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 PMNs

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 Meningitis Treatment

Anti-fungal: induction, consolidation, maintenance Pressure management
Elevated pressure
75% > 200 25% > 350

One More Thing

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 ARVs

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 PMNs 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

Sns or Sxs of CNS Disease

CD 4 > 200

Glucose Calcium

CD 4 < 200

Evaluate for NonHIV Related Diagnosis

Sodium Blood Gas Drugs

If Focal Signs

If No Focal Signs

Image

Lumbar Puncture

India Ink
Imaging Negative

Cryptococcal Ag Cytology

Imaging Positive

TB culture Routine Culture

Treat for Toxoplasmosis ?

Approach to Patient (cont)

Treat for Toxoplasmosis

Response

No Response

Continue Treatment

Treat for TB

Response

No Response

Continue Treatment

Brain Biopsy

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