Muscle Disease in Children: A Practical Approach Marc C ......in the acquisitionof language and....

DOI: 10.1542/pir.12-3-731990;12;73Pediatrics in Review

Marc C. Patterson and Manuel R. GomezMuscle Disease in Children: A Practical Approach

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The questions below should help

focus the reading of this article.

1. What clinical findings help differ-entiate between primary muscle dis-eases and diseases with widespreadneuropathology?

2. What physical examination findingssuggest denervated muscles?

3. What are typical signs and symp-toms of neuromuscular disorders?

4. What are characteristic laboratoryfindings of Duchenne muscular dys-trophy?

5. What clinical features help distin-guish between various congenitalneuromuscular disorders and infan-tile botulism?

EDUCATIONAL OBJECTIVES

29. The pediatrician should haveknowledge to make an appropriateevaluation of a 5-year-old boy whohas always been “clumsy,” has dif-ficulty running and skipping, andwhose school performance hasbeen poor, differentiating amongDuchenne muscular dystrophy,limb girdle muscle atrophy, juve-nile spinal muscular atrophy, con-genital myopathy, nonspecific hy-potonia of undetermined etiology,mild developmental delay, cami-tine deficiency, polymyositis, me-chanical clumsiness (hyperexten-sibility), and cerebral palsy, and beable to develop an appropriateplan for management. (Topics, 90/91)125. The pediatrician should haveappropriate knowledge of the ge

netic factors, clinical appearance,and course of congenital myotonicdystrophy. (Recent Advances, 90/91)

TABLE 1. Causes of EnlargedMuscles

Duchenne muscular dystrophyBecker muscular dystrophyGlycogen storage diseases of

muscleHypothyroidism (Hoffmann syn-

drome in adult myxedema orKocher-Debr#{233}-S#{233}m#{233}laignesyn-drome in cretinism)

Myotonia congenita (Thomsen dis-ease)

Paramyotonia congenita (Eulen-berg disease)

Schwartz-Jampel syndrome (my-otonic chondrodystrophy)

Chronic spinal muscular atrophy(SMA type 3)

CysticercosisAmyloidosis

pediatrics in review vol. 12 no. 3 september 1990 PIR 73

Muscle Disease in Children: A Practical ApproachMarc C. Patterson* and Manuel R. Gomezj

Advances in the basic scienceshave enhanced the investigation andunderstanding of muscle diseasesduring the past three decades.Nevertheless, the history and physi-cal examination remain the corner-stones of diagnosis for children withmuscle disease.

MEDICAL AND DEVELOPMENTALHISTORY

Most children with muscle diseasehave weakness, muscle wasting orenlargement, deformities, or pain.Whenever possible, open-endedquestions should be directed to thechild; more often, the physician mustrely on history given by the parentsor guardians. In taking the history, itis important to seek answers to threequestions: (1) When did the symp-toms begin?; (2) Is the disease staticor progressive?; and (3) Is the dis-ease confined to the muscle or theneuromuscular unit, or does it alsoaffect the brain or other organs? Asis the case with other neuromusculardiseases, onset may occur in uteroand the quickening may be delayedor reduced in quantity or intensity.

“Senior Clinical Fellow, Section of Pediatric

Neurology, Mayo Clinic and Mayo Foundation,Rochester, Minnesota.tConsultant, Section of Pediatric Neurology,Mayo Clinic and Mayo Foundation, Rochester,Minnesota.

Polyhydramnios secondary to fetaldysphagia may be the first clinicalfeature of some neuromuscular dis-eases, particularly neonatal myotonicdystrophy.

Delayed attainment of motor mile-stones alone can be accounted forby neuromuscular disease, but delayin the acquisition of language andsocial adaptive behavior points tocerebral pathology. Similarly, impair-ment of somatosensory sensation, vi-sion, and hearing indicates wide-spread neuropathology. Central nerv-ous system and primary musclediseases may coexist, as is the casewith some patients with Duchennemuscular dystrophy, Fukuyama dys-trophy, myotonic dystrophy, and themitochondrial diseases.

Weakness, the primary symptomof a neuromuscular disease, gener-ally appears initially as functional im-pairment: difficulty in running, climb-ing stairs, rising from a chair or fromthe floor, dressing, or walking. Thepattern of weakness gives importantdiagnostic clues; proximal weaknessis manifest by difficulty rising from achair or climbing stairs (weak pelvicgirdle muscles) or in raising the armsabove the head (weak shoulder girdlemuscles) and strongly suggests a pri-mary muscle disease. However, sucha pattern may be replicated occasion-ally by acute inflammatory demyeli-

nating polyradiculopathy, myastheniagravis, or progressive muscular atro-phy.

In addition to weakness, there maybe a history of muscle wasting orenlargement (Table 1 ). Wasting mayoccur with either myopathic or neu-ropathic disorders. “Jumping mus-des,” or fasciculations, signal involve-ment of the lower motor neuron.

Pain frequently accompanies in-flammatory muscular disorders, par-ticularly polymyositis and dermato-myositis. Viral or bacterial myositisand parasitic muscle infestation aretypically painful. It should be notedthat dermatomyositis has a charac-teristic skin rash and that many con-nective tissue disorders are associ-ated with painful joints. Other neuro-muscular diseases of acute onset,such as polyradiculoneuropathy andanterior poliomyelitis, also causemyalgia, paralysis, and wasting.

