1. Cryptococcal Meningitis in Patients with AIDS

2. 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?

3. Cryptococcus neoformans

4. 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

5. 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)

6. Overview Prompt diagnosis and treatment crucial Fatal if untreated Less frequent since introduction of HAART

7. 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

8. 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)

9. 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

10. 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%)

11. More on Diagnosis Blood cultures (positive in 50–70%) Serum cryptococcus antigen (positive in >95%)

12. 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

13. Diagnostic Imaging Studies CNS Imaging – Indicated in patients with focal neurologic signs, papilledema and/or obtundation – To diagnose lesions that contraindicate lumbar puncture (cryptococcomas)

14. 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

15. Pharmacological Treatment Maintenance Phase: – Fluconazole 200 mg po daily – Can be discontinued following immune reconstitution with HAART – Otherwise fluconazole may be needed for lifetime

16. 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

17. 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

18. Toxicities Related to Drugs Flucytosine Bone marrow suppression Fluconazole GI and hepatotoxicity Amphotericin B Renal toxicity and electrolyte abnormalities

19. 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)

20. Prognostic Indicators Poor Prognosis Increased intracranial pressure Altered mental status Low white blood cell count on CSF Positive India ink

21. 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

22. 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

23. 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.

24. 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.