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myopathy

Severe wasting from repeated infections, malignancy, malabsorption, and nutritional deficiency often account for weakness and disability in patients with the acquired immunodeficiency syndrome (AIDS). Weakness may also be due to central and peripheral nervous system involvement from infections or immunologically mediated neuropathies in these patients ]. However, the possibility of skeletal muscle disease should not be overlooked since several specific skeletal muscle disorders causing weakness have been identified in HIV-infected patients .

HIV myopathy:

1. Zidovudine (AZT) myopathy

2. Muscle infections

3. Other muscle disorders such as rhabdomyolysis, non-Hodgkins lymphoma, myasthenia gravis, nemaline (rod) myopathy

This card will review muscle disease in patients infected with HIV. A discussion of the arthritis associated with this virus is presented separately.

HIV MYOPATHY :  A myopathy resembling idiopathic polymyositis (PM) can occur in patients with HIV infection . Affected patients present with myalgias, muscle tenderness, and symmetric proximal muscle weakness with a predilection for the lower extremities. Myopathy may be the presenting manifestation of HIV infection , or may occur in the setting of already established AIDS . The development of myopathy does not correlate with the degree of immunosuppression or the level of CD4+ T cells in the circulation .

Pathogenesis : The pathogenesis of HIV myositis has not been established. It is possible that muscle damage is caused by direct invasion of muscle cells by HIV itself, a cell-mediated immunologic mechanism, or some combination of both. The direct invasion theory is supported by studies of simian AIDS; infected monkeys develop a myopathy in which the putative retrovirus has been isolated from muscle tissue and shown to be capable of infecting normal muscle in tissue culture.

However, attempts to identify HIV antigens in human muscle cells by electron microscopy or immunocytochemical techniques have been unsuccessful. Antigen has been demonstrated in T cells infiltrating the muscle , and HIV DNA has been demonstrated in muscle tissue after amplification by polymerase chain reaction .

The inability to identify HIV directly in muscle tissue could be due to sampling variability. Alternatively, HIV invasion of muscle may be transient but able to induce an antigenic change in muscle tissue that subsequently triggers an immunologically-mediated inflammatory infiltrate and myositis. It has been suggested that the cases of rhabdomyolysis reported in early HIV infection or with HIV seroconversion (see below) are evidence of direct viral invasion and damage to muscle early in the course of HIV infection .

MHC class I antigens are expressed on both infiltrating CD8+ T cells and muscle cells in patients with HIV myopathy. In addition, activated T cells release cytokines that stimulate the expression of class I antigens on muscle cells that are then recognized by cytotoxic CD8+ T cells. These changes also occur in idiopathic PM, suggesting that, in both diseases, a T-cell mediated MHC restricted cytotoxic immune process is responsible (at least in part) for the myopathic changes . section on Muscle biopsy and immunopathogenesis).

Diagnosis : The clinical challenge in making the diagnosis of HIV myopathy may involve distinguishing between this disorder and zidovudine myopathy (see below). Successful distinction often requires a trial of stopping AZT and monitoring the response. Muscle enzymes are typically increased up to ten-fold in patients with both disorders.

Electromyography and muscle biopsy may assist in making the diagnosis:

1. Electromyography in patients with HIV myopathy shows myopathic changes with increased insertional activity, fibrillations, and polyphasic potentials characteristic of membrane irritability and indistinguishable from idiopathic PM.

2. Histologic changes on muscle biopsy include an endomysial mononuclear cell infiltrate with lesser accumulation of inflammatory cells around vessels or in the interfascicular space (show histology 1). The cellular infiltrate is predominantly CD8+ T lymphocytes and macrophages.

Treatment : High dose steroids, as used in idiopathic PM, have been shown some efficacy in HIV myopathy . Corticosteroid therapy is initiated with prednisone in a dose of 1 mg/kg per day. Normalization of muscle enzymes and improvement in strength in responders usually occur within one to two months of corticosteroid therapy. There is no literature concerning the treatment of steroid nonresponders with HIV myopathy. Methotrexate and azathioprine, which are used in this setting in idiopathic PM, are contraindicated in HIV myopathy.

