HIV Infection and the CNS

Stephen J. Gluckman, M.D.University of Pennsylvania

Botswana-Penn Partnership

Plan

• Review features of the major diagnostic possibilities

• Suggest approach to the patient

Recurring Themes

• CSF results are generally not helpful

• Imaging studies are rarely diagnostic

• Empiric management is often necessary – anywhere in the world

CNS Manifestations of HIV

• Space Occupying Lesions

– Toxoplasmosis– Lymphoma– PML– Tuberculoma– Cryptococcoma– Pyogenic abscess– Nocardia– CNS Syphilis (gumma)

• Diffuse Disease– Cryptococcal Meningitis– Acute Infection– HIV Dementia– Tuberculous Meningitis– CNS Syphilis– Toxoplasma encephalitis– Cytomegalovirus encephalitis

• Two key things to ALWAYS remember in the management of HIV infected patients– HIV infection does not prevent the

development of a non-HIV related problem– Opportunistic problems are related to the CD4

(+) cell count.• If the count is > 200-300, the problem is probably

not related to the HIV infection.

Space Occupying Lesions

Toxoplasmosis

• The most common in the west of the CNS space occupying lesions in a person with a CD4 count <200 (usually < 100)– Prevalence of toxoplasma CNS disease is unknown in Botswana– Seroprevalence is low

• Reactivation disease– Cat feces– Meat

• Presentation is typically sub acute and focal– May be seizures

• Multiple ring enhancing lesions– 1/3 single lesion

• CSF is normal or non-specific

Toxoplasmosis

• Other than a biopsy there is no good diagnostic test– Antibody testing is very non-specific and

occasionally insensitive– Usual “diagnostic” test is response to Rx

• Expect response to treatment in 2 weeks

Toxoplasmosis

• Things that make toxo unlikely– Negative toxo serology– Patient taking Co-trimoxazole prophylaxis– CD4 count > 100

• Treatment– Pyrimethamine (50-100 mg QD) plus leucovorin and

Sulfadiazine (1 gm QID)– Alternatives

• Fansidar 2-3 daily• Atovoquone 750 mg QID• Azithromycin 1200 mg QD• Clindamycin 600 QID• Co-trimoxazole 10mg/kg/day of trimethoprim• Dapsone 100 mg QD

Primary CNS Lymphoma

• Subacute and focal• CD4 count typically <50• Single ring enhancing lesion is more common

than toxoplasmosis• Associated with EBV infection• CSF is normal or non-specific

– CSF cytology is negative– 90% are PCR (+) on CSF for EBV

• Diagnosis by biopsy

PML

• Reactivation of JC virus (Papova virus)

• CD4 counts typically <100

• Subacute evolution of focal disease

• CSF usually normal

• “Diagnostic” CT appearance: Subcortical white matter disease without evidence of inflammation or edema

• Diagnosis: PCR on CSF for JCV (90%)

Tuberculoma

• Presents like any other mass lesion• CT appearance

– Looks like an abscess or a tumor• Nothing characteristic about CT appearance• May be ring enhancing

• CSF– Non-specifically abnormal or completely normal

• Diagnosis: brain biopsy• Treatment: standard drugs though the duration

has not been studied– Many people treat longer than pulmonary TB

Pyogenic Brain Abscess

• Presents like a mass rather than like infection– May not have fever

• CT– Ring enhancing lesion(s)

• CSF– Non-specifically abnormal

Pyogenic Brain Abscess

• Microbiology– Depends upon the underlying cause

• Sinusitis or otitis or mastoiditis or dental: mixed organisms• Bronchiectasis or lung abscess or empyema: mixed

organisms• Paradoxical embolus: single organism• Endocarditis: single organism usually Staphylococcus aureus

– About 30% do not have an underlying cause.• These tend to have multiple organisms so are presumed to

come form sub-clinical sinus, ear, or pulmonary source

Pyogenic Brain Abscess

• Diagnosis– Brain aspirate or biopsy to prove abscess and obtain

proper microbiology

• Anti-microbiol management– If known single bacterium: treat the bug– If mixed or presumed mixed focus

• Chloramphenicol 50 mg/kg/day in 4 divided doses OR• Cefotaxime 2 gm Q4H and metronidazole 500 mg Q6H

– Treat for several months until CT scan is normal or looks inactive

Nocardia

• Nocardia brain abscess– Presents like other brain abscesses, but some

predisposition to involve the brain stem– Can only be diagnosed by biopsy

• Often diagnosed presumptively by finding nocardia elsewhere

– Treatment• Initial

– Cefotaxime 2 gm Q6H and Amikacin 7.5mg/kg Q12H or– Co-trimoxazole15 mg/kg/day IV x 3-6 weeks

