A Pattern Recognition Approach To Myopathy. CONTINUUM

Review Article
Address correspondence to
Dr Carlayne Jackson, 8300
Floyd Curl Drive, Mail Code
7883, San Antonio, Texas,
78229-3900,
jacksonce@uthscsa.edu.
Relationship Disclosure:
Dr Jackson has received
research support from Biogen
Idec; Cytokinetics, Inc; Knopp
Neurosciences, Inc; the
National ALS Association;
Phillips Respironics; and
the US Food and Drug
Administration Office of
Orphan Products Development.
Dr Barohn has served on the
speakers bureaus of Genzyme
Corporation and Grifols;
on the advisory boards of
MedImmune, LLC, and
Novartis Corporation; and
as a consultant for NuFACTOR.
Dr Barohn has received
research support from Biogen
Idec; BioMarin Pharmaceutical
Inc; Cytokinetics, Inc;
Genzyme Corporation; Knopp
Neurosciences, Inc; Neuraltus
Pharmaceuticals, Inc; the
National Institute of
Neurological Disorders
and Stroke; the NIH; PTC
Therapeutics; Sangamo
BioSciences, Inc; Teva
Pharmaceutical Industries Ltd;
and the US Food and Drug
Administration Office of
Orphan Products Development.
Unlabeled Use of
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Use Disclosure:
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* 2013, American Academy
of Neurology.
A Pattern
Recognition Approach
to Myopathy
Carlayne E. Jackson, MD, FAAN; Richard J. Barohn, MD, FAAN
ABSTRACT
Purpose of Review: Myopathies are a heterogeneous group of disorders that can
be challenging to diagnose. The purpose of this review is to provide a diagnostic
approach based predominantly on the clinical history and neurologic examination.
Laboratory testing that can subsequently be used to confirm the suspected diagnosis based on this pattern recognition approach will also be discussed.
Recent Findings: Over the past decade, numerous discoveries have allowed
clinicians to diagnose myopathies with genetic testing. Unfortunately, the testing is
extremely expensive and frequently not covered by insurance.
Summary: Careful consideration of the pattern of muscle weakness in addition to
other aspects of the physical examination and diagnostic testing should assist the
clinician in making a timely and accurate diagnosis and minimize the expense of
confirmatory genetic testing.
Continuum (Minneap Minn) 2013;19(6):16741697.
EDITORS NOTE
The article A Pattern Recognition Approach to Myopathy by Drs
Carlayne Jackson and Richard Barohn reflects the thoughtful approach
that these experts have used, taught, and published for a number of years.
The original version of this material was written by Dr Barohn and
published in the 2000 edition of Cecil Textbook of Medicine (published in
1999), and subsequent updated and evolved versions of this information
(by Dr Barohn or Dr Jackson) appeared in editions of Cecil Textbook of
Medicine in 2004 and 2008 (now published by Elsevier), issues of
Continuum: Lifelong Learning in Neurology in 2000 and 2006, an issue of
Seminars of Neurology in 2008, and course syllabi from the American
Academy of Neurology (AAN) as well as the American Association of
Neuromuscular & Electrodiagnostic Medicine (AANEM). Because we feel
that the material presented in this article continues to be important for
our readers so that they can use this approach in the assessment and care
of their patients with muscle disease, we include an updated version in this issue.
INTRODUCTION
The approach to myopathy, which is
reviewed in this chapter, is like a story
handed down from one generation to
another. This was the approach that
Dr Barohn learned at The Ohio State
University from Drs John Kissel and Jerry
1674
Mendell and was passed down to me by

Dr Barohn during my residency and
fellowship. The approach was developed
before significant genetic testing was
available and at a time when a diagnosis
was based largely on the patients history
and physical examination.
www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
December 2013
When the approach was originally

published by Dr Barohn in Cecil Textbook of Medicine in 1999, he described six patterns of weakness.
With the genetic breakthroughs over
the intervening years, the approach now
includes 10 patterns of weakness, and
the differential diagnoses have broadened. Despite all of the advances in
diagnostic testing, reliance on answering the key questions and then placing
the patient into one of the patterns of
weakness remains the cornerstone of
how a clinician should approach the
patient with a suspected myopathy.
Like a timeless story, we are hopeful that, by including this article in this
, we will have
issue of
the opportunity to pass this approach
down to our readers who continue to
have the responsibility of making a
timely and accurate diagnosis for these
very complex patient groups.
Myopathies are disorders affecting
the channel, structure, or metabolism
of skeletal muscle. Myopathies have
distinctive clinical and laboratory features that can distinguish them from
other disorders of the motor unit,
including the neuromuscular junction,
peripheral nerve, or motor neuron.
Therefore, the first goal in evaluating a
patient with a suspected muscle disorder is to determine the site of the
lesion. Once the lesion is localized to
the muscle, the next step is to identify
whether the myopathy is due to an
abnormality in the muscle channel, an
abnormality in the muscle structure, or a
dysfunction in muscle metabolism. The
second goal is to determine the cause of
the myopathy. In general, myopathies
can be classified into acquired or
hereditary disorders (Table 8-11). Finally, the third goal is to determine
whether a therapy is available and, if
not, to optimally manage the patients
symptoms in order to maximize his
or her function and quality of life
Continuum (Minneap Minn) 2013;19(6):16741697
KEY POINT
h In approaching the
of
TABLE 8-1 Classification
Myopathiesa
evaluation of a patient
with a suspected
myopathy, one of the
most important
components is a
comprehensive medical
history.
b Acquired
Drug-induced myopathies
Endocrine myopathies
Inflammatory/immune
myopathies
Myopathies associated with
other systemic illness
Toxic myopathies
b Hereditary
Channelopathies
Congenital myopathies
Metabolic myopathies
Mitochondrial myopathies
Muscular dystrophies
Myotonias
a
Reprinted from Barohn RJ, Saunders.1

B 2008, with permission from Elsevier.
(for more on this topic, refer to the

article Multidisciplinary Management
of Myopathies by Dr John T. Kissel
and Wendy King in this issue of
).
CLINICAL EVALUATION
In approaching the evaluation of a
patient with a suspected myopathy,
one of the most important components is a comprehensive medical
history. The history should allow the
clinician to determine whether the
patient has an acquired or hereditary
disorder (Table 8-11). The distribution
of muscle weakness and additional
findings on the physical examination
should provide more information to
help determine the correct diagnosis.
The results of laboratory studies (blood
tests, electrodiagnostic studies, muscle
biopsy, molecular genetic studies) then
play a confirmatory diagnostic role.
The first step in this clinical approach is to ask six key questions regarding the patients symptoms:
1675
Pattern Recognition Approach to Myopathy

KEY POINTS
h The most common

negative symptom
reported by a patient
with muscle disease is
weakness.
h Because metabolic
and mitochondrial
myopathies can cause
abnormal fatigability
after exercise, it is
always important to
define the intensity and
duration of exercise that
provokes the fatigue.
(1) Which positive and/or negative

symptoms does the patient experience? (2) What is the temporal
evolution? (3) Does the patient have
a family history of a myopathic disorder? (4) Are there precipitating factors that trigger episodic weakness or
stiffness? (5) Are any associated systemic symptoms or signs present? (6)
What is the distribution of weakness?
Which Negative and/or
Positive Symptoms Does
the Patient Experience?
Patient reports of the symptoms of
myopathy can be divided into those
that are negative, such as exercise
intolerance, fatigue, muscle atrophy,
and weakness, and those that are
positive, such as contractures, cramps,
muscle stiffness, myalgias, and myoglobinuria (Table 8-22).
The most common negative symptom reported by a patient with muscle
disease is weakness. As a result of
TABLE 8-2 Symptoms Associated

With Myopathiesa
b Negative
Exercise intolerance
Fatigue
Muscle atrophy
Weakness
b Positive
Cramps
Contractures
Muscle hypertrophy
Myalgia
Myoglobinuria
Stiffness
a
1676
Updated from Jackson CE, Continuum

