand on the
table under the patients distal thigh to stabilize it.
Patient then extends the knee against resistance.
If these muscles are weak, the tensor fascia latae
substitutes with medial thigh rotation.

ON=obturator nerve

15

FEMORAL NEUROPATHY, OBTURATOR NEUROPATHY, AND LUMBAR PLEXOPATHY

The patient should be relaxed and lying down and then be


instructed to use their index finger to delineate the area of sensory
deficit without use of visual input. Later in the examination, it
may be helpful to have them outline it again, still without visual
input for consistency. By not allowing the patient to see where
they are outlining their area of numbness, they are compelled to
rely solely on their tactile perception to define their area of loss.
Allowing visual input may serve to confuse them. The borders
of the area outlined by the patient can be lightly defined with a
marking pen. Still later, a pin or sharp instrument can be used
to confirm the area of sensory loss by starting in the region of
maximum sensory deficit and moving toward the boundaries. In
other words, testing for an area of numbness is best performed
by moving from the area of greatest sensory loss to the least (i.e.,
border of the lesion). The areas of sensory deficit (subjective
and objective) will not necessarily be congruent, but should be
similar in size and shape.14,24 The final rule in sensory testing is
that for the beginner the amount of information obtained from it
is inversely proportional to the time spent on it. In other words:
be direct and decisive and do not dither.

Pain
Subjective pain is of little value as a dependable marker in
localization of a lesion. For instance, due to the close proximity
between the upper LP sensory branches, it is often difficult to
isolate them. Referred pain from sclerotomes may also confound
localization.14 This concept is similar to the dermatome map of
the skin surface that outlines regional representation of the skin
by specific nerve roots. Sclerotomes are regional representations
of the skeletal structure, based on the nerve root supply of its
pain sensitive elements (e.g., periosteum). Both may help
localize lesions.
When there is entrapment of the LCNT at the inguinal
ligament, gentle pressure (as opposed to a Tinel sign) may
elicit paresthesias or a painful response in its distal distribution.
Though nonspecific, the femoral stretch test may be positive in
upper lumbar radiculopathy or femoral neuropathy. Here, the
patient typically stands facing the examination table, placing
their hands on it for support. The examiner places their hand on
the patients anterior thigh and brings it back into hip extension,
stretching the anterior elements such as the FN.

DIFFERENTIAL DIAGNOSIS
Lumbar radiculopathies may show similar sensorimotor
deficits as a LP or discrete nerve lesion. Nonstructural
processes may result in pseudo LP or FN deficits. In addition,
non-neuropathic etiologies may occur in the LP region
resulting in mimic conditions.

Lumbar Plexopathy
Given the anatomic proximity of the LP to the adjacent sacral
plexus, the two may be concurrently affected by disease
processes. Hence, their distinction is more for anatomic than
functional purposes. When confronted with a potential lesion
affecting the LP, it is critical to ascertain that it truly localizes
to the LP and that there is no subclinical involvement outside
of its anatomic boundaries. A practical point to consider is that
in a pure LP lesion there may be involvement of the tibialis
anterior muscle simply because its innervation derives from the
lumbosacral trunk which originates in the LP. Various etiologies
are thoroughly reviewed by Stewart.24 These include mass lesions
(e.g., tumor, abscess, hematoma), radiation, arterial disorders,
pregnancy and parturition, trauma, and inflammation.7,12,15,16,25,26
Table 4 summarizes usual causes of lesions of the primarily
cutaneous branches of the LP. Given their common origin from
the T12, L1, and L2 roots, structural lesions such as hematoma,
abscess, or tumor in the musculature at their origin or along their
course, or retroperitoneal, may produce dysfunction. Lesions
and disorders involving the upper three primarily cutaneous
branches are relatively uncommon.

Femoral Neuropathy
Femoral neuropathy is most frequently the result of trauma
(penetration or stretch), particularly iatrogenic (from surgical
procedures, especially hip arthroplasty, and surgical positioning
in the lithotomy position).1,24,26 As with the cutaneous nerves of
the upper LP, structural lesions (e.g., either retroperitoneal or
femoral sheath hematoma, abscess, or tumor) may occur in the
musculature or other structures along the course of the FN from
its origin to at least the femoral triangle. A considerable number
of femoral neuropathies are idiopathic, including the entity

Table 4. Lesions of the primarily cutaneous nerves of the lumbar plexus14,24,26

Nerve
Iliohypogastric
Ilioinguinal
Genitofemoral
Lateral cutaneous
nerve of the thigh

16

Symptom or signs
Pain or sensory loss in appropriate
distribution. Ilioinguinal neuropathy
may be a cause of dyspareunia.

Etiology
Other than intrinsic structural lesions, consider trauma from
penetrating injuries, or surgery (particularly herniorrhaphy for the
ilioinguinal nerve). Some may be idiopathic.

Pain with or without sensory loss


(called meralgia paresthetica). The
patterns of sensory loss may be
variable and not necessarily include
the entire lateral thigh.

May occur with structural lesions along the proximal course


(as described in the text) to under the inguinal ligament where
it emerges. Most cases are idiopathic. Other causes include
external compression from prolonged activities such as bicycling,
squatting, or wearing compressive clothing. Damage may result
from penetrating injuries and surgery, including (rarely) surgical
positioning. It also occurs with acute weight loss after bariatric
surgery; however, its relationship to obesity is uncertain.

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

of idiopathic progressive mononeuropathy seen in younger


individuals.13 If both femoral nerves are symmetrically involved
in a nondiabetic patient, sarcoidosis should be considered.
Finally, and most importantly, it is important to consider the FNs
relationship to diabetes which may affect the FN, or involve the
ON, LP, and upper lumbar/lower thoracic nerve roots.

surgery, laparoscopy, and femoral artery surgery. Surgical


positioning (lithotomy) may also injure the ON. The ON can be
compressed by tumors, hematoma, and abscess similar to the FN.
There may be entrapment in the obturator foramen or damage
from a leg tourniquet during some types of leg surgery.24.26

THE MIMICS
Obturator Neuropathy
Obturator neuropathy in isolation is uncommon, though
probably more common than appreciated when occurring as a
complication of vaginal childbirth. In this instance, the ON is
usually minimally affected and recovers before it is noticed.
Iatrogenic causes from surgery include hip procedures, pelvic

Fortunately, there are few non-neurologic mimics of the


anatomic region under consideration or diffuse processes that
given their asymmetric nature imply a focal structural lesion.
However, there are a few key neuromuscular entities of which
to be aware (Table 5).

Table 5. Femoral plexopathy or femoral neuropathy mimics

Entity
Diabetic lumbosacral
radiculoplexus neuropathy

Nondiabetic lumbosacral
radiculoplexus neuropathy
Lumbosacral plexopathy

Amyotrophic lateral sclerosis

Kennedys disease

Adult onset spinal muscular


atrophy
Myopathy

Inclusion body myositis

Osteoarthritis of the hip

Trochanteric bursitis

Comment
This entity continues to be debated regarding its classification and causation, but it is thought to
be a microvasculitis of the vaso nervorum. It typically occurs in relatively recent onset diabetics
who have experienced weight loss. Onset is usually abrupt, with a stabbing pain in the thighs,
and it may be very asymmetric to symmetric. Needle EMG may show diffuse denervation
outside the area of clinical involvement (e.g., mid-to-lower thoracic paraspinal muscle). Most
patients have some level of recovery. Can be recurrent.11,18
Similar to the diabetic type, except that this group does not develop diabetes mellitus. The pain
and weakness begins more insidiously than its diabetic counterpart. Longterm recovery is rarely
complete and some recurrence of symptoms may occur.11
These represent involvement of the lumbar plexus plus the sacral plexus.16 They may be
inflammatory,7 due to the structural lesions as described for the femoral plexus,15 or they may be
associated with intragluteal injection.25
Onset may be in the lumbar region, symmetric or asymmetric. Hip flexor weakness is common,
often with increased myotatic tendon responses. While distal weakness in ankle dorsiflexors
may occur, knee extensors are usually involved much later in the disease course. Need to
carefully check other regions for subtle weakness, especially the lateral hand.27 The presence of
fasciculation potentials should also raise suspicion.
Also called X-linked bulbospinal muscular atrophy. Patients may have diabetes and
gynecomastia. It is rare to have only the lower extremity involved first. Need to assess for
proximal arm and bulbar involvement. Needle EMG shows enlarged motor unit potentials and
absent sensory potentials. Family history and genetic testing usually ascertains diagnosis.6
Usually occurs in younger adulthood, affecting the proximal upper and lower extremity muscles.
May manifest in the lower extremities first.23
Inflammatory, congenital, or dystrophic conditions may manifest in the hip or knee flexors early.
Although weakness may be asymmetric, it should be bilateral. Needle EMG should readily
differentiate a myopathy from a neuropathic process.11
Characterized by insidious, progressive weakness in the knee extensors, which may be quite
asymmetric. In the upper extremity, wrist and finger flexors are disproportionately affected
compared to their extensor counterparts. Most common in older Caucasian males. About 25%
have a peripheral neuropathy. Needle EMG should readily define this as a myopathic process
and muscle biopsy should be definitive. It is important to select a minimally involved muscle for
biopsy. Some report neuropathic motor unit potentials in this disease: avoid sampling muscles
that may be affected by polyneuropathy when present.2,8
Hip arthritis is a common entity among the elderly. This may be associated with unilateral
thigh atrophy and hip flexor/knee extensor weakness. Strength in abduction and adduction
may also be decreased.9
This presents as pain in the lateral thigh but is an inflammation of soft tissue. Thus, there should
be no sensorimotor compromise.

EMG=electromyography

17

FEMORAL NEUROPATHY, OBTURATOR NEUROPATHY, AND LUMBAR PLEXOPATHY

CLINICAL NEUROPHYSIOLOGY
EDX testing is very helpful in analyzing lesions of the LP,
FN, and ON, butcompared to the longer nerves supplying
the foot musclesoptions for motor nerve conduction studies
(NCSs) above the knee are limited. This review focuses on only
those EDX techniques directly related to the structures being
discussed. In evaluating these problems, the distal motor and
sensory nerves should also be studied.

Motor Nerve Conduction Studies


Stimulation of the FN at the femoral triangle can evoke a
compound muscle action potential (CMAP), recording from
the quadriceps.3,5,11,19,21,22 Technical problems are common.
When recording over the anterior thigh (especially when
large), volume conduction may attenuate the response. It is also
important to optimize the recording electrode placement so as
to obtain maximal amplitude. The size of the surface electrode
will influence the size of the CMAP.3 The larger the recording
electrode, the smaller the evoked response. It is also important
to record both sides when looking for abnormality to determine
relative asymmetry, if any. Finally, stimulation in the femoral
triangle is not comfortable so it must be deemed useful before
embarking upon it.

level. The iliacus (like other deeper muscles) is remarkable in


that occasional complex repetitive discharges may be recorded
even in normal subjects.19 As an isolated finding, these should be
interpreted with caution.
The distal adductor magnus usually receives motor twigs from
the peroneal portion of the sciatic nerve. Thus, the adductors
should be studied by proximal needle electrode insertions (this
point tends to be a favorite on examinations). The tibialis anterior
muscle is considered the only muscle below the knee to have L4
innervation via the lumbosacral trunk (or nervus furcalis).
The motor unit potentials in the quadriceps femoris group
differ from those of the iliacus and adductor group. As a rule,
the quadriceps femoris group tend to have a relatively higher
amplitude approaching 2 mV or slightly higher. They are usually
simple (i.e., not complex), triphasic (unless near the endplate
region), and have robust durations in the range of 12-18 ms.
The iliacus and adductor group appear smaller in amplitude in
the range of 1 mV, have shorter durations in the range of 10-15
ms, and frequently appear complex (i.e., increased amplitudes
and turns). The main spike durations appear thinner (i.e., less
area and duration) than the quadriceps femoris group. Thus, it
is important to realize that compared to the adductor group, the
quadriceps femoris group might appear enlarged or neurogenic
when in reality this is their normal appearance.4

Sensory Nerve Conductions Studies


There are two sensory NCSs relating to the structures under
discussion. The LCNT sensory NCS may be technically difficult,
particularly in large individuals. Stimulation may be performed
above or below the inguinal ligament. To be useful, both sides
need to be studied unilaterally. If the process is bilateral, one
might question its benefit. Various recording techniques have
been described. Given that the lower limit of reference data may
be 3-4 V22 and that baseline noise may easily approach these
values, a large number of responses would need be averaged
and the study repeated to avoid mistaking artifact for a genuine
sensory response.11,19,20,22
The second sensory study that might be performed would be
a saphenous sensory NCS. The saphenous nerve is the distal
portion of the femoral nerve that supplies cutaneous sensation
to the anteromedial distal leg. It is the only NCS for a LP or
FN lesion that is performed distal to the knee. Again, various
techniques have been described.22 The technical issues are
similar to the LCNT with respect to the expected size of the
sensory responses. Thus, bilateral recording is again critical to
determine the significance of any response obtained (if any). It is
prudent to start with the unaffected side.

Needle Electrode Examination


The concentric or nonpolar needle electrode examination is
the basic mainstay in localizing lesions of the LP, FN, and ON
(Table 6). A few technical comments may be in order. The iliacus
is localized for insertion just lateral to the neurovascular bundle
in the femoral triangle.4 Note that that did not say iliopsoas.
Although they run adjacent to each other, the psoas major is not
accessible to standard needle electrode insertion at that anatomic
18

EDX testing of the LP and related structures may not always


provide the incisive diagnostic study that one might wish. Given
that the number of NCSs that can be performed and the number
of muscles amenable to study are limited (i.e., compared to
the brachial plexus), there may still be some concern that what
appears to be a LP lesion may also actually involve its derivative
roots. Hence, experience and skill is critical in reducing EDX
uncertainty to a minimum.
Table 6. Summary of expected abnormal findings (+) on the needle electrode
examination in muscles based on anatomic localization of lesion4,17,27

A 0 means no abnormality expected.


Muscle
Upper lumbar
paraspinal
Iliacus
Vastus lateralis
Vastus intermedius
Rectus femoris
Sartorius
Adductor brevis
Adductor longus
Adductor magnus
Gracilis

L2, L3, L4
FP FN LCNT ON
radiculopathy
+

+
+
+
+
+
+
+
+
+

+
+
+
+
+
+
+
+
+

0
+
+
+
+
0
0
0
0

0
0
0
0
0
0
0
0
0

0
0
0
0
0
+
+
+
+

FN=femoral nerve FP=femoral plexus


LCNT=lateral cutaneous nerve of the thigh
ON=obturator nerve

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Limiting discussion of diagnostic procedures to only EDX ones


would make for a rather myopic presentation. EDX studies
should be complemented as indicated with structural studies
such as magnetic resonance imaging and computed tomography,
as well as the clinical neuromuscular examination, laboratory
studies, and perhaps muscle or nerve biopsy, if appropriate.
Finally, the emergence of ultrasound has shown great promise
in imaging nerves, particularly the smaller ones of the upper
femoral plexus.

SUMMARY
This discussion should enable the reader to improve their
understanding of the LP, FN, and ON and enhance their
expertise in recognizing and testing for the disorders that affect
these structures.

19

FEMORAL NEUROPATHY, OBTURATOR NEUROPATHY, AND LUMBAR PLEXOPATHY

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BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Sacral Plexopathies and Sciatic Neuropathies


Zachary Simmons, MD
Professor of Neurology
Penn State College of Medicine
Director, Neuromuscular Program and ALS Center
Penn State Hershey Medical Center
Hershey, Pennsylvania

INTRODUCTION
For patients referred to the neuromuscular specialist or
electrodiagnostic (EDX) medicine consultant due to weakness,
pain, or numbness of a lower limb, lumbar or sacral plexopathy
or sciatic neuropathy should be considered. This review will
provide an understanding of the regional anatomy, clinical
findings, and the approach to electrodiagnosis that should
result in proper localization, benefiting both the patient and the
clinician and fostering best patient care.

ANATOMY OF THE SACRAL PLEXUS AND


ITS MAJOR BRANCHES
The lumbosacral plexus is a very large structure. It is formed
from the anterior (ventral) rami of nerve roots from the L1S3 levels, and it gives rise to all the lower extremity nerves.
Structurally and functionally, it is organized into the lumbar
plexus and the sacral plexus. The lumbar plexus is formed
from the L1-4 nerve roots. It gives rise to several major lower
extremity nerves:
Iliohypogastric nerve (L1)
Ilioinguinal nerve (L1)
Genitofemoral nerve (L1-2)
Lateral femoral cutaneous nerve (L2-3)
Femoral nerve (L2-4)
Obturator nerve (L2-4)
The focus here is on the sacral plexus. It is formed primarily
from the ventral rami of the L5-S3 nerve roots. There is some
contribution from the L4 root as the furcal (forked) nerve,
which combines with the ventral primary ramus of L5 to form

the lumbosacral trunk. It then joins the ventral rami of the S1-3
roots. The resulting structure, the sacral plexus, gives rise to
several lower extremity nerves.

Sciatic Nerve
The sciatic nerve is the major nerve arising from the sacral
plexus. It is derived from the anterior (ventral) primary rami of
the L4-S3 roots, and it is the largest nerve in humans. This nerve
or its branches supply all the muscles of the posterior thigh, leg,
and foot. It exits the pelvis via the sciatic notch (greater sciatic
foramen), usually under the piriformis muscle. It then runs
between the ischial tuberosity and the greater trochanter of the
femur. In the leg, it provides innervation to: (1) knee flexors (i.e.,
medial hamstrings [semimembranosus, semitendinosus] and
lateral hamstrings [short and long heads of biceps femoris]) and
(2) the adductor magnus, lateral division. The sciatic nerve has
a lateral division whose fibers will become the peroneal nerve
and a medial division whose fibers will eventually form the
tibial nerve. These separate from one another in the mid thigh.
All sciatic-innervated muscles in the thigh are innervated by the
tibial division except for the short head of the biceps femoris
muscle, which is innervated by the peroneal division. This
muscle is the only peroneal-innervated muscle above the fibular
head. This assumes particular importance when distinguishing
sciatic neuropathies and more proximal lesions from peroneal
neuropathies. Continuing as the peroneal and tibial nerves, the
sciatic nerve supplies all motor innervation below the knee.
It also supplies all sensory innervation to the lower leg below
the knee, except for the medial calf, which is supplied by the
saphenous nerve, a branch of the femoral nerve.
21

SACRAL PLEXOPATHIES AND SCIATIC NEUROPATHIES

Superior Gluteal Nerve

Table 1. General guidelines for nerve conduction studies

The superior gluteal nerve is derived from the ventral


rami of the L4-S1 roots, with the major contribution
usually being L5. It exits the greater sciatic foramen along
with the sciatic nerve. It is exclusively a motor nerve, and
it provides innervation to muscles that produce thigh
abduction and internal rotation: (1) the tensor fascia latae,
(2) the gluteus medius, and (3) the gluteus minimus.

Inferior Gluteal Nerve


Derived from the ventral rami of the L5-S2 roots, with the
major contribution usually being S1, the inferior gluteal
nerve exits the greater sciatic foramen along with the sciatic
nerve. Like the superior gluteal nerve, it is exclusively
motor. It supplies innervation to only one muscle, the
gluteus maximus, which produces hip extension.

Posterior Cutaneous Nerve of the Thigh


The posterior cutaneous nerve of the thigh, a sensory nerve, is
derived from the S1-3 roots, with the major contribution being
S2. It exits the pelvis adjacent to the sciatic nerve and supplies
sensation to the lower buttock and posterior thigh. It gives rise
to the pudendal nerve which is important in bladder, bowel, and
sexual function, and it terminates in the inferior rectal nerve,
perineal nerve, and dorsal nerve of the penis/clitoris.

Other Nerves of the Sacral Plexus


There are several other nerves of the sacral plexus that are less
relevant clinically, particularly to the EDX consultant: (1) the
nerve to the quadratus femoris and inferior gemellus muscles
(L4-S1), (2) the nerve to the obturator internus and superior
gemellus muscles (L5-S2), and (3) the nerve to the piriformis
muscle (S1-2).

ELECTRODIAGNOSIS: CENTRAL
PRINCIPLES
The goal of the EDX study in the lower limb is the localization
of the abnormality, in particular to differentiate plexopathies
from mononeuropathies and radiculopathies. Sensory nerve
conduction studies (NCSs) and needle electromyography (EMG)
of paraspinal muscles are the keys to this differentiation.

Sensory Nerve Conduction Studies


Sensory NCSs are normal the majority of the time in
radiculopathies, and they usually are abnormal in plexopathies
(Table 1). Like most principles, this is not true 100% of the time.
Root lesions may at times compromise the dorsal root ganglia
and result in abnormal sensory studies. It is important to perform
side-to-side comparisons of sensory studies (Table 1).

22

Sensory nerve conduction studies can distinguish plexopathies


from radiculopathies.
Radiculopathy=lesion proximal to the dorsal root ganglion
Sensory nerve conduction studies are NORMAL, because
the sensory nerve is intact from the level of its cell body
(the dorsal root ganglion) to the level of the skin.
Plexopathies=lesion at or distal to the dorsal root ganglion
Sensory nerve conduction studies are ABNORMAL, because
of axon loss from the level of the cell body to the skin.
Side-to-side comparisons of amplitudes are helpful.
A sensory or motor nerve action potential amplitude on
the symptomatic side which is less than half of that on the
asymptomatic side is considered to be abnormal, even if the
absolute value of the amplitude falls within the normal range.

Needle Electromyography of the Paraspinal


Muscles
The needle EMG examination of the paraspinal muscles usually is
abnormal in radiculopathies because these muscles are innervated
from the posterior primary rami that come off prior to the formation
of the plexus. The paraspinal muscle needle EMG examination
is normal in plexopathies. However, as mentioned earlier, not all
principles are consistently true. The needle examination of the
paraspinal muscles may be normal in a radiculopathy due to a
variety of reasons: (1) sampling error, (2) reinnervation, and (3)
fascicular sparing of some nerve fibers. Also, there may be poor
relaxation and suboptimal testing, leading to an inconclusive study
of the paraspinal muscles.

Timing of the Study


A study performed soon after the onset of nerve damage or
injury may be normal or nondiagnostic because of the timing
of Wallerian degeneration. The needle EMG examination also
evolves over time, and there is a delay in the appearance of
needle EMG findings after nerve injury (Table 2).
Table 2. The role of timing in the performance of electrodiagnostic
testing

Nerve conduction studies


Wallerian degeneration of nerves requires a few days
after the nerve lesion.
Compound muscle action potentials generally require
2-4 days to be affected (peak effect 6-7 days).
Sensory nerve action potentials generally require 5-6
days to be affected (peak effect 9-10 days).
Needle electromyography
Within a few days of the nerve injury, there is often
only decreased recruitment.
For distal muscles after a proximal nerve injury, 3-4
weeks may be required to demonstrate fibrillation
potentials and positive sharp waves.
For a more proximal muscle after a proximal nerve
injury, the interval may be as short as a week.

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Specific Nerves and Muscles


There are no direct studies that are usually performed on the sacral
plexus, or on the sciatic, superior gluteal, and inferior gluteal
nerves. Abnormalities of these structures are assessed via NCSs on
standard nerves such as the sural, superficial peroneal sensory,
peroneal motor, and tibial motor nerves, often with the use of
late responses (F waves and H reflexes). A detailed needle EMG
examination is also necessary to arrive at the correct diagnosis.
It is important to have a broad understanding of how to combine
these findings in order to arrive at a correct diagnosis of sacral
plexopathy, sciatic neuropathy, superior gluteal neuropathy, or
inferior gluteal neuropathy. (Though several of these will also be
discussed by others in this course, the presentation of techniques
and normal values from more than one laboratory can be instructive
and educational.) Techniques from the authors laboratory are
illustrated in Dr. Ahmeds paper (Figures 1, 2, 4, and 5, pages
8-10), and normal values are provided in Table 3. F waves and H

reflexes, also known as H-responses, may be of value, and they


will be discussed in the context of specific nerve lesions. F wave
normal values appear in Table 4. H-reflex techniques are shown in
Dr. Ahmeds paper (Figure 3, page 9).

SACRAL PLEXOPATHY
Etiology
There are a variety of structural and nonstructural causes of
sacral plexopathy.1,2 The major ones appear in Table 5. Several
warrant further discussion.

