Doctors Revision

Neurological System

Cryptococcal Meningitis

A serious fungal infection of the meninges caused by Cryptococcus neoformans (or C. gattii). Primarily affects individuals with severely weakened immune systems, most commonly those with advanced HIV infection (CD4 count typically <100 cells/µL).

Also known as: Crypto Meningitis, CM

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Referral and warning signs

When to refer

ALL suspected cases of Cryptococcal Meningitis MUST be referred urgently to Hospital (H) for LP, diagnosis, initiation of antifungal therapy (often requiring IV Amphotericin B), management of raised ICP (therapeutic LPs), and monitoring.

Red flags

  • Headache, fever, or altered mental status in severely immunocompromised patient (esp. HIV with CD4 <100)
  • Signs of raised intracranial pressure (papilledema, vision changes, severe headache, vomiting)
  • Neck stiffness (may be subtle)
  • Seizures
  • Positive serum CrAg test

Signs and symptoms

  • Often subacute onset (developing over days to weeks, can be acute).
  • Headache (most common symptom, often severe and persistent).
  • Fever (may be low-grade or absent).
  • Malaise, fatigue, lethargy.
  • Nausea, vomiting.
  • Altered mental status (confusion, drowsiness, personality changes, memory loss, coma).
  • Neck stiffness (may be less pronounced than in bacterial meningitis).
  • Photophobia.
  • Visual changes (blurred vision, diplopia, vision loss - due to raised ICP or optic nerve involvement).
  • Seizures.
  • Focal neurological deficits (less common).
  • Symptoms of raised intracranial pressure (ICP) are common.

Risk factors

  • Advanced HIV infection (CD4 count <100 cells/µL).
  • Other immunocompromising conditions: Organ transplant recipients, long-term high-dose corticosteroid use, certain cancers (lymphoma), sarcoidosis.
  • Not typically seen in immunocompetent individuals (unless C. gattii).

Diagnosis

Clinical assessment

Suspect in any immunocompromised patient (especially advanced HIV) presenting with subacute headache, fever, and/or altered mental status. Neck stiffness may be minimal.

Investigations

  • Lumbar Puncture (LP) and CSF Analysis: Essential.
  • - Measure Opening Pressure (OP): Often significantly elevated (>20-25 cmH2O).
  • - India Ink Stain: Microscopic visualization of encapsulated yeast cells (positive in ~70-80%, depends on fungal load and expertise).
  • - CSF Cryptococcal Antigen (CrAg) Test: Latex agglutination or Lateral Flow Assay (LFA). Highly sensitive (>95%) and specific; rapid diagnostic test. Preferred diagnostic method.
  • - CSF Fungal Culture: Gold standard for confirmation, allows species identification and susceptibility testing, but takes days.
  • - CSF Cell Count/Differential: Typically lymphocytic pleocytosis (can be low cell count if severely immunocompromised).
  • - CSF Glucose: Usually low.
  • - CSF Protein: Usually elevated.
  • Serum CrAg Test: Highly sensitive screening test in HIV patients (can detect antigen before meningitis symptoms). If positive, warrants LP.
  • HIV Test (if status unknown).
  • CD4 Count.
  • Consider Brain Imaging (CT/MRI): Before LP if focal signs or markedly depressed consciousness, to rule out mass lesions (cryptococcomas - rare). May show signs of raised ICP or hydrocephalus.

Diagnostic criteria

Clinical suspicion in at-risk patient + Positive CSF India Ink stain OR Positive CSF CrAg test OR Positive CSF fungal culture.

Management

Non-pharmacological management

  • Immediate referral to hospital (H).
  • Management of Raised Intracranial Pressure (ICP): CRITICAL. If opening pressure is elevated (>20-25 cmH2O), perform therapeutic LPs (drain CSF to reduce pressure by 50% or to <20 cmH2O) daily or as needed to control symptoms (headache, visual changes, altered mental status). Acetazolamide or steroids NOT recommended for ICP management in CM.
  • Supportive Care: IV hydration, nutrition, manage seizures, monitor neurological status.

