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A CLINICAL APPROACH

TO THE PATIENT WITHSUSPECTED MYOPATHYCarlayne E. Jackson

ABSTRACT

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

INTRODUCTION

Myopathies are disorders in which aprimary functional or structural im-pairment of skeletal muscle exists.Myopathies can be distinguished fromother disorders of the motor unit,including motor neuron disorders,peripheral neuropathies, and neuro-muscular junction diseases, by charac-teristic clinical and laboratory features.Therefore, the first goal in approach-ing a patient with a suspected muscledisease is to determine the correct siteof the lesion. Once localized to themuscle, the next step is to identify

whether the myopathy is due to a

defect in the muscle channel, musclestructure, or a dysfunction in musclemetabolism. The second goal is todetermine the cause of the myopathy.In general, myopathies can be classi-fied into hereditary and acquireddisorders (Table 1-1 ). The third goalis to determine whether a specifictreatment is available and if not, tooptimally manage the patients symp-toms to maximize his or her functionalabilities and enhance quality of life.

CLINICAL EVALUATION

The most important element of evalu-ating a patient with a suspected myopa-thy is obtaining a thorough history.This should allow the physician tomake a reasonable preliminary diag-nosis that places the patient into oneof the categories in Table 1-1. Thefindings on the physical examination,and in particular the distribution ofmuscle weakness, should provide ad-ditional information in determining thecorrect diagnosis. The results of thelaboratory studies (blood tests, elec-tromyogram [EMG], muscle biopsy,molecular genetic studies) then play

a confirmatory diagnostic role.The first step in approaching apatient is to ask six key questions basedon the patients symptoms and signs.(1) Which negative and/or posi-tive symptoms and signs does thepatient demonstrate?

Symptoms and signs of muscle dis-ease (Table 1-2 ) can be divided intonegative complaints such as weakness,exercise intolerance, fatigue, and mus-cle atrophy, and positive complaints

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such as myalgias, cramps, contractures,myoglobinuria, and muscle stiffness(Barohn, 2004).

Weakness is by far the most commonnegative symptom reported by a patient

with muscle disease. If the weaknessinvolves the lower extremities, patients

will complain of difficulty climbingstairs, arising from a low chair or toilet,or getting up from a squatted position.

When the upper extremities are involved, patients notice trouble liftingobjects over their head and brushingtheir hair. These symptoms in the arms

and legs indicate proximal muscle weakness, which is probably the mostcommon type of weakness in a myo-pathic disorder (see below). Less com-monly, patients with myopathies cancomplain of distal weakness manifestedas difficulty opening jars, inability toturn a key in the ignition, or trippingdue to footdrop. Some myopathies mayalso result in cranial muscle weakness,resulting in complaints of dysarthria,dysphagia, or ptosis.

Fatigue is a much less useful nega-tive symptom, as it is nonspecific andmay reflect a patients cardiopulmo-

nary status, level of conditioning, over-all health, sleeping habits, or emotionalstate. Many patients who complain ofdiffuse global weakness or fatigue donot have a muscle disorder, particularlyif the neurological examination is nor-mal. On the other hand, abnormal fati-gability after exercise can result fromcertain metabolic and mitochondrialmyopathies, and it is important to de-fine the duration and intensity of exer-cise that provokes the fatigue.

Positive symptoms associated withmyopathies mayinclude myalgias,cramps,contractures, myotonia, or myoglo-binuria. Myalgia, like fatigue, is anothernonspecific symptom of some myopa-thies ( Table 1-3 ). Myalgias may beepisodic (metabolic myopathies) ornearly constant (inflammatory muscledisorders). However, pain is usuallynot common in most muscle diseasesand is more likely to be due to or-thopedic or rheumatological disorders

(Kincaid, 1997). It is rare for a muscledisease to be responsible for vague

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TABLE 1-1 Classification ofMyopathies

" Hereditary

Muscular dystrophies

Myotonias

Channelopathies

Congenital myopathies

Metabolic myopathies

Mitochondrial myopathies

" Acquired

Inflammatory myopathies

Endocrine myopathies

Myopathies associated withother systemic illness

Drug-induced myopathies

Toxic myopathies

TABLE 1-2 Symptoms andSigns AssociatedWith Myopathies

" Negative

Weakness

Fatigue

Exercise intolerance

Muscle atrophy

" Positive

Myalgias

Cramps

Contractures

Myotonia

Myoglobinuria

KEY POINTS:

A Weakness is

by far the

most common

negativesymptom

reported by

a patient

with muscle

disease.

A Abnormal

fatigability

after exercise

can result

from certain

metabolic and

mitochondrialmyopathies,

and it is

important to

define the

duration and

intensity of

exercise that

provokes

the fatigue.

A It is rare for

a muscle

disease tobe responsible

for vague aches

and muscle

discomfort in

the presence

of a normal

neuromuscular

examination

and laboratory

studies.

"SUSPECTED MYOPATHY



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aches and muscle discomfort in thepresence of a normal neuromuscularexamination and laboratory studies.

A specific type of muscle pain is theinvoluntary muscle cramp. Cramps maylast from seconds to minutes and areusually localized to a particular muscleregion. They are typically benign, occur-ring frequently in normal individuals,and are seldom a feature of a primarymyopathy. Cramps are characterized byrapidly firing motor unit discharges,

which can be demonstrated on needleEMG. Cramps can occur with dehydra-tion, hyponatremia, azotemia, and myx-edema and in disorders of the nerve ormotor neuron (especially amyotrophiclateral sclerosis).

Muscle contractures are uncommonbut can superficially resemble a cramp.They are typically provoked by exercise

in patients with glycolytic enzyme de-fects. Contractures differ from crampsin that they usually last longer and areelectrically silent with needle EMG.Mus-cle disorders that are associated withcontractures are listed in Table 1-4.

Myotonia is the phenomenon of im-paired relaxation of muscle after force-ful voluntary contraction and mostcommonly involves the hands and eye-lids. Myotonia is due to repetitive de-polarization of the muscle membrane.