Trauma is a common cause of sacral plexopathy due to a variety of


reasons including gunshots, other missile injuries, or penetrating
knife wounds. The trauma may also be iatrogenic, with sacral
plexopathy following pelvic or orthopedic surgery. Local invasion
by tumors of the bladder, cervix, uterus, ovary, prostate, colon,
or rectum, or invasion of nerves by lymphoma
or by pelvic endometriosis may produce
Table 3. Penn State Hershey Medical Center lower extremity normal values
diffuse plexus abnormalities. Intrinsic nerve
Normal values
12-20
21-60
>60 years Standard adult
abnormalities (e.g., plexiform neurofibromas
years
years
normal values
in patients with neurofibromatosis 1,
Motor conduction
neurofibromas,
schwannomas,
and
perineuriomas) may be causes as well.
Peroneal motor
Retroperitoneal hemorrhages usually occur
Amplitude (mV)
4-13
2-11
1.5-9.0
2-12
in the setting of trauma or in patients with
CV (m/s)
46-61
39-58
35-48
41-57
an increased risk of bleeding, such as those
DL (ms)
3.6-6.0
3.3-6.4
3.4-6.1
3.3-6.1
who are anticoagulated or have hemophilia
Distance (mm)
90
90
90
90
or disseminated intravascular coagulation. If
Tibial motor
the hemorrhage occurs in the psoas muscle,
3-26
Amplitude (mV)
3.5-2.2
3-30
3-20
the resulting compression is most likely to
41-53
CV (m/s)
44-58
40-60
38-68
affect the lumbar plexus rather than the sacral
2.7-6.1
DL (ms)
2.3-5.3
3.0-6.3
3.5-6.6
plexus, but a large hematoma may extend to
80
80
Distance (mm)
80
80
compress the sacral plexus. Other compressive
Sensory conduction
lesions may include aneurysms of the
common or internal iliac arteries. Inadvertent
Sural
arterial injections of substances such as
6-47
5-50
4-35
8-40
Amplitude (V)
chemotherapeutic agents have caused sacral
>40
40-58
40-51
44-58
CV (m/s)
plexopathy. Nerve infarction associated with
3.2-4.2
2.5-4.4
3.3-5.1
DL (ms)
3.0-4.1
mononeuritis multiplex and vasculitis should
140
140
140
140
Distance (mm)
also be considered when attempting to identify
Superficial peroneal
the cause of sacral plexopathy, particularly if
Amplitude (V)
6
the onset is abrupt and painful, if nerves in
CV (m/s)
40
other distributions are affected, or if the patient
DL (ms)
4.4
has a known underlying autoimmune disorder.
Distance (mm)
140

CV=conduction velocity, DL=distal latency


Table 4. Normal F-wave latencies

Nerve
Median
Ulnar
Peroneal
Tibial

Minimal F latency (ms)


31
32
56
56

These values are for subjects of average height. F-wave latencies are
dependent on height and limb length, and they should be adjusted
for height. 14

Table 5. Causes of sacral plexopathy

Trauma Radiation plexopathy


Radiculoplexus neuropathy
Surgical injuries
Diabetic
Malignancies
Nondiabetic
Pelvic tumors
Intra-arterial injection
Lymphoma
Plexiform neurofibromas Infarction
Mononeuritis multiplex/vasculitis
Pelvic endometriosis
Hemorrhage Postpartum injury
Aneurysms
23

SACRAL PLEXOPATHIES AND SCIATIC NEUROPATHIES

Radiculoplexus neuropathies are an important cause, and


they may be diabetic or nondiabetic. Diabetic lumbosacral
radiculoplexus neuropathy (DLRPN), also known as diabetic
amyotrophy and proximal diabetic neuropathy, is perhaps more
commonly recognized. It occurs in those with type II diabetes,
although diabetic control generally is not particularly poor.
The median age is 65 years, and generally there is associated
weight loss. The initial symptom is commonly pain, which
may be excruciating, followed by weakness. It usually begins
focally and unilaterally, most commonly in the hip and thigh
(implying the lumbar plexus), but it may occur in the leg and
foot. Although most physicians recognize the proximal form
as being typical, studies from Mayo Clinic found that 12/33
patients had onset in the foot or leg, implying sacral plexus
involvement.3 Not uncommonly, symptoms spread to become
bilateral and asymmetric. If the lumbar plexus is primarily
affected, quadriceps muscles often are weak, causing the
patient to fall due to the knee buckling. If the sacral plexus
is primarily involved, foot drop is common. The pain usually
improves over weeks, but improvement in strength is slower
and often incomplete, over months to 1-2 years. Residual foot
drop is common. Polyneuropathy often is present concurrently,
leading to more distal and sensory loss, weakness, and reduced
or absent Achilles reflexes (ankle jerks) bilaterally and relatively
symmetrically, superimposed upon the asymmetric DLRPN. The
etiology is microvasculitis with resulting nerve ischemia. The
nondiabetic form is almost identical clinically, including age of
onset (median 69 years versus 65 in diabetics), frequent distal
involvement, frequent incomplete recovery, and the presence of
a microvasculitis on histopathological study.4
Radiation plexopathy may present in an unexpected manner,
usually years after radiation exposure for treatment of a
malignancy. The median time from radiation treatment to
the onset of plexopathy is 5 years, but intervals as long as 31
years and a short as 1 month have been reported.5 It is slowly
progressive, and usually painless, with motor symptoms
more prominent than sensory. The distribution of weakness
and sensory loss depend upon the radiation field. Clinically,
patients may demonstrate myokymia (i.e., rippling, wormlike
movement of muscles and skin). The needle EMG usually
shows myokymic discharges, a feature not seen in plexopathies
arising from most other causes.6 After a period of progression
that may last for a month or longer, the patient eventually
stabilizes, but often with significant deficits.

findings can be mistaken for those of peroneal neuropathy at the


fibular head. The underlying mechanism is compression leading
to ischemia and mechanical deformation of nerves, resulting in
demyelination, and (if sufficiently severe) axonal loss. Prognosis
is excellent, with most patients experiencing a full recovery.

Clinical Features
A sacral plexopathy may resemble radiculopathy, and EDX
studies often are critical in making the distinction. In most cases,
there is pain deep in pelvis (radiation plexopathy is a notable
exception), which can radiate posteriorly into the thigh and into
the posterior and lateral calf. Motor examination demonstrates
weakness of several key muscle groups: (1) hip extensors (i.e.,
gluteus maximus), (2) thigh abductors and internal rotators (i.e.,
gluteus medius and minimus, tensor fascia latae), (3) knee flexors
(i.e., hamstrings), and (4) peroneal- and tibial-innervated muscles
(i.e., ankle dorsiflexion, ankle plantar flexion, and ankle inversion
and eversion). Thus, patients with sacral plexopathy may present
by holding their leg in flexion at the hip and externally rotated.
The Achilles reflex (ankle jerk) usually is decreased or absent.
Sensory examination reveals sensation to be altered or absent over
the posterior thigh, posteriorlateral calf, and foot.

Electrodiagnosis
Sensory Nerve Conduction Studies

Sural and superficial peroneal sensory NCSs commonly reveal


low amplitudes or absent responses if there is axonal loss. The
saphenous sensory NCS is abnormal in lumbar plexopathies at
the L2-4 level or in femoral neuropathies, but it is normal in
sciatic neuropathies.

Motor Nerve Conduction Studies


Peroneal motor NCSs demonstrate low amplitudes and normal
to mildly slowed conduction velocities if there is axonal loss.
Responses will be absent if the sciatic neuropathy is severe. If
there is no response when recording from the extensor digitorum
brevis muscle, then record from tibialis anterior muscle to make
certain the absent response is not due simply to local trauma to
foot muscles (e.g., from tight shoes or previous injury). Tibial
motor NCSs also usually demonstrate low amplitudes and
normal to mildly slowed conduction velocities if there is axonal
loss. Responses are absent if the sciatic neuropathy is severe.

Late Responses
Postpartum injuries occur when the fetal head compresses the
plexus.7,8 The injury usually is to the lumbosacral trunk (L4-5
levels). This structure is exposed at the point where it crosses
the pelvic outlet and is not protected by the psoas muscle, and
so it can be compressed between the fetal head and the bones of
the sacrum. The superior gluteal nerve also may be compressed.
Weakness usually is noted at or shortly after delivery. The
presentation is usually is one of weakness of ankle dorsiflexion,
knee flexion (hamstrings), hip abduction and internal rotation
(gluteus medius and minimus), and hip extension (gluteus
maximus). There often is accompanying sensory loss over the
dorsum of the foot and lateral calf and posterior thigh. Often
the primary clinical symptom and sign is foot drop, and the
24

F-wave studies may be helpful, and they often demonstrate


prolonged latencies or are absent. This does not permit distinction
of radiculopathy from plexopathy or neuropathy, but suggests a
more proximal lesion if the NCSs are normal. H-reflex studies
are abnormal in lesions that involve nerve fibers originating from
the S1 root. H reflexes may be abnormal in S1 radiculopathy,
sacral plexopathy, sciatic neuropathy, and polyneuropathy, but
the abnormality suggests a more proximal lesion if the tibial
motor study and sensory studies are normal.

Additional Key Points for Nerve Conduction Studies


Bilateral studies usually are preferred, so that side-to-side
comparisons can be made. If NCSs are abnormal bilaterally,

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

this raises the question as to whether there is a more generalized


process, such as a polyneuropathy. Consider an upper extremity
study in such cases.

Needle Electromyography
Needle EMG in a sacral plexopathy will show the following:
Denervation of peroneal-innervated muscles and reduced or
absent recruitment if there is axon loss. Reduced or absent
recruitment only if there is demyelination or minimal axon loss,
or if the examination occurs very soon after lesion onset.
Denervation of tibial-innervated muscles with reduced or
absent recruitment if there is axon loss. Reduced or absent
recruitment if there is demyelination or minimal axon loss, or if
the examination occurs very soon after lesion onset.
Denervation of the gluteus maximus muscle with reduced or
absent recruitment if there is axon loss. Reduced or absent
recruitment only if there is demyelination or minimal axon loss,
or if the examination occurs very soon after lesion onset.
Denervation of the gluteus medius or tensor fascia latae
muscle with reduced or absent recruitment if there is axon loss.
Reduced or absent recruitment only if there is demyelination
or minimal axon loss, or if the examination occurs very soon
after lesion onset.
Denervation of sciatic-innervated muscles with reduced or
absent recruitment if there is axon loss. Reduced or absent
recruitment only if there is demyelination or minimal axon loss,
or if the examination occurs very soon after lesion onset.

Normal studies of femoral-innervated muscles (excludes
involvement of the femoral nerve and/or lumbar plexus).
Normal studies of obturator-innervated muscles (excludes
involvement of the obturator nerve and/or lumbar plexus).
Normal studies of paraspinal muscles (excludes radiculopathy).

SCIATIC NEUROPATHY
Etiology
As with sacral plexopathy, there are many possible causes for
sciatic neuropathy (Table 6).1,8 The nerve can be damaged in
the sciatic notch/gluteal region, or in the thigh. Trauma is a
common cause, following hip or femur fractures or dislocations,
or as a consequence of penetrating injuries such as gunshot
and knife injuries. Surgery, such as hip arthroplasty, may
result in sciatic nerve injuries. External compression of the
sciatic nerve resulting in sciatic neuropathy may be seen in
individuals who are immobile due to altered consciousness, such
as those in coma, those receiving anesthesia, or those who are
intoxicated. Bicyclists often report sciatic neuropathies because
of compression from the seat. Other sources of compression that
have been reported include hematomas, aneurysms, vascular
malformations, endometriosis, and tumors of the popliteal
fossa such as Bakers cysts. An intrinsic nerve tumor, such as a
neurofibroma, schwannoma, or perineurioma, or an infiltrating
nerve tumor, such as a lymphoma, may be the cause. Misplaced
injections into the buttocks were a more common cause in the
past, particularly in thin individuals and children, but they
have been minimized by giving injections into the upper outer

quadrant of the buttock or into the thigh. Nerve infarction


associated with mononeuritis multiplex and vasculitis should
also be considered, particularly if the onset is abrupt and painful,
if nerves in other distributions are affected, or if the patient has a
known underlying autoimmune disorder.
Piriformis syndrome is a diagnosis that is often considered,
but less often proven. The sciatic nerve runs under or through
the piriformis muscle as it leaves the pelvis. If hypertrophied,
the piriformis muscle could compress the sciatic nerve. This
compression has been called a piriformis syndrome. Clinically
and electrodiagnostically, the patient must demonstrate sciatic
neuropathy, surgical exploration must show compression of the
sciatic nerve, and surgical decompression must result in relief of
symptoms. The flexion, adduction, and internal rotation (FAIR)
test of the hip should exacerbate symptoms by stretching the
piriformis muscle.9

Clinical Features
Patients with a sciatic neuropathy often have pain in the proximal
thigh, radiating into the leg posteriorly and laterally. Usually
there is no back pain, which may help to distinguish this from
radiculopathy. Examination reveals weakness of knee flexion,
ankle dorsiflexion, ankle plantar flexion, and ankle inversion and
eversion. The Achilles reflex (ankle jerk) is usually decreased or
absent. This is similar to sacral plexopathy except for sparing of the
gluteal-innervated muscles (i.e., hip extension, thigh abduction,
and thigh internal rotation). Commonly, there is sensory loss
over the leg below the knee except for the medial calf (i.e., the
saphenous nerve, a branch of the femoral nerve). These patients
do not have sensory loss over the posterior thigh such as that seen
in sacral plexopathies. Importantly, peroneal fibers are more likely
to be affected than tibial fibers, thus leading often to a foot drop
mimicking a peroneal neuropathy. One study of 68 patients with
a sciatic neuropathy showed that 57% resulted in damage to the
lateral (peroneal) portion, 9% predominantly to the medial (tibial)
portion, and 34% to both portions equally.10 The role of the EDX
examination in making this distinction is very important. Also,
small differences in the neurological examination can be helpful;
even if the peroneal division is preferentially involved, there
often is some tibial division involvement leading to some degree
of weakness of ankle plantar flexion (ask the patient to push up
on their toes), toe flexion, foot inversion, and knee flexion. The
examiner also should look for sensory loss over the sole and very
lateral portion of the foot.

Electrodiagnosis
Sensory Nerve Conduction Studies

Sural and superficial peroneal sensory NCSs commonly reveal


low amplitudes or absent responses if there is axonal loss. The
saphenous sensory NCS is abnormal in lumbar plexopathies at
the L2-4 level or in femoral neuropathies, but it is normal in
sciatic neuropathies..

Motor Nerve Conduction Studies


Peroneal motor NCSs demonstrate low amplitudes and normal
to mildly slowed conduction velocities if there is axonal loss.
Responses will be absent if the sciatic neuropathy is severe. If
25

SACRAL PLEXOPATHIES AND SCIATIC NEUROPATHIES


Table 6. Causes of sciatic neuropathy

External compression
Trauma
Coma
Surgical injuries
Anesthesia
Nerve tumor
Intoxication
Neurofibroma
Bicycle seat
Schwannoma
Bakers cyst
Perineurioma
Hematoma
Lymphoma
Aneurysms, vascular malformations
Misplaced injection
Infarction
Endometriosis
Mononeuritis multiplex/vasculitis
Piriformis syndrome
there is no response when recording from the extensor digitorum
brevis muscle, then record from tibialis anterior muscle to make
certain the absent response is not due simply to local trauma to
foot muscles (e.g., from tight shoes or previous injury). Tibial
motor studies also usually demonstrate low amplitudes and
normal to mildly slowed conduction velocities if there is axonal
loss. Responses are absent if the sciatic neuropathy is severe.

Late Responses
F-wave studies may be helpful, and they often demonstrate
prolonged latencies or are absent. This does not permit distinction
of radiculopathy from plexopathy or neuropathy, but it suggests
a more proximal lesion if the NCSs are normal. H-reflex studies
are abnormal. H reflexes may be abnormal in S1 radiculopathy,
sacral plexopathy, sciatic neuropathy, and polyneuropathy, but
the abnormality suggests a more proximal lesion if the tibial
motor study and sensory studies are normal.

Additional Key Points for Nerve Conduction


Studies
Bilateral studies usually are preferred, so that side-to-side
comparisons can be made. If NCSs are abnormal bilaterally,
this raises the question as to whether there is a more generalized
process such as a polyneuropathy. In such cases, consider an
upper extremity study.

Needle Electromyography
Needle EMG in a sciatic neuropathy will show the following:
Denervation of peroneal-innervated muscles and reduced or
absent recruitment if there is axon loss. Reduced or absent
recruitment only if there is demyelination or minimal axon loss,
or if the examination occurs very soon after lesion onset.
Denervation of tibial-innervated muscles with reduced or
absent recruitment if there is axon loss. Reduced or absent
recruitment if there is demyelination or minimal axon loss, or if
the examination occurs very soon after lesion onset.
Denervation of sciatic-innervated muscles with reduced or
absent recruitment if there is axon loss. Reduced or absent
recruitment only if there is demyelination or minimal axon
loss, or if the examination occurs very soon after lesion onset.
The short head of the biceps femoris muscle is of particular
importance if the patient demonstrates primarily or exclusively
foot drop. This muscle is spared in peroneal neuropathy at
the fibular head, but it is abnormal in sciatic neuropathy more
proximally.
26

Normal studies the gluteus maximus muscle (distinguishes


sacral plexopathy from sciatic neuropathy).
Normal studies of the gluteus medius or tensor fascia latae muscle
(distinguishes sacral plexopathy from sciatic neuropathy).
Normal studies of femoral-innervated muscles.
Normal studies of obturator-innervated muscles.
Normal studies of paraspinal muscles.
If piriformis syndrome is suspected, the FAIR test may be
used. This is performed with the patient lying supine with the
hip in flexion, adduction, and internal rotation. The H reflex
is performed on the symptomatic side without and with this
positioning. One large series found a sensitivity of 88% and a
specificity of 83% using the FAIR test.9 However, the entity of
piriformis syndrome remains controversial.

SUPERIOR GLUTEAL NEUROPATHY


Etiology
Usually, superior gluteal neuropathy occurs in conjunction
with damage to other nerves in the region of the sciatic notch,
including the sciatic and inferior gluteal nerves and the posterior
cutaneous nerve of thigh. Rarely, it may be damaged in isolation.
A common cause is hip arthroplasty; various series note
damagedetermined either clinically or by needle EMGto
the superior gluteal nerves in 23-77% of patients undergoing
this procedure, sometimes diagnosed by EMG when patients
are asymptomatic.11-13 Other causes include hip fracture and
dislocation, misplaced injections, direct trauma to the buttock,
compression by an iliac artery aneurysm, and endometriosis.

Clinical Features
Usually this neuropathy occurs concurrently with neuropathy
involving the sciatic or inferior gluteal nerve. Weakness of hip
abduction and internal rotation without sensory deficits result
from lesions of this nerve.

Electrodiagnosis
Nerve Conduction Studies

NCSs of the sural sensory, superficial peroneal sensory, peroneal


motor, and tibial motor nerves will be normal. F waves and the
H reflex will also be normal.

Needle Electromyography
Needle EMG will show denervation of the gluteus medius and
tensor fascia latae muscles with reduced or absent recruitment if
there is axon loss and reduced or absent recruitment only if there
is demyelination or minimal axon loss, or if the examination
occurs very soon after lesion onset. Other muscles will be normal.

INFERIOR GLUTEAL NEUROPATHY


Etiology
The inferior gluteal nerve is almost always damaged in
association with damage to other nerves of the sciatic notch,
such as the sciatic and superior gluteal nerves and the posterior

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

cutaneous nerve of thigh. The causes of the damage are the same
as those for the superior gluteal nerve.

REFERENCES
1.

Clinical Features
Usually, inferior gluteal neuropathy occurs concurrently with
neuropathy involving the sciatic or superior gluteal nerve.
Weakness of hip extension without sensory deficits result from
lesions of this nerve.

2.
3.

Electrodiagnosis
4.

Nerve Conduction Studies

NCSs of the sural sensory, superficial peroneal sensory, peroneal


motor, and tibial motor nerves will be normal. F waves and the
H reflex will also be normal.

Needle Electromyography
Needle EMG will show denervation of the gluteus maximus
muscle with reduced or absent recruitment if there is axon loss
and reduced or absent recruitment only if there is demyelination
or minimal axon loss, or if the examination occurs very soon
after lesion onset. Other muscles will be normal.

5.

6.
7.
8.
9.

10.
11.

12.

13.

14.

15.

Dumitru D, Zwarts MJ. Lumbosacral plexopathies and proximal


mononeuropathies. In: Dumitru D, Amato AA, Zwarts MJ, eds.
Electrodiagnostic medicine, 2nd ed. Philadelphia: Hanley &
Belfus; 2002. pp 837-883.
Stewart JD. Focal peripheral neuropathies, 4th ed. West
Vancouver, Canada: JBJ Publishing; 2010. pp 406-431.
Dyck PJB, Norell JE, Dyck PJ. Microvasculitis and ischemia
in diabetic lumbosacral radiculoplexus neuropathy. Neurology
1999;53:2113-2121.
Dyck PJB, Norell J, Dyck PJ. Non-diabetic lumbosacral
radiculoplexus neuropathy: natural history, outcome and
comparison with the diabetic variety. Brain 2001;124:1197-1207.
Thomas JE, Cascino TL, Earle JD. Differential diagnosis
between radiation and tumor plexopathy of the pelvis. Neurology
1985;35:1-7.
Katirji B, Wilbourn AJ, Scarberry SL, et al. Intrapartum maternal
lumbosacral plexopathy Muscle Nerve 2002;26:340-347.
Feasby TE, Burton SR, Hahn AF. Obstetrical lumbosacral plexus
injury. Muscle Nerve 1992;15:937-940.
Stewart JD. Focal peripheral neuropathies, 4th ed. West
Vancouver, Canada, JBJ Publishing; 2010. pp 432-471.
Fishman LM, Dombi GW, Michaelsen C, Ringel S, Rozbruch J,
Rosner B, Weber C. Piriformis syndrome: diagnosis, treatment, and
outcome: a 10-year study. Arch Phys Med Rehabil 202;83:295-301.
Johnson W, Stewart JD. Sciatic neuropathies: a 10 year experience.
Can J Neurol Sci 1990;17:249.
Abitbol JJ, Gendron D, Laurin CA, et al. Gluteal nerve damage
following total hip arthroplasty. A prospective analysis. J
Arthroplasty 1990;5:319-322.
Ramesh M, OByrne JM, McCarthy N, et al. Damage to the
superior gluteal nerve after the Hardinge approach to the hip. J
Bone Joint Surg Br 1996;78:903-906.
Picado CH, Garcia F, Marques W. Damage to the superior gluteal
nerve after direct lateral approach to the hip. Clin Orthop Relat
Res 2007;455:209-211.
Preston DC, Shapiro BE. Electromyography and neuromuscular
disorders: clinical-electrophysiologic correlations, 3rd ed.
London: Elsevier Saunders; 2013. pp 37-41.
Preston DC, Shapiro BE. Electromyography and neuromuscular
disorders: Clinical-Electrophysiologic Correlations, 3rd ed.
London: Elsevier Saunders; 2013. p 44.

27

28

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

The Peroneal and Tibial Nerves


Kerry H. Levin, MD
Chairman, Department of Neurology
Director, Neuromuscular Center
Professor of Medicine (Neurology)
Cleveland Clinic
Cleveland, Ohio

THE PERONEAL (FIBULAR) NERVE


Anatomy
The sciatic nerve bifurcates in the distal thigh or proximal popliteal
fossa to form the common peroneal and tibial nerve trunks (Fig.
1). The peroneal nerve is constituted from the lateral sciatic trunk,
and so contains fibers originating in the posterior divisions of the
ventral rami of the L4-S2 spinal roots. In the popliteal fossa it gives
off branches to the sural and lateral cutaneous nerve of the calf.
Descending through the lateral aspect of the popliteal fossa, the
peroneal nerve travels between the tendon of the biceps femoris
and the lateral head of the gastrocnemius muscle.16 It enters the
foreleg behind the fibular head, winding around its neck, where
it lies just beneath the skin. It reaches the anterior compartment
by passing through the superficial head of the peroneus longus
muscle, which, along with various fibrous structures, forms the
fibular tunnel. Within the tunnel, the nerve turns acutely to pass
deep to the peroneus longus, where it divides into the superficial
peroneal and deep peroneal nerves.
The superficial peroneal nerve travels along the fibula in the
lateral compartment of the foreleg, along the peroneus longus
and brevis muscles, which it innervates. Various cutaneous
branches supply the skin of the anterolateral foreleg. Several
centimeters above the lateral malleolus, it passes through a
plane of deep fascia and divides into medial and lateral terminal
branches. These travel over the front of the ankle and innervate
the skin of the dorsum foot, except for the first web space, which
is supplied by the deep peroneal nerve.
The deep peroneal nerve travels down the anterior compartment
of the foreleg, between the tibialis anterior (TA) and extensor
hallucis longus (EHL) muscles and tendons. Along its course it
innervates the TA, EHL, extensor digitorum longus, and peroneus

Figure 1. Course of the peroneal nerve in the leg.

29

THE PERONEAL AND TIBIAL NERVES

tertius muscles. After passing under the crural cruciate ligament


at the ankle, the nerve divides into a lateral branch that supplies
the extensor digitorum brevis (EDB) muscle (the only peroneal
innervated muscle of the foot) and a medial branch branch that
innervates the skin of the first web space.
In about a third of individuals, an accessory deep peroneal nerve
branches off the main nerve at the fibular head, descending down
the lateral foreleg and winding around the lateral malleolus to
supply a variable amount of the EDB muscle.

Differential Diagnosis
Peripheral nerve disorders that can masquerade as focal peroneal
neuropathy or present with foot drop include sciatic neuropathy
(especially when occurring in the setting of total hip arthroplasty),
sacral plexopathy, lumbosacral trunk neuropathy, and L5
radiculopathy. Motor neuron disease of the amyotrophic lateral
sclerosis type can present with foot drop. Central nervous system
disorders that can present with foot drop and foot dorsiflexor
weakness include multiple sclerosis, vertex interhemispheric mass
lesions, and cervical or thoracic myelopathy. All of these should
be distinguishable from peroneal neuropathy by EDX testing.