• Continuation– Co-trimoxazole 480/2400 BD PO x 6-12 months

Syphilis(gumma)

• Rare manifestation

• Presents as a mass– Looks like a brain tumor

• Diagnosis suggested by positive serology

• Diagnosis proven by biopsy

• Treatment– Pen G 18-24 million units/day x 14 days

NON-FOCAL CNS DISEASE

Cryptococcal Meningitis

• Clinical Presentations– Typical

• Subacute onset of fever and headache• Photophobia and/or meningeal signs in only 25%

– Less typical• Seizures• Confusion• Progressive dementia• Visual or hearing impairment• FUO

– Diagnosis• Very rare if CD 4 (+) cell count is > 100• CSF: may be deceptively normal• Serum CRAG: > 99% sensitive in AIDS patients

Cryptococcal Meningitis

• In 2003 there were 193 (+) CSF cultures for cryptococcus from PMH *– Leucocytes

• No leucocytes in 31%• Only 1-10 leucocytes in 23%• 7% had > 250 leucocytes

– 30% of these had predominately PMN’s

– 95% (+) India Ink– 1% (-) cryptococcal antigen

*Bisson et al

Treatment**Modified IDSA Guidelines

– Immunosuppressed (pulmonary, cutaneous, or meningitis)

• Induction– Amphotericin B 0.7-1 mg/kg/day plus 5-flucytosine

100mg/kg/day x 2 weeks then

• Consolidation– Fluconazole 400 mg/day x 6-10 weeks then

• Suppression – Fluconazole 200 mg/day x ?

Cryptococcal MeningitisTreatment

One More Thing• Anti-fungal: induction, consolidation, maintenance• Pressure management

– Elevated pressure• 75% > 200• 25% > 350

– Repeated lumbar punctures• Increased pressure: daily until normal x several days• Normal pressure: recheck at 2 weeks prior to switching to

fluconazole– Lumbar drain– VP shunt: if still elevated at 1 month– No role for

• acetazolamide, mannitol– Steroids: ?

Acute HIV Infection

• Aseptic Meningitis– Indistinguishable from other causes of aseptic meningitis unless

associated with the other features of the acute syndrome• Adenopathy• Rash• Pharyngitis

• Encephalitis– Needs to be considered in the differential diagnosis of acute

encephalitis• Remember as with other manifestations of the acute

infection HIV antibody may be negative. So consider:– Seroconversion– PCR– P24 antigen

HIV Dementia

• Diagnosis of exclusion that is supported by– Atrophy on CT scan– CSF normal or elevated protein

• Typical feature is withdrawn appearance but can be anything

• Can have a dramatic response to ARV’s

Tuberculous Meningitis

• Similar presentation to cryptococcal meningitis, though can be a bit more acute

• Diagnosis made by CSF, but insensitive– Typically lymphocytic predominance, but may have

PMN’s early– Moderate low glucose– AFB smear (+) in 5%– Culture (+) in 50%

• Usually “diagnosed” by finding a sub-acute onset lymphocytic meningitis that is cryptococus and cytology negative.

• Treatment the same as pulmonary TB

CNS Syphilis

• Secondary– Aseptic meningitis

• Tertiary– Meningovascular– General Paresis– Tabes Dorsalis– Asymptomatic neurosyphilis

• Toxoplasma encephalitis– Toxoplasma may occasionally present as

diffuse CNS disease rather than an abscess

• CMV encephalitis– Relatively rare– Diagnosed by PCR on CSF, NOT BY

SEROLOGY

Sn’s or Sx’s of CNS Disease

CD 4 > 200 CD 4 < 200

Evaluate for Non-HIV Related Diagnosis

If Focal Signs

Image

If No Focal Signs

Lumbar Puncture

Imaging Negative

Imaging Positive

Treat for Toxoplasmosis ?

Glucose

Calcium

Sodium

Blood Gas

Drugs

India Ink

Cryptococcal Ag

Cytology

TB culture

Routine Culture

Approach to Patient(cont)

Treat forToxoplasmosis

Response No Response

Continue Treatment Treat for TB

Response No Response

Brain BiopsyContinue Treatment

Approach to the Patient

• Try to avoid the use of steroids because the “diagnostic” test is response to therapy

• If there is significant neurological deficit and/or concerns about herniation then– Have no choice but to use steroids– May want to treat for several things

• If a brain biopsy is not obtainable

Recurring Themes

• As with all problems in HIV patients the differential diagnosis is CD 4 count dependent

• As with all problems in HIV patients we must never forget to consider non-HIV related explanations for the symptoms

• CSF results are generally not helpful– Cryptococcus is an exception

• Imaging studies are rarely diagnostic– PML is an exception

• Empiric management is often necessary – anywhere in the world