Fungal meningitis overview: Difference between revisions

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{{Fungal meningitis}}
{{Fungal meningitis}}  
{{CMG}}; '''Assistant Editor(s)-in-Chief:''' [[User:Rim Halaby|Rim Halaby]]
{{CMG}}; {{AE}} [[User:Rim Halaby|Rim Halaby]]; {{PTD}}


==Overview==
==Overview==
[[Fungal meningitis]] results from the infection of the [[meninges]] by [[fungi]], most commonly [[cryptococcus]]. While cryptococcal meningitis occurs worldwide, other [[fungal meningitis]] are endemic to specific regions of the world. [[Fungal meningitis]] usually affects immunocompromised patients like [[HIV]] patients and transplant recipients on chronic immunosuppression medications. The course of the disease is progressive and might lead to complications if a high dose long term treatment with [[antifungals]] was not initiated.
[[Fungal meningitis]] results from the infection of the [[meninges]] by [[fungi]], most commonly [[cryptococcus]]. While cryptococcal meningitis occurs worldwide, other [[fungal meningitis]] are endemic to specific regions of the world.<ref name="pmid16696655">{{cite journal| author=Bovers M, Hagen F, Kuramae EE, Diaz MR, Spanjaard L, Dromer F et al.| title=Unique hybrids between the fungal pathogens Cryptococcus neoformans and Cryptococcus gattii. | journal=FEMS Yeast Res | year= 2006 | volume= 6 | issue= 4 | pages= 599-607 | pmid=16696655 | doi=10.1111/j.1567-1364.2006.00082.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16696655  }} </ref> [[Fungal meningitis]] usually affects [[immunocompromised]] patients like [[HIV]] patients and [[transplant]] recipients on [[chronic]] [[immunosuppression]] medications. The course of the disease is progressive and may lead to complications if a high dose long term treatment with [[antifungals]] are not initiated.<ref name="pmid11051295">{{cite journal| author=Gottfredsson M, Perfect JR| title=Fungal meningitis. | journal=Semin Neurol | year= 2000 | volume= 20 | issue= 3 | pages= 307-22 | pmid=11051295 | doi=10.1055/s-2000-9394 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11051295  }} </ref>
 
==Historical perspective==
The first report of human [[cryptococcosis]] was published by Busse and Busckhe more than 100 years ago; 10 years later, it was identified as the cause of human [[meningitis]]. [[Cryptococcus neoformans]], an encapsulated basidiomycetous [[yeast]], represents one of the most common [[CNS]] pathogens encountered in clinical practice today. In 1661, Thomas Willis first described the [[inflammation]] of [[meninges]] and an [[epidemic]] of [[meningitis]]. In 1891, Heinrich Quincke provided an early analysis of [[CSF]] by introducing a new technique of [[lumbar puncture]]. Some specific historical feature usually surround the outbreak of rare causes of fungal meningitis. For example, outbreaks of fungal meningitis in 2002 with [[Exophiala]] dermatitidis and more recently in 2012 with Exserohilum rostratum were associated with [[contamination]] of compounded [[corticosteroids]] with resultant severe complications.<ref name="pmid12532960" /><ref name="pmid23252499" /><ref name="pmid23465119" /> The 1980s witnessed an increase in the number of cases of [[cryptococcus]] meningitis in the United States and certain African countries  largely due to [[HIV AIDS|HIV infection]]
 
==Classification==
