Toxic Myopathies




INTRODUCTION



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Many drugs can cause a myopathy.110 The pathophysiological mechanisms are diverse and, in many instances, unclear. Medications can have either a direct or an indirect adverse effect on muscle. The direct effect can be focal, as might occur secondary to a drug being injected into tissue, or more commonly generalized. Indirect toxic effects may result from the agent creating an electrolyte imbalance or inducing an immunological reaction. Muscle fibers may undergo necrosis as a result of the drug directly disrupting the sarcolemma, nuclear or mitochondria function, or that of other organelles. In this chapter, we classify the toxic myopathies according to their presumed pathogenic mechanisms (Table 35-1).




TABLE 35-1.TOXIC MYOPATHIES




NECROTIZING MYOPATHIES



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A number of drugs can cause a generalized necrotizing myopathy. Affected individuals may complain of myalgias or weakness, or they might just have asymptomatic elevations of their serum creatine kinase (CK) levels. Severe necrotizing myopathy may be complicated by myoglobinuria and renal failure. The degree of serum CK elevation is proportionate to the amount of muscle damaged.



CHOLESTEROL-LOWERING DRUGS



Cholesterol-lowering medications including 3-hydroxy-3-methylglutaryl-coenzyme A (3-HMG-CoA) reductase inhibitors,1119 fibric acid derivatives,16,2030 niacin,31,32 and ezetimibe3336 may cause a toxic myopathy. Most patients just have mild elevations in serum CK without any symptoms. Others have myalgias and less frequently weakness. Myoglobinuria is a rare event but can be complicated by death. With discontinuation of the offending agent, the myalgias, weakness, and elevated serum CK levels tend to completely resolve, but it may take several days to months. However, rarely these agents may trigger an immune-mediated inflammatory myopathy, usually necrotizing, that requires treatment with immunosuppressive medications.



HMG-CoA REDUCTASE INHIBITORS



Clinical Features


Statin agents inhibit 3-HMG-CoA reductase, the rate controlling enzyme in cholesterol synthesis (Fig. 35-1). Adverse side effects including asymptomatic hyper-CK-emia, myalgias, proximal weakness, and, less commonly, myoglobinuria occur with all of the major HMG-CoA reductase inhibitors: lovastatin,13,16,18,19,32,37,38 simvastatin,12,14,15,38,39 provastatin,17,38 atorvastatin,11,38,40 fluvastatin,38 and cerivastatin.38,41,42 The nomenclature regarding statin-induced toxic myopathies in the published literature is unfortunately quite unsatisfactory, listing “myalgias,” “myositis,” and “myopathy” as three independent types of muscle disorders caused by statin use, when these three subtypes may just reflect the spectrum of severity of the myopathy.4345




Figure 35-1.


Hydroxy-3methyl-glutaryl-coenzyme A pathway. (Reproduced with permission from Greenberg SA, Amato AA. Statin myopathies. Continuum. 2006;12(3):169–184.)





Reviews discussing statin myopathies cite a 2–7% incidence of myalgias, 0.1–1.0% incidence of weakness or elevated CK, and myoglobinuria developing in <0.5% of patients.1,43,4649 The National Heart Lung and Blood Institute advisory panel estimated the incidence of severe myopathy to be approximately 0.08% for lovastatin, simvastatin, and pravastatin.44 The risk of toxic myopathy increases with the concomitant use of fibric acids,18,19,27,31,32,40 niacin,31,32 cyclosporine,18,19 ezetimibe,3336 triazole antibiotics,50 rapamycin,51 and sirolimus48 as well as in the presence of renal insufficiency or hepatobiliary dysfunction. In this regard, 5% of patients taking both lovastatin and gemfibrozil developed a severe myopathy,27 while a severe myopathy complicated as many as 30% of patients receiving both lovastatin and cyclosporine.13,18,19



Most patients with a statin myopathy improve within a few weeks of stopping the agent. One dilemma we face is if patients who exhibited symptoms or signs of statin-intolerance might be rechallenged once the muscle symptoms have resolved. In one study of 51 patients, who previously experienced myalgias or elevated transaminase levels on a variety of different statins, 37 (72.5%) were able to tolerate every other day rosuvastatin.52



