A CLINICAL APPROACH

TO THE PATIENT WITH

SUSPECTED MYOPATHY
Carlayne E. Jackson

ABSTRACT
Myopathies are a heterogeneous group of disorders that affect the muscle channel,
structure, or metabolism. This chapter will provide a diagnostic approach to a pa-
tient with suspected muscle disease based upon clinical history and examination. It
will also provide a phenotypical approach to diagnosis based on the predominant
pattern of weakness. Finally, laboratory testing that can be performed to confirm
the suspected diagnosis of myopathy will be discussed.

INTRODUCTION CLINICAL EVALUATION

Myopathies are disorders in which a
primary functional or structural im-
pairment of skeletal muscle exists.
Myopathies can be distinguished from
other disorders of the motor unit,
including motor neuron disorders,
peripheral neuropathies, and neuro-
muscular junction diseases, by charac-
teristic clinical and laboratory features.
Therefore, the first goal in approach-
ing a patient with a suspected muscle
disease is to determine the correct site
of the lesion. Once localized to the
muscle, the next step is to identify
whether the myopathy is due to a
defect in the muscle channel, muscle
structure, or a dysfunction in muscle
metabolism. The second goal is to
determine the cause of the myopathy.
In general, myopathies can be classi-
fied into hereditary and acquired
disorders (Table 1-1). The third goal
is to determine whether a specific
treatment is available and if not, to
optimally manage the patient’s symp-
toms to maximize his or her functional
abilities and enhance quality of life.
The most important element of evalu-
ating a patient with a suspected myopa-
thy is obtaining a thorough history.
This should allow the physician to
make a reasonable preliminary diag-
nosis that places the patient into one
of the categories in Table 1-1. The
findings on the physical examination,
and in particular the distribution of
muscle weakness, should provide ad-
ditional information in determining the
correct diagnosis. The results of the
laboratory studies (blood tests, elec- 13
tromyogram [EMG], muscle biopsy,
molecular genetic studies) then play
a confirmatory diagnostic role.
The first step in approaching a
patient is to ask six key questions based
on the patient’s symptoms and signs.
(1) Which negative and/or posi-
tive symptoms and signs does the
patient demonstrate?
Symptoms and signs of muscle dis-
ease (Table 1-2) can be divided into
negative complaints such as weakness,
exercise intolerance, fatigue, and mus-
cle atrophy, and positive complaints

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 " SUSPECTED MYOPATHY

KEY POINTS:
Fatigue is a much less useful nega-
A Weakness is
Classification of tive symptom, as it is nonspecific and
by far the TABLE 1-1
Myopathies may reflect a patient’s cardiopulmo-
most common
negative nary status, level of conditioning, over-
" Hereditary all health, sleeping habits, or emotional
symptom
reported by Muscular dystrophies state. Many patients who complain of
a patient Myotonias diffuse global weakness or fatigue do
with muscle not have a muscle disorder, particularly
Channelopathies
disease. if the neurological examination is nor-
A Abnormal
Congenital myopathies mal. On the other hand, abnormal fati-
fatigability Metabolic myopathies gability after exercise can result from
after exercise certain metabolic and mitochondrial
Mitochondrial myopathies
can result myopathies, and it is important to de-
from certain " Acquired fine the duration and intensity of exer-
metabolic and Inflammatory myopathies cise that provokes the fatigue.
mitochondrial Positive symptoms associated with
myopathies, Endocrine myopathies
myopathies may include myalgias, cramps,
and it is Myopathies associated with contractures, myotonia, or myoglo-
important to other systemic illness
binuria. Myalgia, like fatigue, is another
define the
Drug-induced myopathies nonspecific symptom of some myopa-
duration and
Toxic myopathies thies (Table 1-3). Myalgias may be
intensity of
exercise that episodic (metabolic myopathies) or
provokes nearly constant (inflammatory muscle
the fatigue. disorders). However, pain is usually
such as myalgias, cramps, contractures, not common in most muscle diseases
A It is rare for
and is more likely to be due to or-
a muscle
myoglobinuria, and muscle stiffness
(Barohn, 2004). thopedic or rheumatological disorders
disease to
be responsible Weakness is by far the most common (Kincaid, 1997). It is rare for a muscle
for vague aches negative symptom reported by a patient disease to be responsible for vague
and muscle with muscle disease. If the weakness
discomfort in involves the lower extremities, patients
the presence will complain of difficulty climbing TABLE 1-2 Symptoms and
of a normal Signs Associated
stairs, arising from a low chair or toilet,
neuromuscular With Myopathies
or getting up from a squatted position.
examination When the upper extremities are in-
14 and laboratory
volved, patients notice trouble lifting
" Negative
studies. Weakness
objects over their head and brushing
their hair. These symptoms in the arms Fatigue
and legs indicate proximal muscle Exercise intolerance
weakness, which is probably the most
Muscle atrophy
common type of weakness in a myo-
pathic disorder (see below). Less com- " Positive
monly, patients with myopathies can Myalgias
complain of distal weakness manifested
Cramps
as difficulty opening jars, inability to
turn a key in the ignition, or tripping Contractures
due to footdrop. Some myopathies may Myotonia
also result in cranial muscle weakness,
Myoglobinuria
resulting in complaints of dysarthria,
dysphagia, or ptosis.

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 KEY POINT:

