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Peripheral Neuropathy in HIV Disease

Neurologic disorders are among the most common and devastating complications of HIV infection and AIDS.¹ As patients with HIV infection survive longer in the era of HAART, it is likely that the prevalence of these disorders will increase. Peripheral nerve disorders are the most common neurologic complication of HIV disease.² HIV-related peripheral nerve disorders include distal symmetric polyneuropathy (DSP), acute or chronic inflammatory demyelinating polyneuropathy (IDP), mononeuritis multiplex (MM), progressive polyradiculopathy (PP), and autonomic neuropathy (AN). Data from ACTG protocol 175 indicate that neuropathy is frequently misdiagnosed, even by experienced clinicians.³ In order to provide effective treatment, it is essential to distinguish among the various forms of neuropathy and to correctly attribute them to primary HIV infection or to other causes, such as the neurotoxic effects of antiviral agents. Although peripheral neuropathy is generally not a life-threatening disease, the debilitating pain can severely impair the quality of life of affected individuals. Of particular importance is distal sensory polyneuropathy (DSP), the most common form of peripheral neuropathy and the only one associated with the use of antiretroviral therapy.

Distal Symmetric Polyneuropathy

DSP affects over one third of patients with AIDS. It is rarely seen in children and is most common in the late stages of HIV disease. The clinical symptoms of DSP are numbness, burning, and tingling sensations in the feet, usually in a symmetric pattern; paresthesias or aching distally in the lower extremities; and hyperesthesia (e.g., contact sensitivity, such as with bedsheets or socks). Individuals with DSP may alter their gait in order to avoid painful pressure on their feet, which can result from even light contact. In late stages of DSP, the upper extremities may also be affected, although to a milder degree.

Neurologic examination reveals depressed or absent ankle reflexes relative to the knees. While this is a hallmark of DSP, it is important to note that as HIV disease progresses, DSP is often combined with central nervous system disease, such as dementia or myelopathy. In this case, reflex testing may reveal hyperactive or brisk knee reflexes with normal ankle reflexes. Other clinical features of DSP include increased vibratory thresholds and reduced pinprick and temperature sensation in a stocking and glove distribution. Muscle strength and joint position sensation are relatively normal. Symptomatic weakness appears late in the disease and is generally restricted to the distal intrinsic foot muscles. Nerve conduction studies can be useful to confirm the diagnosis of DSP by revealing abnormal sensory nerve potential amplitudes and conduction velocity, especially of the sural nerve.

Other Causes of DSP

It is critical to differentiate HIV-related DSP from DSP resulting from other causes, such as diabetes mellitus, vitamin B₁₂ deficiency, alcohol abuse, or drug toxicities (e.g., vincristine, used to treat Kaposi's sarcoma and lymphoma; isoniazid; and thalidomide, used to treat aphthous ulcers).⁴

Although the pathogenesis of DSP is unclear, the condition is associated with deterioration of the patient's immune system. A primary viral etiology is unlikely, since HIV does not infect peripheral nerve Schwann cells or axons.⁵ The similarities in clinical and pathologic findings of HIV-associated DSP and vitamin B₁₂ deficiency-related peripheral neuropathy have led some investigators to propose vitamin B₁₂ deficiency as a possible pathogenic mechanism in HIV-associated DSP.⁶ Mounting evidence suggests that cytokines (e.g., tumor necrosis factor-alpha, interleukin-1) may be involved in DSP by inhibiting nerve growth factor.⁷

Differentiating HIV-Related DSP from Neurotoxic Neuropathy

The major antiretroviral neurotoxins are the dideoxynucleoside analogues didanosine (ddI), zalcitabine (ddC), and stavudine (d4T). Patients with a prior history of neuropathy from HIV infection or other causes are more susceptible to the peripheral nerve toxicity of these agents. The clinical features of nucleoside-related DSP and DSP resulting from primary HIV infection are so similar as to be virtually indistinguishable on bedside examination. Simpson et al. reported that the prevalence of HIV-associated neuropathy increases as immune function deteriorates.⁸ This relationship suggests that a patient presenting with high CD4 counts may not be suffering from HIV-associated DSP alone, but also from neurotoxicity or other underlying conditions.

When a patient with DSP is receiving a known neurotoxin, drug withdrawal or dose reduction should be considered. In ACTG protocol 175, Simpson et al. found that the treatment regimen most often associated with DSP was AZT + ddC, with an incidence of 6%.³ This incidence was significantly higher than that of the other treatment arms (AZT, ddI, AZT + ddI). Fifty-four percent of patients with DSP continued the study drug at a full or reduced dose after developing neuropathy. In 42 of the 50 subjects evaluated, the neuropathy returned to minimal (grade 1) or resolved. Therefore, it is often possible to "treat through" DSP with ddC, particularly if the viral load is under control.