Although the term “myositis” has been used to denote cases associated with markedly elevated serum CK levels, histopathological confirmation is lacking in most cases. “Myositis” denotes an autoimmune attack on muscle. True cases of myositis, particularly dermatomyositis, have been described in association with statin use.17,5360 More recently, an immune-mediated necrotizing myopathy has been reported to occur in the setting of statin use (discussed in greater detail in Chapter 33).49,6164 In these cases weakness continues to progress despite discontinuation of the statin, and only improves if the patients are treated with immunosuppressive agents. Furthermore, disease activity often flares, if the immunosuppressive medications are discontinued.



Laboratory Features


Asymptomatic elevation of serum CK is common in patients taking statin medications. Marked elevations of CK occur in patients with severe weakness and myoglobinuria. Routine motor and sensory nerve conduction studies (NCS) are normal. Fibrillation potentials, positive sharp waves, and myotonic discharges with early recruitment of small-duration motor unit action potentials (MUAPs) are apparent in weak muscles.65 Electromyography (EMG) in patients with asymptomatic serum CK elevations is often normal.



Interestingly, autoantibodies directed against HMG-CoA reductase have been reported in cases of statin-associated immune-mediated necrotizing myopathies.61,62 These antibodies are not usually seen in patients who just take statin medications or those that have the more typical statin myotoxicity that resolves upon discontinuation of the offending medication.



Histopathology


Muscle biopsies reveal muscle fiber necrosis with phagocytosis and small regenerating fibers in patients with elevated serum CKs and weakness or myalgias (Fig. 35-2). Lipid-filled vacuoles within myofibers and cytochrome oxidase–negative myofibers may be appreciated, but these are not consistent findings.66 Patients with statin-induced necrotizing myopathy often have increased expression of major histocompatibility antigen 1 (MHC1) and membrane attack complex deposition on the sarcolemma of non-necrotic muscle fibers.6164




Figure 35-2.


Statin myopathy. Muscle biopsy demonstrates scattered necrotic muscle fibers. Modified Gomori trichrome.





Pathogenesis


The pathogenesis of the myopathy secondary to HMG-CoA reductase inhibitors is unclear, as several pathways may potentially be interrupted downstream (Fig. 35-1).1,49,67 Mevalonate is the immediate product of HMG-CoA reductase metabolism. Subsequently, mevalonate is metabolized to farnesol, which is converted to either squalene or geranylgeraniol. Squalene is the first metabolite committed to the synthesis of cholesterol. In contrast, geranylgeraniol is important in the biosynthesis of coenzyme Q10 [a mitochondrial enzyme important in the production of adenosine triphosphate (ATP)], dolichol (important in glycoprotein synthesis), and isopentylamine (a component of tRNA), and in the activation of regulatory proteins (G-proteins). It is possible that statins could diminish cholesterol within muscle membranes, thereby predisposing the muscle fibers to rhabdomyolysis. However, the depletion of metabolites of geranylgeraniol, and not the inhibition of cholesterol synthesis, may be the primary cause of myotoxicity. In this regard, HMG-CoA reductase inhibitors decrease the levels of coenzyme Q, which could impair energy production.



A couple genome-wide association study conducted in patients with suspected statin-induced toxic myopathy revealed a strong association of myopathy with a single nucleotide polymorphism (SNP), rs4363657, located within the SLCO1B1 gene on chromosome 12.68 This gene encodes a protein that regulates the hepatic uptake of statins. Of note, more than 60% statin myopathy patients carried this SNP. No SNPs in any other region were clearly associated with myopathy, including those genes associated with metabolic myopathies.