Major Peroneal Nerve Disorders


Electrodiagnosis
The major causes of common peroneal neuropathy are listed in
Table 1. Most peroneal neuropathies occur in the vicinity of the
fibular head, where the nerve is most exposed. The most common
cause (in the authors experience) is habitual leg crossing,
especially in the setting of weight loss. The lesion usually is
a combination of demyelinating conduction block (CB) at the
fibular head and axon loss, compared to the situation with the
radial nerve at the spiral groove that occurs with Saturday night
palsy, which is often purely CB.
Table 1. Causes of common peroneal neuropathy (Stewart)

Trauma
Blunt injury, laceration
Fibular fracture
Knee dislocation
External compression
Restraints across the fibular head
Casts, leg braces
Habitual leg crossing (especially when associated with
weight loss)
Prolonged squatting, kneeling, sitting crossed-legged
Mass lesions
Ganglion or Bakers cyst, fibular tumor or osteoma
Tumors
Nerve sheath tumor
Entrapment
In the fibular tunnel
Anterior compartment syndrome
Vascular
Popliteal aneurysm
Vasculitic nerve infarction
Mononeuropathy multiplex syndromes
Diabetes, multifocal motor
Trauma is a common cause of peroneal neuropathy. It can be
associated with fracture of the fibula, knee dislocation, and
laceration. It can be iatrogenic, in the setting of total knee
arthroplasty, arthroscopic surgery, varicose vein stripping, and
misplaced restraining straps across the forelegs on operating
room tables. Acute plantar flexion/ankle inversion injury can
lead to severe sprain or fracture of the distal tibia and fibula.
In one study of 66 patients with severe enough sprain to cause
rupture of the lateral or lateral and medial ankle ligament, 17%
of those with lateral ligament rupture and 86% of those with
more severe ankle injury demonstrated peroneal nerve injury by
electrodiagnostic (EDX) studies.9
30

The routine peroneal motor nerve conduction study (NCS)


involves recording from the EDB and just above the ankle. A
conduction velocity (CV) is derived after stimulating proximally
in the lateral popliteal fossa. Overstimulation at the popliteal
fossa produces costimulation of the peroneal and tibial nerves,
producing a characteristic fused contraction of ankle dorsi
and plantar flexion. There should be less than 15-20% drop in
compound muscle action potential (CMAP) amplitude with
proximal stimulation compared with ankle stimulation. If the drop
is greater than 20%, nerve stimulation should be performed just
below the fibular head to assess for a CB across the fibular head.
If the CMAP amplitude is higher with popliteal fossa stimulation
than at the ankle, stimulation should be performed behind the
lateral malleolus to assess for anomalous innervation of the EDB.
When the CMAP amplitude is reduced at all sites of
stimulation, a peroneal NCS recording from the TA muscle
can help discriminate between peroneal neuropathy and distal
peripheral polyneuropathy. Sometimes, the peroneal/TA
NCS can demonstrate a CB across the fibular head when the
peroneal/EDB NCS did not. When peroneal CMAP amplitudes

Bifurcation
of superficial
peroneal n.
Medial dorsal
cutaneous n.

Lateral dorsal
cutaneous n.
Intermediate dorsal
cutaneous n.

Deep
peroneal n.

Figure 2. Terminal branches of the superficial peroneal nerve.3


Used with permission.

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

studies of the superficial peroneal SNAP


have demonstrated increasing amplitude as
the G1 electrode is placed more proximally.
This response should be intact in patients
with pure deep peroneal nerve lesions.
Common peroneal neuropathies at the
fibular head or above should be associated
with an abnormality of the superficial
peroneal SNAP, but this is not always the
case. One study found 17 of 37 cases of
common peroneal neuropathy did not show
abnormalities of the superficial peroneal
SNAP.2
Precise localization by NCS is only possible
with identification of a focal abnormality
across the fibular head, in the form of CB
or CV slowing. Caution is recommended in
making the diagnosis based solely on CV slowing, as this finding
does not correlate with weakness (only CB or axon loss can).
In the absence of focal localization, the needle electrode (NEE)
becomes the critical component of the NCS. The short head of
the biceps femoris is an important muscle to examine, because,
if abnormal, the peroneal lesion can be localized to a point at or
proximal to the branch point of its innervation from the peroneal
division of the sciatic nerve (mid-posterior thigh).
The NEE is a critical component of the localizing process in
focal peroneal neuropathy. The workup strategy in the authors
laboratory is listed in Table 2.

Figure 3. G1 electrode array to maximize the peroneal sensory nerve action potential amplitude.3
Used with permission.

are reduced at both recording sites, the differential diagnosis


includes axon loss peroneal neuropathy, L5 radiculopathy, sciatic
neuropathy, sacral plexopathy, diffuse myopathy, Lambert
Eaton myasthenic syndrome, and motor neuron disease. Many
of these disorders can be distinguished by additional NCSs and
needle electromyography (EMG).
The superficial peroneal sensory NCS is conducted with the G1
recording electrode over the lateral dorsum foot, stimulating
14 cm proximally3 (Figs. 2, 3). A response may not be found in
normal individuals older than 50 years. In the authors laboratory,
this NCS is performed in all patients referred for a question of
peroneal neuropathy and in all patients who demonstrate a low
peroneal CMAP amplitude. It is important to check the response
on the opposite side if symptoms are unilateral, especially
when the sensory nerve action potential (SNAP) amplitude is
borderline or in the mid-to-normal range. Other more recent

Peroneal Neuropathy Case Report


A 13-year-old male experienced an abrupt onset of left big toe
numbness, followed within several days by progressive weakness
of foot dorsiflexion.5 The patient denied pain or frequent leg
crossing. No subsequent worsening occurred. Physical examination

Table 2. Routine workup for peroneal or tibial neuropathy

NCSs
Basic examination
Superficial peroneal SNAP
Sural SNAP
Peroneal CMAP (recording from the extensor digitorum
brevis), stimulating at the ankle, below the fibular head,
and above the fibular head, noting CMAP amplitudes and
waveforms, latencies, and segmental velocities

Tibial CMAP (recording from the abductor hallucis),
stimulating at the ankle and at the popliteal fossa.
Tibial H-reflex (may require comparison on opposite side)
Tibial F wave
Additional examination
Plantar (medial and/or lateral)
Peroneal CMAP (recording from the tibialis anterior),
stimulating above and below the fibular head, if extensor
digitorum brevis response is abnormal, or if more support for
a focal conduction block across the fibular head is needed
CMAP=compound muscle action potential
NCS=nerve conduction study

Needle EMG
Basic examination
Extensor digitorum brevis
Abductor hallucis
Posterior tibialis or flexor digitorum longus
Tibialis anterior
Peroneus longus
Medial gastrocnemius
Rectus femoris or vastus lateralis
Biceps femoris (short head)
Gluteus medius
Additional examination
Abductor digiti quinti pedis
Extensor hallucis longus
Semitendinosus
Tensor fascia lata
High sacral paraspinal

EMG= electromyography
SNAP=sensory nerve action potential

31

THE PERONEAL AND TIBIAL NERVES

revealed profound weakness of the EDB and EHL with mild


weakness of the TA. There was reduced pinprick sensation over
the left big toe. Ten months after the onset of symptoms, NCSs
demonstrated normal and symmetric superficial peroneal sensory
responses. The left peroneal motor (EDB) response was absent
and the peroneal motor (TA) response was about 40% reduced
in amplitude compared with the right, with a normal CV. The
NEE disclosed fibrillation in the TA, EDB, and EHL. Chronic
neurogenic motor unit action potential (MUAP) changes were
observed in those muscles except in the EDB, where no MUAPs
could be activated. The peroneus longus was normal. These EDX
findings supported an axonal loss deep peroneal mononeuropathy,
sparing the superficial peroneal sensory responses. Computed
tomography (CT) demonstrated an elongated osteochondroma
arising from the proximal tibia, projecting laterally and inferiorly,
and ending anterior to the proximal diaphysis of the fibula. At
operation, the deep peroneal nerve was found flattened by the
exostosis, which was excised. Clinical and EDX followup 8
months later revealed no improvement.

Once separated from the peroneal nerve, the tibial nerve lies deep
to the semimembranosus muscle as it enters the popliteal fossa and
lies over the popliteus muscle in the fossa. In the proximal portion
of the fossa, it lies relatively close to the skin surface, superficial
and lateral to the popliteal artery and vein, and covered only by
fascia. Distally, it travels deep to and between the two heads of
the gastrocnemius and plantaris muscles, as it enters the proximal
foreleg. At the level of the knee joint, the tibial nerve is adjacent
to the popliteal artery. In the proximal fossa, nerve branches arise
from the main trunk, destined for the gastrocnemius, soleus,
popliteus, and plantaris. These muscular branches enter the medial
and lateral gastrocnemius and plantaris muscles at the level of
the mid and distal popliteal fossa. A branch to the soleus muscle
arises in the mid-to-distal popliteal fossa. A branch to the popliteus
descends along that muscle, and gives off a branch to the tibialis
posterior (TP) muscle. The tibial contribution to the sural sensory
nerve arises from the tibial nerve in the proximal popliteal fossa
about 3-5 cm above the knee joint, and it descends between the
two heads of the gastrocnemius.

THE TIBIAL NERVE

Based on dissections of 40 cadavers, Sunderland compiled


precise information regarding the exact points at which muscular
branches arise from the tibial nerve in the popliteal fossa.17
The sural nerve and the branches to the medial head of the
gastrocnemius and proximal soleus arise about 30 mm proximal
to the knee joint, while the branch to the lateral gastrocnemius
arises level with the knee joint. Branches supplying the TP, flexor
digitorum longus (FDL), and flexor hallucis brevis arise 90-300
mm distal to the knee joint.

Anatomy
The sciatic nerve bifurcates into the peroneal (fibular) and
tibial nerves at some point in the distal third of the posterior
thigh (Fig. 4). In the upper-to-mid thigh, muscular branches
from the tibial division of the sciatic nerve are given off to the
semimembranosus, semitendinosus, adductor magnus, and long
head of the biceps femoris, while the short head of the biceps
femoris is innervated by the peroneal division.

As the tibial nerve exits the popliteal fossa, it travels beneath the
tendinous arch of the origin of the soleus muscle, closely applied
to the popliteus muscle. The muscular branch to the soleus and
the sural sensory nerve trunk pass superficial to the arch. The
tibial nerve descends through the leg in a plane framed posteriorly
by the soleus and gastrocnemius muscles and anteriorly by the
posterior tibialis muscle. Muscular branches are given off to the
soleus, TP, FDL, and flexor hallucis longus.
The sural sensory nerve trunk descends between the two heads
of the gastrocnemius, piercing the deep fascia in the middle third
of the leg. It continues superficially along the gastrocnemius
muscles, at which point it is joined by the sural communicating
branch of the common peroneal nerve. Cutaneous branches are
given off to the posterior and lateral aspects of the leg. As it
rounds the lateral malleolus, the sural nerve lies just posterior to
the peroneal tendons, at which point it gives off a lateral calcaneal
branch to the ankle and heel. The sural nerve provides cutaneous
branches to the lateral aspects of the ankle, foot, and little toe.
It can give off a communicating branch to the intermediate
cutaneous branch of the superficial peroneal nerve.

Figure 4. Course of the tibial nerve in the leg.

32

At the ankle, the tibial nerve trunk descends behind the medial
malleolus and under the flexor retinaculum, where it gives off
a medial calcaneal branch that pierces the retinaculum and
supplies the skin and fascia of the heel and posterior foot (Fig.
5). The tibial nerve terminates in the medial and lateral plantar
nerves, described sometimes as mixed plantar nerves because
they carry both motor and sensory fibers.

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

The lateral plantar nerve is homologous with the ulnar nerve. It


gives off a muscular branch (inferior calcaneal nerve) to abductor
digiti quinti (ADQ). The superficial branch innervates the flexor
digiti minimi brevis, and a variable number of interossei, and it
provides cutaneous innervation to the ring toe and little toe. The
deep branch supplies the interossei, adductor hallucis, and the
lateral three lumbricals.

Tibial Nerve Vulnerability to Injury

Figure 5. Course of the tibial nerve at the ankle.

The medial plantar nerve is homologous with the median nerve


in the hand, and gives off branches to the abductor hallucis (AH)
and flexor digitorum brevis (Fig. 6). The nerve arborizes into
interdigital nerves which in turn bifurcate to provide cutaneous
sensation to the facing surfaces of adjacent toes. The medial plantar
proper digital nerve reaches the ball of the big toe, and gives off
a muscular branch to the flexor hallucis brevis, and cutaneous
branches to the medial foot, the ball, and medial aspect of the big
toe. The most medial of the three common plantar digital nerves
supplies the first lumbrical muscle; all three provide innervation to
the skin of all digits except the little toe.

In spite of relatively similar pathways in the thigh and popliteal


fossa, the peroneal and tibial nerves have strikingly different
vulnerabilities to injury.6 Exposed to the same forces, the peroneal
nerve suffers more damage than the tibial nerve in almost all
cases. A number of anatomical and vascular differences at least
in part explain this tendency.
First of all, below the bifurcation of the sciatic nerve in the
thigh, the peroneal nerve travels in a single large bundle of
nerve fibers, and its arterial supply rests exposed on its
surface.17 In contrast, the tibial nerve is composed of multiple
small bundles, with its main arterial vascular supply occupying
crevices between the bundles. This orientation decreases the
effect of any compressive force on the tibial nerve fibers and
vessels. Furthermore, in the popliteal fossa the tibial nerve
receives more nutrient arteries than the peroneal nerve, owing
to its closer proximity to the popliteal artery.
Second, except in the proximal most aspect of the popliteal fossa,
the tibial nerve is more deeply situated and less exposed than
the peroneal nerve to external sources of compression. Third,
there is more connective tissue and adipose between fascicles of
the tibial nerve, providing further protection. Finally, the tibial
nerve appears to be less fixed in position than the peroneal nerve,
allowing it more give when being stretched or distorted. The
peroneal nerve is more fixed by its adjoining tissues at the sciatic
notch and the fibular head, while the tibial nerve appears to be
fixed in large part only by the muscles it innervates.

Tibial Nerve Lesions in the Popliteal Fossa


In the popliteal fossa, the tibial nerve is more vulnerable to
injuries than in the thigh, owing to its proximity of the knee joint
and the popliteal artery. However, as is the case elsewhere, the
peroneal nerve is at least as vulnerable. Thus, in severe injuries to
the knee from dislocation or fracture, a combination of tibial and
peroneal lesions is seen, resulting from compression or stretch
injury. Mild knee injuries often spare the tibial nerve entirely.
Blunt and penetrating trauma to the knee region can lead to
vascular disruption and hemorrhage. Space occupying lesions in
the popliteal fossa can also produce tibial neuropathy. A Bakers
cyst arising from the knee joint may compress it separately or
along with the peroneal nerve. Severe ankle sprains have been
reported to produce stretch injury to the tibial nerve.

Electrodiagnosis
Figure 6. Course of the tibial nerve branches in the foot.

Tibial nerve lesions in the popliteal fossa tend to occur distal


to the branch points of the motor nerves to the gastrocnemius
and soleus muscles, and distal to the branch point of the sural
sensory nerve, decreasing the likelihood of involvement of those
33

THE PERONEAL AND TIBIAL NERVES

structures. NCSs show reduced tibial CMAP amplitude when


recording over the AH and ADQ pedis, as well as reduced mixed
plantar nerve action potential amplitude.
The tibial H reflex and the soleus M response should be preserved
since nerve fibers to the gastrocnemius/soleus complex branch
from the tibial nerve trunk high in the popliteal fossa. Most
published studies have lacked H reflex data, but some clinical
reports have called attention to reduction of the ankle muscle
stretch reflex. There are several reasons why the H reflex may
be affected in lesions at this level. First, the motor branch to the
lateral gastrocnemius tends to leave the main trunk in the mid
portion of the popliteal fossa, and secondary nerve twigs to the
soleus and gastrocnemius branch from the tibial nerve distal to
the popliteal fossa. Second, the H reflex is vulnerable to subtle
changes in tibial nerve integrity so that relatively minor lesions
not obvious clinically or by NEE could be sufficient to decrease
the H reflex. Finally, the exact location of a tibial nerve lesion
in the popliteal fossa is difficult to define in relation to branches
that subserve the H reflex.
The NEE in popliteal fossa lesions will show axon loss
principally in tibial-innervated foot muscles and in distal foreleg
muscles including TP and FDL. The gastrocnemius and soleus
muscles are much less likely to show changes unless the tibial
nerve trunk damage is severe and the territory of popliteal fossa
damage is wide. As will be noted later on, both the clinical and
EDX features of early tibial nerve lesions at the popliteal fossa
(or above) can mimic much more distal lesions, such as distal leg
and tarsal tunnel disorders.

Tibial Neuropathy Case Report


A 40-year-old woman presented with tingling sensations in
the right big toe 3 years prior to admission. Over the next 2
years, the paresthesias and subsequent pain spread to the entire
right foot. She was unable to sleep because of the pain. The
assessment of muscle strength was difficult, but there was no
clear weakness in the right leg and foot muscles. The right
ankle muscle stretch reflex was absent. Subtle involuntary
continuous writhing movements were noted in all right toes,
except the big toe, but were not perceived by the patient. NCS
results are found in Table 3.
Table 3. Nerve conduction study results of the tibial neuropathy
case study

Nerve
Sural
Medial plantar
Tibial (AH)
Tibial (ADQP)
H reflex
Soleus M response
Superficial peroneal

Right
15 V
NR
10 mV
5 mV
NR
10 mV
12 V

ADQ=abductor digiti quinti pedis


AH=abductor hallucis
NR=no response

34

Amplitude
Left
15 V
20 V
16 mV
18 mV
1.2 mV
13 mV
10 V

Normal
>6 V
>5 V
>4 mV
>2 mV
>1 mV
>5 mV
>5 V

Tibial Nerve Lesions Below the Popliteal Fossa


Just distal to the popliteal fossa, the tibial nerve crosses
underneath the tendinous arch formed at the origin of the two
heads of the soleus muscle. Several case reports have described
tibial neuropathy secondary to entrapment of the nerve at that
site, confirmed at surgery. This rare disorder appears to present
with pain and sensory loss in the medial foot, mimicking tarsal
tunnel syndrome (TTS).
Between the popliteal fossa and the ankle, the tibial nerve is subject
to the same intrinsic lesions, such as schwannomas and hypertrophic
mononeuropathies, as seen elsewhere along the nerve trunk.

Tibial Neuropathies at the Ankle


Collectively, lesions at this site are described as TTS. While
a number of clinical reports and EDX techniques have been
published on these disorders, lesions at this site are rare.
In the authors EDX laboratory, less than 10 nontraumatic,
noniatrogenic cases have been identified out of more than 50,000
needle EMG studies performed over a 20-year period.

Clinical Diagnosis
Characteristic clinical features of TTS include pain in the ankle
or foot (sometimes with radiating symptoms), and paresthesia
of the sole or heel, or both. A classic feature is the tendency for
the pain and paresthesia in the sole to intensify with walking and
standing, and to diminish with rest. The observation of unilateral
atrophy of the AH or ADQ lends support for the diagnosis, but
clear identification of weakness is difficult because normal
subjects may have difficulty with maneuvers such as fanning the
toes. On the other hand, an isolated plantar neuropathy distal to
the tarsal tunnel can masquerade as TTS (see below).
Table 4 provides a selected list of causes of TTS. Magnetic
resonance imaging (MRI) studies have markedly improved the
ability to make precise anatomical diagnoses in this area.
Table 4. Causes of tibial nerve lesions in the tarsal tunnel

Idiopathic
Fibrosis and thickening of the flexor retinaculum
Hypertrophy of the abductor hallucis muscle
Accessory flexor digitorum longus muscle
Other
Traumatic
Fracture, blunt trauma
Forced flexion, eversion, hypermobility
Post-traumatic fibrous scarring
Running
Foot wear
Mass lesions
Schwannomas
Nerve sheath and intraneural cysts
Tenosynovial tendon sheath or joint cysts (ganglia)
Lipomas
Rheumatoid arthritis
Leprosy
Hypothyroidism

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

Differential Diagnosis
A number of neurogenic disorders can simulate TTS. Distal
mononeuropathies (such as medial plantar neuropathy) and proximal
neuropathies (such as tibial nerve lesions in the popliteal fossa)
can mimic TTS clinically and electrically. Ischemic monomelic
neuropathya disorder characterized by acute-onset burning pain in
the toes or foot due to arterial occlusion usually between the hip and
kneemay be confused with TTS when it occurs spontaneously.4
Incomplete sciatic neuropathy and S1 radiculopathy can present
with symptoms limited to the sole of the foot.
A number of non-neurogenic disorders can simulate TTS.
Soft tissue injuries, such as plantar fasciitis, may present with
symptoms similar to TTS. Plantar fasciitis characteristically
produces heel pain upon arising in the morning localized at the
origin of the plantar fascia at the calcaneus, while TTS tends to
produce medial heel and arch pain along the AH muscle. With
stretching and a graded exercise program plantar fasciitis may
improve, while those maneuvers may worsen the symptoms of
TTS. Foot pain may also be a characteristic of rheumatological
disorders such as arthritis and gout. Orthopedic disorders such
as prolapsed metatarsal heads, longitudinal arch sprain, and
acute foot strain may have a superficial resemblance to TTS. A
selected list of neurogenic and non-neurogenic mimics of TTS
appears in Table 5.
Table 5. Differential diagnosis of tarsal tunnel syndrome

Neuropathic disorders
Ischemic monomelic neuropathy
Compression of the calcaneal nerve
Compression of the medial or lateral plantar nerve
Proximal tibial neuropathy
Sciatic neuropathy
S1 radiculopathy
Soft tissue disorders
Plantar fasciitis
Reiters syndrome
Rheumatoid arthritis
Gout
Ankylosing spondylitis
Orthopedic disorders
Prolapsed metatarsal heads
Longitudinal arch sprain
Acute foot strain

to measure latency and derive CV.10 Sensory NCSs were more


sensitive than tibial motor NCSs. Absence of the medial plantar
response was seen in 52%, and slowed CV was observed in 24%.
In 3 of the 18 patients who underwent both medial and lateral
plantar NCSs, only the lateral plantar NCS was abnormal. Another
group compared digital sensory NCSs with mixed plantar nerve
NCSs, and they found that the digital sensory NCSs were highly
sensitive but lacked specificity. The lack of specificity was
attributed to a number of factors, including very low amplitude
responses in normal subjects, the absence of responses in 8% of
normal subjects, and the tendency for responses to be lost with
minimal degrees of peripheral polyneuropathy.1 Mixed plantar
responses were found to be more specific but less sensitive.
They were abnormal in 85% of patients with TTS. Lateral
plantar responses were more frequently abnormal than medial
plantar responses. CV slowing as the primary determinant of
abnormality was seen in only 3 of 13 cases. Distal tibial motor
latency was found to be prolonged in only 21% of their patients.
Yet another study evaluated 59 patients with tibial motor NCSs
and medial and lateral digital sensory NCSs, recording by needle
electrode at the flexor retinaculum.8 Sensory responses were
absent or slowed in 77%, and slowed in comparison with the
opposite side or with the ipsilateral sural response in 14%. In 9%
of cases with clinical features of TTS, no sensory abnormalities
could be found. The tibial distal motor latency was prolonged in
55%, and neurogenic changes by needle electrode examination
were seen in foot muscles in 45%.
Among the studies cited above, and in general clinical practice,
the criteria used for diagnosis have varied. In determining
sensory and motor amplitude abnormality, the most reliable
measure is a difference of 50% or more. There is no general
agreement regarding normal side-to-side latency variation.
Normative data for these EDX studies vary widely depending
on the stimulating and recording techniques used. In the authors
laboratory, mixed plantar orthodromic responses are obtained
by stimulating percutaneously in the mid sole and recording
just posterior to the medial malleolus. The recording distance
varies widely with foot length, and it is about 3-5 cm longer for
the lateral plantar NCS. The lateral plantar response may not be
obtainable in all normal individuals with percutaneous methods
of stimulation, and plantar responses in general may be absent in
normal subjects over the age of 50 years. Normal data for tibial
motor NCSs in the authors laboratory are provided in Table 6.

Electrodiagnosis
A number of EDX techniques have been
developed to aid in the diagnosis of TTS.
The earliest sensory NCSs involved
digital nerve stimulation with orthodromic
medial plantar nerve recordings performed
with needle electrodes.
A number of studies have reported the
value of EDX studies in the evaluation
of patients with TTS. Oh and colleagues
reported their experience with 21 cases
of TTS, using digital nerve stimulation

Table 6. Tibial motor conduction studies: normal values

Nerve

Tibial
(AH)
Tibial
(ADQ)

< 30 years
Amp
DL
CV
(mV) (ms) (m/s)
>8
<5.8
>41
>4

<6.0

>41

ADQ=abductor digiti quinti pedis


CV=conduction velocity

< 50 years
Amp
DL
CV
(mV) (ms) (m/s)
>8
<6.0
>40
>4

<6.5

>40

AH=abductor hallucis
DL=distal latency

>50 years
Amp
DL
CV
(mV)
(ms)
(m/s)
>4
<6.0
>40
>3

<6.5

AMP=amplitude

>40

35

THE PERONEAL AND TIBIAL NERVES

Lateral Plantar Neuropathy

Figure 7. Cutaneous distribution of sensory nerves in the foot.16


Used with permission.

Disorders of the Plantar and Calcaneal Nerves


Plantar Neuropathies
The plantar nerves constitute the terminal branches of the tibial
nerve, arising in the tarsal tunnel (Fig. 7). The conditions leading
to lesions of either the medial or lateral plantar nerves include the
same processes affecting the tibial nerve at more proximal sites,
such as fractures, tumors, nerve sheath and tendon tenosynovial
cysts, and blunt trauma. A selected list of causes of plantar
neuropathies is found in Table 7.
The patient with plantar neuropathy often describes foot or ankle
pain, but they must also have paresthesia or numbness in the
distribution of a plantar nerve. The examination often discloses
loss of sensation in the plantar distribution in question, but
weakness and atrophy may be difficult to appreciate in the intrinsic
foot muscles, since a number of normal individuals are not able to
fan the toes, and normal function of more proximal long toe flexor
muscles may mask weakness in the intrinsic toe flexors.
Table 7. Causes of plantar nerve lesions

Idiopathic
Hypertrophy or fibrosis of the abductor hallucis muscle
Traumatic
Fractures and sprains of the foot
Mass lesions
Schwannomas
Lipomas
Nerve sheath and intraneural cysts
Tenosynovial tendon sheath or joint cysts (ganglia)

Medial Plantar Neuropathy


The medial plantar nerve usually branches from the posterior
tibial trunk in the tarsal tunnel within about 1 cm of the malleolar
calcaneal axis, but significant variability exists. Few cases have
been documented, often associated with trauma, such as ankle
sprain, crush, or running, although some idiopathic cases may
represent entrapment neuropathy.
Differentiation between medial plantar neuropathy and TTS
affecting the medial plantar branch can be difficult. Clinically,
this may be accomplished by identifying a Tinel sign over the
abductor tunnel as opposed to over the tarsal tunnel. Otherwise,
the clinical presentation may be identical. Likewise, EDX studies
are not likely to distinguish these two sites of nerve damage.
36

Few cases of lateral plantar neuropathy have been reported in the


literature. The nerve appears to be most vulnerable to damage
as it passes through openings in the AH muscle, the so-called
abductor tunnel, on its way to innervate the skin and muscles of
the lateral plantar aspect of the foot. TTS can be confused with
lateral plantar neuropathy when the lateral plantar branch within
the tarsal tunnel is preferentially involved in the lesion.
Some authors have reported isolated damage to the first branch of
the lateral plantar nerve, also described as the inferior calcaneal
nerve. This nerve may originate from the tibial nerve proper, or
from the lateral plantar nerve after bifurcating from the tibial
nerve in the tarsal tunnel. Park and Del Toro reported on the
EDX pattern in a patient with this condition.15 NCSs showed
that the posterior tibial CMAP, recording over the ADQ, was
reduced, and fibrillation potentials and neurogenic recruitment
of motor unit potentials were seen in that muscle.

