Epidemiology and clinical features of HIV-1 associated neuropathies

Journal of the Peripheral Nervous System 6:8–13 (2001)

© 2001 Peripheral Nerve Society, Inc.

8

Blackwell Science Publishers

SYMPOSIUM: HIV-PNS

Epidemiology and clinical features of HIV-1 associated neuropathies

Ashok Verma

Department of Neurology, University of Miami School of Medicine and Jackson Memorial Hospital, Miami, Florida

Abstract

Peripheral neuropathy is common in human immunodeficiency virus type-1(HIV-1) infection. Peripheral neuropathies complicate all stages of the HIV-1 disease andcause considerable morbidity and disability in HIV-1 infected individuals and acquired im-munodeficiency syndrome (AIDS) patients. Whereas symptomatic neuropathies occur inapproximately 10% to 15% of HIV-1-infected patients overall, pathologic evidence of pe-ripheral nerve involvement is present in virtually all end-stage AIDS patients. There are 6major clinical types of HIV-associated neuropathies that are regularly seen in large HIV-1clinics. Distal sensory polyneuropathy (DSP) is the most common among the HIV-1-asso-ciated neuropathies. DSP generally occurs in later stages of HIV-1 infection and it followsan indolent and protracted clinical course. The dominant clinical features in DSP includedistal pain, paresthesia and numbness in a typical length-dependent fashion with proximalto distal gradient. Whereas toxic neuropathies—secondary to certain antiretroviralagents—are clinically similar to DSP, their temporal relation to neurotoxic medicationhelps distinguish them from other HIV-1-associated neuropathies. DSP and toxic neuropa-thy may coexist in a single patient. Acute and chronic inflammatory demyelinating poly-radiculoneuropathies (AIDP and CIDP) produce global limb weakness. AIDP may occur atseroconversion and it can therefore be the initial manifestation of HIV-1 infection. CIDPgenerally occurs in the mid to late stages of HIV-1 infection. Progressive polyradiculopa-thy (PP) occurs in patients with advanced immunodeficiency and is generally caused bythe opportunist cytomegalovirus (CMV) infection. Mononeuropathy multiplex (MM) inearly stages of HIV-1 infection is immune mediated, whereas in advanced AIDS it iscaused by the CMV infection. Finally, subclinical autonomic nervous system involvementis common in all stages of HIV-1 infection. Because HIV-1-associated neuropathies are di-verse in their etiology and pathogenesis, a precise clinical diagnosis is required to formu-late a rational therapeutic intervention.

Key words:

HIV-1, AIDS, epidemiology, neuropathy

Introduction

In the beginning of the human immunodeficiencyvirus type-1 (HIV-1) epidemic in the 1980s, the peripheralnervous system involvement in HIV-1 infection was notwidely appreciated. But as the number of HIV-1 and ac-

quired immunodeficiency syndrome (AIDS) cases grew,it became clear that not only peripheral neuropathieswere common in HIV-1 infection, but they occurred in allstages of HIV-1 infection, from seroconversion throughterminal immunodeficiency. It also became known thatthe neuropathic complications in HIV-1 infection andAIDS occurred as a result of a variety of pathologic pro-cesses

(Griffin et al., 1994; Verma and Bradley, 2000)

(Table 1).

Address correspondence to:

Ashok Verma, M.D., D.M., AssistantProfessor of Neurology, Professional Arts Center, Suite 603, 1150NW 14th Street, Miami, FL 33136 USA. Tel: 305-243-7519; Fax:305-243-7525; E-mail: averma@ med.miami.edu

Verma Journal of the Peripheral Nervous System 6:8–13 (2001)

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The first report to concentrate on peripheral neu-ropathy appeared in 1985 with the recognition of dys-immune inflammatory polyneuropathy

(Lipkin et al.,1985).

Unlike early recognition of a variety of centralnervous system opportunistic and reactivated infec-tions in AIDS, it was not until 1986 that the truly oppor-tunistic infection—cytomegalovirus (CMV)—of the pe-ripheral nerve was documented

(Eidelberg et al., 1986).

As experience with the clinical neurological manifesta-tions of AIDS grew, a novel disorder representing director indirect effects of HIV-1 infection on peripheralnerves became recognized

(Bailey et al., 1988; de laMonte et al., 1988; Barohn et al., 1993).