There are several reports of patients treated with statins who developed dermatomyositis5557,59,60 or polymyositis.17,53,54,58 The most common myositis that we and others have seen in patients on a statin medication is a necrotizing myopathy.6164 Unlike polymyositis, muscle biopsies in these cases many necrotic fibers without much in the way of endomysial inflammation, except around and within the necrotic fibers. In many instances, the myositis does not improve following discontinuation of the statin medication (after 6 months or more) and only improves after treatment with an immunosuppressant medication. In addition, the myopathy may worsen after discontinuation of the immunosuppressant agent and improve once again upon reinstituting immunotherapy. In addition, as noted previously, autoantibodies directed against the HMG-CoA reductase have been reported in these cases of statin-associated necrotizing myopathies.61,62 These features suggest that these rare cases of necrotizing myopathy do not represent a “toxic” myopathy per se, but a distinct immune-mediated process.



FIBRIC ACID DERIVATIVES



Clinical Features


Clofibrate and gemfibrozil are branched-chain fatty acid esters, which are used to treat hyperlipidemia. These fibric acid derivatives can cause a myopathy that typically presents within 2 or 3 months after starting the drug.16,2030,40 However, the toxic myopathy may develop up to 2 years following initiation of treatment. Affected individuals complain of generalized weakness, myalgias, and cramps. Myoglobinuria is also a rare complication. Patients with renal insufficiency, those taking both clofibrate and gemfibrozil, and especially also those receiving an HMG-CoA inhibitor, are particularly at increased risk of developing myotoxicity.



Laboratory Features


Elevated serum CK levels are usually noted. Motor and sensory NCS are normal.22,24,28 Needle EMG may demonstrate fibrillation potentials, positive sharp waves, complex repetitive discharges, myotonic discharges, and short-duration, small-amplitude polyphasic MUAPs in affected muscle groups.20,21,25,29,69



Histopathology


Muscle biopsies demonstrate scattered necrotic muscle fibers. In animal models, clofibrate is also known to result in noninflammatory necrosis of muscle tissue with fiber size variation and groups of small atrophic muscle fibers.70



Pathogenesis


The pathogenic mechanism of the myopathy associated with fibric acid derivatives is not known. These medications might somehow destabilize the lipophilic muscle membrane leading to muscle fiber degeneration.27



NIACIN



Rarely, niacin use is complicated by myalgias and cramps.31 Serum CK levels can be elevated as much as 10-fold. The symptoms improve and CK levels normalize after discontinuation of niacin. Electrodiagnostic studies and muscle biopsies have not been reported in detail. In most cases, rhabdomyolysis occurred in patients who were also taking a statin agent.31 Of note, niacin can inhibit HMG-CoA reductase; therefore, the pathogenic mechanism of the myopathy is likely similar to that of the statins.



EZETIMIBE



Ezetimibe selectively inhibits the absorption of intestinal cholesterol. There are a few reports of ezetimibe-induced myopathy.33,36,71 Similar to other cholesterol-lowering agents, patients may develop hyper-CK-emia with or without myalgias or weakness. Most cases occur in patients who are already on a statin agent, but some occur with Ezetimibe monotherapy. The toxic myopathy usually resolves within a few weeks after the medication is discontinued. However, we have also seen rare cases of what appear to be an immune-mediated necrotizing myopathy as discussed in the statin section in which the myopathy improved only after the affected patients were treated with immunosuppressive agents.



USE OF CHOLESTEROL-LOWERING AGENTS IN PATIENTS WITH KNOWN MYOPATHIES



A common question posed to neuromuscular specialists is if patients with known myopathies (e.g., muscular dystrophy, metabolic myopathies, polymyositis) can be treated with cholesterol-lowering agents to control their hypercholesterolemia. There is very little evidence that there is increased risk of statin-induced myotoxicity in patients with an underlying myopathy (aside from those that have the rare statin-induced immune-mediated necrotizing myopathy). Furthermore, there is no strong evidence that statin medications (or other lipid-lowering agents) can exacerbate any underlying myopathy. Given the well-known benefits of statins in patients at risk for cardiovascular disease and lack of any strong evidence of increased risk of these medications in patients with underlying myopathy, we again see no contraindication to their use in most patients. We do tend to follow them closer and periodically check their CK levels.