Pharmacological treatment

  • Antifungal Therapy (Phased Approach):
  • - Induction Phase (Typically 2 weeks): Goal is rapid fungal clearance.
  • - Preferred Regimen (if available): Amphotericin B deoxycholate (AmB-d) 0.7-1.0 mg/kg/day IV PLUS Flucytosine (5-FC) 100 mg/kg/day PO (divided q6h).
  • - Alternative Regimens (based on availability/toxicity):
  • - High-dose Fluconazole (1200mg/day PO/IV) + Flucytosine (100mg/kg/day PO).
  • - Amphotericin B (0.7-1.0mg/kg/day IV) + Fluconazole (1200mg/day PO/IV).
  • - High-dose Fluconazole (1200mg/day PO/IV) alone (less effective).
  • - Liposomal Amphotericin B (L-AmB) 3-4 mg/kg/day IV (preferred over AmB-d if available due to lower nephrotoxicity) + Flucytosine.
  • - Consolidation Phase (Typically 8 weeks): Goal is to prevent relapse.
  • - Fluconazole 800 mg/day PO.
  • - Maintenance Phase (Secondary Prophylaxis): Lifelong or until sustained immune reconstitution on ART.
  • - Fluconazole 200 mg/day PO.
  • Monitoring during Amphotericin B therapy: Renal function (urea, creatinine), electrolytes (Potassium, Magnesium) frequently - risk of nephrotoxicity and electrolyte wasting. Pre-hydration with Normal Saline may reduce risk.
  • Timing of Antiretroviral Therapy (ART) in HIV patients:** For ART-naive patients diagnosed with CM, defer ART initiation for 4-6 weeks after starting antifungal therapy to reduce risk of Immune Reconstitution Inflammatory Syndrome (IRIS). If already on ART, continue ART.
  • Follow specific Ugandan treatment algorithms/guidelines for HIV/OI management.

Monitoring

Monitor clinical response (headache, fever, mental status). Monitor CSF opening pressure (therapeutic LPs). Repeat LP with CSF analysis (cell count, CrAg titre, culture) may be done at end of induction (e.g., 2 weeks) to assess response (CSF sterilization). Monitor for drug toxicity (renal function, electrolytes with AmB; bone marrow suppression with Flucytosine; liver function with azoles). Monitor for signs of IRIS after ART initiation.

Complications

  • Raised Intracranial Pressure (ICP) causing herniation, vision loss, death.
  • Hydrocephalus.
  • Permanent neurological deficits (cognitive impairment, blindness, hearing loss).
  • Seizures / Epilepsy.
  • Cryptococcomas (brain granulomas).
  • Immune Reconstitution Inflammatory Syndrome (IRIS) after starting ART.
  • Relapse of infection (if inadequate treatment or poor adherence to maintenance).
  • Drug toxicity (nephrotoxicity, electrolyte imbalance, anemia).

Prevention

  • Primary Prevention (for HIV+ with CD4 <100): Consider Fluconazole prophylaxis (e.g., 100-200mg daily or 400mg weekly) where CrAg screening is not available or feasible (controversial, weigh against resistance risk).
  • CrAg Screening: Recommended strategy for HIV+ patients with CD4 <100-200. If serum CrAg positive, perform LP. If CSF positive, treat for CM. If CSF negative, start pre-emptive Fluconazole (e.g., 800mg/day for 2 weeks, then 400mg/day for 8 weeks, then 200mg/day maintenance).
  • Effective ART to achieve immune reconstitution (CD4 >100-200) is key long-term prevention.

Patient education

  • Explain the nature of the fungal infection and its link to weakened immunity (HIV).
  • Stress the importance of prolonged antifungal treatment (induction, consolidation, maintenance phases).
  • Explain the critical need for managing brain pressure (therapeutic LPs).
  • Educate on potential drug side effects and need for monitoring.
  • Emphasize importance of adherence to both antifungal and ART medications.
  • Discuss timing of ART initiation/continuation.
  • Explain CrAg screening for prevention in eligible HIV patients.

Uganda-specific notes

Cryptococcal meningitis is the most common cause of adult meningitis in many parts of Uganda due to high HIV prevalence. Serum and CSF CrAg Lateral Flow Assays (LFAs) are often available and crucial for rapid diagnosis. Amphotericin B deoxycholate and Fluconazole are typically available; Flucytosine availability is often limited/expensive. Management of raised ICP via repeated LPs is a cornerstone of care. WHO and National HIV guidelines provide detailed treatment protocols. CrAg screening programs are being implemented.

References

  • Uganda Clinical Guidelines (UCG) 2023

    Chapter 2, Section 2.1.5.2

  • Uganda Consolidated Guidelines for Prevention and Treatment of HIV and AIDS

    (Refer to latest version for detailed CM management protocols, CrAg screening, ART timing)

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