neurological manifestations of hiv infection: a practical ...neurological manifestations of hiv...
TRANSCRIPT
!"#"$%&%#'()* (+)&&)#(#%,-).)$/+".(0/1%"1%1(/#(23456378
69/#0-"(:"';<-)*%11)-=(:%,-).)$>("#0(:%,-)1+/%#+%
7/-%+')-=(7/9/1/)#()* (:%,-)/&&,#).)$>("#0(:%,-).)$/+".(3#*%+'/)#1
!"#$%&'"()*$%&+$*,-.%*/0123/*4".-
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
HIV clades worldwide
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Neurological Manifestations of HIV infectionDirectly due to HIV
Sensory neuropathyVacuolar myelopathyDementia
Unmask autoimmune diseasespolymyositismyasthenia gravisAcute inflammatory demyelinating neuropathy (GBS)Multiple sclerosis
Opportunistic infectionsComplications of ART
Immune reconstitution syndrome
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
?)+".5(."'%-"./@/#$(1/$#1
ABB)-',#/1'/+(/#*%+'/)#1
C:8(.>&B;)&"Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
:)#D*)+".(1/$#1E
C)$#/'/9%(0%+./#%=(-%'-)B,.1/)#=(./&F(-/$/0/'>(
"#0(;>B%--%*.%G/"
!%#/#$/'/1()-
234(0%&%#'/"Int
ernati
onal
Neuroi
nfecti
ous D
iseas
e Con
feren
ce
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
7/**%-%#'/"'/)#()* (%#+%B;".)B"';>(/#(6378
HIV Dementia CMV encephalitis
PML
Clinical Features
Psycho-motor slowing
Delirium, seizures, brainstem signs
Focal signs
Course months Days-weeks Weeks-months
CD4 count <500 <100 <100
MRI Diffuse atrophy/WM hyperintensities
periventriculitis Subcortical WM lesions
CSF Non-specific PCR+90% PCR+80%Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
8,F+)-'/+".(H;/'%(&"''%-(.%1/)#1I(:)(
%#;"#+%&%#'(H/';(+)#'-"1'
7%%B(H;/'%(&"''%-(
;>B%-/#'%#1/'/%1I(:)(%#;"#+%&%#'(H/';(+)#'-"1'
7%%B(H;/'%(&"''%-(
;>B%-/#'%#1/'>I(:)(
%#;"#+%&%#'(H/';(+)#'-"1'
<%-/9%#'-/+,."-(.%1/)#1
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
<-)$-%11/)#()*(234(0%&%#'/"E(+./#/+".(*%"',-%1
J(&)#';1(&%"#(B-)$-%11/)#(,#'-%"'%01%9%-%("B"';>("#0(B1>+;)&)')-(
1.)H/#$&%&)->(.)11=(B))-(/#1/$;'$"/'(K(&)')-(/&B"/-&%#'1=('-%&)-=(
;>B%-D-%*.%G/"=(;>B%-')#/""11)+/"'%0(1>#0-)&%1E
&>%.)B"';>1%#1)->(#%,-)B"';>Int
ernati
onal
Neuroi
nfecti
ous D
iseas
e Con
feren
ce
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
:%,-).)$/+".(8/$#1(,1%*,.(/#(7/"$#)1/1()* (234D0%&%#'/"
Slow rapid eye movements, Slow limb movementsPostural instabilityHyperreflexia Hypertonia Frontal release signs
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
!)0/*/%0(234(0%&%#'/"(1+".%E
-)F,1'(1+-%%#/#$(')).=F,'(#)'(1B%+/*/+
1%#1/'/9/'>(L(MNO1B%+/*/+/'>(L(MPO
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
C8?