Once the full response has occurred, prednisone is tapered gradually, while the patient's muscle strength and plasma enzymes are monitored for signs of relapse. There is no standard tapering schedule, but one reasonable approach is to decrease by 5 mg/week down to 20 mg/day, then by 2.5 mg every two weeks down to 10 mg/day, and then by one mg/month until steroids are discontinued. Alternate day steroids (50 to 60 mg every other day) can be used from the outset in mild cases, or after the disease is well controlled in more severe cases.

The patient should be carefully monitored during the tapering period, watching for signs of recurrent weakness and for signs of corticosteroid toxicity.  Alternative diagnoses and steroid myopathy should be considered in patients who fail to respond to prednisone (eg, do not achieve normalizations of muscle enzymes and the return of muscle strength). The latter diagnosis is suggested by weakness in the setting of normal muscle enzymes. An empiric trial of lowering the prednisone dose and observing the muscle strength response is an effective and practical approach to this dilemma.

ZIDOVUDINE MYOPATHY : Zidovudine is widely used in the treatment of HIV infection and is associated with a myopathy that clinically resembles idiopathic PM and HIV myopathy . These similarities have led some investigators to question whether this myopathy is a distinct entity from HIV myopathy . Patients present with myalgias, muscle tenderness, proximal muscle weakness, and often prominent muscle atrophy.

One study of patients with AIDS found that 7 of 41 (17 percent) who had been receiving AZT for more than 270 days developed clinical and biochemical evidence of proximal myopathy . No patients receiving short-term therapy with AZT and no control patients had evidence of muscle disease. Affected individuals had received AZT for an average of 371 days with a mean cumulative dose of 0.41 kg. The incidence of AZT myopathy was more frequent than HIV myopathy.

Diagnosis – The diagnosis should be suspected in patients who develop characteristic clinical features in the setting of months of AZT therapy. CK levels are elevated usually upto ten-fold normal, overlapping with HIV myopathy. EMG may demonstrate mild myopathic changes or is normal.

In contrast to patients with HIV myopathy, light microscopy of the affected muscle in patients with AZT myopathy generally shows no inflammatory infiltrate or a very mild endomysial collection of T lymphocytes, scattered muscle fiber necrosis, and variable muscle fiber atrophy. Most investigators have found evidence of a mitochondrial myopathy [13], including the presence of ragged red fibers, abnormal accumulation of glycogen and lipid, and the presence of abnormal mitochondria [9,10]. This may result from AZT-induced inhibition of mitochondrial DNA synthesis [9,14]. Mitochondrial myopathies may be associated with lactic acidosis.

Cytochrome C oxidase deficiency can be identified on muscle biopsy by special stain [15]. This finding may help further to distinguish AZT myopathy from HIV myopathy.

Treatment : If AZT myopathy is suspected clinically or evidence of a mitochondrial myopathy is found on muscle biopsy, the response to discontinuing the drug should be determined. Muscle enzymes and strength generally return to normal one to two months after the drug is discontinued in patients with AZT myopathy . If there is partial or no response to discontinuing the drug, it is likely that HIV myopathy is present.

Nonsteroidal antiinflammatory drugs may help to relieve myalgias pending the response to cessation of AZT . There is in-vitro evidence that administration of carnitine may both prevent the development of AZT myopathy, and prevent progression with continued AZT administration . The clinical efficacy of this approach remains to be determined.

2',3'-dideoxyinosine (ddI) and 2',3'-dideoxycytidine (ddC) appear to be safe alternatives in those patients whose myopathy improves after discontinuing AZT, but who require antiretroviral therapy for their underlying HIV infection .

MUSCLE INFECTIONS – Pyomyositis due to pyogenic bacteria has been reported in patients with HIV infection [19]. While these infections may sometimes cause diagnostic confusion with HIV or AZT myopathies, skeletal muscle involvement is usually more focal with infections, and localized muscle tenderness and swelling are more prominent findings than true muscle weakness.

Toxoplasmosis – Muscle infection with toxoplasmosis may present more similarly to HIV and AZT myopathies than to other muscle infections (show table 1) [20]. Diffuse muscle wasting, weakness, and tenderness commonly occur, often in association with central nervous system toxoplasmosis. Muscle enzymes are usually elevated.

