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Infectious Diseases

Cryptococcal Meningitis

A fungal meningitis caused by Cryptococcus neoformans (or C. gattii), typically occurring in individuals with severe immunosuppression, most commonly advanced HIV infection (CD4 count <100 cells/µL).

Also known as: Crypto Meningitis

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Referral and warning signs

When to refer

IMMEDIATE URGENT REFERRAL/ADMISSION to Hospital (H/RR) for ALL suspected cases, for LP, management of raised ICP, and initiation of appropriate antifungal therapy.

Red flags

  • Altered mental status in HIV+ patient.
  • Severe headache in HIV+ patient.
  • Signs of raised ICP (papilloedema, vomiting, CN VI palsy).
  • Seizures.
  • Positive Serum CrAg test.
  • Visual loss.

Signs and symptoms

  • Subacute onset (usually over 1-2 weeks, can be longer).
  • Headache (often severe, persistent).
  • Fever (may be low-grade or absent).
  • Malaise, fatigue.
  • Nausea, vomiting.
  • Altered mental status (confusion, lethargy, personality changes, memory loss).
  • Photophobia.
  • Neck stiffness (may be mild or absent, especially in severely immunocompromised).
  • Visual changes (blurred vision, diplopia - due to raised ICP or optic nerve involvement).
  • Seizures.
  • Focal neurological deficits (less common).
  • Signs of raised intracranial pressure (ICP) - papilloedema (may be absent).

Risk factors

  • Advanced HIV infection (CD4 count <100 cells/µL).
  • Other forms of immunosuppression (organ transplant recipients, long-term high-dose corticosteroids, certain malignancies like lymphoma).
  • Exposure to bird droppings (especially pigeons - environmental source).

Diagnosis

Clinical assessment

Suspicion in an immunosuppressed patient (especially HIV+) presenting with subacute headache, fever, and altered mental status. Classic signs of meningitis may be subtle or absent.

Differential diagnosis

  • Tuberculous meningitis.
  • Bacterial meningitis (usually more acute).
  • Viral encephalitis.
  • Cerebral toxoplasmosis (in HIV+).
  • Progressive Multifocal Leukoencephalopathy (PML) (in HIV+).
  • CNS Lymphoma (in HIV+).
  • Other fungal meningitis.
  • Brain abscess.

Investigations

  • Lumbar Puncture (LP) and CSF Analysis: Essential. Perform unless clear contraindications.
  • - CSF Opening Pressure: CRITICAL to measure. Often markedly elevated (>20-25 cmH2O). Raised ICP is major cause of morbidity/mortality.
  • - CSF India Ink Stain: Microscopic examination reveals encapsulated yeast cells (positive in ~50-80%).
  • - CSF Cryptococcal Antigen (CrAg) Test: Highly sensitive and specific (>95%). Can be detected by Latex Agglutination (LA) or Lateral Flow Assay (LFA). LFA is rapid, point-of-care test.
  • - CSF Cell Count: Variable, often low WBC count with lymphocytic predominance (paucicellular response common in HIV).
  • - CSF Glucose: Often low.
  • - CSF Protein: Often elevated.
  • - CSF Fungal Culture: Gold standard for confirmation, but slow.
  • Serum Cryptococcal Antigen (CrAg) Test: Useful screening tool in high-risk HIV+ patients (CD4<100). Positive serum CrAg strongly suggests risk of meningitis and may warrant pre-emptive treatment or LP.
  • HIV testing (if status unknown), CD4 count.
  • Consider CT/MRI Head before LP if focal signs, seizures, or markedly altered GCS.

Diagnostic criteria

Clinical suspicion + Positive CSF India Ink OR Positive CSF CrAg OR Positive CSF Fungal Culture.

