HIV Neurology

Graeme Meintjes
Department of Medicine, GF Jooste Hospital Institute of Infectious Diseases and Molecular Medicine University of Cape Town

Population :

46 million people

HIV infected:
On HAART:

5-6 million
130 000

The HIV Epidemic in SA

5-6 million people infected 11.4% of the total population Incidence = 2.1% (2000)
+/- 2400 new infections each day

Deaths
40% of all deaths are due to AIDS

OVERALL PREVALENCE Women = 15% Men = 11,5%

GF Jooste Hospital

Secondary Referral Hospital

6 Antiretroviral Clinics 8 Day Hospitals 16 TB Clinics

GF JOOSTE
Outpatient and inpatient service

4500 patients on HAART in our referral area

HIV and the brain (1)

Meningitis
HIV itself TB Cryptococcal Syphilitic

Space occupying lesions

Toxoplasmosis Tuberculomas Lymphoma

HIV and the brain (2)

Encephalitis
HIV dementia Progressive multifocal leukoencephalopathy (PML) CMV, HSV, HZV encephalitis Toxoplasmosis

Strokes and intracerebral haemorrhage

HIV and the spinal cord

Vacuolar myelopathy Syphilis HZV, HSV, CMV, HTLV-1 TB Lymphoma

HIV and the peripheral nervous system (1)

Radiculopathy
TB CMV

Inflammatory demyelinating polyneuropathies

Guillain-Barre CIDP

HIV and the peripheral nervous system (2)

Distal sensory neuropathy Mononeuropathies, mononeuritis multiplex Drugs
INH D4T, ddI

D4T associated HIV neuromuscular weakness syndrome Diffuse Infiltrative Lymphocytosis Syndrome (DILS) Nutritional neuropathies

HIV and the muscles

HIV myopathy DILS AZT myopathy Pyomyositis

TODAY
Seizures in HIV Space occupying lesions Cryptococcal Meningitis D4T neuropathies

Immune Reconstitution Inflammatoy Syndrome (IRIS)

CASE Seizures in an HIV-infected patient

 25 year old woman Stage 3 HIV (oral candida) CD4 = 103 Partial seizure involving left arm and leg with secondary generalisation Post-ictal confusion (GCS = 11/15) with left hemiparesis and no meningism

Causes of new-onset seizures in HIV

Toxoplasmosis Primary CNS lymphoma Cryptococcal Meningitis AIDS-Dementia Complex TB Meningitis or Tuberculoma HIV-related aseptic meningitis Progressive multifocal leukoencephalopathy Encephalitis due to CMV, HSV or HZV Metabolic abnormailities (eg. Renal failure)

New-onset seizures in HIV

Mass lesion or meningitis in 75% Many of the rest may be related to HIV itself Late HIV Commonest causes
USA = Toxoplasmosis Baragwanath = TBM or tuberculomas
Modi, Neurology 2000, 55: 1558-1561

INVESTIGATIONS
Blood chemistry Chest X-Ray VDRL CT HEAD If no contra-indication on CT scan then LP

CASE

Left hemiparesis

 32 year old man HIV+ 3 week history of worsening weakness of left arm and leg Now unable to walk

CT HEAD
Single ring enhancing lesion in right internal capsule area

 What are the possible causes and how would you investigate and treat?

Single SOL
38 biopsied cases in Durban
Toxoplasmosis = 15 Brain abscess = 6 Tuberculoma or tubercular abscess = 4 Encephalitis = 7 Cryptococcoma = 2 Infarct = 1 No diagnosis =3 No cases of Primary CNS Lymphoma
Bhigjee, SAMJ 1999; 89(12): 284-8

Single ring-enhancing lesion

CD4 CXR and evaluation for features of TB elsewhere Toxoplasmosis IgG LP if no features of midline shift or raised ICP

Toxo IgG POS

Toxo IgG NEG or if features of TB elsewhere TB treatment Reassess at 10-14 days, or earlier if deteriorates

