Cryptococcal Meningitis in HIV

Cryptococcal meningitis is subacute meningoencephalitis by Cryptococcus neoformans (and C. gattii), a major cause of death in advanced HIV in Africa, usually when CD4 is under 100 cells/mm3. Infection follows inhalation of spores, with reactivation in immunosuppression.

• Serum cryptococcal antigen becomes positive weeks before meningitis, so pre emptive screening and therapy prevent disease.
• Mortality 20 to 40 percent even with treatment, higher with raised intracranial pressure.

Headache for 1 to 2 weeks, fever, nausea, vomiting, confusion, personality change, visual blurring, cranial nerve palsies (VI), papilloedema, seizures and coma; neck stiffness is often absent or mild.

• Skin lesions resembling molluscum, pulmonary nodules and lymphadenopathy in disseminated disease.
• Differential diagnosis: tuberculous meningitis, cerebral toxoplasmosis, bacterial meningitis, cerebral malaria, progressive multifocal leucoencephalopathy, CNS lymphoma, neurosyphilis, HIV encephalopathy, talaromycosis, histoplasmosis.
• Complications: raised intracranial pressure, blindness, hydrocephalus, cranial neuropathy, seizures, cryptococcoma, relapse, immune reconstitution inflammatory syndrome, drug toxicity (renal failure, hypokalaemia, anaemia), death.

Cryptococcal antigen is the key test.

• Serum or plasma cryptococcal antigen (lateral flow assay; if positive, lumbar puncture); CSF opening pressure, India ink, CSF cryptococcal antigen (sensitivity over 95 percent), fungal culture; CSF often has few cells (under 20/mm3), mildly raised protein, low glucose.
• CT head before lumbar puncture only when focal signs or seizures; do not delay.
• CD4 count, creatinine, potassium, magnesium, full blood count, liver tests, tuberculosis screen (urine lipoarabinomannan).

Induction with amphotericin, consolidation with fluconazole, active control of intracranial pressure, and delayed antiretroviral therapy.

• Supportive: pre hydration with 1 L of 0.9 percent saline with potassium chloride 20 mmol daily before each amphotericin dose, potassium and magnesium replacement (magnesium 8 mmol twice daily), monitor creatinine and potassium, therapeutic lumbar puncture, nutrition, treat headache.
• Pharmacological: induction for 1 week: liposomal amphotericin B 3 to 4 mg/kg IV daily (or deoxycholate amphotericin B 1 mg/kg daily) with flucytosine 100 mg/kg/day orally in four divided doses, then fluconazole 800 mg daily for week 2. Single high dose alternative: liposomal amphotericin B 10 mg/kg IV once on day 1 with flucytosine 100 mg/kg/day and fluconazole 1200 mg daily for 14 days. If flucytosine is unavailable: amphotericin B deoxycholate 1 mg/kg daily with fluconazole 800 to 1200 mg daily for 2 weeks. Consolidation: fluconazole 800 mg daily for 8 weeks (children 12 mg/kg/day), then maintenance fluconazole 200 mg daily for at least 12 months and until CD4 is over 200 for 6 months. Antiretroviral therapy delayed to 4 to 6 weeks after starting antifungal therapy. Pre emptive treatment for positive serum antigen without meningitis: fluconazole 800 mg daily for 2 weeks then 400 mg daily for 8 weeks then 200 mg daily. Do not give corticosteroids or acetazolamide.
• Procedures: therapeutic lumbar puncture removing 20 to 30 mL of CSF when opening pressure is over 25 cm CSF, repeating daily until pressure is under 20 cm CSF or halved; lumbar drain or ventriculoperitoneal shunt for refractory pressure.
• Special groups: pregnancy, amphotericin B (liposomal) as the induction agent and avoid fluconazole in the first trimester and flucytosine; children, amphotericin B 1 mg/kg/day with flucytosine 100 mg/kg/day, then fluconazole 12 mg/kg/day; renal impairment, liposomal amphotericin preferred; tuberculosis coinfection, treat both with specialist input.
• Red flags: opening pressure over 25 cm CSF, falling consciousness, visual loss, seizures, creatinine rising, potassium under 3 mmol/L, relapse symptoms, immune reconstitution syndrome after antiretroviral therapy.
• Follow-up: repeat lumbar puncture at 2 weeks for culture; creatinine, potassium and full blood count twice weekly during amphotericin; monitor adherence to fluconazole; stop maintenance only after CD4 is over 200 for 6 months.