AIDS and AIDS-treatment NeuropathiesDerek Williams, R-PA, Anthony Geraci, MD, and David M. Simpson, MD

AddressNeuro-AIDS Research Program, Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1052, New York, NY 10029, USA. E-mail: Anthony.Geraci@mssm.eduCurrent Neurology and Neuroscience Reports 2001, 1:533–538Current Science Inc. ISSN 1528-4042Copyright © 2001 by Current Science Inc.

IntroductionThe face of AIDS is changing. The life expectancy ofindividuals infected with HIV has increased dramatically dueto a better understanding of HIV infection, which in turn hasled to advances in medications used to treat HIV and associ-ated opportunistic infections. Along with increased survival,there has been a decrease in the incidence of some neuro-logic complications of HIV infection. In the era of highlyactive antiretroviral therapy (HAART), there has been adecline in the incidence of neurologic diseases, such as AIDSdementia, toxoplasmosis, and cytomegalovirus (CMV)infections. [1,2]. Evidence that HAART improves bothneurocognitive and sensory nerve function in HIV-infectedpatients is encouraging [3••,4], and provides a rationale forfuture studies on the nervous system effects of aggressiveantiretroviral therapy.

The neuromuscular complications of HIV are common(Table 1) [5]. The most common peripheral nerve disorderis distal symmetrical polyneuropathy (DSP), which occursin over 30% of patients with AIDS [6,7•]. AsymptomaticDSP (signs of peripheral nerve dysfunction withoutsubjective pain) may occur in more than half of patientswith less advanced disease [8], and can be demonstrated byabnormal nerve conduction studies (NCS) [7•]. Currentanti-HIV therapies incorporating nucleoside analogue

derivatives have well documented dose-dependent toxicities,including DSP [9]. The relative benefit versus toxicity ofthese medications when used for aggressive HIV viralsuppression in those predisposed to developing symp-tomatic DSP is currently a subject of investigation.

Clinical Presentation and DiagnosisThe cardinal feature of DSP is pain. Classically, patientspresent with symmetrical paresthesias, dysthesias, anddistal numbness in the lower extremities. In advanced DSP,there may be similar symptoms in the upper extremities, aswell as weakness of distal intrinsic muscle groups [10].Symptoms usually have an insidious onset, except whenDSP is related to antiretroviral drugs, in which case thesymptoms may appear more rapidly [11]. The pain of DSPis often described as burning, and patients may complainof hypersensitivity in their feet. Often, the degree of painreported by the patient is disproportionate to objectivefindings on neurologic examination. The patient may havean antalgic gait and be unable to tolerate even light contactwith clothing or bedsheets. Wearing socks or shoesincreases their discomfort.

Neurologic examination demonstrates decreased orabsent ankle reflexes, elevated vibratory threshold, andreduction in pin sensation or hyperalgesia in a stockingand glove distribution. There may also be a decrease inpain and temperature sensation, but joint proprioceptionis typically relatively normal [10]. Depressed or absentankle reflexes are the most common sign of DSP [6,7•],and may be the only sign of neuropathy. Relatively normalankle reflexes, together with hyperactive knee reflexes,might indicate coexisting myelopathy, particularly whenextensor plantar responses are present.

The diagnosis of DSP is usually straightforward and canbe made based on signs and symptoms in conjunctionwith a comprehensive history and neurologic examination.Marra et al. [8] demonstrated that trained nonphysicianclinicians, such as physician assistants and nurse practit-ioners, can diagnose DSP with a sensitivity that is compa-rable to a neurologist’s examination. Confirmation of DSPcan be made by nerve conduction studies (NCS).

The primary pathologic feature of DSP is axonal degen-eration, as evidenced by a disproportionate loss of largemyelinated fibers of both sensory and motor nerves.[7•,12,13] There is a percentage of patients with DSP,however, who have normal NCS, as well as those withoutclinical signs and symptoms of DSP with abnormal NCS.

AIDS and AIDS-treatment neuropathies are common in individuals infected with HIV. As patients live longer due to improved antiretroviral therapies, the impact of painful neuropathy on patients’ lives may increase. Several anti-retroviral medications are known to cause toxic neuro-pathy in AIDS patients, but this may be outweighed by the beneficial effects of viral suppression. Current theories on the pathogenesis of AIDS neuropathies include mitochondrial toxicity secondary to γ-DNA polymerase inhibition and subsequent abnormal mitochondrial DNA synthesis. Treatment of AIDS neuropathies is directed toward relief of symptoms, however, new evidence suggests that aggressive antiretroviral therapy may also be effective.