In neurotoxic DSP, the standard time to resolution of neuropathy after discontinuation of the neurotoxin is at least eight weeks. Many patients improve within one to three weeks following discontinuation of ddC, but resolution of DSP may also take considerably longer: Berger et al. found that patients taking higher doses of ddC (e.g., 0.06 mg/kg/ day) experienced a "coasting period" of three to six months following withdrawal of the drug, during which time the symptoms of neuropathy intensified before improving.⁹

A maximum ddI dosage of 12.5 mg/ kg/day has been suggested to avoid the development of DSP. Immunosuppressed patients with low CD4 cell counts may develop ddI-associated neuropathy at lower doses, though.⁸ Reversible neuropathy related to ddI was reported in 23% of patients who received nearly double the standard dose of ddI and were followed for at least 10 months.¹⁰ Once neuropathic symptoms had resolved, most patients tolerated ddI rechallenge at half-dose. Thus, ddI therapy appears to exert a dose-limiting effect on DSP.

Pollard et al. found that the incidence of peripheral neuropathy was reduced when dideoxynucleosides were introduced earlier in the course of HIV disease.¹¹ The incidence of DSP was 15% at a 20-mg twice daily dose of d4T and 21% at a 40-mg twice daily dose.12 In a randomized, double-blind protocol, d4T (40 mg twice daily) was added to continued AZT therapy (600 mg/day) in 822 HIV patients. At the one-year follow-up, 12% of patients in the d4T + AZT treatment arm had developed neuropathy, compared to 6% in the AZT group.¹² After discontinuation of d4T, peripheral neuropathy resolved in most patients, and 63% were successfully rechallenged.

Treatment of DSP

Until recently, the treatment of HIV-associated DSP has primarily been symptomatic. Correcting metabolic and nutritional abnormalities may be helpful in managing DSP. Pain management should be individualized. 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 may provide added benefit. Amitriptyline may be started at 10 to 25 mg at bedtime and increased by 25 mg increments on a weekly basis to a maximum of 100 to 150 mg. Dose-limiting side effects include manifestations of anticholinergic toxicity: dry mouth, sedation, orthostatic hypotension, and urinary hesitancy. If these side effects persist and limit dose escalation, a tricyclic antidepressant with a lower anticholinergic profile may be used (e.g., nortriptyline or desipramine). However, a controlled study of amitriptyline and mexiletine showed no significant benefit over placebo in ACTG protocol 242.¹³

Anticonvulsants such as phenytoin, carbamazepine, and gabapentin may also provide relief from pain. Lamotrigine, a novel anticonvulsant, is the first agent shown to have significant efficacy in reducing pain in HIV-associated neuropathy. In a small, controlled trial, we found that lamotrigine was significantly more effective than placebo in reducing pain in HIV-associated neuropathy.¹⁴ The most frequently reported side effect of lamotrigine in this study was rash. It is important to note that lamotrigine doses should be increased slowly and in small increments, to minimize the potential for rash.

Plasmapheresis has been ineffective in reducing symptoms of DSP in several patients.¹⁵ Topical capsaicin may reduce the pain of DSP, although reports on its efficacy have varied.¹⁶ When increasing levels of disabling pain are refractory to the above-mentioned agents, a strong opioid or long-lasting opioid agonist (e.g., methadone or long-acting morphine or fentanyl) may be considered.¹⁶

Experimental Treatments for DSP

Peptide T proved ineffective in relieving painful DSP in our blinded, placebo-controlled study.¹⁷ Peptide T was also ineffective in producing clinical or electrophysiologic improvement. Recombinant human nerve growth factor (rhNGF), a trophic factor expressed in peripheral nerves, is a pathogenesis-based investigational treatment for DSP. Apfel et al. reported preclinical animal studies in which rhNGF prevented the toxic neuropathy of cisplatinum and taxol.¹⁸ In 1996 these investigators compared rhNGF with placebo in a phase II study of diabetic neuropathy treatments. The study revealed that rhNGF was significantly better than placebo in terms of several quantitative measures of neuropathy, including cooling detection thresholds, heat-pain thresholds, and lower limb neuropathy impairment scores.¹⁹ In the recent ACTG protocol 291, rhNGF was significantly better than placebo in relieving pain in HIV-associated DSP. However, secondary measures of neuropathy, including most clinical examination scores, quantitative sensory testing, and epidermal nerve fiber density, were not significantly different between treatment arms. Adverse events recorded in this study included local hyperalgesia at the injection site, which compromised the blinding of the study.²⁰

Lidoderm (5% lidocaine gel) is another experimental agent in the treatment of DSP-related pain. In a small open-label trial we found that Lidoderm was well tolerated and effective in reducing pain.²¹ A multicenter, double-blind, placebo-controlled study of Lidoderm in the treatment of painful HIV-associated DSP is currently underway. Trials of prouridine and acetyl carnitine are also planned.