Patients may complain of muscle stiff-ness or tightness resulting in difficultyreleasing their handgrip after a hand-shake, unscrewing a bottle top, or

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TABLE 1-3 Muscle Disorders Associated With Myalgias

" Mitochondrial myopathies

" Inflammatory myopathies (polymyositis, dermatomyositis)

" Infectious myositis (especially viral)

" Drug-induced myopathies (lovastatin, chloroquine)

" Hypothyroid myopathy

" Myoadenylate deaminase deficiency

" Tubular aggregate myopathy

" X-linked myalgia and cramps (Becker dystrophy variant)

" Eosinophilia-myalgia syndrome

TABLE 1-4 MyopathiesAssociatedWith Muscle

Contractures

" Glycolytic/glycogenolyticenzyme defects

Myophosphorylase deficiency(McArdles disease)

Phosphofructokinasedeficiency

Phosphoglycerate kinasedeficiency

Phosphoglycerate mutase

deficiencyLactate dehydrogenasedeficiency

Debrancher enzymedeficiency

" Paramyotonia congenita


" Brodys disease

" Rippling muscle disease

KEY POINT:

A Cramps may

last from

seconds to

minutes andare usually

localized to

a particular

muscle region.

They are

typically

benign,

occurring

frequently in

normal

individuals,

and are seldom

a feature of

a primary

myopathy.



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opening their eyelids if they forcefullyshut their eyes. Myotonia classicallyimproves with repeated exercise. Incontrast, patients with paramyotoniacongenita demonstrate paradoxicalmyotonia in that symptoms are typi-cally worsened by exercise or repeatedmuscle contractions. Exposure to coldresults in worsening of both myotoniaand paramyotonia. The muscle disor-ders associated with muscle stiffness are

listed in Table 1-5.

Myoglobinuria is a relatively uncom-mon manifestation of muscle disease

and is caused by the excessive release of

myoglobin from muscle during periodsof rapid muscle destruction (rhabdo-

myolysis). Severe myoglobinuria canresult in renal failure due to acute tu-

bular necrosis. If patients complain ofexercise-induced weakness and myal-gias, they should be asked if their urine

has ever turned cola-colored or redduring or after these episodes.

Recurrent myoglobinuria is usually

due to an underlying metabolic my-

opathy (Table 1-6 ), whereas isolated

episodes, particularly occurring afterunaccustomed strenuous exercise, are

frequently idiopathic.(2) What is the temporal evolu-tion?

It is obviously important to deter-

mine the onset, duration, and evolution

of the patients symptoms and signs of

muscle disease. Did the weakness (or

other symptoms) first manifest at birth,

or was the onset in the first, second,

third, or a later decade ( Table 1-7)?

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TABLE 1-5 MyopathiesAssociated WithMuscle Stiffness

" Myotonic dystrophy

" Myotonia congenita

" Paramyotonia congenita

" Proximal myotonic myopathy

" Hyperkalemic periodicparalysis


TABLE 1-6 Causes of Myoglobinuria

" Prolonged, intensive exercise

" Viral and bacterial infections

" Drugs and toxins (especially alcohol)

" Neuroleptic malignant syndrome

" Heat stroke

" Trauma (crush injuries)

" Severe metabolic disturbances, including prolonged fever

" Inflammatory myopathies (rare)

" Limb-girdle muscular dystrophy 2C-2F (sarcoglycanopathies)

" Metabolic myopathies

Glycogenoses (myophosphorylase deficiency)

Lipid disorders (carnitine palmitoyltransferase deficiency)

" Malignant hyperthermia (central core myopathy, Duchennemuscular dystrophy)

KEY POINT:

A Recurrent

myoglobinuria

is usually

due to anunderlying

metabolic

myopathy,

whereas

isolated

episodes,

particularly

occurring after

unaccustomed

strenuous

exercise, are

frequently

idiopathic.

"SUSPECTED MYOPATHY



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

" Myopathies Presenting at Birth

Congenital myotonic dystrophy

Centronuclear (myotubular) myopathy

Congenital fiber-type disproportion

Central core disease

Nemaline (rod) myopathy

Congenital muscular dystrophy

Lipid storage diseases (carnitine deficiency)

Glycogen storage diseases (acid maltase and phosphorylase deficiencies)

" Myopathies Presenting in Childhood


Duchenne

Becker

Emery-Dreifuss

Facioscapulohumeral

Limb-girdle

Congenital


Dermatomyositis

Polymyositis (rarely)


Nemaline

Centronuclear

Central core

Lipid storage disease (carnitine deficiency)

Glycogen storage disease (acid maltase deficiency)


Endocrine-metabolic disorders

Hypokalemia

Hypocalcemia

Hypercalcemia

" Myopathies Presenting in Adulthood


Limb-girdle

Continued on next page



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Identifying the age that symptomsbegan can provide crucial informationleading to the correct diagnosis. Forexample, symptoms of Duchenne mus-cular dystrophy usually are identified by

age 3, whereas most facioscapulohum-eral and limb-girdle muscular dystro-phies (LGMDs) begin in adolescence orlater. Of the inflammatory myopathies,dermatomyositis occurs in children and

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TABLE 1-7 Continued

Facioscapulohumeral

Becker

Emery-Dreifuss


Polymyositis

Dermatomyositis

Inclusion body myositis

Viral (human immunodeficiency virus [HIV])


Acid maltase deficiency

Lipid storage diseases

Debrancher deficiency

Phosphorylase b kinase deficiency


Endocrine myopathies

Thyroid

Parathyroid

Adrenal

Pituitary disorders

Toxic myopathies

Alcohol

Corticosteroids

Local injections of narcotics

Colchicine

Chloroquine

Statins

Myotonic dystrophy

Distal myopathies

Nemaline myopathy

Centronuclear myopathy

"SUSPECTED MYOPATHY



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adults; polymyositis occurs rarely inchildren but at any decade in the adult

years; and inclusion body myositis oc-

curs most commonly in the elderly.It is also imperative to determine theevolution and duration of the disease.Myopathies can present with eitherconstant weakness (muscular dystro-phies, inflammatory myopathies) orepisodic periods of weakness withnormal strength interictally (periodicparalysis, metabolic myopathies due tocertain glycolytic pathway disorders).The episodic disorders have acute

weakness that can return to normal

strength within hours or days. Thetempo of the disorders with constant

weakness can vary among: (1) acute orsubacute progression in some inflam-matory myopathies (dermatomyositisand polymyositis); (2) chronic slowprogression over years (most musculardystrophies); or (3) nonprogressive

weakness with little change over de-cades (congenital myopathies). Finally,both constant and episodic myopathicdisorders can have symptoms that maybe monophasic or relapsing. For exam-ple, polymyositis can occasionally havean acute monophasic course with com-plete resolution of strength within

weeks or months. Patients with periodicparalysis or metabolic myopathies canhave recurrent attacks of weaknessover many years, whereas a patient withacute rhabdomyolysis due to cocainemay have a single episode.(3) Is there a family history of a

myopathic disorder?Since many myopathies are inher-ited, obtaining a thorough family his-tory is clearly of great importance inmaking a correct diagnosis. A detailedfamily tree should be completed to lookfor evidence of autosomal dominant,autosomal recessive, and X-linked pat-terns of transmission. Questions regard-ing family members use of canes or

wheelchairs, skeletal deformities, orfunctional limitations are usually more

informative than questions such as,Does any member of your family havea muscle disease? Identifying a particu-

lar hereditary pattern not only may helpin correctly diagnosing the specificmyopathy (Table 1-8 ) but is also oftremendous importance in providingappropriate genetic counseling.(4) Are there precipitating factors thattriggerepisodicweaknessor myotonia?