534 Infection

Tagliati et al. [7•] documented that 12 of 63 patients(19%) with clinical DSP had normal results of NCS, and26 of 103 patients (25%) without clinical DSP had abnor-mal results. A negative exam in the presence of clinicaldisease could be a result of an abnormality of small nervefibers [3••,7•], which are not examined by conventionalNCS. The most common NCS abnormality seen in patientswith DSP is reduced or absent sural nerve action potentials[7•]. In spite of the predominance of sensory complaints,motor fibers are usually affected as well. Generally, how-ever, motor nerve conduction velocities are only mildlyreduced in relation to the reduction in amplitude [14].NCS of the upper extremities may reveal reduced sensoryand motor amplitudes of the median or ulnar nerves.F-wave and H-reflex latencies may be prolonged [7•]. Diag-nostic modalities, such as quantitative sensory testing andpunch skin biopsy, are generally reserved for the researchsetting [15,16]. Invasive studies, such as sural nerve biopsy,are rarely necessary in diagnosing DSP, but may be helpfulin complicated cases with atypical features. The electro-physiologic abnormalities in drug-induced and HIV-related DSP are indistinguishable [17].

In an ongoing attempt to develop more sensitive screen-ing examinations for DSP, some investigators have employedother tests or combinations of standard tests. Bouhassira etal. [18] compared quantitative sensory testing (QST) withestablished electrodiagnostic studies, such as NCS. Theyfound that in NCS-confirmed painful and nonpainful DSP,QST revealed increases in thermal and mechanical thresh-olds, as well as pain thresholds. They concluded that QST canbe helpful in detecting sensory alterations in patients withpainful neuropathies, which might prove useful in quantify-ing DSP clinically, and for following the effects of treatmentson neuropathic pain [18].

PathophysiologySeveral observations support multifactorial etiologies forthe development and severity of DSP. Tagliati et al. [7•]

reported that increased age and advanced HIV infection, asreflected by reduced CD4 lymphocyte counts, are associ-ated with DSP. Low hemoglobin levels also correlated withDSP in that study, likely as a surrogate for advanced diseaseand a relatively debilitated state. Plasma HIV RNA is animportant predictor of neurologic outcomes. Individualswith plasma HIV RNA levels greater than 10,000 copies/mLhave a 2.3-fold greater hazard of sensory neuropathy thanthose with less than 500 copies/mL [19••]. Accordingly,aggressive antiretroviral therapy and suppression of plasmaHIV-1 viral burden improves sensory function in HIV-infected patients, as measured by quantitative sensorytesting [3••]. There are no data corroborating thisobservation or to indicate whether effective antiretroviraltherapy leads to clinical improvement in DSP. Although thespecific pathogenesis of this neuropathy has not yet beendelineated, it has been linked to the use of nucleoside ana-logue reverse transcriptase inhibitors (NRTI) [9,17,20•].Commonly referred to as d-drugs, didanosine (ddI),zalcitabine (ddC), and stavudine (d4T) are the NRTIs mostimplicated in DSP. Combinations of these medicationswith each other or with hydroxyurea [9,20•] and with othermedications used to treat HIV-related conditions, such asisoniazid (INH) [21], vincristine [22], and thalidomide[23], are also known to cause DSP. Putative contributingfactors to the development of neuropathy include acetyl-cartinine and vitamin B12 deficiencies [5,24], and neuro-toxicity caused by cytokines [25].

Antiretroviral Agents and Mitochondrial ToxicityDistal symmetrical polyneuropathy related to nucleosideanalogue toxicity is dose-dependent [26]. The dideoxynucle-oside analogues ddI, ddC, and d4T produce well-recognizedperipheral neurotoxicity (Table 2) [9]. Peripheral neuropathywas first described in patients receiving ddC [27] and isclinically and electrophysiologically similar to HIV-relatedperipheral neuropathy. It has been theorized that the neuro-toxin is actually unmasking an existing, silent peripheralneuropathy. Clinical and electrophysiologic abnormalitiesare similar to those in HIV-related neuropathy and indicatedistal axonopathy [7•,17,27]. Stavudine may also causeperipheral neurotoxicity. In a study of 36 patients taking amaximum d4T dose of 2 mg/kg/d, 20 (55%) developeddose-limiting peripheral neuropathy with identical featuresto ddC- and ddI-induced neuropathy [28].