Fungal meningitis is usually classified according to the causative [[organism]] if identified. It may also be additionally classified according to the severity and duration of the disease as mild, moderate, severe, acute, subacute, chronic and recurrent fungal meningitis.<ref name="pmid26792138">{{cite journal| author=Zheng H, Chen Q, Xie Z, Wang D, Li M, Zhang X et al.| title=A retrospective research of HIV-negative cryptococcal meningoencephalitis patients with acute/subacute onset. | journal=Eur J Clin Microbiol Infect Dis | year= 2016 | volume= 35 | issue= 2 | pages= 299-303 | pmid=26792138 | doi=10.1007/s10096-015-2545-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26792138  }} </ref><ref name="pmid23221842">{{cite journal| author=Zunt JR, Baldwin KJ| title=Chronic and subacute meningitis. | journal=Continuum (Minneap Minn) | year= 2012 | volume= 18 | issue= 6 Infectious Disease | pages= 1290-318 | pmid=23221842 | doi=10.1212/01.CON.0000423848.17276.21 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23221842  }} </ref><ref name="pmid20097705">{{cite journal| author=Chimalizeni Y, Tickell D, Connell T| title=Evidence behind the WHO guidelines: hospital care for children: what is the most appropriate anti-fungal treatment for acute cryptococcal meningitis in children with HIV? | journal=J Trop Pediatr | year= 2010 | volume= 56 | issue= 1 | pages= 4-12 | pmid=20097705 | doi=10.1093/tropej/fmp123 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20097705  }} </ref><ref name="pmid7711408">{{cite journal| author=Malessa R, Krams M, Hengge U, Weiller C, Reinhardt V, Volbracht L et al.| title=Elevation of intracranial pressure in acute AIDS-related cryptococcal meningitis. | journal=Clin Investig | year= 1994 | volume= 72 | issue= 12 | pages= 1020-6 | pmid=7711408 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7711408  }} </ref><ref name="pmid1727236">{{cite journal| author=Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK et al.| title=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. | journal=N Engl J Med | year= 1992 | volume= 326 | issue= 2 | pages= 83-9 | pmid=1727236 | doi=10.1056/NEJM199201093260202 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1727236  }} </ref><ref name="pmid18843697">{{cite journal| author=Sloan D, Dlamini S, Paul N, Dedicoat M| title=Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings. | journal=Cochrane Database Syst Rev | year= 2008 | volume=  | issue= 4 | pages= CD005647 | pmid=18843697 | doi=10.1002/14651858.CD005647.pub2 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18843697  }} </ref><ref name="pmid8838190">{{cite journal| author=Witt MD, Lewis RJ, Larsen RA, Milefchik EN, Leal MA, Haubrich RH et al.| title=Identification of patients with acute AIDS-associated cryptococcal meningitis who can be effectively treated with fluconazole: the role of antifungal susceptibility testing. | journal=Clin Infect Dis | year= 1996 | volume= 22 | issue= 2 | pages= 322-8 | pmid=8838190 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8838190  }} </ref><ref name="pmid26392507">{{cite journal| author=Morgand M, Rammaert B, Poirée S, Bougnoux ME, Tran H, Kania R et al.| title=Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole. | journal=Antimicrob Agents Chemother | year= 2015 | volume= 59 | issue= 12 | pages= 7857-61 | pmid=26392507 | doi=10.1128/AAC.01506-15 | pmc=4649149 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26392507  }} </ref><ref name="pmid16291364">{{cite journal| author=Banarer M, Cost K, Rychwalski P, Bryant KA| title=Chronic lymphocytic meningitis in an adolescent. | journal=J Pediatr | year= 2005 | volume= 147 | issue= 5 | pages= 686-90 | pmid=16291364 | doi=10.1016/j.jpeds.2005.07.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16291364  }} </ref>


==Pathophysiology==
==Pathophysiology==
The pathophysiology of [[fungal meningitis]] is not very well studied but it is known to have a lot of similarities with bacterial meningitis. [[Fungal meningitis]] usually occurs in [[immunocompromised]] patients.
