How should I diagnose fungal meningitis in an immunocompromised patient presenting with subacute headache, fever, neck stiffness, altered mental status, or visual changes, especially if there are signs of increased intracranial pressure?

Diagnosis of Fungal Meningitis

Diagnose fungal meningitis through cerebrospinal fluid (CSF) analysis with India ink stain, cryptococcal antigen testing, and fungal culture in any patient presenting with subacute headache, fever, altered mental status, or visual changes—especially in immunocompromised hosts—because clinical features alone cannot distinguish fungal from bacterial or viral meningitis and delayed diagnosis is associated with mortality rates approaching 100%. 1, 2

Clinical Presentation: Key Distinguishing Features

Temporal Pattern

• Fungal meningitis typically presents as a subacute or chronic process over days to weeks, contrasting with the acute presentation of bacterial meningitis. 1
• Patients often present after multiple healthcare visits with persistent, gradually worsening symptoms rather than fulminant illness. 3

Core Symptoms to Document

• Headache, fever, neck stiffness, altered mental status, and visual disturbances are the primary manifestations, though the classic triad (fever, neck stiffness, altered mental status) is present in fewer than 50% of cases. 4, 2, 5
• Visual disturbances and cranial nerve palsies (particularly sixth nerve) are more suggestive of fungal or tuberculous meningitis than typical bacterial causes. 6, 2
• Altered mental status occurs in 54-69% of adults but may be subtle initially, presenting as confusion or personality changes rather than frank obtundation. 4, 7

Critical Pitfall

• Do not rely on fever or neck stiffness to make or exclude the diagnosis—neck stiffness has only 31% sensitivity, and immunocompromised or elderly patients frequently lack fever. 4, 8
• Kernig's and Brudzinski's signs have 5-11% sensitivity and should not guide clinical decision-making. 9, 4, 8

Diagnostic Algorithm

Step 1: Identify High-Risk Populations

• Immunocompromised patients (HIV/AIDS, solid organ transplant recipients, chronic corticosteroid use) are at highest risk, but fungal meningitis can occur in immunocompetent hosts. 1, 3, 7
• Maintain high clinical suspicion even in apparently immunocompetent patients with subacute symptoms, as outcomes are worse when diagnosis is delayed. 3, 7

Step 2: Immediate Hospital Referral

• All patients with suspected meningitis require immediate hospital transfer with arrival within 1 hour for urgent evaluation and lumbar puncture consideration. 9, 4

Step 3: Neuroimaging Before Lumbar Puncture

• Obtain CT or MRI before lumbar puncture if the patient has altered consciousness, focal neurological deficits, or signs of increased intracranial pressure, as fungal meningitis frequently causes hydrocephalus and mass lesions. 4, 1
• Focal neurological abnormalities occur in 11-34% of fungal/bacterial meningitis cases and are uncommon in viral meningitis. 8

Step 4: CSF Analysis—The Definitive Diagnostic Test

CSF examination remains the principal diagnostic test and must be performed in every patient with suspected fungal meningitis. 4

Essential CSF Studies:

• India ink stain for direct visualization of encapsulated yeast (particularly Cryptococcus). 1
• Cryptococcal antigen (CrAg) testing in both CSF and serum—highly sensitive and specific for cryptococcal meningitis. 2
• Fungal culture (requires extended incubation; may take days to weeks). 1
• Cell count with differential, protein, and glucose—typically shows lymphocytic pleocytosis, elevated protein, and low glucose, though CSF may be normal in early or mild cases. 6, 1

Expected CSF Profile:

• CSF typically shows clear or slightly turbid fluid with lymphocytic predominance, elevated protein, and low glucose, but these findings are nonspecific and overlap with tuberculous and viral meningitis. 6, 1
• CSF may be completely normal with negative smears and sterile cultures in early fungal meningitis, so negative initial studies do not exclude the diagnosis. 1

Step 5: Adjunctive Diagnostic Tests

• Serum cryptococcal antigen testing can support the diagnosis when CSF cannot be safely obtained. 2
• Obtain detailed travel history and exposure history (bird droppings for Cryptococcus, endemic fungi in specific geographic regions). 1
• Chest imaging to identify pulmonary involvement, as most pathogenic fungi cause primary pulmonary infection with subsequent hematogenous dissemination to the CNS. 1

Common Diagnostic Pitfalls

Atypical Presentations

• Fungal meningitis may present with isolated headache, dental pain, or sinusitis without classic meningeal signs, leading to multiple ED visits before diagnosis. 3, 5
• Elderly patients are more likely to have altered consciousness and less likely to have neck stiffness or fever. 9, 4

False-Negative Results

• Smears for fungi in CSF are frequently negative even in confirmed cases, and nucleic acid amplification may also be negative despite active disease. 6, 1
• Do not exclude fungal meningitis based on negative initial CSF studies if clinical suspicion remains high; repeat lumbar puncture or empiric treatment may be necessary. 1

Delayed Diagnosis

• The interval between first medical contact and diagnosis must be minimized, as delayed treatment significantly increases mortality and neurological morbidity. 6, 2
• Without treatment, mortality approaches 100%; even with treatment, outcomes are often poor due to limited drug choices and drug resistance. 1, 2

When to Initiate Empiric Antifungal Therapy

Start empiric antifungal therapy (amphotericin B with or without fluconazole) immediately in immunocompromised patients with subacute meningitis and CSF abnormalities consistent with fungal infection, even before culture confirmation, because delayed treatment is associated with high mortality. 6, 1, 2