This disorder,known as distal sensory polyneuropathy (DSP), eventu-ally was recognized to be the most common form ofHIV-1-associated neuropathy

(Parry et al., 1997; Wulffet al., 2000).

Finally, with widespread therapeutic useof nucleoside reverse transcriptase inhibitors (NRTIs),toxic neuropathies related to some of these agentswere added to the list

(Berger et al., 1993; Moore et al.,2000).

Peripheral nerve involvement has been detectedin 30%

(So et al., 1988)

to virtually 100 %

(Moore et al.,2000; Cornblath, 1988)

of individuals in late stages ofHIV-1 infection, depending on the method of detection.

Electrophysiological evidence of PNS involvementmay exist in persons with early asymptomatic HIV-1 in-fection

(Parry et al., 1997; Farizo et al, 1992).

In a retro-spective review of medical records of 7636 HIV-1-infectedasymptomatic patients with CD

4

cell counts

.

500/mm

3

,Farizo et al.

(1992)

noted symptomatic neuropathy in 2%of the cases. In a nationwide survey of neurological man-

ifestations of HIV-1 infection in Japan, clinically significantneuropathy was reported in 2.6% of the cases

(Naka-gawa et al., 1997)

. Such retrospective analyses and ca-sual surveys have obvious ascertainment problems; mildclinical and subclinical neuropathies remained unappre-ciated in these studies. In one careful screening neuro-logical examination, DSP was detected in 42 of 199HIV-1-infected individuals (21%) and, as expected, 30(71%) of these 42 patients had no major neuropathysymptoms

(Marra et al., 1998).

The incidence of peripheral neuropathy increasesas the CD

4

counts decrease and the immunodeficiencyprogresses. In one study of 798 HIV-1-positive men

(dela Monte et al., 1988)

, peripheral neuropathy was rarein early infection but occurred in 17% of those withAIDS. Gastaut et al.

(1989)

studied 56 patients with thefull spectra of HIV disease. On clinicophysiologic crite-ria, peripheral nerve involvement occurred in 89% andit was more frequent in the later stages of disease; itwas found in 2 of 5 asymptomatic carriers and in 100%of 29 AIDS cases. In another study

(Parry et al., 1997)

,the prevalence of peripheral neuropathy was 44% inHIV-1-infected population, subclinical neuropathy ac-counting for 56% of them. In a recent cross-sectionalstudy of HIV-1-infected pediatric population

(Araujo etal., 2000)

, clinical DSP was present in 34%. Similar highprevalence rates of autonomic nervous system dys-function have been reported in HIV-1 infection

(Gluck etal., 2000).

In one pathologic study

(de la Monte et al.,1988)

, 19 (95%) of 20 peripheral nerves examined in agroup of symptomatic HIV infection and AIDS casesshowed histopathologic changes of neuropathy. Themajor pathologic finding in sural nerve biopsies was areduction in the number of large myelinated fibers

(Moore et al., 2000).

Several clinical series have addressed the questionof the incidence of DSP, the most common form ofHIV-1-associated neuropathy. It has been reported in upto 35% to 44% of patients with AIDS

(So et al., 1988;Araujo et al., 2000; Gluck et al., 2000)

, but the preva-lence in the overall HIV-1-infected population is close to10%. Acute and chronic inflammatory demyelinatingpolyradiculoneuropathies (AIDP and CIDP) also occurwith increased frequency in HIV-1-seropositive individu-als

(Barohn et al., 1993; Wulff et al., 2000; Parry et al.,1997; Cornblath, 1988; Cornblath and McArthur, 1988;Fuller et al., 1989; Verma and Bradley, 2000).

The fre-quency of HIV-1-associated AIDP and CIDP is unknownbut is thought to be rare

(Fuller et al., 1989; Nakagawaet al., 1997; Wulff et al., 2000).

The impact of recently introduced highly activeantiretroviral therapy (HAART) on the epidemiology ofHIV-1-associated neuropathies has just begun to un-fold. Intuitively, if a high level of systemic retroviral load“drives” the initiation of HIV-1-associated neuropathy,

Table 1.