TABLE 1-3 Muscle Disorders Associated With Myalgias A Cramps may

last from
seconds to
" Mitochondrial myopathies
minutes and
" Inflammatory myopathies (polymyositis, dermatomyositis) are usually
localized to
" Infectious myositis (especially viral)
a particular
" Drug-induced myopathies (lovastatin, chloroquine) muscle region.
" Hypothyroid myopathy They are
typically
" Myoadenylate deaminase deficiency benign,
" Tubular aggregate myopathy occurring
frequently in
" X-linked myalgia and cramps (Becker dystrophy variant)
normal
" Eosinophilia-myalgia syndrome individuals,
and are seldom
a feature of
a primary
aches and muscle discomfort in the Patients may complain of muscle stiff- myopathy.
presence of a normal neuromuscular ness or tightness resulting in difficulty
examination and laboratory studies. releasing their handgrip after a hand-
A specific type of muscle pain is the shake, unscrewing a bottle top, or
involuntary muscle cramp. Cramps may
last from seconds to minutes and are
usually localized to a particular muscle
region. They are typically benign, occur- TABLE 1-4 Myopathies
ring frequently in normal individuals, Associated
and are seldom a feature of a primary With Muscle
Contractures
myopathy. Cramps are characterized by
rapidly firing motor unit discharges,
" Glycolytic/glycogenolytic
which can be demonstrated on needle enzyme defects
EMG. Cramps can occur with dehydra-
Myophosphorylase deficiency
tion, hyponatremia, azotemia, and myx-
(McArdle’s disease)
edema and in disorders of the nerve or
motor neuron (especially amyotrophic Phosphofructokinase
deficiency
lateral sclerosis).
Muscle contractures are uncommon Phosphoglycerate kinase
15
but can superficially resemble a cramp. deficiency
They are typically provoked by exercise Phosphoglycerate mutase
in patients with glycolytic enzyme de- deficiency
fects. Contractures differ from cramps Lactate dehydrogenase
in that they usually last longer and are deficiency
electrically silent with needle EMG. Mus- Debrancher enzyme
cle disorders that are associated with deficiency
contractures are listed in Table 1-4.
Myotonia is the phenomenon of im-
" Paramyotonia congenita

paired relaxation of muscle after force- " Hypothyroid myopathy

ful voluntary contraction and most " Brody’s disease
commonly involves the hands and eye-
" Rippling muscle disease
lids. Myotonia is due to repetitive de-
polarization of the muscle membrane.

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 " SUSPECTED MYOPATHY

KEY POINT:
Myoglobinuria is a relatively uncom-
A Recurrent
Myopathies mon manifestation of muscle disease
myoglobinuria TABLE 1-5
Associated With and is caused by the excessive release of
is usually Muscle Stiffness
due to an myoglobin from muscle during periods
underlying of rapid muscle destruction (rhabdo-
" Myotonic dystrophy
metabolic myolysis). Severe myoglobinuria can
myopathy, " Myotonia congenita result in renal failure due to acute tu-
whereas " Paramyotonia congenita bular necrosis. If patients complain of
isolated exercise-induced weakness and myal-
episodes,
" Proximal myotonic myopathy
gias, they should be asked if their urine
particularly " Hyperkalemic periodic
has ever turned cola-colored or red
occurring after paralysis
during or after these episodes.
unaccustomed " Hypothyroid myopathy
strenuous
Recurrent myoglobinuria is usually
exercise, are due to an underlying metabolic my-
frequently opathy (Table 1-6), whereas isolated
idiopathic. opening their eyelids if they forcefully episodes, particularly occurring after
shut their eyes. Myotonia classically unaccustomed strenuous exercise, are
improves with repeated exercise. In frequently idiopathic.
contrast, patients with paramyotonia (2) What is the temporal evolu-
congenita demonstrate ‘‘paradoxical tion?
myotonia’’ in that symptoms are typi- It is obviously important to deter-
cally worsened by exercise or repeated mine the onset, duration, and evolution
muscle contractions. Exposure to cold of the patient’s symptoms and signs of
results in worsening of both myotonia muscle disease. Did the weakness (or
and paramyotonia. The muscle disor- other symptoms) first manifest at birth,
ders associated with muscle stiffness are or was the onset in the first, second,
listed in Table 1-5. third, or a later decade (Table 1-7)?

TABLE 1-6 Causes of Myoglobinuria

" Prolonged, intensive exercise

" Viral and bacterial infections
" Drugs and toxins (especially alcohol)
16 " Neuroleptic malignant syndrome
" Heat stroke
" Trauma (crush injuries)
" Severe metabolic disturbances, including prolonged fever
" Inflammatory myopathies (rare)
" Limb-girdle muscular dystrophy 2C-2F (sarcoglycanopathies)
" Metabolic myopathies
Glycogenoses (myophosphorylase deficiency)
Lipid disorders (carnitine palmitoyltransferase deficiency)
" Malignant hyperthermia (central core myopathy, Duchenne
muscular dystrophy)

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TABLE 1-7 Diagnosis of Myopathy Based on Age of Onset

" Myopathies Presenting at Birth

Congenital myotonic dystrophy
Centronuclear (myotubular) myopathy
Congenital fiber-type disproportion
Central core disease
Nemaline (rod) myopathy
Congenital muscular dystrophy
Lipid storage diseases (carnitine deficiency)
Glycogen storage diseases (acid maltase and phosphorylase deficiencies)
" Myopathies Presenting in Childhood
Muscular dystrophies
Duchenne
Becker
Emery-Dreifuss
Facioscapulohumeral
Limb-girdle
Congenital
Inflammatory myopathies
Dermatomyositis
Polymyositis (rarely)
Congenital myopathies
Nemaline
Centronuclear
Central core
Lipid storage disease (carnitine deficiency) 17
Glycogen storage disease (acid maltase deficiency)
Mitochondrial myopathies
Endocrine-metabolic disorders
Hypokalemia
Hypocalcemia
Hypercalcemia
" Myopathies Presenting in Adulthood
Muscular dystrophies
Limb-girdle
Continued on next page

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 " SUSPECTED MYOPATHY

TABLE 1-7 Continued

Facioscapulohumeral
Becker
Emery-Dreifuss
Inflammatory myopathies
Polymyositis
Dermatomyositis
Inclusion body myositis
Viral (human immunodeficiency virus [HIV])
Metabolic myopathies
Acid maltase deficiency
Lipid storage diseases
Debrancher deficiency
Phosphorylase b kinase deficiency
Mitochondrial myopathies
Endocrine myopathies
Thyroid
Parathyroid
Adrenal
Pituitary disorders
Toxic myopathies
Alcohol
Corticosteroids
Local injections of narcotics
Colchicine
18 Chloroquine
Statins
Myotonic dystrophy
Distal myopathies
Nemaline myopathy
Centronuclear myopathy

Identifying the age that symptoms age 3, whereas most facioscapulohum-

began can provide crucial information eral and limb-girdle muscular dystro-
leading to the correct diagnosis. For phies (LGMDs) begin in adolescence or
example, symptoms of Duchenne mus- later. Of the inflammatory myopathies,
cular dystrophy usually are identified by dermatomyositis occurs in children and

