Neuromuscular and Myopathic Complications of HIV

Updated: Nov 01, 2016
  • Author: Erik Z Krause, DO; Chief Editor: Niranjan N Singh, MD, DM  more...
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Overview

Overview

HIV-infected patients are susceptible to a wide spectrum of HIV-associated neuromuscular and myopathic conditions. [1, 2, 3, 4, 5] Of course, patients also are susceptible to the same neuromuscular diseases as the general public (eg, carpal tunnel syndrome in an HIV-positive barber or computer operator). However, since the introduction of highly active antiretroviral therapy (HAART), HIV-associated neurologic complications have decreased markedly.

Neuromuscular conditions associated with HIV infection include the following:

  • Acute or chronic inflammatory demyelinating polyradiculoneuropathy
  • Distal, symmetric, often painful, and predominantly sensory polyneuropathy
  • Autonomic neuropathy (eg, erectile dysfunction)
  • Antiretroviral-associated (eg, zidovudine) neuropathy
  • Polyradiculopathy
  • HIV myopathy
  • Polymyositis and dermatomyositis
  • Inclusion body myositis
  • Nemaline (rod) myopathy
  • Pyomyositis
  • Neuropathies associated with diffuse infiltrative lymphocytosis syndrome (DILS)
  • Myopathy caused by local neoplasm
  • Myopathy caused by local infection
  • Myasthenic syndrome and chronic fatigue
  • Medication-induced myopathy (e.g., zidovudine)
  • HIV wasting syndrome

Asymptomatic elevations in CK, myaglias, and rhabdomyolysis are all possible complications of HIV. Particular types of myopathies reflect the clinical status of the patient and the stage of HIV disease. [6] For example, nonspecific myalgias occur as part of the flulike illness during seroconversion. Treated patients may develop inflammatory myopathy related to immune restoration or drug-induced muscle involvement. HIV wasting syndrome and opportunistic muscle infections are encountered in untreated patients with advanced disease.

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Pathophysiology

HIV induces muscle fibers to express major histocompatibility complex–1 (MHC-1) on their surface, triggering T cell–mediated muscle fiber injury. Other relevant pathophysiologic mechanisms include the following:

  • Nutritional deficits (eg, vitamin B-12) can be secondary to enteropathies and malabsorption caused by intestinal HIV, cytomegalovirus (CMV) infection, or herpes simplex virus infection [5]
  • Zidovudine is associated with myopathy
  • Didanosine, zalcitabine, indinavir, ritonavir, saquinavir, and stavudine can cause polyneuropathy, possibly in part due to mitochondrial toxicity and in a dose-dependent fashion [7, 8]
  • Autoimmune mechanisms result in inflammatory demyelinating neuropathies, mononeuropathy multiplex, polymyositis, and myasthenic syndrome
  • Co-infection with CMV, herpes simplex virus, varicella-zoster virus, Mycobacterium avium complex, Treponema pallidum, and other bacteria can cause neuromuscular complications [9]

The likelihood of a particular syndrome correlates with viral load and CD4+ lymphocyte counts. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barré syndrome) and isolated acute cranial nerve palsies are common at seroconversion. Distal symmetric, often painful sensorimotor polyneuropathy and CMV infection are more common in the late stages of AIDS.

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may be the initial manifestation of disease, related to autoimmune dysfunction. AIDP has also been associated with immune reconstitution illnesses after initiation of highly active antiretroviral therapy (HAART). [10] The cerebrospinal fluid shows pleocytosis and increased protein. Nerve conduction studies and biopsy findings are compatible with demyelination.

Distal symmetric polyneuropathy (DSP) is the most common neurologic complication of HIV. This most often presents with pain, numbness, and/or paresthesias in a symmetric and distal fashion. Although this is commonly due to primary HIV, antiretroviral therapy can cause toxic neuropathy. [11]

Mononeuropathy multiplex is an inflammatory response in the early stages of disease. Late mononeuropathy multiplex is typically associated with CMV infection; it may appear as inflammatory demyelinating polyradiculoneuropathy or progressive polyradiculopathy. Electromyography (EMG) and nerve conduction studies show axonal degeneration and asymmetric involvement. CSF shows pleocytosis and an elevated protein level.

Progressive polyradiculopathy is typically associated with CMV and other herpesvirus infections. HAART has reduced the incidence of progressive polyradiculopathy. CSF shows pleocytosis and elevated protein level. It typically presents with a cauda equina–like picture, and EMG shows denervation of the lower extremities. Nerve conduction studies are mildly slow.