The pathophysiology of [[fungal meningitis]] is not very well studied however, it is known to have a lot of similarities with [[bacterial meningitis]]. [[Fungal meningitis]] usually occurs in [[immunocompromised]] [[patients]]. The initial step in [[fungal meningitis]] is the [[pulmonary]] exposure to the [[fungi]] by the inhalation of [[Airborne transmission|airborne]] fungal spores. The [[pulmonary]] [[infection]] is usually self limited and maybe asymptomatic. Fungal infections are not [[contagious]] so they do not spread from one person to another.With an associated impaired immune response the fungus may disseminate. For instance in [[Cryptococcosis|cryptococcal]] infection, the fungus may remain dormant in the lungs until the immune system weakens and then can reactivate and disseminate to the CNS. [[Cryptococcus]] has predilection for CNS dessimination. Although this remains unclear, the presence of a receptor on [[Glial cell|glial cells]] for a [[ligand]] on the organism has been suggested to enhance its invasion.<ref name="pmid8483058" />  [[Cryptococcal Meningitis|Cryptococcal meningitis]] is most common due to the [[virulence factors]] of the organism that enhancing invasion of the blood brain barrier. These factors include: [[polysaccharide]] capsule which makes the organism withstand  [[phagocytosis]] and host immune system, [[melanin]] production, ability to thrive at mammalian body temperatures, [[urease]] production and [[phospholipase]] production.<ref name="pmid3928681">{{cite journal| author=Granger DL, Perfect JR, Durack DT| title=Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide. | journal=J Clin Invest | year= 1985 | volume= 76 | issue= 2 | pages= 508-16 | pmid=3928681 | doi=10.1172/JCI112000 | pmc=423853 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3928681  }} </ref><ref name="pmid22418440">{{cite journal| author=Jong A, Wu CH, Gonzales-Gomez I, Kwon-Chung KJ, Chang YC, Tseng HK et al.| title=Hyaluronic acid receptor CD44 deficiency is associated with decreased Cryptococcus neoformans brain infection. | journal=J Biol Chem | year= 2012 | volume= 287 | issue= 19 | pages= 15298-306 | pmid=22418440 | doi=10.1074/jbc.M112.353375 | pmc=3346080 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22418440  }} </ref><ref name="pmid3079732">{{cite journal| author=Kwon-Chung KJ, Rhodes JC| title=Encapsulation and melanin formation as indicators of virulence in Cryptococcus neoformans. | journal=Infect Immun | year= 1986 | volume= 51 | issue= 1 | pages= 218-23 | pmid=3079732 | doi= | pmc=261090 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3079732  }} </ref><ref name="pmid2117574">{{cite journal| author=Polacheck I, Platt Y, Aronovitch J| title=Catecholamines and virulence of Cryptococcus neoformans. | journal=Infect Immun | year= 1990 | volume= 58 | issue= 9 | pages= 2919-22 | pmid=2117574 | doi= | pmc=313587 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2117574  }} </ref><ref name="pmid1898925">{{cite journal| author=Jacobson ES, Emery HS| title=Catecholamine uptake, melanization, and oxygen toxicity in Cryptococcus neoformans. | journal=J Bacteriol | year= 1991 | volume= 173 | issue= 1 | pages= 401-3 | pmid=1898925 | doi= | pmc=207201 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1898925  }} </ref><ref name="pmid8226653">{{cite journal| author=Jacobson ES, Tinnell SB| title=Antioxidant function of fungal melanin. | journal=J Bacteriol | year= 1993 | volume= 175 | issue= 21 | pages= 7102-4 | pmid=8226653 | doi= | pmc=206840 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8226653  }} </ref><ref name="pmid8007987">{{cite journal| author=Chang YC, Kwon-Chung KJ| title=Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence. | journal=Mol Cell Biol | year= 1994 | volume= 14 | issue= 7 | pages= 4912-9 | pmid=8007987 | doi= | pmc=358863 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8007987  }} </ref><ref name="pmid10639402">{{cite journal| author=Cox GM, Mukherjee J, Cole GT, Casadevall A, Perfect JR| title=Urease as a virulence factor in experimental cryptococcosis. | journal=Infect Immun | year= 2000 | volume= 68 | issue= 2 | pages= 443-8 | pmid=10639402 | doi= | pmc=97161 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10639402  }} </ref><ref name="pmid11123698">{{cite journal| author=Cox GM, McDade HC, Chen SC, Tucker SC, Gottfredsson M, Wright LC et al.| title=Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans. | journal=Mol Microbiol | year= 2001 | volume= 39 | issue= 1 | pages= 166-75 | pmid=11123698 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11123698  }} </ref> Once the fungi cross the [[blood brain barrier]] they cause an inflammation of the [[meninges]] and [[arachnoid space]]. The inflammation promotes [[cytokine]] release mainly [[tumor necrosis factor]] (TNF), [[interleukin 1]],  [[interleukin 1|interleukin 2 ,]] [[interleukin 6]],  [[interleukin 1|interleukin 12]],  colony-stimulating factors, and interferon-λ.<ref name="pmid7682573" /><ref name="pmid8014494" /><ref name="pmid3110308" /> The cytokines lead to modulation of host system resuting in [[fever]], increase in the permeability of the [[blood brain barrier]] and subsequent [[cerebral edema]] and increase in the [[intracranial pressure]]. The increase in the permeability of the [[blood brain barrier]] is the cause of the observed elevation of the protein level in the [[cerebral spinal fluid]].<ref name=":0" />
The initial step in [[fungal meningitis]] is the pulmonary exposure to the fungi by the inhalation of airborne fungal spores. The pulmonary infection is usually self limited and maybe asymptomatic. Fungal infections are not contagious so they do not spread from one person to another. In most cases of [[fungal meningitis]], the fungi then undergo hematogenous spread and crosses the blood brain barrier causing an infection of the [[meninges]].
