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Muscle diseases.

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MUSCLE DISEASES
196
vivors 6.5 to 21 years after presentation (C211). Twothirds of these patients had no abnormalities and another 10% had only minor urinary abnormalities. Approximately 10% had chronic renal failure, 5% had died,
and 5% had heavy proteinuria. Neither the clinical presentation nor the renal morphology were precise determinants of outcome. It was recognized that renal deterioration may be a relatively late occurrence. [This
series is biased toward children presenting with serious
renal disease. Ed.] In a 6-year followup of 30 patients
hospitalized for acute HSP, 28 of 30 were clinically well
and 25 of 30 had normal renal status, suggesting a good
overall prognosis (E48). [This study is unfortunately
flawed since 30%of the original patients were lost to followup, obscuring the true prognosis. Ed.]
The clinical features and nephritis of HSP were
compared with primary IgA glomerulonephritis (N 1 1).
Primary IgA nephritis is generally discovered by
asymptomatic proteinuria, and systemic symptoms are
relatively uncommon. Conversely, with HSP, purpura is
the characteristic feature and systemic symptoms are
common. In both diseases, hematuria is conspicuous
and proteinuria is modest, while normal renal function
is the rule. Pathologically, mesangial proliferation and
focal and segmental lesions were seen in both disorders,
and immunopathologic alterations including epimembranous granular deposition of IgA were indistinguishable. Electron microscopic evaluation of a patient with HSP nephropathy also showed subepithelial
electron dense deposits (U 14).
Immunologic studies of HSP demonstrated the
presence of cryoglobulins in 47% of patients with acute
disease, 64% of patients with chronic nephritis second-
ary to HSP, and 0% of those who had completely recovered from the acute illness, suggesting an immune complex pathogenesis for the disorder (G22). Complement
(CH50) was low in 39% and properdin was decreased in
30% of patients with acute HSP, but Clq, C4, and C3
were normal (G23). Complement components were normal in chronic HSP. Further studies of the complement
system in HSP also demonstrated normal classical pathway activity and reduced levels of properdin, pointing
to alternate pathway activation (S323).
HSP is generally believed to be associated with
normal hemostatic function, despite the purpuric nature
of the disorder. However, decrease in Factor XI11 was
found in 13 of 17 consecutive children with HSP
(H110). It was postulated that the decrease was due to
specific degradation by proteolytic enzymes liberated
from inflammatory cells, resulting in defective local hemostasis. Treatment of 1 patient with Factor XI11 and
an antifibrinolytic agent controlled a life-threatening
gastrointestinal bleeding episode. An unusual complication of HSP was a hemorrhagic diathesis secondary to
vitamin K deficiency, postulated to be due to defective
bowel absorption secondary to gastrointestinal vasculitis (M163). The patient was responsive to parenteral
administration of vitamin K.
An unusual feature of Henoch-Schonlein purpura was transitory submucosal bleeding in the colon
similar to that seen in the small bowel (N80). Scrotal
swelling is an uncommon feature but may be very helpful diagnostically early in unclear cases. Scrotal imaging
may be of assistance in such cases, since it may distinguish testicular torsion (reduced blood flow) from hyperemic states (N7).
MUSCLE DISEASES
Polymyositis and dermatomyositis
Based on a computer analysis of 153 patients, the
most useful criteria for the diagnosis of polymyositisdermatomyositis (PM-DM) were: 1) proximal muscle
weakness, 2) elevation of muscle enzymes, 3) the characteristic electromyographic triad, 4) typical muscle histology, and 5) the classic skin rash of dermatomyositis
(B190). Steroid responsiveness was not a useful diagnostic criterion. The most sensitive criteria were the serum
enzymes and proximal muscle weakness. Normal serum
enzymes were found in only 1.8% of patients with active
disease. In this study, which should be regarded as a
classic in its field, a number of conventional conclusions
regarding the disease were critically examined.
A second report from the same institution described the spectrum of PM-DM (P62). The updated
classification of these disorders was: 1) polymyositis in
adults, 2) typical dermatomyositis, 3) inflammatory
myositis associated with malignancy, 4) childhood myositis, and 5) myositis associated with the overlap syndromes. The clinical manifestations associated with
these various disease subtypes were described.
Diagnostic features. As noted, serum muscle en-
MUSCLE DISEASES
zymes are elevated in nearly every patient with PMDM. Creatine phosphokinase (CPK) has proved to be
the most sensitive of these enzymes. Several assays for
the isoenzymes of CPK were described which permitted
ready distinction between MM (skeletal muscle), BB
(brain), and MB (the hybrid form present in cardiac and
smooth muscle) forms (FI3,L195,N46). The presence of
different CPK isoenzymes in cardiac and skeletal
muscle was verified (N78,T59). Elevations of CPK were
noted after vigorous exercise (L30). Massive elevations
of CPK were associated with psychosis of unknown origin (T29). CPK activity was shown to be genetically
controlled (L116).
A characteristic small amplitude, short duration,
polyphasic motor unit potential was observed in the
electromyogram of approximately 90% of patients with
PM-DM (B 190,H109). Increased membrane irritability
manifested by spontaneous fibrillation was seen in 75%,
and bizarre high frequency discharges were noted in
about 40%. The electromyogram was normal in 11%
with otherwise classic presentations.
