1

Neurological Neurological Manifestations of Manifestations of

HIV/AIDSHIV/AIDSDavid M. Simpson, MDDavid M. Simpson, MD

Professor of NeurologyProfessor of NeurologyDirector, Director, NeuroNeuro--AIDS Research ProgramAIDS Research ProgramDirector, Clinical Neurophysiology LabsDirector, Clinical Neurophysiology Labs

The Mount Sinai Medical CenterThe Mount Sinai Medical CenterNew York, New YorkNew York, New York

Declining Mortality with ARV in USA Declining Mortality with ARV in USA 19941994--19971997

2

History of Neuro-AIDS

Snider W, Simpson D, et al. Ann Neurol 1983;14:403-418

HIV and the Nervous System: HIV and the Nervous System: Major IssuesMajor Issues

•• 40% to 70% of patients with HIV have central or 40% to 70% of patients with HIV have central or peripheral nervous system involvementperipheral nervous system involvement

•• Neurologic disorders frequently misdiagnosedNeurologic disorders frequently misdiagnosed•• Viral differences in CNS and plasmaViral differences in CNS and plasma•• Role of hepatitis C coinfectionRole of hepatitis C coinfection•• AntiretroviralsAntiretrovirals

-- Penetration of blood brain barrierPenetration of blood brain barrier

-- Efficacy in dementiaEfficacy in dementia

-- Toxicity: CNS (EFV), PNS (Toxicity: CNS (EFV), PNS (““dd--drugsdrugs””))

3

NeuroNeuro--AIDS: Types of ComplicationsAIDS: Types of Complications

•• Secondary neurologic complicationsSecondary neurologic complications-- 2200 immune suppression (opportunistic immune suppression (opportunistic

infection, lymphoma)infection, lymphoma)-- ↓↓ incidence postincidence post--HAARTHAART

•• Primary neurologic disorders Primary neurologic disorders enigmaticenigmatic-- HIV dementia in adultsHIV dementia in adults-- Encephalopathy in childrenEncephalopathy in children-- HIVHIV--associated (vacuolar) myelopathyassociated (vacuolar) myelopathy-- Distal peripheral neuropathyDistal peripheral neuropathy

Prevalence of NeurologicPrevalence of NeurologicComplications in HIV/AIDSComplications in HIV/AIDS

< 5< 5MyopathyMyopathy

< 5< 5NeuroNeuro--syphilissyphilis

55--10?10?MyelopathyMyelopathy

2020

Minor Minor cognitive cognitive motor motor disorderdisorder

1010--15 15 ((↓↓))DementiaDementia

2525--3535NeuropathyNeuropathy%%

??Immune Immune ReconstReconst. . SyndromeSyndrome

< 5< 5CMV neuroCMV neuro< 5< 5StrokeStroke

< 5< 5Cryptococcal Cryptococcal meningitismeningitis

< 5< 5CNS lymphomaCNS lymphoma55ToxoplasmosisToxoplasmosis

< 5< 5PMLPML%%

4

Incidence of Neurologic Complications Incidence of Neurologic Complications of HIV Infection: MACSof HIV Infection: MACS

Calendar year

Incidence rate (per 1000 person-years)

Sacktor N. J NeuroVirology. 2002;8(supp 2):115-121.

Introductionof HAART

0

1

2

3

4

5

6

7

'90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00

CryptoToxoPMLPCNSL

0

5

10

15

20

25

30

35

'90 '92 '94 '96 '98 '00

HIVD

Introductionof HAART

Rising Prevalence of HIV Rising Prevalence of HIV DementiaDementia

0

5

10

15

1994 1996 1998 2000 2001

Prop

ortio

n w

ith H

IV D

emen

tia

Courtesy of S Letendre; Adapted from McArthur, et al, JNV, 2003

5

Terminology of Cognitive Terminology of Cognitive ImpairmentImpairment

•• HIVHIV--Associated Associated NeurocognitiveNeurocognitiveDisorders (HAND) Disorders (HAND) -- HIVHIV--Associated Dementia (HAD)Associated Dementia (HAD)

