a pattern recognition approach to myopathy. continuum

7/26/2019 A Pattern Recognition Approach to Myopathy. CONTINUUM

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A PatternRecognition Approachto Myopathy

Carlayne E. Jackson, MD, FAAN; Richard J. Barohn, MD, FAAN

ABSTRACT

Purpose of Review: Myopathies are a heterogeneous group of disorders that canbe challenging to diagnose. The purpose of this review is to provide a diagnosticapproach based predominantly on the clinical history and neurologic examination.Laboratory testing that can subsequently be used to confirm the suspected diag-

nosis based on this pattern recognition approach will also be discussed.Recent Findings: Over the past decade, numerous discoveries have allowedclinicians to diagnose myopathies with genetic testing. Unfortunately, the testing isextremely expensive and frequently not covered by insurance.Summary:Careful consideration of the pattern of muscle weakness in addition toother aspects of the physical examination and diagnostic testing should assist theclinician in making a timely and accurate diagnosis and minimize the expense ofconfirmatory genetic testing.

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

INTRODUCTION

The approach to myopathy, which isreviewed in this chapter, is like a storyhanded down from one generation toanother. This was the approach thatDr Barohn learned at The Ohio StateUniversity from Drs John Kissel and Jerry

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.

Address correspondence toDr Carlayne Jackson, 8300Floyd Curl Drive, Mail Code7883, San Antonio, Texas,78229-3900,[email protected].

Relationship Disclosure:Dr Jackson has receivedresearch support from BiogenIdec; Cytokinetics, Inc; KnoppNeurosciences, Inc; theNational ALS Association;Phillips Respironics; andthe US Food and DrugAdministration Office ofOrphan Products Development.Dr Barohn has served on thespeakers bureaus of GenzymeCorporation and Grifols;on the advisory boards ofMedImmune, LLC, and

Novartis Corporation; andas a consultant forNuFACTOR.Dr Barohn has receivedresearch support from BiogenIdec; BioMarin PharmaceuticalInc; Cytokinetics, Inc;Genzyme Corporation; KnoppNeurosciences, Inc; NeuraltusPharmaceuticals, Inc; theNational Institute ofNeurological Disordersand Stroke; the NIH; PTCTherapeutics; SangamoBioSciences, Inc; TevaPharmaceutical Industries Ltd;and the US Food and DrugAdministration Office ofOrphan Products Development.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Drs Jackson and Barohnreport no disclosures.

* 2013, American Academyof Neurology.

EDITORS NOTE

The article A Pattern Recognition Approach to Myopathy by DrsCarlayne Jackson and Richard Barohn reflects the thoughtful approachthat 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 ofCecil Textbook of Medicine (published in1999), and subsequent updated and evolved versions of this information(by Dr Barohn or Dr Jackson) appeared in editions of Cecil Textbook ofMedicinein 2004 and 2008 (now published by Elsevier), issues ofContinuum: Lifelong Learning in Neurologyin 2000 and 2006, an issue ofSeminars of Neurology in 2008, and course syllabi from the American

Academy of Neurology (AAN) as well as the American Association ofNeuromuscular & Electrodiagnostic Medicine (AANEM). Because we feelthat the material presented in this article continues to be important forour readers so that they can use this approach in the assessment and care

of their patients with muscle disease, we includean updated version in this issue.

1674 www.ContinuumJournal.com December 2013

Review Article

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
mailto:[email protected]:[email protected]


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When the approach was originallypublished by Dr Barohn in Cecil Text-

book of Medicine in 1999, he de-scribed six patterns of weakness.

With the genetic breakthroughs overthe intervening years, the approach nowincludes 10 patterns of weakness, andthe differential diagnoses have broad-ened. Despite all of the advances indiagnostic testing, reliance on answer-ing the key questions and then placingthe patient into one of the patterns of

weakness remains the cornerstone ofhow a clinician should approach the

patient with a suspected myopathy.Like a timeless story, we are hope-ful that, by including this article in thisissue of , we will havethe opportunity to pass this approachdown to our readers who continue tohave the responsibility of making atimely and accurate diagnosis for these

very complex patient groups.Myopathies are disorders affecting

the channel, structure, or metabolismof skeletal muscle. Myopathies havedistinctive clinical and laboratory fea-

tures that can distinguish them fromother disorders of the motor unit,including the neuromuscular junction,peripheral nerve, or motor neuron.Therefore, the first goal in evaluating apatient with a suspected muscle dis-order is to determine the site of thelesion. Once the lesion is localized tothe muscle, the next step is to identify

whether the myopathy is due to anabnormality in the muscle channel, anabnormality in the muscle structure, or a

dysfunction in muscle metabolism. Thesecond goal is to determine the cause ofthe myopathy. In general, myopathiescan be classified into acquired orhereditary disorders (Table 8-11). Fi-nally, the third goal is to determine

whether a therapy is available and, ifnot, to optimally manage the patientssymptoms in order to maximize hisor her function and quality of life

(for more on this topic, refer to thearticle Multidisciplinary Managementof Myopathies by Dr John T. Kisseland Wendy King in this issue of

).

CLINICAL EVALUATION

In approaching the evaluation of apatient with a suspected myopathy,one of the most important compo-nents is a comprehensive medicalhistory. The history should allow theclinician to determine whether thepatient has an acquired or hereditarydisorder (Table 8-11). The distributionof muscle weakness and additional

findings on the physical examinationshould provide more information tohelp determine the correct diagnosis.The results of laboratory studies (bloodtests, electrodiagnostic studies, musclebiopsy, molecular genetic studies) thenplay a confirmatory diagnostic role.

The first step in this clinical ap-proach is to ask six key questions re-garding the patients symptoms:

KEY POINT

h In approaching the

evaluation of a patient

with a suspected

myopathy, one of the

most important

components is a

comprehensive medical

history.

TABLE 8-1 Classification ofMyopathiesa

b Acquired

Drug-induced myopathies

Endocrine myopathies

Inflammatory/immunemyopathies

Myopathies associated withother systemic illness

Toxic myopathies

b Hereditary

Channelopathies

Congenital myopathies

Metabolic myopathies

Mitochondrial myopathies

Muscular dystrophies

Myotonias

a Reprinted from Barohn RJ, Saunders.1

B2008, with permission from Elsevier.

1675Continuum (Minneap Minn) 2013;19(6):16741697 www.ContinuumJournal.com



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(1) Which positive and/or negativesymptoms does the patient experi-

e nce? (2) What is the temporalevolution? (3) Does the patient havea family history of a myopathic disor-der? (4) Are there precipitating fac-tors that trigger episodic weakness orstiffness? (5) Are any associated sys-temic symptoms or signs present? (6)

What is the distribution of weakness?

Which Negative and/orPositive Symptoms Doesthe Patient Experience?

Patient reports of the symptoms ofmyopathy can be divided into thosethat are negative, such as exerciseintolerance, fatigue, muscle atrophy,and weakness, and those that arepositive, such as contractures, cramps,muscle stiffness, myalgias, and myo-globinuria (Table 8-22).