Similarly, a normal muscle biopsy was seen in
12.5% of a large series (B190). A study of muscle pathology in systemic lupus erythematosus (SLE), rheumatoid
arthritis (RA), and polyarteritis nodosa (PAN) showed
that these conditions could be readily distinguished
from PM-DM by light microscopy (P122).
Attempts to characterize the antinuclear antibody found in about 15% of patients with PM-DM led
to the description of a new precipitin reaction, provisionally called PM- 1, between calf thymus nuclear extract and PM serum (W168). This reaction was demonstrated in 17 of 28 patients with PM, but in none of 460
patients with other diseases. Because of this apparent
strong specificity, it was suggested that the PM- 1 system
might represent a useful marker antibody for PM-DM.
It was suggested that the estimation of myoglobin might be useful in diagnosis and assessment of
disease activity in patients with muscle diseases and a
radioimmunoassay for serum myoglobin was described
(N6 1). Serum myoglobin values were significantly
higher than normal in 50% of patients with PM and the
levels fluctuated in a more sensitive fashion than CPK
or SGOT. Estimation of both CPK and myoglobin was
suggested for following disease activity (K4,N61). A circulating autoantibody directed against myoglobin was
also described, but was of doubtful significance (N60).
Acute renal failure due to myoglobinuria continued to
be recognized (K 163,S247).
There was suggestion that increased soft tissue
uptake of technetium phosphate complexes might result
in detection of nonosseous conditions (S365).
197
Electrocardiographic and cardiac abnormalities
in PM-DM included nonspecific ST-T wave changes,
arrhythmia, abnormal Q waves, bundle branch block,
congestive heart failure, prolonged PR interval, and
high grade heart block (B190,L116,117,027). Syncope
and complete heart block have also been reported in
PM-DM, but such cases have been rare (G 174,s 172).
Association with malignancy. Approximately
15% of patients with acute DM-PM were stated to have
associated malignancy (T1 1). This association was
noted after age 40. The malignancy might either precede or follow the muscle disease by one or more years.
Most patients with an associated malignancy had skin
lesions, but there were no unique clinical or laboratory
features to distinguish them from patients without malignancy. Extensive muscle necrosis was suggested as a
feature of PM-DM associated with malignancy (M84)
and it was noted that the clinical course in such patients
was frequently rapidly progressive and relentless, with
failure of the respiratory and pharyngeal muscles (TI 1).
A case of DM complicated by the development of acute
granulocytic leukemia was reported (G 150).
Childhood dermatomyositis. In a review of 41
children with DM, symmetric progressive proximal
muscle weakness was present for periods ranging from 2
weeks to 1 year prior to presentation (S408). Approximately 60% had palpable muscle discomfort, as well as
pain on muscle activity. Fever to 100"F, present in onethird, usually followed muscle weakness. After introduction of steroid therapy, fever usually disappeared
within 48 hours and muscle enzymes returned to normal
within several weeks. Muscle strength continued to improve thereafter and required a minimum of 8 weeks
before approaching normal. Patients were usually
treated for 2 years, after which therapy was discontintied or reevaluated on an individual basis. On occasion,
the use of immunosuppressive agents was required
(A1 17,S408).
Others reported that childhood DM may persist
in activity beyond the initial presentation and remission
(M249). A study of children followed for 5 or more
years revealed an unexpectedly high prevalence of
slowly progressive morbid or functional problems, including continuation of DM, soft tissue calcinosis,
muscle weakness, arthritis, nephritis, iridocyclitis, and
pericarditis. Thus, previous observations that childhood
DM is a self-limiting acute disease may not be correct.
Etiology and pathogenesis. The etiology and
pathogenesis of PM-DM remain unknown. Unfortunately, there are no well characterized animal models
that can be used to study this syndrome. Studies of human muscle in tissue culture have suggested that the
MUSCLE DISEASES
198
polymyositis and muscle destruction are mediated by
thymic dependent lymphocytes. The HLA types of I 1
children with DM were determined (C31). There appeared to be an increase in the phenotypes HLA-1 and
HLA-B8, but this remains to be confirmed.
Although a variety of viral infections, including
hepatitis B, may simulate myositis, such infections do
not appear to be involved in all patients with myositis or
DM-like syndromes and suggest that myositis is a syndrome of multiple etiologies (D52,M229,P137,S 124).
However, there does appear to be an association of
ECHO virus infection, DM, and hypogammaglobulinemia (B28,W59). In a brief report of a 19-year-old black
woman with transient postviral (influenza) myositis, it
was suggested that an abnormal host immune response
might perpetuate such an injury to produce chronic inflammatory muscle disease (G207). Although the presence of circulating soluble immune complexes has been
studied, as well as quantitative measurement of complement levels, there is p l y circumstantial evidence
that humoral immunity and complement components
play a significant role in the pathogenesis of this disease
(B74). An ultrastructural study did confirm small vessel
involvement in childhood dermatomyositis (L 192).
