Introduction

euromuscular disorders are the most frequent of the neurological complications that occur in association with HIV infection and AIDS (1) (2). However, these neuromuscular disorders are frequently misdiagnosed, particularly by non-neurological clinicians (3). Severe systemic disease or central nervous system (CNS) abnormalities may mask the symptoms and signs of peripheral neuropathy or myopathy. The type, frequency, and mechanisms of peripheral neuropathies in the human immunodeficiency virus (HIV) infection vary with the stage of immunosuppression (4) The use of certain antiretroviral agents, such as didanosine (ddI), zalcitabine (ddC) and stavudine (d4T) in acquired immunodeficiency syndrome (AIDS) may be limited by peripheral nervous system (PNS) side effects. We review the spectrum of neuromuscular manifestations associated with HIV-infection, neurotoxicity of antiretroviral agents, treatment strategies and clinical trials available for these complications.

Peripheral neuropathy

The Multicenter AIDS Cohort Study data indicate that peripheral neuropathy is the most common neurological disorder associated with HIV infection (2). The occurrence of different forms of peripheral neuropathy is related in part to the degree of immunosuppression. Inflammatory demyelinating polyneuropathy (IDP) may be the initial clinical manifestation occuring at the time of HIV seroconversion. The frequency of distal symmetrical polyneuropathy (DSP) increases with decline in CD4 lymphocyte count and clinical progression to AIDS (4). In severely immunosuppressed patients (CD4 lymphocyte count <50 cells/mL), cytomegalovirus (CMV) may directly infect peripheral nerves, presenting as progressive polyradiculopathy (PP) or mononeuropathy multiplex (MM).

(1) Distal symmetrical polyneuropathy

Clinical features:
Distal symmetrical polyneuropathy (DSP) may be clinically diagnosed in approximately 25%-30% of patients with AIDS (4)(5). The incidence and prevalence of DSP increases with the progressive immunosuppression that characterizes HIV-infection (4)(6)(7). It is important to differentiate DSP from other neuromuscular disorders associated with AIDS. Characteristic clinical symptoms of DSP include distal numbness, paresthesias and dysesthesias (painful, burning feet) generally beginning at the level of the toes and ascending to the feet, ankles and foreleg (8)(9). In advanced cases distal and symmetrical involvement of the upper extremities and muscle weakness may be observed. The most important neurological signs are depressed or absent ankle reflexes relative to the knees, increased vibratory thresholds at the toes and ankles, reduced pain and temperature sensation in a stocking and glove distribution, and relatively normal joint position sensation. Hyperactive knee reflexes in the presence of DSP may indicate concurrent AIDS-associated CNS dysfunction, such as myelopathy (9).

Pathogenesis:
The mechanism of AIDS-associated DSP is unknown. Numerous factors, including advanced age, nutritional status, chronic disease, low hemoglobin level, HIV itself, neurotoxic cytokines, HIV glycoprotein gp-120, and low CD4 counts, have been correlated with clinical and electrophysiological presence of peripheral nervous system (PNS) dysfunction (4)(10)(11). Several therapeutic agents, such as vincristine (12), isoniazid (13), and thalidomide (14) are neurotoxic. DSP is associated with use of the dideoxynucleotide analogues ddI, ddC, and d4T (15)(16). The dose-dependent neurotoxicity of these agents may be the result of interference with mitochondrial DNA synthesis, possibly associated with reduced levels of acetyl-carnitine (17). Patients with a previous history of neuropathy are more susceptible to the peripheral nerve toxicity of these agents.

Diagnosis:
The diagnosis of DSP can usually be established by an experienced clinician. Marra et al. have reported that a relatively simple screening and examination for neuropathy correlates with a neurologist's diagnosis (18). The diagnostic approach to patients with DSP includes: (1) a comprehensive history to exclude other potential causes of neuropathy including diabetes mellitus, alcoholism, neurotoxin exposure, hereditary factors, and vitamin deficiency; (2) neurological examination; (3) electrophysiology and (4) appropriate blood studies. Electrophysiological studies (i.e. nerve conduction tests, electromyography) are usually not necessary for the clinical diagnosis of DSP in most patients, but may be helpful in complex cases. The main electrophysiologic abnormalities of DSP are: (a) reduction in sensory nerve conduction velocity and amplitude, particularly of the sural nerve; (b) prolonged late response latencies; (c) active or chronic partial denervation with reinnervation in distal leg muscles, on needle electromyography (EMG) (4)(19)(20). These features are consistent with distal axonal sensory and motor polyneuropathy.

Treatment:
The clinical features of nucleoside-related DSP are indistinguishable from those of HIV-associated DSP. Drug withdrawal or dose reduction should be considered when a patient with neuropathy is receiving a neurotoxin. The time frame for resolution of neuropathic symptoms after discontinuation of the neurotoxin may be as long as 8-16 weeks (16). Following the withdrawal of a neurotoxic agent, there may be a "coasting period" lasting 4-8 weeks, during which time the symptoms of DSP intensify before improving. However, a cost-benefit analysis occasionally favors continuing treatment with a neurotoxic antiretroviral when virological control is optimal, particularly if there are limited options available for other antiretroviral agents. In this setting alternative treatments for DSP may be attempted.