A history of precipitating factors thatmight trigger or exacerbate symptoms

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TABLE 1-8

Diagnosis of

Myopathy Basedon Pattern ofInheritance

" X-Linked

Duchenne musculardystrophy

Becker muscular dystrophy

Emery-Dreifuss musculardystrophy

" Autosomal Dominant

Facioscapulohumeraldystrophy

Limb-girdle musculardystrophy

Oculopharyngeal musculardystrophy

Myotonic dystrophy

Periodic paralysis

Paramyotonia congenita

Thomsen disease

Central core myopathy

" Autosomal Recessive

Limb-girdle musculardystrophy


Becker myotonia

" Maternal Transmission


KEY POINT:

A Myopathies

can present

with either

constantweakness

(muscular

dystrophies,

inflammatory

myopathies)

or episodic

periods of

weakness

with normal

strength

interictally

(periodic

paralysis,

metabolic

myopathies

due to certain

glycolytic

pathway

disorders).



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of weakness or myotonia should be ex-plored. It is important to ask the patientif there is any history of either illegal

drug or prescription medication usethat might produce a myopathy. Ahistory of weakness, pain, and/or myo-globinuria that is provoked by exercisemight suggest the possibility of a gly-colytic pathway defect. Episodes of

weakness that occur in association witha fever would be supportive of a diag-nosis of carnitine palmityl transferasedeficiency. Periodic paralysis is charac-teristically provoked by exercise or in-gestion of a carbohydrate meal followed

by a period of rest. Patients with para-myotonia congenita frequently reportthat cold exposure may precipitate theirsymptoms of muscle stiffness.(5) Are associated systemic symp-toms or signs present?

Involvement of organs or tissues otherthan muscle may also provide helpfulclues in making the appropriate diag-nosis. Cardiac disease (Table 1-9) maybe associated with myotonic dystrophy,Duchenne or Becker muscular dystro-phies, LGMD1B (laminopathy), LGMD2I(fukutin-related protein), LGMD2C2F(sarcoglycanopathies), LGMD2G (tele-thoninopathy), Emery-Dreifuss muscu-lar dystrophy, and Andersen syndrome.

Respiratory failure may be the pre-senting symptom of myotonic dystro-phy, centronuclear myopathy, nemalinemyopathy, or acid maltase deficiency(Table 1-10). Eventually, most myopa-thies will affect respiratory muscle

strength, highlighting the need forconsistent monitoring of pulmonaryfunction studies throughout the dis-ease course. Once symptoms of hypo-

ventilation are evident, supportive carewith noninvasive positive pressure ven-tilation and assistive devices for clear-ance of upper airway secretions shouldbe used.

Hepatomegaly may be seen in myopa-thies associated with deficiencies inacid maltase, debranching enzyme, and

carnitine. The presence of cataracts,frontal balding, and mental retardationstrongly suggests the diagnosis of myo-

tonic dystrophy. Dysmorphic featuresmay be associated with the congenitalmyopathies. The presence of a rash isextremely helpful in confirming thediagnosis of dermatomyositis. Muscu-loskeletal contractures can occur inmany myopathies of long-standing du-ration. However, contractures develop-ing early in the course of the disease,especially at the elbows, can be a clueto Emery-Dreifuss dystrophy, LGMD1B(laminopathy), and Bethlem myopathy.

Evidence of diffuse systemic disease canindicate amyloidosis, sarcoidosis, endo-crinopathy, collagenvascular disease,

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TABLE 1-9 MyopathiesAssociated WithCardiac Disease

" Arrhythmias

Kearns-Sayre syndrome

Andersens syndrome

Polymyositis


Myotonic

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

Emery-Dreifuss

" Congestive Heart Failure


Duchenne

Becker

Emery-Dreifuss

Myotonic

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

Nemaline myopathy


Carnitine deficiency

Polymyositis

KEY POINTS:

A Periodic

paralysis is

characteristically

provoked byexercise or

ingestion of a

carbohydrate

meal followed

by a period

of rest.

A Involvement

of organs or

tissues other

than muscle

may also

provide helpfulclues in making

the appropriate

diagnosis.

"SUSPECTED MYOPATHY



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infectious disease, or a mitochondrialdisorder.(6) What is the distribution ofweakness?

To determine the distribution ofmuscle weakness, it is important toknow which muscles to test and how tograde their power. Muscle strengthcan be tested by manual testing and

from observation of functional activity( Table 1-11 ) (Brooke, 1986). Func-tional testing is particularly informativein young children who usually cannotcooperate with formal manual muscletesting and in adults with give-way

weakness who present with complaintsof muscle pain.

In performing manual muscle testingof the upper extremities, it is necessaryto assess shoulder abduction and exter-nal and internal rotation; elbow flexion

and extension; wrist flexion and exten-sion; and finger and thumb extension,flexion, and abduction. Muscle groups

that should be tested in the lower ex-tremities include hip flexion, extension,and abduction; knee flexion and exten-sion; ankle dorsiflexion, plantar flexion,inversion, and eversion; and toe exten-sion and flexion. All muscle groupsshould be tested bilaterally and prefer-ably against gravity. Neck flexors shouldbe assessed in the supine position andneck extensors in the prone position.Knee extension and hip flexion shouldbe tested in the seated position, knee

flexion should be tested in the proneposition, and hip abduction should betested in the lateral decubitus position.If testing against gravity is not done, thepresence of significant muscle weaknesscan escape recognition. Assessment ofmuscle strength is usually based onthe expanded Medical Research Council(MRC) of Great Britain grading scale of0 to 5 (Table 1-12) (Medical ResearchCouncil, 2000). Finally, cranial nervemuscles such as the orbicularis oculiand oris, extraocular muscles, tongue,and palate should be examined. Thesemay be best tested by observation of thepatient performing functional activitiessuch as whistling, sucking from a straw,and smiling.

