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.
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