Autonomic neuropathy usually presents as sexual dysfunction, diarrhea, orthostatic hypotension, and bladder dysfunction. It can be related to medication effects.

HIV muscle wasting syndrome is associated with elevated levels of proinflammatory cytokines produced by macrophages and induced by HIV, including cachectin/tumor necrosis factor–alpha (which may interfere with lipid metabolism in muscle) and interleukin-1 beta. Other potential mediators include growth hormone, deficiency of testosterone and insulin-like growth factor I, and excess myostatin. [12, 13]

Diffuse infiltrative lymphocytosis syndrome (DILS) is an uncommon complication of HIV infection characterized by persistent CD8 hyperlymphocytosis and multivisceral CD8+ T-cell infiltration. DILS most often involves the lungs and the salivary glands (particularly the parotid glands) but may also affect the GI tract, kidneys, and nerves. This can often mimic Sjogren's Syndrome. Patients may present with peripheral nervous system (PNS) manifestations, including multifocal or symmetric, acute or subacute neuropathy. Rarely, DILS is associated with myositis. [14]

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Epidemiology

It is estimated that more than 50% of patients with advanced HIV have evidence of distal symmetric polyneuropathy. [11]

According to some studies, up to 25% of AIDS patients suffer from a myopathic disease. In one study, mild inflammation, type II fiber atrophy, or evidence of denervation was detected in more than half of asymptomatic, untreated HIV-seropositive patients without weakness. In another study, myalgias were present in 8% of patients treated with zidovudine (AZT). Other estimates of the frequency of AZT myopathy reach 17%. [4]

HIV wasting syndrome prevalence is estimated to be between 14–38%. [15]

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Detection and Differentiation

Although certain neuromuscular complications of HIV, such as distal symmetric polyneuropathy, have decreased since the advent of highly active antiretroviral therapy (HAART), HIV-1–associated neuromuscular complications are still clinically apparent in more than 30% of patients. [16] Neuropathies are much more common in adults than in the pediatric HIV population.

These disorders can be clinically silent, and many additional neuromuscular abnormalities are detected by electromyography, nerve conduction studies, biopsy, or autopsy. In one study, inflammatory changes, type II fiber atrophy, or denervation were detected in more than half of asymptomatic HIV-seropositive patients without weakness. In another report of untreated patients with mild muscle wasting, inflammation and fiber necrosis were found in one third of patients, type II atrophy in more than one half, and denervation in more than three fourths.

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Prognosis

The prognosis and best course of treatment are not well established. The largest case series of HIV-associated polymyositis (n=13) indicated that more than half of those treated with corticosteroids attained complete remission and were able to discontinue therapy after a mean of 9 months. The remainder of the patients improved over months to years. [17] This result has not been duplicated further. Overall, the response to these immunomodulators remains modest.

Prognosis also depends on the general condition of the patient and on the stage of HIV infection. Early diagnosis and treatment are important.

Improvement of zidovudine (AZT) myopathy begins several months after dose reduction or discontinuation. Recovery may be incomplete, however.

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Clinical Presentation

The following may be evident in early HIV infection:

  • Nemaline rod myopathy - Slowly progressive weakness and wasting, negative family history, possibly autoimmune
  • Immune-mediated polymyositis and dermatomyositis - Similar presentation as in non-HIV patients; usually generalized symptoms, occasionally focal; polymyositis also possible as part of highly active antiretroviral therapy (HAART)–associated immune reconstitution syndrome

The following may be evident in early or late HIV infection:

  • Zidovudine (AZT) myopathy - Fatigue; proximal muscle pain, weakness, and atrophy; seen especially after a lifetime dose greater than 200 g
  • Rhabdomyolysis - Same as in non-HIV population; caused by didanosine, other drugs, intercurrent illnesses (eg, cytomegalovirus [CMV] infection), or possibly HIV itself; at times associated with seroconversion
  • Myasthenic syndrome–myasthenia gravis - Reported occasionally; manifests as fluctuating weakness improving with immunosuppression
  • Diffuse infiltrative lymphocytosis syndrome - Parotid gland enlargement, multiorgan infiltration, polyneuropathy, and polymyositis; occurs predominantly in middle-aged African-American men

The following may be evident in late HIV infection:

  • Myopathy caused by local infection - Focal or multifocal painful swollen muscles, fever; sepsis, fluctuance, and destruction of involved muscles in late stages
  • Myopathy caused by local neoplasm – Painful swollen muscles, low-grade fever, HIV wasting syndrome (painless proximal weakness and atrophy in the setting of significant weight loss, diarrhea, and fever)

Some HIV-1 associated neuromuscular complications, such as CMV polyradiculopathy, are often rapidly progressive and quickly lead to death unless expeditiously treated. Although its clinical and cerebrospinal fluid patterns are fairly typical, the clinician must be careful not to ascribe progression of pain and weakness to a chronic painful distal neuropathy without evaluating other causes by electromyogram/nerve conduction study (EMG/NCS) and CSF analysis. Failure to do so may be seen as a deviation from standard medical care.