Treat for 10-14 days then re-evaluate Clinically +/- CT HEAD

If no improvement biopsy or add TB treatment

If no improvement,Toxo treatment or biopsy

Patients unlikely to benefit from aggressive search for Lymphoma

CEREBRAL TOXOPLASMOSIS
Reactivation of latent infection Toxo seroprevalence 12-46% (SA) IgG indicates past infection (FN <3-6%)

CD4 > 200 virtually excludes Toxo Over 80% have CD4 < 100
Typically multiple ring enhancing lesions on CT/MRI 27-43% have single lesions Up to 10% may have diffuse encephalitis without any visible focal lesions

Toxoplasmosis Clinical Features

Usually subacute over weeks Headache Fever Behaviour changes Confusion Focal signs Seizures 50% 45% 40% 15-52% 24-29%

Toxoplasmosis treatment
Sulphadiazine and Pyrimethamine is first choice Co-trimoxazole (80/400mg) 4 tablets BD x 4/52 then 2 tablets BD x 8/52 Long term secondary prophylaxis 2 tabs DLY Till sustained CD4 > 200

86% show clinical improvement by 7 days 95% show CT improvement by 14 days

CT - Multiple ring enhancing lesions

Toxo more likely Tuberculomas still possible

Cryptococcal meningitis

BUG
C. neoformans Ecology Identification

HOST
Immune Response
Pathology

Cryptococcal meningitis
Epidemiology Clinical: prognostic features

DRUGS
Treatment guidelines Difficulties with treatment

Summary of evidence

The Organism: Cryptococcus neformans

Isolated in 1894 from granulomatous lesion tibia Varieties neoformans and gattii Ecology: Avian excreta (pigeons), trees Ubiquitous spores. Aerosol => lungs => dissemination Identification India Ink CLAT: Latex antibody to capsule polysaccharide Culture: 48-72 hrs ordinary media, special tests Histology

India Ink stain of C. neoformans

Budding encapsulated yeast

Comparison of cryptococcal diagnostic methods

Test India Ink Specificity 80% Sensitivity 80% Pros/Cons
Needs organism burden >103 CFU/ml

CLAT
Culture

95%
100%

95%
85%

Diagnostic CSF titre prognostic. Not useful in monitoring Rx

Gold standard. May be negative if on fluconazole
Not useful in acute diagnosis. Problems in I/S patients

Serology

N/A

The Host
Universal exposure Inhalation=> (asymp.) pneumonia=> latency=> dissemination, esp. CNS Immunosuppressed (95%) HIV (CD4<100)
Organ transplant Corticosteroids Malignancy Organ failures

Immunology/Pathology
Cell-mediated immunity crucial defense Cytokines: TH1 pattern (IFN-) and macrophage-derived (TNF-, IL-6) important: potential for immunotherapy DTH: Granulomatous response: TH cells and giant cells (macrophages) presence or absence defines whether FOCAL (nodular) or DISSEMINATED disease (meningoencephalitis, extracellular yeasts+++)

Cryptococcal meningoencephalitis in HIV

Common OI in AIDS: 5-10% incidence in US but higher in Africa/Asia Frequent cause of death in African HIV cohorts (13-44%) Due to high HIV prevalence, becoming commonest cause of adult meningitis in many parts of Africa (Hakim et al. AIDS 2000; 14:1401. Zimbabwe).

Clinical features
Headache often only symptom Meningism: ~50% only Fever: ~70% Focal neurology: 1 in 5 Altered mental status Adverse prognostic indicators
1. Abnormal mental status 2. High fungal burden (baseline CSF CFU, CSF CLAT titre) 3. CSF opening pressure 4. Poor CSF inflammatory response (WBC<20)

Antifungal drugs
Drug Class Target
Cell membrane (ergosterol)
Cell membrane (ergosterol) DNA/ RNA synthesis

Action
Cidal

Toxicity Resistance
Nephro Rare

Amphotericin Polyene B
Fluconazole Triazole

Static

Hepatic, rash

Increasing (usually secondary) One-step: avoid monotherapy

Flucytosine (5-FC)

