Fungal Meningitis. Stefan Zimmerli Institute for infectious diseases University of Bern Friedbühlstrasse Bern

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1 Fungal Meningitis Stefan Zimmerli Institute for infectious diseases University of Bern Friedbühlstrasse Bern

2 Death due to infectious diseases in sub-saharan Africa Park BJ. Et al AIDS 2009;23:525

3 Causes of meningits Harare, Zimbabwe conscecutive patients with meningitis Hakim JG. Et al. AIDS 2000;14:1401

4 Cryptococcal meningitis Approx. 1 Mio cases/year with deaths 75% of cases and 80% of deaths occur in Sub-Saharan Africa Park BJ. Et al AIDS 2009;23:525 Kambugu A. et al. CID 2008;46:1694

5 Fungal meningitis Rare diseases except for cryptococcal meningitis in HIV Subacute and chronic meningitis leading presentation Acute meningitis rare Complications: abscesses or consequences of vascular occlusion

6 Subacute or chronic meningitis Yeasts Cryptococcus neoformans Candida Coccidioidomycosis Molds (rare) Aspergillus Scedosporium/Pseudallescheria Histoplasmosis Blastomycosis

7 Parenchymal CNS infections Infarction and hemorrhagic necrosis due to vascular invasion Aspergillus Agents of mucormycosis Abscesses Aspergillus Agents of mucormycosis Agents of phaeohyphomycosis

8 Portals of entry Hematogenous spread from pulmonary focus Local extension from paranasal sinuses Trauma surgery ventricular shunts lumbar puncture with injection of drugs head trauma

9 50 y-o female Known HIV+ for 24y, no AIDS defining diseases, no treatment, 107 CD4 + cells Increasing headaches for 3 weeks, fatigue Discrete stiff neck, paresis left abducens nerve, hyperreflexia Hb 101 g/l; L 4; T 241; CRP <3 CSF opening pressure 400 mm H 2 O. CSF WBC 300/mL (100% mononuclear), CSF glucose 1.1 mmol/l (22% of blood glucose) CSF protein 1.4 g/l CT scan normal

10 Cryptococcosis, disseminated w/meningitis Cryptococcus neoformans cultured from blood and CSF. Cryptococcus antigen (CRAG) in blood (1:640) and CSF (1:512) Gomori-methenamine

11 Treatment and evolution d 1 : RMP, INH, PYR, ETH and Fluconazole 800 mg qd d 4 : AmB + 5FC d 4 : acute deterioration; malresorptive hydrocephalus, ICU, mechanical ventilation, ventricular drainage d16 : Extubation, removal of ventricular drainage, CSF GRAG 1:2, CSF no growth, switch to Fluconazole d 27 : Start cart, no complications

12 Cryptococcal meningitis In sub-saharan Africa the most common fatal CNS infection in patients with AIDS in 20 30% of patients with advanced AIDS dye of cryptococcal meningitis Rate in Uganda = 40/1000 person-years (2x US rate in HIV-infected prior to cart) median duration of survival = 26 d Park BJ. Et al AIDS 2009;23:525 Kambugu A. et al. CID 2008;46:1694

13 Causes of suspected meningits: Harare 1994 Cryptococcal meningitis is a disease of the immunocompromised (HIV+, hematological cancer, solid-organ transplantation. Rare in the apparently immunocompetent Hakim JG. Et al. AIDS 2000;14:1401

14 Cryptococcal meningitis Primary infection generally pulmonary Hematogenous dissemination Tropism for meninges Meningitis concurrent or years after primary infection Fever or headache or both for weeks before nausea or vomitus or cerebral nerve palsies or obtundation occur

15 Cryptococcal vs. other meningitis Hakim JG. Et al. AIDS 2000;14:1401

16 Clinical characteristics of Cryptococcal vs. other meningitis Hakim JG. Et al. AIDS 2000;14:1401

17 Diagnosis of cryptococcal meningitis In HIV+ blood cultures are positive in ~50% Serum CRAG has a sensitivity of 96% CSF opening pressure is often increased CSF findings may be normal in patients with advanced cellular immunodeficiency CSF may show mononuclear pleocytosis, elevated protein and decreased glucose levels in less severely immunocompromised

18 Fungicidal treatment effect in cryptococcal meningitis Combination of AmB + 5FC is more rapidly fungicidal than AmB alone 5FC is prohibitively expensive in most settings where the disease is common Brouwer, Lancet 2004;363:1764

19 Treatment of cryptococcal meningitis Amphotericin B 0.7-1mg/kg/d x 14 d + 5-Flucytosine 100 mg/kg/d in 4 divided doses x 14 d Follow-up therapy with oral fluconazole 400 mg/d for at least 10 weeks Mainenance therapy in HIV+ until CD4+ cells >100/µl under successful cart large-volume lumbar punctures or ventricular drainage or ventriculoperitoneal shunting often needed to reduce increased intracranial pressure. Do not use adjunctive corticosteroids.