The most common negative symp-tom reported by a patient with muscledisease is weakness. As a result of

upper extremity weakness, patientsmay report difficulty brushing their

teeth, combing their hair, or liftingobjects overhead. If the weaknessinvolves the lower extremities, pa-tients will report difficulty rising froma low chair or toilet, getting up from asquatted position, or climbing stairs.These symptoms suggest proximalmuscle weakness (probably the mostcommon distribution of weakness inmyopathies). Less commonly, patients

with myopathies may report difficultyturning a key or opening jars or gait

instability due to footdrop, whichindicates involvement of the distalmuscles. Cranial muscle weaknessresulting in symptoms of slurredspeech, difficulty swallowing, ptosis,or double vision may also be reported.

Fatigue is another negative symptomthat can be reported by patients withmyopathy; however, it is nonspecificand more commonly occurs as a resultof a patients overall health, cardiopul-monary status, emotional state, level ofconditioning, or sleeping habits. The

large majority of patients who reportgeneralized weakness or fatigue will nothave a primary muscle disorder, partic-ularly if the neurologic examination isunremarkable. Because metabolic andmitochondrial myopathies can causeabnormal fatigability after exercise,however, it is always important todefine the intensity and duration ofexercise that provokes the fatigue.

Positive symptoms associated withmyopathies may include cramps, con-

tractures, myalgias, muscle stiffness,or myoglobinuria. Myalgia, like fatigue,is another nonspecific symptom ofsome myopathies (Table 8-32).2 Myal-gias may be episodic (such as inmetabolic myopathies) or nearly con-stant (such as in inflammatory musclediseases); however, muscle pain is notcommon in most muscle diseases andis more likely to be due to orthopedic

KEY POINTS

hThe most common

negative symptom

reported by a patient

with muscle disease is

weakness.

hBecause 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.

TABLE 8-2 Symptoms AssociatedWith Myopathiesa

b Negative

Exercise intolerance

Fatigue

Muscle atrophy

Weakness

b Positive

Cramps

Contractures

Muscle hypertrophy

Myalgia

Myoglobinuria

Stiffness

a Updated from Jackson CE, Continuum(Minneap Minn).2 B2006, AmericanAcademy of Neurology. journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx.


Pattern Recognition Approach to Myopathy

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or rheumatologic disorders. It isextremely uncommon for a myopathyto be responsible for vague aches andmuscle discomfort in the presence ofnormal findings from a neuromuscularexamination and laboratory studies.

Muscle cramps are a specific type ofmuscle pain that occurs frequently innormal individuals, are typically be-nign, and are seldom a feature of a

primary myopathy. Cramps most com-monly occur because of azotemia,dehydration, hyponatremia, myxedema,

and disorders of the nerve or motorneuron (especially ALS). Crampstypically last for less than severalminutes and are usually localized to aparticular muscle region, such as thecalves. On needle EMG, cramps arecharacterized by rapidly firing motorunit discharges. Muscle contracturesoccur in patients with glycolytic en-zyme defects and are typically pro-

voked by exercise (Table 8-4

3

).Contractures can superficially resem-ble a cramp but differ in that contractures

KEY POINT

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.

TABLE 8-3 Muscle Diseases Associated With Myalgiasa

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 ofNeurology. journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx.

TABLE 8-4 Myopathies Associated With Muscle Contracturesa

b Brody disease

b Glycolytic/glycogenolytic enzyme defects

Myophosphorylase deficiency (McArdle disease)

Phosphofructokinase deficiency

Phosphoglycerate kinase deficiency

Phosphoglycerate mutase deficiency

Lactate dehydrogenase deficiencyDebrancher enzyme deficiency


b Paramyotonia congenita

b Rippling muscle disease

a Updated from Kissel J, ed, Continuum (Minneap Minn).3 B 2000, American Academy ofNeurology. journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspx.


http://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx


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usually last longer and are electricallysilent with needle EMG. Muscle con-tractures should not be confused withfixed tendon contractures.

Myotonia is a result of repetitivedepolarization of the muscle mem-brane resulting in impaired relaxationof muscle after forceful voluntarycontraction. The muscle disorders

associated with myotonia are listedin Table 8-5.3 Myotonia is most com-

monly demonstrated in the eyelids andhands (for more on this topic, refer toMuscle Channelopathies: the Non-dystrophic Myotonias and Periodic Pa-ralyses by Drs Barohn and Statland inthis issue of ). As a result,patients may report muscle stiffness ortightness that causes difficulty releasingtheir grip after a forceful handshake ortrouble opening their eyelids aftersqueezing their eyes tight. Myotoniaclassically improves with repeated mus-cle contractions, whereas in paramyoto-nia congenita, patients demonstrateparadoxical myotonia, in that symp-toms are typically worsened by exercise.Cold exposure results in worsening ofboth myotonia and paramyotonia.

Myoglobinuria is caused by the ex-cessive release of myoglobin into theurine during periods of rapid muscledestruction (rhabdomyolysis) and is arare manifestation of muscle disease(Table 8-63). It is important to identifyand treat aggressively since severe

KEY POINT

hMyotonia 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 MyopathiesAssociated With

Muscle Stiffnessa

b Hyperkalemic periodicparalysis


b Myotonia congenita

b Myotonic dystrophy

b Paramyotonia congenita

b Proximal myotonic myopathy

a Updated from Kissel J, ed, Continuum(Minneap Minn).3 B 2000, AmericanAcademy of Neurology. journals.lww.com/continuum/Citation/2000/06020/

Approach_to_the_Patient_With_Suspected_Muscle.2.aspx.

TABLE 8-6 Causes of Myoglobinuriaa

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 Updated from Kissel J, ed, Continuum (Minneap Minn).3 B 2000, American Academy ofNeurology. journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspx.



http://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Citation/2000/06020/Approach_to_the_Patient_With_Suspected_Muscle.2.aspx


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myoglobinuria can cause acute tubularnecrosis resulting in renal failure.

Patients who report exercise-inducedwea kness and myalgia should beasked if their urine has ever turnedred or cola-colored during or afterthese episodes. Isolated episodes ofmyoglobinuria, particularly occurringafter unaccustomed strenuous exer-cise, are frequently idiopathic, where-as recurrent episodes are usually dueto an underlying metabolic myopathy.

What Is the Temporal Evolution?

Of obvious importance is the determi-nation of the onset, duration, andevolution of the patients symptoms.Identifying the age at which a patientssymptoms began (ie, whether thesymptoms first manifested at birth oronset occurred in the first, second, third,or later decade of life [Table 8-72]) canprovide crucial information leading tothe correct diagnosis. Symptoms ofDuchenne muscular dystrophy, forexample, are usually identified be-tween 3 and 5 years of age, whereas

most types of limb-girdle muscular dys-trophy (LGMD) begin in adolescence orlater. Of the inflammatory myopathies,dermatomyositis may occur in child-hood or adulthood, polymyositis rarelybegins in childhood but occurs at anydecade in adulthood, and inclusionbody myositis occurs most commonlyover the age of 50 years.

