HIV1Related Myopathies

Muscle disorders related to HIV-1 infection include HIV-1-associated polymyositis, ZDV toxic myopathy, pyomyositis or infectious myopathy, cardiomyopathy, and the so-called wasting syndrome myopathy. Of these conditions, HIV-1-associated polymyositis and toxic myopathy related to ZDV are the most common. Distinguishing between these two forms of myopathy at times may be difficult.

Pathogenesis and Pathophysiology. The pathophysiological mechanisms underlying HIV-related myopathy are uncertain. A wide spectrum of histopathological findings has been described including inflammatory infiltrates W y?] noninflammatory myofiber degeneration,^1 nemaline rod bodies,^] , [158| cytoplasmic bodies, and mitochondrial abnormalities. [160 Muscle biopsy examination usually shows characteristic myopathic features such as variation in fiber size or degenerating muscle fibers. Features of polymyositis (necrotic fibers and lymphocytic infiltrates in the perimysium and perivascular space) are also noted in some patients, although the degree of these changes is variable. Wi1 In a subset of patients, gomori trichrome-stained sections of muscle show prominent abnormalities of mitochondria giving the appearance of ragged-red fibers.[162] [163] [164] In other subsets of patients, electron microscopy examination shows granular material that appears as electron-dense rod bodies.[158] Variable amounts of inflammatory infiltrates have been described in both of these types.

Before the widespread use of ZDV, overt myopathy or a polymyositis-like syndrome was reported but not frequently. With increasing use of ZDV, and especially at the initially high 1200 mg/d dosage, reports of myopathy in ZDV-treated patients and those who improved following ZDV withdrawal appeared in the literature. [164] ^aa] Studies showed ZDV to be an inhibitor of the gamma-polymerase of the mitochondrial matrix, W1 and ZDV toxicity in skeletal muscle mitochondria was demonstrated in some[160 , [163] , [165] , [168| [169] ^70 but not all studies. ,

Investigators have suggested that muscle changes may be due to the virus, the length of time of the patient's infection, and length of time taking ZDV. Whether there are pathological features that distinguish between HIV-1- and ZDV-related myopathies remains uncertain. , yd , , [171] One clinical study of HIV-related myopathy conducted in unselected patients of all disease stages found that none of the patients taking ZDV had symptomatic myopathy thought to be related to ZDV. However, some patients had characteristic ZDV morphological changes on muscle biopsy. The clinical relevance of the structural changes

described earlier, the causal role of ZDV, and thus, the pathogenesis of HIV-related myopathy remain unclear and the subject of controversy.

HIV-1 has been localized in infiltrating monocyte/macrophage cells by immunocytochemistry. Myofibers do not appear to be directly infected. [158] This suggests that it is unlikely that HIV-1 has a direct role in myopathy. As in other forms of polymyositis (see Cha.p.te,r..5.0 ), immunemediated mechanisms are proposed. It is postulated that activated macrophages secrete toxic factors (cytokine hypothesis) that mediate myofiber damage. Tumor necrosis factor, which causes cachexia in laboratory animals, produced mainly by monocytes is also implicated as is interleukin-1 alpha (shown to accumulate in muscle fibers of HIV- infected patients). HIV-1-infected CD8+ cells produce cytokines that expose muscle fiber antigens against which there is no self-tolerance. It has also been suggested that homology between viral GAG protein and muscle ribonucleoproteins triggers an autoimmune process leading to cellular infiltration and myofiber damage. W

Epidemiology and Risk Factors. Risk factors are not yet clearly defined. One study of 50 unselected patients in all stages of HIV-1 infection found that 26 percent of patients had myopathy. An autopsy series reported myopathic changes in 26 percent of AIDS cases. W A retrospective analysis of patients enrolled in an antiretroviral clinical trial showed a 0.4 percent incidence of myopathy in patients not treated with ZDV (placebo group), which rose to 3 percent in ZDV-treated patients (D. Simpson, personal communication). HIV-associated myopathy may develop in patients in all stages of HIV-1 infection and does not appear to be associated with degree of immunosuppression.^

Clinical Features and Associated Disorders. Muscle weakness is the predominant sign and symptom.^1 , W1 Patients present with slowly progressive symmetrical and predominantly proximal weakness of the upper and lower limbs. Patients have difficulty arising from a chair or climbing stairs. Myalgia is present in 25 to 50 percent of affected patients. Neurological examinations reveal symmetrical weakness of proximal muscle groups with prominent involvement of neck and hip flexors. HIV-1-associated polymyositis can occur at any stage of HIV-1 infection. Presentation is similar to sporadic polymyositis with proximal muscle weakness, myalgias, and elevated CK.