(Minneap Minn).2 B 2006, American
Academy of Neurology. journals.lww.
com/continuum/Fulltext/2006/06000/
A_Clinical_Approach_to_the_Patient_
With_Suspected.3.aspx.
upper extremity weakness, patients

may report difficulty brushing their
teeth, combing their hair, or lifting
objects overhead. If the weakness
involves the lower extremities, patients will report difficulty rising from
a low chair or toilet, getting up from a
squatted position, or climbing stairs.
These symptoms suggest proximal
muscle weakness (probably the most
common distribution of weakness in
myopathies). Less commonly, patients
with myopathies may report difficulty
turning a key or opening jars or gait
instability due to footdrop, which
indicates involvement of the distal
muscles. Cranial muscle weakness
resulting in symptoms of slurred
speech, difficulty swallowing, ptosis,
or double vision may also be reported.
Fatigue is another negative symptom
that can be reported by patients with
myopathy; however, it is nonspecific
and more commonly occurs as a result
of a patients overall health, cardiopulmonary status, emotional state, level of
conditioning, or sleeping habits. The
large majority of patients who report
generalized weakness or fatigue will not
have a primary muscle disorder, particularly if the neurologic examination is
unremarkable. Because metabolic and
mitochondrial myopathies can cause
abnormal fatigability after exercise,
however, it is always important to
define the intensity and duration of
exercise that provokes the fatigue.
Positive symptoms associated with
myopathies may include cramps, contractures, myalgias, muscle stiffness,
or myoglobinuria. Myalgia, like fatigue,
is another nonspecific symptom of
some myopathies (Table 8-32).2 Myalgias may be episodic (such as in
metabolic myopathies) or nearly constant (such as in inflammatory muscle
diseases); however, muscle pain is not
common in most muscle diseases and
is more likely to be due to orthopedic
December 2013
KEY POINT
a
TABLE 8-3 Muscle Diseases Associated With Myalgias
h It is extremely
uncommon for a
myopathy to be
responsible for vague
aches and muscle
discomfort in the
presence of normal
findings from a
neuromuscular
examination and
laboratory studies.
b Eosinophilia-myalgia syndrome
b Hypothyroid myopathy
b Inflammatory myopathies (dermatomyositis, polymyositis)
b Infectious myositis (especially viral)
b Mitochondrial myopathies
b Myoadenylate deaminase deficiency
b Toxic myopathies (statins, chloroquine)
b Tubular aggregate myopathy
b X-linked myalgia and cramps (Becker dystrophy variant)
a
Updated from Jackson CE, Continuum (Minneap Minn).2 B 2006, American Academy of
Neurology. journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_
Patient_With_Suspected.3.aspx.
or rheumatologic disorders. It is
extremely uncommon for a myopathy
to be responsible for vague aches and
muscle discomfort in the presence of
normal findings from a neuromuscular
examination and laboratory studies.
Muscle cramps are a specific type of
muscle pain that occurs frequently in
normal individuals, are typically benign, and are seldom a feature of a
primary myopathy. Cramps most commonly occur because of azotemia,
dehydration, hyponatremia, myxedema,
and disorders of the nerve or motor

neuron (especially ALS). Cramps
typically last for less than several
minutes and are usually localized to a
particular muscle region, such as the
calves. On needle EMG, cramps are
characterized by rapidly firing motor
unit discharges. Muscle contractures
occur in patients with glycolytic enzyme defects and are typically provoked by exercise (Table 8-43).
Contractures can superficially resemble a cramp but differ in that contractures
a
TABLE 8-4 Myopathies Associated With Muscle Contractures
b Brody disease
b Glycolytic/glycogenolytic enzyme defects
Myophosphorylase deficiency (McArdle disease)
Phosphofructokinase deficiency
Phosphoglycerate kinase deficiency
Phosphoglycerate mutase deficiency
Lactate dehydrogenase deficiency
Debrancher enzyme deficiency
b Paramyotonia congenita
b Rippling muscle disease
a
Updated from Kissel J, ed, Continuum (Minneap Minn).3 B 2000, American Academy of
Neurology. journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_
Suspected_Muscle.2.aspx.
1677

KEY POINT
h Myotonia classically
improves with repeated
muscle contractions,
whereas in paramyotonia
congenita, patients
demonstrate paradoxical
myotonia, in that
symptoms are typically
worsened by exercise.
TABLE 8-5 Myopathies

Associated With
Muscle Stiffnessa
b Hyperkalemic periodic
paralysis
b Myotonia congenita
b Myotonic dystrophy
b Paramyotonia congenita
b Proximal myotonic myopathy
a
Updated from Kissel J, ed, Continuum

com/continuum/Citation/2000/06020/
Approach_to_the_Patient_With_Suspected_
Muscle.2.aspx.
usually last longer and are electrically

silent with needle EMG. Muscle contractures should not be confused with
fixed tendon contractures.
Myotonia is a result of repetitive
depolarization of the muscle membrane resulting in impaired relaxation
of muscle after forceful voluntary
contraction. The muscle disorders
associated with myotonia are listed

in Table 8-5.3 Myotonia is most commonly demonstrated in the eyelids and
hands (for more on this topic, refer to
Muscle Channelopathies: the Nondystrophic Myotonias and Periodic Paralyses by Drs Barohn and Statland in
this issue of
). As a result,
patients may report muscle stiffness or
tightness that causes difficulty releasing
their grip after a forceful handshake or
trouble opening their eyelids after
squeezing their eyes tight. Myotonia
classically improves with repeated muscle contractions, whereas in paramyotonia congenita, patients demonstrate
paradoxical myotonia, in that symptoms are typically worsened by exercise.
Cold exposure results in worsening of
both myotonia and paramyotonia.
Myoglobinuria is caused by the excessive release of myoglobin into the
urine during periods of rapid muscle
destruction (rhabdomyolysis) and is a
rare manifestation of muscle disease
(Table 8-63). It is important to identify
and treat aggressively since severe
a
TABLE 8-6 Causes of Myoglobinuria
b Drugs and toxins (especially alcohol)

b Heatstroke
b Inflammatory myopathies (rare)
b Limb-girdle muscular dystrophy types 2C, 2D, 2E, and 2F
(sarcoglycanopathies) and 2I (FKRP)
b Neuroleptic malignant syndrome
b Metabolic myopathies
Glycogenoses (myophosphorylase deficiency)
Lipid disorders (carnitine palmitoyltransferase deficiency)
Malignant hyperthermia (central core myopathy, Duchenne muscular dystrophy)
b Prolonged, intensive exercise
b Severe metabolic disturbances, including prolonged fever
b Trauma (crush injuries)
b Viral and bacterial infections
a
1678
Updated from Kissel J, ed, Continuum (Minneap Minn).3 B 2000, American Academy of
Neurology. journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_
With_Suspected_Muscle.2.aspx.
December 2013
myoglobinuria can cause acute tubular

necrosis resulting in renal failure.
Patients who report exercise-induced
weakness and myalgia should be
asked if their urine has ever turned
red or cola-colored during or after
these episodes. Isolated episodes of
myoglobinuria, particularly occurring
after unaccustomed strenuous exercise, are frequently idiopathic, whereas recurrent episodes are usually due
to an underlying metabolic myopathy.
What Is the Temporal Evolution?
Of obvious importance is the determination of the onset, duration, and
evolution of the patients symptoms.
Identifying the age at which a patients
symptoms began (ie, whether the
symptoms first manifested at birth or
onset occurred in the first, second, third,
or later decade of life [Table 8-72]) can
provide crucial information leading to
the correct diagnosis. Symptoms of
Duchenne muscular dystrophy, for
example, are usually identified between 3 and 5 years of age, whereas
most types of limb-girdle muscular dystrophy (LGMD) begin in adolescence or
later. Of the inflammatory myopathies,
dermatomyositis may occur in childhood or adulthood, polymyositis rarely
begins in childhood but occurs at any
decade in adulthood, and inclusion
body myositis occurs most commonly
over the age of 50 years.
It is also important to determine
the evolution and duration of the
symptoms. Is the course monophasic,
progressive, or relapsing? Myopathies
can present with either episodic periods of weakness with normal
strength interictally (eg, metabolic
myopathies due to certain glycolytic
pathway disorders, periodic paralysis)
or constant weakness (eg, inflammatory myopathies, muscular dystrophies). The episodic disorders are
characterized by acute loss of strength
KEY POINTS
TABLE 8-7 Diagnosis of

