Chapter 32 Toxic myopathies

Clinical Neurophysiology of Disorders ofMuscle and Neuromuscular Junction, Including Fatigue Handbook of Clinical Neurophysiology, Vol. 2 Erik Stalberg (Ed.) © 2003 Elsevier B. V. All rights reserved

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CHAPTER 32

Toxic myopathies Devon I. Rubin* Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA

32.1. Overview Toxic and drug-induced myopathies constitute a unique, yet under-recognized, category of neuromuscular disease. The unique properties of skeletal muscle that increase its exposure to exogenous drugs and predispose it to their toxic effects include its large constituent of total body weight, high metabolic rate, and high blood flow. Consequently, as more pharmacologic and environmental agents are developed the potential for adverse effects on muscle is increased. These effects may be further potentiated when co-morbidities, such as renal or hepatic failure, impair drug metabolism. From a clinical standpoint, the most important toxic myopathies are those due to medications commonly used in routine medical practice, however illicit drugs and environmental or occupational toxins may also adversely affect muscle. Early recognition of toxic myopathies is crucial, since identification and withdrawal of the offending agent often leads to improvement or resolution of the symptoms, and may prevent life-threatening reactions such as rhabdomyolysis, renal failure, or even death. Historically, toxic myopathies have been important in providing insight into the mechanisms leading to muscle fiber dysfunction. Drugs and toxins have been shown to produce: (1) direct, widespread or focal muscle fiber necrosis; (2) immune-mediated inflammation with secondary muscle fiber destruction; (3) autophagic vacuole formation; (4) hypokalemia-mediated dysfunction; and (5) selective atrophy of muscle fibers. The amphiphilic properties of many drugs allow for

* Correspondence to: Dr. Devon I. Rubin, M.D., Department of Neurology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA E-mail address: [email protected] Tel.: + I (904) 953-7104; fax: + I (904) 953-7233.

interaction with membranes of muscle fibers or intracellular organelles, such as lysosomes, which eventually lead to membrane instability, alterations of membrane receptors, or signal transport. Over the years, a number of thorough reviews have de.ailed the salient clinical, histologic, and pathophysiologic features of toxic and drug-induced myopathies (Baker, 1983; Kuncl and Wiggins, 1988; Mastaglia, 1992; Zuckner, 1994; George and Pourmand, 1997; Pascuzzi, 1998; Wald, 2000). Due to the diverse categories of drugs, the multiple mechanisms by which each drug may produce muscle fiber dysfunction, and the variability of clinical manifestations, a unifying classification has not been developed. This chapter will review the clinical, electrophysiologic, and histopathologic manifestations of toxic myopathies that occur in humans according to the known pathologic effects on the muscle fiber, with special attention placed upon the electrophysiologic features (Table 1),

32.2. Clinical evaluation of toxic myopathies The evaluation of patients with suspected toxic myopathies should begin with a thorough general medical and focused neuromuscular assessment, followed by supportive laboratory and electrodiagnostic investigations. Identification of systemic manifestations such as cardiomyopathy or skin rash may help to identify some toxic myopathies. The presence of concomitant renal or hepatic failure is crucial to note, since these conditions may reduce the metabolism of drugs, raise circulating levels of toxins, and thereby increase the risk of drug-induced myopathies. A thorough review of the medication history should include the dosage of each medication and the temporal relationship between the date of drug initiation and onset of symptoms. Any recently introduced medication in a patient with new neuromuscular symptoms should be considered a

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Table I Classification of drug-induced myopathies. Myopathies with prominent muscle fiber necrosis

Myopathies with mitochondrial dysfunction

Myopathies with autophagic vacuoles

Myopathies with inflammatory changes

Acute alcohol myopathy Cholesterol-lowering agents Clofibrate, bezafibrate, fenofibrate Gemfibrozil Lovastatin, simvastatin, pravastatin, fluvastatin Nicotinic acid Emetine Epsilon-aminocaproic acid

Azidothymidine (AZT) Cyclosporin A

Chloroquine Hydroxychloroquine Amiodarone Colchicine (Emetine)

PeniciIlamine L-tryptophan Cimetidine

Hypokalemic myopathies

Corticosteroid myopathy

Rare, unclassified myopathies

Focal myopathies with muscle fiber necrosis

Glycyrrhic acid (licorice) Thiazide diuretics Mineralocorticoids Alcohol

Acute Chronic

Beta-blockers Propranolol, labetalol, sotalol, fenoterol Rifampicin Phenytoin Clozapine Tetracycline Perhexiline Etretinate Adenine arabinoside Phenforrnin-fenfluramine Mercaptopropionyl glycine Leuprolide acetate Cimetidine

Drugs of abuse Pentazocine Meperidine Heroin Local anesthetics Lidocaine Bupivacaine Intramuscular antibiotics Oxacillin, kanamycin, Nafcillin, penicillin "Needle myopathy"

Amphotericin B Azathioprine Barium Carbenoxolone Chlorthalidone Lithium

potential culprit. A careful review of illicit drug use and environmental toxin exposure should not be overlooked. The neuromuscular examination should pay special attention to the degree, distribution, and symmetry of muscle weakness, as well as sensory or myotactic reflex abnormalities. With few exceptions, most toxic myopathies produce symmetric proximal weakness with preserved or mildly reduced reflexes and normal sensation. In patients demonstrating asymmetric findings, predominantly distal weakness, or prominent sensory loss, alternative sites of pathology such as peripheral nerve or multiple roots should be considered.

32.3. Electrodiagnostic evaluation Electrodiagnostic testing plays an important role in the evaluation of myopathies by confirming a clinically suspected process affecting the muscles, determining the severity and distribution of disease, and quantifying the degree of abnormality in some instances. However, electrodiagnostic studies also have significant limitations. Routinely performed studies are less sensitive in identifying myopathies, especially mild cases or those presenting early in the course, than in identifying neurogenic processes. In many cases, the pathologic involvement of the muscle is not uniform and electrophysiologic abnor-

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Table 2 Medications producing myopathy and other neuromuscular disorders. Peripheral Neuropathy

Neuromuscular Junction Defect

Alcohol Amiodarone Azidothymidine (AZT) Chloroquine Colchicine Cyclosporin Hydroxychloroquine L-tryptophan Perhexiline Procainamide

Botulinum toxin Chloroquine Interferon alpha Penicillamine

malities may be patchy, requiring diligence in the examination of multiple muscles to identify abnormalities. Furthermore, electromyography is limited in ability to determine the etiology of a myopathy, since most electrophysiologic abnormalities occur in a wide variety of muscle diseases and are not unique to toxic myopathies. Several electrodiagnostic methods are available to evaluate myopathies and these have been detailed previously in this volume. Nerve conduction studies (NCS) and needle electromyography (EMG) are the most widely utilized techniques. In most myopathies, regardless of the etiology, NCS performed on motor nerves with surface recording over the muscle are normal unless a severe loss of muscle fibers has occurred, leading to reduction in compound muscle action potential (CMAP) amplitudes. Sensory nerve action potential (SNAP) amplitudes are expected to be normal. However, in toxic myopathies, the utility of NCS resides in the identification of concomitant disease involving the peripheral nerve or neuromuscular junction, which may occur with a number of medications (Table 2). Needle EMG is more sensitive than NCS in the detection of diseases affecting muscle fibers and findings may be correlated with the underlying pathologic changes (Hausmanowa-Petrusewicz and Jedrzejowska, 1971). Needle EMG records the action potentials of muscle fibers from motor units in a muscle. In a resting muscle, muscle fibers are electrically silent with the exception of the brief electrical discharges recorded from muscle fibers damaged by the recording electrode (insertion activ-

ity). Drugs and toxins that produce muscle fiber necrosis or splitting, intracellular vacuole formation, or other pathologic alterations in the muscle fiber membrane cause functional denervation of the fiber from its nerve terminal at the endplate zone. This leads to instability and fluctuation of the resting potential across the muscle fiber membranes, producing fibrillation potentials and positive sharp waves (Table 3). A number of toxins may also alter sodium or chloride channel function, which are critical to excitation-contraction coupling, producing rapidly repetitive firing muscle fiber action potentials Table 3 Toxic myopathies commonly associated with fibrillation potentials. Alcoholic (acute myopathy) Amiodarone Azidothymidine (AZT) Chloroquine Colchicine Corticosteroids (acute, high dose, with NMBA) Cyclosporin Emetine Epsilon-arninocaproic acid Gemfibrozil Hydroxychloroquine Lovastatin L-tryptophan Mineralocorticoids (with hypokalemia) Penicillamine Rhabdomyolysis (heroin, phencyclidine, coma)

624 Table 4 Toxic myopathies associated with myotonic discharges. Alcohol Clofibrate Chloroquine Emetine Epsilon-aminocaproic acid Lovastatin Organophosphates Pentazocine Propranolol Suxamethonium

that change exponentially in amplitude and rate (myotonic discharges) (Table 4). When destruction or inactivation of individual muscle fibers of a motor unit develops, changes in the configuration of voluntarily activated motor unit potentials (MUPs) may occur. Most commonly, loss of individual muscle fibers leads to reduction in the duration and amplitude of the MUPs, and desynchronization of the firing of the remaining muscle fibers is manifest as increased phases or turns. The MUP parameters can be assessed by semi-quantitative analysis, however a number of automated computer analysis methods, such as manual MUP analysis, multi-MUP analysis, interference pattern analysis. and macro-EMG are available to more precisely quantitate each of the parameters. A critical literature review of the electrodiagnostic findings in toxic myopathies is limited by the dearth of detailed reports in the literature and the reliance on findings in single or small numbers of cases. Furthermore, many patients with reported toxic myopathies had experienced other medical diseases or co-morbidities that may have produced peripheral nerve or muscle disease. Little has been written on the use of more advanced electrophysiologic techniques to evaluate or quantify the extent of muscle disease in toxic myopathies. This chapter will describe the clinical, electrodiagnostic, and histopathologic features of druginduced and toxic myopathies. Table 1 is an extensive list of medications that have been reported to cause muscle dysfunction. However, only those drugs whose clinical and electrophysiologic findings have been substantially documented in humans in the literature will be discussed in detail.

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32.4. Myopathies characterized by prominent muscle fiber necrosis 32.4.1. Alcohol myopathy Alcohol abuse is endemic throughout the world. The adverse effects of alcohol on skeletal muscle have been known for decades. Numerous thorough reviews have detailed the salient, but variable. clinical, biochemical, and histopathologic findings in alcohol myopathy (Perkoff, 1971; Oh, 1972; Martin et al., 1982; Haller and Knochel, 1984). In general, two forms of alcohol myopathy have been described. an acute and a chronic form, although co-occurrence of each may be seen in individual patients. Alcohol may also produce muscle fiber damage through the effect of hypokalemia, which will be described later. Although only the acute form of alcohol myopathy is characterized histologically by prominent muscle fiber necrosis, both types will be discussed in this section.