Management

Non-pharmacological management

  • Urgent Hospital Admission.
  • Management of Raised Intracranial Pressure (ICP): CRITICAL component.
  • - Therapeutic Lumbar Punctures: Repeated daily or alternate-day LPs to remove CSF and lower opening pressure (aim for <20 cmH2O or 50% reduction from initial). Remove 20-30mL CSF or until pressure goal reached. Essential for symptom relief (headache) and preventing neurological damage/blindness.
  • - CSF shunting (VP shunt) if refractory raised ICP (specialist neurosurgical procedure).
  • Supportive care (analgesia for headache, antiemetics, seizure management).

Pharmacological treatment

  • Antifungal Therapy (Phased Approach): (LOC: H/RR)
  • - Induction Phase (2 weeks): Goal is rapid fungal clearance.
  • - Preferred: Amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV) PLUS Flucytosine (100 mg/kg/day PO divided Q6H).
  • - Alternative (if Flucytosine unavailable): Amphotericin B deoxycholate (0.7-1.0 mg/kg/day IV) PLUS Fluconazole (1200 mg/day PO/IV).
  • - Alternative (if Amphotericin B unavailable/contraindicated): High-dose Fluconazole (1200 mg/day PO/IV) PLUS Flucytosine (100 mg/kg/day PO divided Q6H).
  • - (Liposomal Amphotericin B preferred if available due to lower toxicity, but costly).
  • - Consolidation Phase (8 weeks): Goal is to prevent relapse.
  • - Fluconazole 800 mg PO daily.
  • - Maintenance Phase (Long-term/Lifelong unless immune reconstitution): Goal is secondary prophylaxis.
  • - Fluconazole 200 mg PO daily.
  • Timing of ART Initiation (in HIV+):
  • - Defer ART initiation for 4-6 weeks after starting antifungal therapy. Starting ART earlier increases risk of Immune Reconstitution Inflammatory Syndrome (IRIS), which can worsen outcomes.
  • Management of Complications: (e.g., seizures).

Monitoring

Monitor clinical response (headache, mental status). Monitor CSF opening pressure with therapeutic LPs. Monitor for drug toxicity (Amphotericin B: renal function, electrolytes - K+, Mg++; Flucytosine: bone marrow suppression). Monitor CD4 count response to ART (guides potential stopping of maintenance therapy - specialist decision).

Complications

  • Raised Intracranial Pressure -> Brain herniation, vision loss (optic neuropathy), hearing loss.
  • Hydrocephalus.
  • Neurological deficits.
  • Seizures.
  • Immune Reconstitution Inflammatory Syndrome (IRIS) upon starting ART.
  • Relapse of infection.
  • Drug toxicity.
  • Death.

Prevention

  • Primary Prophylaxis (Pre-emptive therapy): Consider Fluconazole for HIV+ patients with CD4 <100 AND positive Serum CrAg test (prevents progression to meningitis).
  • Early initiation of ART in HIV infection to maintain higher CD4 counts.
  • Secondary Prophylaxis: Lifelong Fluconazole 200mg daily after successful induction/consolidation therapy, until sustained immune reconstitution on ART (CD4>100-200 for >6m, undetectable viral load - specialist decision to stop).

Patient education

  • Explanation of the serious fungal brain infection.
  • Need for hospitalization, LP (potentially multiple), and prolonged IV/oral antifungal treatment.
  • Importance of managing raised head pressure.
  • Adherence to antifungal medication.
  • If HIV+, importance of ART (but delayed start) and lifelong maintenance therapy.
  • Need for long-term follow-up.

Uganda-specific notes

Cryptococcal meningitis is the most common cause of adult meningitis in Uganda, primarily due to HIV. Serum CrAg screening (LFA) implemented for HIV patients with CD4<100. Management relies heavily on Amphotericin B + Fluconazole (as Flucytosine often unavailable). Aggressive management of raised ICP via therapeutic LPs is critical but resource-intensive. Deferring ART start is key.

References

  • Uganda Clinical Guidelines (UCG) 2023

    Chapter 2, Section 2.1.5.2

  • Uganda Clinical Guidelines (UCG) 2023

    Chapter 7 (HIV Care - OIs)

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