It is also important to determinethe evolution and duration of thesymptoms. Is the course monophasic,

progressive, or relapsing? Myopathiescan present with either episodic pe-r i od s o f w ea k ne s s w it h n o rm a lstrength interictally (eg, metabolicmyopathies due to certain glycolyticpathway disorders, periodic paralysis)or constant weakness (eg, inflamma-tory myopathies, muscular dystro-phies). The episodic disorders arecharacterized by acute loss of strength

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.

h Identifying the age at

which a patients

symptoms began can

provide crucial

information leading to

the correct diagnosis.

TABLE 8-7 Diagnosis ofMyopathy Based

on Age of Onseta

bMyopathies Presenting at Birth

Central core disease

Centronuclear (myotubular)myopathy

Congenital fiber-typedisproportion

Congenital muscular dystrophy

Congenital myotonic dystrophy

Glycogen storage diseases(acid maltase and

phosphorylase deficiencies)

Lipid storage diseases(carnitine deficiency)

Nemaline (rod) myopathy

b Myopathies Presenting inChildhood


Nemaline

Centronuclear

Central core

Endocrine-metabolic disorders

HypokalemiaHypocalcemia

Hypercalcemia

Glycogen storage disease (acidmaltase deficiency)

Inflammatory myopathies

Dermatomyositis

Polymyositis (rarely)

Lipid storage disease(carnitine deficiency)



Congenital

Duchenne

Becker

Emery-Dreifuss

Facioscapulohumeral

Limb-girdle

Continued on next page




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that can return to normal within hoursor days. The tempo of the disorders

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 ) nonprogre ssive w e akness

with little change over decades (eg,congenital myopathies). Finally, bothconstant and episodic myopathic dis-orders can have symptoms that may bemonophasic or relapsing. For example,polymyositis can occasionally have anacute monophasic course with return

to baseline level of strength withinweeks or months. Patients with meta-bolic myopathies or periodic paralysiscan have recurrent episodes of weak-ness over years, while a patient withrhabdomyolysis due to cocaine inges-tion may have an isolated episode.

Does the Patient Have a FamilyHistory of a Myopathic Disorder?

Obtaining a thorough family history isof tremendous importance sincemany myopathies are hereditary. A

detailed family tree should be com-pleted to determine whether evidencesuggests an autosomal dominant, au-tosomal recessive, or X-linked patternof inheritance (Table 8-82). Specificquestions regarding family membersuse of adaptive equipment or function-al limitations are usually more informa-tive than inquiring about a familyhistory of muscle disease. Identifyinga particular pattern of inheritance isnot only helpful in making a correct

diagnosis but also of critical impor-tance in providing genetic counseling.

Are There Precipitating FactorsThat Trigger Episodic Weaknessor Stiffness?

It is important to ask the patientwhether any precipitating factors existthat might trigger or worsen theirsymptoms of weakness or myotonia.

TABLE 8-7 Diagnosis ofMyopathy Based

on Age of Onseta

(continued)

b Myopathies Presenting inAdulthood

Centronuclear myopathy

Distal myopathies

Endocrine myopathies

Thyroid

Parathyroid

Adrenal

Pituitary disorders


Polymyositis

Dermatomyositis, inclusionbody myositis, viral (HIV)


Acid maltase deficiency

Lipid storage diseases

Debrancher deficiency

Phosphorylase b kinasedeficiency



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 Updated from Jackson CE, Continuum

(Minneap Minn).2 B2006, AmericanAcademy of Neurology. journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx.



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Patients should specifically be askedabout their use of either illegal drugs

or prescription medications that mightproduce a myopathy (Table 8-94). Ahistory of pain, weakness, or myo-globinuria triggered by exercise wouldraise the possibility of a glycolyticpathway defect. Episodic weaknessthat occurs in association with a feveror heat exposure would be supportiveof a diagnosis of carnitine palmitoyl-transferase deficiency. Periodic paraly-

sis is typically provoked by exerciseand ingestion of a high-carbohydrate

meal followed by a period of rest.Patients with myotonic disorders fre-quently report that cold exposure mayprecipitate or worsen their symptomsof muscle stiffness.

TABLE 8-8 Diagnosis OfMyopathy Based

on Pattern ofInheritancea

b X-Linked

Becker muscular dystrophy

Duchenne muscular dystrophy

Emery-Dreifuss musculardystrophy

b Autosomal Dominant

Central core myopathy

Fascioscapulohumeralmuscular dystrophy

Limb-girdle musculardystrophy type 1

Oculopharyngeal musculardystrophy

Myotonic dystrophy

Paramyotonia congenita

Periodic paralysis

Thomsen disease

b Autosomal Recessive

Becker myotonia

Limb-girdle musculardystrophy type 2


b Maternal Transmission



TABLE 8-9 Drugs That CanCause ToxicMyopathiesa

b Inflammatory

Cimetidine

D-penicillamine

Procainamide

L-tryptophan

Levodopa

b Noninflammatory Necrotizing orVacuolar

Alcohol

Cholesterol-lowering agents

Chloroquine

Colchicine

Cyclosporine and tacrolimus

Emetine

(-aminocaproic acidIsoretinoic acid (vitamin Aanalogue)

Labetalol

Vincristine

b Rhabdomyolysis andMyoglobinuria

Alcohol

Amphetamine

Cholesterol-lowering drugs

Cocaine

Heroin

Toluene

(-aminocaproic acid

b Myosin Loss

Nondepolarizingneuromuscular blocking agents

Steroids




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Are Any Associated SystemicSymptoms or Signs Present?

Helpful clues in making the appropri-ate diagnosis can also be obtained byidentifying involvement of organs ortissues other than muscle. Cardiac

disease may be associated with a num-ber of myopathies (Table 8-102).Respiratory insufficiency is asso-

ciated with a number of myopathies(Table 8-112), and respiratory failuremay be the presenting symptom of acidmaltase deficiency, centronuclear myop-athy, myotonic dystrophy, or nemalinemyopathy. Ultimately, many myopathies

will affect respiratory muscle function,

emphasizing the need for consistentmonitoring of pulmonary function stud-

ies throughout the disease course.Once symptoms or signs of nocturnalhypoventilation are evident, supportivecare should be initiated with bilevelpositive pressure ventilation and assis-tive devices for clearance of upperairway secretions, such as high-frequency chest wall oscillation devicesor mechanical insufflator-exsufflators.