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 KEY POINT:
adults; polymyositis occurs rarely in informative than questions such as,
A Myopathies
children but at any decade in the adult ‘‘Does any member of your family have
can present
years; and inclusion body myositis oc- a muscle disease?’’ Identifying a particu- with either
curs most commonly in the elderly. lar hereditary pattern not only may help constant
It is also imperative to determine the in correctly diagnosing the specific weakness
evolution and duration of the disease. myopathy (Table 1-8) but is also of (muscular
Myopathies can present with either tremendous importance in providing dystrophies,
constant weakness (muscular dystro- appropriate genetic counseling. inflammatory
phies, inflammatory myopathies) or (4) Are there precipitating factors that myopathies)
episodic periods of weakness with trigger episodic weakness or myotonia? or episodic
normal strength interictally (periodic A history of precipitating factors that periods of
weakness
paralysis, metabolic myopathies due to might trigger or exacerbate symptoms
with normal
certain glycolytic pathway disorders).
strength
The episodic disorders have acute interictally
weakness that can return to normal Diagnosis of (periodic
TABLE 1-8
strength within hours or days. The Myopathy Based paralysis,
tempo of the disorders with constant on Pattern of metabolic
weakness can vary among: (1) acute or Inheritance myopathies
subacute progression in some inflam- due to certain
matory myopathies (dermatomyositis " X-Linked glycolytic
and polymyositis); (2) chronic slow Duchenne muscular pathway
progression over years (most muscular dystrophy disorders).
dystrophies); or (3) nonprogressive Becker muscular dystrophy
weakness with little change over de-
Emery-Dreifuss muscular
cades (congenital myopathies). Finally,
dystrophy
both constant and episodic myopathic
disorders can have symptoms that may " Autosomal Dominant
be monophasic or relapsing. For exam- Facioscapulohumeral
ple, polymyositis can occasionally have dystrophy
an acute monophasic course with com- Limb-girdle muscular
plete resolution of strength within dystrophy
weeks or months. Patients with periodic Oculopharyngeal muscular
paralysis or metabolic myopathies can dystrophy
have recurrent attacks of weakness
Myotonic dystrophy
over many years, whereas a patient with
acute rhabdomyolysis due to cocaine Periodic paralysis 19
may have a single episode. Paramyotonia congenita
(3) Is there a family history of a
Thomsen disease
myopathic disorder?
Since many myopathies are inher- Central core myopathy
ited, obtaining a thorough family his- " Autosomal Recessive
tory is clearly of great importance in Limb-girdle muscular
making a correct diagnosis. A detailed dystrophy
family tree should be completed to look
Metabolic myopathies
for evidence of autosomal dominant,
autosomal recessive, and X-linked pat- Becker myotonia
terns of transmission. Questions regard- " Maternal Transmission
ing family members’ use of canes or
Mitochondrial myopathies
wheelchairs, skeletal deformities, or
functional limitations are usually more

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 " SUSPECTED MYOPATHY
KEY POINTS:
of weakness or myotonia should be ex-
A Periodic
plored. It is important to ask the patient
paralysis is
characteristically if there is any history of either illegal
provoked by drug or prescription medication use
exercise or that might produce a myopathy. A
ingestion of a history of weakness, pain, and/or myo-
carbohydrate globinuria that is provoked by exercise
meal followed might suggest the possibility of a gly-
by a period colytic pathway defect. Episodes of
of rest. weakness that occur in association with
A Involvement a fever would be supportive of a diag-
of organs or nosis of carnitine palmityl transferase
tissues other deficiency. Periodic paralysis is charac-
than muscle teristically provoked by exercise or in-
may also gestion of a carbohydrate meal followed
provide helpful by a period of rest. Patients with para-
clues in making myotonia congenita frequently report
the appropriate
that cold exposure may precipitate their
diagnosis.
symptoms of muscle stiffness.
(5) Are associated systemic symp-
toms or signs present?
Involvement of organs or tissues other
than muscle may also provide helpful
clues in making the appropriate diag-
nosis. Cardiac disease (Table 1-9) may
be associated with myotonic dystrophy,
Duchenne or Becker muscular dystro-
phies, LGMD1B (laminopathy), LGMD2I
(fukutin-related protein), LGMD2C–2F
(sarcoglycanopathies), LGMD2G (tele-
thoninopathy), Emery-Dreifuss muscu-
lar dystrophy, and Andersen syndrome.
Respiratory failure may be the pre-
senting symptom of myotonic dystro-
phy, centronuclear myopathy, nemaline
20 myopathy, or acid maltase deficiency
(Table 1-10). Eventually, most myopa-
thies will affect respiratory muscle
strength, highlighting the need for
consistent monitoring of pulmonary
function studies throughout the dis-
ease course. Once symptoms of hypo-
ventilation are evident, supportive care
with noninvasive positive pressure ven-
tilation and assistive devices for clear-
ance of upper airway secretions should
be used.
Hepatomegaly may be seen in myopa-
thies associated with deficiencies in
acid maltase, debranching enzyme, and
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carnitine. The presence of cataracts,
frontal balding, and mental retardation
strongly suggests the diagnosis of myo-
tonic dystrophy. Dysmorphic features
may be associated with the congenital
myopathies. The presence of a rash is
extremely helpful in confirming the
diagnosis of dermatomyositis. Muscu-
loskeletal contractures can occur in
many myopathies of long-standing du-
ration. However, contractures develop-
ing early in the course of the disease,
especially at the elbows, can be a clue
to Emery-Dreifuss dystrophy, LGMD1B
(laminopathy), and Bethlem myopathy.
Evidence of diffuse systemic disease can
indicate amyloidosis, sarcoidosis, endo-
crinopathy, collagen–vascular disease,
Myopathies
TABLE 1-9
Associated With
Cardiac Disease
" Arrhythmias
Kearns-Sayre syndrome
Andersen’s syndrome
Polymyositis
Muscular dystrophies
Myotonic
Limb-girdle 1B, 2C-2F, 2G
Emery-Dreifuss
" Congestive Heart Failure
Muscular dystrophies
Duchenne
Becker
Emery-Dreifuss
Myotonic
Limb-girdle 1B, 2C-2F, 2G
Nemaline myopathy
Acid maltase deficiency
Carnitine deficiency
Polymyositis