Differential Diagnosis
The differential diagnosis of plantar neuropathy is broad. A
selected list is found in Table 8. As noted above, more proximal
tibial neuropathies may present, especially early on, in a fashion
similar to a distal lesion, with symptoms and signs limited to the
sole of the foot. Lesions of the sural nerve give rise to sensory
symptoms and sensory loss on the lateral edge of the foot, and
they may be confused with a lateral plantar neuropathy. The
distal saphenous sensory nerve trunk is susceptible to injury,
either by direct trauma or during saphenous vein harvesting
for cardiovascular bypass surgery, especially at the medial
ankle where it is subcutaneous and anterior to the bony medial
malleolus. Such a lesion can potentially produce symptoms
isolated to its terminal cutaneous distribution in the medial aspect
of the arch of the foot, and it may be confused with a medial
plantar neuropathy. A lesion of the calcaneal nerve will produce
numbness of the heel, and involvement of this nerve branch
may coexist with plantar nerve lesions in the tarsal tunnel. Nonneurological causes of foot pain and cutaneous symptoms on
the sole of the foot include arthritis, plantar fasciitis, orthopedic
disorders, and arterial insufficiency.
Table 8. Differential diagnosis of plantar mononeuropathy

Neurogenic
Proximal tibial neuropathy
Calcaneal neuropathy
Sural neuropathy
Distal saphenous neuropathy
Non-neurogenic
Arthritis
Orthopedic disorders of the foot
Plantar fasciitis
Arterial insufficiency

Electrodiagnosis
Techniques used for the diagnosis of plantar neuropathy are
identical to those described above for the diagnosis of TTS.
Motor NCSs with stimulation of the tibial nerve behind and
above the medial malleolus, recording over the AH muscle for

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

the medial plantar nerve and the ADQ for the lateral plantar
nerve, will reliably identify axon loss lesions of the mixed
plantar nerve trunk when 50% or more of motor fibers have been
lost. Stimulation of the mixed medial or lateral plantar nerve
trunks in the sole of the foot, with surface electrode orthodromic
recording over the tibial nerve behind the medial malleolus, will
identify significant plantar sensory fiber loss (greater than 50%
loss of amplitude of the nerve action potential compared to the
asymptomatic side), as long as the lesion is at or proximal to the
stimulation point. For plantar nerve lesions distal to the mid sole,
digital nerve stimulation using ring electrodes with orthodromic
recordings at the medial malleolus are required but difficult to
interpret because normal responses tend to be very small and
may not be found with advancing age. As with any unilateral
lesion, comparison with findings on the asymptomatic side
increases diagnostic reliability and sensitivity.
A number of studies by Oh and colleagues have proposed
superior localizing value of near nerve needle recording.12,13 The
technique uses near nerve recording at the medial malleolus, with
stimulation of digital nerves with ring electrodes and stimulation
of interdigital nerves with surface electrodes.

calcaneal branch arises from the sural nerve trunk as it rounds


the lateral malleolus. Its contribution to cutaneous sensation is
uncertain since most patients with sural nerve lesions above the
ankle do not describe heel symptoms.
Electrodiagnosis of the calcaneal nerve has been described.14
Using surface electrodes to stimulate the tibial nerve proximal
to the ankle and record over the nerve trunk at the far distal and
posterior aspect of the medial ankle, a response with peak latency
of 2.2-2.8 ms and amplitude of 8-34 V was obtained. Whether
this represents a true medial calcaneal nerve action potential is
subject to some question.

Lesions of the Digital Nerves of the Foot


Mortons metatarsalgia and Joplins neuroma are the two major
clinical entities involving digital nerves of the foot. Because of
their focal nature and relatively stereotyped symptomatology,
they are seldom confused with more proximal lesions (Fig. 8).

Oh and colleagues studied 8 patients with lateral plantar


neuropathy.13 In one of 6 tested cases, the CMAP to the ADQ
muscle was reduced in amplitude. Near nerve recording studies
identified abnormalities in all 8 patients.
The NEE of plantar innervated muscles is of great potential
value in the diagnosis of axon loss in the tibial or plantar motor
nerve fibers, since the clinical examination of those muscles is
not as reliable. The presence of fibrillation potentials in tibialinnervated foot muscles of healthy persons has been reported,
thought to be the result of normal aging or chronic local trauma
to nerves and muscles of the feet. While the presence of definite
fibrillation potentials in a tibial-innervated muscle should
never be considered normal, the etiology may not necessarily
reflect a clinically relevant disorder. Especially in the elderly,
the interpretation of such a finding as pathological requires
correlation with NCSs and the clinical setting.

Calcaneal Neuropathy
The medial calcaneal nerve branches arise in the tarsal tunnel,
and damage to it may coexist with lesions of other tibial nerve
branches in the tarsal tunnel. The origin of the medial calcaneal
nerve is highly variable. According to one study, it branches
directly from the tibial nerve in almost 60%, from the tibial
bifurcation in about 20%, and from the lateral plantar nerve
in about 20%. In that study, the nerve did not arise deep to the
flexor retinaculum in 30% of cases.
An isolated lesion of the medial calcaneal branch produces pain
or numbness over the heel. A proposed site of entrapment lies
between the deep fascia of the proximal AH muscle and the
medial aspect of the calcaneus. Symptoms may be associated
with weightbearing, and tenderness may be elicited by palpation
at the anterior aspect of the medial plantar heel pad. This site
of tenderness should be distinguished from tenderness more
anteriorly, which is characteristic of plantar fasciitis. A lateral

Figure 8. Cutaneous distribution of digital sensory nerves in the foot.16


Used with permission.

Mortons Metatarsalgia
Mortons metatarsalgia arises from compression of an interdigital
nerve between two adjoining metatarsal heads (usually the third
and fourth). Another proposed etiology is entrapment of the
interdigital nerve across the anterior edge of the deep transverse
metatarsal ligament. The pathological finding is a fibrous nodule
in the interdigital nerve, rather than a nodule of neural tissue,
so the disorder is not strictly speaking a neuroma. Because the
compression occurs proximal to the interdigital nerves division
into its individual digital nerves, the characteristic clinical
presentation is paresthesia and numbness on the facing surfaces
of two adjoining toes. Other typical features include pain in the
forefoot with radiation into the involved toes. Women are more
prone to the disorder. Symptoms are worsened by standing and
walking in shoes and are relieved by sitting and removing shoes.
Although most cases can be diagnosed by way of the history and
clinical examination, a number of techniques have been used
to support the diagnosis, including ultrasound and MRI. NCSs
performed by stimulation of the digital nerve at the toe and needle
electrode recording of the tibial nerve response at the ankle have
been reported to aid the diagnosis of interdigital neuropathy.11
37

THE PERONEAL AND TIBIAL NERVES

Joplins Neuroma
Joplins neuroma arises from damage to the medial plantar
proper digital nerve as it crosses the first metatarsophalangeal
joint, or as it reaches the medial aspect of the big toe, where
it provides cutaneous innervation to the medial aspect of the
big toe. The pathological finding is perineural fibrosis at the
entrapment site, so the term neuroma is a misnomer. Precipitants
include tightly fitted shoes, blunt trauma, lacerations, and scar
formation following bunionectomy. Patients present with pain
and paresthesia along the medial side of the big toe, especially
when wearing shoes and walking. Occasionally, sensory loss can
be documented in that distribution. An EDX technique has been
described for the evaluation of Joplins neuroma.15

Sural Mononeuropathy
Above the mid calf, the sural nerve is rarely involved in isolation.
Most often, it is affected along with the tibial and peroneal nerve
trunks by severe lesions in the popliteal fossa, as described above.
Below the mid calf the sural nerve runs a superficial course, and it
is subject to iatrogenic trauma (varicose vein stripping), external
compression (tightly fitting boots, tight hose, resting heavy
objects on the lateral lower leg, and trauma such as lacerations.
At the ankle sural mononeuropathy can occur due to lacerations,
fractures, and severe ankle sprains causing nerve stretch.
Internal masses can lead to nerve compression, including
osteochondromas, cysts, ganglions, and sesamoid bones arising
from the peroneal tendons or ankle joint.75
In the foot proper, the inferior branch of the sural nerve can be
damaged by fracture of the base of the fifth metatarsal bone,
leading to persistent symptoms of pain and paresthesia in the
presence of a compressive bony fragment.35

Figure 9. Cutaneous distribution of the sural nerve.16


Used with permission.

38

The clinical presentation of sural mononeuropathy is purely


sensory. Symptoms of pain, paresthesia, or numbness usually
are limited to the lateral edge of the foot (Fig. 9). A lesion at or
proximal to the lateral malleolus may also produce symptoms in
the distribution of the lateral calcaneal nerve, which branches from
the sural nerve as it rounds the ankle. With lesions above the mid
calf, symptoms may be apparent in the posterolateral calf as well.
A Tinel sign may be identifiable over the nerve near the lesion.
EDX studies are useful to confirm the presence of a sural
mononeuropathy, and to exclude other disorders such as sacral
plexopathy, sciatic neuropathy, tibial neuropathy, and S1
radiculopathy. In the absence of an obvious traumatic event,
imaging studies or ultrasound should be considered to exclude a
compressive mass lesion.

BASICS OF LOWER EXTREMITY CLINICAL AND ELECTRODIAGNOSTIC EVALUATION

REFERENCES
1.

Galardi G, Amadio S, Maderna L, Meraviglia MV, Brunati


L, Dal Conte G, Comi G. Electrophysiologic studies in
tarsal tunnel syndrome: diagnostic reliability of motor
distal latency, mixed nerve and sensory nerve conduction
studies. Am J Phys Med Rehabil 1994;73:193-198.
2. Kang PB, Preston DC, Raynor EM. Involvement of
superficial peroneal sensory nerve in common peroneal
neuropathy. Muscle Nerve 2005;31:725-729.
3. Levin KH, Stevens JC, Daube, JR. Superficial peroneal
nerve conduction studies for electromyographic diagnosis.
Muscle Nerve 1986;9:322-326.
4. Levin KH. Ischemic monomelic neuropathy. Muscle Nerve
1989;12:791-795.
5. Levin KH, Wilbourn AJ, Jones HR Jr. Childhood peroneal
neuropathy from bone tumors. Pediatr Neurol 1991;7:308309.
6. Levin KH. Tibial neuropathies. In: Clinical neurophysiology
and neuromuscular disease. Brown W, Bolton C, Aminoff
M, eds. Philadelphia: WB Saunders; 2002. pp 965-980.
7. Mitsumoto H, Levin KH, Wilbourn AJ, Chou SM.
Hypertrophic posterior tibial nerve mononeuritis clinically
presenting with painful legs and moving toes. Muscle
Nerve 1990;13:215-221.
8. Mondelli M, Giannini F, Reale F. Clinical and
electrophysiological findings and follow up in tarsal
tunnel syndrome. Electroencephalogr Clin Neurophysiol
1998;109:418-425.
9. Nitz AJ, Dobner JJ, Kersey D. Nerve injury and grades II
and III ankle sprains. Am J Sports Med 1985;13:177-182.
10. Oh SJ, Sarala PK, Kuba T, Elmore RS. Tarsal tunnel
syndrome: electrophysiological study. Ann Neurol
1979;5:327-330.
11. Oh SJ, Kim HS, Ahmad BK. Electrophysiological
diagnosis of interdigital neuropathy of the foot. Muscle
Nerve 1984;7:218-225.
12. Oh SJ, Lee KW. Medial plantar neuropathy. Neurology
1987;37:1408-1410.
13. Oh SJ, Kwon KH, Hah JS, Kim DE, Demirci M. Lateral
plantar neuropathy. Muscle Nerve 1999;22:1234-1238.
14. Park T, Del Toro DR. The medial calcaneal nerve: anatomy
and nerve conduction technique. Muscle Nerve 1995;18:3238.
15. Park T, Del Toro DR. Isolated inferior calcaneal neuropathy.
Muscle Nerve 1996;19:106-108.
16. Stewart JD. Focal peripheral neuropathies, 4th ed. West
Vancouver, Canada: JBJ Publishing; 2010.
17. Sunderland S. Nerves and nerve injuries, 2nd ed. Edinburgh:
Churchill Livingstone; 1978. pp 968-969.

39

40

Basics of Lower Extremity Clinical and


Electrodiagnostic Evaluation
CME Questions:
1.

Findings or complaints that your patient describes that are


suggestive of lumbosacral radiculopathy include all of the
following EXCEPT:
A. Paresthesias.
B. Weakness of the certain muscles.
C. Lower back pain.
D. Paralysis of muscles.

7.

Which of the following BOTH extends the knee and


flexes the hip?
A. Vastus medialis.
B. Rectus femoris.
C. Sartorius.
D. Vastus lateralis.
E. Vastus intermedius.

2.

What electrodiagnostic (EDX) findings can usually help to


separate lumbosacral radiculopathy from plexopathy?
A. Normal sensory nerve conduction studies.
B. Reduced motor amplitudes.
C. Prolonged F responses.
D. Denervation of muscles on needle electromyography
(EMG).

8.

The lateral cutaneous nerve of the thigh usually enters the


thigh:
A. Just medial to the anterior superior iliac spine.
B. Superior to the inguinal ligament.
C. Just lateral to the anterior superior iliac spine.
D. Just lateral to the posterior superior iliac spine.
E. Just medial to the posterior superior iliac spine.

3.

The H reflex includes all of the following EXCEPT:


A. Supramaximal stimulation levels.
B. Ia muscle spindle as afferent.
C. motor neuron as efferent.
D. Contralateral side comparison.

9.

4.

All of the following are CORRECT regarding the F


response EXCEPT:
A. It evaluates the proximal segment of the nerve.
B. It can be performed for any motor nerve.
C. Supramaximal stimulation is used.
D. Afferent is sensory.

Which of the following would be the MOST LIKELY


cause of very slowly progressive, painless, asymmetric
anterior thigh weakness and wasting in an adult?
A. Progressive muscular atrophy.
B. Hexosaminidase deficiency.
C. Inclusion body myositis.
D. Lumbosacral plexopathy.
E. Scapuloperoneal syndrome.

5.

Needle EMG findings in radiculopathy include all of the


following EXCEPT:
A. Small motor unit action potentials.
B. Fibrillation potentials.
C. Reduced recruitment.
D. Polyphagia.

6.

Which of the following nerves is NOT derived from the


lumbar plexus?
A. Nervus furcalis.
B. Ilioinguinal nerve.
C. Lateral cutaneous nerve of the thigh.
D. Obturator nerve.
E. Posterior cutaneous nerve of the thigh.

10. Which of the following steps in a femoral motor


conduction would be LEAST helpful in obtaining an
optimal response?
A. Move the stimulator to ensure that the cathode is
directly over the nerve.
B. Compare the results to the contralateral femoral
response.
C. Place the E2 (reference) electrode over the patella.
D. Perform a companion study of the saphenous nerve.
E. Move the E1 (active) electrode around to find the
largest recordable response.
11. The sciatic nerve provides innervation to which of the
following muscles?
A. Vastus medialis and semimembranosus.
B. Short head of biceps femoris and semitendinosus.
C. Adductor magnus lateral division and gluteus
maximus.
D. Long head of biceps femoris and gluteus medius.
41

CME QUESTIONS

12. Which of the following describes a lumbosacral


radiculoplexus neuropathy?
A. It is usually painless.
B. It is usually bilateral and symmetric.
C. It is generally associated with weight gain.
D. It is similar in diabetic and in nondiabetic individuals.
13. Which of the following describes a radiation plexopathy?
A. It may occur many years after radiation exposure.
B. It is usually associated with severe pain.
C. It progresses rapidly in most patients.
D. It is characterized by sensory more than motor
symptoms.
14. Which of the following describes EDX studies of the
lower extremities in patients with sacral plexopathy?
A. They typically show normal superficial peroneal
sensory responses.
B. They demonstrate denervation of the vastus medialis
muscle on needle EMG.
C. They commonly show myokymia in patients with
radiation plexopathy.
D. They reveal denervation of L4-S3 paraspinal muscles
on needle EMG.
15. Patients with sciatic neuropathy:
A. Commonly demonstrate foot drop.
B. Have weakness of hip extension.
C. Demonstrate sensory loss over the posterior thigh.
D. Have normal sural sensory responses.
16. A peroneal nerve lesion above the knee can be confirmed
by finding an abnormality on needle EMG of which of the
following muscles?
A. Tensor fascia lata.
B. Semitendinosus.
C. Biceps femoris short head.
D. Gluteus medius.
17. Which of the following EDX features correlates most
closely with the presence of foot drop?
A. A 20 m/s conduction velocity measurement across
the fibular head.
B. A 30% conduction block across the fibular head.
C. A 30% latency prolongation of the peroneal (tibialis
anterior) distal latency.
D. An absent peroneal (extensor digitorum brevis) F
wave response.
18. An axon loss tibial neuropathy in the distal popliteal fossa
would be expected to demonstrate which of the following
abnormalities?
A. An absent H reflex.
B. An absent sural response.
C. Denervation in the medial gastrocnemius muscle.
D. A reduced amplitude plantar response.

42

19. A pure superficial peroneal neuropathy with motor and


sensory findings would be expected to occur with a lesion
at which of the following sites?
A. Distal to the fibular head.
B. In the distal popliteal fossa.
C. At the peroneal-tibial bifurcation of the sciatic nerve.
D. In the distal foreleg.
20. Given the same force of injury, the tibial nerve is more
protected than the peroneal nerve in the popliteal fossa for
which of the following reasons?
A. The tibial nerve has better vascular supply.
B. The tibial nerve is more superficially situated in the
fossa.
C. There is less adipose tissue surrounding the tibial
nerve.
D. The tibial nerve is more anchored by connective
tissue.

Polyneuropathy

Thomas H. Brannagan III, MD


Peter D. Donofrio, MD
P. James B. Dyck, MD
James W. Teener, MD

AANEM 61st Annual Meeting


Savannah, Georgia

Copyright October 2014


American Association of Neuromuscular
& Electrodiagnostic Medicine
2621 Superior Drive NW
Rochester, MN 55901
Printed by Johnson Printing Company, Inc.

Please be aware that some of the medical devices or pharmaceuticals discussed in this handout may not be cleared by the FDA or cleared by the FDA for
the specific use described by the authors and are off-label (i.e. use not described on the products label). Off-label devices or pharmaceuticals may be
used if, in the judgment of the treating physician, such use is medically indicated to treat a patients condition. Information regarding the FDA clearance
status of a particular device or pharmaceutical may be obtained by reading the products package labeling, by contacting a sales representative or legal
counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at 1-800-638-2041.

Polyneuropathy

Table of Contents
Program Committee & Course Objectives

Faculty 5
Metabolic Peripheral Neuropathies
P. James B. Dyck, MD

Neuropathies in Systemic Disease


James W. Teener, MD

15

GuillainBarr Syndrome, Chronic Inflammatory Demyelinating Polyradiculoneuropathy,


Paraproteinemia, and Amyloidosis
Thomas H. Brannagan III, MD

21

Miscellaneous Polyneuropathies
Peter D. Donofrio, MD

25

CME Questions

33

No one involved in the planning of this CME activity had any relevant financial relationships to disclose.
Chair: Peter D. Donofrio, MD

The ideas and opinions expressed in this publication are solely those of the specific authors
and do not necessarily represent those of the AANEM.

Objectives
Objectives - Participants will acquire skills to (1) Discuss the most common causes of polyneuropathy including diabetes, alcohol abuse, inflammatory
neuropathies, and polyneuropathies from systemic illnesses, (2) review the evaluation of patients with polyneuropathies for treatable and reversible
forms, and (3) explain the role of electrodiagnosis in the characterization of polyneuropathies.
Target Audience:
Neurologists, physical medicine and rehabilitation and other physicians interested in neuromuscular and electrodiagnostic medicine
Health care professionals involved in the diagnosis and management of patients with neuromuscular diseases
Researchers who are actively involved in the neuromuscular and/or electrodiagnostic research
Accreditation Statement - The AANEM is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide
continuing medical education (CME) for physicians.
CME Credit - The AANEM designates this live activity for a maximum of put in 3.25 AMA PRA Category 1 Credits. If purchased, the AANEM
designates this enduring material for a maximum of 5.75 AMA PRA Category 1 Credits. This educational event is approved as an Accredited Group
Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada. Physicians should claim on the credit commensurate with the extent of their
participation in the activity. CME for this course is available 10/2014 10/2017.
CEUs Credit - The AANEM has designated this live activity for a maximum of 3.25 AANEM CEUs. If purchased, the AANEM designates this
enduring material for a maximum of 5.75 CEUs.

2013-2014 Program Committee


Zachary Simmons, MD, Co-Chair
Hershey, PA

Elizabeth A. Giles, CNCT


Medina, TN

Vern C. Juel, MD
Durham, NC

Holli A. Horak, MD, Co-Chair


Tucson, AZ

Taylor B. Harrison, MD
Atlanta, GA

A. Arturo Leis, MD
Jackson, MS

Amanda Casey, CNCT


Jackson, TN

Robert W. Irwin, MD
Miami, FL

Samuel D. Nortman, MD
Denver, CO

Jasvinder P. Chawla, MBBS, MD, MBA


Darien, IL

Shawn Jorgensen, MD
Queensbury, NW

Katalin Scherer, MD
Tucson, AZ

Urvi G. Desai, MD
Charlotte, NC

2013-2014 AANEM President


Francis O. Walker, MD
Winston Salem, NC

Polyneuropathy
Faculty

Thomas H. Brannagan III, MD

P. James B. Dyck, MD

Peripheral Neuropathy Center


Columbia University College of Physicians and Surgeons
New York-Presbyterian Hospital
Columbia University Medical Center
New York, NY

Professor Department of Neurology


Mayo Clinic
Rochester, MN

Dr. Brannagan earned his medical degree from the University of Virginia.
He completed his residency and fellowship in electromyography
and neuromuscular disease at the Neurological Institute at Columbia
University. He also completed a neuroimmunology fellowship in
the laboratory of Dr. Norman Latov. Dr. Brannagan is a professor of
neurology and director of the Peripheral Neuropathy Center at the
Columbia University College of Physicians and Surgeons in New
York, New York, as well as co-director of the EMG Laboratory at New
York-Presbyterian Hospital/Columbia University Medical Center.
Dr. Brannagan is a member of a number of professional societies,
including the American Academy of Neurology, American Neurology
Association, AANEM, Neuropathy Association, and Peripheral
Nerve Society. He serves as the Medical Advisor for the Neuropathy
Association, is on the editorial board for Muscle & Nerve and is associate
editor of BMC Neurology. In addition, he is an ad hoc reviewer for more
than 30 publications, including the New England Journal of Medicine
and Neurology. Dr. Brannagan has authored or co-authored more
than 60 articles in peer-reviewed scientific journals and more than 70
abstracts, contributed to more than 20 books, and participated in dozens
of clinical trials. His major interest is the evaluation and treatment of
peripheral neuropathies, particularly immune-mediated neuropathies.

Peter D. Donofrio, MD
Department of Neurology
Vanderbilt University Medical Center
Nashville, TN
Dr. Donofrio is a graduate of The Ohio State University School of
Medicine. He completed an internal medicine residency at Good Samaritan
Hospital in Cincinnati, OH, and a neurology residency and neuromuscular
fellowship at the University of Michigan. After several years on the faculty
at the University of Michigan, he moved to Wake Forest University where
he remained for 20 years before moving to Vanderbilt University Medical
Center. He is professor of neurology and chief of the neuromuscular
section, the EMG laboratory, the Muscular Dystrophy Association Clinic,
and the Amyotrophic Sclerosis (ALS) Clinic at Vanderbilt. His research
interests include clinical trials in ALS, inflammatory neuropathies, and
electrodiagnosis of peripheral neuropathy. Dr. Donofrio has served on
the Board of Directors of the American Association of Neuromuscular &
Electrodiagnostic Medicine and is a past president of the association. He
is board certified by the American Board of Electrodiagnostic Medicine,
the American Board of Psychiatry and Neurology, and the the American
Board of Internal Medicine

Dr. Dyck received his medical degree from the University of Minnesota
School of Medicine, performed an internship at Virginia Mason
Hospital in Seattle, Washington, and a residency at Barnes Hospital and
Washington University in Saint Louis, Missouri. He then performed
fellowships at the Mayo Clinic in Rochester, Minnesota in peripheral
nerve and electromyography. He is currently a professor of neurology
at the Mayo Clinic. Dr. Dyck is a member of several professional
societies, including the AANEM, the American Academy of Neurology,
the Peripheral Nerve Society, the Society of Clinical Neurologists, and
the American Neurological Association. His current research interests
include inflammatory diabetic neuropathies, use of targeted fascicular
nerve biopsies from MRI lesions, pathological studies of peripheral
nerve disorders, and clinical trials in peripheral neuropathies

James W. Teener, MD
Neuromuscular Program
Department of Neurology
University of Michigan Health System
Ann Arbor, MI
Dr. Teener earned his medical degree at the University of Michigan. He
completed a residency in neurology and a neuromuscular fellowship at the
University of Pennsylvania. Dr. Teener is director of the neuromuscular
program, co-director of the EMG laboratory, and associate professor at the
University of Michigan. He completed his residency in neurology and a
neuromuscular fellowship at the University of Pennsylvania. Dr. Teener
is certified by the American Board of Electrodiagnostic Medicine. His
research interests include neuromuscular disorders associated with
critical illness and intensive care treatment of severe neuromuscular
disease. His clinical interests include the full spectrum of neuromuscular
disease. He collaborates widely and provides electrodiagnostic expertise
to a wide variety of research projects.