 
==Causes==
==Causes==
[[Fungal meningitis]] is initially caused by the inhalation of airborne fungal spores. The pulmonary infection is usually self limited and can be asymptomatic. The most common cause of fungal infection is ''[[C. neoformans]]'' which is usually found in soil and bird excreta.<ref>Koroshetz WJ. Chapter 382. Chronic and Recurrent Meningitis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.</ref>
[[Fungal meningitis]] is initially caused by the inhalation of airborne fungal spores. The pulmonary infection is usually self limiting and can be asymptomatic. The most common cause of fungal infection is [[cryptococcus neoformans]] which is usually found in soil and bird excreta.<ref>Koroshetz WJ. Chapter 382. Chronic and Recurrent Meningitis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.</ref> Other common causes of fungal meningitis include; ''[[Aspergillus]] spp.,'' ''[[Blastomyces dermatitidis]],'' ''[[Coccidioides immitis]],'' ''[[Candida]] spp.,'' ''[[Histoplasma capsulatum]]'' and ''[[Sporothrix schenckii]].''<ref name="pmid12751260">{{cite journal| author=Chiller TM, Galgiani JN, Stevens DA| title=Coccidioidomycosis. | journal=Infect Dis Clin North Am | year= 2003 | volume= 17 | issue= 1 | pages= 41-57, viii | pmid=12751260 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12751260  }} </ref><ref name="pmid11429020">{{cite journal| author=Singh N, Husain S| title=Infections of the central nervous system in transplant recipients. | journal=Transpl Infect Dis | year= 2000 | volume= 2 | issue= 3 | pages= 101-11 | pmid=11429020 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11429020  }} </ref><ref name="pmid11229838">{{cite journal| author=Rosenstein NE, Emery KW, Werner SB, Kao A, Johnson R, Rogers D et al.| title=Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995-1996. | journal=Clin Infect Dis | year= 2001 | volume= 32 | issue= 5 | pages= 708-15 | pmid=11229838 | doi=10.1086/319203 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11229838  }} </ref><ref name="pmid11051295">{{cite journal| author=Gottfredsson M, Perfect JR| title=Fungal meningitis. | journal=Semin Neurol | year= 2000 | volume= 20 | issue= 3 | pages= 307-22 | pmid=11051295 | doi=10.1055/s-2000-9394 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11051295  }} </ref><ref name="pmid10775973">{{cite journal| author=del Brutto OH| title=[Central nervous system mycotic infections]. | journal=Rev Neurol | year= 2000 | volume= 30 | issue= 5 | pages= 447-59 | pmid=10775973 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10775973  }} </ref> Rarely, fungal meningitis may be caused by ''Xylohypha'' (formerly ''[[Cladosporium]]'') ''trichoides,'' ''[[Curvularia]],''  ''[[Mucor]]'', Arthrographis kalrae, [[Pneumocystis jirovecii|Pneumocystis jirovecii,]]<ref name="pmid9495679">{{cite journal| author=Villanueva JL, Cordero E, Caballero-Granado FJ, Regordan C, Becerril B, Pachón J| title=Pneumocystis carinii meningoradiculitis in a patient with AIDS. | journal=Eur J Clin Microbiol Infect Dis | year= 1997 | volume= 16 | issue= 12 | pages= 940-2 | pmid=9495679 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9495679  }} </ref><ref name="pmid9629775">{{cite journal| author=Baena Luna MR, Muñoz García J, Grancha Bertolín L, Sanz García M| title=[Presence of Pneumocystis carinii in cerebrospinal fluid]. | journal=An Med Interna | year= 1998 | volume= 15 | issue= 5 | pages= 265-6 | pmid=9629775 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9629775  }} </ref> [[Cryptococcus]] albidus,<ref name="pmid7185917">{{cite journal| author=Melo JC, Srinivasan S, Scott ML, Raff MJ| title=Cryptococcus albidus meningitis. | journal=J