32.4.1.1. Acute alcohol myopathy The most severe form of alcohol myopathy occurs in chronic alcoholics during or immediately following a period of marked increase in alcohol consumption (Hed et aI., 1962). Acute alcohol myopathy is estimated to occur in less than I % of alcoholics (Oh, 1972). Some patients have a coexisting chronic alcohol myopathy (described below), although many have no underlying neuromuscular disorder at the time of presentation (Pittman and Decker, 1971). The characteristic clinical features include an abrupt onset, over hours to days, of generalized or focal muscle pain, often with prominent swelling and weakness. Although any muscle may be affected, the legs are more commonly affected than the arms and focal symptoms in the leg may mimic deep venous thrombosis (Hed et aI., 1962). In severe cases rhabdomyolysis and myoglobinuria. sometimes resulting in acute renal failure or death, may occur. With supportive measures and abstention from alcohol symptoms improve and usually resolve after 1-2 weeks, although recurrence is not uncommon following repeated heavy alcohol consumption. The serum creatinine phosphokinase (CPK) levels are markedly elevated during the symptomatic period and fall during clinical recovery. Studies in asymptomatic alcoholics following binge drinking

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have also demonstrated CPK elevation, indicating that a direct toxic effect of alcohol may cause subclinical muscle necrosis (Lafair and Myerson, 1968). The mechanism of alcohol myotoxicity is unclear, however altered cell membrane activity, inhibition of calcium uptake by the sarcoplasm reticulum, and inhibition of energy production have all been implicated. (Mastaglia, 1992) Histopathology shows patchy muscle fiber necrosis with fiber degeneration and regeneration, preferentially affecting type I fibers.

32.4.1.1.1. Electrophysiology. Nerve conduction studies in acute alcohol myopathy typically demonstrate normal CMAP and SNAP amplitudes, although slowed motor and sensory conduction velocities suggesting an underlying peripheral neuropathy have been reported (Mayer et al., 1968; Curran and Wetmore, 1972). On needle EMG, fibrillation potentials and short duration, low amplitude, polyphasic, MUP are common and often prominent in clinically affected muscles, reflecting the underlying degree of muscle fiber necrosis (Mayer et al., 1968; Curran and Wetmore, 1972; Oh, 1972). Myotonic discharges following percussion of the muscle have rarely been reported (Mayer et al., 1968). 32.4.1.2. Chronic alcohol myopathy The first report of a chronic form of alcohol myopathy is credited to Ekbom in 1964 (Ekbom et aI., 1964). Since the original report, it has been estimated that approximately one-third of alcoholics will develop an indolent, proximal myopathy, however subclinical muscle weakness may be underrecognized and more prevalent (Faris et al., 1967; Martin et al., 1985; Urbane-Marquez et al., 1989). Reduced proximal muscle strength compared to nonalcoholic controls occurs in approximately 35% of asymptomatic alcoholics, whereas histologic features of myopathy have been demonstrated in 50% (Urbano-Marquez et al., 1989). The development of myopathy appears to be related to the dose and duration of alcohol intake and, the threshold for developing myopathy may be lower in women than in men (Urbano-Marquez et al., 1989; UrbanoMarquez et al., 1995). In contrast to acute alcohol myopathy, the onset of proximal pelvic and shoulder girdle weakness is

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insidious and slowly progressive. Muscle pain and swelling are absent, whereas muscle atrophy, particularly in quadriceps muscles, is common. Many patients also have a coexistent alcohol-induced peripheral neuropathy with distal sensory loss and weakness (Worden, 1976). Serum CPK levels may be normal or mildly elevated. Muscle biopsy demonstrates predominantly type 2 muscle fiber atrophy without necrosis or inflammatory cell infiltration, although with longstanding alcohol abuse type 1 fibers may also become atrophic. The pathogenesis of chronic alcohol myopathy is not completely known, although a direct toxic effect of alcohol or its metabolites on protein synthesis, potassium or other electrolyte depletion, and interference with energy metabolism all have been implicated (Martin et al., 1982; Haller and Knochel, 1984; Preedy et al., 1994).

32.4.1.2.1. Electrophysiology. Electrophysiologic findings are variable in chronic alcohol myopathy. The NCS may be normal, however slowed conduction velocities or low SNAP amplitudes, indicating a superimposed peripheral neuropathy occur in over 50% of patients (Faris et al., 1967; Oh, 1972). Needle EMG may also be normal, but short duration, low amplitude MUP, with or without fibrillation potentials, can be identified in proximal more than distal muscles (Ekbom et aI., 1964; O'Brien and Goldstraw, 1969; Perkoff, 1969, 1971). In the early report by Perkoff et al., 6 of 10 patients with clinical manifestations of a chronic myopathy underwent EMG studies, and three demonstrated "minimal fibrillations" with short duration MUP, compatible with a myopathy (Perkoff, 1969). In a more extensive electrophysiologic study in 191 alcoholics admitted for detoxification, needle EMG demonstrated fibrillation potentials or positive sharp waves in 43% of patients, and low amplitude, short duration MUP in 46% (Worden, 1976). Nerve conduction studies showed slowed median and peroneal conduction velocities in 50-63% of patients. The investigators interpreted these abnormalities as consistent with a myopathy alone in 6%, whereas myopathy with peripheral neuropathy occurred in 56% of patients. Finally, EMG may be useful to assess for early or subclinical myopathy, as up to 45% of chronic alcoholics without clinical signs of weakness may demonstrate abnormalities on needle EMG (Faris et aI., 1967),

626 32.4.2. Cholesterol-lowering agents The use of medications to reduce hyperlipidemia in the prevention of cardiac and cerebrovascular disease has dramatically increased in recent years. With this increase the number of adverse effects on muscle has also risen, and these drugs have become one of the more prevalent iatrogenic causes of myopathy. The spectrum of muscle involvement with cholesterol-lowering agents ranges from mild myalgias to severe, progressive quadriparesis. Most of the available agents used to reduce cholesterol or triglycerides have been associated with the development of myopathy.

32.4.2.1. Clofibrate, bezafibrate, fenofibrate Clofibrate, bezafibrate, and fenofibrate are branched-chain fatty acid esters that have been available since 1966 for the treatment of hyperlipidemia. In 1968, Langer and Levy first described an acute muscle syndrome in 5 of 60 patients treated with clofibrate (Langer and Levy, 1968). Three of these patients were asymptomatic but demonstrated elevation of serum CPK and transaminases, while two patients experienced muscle cramping, stiffness, and weakness, all of which resolved following discontinuation of clofibrate. Since this initial description, subsequent reports have emerged, further detailing the range of clinical and laboratory manifestations (Sekowski and Samuel, 1972; Pierides et al., 1975; Rimon et al., 1984; Clouatre et al., 1999; Weissgarten et al., 1999). Myopathy develops in 2-16% of patients administered clofibrate (Langer and Levy, 1968; Afifi et al., 1984). Symptoms are temporally related to drug initiation and begin within several weeks to three months (range 36 hours to 2 years) (Rush et al., 1986). The development of myopathy is more likely to occur in patients with renal failure due to impaired renal excretion of the drug and hypoalbuminemia, since the drug is highly bound to albumin (Bridgman et al., 1972; Pierides et al., 1975; Rumpf et al., 1976; Weissgarten et al., 1999). The characteristic clinical manifestations include myalgias, cramps, muscle tenderness, and a variable degree of weakness. Muscle pain may be severe, and affect proximal and distal muscles. Weakness is present in up to 58% of patients and involves the proximal muscles of the lower extremities more than the arms (Rimon et al., 1984) Serum CPK is

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elevated, and may be an early precursor to subclinical muscle involvement in some patients (Belaiche et al., 1977). Withdrawal of clofibrate leads to clinical and serologic improvement within days to weeks (Katsilambros et al., 1972; Geitner et al., 1975). Histologic features on muscle biopsy include fiber necrosis with fiber size variation.

32.4.2.1.1. Electrophysiology. The electrophysiologic findings in clofibrate-induced myopathy are variable. Nerve conduction studies and needle EMG may be normal, although low amplitude, short duration, polyphasic MUPs occur in more severe cases (Bridgman et al., 1972; Denizot et al., 1973; Kra, 1974; Pierides et al., 1975; Gabriel and Pearce, 1976; Pokroy et al., 1977; Abourizk et al., 1979; Cario et al., 1979; Rimon et al., 1984; Rush et al., 1986). Increased insertional activity and fibrillation potentials have not been described. In one case, "myopathic changes" on EMG promptly resolved within 2 weeks after discontinuing clofibrate, but recurred after 10 days following rechallenge with the drug (Geltner et al., 1975). Interestingly, electrophysiologic myotonia has been demonstrated in rats treated with clofibrate, similar to what has been shown experimentally with the anti-cholesterol agent 20,25-diazecholesterol (Dromgoole et al., 1975; Teravainen et al., 1977; Eberstein et al., 1978; Kwiecinski, 1978; Afifi et al., 1984). The mechanism of production of myotonic discharges is unclear, but reduction in chloride channel conductance along the muscle fiber membrane has been speculated (Peter and Fiehn, 1973; Kwiecinski, 1978). Clinical or electrical myotonia has not been reported in humans treated with clofibrate, although there have been a few reports of "myotonic-like" discharges in several patients treated with 20,25-diazacholesterol (Somers and Winer, 1966). 32.4.2.2. Gemfibrozil Gemfibrozil, a fibric acid derivative similar to clofibrate, has rarely been reported to cause myopathy. In most reports, gemfibrozil was used in conjunction with lovastatin or other cholesterol lowering agents, however a small number of cases have occurred with gemfibrozil alone (Pierce et al., 1990; Magarian et al., 1991). The average age of patients developing myopathy is 55 years, and males

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and females are equally affected. Serum CPK levels are elevated up to 10-20 fold. Electrophysiologic findings have not been reported in patients on gemfibrozil monotherapy. 32.4.2.3. HMG-CoA reductase inhibitors A number of medications that inhibit 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme which plays a role in converting HMG-CoA to mevalonate in cholesterol biosynthesis, has been recently developed (atorvastatin, lovastatin, cerivastatin, fluvastatin, simvastatin, pravastatin). As a group, these "statins" have become first line agents in the treatment of hypercholesterolemia in general medical practice. Myopathy has been reported with pravastatin, lovastatin, simvastatin, atorvastatin, and fluvastatin (Deslypere and Varmeulen, 1991; London et aI., 1991; Schalke et aI. 1992; Wiklund et al., 1993; Scalvini et al., 1995; Ucar et aI., 2000; Meriggioli et al., 2001). Over a one-year period from 1987-88, 63 reports of "adverse muscle reactions" from lovastatin were identified, although the details of the manifestations were not reported (Pierce et al., 1990). The mean age at onset of symptoms was 56 years and the majority occurred in males. The overall incidence of myopathy due to lovastatin has been estimated at 0.5%, although a much higher number of patients experience myalgias (Tobert, 1988; Ucar et al., 2000). The risk of developing myopathy associated with HMG CoA reductase inhibitors is dose-dependent, but also increases with the addition of other potentially myotoxic agents, such as cyclosporin, erythromycin, itraconazole, nefazodone or other lipid-lowering drugs (Ayanian et al., 1988; Reaven and Witztum, 1988; Tobert, 1988; Goldman et al., 1989). The incidence of lovastatin-induced myopathy increases from 0.5% to 5% with concomitant administration of gemfibrozil, and the combination of pravastatin and gemfibrozil has been shown to produce CPK elevation and an increase in musculoskeletal symptoms compared to pravastatin alone (Tobert, 1988; Marais and Larson, 1990; London et al., 1991; Chucrallah et al., 1992; Wiklund et al., 1993). In some patients taking multiple myotoxic drugs, such as following organ transplantation, there is an increased risk of more severe muscle damage with rhabdomyolysis and renal failure, often with marked elevation of serum CPK levels 20- to 30-fold higher than those with myopathy associated with