POLYNEUROPATHY

Metabolic Peripheral Neuropathies


Charles D. Kassardjian, MD
Neuromuscular Medicine Fellow
Department of Neurology
Mayo Clinic
Rochester, Minnesota
P. James B. Dyck, MD
Professor
Department of Neurology
Head of Peripheral Nerve Section and Peripheral Nerve Laboratory
Mayo Clinic
Rochester, Minnesota

HEPATIC DISEASE
Peripheral neuropathies occur in the context of primary liver diseases
or as a result of multisystemic disorders that affect the hepatobiliary
and nervous systems. The focus here will be on the former.

commonly. Forty-eight percent of the cohort had evidence of


autonomic neuropathy based on small fiber quantitative testing
and heart rate and blood pressure changes on the tilt table, as
well as heart rate changes to deep breathing.

Advanced Hepatic Disease


Advanced hepatic disease is associated with both sensorimotor
and autonomic peripheral neuropathies, particularly in the
context of cirrhosis. Because alcohol is a common cause of
hepatic failure and cirrhosis, separating the effect of alcohol
on the peripheral nervous system (PNS) from other causes of
hepatic failure can be challenging.
In a large prospective study, Chaudhry and colleagues evaluated
58 patients with end-stage liver disease from varied causes.1 In 12
patients hepatic failure was due to alcohol. In this series, 71% of
patients had evidence of neuropathy, which was usually mild and
sensory-predominant. In 35% the neuropathy was subclinical,
detected only on laboratory testing. The most commonly reported
symptoms included cramps, paresthesias, and numbness. Distal
sensory loss to vibration and pinprick, along with absent ankle
jerks, were the most common examination findings. Weakness
was not prominent. Nerve conduction studies (NCSs) revealed
a mainly axonal pattern of abnormality, with reduced or absent
sural sensory amplitudes and reduced peroneal amplitudes most

There is a positive correlation between the severity of the


neuropathy and the severity of liver failure.1,2 In addition, the
presence of autonomic nervous system dysfunction predicted a
poorer prognosis.2
In addition to diffuse peripheral neuropathy, there is an increased
incidence of median neuropathy at the wrist in patients with liver
failure (33% of the series by Chaudhry and colleagues).1

Hepatic Infections
Hepatitis C infection is most commonly associated with
vasculitic neuropathy in the context of essential mixed
cryoglobulinemia.3 Cryoglobulins are immunoglobulins that can
be monoclonal (type I), polyclonal (type III), or mixed monoand polyclonal (type II), and they are termed essential when
they are not associated with an underlying disorder. Hepatitis C
is now recognized as the most common cause of essential mixed
cryoglobulinemia (types II and III). Up to 50% of patients with
hepatitis C have essential mixed cryoglobulinemia.3
7

METABOLIC PERIPHERAL NEUROPATHIES

Vasculitic neuropathy associated with hepatitis C and


cryoglobulins presents as an acute or subacute mononeuropathy
multiplex in the majority of cases. However, symmetric or
asymmetric length-dependent polyneuropathy can also occur,
making the diagnosis challenging. Other manifestations include
palpable purpura, glomerulonephritis, leg ulcers, and sicca
syndrome.4 Nerve biopsies demonstrate generalized fiber loss,
epineurial perivascular inflammatory infiltrates with infiltration
of vessel walls, and may show fibrinoid necrosis.5 Treatment of
hepatitis C-associated cryoglobulinemic neuropathy is usually
with a combination of immunosuppression and antiviral therapy.4
The standard antiviral therapy would be pegylated interferon-
and ribavirin.6 Corticosteroids, cyclophosphamide, plasma
exchange (PE), or rituximab have all been used. In particular,
there is recent evidence for the efficacy of rituximab in the
treatment severe mixed cryoglobulinemic syndrome.6

and burning pain in the feet.5 Examination reveals distalpredominant impairments in vibration sensation, muscle
atrophy and weakness, and reduction or absence of deep
tendon reflexes. Rarely, rapidly progressive polyneuropathy
can occur in the context of ESRD, with severe sensorimotor
deficits developing over days to weeks.5 The possibility of a
coincidental inflammatory demyelinating neuropathy cannot be
totally excluded in these rapidly progressive cases, and it should
be considered before concluding that the acute neuropathy
is due to ESRD. Electrodiagnostic (EDX) testing in uremic
neuropathy may demonstrate conduction velocity slowing in
sensory and motor nerves (some demyelinating features), but
the predominant findings are those of an axonal sensorimotor
neuropathy. The amplitude of the sural sensory response appears
to be the most sensitive electrophysiological indicator of uremic
neuropathy, along with the peroneal motor conduction velocity.

Hepatitis C may also cause a vasculitic neuropathy in the


absence of cryoglobulins where it presents as a severe
neuropathy with features similar to polyarteritis nodosa.4 Other
neuropathies associated with hepatitis C infection include small
fiber neuropathy without cryoglobulins and acute inflammatory
demyelinating polyradiculoneuropathy (AIDP).5

Detailed and careful pathological studies from nerve biopsies in


uremic neuropathy have demonstrated that axonal degeneration
and axonal atrophy were the primary pathological abnormality,
with demyelination being secondary to axonal atrophy and
loss. Distal nerve segments were most affected, with proximal
segments relatively spared.5,8

Hepatitis B is most commonly associated with multiple


mononeuropathies in the context of hepatitis B virus (HBV)associated polyarteritis nodosa (PAN). Up to 10-55% of PAN
cases have positive HBV serology, and 80% develop neuropathy.
The clinical course may be monophasic, but it can be severe and
even fatal if untreated. No randomized controlled trial data exist
to guide therapy, but most treat with high-dose corticosteroids,
and in severe cases add PE. In patients with HBV-associated
PAN neuropathy, a hepatologist should be involved in order
to guide the initiation and management of antiviral therapy in
addition to immunosuppression.

There is debate about whether hemodialysis improves uremic


neuropathy, with the most recent data suggesting that the
neuropathy generally does not improve with dialysis alone.
Conversely, renal transplantation does result in improvement in
neuropathy symptoms and NCS parameters.7 After transplantation,
patients note a rapid improvement in distal sensory and motor
function, followed by a gradual improvement over time.

Other Neuropathies Associated With Liver


Disease
Low vitamin E levels associated with chronic cholestatic liver
disease in children can produce a syndrome of ataxia, vision
loss, ophthalmoparesis, and a sensory-predominant peripheral
neuropathy.5 Pathologically, there is degeneration in the cuneate
and gracile nuclei, spinocerebellar tracts, and loss of neurons
in the dorsal root ganglia. There is clinical improvement with
vitamin E supplementation.

RENAL DISEASE
Uremic Neuropathy
Renal disease, and particularly end-stage renal disease (ESRD),
is a well-studied cause of neuropathy. The prevalence remains
high, despite reductions in rates of uremic neuropathy with the
earlier use of dialysis and renal transplantation.
Uremic neuropathy most commonly presents as a lengthdependent symmetric sensorimotor neuropathy.7 Onset and
progression are usually slow, over months or years. Symptoms
include cramps, restless legs, weakness, paresthesias,
8

The etiology of uremic neuropathy remains under debate.


The prevailing hypothesis suggests that a neurotoxic middle
molecule is present, which is not well-cleared by hemodialysis
membranes. Candidate middle molecules that have been
investigated include parathyroid hormone and 2-microglobulin.
However, a clearly neurotoxic middle molecule remains elusive.
More recent data utilizing nerve excitability studies suggest
that potassium (hyperkalemia) may be the toxic substrate that
underlies uremic neuropathy, as it satisfies many of the criteria
for a neurotoxic substance that accumulates in renal failure (see
Krishnan and Kiernan7 for a review of uremic neuropathy and
pathogenesis).

Mononeuropathies in Renal Disease


Median neuropathy at the wrist causing carpal tunnel syndrome
(CTS) is relatively common in ESRD (6-31%).5,7 Longer
hemodialysis duration is a risk factor, due to deposition of 2microglobulin amyloid in both the nerve and flexor retinaculum.
Ulnar neuropathy at the elbow and peroneal neuropathies at the
fibular head can also occur in chronic renal patients. Ischemic
monomelic neuropathy is a rare neuropathy resulting from upperlimb arteriovenous fistulas created for hemodialysis. Excessive
shunting of blood through the fistula diverts blood away from
the distal arm and hence distal nerve branches, and it produces
nerve ischemia. The median, ulnar, and radial nerves are most
commonly affected, and neurological recovery is usually
incomplete after closure of the fistula.

POLYNEUROPATHY

HYPOTHYROIDISM
The most common neuropathy in patients with hypothyroidism
is median neuropathy at the wrist, causing CTS (in up to 29% of
hypothyroid patients).5 Clinical features are similar to those of
CTS from other etiologies. The pathophysiology is thought to be
due to reduced space beneath the flexor retinaculum, likely due
to deposition of mucopolysaccharides within the tendons and
synovial sheaths. Adequate treatment with thyroid replacement
often alleviates symptoms within weeks or months, and it may
relate to clearing of the mucopolysaccharide complexes.5,9

prospective study, 14% of hyperthyroid patients had distal


sensory disturbances, and 19% had physical examination findings
of sensory disturbances and absent ankle jerks consistent with
polyneuropathy.10

DIABETES MELLITUS
Diabetes mellitus (DM) is thought to be the most common cause
of peripheral neuropathy in Western nations. There are multiple
different types of peripheral neuropathy associated with diabetes,
and these can be classified in different ways, including by pattern
of involvement (Table 1) or presumed pathophysiology (Table
2). Based on data from the Rochester Diabetic Neuropathy Study
(RDNS), the rate of any neuropathy in diabetes was 59% for type
2 DM and 66% for type 1 DM.

Hypothyroidism is associated with a sensory-predominant,


length-dependent polyneuropathy. Clinically, patients develop
paresthesias, numbness, and occasionally pain in the lower
limbs and to a lesser degree the hands. Large fiber sensory
modalities tend to be preferentially affected, and the patient
may have an unsteady gait due to sensory
loss. Distal weakness is usually absent, but
Table 1. Classification of diabetic neuropathies by pattern of involvement
mild weakness may occur. Proximal weakness
Symmetric
Diabetic polyneuropathy
may occur if there is an accompanying
Diabetic autonomic neuropathy
hypothyroid myopathy. Reflexes are usually
Painful distal neuropathy with weight loss (diabetic cachexia)
diminished, and they may show a delay in the
Treatment related neuropathy (insulin neuritis)
relaxation phase seen in hypothyroidism. EDX
Polyneuropathy after ketoacidosis
testing has demonstrated conflicting results,
CIDP in DM
with reports of both a predominantly axonal
Polyneuropathy in impaired glycemia
sensory polyneuropathy,10 and evidence of
Asymmetric
Radiculoplexus neuropathy
demyelination with prolonged distal latencies
Lumbosacral
and slowed conduction velocities in others.5,11
Thoracic
In 2 cases of hypothyroid polyneuropathy, Dyck
Cervical
and Lambert demonstrated markedly prolonged
Mononeuropathies
distal latencies and slowed conduction velocities
Median neuropathy at the wrist
with temporal dispersion of both in vivo and
Ulnar neuropathy at the elbow
in vitro nerves, suggesting demyelination
Peroneal neuropathy at the fibular head
and remyelination.11 Pathologically, there is a
Cranial
neuropathies
reduction in the number of large myelinated
fibers, and an alteration of the size distribution of CIDP=chronic inflammatory demyelinating polyradiculoneuropathy
DM=diabetes mellitus
myelinated fibers to fibers with smaller
diameters, with relative preservation
Table 2. Classification of diabetic neuropathies by pathophysiology
of unmyelinated fibers. Grouped
Metabolicmicrovascularhypoxic Diabetic polyneuropathy
regions of segmental demyelination
Diabetic autonomic neuropathy
and remyelination along myelinated
Inflammatory-immune
Radiculoplexus neuropathy
nerve fiber lengths (secondary
Lumbosacral
demyelination to axonal atrophy) was
11
Thoracic
also observed by Dyck and Lambert.
Cervical
Despite their deposition in the soft
Cranial
neuropathies
tissues, it does not appear that there
Painful
distal
neuropathy with weight loss
is a significant accumulation of
11
(diabetic
cachexia)
mucopolysaccharides in nerve.
CIDP in DM
Compression
Mononeuropathies
Management of hypothyroid-related
Median neuropathy at the wrist
neuropathies involves treatment of the
Ulnar neuropathy at the elbow
underlying hypothyroidism.
Peroneal neuropathy at the fibular head
HYPERTHYROIDISM
Complications of diabetes
Polyneuropathy after ketoacidosis
Polyneuropathy associated with uremia
The presence of polyneuropathy
Treatment related
Treatment related neuropathy (insulin neuritis)
associated with hyperthyroidism is
Hyperinsulin neuropathy
not well-established. In one recent
CIDP=chronic inflammatory demyelinating polyradiculoneuropathy

DM=diabetes mellitus

METABOLIC PERIPHERAL NEUROPATHIES

Diabetic Sensorimotor Polyneuropathy


Diabetic sensorimotor polyneuropathy (DPN) can be divided
into typical and atypical DPN. Typical DPN is the prototypical
neuropathy associated with DM. Typical DPN usually presents as
a chronic length-dependent sensorimotor peripheral neuropathy,
with prominent sensory involvement and little weakness.
Symptoms tend to be more prominent in the lower limbs. If
there are prominent upper limb sensory or motor features, then
one has to consider coexisting mononeuropathies (e.g., median
neuropathy at the wrist or ulnar neuropathy at the elbow). Major
risk factors are prolonged hyperglycemia (duration of DM) and
poor glycemic control. In addition, a strong association exists
between DPN and both retinopathy and nephropathy. Therefore,
other causes of polyneuropathy should be sought in diabetic
patients with symptoms of neuropathy, but without retinopathy or
nephropathy. Other types of neuropathy associated with diabetes
(i.e., not DPN) are not associated with diabetic retinopathy or
nephropathy. Contrary to common belief, typical DPN often
lacks significant neuropathic pain. Atypical DPN is a smallfiber predominant polyneuropathy, associated with unpleasant
positive sensory symptoms and varieties of pain.

Differential Diagnosis
Even in patients with DM, the clinician should consider alternate
causes of peripheral neuropathy, especially treatable varieties.
This is particularly true in diabetic patients without retinopathy
and nephropathy. Other causes that need to be considered include
infectious diseases (e.g., human immunodeficiency virus,
Lyme disease), metabolic conditions (e.g., hypothyroidism,
uremia), inflammatory varieties (e.g., connective tissue disease
associated), malnutrition (e.g., vitamin or protein deficiency,
malabsorption
syndromes,
alcoholism),
paraneoplastic
conditions, toxins, inherited neuropathies, and others.

Pathogenesis of Diabetic Sensorimotor


Polyneuropathy
The pathogenesis of DPN remains unknown, with both metabolic
and vascular hypotheses. The metabolic hypothesis postulates
that chronic hyperglycemia induces a metabolic derangement
that is directly toxic to nerves and their supporting structures (i.e.,
axons, Schwann cells). For example, there is evidence that myoinositol uptake is reduced in diabetic nerves, resulting in altered
function of the sodium-potassium ATPase. However, clinical
trials showed no benefit from myo-inositol supplementation.
Hyperglycemia is also thought to activate aldose reductase,
resulting in accumulation of sorbitol and fructose, and
contributing to oxidative stress. In the vascular hypothesis,
chronic hyperglycemia causes metabolic derangements that lead
to altered structure of microvessels and resulting hypoxia of
nerves. A variety of abnormalities of endoneurial microvessels
are observed in DPN, including thickening or reduplication of
the capillary wall basement membrane, endothelial and pericyte
degeneration, and endothelial fenestration and disjunction. The
severity of microvascular changes has been associated with the
severity of DPN.5,12 Multifocal fiber loss seen in sural nerve
biopsies from DPN is further support of a vascular etiology.

10

Treatment of Diabetic Sensorimotor


Polyneuropathy
Good glycemic control reduces the risk of developing DPN, as
shown in the Diabetes Control and Complications Trial (DCCT)
where patients treated with more intensive insulin therapy had
a reduced incidence of neuropathy.13 Other pharmacological
methods have not yet been shown to be successful, such as
aldose reductase inhibitors, myo-inositol supplementation,
or recombinant nerve growth factor. Thus, aiming for
normoglycemia and symptomatic treatment of neuropathic pain
are the mainstay of treatment presently.

Polyneuropathy Associated With Impaired


Glycemia
There has been much research in the last decade on the association
between impaired glycemia (e.g., impaired glucose tolerance or
impaired fasting glucose) and DPN. Most initial studies were
retrospective and nonpopulation based, using historical control
subjects, and they looked for the presence of impaired glycemia
in patients with already diagnosed otherwise idiopathic peripheral
neuropathy.14,15 The neuropathy associated with impaired glycemia
is a length-dependent sensory-predominant and painful axonal
neuropathy (small fiber neuropathy). However, in a study using
a prospectively recruited control group to identify the etiologies
of chronic idiopathic axonal polyneuropathy (CIAP), Hughes and
colleagues found an association with hypertriglyceridemia but not
impaired glycemia.16 Similarly, a recent prospective study of the
association between the metabolic syndrome and CIAP showed
an increased prevalence of abdominal obesity and hypertension,
but not impaired glycemia.17 In the prospective Olmsted County
Impaired Glycemia (OC-IG) trial of matched impaired glycemia
and control subjects, studied in a semi-masked fashion, all living
in one community, there was no increased prevalence of peripheral
neuropathy either narrowly or broadly defined in the impaired
glycemia group.18 Also there was not an association of impaired
glycemia with retinopathy or nephropathy. However, in newly
diagnosed DM, there was an increase of DPN found compared
to patients with normal blood sugar. Therefore, the association
between impaired glycemia and DPN is not clearly established,
and physicians should look for alternative causes of neuropathy
before assuming the neuropathy is due to impaired glycemia.

Diabetic Autonomic Neuropathy


Autonomic involvement in DM is likely on the spectrum of
DPN, with involvement of small unmyelinated autonomic nerve
fibers. Autonomic impairment usually is not present at the time
of diagnosis of DM, but it relates to the duration and severity
of DM and also patient age. Diabetic autonomic neuropathy
(DAN) and DPN often occur in the same patient, but autonomic
neuropathy can occur in other forms of diabetic neuropathy
such as diabetic lumbosacral radiculoplexus neuropathy and
others. Symptoms include orthostatic hypotension, syncope,
gastroparesis, postprandial sweating, urinary or bowel complaints,
impaired pupillary light response, and erectile dysfunction.19
There is a perception that DAN is associated with sudden cardiac
death, but a prospective study showed that sudden cardiac death
in community diabetic patients correlated more strongly with

POLYNEUROPATHY

atherosclerotic heart disease and nephropathy than with DAN.20


Investigations useful in confirming the presence and severity of
autonomic involvement include quantitative sudomotor axon
reflex test (QSART), beat-to-beat heart rate variability, and
blood pressure and heart rate response to Valsalva.

Acute Painful Diabetic Neuropathy (Diabetic


Cachexia)

DKA is a proposed mechanism,23 with ischemia causing the


neuropathy. However, the speed of recovery would be unusual
for a vascular etiology. Because polyneuropathy after DKA
is rare, no studies exist to help decide whether measures to
counteract diffuse intravascular coagulation would be beneficial.
The most important step in management is early recognition and
correction of the DKA.

Diabetic Radiculoplexus Neuropathies


Acute painful diabetic neuropathy is an uncommon diabetic
neuropathy in which patients develop weight loss and a symmetric
sensory neuropathy associated with painful dysesthesias
over the limbs and trunk.12 Weakness is usually not a feature.
Contact allodynia or hyperalgesia is common, but the degree of
objective sensory loss on examination is minimal compared to
the degree of painful dysesthesias. Unlike DPN, acute painful
diabetic neuropathy is not related to the duration of DM and
does not share the same strong association with retinopathy or
nephropathy. The syndrome usually occurs in the context of
poorly controlled diabetes, and treatment involves improved
blood sugar control and medications for neuropathic pain. The
syndrome usually improves over weeks or months.

Treatment-Induced Diabetic Neuropathy


(Insulin Neuritis)
Treatment-induced diabetic neuropathy is a syndrome of
acute painful sensory neuropathy beginning after the initiation
of intensive glycemic control with insulin. It may be associated
with weight loss, and it occurs in conjunction with worsening
retinopathy. Autonomic neuropathy is common (up to 70%), with
orthostatic hypotension being most common.21 This syndrome
is reversible, with pain improving over months of glycemic
control.21 The pathophysiology is unclear, but it may relate to
overaggressive correction of hyperglycemia.

Hypoglycemic Neuropathy
A distal symmetric polyneuropathy may develop in patients
with hypoglycemia from excessive insulin (e.g., insulinoma or
insulin shock therapy for psychiatric disorders).22 This condition
is very rare. It is difficult to assess the contribution of repeated
hypoglycemic episodes in a diabetic patient to the development
of neuropathy because of the concomitant neurotoxic effect of
chronic hyperglycemia. Also one would assume that in repeated
hypoglycemia, central nervous system (CNS) damage would
occur earlier and more profoundly than PNS damage since CNS
neurons are more dependent on glucose metabolism. However,
most of these patients were not found to have sustained
brain injury. Consequently, the occurrence of hypoglycemic
neuropathy in diabetic patients is not clear.

Polyneuropathy in Ketoacidosis
Acute lower motor neuron disorders and cranial neuropathies
have been associated with diabetic ketoacidosis (DKA). This
may present as an acute motor neuropathy. The condition
is monophasic, with improvement usually in weeks, as the
metabolic derangements and DKA resolve. Diffuse intravascular
coagulation in the context of a prothrombotic state as part of

The diabetic radiculoplexus neuropathies are a group of asymmetric


and usually painful peripheral neuropathies that occur in diabetic
patients. They can involve the cervical, thoracic, or lumbosacral
levels, or multiple levels. Diabetic lumbosacral radiculoplexus
neuropathy is the most common subtype and has been referred
to as diabetic amyotrophy, diabetic polyradiculopathy, proximal
diabetic neuropathy, the BrunsGarland syndrome, and other
names. However, the term diabetic radiculoplexus neuropathy
(DRPN) is used here to emphasize that pathology can be at the
root, plexus, or peripheral nerve level. These usually occur in
patients with mild DM2, with an acute-to-subacute asymmetric
onset of pain followed by weakness. The weakness is distal and
proximal and can be profound, resulting in the patient requiring
a wheelchair. Muscle atrophy is common. Symptoms may
spread to involve other levels (e.g., from one lower limb to the
other, or to the upper limb or thoracic levels). The syndrome
is often associated with weight loss often of large magnitude.
Although the illness is classically monophasic, recovery is often
incomplete and patients are left with significant pain and motor
impairment. Although the lower limb form of lumbosacral
DRPN (DLRPN) is the most commonly-recognized, the clinical
and laboratory features of the upper limb form of cervical DRPN
have been recently characterized.24 These differ from traditional
inflammatory brachial plexopathy in that the lower trunk of the
plexus (resulting in hand symptoms) is frequently involved.
DRPN can also involve the trunk as thoracic radiculopathies, and
patients will present with outpouching of the belly wall muscles
and bands of pain around the belly and chest.
EDX studies may demonstrate an asymmetric axonal peripheral
neuropathy, with needle examination showing neurogenic
changes in proximal and distal muscles, as well as paraspinal
muscles. Cerebrospinal fluid (CSF) analysis often shows
an elevated protein, and magnetic resonance imaging of the
roots and plexus may show T2 hyperintensity, suggesting an
inflammatory process.
The pathophysiological basis of DLRPN is ischemic injury
from microvasculitis.25 The findings in distal cutaneous nerves
of DLRPN are multifocal fiber loss, perineurial thickening,
neovascularization, and abortive regeneration of nerve fibers
forming microfasciculi. These histopathological abnormalities
are consistent with primary axonal degeneration from ischemic
injury. Prominent inflammation is seen in most biopsies of
patients with DLRPN and often disrupts and destroys the walls
of small arterioles, venules, or capillaries. Hemosiderin laden
macrophages (i.e., evidence of previous bleeding due to vessel
damage) are commonly associated with vessel damage. Unlike
DPN, degeneration of pericytes and reduplication of basement
membranes usually are not seen in the microvessels of DLRPN
11

METABOLIC PERIPHERAL NEUROPATHIES

nerves.25 Clinically, a vasculitic process could explain the pattern


of a subacute, painful, asymmetric neuropathy. The small size
of the blood vessels involved and their anatomic location likely
explains the patchy, widespread, asymmetric process. Further
evidence of the microvasculitic hypothesis over a metabolic one
is the strong similarity in the clinical and the pathologic findings
of the diabetic and the nondiabetic lumbosacral radiculoplexus
neuropathies.25,26 As the latter patients are not diabetic, it
is difficult to implicate hyperglycemia as a cause for their
neuropathy. Nonetheless, hyperglycemia is likely a risk factor in
developing DLRPN.
Because DRPN is usually a monophasic disease, treatment is
mainly directed at pain control. However, since the pathogenesis
is thought to an inflammatory microvasculitis, immune
therapy would be expected to be beneficial. In one prospective
controlled trial of intravenous methylprednisolone, using time
to improvement by 4 points of the Neuropathy Impairment
Score as the primary endpoint of this study, efficacy was not
demonstrated. However, many secondary endpoints measuring
pain and sensory symptoms were significantly better in the
methylprednisolone group than in the control group.27 The
authors believed that the methylprednisolone may have been
instituted too late in the disease process to affect impairments.
This suggests that methylprednisolone is helpful in DLRPN and
should be used early, but these results are not definitive.
More recently described is a painless lower limb motorpredominant diabetic neuropathy that presents with insidious
lower limb weakness. The pathology of this condition has been
shown to be ischemic injury and microvasculitis, rather than
inflammatory demyelination as seen in chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP), and therefore it
represents a painless, motor-predominant form of DRPN and not
diabetic CIDP.