Hepatomegaly may occur in myopa-thies associated with deficiencies inacid maltase, carnitine, and debranch-

ing enzyme. The clinical features ofcataracts, frontal balding, and cognitivedysfunction strongly suggest the diag-nosis of myotonic dystrophy type 1.Dysmorphic features may be associated

TABLE 8-11 MyopathiesAssociated WithRespiratoryInsufficiencya

bMuscular Dystrophies

Becker

Duchenne

Congenital

Emery-Dreifuss

Limb-girdle 2A, 2I

Myotonic

bMetabolic Myopathies


Debrancher deficiency

bMitochondrial Myopathies

bCongenital Myopathies

Centronuclear

Nemaline

b Inflammatory Myopathies

Polymyositis


TABLE 8-10 MyopathiesAssociated 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

Becker

Emery-Dreifuss

Myotonic

Limb-girdle types 1B, 2C-F,and 2G

Nemaline myopathy

Polymyositis

a

Updated from Jackson CE, Continuum(Minneap Minn).2 B2006, AmericanAcademy of Neurology. journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx.



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with the congenital myopathies. Thepresence of a rash is extremely useful

in the diagnosis of dermatomyositis.Musculoskeletal contractures com-monly occur in many long-standingmyopathies as a result of limited rangeof motion. However, contractures de-

veloping early in the course of thedisease, before the development ofsignificant weakness, can be a clue toBethlem myopathy, Emery-Dreifussd y st r op h y, a n d L G MD t y pe 1 B(laminopathy). Evidence of diffuse sys-temic disease can indicate amyloido-

sis, sarcoidosis, an endocrinopathy,collagen-vascular disease, an infectiousdisease, or a mitochondrial disorder.

What Is the Distribution ofWeakness?

It is important to test muscle strength,both by formal manual muscle testingand from observation of functionalactivity (Table 8-122), in order todetermine the distribution of muscle

weakne ss.5 Functional testing can

be particularly informative in youngchildren, who are often unable to

cooperate with formal manual muscletesting, and in adults with give-way

weakness secondary to pain.The expanded Medical Research

Council (MRC) grading scale of 0 to 5is the most commonly used bench-mark for assessing muscle strength(Table 8-136).6 All muscle groupsshould be tested bilaterally in order toassess symmetry. The patient should bepositioned, if possible, to test all musclesagainst gravity. The presence of signifi-

cant muscle weakness can escape recog-nition if testing against gravity is notperformed. In addition, the cranial nervemuscles, such as the extraocular muscles,orbicularis oculi and oris, tongue, and

palate, should be evaluated. These mus-cles may be best tested by observation ofactivities, such as asking the patient tosuck from a straw, whistle, and smile.

In addition to the assessment ofmuscle strength, muscles should beinspected 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.

TABLE 8-12 Functional Assessment of Muscle Weaknessa

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 aspirationpneumonia, cough during meals

Neck Poor head control

Trunk Scoliosis, lumbar lordosis, protuberant abdomen,difficulty sitting up

Shoulder girdle Difficulty lifting objects overhead, scapular wingingForearm/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 musclesa 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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hypertrophy. Atrophy of proximal up-per and lower extremity muscles iscommonly identified in most chronicmyopathies. However, certain myopa-thies demonstrate atrophy in specific

muscle groups that may provide addi-tional diagnostic clues. Atrophy of theperiscapular muscles associated withscapular winging, for example, ischaracteristic of facioscapulohumeraldystrophy and of LGMD types 1B(laminopathy), 2A (calpainopathy),and 2C through 2F (sarcoglycano-pathies). Distal myopathies may haveselective atrophy of the anterior orposterior lower extremity compart-ments. Asymmetric atrophy of the

quadriceps muscles and forearm flexormuscles is highly suggestive of inclusionbody myositis. On the other hand, inmyotonia congenita, muscles can showevidence of hypertrophy. Muscle hyper-trophy is also seen in some systemicdisorders, including amyloidosis, sar-coidosis, and hypothyroid myopathy.In Duchenne and Becker musculardystrophies, pseudohypertrophy of

the calf muscles occurs because ofreplacement with connective tissueand fat. Calf muscle hypertrophy is alsocharacteristically seen in LGMD types2C through 2F (sarcoglycanopathies)

and 2I (fukutin-related proteinopathy).In LGMD type 2G (telethoninopathy),50% of patients will show calf hyper-trophy and the other 50% will demon-strate calf atrophy. Focal muscleenlargement can also be caused by aninflammatory or neoplastic process,tendon rupture, ectopic ossification, orpartial denervation.

PATTERN RECOGNITIONAPPROACH TO MYOPATHIC

DISORDERSAfter answering the six key questionsoutlined above from the history andneurologic examination, one can at-tempt to classify a myopathic disorderinto one of 10 distinctive patterns ofmuscle weakness, each with a specificdifferential diagnosis. While this mayseem like an oversimplification, therecognition of these patterns will usually

TABLE 8-13 Expanded Medical Research Council Scale for ManualMuscle Testinga

Modified MRC Grade Degree of Strength

5 Normal power

5j Equivocal, barely detectable weakness

4+ Definite but slight weakness

4 Able to move the joint against combination ofgravity and some resistance

4j Capable of minimal resistance

3+ Capable of transient resistance but collapses abruptly

3 Active movement against gravity

3j Able to move against gravity but notthrough full range

2 Able to move with gravity eliminated

1 Trace contraction

0 No contraction

MRC = Medical Research Council.a Reprinted from Medical Research Council, Balliere Tindall.6 B2000, with permission from Elsevier.





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allow the clinician to come very closeto the final diagnosis, which can then

be confirmed based on a selectivenumber of laboratory evaluations.

Pattern 1: Proximal Limb-GirdleWeakness

The most common pattern of muscleweakness in myopathies is symmetricweakness predominantly affecting theproximal muscles of the legs and arms(the limb-girdle distribution). The dis-tal muscles are usually involved to amuch lesser extent as the disease

progresses. Neck flexor and extensormuscles are also commonly affected.Because this pattern of weakness isseen in most hereditary and acquiredmyopathies, it is the least specific inarriving at a particular diagnosis.

Pattern 2: Distal Weakness

This pattern of weakness predominantly

involves the distal muscles of the upperor lower extremities (anterior or poste-rior compartment muscle groups)(Table 8-141). Proximal muscles mayalso be affected, depending on theduration and severity of the disease.The pattern of muscle involvement isusually symmetric. Because selective

weakness and atrophy in distal extrem-ity muscles are more commonly afeature of a peripheral neuropathy, itis important to perform a thorough

sensory examination when patientspresent with this particular phenotype.

Pattern 3: Proximal Arm/DistalLeg (Scapuloperoneal) Weakness

The proximal arm/distal leg pattern ofwea kness aff ects the peris capul armuscles of the proximal upper ex-tremity and the anterior compartmentmuscles of the distal lower extremity;therefore, it is also known as thescapuloperoneal distribution of

weakness. When this pattern is asso-ciated with facial weakness, it is highlysuggestive of a diagnosis of facio-scapulohumeral muscular dystrophy.

Weakness in this pattern is typically

KEY POINTS

h 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).

h When the

scapuloperoneal pattern

of weakness is

associated with facial

weakness, it is highly

suggestive of a

diagnosis of

facioscapulohumeralmuscular dystrophy.