Classification of HIV-1 associated neuropathies

Early stages (immune dysregulation)Acute inflammatory demyelinating polyradiculoneuropathy

(AIDP)Chronic inflammatory demyelinating polyradiculoneuropathy

(CIDP)Vasculitic neuropathyBrachial plexopathyCranial mononeuropathyMultiple mononeuropathies

Mid and late stages (HIV-1-replication driven)Distal sensory polyneuropathyAutonomic neuropathy

Late stages (opportunistic infection, malignancy)CMV polyradiculopathyCMV mononeuropathy multiplexZosteric ganglionitisSyphilitic radiculopathyTuberculous polyradiculomyelitisLymphomatous polyradiculopathyNutritional neuropathy (vitamin B

12

, B

6

)AIDS-cachexia neuropathy

All stages (toxic neuropathy)Nucleoside reverse transcriptase inhibitors (ddI, ddC, d4T)Other drugs (vincristine, INH, ethambutol, thalidomide)

Source: Verma and Bradley, 2000


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effective viral suppression may reduce or delay the inci-dence of peripheral neuropathy

(Maschke et al., 2000).

Likewise, CMV-associated PP now appears to be onthe decline. On the other hand, it is also likely that theprevalence of at least some forms of neuropathy will in-crease as more effective therapy for HIV-1 suppressionand control of opportunistic infections lengthen survivalof the HIV-1-infected population. Additionally, many cur-rently available and increasingly used NRTIs, such as di-adanosine (ddI), zalcitabine (ddC) and stavudine (d4T),have inherent neurotoxin potential

(Fuller et al., 1989;Berger et al., 1993; Moore et al., 2000).

In one report

(Moyle and Sadler, 1998)

, the incidence of clinical neu-ropathy was found to significantly increase with NRTIuse and with more advanced HIV disease. The relativeincidence of toxic neuropathy appears to increase syn-ergistically with combination therapy utilizing multipledrugs with toxic potentiality and concomitant use of hy-droxyurea


In one carefully plannedstudy, the relative risk for neuropathy, compared withddI alone, was estimated to be 1.39 for d4T alone, 2.35for ddI and hydroxyurea, 3.50 for ddI and d4T, and 7.80for ddI, d4T and hydroxyurea


HIV-1-associated neuropathic syndromes

It is important to remember that HIV-1 disease mayaffect virtually every part of the nervous system. Multi-ple pathologies, therefore, may coexist at different lev-els of the neuraxis, and more than one pathology maysimultaneously, or in concert with, involve the samepart of the nervous system in the same patient. For ex-ample, HIV-1-associated neuropathy may exist, but mayremain undiagnosed in presence of AIDS dementia orHIV-1 myelopathy. DSP may coexist with toxic neuro-pathy or it may complicate the residual deficit fromAIDP. It is unclear whether the neuropathic effects inlatter situations are additive or synergistic, but early rec-ognition and appropriate therapeutic manipulation isclearly important in many of these complex situations.

Distal sensory polyneuropathy

This most common form of neuropathy occurs inmid to late stages of HIV-1 disease, when patients havemostly low CD

4

cell counts and often AIDS-defining ill-nesses. The clinical features in DSP are characteristic

(de la Monte et al., 1988; Barohn et al., 1993; Wulff etal., 2000; Parry et al., 1997; So et al., 1988; Araujo et al.,2000; Fuller et al., 1989; Verma and Bradley, 2000; Simp-son and Tagliati, 1997).

The neuropathic symptoms oc-cur in a characteristic length-dependent fashion with aproximal to distal gradient. Dysesthesias first appear inthe soles. Shortly thereafter, the dysesthetic sensation

gradually ascends and, when it reaches approximatelyto the mid-leg level, similar symptoms may begin at thefingertips. The symptoms can be painful and very dis-abling, even precluding the patient from walking. Thesoles may be tender to the touch and the patient’s gaitantalgic. Subjective and objective motor deficit is mini-mum and is generally confined to the intrinsic foot mus-cles. Ankle reflexes are absent or reduced. After initialprogression, the sensorimotor symptoms may plateauand cease to progress, but these patients may not sur-vive long enough because of their advanced immuno-deficiency status and AIDS-related illnesses.

Laboratory evaluation in DSP has been relativelyunrevealing. Spinal fluid is mostly acellular but proteinmay be slightly elevated in a small proportion of pa-tients. The presence of CSF pleocytosis should raisethe possibility of concurrent CNS infection. The electro-physiological findings show predominantly axonal neu-ropathy. Both sensory and motor axons are involved.

