Neurology of AIDS in

Post-HAART era
Surat Tanprawate, MD, MSc(Lond.), FRCP(T)
The Northern Neuroscience Center and Division of Neurology
Faculty of Medicine, Chiangmai University
7 Sword in Neurology
3-5-2014, Pullman Hotel, Bangkok
Fact about AIDS and
Neurology

10-15% of AIDS patients present with neurologic

symptoms only

35-50% of AIDS patients have neurologic

symptoms during life

75-90% have neuropathologic abnormalities at

death
1) Brouwman et al, Neurology. 1998 ; 50:1814-20.
2) McArthur J Neuroimmunol 2004; 157 : 3-10
3) Vago et al., AIDS. 2002;16:1925-8.
Primary HIV-induced neurologic syndromes
OIs
Primary HIV-induced neurologic syndromes
Treatment associated neurological complication
Primary HIV-induced neurologic syndromes
IRIS
Impact of HAART on the Incidence of
Opportunistic Infections
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Year
1992 1993 1994 1995 1996 1997
PCP
MAC
CMV Retinitis
Toxoplasmosis
HAART
Increase incidence of treatment related complication
Increase incidence of IRIS
Increase incidence of HIV related condition due to longer life
HIV-related neurologic
disease
CNS
CD4/viral load
HAART
(duration/time to start HAART)
Immune status Clinical symptoms
Meningeal s/s: headache,
stiffness of neck, cranial
neuropathy
Parenchymal s/s:
-
Focal
-
Multifocal
-
Diffuse: eg cognitive
decline
Radiologic nding
- focal/multifocal/diffuse
lesion
-
brain edema?
-
contrast enhancement?
Serology/other
-
viral PCR/ culture
-
treatment response
Clinical scenario
Patients with the AIDS dementia complex
present with a variable, yet characteristic,
constellation of abnormalities in cognitive,
motor, and behavioral function. Perhaps
the salient aspects of the disorder are the
slowing and loss of precision in both
mentation and motor control . These
patients often lose interest in their work as
well as in their social and recreational
activities. (Price et al., 1988)
HIV-associated Neurocognitive Disorders
(HAND)

HIV-1-Associated Dementia (HIV-D)

AIDS Dementia Complex (ADC)

HIV-associated Cognitive/Motor Complex
HIV-associated Mild Neurocognitive Disorder

Asymptomatic Neurocognitive Impairment

HIV-Associated Mild Cognitive/Motor Disorder
J.C. McArthur / Journal of Neuroimmunology 157 (2004) 310
Neurocognitive
Impairment
(Neuropsychological
Testing)
Functional Impairment
(Activities of Daily Living)
Asymptomatic
Neurocognitive
Impairment (ANI)
! Mild None
Mild Neurocognitive
Disorder (MND)
! Mild > Mild
HIV-Associated Dementia
(HAD)
! Moderate > Moderate
HIV-Associated Neurocognitive Disorder (HAND)
Woods, SP, et. al. Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV.
Journal of Clinical and Experimental Neuropsychology, 2004,26, p 759-778.

Antinori A, et al. Neurology 2007; 69;1789-1799
HIV-D

Essential features

disabling cognitive impairment accompanying by

motor dysfunction, and behavioural change

HIV dementia symptoms are more associated

with motor slowing and loss of executive control
than with language and memory disturbance.

Subcortical dementia
Janssen et al. Neurology 1991. 41:778-785
White-matter abnormalities on CT and MRI
Left: CT scan showing ventricular enlargement and white-matter
hypodensity.
Right: FLAIR MRI showing both cortical and central atrophy,
and characteristic conuent signal abnormalities deep within the
white matter.
Operational denition of HIV-D and clinical
features of use for diagnosis

HIV-1 seropositivity

History of acquired and commonly progressive cognitive-behavioural decline,

with apathy, memory loss, and slowed mental processing

Neurological examination: diffuse and symmetrical CNS signs, including slowed

eye and limb movements, apraxia, hyperreexia, hypertonia, and release signs

Neuropsychological assessment: impairment in at least two domains, including

frontal lobe, psychomotor speed, and non-verbal memory

CSF analysis: exclusion of neurosyphilis, TB, and cryptococcal meningitis

CT and MRI: diffuse cerebral atrophy with symmetrical deep white-matter

hyperintensities.

