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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
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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””))
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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%%
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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
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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
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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)
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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
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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
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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.
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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
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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
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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
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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)
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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
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CNS
Lymph nodes
Testes
Peripheralblood
Lymph nodes
Importance of Attacking Importance of Attacking All HIV ReservoirsAll HIV Reservoirs
Kidneys
BloodBlood--Brain BarrierBrain Barrier
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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
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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.
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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
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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
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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
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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)
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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
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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
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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
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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.
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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