•• AIDS Dementia Complex (ADC)AIDS Dementia Complex (ADC)

-- Mild Neurocognitive DisorderMild Neurocognitive Disorder•• Minor Cognitive Motor Disorder (MCMD)Minor Cognitive Motor Disorder (MCMD)

-- Asymptomatic Neurocognitive ImpairmentAsymptomatic Neurocognitive Impairment

HIV ASSOCIATED HIV ASSOCIATED NEUROCOGNITIVE DISORDERS NEUROCOGNITIVE DISORDERS

(HAND) CRITERIA(HAND) CRITERIA

> Mod> MildNoneFUNCTIONAL IMPAIRMENT

> Mod> Mild> MildNEUROCOGN. IMPAIRMENT

HIV-ASSOCIATED

DEMENTIA

MILD NEUROCOGN

DISORDER

ASYMPTOMATIC NEUROPSYCH IMPAIRMENT

6

CrossCross--sectional sectional NeurocognitiveNeurocognitivePerformancePerformance

N = 1308N = 1308

0%

10%

20%

30%

40%

50%

60%

Normal Mild Mild-Moderate

Moderate Moderate-Severe

Severe

NC Normal

NC Impaired

CHARTER 2008

NC Impairment in the PreNC Impairment in the Pre--ARV, ARV, PrePre--HAART and HAART ErasHAART and HAART Eras

0%

25%

50%

75%

100%

HIV- CDC-A CDC-B CDC-C

Perc

ent I

mpa

ired

Grant (1987) HNRC-500 (1995) CHARTER (2008)

7

ALLRT Study DesignALLRT Study Design•• Prospective, observational cohort Prospective, observational cohort

•• N = 1160 subjects participating in ACTG N = 1160 subjects participating in ACTG clinical trialsclinical trials

•• Median age = 41 yearsMedian age = 41 years

•• ≥≥ 3 ARV agents for 3 ARV agents for ≥≥ 20 weeks 20 weeks -- 50% Rx50% Rx--naive and 50% experiencednaive and 50% experienced

•• Neuro Neuro substudysubstudy: : NeurocognNeurocogn. and PN . and PN batteriesbatteries

Robertson K, et al. AIDS. 2007;21:1915-1921.

ALLRT

ALLRT: ACTG Longitudinal Linked Randomized TrialsACTG: AIDS Clinical Trials Group

Prevalent Mild Prevalent Mild NeurocognitiveNeurocognitiveImpairment in ALLRTImpairment in ALLRT

Robertson K, et al. AIDS 2007;21:1915-1921.

ALLRT

Baseline Test

• Mild impairment61%

unimpaired

39%impaired

n=1160

Baseline: 20 weeks on ART in parent ACTG study

8

Sustained Neurocognitive Sustained Neurocognitive Impairment in ALLRTImpairment in ALLRT

Robertson K, et al. AIDS 2007;21:1915-1921.

ALLRT

• Baseline impaired• Follow-up at 48 wk• Sustained impairment 78%

unimpaired

22%impaired

n=991

Incident Neurocognitive Incident Neurocognitive Impairment in ALLRTImpairment in ALLRT

Robertson K, et al. AIDS. 2007;21:1915-1921.

ALLRT

79%unimpaired

21%impaired

• Baseline unimpaired• Follow-up at 48 wk• Developed impairment

n=615

9

Factors Associated with Sustained Factors Associated with Sustained Mild Cognitive Impairment (n=991)Mild Cognitive Impairment (n=991)

Robertson K, et al. AIDS. 2007;21:1915-1921.