Myopathy Based
on Age of Onseta
b Myopathies Presenting at Birth
Central core disease
Centronuclear (myotubular)
myopathy
Congenital fiber-type
disproportion
Congenital muscular dystrophy
Congenital myotonic dystrophy
Glycogen storage diseases
(acid maltase and
phosphorylase deficiencies)
h Isolated episodes of
myoglobinuria,
particularly occurring
after unaccustomed
strenuous exercise, are
frequently idiopathic,
whereas recurrent
episodes are usually due
to an underlying
metabolic myopathy.
h Identifying the age at

which a patients
symptoms began can
provide crucial
information leading to
the correct diagnosis.
Lipid storage diseases

(carnitine deficiency)
Nemaline (rod) myopathy
b Myopathies Presenting in
Childhood
Nemaline
Centronuclear
Central core
Endocrine-metabolic disorders
Hypokalemia
Hypocalcemia
Hypercalcemia
Glycogen storage disease (acid
maltase deficiency)
Inflammatory myopathies
Dermatomyositis
Polymyositis (rarely)
Lipid storage disease
(carnitine deficiency)
Congenital
Duchenne
Becker
Emery-Dreifuss
Facioscapulohumeral
Limb-girdle
Continued on next page
1679
TABLE 8-7 Diagnosis of

Myopathy Based
on Age of Onseta
(continued)
b Myopathies Presenting in
Adulthood
Centronuclear myopathy
Distal myopathies
Endocrine myopathies
Thyroid
Parathyroid
Adrenal
Pituitary disorders
Polymyositis
Dermatomyositis, inclusion
body myositis, viral (HIV)
Acid maltase deficiency
Debrancher deficiency
Phosphorylase b kinase
deficiency
Limb-girdle
Facioscapulohumeral
Becker
Emery-Dreifuss
Myotonic dystrophy
Nemaline myopathy
Toxic myopathies
Alcohol
Corticosteroids
Local injections of narcotics
Colchicine
Chloroquine
HIV = human immunodeficiency syndrome.
a

that can return to normal within hours

or days. The tempo of the disorders
1680
with constant weakness can vary from

(1) acute or subacute progression in
some inflammatory myopathies (eg,
dermatomyositis and polymyositis) to
(2) chronic slow progression over
years (eg, most muscular dystrophies)
or (3) nonprogressive weakness
with little change over decades (eg,
congenital myopathies). Finally, both
constant and episodic myopathic disorders can have symptoms that may be
monophasic or relapsing. For example,
polymyositis can occasionally have an
acute monophasic course with return
to baseline level of strength within
weeks or months. Patients with metabolic myopathies or periodic paralysis
can have recurrent episodes of weakness over years, while a patient with
rhabdomyolysis due to cocaine ingestion may have an isolated episode.
Does the Patient Have a Family
History of a Myopathic Disorder?
Obtaining a thorough family history is
of tremendous importance since
many myopathies are hereditary. A
detailed family tree should be completed to determine whether evidence
suggests an autosomal dominant, autosomal recessive, or X-linked pattern
of inheritance (Table 8-82). Specific
questions regarding family members
use of adaptive equipment or functional limitations are usually more informative than inquiring about a family
history of muscle disease. Identifying
a particular pattern of inheritance is
not only helpful in making a correct
diagnosis but also of critical importance in providing genetic counseling.
Are There Precipitating Factors
That Trigger Episodic Weakness
or Stiffness?
It is important to ask the patient
whether any precipitating factors exist
that might trigger or worsen their
symptoms of weakness or myotonia.
December 2013
TABLE 8-8 Diagnosis Of

Myopathy Based
on Pattern of
Inheritancea
b X-Linked
Becker muscular dystrophy
sis is typically provoked by exercise

and ingestion of a high-carbohydrate
meal followed by a period of rest.
Patients with myotonic disorders frequently report that cold exposure may
precipitate or worsen their symptoms
of muscle stiffness.
Duchenne muscular dystrophy

Emery-Dreifuss muscular
dystrophy
b Autosomal Dominant
Central core myopathy
Fascioscapulohumeral
muscular dystrophy
TABLE 8-9 Drugs That Can

Cause Toxic
Myopathiesa
b Inflammatory
Cimetidine
D-penicillamine
Limb-girdle muscular
dystrophy type 1
Procainamide
L-tryptophan
Oculopharyngeal muscular
dystrophy
Myotonic dystrophy
Paramyotonia congenita
Levodopa
b Noninflammatory Necrotizing or
Vacuolar
Periodic paralysis
Alcohol
Thomsen disease
Cholesterol-lowering agents
Chloroquine
b Autosomal Recessive
Becker myotonia
Colchicine
Limb-girdle muscular
dystrophy type 2
Cyclosporine and tacrolimus
(-aminocaproic acid
Emetine
Isoretinoic acid (vitamin A
analogue)
b Maternal Transmission
a

Labetalol
Vincristine
b Rhabdomyolysis and
Myoglobinuria
Alcohol
Amphetamine
Cholesterol-lowering drugs
Patients should specifically be asked

about their use of either illegal drugs
or prescription medications that might
produce a myopathy (Table 8-94). A
history of pain, weakness, or myoglobinuria triggered by exercise would
raise the possibility of a glycolytic
pathway defect. Episodic weakness
that occurs in association with a fever
or heat exposure would be supportive
of a diagnosis of carnitine palmitoyltransferase deficiency. Periodic paralyContinuum (Minneap Minn) 2013;19(6):16741697
Cocaine
Heroin
Toluene
(-aminocaproic acid
b Myosin Loss
Nondepolarizing
neuromuscular blocking agents
Steroids
a

1681

Associated With
Cardiac Diseasea
b Arrhythmias
Andersen-Tawil syndrome
Kearns-Sayre syndrome
Polymyositis
Myotonic
Limb-girdle types 1B, 2C-F,
and 2G
Emery-Dreifuss
b Congestive Heart Failure
Carnitine deficiency
Duchenne
emphasizing the need for consistent

monitoring of pulmonary function studies throughout the disease course.
Once symptoms or signs of nocturnal
hypoventilation are evident, supportive
care should be initiated with bilevel
positive pressure ventilation and assistive devices for clearance of upper
airway secretions, such as highfrequency chest wall oscillation devices
or mechanical insufflator-exsufflators.
Hepatomegaly may occur in myopathies associated with deficiencies in
acid maltase, carnitine, and debranching enzyme. The clinical features of
cataracts, frontal balding, and cognitive
dysfunction strongly suggest the diagnosis of myotonic dystrophy type 1.
Dysmorphic features may be associated
Becker
Emery-Dreifuss
Myotonic
Limb-girdle types 1B, 2C-F,
and 2G

Associated With
Respiratory
Insufficiencya
Nemaline myopathy
Polymyositis
a
b Muscular Dystrophies
Becker

Duchenne
Congenital
Emery-Dreifuss
Limb-girdle 2A, 2I
Myotonic
Are Any Associated Systemic

Symptoms or Signs Present?
Helpful clues in making the appropriate diagnosis can also be obtained by
identifying involvement of organs or
tissues other than muscle. Cardiac
disease may be associated with a number of myopathies (Table 8-102).
Respiratory insufficiency is associated with a number of myopathies
(Table 8-112), and respiratory failure
may be the presenting symptom of acid
maltase deficiency, centronuclear myopathy, myotonic dystrophy, or nemaline
myopathy. Ultimately, many myopathies
will affect respiratory muscle function,
1682
b Metabolic Myopathies
Debrancher deficiency
b Mitochondrial Myopathies
b Congenital Myopathies
Centronuclear
Nemaline
b Inflammatory Myopathies
Polymyositis
a