Myopathies
TABLE 1-10
Associated With
Respiratory
Insufficiency
" Muscular Dystrophies
Duchenne
Becker
Emery-Dreifuss
Limb-girdle
Myotonic
Congenital
" Metabolic Myopathies
Acid maltase deficiency
Carnitine deficiency
" Mitochondrial Myopathies
" Congenital Myopathies
Nemaline
Centronuclear
" Inflammatory Myopathies
Polymyositis
infectious disease, or a mitochondrial
disorder.
(6) What is the distribution of
weakness?
To determine the distribution of
muscle weakness, it is important to
know which muscles to test and how to
grade their power. Muscle strength
can be tested by manual testing and
from observation of functional activity
(Table 1-11) (Brooke, 1986). Func-
tional testing is particularly informative
in young children who usually cannot
cooperate with formal manual muscle
testing and in adults with ‘‘give-way’’
weakness who present with complaints
of muscle pain.
In performing manual muscle testing
of the upper extremities, it is necessary
to assess shoulder abduction and exter-
nal and internal rotation; elbow flexion
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KEY POINT:
and extension; wrist flexion and exten-
A Functional
sion; and finger and thumb extension,
testing is
flexion, and abduction. Muscle groups particularly
that should be tested in the lower ex- informative
tremities include hip flexion, extension, in young
and abduction; knee flexion and exten- children,
sion; ankle dorsiflexion, plantar flexion, who usually
inversion, and eversion; and toe exten- cannot
sion and flexion. All muscle groups cooperate
should be tested bilaterally and prefer- with formal
ably against gravity. Neck flexors should manual
muscle testing,
be assessed in the supine position and
and in
neck extensors in the prone position.
adults with
Knee extension and hip flexion should ‘‘give-way’’
be tested in the seated position, knee weakness who
flexion should be tested in the prone present with
position, and hip abduction should be complaints of
tested in the lateral decubitus position. muscle pain.
If testing against gravity is not done, the
presence of significant muscle weakness
can escape recognition. Assessment of
muscle strength is usually based on
the expanded Medical Research Council
(MRC) of Great Britain grading scale of
0 to 5 (Table 1-12) (Medical Research
Council, 2000). Finally, cranial nerve
muscles such as the orbicularis oculi
and oris, extraocular muscles, tongue,
and palate should be examined. These
may be best tested by observation of the
patient performing functional activities
such as whistling, sucking from a straw,
and smiling.
In addition to manual muscle testing
and functional testing, muscles should
be inspected for evidence of atrophy or 21
hypertrophy. Atrophy of proximal limb
muscles is common in most chronic
myopathies. However, certain myopa-
thies may demonstrate atrophy in spe-
cific groups that correspond to severe
weakness in those muscles and provide
additional diagnostic clues. For exam-
ple, atrophy of the periscapular muscles
associated with scapular winging is
characteristic of facioscapulohumeral
dystrophy. Scapular winging is also
seen in patients with LGMD1B (la-
minopathy), LGMD2A (calpainopathy),
and LGMD2C–2F (sarcoglycanopathies).
 " SUSPECTED MYOPATHY

TABLE 1-11 Functional Assessment of Muscle Weakness

Location Signs or Symptoms of Weakness

Facial Inability to bury eyelashes, horizontal smile, inability to whistle

Ocular Double vision, ptosis, dysconjugate eye movements
Bulbar Nasal speech, weak cry, nasal regurgitation of liquids, poor suck, difficulty
swallowing, recurrent aspiration pneumonia, cough during meals
Neck Poor head control
Trunk Scoliosis, lumbar lordosis, protuberant abdomen, difficulty sitting up
Shoulder girdle Difficulty lifting objects overhead, scapular winging
Forearm/hand Inability to make a tight fist, finger or wrist drop, inability to prevent
escape from hand grip
Pelvic girdle Difficulty climbing stairs, waddling gait, Gowers sign
Leg/foot Footdrop, inability to walk on heels or toes
Respiratory Use of accessory muscles

Selective atrophy of the quadriceps PATTERN-RECOGNITION

muscles and forearm flexor muscles
is highly suggestive of inclusion body
myositis. Distal myopathies may have
profound atrophy of the anterior or
posterior lower extremity compart-
ments. On the other hand, muscles
can show evidence of hypertrophy in
some myotonic conditions such as
myotonia congenita. Muscle hypertro-
phy is also a characteristic of disor-
ders including amyloidosis, sarcoido-
sis, and hypothyroid myopathy. In
22 Duchenne and Becker dystrophy, the
APPROACH TO MYOPATHIC
DISORDERS
After answering the six key questions
obtained from the history and neuro-
logical examination outlined above, one
can attempt to classify a myopathic dis-
order into one of six distinctive patterns
of muscle weakness, each with a limited
differential diagnosis. The final diagno-
sis can then be confirmed based on in-
formation from a selective number of
laboratory studies.

calf muscles demonstrate ‘‘pseudo-

hypertrophy’’ due to replacement with
connective tissue and fat. Calf muscle
hypertrophy is also characteristically
seen in LGMD2C–2F (sarcoglycanopa-
thies) and LGMD2I (fukutin-related
protein). In LGMD2G (telethoninopa-
thy), 50% of the patients will show
calf hypertrophy and 50% will demon-
strate calf atrophy. Focal muscle en-
largement can also be due to a neo-
plastic or inflammatory process, ectopic
ossification, tendon rupture, or partial
denervation.
Pattern 1: Proximal Limb-Girdle
Weakness
The most common pattern of muscle
weakness in myopathies is symmetri-
cal weakness affecting predominantly
the proximal muscles of the legs and
arms, or the so-called limb-girdle dis-
tribution. The distal muscles are usu-
ally involved, but to a much lesser
extent. Neck extensor and flexor mus-
cles are also frequently affected. This
pattern of weakness is seen in most
hereditary and acquired myopathies