Laboratory studies depend on the type of neuromuscular complication that is suspected. Typically, the workup includes serum laboratory testing, CSF examination, EMG/NCSs, and possible nerve and/or muscle biopsy.

HIV RNA and/or virus have been detected in nerve and dorsal root ganglia. Infected cells include satellite and mononuclear cells and occasional dorsal root ganglion neurons. In the skin, epidermal nerve fiber densities are reduced in symptomatic and asymptomatic distal HIV polyneuropathy compared with controls. [18, 19]

Myopathy produces proximal weakness and is confirmed with EMG. Elevated creatine kinase (CK) may also be seen, and muscle biopsy can be helpful, demonstrating necrosis and inflammation. HIV-related myopathy must be differentiated from toxin-related (zidovudine) myopathies.

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Differential Diagnosis

The differential diagnosis of HIV-associated myopathies includes the following:

Other problems to be considered include hereditary adult-onset myopathies, viral myositis, deep venous thrombosis, rhabdomyolysis caused by severe illness, and non-Hodgkin lymphoma.

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Diagnostic Testing

The workup in HIV-infected patients with myopathies includes measurement of serum creatine kinase (CK), electromyography (EMG), and nerve conduction studies (NCS). Assays of other muscle enzymes (e.g., aldolase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase) may also show elevations. Muscle biopsy may be required to distinguish different etiologies and guide treatment.

Blood cultures are occasionally positive in pyomyositis. Needle aspiration may be diagnostic in pyomyositis.

Minor salivary gland biopsy and gallium-67 (67 Ga) scintigraphy may provide major diagnostic help when diffuse infiltrative lymphocytosis syndrome (DILS) is suspected.

Radiologic studies (eg, CT, MRI with contrast,67 Ga scan, ultrasound) are helpful when pyomyositis is suggested. MRI may distinguish infectious and neoplastic myopathies: with infection, no changes are evident in subcutaneous tissue; with lymphoma and Kaposi sarcoma, cutaneous and subcutaneous involvement can be seen.

Creatine kinase

Serum creatine kinase levels vary with different myopathies, as follows:

  • Polymyositis and dermatomyositis - Normal or high
  • Inclusion body myositis - High
  • Zidovudine (AZT) myopathy and rhabdomyolysis - High
  • HIV wasting syndrome - Normal
  • Infectious or neoplastic focal myopathy - Normal or high

Electromyography and nerve conduction studies

Electromyography and nerve conduction studies may indicate the following:

  • Myopathic (brief, low-amplitude, polyphasic) motor unit potentials, increased insertional activity and spontaneous activity
  • Positive sharp waves
  • Fibrillation potentials
  • Often associated neuropathic features

Muscle biopsy

Muscle biopsy permits histologic differentiation of various clinical phenotypes and identification of causative infectious agents by staining and culture. HIV rarely is identified by in situ hybridization or electron microscopy in infiltrating inflammatory cells and never in muscle fibers.

Several types of pathology may coexist (eg, polymyositis, AZT myopathy):

  • Polymyositis - Fiber necrosis, inflammatory infiltrates of CD8 + lymphocytes and macrophages
  • Inclusion body myositis - red-rimmed vacuoles, endomysial T-cell infiltrates (CD8+ cells and macrophages), cytoplasm inclusions, atrophic fibers, and amyloid deposits
  • AZT myopathy - Myopathic changes, dose-dependent numbers of ragged red fibers, cytochrome C oxidase-negative fibers, rods, lipid and glycogen accumulation, inflammatory infiltrates, paracrystalline mitochondrial inclusions, decreased numbers of mitochondria (reversible over several months, if AZT administration is stopped)
  • Nemaline rod myopathy - Muscle fiber necrosis, variable inflammation, red-blue cytoplasmic structures in small type I fibers best observed in Gomori trichrome stain
  • Neoplastic myopathy - Evidence of lymphoma or Kaposi sarcoma
  • Infectious myopathy - Histologic evidence for the responsible organism, frank pus, or positive cultures; necrotic or degenerating fibers; inflammatory infiltrates
  • Diffuse infiltrative lymphocytosis syndrome - Histologic confirmation of CD8 + T-cell infiltration; presence of thin intranuclear inclusion helps distinguish DILS-associated myositis from polymyositis
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Treatment of Steroid-Responsive Myopathies

Treatment varies with the type of myopathy.

