neurological manifestations of hiv infection: a practical ...neurological manifestations of hiv...

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HIV clades worldwide

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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

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HIV Dementia CMV encephalitis

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

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Slow rapid eye movements, Slow limb movementsPostural instabilityHyperreflexia Hypertonia Frontal release signs

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MRI scan (Age:15ys)PET scan

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on Feb

HIV associated Neurocognitive Disorders (HAND)

Asymptomatic

Dementia

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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

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Prevalence of HAND in aviremicpatients (Simioni et al. 2009)

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Cumulative Incidence of HIV-DementiaDANA vs. NEAD cohorts

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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

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AnxietyDepressionAlcoholRecreational drugsMedication side effectsMetabolic encephalopathyHypothyroidismVitamin B12 deficiency

Drug interactions with protease inhibitors

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Pathology of HAND

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on Feb

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Productive Infection in

perivascular macrophages

Jones et al., 2000; Kruman et al., 1998

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on Feb

Dentate Gyrus

normal HIV no encephalitis

HIVE HIVE + drug abuse

Jones, Bell and Nath (unpublished)

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on Feb

virotoxinsCellular toxins

chemokines

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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

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on Feb

C8?(B%#%'-"'/#$(6RS1(7%*/#/'/)#E(CSF level exceeds the level needed to inhibit replication of HIV

stavudine (D4T) zidovudine (ZDV)abacavir (ABV)

NNRTIefavirenz (EFV) nevirapine (NVP)

Protease Inhibitorsindinavir (IDV)

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Poor penetration across BBBP-glycoproteinorganic transporters

Drug resistanceNo effect post viral integration

viral reservoirs sparedearly viral proteins still producedInt

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on Feb

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on Feb

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on Feb

HIV infection andCerebellar degeneration

(Tagliati et al., Neurology 1998;50:244-51)

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on Feb

HIV+ Cocaine(Meltzer et al., AJNR 1998;19:83-9)

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on Feb

8yr old with congenital HIV infection with microcephaly and developmental delay developed sudden onset of hemiparesis. CT showed subarachanoid hemorrhage

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on Feb

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on Feb

Riedel et al., Nature Neurol 2006

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on Feb

methylprednisone 1g/day x 5 days

Dramatic improvement in mental status

Discharged on prednisone 60mg/day

tenofovir, lopinavir/ritonavir, zidovudine

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on Feb

worseningclinical condition that is paradoxicallyattributable to the recovery of the immune system after initiation of ART

Immune Reconstitution Inflammatory Syndrome

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on Feb

15-25%

Patients on HAART

20-45%

Patients with OI on HAART

Shelburne et al., 2006

EPIDEMIOLOGY of IRIS

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0 10 20 30 40 50 60 70 800

Patients with IRIS (%)

Shelburne et al., AIDS, 2005 Johnson and Nath NYAS 2010

Time between of Initiation of HAART and IRIS

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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

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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)

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on Feb

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on Feb

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on Feb

Peripheral Nervous System with HIV

RadiculopathyGBSMononeuritis multiplexSensory motor neuropathy

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on Feb

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

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on Feb

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on Feb

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

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on Feb

Incidence of neuropathyLichenstein CID 2004

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on Feb

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

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on Feb

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

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Skin biopsy technique

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on Feb

Skin biopsy assesses unmyelinated nerve fibers

Thigh: normal density Distal leg: reduced density and nerve fiber

swellings

HIV sensory neuropathies

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neurological manifestations of hiv infection: a practical ...neurological manifestations of hiv...

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