627 monotherapy (Ayanian et al., 1988; Corpier et al., 1988; East et al., 1988; Reaven and Witztum, 1988; Goldman et al., 1989; Pierce et aI., 1990; Ucar et al., 2000). This increased risk with multiple myotoxic agents is likely due to reduction in hepatic or renal metabolism of the drugs, leading to an increased bioavailability of each drug and potentiation of their toxic effects on muscle fibers. The clinical manifestations of myopathy related to HMG-CoA reductase inhibitors are similar among the different agents. Myalgias, muscle tenderness, and proximal weakness are the predominant features, but facial and respiratory weakness has also rarely been described (Meriggioli et al., 200 I). In a few cases, cutaneous manifestations mimicking dermatomyositis, such as heliotrope rash, Gottron's nodules and periungual telangiectasias have been reported with atorvastatin and pravastatin (Schalke et al., 1992; Noel et aI., 2001). Symptoms develop between I and 36 months following drug initiation. The median serum CPK has been reported at 465 UIL, although levels may be elevated as high as loo-fold (Pierce et al., 1990; Meriggioli et aI., 2001). In severe cases, rhabdomyolysis with acute renal failure may occur (Marais and Larson, 1990; Pierce et al., 1990). Clinical and serologic findings resolve within several weeks following discontinuation of the offending agent. The mechanism of production of myopathy due to HMG-CoA reductase inhibitors in not well understood. These drugs reduce cholesterol production, which may directly affect the sarcoplasmic reticulum and membranes of cellular organelles and produce increased release or reduced uptake of calcium, thereby altering the excitation-contraction coupling of muscle fibers (Meriggioli et al., 200 I). Furthermore, increase in intracellular calcium may alter the chloride channel functioning, producing electrical myotonia. Muscle biopsy has demonstrated muscle fiber necrosis and regeneration, with perimysial and endomysial T-Iymphocytes and macrophages, and type 2 fiber atrophy (Chucrallah et aI., 1992; Schalke et al., 1992; Meriggioli et al., 2001). 32.4.2.3.1. Electrophysiology. Electromyographic findings have only been described in a few papers (London et al., 1991; Schalke et al., 1992; Meriggioli et al., 2001). Motor and sensory NCS are normal. Short-duration, low amplitude, polyphasic MUP are characteristic on EMG, and increased

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insertional activity with patchy or widespread fibrillation potentials and occasional complex repetitive discharges may be seen. Myotonic discharges have been identified in the lumbar paraspinal muscles in rabbits administered simvastatin experimentally, and in one human series, all five patients reported were found to have myotonic discharges on EMG (Nakahara et aI., 1992; Meriggioli et al., 2001).

32.4.2.4. Nicotinic acid (niacin) Nicotinic acid is a commonly used lipid-lowering agent. Several cases of weakness developing 1 week to 4 months following nicotinic acid administration have been reported (Litin and Anderson, 1989; Gharaviet al., 1994). Serum CPK and aminotransferase levels are mildly elevated. Symptoms promptly resolve within 2-14 days following discontinuation. Electrophysiologic findings have not been described. 32.4.3. Emetine (Ipecac) Emetine is a direct acting amebicide that has been used in the treatment of amebic dysentery and hepatitis, alcohol aversion therapy, and as an emetic agent following acute poisoning. It is also a common agent of abuse by people with anorexia nervosa and bulimia. Emetine toxicity may affect the gastrointestinal and cardiovascular systems as well as the neuromuscular system. Electrocardiograph alterations, including T-wave flattening or inversion and prolongation of the PR or QT intervals are common. Myopathy associated with chronic ingestion of emetine has been well described in the literature (Bennett et al., 1982; Sugie et al., 1984; Mateer et al., 1985; Palmer and Guay, 1985). Most patients are younger women who have been abusing the drug on a regular basis over months to years. The clinical manifestations classically include slowly progressive weakness involving proximal more than distal muscles and, rarely, oropharyngeal muscles. In contrast to most other toxic myopathies, the weakness is usually painless although mild myalgias may occur. The serum CPK levels and transaminases are normal or mildly elevated (up to 5-fold). Weakness is reversible within several weeks to months following discontinuation of emetine. Muscle biopsy demonstrates scattered muscle fiber necrosis and regeneration, type 2 fiber atrophy, and occasional distinct, irregularly shaped cyto-

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plasmic granules containing inclusions with foci of myofibrillar disorganization (Bennett et aI., 1982; Mateer et al., 1985). Experimental studies in rats have demonstrated similar findings, along with a decrease in oxidative enzyme activity and evidence of mitochondrial degeneration on electron microscopy (Duane and Engel, 1970). Disruption of the mitochondria and proliferation of the sarcoplasmic reticulum result in the production of autophagic vacuoles, similar to those seen in chloroquine myopathy. 32.4.3. I. Electrophysiology Electrodiagnostic studies demonstrate normal motor and sensory NCS without decrement on repetitive motor nerve stimulation (Brotman et al., 1981; Bennett et al., 1982; Mateer et al., 1985; Palmer and Guay, 1985). However, tetanic stimulation of nerves in animals treated with emetine experimentally demonstrated block of neuromuscular transmission that was reversed with neostigmine, suggesting a mechanism of action of the drug at the neuromuscular junction or muscle fiber endplate region (Salako, 1970). Needle EMG has shown increased insertional activity with occasional fibrillation potentials in some patients and no abnormal spontaneous activity in others. Short duration, low amplitude, polyphasic MUPs are typically seen in proximal more than distal muscles (Brotman et aI., 1981; Bennett et al., 1982; Mateer et al., 1985; Palmer and Guay, 1985). Despite discontinuation of the drug and clinical resolution of weakness, MUP configurational abnormalities may persist although fibrillation potentials disappear.

32.4.4. Epsilon-aminocaproic acid Epsilon-aminocaproic acid is a drug that prevents the conversion of plasminogen to plasmin, and has been used to enhance hemostasis in a variety of hemorrhagic disorders. A reversible myopathy related to the dose and duration of administration has been described (Lane et al., 1979; Brown et aI., 1982; Vanneste and Wijngaarden, 1982; Van Renterghem et al., 1984; Seymour and Rubinger, 1997). In most cases, patients present 1-3 months following treatment with progressive muscle weakness and tenderness. Weakness is most pronounced in the pelvic and shoulder girdle musculature, and rarely respiratory muscles are affected (Vanneste and Wijngaarden, 1982). In severe cases, myoglobinuria

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with acute tubular necrosis also develops. Serum CPK, aldolase, and transaminases are typically elevated. Clinical and serologic resolution occurs following withdrawal of the medication. The mechanism of muscle necrosis is uncertain, but a direct effect on the muscle fibers, a defect in aerobic energy production, and ischemia of muscle fibers have all been speculated. Histologic findings include muscle fiber necrosis preferentially involving type I fibers with a small degree of endomysia! mononuclear cell infiltration (Britt et al., 1980; Kennard et al., 1980; Vanneste and Wijngaarden, 1982).

32.4.4./. Electrophysiology Nerve conduction studies, although rarely reported, are normal (Vanneste and Wijngaarden, 1982; Morris et aI., 1983). Needle EMG characteristically shows fibrillation potentials, sometimes profuse, with short duration, low amplitude, polyphasic MUPs, although minimal or no abnormalities may occur. Occasional complex repetitive discharges or myotonic discharges are seen (MacKay et aI., 1978; Lane et al., 1979; Britt et aI., 1980; Kennard et al., 1980; Brown et al., 1982; Vanneste and Wijngaarden, 1982; Morris et aI., 1983). 32.5. Myopathies characterized by mitochondrial dysfunction

32.5./. Zidovudine (azidothymidine, AZT) AZT is a pyrimidine nucleoside analogue introduced in 1986 for the treatment of human immunodeficiency virus (HIV) infection. Reports of myopathy associated with AZT therapy emerged shortly after its introduction (Bessen et al., 1988; Gorard et al., 1988; Helbert et aI., 1988). However, in these early reports, the criteria for identification of myopathy were not well defined or were based solely on CPK elevation or the presence of myalgias without objective clinical, electromyographic, or histologic abnormalities. Furthermore, the identification of myopathy due to primary HIV infection in patients not taking AZT has led to continued debate regarding the presence of AZT myopathy as a distinct entity (Simpson et aI., 1993; Simpson et al., 1997). In 1990, Dalakas et al. solidified AZT myopathy as a unique entity when they identified distinct histopathologic features in 15 of 20 AIDS

629 patients who were receiving AZT at the time of biopsy (Dalakas et aI., 1990). In all 15 patients, muscle biopsy revealed abundant ragged red fibers, endomysial inflammatory cell infiltrates, and abnormal mitochondria on electron microscopy, suggesting that the production of myopathy resulted from AZT-inhibition of DNA polymerase in the mitochondrial matrix. Subsequently, Chalmers et al identified 18 patients with suspected AZT myopathy based on histologic findings and clinical improvement following discontinuation of the medication (Chalmers et al., 1991). These findings and other detailed clinical and histopathologic reports support the presence of AZT myopathy as a distinct entity. The true incidence of myopathy related to AZT administration is unknown, but it is estimated that up to 8% of patients receiving the drug experience myalgias, and serum CPK elevation occurs in 15% (Richmond et al., 1987; Peters et al., 1993). In one prospective study of AIDS patients receiving AZT. no patients developed myopathy within 9 months of AZT initiation whereas 17% of patients receiving treatment for longer than 9 months developed myopathy, suggesting that long-term therapy increases the risk of development of myopathy (Peters et aI., 1993). The clinical features of AZT myopathy are indistinguishable from HIV myopathy (Simpson et aI., 1993). The onset of symptoms is temporally related to the duration of treatment, and develop between 3 and 30 months (mean of 16 months) following initiation of treatment (Helbert et al., 1988; Dalakas et al., 1990; Chalmers et aI., 1991). Weakness may be mild or severe, involve the proximal muscles in the pelvic and shoulder girdle more than distal muscles, and is often associated with myalgias. Serum CPK is moderately elevated up to lO-fold. Clinical symptoms improve rapidly within days to weeks following discontinuation of AZT.