In addition to manual muscle testingand functional testing, muscles shouldbe inspected for evidence of atrophy orhypertrophy. Atrophy of proximal limbmuscles is common in most chronic

myopathies. However, certain myopa-thies may demonstrate atrophy in spe-cific groups that correspond to severe

weakness in those muscles and provideadditional diagnostic clues. For exam-ple, atrophy of the periscapular musclesassociated with scapular winging ischaracteristic of facioscapulohumeraldystrophy. Scapular winging is alsoseen in patients with LGMD1B (la-minopathy), LGMD2A (calpainopathy),and LGMD2C2F (sarcoglycanopathies).

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TABLE 1-10 MyopathiesAssociated WithRespiratory

Insufficiency

" Muscular Dystrophies

Duchenne

Becker

Emery-Dreifuss

Limb-girdle

Myotonic

Congenital

" Metabolic Myopathies


Carnitine deficiency

" Mitochondrial Myopathies

" Congenital Myopathies

Nemaline

Centronuclear

" Inflammatory Myopathies

Polymyositis

KEY POINT:

A Functional

testing is

particularly

informativein young

children,

who usually

cannot

cooperate

with formal

manual

muscle testing,

and in

adults with

give-way

weakness who

present with

complaints of

muscle pain.



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Selective atrophy of the quadricepsmuscles and forearm flexor musclesis highly suggestive of inclusion bodymyositis. Distal myopathies may haveprofound atrophy of the anterior orposterior lower extremity compart-ments. On the other hand, musclescan show evidence of hypertrophy insome myotonic conditions such asmyotonia congenita. Muscle hypertro-phy is also a characteristic of disor-ders including amyloidosis, sarcoido-sis, and hypothyroid myopathy. InDuchenne and Becker dystrophy, thecalf muscles demonstrate pseudo-hypertrophy due to replacement with

connective tissue and fat. Calf musclehypertrophy is also characteristicallyseen in LGMD2C2F (sarcoglycanopa-thies) and LGMD2I (fukutin-relatedprotein). In LGMD2G (telethoninopa-thy), 50% of the patients will showcalf hypertrophy and 50% will demon-strate calf atrophy. Focal muscle en-largement can also be due to a neo-plastic or inflammatory process, ectopicossification, tendon rupture, or partialdenervation.

PATTERN-RECOGNITIONAPPROACH TO MYOPATHICDISORDERS

After answering the six key questions

obtained from the history and neuro-logical examination outlined above, onecan attempt to classify a myopathic dis-order into one of six distinctive patternsof muscle weakness, each with a limiteddifferential diagnosis. The final diagno-sis can then be confirmed based on in-formation from a selective number oflaboratory studies.

Pattern 1: Proximal Limb-GirdleWeakness

The most common pattern of muscle weakness in myopathies is symmetri-cal weakness affecting predominantlythe proximal muscles of the legs andarms, or the so-called limb-girdle dis-tribution. The distal muscles are usu-ally involved, but to a much lesserextent. Neck extensor and flexor mus-cles are also frequently affected. Thispattern of weakness is seen in mosthereditary and acquired myopathies

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TABLE 1-11 Functional Assessment of Muscle Weakness

Location Signs or Symptoms of Weakness

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

Ocular Double vision, ptosis, dysconjugate eye movements

Bulbar Nasal speech, weak cry, nasal regurgitation of liquids, poor suck, difficultyswallowing, 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 preventescape from hand grip

Pelvic girdle Difficulty climbing stairs, waddling gait, Gowers sign

Leg/foot Footdrop, inability to walk on heels or toes

Respiratory Use of accessory muscles

"SUSPECTED MYOPATHY



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and therefore is the least specific in ar-riving at a particular diagnosis (Kisseland Mendell, 1999; Wickland and

Mendell, 2003).

Pattern 2: Distal Weakness

This pattern of weakness predomi-nantly involves the distal muscles ofthe upper or lower extremities (ante-rior or posterior compartment musclegroups) (Table 1-13) (Saperstein et al,2001). Depending on the diagnosis andseverity of disease, proximal musclesmay also be affected. The involvementis usually, although not invariably,symmetrical. Selective weakness andatrophy in distal extremity muscles ismore commonly a feature of neuropa-thies, and therefore a careful sensoryand reflex examination must always beperformed in patients presenting withthis phenotype.

Pattern 3: Proximal Arm/DistalLeg Weakness

This pattern of weakness affects the

periscapular muscles of the proxi-mal arm and the anterior compart-

ment muscles of the distal lowerextremity or the so-called scapulope-roneal distribution (Table 1-13 ). Thescapular muscle weakness is usuallycharacterized by scapular winging.

Weakness can be very asymmetri-

cal. When this pattern is associated

with facial weakness, it is highly sug-gestive of a diagnosis of facioscapu-lohumeral dystrophy. Other heredi-

tary myopathies that are associated with a scapuloperoneal distribution

of weakness include scapuloperonealdystrophy, Emery-Dreifuss dystrophy,

LGMD1B, LGMD2A, LGMD2C2F, con-genital myopathies, and acid maltasedeficiency.

23

TABLE 1-12 Expanded Medical Research Council Scale for Manual

Muscle Testing

Modified MedicalResearch CouncilGrade Degree of Strength

5 Normal power

5 Equivocal, barely detectable weakness

4+ Definite but slight weakness

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

4

Capable of minimal resistance3+ Capable of transient resistance but collapses

abruptly

3 Active movement against gravity

3 Able to move against gravity but not throughfull range

2 Able to move with gravity eliminated

1 Trace contraction

0 No contraction

KEY POINTS:

A The most

common

pattern

of muscleweakness in

myopathies is

symmetrical

weakness

affecting

predominantly

the proximal

muscles of

the legs and

arms, or the

so-called

limb-girdle

distribution.

A A pattern of

weakness

affecting the

periscapular

muscles of the

proximal upper

extremity and

the anterior

compartment

muscles of

the distal lower

extremity isreferred to as a

scapuloperoneal

distribution.

When this

pattern is

associated

with facial

weakness,

it is highly

suggestive of

a diagnosis of

facioscapulo-humeral

dystrophy.



