| Presentation | • Headache, fever & malaise • Develops over 2 weeks (subacute) • Can be more acute & severe in patients with HIV | | --- | --- | | Diagnosis | Cerebrospinal fluid: • High opening pressure • Low glucose, high protein • White blood cells <50/mm3 with mononuclear predominance • Transparent capsule seen with India ink stain • Cryptococcal antigen positive • Culture on Sabouraud agar | | Treatment | • Initial: amphotericin B with flucytosine • Maintenance: fluconazole |

is a common AIDS-defining illness in patients with HIV who have CD4 counts <100/mm3.

Symptoms usually develop due to progressive obstruction of cerebrospinal fluid (CSF) outflow by cryptococcal proteins.  Manifestations arise over 1-2 weeks and typically include headache, fever, and malaise; a minority of patients develop vomiting, stiff neck, and papilledema.  In severe cases, coma and death can occur.

Diagnosis is made when encapsulated yeasts (Cryptococcus neoformans) are identified in cerebrospinal fluid.

Patients with HIV who have suspected meningitis require neuroimaging prior to consideration of lumbar puncture.  Brain imaging (eg, noncontrast head CT) can be normal in patients with cryptococcal meningitis (as in this case), but it can also reveal leptomeningeal enhancement, micronodules, coalescing gelatinous pseudocysts ("soap bubbles"), and ventriculomegaly.  Patients with no significant alterations on neuroimaging should undergo lumbar puncture, which helps establish the diagnosis.  CSF analysis usually shows elevated opening pressure, low glucose, high protein, and a lymphocytic pleocytosis (although white cells may be reduced in patients with HIV).  Diagnosis can be confirmed with India ink stain (encapsulated yeast), culture on Sabouraud agar, or identification of cryptococcal antigen in CSF.  In addition to antifungal therapy, some patients require serial lumbar punctures to control intracranial pressure.

Patients with cryptococcal meningitis usually require 3 successive phases of treatment, as follows:

• Induction therapy with intravenous liposomal amphotericin B plus flucytosine is given for ≥2 weeks until acute symptoms resolve and/or cerebrospinal fluid becomes sterile.
• Consolidation therapy with high-dose oral fluconazole is given for ≥8 weeks to prevent disease relapse.
• Maintenance therapy with low-dose oral fluconazole is given indefinitely or until CD4 counts rise to >100/mm3 for >3 months on antiretroviral therapy (ART).

ART should be initiated in all patients with HIV.  However, due to the risk of life-threatening CNS complications from immune reconstitution syndrome (worsening of infections after ART initiation due to increased inflammation), ART initiation is generally delayed for approximately 2 weeks after treatment begins for Cryptococcus.

Intrathecal AmB may be considered as salvage therapy for patients who have failed systemic therapy or developed significant adverse effects to intravenous medications. Serial lumbar punctures may be required to reduce increased intracranial pressure (associated with increased morbidity and mortality).

• EDUCATIONAL OBJECTIVES

(Choice C)  Itraconazole can be used for consolidation therapy in those unable to take fluconazole.  However, it is considered a second-line agent because it is less effective at preventing relapse and has more adverse effects and drug interactions.

(Choice D)  Cessation of treatment after induction therapy is associated with a high rate of relapse; patients need to have consolidation therapy to prevent recurrence.

(Choice E)  Although corticosteroids are used as an adjuvant treatment to limit inflammation in some opportunistic infections (eg, severe Pneumocystis pneumonia, tuberculous meningitis), corticosteroids do not improve outcomes in patients with cryptococcal meningitis and may slow clearance of the organism from the CNS.  Therefore, corticosteroids are not recommended as part of standard treatment.

(Choice D)  Itraconazole can be used as an alternate to fluconazole in pulmonary cryptococcal infection.  However, compared to fluconazole, it has less reliable drug levels in CSF and is associated with more side effects.  It can sometimes be used as a second-line agent for consolidation and maintenance therapy for cryptococcal meningoencephalitis if fluconazole is not tolerated or not available.