December 2013
with the congenital myopathies. The

presence of a rash is extremely useful
in the diagnosis of dermatomyositis.
Musculoskeletal contractures commonly occur in many long-standing
myopathies as a result of limited range
of motion. However, contractures developing early in the course of the
disease, before the development of
significant weakness, can be a clue to
Bethlem myopathy, Emery-Dreifuss
dystrophy, and LGMD type 1B
(laminopathy). Evidence of diffuse systemic disease can indicate amyloidosis, sarcoidosis, an endocrinopathy,
collagen-vascular disease, an infectious
disease, or a mitochondrial disorder.
What Is the Distribution of
Weakness?
It is important to test muscle strength,
both by formal manual muscle testing
and from observation of functional
activity (Table 8-122), in order to
determine the distribution of muscle
weakness. 5 Functional testing can
be particularly informative in young

children, who are often unable to
cooperate with formal manual muscle
testing, and in adults with give-way
weakness secondary to pain.
The expanded Medical Research
Council (MRC) grading scale of 0 to 5
is the most commonly used benchmark for assessing muscle strength
(Table 8-136).6 All muscle groups
should be tested bilaterally in order to
assess symmetry. The patient should be
positioned, if possible, to test all muscles
against gravity. The presence of significant muscle weakness can escape recognition if testing against gravity is not
performed. In addition, the cranial nerve
muscles, such as the extraocular muscles,
orbicularis oculi and oris, tongue, and
palate, should be evaluated. These muscles may be best tested by observation of
activities, such as asking the patient to
suck from a straw, whistle, and smile.
In addition to the assessment of
muscle strength, muscles should be
inspected for evidence of atrophy or
KEY POINT
h Functional testing can

be particularly
informative in young
children, who are often
unable to cooperate
with formal manual
muscle testing, and in
adults with give-way
weakness secondary to
pain.
a
TABLE 8-12 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, disconjugate 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, Gower sign
Leg/foot
Footdrop, inability to walk on heels or toes
Respiratory
Use of accessory muscles
1683
Research Council Scale for Manual

TABLE 8-13 Expanded Medical
Muscle Testinga
Modified MRC Grade
Degree of Strength
Normal power
5j
Equivocal, barely detectable weakness
4+
Definite but slight weakness
Able to move the joint against combination of

gravity and some resistance
4j
Capable of minimal resistance
3+
Capable of transient resistance but collapses abruptly
Active movement against gravity
3j
Able to move against gravity but not

through full range
Able to move with gravity eliminated
Trace contraction
No contraction
MRC = Medical Research Council.

a
Reprinted from Medical Research Council, Balliere Tindall.6 B 2000, with permission from Elsevier.
hypertrophy. Atrophy of proximal upper and lower extremity muscles is

commonly identified in most chronic
myopathies. However, certain myopathies demonstrate atrophy in specific
muscle groups that may provide additional diagnostic clues. Atrophy of the
periscapular muscles associated with
scapular winging, for example, is
characteristic of facioscapulohumeral
dystrophy and of LGMD types 1B
(laminopathy), 2A (calpainopathy),
and 2C through 2F (sarcoglycanopathies). Distal myopathies may have
selective atrophy of the anterior or
posterior lower extremity compartments. Asymmetric atrophy of the
quadriceps muscles and forearm flexor
muscles is highly suggestive of inclusion
body myositis. On the other hand, in
myotonia congenita, muscles can show
evidence of hypertrophy. Muscle hypertrophy is also seen in some systemic
disorders, including amyloidosis, sarcoidosis, and hypothyroid myopathy.
In Duchenne and Becker muscular
dystrophies, pseudohypertrophy of
1684
the calf muscles occurs because of

replacement with connective tissue
and fat. Calf muscle hypertrophy is also
characteristically seen in LGMD types
2C through 2F (sarcoglycanopathies)
and 2I (fukutin-related proteinopathy).
In LGMD type 2G (telethoninopathy),
50% of patients will show calf hypertrophy and the other 50% will demonstrate calf atrophy. Focal muscle
enlargement can also be caused by an
inflammatory or neoplastic process,
tendon rupture, ectopic ossification, or
partial denervation.
PATTERN RECOGNITION
APPROACH TO MYOPATHIC
DISORDERS
After answering the six key questions
outlined above from the history and
neurologic examination, one can attempt to classify a myopathic disorder
into one of 10 distinctive patterns of
muscle weakness, each with a specific
differential diagnosis. While this may
seem like an oversimplification, the
recognition of these patterns will usually
December 2013
allow the clinician to come very close

to the final diagnosis, which can then
be confirmed based on a selective
number of laboratory evaluations.
Pattern 1: Proximal Limb-Girdle
Weakness
The most common pattern of muscle
weakness in myopathies is symmetric
weakness predominantly affecting the
proximal muscles of the legs and arms
(the limb-girdle distribution). The distal muscles are usually involved to a
much lesser extent as the disease
progresses. Neck flexor and extensor
muscles are also commonly affected.
Because this pattern of weakness is
seen in most hereditary and acquired
myopathies, it is the least specific in
arriving at a particular diagnosis.
TABLE 8-14 Pattern 2:

Myopathies
Characterized by
Predominantly
Distal Weaknessa
b Distal myopathies
Late-adult-onset distal
myopathy type 1 (Welander)
Late-adult-onset distal
myopathy type 2 (Markesbery/Udd)
Early-adult-onset distal myopathy
type 1 (Nonaka)
type 2 (Miyoshi)
type 3 (Laing)
Pattern 2: Distal Weakness

This pattern of weakness predominantly
involves the distal muscles of the upper
or lower extremities (anterior or posterior compartment muscle groups)
(Table 8-141). Proximal muscles may
also be affected, depending on the
duration and severity of the disease.
The pattern of muscle involvement is
usually symmetric. Because selective
weakness and atrophy in distal extremity muscles are more commonly a
feature of a peripheral neuropathy, it
is important to perform a thorough
sensory examination when patients
present with this particular phenotype.
b Emery-Dreifuss
humeroperoneal dystrophy
a

h When the
scapuloperoneal pattern
of weakness is
associated with facial
weakness, it is highly
suggestive of a
diagnosis of
facioscapulohumeral
muscular dystrophy.
b Acid maltase deficiency

b Central core myopathy
b Myofibrillar myopathy
pattern of muscle
weakness in myopathies
is symmetric weakness
predominantly affecting
the proximal muscles of
the legs and arms (the
limb-girdle distribution).

Scapuloperoneal
Pattern of
Weakness
b Debrancher deficiency
b Inclusion body myositis
h The most common
Pattern 3: Proximal Arm/Distal

Leg (Scapuloperoneal) Weakness
The proximal arm/distal leg pattern of
weakness affects the periscapular
muscles of the proximal upper extremity and the anterior compartment
muscles of the distal lower extremity;
therefore, it is also known as the
scapuloperoneal distribution of
weakness. When this pattern is associated with facial weakness, it is highly
suggestive of a diagnosis of facioscapulohumeral muscular dystrophy.
Weakness in this pattern is typically
b Centronuclear myopathy
b Hereditary inclusion body
myopathy
KEY POINTS
b Facioscapulohumeral dystrophy
b Limb-girdle dystrophy 2A
(calpain), 2C-F (sarcoglycans),
2I (FKRP)
b Nemaline myopathy
b Scapuloperoneal dystrophy
1685