Weakness or pain following exer-cise is a feature of certain metabolicmyopathies. Postexertional pain and



TABLE 2. Some Drugs andToxins Associated withNeuromuscular Disease

Peripheral neuropathyAlcoholAnestheticsAnticonvulsantsAntimicrobialsCardiovascular agentsCytotoxicsHeavy metalsSolventsToxins

CiguateraDiphtheria

Vitamins: B6 (pyridoxine)Vaccines

Neuromuscular junction disordersAnticonvulsantsAntimicrobials: aminoglycosidesCardiovascular agentsImmunosuppressive agentsLithiumOrganophosphatesToxins

BotulinumTick toxinTetrodotoxin (fugu or puffer-

fish)

MyopathyAgents acting on microtubulesAlcoholAntimalarialsAntiparasiticSteroids

TABLE 3. Signs of Neuromuscular Disease on Inspection (With Examples)

FaceLack of expression (FSH, MG)*“Bouche de tapir” (Tapir mouth, FSH)Tented mouth (neonatal myotonic dystrophy)Snarl (MG)Slack jaw (MG)Ptosis (myotonic dystrophy, MG, oculopharyngeal dystrophy)Ophthalmoplegia (Keams-Sayre syndrome)Myotonia of lids (myotonia congenita)Protuberant auncles (DMD)Pursed lips (myotonic chondrodystrophy)

NeckSwan neck (myotonic dystrophy)Flexor weakness (DMD, inflammatory myopathies)Extensor weakness (MG)Paraspinal muscle-tendon contracture (rigid spine syndrome, Emery-Dreifuss

dystrophy)

Shoulder girdle/upper limbsWinged scapula (FSH)Internal rotation of arms; palms face dorsally (limb girdle muscle atrophy)Pectoral crease; shoulders rotated down (scapuloperoneal dystrophy)Simian hand; thenar muscle weakness (myotonic dystrophy)Claw hand (ulnar neuropathy, motor neuron disease)Contractures of elbow (Emery-Dreifuss dystrophy, DMD)

TrunkKyphosis (DMD)Scoliosis (DMD)Lordosis with protuberant abdomen (DMD)Rigid spine (rigid spine syndrome)

Pelvic girdle/lower limbs“Sabre edge” tibia (wasted tibialis anterior)“Inverted champagne bottle” (peroneal muscular atrophy)Hypertrophy of calves (DMD, spinal muscular atrophy (type 3))Hypertrophy of extensor digitorum brevis (DM0, scapuloperoneal dystrophy)Pes cavus (Fnedreich ataxia, spinal dysraphism)Pes planus (certain congenital myopathies)Talipes equinovarus (DMD, CMD)Posterior displacement of calcaneus (CMD)

* FSH, facioscapulohumeral dystrophy; MG, myasthenia gravis; DMD, Duchennemuscular dystrophy; CMD, congenital muscular dystrophy.

Muscle Disease

PIR 74 pediatrics in review #{149}vol. 12 no. 3 september 1990

weakness or painful cramps aresometimes accompanied by myo-globinuria. Pain is usually not a fea-ture of muscular dystrophies.

The ambient temperature may bea factor to consider: cold typicallyprecipitates stiffness and weaknessin myotonic muscles, which improvewith warming and exercise.

The temporal profile of symptomsis another valuable diagnostic tool.Weakness that progresses during theday and is relieved by rest and, inparticular, specific weakness involv-ing the extraocular and the bulbarmuscles strongly suggest the diag-nosis of myasthenia gravis.

The family history is crucial to thediagnosis of any type of neuromus-cular disease, not just primary muscledisease, in children. It is not sufficientto ask parents if there is any relativewith nerve or muscle disease, onemust take a detailed family history

and construct a pedigree with at leasttwo generations, if necessary, withthe help of other family members. Itis often convenient to examine alldirect and alleged affected relativesand examine the mother for signs ofmyotonic dystrophy when the diag-nosis of neonatal myotonic dystrophyis considered. Medical records of af-fected relatives should also be ob-tained and reviewed.

Finally, one should inquire aboutthe child’s exposure to drugs andtoxins which may account for or con-tribute to the symptoms (Table 2).The presence of systemic illness is

obviously of great importance. Intes-tinal malabsorption of the type foundwith celiac disease or with cystic fi-brosis may be associated with mus-cle weakness and atrophy throughgeneral malnutrition or vitamin E ormineral deficiencies.

Having obtained a detailed history,the clinician is often able to approachthe physical examination armed withspecific diagnostic hypotheses.

PHYSICAL EXAMINATION

Examination should begin as thepatient enters the office, noticing pos-



TABLE 4. Causes of ToeWalking

Intraspinal and filum terrninale tu-mors

Spastic diplegiaSpinal dysraphismProgressive dystoniaProgressive motor neuropathyMuscular dystrophyTight Achilles tendon without other

evidence of neurological diseaseNormal child may do by choice

Fig 1. Gowers sign. Patient with Duchennemuscular dystrophy photographed with strobelight as he gets up.

MUSCULOSKELETAL DISEASE

pediatrics in review #{149}vol. 12 no. 3 september 1990 PIR 75

ture, gait, and other spontaneous ac-tivity. After forming an initial impres-sion regarding the child’s habitus, af-fect, and state of nutrition, a regionalsurvey is undertaken. The signs forwhich to search are detailed in Table3.

Children with proximal muscleweakness compensate for it with cer-tam maneuvers. One good exampleis well known as the Gowers sign:when attempting to get up off thefloor, the child begins sitting up withlegs outstretched and initially turnshis trunk toward the weaker side,then draws the knees up under thebody before raising his hips in the air;he then raises his trunk by “climbingup” his legs and thighs. Variations onthis maneuver may be seen whenpatients attempt to rise from a chairinstead of the floor (Fig 1).

The child’s gait should be ob-served, in particular noting the stabil-ity of the pelvis (hip weakness pro-duces a waddle), knee, and anklejoints. Weakness of the quadricepsresults in “back kneeing” in which theknee joints are hyperextended to pro-duce mechanical locking. Similarly,the gait may be modified to accom-modate weakness of the dorsiflexorsof the ankles, producing a slappingor stamping gait. Toe walking is usu-ally obvious (Table 4).

