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
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Cryptococcoma
Pyogenic abscess
Nocardia
CNS Syphilis (gumma)
• Diffuse Disease
– Cryptococcal Meningitis
– Acute Infection
– HIV Dementia
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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
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•
•
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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
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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
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•
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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 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: ?
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
Glucose
CD 4 > 200
CD 4 < 200
Calcium
Evaluate for NonHIV Related
Diagnosis
Image
Sodium
If Focal Signs
If No Focal Signs
Blood Gas
Drugs
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
Continue Treatment
No Response
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