Polymyositis and dermatomyositis

Polymyositis and dermatomyositis improve with steroids. Pulsed IV methylprednisolone is preferable to long-term oral prednisone to minimize immunosuppression.

Other steroid-responsive myopathies

Patients with nemaline myopathy have responded to steroid therapy.

Myasthenic syndrome is treated similar to myasthenia gravis, with steroids, intravenous immunoglobulin G, pyridostigmine, and HAART.

Corticosteroids are effective in treating life-threatening manifestations of diffuse infiltrative lymphocytosis syndrome, including rapidly progressive neuromuscular complications. Intravenous immunoglobulin may also be helpful. [14]

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Treatment of Antiretroviral Myopathies

In zidovudine (AZT) myopathy, discontinue AZT or decrease the dose and begin an alternative drug. Muscle enzymes and strength return to normal 1-2 months after the drug is discontinued. Carnitine (1500 mg orally, twice daily) has been shown to prevent development of AZT myopathy and impede its progression when the condition is already present. [4, 20]

The mainstay of treatment for myopathy from other nucleoside reverse transcriptase inhibitors (NRTIs), such as didanosine-induced rhabdomyolysis, is to discontinue the probable causative agent, and perhaps substitute an alternative NRTI. [8]

Stavudine, uncommonly used in developed countries, has been found to cause HIV-Associated Neuromuscular Weakness Syndrome (HANWS), which can present similarly to Guillain-Barre Syndrome with associated lactic acidosis, lipoatrophy, nausea, and hepatomegaly. [21]

Raltegravir has been reported as causing CK elevation and muscle symptoms in treated patients. For this reason, it is reasonable to monitor patients receiving raltegravir, especially when co-administered with atazanavir. [22]

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Treatment of Infectious Myopathies

A 3-drug regimen (rifabutin, clarithromycin, ethambutol) is the treatment of choice for Mycobacterium aviumcomplex myopathy. The treatment is suppressive and not curative, and as a result it must be continued for life. An alternative 4-drug regimen consists of rifampicin, clofazimine, ciprofloxacin, and ethambutol. In the situation of a relapse that is not caused by noncompliance or insufficient dosing, clarithromycin alone or combined with pyrimethamine,sulfadiazine, and minocycline may be used. [23]

In treating cytomegalovirus (CMV) myopathy, either ganciclovir or foscarnet is recommended. [24] Use a ganciclovir-foscarnet combination in cases of prior therapy. Prompt initiation of antiviral treatment is essential. The goal of antivirals for CMV myositis is to shorten the clinical course, to prevent complications and the development of latency and/or subsequent recurrence, and to decrease transmission and established latency. [23]

Use the combination of pyrimethamine/sulfadiazine to treat toxoplasma myopathy. To prevent bone marrow suppression, folinic acid is recommended. Treatment often continues for life; however, discontinuation of secondary prophylaxis is a reasonable consideration in asymptomatic patients who have had a sustained increase in their CD4+ T-cell counts of greater than 200 cells/μL. [13]

Empiric antimicrobial therapy should cover all likely pathogens in the clinical setting. Antibiotic combinations are recommended to prevent the emergence of resistant strains and to provide an additive or synergistic effect.

Folic acid derivatives are used to rescue cells from the deleterious effects of folate antagonists.

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Treatment of HIV Wasting Syndrome

Pharmacologic treatments for HIV wasting syndrome include recombinant human growth hormone, testosterone, and anabolic steroids (eg, nandrolone decanoate). [25] Recombinant human growth hormone, which is approved by the US Food and Drug Administration (FDA) for this indication, may offer advantages in terms of improved functional capacity and quality of life.

Progressive resistance exercise training appears to be just as effective as anabolic steroids. [12] Nutritional supplementation is also a potential treatment. [13]

Appetite stimulants such as megestrol acetate or dronabinol may be helpful. Dronabinol has been shown to be a well-tolerated appetite stimulant. Thalidomide has also been shown to be effective via cytokine production modulation. [26, 15]

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