:)-&".()-(1./$;'(/#+-%"1%(/#(+%..1()-(B-)'%/#
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
MRI scan (Age:15ys)PET scan
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
HIV associated Neurocognitive Disorders (HAND)
Asymptomatic
Mild
Dementia
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
0
Time
Reversible
Chronic Inactive
Chronic Active
Subacute
High HIV RNA, no HAART or high level resistance
Low-mod HIV RNA, on HAART:Low level resistance/poor adherence
Low HIV RNA, on HAARTNo resistance/good adherence
C),-1%()* (26:7(/#(';%(Q-"()* (266RS
C),-'%1>T(U,1'/#(!+6-';,-
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Prevalence of HAND in aviremicpatients (Simioni et al. 2009)
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
C8?(9/-".(.)"0(+)--%."'%1(H/';(1%9%-/'>()* (7%&%#'/"(V<-%D266RS(%-"W
C),-'%1>T(U,1'/#(!+6-';,-
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Cumulative Incidence of HIV-DementiaDANA vs. NEAD cohorts
8"+X')-(:I((U(:%,-)9/-).I(YNNY
76:6(PZZ[DME(C7[(\YNN
:Q67(PZZM(D E(C7[(\YNN
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
R/1X(?"+')-1(*)-(234("11)+/"'%0(:%,-)+)$#/'/9%(7/1)-0%-1(V26:7W
Unsuppressed plasma or CSF HIV RNA
CD4 <200
Extremes of age
History of drug abuse
Anemia
Low body weight
Genetic factorsApoE4MCP-1, CCR-2TNF receptor polymorphisms
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
AnxietyDepressionAlcoholRecreational drugsMedication side effectsMetabolic encephalopathyHypothyroidismVitamin B12 deficiency
Drug interactions with protease inhibitors
7/**%-%#'/".(7/"$#)1/1()* (26:7
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Pathology of HAND
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
R"#X/(%'(".I=(PZZ]
^"'%#'(3#*%+'/)#(/#("1'-)+>'%1
Productive Infection in
perivascular macrophages
Jones et al., 2000; Kruman et al., 1998
Tat
gp120
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Dentate Gyrus
normal HIV no encephalitis
HIVE HIVE + drug abuse
Jones, Bell and Nath (unpublished)
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
virotoxinsCellular toxins
chemokines
M
Astro
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Principles of Therapy for HIV CNS infection
Maximize antiretrovirals to suppress CSF HIV RNA
Preferably use CNS-
Construct simplified regime - BD or QD
Supervised therapy:Int
ernati
onal
Neuroi
nfecti
ous D
iseas
e Con
feren
ce
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
C8?(B%#%'-"'/#$(6RS1(7%*/#/'/)#E(CSF level exceeds the level needed to inhibit replication of HIV
:RS3
stavudine (D4T) zidovudine (ZDV)abacavir (ABV)
NNRTIefavirenz (EFV) nevirapine (NVP)
Protease Inhibitorsindinavir (IDV)
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
<-)F.%&1(H/';(+,--%#'(6RS
Poor penetration across BBBP-glycoproteinorganic transporters
Drug resistanceNo effect post viral integration
viral reservoirs sparedearly viral proteins still producedInt
ernati
onal
Neuroi
nfecti
ous D
iseas
e Con
feren
ce
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
8>&B')&"'/+(S;%-"B>
:%,-).%B'/+1E(Atypical antipsychotics6#'/0%B-%11"#'1E(Low dose fluoxetine (Prozac)6#'/+)#9,.1"#'1E 9".B-)"'%=(levitarecetam, gabapentin or topiramate. 2%"0"+;%1E Triptans interact with Protease inhibitors<"-X/#1)#/1&E poor response to dopamine agonists8.%%B(0/1',-F"#+%E Sleep apnea-protease inhibitors; Insomnia-efaverinz
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
HIV infection andCerebellar degeneration
(Tagliati et al., Neurology 1998;50:244-51)
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
HIV+ Cocaine(Meltzer et al., AJNR 1998;19:83-9)
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
8yr old with congenital HIV infection with microcephaly and developmental delay developed sudden onset of hemiparesis. CT showed subarachanoid hemorrhage
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Riedel et al., Nature Neurol 2006
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
methylprednisone 1g/day x 5 days
Dramatic improvement in mental status
Discharged on prednisone 60mg/day
tenofovir, lopinavir/ritonavir, zidovudine
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
worseningclinical condition that is paradoxicallyattributable to the recovery of the immune system after initiation of ART
Immune Reconstitution Inflammatory Syndrome
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
15-25%
Patients on HAART
20-45%
Patients with OI on HAART
Shelburne et al., 2006
EPIDEMIOLOGY of IRIS
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
0 10 20 30 40 50 60 70 800