Muscle biopsy shows necrosis and a variable degree of inflammation, usually with more neutrophils present than in idiopathic PM or HIV myopathy. The presence of intracellular cysts containing T. gondii organisms establishes the diagnosis. Toxoplasma serology may be positive.

Since toxoplasmosis infection of muscle responds to appropriate antibiotic therapy, it is important to consider this diagnosis in HIV-infected patients presenting with myopathy. Such patients typically have disseminated toxoplasmosis and may have involvement of the central nervous system. The combination of pyrimethamine and sulfadiazine is the regimen of choice for treatment of extrapulmonary toxoplasmosis. A 200 mg loading dose of pyrimethamine is given initially and is followed by 50 to 75 mg/day, while sulfadiazine is given at 4 to 6 grams/day. Leucovorin (10 to 20 mg/day) is usually given to reduce the hematologic toxicity of these drugs. Clindamycin (at a dose of 600 mg every six hours) can be used in combination with pyrimethamine in patients with sulfa intolerance. Side effects of these drugs are common (show table 2).

OTHER MUSCLE DISORDERS – Several other muscle disorders may be seen in association with HIV infection.

Rhabdomyolysis : Rhabdomyolysis is a syndrome of extensive muscle necrosis associated with myoglobinuria and acute renal failure. It has numerous causes in the non-HIV infected patient including trauma and crush injuries, seizures, alcohol or cocaine abuse, viral myositis, drug-induced myositis, pyomyositis, inherited metabolic myopathies, and electrolyte abnormalities (such as hypokalemia and hypophosphatemia).

Rhabdomyolysis may be seen in HIV infected patients in a variety of circumstances . A review of 20 reported cases found that rhabdomyolysis occurred at all stages of HIV infection, and could be classified into three groups with roughly equal frequency :

1. HIV-associated rhabdomyolysis, including rhabdomyolysis associated with primary HIV infection, recurrent rhabdomyolysis, and isolated rhabdomyolysis

2. Rhabdomyolysis induced by drugs, including didanosine

3. Rhabdomyolysis at the end stage of AIDS, including opportunistic infections of muscle and rhabdomyolysis without a definite cause

In addition, seizures and electrolyte disturbances may precipitate rhabdomyolysis at any stage of disease.

Rhabdomyolysis due to drugs or infection are particularly important to recognize since removal of the offending drug and appropriate treatment of the infection may improve the prognosis of this disorder. Treatment is otherwise supportive.

Non-Hodgkin's lymphoma : Non-Hodgkin's lymphoma may present as a localized, painful muscle mass. This needs to be distinguished from other causes of localized limb swelling including pyomyositis, deep venous thrombosis, and Kaposi's sarcoma originating in skeletal muscle . Magnetic resonance imaging (MRI) may help to distinguish infectious causes of localized muscle swelling from neoplasms; the finding of a hyperintense ring around the mass on T1-weighted images favors pyomyositis, while prominent involvement of subcutaneous tissue favors lymphoma or Kaposi's sarcoma .

Myasthenia gravis : Myasthenia gravis has been reported in a few patients with HIV infection . It is unclear whether this was a coincidence or an immunologically-mediated manifestation of HIV infection. Affected patients responded to anticholinesterase therapy, In most cases, the myasthenia was transient and improved in parallel with progressive immunodeficiency and declining CD4+ cell counts.

Nemaline (rod) myopathy – Nemaline (rod) myopathy is a rare disorder in adults without HIV infection, and there have been case reports in HIV-infected individuals [4,29,30]. These patients present with a slowly progressive proximal myopathy, mildly elevated serum CK concentrations, and a characteristic muscle biopsy showing abundant nemaline bodies or rod structures in atrophic fibers on electron microscopy. Inflammatory changes are either not present or are very mild. In some reported cases, there has been a response to corticosteroids in doses similar to those used for HIV myopathy .

There is a congenital form of nemaline myopathy, which is usually inherited as an autosomal recessive trait. The nemaline bodies are composed of proteins derived from the thin filament and Z disc. The primary defect in this disorder appears to be a mutation in the nebulin gene . The nebulin protein is found in the thin filaments of skeletal muscle.

An autosomal dominant form has also been described in which the defect is in the alpha-tropomyosin gene . The myopathy in this setting is associated with reduced calcium-induced sensitivity to contraction .