TABLE 8-15 Pattern 3:ScapuloperonealPattern ofWeakness

b Acid maltase deficiency

b Central core myopathy

b Emery-Dreifusshumeroperoneal dystrophy

b Facioscapulohumeral dystrophy

b Limb-girdle dystrophy 2A(calpain), 2C-F (sarcoglycans),2I (FKRP)

b Nemaline myopathy

b Scapuloperoneal dystrophy

TABLE 8-14 Pattern 2:MyopathiesCharacterized byPredominantlyDistal Weaknessa

b Distal myopathies

Late-adult-onset distalmyopathy type 1 (Welander)

Late-adult-onset distalmyopathytype2 (Markesbery/Udd)

Early-adult-onset distal myopathytype 1 (Nonaka)

Early-adult-onset distal myopathytype 2 (Miyoshi)

Early-adult-onset distal myopathytype 3 (Laing)

b Centronuclear myopathy

b Debrancher deficiency

b Hereditary inclusion bodymyopathy

b Inclusion body myositis

b Myofibrillar myopathy







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very asymmetric. The scapular muscleweakness results in winging of the

scapula when patients are asked toextend their arms forward. Other he-reditary myopathies that are associated

with a scapuloperoneal distribution ofweakness are listed inTable 8-15.

Pattern 4: Distal Arm/ProximalLeg Weakness

The distal arm/proximal leg pattern isassociated with upper extremity weak-ness affecting the distal forearm muscles(wrist and finger flexors) and proximal

lower extremity weakness affecting theknee extensors (quadriceps). Facialmuscles are typically spared, and in-

volvement of other muscles is variable.In addition, the weakness is characteris-tically asymmetric. This pattern is essen-tially pathognomonic for inclusion body

myositis (Case 8-1) and may alsorepresent an uncommon presentation

of myotonic dystrophy type 1; how-ever, muscle weakness is symmetric.

Pattern 5: Ptosis With orWithout Ophthalmoparesis

Myopathies presenting with predomi-nant involvement of ocular or pharyn-geal muscles include a relatively limitedgroup of disorders (Table 8-161). Theocular muscle weakness principallyresults in ptosis and ophthalmo-paresis, which almost invariably occurs

without symptoms of diplopia. Facialweakness may also commonly occur,and extremity weakness is extremely

variable, depending on the diagnosis.The combination of ptosis, ophthal-

moparesis without diplopia, and dys-phagia is strongly supportive of the

KEY POINTS

hThe 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).

hThe distal arm/proximal

leg pattern is essentially

pathognomonic for

inclusion body myositis.

Case 8-1A 68-year-old man without significant medical history was referred forevaluation of slowly progressive muscle weakness for the past 5 years. Hissymptoms initially began with difficulty walking down stairs due to hisright knee giving out. He currently had difficulty rising from a chair

and grasping objects with his right hand. Two years ago, he was evaluatedby a neurologist whose workup included a creatine kinase level of 500 IU/Land a left quadriceps muscle biopsy that appeared to be consistentwith polymyositis. The patient had been treated with a variety ofimmunosuppressive medications, including prednisone, methotrexate,and azathioprine, with continued progression of his weakness. Currentexamination revealed intact cranial nerves, sensation, and muscle stretchreflexes. Motor examination in the right upper extremity showedMedical Research Council (MRC) grade 5 shoulder abduction, 5 elbowflexion/extension, 4 wrist flexion, 5 wrist extension, and 3j finger flexion.Strength in the left upper extremity was normal except for grade 4+ fingerflexion. In the left lower extremity, the patient exhibited grade 4+ hipflexion, 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 thispatient are most consistent with a diagnosis of inclusion body myositis.In many cases, initial muscle biopsy fails to identify vacuoles, and patientsare inappropriately treated with immunosuppressant medications forpresumptive polymyositis. In patients with a phenotype consistentwith inclusion body myositis, particularly if they are refractory toimmunosuppressive treatment, a repeat biopsy may be necessary to clarifythe diagnosis.





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diagnosis of oculopharyngeal dystro-phy, especially if the patient has a

positive family history and onset is inmiddle age or later (Case 8-2). Ptosisand ophthalmoparesis without promi-nent pharyngeal involvement are keyfeatures of many of the mitochondrialmyopathies. Ptosis and facial weak-ness without ophthalmoparesis arehallmarks of myotonic dystrophy andfascioscapulohumeral dystrophy.

Pattern 6: Prominent NeckExtensor Weakness

The term dropped head syndromehas been used in the past to describethis clinical phenotype characterizedby selective weakness of the neckextensor muscles (Table 8-171). In-

volve men t of the neck fle xor s isvariable. Extremity weakness is depen-dent on the diagnosis and may followone of the previously outlined patternsof weakness. For example, a patient

with a limb-girdle pattern of weakness

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.

Case 8-2A 70-year-old woman with a family history of myasthenia gravis presentedfor evaluation of a 10-year history of progressive dysphagia and weakness.She specifically denied any symptoms of diplopia and stated that hersymptoms did not fluctuate during the day or when she became fatigued.She had noted no improvement with a course of prednisone 60 mg/d andpyridostigmine 60 mg 4 times daily. Cranial nerve examination wasremarkable for bilateral ptosis, incomplete abduction and adduction ofboth eyes, mild orbicularis oris weakness, and mild tongue weakness.Motor examination revealed bilateral and symmetric Medical ResearchCouncil (MRC) grade 4 neck flexion, 4 shoulder abduction, 4+ elbowflexion, 5 finger extension, 4 hip flexion, 5 knee extension, and 5 ankledorsiflexion and plantar flexion. Sensory, cerebellar, and reflexexamination findings were normal. Workup by a referring physicianwas remarkable for a creatine kinase level of 350 IU/L and a negativeacetylcholine 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 ofoculopharyngeal muscular dystrophy. The absence of symptoms ofdiplopia and muscle fatigability and the patients slowly progressive coursestrongly argues against the diagnosis of a neuromuscular junction disordersuch as myasthenia gravis.

TABLE 8-16 Pattern 5:Myopathies With

Ptosis orOphthalmoparesisa

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 musculardystrophy

Oculopharyngodistal myopathy

Neuromuscular junctiondisease (myasthenia gravis,Lambert-Eaton myasthenicsyndrome, botulism)






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may also have significant neck extensorinvolvement. Isolated neck extension

weakness represents a distinct muscledisorder called isolated neck extensormyopathy. ALS and myasthenia gravisalso commonly present with promi-nent neck extensor weakness.

Pattern 7: Bulbar Weakness

Bulbar weakness (ie, tongue and

pharyngeal weakness) is manifested bysymptoms of dysarthria and dysphagia.

While a number of myopathies canhave some bulbar involvement, themuscular dystrophy that has bulbarinvolvement as a primary manifestationis oculopharyngeal muscular dystrophy.LGMD type 1A (myotilinopathy) canpresent with isolated bulbar weakness,and the inflammatory myopathies mayrarely present in this manner. Neuro-muscular junction disorders such as

myasthenia gravis and Lambert-Eatonmyasthenic syndrome also frequentlyhave bulbar symptoms and signs. Thispattern is considered an overlap pattern

with ALS and other motor neurondisorders that can have significant bul-bar involvement.