A number of unique or rare features were noted
in DM, including spontaneous pneumothorax (S23 I),
carcinoid (Y5), and myasthenia (V30). Unilateral PM
was described (S340). There was also a report of longitudinal muscle spli$jng in the PM but the significance
appeared moot (S420). Finally, PM and Chagas disease
(C208), DM and the atypical cholinesterase enzyme
(E33), and PM anq palabsorption were reported (T85).
Treatment. Steroids have been the drugs most
frequently used in tpe treatment of PM. Unfortunately,
there is little $atistigal information regarding the influence of these ageqts on survival or disease morbidity. In
one study, 3 1 PM patients treated with low dose corticosteroids were coqpared with age- and sex-matched patients treated witg high dose corticosteroids (C45). Although disease severity at the onset of the study was
similar in both Groups, no statistically significant difference in survivd was found. Unfortunately, long-term
followup was not performed.
In fact, it has been emphqsized that the therapeutic effects of corticosteroids in PM-DM may be classified as studies based on fiction, kancy, and fact (514).
Further, misinterpretation of series of patients in which
doubleblind studies were not performed has resulted in
skepticism on the part of some physicians and overenthusiasm by others. The overall experience suggests,
however, that steroids are the mainstay of treatment
and generally induce remission in most patients.
If life-threatening PM is not controlled with steroids, particularly in children, azathioprine and/or
methotrexate are helpful ancillary agents. However,
such agents are not without toxicity. Patients must be
monitored carefully (E39,J 1 1,M84,S34). Two children
with inactive DM but with local and systemic inflammatory signs secondary to extensive calcium deposits in
subcutaneous and periarticular tissues were reported to
have displayed a prompt response to colchicine (TI).
Other variants of polymyositis. Recently a painful inflammatory nodular myopathy in young and
middle-aged adult males was described (L47). This
nadular process generally evolved into a diffuse proximal myopathy accompanied by dysphagia and resembling the so-called fascioscapulohumeral syndrome.
The electromyographic abnormality in all patients was
myopathic and muscle biopsy revealed an intense, predominantly interstitial, pleomorphic infiltration of
muscle along with muscle fiber destruction and degeneration. This syndrome appeared to be a variant expression of PM.
In contrast, in 3 patients with subacute PM,
muscle biopsies were uniquely remarkable for showing
intense infiltration by eosinophils (C236). Although the
inflammatory infiltrate of PM was typically composed
of lymphocytes, plasma cells, histiocytes, and occasional
neutrophils, eosinophilic infiltrates appeared to fit into a
new syndrome known as disseminated eosinophilic collagen disease, or hypereosinophilic syndrome. Systemic
manifestations of such patients included eosinophilia,
anemia, hype rg a m mag lo bulinemia, vascular involvement, skin rash, subcutaneous edema, pulmonary
infiltrates with pleuritis, congestive heart failure, arrhythmia, heart block, pericarditis, and peripheral neuropathy. The prognosis of this disease was poor, although only 3 or 4 patients have been studied. The
average survival was 9 months after onset of the disease.
Other muscle diseases
It is relatively common for patients to come to
rheumatic disease clinics with complaints primarily referrable to muscles. Such complaints, if not directly attributable to the more common collagen vascular disorders or PM-DM, often fall within the area of a large
number of ill-defined and poorly understood clinical
entities. To understand or begin to evaluate these problems, a basic introduction in normal muscle strength, fiber types, and enzymatic activities in human beings is
necessary. Such an approach has recently been presented in an attempt to relate the histochemical profiles
and biochemical characteristics of human skeletal
muscle with its mechanical properties (T58).
MUSCLE DISEASES
The association between the contractile properties of muscle and its morphologic and biochemical
characteristics has long been known. Moreover, the distribution of distinct muscle fiber types and histochemical analysis of muscles with fast and slow contraction
times had led to the conclusion that muscle units can be
classified into 2 main types, slow twitch (ST, or type I)
and fast twitch (FT, or type 11) (T58). The muscle fibers
belonging to each type of motor unit have been shown
to be homogeneous. Further, they can be identified histochemically. Maximal tetanic tension appears to be
higher for FT than for ST motor units, even when tension is related to unit cross sectional area. Such data
were primarily dependent on studies of animals.
However, study of muscle derived from human
cadavers has disclosed that most human skeletal muscle
consists of a mixture of muscle fiber types. Contractile
activity in such muscle was controlled by magnesiumstimulated ATPase regulation of the actomyosin of
myofibrils. A high correlation existed between the speed
of muscle contraction and the activity of this enzyme in
both myosin and actomyosin. More detailed information about the distribution of these enzymes is being obtained with isozymes, and alterations of these muscle fibers may be important for specific muscle activities, and
possibly in disease states (T58).
The physiology of human muscle was studied
with structural analyses performed after disuse (S30).
Atrophy of affected limb and loss of muscle power followed immobilization in a long plastic cast after fracture reduces the fat-free volume of the affected limb by
12%, accompanied by a similar fall in maximum oxygen
uptake (T58).
The assessment of muscle function is now a necessary part of clinical rheumatology. Since the object of
muscle is to develop tension, muscle function must be
assessed in studies of force generation. This is perhaps
best done by testing patient performance in such activities as arising from a chair, walking, or climbing stairs.