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Pattern 4: Distal Arm/ProximalLeg Weakness

This pattern is associated withdistal arm

weakness involving the distal forearmmuscles (wrist and finger flexors) and

proximal leg weakness involving theknee extensors (quadriceps). The facialmuscles are usually spared. Involve-

ment of other muscles is extremely variable. In addition, the weakness isoften asymmetrical between the twosides, which is uncommon in mostmyopathies. This pattern is essentiallypathognomonic for inclusion bodymyositis (IBM). This pattern may alsorepresent an uncommon presentationof myotonic dystropy; however, unlikeIBM, muscle weakness is usually sym-metrical (Case 1-1).

Pattern 5: Ptosis With orWithout Ophthalmoplegia

Myopathies presenting with predomi-nant involvement of ocular and/or pha-ryngeal muscles represent a relativelylimited group of disorders. (Table 1-14).The eye involvement principally resultsin ptosis and ophthalmoplegia, whichusually, although not always, occurswithout symptoms of diplopia. Facial

weakness is not uncommon, and ex-tremity weakness is extremely variable,depending on the diagnosis.

The combination of ptosis, ophthal-moplegia without diplopia, and dyspha-gia should suggest the diagnosis ofoculopharyngeal dystrophy, especiallyif the onset is in middle age or later(Case 1-2). Ptosis and ophthalmoplegia

without prominent pharyngeal involve-ment is a hallmark of many of themitochondrial myopathies. Ptosis and

facial weakness without ophthalmople-gia is a common feature of myotonicdystrophy.

Pattern 6: Prominent NeckExtensor Weakness

This pattern is characterized by severeweakness of the neck extensor muscles.The term dropped head syndromehas been used in this situation (Table1-15). Involvement of the neck flexors

24

TABLE 1-13 MyopathiesCharacterized byPredominantlyDistal Weakness

" Distal Myopathies

Late adult-onset distalmyopathy type 1 (Welander)

Late adult-onset distalmyopathy type 2(Markesbery/Udd)

Early adult-onset distalmyopathy type 1 (Nonaka)

Early adult-onset distalmyopathy type 2 (Miyoshi)

Early adult-onset distalmyopathy type 3 (Laing)

Desmin myopathy

Childhood-onset distal

myopathy" Myotonic Dystrophy

" FacioscapulohumeralDystrophy*

" Scapuloperoneal Myopathy*

" Oculopharyngeal Dystrophy

" Emery-DreifussHumeroperoneal Dystrophy*

" Inflammatory Myopathies

" Inclusion Body Myositis

" Metabolic Myopathies

Debrancher deficiency

Acid-maltase deficiency*

" Congenital Myopathies

Nemaline myopathy*

Central core myopathy*


*Scapuloperoneal pattern can occur.

KEY POINTS:

A A pattern

of weakness

characterized

by distalforearm muscles

(wrist and

finger flexors)

and proximal

leg weakness

involving the

knee extensors

(quadriceps)

is essentially

pathognomonic

for inclusion

body myositis.

A The combination

of ptosis,

ophthalmoplegia

without

diplopia, and

dysphagia should

suggest the

diagnosis of

oculopharyngeal

dystrophy,

especially

if the onset is

in middle ageor later.

"SUSPECTED MYOPATHY



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is variable. Extremity weakness is de-pendent on the diagnosis and mayfollow one of the previously outlinedphenotypical patterns. For example, a

patient with a limb-girdle pattern ofweakness may also have significant neck

extensor involvement. Isolated neckextension weakness represents a dis-tinct muscle disorder called isolatedneck extensor myopathy. Prominent

neck extensor weakness is also commonin two other neuromuscular diseases:

25

Case 1-1A 51-year-old man without significant past medical history is referred for evaluation of slowly

progressive muscle weakness for the past 7 years. His symptoms initially began with difficultywalking down stairs because his left knee would give out. He currently has difficulty arisingfrom a chair and grasping objects with his right hand. When a neurologist initially evaluated him2 years ago, the workup included a creatine kinase (CK) level of 500 IU/L and a left quadricepsmuscle biopsy, which was consistent with polymyositis. The patient has been treated witha variety of immunosuppressive medications, including prednisone, methotrexate, andazathioprine, with continued progression of his weakness. Current examination reveals intactcranial nerves, sensation, and muscle stretch reflexes. Motor examination in the right upperextremity shows MRC grade 5 shoulder abduction, grade 5 elbow flexion/extension, grade 4 wristflexion, grade 5 wrist extension, and grade 3 finger flexion. Strength in the left upper extremityis normal except for grade 4+ finger flexion. In the left lower extremity, the patient exhibits grade4+ hip flexion, grade 3+ knee extension, and grade 4+ ankle dorsiflexion. In the right lowerextremity, strength is normal except for grade 4+ knee extension.

Comment. The chronic onset, asymmetrical distribution of weakness, and selective involvementof wrist/finger flexion and knee extension are most consistent with a diagnosis of IBM. Inmany cases, initial muscle biopsy fails to identify vacuoles, and patients are inappropriatelytreated with immunosuppressant medications for presumptive polymyositis. In patients witha phenotype consistent with IBM, particularly if they are refractory to treatment, a repeatbiopsy may be necessary to clarify the diagnosis.

TABLE 1-14 Myopathies With Ptosis or Ophthalmoplegia

" Ptosis Without Ophthalmoplegia

Myotonic dystrophy



Nemaline myopathy

Central core myopathy

Desmin (myofibrillary) myopathy

" Ptosis With Ophthalmoplegia

Oculopharyngeal muscular dystrophy

Oculopharyngodistal myopathy

Chronic progressive external ophthalmoplegia (mitochondrial myopathy)

Neuromuscular junction disease (myasthenia gravis, Lambert-Eaton, botulism)



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amyotrophic lateral sclerosis and my-asthenia gravis.

LABORATORY APPROACH IN THEEVALUATION OF A SUSPECTEDMYOPATHY

Creatine Kinase

CK is the single most useful laboratorystudy for the evaluation of patients

with a suspected myopathy. The CK iselevated in the majority of patients

with muscle disease but may be normalin slowly progressive myopathies. Thedegree of CK elevation can also behelpful in distinguishing different formsof muscular dystrophy. For example,in Duchenne dystrophy, the CK levelis invariably at least 10 times (and oftenup to 100 times) normal, whereas in

most other myopathies the CK eleva-tion is lower. The other exceptionsare LGMD1C (caveolinopathy), LGMD2A(calpainopathy), and LGMD2B (dysfer-linopathy), where CK may also bemarkedly elevated. The CK level maynot be elevated in some myopathiesor may even be lowered by a num-ber of factors, including profound mus-cle wasting, corticosteroid administra-tion, collagen diseases, alcoholism, orhyperthyroidism.