The child should be asked to walkon the toes to detect weakness ofankle flexors and on heels to detectweak dorsiflexors. He or she shouldalso be asked to hop on one foot.Ability to walk on the heels but notthe toes suggests intraspinal dis-ease.

The muscles should be palpated.Denervated muscles are typicallyflabby and soft and may exhibit wast-ing and fasciculation. In contrast isthe rubbery or woody feeling of thecalf muscles of the child with Duch-enne muscular dystrophy or glyco-gen-infiltrated muscles characteristicof acid maltase deficiency (Pompedisease). Palpable hard nodules inmuscle occur with progressive myos-itis ossificans, and subcutaneous cal-cifications are found in advanced or“burnt out” cases of dermatomyosi-tis.

Percussion provides evidence ofrnyotonia or myoedema. The formeris a sustained muscle contractionelicitable by a sharp blow with thereflex hammer to the thenar emi-nence, which causes a sustained ad-duction of the thumb as the myotonicmuscle slowly relaxes. Percussion ofthe belly of a digit extensor is anotherway to elicit myotonia. Percussion ofthe belly of the deltoid produces asustained contraction of a strip ofmuscle, appearing as a depression.

Myoedema or “mounding” is a phe-nomenon seen in association with hy-pothyroidism and certain other met-abolic abnormalities. Following per-cussion, there is a period ofdepression of the muscle before itrises up in a small mound.

When possible, manual testing ofmuscle strength should be per-formed. Details of the techniques are

included in the texts listed. The deeptendon reflexes should also be elic-ited; these are usually reduced orabsent with neuromuscular disease.Such reflexes may be difficult to elicitin neonates, but knee jerk reflexesare always present in a normal full-term baby. Muscle tone should beassessed by passively moving jointsthrough their range of motion, withthe child as relaxed as possible. Thechild’s posture and gait may also re-flect abnormal muscle tone, as in thecase of the hypotonic infant with headlag and a “frog-leg” posture or thespastic child with a “scissor” gait.

The examination for neuromuscu-lar disease must always be per-formed in the context of a generalmedical examination, because neu-romuscular symptoms may be a man-ifestation of systemic disease and,similarly, primary muscle disease mayproduce cardiac, gastrointestinaltract, or skeletal signs.

LABORATORY INVESTIGATIONS

In most cases, the history andphysical examination will enable theexperienced examiner to come to aprovisional diagnosis or restricted dif-ferential diagnosis in the child withneuromuscular disease. Laboratoryinvestigations are selected accordingto their diagnostic utility, cost, andassociated risks.

Measurement of serum enzymes isa useful but nonspecific test (Table5). The serum creatine kinase levelshould be measured before doing anelectromyogram, because this pro-cedure might elevate the creatine ki-nase value. Serum creatine kinase iselevated in children with active pri-mary muscle disease. With chronicmyopathies, the creatine kinase valueis related to the stage of illness. Ele-vation of serum creatine kinase isalso a sign found in inflammatory my-opathies. The serum creatine kinasevalue may remain elevated after thedisease is in remission. As with serumcreatine kinase, the increment of theserum aspartate transaminase, ala-nine aminotransferase, and lactatedehydrogenase concentrations re-flects the egress of these proteinsthrough defective muscle fiber mem-branes.

When autoimmune myasthenia



TABLE 5. Causes of Elevated Serum Creatine Kinase

Primary neuromuscular diseasesMuscular dystrophies (Duchenne, Becker, facioscapulohumeral, myotonic,

limb girdle)Inflammatory myopathies (dermatomyositis, polymyositis)Metabolic myopathies (acid maltase deficiency, camitine deficiency, my-

ophosphorylase deficiency, phosphofructokinase deficiency)Infectious (bacterial myositis, viral myositis, trichinosis, toxoplasmosis)Malignant hyperpyrexiaChronic spinal muscular atrophy

Other sourcesMuscle originTrauma (including intramuscular injections and needle electromyography,

bums, electric shock, lightning injury, muscle hemorrhage, surgery, alco-holism, muscle hypertrophy, hypokalemia, involuntary muscle contractions(seizures, tetanus, neuroleptic malignant syndrome), hypothermia, hyper-thermia, hypothyroidism, ischemic myopathy, sarcoid myopathy, carcino-matous neuromyopathy, “idiopathic hyper-creatine kinase-emia”)

MyocardiumAcute myocardial infarction, electrical cardioversion, mediastinal irradiation

Central nervous systemStroke (cerebral infarct or subarachnoid hemorrhage), bacterial meningitis,

head injury

LungPneumonia, pulmonary infarction, metastatis carcinoma

BowelColonic infarction,metastatic carcinoma

Miscellaneous/multifactonalSepsisShockAcute asthmaAcute psychosisHymenopteran envenomationMcLeod syndromeDrugs: clofibrate, aminocaproic acid

TABLE 6. Causes ofMyoglobinuna

Genetic disordersMyophosphorylase deficiencyPhosphofructokinase deficiencyPhosphoglycerate kinase defi-

ciencyPhosphoglycerate mutase defi-

ciencyLactate dehydrogenase defi-

ciencyCamitine palmityltransferase de-

ficiencyIdiopathic recurrent myoglobinu-

na (sporadic or familial)Malignant hyperpyrexia

Acquired muscle diseaseDermatomyositisPolymyositis

Overuse or injury

Abnormal body temperatureHypothermiaHyperthermia

InfectionsBacteriaViralKawasaki syndrome

Metabolic disordersDiabetes mellitusSodium (hyponatremia, hypema-

tremia)Potassium (hypokalemia)Phosphate (hypophosphatemia)Acidosis (renal tubular)

Drugs and toxins (through the fol-lowing mechanisms)