Pattern 8: Episodic Pain,Weakness, and Myoglobinuria

A history of episodic pain, weakness,and myoglobinuria characterizes a pat-tern that may be related to a variety ofconditions, many of which are not due

TABLE 8-17 Pattern 6:Myopathies With

Prominent NeckExtensorWeaknessa

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


TABLE 8-18 Pattern 8: Myopathies With Episodic Pain, Weakness,and Myoglobinuria/Rhabdomyolysisa

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 syndromeStatus epilepticus

Drugs/toxins

Malignant hyperthermia

Polymyositis/dermatomyositis (rarely)

Viral/bacterial infections

a Reprinted from Barohn R, American Association of Neuromuscular and ElectrodiagnosticMedicine.7 BAANEM.





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to an underlying muscle disorder(Table 8-187). When these symptoms

are triggered by exercise, a metabolicmyopathy is most likely. However, anumber of patients may develop myo-globulinuria because they are inactiveindividuals who are suddenly requiredto do an overwhelming amount of exer-cise (ie, the couch potato syndrome).

Pattern 9: Episodic WeaknessDelayed or Unrelated to Exercise

A pattern of episodic weakness delayedor unrelated to exercise applies to thedisorders of periodic paralysisVboththe genetic autosomal dominant chan-nelopathies (Table 8-197) and thesecondary periodic paralyses, such asthose due to thyrotoxicosis. Also, for thesake of completeness, it is reasonable toinclude the neuromuscular junction dis-orders in this pattern. In all of theseconditions, the weakness can occur dur-ing or after exercise, or often the weak-ness is unrelated to physical exertion.

Pattern 10: Stiffness and

Decreased Ability to RelaxA pattern of stiffness and decreasedability to relax is seen in all of the

disorders that produce myotonia andparamyotonia and includes the hered-

itary disorders involving sodium andchloride channelopathies (Table 8-208

and Table 8-217) as well as myotonicdystrophy types 1 and 2. Both myo-tonic dystrophies usually have fixedmuscle weakness as well, with pre-dominantly distal weakness in myo-tonic dystrophy type 1 and proximal

weakness in myotonic dystrophy type2. The autosomal recessive form ofchloride channelopathies, Becker dis-ease, also has fixed proximal weak-

ness. In addition, other less commondisorders that fit this pattern includeBrody disease, neuromyotonia, andthe CNS disorder stiff-person syn-drome (see Table 8-208).

Table 8-227 summarizes these 10

patterns of presentation of muscledisease. Once the key questionsreviewed above have been answeredand the patient has been placed intoone of these 10 patterns of weakness,laboratory studies can then be used toconfirm the diagnosis.

LABORATORY APPROACH TOEVALUATING A SUSPECTEDMYOPATHYCreatine Kinase

Creatine kinase (CK) is an extremelyuseful and inexpensive laboratory testfor the evaluation of patients with asuspected myopathy (Table 8-232).CK levels are elevated in the majorityof patients with muscle disease butmay be normal in those with slowly

progressive myopathies. The degreeof CK elevation can also be helpful indistinguishing different forms of mus-cular dystrophy. For example, inDuchenne muscular dystrophy, the CKis often up to 100 times normal levels,

whereas elevations are less significant inmost other myopathies. The otherexceptions are LGMD types 1C (caveo-linopathy), 2A (calpainopathy), and 2B

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.

TABLE 8-19 Pattern 9: EpisodicWeakness Delayedor Unrelated toExercisea

b Periodic paralysis

Ca++ channelopathies(hypokalemic)

Na++ channelopathies

(hyperkalemic)Andersen-Tawil syndrome

Secondary periodic paralysis(thyrotoxicosis)

b Other: Neuromuscular junctiondiseases

a Reprinted from Barohn R, AmericanAssociation of Neuromuscular andElectrodiagnostic Medicine.7 BAANEM.




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(dysferlinopathy), in which CK may alsobe markedly elevated. In some myopa-thies, the CK may be normal or lowered

by several factors, including profoundmuscle wasting, collagen diseases, cor-ticosteroid administration, alcoholism,or hyperthyroidism.

An elevation of serum CK does notnecessarily imply the presence of aprimary myopathic disorder. The CKmay rise modestly (usually to less than10 times normal) in motor neurondisease; uncommonly, CK elevations

may be seen in Charcot-Marie-Toothand Guillain-Barre syndromes. Hypothy-roidism and hypoparathyroidism can

also be associated with high CK levels.Causes of CK elevation other than neu-romuscular disease include strenuousexercise, viral illnesses, muscle trauma(falls, IM or subcutaneous injections,EMG studies), or seizures. In thesecases, CK elevations are usually lessthan 5 times normal and not sustained.

Sex and race can also affect se-rum CK (Table 8-249). CK levels are

KEY POINT

hAn elevation of serum

creatine kinase does not

necessarily imply the

presence of a primary

myopathic disorder.

TABLE 8-20 Channelopathies and Related Disordersa

Disorder Clinical FeaturesPattern ofInheritance Chromosome Gene

Chloride channelopathies

Myotonia congenita

Thomsen disease Myotonia Autosomal dominant 7q35 CLC-1

Becker type Myotonia + weakness Autosomal recessive 7q35 CLC-1

Sodium channelopathies

Paramyotonia congenita Paramyotonia Autosomal dominant 17q13.1Y13.3 SCNA4A

Hyperkalemic periodicparalysis

Periodic paralysisand myotonia andparamyotonia

Autosomal dominant 17q13.1Y13.3 SCNA4A

Potassium-aggravated

myotonias

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

Calcium channelopathies

Hypokalemic periodicparalysis

Periodic paralysis Autosomal dominant 1a31Y32 Dihydropyridinereceptor

Schwartz-Jampel syndrome(Chondrodystrophic myotonia)

Myotonia; dysmorphic Autosomal recessive 1p34.1Y36.1 Perlecan

Rippling muscle disease Muscle mounding/stiffness

Autosomal dominant 1q41 3p25 UnknownCaveolin-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-induceddelayed relaxation

Autosomal dominant 19q13.1 Ryanodinereceptor

a Modified from Barohn RJ, Saunders.8 B2000, with permission from Elsevier.





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frequently above the laboratorys nor-mal range in black patients and in those

with enlarged muscles. Occasionally,benign elevations of CK appear on agenetic basis. It is extremely unusual fora slightly elevated CK (threefold or less)to be associated with an underlyingmyopathy in the absence of pain orobjective muscle weakness. Enzymessuch as aspartate aminotransferase

(AST), alanine aminotransferase (ALT),and lactate dehydrogenase (LDH) maybe slightly elevated in myopathies. Since

AST, ALT, and LDH are often measuredin screening chemistry panels, theirelevation should prompt CK measure-ment to determine whether the sourceis from muscle or liver. If a patient withan inflammatory myopathy is treated

with an immunosuppressive agent that

may cause hepatotoxicity, the liver-specific enzyme ,-glutamyltransferase

(GGT) should be monitored.In general, CK isoenzymes are not

helpful in evaluating myopathies. CK-MM elevations are typical of muscledisease, but CK-MB is also elevated inmyopathies and does not indicate thatcardiac disease is present.

