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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
Products/Investigational
Use Disclosure:
Drs Jackson and Barohn
report no disclosures.
* 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
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December 2013
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
1675
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.
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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,
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 Hypothyroid myopathy
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.
www.ContinuumJournal.com
1677
h Myotonia classically
improves with repeated
muscle contractions,
whereas in paramyotonia
congenita, patients
demonstrate paradoxical
myotonia, in that
symptoms are typically
worsened by exercise.
a
TABLE 8-6 Causes of Myoglobinuria
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.
www.ContinuumJournal.com
December 2013
KEY POINTS
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.
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1679
(continued)
b Myopathies Presenting in
Adulthood
Centronuclear myopathy
Distal myopathies
Endocrine myopathies
Thyroid
Parathyroid
Adrenal
Pituitary disorders
Inflammatory myopathies
Polymyositis
Dermatomyositis, inclusion
body myositis, viral (HIV)
Metabolic myopathies
Acid maltase deficiency
Lipid storage diseases
Debrancher deficiency
Phosphorylase b kinase
deficiency
Mitochondrial myopathies
Muscular dystrophies
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
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December 2013
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
Metabolic myopathies
(-aminocaproic acid
Emetine
Isoretinoic acid (vitamin A
analogue)
b Maternal Transmission
Mitochondrial myopathies
a
Labetalol
Vincristine
b Rhabdomyolysis and
Myoglobinuria
Alcohol
Amphetamine
Cholesterol-lowering drugs
Cocaine
Heroin
Toluene
(-aminocaproic acid
b Myosin Loss
Nondepolarizing
neuromuscular blocking agents
Steroids
a
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1681
Becker
Emery-Dreifuss
Myotonic
Limb-girdle types 1B, 2C-F,
and 2G
Nemaline myopathy
Polymyositis
a
b Muscular Dystrophies
Becker
Duchenne
Congenital
Emery-Dreifuss
Limb-girdle 2A, 2I
Myotonic
1682
b Metabolic Myopathies
Acid maltase deficiency
Debrancher deficiency
b Mitochondrial Myopathies
b Congenital Myopathies
Centronuclear
Nemaline
b Inflammatory Myopathies
Polymyositis
a
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December 2013
KEY POINT
a
TABLE 8-12 Functional Assessment of Muscle Weakness
Location
Facial
Ocular
Bulbar
Neck
Trunk
Pelvic girdle
Leg/foot
Respiratory
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.
www.ContinuumJournal.com
1683
Degree of Strength
Normal power
5j
4+
4j
3+
3j
Trace contraction
No contraction
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December 2013
b Emery-Dreifuss
humeroperoneal dystrophy
b Myotonic 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 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).
b Debrancher deficiency
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
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1685
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.
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December 2013
KEY POINT
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.
www.ContinuumJournal.com
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December 2013
KEY POINT
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
www.ContinuumJournal.com
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
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
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
Malignant hyperthermia
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.
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December 2013
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
Continuum (Minneap Minn) 2013;19(6):16741697
1691
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)
Oculopharyngeal
dystrophy, myasthenia
gravis, myotonic
dystrophy, mitochondrial
(Others)
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.
www.ContinuumJournal.com
December 2013
KEY POINT
www.ContinuumJournal.com
1693
Group
Constituents
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.
Clinical Utility
Gomori trichrome
General histology
Oil Red O
Periodic acid-Schiff
Myophosphorylase
McArdle disease
Phosphofructokinase
Phosphofructokinase deficiency
Myoadenylate deaminase
Dystrophin immunostain
Dysferlin immunostain
Dermatomyositis
1694
Reprinted 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.
www.ContinuumJournal.com
December 2013
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.
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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.
www.ContinuumJournal.com
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