Convulsions or agitated deliriumMembrane effectHypokalemiaIschemiaMetabolic depression

Muscle Disease


gravis is suspected, determination ofantibodies directed against differentcomponents of the muscarinic ace-tylcholine receptor helps to confirmthe diagnosis. This is not the caseregarding ocular myasthenia. Anti-bodies directed against DNA or RNAmay be found in children with con-nective tissue diseases. Leuko-cytosis suggests inflammatory orautoimmune disorders, includingdermatomyositis and polymyositis.Eosinophilia suggests allergic orparasitic etiology. The electrocardio-gram shows tall R waves and deepQ waves with Duchenne musculardystrophy; A-V block is frequentwith Ernery-Dreifuss myopathy andKeams-Sayre syndrome. Measure-ment of myoglobin levels in urine may

be useful in patients with exercise-related symptoms and/or a history ofdiscolored urine (Table 6).

In recent years, molecular geneticshas contributed to locating the genelocus for Duchenne muscular dystro-phy on Xp21 and to determining thepresence of the gene in heterozy-gotes and asymptomatic hemizy-gotes antenatally. Such studies arecostly and require many blood sam-ples from affected and nonaffectedfamily members.

Electrophysiological studies play amajor role in the investigation of neu-romuscular disease. These tests mayanswer three questions: (1) What isthe level of the lesion (nerve, neuro-muscular junction, or muscle)?; (2)What muscles and nerves are in-

volved?; and (3) How active is thedisease process? The findings in themajor categories of neuromusculardisease are summarized in Table 7.

The gold standard of investigationis the muscle biopsy. Indications arelisted in Table 8. The biopsy shouldbe taken from a moderately weakmuscle that is not the site of an un-related disease process (eg, radicu-lopathy). A severely weak muscleshould not be used in a chronic proc-ess, but may be appropriate in a pa-tient with acute generalized weak-ness. Biopsies should not be taken



TABLE 7. Electromyography in Neuromuscular Disease

Nerve

locity

Repetitive Stimulation

Needle Electromyography

Fibrilla- Motor UnitstiOris

Neuropathy

Myastheniagravis

Myopathy

N or �

N

N

N

Decrement in amplitudeof evoked compoundmuscle action potential

N

+ IDurationlAmplitude

±Polyphasic± Variable amplitude

± J,DurationJ,Amplitude

Myotonic dis-charges

N, normal; +, present; ±, sometimes present. This table is an oversimplification.

Findings on electromyography depend on activity and duration of diseaseprocess and are rarely specific.

TABLE 8. Indications for MuscleBiopsy

Muscular dystrophiesMetabolic myopathiesMitochondnal diseasesInflammatory myopathiesCongenital myopathiesPrimary muscle tumorInfantile spinal muscular atrophy

r

TABLE 9. Muscle Diseases inChildhood

Muscular dystrophiesDisorders of neuromuscular trans-

missionInflammatory myopathiesMetabolic muscle diseasesMyopathies associated with sys-

temic illnessCongenital myopathiesCongenital dystrophiesMyotonic disorders


podI6trIca In r8visw ‘ vol, 12 no, 3 .eptcmbcr 19�Q PIR 77

from muscles traumatized by intra-muscular injections or needle electro-myogram or from cosmetically impor-tant sites such as the face, neck, orhand. Muscles for which normal val-ues are well established include tn-ceps, biceps, and vastus lateralis.

The amount of tissue required fora muscle biopsy vanes with the na-ture and number of investigations tobe performed upon it. It is essentialto communicate with the pathologistand surgeon beforehand to selectboth site and quantity of tissue to beobtained. A technically inadequate bi-opsy is worse than none.

SPECIFIC DISEASES (Table 9)

Muscular Dystrophies

The muscular dystrophies are aninherited group of progressive musclediseases which share some histopa-thology. The most thoroughly char-acterized disorder is Duchenne mus-cular dystrophy (also known as pseu-dohypertrophic muscular dystrophy),

an X-linked recessive disorder with aprevalence in the total population ofabout 3/1 00 000. Development isnormal until the child begins to walk.Gradually the child begins to sufferrepeated falls and to walk on tiptoe.

The hallmarks of the disease arethe enlarged rubbery calves, markedlumbar lordosis, and contractures,particularly of the Achilles tendonsbut involving otherjoints in the wheel-chair-bound patient (Fig 2). Later inthe course of the illness, children maydevelop kyphoscoliosis. The diseaseprogresses relentlessly; most boysare wheelchair-bound by 1 3 years ofage, and death occurs in the 20s fromcardiac or respiratory failure. Al-though pathologic changes onlyrarely have been described in thecentral nervous system, approxi-mately one fourth of boys with Ouch-enne dystrophy are mentally subnor-mal.

Typically, the serum creatine ki-

Fig 2. Typical stance in Duchenne musculardystrophy. Note the lumbar lordosis, calf hy-pertrophy, and contracture of Achilles tendon.

nase level is more than tenfold normalvalues early in the course of the ill-ness. A serum creatine kinase valuegreater than 2000 U/L in an infantolder than 3 months is indicative ofDuchenne dystrophy. As the illnessprogresses, the serum creatinine ki-nase levels, which may peak in thetens of thousands of units per liter,gradually fall back toward normal.Electromyography reveals short du-ration polyphasic motor unit poten-tials and occasional fibrillation poten-tials. Nerve conduction studies arenormal. Muscle biopsy demonstratesnecrotic muscle fibers, phagocytosis,regenerating fibers, circular fibers,variation in fiber size, fiber splitting,increased central nucleation of fibers,and increased perimysial fibrosis.

