Infectious Disease · Central Nervous System Infections
The facts most likely to be tested
Press 1–5 to rate · ↑↓ to navigate
Cryptococcal meningitis is the most common opportunistic fungal infection of the central nervous system in patients with advanced HIV/AIDS (CD4 count < 100 cells/mm³).
The causative organism, Cryptococcus neoformans, is an encapsulated yeast typically acquired via inhalation of aerosolized spores from pigeon droppings.
The most sensitive and specific diagnostic test is detection of cryptococcal antigen (CrAg) in the cerebrospinal fluid (CSF) via latex agglutination or lateral flow assay; CSF culture remains the technical gold standard.
CSF analysis typically reveals elevated opening pressure, lymphocytic pleocytosis, low glucose, and elevated protein.
India ink staining of the CSF demonstrates the classic encapsulated yeast with a wide halo appearance.
Induction therapy is liposomal amphotericin B (3–4 mg/kg IV daily) plus flucytosine for 2 weeks; a single high-dose (10 mg/kg) liposomal amphotericin B regimen with flucytosine plus fluconazole is the preferred alternative in resource-limited settings. Amphotericin B deoxycholate is now an alternative rather than preferred.
Delayed initiation of antiretroviral therapy (ART)—generally 4 to 6 weeks after starting antifungal treatment—is recommended to reduce mortality and the risk of immune reconstitution inflammatory syndrome (IRIS).
Vignette unlocked
A 38-year-old male with a history of untreated HIV presents to the emergency department with a two-week history of progressive headache, nausea, and confusion. Physical examination reveals nuchal rigidity and papilledema. His CD4 count is 45 cells/mm³. A lumbar puncture is performed, revealing an opening pressure of 28 cm H2O, a white blood cell count of 40/µL with lymphocytic predominance, a glucose of 35 mg/dL, and an elevated protein level.
What is the most appropriate initial diagnostic test to confirm the suspected diagnosis?
Cryptococcal antigen (CrAg) testing of the CSF
The patient's presentation of subacute meningitis in the setting of severe immunosuppression is classic for cryptococcal meningitis, and the CrAg test is the most sensitive and specific diagnostic modality.
Full handout
High yield triage
Etiology / Epidemiology
Caused by Cryptococcus neoformans; primarily affects HIV/AIDS patients with CD4 < 100 cells/µL.
Clinical Manifestations
Presents as subacute meningitis with headache, fever, and elevated intracranial pressure.
Diagnosis
Cryptococcal antigen (CrAg) in CSF is the most sensitive and specific initial test (CSF culture is the technical gold standard); India ink stain shows encapsulated yeast.
Treatment
Induction: Liposomal amphotericin B plus flucytosine × 2 weeks; consolidation: fluconazole 800 mg daily for ≥8 weeks.
Prognosis
High mortality if untreated; increased intracranial pressure is the primary cause of early death.
Full handout
Epidemiology & Etiology
Caused by the encapsulated yeast Cryptococcus neoformans, typically acquired via inhalation of aerosolized spores from pigeon droppings. It is an AIDS-defining illness, most often at CD4 <100 cells/µL, but also occurs in HIV-negative hosts: patients on chronic corticosteroids, solid-organ transplant recipients, and those with cirrhosis or hematologic malignancy; Cryptococcus gattii can infect apparently immunocompetent hosts.
Pertinent Anatomy
The yeast has a predilection for the central nervous system, crossing the blood-brain barrier to cause meningoencephalitis. The thick polysaccharide capsule inhibits phagocytosis, leading to massive fungal burden in the subarachnoid space.
Pathophysiology
Inhalation leads to pulmonary colonization, followed by hematogenous dissemination to the meninges. The polysaccharide capsule prevents immune clearance; accumulated yeast and capsular polysaccharide obstruct CSF outflow at the arachnoid granulations, producing communicating hydrocephalus and markedly elevated opening pressure on lumbar puncture.
Clinical Manifestations
Presentation is often indolent, evolving over weeks. Look for headache, nuchal rigidity, and altered mental status. Red flag: elevated intracranial pressure manifesting as papilledema, cranial nerve palsies, or vision loss. Unlike bacterial meningitis, nuchal rigidity may be absent in up to 50% of patients.
Diagnosis
Perform lumbar puncture; CSF Cryptococcal antigen (CrAg) is the most sensitive and specific test. India ink stain of CSF reveals encapsulated yeast with a clear halo. Opening pressure is elevated (>20 cm H2O) in the majority of patients; therapeutic CSF drainage is indicated when opening pressure is ≥25 cm H2O or there are symptoms of raised ICP, removing CSF to reduce pressure by ~50% or to <20 cm H2O, repeated daily until stable.
Treatment
Induction: Amphotericin B plus Flucytosine for at least 2 weeks. Caution: Flucytosine requires dose adjustment in renal failure and monitoring for bone marrow suppression. Consolidation: Fluconazole 800 mg daily for ≥8 weeks (may reduce to 400 mg once CSF cultures are sterile and ART started), then maintenance fluconazole 200 mg daily for ≥1 year from the start of antifungal therapy. Maintenance may be stopped when the patient is asymptomatic with CD4 ≥100 cells/mm³ and suppressed HIV RNA on effective ART; restart if CD4 falls below 100.
Prognosis
Early mortality is driven by increased intracranial pressure; serial lumbar punctures are often required. Immune Reconstitution Inflammatory Syndrome (IRIS) is a major risk if ART is started too early; ART is generally deferred 4–6 weeks after antifungal initiation.
Differential Diagnosis
Bacterial meningitis: rapid onset with high CSF neutrophils
Tuberculous meningitis: basilar meningeal enhancement on MRI
Viral meningitis: lymphocytic pleocytosis with normal glucose
Neurosyphilis: positive VDRL/RPR in CSF
Primary CNS lymphoma: ring-enhancing lesions on MRI