Although these tests are influenced by many factors
other than the state of muscles themselves, they do aid
enormously in patient management. Nonetheless, it has
been emphasized that they are not significant in understanding etiology of a specific muscle disorder (Y18).
The study of normal muscle activity is perhaps
best illustrated by examining the effect of denervation
on the production of experimental myopathy. The organophosphorous cholinesterase inhibitor, paraoxon,
was administered to rats to produce a proximal myopathy characterized by the appearance of central nuclei,
fiber splitting, and loss of fiber architecture (W62). If
the muscle was denerved 2 weeks before paraoxon ad-
199
ministration, myopathy was prevented in the denervated muscle and necrosis induced in the contralateral
innervated muscle (W61). Indeed, it was apparent that
changes in denervation, and by analogy, muscle repair
and injury, can be related to changes both in muscle
contractile activity and cholinesterase activity.
Similar observations were applied in studies of
cyclic nucleotides in the regulation of muscle contraction (N79). Cyclic nucleotides mediate the intercellular effects of a variety of organ functions. To explore the possibility that nerve-muscle influences are
mediated by cyclic nucleotides, one group studied the
effects of denervation on the cyclic enzymes of rabbit
gastrocnemius using the contralateral unoperated limb
as control (N79). It was noted that adenyl cyclase activity significantly decreased after denervation, while
guanylate cyclase activity increased severalfold. It was
suggested that critical changes in cyclase activity after
denervation might result in alteration of nerve/muscle
interactions.
The relationship of normal activity of human
skeletal muscle to muscle fiber type was determined by
studying the muscle usage patterns of 12 normal males
between the ages of 20 and 35 years continuously over
an 8-hour working day (M285). Muscle usage was based
on the electrical activity of the muscles during contraction as recorded on an electromyogram. Recordings
were made simultaneously from 2 functionally linked
but histochemically different muscles, and the analysis
of pattern times and percentage of time active could
thereby be compared from day to day. All activity patterns were recorded with pocket tape recorders, assuring
unobtrusive data collection. Finally, selection of the
population of muscles was influenced by the available
data on metabolic profiles of normal human skeletal
muscle.
It was found that the muscle activity of such normal ambulatory patients had several distinct patterns.
These patterns were related to the average percentage of
time active. Indeed, active muscle was highly correlated
with percentage of type I fibers within a given muscle.
Such changes perhaps can be correlated with electron
microscopic x-ray analysis of normal and diseased human muscle (M117). An elevated calcium to phosphorus ratio was found in both myonuclei and interstitial cell nuclei in diseased muscle compared to
controls. Indeed, it is suggested that differences in element concentration may be associated with structural
abnormalities of muscle.
Malignant hyperthermia associated with myopathy. Malignant hyperthemia induced by anesthesia is a
well documented entity (G212). This disorder is charac-
200
terized by a rapid rise in body temperature accompanied by metabolic acidosis, tachycardia, tachypnea,
and cyanosis with or without muscle stiffness. There
have been numerous predisposing states to malignant
hyperthermia. These include patients with various clinical or subclinical myopathies and neuropathies. There
has even been a specific phenotype proposed, characterized as a man of short stature with spinal deformity,
pectus carinatum, cryptorchidism, mandibular hypoplasia with crowded teeth, ptosis, low set ears, webbed
neck, and weakness of serrati muscles (K30). Since 1950
when this disorder was first described, more than 600
cases have been reported, with an average incidence of
1 :60,000 to 1 :70,000 anesthesias (G212). Although the
halogenated inhalants and general anesthetics are most
commonly incriminated, other drugs have also initiated
this discorder (G212,M109).
Malignant hyperthermia carries with it an extremely high mortality but it was emphasized that the
disease need not be fatal (T48). Treatment should be
aimed at improving conditions for heat exchange by
vigorous external and internal cooling, controlling biochemical disturbances, primarily acidosis and hyperkalemia, aiming eventually at relieving muscular rigidity. Procaine or procainamide has been recommended
for this purpose, but both are often criticized because of
their cardiac suppression. Other workers have suggested
hydrocortisone (G2 12,M109,T48).
Many groups have examined the possibility of
distinguishing patients who might be susceptible to
these hyperthermic crises. It is now believed that susceptibility can be diagnosed by skeletal muscle biopsy
and exposure of this tissue to caffeine, and caffeine plus
halothane, with simultaneous measurements of isometric or resting tension (K13). Muscles from patients susceptible to malignant hyperthermia exhibited marked
increase in contracture after exposure to these agents. In
addition, light and electron microscopic changes were
highly suggestive but not diagnostic of disease. Some of
these altered structural changes, when studied in patients undergoing cardiac arrest, demonstrated areas of
myofiber overstretching adjacent to contraction bands
and foci of extensive myofiberlysis associated with destruction of sarcolemma (F29,H209). It was believed
that these altered structural findings were responsible
for the hyperkalemia reported in these patients and not
a cause of the ventricular arrhythmia seen.