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 KEY POINTS:
and therefore is the least specific in ar- Pattern 3: Proximal Arm/Distal
A The most
riving at a particular diagnosis (Kissel Leg Weakness
common
and Mendell, 1999; Wickland and This pattern of weakness affects the pattern
Mendell, 2003). periscapular muscles of the proxi- of muscle
mal arm and the anterior compart- weakness in
Pattern 2: Distal Weakness ment muscles of the distal lower myopathies is
extremity or the so-called scapulope- symmetrical
This pattern of weakness predomi- weakness
nantly involves the distal muscles of roneal distribution (Table 1-13). The
affecting
the upper or lower extremities (ante- scapular muscle weakness is usually
predominantly
rior or posterior compartment muscle characterized by scapular winging. the proximal
groups) (Table 1-13) (Saperstein et al, Weakness can be very asymmetri- muscles of
2001). Depending on the diagnosis and cal. When this pattern is associated the legs and
severity of disease, proximal muscles with facial weakness, it is highly sug- arms, or the
may also be affected. The involvement gestive of a diagnosis of facioscapu- so-called
is usually, although not invariably, lohumeral dystrophy. Other heredi- limb-girdle
symmetrical. Selective weakness and tary myopathies that are associated distribution.
atrophy in distal extremity muscles is with a scapuloperoneal distribution A A pattern of
more commonly a feature of neuropa- of weakness include scapuloperoneal weakness
thies, and therefore a careful sensory dystrophy, Emery-Dreifuss dystrophy, affecting the
and reflex examination must always be LGMD1B, LGMD2A, LGMD2C–2F, con- periscapular
performed in patients presenting with genital myopathies, and acid maltase muscles of the
this phenotype. deficiency. proximal upper
extremity and
the anterior
compartment
muscles of
TABLE 1-12 Expanded Medical Research Council Scale for Manual the distal lower
Muscle Testing extremity is
referred to as a
Modified Medical scapuloperoneal
Research Council distribution.
Grade Degree of Strength When this
pattern is
5 Normal power
associated
5 Equivocal, barely detectable weakness with facial
4+ Definite but slight weakness weakness,
it is highly
23
4 Able to move the joint against combination of suggestive of
gravity and some resistance
a diagnosis of
4 Capable of minimal resistance facioscapulo-
humeral
3+ Capable of transient resistance but collapses
abruptly dystrophy.

3 Active movement against gravity

3 Able to move against gravity but not through
full range
2 Able to move with gravity eliminated
1 Trace contraction
0 No contraction

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 " SUSPECTED MYOPATHY

KEY POINTS:
Pattern 4: Distal Arm/Proximal proximal leg weakness involving the
A A pattern
Leg Weakness knee extensors (quadriceps). The facial
of weakness
characterized This pattern is associated with distal arm muscles are usually spared. Involve-
by distal weakness involving the distal forearm ment of other muscles is extremely
forearm muscles muscles (wrist and finger flexors) and variable. In addition, the weakness is
(wrist and often asymmetrical between the two
finger flexors) sides, which is uncommon in most
and proximal TABLE 1-13 Myopathies myopathies. This pattern is essentially
leg weakness Characterized by pathognomonic for inclusion body
involving the Predominantly
Distal Weakness myositis (IBM). This pattern may also
knee extensors represent an uncommon presentation
(quadriceps)
" Distal Myopathies of myotonic dystropy; however, unlike
is essentially
IBM, muscle weakness is usually sym-
pathognomonic Late adult-onset distal
for inclusion myopathy type 1 (Welander)
metrical (Case 1-1).
body myositis.
Late adult-onset distal
A The combination myopathy type 2 Pattern 5: Ptosis With or
of ptosis, (Markesbery/Udd)
Without Ophthalmoplegia
ophthalmoplegia Early adult-onset distal Myopathies presenting with predomi-
without myopathy type 1 (Nonaka)
nant involvement of ocular and/or pha-
diplopia, and
Early adult-onset distal ryngeal muscles represent a relatively
dysphagia should
myopathy type 2 (Miyoshi) limited group of disorders. (Table 1-14).
suggest the
diagnosis of Early adult-onset distal The eye involvement principally results
oculopharyngeal myopathy type 3 (Laing) in ptosis and ophthalmoplegia, which
dystrophy, Desmin myopathy usually, although not always, occurs
especially without symptoms of diplopia. Facial
Childhood-onset distal
if the onset is weakness is not uncommon, and ex-
myopathy
in middle age tremity weakness is extremely variable,
or later. " Myotonic Dystrophy
depending on the diagnosis.
" Facioscapulohumeral The combination of ptosis, ophthal-
Dystrophy* moplegia without diplopia, and dyspha-
" Scapuloperoneal Myopathy* gia should suggest the diagnosis of
" Oculopharyngeal Dystrophy
oculopharyngeal dystrophy, especially
if the onset is in middle age or later
" Emery-Dreifuss (Case 1-2). Ptosis and ophthalmoplegia
24 Humeroperoneal Dystrophy*
without prominent pharyngeal involve-
" Inflammatory Myopathies ment is a hallmark of many of the
" Inclusion Body Myositis mitochondrial myopathies. Ptosis and
facial weakness without ophthalmople-
" Metabolic Myopathies
gia is a common feature of myotonic
Debrancher deficiency dystrophy.
Acid-maltase deficiency*
" Congenital Myopathies
Pattern 6: Prominent Neck
Nemaline myopathy* Extensor Weakness
Central core myopathy* This pattern is characterized by severe
Centronuclear myopathy weakness of the neck extensor muscles.
The term ‘‘dropped head syndrome’’
*Scapuloperoneal pattern can occur.
has been used in this situation (Table
1-15). Involvement of the neck flexors

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 Case 1-1
A 51-year-old man without significant past medical history is referred for evaluation of slowly
progressive muscle weakness for the past 7 years. His symptoms initially began with difficulty
walking down stairs because his left knee would ‘‘give out.’’ He currently has difficulty arising
from a chair and grasping objects with his right hand. When a neurologist initially evaluated him
2 years ago, the workup included a creatine kinase (CK) level of 500 IU/L and a left quadriceps
muscle biopsy, which was consistent with ‘‘polymyositis.’’ The patient has been treated with
a variety of immunosuppressive medications, including prednisone, methotrexate, and
azathioprine, with continued progression of his weakness. Current examination reveals intact
cranial nerves, sensation, and muscle stretch reflexes. Motor examination in the right upper
extremity shows MRC grade 5 shoulder abduction, grade 5 elbow flexion/extension, grade 4 wrist
flexion, grade 5 wrist extension, and grade 3 finger flexion. Strength in the left upper extremity
is normal except for grade 4+ finger flexion. In the left lower extremity, the patient exhibits grade
4+ hip flexion, grade 3+ knee extension, and grade 4+ ankle dorsiflexion. In the right lower
extremity, strength is normal except for grade 4+ knee extension.
Comment. The chronic onset, asymmetrical distribution of weakness, and selective involvement
of wrist/finger flexion and knee extension are most consistent with a diagnosis of IBM. In
many cases, initial muscle biopsy fails to identify vacuoles, and patients are inappropriately
treated with immunosuppressant medications for presumptive polymyositis. In patients with
a phenotype consistent with IBM, particularly if they are ‘‘refractory’’ to treatment, a repeat
biopsy may be necessary to clarify the diagnosis.