CYCLOSPORINE AND TACROLIMUS



Clinical Features


The immunophilins (i.e., cyclosporine and tacrolimus) are commonly used as immunosuppressive agents, especially in patients requiring transplantation.72 Rarely, generalized myalgias and proximal muscle weakness develop within months after starting these medications.7277 Myoglobinuria can also occur, particularly in patients receiving cyclosporine or tacrolimus concurrent with cholesterol-lowering agents or colchicine.18,19,7881 Tacrolimus has also been associated with hypertrophic cardiomyopathy and congestive heart failure.82 Myalgias, muscle strength, and cardiac function improve with reduction or discontinuation of the offending cyclophilin.



Laboratory Features


Serum CK is usually elevated. NCS are normal. EMG often reveals increased muscle membrane instability with fibrillation potentials, positive sharp waves, and myotonic potentials.74 Early recruitment of small-amplitude, short-duration MUAPs may be demonstrated in weak muscle groups.



Histopathology


Muscle biopsies demonstrate necrosis, vacuoles, and type 2 muscle fiber atrophy.



Pathogenesis


The pathogenic basis of immunophilin-induced myopathy and cardiomyopathy is not known. Perhaps, the agents destabilize the lipophilic muscle membrane leading to muscle fiber degeneration, similar to the cholesterol-lowering agents. In this regard, cyclosporine itself has a cholesterol-lowering effect. This may explain the increased risk of myopathy in patients receiving cyclosporine and the more classic lipid-lowering agents (e.g., fibric acid derivatives and statins).



LABETALOL



Clinical Features


There are a few reports of necrotizing myopathy associated with the use of the antihypertensive agent, labetalol.83,84 Patients can develop acute or insidious onset of proximal weakness or myalgias, which resolve following discontinuation of the medication.



Laboratory Features


Serum CK can be markedly elevated. EMG may demonstrate increased insertional and spontaneous activity with fibrillation potentials and positive sharp waves. Short-duration, small-amplitude, polyphasic MUAPs, which recruit early, are evident.



Histopathology


Routine light microscopy can be normal83 or can reveal necrotic and regenerating fibers.84 Electron microscopy (EM) revealed subsarcolemmal vacuoles in one case.83



Pathogenesis


The pathogenic etiology for the muscle necrosis seen is not known.



PROPOFOL



Clinical Features


Propofol is an anesthetic agent that is frequently used for sedating patients who are mechanically ventilated and sometimes for the treatment of status epilepticus. Myoglobinuria, metabolic acidosis, hypoxia, and myocardial arrest are rare adverse events associated with the use of propofol.8587 Propofol does not appear to be associated with malignant hyperthermia. Acute quadriplegic myopathy (AQM) in the intensive care unit (ICU) has also developed in patients treated with propofol in combination with high-dose intravenous corticosteroids.88 The myopathy in these individuals could be explained by the high-dose corticosteroids rather than the use of propofol. It remains to be determined if propofol is an independent risk factor for the development of AQM.



Laboratory Features


Serum CK levels are markedly elevated. Electrophysiologic studies have not been performed or were not reported in the cases associated with rhabdomyolysis in children. The adult patients with AQM have low-amplitude compound muscle action potentials (CMAPs), profuse fibrillation potentials, positive sharp waves, and early recruitment of short-duration, small-amplitude polyphasic MUAPs.88



Histopathology


Muscle biopsies reveal necrosis of skeletal and cardiac muscle.8587 Patients with AQM, may have prominent necrosis and loss of thick filaments.88



Pathogenesis


The mechanism for muscle destruction is unknown.



Treatment


Propofol should be discontinued and supportive therapy instituted for myoglobinuria, metabolic acidosis, hyperkalemia, and renal failure.



AMPHIPHILIC DRUG MYOPATHY (DRUG-INDUCED AUTOPHAGIC LYSOSOMAL MYOPATHY)



Amphiphilic drugs contain separate hydrophobic and hydrophilic regions, which allow the drugs to interact with the anionic phospholipids of cell membranes and organelles. In addition to a myopathy, these agents can also cause a toxic neuropathy that is even more severe than the direct toxicity on muscle.