32.5.1.1. Electrophysiology Electrophysiologic findings in AZT myopathy have been well described (Gertner et al., 1989; Chalmers et al., 1991; Peters et aI., 1993). Nerve conduction studies are usually normal, although findings of a mild axonal neuropathy have been reported (Mhiri et al., 1991; Peters et aI., 1993). Since a polyneuropathy may occur with HIV infection, it is difficult to ascribe these findings to

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AZT alone. In 16 of 18 patients with AZT myopathy described by Chalmers et aI., abnormal EMG findings included a mild to moderate degree of fibrillation potentials and short duration, low amplitude, polyphasic MUPs with rapid recruitment. Eleven patients underwent a second EMG following discontinuation of AZT, and, although quantitative EMG studies were not performed, ten demonstrated a "significant reduction" or resolution in the degree of fibrillation potentials. A subsequent study longitudinally evaluated 56 HIV patients treated with AZT with clinical, serologic, and electromyographic studies (Spadaro et al., 1993). Of these patients, 21 had proximal weakness, CPK elevation, and short duration, low amplitude, polyphasic MUPs in proximal muscles on EMG. In this group, 8 patients underwent muscle biopsy followed by discontinuation and re-exposure to AZT. Although no details of the EMG findings are provided, there was a reported decrease in abnormal MUP morphology with discontinuation of AZT and re-emergence with re-exposure of the drug. Furthermore, 16 patients without clinical neuromuscular symptoms or signs of myopathy demonstrated mild electrophysiologic findings of rare polyphasic MUPs that improved with discontinuation of the medication, which may have indicated subclinical myopathy (Spadaro et al., 1993). Details of spontaneous activity and of distribution or severity of findings were not provided.

32.5.2. Cyclosporin A Cyclosporin A is an immunosuppressant agent used in the prevention of graft rejection following organ transplantation and in the treatment of autoimmune disorders. Myopathy occurs at an estimated incidence rate of 0.17%, however in most reported cases there was concomitant use of other potentially myotoxic drugs, including corticosteroids, cholesterol-lowering agents, or colchicine (Fernandez-Sola et aI., 1990; Arellano and Krupp, 1991; Breil and Chariot, 1999). The median age of patients developing muscular symptoms is 53 years. Myalgias and muscle cramps are the most common symptoms, whereas objective weakness is less prominent. Symptoms develop between 5 days and 9 years following initiation of cyclosporin, and resolve following dose reduction or discontinuation. In less than 0.05% of patients on cyclosporin, rhabdomyolysis occurs, although these cases are usually

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associated with concomitant use of other myotoxic medications. The pathogenesis of cyclosporin-induced myopathy is unclear, although experimental studies have suggested a defect in mitochondrial respiratory chain function. Muscle biopsy demonstrates variable findings, including type 2 fiber atrophy, necrotic fibers with central nuclei, and accumulation of mitochondria with occasional ragged red fibers (Lamer et aI., 1994; Breil and Chariot, 1999) A role of hypomagnesemia has also been speculated as a contributing factor (Lamer et al., 1994).

32.5.2.1. Electrophysiology Interpretation of the electrophysiologic findings related to cyclosporin use is confounded by the concomitant use of other medications that have also been shown to produce myopathy and EMG abnormalities. In several patients, NCS demonstrated findings consistent with a peripheral neuropathy, but were normal in others (Goy et aI., 1989; Grezard et al., 1989). In most cases, EMG findings are reported as showing findings of "acute myositis", without further details provided (Grezard et al., 1989; Arellano and Krupp, 1991; Lamer et al., 1994). Fibrillation potentials mayor may not be present. Several reports have described short duration, low amplitude, polyphasic MUPs, although no changes in the MUP morphology may occur as well (Noppen et al., 1987; Goy et al., 1989; Breil and Chariot, 1999). Goy et aI. performed quantitative EMG in the vastus lateralis in one case, and showed a decreased mean MUP duration (Goy et al., 1989).

32.6. Myopathies characterized by autophagic vacuole production The amphiphilic properties of several drugs lead to interactions with intracellular lysosomes that ultimately produce muscle fiber dysfunction. Some drugs, such as chloroquine and amiodarone, form complexes that develop between the hydrophilic region of the drugs and the lipid contents of lysosomal debris, which accumulate within Iysosomes and lead to autophagic degeneration and phospholipid accumulation within muscle fibers. Other drugs, such as colchicine, interfere with microtubule formation, inhibit lysosomal transport, and thereby lead to accumulation of lysosomes within vacuoles. These vacuolar changes are readily

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identified on muscle biopsy and interfere with the normal excitation-contraction functioning of fibers. The prototypic drugs that produce autophagic vacuolar changes are chloroquine and colchicine, although amiodarone and vincristine have also shown similar histopathologic findings. Vincristine, which produces peripheral neuropathy has not been convincingly shown to produce clinical or electrophysiologic evidence of myopathy, so this drug will not be discussed further. 32.6. J. Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine are 4-aminoquinolone compounds originally developed as anti-malaria and anti-amebic agents, but currently are more commonly used in the treatment of connective tissue disorders such as rheumatoid arthritis and systemic lupus erythematosus. In 1963, Whisnant et aI. first described a small series of patients who experienced slowly progressive muscle pain and weakness following chloroquine administration in doses of 250-500 milligrams (Whisnant et aI., 1963). The clinical manifestations are similar in most patients, are dose-dependent, and are related to prolonged administration of the drug. The onset of symptoms may range from 7 months to 16 years after drug initiation. Patients develop progressive distal and proximal muscle weakness, which is often painless and involves legs more than arms. Myotactic reflexes are reduced. Serum CPK is often elevated. The unique histopathologic feature of chloroquine myopathy consists of prominent vacuolar inclusions. These vacuoles occur predominantly in type I fibers, and contain accumulations of cytoplasmic degradation products (called myeloid bodies) and curvilinear bodies within the muscle. Accumulation of the phospholipid complexes within the lysosomes is the most likely cause of vacuole formation. This leads to a rise in intra-lysosomal pH, which inhibits the function of acidic lysosomal hydrolases, thereby leading to accumulation of glycogen, phospholipid, and curvilinear bodies (Estes et al., 1987). 32.6.1.1. Electrophysiology Electrophysiologic findings in chloroquine myopathy have been well detailed. In the five patients reported by Whisnant et al., NCSs were normal although later reports have demonstrated slowing of

motor and sensory conduction velocities and reduction in SNAP amplitudes, indicating the presence of a concomitant peripheral neuropathy (Whisnant et aI., 1963; Estes et aI., 1987). Needle EMG shows a variable degree of increased insertional activity with prominent fibrillation potentials in distal and proximal muscles (Whisnant et aI., 1963; Eadie and Ferrier, 1966; Hughes et al., 197I; Mastaglia et al., 1977; Estes et al., 1987). In some instances, myotonic discharges and complex repetitive discharges may occur (Blomberg, 1965; Mastaglia et aI., 1977; Estes et al., 1987). Rapidly recruited short duration, low amplitude, polyphasic MUP are seen in predominantly proximal muscles. Marked improvement or resolution of clinical and electromyographic findings occurs following discontinuation of the medication. The distinction between chloroquine-induced vacuolar myopathy and an inflammatory myopathy related to an underlying connective tissue disease may be difficult since the clinical and electrophysiologic features may be identical. This conflict may necessitate a "diagnostic" withdrawal of the medication for a period of time to assess for clinical improvement. In some cases, muscle biopsy may be the only way to accurately distinguish between the two disorders. 32.6.2. Colchicine

Colchicine is an anti-inflammatory agent used in the treatment of gout. The most frequent adverse effects involve the gastrointestinal tract although bone marrow suppression and cardiac arrhythmias have also been reported. Early reports detailed patients who developed progressive proximal weakness with or without peripheral neuropathy following administration of excessively high doses of colchicine (Kontos 1962; Riggs et al., 1986). However, Kuncl et al. described twelve patients who developed myopathy and peripheral neuropathy on standard doses of colchicine, refuting the idea that these adverse neuromuscular effects only occurred with excessive doses (Kuncl et al., 1987). Patients with colchicine myopathy are most commonly men between 50 and 70 years and have been taking the drug for several years. The presence of chronic renal insufficiency may predispose patients to developing myopathy, since clearance of the drug is reduced in renal failure (Kunc1 er al.,

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1987). The characteristic presentation is subacute proximal weakness involving the arms and legs, although predominant lower extremity involvement has been described. Pain is uncommon, but many patients experience mild distal sensory loss indicating a concomitant peripheral neuropathy. Deep tendon reflexes are reduced or absent. Serum CPK levels is increased up to 20-fold. Discontinuation of colchicine leads to clinical and serologic improvement or recovery within several weeks. Muscle histology in colchicine myopathy is distinct and demonstrates degenerating fibers with prominent vacuole formation mostly confined to the central or subsarcolemmal regions of the fibers (Riggs et al., 1986; Kuncl et al., 1987). These autophagic vacuoles are present in non-necrotic muscle fibers and stain positive for acid phosphatase since they are related to lysosomal dysfunction. Electron microscopy shows lysosomal particles within autophagic vacuoles. In contrast to chloroquine, colchicine is only weakly amphiphilic and the formation of vacuoles is related to an antimicrotubule effect on lysosomal motility rather than to accumulation of drug-lipid complexes within lysosomes.

32.6.2.1. Electrophysiology In the majority of patients with colchicine myopathy, with or without clinical manifestations of peripheral neuropathy, NCS demonstrate low CMAP and SNAP amplitudes, with mild prolongation of distal latencies and F-wave latencies and slowing of conduction velocities, indicating an axonal neuropathy (Riggs et al., 1986; Kuncl et al., 1987; Kuncl et al., 1989). Needle EMG demonstrates fibrillation potentials, positive sharp waves and occasional complex repetitive discharges in 60%, and short duration, low amplitude, polyphasic MUPs in 64%, of proximal muscles (Kontos, 1962; Kuncl et al., 1987; Kuncl et al., 1989; Younger et al., 1991). Additionally, patients with clinical findings of a peripheral neuropathy demonstrate fibrillation potentials and long duration MUP with reduced recruitment in distal muscles. However, even in patients without clinical evidence of a peripheral neuropathy, similar spontaneous abnormalities and long duration, high amplitude MUPs may be seen in distal muscle, reflecting a subclinical underlying neuropathy (Kontos, 1962; Kuncl et al., 1987). The EMG findings related to the myopathy resolve

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within several weeks following discontinuation of colchicine.