The X-linked recessive transmis-sion of the disorder has long beenrecognized, and recently the geneticdefect was mapped to the chromo-some Xp21 region. Even more re-cently, the gene product lacking inpatients with Duchenne musculardystrophy was identified. Named“dystrophin,” this protein now isbeing studied intensively. It has beenproposed to treat dystrophic childrenexperimentally with dystrophin in-jected into muscle. The use of DNAprobes to detect linkage of restrictionfragment length polymorphisms withthe gene for Duchenne muscular dys-



II

Fig 4. Expressionless facies and should�”r gir-dle wasting inpatient with facioscapulohumeraldystrophy. Note the contour of the shoulders,horizontal position of the clavicles and the pec-toral crease.

Fig 3. Calf hypertrophy in patient with Beckerdystrophy.

Muscle Disease


trophy has made prenatal diagnosispossible in a conceptus at risk. How-ever, the test is not necessary fordiagnosis in most cases.

Although the identification of dys-trophin deficiency presents a numberof exciting possibilities for Duchennedystrophy, for the time being, man-agement remains supportive withemphasis on the use of physiother-apy to maintain joint mobility, splintsto prevent the development of con-tractures, and bracing to maintain in-dependent mobility as long as possi-ble. The treating physician shouldbear in mind that this disease hasimplications for all members of thefamily, both in practical as well asgenetic terms, and a great deal ofsupport is required for the patient andhis family. Involvement with appropri-ate parent organizations, and espe-cially with the Muscular DystrophyAssociation, may be of enormousbenefit.

Some boys present a clinical pic-ture resembling that of Duchennedystrophy, but the symptoms ariselater in life and have a much slowercourse. The disease, first describedby Becker, also results from a geneabnormality in the Xp21 region, andpatients are characterized by verylarge calves (Fig 3). Laboratory inves-tigations generally yield results similarto those found with Duchenne dystro-phy. The electrocardiographic abnor-

malities are somewhat less frequentand less severe.

Facioscapulohumeral (Landouzy-D#{233}j#{233}nne)Dystrophy

This autosomal dominant myopa-thy principally affects the muscles ofthe face, shoulder girdle, and upperarms. It is slowly progressive and, inretrospect, symptoms may often betraced to the first decade of life. Thepatient often gives a history of inabil-ity to whistle or difficulty usingstraws. The patient may never haveclosed the eyes fully during sleep andyet, because the extraocular musclesare spared, the Bell phenomenon re-mains and consequently the corneais protected. The patient typically hasa smooth, unlined face with ptosis,somewhat protuberant lips, and ahorizontal smile. Wasting around theshoulder girdle produces winging ofthe scapulae with prominence of thebony contours. Muscles of the armsare wasted, but those in the forearmare spared. The lower limbs may beaffected later (Fig 4).

In an infantile variety, the childrenare born with facial weakness, andthe weakness involves other skeletalmuscles fairly rapidly. The absenceof a smile or the inability to close theeyes during sleep generally is notedin the first 2 years of life. Muscleweakness chiefly affects the trunkand lower limbs. There is a severelumbar lordosis so that the sacrummay adopt a horizontal position whenthe patient stands. Ambulation maybe lost before the end of the firstdecade. Sensorineural deafness andCoats disease (exudative retinopa-thy) have been associated with fa-cioscapulohumeral dystrophy.

Laboratory investigations of thechild usually show an elevated serumcreatine kinase value, and the elec-tromyogram discloses a “myopathic”pattern. Histologic examination of themuscle in some cases has shownsigns of inflammation in addition todegenerative changes. Treatmentwith corticosteroids has been unsuc-cessful, however.

Physical therapy and occasional or-thopedic intervention (particularly fix-ation of the scapula) are the main-stays of treatment of this disorder.The affected parent of the child with

such severe weakness may have solittle involvement that the disease

goes undetected, but electromyo-graphic studies will be abnormal inthat parent.

Scapuloperoneal Dystrophy

Closely related to facioscapulohu-meral dystrophy, scapuloperonealdystrophy has clinical features thatmay overlap with the former. Typi-cally, the peroneal and anterior com-partment muscles of the lower limbsare first affected. The first sign is footdrop followed by upper limb weak-ness. The face is spared. Both auto-somal dominant and X-Iinked reces-sive patterns of inheritance havebeen described.

Emery-Dreifuss Dystrophy

This disease of X-linked recessiveinheritance is a humeroperoneal mus-cular dystrophy and is better knownas Emery-Dreifuss dystrophy. In ad-dition to the muscular wasting andweakness involving the periscapular,upper and lower limb muscles, thepatients develop striking contrac-tures at the elbows at an earlier stagethan one would anticipate merely asa consequence of weakness and re-duced mobility. Contractures of the



TABLE 10. Diagnosis of Myasthenia Gravis and Myasthenic Syndromes

TensilonTest

AcetylcholineReceptor

Antibodies

RepetitiveStimulation

Myasthenia gravis + 90-100% + DLambert-Eaton myasthenic syndrome - - 0

ICongenital myasthenic syndromes ± - 0Botulism ± - 0

I+, positive; ±, sometimes positive; -, negative or absent; D, dec-

rement at 2 Hz; I, increment at >10 Hz.



cervical paraspinal muscles severelylimit neck flexion and extension. Elec-tromyographic and muscle biopsyfindings are not specific. Patients withEmery-Dreifuss dystrophy often suf-fer cardiac arrhythmia with failure ofatrioventricular conduction. Suddendeath has been reported.

Limb Girdle Dystrophy

This category of muscular dystro-phy is controversial. It is perhaps nota distinct entity but a heterogenouscondition made up of a variety ofdystrophies, with overlapping clinicalfeatures but various types of inherit-ance and modes of progression. Thecommon features are weakness ofthe hips and shoulders and the his-tologic changes in muscle. The symp-toms may not begin until the seconddecade of life.