The occurrence of dideoxynucleoside toxic neuropathyis related to both daily and cumulative dosage [17], andappears to be most frequent with ddC. In a clinical trialcomparing four different treatment regimens (ZDV alone,ddI alone, ZDV plus ddI, ZDV plus ddC), the 6% incidenceof HIV-related neuropathy was highest in the ZDV plusddC arm [29]. Risk factors for dideoxynucleoside toxicneuropathy include a previous history of neuropathy, olderage, poor nutrition, and more advanced HIV disease

Table 1. Neuromuscular complications ofHIV infection

NeuropathyCommon

Distal symmetrical polyneuropathyHIV-relatedNucleoside analogue-related

Less commonInflammatory polyneuropathy

Chronic inflammatory demyelinating polyneuropathyNeuropathy due to opportunistic infections

Progressive polyradiculopathy (cytomegalovirus)Mononeuritis multiplex (cytomegalovirus, hepatitis C)

MyopathyHIV? Nucleoside analogue-related

AIDS and AIDS-treatment Neuropathies • Williams et al. 535

[7•,30]. Based on data from the Moore Clinic at JohnsHopkins University, the risk of dideoxynucleoside toxicneuropathy is additive or even synergistic for regimenscontaining ddI plus d4T combination when comparedwith ddI or d4T alone [20•]. We anticipate that as combi-nation dideoxynucleoside therapy is employed morewidely and for longer periods, the incidence of drug-induced neuropathy will probably rise in patients withadvanced HIV disease [20•].

Nucleoside analogue-related neuropathy may be due, inpart, to their effects on mitochondrial DNA synthesis[27,31,32]. There are several mechanisms by which NRTIsare believed to interfere with mitochondrial DNA synthesis.These may be linked by the fact that they provide analternative substrate for mitochondrial γ-DNA polymerasebecause they are derivatives of the endogenous nucleosides:adenosine, guanosine, thymidine, and cytidine [31]. The fivemajor human cellular DNA polymerases are alpha (α), beta(β), delta (δ), epsilon (ε), and gamma (γ). Only γ-DNApolymerase is located in mitochondria, whereas the othersreside in the nucleus [31]. Inhibition of γ-DNA polymeraseactivity would be expected to result in mitochondrial(mt)DNA depletion. However, although inhibition of γ-DNA polymerase occurs with nucleoside analogue use, tis-sue-specific effects are not well understood [33], and thereare no data that establish an association of mitochondrialdysfunction with peripheral neuropathy in patients takingthese medications. Brinkman et al. [34•] have hypothesizedthat mitochondrial toxicity due to nucleoside analoguereverse transcriptase inhibitors is, in part, responsible forantiretroviral-related lipodystrophy. This syndrome bearsresemblance to multiple symmetrical lipomatosis, whichincludes peripheral neuropathy as a prominent feature.

Several investigators have demonstrated point mutationsand multiple or single mtDNA deletions in this disorder andother inherited mitochondrial diseases, leading to impairedcytochrome C oxidase function [35]. This in turn leads toimpaired oxidative phosphorylation, anaerobic glycolysis,and formation of lactate. Other theories on the causes ofmitochondrial toxicity include the development of oxygen-free radicals that damage deoxyguanosine [36], involvementof the other DNA nucleosides [32], and mitochondrial-induced apoptosis [31,37].

HydroxyureaHydroxyurea is an antimetabolite that is used for salvagetherapy in patients failing multiple antiretroviral regimens.When this agent is added to nucleoside analogue therapy,the incidence of peripheral neuropathy is increased [38].When combined with didanosine and/or stavudine,hydroxyurea increases the risk of DSP by several-fold [39].The combination of ddI plus d4T also increases the risk ofneuropathy, but not to the same extent as when hydrox-yurea is added [20•,38]. It is thought that hydroxyureasupports the integration of ddI, and possibly also d4T, intothe mitochondrial matrix, thereby increasing the neurotox-icity of the latter two medications [20•].