32.6.3. Amiodarone Amiodarone is an anti-arrhythmic drug known to produce systemic and neurologic side effects, including hypothyroidism, keratopathy, gastrointestinal symptoms, tremor, and peripheral neuropathy. The occurrence of myopathy related to amiodarone has been described but is controversial. In 1979. Meier et al. describe a patient treated for three years with arniodarone who clinically developed a distal sensorimotor peripheral neuropathy (Meier et al., 1979). Electrodiagnostic findings were compatible with a neuropathy, without evidence of a myopathy; however muscle biopsy demonstrated vacuolar degeneration of individual muscle fibers, increased variability of fiber diameter, and increased central nuclei, suggesting concomitant primary muscle involvement. In a later report, an 80-year-old patient developed proximal and distal weakness, muscle tenderness. myoglobinuria, and markedly elevated CPK four months after initiation of amiodarone. Needle EMG demonstrated occasional fibrillation potentials with low amplitude, polyphasic MUPs and a "reduction in interference pattern" in several muscles (Clouston and Donnelly, 1989). Repeat studies two months later showed low median and ulnar SNAP amplitudes with normal conduction velocities. and an absent tibial CMAP response, consistent with an axonal sensorimotor peripheral neuropathy. Although this patient did not demonstrate clinical signs, laboratory studies demonstrated evidence of hypothyroidism, which makes a definitive causal relationship of arniodarone to the development of myopathy unclear. A further report described a 62-year-old man, who had been asymptomatic for seven years while on colchicine, who developed proximal muscle weakness and a 30-fold CPK elevation one month after initiation of arniodarone (Roth et al., 1990). Nerve conduction studies demonstrated "slowed conduction velocities" with low SNAP amplitudes, and EMG demonstrated fibrillation potentials and positive sharp waves, findings ascribed to an "acute neuropathy". The muscle biopsy demonstrated a vacuolar myopathy. The authors acknowledged that colchicine may have contributed to these findings,

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although clinical and histologic abnormalities resolved after discontinuation of amiodarone despite continued use of colchicine. 32.7. Myopathies characterized by inflammatory

cell infiltration

32.7.1. Penicillamine Penicillamine, a chelating agent used in the treatment of Wilson's disease and rheumatoid arthritis. has been associated with several systemic adverse effects, including the development of systemic lupus erythematosus, glomerulonephritis, Goodpasture's syndrome, and pemphigus. The most common adverse neuromuscular effect associated with penicillamine is production of or exacerbation of myasthenia gravis. Myopathy related to penicillamine is a rare complication with an estimated incidence of 0.2-1.4% (Dawkins et al., 1981; Takahashi et al., 1986; Taneja et al., 1990). Muscle weakness develops within the first six months, but may begin as late as 14 months, following drug initiation (Halla et al., 1984). In some instances a maculopapular, erythematous rash on the surfaces of the extremities, chest, and trunk, similar to the type seen in idiopathic dermatomyositis, may develop. Serum CPK levels (up to 100-fold) and transaminases are characteristically elevated, and antinuclear antibodies, rheumatoid factor, or peripheral eosinophilia may occasionally be present. Clinical and laboratory features improve, often rapidly, following discontinuation of the medication. The etiology of penicillamine-induced myopathy is unknown, but a cell-mediated response targeted towards muscle fibers is speculated. Pathologic findings on muscle biopsy include interstitial mononuclear cell infiltration of muscle fibers with scattered degenerative fibers with fiber size variation and necrosis, similar to the findings seen in idiopathic polymyositis.

32.7.1.1. Electrophysiology Electromyography demonstrates fibrillation potentials and short duration, low amplitude, polyphasic MUPs in proximal more than distal muscles, findings that are indistinguishable from idiopathic polymyositis (Doyle et al., 1983; Halla et al., 1984; Taneja et al., 1990). In one patient, prominent fasciculations without weakness were seen clinically following escalation of the dose of penicillamine for

arthritis (Pinals, 1983). The EMG demonstrated prominent fasciculation potentials without fibrillation potentials or MUP abnormalities that resolved within one week after dose reduction. In another report, prominent spontaneous discharges, called "neuromyotonia" by the authors were identified, although close scrutiny of the 10-30 Hz firing rate makes these more likely myotonic discharges (Reeback et al., 1979). These discharges improved after phenytoin administration. 32.7.2. Tryptophan L-tryptophan is an essential amino acid normally ingested in dietary protein. Supplemental L-tryptophan has been used for the treatment of depression and insomnia. In 1989, the "eosinophilia-myalgia syndrome" was first recognized as an adverse effect and over 1300 cases have been reported in the United States (Hzmann et al., 1990; Kaufman and Seidman, 1991). The development of the eosinophilia-myalgia syndrome is more common in middle-aged females, but occurs in males and females between 20 and 80 years old. The median dose of tryptophan is approximately 1500 mg per day and median duration of use is 8 months. The insidious onset, over 1-2 months, of rash and induration of the skin, fever, fatigue, myalgias, paresthesiae of the extremities, arthralgias, and alopecia, with peripheral blood eosinophilia characterize this syndrome (Hzmann et al., 1990; Hzmann et al., 1995). Muscle cramps occur in approximately 57% of patients and 60% experience subjective weakness. Between one-third and two-thirds of patients demonstrate objective clinical signs of myopathy. Weakness is most prominent in proximal muscles, and is often associated with muscle atrophy. Furthermore, 27% of patients develop signs of a peripheral neuropathy. The disease may become chronic even after the exposure to L-tryptophan ceases. Death is uncommon but it usually occurs as a result of diffuse peripheral nerve and root involvement, primary pulmonary involvement, or primary cardiac failure. Laboratory abnormalities consist of eosinophilia of greater than 1000 cells/rum', elevated transaminases, and an elevated sedimentation rate in one-third of patients. Serum CPK is usually normaL Histopathology demonstrates lymphohistiocytic inflammatory changes, with rare eosinophils, most

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prominently in the epimysial-fascial and perimysial compartments, without muscle fiber necrosis (Verity et aI., 1991). 32.7.2. J. Electrophysiology Despite the fact that a large number of patients have developed eosinophilia-myalgia syndrome, electrophysiologic studies are relatively rare. Nerve conduction studies are usually normal, but mildly reduced median and ulnar CMAP amplitudes with normal conduction velocities, distal latencies, and SNAP amplitudes have been reported (Sagman and Melamed, 1990; Tanhehco et aI., 1992). The low CMAP amplitudes were thought to reflect direct muscle fiber loss, although intramuscular nerve branch involvement could not be excluded. In some cases, more profound reduction in CMAP and SNAP amplitudes indicates an underlying peripheral neuropathy. Several patients have been reported with prominent conduction blocks, temporal dispersion, and slowing of conduction velocities in motor and sensory nerves, indicating a severe segmental demyelinating polyradiculoneuropathy (Heiman-Patterson et aI., 1990; Donofrio et aI., 1992). Findings on needle EMG may also be normal, although some patients demonstrate rapidly recruited short duration, low amplitude, polyphasic MUPs with occasional fibrillation potentials in proximal and distal muscles (Hzmann et aI., 1990; Martin et al., 1990; Sagman and Melamed, 1990; Verity et al., 199I; Tanhehco et al., 1992). In those patients described with findings of a severe polyradiculopathy, prominent fibrillation potentials and long duration MUPs developed in distal muscles indicating the development of progressive axonal loss (Heiman-Patterson et al., 1990). On single fiber EMG, mild increased jitter without blocking has been demonstrated and fiber density may be mildly increased. Following treatment and discontinuation of tryptophan, the degree of fibrillation potentials and positive waves typically improves although MUP changes and increased jitter may persist (Tanhehco et al., 1992).

32.7.3. Cimetidine Cimetidine, a histamine H2-receptor antagonist used in the treatment of peptic ulcer disease, has been shown to produce a syndrome identical to polymyositis (Watson et al., 1983). In the patient

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reported, progressive myalgias and weakness occurred over six months following drug initiation, and was associated with peripheral eosinophilia and interstitial nephritis. Serum CPK and aldolase levels were elevated IO-fold, and muscle biopsy demonstrated focal areas of T-cell lymphocytic infiltrates, often surrounding blood vessels, and areas of regeneration. The muscular and renal manifestations improved following discontinuation of cimetidine and treatment with corticosteroids. The EMG findings "were consistent with polymyositis" but were not described. The findings implicated activation of cell-mediated immune system by cimetidine as the mechanism of muscle and kidney damage. 32.8. Hypokalemic myopathies Several medications, such as thiazide diuretics, amphotericin B, bisacodyl, fluoroprednisolone, and licorice-containing compounds, have a mechanism of action that lowers serum potassium. When reduction in serum potassium occurs to a sufficient degree, progressive, generalized, painless muscle weakness may develop.

32.8.1. Glycyrrhic acid (licorice) Glycyrrhic acid, an active component in licorice, chewing tobacco and snuff preparations, and some anti-ulcer medications, is a substance that inhibits cortisol oxidase, an enzyme that plays a role in the conversion of cortisol to cortisone. Chronic intoxication with glycyrrhic acid leads to excess cortisol, thereby producing a mineralocorticoid effect with secondary hypokalemia. Systemic manifestations include hypertension, sodium and water retention, and hypokalemia. Several reports describe the development of an acute myopathy related to hypokalemia in persons chronically administered glycyrrhic acid-containing substances such as licorice (Cayley, 1950; Mohamed and Champman, 1966; Cumming et aI., 1980; Valeriano et aI., 1983; Caradonna et al., 1992; Shintani et al., 1992). The mean age of development of myopathy is 55 years (range of 15-86 years) and males and females are equally affected (Shintani et aI., 1992). The common factor in the development of muscle weakness in all patients is the prolonged use, over months to years, of substances containing glycyrrhic acid although the quantity of ingestion at one time is not important. Patients with a history of alcohol

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abuse, chronic diarrhea, or concomitant use of other agents that may produce hypokalemia are at a higher risk of developing myopathy. The common clinical manifestations include muscle weakness and cramps, which occurs over days to weeks. Weakness is generalized but often involves proximal more than distal muscles and myalgias occur in one-third of patients. In severe cases, profound quadriparesis or complete paralysis may occur and may be associated with rhabdomyolysis and myoglobinuria (Caradonna et al., 1992; Shintani et al., 1992). Laboratory studies demonstrate low serum potassium levels. In most patients with clinical weakness, the potassium level is less than 2.0 mEqll (Shintani et al., 1992). Serum CPK may be normal but more often is elevated (up to lOO-fold). Symptoms improve after potassium replacement. Muscle biopsies have been performed in some patients and have demonstrated occasional scattered necrotic fibers, sporadic vacuolar degeneration, and cellular infiltration around necrotic fibers. 32.8.1.1. Electrophysiology In only a few cases the electromyographic findings have been reported, and have demonstrated low amplitude and short duration MUPs (Mohamed and Champman, 1966; Shintani et aI., 1992). 32.8.2. Mineralocorticoids

Hypokalemia is a secondary effect of congenital or iatrogenic mineralocorticoid excess. Two patients have been reported who experienced progressive, painful proximal weakness, hypotonia, and elevation of CPK after 2-4 months of overuse of intranasal administration of fluoroprednisolone for rhinitis (Cantello, 1982; Vita et al., 1986). A similar case was reported of a young patient with hypokalemia due to 17a-hydroxylase deficiency (Yazaki et al., 1982). In these patients, weakness affects proximal more than distal muscles and may be associated with muscle tenderness. Myotactic reflexes are normal or mildly reduced. Serum potassium levels at presentation were 1.2-1.7 mEqll and serum CPK levels are elevated 20 to IDO-fold. In addition to the neuromuscular symptoms, other associated systemic features of mineralocorticoid excess, such as hypertension and metabolic alkalosis, are present. With discontinuation of the offending agent and replacement of potassium, clinical and serologic abnormalities rapidly improve over days.