<0.01<0.011.18, 2.551.18, 2.551.731.73Nadir CD4 cell count, cells/mmNadir CD4 cell count, cells/mm33

<200 vs >350<200 vs >350

0.010.011.12 , 2.701.12 , 2.701.741.74CD4 cell count, cells/mmCD4 cell count, cells/mm33

<200 vs >350<200 vs >350

pp--valuevalue95% CI95% CIOdds RatioOdds RatioVariableVariable

Adjusted for race, education, age, sex, and antiretroviral history

Virologic response at 16 weeks and baseline HIV-1 RNA was not significantly associated with prevalent impairment

ALLRT

Multivariate Analysis

Other Causes of Neurocognitive Other Causes of Neurocognitive Impairment Impairment NotNot Related to HIVRelated to HIV

•• Medical conditionsMedical conditions-- Nutritional/metabolic Nutritional/metabolic

causescauses11

-- Vascular diseaseVascular disease22

-- Hepatitis CHepatitis C33

-- Depression/other Depression/other psychiatric psychiatric conditionsconditions11

-- Sleep disordersSleep disorders44

•• Concomitant Concomitant medicationsmedications11

•• Substance useSubstance use22

•• Increased survival of Increased survival of HIVHIV--infected individualsinfected individuals55

-- Effects of agingEffects of aging-- Overlap with Overlap with

AlzheimersAlzheimers1http://clinicaloptions.com 2Ghafouri M, et al. Retrovirology 2006;3:1-11.3Letendre S, et al. 4th IAS 2007: Oral WeAb201.4Nokes K, et al. J Assoc Nurs AIDS Care 2001:12:17-22.5Robertson K, et al. AIDS 2007;21:1915-1921.

10

Clinical Features of HIVClinical Features of HIV--Associated Associated Neurocognitive Impairment (NI)Neurocognitive Impairment (NI)

CognitionMemory loss

ConcentrationMental slowingComprehension

BehaviorApathy

DepressionAgitation, mania

MotorUnsteady gait

Poor coordinationTremor

Clinical FeaturesClinical FeaturesFunctional ImpairmentFunctional Impairment

•• Activities of daily livingActivities of daily living-- Medication adherenceMedication adherence

-- Driving (2Driving (2--3 times as likely to fail tests)3 times as likely to fail tests)-- HHousehold financesousehold finances-- MMeal preparationeal preparation

•• Vocational functioningVocational functioning-- 5 times more likely to complain of problems 5 times more likely to complain of problems

performing their jobsperforming their jobs-- Twice as likely to be unemployedTwice as likely to be unemployed

Courtesy of S Letendre

11

MCMD(n=49)

NPI(n=109)

NL(n=256)

1.0

0.8

0.6

0.4

0.2

0.00

(n=414)2

(n=274)4

(n=66)6

(n=17)Years From Baseline Evaluation

8

Prop

ortio

n R

emai

ning

Aliv

e

Clinical FeaturesClinical FeaturesEarlier MortalityEarlier Mortality

Ellis R. Arch Neurol 1997;54:46-424

Clinical Features of HIVD in AdultsClinical Features of HIVD in Adults

•• Clinical symptoms manifest in:Clinical symptoms manifest in:-- CognitionCognition-- BehaviorBehavior-- Motor skillsMotor skills

•• Diagnosis of exclusion:Diagnosis of exclusion:-- Mass lesions, meningitis, Mass lesions, meningitis,

drugs, psychological changesdrugs, psychological changes-- W/U: Bloods, radiology, CSFW/U: Bloods, radiology, CSF

12

Neuroradiologic Features of HIVNeuroradiologic Features of HIV--DD

•• Cerebral atrophyCerebral atrophy•• White matter White matter abnlabnl

-- SymmetricalSymmetrical

-- ConfluentConfluent

•• Distinguish from Distinguish from multifocal lesionsmultifocal lesions

T2-weighted coronal (left) and axial (right) MRI

Pathogenesis of HIV DementiaPathogenesis of HIV Dementia

•• MultifactorialMultifactorial

•• Direct vs. indirect mechanisms of HIV Direct vs. indirect mechanisms of HIV effect on braineffect on brain-- Direct: microglial HIV infection, CSF HIV viral Direct: microglial HIV infection, CSF HIV viral

loadload

-- Indirect: cytokines (TNFIndirect: cytokines (TNF--αα), cellular channels ), cellular channels (Ca, NMDA)(Ca, NMDA)

13

Possible Causes of Neurocognitive Possible Causes of Neurocognitive Impairment Related to HIVImpairment Related to HIV

•• Ongoing HIV replication in the Ongoing HIV replication in the brainbrain11

•• Discordant viral load in the plasma Discordant viral load in the plasma and CSFand CSF22

•• Different viral strains in brain and Different viral strains in brain and plasmaplasma33

1McArthur J, et al. J Neurovirol 2003;9:205-221. 2Lanier E, et al. AIDS 2001;15:747-751.3Letendre S, et al. 4th IAS 2007: Oral WeAb201.