The existence of a difference in the structural or
functional integrity of membranes of animals susceptible to malignant hyperthermia appears similar to the
situation in humans. However, in the case of guinea
pigs, there has been some interest in studying the func-
MUSCLE DISEASES
tional integrity of mitochondria1 membranes (C103). It
was believed that the underlying mechanism responsible for the series of biochemical events included an increase in serum calcium leading to membrane imbalances (B87,H102).
Dantrolene sodium administered orally was
shown to prevent the development of malignant hyperthermia in susceptible pigs (H68). No conclusion could
be reached regarding effectiveness of the drug on the
basis of administration to a single human subject, and it
was emphasized that careful selection of local and general anesthetic agents remains the best form of protection against the condition (F102).
Tropical pyomyositis. Tropical pyomyositis is a
suppurative infection of skeletal muscles of unknown
etiology, commonly seen in the tropics. It is characterized by abscess formation within single or multiple regions. Although many etiologies have been suggested,
the underlying disorder remains unknown, although the
most frequent infecting organism remains Staphylococcus aureus. Patients with this disorder have elevated
serum muscle enzymes. Although most patients respond
well to a combination of incision, drainage, and antibiotics, there are a variety of complications, including
metastatic abscesses, myocarditis, hypotension, acute
tubular necrosis, confusion, and coma. This disease is
rare in the temperate areas of the world, but isolated
case reports emphasize that the differential diagnosis
continues to receive attention (A136,G241,L4,T61,100).
Drug-induced muscle disease. It is well known
that muscle necrosis can be induced experimentally.
Three drugs that have been extensively studied in this
regard are paraoxon, an irreversible organophosphorus
chohesterase inhibitor; pargyline, a monoamine oxidase
inhibitor; and serotonin, a neuromuscular transmitter
(R 17). The mechanisms involved in these drug-induced
myopathies are unknown. However, it was observed
that prior denervation abolishes or alters the ability of
these drugs to induce muscle disease damage. These
studies have been carried out primarily in animals. One
study produced experimental serotonin myopathy by
injecting rats with 20 mg/kg serotonin, or imipramine
20 mg/kg for up to 18 weeks (M341). A myopathy was
produced, characterized by preferential damage to myofibers with high oxidative capacity, prominent regenerative activity occurring as early as 48 hours, and degeneration of capillary endothelium. Although an interesting
animal model, this myopathy did not appear analogous
to human muscle diseases.
There were, however, a number of other drug-induced myopathies in animals which may have similarity
to human diseases. For example, rats injected with clofi-
MUSCLE DISEASES
brate, a drug commonly used in humans, developed severe myopathic changes (T43). This was interesting in
that treatment of humans with clofibrate occasionally
induces a syndrome characterized by weakness, pain,
and muscle tenderness, and an increase in SGOT and
CPK. The mechanism for these changes remains unknown, but perhaps is similar to the proximal myopathy
seen in 1 patient after treatment with perhexiline for
angina (T72).
A review of drug-induced myopathies in humans
reveals that iatrogenic muscle diseases were uncommon
in severe form, but may be very prevalent in mild forms
(L21). Indeed, because muscle represents 45% of total
body weight and therefore plays a significant role in human metabolism, changes in its function may be reflected in a variety of ways. For example, serum CPK
may be elevated after intramuscular injection of a variety of drugs. Further, some drugs such as chloroquine
may also have a local toxic effect, whereas other drugs
such as opiates and chlorpromazine may cause damage
or histamine release. Similarly, paraldehyde, a drug
now used very infrequently by intramuscular injection
may be intensely irritating and produce sterile abscesses
with elevation of muscle enzymes. These types of
muscle disorders are not chronic, but some forms may
be confusing when serum CPK is needed for appropriate clinical diagnosis, i.e., as in myocardial infarction.
There are a growing number of drugs that may
produce rapidly evolving syndromes of muscle pain,
tenderness, and weakness. These usually involve proximal limb and axial muscles, but can become more generalized. Examples include clofibrate, epsilon aminocaproic acid, and emetine (M8). Similar syndromes may
occur in alcoholics and heroin addicts. Serum enzyme
levels may be elevated and myoglobulinemia occurs.
Such a syndrome can be produced in rats by potassium
depletion or in patients taking diuretics, purgatives, and
licorice (K26). Chronic hypokalemia, however, resulted
most often in pain, weakness, and hypotonia (K26,L2 1).
The role of hypokalemia in the myopathy of chronic alcoholism was stressed (K84a).
A number of drugs, as well as parathyroidectomy with calcium supplements, may cause a severe and
necrotizing myopathy resulting in rhabdomyolysis
(L21,W 183). This potentially fatal condition has been
associated with heroin addiction, amphetamine poisoning, phencyclidine abuse, and alcoholism. It is characterized by muscle pain, tenderness, and swelling that
may be severe enough to require fasciotomy. In addition, acute quadriparesis and acute renal failure may
result. Serum enzyme levels are elevated and muscle
biopsy shows widespread necrosis and mild inflamma-
20 1
tory changes, often with profuse degenerative activity.
The most frequent type of drug-induced myopathy results from corticosteroids (L2 1). Although severe
myopathy is unusual, milder forms may occasionally be
overlooked. Steroid myopathy occurs with long-term
use of steroids, particularly with dexamethasone, betamethasone, or triamcinolone. Proximal muscles are
symmetrically involved, especially the quadriceps. Although reflexes are preserved and serum enzymes are
normal, electromyography shows myopathic changes.