The major neuropathologic features in DSP includeloss of unmyelinated axons in the distal regions of sen-sory nerves and later Wallerian degeneration of the dis-tal myelinated fibers. Some degree of demyelinationand remyelination and epineurial perivascular lympho-cytic infiltration has also been reported

(Barohn et al.,1993).

Distal axonal degeneration may affect both cen-tral and peripheral projections of the dorsal ganglioncells. Selective gracile tract degeneration in upper thor-acic and cervical segments has been detected in DSPcases

(Cornblath and McArthur, 1988).

The pathogenesis of DSP is unknown. Direct HIV-1or other concurrent viral infection of the peripheralnerve and indirect nerve damage by cytokine cascade

(Shapshak et al., 1995)

, vitamin B

12

deficiency, AIDScachexia

(Wulff et al., 2000; Verma and Bradley, 2000;Simpson and Tagliati, 1997)

, or still other unknown fac-tors have been postulated in its etiopathogenesis. Be-cause the cause of this disorder is unknown, therehave been few targeted attempts at therapeutic inter-vention. There have been reports that antiretroviraltherapy may delay or improve this syndrome

(Childs etal., 1999)

, but this has not been systematically studiedin large series. The first step in the treatment of DSP,after metabolic and other causes of neuropathy havebeen excluded, is the consideration of withdrawal, ordose reduction, of neurotoxic NTRIs or other drugs. Be-cause neuropathic pain, rather than weakness, is themain feature in most DSP cases, an attempt should bemade to aggressively control the pain symptom. Anal-gesic drugs, pain-blocking agents (such as amitriptyline,carbamazepine, and selective serotonin reuptake inhibi-tors), mexiletine, gabapentin, lamotrigene, and topicalagents (such as capsaicin or lidocaine), alone or in com-binations, may greatly alleviate pain and functional dis-ability.


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Inflammatory demyelinating polyradiculoneuropathy

Both AIDP and CIDP occur with increased fre-quency in HIV-1 seropositive people

(Barohn et al.,1993; Wulff et al., 2000; Parry et al., 1997; Cornblath,1988; Moyle and Sadler, 1998; Simpson and Tagliati,1997; Snider et al., 1983).

AIDP occurs mostly at sero-conversion, soon thereafter, or in the early stage of in-fection, when patients are otherwise asymptomatic.CIDP generally occurs later, as the HIV-1 diseaseprogresses. CIDP may follow a progressive or exacer-bating clinical course. The etiology of HIV-1-associatedIDP is thought to be autoimmune. The clinical featuresof AIDP and CIDP are similar in patients with and with-out HIV-1 infection.

Whether AIDP and CIDP are part of the spectrumof a single disease or are different diseases is uncer-tain. However, AIDP and CIDP share many clinical andelectrophysiological features. In both these disorders,the motor deficit predominates; sensory symptoms arerelatively minor. Electrophysiology demonstrates slowconduction, delayed latencies and conduction blocks,suggesting a predominant demyelinating neuropathy.Variable degrees of superimposed axonal loss may co-exist. Spinal fluid protein in IDP is usually elevated. Alymphocytic pleocytosis of 10–50 cells/mm

3

is presentin most HIV-1-infected patients with IDP

(Snider et al.,1983)

, which serves to distinguish them from HIV-1-negative subjects. Pathologically, both disorders showsimilar features, primarily perivenular lymphocytic infil-trates and macrophage-mediated segmental demyeli-nation

(Snider et al., 1983).

CIDP is differentiated clinically from AIDP by itsslower course of evolution (weeks to months), lack ofassociation with antecedent infection (usually viral), andless favorable long-term prognosis, mainly because ofthe greater degree of axonal loss over a longer time-course. AIDP, unlike CIDP, is characteristically monopha-sic in its clinical course with maximum clinical deficit indays to a few weeks.

In the absence of large series and systematicallydesigned controlled trials, definitive statements regard-ing the natural history and therapy of HIV-1-associatedIDP cannot be made. However, the clinical course andresponse to treatment in HIV-seropositive patients ap-pear to be similar to those in seronegative individualswith IDP. High-dose intravenous immunoglobulin ther-apy or plasmapheresis generally arrests the clinical pro-gression and enhances recovery in AIDP

(Cornblath,1988; Shapshak et al., 1995; Snider et al., 1983).