The current treatment of DSP is suboptimal and is primarily symptomatic. The World Health Organization (WHO) has developed an "analgesic ladder" to guide clinicians in optimal pain management (21). The guidelines suggest that for patients with mild pain, one may begin with nonopioid analgesics, such as acetaminophen and nonsteroidal anti-inflammatory agents. With persistent and more disabling pain, adjuvant agents such as tricyclic antidepressants or anticonvulsants may provide added benefit. Increasing levels of pain call for a mild opioid combination (e.g. acetaminophen and codeine) with an adjuvant. For severe pain, a potent opioid or long-lasting opioid agonist (e.g. methadone, morphine or fentanyl) should be considered.

We have reported a small, placebo-controlled study indicating that the anticonvulsant lamotrigine was effective in the reduction of pain in AIDS neuropathy (22). Its primary dose-limiting side effect was rash. In order to minimize allergic rash, lamotrigine should be initiated at 25 mg/day, and escalated slowly over approximately 6 weeks to 300 mg/day. A larger controlled study of lamotrigine is under development in order to replicate these results.

Topical agents are often employed in the management of painful peripheral neuropathy. We have recently reported an open label trial indicating that Lidoderm® (5% topical lidocaine) is effective in reducing pain in AIDS neuropathy (23). The results of a placebo-controlled trial of this agent are under analysis. A controlled study of acupuncture in AIDS neuropathy did not demonstrate that this technique was effective in pain relief (24). Recombinant human nerve growth factor (rhNGF), a trophic factor expressed in peripheral nerve, is a pathogenesis-based investigational treatment for DSP. In a 270 patient trial (AIDS Clinical Trials Group 291), subcutaneously administered rhNGF was superior to placebo in the reduction of pain after 18 weeks of blinded treatment (25). While most secondary measures of neuropathy did not change in this relatively brief trial, results of a 70 week open label extension period are under analysis. A clinical trial with another pathogenesis-based agent, prouridine, is under development.

(2) Inflammatory Demyelinating Polyneuropathy

Clinical features:
Inflammatory demyelinating polyneuropathy (IDP) is an infrequent complication of HIV infection. It is clinically characterized by: (a) rapidly progressive muscle weakness involving two or more extremities, (b) generalized areflexia, (c) cranial nerve involvement (e.g. bilateral facial nerve paresis) (26). The acute form (AIDP) often occurs at the time of HIV seroconversion. The chronic form (CIDP) has a slower onset and gradual progression.

Pathogenesis:
The pathogenesis of IDP is unknown. Detection of anti-peripheral nerve myelin antibodies, at titers that parallel the course of illness, supports an autoimmune mechanism (27). In advanced immunosuppression (CD4 count <50 cells/mL), CMV may directly infect peripheral nerve, manifesting clinically as IDP (28).

Diagnosis:
Electrophysiological studies in IDP reveal evidence of acquired demyelination (e.g. conduction block) and axonal degeneration, usually more prominent in the chronic form of disease. Cerebrospinal fluid (CSF) contains a lymphocytic pleocytosis (10 to 50 cell/ml), compared with the typical acellular CSF of HIV-negative IDP, and an elevation of CSF protein (50 to 200 mg/dL).

Treatment:
IDP may respond to immunomodulation therapy, such as corticosteroids, plasmapheresis (29), and high-dose intravenous immunoglobulin. When diagnostic studies, such as polymerase chain reaction assay (PCR) of CSF or nerve biopsy, reveal evidence of CMV infection, therapy with ganciclovir, foscarnet, or cidofovir, singly or in combination, is recommended (30).

(3) Progressive polyradiculopathy

Clinical features:
Progressive polyradiculopathy (PP) occurs mainly in late stages of AIDS disease (31)(32). Patients with PP generally present with radiating pain and paresthesias in the cauda equina distribution, rapidly progressive flaccid paraparesis, lower extremity areflexia, mild sensory loss, and sphincter dysfunction, often manifesting as urinary retention. In certain occasions a thoracic sensory level is present, suggesting concurrent myelopathy (31).

Diagnosis:
The diagnosis of PP may be difficult, due to overlapping features of IDP, mononeuropathy multiplex and myelopathy. Electrophysiologic studies reveal widespread denervation in lower extremity and lumbar paraspinal muscles on needle EMG. CSF is characterized by the presence of marked polymorphonuclear pleocytosis, elevated protein, and hypoglycorrhachia. The diagnostic assay of choice is CSF PCR for CMV (30). Pathological studies indicate that HIV-related PP is usually a direct result of CMV infection. However, other causes such as neurosyphilis and lymphomatous meningitis may be responsible.