In contrast to experimental cortisone myopathy of animals, the histologic changes of steroid myopathy of humans are inconspicuous. The ultrastructural findings in
muscle in Cushing’s syndrome included pronounced
mitochondria1 damage, thickening and deep invagination of the sarcolemmal basement membrane, and
thickening of the basement membrane of capillaries
(D116). Muscle fibers showed marked disarray, wide interfibrillar spaces, and many vacuoles.
A number of drugs can produce a myasthenialike syndrome or potentially aggravate preexisting
myasthenia (L2 1). Such drugs include polymyxins and
aminoglycoside antibiotics. These drugs have Ach-like
activity and may cause a depolarizing block. Other
drugs that may interfere with neuromuscular transmission should be used with caution in myasthenia gravis.
These include plaquenil, propranolol, chlorpromazine,
procainamide, trimethadione, colchicine, and thyroid
hormones. Myotonic discharges may be found in specific entities such as chloroquinine-induced myopathy
(M104). Many of these observations were based on
single case reports and will require further observation
for definitive conclusions. Finally, catecholamines injected into rabbits produced an experimental myopathy
resembling human dystrophy, but the significance was
unclear (F27).
Familial and congenital myopathies. Nemaline
myopathy is a congenital myopathy that is characterized
histologically by intracellular threadlike rods. There is
great diversity in both its clinical and histologic expression as well as the hereditary nature of the disorder.
Two major types of nemaline myopathy are recognized.
Congenital nemaline myopathy is present at birth as
hypotonia or weakness; in most instances, the weakness
is not progressive and the prognosis is good (B264).
Adult onset nemaline myopathy first produces symptoms during adult life and has a guarded prognosis.
This disorder, which has a more frequent onset in previously affected families, should be considered in genetic counseling.
The need for histochemical evaluation of affected families was suggested (B8 1). Histochemical
202
changes in the mother of a patient with nemaline myopathy were used to identify her as a gene camer even
though nemaline rods were not present in a muscle
biopsy and she was not weak. The patient and her
mother both had marked type I fiber predominance.
Histochemical changes known to occur in n e m a h e myopathy include smallness and predominance of type I fibers. Such changes supported the concept that this disease may result from subtle defects in innervation since
fiber types are determined by innervation.
-Although this disease is thought to be transmitted by an autosomal dominant means, lack of male
to male transmission and a predominance of female
cases in the literature suggest that this may be: 1) Xlinked dominant, 2) sex-influenced autosomal dominant, or 3) autosomal dominant which is semilethal in
males (A148,G215).
Another familial muscle disease that has been recently identified is a familial visceral myopathy (F18). A
kindred containing 18 members with visceral myopathy
was serially observed. Fifteen had chronic obstruction
of the gastrointestinal or urinary tract. Of 6 patients
with megaduodenum on contrast x-rays, 2 were asymptomatic. Four patients had redundant colon on barium
enema examination and 4 had megacystitis. Specimens
from duodenum, jejunum, ileum, colon, or urinary
bladder from 5 patients showed thinning and extensive
collagen replacement of the longitudinal muscle layer;
ganglion cells were normal by light and electron microscopy. Esophageal manometry in 3 patients showed decreased gastroesophageal sphincter pressures and no
contractions in the smooth muscle segment of the
esophagus; duodenal manometry showed a low frequency and amplitude of contractions. Three patients
developed fever and signs of peritonitis after operation
to bypass dilated segments. This seems to be a generalized smooth muscle disease with variable clinical manifestations and an autosomal dominant or sex-linked
dominant mode of inheritance.
A number of other new or uncommon recurrent
and familial muscle diseases were described. These included recurrent myoglobinuria due to muscle carnitine
palmityl transferase deficiency (R73), a distal myopathy
characterized by an unusual focal granular degeneration that ultrastructurally was composed of homogeneous fine granules devoid of other organelles (M72),
and an autosomal recessive muscle disease characterized by cardiomyopathy and nonprogressive muscle
weakness and lordosis beginning in childhood (D 117),
as well as by tubular aggregates within muscle and some
features of myasthenia.
MUSCLE DISEASES
Perhaps the most interesting of the “new” muscle
diseases was described in a 7-year-old boy who suffered
from increasing stiffness and contractures of the extremities, with pronounced atrophy and absence of tendon reflexes (L202). Electromyography of this child revealed continuous electrical activity during rest, sleep,
after intravenous injection of diazepam, and after peripheral nerve block. Histopathologic examination of
the peroneus muscle disclosed a marked predominance
of type I fibers and slight atrophy of type I1 fibers. Electron microscopic examination of end plates demonstrated marked atrophy of the postsynaptic regions and
widened synaptic clefts. After 1 year of treatment with
phenytoin, the patient showed almost normal muscle
tone.
There are examples of autosomal dominantly inherited “spheroid body myopathies,” and a skeletal
muscle disease (which is steroid responsive) associated
with partial carnitine deficiency (G120,Y18). It is unlikely that these will be encountered by the clinical
rheumatologist, but it must be emphasized that unexplained muscle dysfunction or pain of unknown etiology must be vigorously pursued biochemically.