KEY POINTS
h The distal arm/proximal

leg pattern is associated
with upper extremity
weakness affecting the
distal forearm muscles
(wrist and finger flexors)
and proximal lower
extremity weakness
affecting the knee
extensors (quadriceps).
h The distal arm/proximal

leg pattern is essentially
pathognomonic for
inclusion body myositis.
very asymmetric. The scapular muscle

weakness results in winging of the
scapula when patients are asked to
extend their arms forward. Other hereditary myopathies that are associated
with a scapuloperoneal distribution of
weakness are listed in Table 8-15.
Pattern 4: Distal Arm/Proximal
Leg Weakness
The distal arm/proximal leg pattern is
associated with upper extremity weakness affecting the distal forearm muscles
(wrist and finger flexors) and proximal
lower extremity weakness affecting the
knee extensors (quadriceps). Facial
muscles are typically spared, and involvement of other muscles is variable.
In addition, the weakness is characteristically asymmetric. This pattern is essentially pathognomonic for inclusion body
myositis (Case 8-1) and may also

represent an uncommon presentation
of myotonic dystrophy type 1; however, muscle weakness is symmetric.
Pattern 5: Ptosis With or
Without Ophthalmoparesis
Myopathies presenting with predominant involvement of ocular or pharyngeal muscles include a relatively limited
group of disorders (Table 8-161). The
ocular muscle weakness principally
results in ptosis and ophthalmoparesis, which almost invariably occurs
without symptoms of diplopia. Facial
weakness may also commonly occur,
and extremity weakness is extremely
variable, depending on the diagnosis.
The combination of ptosis, ophthalmoparesis without diplopia, and dysphagia is strongly supportive of the
Case 8-1
A 68-year-old man without significant medical history was referred for
evaluation of slowly progressive muscle weakness for the past 5 years. His
symptoms initially began with difficulty walking down stairs due to his
right knee giving out. He currently had difficulty rising from a chair
and grasping objects with his right hand. Two years ago, he was evaluated
by a neurologist whose workup included a creatine kinase level of 500 IU/L
and a left quadriceps muscle biopsy that appeared to be consistent
with polymyositis. The patient had been treated with a variety of
immunosuppressive medications, including prednisone, methotrexate,
and azathioprine, with continued progression of his weakness. Current
examination revealed intact cranial nerves, sensation, and muscle stretch
reflexes. Motor examination in the right upper extremity showed
Medical Research Council (MRC) grade 5 shoulder abduction, 5 elbow
flexion/extension, 4 wrist flexion, 5 wrist extension, and 3j finger flexion.
Strength in the left upper extremity was normal except for grade 4+ finger
flexion. In the left lower extremity, the patient exhibited grade 4+ hip
flexion, 3+ knee extension, and 4+ ankle dorsiflexion. In the right lower
extremity, strength was normal except for grade 4+ knee extension.
Comment. The chronic onset, asymmetric distribution of weakness, and
selective involvement of wrist/finger flexion and knee extension in this
patient are most consistent with a diagnosis of inclusion body myositis.
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 inclusion body myositis, particularly if they are refractory to
immunosuppressive treatment, a repeat biopsy may be necessary to clarify
the diagnosis.
1686
December 2013

Myopathies With
Ptosis or
Ophthalmoparesisa
b Ptosis Without Ophthalmoparesis
Nemaline myopathy
Central core myopathy
Desmin (myofibrillary) myopathy
Myotonic dystrophy
b Ptosis With Ophthalmoparesis
Centronuclear myopathy
Mitochondrial myopathy
Multicore disease
Oculopharyngeal muscular
dystrophy
Oculopharyngodistal myopathy
Neuromuscular junction
disease (myasthenia gravis,
Lambert-Eaton myasthenic
syndrome, botulism)
a

diagnosis of oculopharyngeal dystrophy, especially if the patient has a

positive family history and onset is in
middle age or later (Case 8-2). Ptosis
and ophthalmoparesis without prominent pharyngeal involvement are key
features of many of the mitochondrial
myopathies. Ptosis and facial weakness without ophthalmoparesis are
hallmarks of myotonic dystrophy and
fascioscapulohumeral dystrophy.
KEY POINT
h The combination of ptosis,

ophthalmoparesis without
diplopia, and dysphagia
is strongly supportive of
the diagnosis of
oculopharyngeal
dystrophy, especially if the
patient has a positive
family history and onset in
middle age or later.
Pattern 6: Prominent Neck

Extensor Weakness
The term dropped head syndrome
has been used in the past to describe
this clinical phenotype characterized
by selective weakness of the neck
extensor muscles (Table 8-171). Involvement of the neck flexors is
variable. Extremity weakness is dependent on the diagnosis and may follow
one of the previously outlined patterns
of weakness. For example, a patient
with a limb-girdle pattern of weakness
Case 8-2
A 70-year-old woman with a family history of myasthenia gravis presented
for evaluation of a 10-year history of progressive dysphagia and weakness.
She specifically denied any symptoms of diplopia and stated that her
symptoms did not fluctuate during the day or when she became fatigued.
She had noted no improvement with a course of prednisone 60 mg/d and
pyridostigmine 60 mg 4 times daily. Cranial nerve examination was
remarkable for bilateral ptosis, incomplete abduction and adduction of
both eyes, mild orbicularis oris weakness, and mild tongue weakness.
Motor examination revealed bilateral and symmetric Medical Research
Council (MRC) grade 4 neck flexion, 4 shoulder abduction, 4+ elbow
flexion, 5 finger extension, 4 hip flexion, 5 knee extension, and 5 ankle
dorsiflexion and plantar flexion. Sensory, cerebellar, and reflex
examination findings were normal. Workup by a referring physician
was remarkable for a creatine kinase level of 350 IU/L and a negative
acetylcholine receptor antibody.
Comment. The patients 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 patients slowly progressive course
strongly argues against the diagnosis of a neuromuscular junction disorder
such as myasthenia gravis.
1687

Myopathies With
Prominent Neck
Extensor
Weaknessa
b Isolated neck extensor myopathy
b Dermatomyositis
b Polymyositis
b Inclusion body myositis
b Carnitine deficiency
b Facioscapulohumeral dystrophy
b Congenital myopathy
b Hyperparathyroidism
a
Updated from Barohn RJ, Saunders.1

may also have significant neck extensor

involvement. Isolated neck extension
weakness represents a distinct muscle
disorder called isolated neck extensor
myopathy. ALS and myasthenia gravis
also commonly present with prominent neck extensor weakness.
Pattern 7: Bulbar Weakness

Bulbar weakness (ie, tongue and
pharyngeal weakness) is manifested by
symptoms of dysarthria and dysphagia.
While a number of myopathies can
have some bulbar involvement, the
muscular dystrophy that has bulbar
involvement as a primary manifestation
is oculopharyngeal muscular dystrophy.
LGMD type 1A (myotilinopathy) can
present with isolated bulbar weakness,
and the inflammatory myopathies may
rarely present in this manner. Neuromuscular junction disorders such as
myasthenia gravis and Lambert-Eaton
myasthenic syndrome also frequently
have bulbar symptoms and signs. This
pattern is considered an overlap pattern
with ALS and other motor neuron
disorders that can have significant bulbar involvement.
Pattern 8: Episodic Pain,
Weakness, and Myoglobinuria
A history of episodic pain, weakness,
and myoglobinuria characterizes a pattern that may be related to a variety of
conditions, many of which are not due
TABLE 8-18 Pattern 8: Myopathies With EpisodicaPain, Weakness,

and Myoglobinuria/Rhabdomyolysis
b Related to Exercise
Couch potato syndrome
Glycogenoses (eg, McArdle disease)
Lipid disorders (carnitine palmitoyltransferase deficiency)
b Not Related to Exercise
Central non-neuromuscular causes
Neuroleptic malignant syndrome
Status epilepticus
Drugs/toxins
Malignant hyperthermia
Polymyositis/dermatomyositis (rarely)
Viral/bacterial infections
a
1688
Reprinted from Barohn R, American Association of Neuromuscular and Electrodiagnostic

Medicine.7 B AANEM.
December 2013
to an underlying muscle disorder

(Table 8-187). When these symptoms
are triggered by exercise, a metabolic
myopathy is most likely. However, a
number of patients may develop myoglobulinuria because they are inactive
individuals who are suddenly required
to do an overwhelming amount of exercise (ie, the couch potato syndrome).
Pattern 9: Episodic Weakness
Delayed or Unrelated to Exercise
A pattern of episodic weakness delayed
or unrelated to exercise applies to the
disorders of periodic paralysisVboth
the genetic autosomal dominant channelopathies (Table 8-197) and the
secondary periodic paralyses, such as
those due to thyrotoxicosis. Also, for the
sake of completeness, it is reasonable to
include the neuromuscular junction disorders in this pattern. In all of these
conditions, the weakness can occur during or after exercise, or often the weakness is unrelated to physical exertion.
Pattern 10: Stiffness and
Decreased Ability to Relax
A pattern of stiffness and decreased
ability to relax is seen in all of the
TABLE 8-19 Pattern 9: Episodic
Weakness Delayed
or Unrelated to
Exercisea
b Periodic paralysis
Ca++ channelopathies
(hypokalemic)
Na++ channelopathies
(hyperkalemic)
Andersen-Tawil syndrome
Secondary periodic paralysis
(thyrotoxicosis)
b Other: Neuromuscular junction
diseases
a
Reprinted from Barohn R, American