Chronic Inflammatory Demyelinating


Polyradiculoneuropathy in Diabetes Mellitus
CIDP can occur in patients with DM, but a recent study did not
find an increased rate of DM in CIDP patients.28 The diagnosis of
CIDP can be challenging in DM, because some DM neuropathies
can have proximal and distal weakness, reduced reflexes, elevated
CSF protein, and demyelinating features on EDX examination.
In addition, a painless lower limb motor-predominant diabetic
neuropathy has been reported. The pathology of this latter
condition is a microvasculitis, as seen in DRPN, rather than
inflammatory demyelination seen in CIDP.29

Cranial Neuropathies
Acute onset cranial nerve palsies develop in diabetic patients.
The most common of these is a diabetic third nerve palsy, which
is classically pupil-sparing, and presents with painful diplopia
and ptosis.30 Unilateral fourth, sixth, and seventh nerve palsies
are also relatively common. Patients usually present with pain,
often retro-orbital in location, and the pathophysiology is thought
to be ischemic in nature. Deficits usually improve over weeks to
months. Imaging is warranted in diabetic patients who do not
improve by 2-3 months to rule out an alternative etiology.
12

Limb Mononeuropathies
Diabetic nerves are believed to be more susceptible to
compression compared to those in nondiabetics. The most
common mononeuropathies are median neuropathy at the
wrist, ulnar neuropathy at the elbow, peroneal neuropathy at the
fibular head, lateral cutaneous femoral neuropathy (meralgia
paresthetica).30 In one study, DM was an independent risk factor
for the development of meralgia paresthetica, when controlling
for obesity, gender and age.31 In the RDNS, CTS was more
common in DM1 and DM2 than the general population and
related to duration of DM. Many patients were asymptomatic.32
More rarely, radial and obturator neuropathies have also been
described in diabetic patients.

POLYNEUROPATHY

REFERENCES
1.

Chaudhry V, Corse AM, OBrian R, Cornblath DR, Klein AS,


Thuluvath PJ. Autonomic and peripheral (sensorimotor) neuropathy
in chronic liver disease: a clinical and electrophysiologic study.
Hepatology 1999;29(6):1698-1703.
2. Fleckenstein JF, Frank S, Thuluvath PJ. Presence of autonomic
neuropathy is a poor prognostic indicator in patients with advanced
liver disease. Hepatology 1996;23(3):471-475.
3. Khella SL, Souayah N. Hepatitis C: a review of its neurologic
complications. Neurologist 2002;8(2):101-106.
4. Gwathmey KG, Burns TM, Collins MP, Dyck PJ. Vasculitic
neuropathies. Lancet Neurol 2014;13(1):67-82.
5. Dyck PJ, Thomas PK, eds. Peripheral neuropathy, 4th ed.
Philadelphia: Elsevier; 2005.
6. Pietrogrande M, De Vita S, Zignego AL, Pioltelli P, Sansonno D,
Sollima S, Atzeni F, Saccardo F, Quartuccio L, Bruno S, Bruno
R, Campanini M, Candela M, Castelnovo L, Gabrielli A, Gaeta
GB, Marson P, Mascia MT, Mazzaro C, Mazzotta F, Meroni P,
Montecucco C, Ossi E, Piccinino F, Prati D, Puoti M, Riboldi P,
Riva A, Roccatello D, Sagnelli E, Scaini P, Scarpato S, Sinico
R, Taliani G, Tavoni A, Bonacci E, Renoldi P, Filippini D, SarziPuttini P, Ferri C, Monti G, Galli M. Recommendations for the
management of mixed cryoglobulinemia syndrome in hepatitis C
virus-infected patients. Autoimmun Rev 2011;10(8):444-454.
7. Krishnan AV, Kiernan MC. Uremic neuropathy: clinical features and
new pathophysiological insights. Muscle Nerve 2007;35(3):273-290.
8. Dyck PJ, Johnson WJ, Lambert EH, OBrien PC. Segmental
demyelination secondary to axonal degeneration in uremic
neuropathy. Mayo Clin Proc 1971;46(6):400-431.
9. Bland JH, Frymoyer JW. Rheumatic syndromes of myxedema. N
Engl J Med 1970;282(21):1171-1174.
10. Duyff RF, Van den Bosch J, Laman DM, van Loon BJ, Linssen
WH. Neuromuscular findings in thyroid dysfunction: a prospective
clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry
2000;68(6):750-755.
11. Dyck PJ, Lambert EH. Polyneuropathy associated with
hypothyroidism. J Neuropathol Exp Neurol 1970;29(4):631-658.
12. Pasnoor M, Dimachkie MM, Kluding P, Barohn RJ. Diabetic
neuropathy part 1: overview and symmetric phenotypes. Neurol
Clin 2013;31(2):425-445.
13. The effect of intensive treatment of diabetes on the development
and progression of long-term complications in insulin-dependent
diabetes mellitus. The Diabetes Control and Complications Trial
Research Group. N Engl J Med 1993;329(14):977-986.
14. Singleton JR, Smith AG, Bromberg MB. Painful sensory
polyneuropathy associated with impaired glucose tolerance.
Muscle Nerve 2001;24(9):1225-1228.
15. Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed
diabetes and impaired glucose tolerance in patients with idiopathic
sensory neuropathy. Muscle Nerve 2001;24(9):1229-1231.
16. Hughes RA, Umapathi T, Gray IA, Gregson NA, Noori M, Pannala
AS, Proteggente A, Swan AV. A controlled investigation of the cause
of chronic idiopathic axonal polyneuropathy. Brain 2004;127(Pt
8):1723-1730.
17. Visser NA, Vrancken AF, van der Schouw YT, van den Berg
LH, Notermans NC. Chronic idiopathic axonal polyneuropathy
is associated with the metabolic syndrome. Diabetes Care
2013;36(4):817-822.

18. Dyck PJ, Clark VM, Overland CJ, Davies JL, Pach JM, Klein CJ,
Rizza RA, Melton LJ 3rd, Carter RE, Klein R, Litchy WJ. Impaired
glycemia and diabetic polyneuropathy: the OC IG Survey. Diabetes
Care 2012;35(3):584-591.
19. Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL,
Weigand SD, OBrien PC, Suarez GA, Dyck PJ. Autonomic
symptoms and diabetic neuropathy: a population-based study.
Diabetes Care 2004;27(12):2942-2947.
20. Suarez GA, Clark VM, Norell JE, Kottke TE, Callahan MJ, OBrien
PC, Low PA, Dyck PJ. Sudden cardiac death in diabetes mellitus:
risk factors in the Rochester diabetic neuropathy study. J Neurol
Neurosurg Psychiatry 2005;76(2):240-245.
21. Gibbons CH, Freeman R. Treatment-induced diabetic neuropathy:
a reversible painful autonomic neuropathy. Ann Neurol
2010;67(4):534-541.
22. Danta G. Hypoglycemic peripheral neuropathy. Arch Neurol
1969;21(2):121-132.
23. Timperley WR, Preston FE, Ward JD. Cerebral intravascular
coagulation in diabetic ketoacidosis. Lancet 1974;1(7864):952-956.
24. Massie R, Mauermann ML, Staff NP, Amrami KK, Mandrekar JN,
Dyck PJ, Klein CJ. Diabetic cervical radiculoplexus neuropathy:
a distinct syndrome expanding the spectrum of diabetic
radiculoplexus neuropathies. Brain 2012;135(Pt 10):3074-3088.
25. Dyck PJ, Norell JE. Microvasculitis and ischemia in
diabetic lumbosacral radiculoplexus neuropathy. Neurology
1999;53(9):2113-2121.
26. Dyck PJ, Norell JE. Non-diabetic lumbosacral radiculoplexus
neuropathy: natural history, outcome and comparison with the
diabetic variety. Brain 2001;124(Pt 6):1197-1207.
27. Dyck PJB OBP, Bosch EP, et al. The multi-center, double-blind
controlled trial of IV methylprednisolone in diabetic lumbosacral
radiculoplexus neuropathy. Neurology 2006;66(5 Suppl 2):A191.
28. Laughlin RS, Dyck PJ, Melton LJ 3rd, Leibson C, Ransom J.
Incidence and prevalence of CIDP and the association of diabetes
mellitus. Neurology 2009;73(1):39-45.
29. Garces-Sanchez M, Laughlin RS, Dyck PJ, Engelstad JK,
Norell JE. Painless diabetic motor neuropathy: a variant of
diabetic lumbosacral radiculoplexus Neuropathy? Ann Neurol
2011;69(6):1043-1054.
30. Pasnoor M, Dimachkie MM, Barohn RJ. Diabetic neuropathy
part 2: proximal and asymmetric phenotypes. Neurol Clin
2013;31(2):447-462.
31. Parisi TJ, Mandrekar J, Dyck PJ, Klein CJ. Meralgia paresthetica:
relation to obesity, advanced age, and diabetes mellitus. Neurology
2011;77(16):1538-1542.
32. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson
DM, OBrien PC, Melton LJ, 3rd, Service FJ. The prevalence by
staged severity of various types of diabetic neuropathy, retinopathy,
and nephropathy in a population-based cohort: the Rochester
Diabetic Neuropathy Study. Neurology 1993;43(4):817-824.

13

14

POLYNEUROPATHY

Neuropathies in Systemic Disease


James W. Teener, MD
Director, Neuromuscular Program
Department of Neurology
University of Michigan Health System
Ann Arbor, Michigan

INTRODUCTION
The list of systemic diseases that can cause neuropathy is
daunting. Many systemic diseases are associated with relatively
mild neuropathies that develop late in the course of disease.10
These are of less concern to the neuromuscular practitioner
faced with finding an explanation for a new neuropathy in a
patient who may not be aware of any ongoing systemic illnesses.
Of greater concern are those systemic medical conditions
that may present with neuropathy very early in the course.
This review will focus on conditions that the neuromuscular
practitioner faces frequently and should consider as viable
considerations in the differential diagnosis of a patients new
neuropathy. It should be noted that several of the systemic
conditions most closely associated with neuropathy such as
diabetes, paraproteinemia, and renal disease, are discussed in
other sections of this course.
The most common polyneuropathy phenotype encountered by
all medical providers is a distal, sensory predominant, axonal
polyneuropathy. This form of neuropathy has myriad causes.
Thankfully, this phenotype does not often cause substantial
disability. When the neuropathy is more aggressive, causing
weakness and/or more severe sensory loss, it does lead to
important disability. In this circumstance, neuromuscular
consultation is often sought, and a specific cause is more likely
to be identified. Table 1 lists particular systemic disorders
to consider as causes of these neuropathies with distinct
phenotypes and more aggressive behavior. This review will
focus particularly on systemic illness that may present with
neuropathy as an early or even initial sign/symptom of disease,
and thus needs to be considered as the cause of idiopathic
neuropathies encountered by the neuromuscular practitioner.

Table 1. Systemic disorders to consider when faced with unusual


neuropathy phenotypes

Acquired demyelinating neuropathy


HIV
Sarcoidosis
Paraproteinemia
Systemic lupus erythematosis
Inflammatory bowel disease
West Nile meningoencephalitis
Sensory neuronopathy/ganglionopathy
Sjgrens syndrome
Vitamin B6 Toxicity
Paraneoplastic (ANNA-1/Anti-Hu)
Mononeuritis multiplex or rapidly progressive axonal
sensory and motor neuropathy
Vasculitis (primary systemic vasculitis or in
connective tissue disease)
Cryoglobulinemia in Hepatitis C
Sarcoidosis
HIV/AIDS
Lyme disease (cranial neuropathies more commonly)
Leprosy (nerves involved preferentially in cooler
body areas)
AIDS=acquired immunodeficiency syndrome
ANNA1=anti-neuronal nuclear antibody 1
HIV-human immunodeficiency virus

15

NEUROPATHIES IN SYSTEMIC DISEASE

CONNECTIVE TISSUE DISEASES


Most connective tissue diseases (CTDs), or rheumatologic
diseases, are occasionally associated with neuropathy,11
including:
Sjgrens syndrome
Rheumatoid arthritis
Systemic lupus erythematosis
Scleroderma
Mixed connective tissue disease
Vasculitis
Polyarteritis nodosa, Wegeners granulomatosis, Churg
Straus vasculitis Microscopic polyangiitis
Secondary to many medical diseases
Many patients with rheumatologic conditions develop a mild
distal predominant sensory neuropathy late in the course of
their rheumatologic disease. The mechanism underlying this
common type of neuropathy is uncertain. A more striking
development is the appearance of an acute neuropathy in
patients with rheumatologic disease. This often is caused by
vasculitis and classically has the phenotype of mononeuritis
multiplex. Vasculitis can also cause what appears to be a more
length-related sensorimotor neuropathy, although it is often
painful and more progressive than the typical indolent distal
predominantly sensory neuropathy. It is important to identify
vasculitis because it does respond to treatment, although the
ultimate prognosis is dependent on the severity of the axonal
loss. Vasculitis may be an early manifestation of a CTD,
perhaps occurring before a secure diagnosis is made. One
challenge faced by neuromuscular consultants is identifying
vasculitis in patients with CTD when it presents in a manner
other than classic mononeuritis multiplex. Table 2 indicates
signs and symptoms that are suggestive of vasculitis. In such
circumstances, a nerve biopsy is often indicated to confirm the
presence of vasculitis, and these features may help guide the
consultant when making a decision about pursuing biopsy.

The clinical presentation of mononeuritis multiplex or an


aggressive axonal sensorimotor polyneuropathy is so suggestive of
vasculitis that a routine laboratory response should be considered.8
The suggested laboratory testing includes complete blood count,
metabolic panel, erythrocyte sedimentation rate, C-reactive
protein, serum protein electrophoresis with immunofixation,
rheumatologic antibodies including antinuclear antibodies,
rheumatoid factor, antineutrophil cytoplasmic antibody, and
extractible nuclear antigens hepatitis B and C serology and
measurement of cryoglobulins. Serum angiotensin converting
enzyme levels and testing for human immunodeficiency virus
(HIV) infection should also be considered.
Sjgrens syndrome deserves special mention because it is
associated with several types of neuropathy.2 In addition to
the mild distal predominant sensory neuropathy and vasculitic
neuropathy discussed above, Sjgrens syndrome is also
associated with a very unique sensory neuronopathy/sensory
ganglionopathy. This condition should be suspected in patients
with profound proprioceptive loss, particularly if the neuropathy
appears to be not strictly length related. This condition may
develop in patients unaware that they have Sjgrens syndrome,
and thus Sjgrens syndrome should be considered in all patients
presenting with this phenotype.4 Trigeminal neuropathies
are another unusual neuropathy seen in patients with CTD,
particularly Sjgrens syndrome.
The arthritis that develops in many CTDs may result in boney
deformities that predispose to focal nerve entrapment. Ulnar
mononeuropathy at the elbow and median mononeuropathy at the
wrist are commonly encountered in these patients. Surgical release
is effective and often necessary to preserve nerve function.
A number of medications used to treat CTD may cause neuropathy.
The tumor necrosis factor antagonists are believed to cause
inflammatory demyelinating neuropathies. Leflunomide may
cause a predominantly sensory neuropathy. Corticosteroids may
induce diabetes, leading to all of the neuropathic complications
associated with that disease.

Table 2. Connective tissue disease and neuropathy

Disease

Neuropathy types

SLE

DSP, MM, CIDP

Scleroderma
MCTD
RA
Sjgrens syndrome

DSP, MM?
DSP (rare)
DSP, MM
DSP, MM, DRG

Serologic abnormalities
detected in more than 20%
of cases
dsDNA, ssDNA, Histones,
Sm, RNP, SSA,
ssDNA, Centromere, Scl-70
Histones, RNP
RF
SSA, SSB

CIDP=chronic demyelinating polyneuropathy


DRG=dorsal root ganglionitis,
DSP=distal symmetric polyneuropathy
MCTD=mixed connective tissue disease
MM=mononeuritis multiplex
RA=rheumatoid arthritis
RF=rheumatoid factor RNP=ribonucleoprotein
SLE=systemic lupus erythematosus
SSA=Sjgrens syndrome A
SSB=Sjgrens syndrome B

16

GASTROINTESTINAL
DISORDERS
Several gastrointestinal disorders are associated
with neuropathy, including:




Hepatic failure
Hepatitis
Celiac disease
Bariatric surgery
Inflammatory bowel disease

Chronic hepatic disease, particularly endstage liver failure of nearly any cause often,
is associated with a relatively mild distal
predominant sensory polyneuropathy.12 The
mechanism underlying the development of this
neuropathy is uncertain, as it often is with this
type of neuropathy. Hepatitis C, in contrast, is

POLYNEUROPATHY

associated with a more aggressive neuropathy. Cryoglobulinemia


due to hepatitis C infection may cause mononeuritis multiplex
or a progressive, often somewhat asymmetric polyneuropathy.
The underlying pathology is vasculitis. When faced with the
clinical presentation of mononeuritis multiplex or a progressive
axonal neuropathy, hepatitis C infection should be considered
as a possible root cause. Celiac disease is also associated with
neuropathy. Neuropathy may predate the development of
gastrointestinal symptoms in some patients. The neuropathy may
improve with a gluten-free diet but it is also apparent that such a
diet is not fully protective against the development of neuropathy.
This suggests that there may be an immune mechanism at least
partially underlying some forms of neuropathy developing in the
setting of celiac disease/gluten sensitivity. The role of immune
manipulation in treatment of this celiac-associated neuropathy
is uncertain. Inflammatory bowel disease, Crohns disease or
ulcerative colitis, is also associated with neuropathy. Although
nutritional deficiency related to poor absorption may play a role
in some such neuropathies, a primary immune mechanism also
appears to cause neuropathy in this group of patients. Some
patients with inflammatory bowel disease develop otherwise
typical chronic inflammatory demyelinating polyneuropathy
(CIDP) that responds to immune manipulation as expected.

RESPIRATORY DISEASE
Respiratory diseases in which a neuropathy can develop include:
COPD and other causes of chronic respiratory failure
Sarcoidosis
Patients with chronic respiratory failure, as seen frequently
in COPD and less commonly with a number of other causes
of chronic respiratory failure, often develop a mild, distal
predominantly sensory neuropathy.6 The severity of this
neuropathy tends to correlate, at least partially, with the degree
of chronic hypoxia, and the neuropathy may partially improve
with improved oxygenation.
Sarcoidosis is associated with several types of peripheral
neuropathy. Approximately 5% of patients with sarcoidosis
have some form of neurologic involvement, a subset of which
is peripheral neuropathy. A distal sensory polyneuropathy (DSP)
without other distinguishing features is likely the most commonly
seen neuropathy in sarcoidosis, and it has an uncertain mechanism.
Vasculitis, often presenting as mononeuritis multiplex, has been
reported with sarcoidosis. It has also been shown to cause an
acute inflammatory demyelinating polyneuropathy (AIDP)-like
polyradiculopathy pattern. Sarcoidosis may also cause small fiber
neuropathy that appears to be responsive to immune therapy.7
Diagnosis of sarcoidosis is most often made on tissue biopsy.
Nerve and muscle biopsy may demonstrate the presence of
non-caseating granulomas. Perhaps more often there is only
nonspecific inflammation within the biopsy specimen and
additional investigation is necessary. Sarcoidosis is particularly
difficult to diagnose because one of the hallmark laboratory
studies, the angiotensin converting enzyme (ACE) level, is
normal in as many as 60% of patients with sarcoidosis. It is

important to identify sarcoidosis as a cause of neuropathy


because it does respond to immune therapy, and the presenting
symptom of sarcoidosis can be neuropathy.

NUTRITIONAL DEFICIENCIES
Multiple nutritional deficiencies cause neuropathy, including:
Vitamin B12
Vitamin B6 (deficiency and toxicity)
Thiamine
Copper
Vitamin E
Alcoholism
Patients particularly at risk for nutritional deficiency include the
homeless, elderly, alcoholics, and people with malabsorption
syndromes caused by surgical procedures or disorders such as
celiac sprue. Nutritional deficiency rarely occurs in isolation,
making it difficult to determine whether other pathogenic factors
may be at play in many patients who develop neuropathy in
the setting of apparent nutrient deficiency. Bariatric surgery
is a particular example of a surgical procedure that may result
in nutritional deficiencies. Other factors are clearly involved
because even with adequate nutritional replacement some
patients develop neuropathy following bariatric surgery. It
has been hypothesized that perhaps there is some role for
autoimmunity in the development of neuropathy following
bariatric surgery.9 Overconsumption of alcohol has long been
linked to the development of peripheral neuropathy. There
remains a debate as to whether the alcohol itself is toxic or the
neuropathy results from nutritional deficiencies. In most cases
there is likely some degree of nutritional deficiency worsened by
the overconsumption of alcohol. It is clear that consumption of
very high doses of alcohol does produce neuropathy.1
The neuropathy associated with alcoholism is a predominantly
sensory DSP. The earliest symptoms are sensory loss in the
feet with dull aching foot pain. Small fiber-related burning
dysesthesias occur in a minority of cases, probably about 20%. As
with most neuropathies of this type, the hands become involved
as the neuropathy progresses and motor signs and symptoms
also become more prominent. The onset is typically indolent,
although much more rapid progression has been reported.
Deficiencies of certain B vitamins, vitamin E, copper, and folate
are clearly linked to the development of neuropathy. Vitamin
B12 deficiency causes a myeloneuropathy. The body stores of
vitamin B12 are quite large and thus it may take several years
to develop symptoms upon cessation of vitamin B12 intake.
Exposure to nitrous oxide can cause accelerated depletion of
vitamin B12 stores. Vitamin B1 (Thiamine) deficiency is also
known as beriberi. Acute thiamine deficiency causes Wernickes
encephalopathy. Chronic deficiency causes central and peripheral
nervous system dysfunction as well as heart failure. Vitamin B6
falls in the unique situation of causing neuropathy both through
deficiency and through toxicity. Violent B6 toxicity is linked
to the development of a sensory neuropathy/ganglionopathy
similar to that which sometimes develops Sjgrens syndrome.
17

NEUROPATHIES IN SYSTEMIC DISEASE

Vitamin B6 deficiency causes a large fiber neuropathy with


resulting weakness and sensory ataxia. Folate deficiency looks
very much like vitamin B12 deficiency but can develop in just
a few weeks of reduced folic acid intake. Vitamin E deficiency
is a rare cause of neuropathy. It is more typically linked with a
spinal cerebellar syndrome but a large fiber neuropathy may be
a contributor to the development of sensory ataxia in vitamin
E deficiency. Ophthalmoparesis may also be present. Copper
deficiency is a relatively recently identified cause of neuropathy.
Myeloneuropathy is the typical neurologic manifestation
of copper deficiency and it is often associated with anemia.
Consumption of excess zinc may deplete copper stores. Repletion
of copper levels often results in recovery.

INFECTIOUS DISEASE

MALIGNANCY

With untreated leprosy becoming a historical footnote in most


of the developed world, HIV infection has become the most
important infectious cause of neuropathy encountered. HIV
infection is associated with several forms of neuropathy. The
prevalence of the various forms seems to vary with the stage
of progression of infection.5 Many HIV treatments also cause
neuropathy, further complicating the picture. AIDP/CIDP is often
seen in the early stages of HIV infection, when the immune system
is fully competent. The patient may not be aware of being infected
with HIV. The neuromuscular practitioner should consider testing
for HIV infection in patients presenting with AIDP or CIDP
who have risk factors for HIV infection. A cerebrospinal fluid
pleocytosis may be present in patients who develop AIDP/CIDP
in the setting of HIV infection, but the cell count may be normal.
As the degree of immunocompromise due to HIV increases, CIDP
becomes more frequently seen than AIDP. These patients respond
to treatment in the same way that patients without HIV infection
respond. Other presumably inflammatory neuropathies that may
be seen in early stages of HIV infection include vasculitis, brachial
plexitis, and cranial neuropathies.