32.8.2.1. Electrophysiology In three patients in whom electrophysiologic findings have been reported, motor and sensory NCSs were normal. Needle EMG demonstrated fibrillation potentials and positive sharp waves in one patient, and low amplitude, short duration, polyphasic MUPs with normal or rapid recruitment in both (Mohamed and Champman, 1966; Cantello, 1982). 32.8.3. Thiazide diuretics

Hypokalemic myopathy has also been identified in patients using thiazide diuretics (Jensen et al., 1977; Shintani et al., 1991). Muscle weakness and tenderness, hyporeflexia, and elevation serum CPK and transaminases may occur as soon as one month following treatment. In severe cases, rhabdomyolysis and myoglobinuria may occur (Shintani et al., 1991). Serum potassium levels are invariably reduced. Muscle biopsy has demonstrated muscle fiber necrosis with vacuole formation. In one report eosinophilic infiltration around the muscle fibers was identified. Clinical and serologic findings improve following potassium replacement and discontinuation of the offending agent. Electromyographic findings in hypokalemic myopathy related to diuretic treatment have not been reported. However, dosedependent electrophysiologic myotonia has been demonstrated experimentally in rats administered the diuretic frusemide (Bretag et a1., 1980). 32.8.4. Alcohol-induced hypokalemic myopathy

Several cases have been reported of chronic alcoholics who have developed acute symmetric, proximal muscle weakness over one to several days (Martin et al., 1971; Rubenstein and Wainapel, 1977). Although the temporal profile was similar to that seen in acute alcohol myopathy. muscle pain, tenderness, and swelling were absent. Serum CPK levels and aminotransferase levels were moderately elevated, but the serum potassium levels were markedly reduced below 2 mEqlliter. With replacement of potassium, clinical and serologic symptoms rapidly improved. Although hypokalemia has been suggested to be a strong contributor in the development of acute alcohol myopathy, studies in rats have shown that the development of acute alcohol myop-

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athy is independent of potassium deficiency (Haller and Knochel, 1984). 32.8.4.1. Electrophysiology Electrodiagnostic studies during the period of clinical weakness demonstrated profuse fibrillation potentials and positive sharp waves in distal muscles in one patient, which completely resolved 5 days following potassium replacement (Rubenstein and Wainapel, 1977). Short duration, low amplitude, polyphasic MUPs, which were present in proximal more than distal muscles, remained following clinical improvement. In addition, NCS showed mildly slowed conduction velocities suggestive of an underlying peripheral neuropathy in one patient. 32.9. Corticosteroid myopathy Corticosteroids are widely used in general medical practice for immunosuppression and treatment of inflammatory and many other medical conditions. The range of systemic adverse effects of steroids is wide and includes Cushing's syndrome, hypertension, hyperglycemia, peptic ulcers, anemia, leukocytosis, psychosis, adrenal suppression, and depression. The most common neuromuscular effect of corticosteroid use is myopathy, and myopathy related to corticosteroids is arguably the most common drug-induced myopathy in the population. Two forms of steroid-induced myopathy may occur: (I) a severe, acute necrotizing myopathy most commonly associated with intensive care treatment and concomitant use of non-depolarizing neuromuscular blocking agents (NDNBA) during asthma crisis ("critical illness myopathy"), and (2) a chronic, slowly progressive myopathy related to prolonged administration steroids. Although both of these entities are associated with steroid administration, the clinical and electrophysiologic findings are distinct from one another. 32.9.1. Acute corticosteroid myopathy Acute corticosteroid myopathy is a rare complication that occurs in patients with acute respiratory impairment, who often require mechanical ventilation in an intensive care setting and are administered high doses of corticosteroids. This disorder has been described in more detail in a previous chapter in this volume (Chapter 29).

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The features associated with the development of myopathy in the setting of acute respiratory failure and intensive care monitoring are not uniform. Many reports implicate high-dose corticosteroids as the predominant offending agent, however most patients have also received NDNMBA while on the ventilator (Leatherman et al., 1996). In some instance, myopathy has also developed in ventilated ICU patients who have not received steroids or have not received NDNMBA, indicating that the development of myopathy is not exclusively related to a single drug (Zochodne et al., 1994; Hanson et al., 1997). Therefore, a synergistic effect of both NDNMBA and corticosteroids in producing muscle fiber damage is likely. The development of myopathy is related to the duration of pharmacologic paralysis while in the ICU, and is less likely to develop in patients paralyzed for less than 24 hours (Leatherman et al., 1996). On clinical examination, severe quadriparesis involving the upper and lower extremities, with muscle atrophy and reduction or absence of myotactic reflexes are the characteristic features (Hirano et al. 1992). Although weakness is generally confined to the extremities, respiratory or bulbar muscles may rarely be affected and cases with ophthalmoparesis have been described (Sitwell et al., 1991). The development of symptoms is rapid, generally noted between 4 days to 2 weeks following administration of NDNMBA, and typically occurs during or shortly after the period of ventilator weaning. The serum CPK level is elevated in approximately one-half of the patients, and may be as high as 400-fold above normal. Histologic findings on muscle biopsy demonstrate widespread atrophy of muscle fibers, excess sarcoplasmic glycogen granules, myofibril disorganization with decrease in myofibrillar protein content, and partial or complete loss of myosin (Hirano, 1992; Larsson et al., 2000). The loss of thick myosin filaments, with relative preservation of thin filaments, is a distinct feature in this entity (Showalter and Engel, 1997; Larsson et al., 2000). 32.9.1.1. Electrophysiology Electrophysiologic testing is extremely useful in patients with weakness in the intensive care unit following ventilation and corticosteroid administration, as the clinical distinction between critical illness polyneuropathy and corticosteroid-induced

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myopathy may be difficult. Characteristic electrodiagnostic features are present in most cases of corticosteroid myopathy, but are sometimes confounded by the additional presence of a severe neuropathy. Nerve conduction studies show a reduction or absence of the CMAP amplitudes with normal or mildly slowed conduction velocities and distal latencies, although in some cases normal responses may be seen. SNAP amplitudes are usually preserved but may be mildly low, unless a superimposed peripheral neuropathy is present, whereby more severe reduction or absence of SNAP amplitudes occurs. The F-wave latencies may be normal or prolonged (Kaplan et aI., 1986; Griffin et aI., 1992; Hirano et aI. 1992; Barohn et al., 1994; Zochodne et aI., 1994; Rich et al., 1996; Hanson et aI., 1997; Showalter and Engel, 1997; David et aI., 1998; Larsson et aI., 2000). Repetitive stimulation studies do not typically demonstrate a significant decrement, although rare reports have shown decrement between 4-14 days following discontinuation of NDNMBA (Kaplan et aI., 1986; Leatherman et aI. 1996; Showalter and Engel, 1997; David et al., 1998; Larsson et aI., 2000). Although this has suggested a defect in neuromuscular transmission, persistent elevation of elevated serum level of vecuronium indicates that residual high levels of NDNMBA contributed to the neuromuscular junction defect (Barohn et al., 1994). Zochodne et al. also demonstrated >5% decrement in 3 of 7 patients with acute quadriplegic myopathy, although their patients were studied less than 7 days after discontinuation of NMBA (Zochodne et aI., 1994). Rich et aI. performed direct needle stimulation of muscle fibers and demonstrated that paralyzed muscles were electrically inexcitable (Rich et aI., 1996). With clinical improvement, muscle fibers became increasingly excitable at lower thresholds than at the time of maximal weakness. This finding led to the proposition that the underlying pathophysiologic process in acute corticosteroid myopathy is an abnormality of muscle membrane excitability. The ultrastructural changes in the muscle sarcolemma shown by Larsson et aI., have also supported this proposition (Larsson et aI., 2000). On needle EMG, short duration, polyphasic MUP are often seen in both proximal and distal muscles, although no configurational alterations in MUP may occur (McFarlane and Rosenthal, 1977; Van Marle and Woods, 1980; Kaplan et aI., 1986; Zochodne et

aI., 1994; Rich et al., 1996; Showalter and Engel, 1997; Larsson et aI., 2000). In patients with complete quadriplegia, there may be no activation of voluntary MUP (Barohn et aI., 1994; Larsson et aI., 2000). In contrast to chronic steroid myopathy, fibrillation potentials are usually present and of severe degree, although may be absent in some cases, and occasional complex repetitive discharges may be seen (Gooch et aI., 1991; Margolis et al., 1991; Barohn et aI., 1994; Leatherman et al., 1996; Rich et aI., 1996; Hanson et al., 1997; Showalter and Engel, 1997; David et aI., 1998; Larsson et al., 2000). Electrophysiologic improvement on NCS, with progressive increase in CMAP amplitudes, and on needle EMG parallels clinical improvement (Kaplan et aI., 1986; Hanson et al., 1997; Larsson et aI.,2oo0). 32.9.2. Chronic corticosteroid myopathy

Progressive muscle weakness is an uncommon complication of long-term steroid use, although chronic corticosteroid myopathy is much more prevalent that acute corticosteroid myopathy. The epidemiologic features associated with the development of myopathy are widely variable; males and females are equally affected although some reports suggest a greater propensity towards women, patients of any age may be affected, and it may occur with many different underlying disorders for which steroids are being administered. Myopathy may occur in association with any of the corticosteroids, although may be higher with fluorinated corticosteroids, such as triamcinolone, betamethasone, and dexamethasone. There is no definite correlation between the steroid dose or duration of use necessary and the development of myopathy. One study reported proximal weakness in 64% of asthmatics taking greater than 40 mg per day of prednisone, whereas 88% of patients on less than 40 mg of prednisone were normal (Bowyer et al., 1985). However, myopathy may also develop in patients on low dose steroids. Alternate day dosing may reduce the risk of development of weakness although this has not been systematically studied. The onset of weakness is insidious and slowly progressive, involves proximal more than distal muscles, preferentially affects legs more than arms, and is painless. Bulbar and sphincter muscles are spared. Weakness may occur as early as several

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weeks or as late as many years following steroid initiation (Afifi et al., 1968). Most patients with steroid myopathy have other manifestations of prolonged steroid use, and in one study 85% of patients with chronic steroid myopathy also showed a Cushingoid appearance (Bowyer et al., 1985). Serum CPK, aldolase, and transaminase levels are normal. Muscle biopsy demonstrates type 2 muscle fiber atrophy without evidence of muscle fiber necrosis or inflammatory cell infiltration (Khaleeli et aI., 1983). Several mechanisms may playa role in steroid-induced muscle dysfunction, including inhibition of muscle protein synthesis, altered oxidative and glycogen metabolism, and impaired calcium uptake by the sarcoplasm reticulum (Mastaglia, 1992). 32.9.2.1. Electrophysiology

Electrophysiologic findings in chronic corticosteroid myopathy are remarkably minimal, even in the context of marked clinical weakness. This clinicalelectrophysiologic dissociation reflects the pathological correlate of atrophy of type 2 muscle fibers, which are rarely assessed on routine EMG. Nerve conduction studies are normal. On needle EMG, normal insertional activity without fibrillation potentials, myotonic discharges, or other spontaneous activity is the rule, although there are rare reports of fibrillation potentials or positive waves in the literature (Golding et al., 1961; Khaleeli et al., 1983; Decramer and Stas, 1992; Olafsson et al., 1994). Voluntary MUP are typically normal, but may be rapidly recruited, short duration, and low amplitude in patients with severe weakness (Afifi et al., 1968; Pleasure et aI., 1970; Dropcho and Soong, 1991). Quantitative MUP analysis has demonstrated significant reduction in MUP duration in patients receiving steroids compared to normal controls (Coomes, 1965;Yates, 1971). A difficult clinical scenario occurs when patients with polymyositis or other connective tissue disorders associated with myopathy develop progressive weakness while taking corticosteroids. In this situation the distinction between a primary myopathy and a steroid-induced myopathy may be difficult on clinical grounds. Electromyography can be exceedinglyhelpful, as the presence of fibrillation potentials and short duration MUP in proximal muscles would argue against corticosteroids as the primary etiology.