CHLOROQUINE



Clinical Features


Chloroquine, a quinoline derivative, is used to treat malaria, sarcoidosis, systemic lupus erythematosus (SLE), and other connective tissue diseases.7,8,8992 Some patients develop slowly progressive, painless, proximal weakness and atrophy, which affect the legs more than the arms. A cardiomyopathy can also occur. Sensation is often reduced as are muscle stretch reflexes, particularly at the ankles, secondary to a concomitant neuropathy. This “neuromyopathy” usually does not occur unless patients take 500 mg a day for a year or more but has been reported with doses as low as 200 mg/day. The neuromyopathy improves after chloroquine discontinuation.



Laboratory Features


Serum CK levels are usually elevated. Motor and sensory NCS reveal mild-to-moderate reduction in the amplitudes with slightly slow velocities in patients with a superimposed neuropathy.90,92 Individuals with only the myopathy usually have normal motor and sensory studies.89 Increased insertional activity in the form of positive sharp waves, fibrillation potentials, and myotonic discharges are seen primarily, but not exclusively, in the proximal limb muscles.89,90,92 Early recruitment of small-amplitude, short-duration polyphasic MUAPs are appreciated in weak proximal muscles. Neurogenic appearing units and reduced recruitment may be seen in distal muscles that are more affected by the toxic neuropathy.



Histopathology


Autophagic vacuoles are evident in as many as 50% of skeletal and cardiac muscle fibers (Fig. 35-3).7,8,8992 Type 1 fibers appear to be preferentially affected. The vacuoles stain positive for acid phosphatase, suggesting lysosomal origin. On EM, the vacuoles are noted to contain concentric lamellar myeloid debris and curvilinear structures. Autophagic vacuoles are also evident in nerve biopsies.




Figure 35-3.


Chloroquine myopathy. Chloroquine can cause a vacuolar myopathy (A), hematoxylin and eosin (H&E). Electron microscopy reveals a bundle of dilated tubules (B). (Reproduced with permission from Wasay M, Wolfe GI, Herrold JM, Burns DK, Barohn RJ. Chloroquine myopathy and neuropathy with elevated CSF protein. Neurology. 1998;51(4):1226–1227.)





Pathogenesis


Chloroquine is believed to interact with lipid membranes, forming drug–lipid complexes that are resistant to digestion by lysosomal enzymes. This results in the formation of the autophagic vacuoles filled with myeloid debris.



HYDROXYCHLOROQUINE



Hydroxychloroquine is structurally similar to chloroquine and can cause a neuromyopathy.90 The myopathy is usually not as severe as seen in chloroquine. Vacuoles are less appreciated on routine light microscopy, but EM still usually demonstrates the abnormal accumulation of myeloid and curvilinear bodies.



AMIODARONE



Clinical Features


Amiodarone is an antiarrhythmic medication that can also cause a neuromyopathy.9397 The neuromyopathy is characterized by severe proximal and distal weakness along with distal sensory loss and reduced muscle stretch reflexes. The legs are more affected than the arms. Some patients develop tremor or ataxia. Amiodarone can also cause hypothyroidism, which may also contribute to proximal weakness. Patients with renal insufficiency are predisposed to developing the toxic neuromyopathy. Muscle strength gradually improves following discontinuation of amiodarone.



Laboratory Features


Serum CK levels are elevated. Motor and sensory NCS reveal reduced amplitudes and slow conduction velocities, particularly in the lower extremities.96,97 EMG demonstrates fibrillation potentials and positive sharp waves in proximal and distal muscles. In proximal muscles, MUAPs are typically polyphasic, short in duration, small in amplitude, and recruit early. Distal muscles are more likely to have large-amplitude, long-duration polyphasic MUAPs with decreased recruitment.



Histopathology


Muscle biopsies demonstrate scattered fibers with autophagic vacuoles. In addition, neurogenic atrophy can also be appreciated, particularly in distal muscles. EM reveals myofibrillar disorganization and autophagic vacuoles filled with myeloid debris. Myeloid inclusions are also apparent on nerve biopsies. These lipid membrane inclusions may be evident in muscle and nerve biopsies as long as 2 years following discontinuation of amiodarone.