Other Dystrophies

Several other anatomic patternshave been recognized, including: dis-tal myopathies, dystrophic processesconfined to the quadriceps muscle orthe laryngeal muscles, oculopharyn-geal dystrophy characterized by pto-sis, facial weakness and dysphagiabeginning in adult life; and ocular my-opathy with ptosis, ophthalmoplegia,facial weakness and (rarely) limbweakness.

DISORDERS OFNEUROMUSCULARTRANSMISSION

Myasthenia Gravis

Myasthenia gravis is an autoim-mune disease in which damage topostsynaptic acetylcholine receptorsresults in impaired neuromusculartransmission. The cardinal clinicalfeature of myasthenia gravis is fatig-able muscle weakness. Involvementof the palpebral levators, and the ex-traocular, facial, tongue, masticatory,palatal and pharyngeal muscles ismanifested by ptosis, diplopia, facialdiplegia, dysarthria, difficulty chew-ing, and dysphagia. There is no sen-sory deficit, muscle wasting is rare,and the deep tendon reflexes are pre-served.

The physician may be able to fa-tigue the affected muscles by exer-

cising the patient and thus detect theweakness. The diagnosis of myas-thenia gravis may be confirmed witha combination of tests, outlined inTable 1 0. Myasthenia gravis istreated with anticholinesterasedrugs, immunosuppressive agentsand, in selected cases, thymectomy.

Transient Neonatal Myasthenia

Transient neonatal myasthenia oc-curs in about 12% of children born tomothers with myasthenia gravis,some of whom may be asympto-matic. The disorder results from thepassive transfer of antiacetylcholinereceptor antibodies across the pla-centa. The disease is self-limited,rarely exceeding a few weeks. Someinfants may have sufficient fatigabilityof muscles needed for swallowing orbreathing to require anticholinest-erase medication and assisted venti-lation.

Congenital Myasthenic Syndromes

Symptoms of uncommon disordersof neuromuscular transmission maybe present at birth or appear duringthe first months of life. The findingsare ptosis, and extraocular, bulbarand limb weakness. These syn-dromes may be caused by one of thefollowing: defective acetylcholinester-ase molecule, defective re-uptake ofcholine to synthesize acetylcholine,prolonged open time of acetylcholine-activated ion channel, or defectivesynthesis or insertion of acetylcho-line receptors. A proper diagnosisrequires sophisticated electrophysio-logic studies in vitro of isolated mus-cle fiber with its end plates and elec-

tromicroscopic examination of theneuromuscular junction.

Botulism

The exotoxin produced by Clostri-dium botulinum is a potent blocker ofacetylcholine release from the nerveterminal of the neuromuscular junc-tion. Botulism begins with musclesinnervated by cranial nerves, spread-ing rapidly to include respiratory mus-des. Infantile botulism results fromingestion of food contaminated withC botuilnum rather than its exotoxin,as occurs later in life. Honey has beenmost often implicated in carrying thespores into the infant’s intestinal tractstill free of normal flora.

The infants’ first symptoms arelethargy and constipation. Later,symptoms include difficulty feedingand weak cry. Paralysis of the pupil-lary sphincter causing mydriasis is aclue to the diagnosis of infantile bot-ulism. Respiratory muscle weaknessmay occur. Confirmation may beachieved by demonstrating the pres-ence of the C botulinum in stools, orof botulin in serum. Electrophysio-logic study of muscle shows an incre-mental response to repetitive stimu-lation at high frequencies. Treatmentis supportive.

INFLAMMATORY MYOPATHIES

The prototype of this group of dis-orders in children is dermatomyositis,an autoimmune disorder character-ized by predominantly proximal mus-cle pain and weakness, associatedwith a characteristic rash of the faceand extensor surfaces of the limbs.In severe cases, there are subcuta-neous deposits of calcium that may



TABLE I 1. Congenital Muscular Dystrophiest

Central

Type Inheritance Findings

Involvement

Course

Undiffer- Autosomal re- Upper body - Nonprogressiveentiated cessive/

sporadicweakness(externalocular mus-

Early deathfrom respira-tory failure

des spared)1’ReflexesContractures,

kyphosis,scoliosis

Fukuyama Autosomal re-cessive/

External ocularmuscles

Seizures(50%)

Death in firstdecade

. sporadic weakContractures,

kyphosis,scoliosis

Pectus exca-vatum

Rarely walks

Mental retar-dation

* -, absent; ,�, decreased.

Muscle Disease


spontaneously extrude through theskin. Vasculitis may produce a myo-carditis and, rarely, congestive car-diac failure and infarction of the gut.

Laboratory investigations show anelevated erythrocyte sedimentationrate and serum creatine kinase value;leukocytosis may be present. Theelectromyogram shows myopathicchanges and fibrillation potentials.The muscle biopsy demonstratesatrophy as well as inflammatorychanges; vasculitis may be apparentin some samples.

Corticosteroids are effective intreatment of this condition. In severecases, Azathioprine has been em-ployed. In addition to immunosup-pressive treatment, children shouldreceive physical therapy and splintingas required. Polymyositis is less corn-mon than dermatomyositis, but thetreatment is the same.

A number of other inflammatorymyopathies have been described, in-cluding eosinophilic fasciitis, inclusionbody rnyositis and sarcoid myopathy.All of these are seen rarely, if ever, inchildren.

METABOLIC MUSCLE DISEASES

The biochemical machinery thatmaintains the integrity of the musclecell as well as generating energy formuscular contraction is complex, anda defect at any stage of this processmay produce muscular weakness.The clinical manifestations depend onboth the impaired biochemical proc-ess and the quantitative degree ofimpairment. Such disorders may re-suIt from total absence or partial de-ficiency of an enzyme or the exist-ence of normal quantities of a struc-turally abnormal and functionallydeficient enzyme.