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32.10. Drugsrarely producing unclassified histopathologic changes 32.10.1. Beta-blockers

A number of beta-blockers,including propranolol, labetalol, sotalol, and fenoterol have anecdotally been reported to produce a myopathy (Blessing and Walsh, 1977; Ricker et al., 1978; Forfar et al., 1979; Teicher et al., 1981; Willis et aI., 1989). Subclinical myotonic dystrophy and myotonia congenita has been unmasked by beta-blocker administration; however patients without underlying neuromuscular diseases have developed muscle pain, weakness, and elevation of CPK one week to six months following initiation of a beta-blocker (Blessing and Walsh, 1977; Ricker et al., 1978). In two children, muscle biopsy revealed patchy necrosis without inflammation, inclusions or vacuoles, and one other patient demonstrated non-staining vacuoles. 32.10.1.1. Electrophysiology

Electromyographic findings included short duration, polyphasic MUPs with or without fibrillation potentials (Forfar et aI., 1979; Teicher et al., 1981; Willis et al., 1989). In all cases without underlying disorders, the clinical and EMG findings resolved following discontinuation of the medication. 32.10.2. Retinoids (etretinate, isotretinoin)

Retinoids or vitaminA derivatives are widely used in the treatment of psoriasis, acne, and other dermatologic disorders. Musculoskeletal symptoms occur in up to 15% of patients using these medications (Hodak et al., 1986). Clinical manifestations include muscle pain and weakness that typically begin 3-5 months, but have been reported as early as several days, after drug initiation. Serum CPK levels may be normal or mildly elevated. In one case, muscle biopsy demonstrated slight variation in muscle fiber size and abnormalities at the neuromuscular junction, including atrophic appearing nerve terminals that lacked synaptic vesicles (Hodak et al., 1986). 32.10.2.1. Electrophysiology

Nerve conduction studies are normal. On EMG, short duration, low amplitude MUPs may occur in proximal muscles (Hodak et aI., 1986). Quantitative EMG has demonstrated short duration MUP in 3 of

TOXIC MYOPATHIES

13 asymptomatic patients receiving the medications (David et aI., 1988). The EMG and clinical findings resolve following discontinuation of the medication. 32.10.3. Rifampicin

A single patient treated with rifampicin and other medications for pulmonary tuberculosis has been reported to develop progressive proximal arm and leg weakness (Jenkins and Emerson, 1981). With discontinuation of all drugs, symptoms resolved within 24 hours, but with rechallenge of rifampicin alone symptoms recurred within one day. Serum CPK was normal during the period of weakness. 32.10.3.1. Electrophysiology Electromyography was performed following discontinuation of rifampicin and was normal, although no details were provided. Muscle biopsy revealed type 2 muscle fiber atrophy and increased connective tissue. 32.10.4. Phenytoin

There have been a few reports of myopathy occurring as an adverse affect of phenytoin administration (Michael and Mitch, 1976; Harney and Glasberg, 1983). In these cases, progressive myalgias and proximal arm weakness developed approximately six weeks following initiation of phenytoin, and were associated with mild CPK elevation and a leukocytosis with prominent eosinophilia. In addition, other systemic signs of hypersensitivity were present, including rash, lymphadenopathy, and hepatomegaly. Muscle biopsy demonstrated scattered necrotic fibers without evidence of inflammatory infiltrates. The myopathy improved after a few months following discontinuation of phenytoin and, in some instances, with steroids. The pathogenesis of phenytoin-induced myopathy is unknown, but is thought to be immune-mediated. 32.10.4.1. Electrophysiology Electromyography in one patient demonstrated "abnormal spontaneous activity" and short duration, low amplitude, polyphasic MUPs with rapid recruitment in proximal muscles (Harney and Glasberg, 1983).

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32.10.5. Clozapine

Clozapine is an antipsychotic agent used in the treatment of schizophrenia and other psychiatric disorders. The most significant side effects include weight gain, tachycardia, and agranulocytosis, but since the risk of extrapyramidal side effects is less than with other antipsychotic agents, it is a first choice in patients with parkinsonism or other neurologic disorders. Neuromuscular symptoms are a less common effect of clozapine. In one study, CPK elevations occurred in 14% of patients receiving clozapine, 6% of patients complained of muscle weakness and pain, and 2% demonstrated mild proximal muscle weakness (Reznik et aI., 2000). 32.10.5.1. Electrophysiology Electrophysiologic studies were performed on five patients and demonstrated normal NCS in all five. Needle examination was normal in three of five patients, but two patients demonstrated short duration, low amplitude, polyphasic MUPs without fibrillation potentials in proximal muscles (Reznik et aI., 2000). The mechanism of myopathy is unknown. 32.10.6. Tetracycline

A single case of presumed tetracycline-induced myopathy has been described (Sinclair and Phillips, 1982). A 15-year-old girl developed proximal leg weakness and ptosis two months following initiation of oral tetracycline for acne. No specific mention of serum CPK level was made, although "biochemical studies were normal" and muscle biopsy was normal. The symptoms resolved four months following discontinuation. An EMG "indicated the presence of a mild myopathic disease ... with superimposed fibrillation potentials." 32.10.7. Procainamide

A few anecdotal cases of an acute and chronic myopathy following procainamide administration have been reported (Fontiveros et aI., 1980; Lewis et aI., 1986). In one case, a man developed arm and leg weakness, with ataxia and "dystonia", and marked CPK elevation four days following intravenous and oral initiation of procainamide. Symptoms rapidly improved after discontinuation of the medication. Electrophysiology. Electrophysiologic studies demonstrated findings of "a sensorimotor polyneurop-

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athy and myopathy" although specific details were not reported. Muscle biopsy was abnormal but did not show inflammatory cell infiltration. 32.10.8. Perhexiline

Perhexiline is an antianginal and antiarrhythmic agent. The most common neurologic adverse effect is peripheral neuropathy. One case of progressive proximal weakness, without sensory loss, and an erythematous rash and desquamation of the skin and mucosa occurring two weeks after initiation has been reported (Tomlinson and Rosenthal, 1977). Serum CPK was normal. 32.10.8. I. Electrophysiology Nerve conduction studies on the tibial nerve were normal and needle EMG demonstrated low amplitude MUPs without fibrillation potentials. Symptoms resolved within two months of discontinuation of perhexiline. 10.9. Adenine arabinoside (ara-A)

Adenine arabinoside is a purine nucleoside used as an antiviral agent. A single report of a 25-year-old man who developed cardiogenic shock and respiratory failure, requiring mechanical ventilation, ten days following administration of ara-A (Mak et aI., 1990). Serum CPK levels were elevated 5-fold. One month into his hospitalization, he demonstrated marked muscle weakness and atrophy. 32.10.9.1. Electrophysiology Electrophysiologic studies showed increased insertional activity without fibrillation potentials, and short duration, polyphasic MUPs. Muscle biopsy demonstrated myofibrillar degeneration with fibrinoid necrosis and occasional myelin bodies. Although the authors hypothesized a causal relationship between ara-A and skeletal muscle injury, the patient had been intubated and received high dose corticosteroids, suggesting the possibility of critical illness myopathy.

32.10.10. Phenformin-fenfluramine A young woman using phenformin and fenfluramine for weight reduction therapy developed progressive, severe generalized weakness, elevation of CPK, and acute renal failure, followed by death,

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two months after increasing the dose of medication (Palmucci et al., 1978). Muscle biopsy showed severe muscle fiber necrosis and phagocytic invasion. No electrophysiologic studies were performed. 32.10.11. Mercaptopropionyl glycine

Mercaptopropionyl glycine is a drug similar in structure to penicillamine, used in the treatment of cystinuria. A 38-year-old woman developed progressive pain, swelling, and weakness isolated to her quadriceps ten days after initiation of the drug (Hales et aI., 1982). Serum CPK level remained normal and muscle biopsy showed no abnormalities. The symptoms reversed with discontinuation of the medication. EMG was not performed. 32.10.12. Leuprolide acetate

Leuprolide acetate (Lupron), a synthetic gonadotropin releasing hormone analog used in the treatment of prostate carcinoma, produces musculoskeletal symptoms such as myalgias in less than 5% of patients. One patient developed nausea, fevers, dyspnea, and progressive severe generalized weakness and muscle pain following two injections (Crayton et al., 1991). Sedimentation rate and serum CPK levels were moderately elevated, and muscle biopsy demonstrated prominent muscle fiber necrosis, degeneration and regeneration, and inflammatory cell infiltration, similar to the changes seen in idiopathic polymyositis. Symptoms rapidly improved over two weeks following treatment with corticosteroids. 32.10.12.1. Electrophysiology The NCS and EMG findings were interpreted as "consistent with a peripheral neuropathy or polyradiculopathy", although no details were provided. 32.11. Focal necrotizing myopathies

A wide variety of medications and illicit drugs injected directly into muscle can produce focal muscle necrosis. Muscle damage may be the result of local toxicity of the administered agent, physical trauma from needle distortion of muscle fibers, or the result of a secondary inflammatory reaction towards the muscle fibers or vessels.