Pathogenesis


The pathogenesis is presumably similar to other amphiphilic medications (e.g., chloroquine).




ANTIMICROTUBULAR MYOPATHIES



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COLCHICINE



Clinical Features


Colchicine is commonly prescribed for individuals with gout. Colchicine can also cause a generalized toxic neuromyopathy. It is weakly amphiphilic, but its toxic effect is believed to arise secondary to its binding with tubulin and prevention of tubulin’s polymerization into microtubular structures.5,8,9 The neuromyopathy usually develops after chronic administration, but it can also develop secondary to acute intoxication.5,98100 Chronic renal failure and age over 50 years are risk factors for the development of neuromyopathy. Patients usually manifest with progressive proximal muscle weakness over several months. Clinical myotonia has been described.101 A superimposed toxic neuropathy leads to distal sensory loss as well as diminished reflexes. The neuromyopathy weakness typically resolves within 4–6 months after discontinuing the colchicine.



Laboratory Features


Serum CK level is elevated up to 50-fold in symptomatic patients. Serum CK may also be mildly elevated in asymptomatic patients taking colchicine. NCS reveal reduced amplitudes, slightly prolonged latencies, and mildly slow conduction velocities of motor and sensory nerves in the arms and legs.98102 Needle EMG demonstrates positive sharp waves, fibrillation potentials, and complex repetitive discharges, which are detected with ease in all muscle regions. Myotonic discharges may also be seen.101 The myopathic MUAP abnormalities can be masked in the distal limb muscles secondary to the superimposed peripheral neuropathy.



Histopathology


Muscle biopsy demonstrates acid phosphatase–positive autophagic vacuoles containing membranous debris (Fig. 35-4). In addition, nerve biopsies can reveal evidence suggestive of a mild axonal neuropathy.




Figure 35-4.


Colchicine myopathy. Colchicine can cause a vacuolar myopathy as evident on modified Gomori trichrome stain (A) and hematoxylin and eosin stain (B).





Pathogenesis


The abnormal assembly of microtubules most likely disrupts intracellular movement or localization of lysosomes, leading to the accumulation of autophagic vacuoles.99



VINCRISTINE



Clinical Features


Vincristine is a chemotherapeutic agent, which disrupts gene transcription and also promotes the polymerization of tubulin into microtubules.8 The dose limiting side effect of vincristine is a toxic axonal sensorimotor polyneuropathy that is associated with distal muscle weakness and sensory loss. Proximal muscle weakness and myalgias are less common.103



Laboratory Features


Serum CK levels have not been reported in patients suspected of having a superimposed myopathy. NCS demonstrate markedly reduced amplitudes of SNAPs and CMAPs, while the distal latencies are slightly prolonged, and conduction velocities are mildly slow.103 Needle EMG demonstrates positive sharp waves, fibrillation potentials, and neurogenic appearing MUAPs in the distally located muscles of the upper and lower extremities.



Histopathology


Biopsies of distal muscles demonstrate evidence of neurogenic atrophy and, occasionally, the accumulation of lipofuscin granules. Proximal muscle biopsies reveal scattered necrotic fibers.103 On EM, there is prominent myofibrillar disarray and subsarcolemmal accumulation of osmiophilic material. In addition, some myonuclei contain membrane-bound inclusions. Autophagic vacuoles with spheromembranous debris have been noted in research animals104,105 but have not been appreciated in humans.103



Pathogenesis


The pathogenic basis of the neuromyopathy is presumably similar to that of colchicine.




DRUG-INDUCED MITOCHONDRIAL MYOPATHY



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ZIDOVUDINE (AZIDOTHYMIDINE)



Clinical Features


Patients with azidothymidine (AZT) myopathy usually present with an insidious onset of progressive proximal muscle weakness and myalgias.106116 However, these clinical features do not help in distinguishing AZT myopathy from other HIV-related myopathies. Other myopathies related to HIV infection are heterogeneous and include inflammatory myopathy, microvasculitis, noninflammatory necrotizing myopathy, and type 2 muscle fiber atrophy secondary to disuse or wasting due to their chronic debilitated state.107,110112,114124 Furthermore, weakness in an HIV-infected patient can also be secondary to peripheral neuropathy (e.g., chronic inflammatory demyelinating polyneuropathy) or myasthenia gravis. Clinically, AZT myopathy and the other myopathic disorders associated with HIV infection are indistinguishable, compounding the diagnostic difficulty. Regardless of etiology of the myopathy, patients manifest with progressive proximal muscle weakness and myalgias. In addition, muscle weakness may be multifactorial.