Treatment:
Case studies have reported that some patients with AIDS-associated PP respond to ganciclovir, foscarnet, and cidofovir singly or in combination (32). However, a controlled trial mounted to assess the efficacy of antiviral therapy in the treatment of CMV neurological disease associated with AIDS was halted due to limited accrual, resulting from declining frequency of CMV disease in the current era of highly active antiretroviral therapy.

(4) Mononeuropathy multiplex (MM)

Clinical features:
Patients with MM present with the acute onset of multifocal sensory or motor abnormalities in the distribution of cranial, mixed or cutaneous nerves (33)(34). The form of mononeuropathy multiplex (MM) that occurs in relatively immunocompetent patients (CD4 lymphocyte counts greater than 200 cells/ml) is probably mediated by immune mechanisms. It is usually self-limited or has good response to immunosuppresive therapy, such as corticosteroids (34). A more extensive and progressive form of MM occurs when CD4 lymphocyte counts drop to low levels. Late stage MM may involve numerous nerves in two or more extremities or multiple cranial nerves. CMV is the most likely pathogen in the late form of MM (35).

Diagnosis:
The diagnostic algorithm for MM is similar for that in PP. Nerve conduction and EMG studies reveal multifocal and asymmetric pathology of cranial, sensory and motor nerves with axonal or demyelinating pathology. CSF analysis, including PCR assay for CMV, and sural nerve biopsy may reveal evidence of primary CMV infection of peripheral nerve (36).

Treatment:
The treatment of MM caused by CMV is similar to that for PP as discussed above.

(5) Autonomic neuropathy

Clinical features:
Several studies indicate that autonomic dysfunction, while often subclinical, is common in HIV infection, particularly in late stages of disease (37). Parasympathetic autonomic nervous system manifestations include resting tachycardia, impotence, and urinary dysfunction. Sympathetic autonomic nervous system dysfunction is characterized by orthostatic hypotension, syncope, diarrhea, and anhidrosis.

Pathogenesis:
Multiple factors may be involved in the mechanism of autonomic dysfunction, including central and peripheral nervous system pathology, dehydration, malnutrition and drugs (e.g. vincristine, tricyclic antidepressants, and pentamidine).

Treatment:The primary treatment is supportive, including fluid management and control of cardiac arrythmias.

(6) Diffuse infiltrative lymphocytosis syndrome

Clinical features:
Diffuse infiltrative lymphocytosis syndrome (DILS) is an unusual complication of HIV infection. It is characterized by CD8 hyperlymphocytosis that may involve peripheral nerve (38). DILS neuropathy may present as: symmetric or asymmetric sensorimotor neuropathy, distal sensory neuropathy, mononeuritis multiplex, or demyelinating polyneuropathy.

Pathogenesis:
Host inflammatory responses to HIV infection are thought to account for peripheral nerve involvement in DILS (39).

Table 1 summarises the diagnosis, disease stage, clinical symptoms, neurological signs, standard therapy, and experimental therapy of all described peripheral neuropathies in HIV-infected patients.

Myopathy

The cardinal clinical feature of myopathy is symmetrical weakness of proximal muscle groups, with prominent involvement of neck and hip flexors on neurological examination (40). Myalgia is a nonspecific symptom in myopathy, particularly in HIV-infected patients (41). Elevated serum CPK levels assist in the diagnosis of myopathy, although this is neither a sensitive nor specific assay for diagnosis (3)(41). Needle EMG and muscle biopsy are more reliable diagnostic studies.

The pathogenesis of HIV myopathy is unknown. Different mechanisms have been proposed, including HIV or its component antigens (42), immune mechanisms (40), toxic effects from cytokines (i.e. tumor necrosis factor-alpha, interleukin-1) (43), zidovudine (AZT) toxicity (40)(44), and AIDS-related opportunistic agents (i.e. Toxoplasma gondii, CMV, Cryptococcus neoformans, Mycobacterium avium intracellulare, and Staphylococcus aureus). Several authors have reported mitochondrial abnormalities in AZT-associated myopathy (43)(44), although Morgello et al. have noted similar such changes in HIV myopathy without AZT therapy (45).

In patients with myopathy who receive AZT therapy, withdrawal of AZT may result in clinical improvement. However, in our experience, AZT withdrawal led to increased muscle strength in only about 25% of patients, suggesting that HIV rather than AZT is the principal cause of myopathy in the majority of patients (40). Prednisone appears to be safe and effective in the treatment of HIV-associated myopathy (46). Small case series have reported clinical response to several other immunomodulating agents including plasmapheresis and intravenous immunoglobulin.

Conclusions

While neuromuscular complications are not usually life threatening disorders in HIV-infected patients, they produce significant disabling symptoms in affected individuals. It is likely that in the current era of highly active antiretroviral therapy and prolonged life, the frequency of neurological disorders will increase. It is important that all clinicians caring for patients with HIV infection are familiar with the diagnosis and treatment of the associated neurological disorders. Currently available therapeutic agents, and those evolving from ongoing clinical trials, may provide significant improvement in the quality of life in these patients.

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