Asmall percent of AIDP patients may develop significantrespiratory weakness, requiring ventilatory support inacute stage. Patients with CIDP generally improve withoral prednisone therapy and may relapse when therapyis stopped

(Snider et al., 1983).

Acute exacerbations in

CIDP may require plasmapheresis or high-dose intrave-nous immunoglobulin therapy. The role of other immu-nosuppressive agents in CIDP has not been systemati-cally studied.

CMV-related progressive polyradiculopathy

Following its first report in 1986

(Eidelberg et al.,1986)

, CMV-related PP was increasingly recognized asa neuropathic complication of AIDS

(Said et al., 1991;Miller et al., 1990).

Because CMV-related PP occurs inadvanced stages of immunodeficiency, many such pa-tients had coexistent systemic CMV infection. In recentyears, with widespread use of HAART regimen, the in-cidence of CMV-associated PP has progressively de-clined.

The clinical features of PP are distinctive. Over afew days or weeks, a neurologically intact individual de-velops a cauda equina syndrome that is comprised ofpredominantly motor deficit in asymmetric distribution.Low back pain with radiation into one leg may be theearliest symptom, followed by urinary incontinence.Shortly thereafter saddle anesthesia develops, alongwith progressive leg weakness. If untreated, the deficitrapidly advances to a flaccid paraplegia with bowel andbladder incontinence and myelopathy, and arm weak-ness may supervene. The majority of untreated individ-uals die within a few weeks. A similar clinical picture isoccasionally seen in syphilitic or tubercular arachnoiditisor in lymphomatous polyradiculopathy

(Gherardi et al.,1998).

Spinal fluid analysis in PP reveals a consistent pic-ture of polymorphonuclear pleocytosis, low glucoselevel, and elevated protein content. CMV can be recov-ered from CSF by culture or, more rapidly, by PCR am-plification of the viral genomic sequences. Electrodiag-nostic study reveals primary evidence of axonal loss inlumbosacral roots with later denervation potentials inleg muscles. Sural nerve biopsies in this syndrome havebeen unrevealing, with only minimal degrees of inflam-mation

(Cornblath, 1988).

Autopsy studies have demonstrated marked in-flammation and extensive necrosis of ventral and dorsalnerve roots

(Eidelberg et al., 1986; Said et al., 1991;Miller et al., 1990).

Vascular congestion, edema, and in-filtrates of polymorphonuclear and mononuclear cellshave been observed in areas of severe necrosis. Focalmyelitis may be seen in the vicinity of the inflamednerve roots

(Said et al., 1991).

CMV has been docu-mented in neural tissue, both by the presence of CMVinclusions and by immunocytochemical studies.

CMV-related PP is a neurological emergency. Gan-ciclovir, an antiviral agent effective against CMV, shouldbe instituted on clinical suspicion of this syndrome, be-fore virologic laboratory study. Treatment often resultsin neurological stabilization followed by improvement


12

(Wulff et al., 2000; Simpson and Tagliati 1997; Miller etal., 1990; Said et al., 1991).

In patients who continue todeteriorate after early therapy, gancyclovir resistanceshould be suspected. In these cases, an alternate anti-viral agent, such as foscarnate, cidofovir, or other newerantiviral agents

(Wulff et al., 2000)

, may be used. Whetherinitial combination therapy with gancyclovir and foscar-nate is superior to a single agent in AIDS and CMV-relatedPP is unknown.

Dideoxynucleoside toxic neuropathy

Combination NRTIs are now increasingly used tomaintain viral suppression and to prevent the emer-gence of the resistant viral strains. Of currently mar-keted and extensively used NRTIs, 3 drugs (ddI, ddCand d4T) have well-recognized peripheral neurotoxicity

(Wulff et al., 2000; Berger et al., 1993; Moore et al.,2000; Verma and Bradley, 2000; Moyle and Sadler,1998; Simpson and Tagliati, 1997).