is variable. Extremity weakness is de- extensor involvement. Isolated neck

pendent on the diagnosis and may
follow one of the previously outlined
phenotypical patterns. For example, a
patient with a limb-girdle pattern of
weakness may also have significant neck
extension weakness represents a dis-
tinct muscle disorder called isolated
neck extensor myopathy. Prominent
neck extensor weakness is also common
in two other neuromuscular diseases:

TABLE 1-14 Myopathies With Ptosis or Ophthalmoplegia

" Ptosis Without Ophthalmoplegia

Myotonic dystrophy 25
Congenital myopathies
Centronuclear myopathy
Nemaline myopathy
Central core myopathy
Desmin (myofibrillary) myopathy
" Ptosis With Ophthalmoplegia
Oculopharyngeal muscular dystrophy
Oculopharyngodistal myopathy
Chronic progressive external ophthalmoplegia (mitochondrial myopathy)
Neuromuscular junction disease (myasthenia gravis, Lambert-Eaton, botulism)

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 " SUSPECTED MYOPATHY

Case 1-2
A 62-year-old white woman with a family history of ‘‘myasthenia gravis’’ presents for evaluation
of an 8-year history of progressive dysphagia and weakness. She specifically denies any
symptoms of diplopia and states that her symptoms do not fluctuate during the day or when
she becomes fatigued. She has noted no improvement with a course of prednisone 60 mg/d and
pyridostigmine 60 mg 4 times daily. Cranial nerve examination is remarkable for bilateral
ptosis, incomplete abduction/adduction of both eyes, mild orbicularis oris weakness, and
moderate tongue weakness. Motor examination reveals MRC grade 4 neck flexion, grade
4 shoulder abduction, grade 4+ elbow flexion, grade 5 finger extension, grade 4 hip flexion,
grade 5 knee extension, and grade 5 ankle dorsiflexion and plantarflexion. Sensory, cerebellar,
and reflex examinations are normal. Workup by a referring physician was remarkable for
a CK level of 350 IU/L and a negative acetylcholine receptor antibody.
Comment. The patient’s distribution of weakness (ptosis, ophthalmoparesis, dysphagia,
and proximal weakness), age of onset, and positive family history would be most suggestive
of a diagnosis of oculopharyngeal muscular dystrophy. The absence of symptoms of diplopia
and muscle fatigability and the patient’s slowly progressive course strongly argue against
a diagnosis of a neuromuscular junction disorder such as myasthenia gravis.

amyotrophic lateral sclerosis and my- It is also important to remember that

asthenia gravis.
LABORATORY APPROACH IN THE
EVALUATION OF A SUSPECTED
MYOPATHY
Creatine Kinase
CK is the single most useful laboratory
study for the evaluation of patients
with a suspected myopathy. The CK is
elevated in the majority of patients
with muscle disease but may be normal
in slowly progressive myopathies. The
degree of CK elevation can also be
helpful in distinguishing different forms
of muscular dystrophy. For example,
26 in Duchenne dystrophy, the CK level
is invariably at least 10 times (and often
up to 100 times) normal, whereas in
most other myopathies the CK eleva-
tion is lower. The other exceptions
are LGMD1C (caveolinopathy), LGMD2A
an elevation of serum CK does not
necessarily imply a primary myopathic
disorder (Table 1-16). Many times the
CK level will rise modestly (usually to
less than 10 times normal) in motor
neuron disease, and, uncommonly, CK
elevations may be seen in Guillain-
Barré syndrome or chronic inflamma-
tory demyelinating neuropathy. Endo-
crine disorders such as hypothyroidism
TABLE 1-15 Myopathies With
Prominent Neck
Extensor
Weakness
" Isolated neck extensor
myopathy
" Polymyositis
" Dermatomyositis

(calpainopathy), and LGMD2B (dysfer- " Inclusion body myositis

linopathy), where CK may also be " Carnitine deficiency
markedly elevated. The CK level may
" Facioscapulohumeral dystrophy
not be elevated in some myopathies
or may even be lowered by a num- " Myotonic dystrophy
ber of factors, including profound mus- " Congenital myopathy
cle wasting, corticosteroid administra-
" Hyperparathyroidism
tion, collagen diseases, alcoholism, or
hyperthyroidism.

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 KEY POINTS:
injections, EMG studies), viral illnesses,
Differential
A The CK is
TABLE 1-16 seizures, or strenuous exercise. In these
Diagnosis of elevated in
cases, CK elevations are usually tran- the majority
Creatine Kinase
sient and less than 5 times normal. of patients
Elevation
Medications can cause serum CK ele- with muscle
" Myopathies vations, either with or without associ- disease but
ated muscle weakness (Table 1-17). may be normal
Muscular dystrophies
Race and gender can also affect serum in slowly
Congenital myopathies CK (Wong et al, 1983). CK levels are progressive
frequently above the normal range myopathies.
Metabolic myopathies
Inflammatory myopathies
in some African American individuals A It is important
and in patients with enlarged muscles. to remember
Drug/toxin-induced Occasionally, benign elevations of CK that an
Carrier state appear on a hereditary basis. It is ex- elevation
(dystrophinopathies) tremely unusual for a slightly elevated of serum CK
CK level (threefold or less) to be as- does not
" Channelopathies
necessarily
sociated with an underlying myopa-
" Motor Neuron Diseases
thy in the absence of objective muscle imply a primary
myopathic
Amyotrophic lateral sclerosis weakness or pain.
disorder.
Spinal muscular atrophy Serum tests for other muscle en-
zymes such as aldolase are significantly A It is extremely
Postpolio syndrome unusual for
less helpful than the determination of
" Neuropathies the CK. Enzymes such as aspartate ami- a slightly
elevated CK
Guillain-Barré syndrome notransferase (AST), alanine amino-
level (threefold
transferase (ALT), and lactate dehydro-
Chronic inflammatory or less) to be
demyelinating polyneuropathy genase (LDH) may be slightly elevated
associated
in myopathies. Since AST, ALT, and LDH with an
" Viral Illness
are often measured in screening chem- underlying
" Medications istry panels, their elevation should myopathy
" Hypothyroidism/ in the absence
Hypoparathyroidism of objective
muscle
" Surgery TABLE 1-17 Medications
Associated With weakness
" Trauma (electromyography Creatine Kinase or pain.
studies, intramuscular or Elevations
subcutaneous injections) 27
" Strenuous Exercise " Lipid-Lowering Drugs
" Increased Muscle Mass Beta-hydroxy-b-methylglutaryl-
coenzyme A (HMG-CoA)
" Race
reductase inhibitors (statins)
" Sex
Fibric acid derivatives
" ‘‘Idiopathic HyperCKemia’’ (gemfibrozil)
Niacin
" Chloroquine

and hypoparathyroidism can also be " Colchicine

associated with high CK levels. Causes " Cyclosporine
of CK elevation other than neuromus-
" Zidovudine (AZT)
cular disease include muscle trauma
(falls, intramuscular or subcutaneous