CSF Viral Load and Cognitive Function in CSF Viral Load and Cognitive Function in Advanced HIV Infection: PreAdvanced HIV Infection: Pre--HAARTHAART

Figure courtesy of Sacktor N

HIV

CSF

log

copi

es/m

L

McArthur 1997Brew 1996Ellis 1997

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

HIV+

NondementedMC/MD Mild Mod Severe

HIV DementiaMC/MD, minor cognitive/motor disorder

14

CNS

Lymph nodes

Testes

Peripheralblood

Lymph nodes

Importance of Attacking Importance of Attacking All HIV ReservoirsAll HIV Reservoirs

Kidneys

BloodBlood--Brain BarrierBrain Barrier

15

Crossing the Blood Brain Barrier

ECS: Extracellular spaceCSF: Cerebrospinal fluid

Adapted from Groothius DR, et al. J Neurovirol 1997;3:387-400

Brain Brain

Brain Brain

CSF

Transport intothe brain

Transportinto the CSF

CSF into plasma

Diffusion

ECS

ECS

Drug Penetration into CNSDrug Penetration into CNS•• Characteristics that affect drug penetration Characteristics that affect drug penetration

into the CNSinto the CNS-- Molecular Weight / SizeMolecular Weight / Size-- LipophilicityLipophilicity-- Protein BindingProtein Binding-- pH / IonizationpH / Ionization-- Molecular pumps (e.g., PMolecular pumps (e.g., P--glycoprotein)glycoprotein)-- Integrity of the bloodIntegrity of the blood--brain barrierbrain barrier-- Intracellular transfer via traffickingIntracellular transfer via trafficking

16

AntiAnti--HIV Drugs: CNS PenetrationHIV Drugs: CNS Penetration

Fusion inhibitorsFusion inhibitors

< 0.05< 0.05TenofovirTenofovir

NANAEnfuvirtideEnfuvirtide

Nucleotide RT InhibitorsNucleotide RT Inhibitors

0.3 0.3 -- 1.351.350.16 0.16 -- 0.970.970.3 0.3 -- 0.420.420.16 0.16 -- 0.190.190.110.110.09 0.09 -- 0.370.370.040.04

Zidovudine (AZT)Zidovudine (AZT)Stavudine (d4T)Stavudine (d4T)Abacavir (ABC)Abacavir (ABC)Didanosine (Didanosine (ddlddl))Lamivudine (3TC)Lamivudine (3TC)Zalcitabine (ddC)Zalcitabine (ddC)EmtricitabineEmtricitabine

CSF/Plasma CSF/Plasma RatioRatio

Nucleoside RT Nucleoside RT InhibitorsInhibitors

CSF/Plasma CSF/Plasma RatioRatio

Nonnucleoside Nonnucleoside RT InhibitorsRT Inhibitors

0.02 0.02 -- 0.760.76< 0.05< 0.05< 0.05< 0.05< 0.05< 0.05< 0.05< 0.05< 0.05< 0.050.00210.0021--0.02260.0226< 0.05< 0.05

IndinavirIndinavirSaquinavirSaquinavirNelfinavirNelfinavirRitonavirRitonavirAmprenavirAmprenavirLopinavirLopinavirAtazanavirAtazanavirFosamprenavirFosamprenavir

Protease InhibitorsProtease Inhibitors

0.28 0.28 -- 0.450.450.020.020.010.01

Nevirapine (NVP)Nevirapine (NVP)DelavirdineDelavirdineEfavirenzEfavirenz

Antinori A, et al. CROI 2002. #438-W. McArthur JC et al. J Neurovirol. 2003;9:205-221. Atazanavir Prescribing Information. Data on file; Gilead Sciences, Inc.