Exclusion criteria: major psychiatric disorder, intoxication or other cause for

dementia; metabolic impairmenteg, hypoxia, sepsis, uraemia; active CNS
opportunistic processes
Janssen RS, et al. Neurology 1991; 41: 77885.
HIV-D CMV encephalitis PML
Features
Memory disturbance,
mental slowing, gait
disturbance
Delirium, seizures,
brainstem sign
Focal neurological signs
Course Several months Days to weeks Weeks to months
MRI
Diffuse atrophy,
symmetrical deep white
matter, diffuse intensities
Normal or
periventriculitis
Scattered, asymmetrical
subcortical white matter
lesions
CSF
Non-diagnostic immune
activation less marked
in patients treated with
HAART
PCR+ for CMV 90%
PCR+ for JC/BK virus
60%
Differentiation of HIV-D from opportunistic infection
Pre- vs Post HAART era

Natural history change from 6 months (mean) to 44 months to death

Altered pattern of neuropsychological decits in such patients, with

tendency for more cortical type

Hypermetabolism location on PET scan

Pre-HAART: basal ganglia

HAART: mesial temporal lobe

CSF biomarker: beta-2 microglobulin and HIV viral load are not
strongly correlated with ADC severity
Navia B, et al. Ann Neurol 1986, 19:517 524.
Dore GJ, et al. AIDS 2003, 17:15391545.
Cysique L, et al. XIVth International AIDS Conference. Spain 2002.
Subtype of HIV-D in the era of HAART
J.C. McArthur / Journal of Neuroimmunology 157 (2004) 310
Treatment of HIV-D

Objective: to maximally suppress HIV replication in CNS

PI containing regimen can reverse neurocognitive

decits
Sacktor N et al. J Neurovirol 2000; 6: 84-88
Opportunistic infection(OIs),
HAART and
Immune Reconstitution
Syndrome (IRIS)
Opportunistic infection in HIV

CNS AIDS dening condition: PML, CNS CMV, CNS

tuberculosis, cryptococcal meningitis, cerebral
toxoplasmosis

typically occur when CD4<200 cell per uL

15% multiple infection

incidence of opportunistic infection in HIV

pre-HAART era: 13.1/1,000 pt.

post-HAART era: 1/1,000 pt.

Characters of opportunistic infection in HIV patient
Ik Lin Tan et al. Lancet Neurol 2012; 11: 60517
Characters of opportunistic infection in HIV patient
Ik Lin Tan et al. Lancet Neurol 2012; 11: 60517
Brain mass in HIV

The concomitance of negative toxoplasmosis

serology + a single lesion on radiographic
imaging -> sufcient to warrant the
performance of a stereotactic biopsy

Median time to response of Toxoplasmosis

74% 7 days -> 91% 14 days

Lymphoma vs Toxoplasmosis

Large lesion size (>4 cm)

Extensive white matter

involvement

Periventricular location/
subependymal spread

Contrast enhancement along

ventricular surface

Extension across or
involvement of corpus
callosum

Large number of lesions

Involvement of basal ganglia

Hemorrhagic lesions

Responses to anti-toxo drugs,

usually within 7-14 days
Favors Lymphoma Favors Toxoplasma
A HIV patient with alteration of consciousness for 3 days
Immune reconstitution
inammatory syndrome (IRIS)

Also known as immune restoration disease (IRD),

or immune reconstitution syndrome (IRS)

preexisting infection, clinically silent

recovery of the immune system

local inammatory reaction

paradoxical deterioration in clinical status

Cryptococcus meningitis

PML

Toxoplasmosis

Expanding intracranial tuberculoma

Tuberculous meningitis

Parvovirus B19 meningitis

CMV ventriculitis

VZV myelitis and encephalitis

infectious IRIS of the CNS
John C Hall et al. 2011 AIDS HIV in the post HAART era
IRIS
Worsening or recurrent
opportunistic infection
Context Onset early (~2 Mo) after start ARV Not related to start of ARV
Plasma HIV RNA
concentration
Decreased Increased
CD4-positive T-cell
count
Increased Decreased
CSF prole
Lymphocytosis, raised protein,
frequency sterile culture
Lymphocytosis less intense than
with IRIS, raise protein, possible
low glucose, positive culture
Neuroradiology
Worsening lesion with cerebral
edema and contrast enhancement
May have worsening lesion,
surrounding edema less intense
than IRIS, contrast enhancement
Treatment Steroid(anecdotal) Anti-microbial
Distinguishing features of IRIS and worsening/recurrent
opportunistic infection
Lancet Neurol 2012; 11: 60517
PML
Classical AIDS-associated
PML in the pre-HAART era