Infect | year= 1980 | volume= 2 | issue= 1 | pages= 79-82 | pmid=7185917 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7185917  }} </ref>, [[Alternaria]] spp,<ref name="pmid13730495">{{cite journal| author=OHASHI Y| title=On a rare disease due to Alternaria tenuis Nees (alternariasis). | journal=Tohoku J Exp Med | year= 1960 | volume= 72 | issue=  | pages= 78-82 | pmid=13730495 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13730495  }} </ref>, [[Rhodotorula]] spp, <ref name="pmid18974495">{{cite journal| author=Shinde RS, Mantur BG, Patil G, Parande MV, Parande AM| title=Meningitis due to Rhodotorula glutinis in an HIV infected patient. | journal=Indian J Med Microbiol | year= 2008 | volume= 26 | issue= 4 | pages= 375-7 | pmid=18974495 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18974495  }} </ref> [[Acremonium]] spp,<ref name="pmid1956281">{{cite journal| author=Fincher RM, Fisher JF, Lovell RD, Newman CL, Espinel-Ingroff A, Shadomy HJ| title=Infection due to the fungus Acremonium (cephalosporium). | journal=Medicine (Baltimore) | year= 1991 | volume= 70 | issue= 6 | pages= 398-409 | pmid=1956281 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1956281  }} </ref> Dreschlera spp,<ref name="pmid4739938">{{cite journal| author=Fuste FJ, Ajello L, Threlkeld R, Henry JE| title=Drechslera hawaiiensis: causative agent of a fatal fungal meningo-encephalitis. | journal=Sabouraudia | year= 1973 | volume= 11 | issue= 1 | pages= 59-63 | pmid=4739938 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4739938  }} </ref> [[Malassezia]] spp,<ref name="pmid15255040">{{cite journal| author=Rosales CM, Jackson MA, Zwick D| title=Malassezia furfur meningitis associated with total parenteral nutrition subdural effusion. | journal=Pediatr Dev Pathol | year= 2004 | volume= 7 | issue= 1 | pages= 86-90 | pmid=15255040 | doi=10.1007/s10024-003-4030-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15255040  }} </ref> [[Scedosporium apiospermum|Scedosporium]] spp,<ref name="pmid16678041">{{cite journal| author=Symoens F, Knoop C, Schrooyen M, Denis O, Estenne M, Nolard N et al.| title=Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient after double-lung transplantation. | journal=J Heart Lung Transplant | year= 2006 | volume= 25 | issue= 5 | pages= 603-7 | pmid=16678041 | doi=10.1016/j.healun.2005.12.011 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16678041  }} </ref> Arthrographis spp,<ref name="pmid11158158">{{cite journal| author=Chin-Hong PV, Sutton DA, Roemer M, Jacobson MA, Aberg JA| title=Invasive fungal sinusitis and meningitis due to Arthrographis kalrae in a patient with AIDS. | journal=J Clin Microbiol | year= 2001 | volume= 39 | issue= 2 | pages= 804-7 | pmid=11158158 | doi=10.1128/JCM.39.2.804-807.2001 | pmc=87827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11158158  }} </ref>  Blastoschizomyces,<ref name="pmid1810730">{{cite journal| author=Girmenia C, Micozzi A, Venditti M, Meloni G, Iori AP, Bastianello S et al.| title=Fluconazole treatment of Blastoschizomyces capitatus meningitis in an allogeneic bone marrow recipient. | journal=Eur J Clin Microbiol Infect Dis | year= 1991 | volume= 10 | issue= 9 | pages= 752-6 | pmid=1810730 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1810730  }} </ref><ref name="pmid2324536">{{cite journal| author=Naficy AB, Murray HW| title=Isolated meningitis caused by Blastoschizomyces capitatus. | journal=J Infect Dis | year= 1990 | volume= 161 | issue= 5 | pages= 1041-2 | pmid=2324536 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2324536  }} </ref> [[Paecilomyces|Paecilomyces,]]<ref name="pmid12588483">{{cite journal| author=Kantarcioğlu