Validation of the CNS Validation of the CNS PenetrationPenetration--Effectiveness Effectiveness

Rank for Quantifying Rank for Quantifying Antiretroviral Penetration Into Antiretroviral Penetration Into the Central Nervous Systemthe Central Nervous System

Letendre S, MarquieLetendre S, Marquie--Beck J, Beck J, CapparelliCapparelli E, Best B, E, Best B, Clifford D, Collier C, Clifford D, Collier C, GelmanGelman B, McArthur J, B, McArthur J,

McCutchanMcCutchan J, Morgello S, Simpson D, Grant I, Ellis RJ, Morgello S, Simpson D, Grant I, Ellis R

Arch Arch NeurolNeurol 2008;65:652008;65:65--70.70.

17

Derivation of CPE Scoring Derivation of CPE Scoring SystemSystem

•• Penetration of ARV drugs was characterized using a Penetration of ARV drugs was characterized using a hierarchical approach based on the best available hierarchical approach based on the best available evidenceevidence-- Data on chemical characteristics, CSF pharmacology, and Data on chemical characteristics, CSF pharmacology, and

effectiveness in the CNS were reviewed effectiveness in the CNS were reviewed -- References included ARV package inserts, published References included ARV package inserts, published

manuscripts, and conference abstractsmanuscripts, and conference abstracts

•• To estimate To estimate neuroeffectivenessneuroeffectiveness, , ARVsARVs were assigned were assigned an individual CPE score:an individual CPE score:1 = High1 = High 0.5 = Intermediate0.5 = Intermediate 0 = Low0 = Low

CHARTER

Letendre S, et al. Arch Neurol 2008;65:65-70.

CNS PenetrationCNS Penetration--Effectiveness ScoreEffectiveness Score11 0.50.5 00

NRTIs Abacavir Emtricitabine DidanosineZidovudine Lamivudine Tenofovir

Stavudine Zalcitabine

NNRTIs Delavirdine EfavirenzNevirapine

PIs Amprenavir/r Amprenavir NelfinavirIndinavir/r Atazanavir RitonavirLopinavir/r Atazanavir/r Saquinavir

Indinavir Saquinavir/rTipranavir/r

Fusion EnfuvirtideInhibitorsInhibitors

CHARTER

Letendre S, et al. 13th CROI 2006:Abstract 74Relationship between CNS penetration and clinical improvement has not been established

18

Study Results Study Results -- Cont.Cont.•• Higher CPE scores Higher CPE scores

correlated with lower correlated with lower HIV RNA levels in CSF HIV RNA levels in CSF (r = (r = --0.10.122, p = 0.008), p = 0.008)11

•• After accounting for After accounting for plasma viral loads, plasma viral loads, eacheach unit decrease in unit decrease in CPE rank was CPE rank was associated with a 2.43associated with a 2.43--fold increase in the fold increase in the odds of having odds of having detectable CSF VLdetectable CSF VL11

•• CPE scores continue to CPE scores continue to be updated as more be updated as more data are generateddata are generated

Letendre S, et al. Arch Neurol 2008;65:65-70.

CHARTER

Oct 2003 – Jan 2006

•• Larger number of CSFLarger number of CSF--penetrating drugs penetrating drugs was associated with greater declines of was associated with greater declines of HIV RNA in CSFHIV RNA in CSF

•• This effect was not attributable to This effect was not attributable to -- Greater number of ARVs per regimenGreater number of ARVs per regimen-- Potency of antiretroviral drugsPotency of antiretroviral drugs

Ann Neurol 2004;56:416-423

19

Neurocognitive Improvement Neurocognitive Improvement & CSF Viral Load Suppression& CSF Viral Load Suppression