Association of Neuromuscular and
Electrodiagnostic Medicine.7 B AANEM.
disorders that produce myotonia and

paramyotonia and includes the hereditary disorders involving sodium and
chloride channelopathies (Table 8-208
and Table 8-217) as well as myotonic
dystrophy types 1 and 2. Both myotonic dystrophies usually have fixed
muscle weakness as well, with predominantly distal weakness in myotonic dystrophy type 1 and proximal
weakness in myotonic dystrophy type
2. The autosomal recessive form of
chloride channelopathies, Becker disease, also has fixed proximal weakness. In addition, other less common
disorders that fit this pattern include
Brody disease, neuromyotonia, and
the CNS disorder stiff-person syndrome (see Table 8-208).
Table 8-227 summarizes these 10
patterns of presentation of muscle
disease. Once the key questions
reviewed above have been answered
and the patient has been placed into
one of these 10 patterns of weakness,
laboratory studies can then be used to
confirm the diagnosis.
KEY POINT
h Creatine kinase levels

are elevated in the
majority of patients with
muscle disease but may
be normal in those with
slowly progressive
myopathies.
LABORATORY APPROACH TO
EVALUATING A SUSPECTED
MYOPATHY
Creatine Kinase
Creatine kinase (CK) is an extremely
useful and inexpensive laboratory test
for the evaluation of patients with a
suspected myopathy (Table 8-232).
CK levels are elevated in the majority
of patients with muscle disease but
may be normal in those with slowly
progressive myopathies. The degree
of CK elevation can also be helpful in
distinguishing different forms of muscular dystrophy. For example, in
Duchenne muscular dystrophy, the CK
is often up to 100 times normal levels,
whereas elevations are less significant in
most other myopathies. The other
exceptions are LGMD types 1C (caveolinopathy), 2A (calpainopathy), and 2B
1689
a
TABLE 8-20 Channelopathies and Related Disorders
Clinical Features
Pattern of
Inheritance
Chromosome
Thomsen disease
Myotonia
Autosomal dominant
7q35
CLC-1
Becker type
Myotonia + weakness Autosomal recessive
7q35
CLC-1
Paramyotonia congenita
Paramyotonia
Autosomal dominant
17q13.1Y13.3 SCNA4A
Hyperkalemic periodic
paralysis
Periodic paralysis
and myotonia and
paramyotonia
Autosomal dominant
17q13.1Y13.3 SCNA4A
Myotonia fluctuans
Myotonia
Autosomal dominant
17q13.1Y13.3 SCNA4A
Myotonia permanens
Myotonia
Autosomal dominant
17q13.1Y13.3 SCNA4A
Acetazolamide-responsive
Myotonia
Autosomal dominant
17q13.1Y13.3 SCNA4A
Periodic paralysis
Autosomal dominant
1a31Y32
Dihydropyridine
receptor
Schwartz-Jampel syndrome
Myotonia; dysmorphic Autosomal recessive
(Chondrodystrophic myotonia)
1p34.1Y36.1
Perlecan
Rippling muscle disease
Muscle mounding/
stiffness
Autosomal dominant
1q41 3p25
Unknown
Caveolin-3
Anderson-Tawil syndrome
Periodic paralysis,
cardiac arrhythmia,
dysmorphic
Autosomal dominant
17q23
KCMJ2-Kir 2.1
Brody disease
Delayed relaxation,
no myotonia
Autosomal recessive
16p12
Calcium-ATPase
Anesthetic-induced
delayed relaxation
Autosomal dominant
19q13.1
Ryanodine
receptor
Disorder
Gene
Chloride channelopathies
Myotonia congenita
Sodium channelopathies
Potassium-aggravated
myotonias
Calcium channelopathies
Hypokalemic periodic
paralysis
Modified from Barohn RJ, Saunders.8 B 2000, with permission from Elsevier.
KEY POINT
h An elevation of serum
creatine kinase does not
necessarily imply the
presence of a primary
myopathic disorder.
1690
(dysferlinopathy), in which CK may also

be markedly elevated. In some myopathies, the CK may be normal or lowered
by several factors, including profound
muscle wasting, collagen diseases, corticosteroid administration, alcoholism,
or hyperthyroidism.
An elevation of serum CK does not
necessarily imply the presence of a
primary myopathic disorder. The CK
may rise modestly (usually to less than
10 times normal) in motor neuron
disease; uncommonly, CK elevations
may be seen in Charcot-Marie-Tooth

and Guillain-Barre syndromes. Hypothyroidism and hypoparathyroidism can
also be associated with high CK levels.
Causes of CK elevation other than neuromuscular disease include strenuous
exercise, viral illnesses, muscle trauma
(falls, IM or subcutaneous injections,
EMG studies), or seizures. In these
cases, CK elevations are usually less
than 5 times normal and not sustained.
Sex and race can also affect serum CK (Table 8-249). CK levels are
December 2013

Stiffness/
Decreased
Ability to Relaxa
b Improves With Exercise
Myotonia: Na or Cl
channelopathy
b Worsens With Exercise/Cold
Sensitivity
Paramyotonia: Na
channelopathy
Brody disease
b With Fixed Weakness
Myotonic dystrophy (DM 1)
Proximal myotonic myopathy
(DM 2)
Becker disease (AR Clchannelopathy)
b Other
Neuromyotonia
Rippling muscle
Stiff-person syndrome
a
Reprinted from Barohn R, American

Association of Neuromuscular and
Electrodiagnostic Medicine.7 B AANEM.
frequently above the laboratorys normal range in black patients and in those
with enlarged muscles. Occasionally,
benign elevations of CK appear on a
genetic basis. It is extremely unusual for
a slightly elevated CK (threefold or less)
to be associated with an underlying
myopathy in the absence of pain or
objective muscle weakness. Enzymes
such as aspartate aminotransferase
(AST), alanine aminotransferase (ALT),
and lactate dehydrogenase (LDH) may
be slightly elevated in myopathies. Since
AST, ALT, and LDH are often measured
in screening chemistry panels, their
elevation should prompt CK measurement to determine whether the source
is from muscle or liver. If a patient with
an inflammatory myopathy is treated
with an immunosuppressive agent that
may cause hepatotoxicity, the liverspecific enzyme ,-glutamyltransferase

(GGT) should be monitored.
In general, CK isoenzymes are not
helpful in evaluating myopathies. CKMM elevations are typical of muscle
disease, but CK-MB is also elevated in
myopathies and does not indicate that
cardiac disease is present.
Electrophysiologic Studies
Electrophysiologic studies, consisting of
nerve conduction studies and EMG,
should be part of the routine evaluation
of a patient with a suspected muscle
disorder. These studies are helpful in
confirming that the muscle is the correct
site of the lesion and that weakness is
not due to motor neuron disease,
neuropathy, or neuromuscular junction
disorder. Nerve conduction studies are
typically normal in patients with myopathy; in advanced myopathies, however,
the compound muscle action potential
amplitudes can be reduced. Needle
EMG examination showing evidence of
brief-duration, small-amplitude motor
units with increased recruitment can be
helpful in confirming the presence of a
myopathy. Abnormal insertional activity,
including fibrillations and positive sharp
waves, can also be seen. In addition,
needle EMG can be used as a guide
when selecting which muscle to biopsy;
however, it is important to realize 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 patients history, neurologic examination,
and laboratory studies.
Muscle Biopsy
If the clinical and electrodiagnostic
features suggest the possibility of a
myopathy, a muscle biopsy may be an
appropriate next step in order to
confirm the diagnosis. Currently,
many forms of hereditary muscle
1691
TABLE 8-22 Clinical Patterns of Muscle Disorders