Pyrimidine analogue

Cidal; synergy BM, GI with AmB

Treatment guidelines (US/UK)

Induction
2 weeks

Consolidation
8 weeks

Maintenance

AmB 0.7-1 mg/kg + 5-FC 100 mg/kg/d

Fluconazole 400 mg/d

Fluconazole 200 mg/d lifelong

(until CD4>200, VL LDL for 6/12)

10-week mortality
US: 10-25% with optimal treatment SE Asia/Africa 20-50% Increasing rationale for trying to reduce mortality expanding access to ART offers prospect of good long-term prognosis provided patients survive initial cryptococcal disease

Brouwer, Rajanuwong, Chierakul, Griffin, Larsen, White, Harrison. Lancet. 2004 363:1764

Key randomised trials of treatment of cryptococcal meningitis in AIDS

(excl liposomal AmB)

Study
Larsen NEJM

Year
1990

No. Treatment
20 AmB 0.7+5FC 150 v FLU 400 AmB 0.4-0.5 v FLU 200-400 (excl coma) AmB 0.7+Placebo v AMB 0.7+5FC 100 (excl coma) FLU 400 v ITR 4002 FLU 200+5FC 150 (2/52) v FLU 200 (excl coma) AmB 0.7 v AmB 0.7+5FC 100 v AmB 0.7+FLU 400 v AmB 0.7+5FC 100+FLU 400

Length (wks)
10

Median time to CSF sterilisation

16d 41d 42d 64d

Deaths
at 10/52
0 4 14% 18% (p 0.48) 9.4%

(p=0.02)

Saag NEJM

1992

194

10

(p=0.25)

Van der Horst NEJM

1997

306

14d (51 v 60 %; p 0.06)

8 8 >60d 50% 65% 22% <14d

Mayanja-Kizza CID* Brouwer Lancet

1998

58

2004

64

Pappas JID

2004

75

AmB 0.7+5FC 100 (FLU 400) +IFN 200/ 400 sc AmB+5FC (FLU 400)+ placebo

10

Trend toward better CSF sterilisation at 2/52 with IFN

Difficulties with treatment

Drug cost, availability, administration and monitoring Monitoring response: CLAT no; symptoms (esp. new neurology), CSF culture yes Fluconazole resistance (MIC 32) secondary. Send relapse isolates for culture and fluconazole sensitivity and compare with initial isolate: if 4fold increase, change to AmB

Difficulties with treatment (cont.)

Raised intracranial pressure: impaired CSF resorption =>Visual/hearing loss, CN palsies, depressed GCS Rx Therapeutic taps/lumbar drains/shunts IRIS: recurrence/worsening of symptoms after starting ART.

Peripheral neuropathy
AIDS Distal Sensory Polyneuropathy (DSP) common
>30% of patients, lower CD4 count Pathogenesis: Pre-existing nerve injury (etoh, nutrition, HepC), macrophage activation, mitochondrial injury peripheral sensitization Presents with distal paraesthesia, beginning in the toes and moving proximally

Screening for HIV-sensory neuropathies Ellis R et al. NARC007

Question: Pain/numbness/tingling in legs? Absent ankle reflexes Reduced vibration threshold in toes (<10 sec) Sensitivity: 46% (neuropathy identified by screen) Specificity: 91.4%

Diagnostic studies for Sensory neuropathies in HIV infection:

Hep C, TSH, VitB12, Evaluate for diabetes Alcoholism Neurotoxic drug: D4T, ddI, INH, dapsone

Kaplan-Meier plots of the probability of neuropathy over time for each NRTI regimen

0.500
Probability of neuropathy

d4T+ddI
0.375

d4T+ddI+HU
0.250

d4T

0.125

ddI+HU

ddI

0.000 0 5 10 15 Time (months) 20 25 30

Moore et al. AIDS 2000; 14: 273 - 278

NRTIs and mitochondrial toxicity

Hyperlactataemia Lactic acidosis Hepatis steatosis Steatohepatitis Pancreatitis Myopathy Cardiomyopathy Peripheral neuropathy HIV-associated neuromuscular weakness syndrome (HANWS) Lipoatrophy Haematological toxicity

Pathogenesis of Lactic Acidosis= Mitochondrial toxicity

Viral RNA

Nucleoside pool

NRTI e.g d4T Reverse transcriptase Viral DNA

Mitochondrial DNA polymerase gamma

Abnormal mitochondrial DNA and proteins..