Cancer can cause peripheral neuropathy through variety of


mechanisms, including:
Direct tumor invasion into root, plexus or nerve
Distal sensory predominant polyneuropathy
Chemotherapy and radiation toxicity
Paraneoplastic (Table 3)
Cancer can directly invade nerves causing focal damage. Direct
invasion typically causes a mononeuropathy, plexopathy,
or radiculopathy, depending on the location of the lesion.
Polyneuropathy or extensive mononeuritis multiplex are not
patterns typically associated with direct tumor invasion.
Cancer can damage nerves through a paraneoplastic phenomenon
(i.e., a remote effect of cancer not related to direct tissue invasion
by tumor). In this circumstance, autoimmunity is triggered by
the cancer with resultant attack on a variety of nervous system
and other organ targets, including peripheral nerve in some
cases.3 The most well-described paraneoplastic neuropathy is the
sensory neuronopathy seen in association with the anti-Hu/antineuronal nuclear antibody 1 (ANNA1), most often in patients
with small cell lung cancer. All patients presenting with this
unique phenotype should have these antibodies measured and
be screened for lung cancer. Other paraneoplastic neuropathies
are less common, but they should be considered in patients with
unexplained progressive neuropathies. Table 3 indicates several
recognized paraneoplastic peripheral neuropathies.
Many patients with cancer develop a mild sensory predominant
polyneuropathy. The pathologic mechanism of this type of
neuropathy is uncertain but may be related to nutritional or other
metabolic effects. In addition, many cancer treatments including
many chemotherapic agents and radiation therapy can damage
peripheral nerves.
Table 3. Factors suggestive of vasculitis in patients with known
connective tissue disease and axonal polyneuropathy

Abrupt symptom onset involvement


Presence of fever, weight loss, and rash
Presence of anemia or elevated erythrocyte
sedimentation rate
18

Infectious diseases in which a neuropathy can develop include:


HIV infection/acquired immunodeficiency syndrome (AIDS)
Antiretroviral therapy
Cytomegalovirus (CMV) polyradiculopathy
West Nile meningoencephalitis
Lyme disease
Herpes simplex polyradiculitis
Varicella zoster radiculitis
Hepatitis B, C related cryoglobulinemia/vasculitis

The most common form of neuropathy seen in association with


HIV is a distal, sensory predominant axonal polyneuropathy
without other distinguishing features. The mechanism underlying
this is uncertain. Nearly all patients have pathologic evidence of
polyneuropathy at end stage, but not all are symptomatic.
Opportunistic infections and malignancy complicate later stages
of HIV infection/AIDS. Polyradiculopathy related to CMV
is a particularly devastating neuropathic complication, often
causing severe, irreversible leg weakness and pain. Syphilitic
radiculopathy, zoster ganglionitis, tuberculous polyradiculitis
and lymphomatous polyradiculopathy also complicate AIDS.
Treatment with antiretroviral drugs may cause neuropathy,
presenting a diagnostic problem because the neuropathy is
indistinguishable from the DSP caused by HIV infection. A trial
suspending the suspected offending medication is often indicated
to see if the neuropathy improves, but the coasting effect often
causes the neuropathy to worsen for 2-4 weeks even after drug
cessation. Stavudine (d4T), didanosine (ddI), zalcitabine (ddC),
lamivudine (3TC), and fialuridine (FIAU), known as nucleoside
reverse transcriptase inhibitors (NRTIs), are all neurotoxic. Of
these, ddC appears to be the most toxic.

POLYNEUROPATHY

SUMMARY

REFERENCES

Although a seemingly endless list of systemic diseases may


cause neuropathy, there are a manageable number of diseases
to consider when faced with a patient with an unexplained
progressive neuropathy. By carefully noting the clinical
phenotype of the neuropathy, the neuromuscular clinician can
pursue a reasonable panel of tests and often arrive at a diagnosis.
In cases where the neuropathy is due to a systemic disease,
the neuropathy may be the presenting symptom and the astute
neuromuscular clinician can aid in the early diagnosis of the
systemic disease, often leading to a more favorable outcome.

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electrophysiological, and biopsy findings. Ann Neurol
1977;2(2):95-110.
2. Birnbaum J. Peripheral nervous system manifestations of
Sjgren syndrome: clinical patterns, diagnostic paradigms,
etiopathogenesis, and therapeutic strategies. Neurologist
2010;16(5):287-297.
3. Graus F, Dalmau J. Paraneoplastic neuropathies. Curr Opin
Neurol 2013;26(5):489-495.
4. Griffin JW, Cornblath DR, Alexander E, et al. Ataxic sensory
neuropathy and dorsal root ganglionitis associated with
Sjgrens syndrome. Ann Neurol 1990;27(3):304-315.
5. Harrison TB, Smith B. Neuromuscular manifestations of
HIV/AIDS. J Clin Neuromuscul Dis 2011;13(2):68-84.
6. Jann S, Gatti A, Crespi S, Rolo J, Beretta S. Peripheral
neuropathy in chronic respiratory insufficiency. J Peripher
Nerv Syst 1998;3(1):69-74.
7. Nemni R, Galassi G, Cohen M, et al. Symmetric sarcoid
polyneuropathy: analysis of a sural nerve biopsy. Neurology
1981;31(10):1217-1223.
8. Schaublin GA, Michet CJ, Dyck Jr PJ, Burns TM. An
update on the classification and treatment of vasculitic
neuropathy. Lancet Neurol 2005;4(12):853-865.
9. Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, Norell
JE, Dyck PJ. A controlled study of peripheral neuropathy
after bariatric surgery. Neurology 2004;63(8):1462-1470.
10. Teener J. Neuropathies secondary to systemic diseases. In:
Donofrio PD, ed. Textbook of peripheral neuropathy. New
York: Demos Medical Publishing; 2012. pp 309-321.
11. Vallat JM, Rabin M, Magy L. Peripheral neuropathies
in rheumatic diseasea guide to diagnosis. Nat Rev
Rheumatol 2012;8(10):599-609.
12. Zochodne DW, Dyck PJ, Thomas PK. Neuropathies
associated with renal failure, hepatic disorders, chronic
respiratory disease, and critical illness. In: Dyck PJ,
Thomas PK, eds

19

20

POLYNEUROPATHY

GuillainBarr Syndrome, Chronic


Inflammatory Demyelinating
Polyradiculoneuropathy, Paraproteinemia,
and Amyloidosis
Thomas H. Brannagan III, MD
Peripheral Neuropathy Center
Columbia University College of Physicians and Surgeons
New York-Presbyterian Hospital
Columbia University Medical Center
New York, New York

GUILLAINBARR SYNDROME

Treatment

GuillainBarr syndrome (GBS) is the most common cause


of acute flaccid paralysis. The progression reaches a nadir
by 4 weeks.44 The incidence of GBS is approximately 0.6-4
cases/100,000.3,28,32 Typically, the symptoms start with distal
paresthesias and weakness which then ascend; however, there
are variations. Respiratory failure develops in 30%. On physical
examination, reflexes are diminished or lost.

Randomized, placebo-controlled studies have demonstrated


that plasma exchange (PE) results in an increased number of
patients improved by one disability grade at 4 weeks. Intravenous
immunoglobulin (IVIg) has been compared to PE and shown
similar benefit. The combination of PE followed by IVIg did
not show a statistically significant improvement in the disability
grade at 4 weeks, compared with IVIg or PE alone. There was also
no statistically significant difference between the combination
or individual treatments with IVIg and PE in secondary
outcome measures (e.g., time to recovery of unaided walking
or discontinuation of mechanical ventilation). Clinical trials of
corticosteroids in GBS did not show benefit, and in some studies
patients did worse in the treatment arm than on placebo.29,40

Nerve conduction studies (NCSs) can confirm demyelination;


however, they may not be diagnostic in the early phases. Older
studies emphasized that NCSs could be normal in the early stages;
however, more recent studies that have tested a large number of
nerves, including F waves, only rarely found normal findings,
though they were not always diagnostic of demyelination at the
onset.2,43 The initial physiologic mechanism in demyelination
is conduction block and the initial sites of involvement relate
to an impaired blood nerve barrier at the proximal roots, distal
nerve terminals, compression sites, and finally nerve trunks.
Abnormalities of the H reflex are the first electrodiagnostic
(EDX) abnormality seen.26
Cerebrospinal fluid (CSF) protein is elevated maximally from
days 4 to 20 and may be normal in the first few days of onset.
There is a cytoalbuminologic disassociation, though human
immunodeficiency virus (HIV) patients who develop GBS may
have an elevated CSF white blood cell count. Not all patients with
HIV who develop GBS, however, have a CSF pleocytosis.12,17

Prognosis
Most patients with GBS improve with time; 33-65% have a
complete recovery and 20-67% have a good recovery, although
15-20% have moderate-to-severe deficits. Approximately 20%
of patients, despite receiving treatment with IVIg or PE, are
unable to walk at 6 months and have disability from residual
nerve damage.17 The Erasmus GBS Outcome Score (EGOS) has
been developed to attempt to predict which patients with a poor
prognosis for recovery would be able to walk at 6 months. The
score depends on the patients age, whether they had preceding
diarrhea, and their disability score at 2 weeks.46 This may be
used for future clinical trials for new interventions designed to
improve the outcome of these patients.
21

GUILLAINBARR SYNDROME, CHRONIC INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY, PARAPROTEINEMIA, AND AMYLOIDOSIS

Variants
Acute inflammatory demyelinating polyneuropathy accounts for
approximately 95% of patients with GBS in the United States
and Western Europe.28 There are several other well characterized
variants of GBS. Acute motor axonal neuropathy occurs as an
epidemic in China following Campylobacter jejuni diarrheal
illness. There is evidence of molecular mimicry involving
ganglioside antibodies. Acute motor and sensory axonal
neuropathy is another variant.23 The MillerFisher syndrome
is characterized by the triad of ophthalmoparesis, ataxia, and
areflexia. The majority of patients have anti-GQ1b antibodies.17,28

CHRONIC INFLAMMATORY DEMYELINATING


POLYRADICULONEUROPATHY
Chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP) is one of the most commonly encountered treatable
forms of neuropathy.21 The incidence is similar to GBS.
Patients have progression for more than 2 months. The course
may be progressive or relapsing and remitting. In the classical
presentation of CIDP, patients have symmetric proximal and
distal weakness and large fiber sensory loss, often resulting in
impaired balance and areflexia. The CSF protein is elevated and
NCSs or nerve biopsy demonstrate demyelination. It is estimated
that 50% of patients have an atypical form, with multifocal
involvement or predominantly distal involvement.8,47
Diagnostic criteria include supportive clinical features, such
as the presence of proximal weakness, though they have
focused primarily on the detection of demyelination on NCSs.
Abnormalities of sufficient degree, beyond what can result from
axonal loss, have been described in conduction velocity slowing,
prolonged distal motor latencies, and prolonged F wave latencies
or absent F wave responses to indicate demyelination. Abnormal
temporal dispersion or conduction block are also signs of acquired
demyelination. At least 14 sets of diagnostic criteria have been
developed, which vary in the number of demyelinating findings
required and in their sensitivity and specificity.13
IVIg, PE, and corticosteroids have been demonstrated to be effective
in placebo-controlled, randomized clinical trials.19, 22 Less than onethird of patients will remain in remission off of treatment.4,27,41
Chemotherapeutic or immunosuppressive medications such as
IV cyclophosphamide or mycophenolate have been reported
to benefit some patients.9,11,24 Placebo-controlled, randomized,
double-blinded studies did not reveal a benefit for azathioprine
or methotrexate.20,42

Comparative Studies
Short-term studies of 6 weeks comparing IVIg and PE and IVIg
and prednisone have shown no difference in efficacy. However,
CIDP is a chronic disease typically requiring longterm treatment.
More recent studies have compared IVIg to IV Solu-Medrol
(methylprednisolone sodium succinate) for 6 months. The
primary outcome was the difference in the number of patients
who discontinued the medication at 6 months because of
lack of efficacy (i.e., absence of improvement after 2 months
22

or worsening after 15 days) or due to side effects or lack of


tolerability. IVIg was more frequently effective and tolerated
(87.5%) compared with IV Solu-Medrol (47.6%). Twentyfour patients were randomized to IVIg and 21 patients to IV
Solu-Medrol. After 6 months treatment was discontinued. In
an analysis (per the protocol) of the following 6 months (after
treatment was stopped), 8/21 IVIg patients and 0/10 Solu-Medrol
patients who had completed the 6 months of treatment worsened
and required further treatment.38 In a followup study, 87% of
those discontinuing IVIg and 79% of those discontinuing IV
Solu-Medrol eventually worsened, requiring further treatment.
The time to relapse was longer after discontinuing IV SoluMedrol (14 months) compared with IVIg (4.5 months).39

PARAPROTEIN ASSOCIATED
NEUROPATHIES
Monoclonal paraproteinemia, or monoclonal gammopathy, is
present in many conditions which may be benign or malignant
and can occur nonspecifically in chronic inflammatory and
infectious diseases. Individual clones of B cells proliferate and
produce excess antibody. These antibodies, called paraproteins
or M-proteins, are monoclonal and identical in heavy and light
chain types, idiotype, and antigen specificity.31
Monoclonal proteins are present in 0.7-1.2% of the normal
population. They are rare under the age of 50, and they increase
with each decade. They are present in 2.4-3.5% of those over the
age of 50, 5% over the age of 70, and 19% over the age of 95.25,36,37
The monoclonal protein can be detected with a serum protein
electrophoresis. An immunofixation electrophoresis is a more
sensitive test. A monoclonal protein may indicate a malignant
condition such as multiple myeloma, lymphoma, chronic
lymphocytic leukemia, Waldenstrms macroglobulinemia, or
it may be due to a monoclonal gammopathy of undetermined
significance (MGUS). A MGUS has a risk of 1% per year of
developing into multiple myeloma, Waldenstrms, amyloidosis,
or a lymphoproliferative disorder, therefore the monoclonal
protein must be followed.35
Monoclonal proteins may cause neuropathy by the action of
the antibody or may be a marker for a disease that results in
neuropathy, such as amyloidosis or POEMS (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and
skin changes) syndrome. IgM antibodies may cause neuropathies
by binding to antigens on nerve. The most common and best
characterized is anti-MAG neuropathy.45 Multifocal motor
neuropathy may also be associated with an IgM monoclonal
protein against GM1, though almost 90% of IgM GM1 antibodies
are not monoclonal but polyclonal.33

POEMS SYNDROME
POEMS syndrome is characteristically a demyelinating
polyneuropathy, associated with a lambda monoclonal protein
and an osteosclerotic myeloma. One-half of patients with
osteosclerotic myeloma have a demyelinating polyneuropathy,
which may be confused with CIDP. A skeletal survey typically
is used to identify the osteosclerotic myeloma, though a positron

POLYNEUROPATHY

emission tomography scan may also be needed for identification.


Vascular endothelial growth factor (VEGF) is a laboratory marker
that is helpful diagnostically when markedly elevated and also
typically falls when the disease is treated. When single or few
osteosclerotic myeloma lesions (plasmacytoma) are present, this
disorder can be treated with radiation. It may also respond to
high-dose chemotherapy with stem cell transplant.18,30

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AMYLOID NEUROPATHIES
Amyloidosis causes peripheral neuropathy, with autonomic
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A misfolded protein forms amyloid fibrils, which deposit in
the nerve, connective tissue, and heart. The protein that forms
amyloid fibrils and causes polyneuropathy typically is a light
chain, which is called systemic amyloidosis or a mutated
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TTR familial amyloid polyneuropathy is a lethal autosomal


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diagnosis, clinical variants, response to treatment and prognosis
of chronic inflammatory

POLYNEUROPATHY

Miscellaneous Polyneuropathies
Peter D. Donofrio, MD
Vanderbilt University Medical Center
Nashville, TN

INTRODUCTION
Peripheral neuropathy is a commonly encountered disorder
evaluated by primary care physicians and neurologists in the
community. Peripheral neuropathy can be subdivided into
three types: mononeuropathy, mononeuropathy multiplex or
mononeuritis multiplex, and polyneuropathy based on the
involvement of a single nerve, multiple single nerves, or many
nerves in a symmetric length-dependent fashion. After a brief
review of the clinical presentation and differential diagnosis of
polyneuropathy, this discussion will focus on the evaluation of
patients with polyneuropathies due to genetic defects, vasculitis,
porphyria, and critical illness.

POLYNEUROPATHY

foot and ankle. Other descriptors include lack of feeling, woody


sensation, sharp jabbing pain, electric shocks, sharp pains, and
ice pick pain. Often, the first motor symptom is gait instability,
particularly walking in the dark or maintaining balance when
the eyes are closed. As the disease advances, patients develop
a foot drop and frequent falls. Cramps are common, particularly
in the distal legs. When the process progresses to the knees,
patients may begin to experience hand weakness and dropping
of items. Atrophy in the hands and feet is common when the
polyneuropathy is severe or longstanding. Somatic neuropathies
of the sensory and motor nerves are commonly accompanied by
involvement of the autonomic fibers that can manifest as lack of
sweating, change in skin color, orthostatic symptoms, change in
bowel or bladder habits, and erectile dysfunction.

Clinical Presentation and Etiologies


The prevalence of polyneuropathy is approximately 2.4%
of the population in mid-life, but it rises to 8% in individuals
older than 55 years. A careful history, physical examination,
electrodiagnostic (EDX) testing, and laboratory testing reveals a
cause in 74-82% of patients.
The clinical presentation of polyneuropathy usually obeys a
sensory and motor length-dependent pattern that make the
diagnosis relatively easy once the history has been elicited and
the examination performed. Patients often state their condition
began with numbness and paresthesia of the toes and soles of the
feet and over time the symptoms advanced proximally to affect the

The neurologic examination in most neuropathies shows a distal


gradient loss from the toes to the more proximal legs and as the
disease advances from the finger tips to the wrists or forearms.
The findings are relatively symmetric and any major asymmetry
suggests a superimposed radiculopathy of a single or multiple
roots, or a plexopathy, a spinal cord process, or a brainstem or
cerebral cortex lesion. If the large sensory fibers are primarily
affected, there is greater loss of vibration, light touch, and joint
position sense than small fiber functions of pain, pin prick, and
cold perception. In most neuropathies, both large and small fibers
are affected. Strength is lost in a similar pattern from the toes
to the ankles and from the intrinsic hand muscles to the finger
flexors and wrist extensors and flexors. In inherited neuropathies
25

MISCELLANEOUS POLYNEUROPATHIES

and longstanding neuropathies, it is common to find high arched


feet, hammer toes, and pronounced distal more than proximal
atrophy, giving rise to the term inverted champagne bottle
legs. Reflexes are diminished or lost in a predictable fashion.
Ankle reflexes are lost first, followed by the knee reflexes,
brachioradialis, and lastly the biceps brachii and triceps reflexes.
If autonomic involvement is present, the examiner may observe
distal extremities that are cold or too warm, erythematous or
blanched color changes, shiny skin, loss of hair over the feet and
distal shins, dystrophic nails, lack of sweating in the axilla and
groin region, and dry mouth, eyes, and mucosa.

Inherited Neuropathies

When first evaluating a patient with a polyneuropathy, it is


a good practice to ask specific questions about prior diseases,
lifestyle, and work and occupational exposure that may give a
clue to the diagnosis. Questions should be asked about diabetes,
alcohol abuse, vitamin deficiencies, dietary habits, use of over
the counter drugs, zinc consumption, gastric bypass surgery,
medications prescribed in the past (especially those used
long term), human immunodeficiency virus (HIV) infection,
family history of neuropathy, foot deformities in the family,
amyloidosis, thyroid disease, chronic renal and liver disease,
malignancy, chemotherapeutic agents, connective tissue
disorders, recreational use of substances, and exposure to heavy
metals, industrial agents, herbicides, and pesticides.

Inherited neuropathies are common and account for approximately


10% of neuropathies seen at large referral centers. Inherited
neuropathies are often lumped together under the term Charcot
MarieTooth (CMT) disease, yet this term applies to an inherited
motor greater than sensory neuropathy typically associated with
foot deformities such as pes cavus. The name CharcotMarieTooth
refers to the three physicians who described this condition in the late
1800s. CMT affects approximately 1 in 2500 people. Most cases
of CMT1A are inherited in an autosomal dominant (AD) mode of
genetic transmission. Some patients without a family history of
neuropathy have a de novo mutation. CMT can present as early as
the first decade of life, but often it is not diagnosed until later in life
and sometimes not until the sixth or seventh decade. In addition to
foot deformities, patients often have atrophy of the feet and hands,
areflexia, mild distal sensory loss, scoliosis, and other orthopedic
abnormalities. Many AD, autosomal recessive (AR), and X-linked
recessive forms have been reported, which has complicated the
ordering of genetic testing in patients with CMT. Genetic tests
are available for rarer causes of inherited neuropathies including
congenital hypomyelinating neuropathy, hereditary neuropathy with
propensity to pressure palsies (HNPP), distal hereditary pure motor
neuropathies, distal hereditary sensory and autonomic neuropathies,
hereditary focal neuropathies, and giant axon neuropathy.

Table 1 lists etiologies for polyneuropathy classified by type. As


is the case in any classification, some disorders are more difficult
to classify and some are so rare as to minimize the need to place
them in a broad table.

Initial classification of CMT divided patients into those who had


primarily a uniform demyelinating neuropathy versus those with
an axon loss neuropathy. This classification has been complicated
by an extensive array of genetic mutations.

Table 1. Etiologies for polyneuropathies

Endocrine: Diabetes mellitus, hypothyroidism, hyperthyroidism


Alcohol abuse
Nutritional deficiencies: B1, B3, B6, B12, folic acid, and
gastric bypass surgery
Vitamin Excess: pyridoxine (B6)
Metabolic: Uremia, liver disease, porphyria
Sarcoidosis
Connective tissue disorders: systemic lupus erythematosus,
rheumatoid arthritis, Sjgrens syndrome, polyarteritis nodosum
Vasculitis
Amyloidosis: secondary and familial
Genetic: CharcotMarieTooth disease and other inherited
neuropathies
Inflammatory: GuillainBarr syndrome, chronic inflammatory
demyelinating polyradiculoneuropathy, plasma cell dyscrasias,
HIV infection, Lyme disease, other infectious causes
Toxic: Industrial, therapeutic agents, chemotherapeutic
agents, tacrolimus, heavy metal poisoning
Paraneoplastic: carcinoma, lymphoma, leukemia
Porphyria
HIV infection and antiretroviral therapy
Critical illness polyneuropathy
Used with permission.4
HIV=human immunodeficiency virus

26

CMT1A is the most common form of CMT and accounts for 50%
of all patients with an inherited neuropathy. Most patients with
CMT1A present in the first 2 decades of life. They commonly
have orthopedic abnormalities of high arches and hammertoes.
They often have frequent ankle sprains and foot fractures.
Tripping and falling is a common complaint. Weakness often
predominates over sensory symptoms of numbness, tingling,
and pain. Patients with CMT1B have a similar phenotype to
those with CMT type 1, but tend to cluster into two groups, the
early onset and the late onset. Some patients with CMT1A have
a postural tremor and, when this is observed, the term Roussy
Lvy syndrome is often applied to the collective presentation of
an inherited neuropathy and a postural tremor.
The genetics of inherited neuropathies is complicated and difficult
to commit to memory. Over 1000 different mutations have been
identified in 80 disease-associated genes. CMT type 1 is shown
to be due to a duplication of the DNA segment on chromosome
17 P 11.2 that contains a genetic codon for peripheral myelin
protein 22 kD (PMP22). Missense or nonsense mutations in
PMP22 have been reported to cause different subtypes of CMT.
CMT1B is caused by missense mutations in a protein gene
encoding myelin protein zero (MPZ).
CMT type 2 constitutes approximately one-third of cases of AD
CMT. The clinical phenotype of CMT type 2 is very similar to
type 1. It is impossible to differentiate between the two types
of CMT without the results of nerve conduction studies (NCSs)
and/or genetic testing.

POLYNEUROPATHY

NCSs can be helpful in differentiating CMT type 1 from type


2 based upon the presence of uniform demyelination in type I
and axonal loss in type 2. Patients with CMT1A have preserved
compound muscle action potential (CMAP) amplitudes in the
setting of profoundly prolonged motor distal latencies, markedly
slowed conduction velocities, and markedly prolonged or absent
F responses. Conversely, patients with CMT2 have reduced
CMAP amplitudes and either normal or slightly prolonged
motor distal latencies and normal or slightly reduced conduction
velocities. In both conditions, sensory responses are often absent.
NCSs are imprecise in differentiating subtypes of CMT type 1
and 2. Presently, there are six types of CMT1, eight forms of
CMT2, and nine forms of CMT4.
The X-linked forms of CMT are due to missense mutations in the
32 kD (connexin 32) gene located on the X chromosome. Over
200 different mutations of connexin have been observed. Since
men only have one X chromosome, they tend to be affected by a
more severe form of CMT type X. NCSs in CMTX usually show
intermediate slowing and asymmetric or nonuniform findings. NCSs
in CMTX may be similar to those recorded in patients with chronic
inflammatory demyelinating polyradiculoneuropathy (CIDP).

A deletion of the same region of chromosome 17p11.2 that


is duplicated in CMT1A causes another type of an inherited
neuropathy, HNPP. It usually presents with a variety of
reversible pressure palsies affecting sensory or motor nerves and
occurring in the peripheral nerve at common pressure points.
Brief compression may cause a mononeuropathy that would not
usually lead to damage in a normal person. Between episodes of
compression palsy, the neurologic examination may demonstrate
minimal abnormalities or may show features of a lengthdependent sensory and motor neuropathy. NCSs commonly show
slowing in motor nerves at sites of common compression such
as the median nerve at the wrist, the ulnar nerve at the elbow,
and the peroneal nerve at the ankle. These abnormalities may
be apparent when the patient does not have active symptoms.
In addition, NCSs may show evidence for a symmetric, distal
greater than proximal, demyelinating neuropathy even when
clinical features are not prominent.
Hereditary brachial plexopathy is a rare genetically defined
form of brachial plexopathy. The brachial plexopathy tends to
be painless but recurrent; recovery is often incomplete between
episodes that can be separated by many years.

Cases of CMT4 are rare and are inherited in an AR transmission.


Those patients often present as a severe inherited neuropathy
associated with cataracts and skeletal deformities.