AS, Hatemi G, Yücel A, De Hoog GS, Mandel NM| title=Paecilomyces variotii central nervous system infection in a patient with cancer. | journal=Mycoses | year= 2003 | volume= 46 | issue= 1-2 | pages= 45-50 | pmid=12588483 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12588483  }} </ref><ref name="pmid7192726">{{cite journal| author=Fagerburg R, Suh B, Buckley HR, Lorber B, Karian J| title=Cerebrospinal fluid shunt colonization and obstruction by Paecilomyces variotii. Case report. | journal=J Neurosurg | year= 1981 | volume= 54 | issue= 2 | pages= 257-60 | pmid=7192726 | doi=10.3171/jns.1981.54.2.0257 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7192726  }} </ref> [[Aureobasidium]],<ref name="pmid22504065">{{cite journal| author=Kutleša M, Mlinarić-Missoni E, Hatvani L, Voncina D, Simon S, Lepur D et al.| title=Chronic fungal meningitis caused by Aureobasidium proteae. | journal=Diagn Microbiol Infect Dis | year= 2012 | volume= 73 | issue= 3 | pages= 271-2 | pmid=22504065 | doi=10.1016/j.diagmicrobio.2012.03.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22504065  }} </ref> Clavispora,<ref name="pmid10030550">{{cite journal| author=Krcmery V, Mateicka F, Grausova S, Kunova A, Hanzen J| title=Invasive infections due to Clavispora lusitaniae. | journal=FEMS Immunol Med Microbiol | year= 1999 | volume= 23 | issue= 1 | pages= 75-8 | pmid=10030550 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10030550  }} </ref>  [[Ustilago|Ustilago,]]<ref name="pmid20991975">{{cite journal| author=MOORE M, RUSSELL WO, SACHS E| title=Chronic leptomeningitis and ependymitis caused by Ustilago, probably U. zeae (corn smut). | journal=Am J Pathol | year= 1946 | volume= 22 | issue=  | pages= 761-77 | pmid=20991975 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20991975  }} </ref> [[Exophiala]] (Wangiella)<ref name="pmid12530707">{{cite journal| author=Centers for Disease Control and Prevention (CDC)| title=Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy--United States, July-November 2002. | journal=MMWR Morb Mortal Wkly Rep | year= 2002 | volume= 51 | issue= 49 | pages= 1109-12 | pmid=12530707 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12530707  }} </ref> and Exserohilum<ref name="pmid23465119">{{cite journal| author=Pettit AC, Pugh ME| title=Index case for the fungal meningitis outbreak, United States. | journal=N Engl J Med | year= 2013 | volume= 368 | issue= 10 | pages= 970 | pmid=23465119 | doi=10.1056/NEJMc1300630 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23465119  }} </ref><br>
==Differentiating (Disease name) from other Conditions==
 
The differential diagnosis of [[fungal meningitis]] includes a range of medical conditions that can be broadly classified into infectious and non infectious. The [[cerebrospinal fluid]] analysis and radiological findings help distinguishing [[fungal meningitis]] from other etiologies.
== Differentiating fungak meningitis from other Conditions ==
The differential diagnosis of fungal meningitis includes a range of medical conditions that can be broadly classified into [[infectious]] and non infectious. The [[cerebrospinal fluid]] analysis and radiological findings help distinguishing [[fungal meningitis]] from other causes of meningitis example bacterial meningeal infection, [[protozoa|protozoal]] [[meningeal]] infection, viral [[meningeal]] infection, and non infectious causes.
 
==Epidemiology and Demographics==
==Epidemiology and Demographics==
While [[cryptococccus]] and [[candida]] infections occur worldwide, other [[fungal infections]] tend to cluster in specific geographical regions. The most common cause of [[fungal meningitis]] is Cryptococcus meningitis.