20 Survival after cryprococcal meningitis: Uganda Treatment with AmB for all 2006 survival rate 6 months after diagnosis was 41%; all under ART Kambugu A. et al. CID 2008;46:1694

21 Cryptococcal meningitis and IRIS Immune reconstitution inflammatory syndrome (inflammation infection) Paradoxical worsening of symptoms under cart (in about 30%) or with reduced immunosuppressive therapy DD symptomatic relapse IRIS with higher opening pressure, CSF glucose and WBC counts

22 39 y-o man advanced liver disease due to hepatitis C and high alcohol intake. ICU due to pneumococcal pneumonia, sepsis and multi-organ failure. Death on ICU d12 despite adequate antibiotic treatment. Meningitis was not diagnosed during life

23 Candida Meningitis

24 Cerebral microabscesses with Candida

25 Candida meningitis Rare Mostly associated with neurosurgery and ventricular drainage Prolonged candidemia rarely leads to meningitis (often associated with microabscesses) Mostly subacute evolution over 2-4 weeks : fever, headache, diminished consciousness, lethargy, and confusion. Meningeal signs may be present.

26 Candida meningitis CSF findings can be indistinguishable from bacterial meningitis although monocytic predominance reported in ~40% Culture from large-volume CSF samples needed for diagnosis Mortality in ventriculostomy-associated cases is 11% Invasion of vessels predominately at the base of the brain may produce infarcts Recommended treatment is amphotericin B mg/kg/d + 5 fluorocytosine 25mg/kg/d in 4 divided doses for a minimum of 4 weeks over the resolution of all signs and symptoms

27 CNS infections due to Aspergillus Disease of immunocompromised patients hematological malignancy undergoing chemotherapy an or bone marrow transplantation Lung is primary focus of infection Hematological dissemination to CNS in 14 40%

28 Invasive pulmonary Aspergillosis

29 hemorrhage ischemic necrosis

30 Cerebral aspergillosis - ischemic necrosis

31 Aspergillus meningitis Very rare Disease of the immunocompetent Extension of sinusitis through skull base into meninges Spinal anesthesia with contaminated syringes Granulomatous inflammation progression over weeks Signs of meningeal irritation unususal Invasion and thrombotic occlusion of vessels at the base of the brain leds to ischemia or hemorrhage

32 Aspergillus meningitis

33 Aspergillus meningitis Lumbar puncture may initially yield normal resuslts Diagnosis may be established by PCR and/or galactomannan determination from CSF Treatment includes surgical débridement of sinus and adjacent bone and voriconazole

34 Rat model of cerebral aspergillosis Intracisternal injection of Aspergillus conidia in non-immunosuppressed 11 d old rats

35 Perivascular inflammation, vascular invasion and thrombosis

36 Evaluation > Survival studies > Monitoring disease progression: - Study animals on day 2, 3, 5 & 11 - Quantitative fungal cultures - Galactomannan determinations by double-antibody-sandwich ELISA - Cytokine determinations by flow-cytometry based assay (Luminex) - MMP-2 & -9 determinations by gelatine zymography - Histopathological evaluation with periodic acid Shiff and Grocott s methenamine silver stainings 36

37 Survival of rats with cerebral aspergillosis 100 p = < survival (%) * Caspofungin (n = 21) Combination CAS + L-AmB (n = 21) Voriconazole (n = 20) Liposomal Amphotericin B (n = 21) Controls (n = 21) days post-infection 37

38 Brain drug levels 1.5 Resistance testing - Caspofungin: mg/l - Amphotericin B: mg/l 1.0 mg/kg day 2 day 3 day 5 day 11 Caspofungin (n = ) Amphotericin B (n = ) 38

39 Summary Fungal meningitis is rare except for Cryptococcal meningitis Commonly presents as subacute or chronic meningitis Diagnosis is straightforward for Cryptococcal meningitis and may be difficult for other causative organisms Fungicidal drugs should be used in the initial treatment phase 39