These disorders may be groupedtogether in terms of those affectingglycogen metabolism and glycolysis,lipid metabolism, and the electrontransport system. Detailed discus-sion of the individual disorders is be-yond the scope of this paper but afew salient features will be men-tioned.

Patients with metabolic muscle dis-ease may demonstrate no abnormal-ity at rest but manifest symptomsonly following exercise. These maytake the form of weakness, muscle

cramps or myoglobinuria. Such dis-orders generally manifest themselvesfirst in childhood or adolescence, butonset in adult life may occur.

Some of these disorders have spe-cific clinical features which will pointto the diagnosis. For example, infan-tile acid maltase deficiency (Pompedisease) is characterized by progres-sive weakness with enlargement ofthe tongue, heart and liver as a con-sequence of glycogen storage. Otherglycogenoses may produce organ-omegaly and progressive muscleweakness. Hypoglycemia may occurin the neonatal period.

Patients with disorders of the elec-tron transport chain, called mitochon-drial cytopathies, may evidence cen-tral nervous system disease, myopa-thy and peripheral neuropathy. Theprototype of these disorders is ocu-locraniosomatic neuromuscular dis-ease, or Kearns-Sayre syndrome. Al-though the clinical manifestations ofthis disorder are protean, the essen-tial features are progressive externalophthalmoplegia, retinitis pigmen-tosa, and heart block. The musclesections stained with trichrome dem-onstrate “ragged red” fibers, a findingtypical of mitochondnal disorders.Lactic acidemia may be present. In-heritance is maternal.

In cases where a metabolic muscle

disorder is suspected but other cluesto the diagnosis are lacking, an ex-ercise test may be useful. Recently,magnetic resonance spectroscopyhas been used to analyze the bio-chemical changes occurring in mus-cle following exercise. Measurementof the serum creatine kinase, serumcarnitine, and screening of blood andurine for myoglobin may contribute tothe diagnosis. Definitive diagnosis re-quires muscle biopsy for histochemi-cal studies. In some instances, theultrastructure of the muscle is char-acteristic for the disorder. In others,little change may be apparent.

Carnitine deficiency may be asso-ciated with lipid myopathy or morediffuse systemic illness. Most casesare secondary to inborn errors of me-tabolism, but many other associa-tions have been reported, includingdietary deficiency, chronic diseasesand drugs (sodium valproate). Thus,a low carnitine level in a patient withmuscle disease is not diagnostic initself, but should prompt further sys-temic investigation.

One subgroup of metabolic muscledisease is characterized by abnor-malities of the muscle membrane.This group includes the so-calledperiodic paralyses in which patientsexperience episodic bouts of weak-ness accompanied by a rise or fall in



* AD, autosomal dominant; AR, autosomal recessive; X, X-linked recessive; N,

normal; K, kyphosis; S, scoliosis; TEV, talipes equinovarus; H, hypotonia; P,high arched palate; CDH, congenital dislocation of hips; EOM, extemal ocularmovements.

TABLE 13. Myotonic Disorders

* AD, autosomal dominant; AR, autosomal recessive.



TABLE 12. Ben ign Congen ital Myopathies

Type Inherit-Findings Biopsy

Central core AD CDH, TEV, K, SLordosis

Central cores

Multicore AR �L EOMHypotoniaWalking

Small coresStreamedZ-bandsAbnormal fibers

Nemaline AD (AR) HypotoniaProximal weak-

nessLong faceP, K, TEVLordosis

Nemaline rodsI Type I fibers

Centronuclear AR Myopathic fades Central pale (“myotube”)(myotubular) X

ADPtosisTEV

‘� type I fibers

Congenital AR Hypotonia Predominance of smallFiber type AD CDH, P, TEV type I fibersDisproportion ,� EOM

Rigid spIne

the plasma potassium level. Typically,these episodes are provoked by ex-ercise or a variety of other stressorsand may last hours, in the case ofhyperkalemic periodic paralysis, or aday or more, in the case of hypoka-lemic periodic paralysis. It is essentialto study the patient during an attackto make the diagnosis with certainty.Hypokalemia and hyperkalemia re-suIting from renal and gastrointestinalderangements are far more commoncauses of muscle weakness thanthese periodic paralyses.

MYOPATHIES ASSOCIATED WITH

SYSTEMIC ILLNESS

Inflammatory myopathy may be as-sociated with connective tissue dis-eases, including systemic lupuserythematosus, polyartentis nodosa,scleroderma and various overlap syn-dromes. In children, these are lesscommonly seen than primary derma-tomyositis. Deranged endocrine func-tion may also produce muscularweakness. Thyrotoxicosis may pro-duce a nonspecific proximal myopa-thy. Other features of the disorder

Type Inheritance Onset Myotonia Other Features Treatment

Myotonic dys-trophy, classicform

AD* Late child-hood

Wanes with age Face, neckand distallimbs (notin allcases)

May beearly

CataractsHypogonadismHeart block

Phenytoin(avoid drugsthat affectcardiac con-dition)

Neonatal onset AD(maternal)

Birth/inutero

May not bepresent in first5 y

Absent Absent HypotoniaPoor suckTented upper lipTalipesPolyhydramnios

Supportive

Myotonic con-genita (Thom-sen disease)

ADAR

Childhood Decreases withexercise andwarming

Absent Present Herculean ap-pearan#{231}e

PhenytoinQuinineQuinidine

Paramyotoniacongenita(Eulenbergdisease)

AD Childhood Increases withexercise

Absent Present EpiSOdic weak-ness (ie, hy-perkalemiCperiodic paral-ysis)

PhenytoinQuinineQuinidine



1Fig 5. Patient with myotonic dystrophy. Notethe ‘swan neck,” “inverted V’ mouth, unlinedface, and protuberant auricles.