Pattern
Proximal Distal
b
Pattern 1
Weakness
Diagnosis
Asymmetric
Symmetric Episodic Trigger
Most myopathies,
hereditary and acquired
(overlap with spinal
muscular atrophy)b
Distal myopathies
(overlap with
neuropathies)b
Fascioscapulohumeral
muscular dystrophy,
Emery-Dreifuss, acid
maltase, congenital
scapuloperoneal
Limb-girdle
Pattern 2b
Distal
Pattern 3
Proximal arm/
distal leg
scapuloperoneal
Pattern 4
Distal arm/
proximal leg
Pattern 5
Arm
Leg
(Fascioscapulohumeral
muscular dystrophy)
(Others)
Leg
Arm
Ptosis/
ophthalmoplegia
Pattern 6b
+
(Myasthenia gravis)
Inclusion body myositis,

myotonic dystrophy
Oculopharyngeal
dystrophy, myasthenia
gravis, myotonic
dystrophy, mitochondrial
(Others)
Isolated neck extensor

myopathy, myasthenia
gravis, (overlap with ALS)b
Myasthenia gravis,
Lambert-Eaton
myasthenic syndrome,
oculopharyngeal
dystrophy (overlap
with ALS)b
McArdle, carnitine
palmitoyltransferase,
drugs, toxins
+/-
Primary periodic
paralysis;
channelopathies:
Na, Ca; secondary
periodic paralysis
+/-
Myotonic dystrophy,
channelopathies,
rippling muscle
(other: stiff-person,
neuromyotonia)
Neck extensor
Pattern 7b
Bulbar (tongue,
pharyngeal)
Pattern 8
Episodic weakness/
pain/rhabdomyolysis
+ trigger
Pattern 9
Episodic weakness
delayed or
unrelated to
exercise
Pattern 10
Stiffness/inability
to relax
a
b
1692
Reprinted from Barohn R, American Association of Neuromuscular and Electrodiagnostic Medicine.7 B AANEM.
Overlap patterns with neuropathy/motor neuron disease.
December 2013
TABLE 8-23 Differential

Diagnosis of
Creatine Kinase
Elevationa
b Myopathies
Carrier state
(dystrophinopathies)
Channelopathies
Drug/toxin-induced
b Motor neuron diseases
ALS
Postpolio syndrome
Spinal muscular atrophy
b Neuropathies
Charcot-Marie-Tooth
Guillain-Barre syndrome
b Others
Idiopathic hyper-CKemia
Increased muscle mass
Hypothyroidism/
hypoparathyroidism
Medications
Race
Sex
Strenuous exercise
Surgery
Trauma (EMG studies,
intramuscular or subcutaneous
injections)
ALS = amyotrophic lateral sclerosis.
a

Academy of Neurology. journals.
lww.com/continuum/Fulltext/2006/
06000/A_Clinical_Approach_to_the_
disorders can be diagnosed with molecular genetic testing, eliminating the

need to perform a muscle biopsy.
Either an open or closed (needle or
punch) biopsy procedure can be
performed in order to obtain a muscle
specimen. The advantages of a needle

biopsy are that it is minimally invasive
and more cosmetically appealing and
multiple specimens can be obtained.
The primary disadvantage of needle
biopsy is the need to ensure that an
adequate amount of tissue is sampled.
Selecting the appropriate muscle to
biopsy is critical. Muscles that are
severely weak (MRC grade 3 or less)
should not be biopsied unless the
onset of weakness is acute (such as
in dermatomyositis) because the results are likely to show only evidence
of end-stage muscle. In addition, muscles that have recently been studied
by needle EMG or injected with an
immunization should be avoided because of the possibility of artifacts
created by needle insertion. Generally,
biopsies should be taken from muscles that demonstrate MRC grade 4
strength. In the upper extremities, the
muscles of choice are either the biceps
or deltoid; in the lower extremities, the
best choice is the vastus lateralis. The
gastrocnemius should be avoided since
its tendon insertion extends throughout the muscle and inadvertent sampling of a myotendinous junction may
cause difficulty with interpretation.
Occasionally, an imaging procedure
such as muscle ultrasound, CT, or MRI
can be used to guide selection of the
appropriate muscle to biopsy.
Biopsy specimens can be analyzed
by light microscopy, electron microscopy, biochemical studies, and immune
staining (Table 8-252). Usually, light
microscopic observations of frozen
muscle tissue specimens are sufficient
to make a pathologic diagnosis. Typical
myopathic abnormalities include central nuclei, split fibers, both small and
large hypertrophic round fibers, and
degenerating and regenerating fibers.
Chronic myopathies frequently show
evidence of increased connective tissue and fat. Inflammatory myopathies
KEY POINT
h Selecting the appropriate

muscle to biopsy is
critical. Muscles that are
severely weak (Medical
Research Council grade 3
or less) should be not be
biopsied, as the results
are likely to show only
evidence of end-stage
muscle.
1693
Gender on Creatine Kinase

TABLE 8-24 Effect of Race and
Measurementsa
Group
Constituents
Upper Limit of Normal

(97.5%)
High
Black males
520 IU/L
Intermediate
Nonblack males
345 IU/L
Black females
Low
a
Nonblack females
145 IU/L
Reprinted with permission from Jackson CE, Semin Neurol.9 B 2008, Thieme Publishing Group.
www.thieme-connect.com/ejournals/abstract/10.1055/s-2008-1062266.
are characterized by the presence of

mononuclear inflammatory cells in the
endomysial and perimysial connective
tissue between fibers and occasionally
around blood vessels. In addition,
atrophy of fibers located on the periphery of a muscle fascicle (perifasci-
cular atrophy) is a common finding in

dermatomyositis.
For general histology, the hematoxylin
and eosin (H&E) and modified Gomori
one-step trichrome are the most useful
stains. The latter is particularly helpful
in identifying ragged red fibers, which
Biopsy Stains and Histochemical

TABLE 8-25 Utility of Muscle
Reactionsa
Histochemical Reactions and Stains
Clinical Utility
Adenosine triphosphatase (ATPase)
Distribution of fiber types
Gomori trichrome
General histology and mitochondrial

disease
Hematoxylin and eosin
General histology
Nicotinamide adenine dinucleotide

glycohydrolase (NADH), succinate
dehydrogenase (SDH), cytochrome
oxidase
Myofibrillar and mitochondrial

abnormalities
Oil Red O
Periodic acid-Schiff
Glycogen storage diseases
Congo red, crystal violet
Detection of amyloid deposition
Myophosphorylase
McArdle disease
Phosphofructokinase
Phosphofructokinase deficiency
Myoadenylate deaminase
Myoadenylate deaminase deficiency
Dystrophin immunostain
Duchenne and Becker muscular

dystrophy
Dysferlin immunostain
Limb-girdle muscular dystrophy type

2B
Membrane attack complex

immunostain
Dermatomyositis
1694
Reprinted from Jackson CE, Continuum (Minneap Minn).2 B 2006, American Academy of
December 2013
TABLE 8-26 Disorders With Commercially Available Molecular

Genetic Studies Performed With Peripheral Blood
Samplesa
b Chronic progressive external ophthalmoplegia (POLG, TWINKLE, ANT1, OPA1)
b Collagen VI disorders (COL6A1, COL6A2, COL6A3)
b Congenital muscular dystrophy (FKRP, FCMD, LAMA2, POMGNT, POMT1, POMT2)
b Duchenne and Becker muscular dystrophies (DMD sequencing)
b Emery-Dreifuss muscular dystrophy (EMD, FHL1)
b Facioscapulohumeral muscular dystrophy (FSHD)
b Hypokalemic and hyperkalemic periodic paralysis (CACNA1S, SCN4A)
b Limb-girdle muscular dystrophy (CAPN3, CAV3, DYSF, FKRP, LMNA, SGCA,
SGCB, SGCD, SGCG, CAPN3, SGCA)
b Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS)
b Myoclonic epilepsy and ragged red fibers (MERRF)
b Myotonic dystrophy (DM1, DM2)
b Myofibrillar myopathy (CRYAB, DES, FLNC, LDB3, MYOT, BAG3)
b Myotubular myopathy (MTM1 mutations)
b Nemaline myopathy (ACTA1 mutations)
b Oculopharyngeal muscular dystrophy (OPMD)
a
might suggest a mitochondrial disorder. In addition to these standard