There are no clinical features that differentiate HIV from ZDV myopathy. ZDV myopathy usually occurs after at least several months of therapy and there appears to be a dose and duration effect. Although some patients may improve after ZDV withdrawal (resolution of muscle pain and a slower recovery of strength), ^J , [165| others do not.[162| To add further confusion, ZDV rechallenge in some patients does not cause a relapse.

Differential Diagnosis. Other myopathic complications of HIV-1 infection include wasting syndrome and infectious myopathies. Patients with advanced HIV-1 disease frequently develop a wasting syndrome (Slim's disease) consisting of fatigue, profound involuntary weight loss, and diffuse weakness. Affected individuals are cachectic, weak, and have a general loss of muscle bulk. The frequent finding of the wasting syndrome in persons with severe HIV-1 infection makes it difficult to delineate a myopathic component. Although a myopathy can also cause a wasting syndrome characterized by involuntary weight loss and chronic muscle weakness,^ at times it is difficult to distinguish between the two. HIV-1-associated myopathy can occur at any stage of HIV-1 infection. Thus, if myopathy develops in early HIV-1 infection before other AIDS-defining illnesses and immunosuppression, the diagnosis of HIV-related myopathy is likely if systemic or nutritional factors have been excluded and criteria for a diagnosis of myopathy are met. The importance of determining a specific diagnosis of myopathy in patients is evidenced by some patients' improvement with prednisone therapy. [175]

Infectious causes of myopathy in patients with AIDS, although infrequent, should be considered in the differential diagnosis. Pathogens reported in muscles of AIDS patients include Toxoplasma gondii,[176] CMV, Microsporidia, Cryptococcus neoformans, Mycobacterium avium-intracellulare, and Staphylococcus aureus. W

HIV-infected individuals may present with acute rhabdomyolysis characterized by a myopathic syndrome (myalagia, muscle weakness) associated with serum CK levels greater than 1,500 IU/L. The cause of acute rhabdomyolysis in HIV-1 disease is unknown, although investigators have suggested several etiologies including HIV-1 itself, drug toxicity (e.g., ddI, sulfadiazine, pentamidine), and opportunistic infections. [177]

Evaluation. The diagnosis of myopathy is made by the presence of limb weakness with CK elevation, supportive electrodiagnostic and muscle biopsy studies. As in the diagnosis of polymyositis (non-HIV-1 related), if three of four features are present, the diagnosis is considered probable, and if two of four features are present, the diagnosis is possible (see Chapter.50 ). Electrophysiological studies show typical myopathic EMG features (small, brief, and polyphasic motor unit potentials that recruit with full interference patterns and fibrillation potentials. [162| Some patients also have NCV abnormalities indicative of coincident DSP. W1

In HIV myopathy, CK levels are usually elevated to a moderate degree, with a median level of approximately 500 IU/L. , ^a?1 ^J The CK elevation parallels the degree of myonecrosis observed in coincident muscle biopsies but does not seem to correlate with weakness and is not a specific marker of HIV myopathy (patients may have elevated CK without clinical features of myopathy).

Muscle biopsy is useful in the evaluation and management of patients. Some investigators propose that the histological finding of ragged-red fibers supports the diagnosis ZDV myopathy.^ , [iesJ However, not all ZDV patients with myopathy have ragged-red fibers on biopsy; thus, the absence of the finding does not exclude a toxic myopathy.

Management. Because it is often difficult to distinguish patients with ZDV-related myopathy from those without, the initial management of patients with significant limb weakness and objective evidence of myopathy includes ZDV withdrawal. An 18 to 100 percent rate of improvement in muscle strength is reported from different series.'^ , 'mi , [i7i] Some patients show further deterioration or no improvement after cessation of ZDV but do respond to treatment with corticosteroids. Thus, if signs and symptoms persist after ZDV withdrawal (about 1 month), a muscle biopsy should be considered. If there are signs of inflammation,

a trial of steroids is warranted. Prednisone may be effective in treatment of polymyositis or rod-body myopathy. '157] , '162]

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