Electrophysiologic Studies

Electrophysiologic studies, consisting ofnerve conduction studies and EMG,should be part of the routine evaluation

of a patient with a suspected muscledisorder. These studies are helpful inconfirming that the muscle is the correctsite of the lesion and that weakness isnot due to motor neuron disease,neuropathy, or neuromuscular junctiondisorder. Nerve conduction studies aretypically normal in patients with myopa-thy; in advanced myopathies, however,the compound muscle action potentialamplitudes can be reduced. NeedleEMG examination showing evidence ofbrief-duration, small-amplitude motor

units with increased recruitment can behelpful in confirming the presence of amyopathy. 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 thatthe EMG can be normal in a patient

with myopathy, and the results ofelectrodiagnostic studies need to beevaluated in the context of the pa-

tients history, neurologic examination,and laboratory studies.

Muscle Biopsy

If the clinical and electrodiagnosticfeatures suggest the possibility of amyopathy, a muscle biopsy may be anappropriate next step in order toconfirm the diagnosis. Currently,many forms of hereditary muscle

TABLE 8-21 Pattern 10:Stiffness/

DecreasedAbility to Relaxa

b Improves With Exercise

Myotonia: Na or Clchannelopathy

b Worsens With Exercise/ColdSensitivity

Paramyotonia: Nachannelopathy

Brody disease

b With Fixed Weakness

Myotonic dystrophy (DM 1)Proximal myotonic myopathy(DM 2)

Becker disease (AR Cl-

channelopathy)

b Other

Malignant hyperthermia

Neuromyotonia

Rippling muscle

Stiff-person syndrome

a Reprinted from Barohn R, AmericanAssociation of Neuromuscular andElectrodiagnostic Medicine.7 BAANEM.




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TABLE 8-22 Clinical Patterns of Muscle Disorders

Pattern Weakness Diagnosis

Proximal Distal Asymmetric Symmetric Episodic Trigger

Pattern 1b

Limb-girdle

+ + Most myopathies,hereditary and acquired(overlap with spinalmuscular atrophy)b

Pattern 2b

Distal

+ + Distal myopathies(overlap withneuropathies)b

Pattern 3

Proximal arm/distal leg

scapuloperoneal

+

Arm

+

Leg

+

(Fascioscapulohumeralmuscular dystrophy)

+

(Others)

Fascioscapulohumeralmuscular dystrophy,Emery-Dreifuss, acid

maltase, congenitalscapuloperoneal

Pattern 4

Distal arm/proximal leg

+

Leg

+

Arm

+ Inclusion body myositis,myotonic dystrophy

Pattern 5

Ptosis/ophthalmoplegia

+ +

(Myasthenia gravis)

+

(Others)

Oculopharyngealdystrophy, myastheniagravis, myotonicdystrophy, mitochondrial

Pattern 6b

Neck extensor

+ + Isolated neck extensormyopathy, myastheniagravis, (overlap with ALS)b

Pattern 7b

Bulbar (tongue,pharyngeal)

+ + Myasthenia gravis,Lambert-Eatonmyasthenic syndrome,oculopharyngealdystrophy (overlapwith ALS)b

Pattern 8

Episodic weakness/pain/rhabdomyolysis+ trigger

+ + + + McArdle, carnitinepalmitoyltransferase,drugs, toxins

Pattern 9

Episodic weaknessdelayed or

unrelated toexercise

+ + + +/- Primary periodicparalysis;channelopathies:

Na, Ca; secondaryperiodic paralysis

Pattern 10

Stiffness/inabilityto relax

+ +/- Myotonic dystrophy,channelopathies,rippling muscle(other: stiff-person,neuromyotonia)

a Reprinted from Barohn R, American Association of Neuromuscular and Electrodiagnostic Medicine.7 BAANEM.b Overlap patterns with neuropathy/motor neuron disease.





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disorders can be diagnosed with mo-lecular genetic testing, eliminating theneed to perform a muscle biopsy.Either an open or closed (needle orpunch) biopsy procedure can beperformed in order to obtain a muscle

specimen. The advantages of a needlebiopsy are that it is minimally invasive

and more cosmetically appealing andmultiple specimens can be obtained.The primary disadvantage of needlebiopsy is the need to ensure that anadequate amount of tissue is sampled.Selecting the appropriate muscle tobiopsy is critical. Muscles that areseverely weak (MRC grade 3 or less)should not be biopsied unless theonset of weakness is acute (such asin dermatomyositis) because the re-sults are likely to show only evidence

of end-stage muscle. In addition, mus-cles that have recently been studiedby needle EMG or injected with animmunization should be avoided be-cause of the possibility of artifactscreated by needle insertion. Generally,biopsies should be taken from mus-cles that demonstrate MRC grade 4strength. In the upper extremities, themuscles of choice are either the bicepsor deltoid; in the lower extremities, thebest choice is the vastus lateralis. Thegastrocnemius should be avoided since

its tendon insertion extends through-out the muscle and inadvertent sam-pling of a myotendinous junction maycause difficulty with interpretation.Occasionally, an imaging proceduresuch as muscle ultrasound, CT, or MRIcan be used to guide selection of theappropriate muscle to biopsy.

Biopsy specimens can be analyzedby light microscopy, electron micros-copy, biochemical studies, and immunestaining (Table 8-252). Usually, light

microscopic observations of frozenmuscle tissue specimens are sufficientto make a pathologic diagnosis. Typicalmyopathic abnormalities include cen-tral nuclei, split fibers, both small andlarge hypertrophic round fibers, anddegenerating and regenerating fibers.Chronic myopathies frequently showevidence of increased connective tis-sue 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.

TABLE 8-23 DifferentialDiagnosis of

Creatine KinaseElevationa

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/

hypoparathyroidismMedications

Race

Sex

Strenuous exercise

Surgery

Trauma (EMG studies,intramuscular or subcutaneousinjections)

ALS = amyotrophic lateral sclerosis.a Updated from Jackson CE, Continuum

(Minneap Minn).2 B 2006, AmericanAcademy of Neurology. journals.lww.com/continuum/Fulltext/2006/

06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx.


http://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspxhttp://localhost/var/www/apps/conversion/tmp/scratch_1/journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx


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are characterized by the presence ofmononuclear inflammatory cells in theendomysial and perimysial connectivetissue between fibers and occasionallyaround blood vessels. In addition,atrophy of fibers located on the pe-riphery of a muscle fascicle (perifasci-

cular atrophy) is a common finding indermatomyositis.