stains, other histochemical reactions
can be used to gain additional information (Table 8-252). The myosin
adenosine triphosphatase (ATPase)
stains (alkaline hydrogen ion concentration [pH] 9.4; 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 pHs and darkly at acidic pHs.
Type 2 fibers (fast twitch, fatigue
prone, glycolytic metabolism) stain
darkly at alkaline pHs and lightly at
acidic pHs. Normally, distribution of
the two fiber types is random, and
there are generally twice as many type
2 as type 1 fibers. In a number of
myopathies, nonspecific type 1 fiber
predominance occurs. Oxidative enzyme stains (cytochrome c oxidase,

reduced-form nicotinamide adenine
dinucleotide [NADH] dehydrogenase,
succinate dehydrogenase) are useful
for identifying mitochondrial and myofibrillar defects. Oil Red O stains may
assist with the diagnosis of a lipid
storage disease, and periodic acidSchiff stains can be helpful in identifying glycogen storage diseases. Alkaline
phosphatase and acid reactions can
highlight regenerating and necrotic
fibers, respectively. Qualitative biochemical enzymes stains can be performed for myoadenylate deaminase
(MAD deficiency), myophosphorylase
(McArdle disease), and phosphofructokinase (PFK deficiency). Amyloid
deposition can be assayed with Congo
red or crystal violet staining. Finally,
1695
immunohistochemical techniques can

stain for muscle proteins that are deficient in some muscular dystrophies (eg,
dystrophin in Duchenne and Becker
dystrophies) or for products that are
increased in certain inflammatory myopathies, such as the membrane attack
complex in dermatomyositis.
Electron microscopy evaluates the
ultrastructural components of muscle
fibers and is not required in order to
make a pathologic diagnosis in the
majority of myopathies. It is important, however, in the diagnosis of
some congenital myopathies and mitochondrial disorders. Findings
detected only by electron microscopy
are seldom of clinical importance.
The muscle tissue can also be
processed for biochemical analysis to
determine a specific enzyme defect in
the evaluation of a possible metabolic
or mitochondrial myopathy. In addition, Western blot determinations from
muscle tissue can be performed for
certain muscle proteins.
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. Examples of commercially
available molecular genetic studies are
included in Table 8-262. This list is
continually updated on www.genetests.
org. Molecular genetic testing frequently eliminates the need for muscle
biopsy. This technology is also extremely helpful for determining carrier
status and performing prenatal testing.
Other Tests
In addition to CK determinations,
other blood tests that can be extremely
helpful in the evaluation of a patient
with a suspected myopathy include serum electrolytes, parathyroid hormone
levels, thyroid function tests, vitamin D
1696
levels, and HIV tests. In patients with an

inflammatory myopathy, serologic determinations for systemic lupus erythematosus, rheumatoid arthritis, and
other immunologic markers (eg, Jo-1
antibodies) can occasionally be useful. A
urinalysis can also be performed to
detect the presence 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 because ischemic exercise may be hazardous in patients with
defects in the glycolytic enzyme pathway. The test is conducted by asking
the patient to perform isometric contractions using a hand grip dynamometer for 1.5 seconds separated by rest
periods of 0.5 seconds for 1 minute. A
resting blood sample for venous 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
response. In certain disorders, the
characteristic elevation of serum lactate after exercise is absent (eg, PFK
deficiency, myophosphorylase deficiency) or reduced (eg, phosphoglycerate mutase deficiency). Forearm
testing is normal in all disorders of fat
metabolism as well as in some glycolytic disorders with fixed muscle weakness, such as acid maltase deficiency.
CONCLUSION
While this pattern recognition approach
to myopathy may have limitations, it
can be extremely helpful in narrowing
the differential diagnosis and thus in
minimizing the number of laboratory
studies that must be ordered to confirm the diagnosis. There will always be
December 2013
patients with a suspected muscle disorder who do not fit neatly into any of
these 10 categories. In addition, patients
with disorders of the motor neuron,
peripheral nerve, or neuromuscular
junction may also frequently present
with one of these patterns. For example,
while proximal greater than distal weakness is most often seen in a myopathy,
patients with acquired demyelinating
neuropathies (Guillain-Barre syndrome
and chronic inflammatory demyelinating polyneuropathy) often have proximal as well as distal muscle involvement.
Careful consideration of the distribution
of muscle weakness and attention to
these common patterns of involvement
in the context of other aspects of the
neurologic examination and laboratory
evaluation, however, will usually lead
the clinician to a timely and accurate
diagnosis.
USEFUL WEBSITES
NIH/GeneReviews
www.ncbi.nlm.nih.gov/sites/GeneTests/
review
Muscular Dystrophy Association
mdausa.org/
Neuromuscular Disease Center
neuromuscular.wustl.edu/
REFERENCES
1. Barohn RJ. General approach to muscle
diseases. In: Goldman L, Bennett JC, eds.
Cecil textbook of medicine. 23rd edition.
Philadelphia, PA: Saunders, 2008:
2816Y2834.
2. Jackson CE. A clinical approach to the patient
with suspected myopathy. Continuum
(Minneap Minn) 2006;12(3):13Y32.
3. Kissel J, ed. Muscle disease. Continuum
(Minneap Minn) 2000;6(2):7Y23.
4. Barohn RJ. Inflammatory and other
myopathies. In: Goldman L, Bennett JC,
eds. Cecil textbook of medicine. 21st
edition. Philadelphia, PA: Saunders; 2000:
2216Y2221.
5. Brooke MH. A clinicians view of
neuromuscular disease. 2nd ed. Baltimore,
MD: Williams & Wilkins, 1986.
6. Medical Research Council. Aids to the
examination of the peripheral nervous
system. 4th edition. London, UK: Balliere
Tindall, 2000.
7. Barohn R. A clinical approach to the patient
with myopathy. Presented at Annual
Meeting of the American Association of
Neuromuscular and Electrodiagnostic
Medicine. October 2008.
8. Barohn RJ. Channelopathies (non-dystrophic
myotonias and periodic paralyses). In:
Goldman L, Bennett JC, eds. Cecil textbook
of medicine. 21st edition. Philadelphia, PA:
Saunders, 2000:2214Y2216.
9. Jackson CE. A clinical approach to muscle
diseases. Semin Neurol 2008: 28(1):
228Y240.
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Review Article

Mendell and was passed down to me by

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When the approach was originally

Reprinted from Barohn RJ, Saunders.1

(for more on this topic, refer to the

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Pattern Recognition Approach to Myopathy

h The most common

(1) Which positive and/or negative

TABLE 8-2 Symptoms Associated

Updated from Jackson CE, Continuum

upper extremity weakness, patients

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and disorders of the nerve or motor

Continuum (Minneap Minn) 2013;19(6):16741697

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Pattern Recognition Approach to Myopathy

TABLE 8-5 Myopathies

Updated from Kissel J, ed, Continuum

usually last longer and are electrically

associated with myotonia are listed

b Drugs and toxins (especially alcohol)

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myoglobinuria can cause acute tubular

TABLE 8-7 Diagnosis of

h Identifying the age at

Lipid storage diseases

Continued on next page

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Pattern Recognition Approach to Myopathy

TABLE 8-7 Diagnosis of

Updated from Jackson CE, Continuum

that can return to normal within hours

with constant weakness can vary from

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TABLE 8-8 Diagnosis Of

sis is typically provoked by exercise

Duchenne muscular dystrophy

TABLE 8-9 Drugs That Can

Cyclosporine and tacrolimus

Updated from Jackson CE, Continuum

Patients should specifically be asked

Reprinted from Barohn RJ, Saunders.4

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Pattern Recognition Approach to Myopathy

TABLE 8-10 Myopathies

emphasizing the need for consistent

TABLE 8-11 Myopathies

Updated from Jackson CE, Continuum

Are Any Associated Systemic

Updated from Jackson CE, Continuum

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

with the congenital myopathies. The

be particularly informative in young

h Functional testing can

Signs or Symptoms of Weakness

Inability to bury eyelashes, horizontal smile, inability to whistle

Double vision, ptosis, disconjugate eye movements

Nasal speech, weak cry, nasal regurgitation of liquids,

Poor head control

Scoliosis, lumbar lordosis, protuberant abdomen,

Shoulder girdle Difficulty lifting objects overhead, scapular winging