CRYPTOCOCCAL MENINGITIS

Crytococcal meningitis is an opportunistic infection caused by a fungus Cryptococcus neoformans.

In Uganda, cryptococcal meningitis (CM) associated mortality is up to 39%. Patients with a CD4 cell count of <100 are at the highest risk, so early screening and management is critical.

Screening In ART-Naive Patients

  • Screen routinely for Cryptococcal Meningitis with the cryptococcal antigen (CrAg) test (a bedside finger prick test):
    • All ART naive individuals with CD4 <100 cells/μL
    • Patients on ART with viral load (VL >1000 copies/ml) or clinical (stage 3 or 4 disease) failure
  • If serum CrAg negative and no signs of meningitis: start ART immediately (or switch regimen)
  • If CrAg positive and/or signs or symptoms of meningitis (headache, presence of seizures, altered consciousness, photophobia, neck stiffness, and a positive Kernigs’ sign)
    • Perform lumbar puncture and test for CSF CrAg (culture if possible)
  • If CSF CrAg positive, diagnose and treat for Cryptococcal Meningitis
  • If CSF CrAg negative but blood CrAg positive, give pre emptive treatment for asymptomatic cryptococcal disease or non CNS cryptococcal disease

Management

Pre-emptive treatment for cryptococcoal disease

Induction Phase

  • Fluconazole 800 mg for 2 weeks or 12 mg /kg/day for individuals below 19 y ears

Consolidation Phase

  • Fluconazole 400 mg (or 6 mg/kg/day up to 400 mg) for 8 weeks

Maintenance dose

  • Fluconazole 200 mg for 14 weeks

Cryptococcal Meningitis

  • It commonly presents with headache, fever, malaise developing over 1-2 weeks, progressing into confusion, photophobia, stiff neck
    • Diagnosis is through identification of the microorganism in the CSF with Indian Ink stain, antigen in CSF or culture

Management

Induction phase (2 weeks)
Recommended:

  • Amphotericin B 0.7-1 mg/kg/day +
  • Flucytosine (100 mg/kg/day in four divided doses)
    OR
    High-dose fluconazole 800 mg/day (12 mg/kg in children)
    OR
  • Amphotericin B short course 5-7 days + highdose fluconazole 800 mg/day, (12 mg/kg in children)

Alternative:

  • Fluconazole 1200 mg/day (12 mg/kg/day in children and adolescents <19kg)

Consolidation phase (8 weeks)

  • Fluconazole 400-800 mg/day (or 6-12 mg/ kg/day in children) if Amphotericin is used in induction phase
  • Fluconazole 800 mg (12 mg/kg/day) if amphotericin short course-high dose fluconazole regimen used
  • Initiate ART 4-6 weeks after starting CM treatment and there is clinical response to antifungal therapy

Maintenance phase

  • Fluconazole 200 mg/day (or 6 mg/kg/day max 200 mg for children)

Criteria for stopping after 1 year of maintenance phase

  • Adults VL <1,000 copies/mm3 & CD4 ≥100 for 6 months or CD4 ≥200 if viral load not available.
  • Children: If CD4% >25% or suppressed viral load

Adequate control of elevated CSF pressure

  • Control of increased intracranial pressure improves survival by 25% in persons with cryptococcal meningitis
  • All patients with a CSF Pressure >250 mmHg will need a therapeutic LP the following day to reduce the CSF pressure to < 200 mmHg
  • In the absence of a manometer, one may use an IV giving set to create an improvised manometer measuring the height with a meter stick.
  • Removing 20-30 mL of CSF (even in the absence of a manometer) may be adequate to decrease CSF pressure. Most patients will need 2-3 LPs
    during the induction phase

Notes

Preventing Amphotericin toxicity:

  • To prevent nephrotoxicity and hypokalaemia, do:
    • Pre-hydration with 1 L Normal saline before starting the daily amphotericin dose;
    • Monitor serum potassium and creatinine levels at initiation and at least twice weekly to detect changes in renal function;
    • Routine administration of 40 mEq/day of potassium chloride can decrease the incidence of amphoteric in related hypokalaemia;
    • Consider alternate day amphotericin if creatinine is >3 mg/dl
  • Other options for treatment are a combination of Flucytosine (100 mg/kg/day in four divided doses) and fluconazole 800-1200 mg daily
  • Fluconazole dose should be increased by 50% for patients on rifampicin
  • Amphotericin and fluconazole are not recommended during pregnancy but use if benefit to mother outweighs risk. Avoid Flucytosine

Relapse Cases

  • Present with a recurrence of symptoms of meningitis and have a positive CSF culture following a prior confirmed diagnosis of cryptococcal meningitis
  • Evaluate for drug resistance:
  • Send CSF to Microbiology reference laboratory (CPHL or Makerere University) for Culture and sensitivity testing
  • If there are no drug resistance results, re-initiate the induction therapy for 2 weeks and complete other phases of treatment.