As the number of genetic defects in hereditable neuropathies


increases, a need arises for an organized approach to ordering
tests for inherited neuropathies. England and colleagues
published a helpful algorithm for the logical progression of
ordering genetic testing for patients
with CMT and other suspected familial
Table 2. Medication-induced neuropathies anatomic site of pathology
neuropathies. According to the algorithm,
Axonopathy
Vinorelbine
Isoniazid
if an inherited neuropathy is suspected,
Almitrine*
Zalcitabine (ddC)
Lamivudine (3TC)
the first test to be pursued should be NCSs
Amiodarone
Anterior Horn Cell
Lansoprazole
and needle electromyography (EMG).
Amitriptyline
Dapsone
Leflunomide
If the family history is positive and the
Ara-C
Dorsal Root Ganglion
Linezolid
neuropathy appears to be demyelinating
Bortezomib
Cisplatin
Lithium
and the inherited pattern is AD, then PMP22
Carbimide*
Carboplatin
Mefloquine
duplication testing should be ordered, and if
Chloramphenicol
Efosfamide
Mercury
negative, one would proceed to testing for
Chloroquine*
Etoposide (VP-16)
Methaqualone
an MPZ mutation and a PMP22 mutation.
Cimetidine
Oxaliplatin
Metronidazole
The testing algorithm is different for AR
Clioquinol
Pyridoxine
Misonidazole
and sex-linked presentations and if the
Clofibrate
Schwann Cell
Nitrofurantoin
family history is negative.
Colchicine
Allopurinol
Nitrous oxide
Cyanate
Cyclosporin
Danosine (ddl)
Dichloroacetate
Disopyramide*
Disulfiram
Docetaxel
Efosfamide
Enalapril*
Ethambutol
Ethionamide
Etretinate
Fialuridine (FIAU)
Fluoroquinolones
Hydralazine
Gold
Glutethimide

Paclitaxel
Phenelzine
Phenytoin
Podophyllin
Propafenone
Sulfapyridine*
Sulfasalazine
Statins
Stavudine (d4T)
Suramin
Tacrolimus
Thalidomide
Tumor necrosis
factor- antagonists
Vancomycin*
Vincristine

Amiodarone
Ara-C
Gentamicin*
Griseofulvin
Indomethacin
L-tryptophan contaminant
Perhexiline
Streptokinase*
Suramin
Tacrolimus
TNF- antagonists
L-tryptophan contaminant
Zimelidine
*isolated case reports

Medication-Induced
Neuropathies
The list of medications that can cause
polyneuropathy increases each year as
new treatments are introduced for the
management of cardiac diseases, neoplasia,
infections, autoimmune, and necrotizing
illnesses. The toxic effects of medications
can act at several levels of the peripheral
nerve including the anterior horn cell, as
is the case for dapsone, the dorsal root
ganglion, which is the mechanism for
toxicity of several of the chemotherapeutic
agents, the peripheral myelin, and the
motor and sensory axon. The majority of
medications cause dysfunction at the level
27

MISCELLANEOUS POLYNEUROPATHIES

of the peripheral axon. Table 2 lists medications for which there


is a reported cause and effect association with polyneuropathy.
Several of the medications deserve special mention. Amiodarone
is a commonly prescribed medication for the treatment of cardiac
arrhythmias. Amiodarone may cause a demyelinating neuropathy
whose presentation resembles CIDP. The same drug can produce
a motor and sensory axon loss neuropathy. The association
between vincristine and polyneuropathy has been known for
decades and is one of the best recognized chemotherapeutic
agents to cause a polyneuropathy. Cisplatin and paclitaxel are
also common causes of polyneuropathy. Both agents affect the
dorsal root ganglion, giving rise to sensory symptoms and gait
ataxia. The effect is dose-related. Coasting (further progression
of the neuropathy after the medication is stopped) may occur
following treatment with these chemotherapeutic treatments.
Nitrofurantoin is a bacteriostatic antibiotic that has been used
to treat urinary tract infections for decades. It is prescribed
frequently on a daily basis to suppress chronic and recurrent
urinary tract infections; some patients may take the medication
for years without interruption. Nitrofurantoin can cause a mildto-severe sensory greater than motor polyneuropathy which in
some patients is irreversible.
Pyridoxine is an essential vitamin that has been consumed in
large doses by individuals to aid in bodybuilding and has been
prescribed as a treatment for premenstrual syndrome, carpal
tunnel syndrome (CTS), schizophrenia, fibromyalgia, autism,
and hyperkinesis. Pyridoxine is almost always prescribed when
isoniazid is given for treatment of tuberculosis or for a recently
converted tuberculin purified protein derivative (PPD) test.
Schaumburg and colleagues reported a large cohort of patients
who developed a severe sensory neuronopathy after taking 2-6
g of pyridoxine daily for 2-40 months. All patients showed
profound loss of most sensory modalities and were areflexic.
All patients improved when pyridoxine was stopped, and two
patients experienced almost complete recovery after 2-3 years of
followup. The authors concluded that vitamin B6 in high doses
was likely toxic to the dorsal root ganglia.
Although pyridoxine sensory neuronopathy is most commonly
observed in individuals taking large doses of the vitamin, toxicity
can be observed in patients consuming much smaller doses and
there are reports of two patients developing a neuropathy who
were taking less than 100 mg per day.
Colchicine can cause not only a neuropathy, but a myopathy.
Thalidomide may cause a sensory polyneuropathy; it is
being prescribed more commonly than in the past now that
it is recognized to be an effective treatment for several
dermatologic conditions, multiple myeloma, HIV infections,
and rheumatologic disorders.

Statins
Statins cause a polyneuropathy infrequently and in less than 1% of
patients, but its potential neurotoxicity must be recognized when
no other etiology is found for a patient referred for an idiopathic
polyneuropathy. The statins are inhibitors of 3-hydroxy-328

methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme


that regulates the synthesis of cholesterol. In 1994, Jacobs reported
the development of a sensory polyneuropathy in a patient who
was treated with lovastatin for 2 years. The patients symptoms
abated when lovastatin was discontinued, but they returned within
2 weeks when pravastatin was substituted for lovastatin.
Substitution of one statin that causes a polyneuropathy for another
may not prevent the reoccurrence of a drug-induced neuropathy.
Ziajka and Wehmeier reported a patient who developed a
neuropathy after taking lovastatin and whose symptoms returned
when treated on separate occasions with simvastatin, pravastatin,
and atorvastatin.
Some physicians have challenged the relationship between
statins and the development of polyneuropathy. Others recognize
the relationship to be low risk, but they acknowledge that
longterm exposure increases the chances for the neuropathy. One
paper estimated the incidence of statin-induced neuropathy to be
approximately 1 case per 10,000 patients taking statins; another
manuscript estimated 60 cases per 100,000.

Industrial and Environmental Agents


Table 3 lists common industrial and environmental agents
that have been associated with causing neuropathy. Most
of them are rare. Arsenic poisoning can lead to an acute
polyradiculoneuropathy which clinically looks strikingly similar
to the acute inflammatory demyelinating polyneuropathy (AIDP)
form of GuillainBarr syndrome (GBS). Patients present with
a gastrointestinal illness of vomiting, nausea, and diarrhea that
is followed by a subacute ascending sensory and motor process
producing weakness, areflexia, a severe length-dependent
sensory loss, and autonomic involvement. Patients typically have
other organ involvement such as a cardiomyopathy, anemia, rash,
hepatitis, and encephalopathy that should clue the physician to
the unlikelihood of classic GBS. Testing for arsenic in the urine
is more sensitive than blood levels, particularly several days
after the poisoning. Mees lines are found in the fingernails of
patients with acute arsenic poisoning, but the lines commonly
do not appear until 6-8 weeks after acute poisoning. Low level
chronic arsenic poisoning results in a painful sensory and motor
length-dependent polyneuropathy that is indistinguishable from
most other chronic neuropathies. Lead intoxication can cause a
motor and sensory length-dependent neuropathy or the clinical
constellation of bilateral wrist and foot drop.

Vasculitis
Vasculitis is a rare cause of peripheral neuropathy; establishing
a diagnosis can be difficult particularly when tissue must be
obtained to secure the diagnosis. The basis for a vasculitis of the
peripheral nervous system is immune-mediated inflammation of
blood vessels that causes secondary damage to peripheral myelin
and axons. If a vasculitis is limited to nerve and muscle, it is
called a nonsystemic vasculitic neuropathy or myopathy. If it
affects other organ systems plus nerve and muscle, it is called
a systemic vasculitic neuropathy. Causes of systemic vasculitic
neuropathy include microscopic polyangiitis, ChurgStrauss
syndrome, polyarteritis nodosa, Wegener granulomatosis,

POLYNEUROPATHY
Table 3. Industrial and environmental toxic neuropathies

Heavy Metals
Arsenic
Cadmium
Mercury
Lead
Thallium
Hexacarbons
N-hexane
Methyl-n-butylketone

Organophosphates
Tri-orthocresylphosphate
Miscellaneous
Acrylamide
Buckthorn toxin
Carbon disulfide
Ciguatera toxin
Diethyl glycol
Ethylene oxide
Ethylene glycol
Hexachlorophene
Methyl bromide
Puffer fish toxin

cryoglobulinemia, small vessel vasculitis, and giant cell arteritis.


Vasculitic neuropathies can also occur secondary to connective
tissue disorders such as rheumatoid arthritis, Sjgrens
syndrome, and systemic lupus erythematosus. Other causes
include sarcoidosis, infection, and paraneoplastic vasculitis.
Vasculitic neuropathies often begin abruptly with pain or
subacutely over days to weeks. Vasculitic neuropathy may
present as a mononeuropathy or in a mononeuritis multiplex
pattern. In other patients it can manifest as an asymmetric
sensory and motor neuropathy. In other patients, the clinical
presentation is a mononeuritis multiplex superimposed upon a
length-dependent symmetric polyneuropathy. Since vasculitis
often affects proximal portions of nerves, and particularly larger
nerves, symptoms in the proximal legs often are the first areas of
weakness. Cranial nerve involvement is rare. Patients often have
systemic symptoms such as fever and weight loss accompanying
the presentation of the vasculitic neuropathy.
Microcytic polyangiitis often presents with a progressive
glomerulonephritis, weight loss, arthralgias, hypertension,
pulmonary disease, and cardiac complications. Most patients
have positive perinuclear antineutrophil cytoplasmic antibody
(p-ANCA) titers. Patients with ChurgStrauss syndrome often
manifest with asthma, sinusitis, pulmonary infiltrates, and
eosinophilia. The blood eosinophilia count is often 10% or higher.
About 50% of patients are positive for p-ANCA. Polyarteritis
nodosum (PAN) may occur on its own, yet it is often associated
with chronic hepatitis B infection. PAN is a vasculitis of the
medium sized rather than large arteries. PAN commonly presents
with peripheral nervous system involvement, renal involvement,
skin changes, gastrointestinal tract dysfunction, and hypertension.
Specific autoantibodies for other types of vasculitis are typically
not detected. The diagnosis is usually confirmed by abdominal
angiography or if necessary biopsy of muscle, nerve, or skin.
Wegeners granulomatosis has a predilection for the upper and
lower respiratory tract, the kidneys, and the peripheral nervous
system. Sinus involvement is a very common initial presentation.
Patients with Wegeners granulomatosis often have a c-ANCA
(cytoplasmic) autoantibody.

A vasculitic neuropathy in patients with rheumatoid arthritis


is rare and, when it occurs, tends to parallel the severity of the
rheumatoid arthritis. Most patients with rheumatoid arthritis
have a relatively mild distal symmetric sensory or sensory
and motor neuropathy, or CTS. If the patient is suspected
to have a vasculitic neuropathy from rheumatoid arthritis,
in most cases a nerve biopsy will be necessary to establish
the diagnosis. Sjgrens syndrome is a relatively common
autoimmune inflammatory disease. Its principal manifestations
are dry eyes and dry mouth (sicca symptoms complex). Patients
may have the autoantibodies, anti-SSA and anti-SSB, but a
minor salivary gland biopsy may be necessary to establish the
diagnosis. The types of neuropathy associated with Sjgrens
syndrome include a mononeuritis multiplex, multiple cranial
neuropathies, a painful sensory neuropathy, a sensory ataxic
neuropathy, trigeminal neuralgia, autonomic neuropathy, and a
polyradiculoneuropathy. Systemic lupus erythematosus (SLE) is
a multisystem autoimmune inflammatory disorder. Patients tend
to have a mild symmetrical distal sensory neuropathy. In some
studies, CTS is the most common peripheral nerve complication
of SLE. A vasculitic mononeuritis multiplex is a relatively
infrequent complication of SLE.
The diagnosis of vasculitic neuropathy, whether systemic
or nonsense systemic, is founded in a careful history and
examination, laboratory studies to rule out other considerations,
positivity of autoantibodies associated with a vasculitis,
electrophysiology, and organ biopsy tissue, often including
nerve and muscle biopsy.
The first line treatment for vasculitic neuropathies is high-dose
corticosteroids, either given intravenously or orally. For rapidly
progressive neuropathies, intravenous cyclophosphamide
should be used. Other immunosuppressants such as azathioprine
and methotrexate may be used to replace steroids or for those
patients who cannot tolerate cyclophosphamide. If the patient
has a mild form of neuropathy and it is stable, observation for
a few months without specific treatment might be advised and
aggressive treatment withheld until the patient worsens.

Porphyria
Porphyria arises from impaired porphrinogen formation or
abnormal heme biosynthesis. It is divided into a group of five
diseases including acute intermittent porphyria, variegate
porphyria, hereditary coproporphyria, acute hepatic porphyrias,
and aminolevulinate dehydratase deficiency porphyria. The
classic triad for porphyria is abdominal pain, psychosis, and
neuropathy. However, in everyday practice, most patients do
not present in this obvious identifiable pattern. Most attacks
of porphyria begin with abdominal pain or mild behavioral
changes. The gastrointestinal symptoms include pain, nausea,
vomiting, constipation, and rarely diarrhea. The abdominal
pain can be dramatic and may lead to unnecessary surgeries for
presumed acute abdomen. Seizures are common during an acute
attack. Attacks are most commonly precipitated by medications
and relative starvation.

29

MISCELLANEOUS POLYNEUROPATHIES

Many types of neuropathy have been reported in the porphyrias


including a pure motor, pure sensory, sensory and motor, small
fiber, and autonomic. A pure motor neuropathy with hyporeflexia
or areflexia is most common and often weakness is greater
proximally than distally, thus, suggesting a myopathic picture.
Porphyric neuropathy can be severe and lead to respiratory
failure from phrenic nerve involvement. NCSs and needle
EMG show the features of a motor axon loss neuropathy. Thus,
one would expect to observe reduced CMAP amplitudes and
normal to borderline-reduced conduction velocities. The needle
examination would show abnormalities consistent with acute
denervation and, depending on the duration of the neuropathy,
chronic neurogenic abnormalities. Cerebrospinal fluid protein
is mildly elevated in approximately half of patients with acute
intermittent porphyria (AIP).
Differentiating the type of porphyria is based upon the
interpretation of heme metabolites excreted in the urine during
an attack. During an attack, the metabolites are excreted in excess
amounts. Each type of porphyria has a characteristic pattern of
urinary and fecal heme precursor excretion.
The first step in diagnosis is a urinary porphobilinogen (PBG)
level. Urinary PBG and aminolevulinic acid (ALA) are increased
in all three acute hepatic porphyrias (acute intermittent porphyria
[AIP], hereditary coproporphyria [HCP], and variegate porphyria
[VP]). In AIP, urinary excretion levels of ALA and PBG are
markedly elevated. Metabolic studies are typically not useful
between attacks because patients often excrete normal amounts
of heme precursors between episodes.
From a genetic approach, porphyria is most commonly transmitted
as an AD trait. Nevertheless, a 50% residual enzyme activity,
provided by the normal chain, does not prevent manifestation of the
disease when the metabolism is stressed. For the hepatic porphyrias
with neuropathy, more than 500 mutations have been mapped.
No specific treatments have been identified for porphyria
neuropathy. During an acute attack, treatment is typically
symptomatic and disease-modifying to abort the attack. Thus,
attention must be directed to management of pain, gastrointestinal
symptoms, hypertension, hyponatremia, respiratory failure,
and restlessness and agitation. Medications must be selected
based on their safety in porphyria. Often, the patient should be
managed in an intensive care unit (ICU) because of the risk of
arrhythmia, tachycardia hypotension, and hypertension. It is
important to emphasize for the longterm treatment of patients
with porphyria the avoidance of fasting, alcohol, and the many
medications associated with precipitating attacks of acute
porphyria. Commonly prescribed drugs that should be avoided
in patients with porphyria include barbiturates, calcium channel
blockers, carbamazepine, chlorpropamide, clonazepam, ergots,
halothane, phenytoin, primidone, sulfonamides, tranquilizers,
and valproic acid.

30

Critical Illness Neuropathy


Critical illness polyneuropathy (CIP) is an acute or subacute
polyneuropathy identified in patients who have sepsis and
multiorgan failure and are admitted to the ICU. Most often, CIP
occurs in patients without predisposing factors for neuropathy. It
is one of the diseases that has been classified with ICU-acquired
weakness (critical illness myopathy) and, not uncommonly,
CIP occurs in patients with critical illness myopathy. Early
in the description of CIP in the early 1980s, the illness was
often confused with GBS or was considered a complication of
medications used in the ICU setting.
CIP has been identified in more than 50% of patients admitted
to the ICU who were evaluated 2 weeks or later after admission.
Almost all patients were experiencing sepsis and the systemic
inflammatory response syndrome or multiorgan failure. Failure
to wean from a respirator in a patient who is weak and areflexic
often raises consideration for CIP. The cardinal features of CIP
are quadriparesis, hyporeflexia or areflexia, and respiratory
failure in patients without other explanations for this neurologic
constellation. Cranial nerve involvement is rare but can be
difficult to assess in patients who are intubated or on bilevel
positive airway pressure (BiPAP). It is often a challenge to
document sensory loss because of uncooperativeness from the
encephalopathy that is often seen in patients with CIP. The
diagnosis is not difficult to make in a patient who has been in the
ICU for several weeks and has multiorgan failure.
NCSs in CIP show evidence for a severe motor and sensory
primarily axonal loss polyneuropathy. Absent sensory and motor
studies are common and should lead the EDX consultant to
study other nerves, often proximal nerves, to identify recordable
nerves. It is important to perform repetitive NCSs to assess for a
neuromuscular junction abnormality such as myasthenia gravis
or botulism. Many EDX consultants perform phrenic NCSs
particularly in patients in whom weaning from the respirator has
been impossible. In a typical patient with CIP, one expects to see
absent or low amplitude CMAPs, normal or slightly prolonged
distal latencies, and normal or mildly reduced NCSs. Sensory
responses are low in amplitude or absent, particularly in the
legs. Features one normally associates with GBS should not be
present, such as conduction block, temporal dispersion, slowed
conduction velocities, and markedly prolonged distal latencies
and F waves. NCSs can be difficult to perform in the ICU
setting because of edema, appliances, electrical interference,
and intravenous and arterial lines. The needle examination
will show changes of acute denervation in proximal and distal
muscles usually by weeks 2 or 3. The findings in proximal
muscles reflect the radicular component to the critical illness
neuropathy. Recruitment can be difficult to elicit in patients who
are encephalopathic or sedated.
Nerve biopsy in patients with CIP shows the expected axon
loss one would expect in a severe polyneuropathy. Primary
demyelination is not observed. In most patients with CIP, a
sural nerve or superficial peroneal nerve biopsy is difficult to
obtain in a patient who is critically ill and cannot be moved from

POLYNEUROPATHY

the ICU setting. In most instances, the biopsy results will not
influence treatment. Muscle biopsies of proximal muscles may
be indicated if critical illness myopathy is a major consideration.
No convincing explanations have been found for the mechanism
and pathophysiology of CIP. Inflammatory mediators have been
proposed because of the association of CIP to sepsis and multiorgan
failure. The inflammatory mediators hypothesized include
interleukins, tumor necrosis factor, platelet activating factors,
prostaglandins, interferon, nitrous oxide, complement, and others.
At this time, none of them have been proven to cause CIP.
No consistently effective treatments exist to abort or reverse
the evolution of CIP. Rapid reversal of sepsis and multiorgan
failure represent the best approach to preventing worsening
of CIP. There is some evidence that intensive insulin therapy,
maintaining blood glucoses between 80 and 110 mg/dl, lessens
the incidence of CIP in those patients with sepsis and multiorgan
failure and reduces mortality in ICU patients. If patients survive
the critical illness, most slowly improve but many are left with
major functional disabilities.

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31

32

Polyneuropathy

CME Questions:

1.

2.

Which of the following has been shown to predict poor


prognosis in peripheral neuropathy associated with
advanced hepatic disease?
A. Absence of the sural sensory nerve action potential
on nerve conduction studies (NCSs).
B. Presence of autonomic dysfunction.
C. Conduction velocity slowing of the tibial and
peroneal motor NCSs.
D. Degree of elevation of liver enzymes.
Which of the following is TRUE regarding uremic
neuropathy?
A. Hemodialysis has been definitively shown to
improve uremic neuropathy.
B. Parathyroid hormone is a clearly toxic middle
molecule and the most likely cause of uremic
neuropathy.
C. Renal transplantation may produce improvements
in both clinical symptoms and NCS parameters in
uremic neuropathy.
D. Demyelination on nerve biopsy in uremic
neuropathy is believed to be the primary
pathological process.

3.

Proximal weakness in a patient with hypothyroidism is


likely due to hypothyroid neuropathy.
A. True.
B. False.

4.

Which of the following is FALSE regarding diabetic


radiculoplexus neuropathies?
A. The illness is monophasic, and patients almost
always recover completely without lasting deficit or
relapse.
B. The pathophysiology is due to ischemic injury from
microvasculitis.
C. There is usually associated weight loss.
D. The lumbosacral version of this disease is believed
to be the most common.

5.

Which one of the following is a risk factor for the


development of diabetic polyneuropathy?
A. Duration of hyperglycemia.
B. Presence of hypothyroidism.
C. Painful dysesthesias.
D. Vitamin B12 deficiency.

6.

Which of the following is NOT a recognized cause of


sensory neuronopathy?
A. Small cell lung cancer with anti-Hu antibodies.
B. Hepatitis C with cryoglobulinemia.
C. Vitamin B6 toxicity.
D. Sjgrens syndrome.

7.

Which of the following diseases is most frequently


associated with cryoglobulinemia and vasculitis?
A. Lyme disease.
B. Hepatitis C.
C. Sjgrens syndrome.
D. Chronic obstructive pulmonary disease.

8.

A patient presents with an acute acquired demyelinating


polyradiculoneuropathy. Lumbar puncture reveals an
elevated protein level and a moderate pleocytosis. Which
of these infections is the LIKELY cause?
A. Hepatitis C.
B. Leprosy.
C. Clostridium jejuni.
D. Human immunodeficiency virus.

9.

Which of the following is NOT thought to cause


myeloneuropathy?
A. Vitamin B12 deficiency.
B. Vitamin B6 deficiency.
C. Copper deficiency.
D. Nitrous oxide abuse.

33

CME QUESTIONS

10. Sjgrens syndrome is associated with several types of


neuropathy. Which of the following is LEAST LIKELY to
be associated with Sjgrens syndrome?
A. Acute acquired demyelinating polyneuropathy.
B. Sensory neuronopathy.
C. Distal sensory-predominant polyneuropathy.
D. Vasculitic neuropathy.
11. Which neuropathy is NOT a demyelinating neuropathy?
A. GuillainBarr syndrome (GBS).
B. Antimyelin-associated-glycoprotein (MAG)
neuropathy.
C. Transthyretin familial amyloid polyneuropathy.
D. POEMS (polyneuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy, and skin
changes) syndrome.
E. Chronic inflammatory demyelinating
polyneuropathy.
12. Which of the following treatments is beneficial for GBS?
A. Plasmapheresis.
B. Intravenous Solu-Medrol (methylprednisolone
sodium succinate).
C. Methotrexate.
D. Cyclophosphamide.
E. Azathioprine.
13. Which laboratory test can be helpful in the diagnosis of
POEMS syndrome?
A. Vascular endothelial growth factor (VEGF).
B. Anti-GM1 antibodies.
C. Anti-sulfatide antibodies.
D. Anti-MAG antibodies.
E. Kappa light chains.
14. What statement is INCORRECT about anti-MAG
antibodies.
A. Placebo controlled studies of rituximab have been
conducted.
B. A bone marrow biopsy is never needed because
patients have a monoclonal gammopathy of
undermined significance (MGUS).
C. Widened myelin lamellae are a characteristic finding
on electron microscopy.
D. Over 95% of patients have an IgM monoclonal
gammopathy.
E. A tremor is common in anti-MAG neuropathy.
15. Which of the following disorders is characteristically an
autonomic neuropathy
A. Idiopathic neuropathy.
B. Transthyretin familial amyloid polyneuropathy.
C. Chronic inflammatory demyelinating
polyneuropathy.
D. Anti-MAG neuropathy.
E. POEMS syndrome.

34

16. In what percentage of patients will a definable cause of


polyneuropathy be found after a careful history, physical
examination, electrodiagnostic testing, and laboratory
testing?
A. 20%.
B. 40%.
C. 60%.
D. 80%.
17. Which of the following is the MOST COMMON
connective tissue disorder that gives rise to a
polyneuropathy?
A. Sjgrens syndrome.
B. Polyarteritis nodosum.
C. Wegeners granulomatosis.
D. Rheumatoid arthritis.
18. Mees lines are observed in which of the following toxic
neuropathies?
A. Lead.
B. Arsenic.
C. Mercury.
D. N-hexane.
19. On needle electromyography and NCSs, critical illness
neuropathy typically shows which of the following
characteristics?
A. Uniform demyelination.
B. Segmental demyelination.
C. Sensory and motor axon loss.
D. Sensory neuropathy.
E. Motor axon loss neuropathy.
20. Which of the following medications is a COMMON cause
of polyneuropathy?
A. Vincristine.
B. Ara-C.
C. Glutethimide.
D. Gentamicin.
E. Indocin (indomethacin).

American Association of
Neuromuscular & Electrodiagnostic Medicine
2621 Superior Drive NW
Rochester, MN 55901
T| 507.288.0100
www.aanem.org

The American Association of Neuromuscular & Electrodiagnostic


Medicine was founded in 1953. We are a nonprofit
membership association dedicated to the advancement of
neuromuscular, musculoskeletal, and electrodiagnostic medicine.
With 4,500 member physicians and allied health professionals,
AANEM works to improve the quality of medical care provided
to patients with muscle and nerve disorders.

61st Annual Meeting

Savannah, Georgia