Cryptococcal Meningitis in Patients with AIDS

Clinical Case

• 30-year-old male with AIDS• CD4 25 cells/mm3• Gradual increasing headache for

past five days• Low-grade fever• Neck stiffness • Nausea

What is your diagnosis?

Cryptococcus neoformans

Learning Objectives

• Upon completion of this activity, participants should be able to:– Describe symptoms of cryptococcal

meningitis– Discuss methods for diagnosing

cryptococcal meningitis – Review treatments for cryptococcal

meningitis

Overview of Cryptococcal Meningitis

• Caused by the fungus Cryptococcus neoformans

• Fungus is found in soil contaminated by bird feces (droppings)

• Inoculation by inhalation of the fungus

• AIDS defining condition (CD4 <100 cells/mm3)

Overview

• Prompt diagnosis and treatment crucial

• Fatal if untreated• Less frequent since introduction of

HAART

Clinical Presentation

• Meningismus or meningeal irritation (neck stiffness)

• Headache, often insidious (gradual)• Low-grade fever• Photophobia (light sensitivity)• Nausea • Can also present with malaise,

confusion, vomiting, obtundation (depressed levels of consciousness), seizure and psychosis

Clinical Presentation of CNS Disease

• Meningitis is the most common presentation of central nervous system (CNS) disease in patients with AIDS

• However, CNS disease can also present as multiple or single focal mass lesions called cryptococcomas (less common)

Increased Intracranial Pressure

• Common in patients with AIDS• Clinical signs and symptoms: focal

neurological signs, papilledema (optic disc swelling caused by increased intracranial pressure), severe headache

• Can lead to herniation, cranial nerve deficit and death

• Treatment aimed at decompressing cerebral spinal fluid (CSF) volume and reducing pressure

Laboratory Diagnosis: CSF Studies

• Examination of the CSF provides useful diagnostic information– Opening pressure (<200mmH2O in 75%)– Cell count and differential (mononuclear

pleocytosis—5–100 mg/dL)– Protein (50–150 mg/dL) – Cryptococcus antigen (positive in >95%)– Fungal culture (positive in >95%)– India ink (positive in 60–80%)

More on Diagnosis

• Blood cultures (positive in 50–70%) • Serum cryptococcus antigen

(positive in >95%)

Lumbar Puncture: Contraindications

• CNS imaging should be performed prior to lumbar puncture in patients with focal neurologic deficits and/or papilledema to evaluate for CNS mass lesions

• Patients with mass lesions within the brain, focal neurologic deficits and/or papilledema should not undergo lumbar puncture due to increased risk of herniation

Diagnostic Imaging Studies

• CNS Imaging – Indicated in patients with focal

neurologic signs, papilledema and/or obtundation

– To diagnose lesions that contraindicate lumbar puncture (cryptococcomas)

Pharmacological Treatment

• Induction Phase:– Amphotericin B IV 0.7–1.0mg/kg daily +

Flucytosine 100–150 mg/kg daily x 14 days

• Lipid formulations of amphotericin B can be used if available for patients with impaired renal function

• Consolidation Phase: – Fluconazole 400 mg po daily for 8–10

weeks

Pharmacological Treatment

• Maintenance Phase:– Fluconazole 200 mg po daily– Can be discontinued following immune

reconstitution with HAART– Otherwise fluconazole may be needed

for lifetime

Alternative Pharmacological Treatment

• Induction Phase– Fluconazole 400 mg daily PO x 8–10

weeks + Flucytosine 100 mg/kg daily PO x 6–10 weeks

• Consolidation Phase – Itraconazole 200 mg twice-daily PO

• Fluconazole 800 mg PO daily x 8 weeks also used in some resource-limited settings for induction and consolidation phases

Treatment of Increased Intracranial Pressure

• CSF drainage for opening pressure >250 mmH2O

• Treatment involves serial LPs, ventriculoperitoneal shunts or lumbar drain aimed at reducing opening pressure to <200 mmH2O

• Repeat lumbar drainage as needed until achieving stable opening pressure

Toxicities Related to Drugs

Flucytosine • Bone marrow suppression

Fluconazole • GI and hepatotoxicity

Amphotericin B• Renal toxicity and electrolyte

abnormalities

Treatment Failure

• Repeat lumbar puncture if no improvement or worsening of symptoms

• Consider alternative diagnosis • Fluconazole and amphotericin

resistance (rare)• Consider immune reconstitution

syndrome (IRIS)

Prognostic Indicators

Poor Prognosis • Increased intracranial pressure• Altered mental status • Low white blood cell count on CSF • Positive India ink

Summary

• Cryptococcus meningitis is fatal if untreated

• Elevated intracranial pressure is associated with a poor prognosis and must be managed promptly

• Obtain brain image prior to lumbar puncture in patients with focal neurological deficits, papilledema and/or obtundation

Summary

• Treatment is a three-phase process of induction, consolidation and maintenance therapy

• Maintenance treatment with fluconazole may be discontinued following immune reconstitution with HAART

• Otherwise fluconazole may be needed for lifetime

References

• Lenders A, Reiss P, Portegies P et al. 1997. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS. 11:1463-71.

• Saag M, Graybill R, Larsen R et al. 2000. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infec Dis. Apr; 30(4):710-8.

• Saag M, Powderly W, Cloud G et al. 1992. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med. Jun; 326:83-9.

References

• Sobel J. 2000. Practice guidelines for the treatment of fungal infections. For the Mycoses Study Group. Infectious Diseases Society of America. Clin Infect Dis. Apr; 30(4):652.

• van de Horst C, Saag M, Cloud G et al. 1997. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. Nov; 337:15-21.