The occurrence ofnucleoside toxic neuropathy is dose dependent and of-ten the neurotoxicity is the dose-limiting factor in anti-retroviral therapy. Toxic neuropathy clinically resemblesDSP that occurs in the late stages of HIV-1 infection.The most common early symptoms are burning, pares-thesias, and aching in the distal lower extremities. Re-duced sensation in a proximal to distal gradient and ab-sent or reduced ankle jerks are typical clinical findingsin these patients. Electrophysiologic abnormalities intoxic neuropathies are similar to those in HIV-1-associ-ated DSP and indicate distal axonopathy.

HIV patients on NRTI regimens require careful clini-cal monitoring, because these agents can not onlycause new neuropathy, but they also can make subclin-ical neuropathy symptomatic or can aggravate the pre-existing clinical neuropathy

(Verma et al., 1999).

Thesubacute onset of neuropathy, in temporal relation topotentially toxic NRTI use, and especially, the effect ofdrug withdrawal, serve to distinguish it from the HIV-1-associated DSP.

Mononeuropathy multiplex

Mononeuropathy multiplex (MM) is an infrequentcomplication but can occur in early or late HIV-1 infec-tion. Mononeuropathy simplex, such as Bell’s palsy,can occur in early HIV-1 infection. MM is clinically char-acterized my multifocal motor, sensory, or mixed so-matic or cranial neuropathy

(Wulff et al., 2000; Vermaand Bradley, 2000; Moyle and Sadler, 1998; Snider etal., 1983).

MM at seroconversion or soon thereafter isusually dysimmune

(Wulff et al., 2000)

or vasculitic

(Bradley and Verma, 1996)

in pathogenesis and it isself-limited in clinical course. In advanced AIDS, whenCD

4

cell count is less than 50/mm

3

, CMV can cause asyndrome of MM. Untreated CMV-related MM is pro-gressive and it generally overlaps a more diffuse neuro-

pathic process, such as DSP or PP. CSF analysis in MMis nonspecific and may reveal mild mononuclear pleocy-tosis and elevated protein. In CMV-related MM, PCRfor viral DNA or nerve biopsy for immunocytology mayprovide more specific diagnostic data.

Autonomic neuropathy

The autonomic nervous system may be involved inthe central or peripheral complications of HIV-1 infec-tion. Several case series have reported subclinical auto-nomic neuropathy in otherwise neurologically asymptom-atic individuals

(Gluck et al., 2000).

Severe autonomicneuropathy generally occurs in patients with AIDS, andthen it is accompanied by other forms of HIV-associ-ated neuropathy. Clinical symptoms depend on thelevel and components of autonomic nervous system in-volvement

(Wulff et al., 2000).

Failure of the parasym-pathetic autonomic system may present clinically asresting tachycardia, palpitation and genitourinary dys-function. Sympathetic nervous system abnormalities in-clude orthostasis, syncope, anhidrosis, and gastrointes-tinal disturbance. A variety of systemic and metabolicfactors, such as fluid depletion, electrolyte imbalance,malnutrition, peripheral and central nervous system le-sions, and medications may contribute to autonomicdysfunction.

Drugs that can potentially cause or aggravate auto-nomic neuropathy should be discontinued or reduced inHIV-1 patients with autonomic neuropathy. Dehydrationshould be corrected and liberal fluid and electrolyte in-take encouraged. Other supportive measures includepressure-gradient stocking, reconditioning exercises,and drugs (such as mineralocorticoids, midodrine, andatropine congeners) in appropriate cases.

Summary

Peripheral neuropathies are common and occur inall stages of HIV-1 infection. The frequency of peripheralneuropathy in HIV-1 infection depends on the HIV-1 andAIDS patient population and the methodology used todetect the nerve involvement. The incidence increasesas the disease and immunodeficiency progresses andpathologic evidence of peripheral nerve involvement ispresent in virtually all patients dying of AIDS. Peripheralneuropathy may be clinically subtle or may remain clini-cally unappreciated in presence of HIV-associated de-mentia, myelopathy or myopathy. More than one formof neuropathy may coexist in the same AIDS patient.For these reasons, a detailed clinical work-up is oftennecessary to delineate the nature and severity of periph-eral neuropathy in HIV-1-infected individuals. Timely di-agnosis and rational therapeutic intervention may resultin the arrest and reversal of neuropathic deficit, relief in


13

neuropathic pain, and improvement in disability andquality of life in HIV-1 and AIDS patients.

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Epidemiology and clinical features of HIV-1 associated neuropathies