25
50
75
100
Patients with IRIS (%)
Tim
e in
terv
al (d
ays)
Shelburne et al., AIDS, 2005 Johnson and Nath NYAS 2010
Time between of Initiation of HAART and IRIS
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Steroids:
Risks from immune suppression
Interruption of HAART/immune restorative therapy:
Risk for resistance to therapy
Re-emegence of IRIS upon restarting HAART/ immune restorative therapy
Treatment options for IRIS are not ideal
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Recommendation for use of steroids in IRIS
Catastrophic IRIS: high dose steroids taper with oral steroids x 1 month (with OI prophylaxis)
Symptomatic IRIS: high dose steroids taper with oral steroids (debatable)
Asymptomatic IRIS: wait and see (debatable)
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
234(!>%.)B"';>
8B"1'/+/'>
8%#1)->("'"G/"
_-/#"->(1>&B')&1
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Peripheral Nervous System with HIV
RadiculopathyGBSMononeuritis multiplexSensory motor neuropathy
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
CMV PolyradiculitisOccurs late in HIV infection; CD4 usually < 100; concurrent CMV infection in >60%Cauda equina syndrome: asymmetric motor, perineal sensory, back pain, sphincter CSF: poly pleocytosis, protein, glucose, + CMV PCR+ in 95%
Rx: Induction: ganciclovir [+ foscarnet]Maintenance: valganciclovir
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
C!4(B).>-"0/+,./'/1%#;"#+/#$(#%-9%(-))'1#%+-)'/+(-))'1C!4(/#+.,1/)#11B/#".(+)-0(/#9).9%&%#'
!R3(1+"#
C),-'%1>E(U,1'/#(!+6-';,-
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
HIV-associated GBS
Increased frequency of GBS relative to general populationSimilar presentation to HIV neg, except that CSF usually cellularUsually presents early in HIV infectionPresumably an immune-mediated phenomenon
Responds to plasmapheresis or IVIG
7%&>%./#"'%0(#%-9%(1%$&%#'1
C),-'%1>E(U,1'/#(!+6-';,-
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
:%-9%(F/)B1>(1;)H1(&"+-)B;"$%(&%0/"'%0(0%&>%./#"'/)#(/#(234D"11)+/"'%0(`a8
C),-'%1>E(U,1'/#(!+6-';,-
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
!)#)#%,-/'/1(&,.'/B.%G(/#(234(/#*%+'/)#
"F-,B'()#1%'1%9%-%(B"/#2%B"'/'/1(a(K(C-%b,/-%1(#%-9%(aGRGE(1'%-)/01
4%11%.()++.,1/)#("#0(/#*."&&"'/)#(/#(H"..
C),-'%1>E(U,1'/#(!+6-';,-
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Incidence of neuropathyLichenstein CID 2004
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Clinical features of HIV sensory neuropathies
Common length-dependent symptoms:Spontaneous pain in feet, paresthesias, Evoked pain ~ touch, rubbing (not cold) Numbness ~ unusual in fingersLancinating pains
Examination:sens. thresholds 85%
96%Distal weakness 33%Atrophy or wasting 30%Fasciculations 0%
Features of HIV distal sensory polyneuropathy and antiretroviral toxic neuropathy are identical. Neuropathic sx. are correlated with plasma HIV RNA
C)-#F."';=(PZccT(S"$./"'/(!=(PZZZC),-'%1>E(U,1'/#(!+6-';,-
52
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Antiretroviral exposure: d4T 8-fold, ddI 4-fold
Diabetes in 11% of HAART recipients; IGT in ~ 20%
Alcohol abuse; hepatitis C
Entrapment neuropathies
Vitamin deficiencies or overuse
C)#*),#0/#$(/..#%11%1(/#(';%("11%11&%#'()* (234(1%#1)->(#%,-)B"';/%1
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
!"#$%&'"()*"#+,-"+,%.*"./*.)0$%."1*$)/0#+,%.*,.*234*#%$$)1"+)5*6,+'*789:;<****!"#$%&'()'*++,-
[]O(
[]OInt
ernati
onal
Neuroi
nfecti
ous D
iseas
e Con
feren
ce
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Skin biopsy technique
!"#$"%&'(#)&*&+&&,""-'.//&012(3
4)"'3&012(3&'56"'
55
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Skin biopsy assesses unmyelinated nerve fibers
Thigh: normal density Distal leg: reduced density and nerve fiber
swellings
HIV sensory neuropathies
%B/0%-&/1
56
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
V,#./+%#1%0W(('-%"'&%#'1(*)-(234(1%#1)->(#%,-)B"';/%1
=">%+$,(,.)?*!"#$%"&&'(410#0$%.,/"+,%.@*$"5'
A%&,$">"+)?*)(*+","+'3)."1*)B#$)+,%.@*6+*1%55@*C,/.)D*5+%.)5
4"E"&).+,.F&$)("E"1,.-#./0'(+"#$"($1*,3)."1*)B#$)+,%.@*)/)>"@*5)/"+,%.
201%B)+,.)?*5)$%+%.,.F.%$)&,.)&'$,.)*338<"05)"@*')&"+%+%B,#,+D
G%>E,."+,%.*+')$"&,)5?*)(*<HI!*5+0/D*%J*("E"&).+,.*K*>%$&',.)
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
6+X#)H.%0$%&%#'1
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
6+X#)H.%0$%&%#'1
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0
Intern
ation
al Neu
roinfe
ctiou
s Dise
ase C
onfer
ence
Addis
Ababa
, Ethi
opia,
on Feb
ruary
27-28
, 201
0