1. HIV Infection and the CNS Stephen J. Gluckman, M.D. University of Pennsylvania Botswana-Penn Partnership

2. Plan Review features of the major diagnostic possibilities Suggest approach to the patient

3. Recurring Themes CSF results are generally not helpful Imaging studies are rarely diagnostic Empiric management is often necessary – anywhere in the world

4. 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

5. 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.

6. Space Occupying Lesions

7. 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

9. 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

10. 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

11. 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

12. 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%)

14. 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

15. Pyogenic Brain Abscess Presents like a mass rather than like infection –May not have fever CT –Ring enhancing lesion(s) CSF –Non-specifically abnormal

16. 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

17. 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

19. 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

22. 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

23. NON-FOCAL CNS DISEASE

24. 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

25. 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

27. Cryptococcal Meningitis Treatment –Pressure management PEOPLE DIE OF PRESSURE NEED TO BE AGGRESSIVE –Antimicrobials Amphotericin B 0.7 mg/kg/day X 2 weeks and if improving Fluconazole –400 mg QD x 6 weeks –200 mg QD until CD 4 > 200

28. 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 ?

29. Cryptococcal Meningitis Treatment 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: ?

30. 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

31. 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

32. 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

33. CNS Syphilis Secondary –Aseptic meningitis Tertiary –Meningovascular –General Paresis –Tabes Dorsalis –Asymptomatic neurosyphilis

34. 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

35. Approach to a Patient

36. Sn’s or Sx’s of CNS Disease CD 4 > 200 Evaluate for Non- HIV Related Diagnosis CD 4 < 200 If Focal Signs Image Imaging Negative Imaging Positive Treat for Toxoplasmosis If No Focal Signs Lumbar Puncture

37. Glucose Calcium Sodium Blood Gas Drugs India Ink Cryptococcal Ag Cytology TB culture Routine Culture

38. Approach to a Patient (Cont)

39. Approach to Patient (cont) Treat for Toxoplasmosis Response Continue Treatment No Response Treat for TB Response Continue Treatment No Response Brain Biopsy

40. 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

41. Summary of Management It is reasonable to treat most focal CNS lesions in HIV infected persons with low CD4(+) cell counts empirically for toxoplasmosis If toxoplasmosis is very unlikely and/or if there is no response to treatment in 2 – 3 weeks a brain biopsy should be the next diagnostic test. If brain biopsy is unavailable - ?

42. 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