Muscle involvement continues to be a major
problem in diagnosis and therapy of a variety of other
diseases. For example, myopathy has been shown to be
associated with amyloid angiopathy (B268), as well as
hepatitis-associated lipid storage disease (R54). Perhaps
more important are a series of myopathies with abnormal mitochondria (K17). These represent new subcategories of muscle disorders. Of 185 patients with myopathy, 22 showed abnormal muscle mitochondria. In
12 of these 22 patients, all of whom had ocular myopathy or the opthalmoplasia-plus syndrome, muscle
biopsies contained 5 to 25% of ragged red fibers. In 4
patients with a fasciohumeral distribution of weakness,
the red fibers were less numerous (3 to 8%). These perhaps are similar to patients initially described in 1973
with benign myopathies characterized by abnormal
mitochondria and lipid-glycogen storage in muscle fibers. Muscle carnitine deficiency is also associated with
accumulation of lipid and glycogen in skeletal muscle.
Muscular weakness in a 25-month-old girl, associated with decreased muscle carnitine content, increased blood lactate and pyruvate concentrations, and
transient ketoacidosis and elevation of free fatty acids,
improved with oral carnitine therapy (D89). Muscle
biopsy revealed vacuolar myopathy with accumulation
of both lipid and glycogen. Progressive muscular weakness in a 51-year-old black woman, associated with
lipid-filled vacuoles in type I muscle fibers, partial car-
MUSCLE DISEASES
nitine deficiency of skeletal muscle, and abnormalities
of liver metabolism, responded strikingly to prednisone
therapy (W97). Skeletal muscle utilization of long-chain
fatty acids, pyruvate, and /I-hydroxybutyrate was depressed and it was postulated that muscle involvement
might result from inability of carnitine to attach to or
penetrate the sarcolemmal membrane.
Deficiency of myoadenylate deaminase was reported as a new muscle disease (F55).Five patients with
muscular weakness or cramping after exercise were
studied. Three were found to have elevated serum CPK.
Muscle biopsies were all histologically normal but
lacked adenylate deaminase by both stain and solution
assay, whereas the erythrocyte isoenzyme was normal.
Although it was not entirely clear that this represented a
new disease of muscle, the only other reported incidence
of adenylate deaminase deficiency was in a patient with
periodic paralysis.
McArdle’s disease. Patients with McArdle’s disease have deficient activity of muscle phosphorylase. In
other tissues, however, enzymatic activity is present
(D106). It is not surprising therefore that McArdle’s disease continued to attract attention. Indeed, this disease
has been the subject of recent study because of the paradoxical appearance of phosphorylase in muscle culture
from patients with McArdle’s disease. It was discovered
by immunologic and biochemical analysis that the
phosphorylase activity found in muscle cultured from
patients with this disease results from an isoenzyme
whose genetic control is different from that of the mature enzyme (D106,S42).
Of interest was the description of McArdle’s disease in a patient 74 years of age; this is a remarkable
event in light of the genetic deficit (H122). In addition,
by use of technetium 99 bone scans, intense muscle
staining was noted in McArdle’s disease (S425). It was
proposed that the cramps of McArdle’s disease produce
muscle damage.
Miscellaneous muscle disease. Papular mucinosis is a rare disorder of unknown etiology presenting
primarily as a diffuse cutaneous deposition of abnormal
mucopolysaccharide (M12 1,V39). A patient with
biopsy-proven papular mucinosis, with the characteristic IgG lambda light chain paraproteinemia, also developed a severe proximal myopathy, seronegative inflammatory polyarthritis, and marked eosinophilia
(V39). Muscle enzymes were elevated, EMG was compatible with polymyositis, and muscle biopsy revealed a
atypical necrotizing vacuolar myopathy. Synovial
biopsy revealed an inflammatory synovitis with class I1
synovial fluid. No mucin deposition was detectable in
203
muscle or synovium. During 7 years of observations,
corticosteroids and various immunosuppressive agents
were administered successively with little benefit. Recently, weekly intravenous methotrexate and low-dose
oral corticosteroids have resulted in clinical and laboratory improvement. It was suggested that the pathology
in papular mucinosis may include serious rheumatic
manifestations in addition to the cutaneous involvement
(M 121).
Myopathies continued to be described in association with tumors. Histoenzymologic studies on noncachectic patients dying of neoplasms, without signs of
neuromuscular involvement, revealed a high incidence
of microcirculatory changes to which the observed
neuromuscular abnormalities were thought to be secondary (S49). Skeletal muscle dysfunction was described in iron deficiency of rats (S308). A myopathy
was also described in Whipple’s disease, with electron
microscopic changes of PAS-positive macrophages in
muscle, alterations similar to those found in the gut
(S42 1). Centronuclear myopathy, arrest of muscle fiber
development at the fetal myotubular state, was described in a 10-year-old girl, with a review of the literature (S156). The authors proposed that the lack of homogeneity of the cases suggested the existence of several
diseases.