It is also important to remember thatan elevation of serum CK does notnecessarily imply a primary myopathicdisorder (Table 1-16). Many times theCK level will rise modestly (usually toless than 10 times normal) in motorneuron disease, and, uncommonly, CKelevations may be seen in Guillain-

Barre syndrome or chronic inflamma-tory demyelinating neuropathy. Endo-crine disorders such as hypothyroidism

26

Case 1-2A 62-year-old white woman with a family history of myasthenia gravis presents for evaluation

of an 8-year history of progressive dysphagia and weakness. She specifically denies anysymptoms of diplopia and states that her symptoms do not fluctuate during the day or whenshe becomes fatigued. She has noted no improvement with a course of prednisone 60 mg/d andpyridostigmine 60 mg 4 times daily. Cranial nerve examination is remarkable for bilateralptosis, incomplete abduction/adduction of both eyes, mild orbicularis oris weakness, andmoderate tongue weakness. Motor examination reveals MRC grade 4 neck flexion, grade4 shoulder abduction, grade 4+ elbow flexion, grade 5 finger extension, grade 4 hip flexion,grade 5 knee extension, and grade 5 ankle dorsiflexion and plantarflexion. Sensory, cerebellar,and reflex examinations are normal. Workup by a referring physician was remarkable fora CK 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 suggestiveof a diagnosis of oculopharyngeal muscular dystrophy. The absence of symptoms of diplopia

and muscle fatigability and the patients slowly progressive course strongly argue againsta diagnosis of a neuromuscular junction disorder such as myasthenia gravis.

TABLE 1-15 Myopathies WithProminent NeckExtensorWeakness

" Isolated neck extensormyopathy

" Polymyositis

" Dermatomyositis

" Inclusion body myositis

" Carnitine deficiency

" Facioscapulohumeral dystrophy

" Myotonic dystrophy

" Congenital myopathy

" Hyperparathyroidism

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and hypoparathyroidism can also beassociated with high CK levels. Causesof CK elevation other than neuromus-cular disease include muscle trauma(falls, intramuscular or subcutaneous

injections, EMG studies), viral illnesses,seizures, or strenuous exercise. In thesecases, CK elevations are usually tran-

sient and less than 5 times normal.Medications can cause serum CK elevations, either with or without associ-ated muscle weakness ( Table 1-17).Race and gender can also affect serumCK (Wong et al, 1983). CK levels arefrequently above the normal rangein some African American individualsand in patients with enlarged muscles.Occasionally, benign elevations of CKappear on a hereditary basis. It is ex-tremely unusual for a slightly elevated

CK level (threefold or less) to be as-sociated with an underlying myopa-thy in the absence of objective muscle

weakness or pain.Serum tests for other muscle en-

zymes such as aldolase are significantlyless helpful than the determination ofthe CK. Enzymes such as aspartate ami-notransferase (AST), alanine amino-transferase (ALT), and lactate dehydro-genase (LDH) may be slightly elevatedin myopathies. Since AST, ALT, and LDHare often measured in screening chem-istry panels, their elevation should

27

TABLE 1-17 MedicationsAssociated WithCreatine KinaseElevations

" Lipid-Lowering Drugs

Beta-hydroxy-b-methylglutaryl-

coenzyme A (HMG-CoA)reductase inhibitors (statins)

Fibric acid derivatives(gemfibrozil)

Niacin

" Chloroquine

" Colchicine

" Cyclosporine

" Zidovudine (AZT)

TABLE 1-16 DifferentialDiagnosis ofCreatine Kinase

Elevation

" Myopathies





Drug/toxin-induced

Carrier state(dystrophinopathies)

" Channelopathies

" Motor Neuron Diseases

Amyotrophic lateral sclerosis

Spinal muscular atrophy

Postpolio syndrome

" Neuropathies

Guillain-Barre syndrome

Chronic inflammatorydemyelinating polyneuropathy

" Viral Illness

" Medications

" Hypothyroidism/Hypoparathyroidism

" Surgery

" Trauma (electromyographystudies, intramuscular orsubcutaneous injections)

" Strenuous Exercise

" Increased Muscle Mass

" Race

" Sex

" Idiopathic HyperCKemia

KEY POINTS:

A The CK is

elevated in

the majority

of patientswith muscle

disease but

may be normal

in slowly

progressive

myopathies.

A It is important

to remember

that an

elevation

of serum CK

does notnecessarily

imply a primary

myopathic

disorder.

A It is extremely

unusual for

a slightly

elevated CK

level (threefold

or less) to be

associated

with anunderlying

myopathy

in the absence

of objective

muscle

weakness

or pain.



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prompt CK measurement to determinewhether the source is muscle or liver. Ifa patient with an inflammatory myopathy

is treated with an immunosuppressiveagent that may cause hepatoxicity, theliver-specific enzyme gamma glutamictransferase (GGT) should be followed.

In general, CK isoenzymes are nothelpful in evaluating myopathies. CK-fraction muscle (MM) elevations aretypical of muscle disease, but CK-myocardial band (MB) is also elevatedin myopathies and does not indicatethat cardiac disease is present.

Electrophysiological StudiesElectrodiagnostic studies, consistingof both nerve conduction studies andEMG, should be part of the routineevaluation of a patient with a suspectedmyopathy (Preston and Shapiro, 2005).These studies are helpful in confirmingthat the muscle is, indeed, the correctsite of the lesion and that weakness isnot the result of an underlying motorneuron disease, neuropathy, or neuro-muscular junction disorder. Nerve con-duction studies are typically normal inpatients with myopathy. Needle EMGexamination showing evidence of brief-duration, small-amplitude motor units

with increased recruitment can be ex-tremely helpful in confirming the pres-ence of a myopathy. Needle EMG canalso provide a clue as to which muscleshave had recent or ongoing muscle in-jury and can be a guide as to whichmuscle to biopsy. It is important to

realize, however, that the EMG can benormal in a patient with myopathy, andthe results of electrodiagnostic studiesneed to be evaluated in the context ofthe patients history, neurological ex-amination, and other laboratory studies.