While [[cryptococcus]] and [[candida]] infections occur worldwide, other [[fungal infections]] tend to cluster in specific geographical regions.<ref name="pmid17921648">{{cite journal| author=Shankar SK, Mahadevan A, Sundaram C, Sarkar C, Chacko G, Lanjewar DN et al.| title=Pathobiology of fungal infections of the central nervous system with special reference to the Indian scenario. | journal=Neurol India | year= 2007 | volume= 55 | issue= 3 | pages= 198-215 | pmid=17921648 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17921648  }} </ref><ref name="pmid11051295">{{cite journal| author=Gottfredsson M, Perfect JR| title=Fungal meningitis. | journal=Semin Neurol | year= 2000 | volume= 20 | issue= 3 | pages= 307-22 | pmid=11051295 | doi=10.1055/s-2000-9394 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11051295  }} </ref> There is an increasing trend of fungal meningitis. This has been attributed  to enlarging population of high-risk [[immunosuppressed]] patients, more successful pharmacological [[immunosuppression]] and chemotherapies, increase in numbers of patients living with [[Human Immunodeficiency Virus (HIV)|human immunodeficiency virus]] (HIV) infection and the [[acquired immunodeficiency syndrome]] (AIDS), migration of susceptible persons into hyperendemic areas and aging of the population.<ref name="pmid11051295" /><ref name="pmid480580" /> Cryptococcal meningitis occurs worldwide but it is highly prevalent in southeast Asia and southern and east Africa where the prevalence of [[HIV]] is high.<ref name=":0" /> The incidence of cryptococcal meningitis is almost the same as in [[meningococcal meningitis]]<ref name="pmid8654513" /> with an incidence of one case per 100,000 persons.<ref name="pmid8654513" />
Prior to the introduction of [[AIDS antiretroviral drugs|highly active antiretroviral therapy]] (HAART) in the United States, yearly incidence rate of cryptococcal meningitis was on ascendancy with incidence of  6600 cases per 100,000 persons with AIDS<ref name="pmid12627365" />  The incidence has decreased with the advent of HAART <ref name="pmid11125898" /> although cases are still reported.<ref name="pmid10930155" /> The worldwide incidence of cryptococcal meningitis is pegged at 1,000,000 annually according to an estimate by Centers for Disease Control and Prevention CDC in 2009<ref name="pmid19182676" /> with approximately half of these resulting in death.<ref name="pmid19182676" /> The prevalence of fungal meningitis does not vary with gender.<ref name="pmid20375357" /> Non-Caucasian race have a higher prediclection to developing fungal meningitis especially coccidioidal meningitis<ref name="pmid7231152" /> The prevalence of fungal meningitis does not vary with age.<ref name="pmid20375357" /> The major factor accounting for age predilection has to do with the clinical state of the patient and the [[immune]] response. For example candida meningitis may occur in older children<ref name="pmid10066050" /><ref name="pmid10987704" /> and in adults with [[neutropenia]], often presenting with [[brain abscesses]] rather than [[meningitis]].<ref name="pmid9810800" /> Children with certain conditions have higher incidence of fungal meningitis example [[myeloperoxidase deficiency]],<ref name="pmid6834633" /><ref name="pmid8381226" /> [[chronic granulomatous disease]] of childhood<ref name="pmid7195647" /><ref name="pmid3706396" /> and [[chronic mucocutaneous candidiasis]].<ref name="pmid8160723" />
 
==Screening==
It is recommended that patients with [[CD4]] counts ≤ 100 cells/μl, should have routine [[Cryptococcosis|cryptococcal]] [[antigen]] screening. Patients with positive result are offered preemptive anti-fungal therapy.<ref name="pmid28166254">{{cite journal| author=Cassim N, Schnippel K, Coetzee LM, Glencross DK| title=Establishing a cost-per-result of laboratory-based, reflex Cryptococcal antigenaemia screening (CrAg) in HIV+ patients with CD4 counts less than 100 cells/μl using a Lateral Flow Assay (LFA) at a typical busy CD4 laboratory in South Africa. | journal=PLoS One | year= 2017 | volume= 12 | issue= 2 | pages= e0171675 | pmid=28166254 | doi=10.1371/journal.pone.0171675 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28166254  }} </ref><ref name="pmid28134711">{{cite journal| author=Greene G, Sriruttan C, Le T, Chiller T, Govender NP| title=Looking for fungi in all the right places: screening for cryptococcal disease and other AIDS-related mycoses among patients with advanced HIV disease. | journal=Curr Opin HIV AIDS | year= 2017 | volume= 12 | issue= 2 | pages= 139-147 | pmid=28134711 | doi=10.1097/COH.0000000000000347 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28134711  }} </ref>
 
==Risk Factors==
==Risk Factors==
Fungal meningitis rarely occurs in otherwise healthy individuals. Co-existing medical conditions, immunosuppression and travel history to areas where specific [[fungi]] are endemic are risk factors for [[fungal meningitis]].