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 " SUSPECTED MYOPATHY
KEY POINTS:
prompt CK measurement to determine
A Many forms
whether the source is muscle or liver. If
of hereditary
muscle a patient with an inflammatory myopathy
disorders can is treated with an immunosuppressive
now be agent that may cause hepatoxicity, the
diagnosed liver-specific enzyme gamma glutamic
with molecular transferase (GGT) should be followed.
genetic testing, In general, CK isoenzymes are not
thereby helpful in evaluating myopathies. CK-
eliminating fraction muscle (MM) elevations are
the need for typical of muscle disease, but CK-
a muscle
myocardial band (MB) is also elevated
biopsy in
in myopathies and does not indicate
every patient.
that cardiac disease is present.
A Muscles that
are severely Electrophysiological Studies
weak (Medical Electrodiagnostic studies, consisting
Research
of both nerve conduction studies and
Council grade
EMG, should be part of the routine
3 or less)
evaluation of a patient with a suspected
should not
be biopsied, myopathy (Preston and Shapiro, 2005).
since the These studies are helpful in confirming
results are that the muscle is, indeed, the correct
likely to show site of the lesion and that weakness is
only evidence not the result of an underlying motor
of end stage neuron disease, neuropathy, or neuro-
muscle disease. muscular junction disorder. Nerve con-
duction studies are typically normal in
patients with myopathy. Needle EMG
examination showing evidence of brief-
duration, small-amplitude motor units
with increased recruitment can be ex-
tremely helpful in confirming the pres-
ence of a myopathy. Needle EMG can
also provide a clue as to which muscles
28 have had recent or ongoing muscle in-
jury and can be a guide as to which
muscle to biopsy. It is important to
realize, however, that the EMG can be
normal in a patient with myopathy, and
the results of electrodiagnostic studies
need to be evaluated in the context of
the patient’s history, neurological ex-
amination, and other laboratory studies.
The Muscle Biopsy
If the clinical features and/or electrodi-
agnostic features suggest the possibility
of a myopathy, a muscle biopsy may be
an appropriate test to confirm the diag-
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
nosis (Dubowitz, 1985). However, many
forms of hereditary muscle disorders
can now be diagnosed with molecular
genetic testing, thereby eliminating the
need for a muscle biopsy in every pa-
tient. A muscle specimen can be ob-
tained through either an open or closed
(needle or punch) biopsy procedure.
The advantage of a needle or punch
biopsy is that it is minimally invasive,
cosmetically more appealing, and mul-
tiple specimens can be obtained. The
disadvantage of the closed biopsy pro-
cedure is that not all laboratories have
the expertise to adequately process the
muscle tissue acquired with this ap-
proach for all the necessary studies. In
addition, a needle biopsy may miss a
focal area of inflammation.
Selection of the appropriate muscle
to biopsy is critical. Muscles that are
severely weak (MRC grade 3 or less)
should not be biopsied, since the results
are likely to show only evidence of end
stage muscle disease. In addition, mus-
cles that have recently been studied by
needle EMG should be avoided because
of the possibility of artifacts created by
needle insertion. Biopsies should gen-
erally be taken from muscles that dem-
onstrate MRC grade 4 strength. For
practical purposes, in the upper extremi-
ties, the muscle of choice is the biceps;
in the lower extremities, the best choice
is the vastus lateralis. The gastrocne-
mius should be avoided, since its ten-
don insertion extends throughout the
muscle and inadvertent sampling of a
myotendinous junction may cause diffi-
culty with interpretation. Occasionally,
an imaging procedure such as muscle
ultrasound, computed tomography, or
magnetic resonance imaging can be
used to guide selection of the appropri-
ate muscle to biopsy.
Biopsy specimens can be analyzed by
light microscopy, electron microscopy,
biochemical studies, and immune stain-
ing (Table 1-18). In most instances,
light microscopic observations of frozen
TABLE 1-18 Utility of Muscle Biopsy Stains and Histochemical Reactions
Histochemical Reactions and Stains
Hematoxylin and eosin
Gomori trichrome
Adenosine triphosphatase (ATPase)
Nicotinamide adenine dinucleotide glycohydrolase
(NADH), succinate dehydrogenase (SDH),
cytochrome oxidase
Periodic acid-Schiff
Oil red O
Congo red, crystal violet
Myophosphorylase
Phosphofructokinase
Myoadenylate deaminase
Dystrophin immunostain
Dysferlin immunostain
Membrane attack complex immunostain
muscle tissue specimens are sufficient
to make a pathological diagnosis. Typi-
cal myopathic abnormalities include
central nuclei, both small and large hy-
pertrophic round fibers, split fibers, and
degenerating and regenerating fibers.
Inflammatory myopathies are character-
ized by the presence of mononuclear
inflammatory cells in the endomysial
and perimysial connective tissue be-
tween fibers and occasionally around
blood vessels. In addition, in dermato-
myositis, perifascicular atrophy, charac-
terized by atrophy of fibers located on
the periphery of a muscle fascicle, is a
common finding. Chronic myopathies
frequently show evidence of increased
connective tissue and fat.
For general histology, the hematoxy-
lin and eosin (H&E) and modified
Gomori trichrome are most useful.
The latter is particularly helpful in
identifying ragged red fibers, which
might suggest a mitochondrial disorder.
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Clinical Utility
General histology
General histology and mitochondrial disease
Distribution of fiber types
Myofibrillar and mitochondrial abnormalities
Glycogen storage diseases
Lipid storage diseases
Detection of amyloid deposition
McArdle’s disease
Phosphofructokinase deficiency
Myoadenylate deaminase deficiency
Duchenne and Becker muscular dystrophies
Limb-girdle muscular dystrophy 2B
Dermatomyositis
In addition to these standard stains,
other histochemical reactions can be
used to gain additional information
(Table 1-19). The myosin adenosine
triphosphatase stains (alkaline pH 9.4
and acidic pH 4.3 and 4.6) allow a
thorough evaluation of histochemistry
fiber types. Type 1 fibers (slow-twitch,
fatigue-resistant, oxidative metabolism)
stain lightly at alkaline and darkly at 29
acidic pH levels. Type 2 fibers (fast-
twitch, fatigue-prone, glycolytic metabo-
lism) stain darkly at alkaline and lightly
at acidic pH levels. Normally, a random
distribution of the two fiber types
occurs, and generally twice as many
type 2 as type 1 fibers are identified. In
a number of myopathies, a nonspecific
type 1 fiber predominance occurs. Oxi-
dative enzyme stains (nicotinamide
adenine dinucleotide [reduced form]
[NADH] dehydrogenase, succinate de-
hydrogenase, cytochrome-c oxidase)
are useful for identifying myofibrillar
 " SUSPECTED MYOPATHY