The Muscle Biopsy

If the clinical features and/or electrodi-agnostic features suggest the possibilityof a myopathy, a muscle biopsy may bean appropriate test to confirm the diag-

nosis (Dubowitz, 1985). However, manyforms of hereditary muscle disorderscan now be diagnosed with molecular

genetic testing, thereby eliminating theneed for a muscle biopsy in every pa-tient. A muscle specimen can be ob-tained through either an open or closed(needle or punch) biopsy procedure.The advantage of a needle or punchbiopsy is that it is minimally invasive,cosmetically more appealing, and mul-tiple specimens can be obtained. Thedisadvantage of the closed biopsy pro-cedure is that not all laboratories havethe expertise to adequately process the

muscle tissue acquired with this ap-proach for all the necessary studies. Inaddition, a needle biopsy may miss afocal area of inflammation.

Selection of the appropriate muscleto biopsy is critical. Muscles that areseverely weak (MRC grade 3 or less)should not be biopsied, since the resultsare likely to show only evidence of endstage muscle disease. In addition, mus-cles that have recently been studied byneedle EMG should be avoided becauseof the possibility of artifacts created byneedle insertion. Biopsies should gen-erally be taken from muscles that dem-onstrate MRC grade 4 strength. Forpracticalpurposes,intheupperextremi-ties, the muscle of choice is the biceps;in the lower extremities, the best choiceis the vastus lateralis. The gastrocne-mius should be avoided, since its ten-don insertion extends throughout themuscle and inadvertent sampling of a

myotendinous junction may cause diffi-culty with interpretation. Occasionally,an imaging procedure such as muscleultrasound, computed tomography, ormagnetic resonance imaging can beused to guide selection of the appropri-ate muscle to biopsy.

Biopsy specimens can be analyzed bylight microscopy, electron microscopy,biochemical studies, and immune stain-ing ( Table 1-18 ). In most instances,light microscopic observations of frozen

28

KEY POINTS:

A Many forms

of hereditary

muscle

disorders cannow be

diagnosed

with molecular

genetic testing,

thereby

eliminating

the need for

a muscle

biopsy in

every patient.

A Muscles that

are severelyweak (Medical

Research

Council grade

3 or less)

should not

be biopsied,

since the

results are

likely to show

only evidence

of end stage

muscle disease.

"SUSPECTED MYOPATHY



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muscle tissue specimens are sufficientto make a pathological diagnosis. Typi-cal myopathic abnormalities includecentral nuclei, both small and large hy-pertrophic round fibers, split fibers, anddegenerating and regenerating fibers.Inflammatory myopathies are character-ized by the presence of mononuclearinflammatory cells in the endomysialand perimysial connective tissue be-tween fibers and occasionally aroundblood vessels. In addition, in dermato-

myositis, perifascicular atrophy, charac-terized by atrophy of fibers located onthe periphery of a muscle fascicle, is acommon finding. Chronic myopathiesfrequently show evidence of increasedconnective tissue and fat.

For general histology, the hematoxy-lin and eosin (H&E) and modifiedGomori trichrome are most useful.The latter is particularly helpful inidentifying ragged red fibers, whichmight suggest a mitochondrial disorder.

In addition to these standard stains,other histochemical reactions can beused to gain additional information( Table 1-19 ). The myosin adenosinetriphosphatase stains (alkaline pH 9.4and acidic pH 4.3 and 4.6) allow athorough evaluation of histochemistryfiber types. Type 1 fibers (slow-twitch,fatigue-resistant, oxidative metabolism)stain lightly at alkaline and darkly atacidic pH levels. Type 2 fibers (fast-twitch, fatigue-prone, glycolytic metabo-

lism) stain darkly at alkaline and lightlyat acidic pH levels. Normally, a randomdistribution of the two fiber typesoccurs, and generally twice as manytype 2 as type 1 fibers are identified. Ina number of myopathies, a nonspecifictype 1 fiber predominance occurs. Oxi-dative enzyme stains (nicotinamideadenine dinucleotide [reduced form][NADH] dehydrogenase, succinate de-hydrogenase, cytochrome-c oxidase)are useful for identifying myofibrillar

29

TABLE 1-18 Utility of Muscle Biopsy Stains and Histochemical Reactions

Histochemical Reactions and Stains Clinical Utility

Hematoxylin and eosin General histology

Gomori trichrome General histology and mitochondrial disease

Adenosine triphosphatase (ATPase) Distribution of fiber types

Nicotinamide adenine dinucleotide glycohydrolase(NADH), succinate dehydrogenase (SDH),cytochrome oxidase

Myofibrillar and mitochondrial abnormalities

Periodic acid-Schiff Glycogen storage diseases

Oil red O Lipid storage diseases

Congo red, crystal violet Detection of amyloid deposition

Myophosphorylase McArdles disease

Phosphofructokinase Phosphofructokinase deficiency

Myoadenylate deaminase Myoadenylate deaminase deficiency

Dystrophin immunostain Duchenne and Becker muscular dystrophies

Dysferlin immunostain Limb-girdle muscular dystrophy 2B

Membrane attack complex immunostain Dermatomyositis



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and mitochondrial abnormalities. Peri-odic acid-Schiff (PAS) stains can behelpful in identifying glycogen storage

diseases and oil red O stains may assist with the diagnosis of a lipid storagedisease. Acid and alkaline phosphatasereactions can highlight necrotic andregenerating fibers, respectively. Quali-tative biochemical enzymes stains canbe performed for myophosphorylase(McArdles disease), phosphofructoki-nase (PFK deficiency), and myoadenyl-ate deaminase (MAD deficiency). Amy-loid deposition can be assayed withCongo red or crystal violet staining.

Finally, immunohistochemical techni-ques can stain for muscle proteins thatare deficient in some muscular dystro-phies (eg, dystrophin in Duchenne andBecker dystrophy) or for products thatare increased in certain inflammatorymyopathies such as the membrane at-tack complex in dermatomyositis.

Electron microscopy evaluates theultrastructural components of musclefibers and is not required in the majorityof myopathies to make a pathologicdiagnosis. Electron microscopy is im-portant, however, in the diagnosis of

some congenital myopathies and mito-chondrial disorders. Findings detectedonly by electron microscopy are seldom

of clinical importance.The muscle tissue can also be pro-cessed for biochemical analysis to de-termine a specific enzyme defect in theevaluation of a possible metabolic ormitochondrial myopathy. In addition,

Western blot determinations from mus-cle tissue can be performed for certainmuscle proteins. This type of analysisis usually limited to dystrophin assays

when immune stains and molecular ge-netic studies are inconclusive in estab-

lishing a diagnosis of either Duchenneor Becker dystrophy.