Plasma HIV Viral Load and CD4+ Cell CountThere is increasing evidence that elevated plasma-HIV RNAlevels may be a risk factor for the development of DSP[3••,19••]. In a retrospective review of 1604 AIDS-freeHIV-positive men from the Multicenter AIDS CohortStudy, Childs et al. [19••] showed that as HIV viral loadincreased, so too did the incidence of sensory neuropathy,and that individuals with viral loads greater than 10,000copies/mL had a greater than twofold increased hazard forDSP [19••]. There was also a trend for increased neuro-pathy risk by over 100% in men with CD4+ counts of lessthan 750 cells/mm3, but the relationship was much weakerthan for plasma HIV viral load.

TreatmentCurrently, there are no treatment modalities that reversethe pathology of HIV-associated DSP. The management ofpolyneuropathy in patients infected with HIV focuses onrelief of pain [40], therefore, therapy is aimed largely atsymptom reduction. To this end, management of DSPemploys various pain-relieving modalities that includemedications to directly control the pain and approachesdirected at the source of the pain. Additionally, as notedabove, HAART is effective in improving nerve function inDSP [3••] and decreasing the incidence of DSP [19••],even when neurotoxic drugs are part of the regimen.The most recent debate in this area centers on the questionof the utility of antiretroviral therapy for HIV RNA

Table 2. Nucleoside analogue-related neuropathy

AgentDideoxynucleoside analogues

StavudineDidanosineZalcitabineSynergistic effect from hydroxyurea

DiagnosisImprovement after withdrawal of offending drug? Elevated serum lactate levels

TreatmentNonsteroidal

anti-inflammatory agentsVariable dose, depending

on agentAcetominophen 500–1000 mg every 4 to 6 hAmitriptyline Up to 150 mg/d, at bedtimeCarbamazepine 200–400 mg three times dailyPhenytoin 100 mg three times dailyGabapentin 300–1200 mg three times dailyLamotrigine 200–250 mg twice dailyTopical analgesics

Lidoderm patch, ointment As neededNarcotic analgesics

Percocet, morphine, fentanyl Variable dose

536 Infection

suppression at the expense of neurotoxicity. Data from theAIDS Clinical Trials Group (ACTG) 291 study of recombi-nant human nerve growth factor indicates that in a cohortof 236 patients, suppression of plasma HIV RNA by nucle-oside analogue drugs resulted in lower maximum and glo-bal pain scores [41]. These data suggest that virologiccontrol might outweigh the potential for dideoxynucleo-side toxicity. Prospective studies are needed to furtherassess this hypothesis.

Discontinuation of neurotoxic agentsAs a first step, metabolic causes of neuropathy, such asunderlying diabetes mellitus, vitamin B12 deficiency, andother forms of neuropathy seen in HIV disease, should beidentified and corrected where possible. Identification andtreatment of alcohol abuse is imperative. Next, consider-ation should be given to neurotoxic medications such asddI, ddC, and d4T as a cause of DSP, and a trial of dosereduction or discontinuation of the offending agent(s)may be beneficial. If the decision is made to stopa nucleoside analogue medication, the clinician andpatient should be aware that it may take 4 to 8 weeks forsymptoms to subside, and during this time the pain mayactually increase. This is referred to as the "coasting period"[17]. In some instances, resolution of pain may take aslong as 16 weeks. Only about two thirds of patients willimprove with antiretroviral drug discontinuation [42].

All patients on nucleoside analogue drug therapy forHIV should be assessed frequently for signs or symptomsof DSP, as this complication may be most easily reversedwhen it is diagnosed early [8]. DSP can often be preventedby modifying the drug dose or by changing to less neuro-toxic antiretroviral agents [42].

AnalgesicsAnalgesics are commonly prescribed for the treatment ofDSP. Clinicians might follow the step-wise recommenda-tions of the World Health Organization for the manage-ment of chronic pain [43]. Some patients with mildsymptoms may respond to nonsteroidal anti-inflammatorydrugs or acetaminophen [9]. For refractory pain, treatmentwith topical lidocaine or capsaicin 0.075% may be benefi-cial. A 5% lidocaine patch (Lidoderm; ENDO Pharmaceu-ticals, Chadds Ford, PA) was recently approved by the Foodand Drug Administration for treatment of postherpeticneuralgia, and it has also shown efficacy in treating DSP-related pain [44]. In a small, open-label study of 30patients with DSP, application of either a 5% lidocainepatch or lidocaine gel applied directly to painful sites dem-onstrated that this medication was effective in providingpain relief [44]. Although use of a topical anestheticappears to be safe in treating the pain due to DSP, it willnot be useful in patients for whom pain is not a primarysymptom. Analysis of data from a larger, double-blind,placebo-controlled study is underway. Ultimately, some

patients with DSP may be in such severe and debilitatingpain that narcotic analgesia is required to provide relief.

