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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 in- volved, 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
" Hypothyroid myopathy
" 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
" Hypothyroid myopathy
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
Muscular dystrophies
Duchenne
Becker
Emery-Dreifuss
Facioscapulohumeral
Limb-girdle
Congenital
Inflammatory myopathies
Dermatomyositis
Polymyositis (rarely)
Congenital myopathies
Nemaline
Centronuclear
Central core
Lipid storage disease (carnitine deficiency)
Glycogen storage disease (acid maltase deficiency)
Mitochondrial myopathies
Endocrine-metabolic disorders
Hypokalemia
Hypocalcemia
Hypercalcemia
" Myopathies Presenting in Adulthood
Muscular dystrophies
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
Inflammatory myopathies
Polymyositis
Dermatomyositis
Inclusion body myositis
Viral (human immunodeficiency virus [HIV])
Metabolic myopathies
Acid maltase deficiency
Lipid storage diseases
Debrancher deficiency
Phosphorylase b kinase deficiency
Mitochondrial myopathies
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
Metabolic myopathies
Becker myotonia
" Maternal Transmission
Mitochondrial myopathies
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
Muscular dystrophies
Myotonic
Limb-girdle 1B, 2C-2F, 2G
Emery-Dreifuss
" Congestive Heart Failure
Muscular dystrophies
Duchenne
Becker
Emery-Dreifuss
Myotonic
Limb-girdle 1B, 2C-2F, 2G
Nemaline myopathy
Acid maltase deficiency
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
Acid maltase deficiency
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*
Centronuclear 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
Congenital myopathies
Centronuclear myopathy
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
"SUSPECTED MYOPATHY
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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 ele- vations, 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
Muscular dystrophies
Congenital myopathies
Metabolic myopathies
Inflammatory 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.
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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.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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" Brooke MH. A clinicians view of neuromuscular disease. 2nd edition.Baltimore: Williams & Wilkins, 1986.
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This paper summarizes current knowledge regarding the genotypes and phenotypes of
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32
"SUSPECTED MYOPATHY
top related