Χ2 = 6.3; p = .01

Impr

ovem

ent i

n G

DS

at F

ollo

w-u

p1.0 -

.5 -

0.0 -

-.5 -Not Suppressed

N=14Suppressed

N=17Letendre et al. Ann Neurol 2004;56:416-423

Rational Therapeutics for HIV DementiaRational Therapeutics for HIV Dementia

MAOMAO--B inhibition; antiB inhibition; anti--apoptoticapoptoticSelegilineSelegiline

AntiAnti--inflammatory; inflammatory; neuroprotectiveneuroprotectiveMinocyclineMinocycline

Platelet activating factor (PAF) Platelet activating factor (PAF) antagonistantagonistLexipafantLexipafant

NMDA channel blockadeNMDA channel blockadeMemantineMemantine

Calcium channel blockadeCalcium channel blockadeNimodipineNimodipine

TNF inhibitionTNF inhibitionThalidomideThalidomide

AntiretroviralAntiretroviralHAARTHAART

Mechanism of ActionMechanism of ActionTherapyTherapy

20

Antiretroviral Efficacy in HIV Antiretroviral Efficacy in HIV DementiaDementia

•• AZT only agent with demonstrated efficacy in AZT only agent with demonstrated efficacy in HIVHIV--associated dementia in RCTassociated dementia in RCT

•• ACTG 005ACTG 005-- AZT 2000 mg/d, 1000 mg/d, placeboAZT 2000 mg/d, 1000 mg/d, placebo-- Greatest neuropsychological improvement in high dose armGreatest neuropsychological improvement in high dose arm-- No data on lower dose AZTNo data on lower dose AZT-- Most other Most other ARVsARVs not studiednot studied-- Methodologic challenges in HAART eraMethodologic challenges in HAART era

•• AbacavirAbacavir vsvs placebo/optimized background ARVplacebo/optimized background ARV-- Negative for Negative for neuropsychneuropsych. improvement. improvement-- ↓↓CSF HIV VLCSF HIV VL

Sidtis JJ et al. Ann Neurol. 1993;33:343-349. Brew B et al. Proc of the 12th World AIDS Conference. Geneva, SZ. 1998.

Source: DHHS Guidelines.

Adverse Effects With Adverse Effects With Antiretroviral ClassesAntiretroviral Classes

NRTIsNRTIs•• Peripheral neuropathy Peripheral neuropathy

(ddC, d4T, ddI)(ddC, d4T, ddI)•• GI intolerance (AZT, ddI)GI intolerance (AZT, ddI)•• Anemia/bone marrow Anemia/bone marrow

suppression (AZT)suppression (AZT)•• Pancreatitis (ddI, ddC)Pancreatitis (ddI, ddC)•• Oral ulcers (ddC)Oral ulcers (ddC)•• Myopathy (AZT, d4T)Myopathy (AZT, d4T)•• Lactic acidosis with hepatic Lactic acidosis with hepatic

steatosis (rare)steatosis (rare)

NNRTIsNNRTIs•• Rash (EFV, DLV, NVP)Rash (EFV, DLV, NVP)

•• Elevated transaminase Elevated transaminase levelslevels

•• CNS effects (EFV)CNS effects (EFV)

PIsPIs•• Metabolic abnormalitiesMetabolic abnormalities

•• GI intoleranceGI intolerance

•• Elevated transaminase Elevated transaminase levelslevels

•• Nephrolithiasis (IDV)Nephrolithiasis (IDV)

21

Neuropathy TypesNeuropathy TypesDistal

Polyneuropathy

Mononeuropathy

MononeuropathyMultiplex

BrachialPlexopathy

Inflammatory DemyelinatingPolyneuropathy

Distal Polyneuropathy: Distal Polyneuropathy: SymptomsSymptoms

•• Numbness/tingling/burning pain in the feetNumbness/tingling/burning pain in the feet

•• Sensory complaints typically symmetricalSensory complaints typically symmetrical

•• Weakness unusual until DSP advancedWeakness unusual until DSP advanced

•• Frequently misdiagnosed (ie, ACTG 175)Frequently misdiagnosed (ie, ACTG 175)