KEY POINT:
and mitochondrial abnormalities. Peri-
A Electron
odic acid-Schiff (PAS) stains can be
microscopy
is important helpful in identifying glycogen storage
in the diagnosis diseases and oil red O stains may assist
of some with the diagnosis of a lipid storage
congenital disease. Acid and alkaline phosphatase
myopathies and reactions can highlight necrotic and
mitochondrial regenerating fibers, respectively. Quali-
disorders. tative biochemical enzymes stains can
Findings be performed for myophosphorylase
detected only (McArdle’s disease), phosphofructoki-
by electron
nase (PFK deficiency), and myoadenyl-
microscopy
ate deaminase (MAD deficiency). Amy-
are seldom
of clinical
loid deposition can be assayed with
importance. Congo red or crystal violet staining.
Finally, immunohistochemical techni-
ques can stain for muscle proteins that
are deficient in some muscular dystro-
phies (eg, dystrophin in Duchenne and
Becker dystrophy) or for products that
are increased in certain inflammatory
myopathies such as the membrane at-
tack complex in dermatomyositis.
Electron microscopy evaluates the
ultrastructural components of muscle
fibers and is not required in the majority
of myopathies to make a pathologic
diagnosis. Electron microscopy is im-
portant, however, in the diagnosis of
some congenital myopathies and mito-
chondrial disorders. Findings detected
only by electron microscopy are seldom
of clinical importance.
The muscle tissue can also be pro-
cessed for biochemical analysis to de-
termine a specific enzyme defect in the
evaluation of a possible metabolic or
mitochondrial myopathy. In addition,
Western blot determinations from mus-
cle tissue can be performed for certain
muscle proteins. This type of analysis
is usually limited to dystrophin assays
when immune stains and molecular ge-
netic studies are inconclusive in estab-
lishing a diagnosis of either Duchenne
or Becker dystrophy.
Molecular Genetic Studies
The specific molecular genetic defect
is now known for a large number of
hereditary myopathies, and mutations
can be identified by peripheral blood
DNA analysis. Molecular genetic studies
that are commercially available are in-
cluded in Table 1-19. Molecular genetic
testing frequently eliminates the need
for muscle biopsy. This technology is
also extremely helpful for determining

TABLE 1-19 Disorders With Commercially Available Molecular

Genetic Studies Performed With Peripheral Blood
Samples

30 " Duchenne and Becker muscular dystrophies

" Facioscapulohumeral muscular dystrophy
" Myotonic dystrophy (types 1 and 2)
" Oculopharyngeal muscular dystrophy
" Limb-girdle muscular dystrophy 1B, 2A, 2C–2F, and 2I
" Congenital muscular dystrophy (FKRP, FCMD, MEB, and POMT1 mutations)
" Nonaka myopathy/inclusion body myopathy type 2
" Nemaline myopathy (ACTA1 mutations)
" Myotubular myopathy (MTM1 mutations)
" Myoclonic epilepsy and ragged red fibers (MERRF)
" Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


carrier status and for performing prena-
tal testing.
Other Tests
In addition to CK determinations, addi-
tional blood tests that can be extremely
helpful in the evaluation of a patient
with a suspected myopathy include se-
rum electrolytes, thyroid function tests,
parathyroid hormone levels, and hu-
man immunodeficiency virus (HIV). In
patients with an inflammatory myopa-
thy, serological determinations for
systemic lupus erythematosus, rheuma-
toid arthritis, and other immunological
markers (eg, Jo-1 antibodies) can oc-
casionally be useful. A urine analysis can
also be performed to detect the pres-
ence of myoglobinuria. This should be
suspected if the urine tests positive
for blood but no red blood cells are
identified.
Forearm exercise testing can be a
critical part of the evaluation of a patient
with a suspected metabolic myopathy.
The exercise test should be carried out
without the blood pressure cuff, since
ischemic exercise may be hazardous in
patients with defects in the glycolytic
enzyme pathway. The test is performed
by asking the patient to perform iso-
metric contractions using a handgrip
dynamometer for 1.5 seconds separated
by rest periods of 0.5 seconds for 1
minute. A resting blood sample for ve-
nous lactate and ammonia is obtained at
baseline and subsequently at 1, 2, 4, 6,
and 10 minutes after the completion
of exercise. A threefold increase in
lactate level represents a normal re-
sponse. The characteristic elevation of
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An excellent review of the pattern-recognition approach to the diagnosis of muscle
disease.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT:
serum lactate after exercise is absent in
A Forearm
phosphofructokinase deficiency and
exercise testing
myophosphorylase deficiency and re- can be a critical
duced in phosphoglycerate mutase defi- part of the
ciency. Forearm testing is normal in all evaluation of
disorders of fat metabolism and also in a patient with
some glycolytic disorders with fixed a suspected
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deficiency. myopathy.
CONCLUSION
While this pattern-recognition approach
to myopathy may have limitations, it
can be extremely helpful in narrowing
the differential diagnosis and therefore
minimizing the number of laboratory
studies that must be ordered to con-
firm the diagnosis. Not all patients
with muscle disease will fit neatly into
any of these six categories. In addition,
patients with involvement of other
areas of the neuraxis, such as the motor
neuron, peripheral nerve, or neuro-
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