SUMMARY

This paper has given an overview

CONGENITAL MYOPATHIES AND of the complexity of childhood muscleDYSTROPHIES. disease. Fortunately, astute history-

taking and physical examination,combined with readily available tests,will usually enable the clinician to for-mulate a diagnosis and plan of man-agement.

Muscle Disease


including increased appetite, weightloss, anxiety, exophthalmos or thy-roid dermopathy draw attention tothe diagnosis.

Hypothyroidism produces “hung-up” ankle jerks and myoedema. Aspecific syndrome has been de-scribed in infants (Kocher-Debr#{233}-Se-rn#{234}laignesyndrome). This disorder ismarked by weakness and diffusemuscle hypertrophy. Symptoms andsigns respond to thyroxine. The cre-atinine kinase value may be up to tentimes normal in hypothyroidism, inthe absence of overt muscle disease.A rare association of hypokalemicperiodic paralysis with thyrotoxicosisshould also be noted. Diabetic neu-ropathy and myopathy are uncom-mon in children and the diagnosis isusually obvious. Parathyroid hypo-function may be associated with tet-any, and proximal myopathy hasbeen described in hyperparathyroid-ism. Hyperadrenocortisonism is as-sociated with a nonspecific proximalmyopathy with selective type II fibreatrophy. Adrenal failure producesnonspecific muscle weakness and, inchronic cases, muscle contractures.

Toxic etiologies of myopathy arelisted in Table 2.

A variety of uncommon primary dis-eases of muscle are grouped underthese names. The congenital dystro-phies are degenerative disorders withonset at birth or soon after. Theirfeatures are summarized in Table 11.In contrast, the congenital myopa-thies are a relatively benign group ofdisorders characterized by hypotoniaat birth, static or very slowly progres-sive proximal weakness and are-flexia. Dysmorphic features are pres-ent in some cases. The clinical fea-tures of the diseases most often re-ported are summarized in Table 12.

MYOTONIC DISORDERS

These disorders share the com-mon feature of myotonia-that is,prolonged relaxation of muscle fol-lowing voluntary or reflex contrac-tions. There is some overlap withother categories: myotonic dystrophywith the muscular dystrophies andparamyotonia congenita with hyper-

kalemic periodic paralysis. Details aresummarized in Table 13 (Fig 5).

SUGGESTED READING

Brooke MH. A Clinician’s Guide to Neuromus-cular Diseases. 2nd ed. Baltimore, MD: Wil-hams & Wilkins; 1986

Brooke MH, Fenichel GM, Griggs RC, et al.Duchenne muscular dystrophy: patterns ofclinical progression and effects of supportivetherapy. Neurology. I 989;39:475-481

Dubowitz V. Muscle Biopsy. A Practical Ap-proach. 2nd ed. London, UK: Bailli#{232}reTindall;1985

Engel AG, Banker BQ. Myology. Basic andClinical. New York, NY: McGraw-Hill; 1986

Gutman DH, Fischbeck KH. Molecular biologyof Duchenne and Becker’s muscular dystro-phy: clinical applications. Ann Neurol.1989;26:1 89-194

Hoffman EP, Kunkel LM, Angelini C, et al.Improved diagnosis of Becker dystrophy bydystrophin testing. Neurology.1989;39:1O1 1-1017

Layzer RB. Neuromuscular Manifestations ofSystemic Disease. Philadelphia, PA: F.A.Davis Company; 1985

Steelman H, Sarkar S. Molecular genetics inbasic myology: a rapidly evolving perspec-tive. Muscle & Nerve. 1988;1 1:668-682

Steelman H, Sarkar, S. Molecular genetics inmuscular dystrophy research: revolutionaryprogress. Muscle & Nerve. 1988;1 1:683-693

Walton J, ed. Disorders of Voluntary Muscle.5th ed. Edinburgh, Scotland: Churchill Liv-ingstone; 1988

Self-Evaluation Quiz

1. Primary muscle disease alone is mostlikely to cause:

A. Delayed acquisition of language.B. Sensory impairment.C. Delayed attainment of motor milestones.D. Delayed social adaptive behavior.E. Impairment of vision.

2. Which of the following is least likely tobe found with denervated muscles?

A. Soft muscles.B. Muscle wasting.C. Fasciculations.D. Myotonia.E. Hypoactive deep tendon reflexes.

3. Each of the following is true about neu-romuscular diseases, except:

A. Distal weakness suggests a primary mus-cle disease.

B. Weakness is the primary symptom.C. Weakness or pain following exercise is a

feature of certain metabolic myopathies.D. Pain is not usually a feature of muscular

dystrophies.E. Deep tendon reflexes are usually reduced

or absent.

4. A 4-year-old boy has repeated falls andwalks on his toes. Physical examination re-veals marked lumbar lordosis, enlarged rub-bery calves, and contractures of Achillestendons. Which of the following findingswould not be consistent with a diagnosis ofDuchenne muscular dystrophy?

A. Marked elevation of serum creatine ki-nase.

B. Abnormal electromyogram.C. Normal nerve conduction studies.D. Abnormal muscle biopsy.E. Antibodies to muscarinic acetylcholine

receptors.

5. A 5-month-old previously healthy infantdeveloped lethargy and constipation 4 daysago. He has had a weak cry and poor suckfor 2 days. On physical examination he isfound to be alert and afebrile and to haveenlarged pupils and generalized hypotoniaand weakness. The most likely diagnosis is:

A. A congenital myasthenic syndrome.B. A myotonic disorder.C. A benign congenital myopathy.D. Infantile botulism.E. Infantile variety of facioscapulohumeral

dystrophy.



DOI: 10.1542/pir.12-3-731990;12;73Pediatrics in Review

Marc C. Patterson and Manuel R. GomezMuscle Disease in Children: A Practical Approach

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