Inflammatory Demyelinating Polyneuropathy

IDP is a relatively infrequent neuropathic complication of HIV infection seen most often in patients who are HIV seropositive but otherwise asymptomatic. The acute form (AIDP) may occur at the time of primary HIV infection.¹⁵ AIDP is clinically characterized by rapidly progressive muscle weakness involving two or more extremities, accompanied by generalized areflexia. Bilateral peripheral facial nerve weakness may be present.²² The chronic form (CIDP) is clinically distinguished by its slower progression; its clinical course may be monophasic or relapsing. Autoimmune mechanisms are probably involved in the pathogenesis of IDP.

Cerebrospinal fluid (CSF) analysis is important in the diagnosis of HIV-associated IDP. The majority of HIV-infected patients have a CSF lymphocytic pleocytosis (10 to 50 cells/mm³), with mild elevation of protein. This finding serves to distinguish them from HIV-negative IDP patients, whose CSF is typically acellular.²³ Electrophysiologic studies reveal evidence of acquired demyelination in patients with IDP.

IDP is primarily treated by immunomodulation (corticosteroids, plasmapheresis, high-dose intravenous immunoglobulin). In severely compromised patients (CD4 count less than 50 cells/mm³), anti-cytomegalovirus (CMV) therapy with ganciclovir, foscarnet, or cidofovir, singly or in combination, is warranted,²⁴ particularly when supportive diagnostic data for CMV neurologic infection are present (see below).

Mononeuritis Multiplex

Multifocal sensory and motor abnormalities in the distribution of cutaneous nerves, mixed nerves, and nerve roots, including cranial neuropathies, constitute the typical neurologic presentation of MM.¹⁵ MM associated with CD4 counts greater than 200 cells/mm³ generally has a limited distribution and is characterized by the acute onset of sensory or motor deficits limited to one or a few peripheral or cranial nerves.²⁵ These deficits usually resolve spontaneously or within several months of receiving immunomodulating therapy.¹⁵ Patients with advanced immunodepression develop an extensive and more rapidly progressive form of MM, which may simulate other peripheral neuropathies, such as IDP or progressive polyradiculopathy.²⁶ In the extensive form of MM, specific diagnostic data may be provided by PCR for CMV DNA in the CSF. Anti-CMV therapy with ganciclovir, foscarnet, or cidofovir, singly or in combination, is the recommended treatment.

Progressive Polyradiculopathy

PP is characterized clinically by radiating pain and paresthesias in the cauda equina distribution, followed by rapidly progressive flaccid paraparesis, mild sensory loss, lower extremity areflexia, and sphincter dysfunction.²⁷ PP is usually a direct result of CMV infection and is accompanied by widespread denervation of lower extremity and lumbar paraspinal muscles.26 The CSF is characterized by marked polymorphonuclear pleocytosis, elevated protein, hypoglycorrhachia, and positive PCR assay for CMV. The treatment of choice is an anti-CMV regimen as described above.

Autonomic Neuropathy

Failure of the sympathetic autonomic nervous system is manifested by orthostatic hypotension, syncope, diarrhea, and anhidrosis. Parasympathetic abnormalities include resting tachycardia, impotence, and urinary dysfunction.²⁸ A variety of factors may contribute to the clinical manifestations of autonomic dysfunction, including malnutrition, dehydration, central and peripheral nervous system abnormalities, and drugs used to treat HIV-associated complications, such as tricyclic antidepressants, vincristine, and pentamidine.²⁹

Conclusion

Distal sensory polyneuropathy is the most common neurologic disorder in individuals infected with HIV. Although distinguishing nucleoside analogue-related peripheral neuropathy from primary HIV neuropathy may be difficult, accurate diagnosis and early treatment are crucial and may significantly affect quality of life in these patients. While the search for the pathogenesis of DSP is ongoing, several treatment options are available, including reducing or discontinuing neurotoxic agents and using analgesics, anticonvulsants, and several experimental agents. Further research is necessary to confirm preliminary findings in order to advance our understanding and provide effective treatments for this debilitating disease.

— Yeraz Markarian, Enrique A. Wulff, MD, and David M. Simpson, MD

Ms. Markarian is Research Coordinator for the Neuro-AIDS Research Program at New York's Mt. Sinai. Dr. Wulff is a Fellow in the Mt. Sinai Neuro-AIDS Research Program. Dr. Simpson is Associate Professor of Neurology, Director of the Clinical Neurophysiology Laboratories, and Director of the Neuro-AIDS Research Program at the same institution.

Published in Journal Watch HIV/AIDS Clinical Care December 1, 1998

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