Neurology of AIDS in Post-HAART eraSurat 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

Inci

denc

e pe

r 10

0 pt

-yea

rs

0

30

60

90

120

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 finding

- 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) 3–10

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 MRILeft: CT scan showing ventricular enlargement and white-matter hypodensity. !Right: FLAIR MRI showing both cortical and central atrophy, and characteristic confluent signal abnormalities deep within the white matter.

Operational definition 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, hyperreflexia, 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 impairment—eg, hypoxia, sepsis, uraemia; active CNS opportunistic processes

Janssen RS, et al. Neurology 1991; 41: 778–85.

HIV-D CMV encephalitis PML

FeaturesMemory disturbance, mental slowing, gait

disturbance

Delirium, seizures, brainstem sign Focal neurological signs

Course Several months Days to weeks Weeks to months

MRIDiffuse 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 deficits 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, 17:1539–1545.

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) 3–10

Treatment of HIV-D

• Objective: to maximally suppress HIV replication in CNS

• PI containing regimen can reverse neurocognitive deficits

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 defining 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: 605–17

Characters of opportunistic infection in HIV patient

Ik Lin Tan et al. Lancet Neurol 2012; 11: 605–17

Brain mass in HIV

• The concomitance of negative toxoplasmosis serology + a single lesion on radiographic imaging -> sufficient 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 inflammatory syndrome (IRIS)

• Also known as immune restoration disease (IRD), or immune reconstitution syndrome (IRS)

• preexisting infection, clinically silent

• recovery of the immune system

• local inflammatory 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 profile 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: 605–17

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 inflammatory infiltrates in brain biopsy

• Progressive evolution and fatal outcome in few months

Journal of NeuroVirology, 9(suppl. 1): 88–92, 2003

Defining a consensus terminology of PML

Atypical presentation of PML in the HAART era

• Paradoxical development of an inflammatory 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

• sufficient number of CD4+ T cells

• presence of JCV-specific CD8+ cytotoxic T lymphocytes in the blood and this infiltrate the brain lesions and destroy JCV-infected cells

• This inflammation 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 inflammatory 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

Classification 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 reflex 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

FreeAsymptomaticSymptomatic

p<.001p<.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

Inci

denc

e, %

0102030

ddId4T

ddI+HU

ddI+d4T

ddI+d4T

+HU

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 NRTI’s (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;12:295–309

Pathogenesis of pain in distal sensory polyneuropathy

Mac Arthur. Lancet Neurol 2005; 4: 543–55

Diffuse infiltrative lymphocytosis syndrome

• acute/subacute painful sensorimotor polyneuropathy (distal and symmetrical)

• first description: sicca syndromes and parotidomegaly

• Normal CD4, but CD8 hyperlymphocytosis (>1000 cell/uL)

• Nerve biopsy: perivascular CD8 infiltration

• Rx: response well to cARTLancet Neurol 2013;12:295–309

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 infiltrations of skeletal muscle

4. Rhabdomyolysis

HIV-associated myopathies and related conditions

• HIV polymyositis

• Inclusion body myositis

• Nemaline myopathy

• HIV wasting syndrome

• Diffuse infitrative 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