For general histology, the hematoxylinand eosin (H&E) and modified Gomorione-step trichrome are the most usefulstains. The latter is particularly helpfulin identifying ragged red fibers, which

TABLE 8-24 Effect of Race and Gender on Creatine KinaseMeasurementsa

Group ConstituentsUpper Limit of Normal(97.5%)

High Black males 520 IU/L

Intermediate Nonblack males

Black females

345 IU/L

Low Nonblack females 145 IU/La 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.

TABLE 8-25 Utility of Muscle Biopsy Stains and HistochemicalReactionsa

Histochemical Reactions and Stains Clinical Utility

Adenosine triphosphatase (ATPase) Distribution of fiber types

Gomori trichrome General histology and mitochondrialdisease

Hematoxylin and eosin General histology

Nicotinamide adenine dinucleotideglycohydrolase (NADH), succinatedehydrogenase (SDH), cytochromeoxidase

Myofibrillar and mitochondrialabnormalities

Oil Red O Lipid storage diseases

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 musculardystrophy

Dysferlin immunostain Limb-girdle muscular dystrophy type2B

Membrane attack compleximmunostain

Dermatomyositis

a Reprinted from Jackson CE, Continuum (Minneap Minn).2 B 2006, American Academy ofNeurology. journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx.



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might suggest a mitochondrial disor-der. In addition to these standardstains, other histochemical reactionscan be used to gain additional in-formation (Table 8-252). The myosinadenosine triphosphatase (ATPase)stains (alkaline hydrogen ion concen-tration [pH] 9.4; acidic pH 4.3 and4.6) allow a thorough evaluation ofhistochemistry fiber types. Type 1fibers (slow twitch, fatigue resistant,

oxidative metabolism) stain lightly atalkaline pHs and darkly at acidic pHs.Type 2 fibers (fast twitch, fatigueprone, glycolytic metabolism) staindarkly at alkaline pHs and lightly atacidic pHs. Normally, distribution ofthe two fiber types is random, andthere are generally twice as many type2 as type 1 fibers. In a number ofmyopathies, nonspecific type 1 fiber

predominance occurs. Oxidative en-zyme stains (cytochrome c oxidase,reduced-form nicotinamide adeninedinucleotide [NADH] dehydrogenase,succinate dehydrogenase) are usefulfor identifying mitochondrial and myo-fibrillar defects. Oil Red O stains mayassist with the diagnosis of a lipidstorage disease, and periodic acid-Schiff stains can be helpful in identify-ing glycogen storage diseases. Alkaline

phosphatase and acid reactions canhighlight regenerating and necroticfibers, respectively. Qualitative bio-chemical enzymes stains can be per-formed for myoadenylate deaminase(MAD deficiency), myophosphorylase(McArdle disease), and phosphofruc-tokinase (PFK deficiency). Amyloiddeposition can be assayed with Congored or crystal violet staining. Finally,

TABLE 8-26 Disorders With Commercially Available MolecularGenetic 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)

bMitochondrial 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 (MTM1mutations)

b Nemaline myopathy (ACTA1 mutations)

b Oculopharyngeal muscular dystrophy (OPMD)

a Updated from Jackson CE, Continuum (Minneap Minn).2 B 2006, American Academy ofNeurology. journals.lww.com/continuum/Fulltext/2006/06000/A_Clinical_Approach_to_the_Patient_With_Suspected.3.aspx.


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immunohistochemical techniques canstain for muscle proteins that are defi-

cient in some muscular dystrophies (eg,dystrophin in Duchenne and Beckerdystrophies) or for products that areincreased in certain inflammatory my-opathies, such as the membrane attackcomplex in dermatomyositis.

Electron microscopy evaluates theultrastructural components of musclefibers and is not required in order tomake a pathologic diagnosis in themajority of myopathies. It is impor-tant, however, in the diagnosis of

some congenital myopathies and mi-t o c ho n d ri a l d i s or d er s . F i nd i n gsdetected only by electron microscopyare seldom of clinical importance.

The muscle tissue can also beprocessed for biochemical analysis todetermine a specific enzyme defect inthe evaluation of a possible metabolicor mitochondrial myopathy. In addi-tion, Western blot determinations frommuscle tissue can be performed forcertain muscle proteins.

Molecular Genetic StudiesThe specific molecular genetic defectis now known for a large number ofhereditary myopathies, and mutationscan be identified by peripheral bloodDNA analysis. Examples of commerciallyavailable molecular genetic studies areincluded in Table 8-262. This list iscontinually updated on www.genetests.org. Molecular genetic testing fre-quently eliminates the need for musclebiopsy. This technology is also ex-

tremely helpful for determining carrierstatus and performing prenatal testing.

Other Tests

In addition to CK determinations,other blood tests that can be extremelyhelpful in the evaluation of a patient

with a suspected myopathy include se-rum electrolytes, parathyroid hormonelevels, thyroid function tests, vitamin D

levels, and HIV tests. In patients with aninflammatory myopathy, serologic deter-

minations for systemic lupus erythe-matosus, rheumatoid arthritis, andother immunologic markers (eg, Jo-1antibodies) can occasionally be useful. Aurinalysis can also be performed todetect the presence of myoglobinuria.This should be suspected if the urinetests positive for blood but no red bloodcells are identified.

Forearm exercise testing can be acritical part of the evaluation of apatient with a suspected metabolic

myopathy. The exercise test shouldbe carried out without the bloodpressure cuff because ischemic exer-cise may be hazardous in patients withdefects in the glycolytic enzyme path-

way. The test is conducted by askingthe patient to perform isometric con-tractions using a hand grip dynamom-eter for 1.5 seconds separated by restperiods of 0.5 seconds for 1 minute. Aresting blood sample for venous lac-tate and ammonia is obtained atbaseline and subsequently at 1, 2, 4,

6, and 10 minutes after the comple-tion of exercise. A threefold increasein lactate level represents a normalresponse. In certain disorders, thecharacteristic elevation of serum lac-tate after exercise is absent (eg, PFKdeficiency, myophosphorylase defi-ciency) or reduced (eg, phosphoglyc-erate mutase deficiency). Forearmtesting is normal in all disorders of fatmetabolism as well as in some glyco-lytic disorders with fixed muscle weak-

ness, such as acid maltase deficiency.

CONCLUSION

While this pattern recognition approachto myopathy may have limitations, itcan be extremely helpful in narrowingthe differential diagnosis and thus inminimizing the number of laboratorystudies that must be ordered to con-firm the diagnosis. There will always be



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patients with a suspected muscle dis-order who do not fit neatly into any of

these 10 categories. In addition, patientswith disorders of the motor neuron,peripheral nerve, or neuromuscularjunction may also frequently present

with one of these patterns. For example,while proximal greater than distal weak-ness is most often seen in a myopathy,patients with acquired demyelinatingneuropathies (Guillain-Barre syndromeand chronic inflammatory demyelinat-ing polyneuropathy) often have proxi-mal as well as distal muscle involvement.

Careful consideration of the distributionof muscle weakness and attention tothes

a pattern recognition approach to myopathy. continuum

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