Immunocompetent but Not Immune: A Prolonged Course of Cryptococcal Meningitis

<i>Cryptococcus neoformans</i> is an encapsulated yeast that typically causes cryptococcal meningitis (CM) in immunocompromised hosts. However, CM can rarely occur in immunocompetent individuals, often with atypical or insidious presentations. Persistently positive cerebrospinal fluid (CSF) cultures despite guideline-directed antifungal therapy are uncommon and pose significant management challenges. In this case report, we describe a previously healthy 40-year-old immunocompetent woman who presented with seizures, progressive headaches, and elevated intracranial pressure (ICP). CSF studies confirmed CM with positive cryptococcal antigen and cultures. She was treated with liposomal amphotericin B and flucytosine and later transitioned to high-dose fluconazole due to medication intolerance. Despite >6 weeks of antifungal therapy, serial CSF cultures remained persistently positive through hospital day 56, with clearance achieved only on day 72. ICP management required serial lumbar punctures, temporary lumbar drainage, and ultimately ventriculoperitoneal (VP) shunt placement on day 80. The patient was discharged on prolonged fluconazole consolidation therapy with resolution of headaches but residual right-eye visual deficits. This case highlights the potential for CM in immunocompetent hosts with protracted culture positivity despite guideline-directed antifungal therapy. Early recognition of antifungal intolerance, aggressive ICP management, and timely surgical intervention may be critical for optimizing outcomes in such complex cases.