Multiple cases of myopathy associated with hypothyroidism in association with deficient type 2b fibers
and elevated CPK were described (E5 1,G145, W95). All
emphasized the need to study CPK isoenzymes to distinguish the source of CPK elevations. Finally, impaired glycogenolysis was noted in hypothyroidism and
thought to play a factor in myopathy (M137).
Hypokalemic myopathy was noted once again in
alcoholism; it was rapidly reversible with potassium
(K83,R 162).
Autoantibodies to myosin were detected in 1 of
55 sera of patients with muscle disease (F4); this was
from a patient with Coxsackie viral pericarditis. An immunologic myopathy characterized by linear IgG staining of the basement membranes of skeletal muscle fibers and of glomerular capillaries was described in a 73year-old woman with progressive myopathy, renal failure, and hemotypsis (583). The presence of an antibody
to a basement membrane antigen shared by muscle and
kidney was suggested, but not demonstrated. The binding of smooth muscle antibodies was found to be dependent on the accessibility of actin (T67).
Six cases of inclusion body myositis, a distinct
but infrequently recognized inflammatory disease of
skeletal muscle, were described (C46). Clinically, this
PURINE METABOLISM A N D GOUT
204
disease differs from PM-DM. It lacks features of collagen vascular disease, has a relatively benign and protracted course, frequently involves distal muscles, is
found mainly in men, and does not improve with corticosteroid treatment. Electron microscopic demonstration of abnormal filaments in muscle cells is necessary
for definite diagnosis, but inclusion body myositis may
be suspected by the finding on cryostat sections of numerous hematoxylinophilic granules in "lined" vacuoles
in muscle cells. These correspond to whorls of cytomembrane. Although in PM-DM the capillary network
is partly destroyed, in this type of myositis it is usually
augmented. A viral etiology has been suggested but remains unproved.
Myositis ossificans is a disorder of unknown origin in which the connective tissue septa of muscle are
replaced by cartilage and bone. Myositis ossificans traumatica is the best-known form and is often associated
with sports injuries. To further the understanding of the
development of this disorder, bone matrix gelatin, prepared by chemical extraction of soluble noncollagenous
proteins, was half-disgested with a chromatographically
purified collagenase (U 13). The residue was placed on 1
side and autologous muscle on the other side of cellulose acetate membranes in diffusion chambers and tissue cultures. In this avascular system, the muscle septa
connective tissue proliferated and differentiated into
cartilage. Muscle tissue cultured in media conditioned
with matrix residues and then transferred, into a vascularized muscle pouch differentiated into cartilage and
bone. These observations form the basis for a working
hypothesis that myositis ossificans is a response of new
populations of proliferating intramuscular connective
tissue cells to a bone matrix-derived diffusible molecule.
The interactions of steroids with skeletal muscle
were extensively updated in an excellent comprehensive
review (M118). Exposure of muscle to glucocorticoids
resulted in protein wasting from a reduction in protein
synthesis and an increase in intracellular proteolysis.
The protease involved in this response appeared to be
located in the myofibrillar fraction and activity was increased by glucocorticoid treatment as well as by starvation, diabetes, and tumor-induced cachexia.
Treatment with androgens caused an anabolic
response in skeletal muscle, mainly due to enhancement
of protein-synthesizing machinery. In rat muscle, 2
classes of receptors are present that bind cortisol and
the synthetic steroids dexamethasone and triamcinolone
acetonide. The cortisol-binding macromolecule resembles cortisol-binding globulin or transcortin in several
of its physicochemical properties. Attempts to identify
specific receptors for androgens in rat skeletal muscle
have not been successful. However, in this tissue, androgens compete, both in vivo and in vitro, with the receptor proteins that bind dexamethasone. Thus, the antagonism of glucocorticoid-induced muscle wasting by
concomitant androgen administration may be a consequence of the competition between these steroids for
the same site on a receptor in muscle that mediates the
catabolic action of glucocorticoids. Current progress in
the area of muscle response to steroidal hormones depends on the development of procedures for the measurement and identification of proteolytic enzymes in
muscles involved in the muscle-wasting diseases.
PURINE METABOLISM A N D GOUT
The current understanding of purine biosynthesis and degradation in normal and pathologic states
in humans was extensively reviewed (H165,K65). Hyperuricemia can result from 4 pathogenetic mechanisms
acting individually or in combination: 1) increased purine biosynthesis de novo, 2) increased catabolism of
nucleic acids, 3) ingestion of excessive purines in the
diet, and 4) decreased renal excretion of uric acid. The
percentage of patients with gout who have as their primary metabolic defect excessive de novo purine biosynthesis has recently been estimated at 15 to 25%, rather
than the previously claimed 75% (H165).
Phosphoribosylpyrophosphate (PP-ribose-P),
glutamine, and purine nucleotides each have an important role in the control of purine biosynthesis. The first
reaction unique to the biosynthetic pathway is catalyzed
by the enzyme amidophosphoribosyl transferase; PP-ribose-P and glutamine are substrates for this enzyme,
and the purine nucleotides act as feedback inhibitors.
Amidophosphoribosyl transferase displays molecular
heterogeneity; it exists in a small form with molecular
weight of 133,000 and large form of 270,000 molecular
weight. The smaller molecule is the active one and is
converted to the large form in vitro by incubation of the
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