CD4+ T cell counts < 200 ul

non-enhancing white matter lesions on MRI, without

edema and mass effect

detectable JCV DNA by PCR in CSF

Absence of inammatory inltrates in brain biopsy

Progressive evolution and fatal outcome in few

months
Journal of NeuroVirology,
9(suppl. 1): 8892, 2003
Dening a
consensus
terminology
of PML
Atypical presentation of PML
in the HAART era

Paradoxical development of an inammatory form

of PML

contrast enhancement PML

may have brain edema

may clinical manifest with seizure, cortical sign

+/- prolong survival

PML-IRIS: MRI Brain with contrast enhancement
NEUROLOGY TODAY | FEBRUARY 19, 2009
Unifying hypothesis

PML can be contained if

sufcient number of CD4+ T cells

presence of JCV-specic CD8+ cytotoxic T lymphocytes in

the blood and this inltrate the brain lesions and destroy JCV-
infected cells

This inammation reaction

cause a break-down of the blood brain barrier and contrast

enhancement on MRI

decrease viral replication in the brain and JCV VL in CSF

PML-d-IRIS: worsening of preexisting PML
PML-s-IRIS: PML and IRIS simultaneously
Tan K. Neurology 2009;72:1458-1464
PML-d-IRIS vs PML-s-IRIS

Duration develop IRIS: PML-d-IRIS < PML-s-IRIS

Lesions load on MRI: PML-d-IRIS > PML-s-IRIS

Shorter survival: PML-d-IRIS < PML-s-IRIS

PML-s-IRIS: example case (Chiangmai U)
4 months
1 years
Practical issue in PML/IRIS
Steroid treatment

Challenge in diagnosis of inammatory PML

Many cases of PML-IRIS appear to have favorable

outcome

Steroid may promote JCV replication

Steroid should be reserved in cases with major

neurological worsening or with clinical or radiologic
signs of impending brain herniation
Neuromuscular
disease in HIV
Classication of HIV-1 associated
neuropathies
HIV and Immune
dysregulation
Opportunistic
infection
Toxic neuropathy
Early stage (immune
dysregulation)
-
AIDP
-
CIPD
-
Vasculitic neuropathy
-
Brachial plexopathy
-
Cranial mononeuropathy
-
Multiple mononeuropathies
Mid and late stage (HIV-1
replication driven)
-
Distal sensory
polyneuropathy
-
Autonomic neuropathy
-
CMV polyradiculopathy
-
CMV mononeuritis
multiplex
-
Zosteric ganglionitis
-
Syphilitic radiculopathy
-
Tuberculous
polyradiculopathy
-
Lymphomatous
polyradiculopathy
-
Nutritional neuropathy
-
AIDS cachexic neuropathy
Nucleoside reverse
transcriptase inhibitors

Other drug; INH, ethambutol,
thalidomide
Verma and Bradley, 2000
Distal sensory
polyneuropathy (DSPN)

The most common form of neuropathy occurs in mid to late stages of

HIV-1 disease

Cause: HIV, Toxic neurpathy (NRTI)

Clinical

pain or uncomfortable positive sensation

length dependent fashion

weakness is very minimum

absent/reduce reex at ankle

NCV: axonal, length dependent sensory polyneuropathy

Rising prevalence of HIV-associated sensory neuropathies
Johns Hopkins HIV Clinical Cohort
0
12.5
25
37.5
50
1994 1996 1998 2000 2001 2002
per 100 persons
Identified risk factors:
age (2-3 fold) or DM
nadir CD4 count
plasma HIV RNA
APOE4/mtDNA haplogroup
d4T or ddI exposure
?? HCV
Richard Moore & Kelly Gebo
Phase I/II trials:
A reversible painful peripheral neuropathy
developed in 10 patients after 6-14 weeks'
treatment with 2',3'-dideoxycytidine.