Mitochondrial dysfunction with NRTIs

Figure 1: Mitochondrial Energy substrate)

Oxidative Phosphorylation
2 Cytochrome C (Fe 3+) 2 Cytochrome C (Fe 2+)

(OXPHOS)
NAD Ubiquinone + 2H Ubiquinone H2O

Reduced energy substrate

NADH +H

O2

ATP synthase

But...

ADP + Pi

ATP

Abnormal mitochondrial protein inefficient oxphos system anaerobic metabolism, lactate build-up

HIV associated neuromuscular weakness syndrome (HANWS)

Aetiology
Postulated to be caused by mitochondrial toxicity attributed to NRTIs, primarily Stavudine. Strongly associated with hyperlactataemia

Frequency
Retrospective US analysis (AIDS 2004):
Total 69 identified with HANWS 27 definite 19 probable 23 possible

30/37 (81%) had hyperlactataemia

Case Definition
New onset limb weakness +- sensory involvement of legs of legs and arms:
Acute (1-2 weeks) Subacute (>2 weeks)

Absence of alternative confounding illnesses:

Guillain-Barre syndrome Myasthenia Gravis Myelopathy Hypokalaemia Stroke

2 groups
1) Rapidly progressive sensorimotor polyneuropathy with areflexia.
Primary axonal pathology (resembling GBS) Rarely demyelinating Can involve Cranial nerves Mechanism = axonal mitochondrial toxicity

2) Subacute progressive proximal muscle weakness

Myopathic features on biopsy Skeletal muscle mitochondrial toxicity Elevated CK

Often overlap of both Both associated with elevated Lactate

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)

DEFINITION
When partial restoration of immune function soon after starting HAART results in an immunopathological reaction with clinical deterioration manifesting as:
A paradoxical worsening of an appropriately treated infection OR Unmasking of an unrecognised infection with an atypical inflammatory presentation OR An auto-immune phenomenon

A CASE OF CM-IRIS
26 year old woman CM 2003
Symptoms resolved on Fluconazole

Commenced HAART in July 2004 with CD4 = 97

 Recurrent headaches 4 weeks after starting HAART LP

Poly Lymph Protein Glucose CLAT Fungal culture 16 74 27.1 0.4 1024 negative

Diagnosis CM-IRIS Therapeutic LPs and increased Fluconazole dose

 Headaches resolved then over 1/12 progressive Vomiting ++ Hiccoughs Coarse nystagmus Intention tremor and ataxia -> bedbound Confusion

MRI demonstrating hydrocephalus and marked periventricular, brainstem and meningeal enhancement

 Repeat LP
Pressure Poly Lymph Glucose Protein Fungal culture 13cm H2O 812 58 < 0.3 >2 negative

Management
Discussion regarding VP shunt with neurosurgeons Prednisone 50mg daily Vomiting resolved, ataxia much improved within days Relapsing-remitting headaches over 6 months

 Difficult wean off steroids with relapsing headaches when weans attempted But now off steroids and well Latest Viral Load = LDL

Manifestations of Cryptocccal-IRIS
Most commonly manifests as culture-negative relapse of meningitis symptoms with raised ICP. Occurs in up to 27%. Encephalitis Cryptococcomas Cavitating pneumonia Lymphadenopathy Skin lesions Subcutaneous abscesses

Suggested management of CM-IRIS

Check adherence with Fluconazole Optimise antifungal therapy Exclude Fluconazole resistance CT Head Serial LPs if raised ICP Consider steroids if marked CSF pleocytosis Continue HAART Consider additional diagnosis (esp. TBM)