Laboratory Features


Serum CK levels are normal or only mildly elevated in AZT myopathy. However, similar elevations are evident in other forms of HIV-related myopathy. An elevated serum CK (e.g., greater than five times the upper limited of normal) is more suggestive of an HIV-associated myositis. Motor and sensory NCS are normal, unless there is a concomitant peripheral neuropathy. Needle EMG may demonstrate positive sharp waves and fibrillation potentials and early recruitment of short-duration, small-amplitude polyphasic MUAPs.114,119,122,125 In addition, small polyphasic MUAPs with early recruitment but no abnormal spontaneous activity was reported in patients with AIDS, along with ultrastructural mitochondrial abnormalities but no inflammation or nemaline rods on biopsy.112



Histopathology


Muscle biopsies are remarkable for the presence of ragged red fibers, suggesting mitochondrial abnormalities in AZT myopathy (Fig. 35-5). The number of ragged red fibers correlates with the cumulative dose of AZT.110,111 In addition, necrotic fibers, cytoplasmic bodies, nemaline rods, and fibers with microvacuolation may be seen in addition to ragged red fibers.107,110,111 In contrast to HIV-associated inflammatory myopathy, significant endomysial inflammation with or without invasion of non-necrotic fibers should not be present in cases of pure AZT myopathy. EM reveals abnormalities of the mitochondria and myofilaments.




Figure 35-5.


Azidothymidine myopathy. Ragged red fibers suggestive of abnormal mitochondria are evident on modified Gomori trichrome stain.





Pathogenesis


AZT acts as a false substitute for the viral reverse transcriptase, thereby inhibiting its enzymatic activity and replication of the HIV virus. However, AZT also inhibits the activity of mitochondrial DNA polymerase, which probably accounts for the mitochondrial abnormalities. When treated with AZT, patients with HIV have a decrease in quantity of mitochondrial DNA and decline in respiratory chain enzymatic activity, compared to untreated infected patients.121,126 The histological and molecular abnormalities on repeated muscle biopsies resolve coinciding with clinical improvement following discontinuation of AZT.127 Although, AZT is responsible for at least some of the mitochondrial abnormalities evident on muscle biopsy, the contribution of these mitochondrial abnormalities to the muscle weakness remains controversial.



Treatment


In the past, anywhere from 18% to 100% of patients with “AZT” myopathy improved following discontinuation of the medication.107,110,112,114,116,119,120,128 AZT is not used as much anymore as other antiviral agents are typical used nowadays in the treatment of HIV (see below).



OTHER ANTIVIRAL AGENTS



The risk of mitochondrial myopathy with other nucleoside reverse transcriptase inhibitors (e.g., lamivudine), zalcitabine, didanosine is probably less than that of AZT.129,130 However, these agents are clearly associated with mitochondrial toxicity, and patients may develop associated hyperlactemia and hepatic steatosis on these medications. The AIDS Clinical Trial group randomized 2,467 patients to receive one of four single or combination regimens with AZT, didanosine, zalcitabine, and their respective placebo.123 Approximately 10% of patients had myalgias prior to treatment and 7% developed myalgia during treatment. There was no significant difference between treatment arms and the rate of myalgia or muscle weakness in any group. Five patients (0.5%) had elevated serum CK (>4× normal) prior to treatment, and 52 (5%) developed increased CK during treatment. Serum CK levels were significantly higher in the AZT-zalcitabine group, but this did not correlate with symptoms of myopathy. Unfortunately, there was no comment on muscle biopsies, and thus it is unclear if the myopathies were secondary to mitochondrial toxicity or myositis.

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