Molecular Genetic Studies

The specific molecular genetic defectis now known for a large number ofhereditary myopathies, and mutationscan be identified by peripheral bloodDNA analysis. Molecular genetic studiesthat are commercially available are in-cluded inTable 1-19. Molecular genetictesting frequently eliminates the needfor muscle biopsy. This technology isalso extremely helpful for determining

30

TABLE 1-19 Disorders With Commercially Available MolecularGenetic Studies Performed With Peripheral BloodSamples

" Duchenne and Becker muscular dystrophies

" Facioscapulohumeral muscular dystrophy

" Myotonic dystrophy (types 1 and 2)

" Oculopharyngeal muscular dystrophy

" Limb-girdle muscular dystrophy 1B, 2A, 2C2F, and 2I

" Congenital muscular dystrophy (FKRP, FCMD, MEB, and POMT1 mutations)

" Nonaka myopathy/inclusion body myopathy type 2

" Nemaline myopathy (ACTA1 mutations)

" Myotubular myopathy (MTM1 mutations)

" Myoclonic epilepsy and ragged red fibers (MERRF)

" Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS)

KEY POINT:

A Electron

microscopy

is important

in the diagnosisof some

congenital

myopathies and

mitochondrial

disorders.

Findings

detected only

by electron

microscopy

are seldom

of clinical

importance.

"SUSPECTED MYOPATHY



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carrier status and for performing prena-tal testing.

Other Tests

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

with a suspected myopathy include se-rum electrolytes, thyroid function tests,parathyroid hormone levels, and hu-man immunodeficiency virus (HIV). Inpatients with an inflammatory myopa-thy, serological determinations forsystemic lupus erythematosus, rheuma-toid arthritis, and other immunological

markers (eg, Jo-1 antibodies) can oc-casionally be useful. A urine analysis canalso be performed to detect the pres-ence of myoglobinuria. This should besuspected if the urine tests positivefor blood but no red blood cells areidentified.

Forearm exercise testing can be acritical part of the evaluation of a patient

with a suspected metabolic myopathy.The exercise test should be carried out

without the blood pressure cuff, sinceischemic exercise may be hazardous inpatients with defects in the glycolyticenzyme pathway. The test is performedby asking the patient to perform iso-metric contractions using a handgripdynamometer for 1.5 seconds separatedby rest periods of 0.5 seconds for 1minute. A resting blood sample for ve-nous lactate and ammonia is obtained atbaseline and subsequently at 1, 2, 4, 6,and 10 minutes after the completion

of exercise. A threefold increase inlactate level represents a normal re-sponse. The characteristic elevation of

serum lactate after exercise is absent inphosphofructokinase deficiency andmyophosphorylase deficiency and re-

duced in phosphoglycerate mutase defi-ciency. Forearm testing is normal in alldisorders of fat metabolism and also insome glycolytic disorders with fixedmuscle weakness, such as acid maltasedeficiency.

CONCLUSION

While this pattern-recognition approachto myopathy may have limitations, itcan be extremely helpful in narrowingthe differential diagnosis and therefore

minimizing the number of laboratorystudies that must be ordered to con-firm the diagnosis. Not all patients

with muscle disease will fit neatly intoany of these six categories. In addition,patients with involvement of otherareas of the neuraxis, such as the motorneuron, peripheral nerve, or neuro-muscular junction, may also frequentlypresent with one of these patterns.For example, while proximal weaknessgreater than distal weakness is mostoften seen in a myopathy, patients withacquired demyelinating neuropathies(Guillain-Barre syndrome and chronicinflammatory demyelinating polyneuro-pathy) often have proximal as well asdistal muscle involvement. Careful con-sideration of the distribution of mus-cle weakness and attention to thesecommon patterns of involvement inthe context of other aspects of theneurological examination and labora-

tory evaluation will usually, however,lead the clinician to a timely and accu-rate diagnosis.

REFERENCES

" Barohn RJ. General approach to muscle diseases. In: Goldman L, Ausiello D,eds. Cecil textbook of medicine. 22nd edition. Philadelphia: WB Saunders,2004;23702379.

An excellent review of the pattern-recognition approach to the diagnosis of muscle

disease.

31

KEY POINT:

A Forearm

exercise testing

can be a critical

part of theevaluation of

a patient with

a suspected

metabolic

myopathy.



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" Brooke MH. A clinicians view of neuromuscular disease. 2nd edition.Baltimore: Williams & Wilkins, 1986.

A classic textbook with a marvelous section on the functional assessment of the patient

with suspected muscle disease.

" Dubowitz V. Muscle biopsy: a practical approach. 2nd edition. London:Bailliere Tindall, 1985.

A comprehensive and practical review of muscle biopsy interpretation.

" Kincaid JC. Muscle pain, fatigue, and fasiculations [sic]. Neurol Clin1997;15:697709.

This article reviews the conditions that cause muscle pain, fatigue, and fasciculations

and includes a general evaluation to be considered for each of these clinical problems.

" Kissel JT, Mendell JR. Muscular dystrophy: historical overview andclassification in the genetic era. Semin Neurol 1999;19:57.

This review presents a historical perspective on the classification of muscular dystrophiesand provides the underpinnings of a genetic classification that can be used both in the

research laboratory and at the bedside.

" Medical Research Council. Aids to the examination of the peripheralnervous system. 4th edition. London: Balliere Tindall, 2000.

The bible in regard to muscle-strength testing.

" Preston DC, Shapiro BE. Electromyography and neuromuscular disorders:clinical electrophysiologic correlations. 2nd edition. Boston:Butterworth-Heinemann, 2005.

A well-written and comprehensive text highlighting the usefulness of electrodiagnostic

studies in the clinical evaluation of patients with suspected myopathy.

" Saperstein DS, Amato AA, Barohn RJ. Clinical and genetic aspects of distalmyopathies. Muscle Nerve 2001;24:14401450.

This review summarizes current knowledge of the clinical and molecular aspects of the

distal myopathies.

" Wicklund MP, Mendell JR. The limb girdle muscular dystrophies: ourever-expanding knowledge. J Clin Neuromusc Dis 2003;5:1228.

This paper summarizes current knowledge regarding the genotypes and phenotypes of

the large group of heterogeneous disorders previously described as limb-girdle

dystrophies.

" Wong ET, Cobb C, Umehara MK et al. Heterogeneity of serum creatine

kinase activity among racial and gender groups of the population. Am JClin Pathol 1983;79:582586.

An important paper discussing the significant variability of the creatine kinase level

on the basis of race and sex.

32

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