Lancet. 1988 Jan 16;1(8577):76-81

ddC neuro-toxicity was noted early
D-Drug Exposure and Neuropathy Status
0
10
20
30
40
50
60
70
DDI D4T ddC
Free
Asymptomatic
Symptomatic
p<.001
p<.001
p<.107
Significantly more with symptomatic SN had been exposed to ddI or
d4T. D4T was more likely to be used currently by ASX (54% v 23-24%)
%
The likelihood of having symptomatic neuropathy at baseline:
< strong association with use of ddI ever (OR=3.21, CI: 1.56, 6.60)
< strong association with use of d4T ever (OR=7.66, CI: 2.89, 20.33)

No association between months of exposure, time off a particular d-drug, hepatitis
C, and presence of metabolic syndrome (Thomas D. AAN 2006)
Neurotoxic Nucleoside RT inhibitors
abbreviation : ddI
preferred name : didanosine
trade name : Videx
2',3'-dideoxyinosine

abbreviation : d4T
preferred name : stavudine
trade name : Zerit
2',3'-didehydro-2',3'-dideoxythymidine
abbreviation : ddC
preferred name : zalcitabine
trade name : Hivid
2',3'-dideoxycytidine
Long-term Complications of ART:
Distal Sensory Peripheral Neuropathy
Etiology
HIV itself
Secondary infections (CMV, syphilis)
Nutritional deficiency
Alcohol abuse
NRTIs (especially stavudine + didanosine)
Characteristics
Pain, numbness, loss of sensation
Tends to involve longest nerves first, hence first evident in feet
Management
Discontinue offending NRTIs
Adjunctive treatments for persistent pain
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HR = hazard ratio; HU = hydroxyurea.

Moore RD, et al. AIDS 2000;14:273-8.
Regimen HR 95% CI P
d4T 1.39 0.84!2.32 0.20
ddI+HU 2.35 0.69!8.07 0.18
ddI+d4T 3.50 1.81!6.77 0.001
ddI+d4T+HU 7.80 3.92!15.5 0.0001
Peripheral Neuropathy by ART Regimen
Pathophysiology of antiretroviral toxic
neuropathy: a role for mitochondrial toxicity ?
elevated serum lactate is a marker of
ATN (Brew B., 2001)

mitochondrial gamma DNA
polymerase is inhibited by specific
NRTIs (Martin JL, 1994)

acute neuromyopathy with LAS
(Marcus, 2001; Simpson 2004)

mitochondrial DNA levels are reduced
with prolonged exposure to d4T or ddI,
and mtDNA haplogroups are risk
factors (Cherry K, 2002; Hulgan T,
2005)
Pathogenesis of distal sensory polyneuropathy
Lancet Neurol 2013;12:295309
Pathogenesis of pain
in distal sensory
polyneuropathy
Mac Arthur. Lancet Neurol 2005; 4: 54355
Diffuse inltrative
lymphocytosis syndrome

acute/subacute painful sensorimotor polyneuropathy

(distal and symmetrical)

rst description: sicca syndromes and parotidomegaly

Normal CD4, but CD8 hyperlymphocytosis (>1000

cell/uL)

Nerve biopsy: perivascular CD8 inltration

Rx: response well to cART

Lancet Neurol 2013;12:295309
Skeletal muscle involvement
in HIV
1. HIV-associated myopathies and related conditions
2. Muscle complications of anti-retroviral therapy:
NRTI
3. Opportunistic infections and tumor inltrations of
skeletal muscle
4. Rhabdomyolysis
HIV-associated myopathies
and related conditions

HIV polymyositis

Inclusion body myositis

Nemaline myopathy

HIV wasting syndrome

Diffuse intrative lymphocytosis syndrome (DILS)

chronic fatigue
Muscle complication of anti-
retroviral therapy

Zidovudine and other NRTI myopathy

Lactic acidosis, hepatic, steatosis, and myopathy

HIV-associated lipodystrophy syndrome

HAART related IRIS

Anti-HIV should be tested in ALS syndrome
Conclusion

In the era of HAART

Complex of AIDs associated disease

increase IRIS and ARV toxicity

Clinical/immune status/imaging/lab test and

follow up: help diagnosis
Thank you for your
kind attention