Adjuvant therapySeveral medications with putative effects on nervemembranes have been investigated for the treatment ofDSP. Tricyclic antidepressants, such as amitriptyline ordesipramine, at doses of up to 150 mg/d can be used. Theantiarrhythmic drug, mexilitine, was investigated due to itsinhibitory effects on sodium conductance at the axonalmembrane. However, neither amitriptyline nor mexilitinewere superior to placebo in a placebo-controlled, double-blind trial [45]. Anticonvulsants, such as phenytoin andcarbamazepine, reduce neuropathic pain in patients withdiabetic neuropathy, and anecdotal experience suggeststhat they may also be effective in the treatment of DSP.Oxcarbazepine, the dihydroketo analogue of carbam-azepine, potentially has a better pharmacokinetic profile inpatients with HIV infection who are taking antiretroviralswith extensive hepatic metabolism. Oxcarbazepine has noautoinduction and low protein binding (Novartis Pharma-ceuticals, unpublished data). Clinical trials to assess theefficacy of this drug are being planned. Lamotrigine andgabapentin are newer anticonvulsants that show promisein the treatment of DSP. Gabapentin is an attractivetherapy for painful neuropathy due to its favorablepharmacokinetic profile and sparse drug-drug interactions.Reports of its effectiveness in AIDS-associated DSP areanecdotal [46], but it has been used successfully in otherneuropathic conditions, particularly diabetes [47].

Lamotrigine, however, appears to be more effective intreating DSP-related pain, as demonstrated in a pilot studyby Simpson et al. [48]. The most common side effectreported from this study was the occurrence of an allergicrash, which resulted in premature discontinuation of studydrug in 25% of patients [10,48]. We have recently concludeda large, multicenter, double-blind, placebo-controlled studyof lamotrigine. In this study, the drug was gradually intro-duced over an 8-week period until a dose of 400 mg/d wasattained. Although the data collected in this study iscurrently being analyzed, it is believed that lamotrigine willbe better tolerated when introduced gradually [10].

Recombinant human nerve growth factorRecombinant human nerve growth factor (rhNGF) hasbeen investigated as a therapy that might reverse or arrestthe neuropathic changes of DSP. Ample laboratory dataand studies of animal models point to rhNGF as apotential treatment for peripheral neuropathy, in particu-lar diabetic and HIV-related neuropathies [49].

In a placebo-controlled ACTG study of 270 patientswith painful HIV neuropathy, subcutaneously administeredrhNGF improved Gracely Pain Scale scores and sensitivityto pinprick. However, in that study, most secondarymeasures of nerve regeneration, including quantitative

AIDS and AIDS-treatment Neuropathies • Williams et al. 537

sensory tests and epidermal skin biopsies, did not improve[50]. In spite of these encouraging results, future develop-ment of rhNGF is uncertain, because phase III studies ofrhNGF in diabetic neuropathy were negative.

Other therapiesSmall studies of capsaicin for painful HIV neuropathy havebeen generally unsuccessful [51]. A more recent study byPaice et al. [52] concluded that capsaicin is ineffective, as itshowed no significant differences in pain relief, sensoryperception, quality of life, or mood [52]. Acupuncture hasshown no significant difference in effectiveness in HIV-associated painful DSP, as compared with sham acupunc-ture points, which were used as placebo [53].

ConclusionsDistal symmetrical polyneuropathy is a frequent neuro-logic complication of HIV infection. Recent advances inantiretroviral therapy have led to an increasingly large poolof individuals who are surviving long enough to become atincreased risk for neurologic complications, such as DSP.Additionally, neurotoxic medications, such as the dideoxy-nucleoside drugs that are widely used in combinations ofHAART regimens, increase the risk of development of pain-ful neuropathy. Current research focuses on identifyingindividuals most at risk for DSP while taking neurotoxicHAART regimens, and on mechanisms of mitochondrialinjury that can lead to neuronal damage.

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