TOXIC MYOPATHIES

32. JJ.J. Pentazocine Pentazocine, a potent opioid analgesic medication administered enterally or parentally for moderate pain, is a prototypic drug causing a focal myopathy. In the early 1970s, cases emerged describing a "fibrous", localized myopathy related to recurrent intramuscular injections of pentazocine. Patients with pentazocine-induced myopathy demonstrate focal weakness and induration of muscles, most commonly the quadriceps or deltoids. Muscles become firm and progressive muscle fibrosis in the arms leads to involuntary, irreducible abduction of the arms, known as the "arm levitation sign" (Levin and Engel, 1975). At other muscle sites, progressive scarring results in muscle contractures and limitation of motion. In addition, typical skin lesions consisting of hyperpigmentation and punctate ulcers at the sites of injection overlie the weakened muscles. Histologic findings demonstrate replacement of muscle with extensive fibrous connective tissue. 32. JJ.J.J. Electrophysiology In 1975, Oh et aI. described the EMG findings in three patients with pentazocine-induced fibrous myopathy (Oh et aI., 1975). Nerve conduction studies were normal in all patients. Needle examination demonstrated decreased or no insertion activity with minimal fibrillation potentials in scattered regions of the affected muscles. Voluntary MUPs were low amplitude and short duration. Subsequent reports have also demonstrated reduced insertion activity indicative of fibrous replacement of muscle fibers. Complex repetitive discharges and occasional myotonic discharges have been rarely reported (Oh et aI., 1975; Mariani et aI., 1981; Choucair and Ziter, 1984). Similar findings have been reported with repeated intramuscular injections of meperidine, heroin, promethazine, prochlorperazine, lidocaine, bupivacaine, oxacillin, kanamycin, and nafcillin (Aberfeld et al., 1968; Johnson et aI., 1971; Mastaglia et al., 1971; Johnson et aI., 1976; Weber et aI., 2000). Electromyography reveals reduced insertional activity and electrical silence with no voluntary MUPs. With discontinuation of injections, short duration, low amplitude, polyphasic MUPs may persist, but abnormal spontaneous activity in affected muscles disappears (Weber et al., 2000). It has been shown experimentally in monkeys that EMG abnormalities

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occur within hours to days following injections, may persist for over one month, and are more prominent when performed near the site of injection (Johnson et al., 1971). 32.11.2. "Needle myopathy" Repeated intramuscular injections of medications or drugs may lead to focal inflammatory changes, muscle fiber necrosis and regeneration, and fibrosis of muscle fibers, as noted previously (Engel, 1967). Similarly, mild elevations of serum CPK levels and focal histologic abnormalities have been identified on muscle biopsy following repeated needle insertions during EMG (Engel, 1967; Chrissian et aI., 1976). 32.11.2.1. Electrophysiology Sandstedt performed frequency analysis during a single quantitative EMG study using five needle insertions in 32 normal volunteers, followed by a repeat study 3-14 days later. In these patients, 79% of the muscles re-examined on days 3 and 5 showed significantly higher high frequency displacement despite needle insertion 0.5-1 cm away from the initial site of examination. This suggested that functional disturbance of muscle fibers due to injury from the needle may occur along the length of the muscle fibers (Sandstedt, 1981). 32.12. Myopathies due to solvents and occupational toxins 32.12.1. Toxic oil syndrome In 1981, ingestion of food contammg a high proportion of denatured rapeseed oil contaminated with an aniline derivative resulted in an epidemic called the "toxic oil syndrome" (Kilbourne et aI., 1991). This syndrome is similar to the eosinophiliamyalgia syndrome, although the onset is more abrupt and pneumonitis with fever, cough, dyspnea, and pulmonary infiltrates is more prominent. The neuromuscular manifestations include myopathy, multiple mononeuropathies, symmetric peripheral neuropathy, and polyradiculopathy. Muscle involvement is usually manifest by muscle pain and tenderness to palpation, atrophy, and weakness involving proximal more than distal muscles. Histologic findings on muscle biopsy consist of perimyositis, perivasculitis, and fasciitis without

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muscle fiber necrosis. There is a microangiopathy with inflammatory infiltrates consisting of plasma cells, lymphocytes, and monocytes with occasional eosinophils. Inflammation and fibrosis of the muscle spindle was a prominent pathologic finding. Treatment with corticosteroids resulted in some improvement of the cutaneous symptoms and reduction in the amount of eosinophils in the blood but other manifestations were often unresponsive. 32.12.1.1. Electrophysiology The EMG findings are variable and may show changes of axonal or demyelinating neuropathy or myopathic changes with fibrillations and short duration, low amplitude, polyphasic MUPs. 32.12.2. Industrial mineral oil

A 47-year-old man has been reported to develop proximal weakness, burning paresthesias, dysphagia, and appetite loss following exposure to inhalation of ash from the combustion of mineral oil while cleaning the boiler at a power station. Serum CPK was elevated and muscle biopsy demonstrated fiber necrosis with occasional phagocytosis. Nerve conduction studies were normal. 32.12.2.1. Electrophysiology Electromyography demonstrated "scant spontaneous activity" and "myogenous damage" (Rossi et aI., 1986). 32.12.3. Toluene

Intentional or accidental toluene exposure produces adverse gastrointestinal, neuropsychiatric, and neuromuscular effects. Myopathy due to excessive toluene exposure has been rarely reported, and is believed to be the result of a direct toxic effect of toluene on muscle fiber membranes (Bennett and Forman, 1980; Streicher et aI., 1981; Siribaddana et al., 1998). In one series, 9 of 25 toluene abusers presented with recurrent episodes of progressive weakness without sensory loss (Streicher et al., 1981). Weakness is generalized, and in severe cases is associated with rhabdomyolysis. In most cases, hypokalemia and hypophosphatemia occur, and serum CPK levels may be normal or mildly elevated.

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32.12.3.1. Electrophysiology Nerve conduction studies revealed slowed motor conduction velocities in the legs, but other EMG details have not been reported. 32.12.4. Gasoline

Gasoline contains a mixture of several toxic substances, including hexane, tetraethyl lead, and benzene. Chronic intentional inhalation of gasoline may produce altered consciousness, ataxia, tremor, or other central nervous system manifestations. There are a few reports of persons who developed recurrent muscle pain and proximal weakness after inhalation of high concentration of gasoline. Most cases have been reported in children or young adults (Boeckx et al., 1977; Robinson, 1978; Kovanen et aI., 1983). Examination demonstrated mild proximal weakness. Serum CPK levels and transaminases were markedly elevated and myoglobinuria was present.

32.12.4. I. Electrophysiology

EMG demonstrated short duration MUPs without fibrillation potentials.

32.12.5. Organophosphate insecticides

The most common neuromuscular manifestation of excessive acute or chronic exposure to organophosphates is peripheral neuropathy, although myopathy with muscle fiber necrosis may occur. A 41-year-old insect exterminator was described who presented with a four-year history of progressive proximal muscle weakness and atrophy associated with mildly elevated CPK levels (Ahlgren et aI., 1979). Nerve conduction studies were normal but serial needle EMG studies demonstrated myotonic discharges and rare positive sharp waves, with short duration, rapidly recruited MUPs. Muscle biopsy demonstrated acute fiber necrosis with a macrocytic inflammatory cell reaction and vacuoles containing dense bodies. Although his presenting signs were those of a myopathy, he eventually developed respiratory and other constitutional symptoms following recurrent exposure to the organophosphate spray. Other reports have described patients with fluctuating weakness related to chronic and repeated exposure to organophosphates. A mechanism of muscle fiber necrosis may be the result of persis-

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TOXIC MYOPATHIES

tently increased levels of acetylcholine at the endplate region (Ahlgren et al., 1979).

32.13. Myopathies due to animal venom The toxic substances contained in venoms of arachnids, snakes, wasps, and other animals may produce muscle fiber necrosis, in addition to neuromuscular blockade. Numerous species of snakes (Western diamondback rattlesnake, South American rattlesnake, prairie rattlesnake, seasnake, mulga, taipan, tiger snake, Jameson's mamba, jumping viper of Costa Rica), spiders (tarantula, brown spider, black widow spider), and wasps may produce muscle fiber necrosis, and rhabdomyolysis with myoglobinuria and renal failure (Mastaglia, 1992). Myoglobinuria, renal failure, and often death commonly follow painful myalgias unless antitoxins are rapidly administered. Histologic findings include marked muscle fiber necrosis with rupture of the

plasma membrane (Shilkin et al., 1972; Ownby and Odell, 1983; Gutierrez et al., 1986). These findings are believed to produce injury to mitochondria and impaired uptake of calcium by the sarcoplasm reticulum (Ownby and Odell, 1983). Electrophysiologic findings in venom-induced rhabdomyolysis have not been performed.

32.14. Rhabdomyolysis Rhabdomyolysis refers to an acute syndrome of severe muscle necrosis, which is manifest by abrupt onset and progression of widespread muscle pain, tenderness, swelling, and weakness, invariably associated with marked elevation of serum CPK (100 to 10,000 fold). The mechanisms of production of rhabdomyolysis are as variable as the mechanisms of milder forms of toxic myopathies. Direct toxicinduced muscle fiber necrosis, severe hypokalemia, muscle compression and ischemia (such as occurs following coma), and excessive neural activation

Table 5 Drugs and toxins known to produce rhabdomyolysis. Medications

Illicit Drugs

Occupational Toxins

Animal Venoms

Amitriptyline Amoxapine Amphotericin B Carbenoxolone Clofibrate Diazepam e-aminocaproic acid Fenfturamine Gemfibrozil Glycyrrhic acid Haloperidol Ibuprofen Lithium Lovastatin Meprobamate Phenformin Phenothiazine Phenylpropanolamine Propofol Salicylates Stelazine Succinylcholine Thiazide diuretics

Alcohol Amphetamines Arsenic Barbiturates Cocaine Cyanide Heroin Methadone Morphine Phencyclidine

Carbon monoxide Ethylene glycol Gasoline Mercuric chloride Strychnine Toluene

Quail ingestion Snake venom Spider venom Wasp venom

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with prolonged muscle hyperactivity may all produce this syndrome. As has already been mentioned. many of the drugs and toxins described in detail in this chapter can produce the syndrome of severe muscle necrosis, myoglobinuria. renal failure, and death. Rhabdomyolysis has also been reported with a vast number of other medications. illicit drugs. and toxins (Table 5) (Chugh et al., 1978; Cogan et al., 1978; Hoogwerf et al., 1979; Abreo et al., 1982; Eiser et al., 1982; Argov and Mastaglia, 1988; Kuncl and Wiggins, 1988; Grob 1990; Mastaglia, 1992; Wald, 2000). 32.14.1. Electrophysiology

The fulminant nature and high morbidity and mortality that is often associated with rhabdomyolysis has precluded detailed electrophysiologic studies. When reported. needle EMG demonstrates prominent fibrillation potentials, reflecting the profound and widespread fiber necrosis. and short duration. polyphasic MUPs (Argov and Mastaglia, 1988). 32.15. Conclusion Drugs and toxins produce a wide array of clinical and histopathologic muscle fiber changes. Despite the different pathologic mechanisms that produce muscle dysfunction, the clinical manifestations of proximal weakness. muscle pain and tenderness, and serum CPK elevation are common to most drugs. Electrophysiologic testing is critical in identifying toxic myopathies, determining the distribution and severity of muscle injury, and in some instances confirming the role of a specific agent. Future detailed electrophysiologic studies on toxic myopathies may help to further elucidate the effects of drugs and toxins on muscle. References Aberfeld, DC et al. (1968) Diffuse myopathy related to meperidine addiction in a mother and daughter. Arch. Neurol., 19: 384-388. Abourizk, N and Khalil, BA et al. (1979) Clofibrateinduced muscular syndrome. J. Neurolog. Sci., 42: 1-9. Abreo, K and Shelp, WD et al. (1982) Amoxapineassociated rhabdomyolysis and acute renal failure: case report. 1. Clin. Psychiatry 43: 426-427.

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