•• Affects quality of life and ARV adherenceAffects quality of life and ARV adherence

22

Distal Polyneuropathy: Distal Polyneuropathy: Clinical SignsClinical Signs

•• Depressed ankle reflexes relative to knees Depressed ankle reflexes relative to knees (caution: combined CNS and PNS)(caution: combined CNS and PNS)

•• Abnormal vibration in feetAbnormal vibration in feet

•• Abnormal pinprick and cold (stockingAbnormal pinprick and cold (stocking--glove distribution)glove distribution)

•• Muscle strength (objective) usually normalMuscle strength (objective) usually normal

Simpson. AIDS and the Nervous System. 2nd ed. Raven Press;1996:189.

CHARTER: Peripheral NeuropathyCHARTER: Peripheral Neuropathy

57% of HIV+ subjects had ≥ 1 sign of PN. Among those with PN signs, Sx including paresthesias and pain affected 61%.

Ellis R, et al. CROI 2009

n = 658

n = 452

n = 429

23

Quality of Life and HIVQuality of Life and HIV--Associated Neuropathic PainAssociated Neuropathic Pain

Ellis R, et al. CHARTER, 2009 (unpubl)

CHARTER: PN Risk FactorsCHARTER: PN Risk Factors

Ellis R, et al. CROI 2009

24

Drugs Associated With PNDrugs Associated With PN•• AntibacterialsAntibacterials

-- dapsonedapsone

-- ethionamideethionamide

-- isoniazidisoniazid (especially if (especially if administered without pyridoxine)administered without pyridoxine)

-- metronidazolemetronidazole

-- streptomycinstreptomycin

•• AntineoplasticsAntineoplastics

-- vinblastinevinblastine sulfatesulfate

-- vincristinevincristine sulfatesulfate

-- cisplatincisplatin

•• ARVsARVs

-- d4Td4T

-- ddCddC

-- ddIddI

-- PIs ?PIs ?

•• Other agentsOther agents

-- phenytoinphenytoin

-- thalidomidethalidomide

Adapted from Moyle. Drug Safety. 1998;Dec 19(6):481.

25

Nucleoside AnalogueNucleoside Analogue--Related DSPRelated DSP

•• ClinClin indistinguishable from indistinguishable from DSP 2DSP 200 HIV (often overlap, HIV (often overlap, espesp with with ↓↓ CD4)CD4)

•• Pain usually resolves Pain usually resolves within 8 wks after drug within 8 wks after drug withdrawalwithdrawal

•• PN signs may persist for PN signs may persist for >>4 months after drug 4 months after drug withdrawalwithdrawal

•• ↓↓ use in US/Europe; use in US/Europe; common in developing common in developing worldworld

•• Associated with:Associated with:

-- Didanosine (Didanosine (ddIddI))

-- Stavudine (d4T)Stavudine (d4T)

-- Zalcitabine (Zalcitabine (ddCddC))

Mount SinaiMount SinaiNeuroNeuro--AIDS Research ProgramAIDS Research ProgramNeurologyNeurologyDavid M. Simpson, MDDavid M. Simpson, MDJessica RobinsonJessica Robinson--Papp, MDPapp, MDKathryn Elliott, MDKathryn Elliott, MD

NeuropsychologyNeuropsychologyDavid Dorfman, PhDDavid Dorfman, PhDElizabeth Ryan, PhDElizabeth Ryan, PhD

Neuropathology/Brain BankNeuropathology/Brain BankSusan Morgello, MDSusan Morgello, MDLetty Mintz, NPLetty Mintz, NP

NeuroradiologyNeuroradiologyCheukCheuk Tang, PhDTang, PhD

NeuroNeuro--AIDS Research TeamAIDS Research TeamMary Catherine George, CoordinatorMary Catherine George, Coordinator

AIDS Center ClinicAIDS Center ClinicFran Wallach, MDFran Wallach, MD

NeuroNeuro--AIDS Research ConsortiumAIDS Research ConsortiumDavid Clifford, MD (PI)David Clifford, MD (PI)Mary GouldMary Gould