[[Fungal meningitis]] rarely occurs in otherwise healthy individuals. Co-existing medical conditions, [[immunosuppression]] and travel history to areas where specific [[fungi]] are endemic are risk factors for [[fungal meningitis]]. <ref name="pmid12751260">{{cite journal| author=Chiller TM, Galgiani JN, Stevens DA| title=Coccidioidomycosis. | journal=Infect Dis Clin North Am | year= 2003 | volume= 17 | issue= 1 | pages= 41-57, viii | pmid=12751260 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12751260  }} </ref><ref name="pmid11429020">{{cite journal| author=Singh N, Husain S| title=Infections of the central nervous system in transplant recipients. | journal=Transpl Infect Dis | year= 2000 | volume= 2 | issue= 3 | pages= 101-11 | pmid=11429020 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11429020  }} </ref><ref name="pmid11229838">{{cite journal| author=Rosenstein NE, Emery KW, Werner SB, Kao A, Johnson R, Rogers D et al.| title=Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995-1996. | journal=Clin Infect Dis | year= 2001 | volume= 32 | issue= 5 | pages= 708-15 | pmid=11229838 | doi=10.1086/319203 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11229838  }} </ref><ref name="pmid11051295">{{cite journal| author=Gottfredsson M, Perfect JR| title=Fungal meningitis. | journal=Semin Neurol | year= 2000 | volume= 20 | issue= 3 | pages= 307-22 | pmid=11051295 | doi=10.1055/s-2000-9394 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11051295  }} </ref><ref name="pmid480580">{{cite journal| author=Fraser DW, Ward JI, Ajello L, Plikaytis BD| title=Aspergillosis and other systemic mycoses. The growing problem. | journal=JAMA | year= 1979 | volume= 242 | issue= 15 | pages= 1631-5 | pmid=480580 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=480580  }} </ref><ref name="pmid7004196">{{cite journal| author=Perfect JR, Lang SD, Durack DT| title=Chronic cryptococcal meningitis: a new experimental model in rabbits. | journal=Am J Pathol | year= 1980 | volume= 101 | issue= 1 | pages= 177-94 | pmid=7004196 | doi= | pmc=1903580 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7004196  }} </ref><ref name="pmid3992427">{{cite journal| author=Perfect JR, Durack DT| title=Chemotactic activity of cerebrospinal fluid in experimental cryptococcal meningitis. | journal=Sabouraudia | year= 1985 | volume= 23 | issue= 1 | pages= 37-45 | pmid=3992427 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3992427  }} </ref><ref name="pmid3899932">{{cite journal| author=Perfect JR, Durack DT| title=Effects of cyclosporine in experimental cryptococcal meningitis. | journal=Infect Immun | year= 1985 | volume= 50 | issue= 1 | pages= 22-6 | pmid=3899932 | doi= | pmc=262129 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3899932  }} </ref>
 
==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==
[[Fungal meningitis]] usually presents with progressive symptoms of [[ headache]], low grade [[feve]]r and fatigue. If left untreated, neurological complications might occur.
If left untreated, [[neurological]] complications might occur. [[Fungal meningitis]] may be complicated by [[abscesses]], bone invasion, fluid collections, neurological deficits, ocular invasion, [[papilledema]], [[Neurodevelopmental disorders|neurodevelopmental]] delays in children, and [[Seizure|seizures]]<ref name="Marx">John Marx. Chapter 107. Central Nervous System Infections. Marx: Rosen's Emergency Medicine, 7th ed. Mosby: Elsevier; 2009.</ref><ref name="pmid27590564">{{cite journal| author=Farrugia MK, Fogha EP, Miah AR, Yednock J, Palmer HC, Guilfoose J| title=Candida meningitis in an immunocompetent patient detected through (1→3)-beta-d-glucan. | journal=Int J Infect Dis | year= 2016 | volume= 51 | issue=  | pages= 25-26 | pmid=27590564 | doi=10.1016/j.ijid.2016.08.020 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27590564  }} </ref><ref name="pmid27638836">{{cite journal| author=Nyazika TK, Hagen F, Machiridza T, Kutepa M, Masanganise F, Hendrickx M et al.| title=Cryptococcus neoformans population diversity and clinical outcomes of HIV-associated cryptococcal meningitis patients in Zimbabwe. | journal=J Med Microbiol | year= 2016 | volume= 65 | issue= 11 | pages= 1281-1288 | pmid=27638836 | doi=10.1099/jmm.0.000354 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27638836  }} </ref><ref name="pmid27583871">{{cite journal| author=Leonhard SE, Fritz D, van de Beek D, Brouwer MC| title=Cryptococcal meningitis complicating sarcoidosis. | journal=Medicine (Baltimore) | year= 2016 | volume= 95 | issue= 35 | pages= e4587 | pmid=27583871 | doi=10.1097/MD.0000000000004587 | pmc=5008555 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27583871  }} </ref><ref name="pmid27210482">{{cite journal| author=Neo WL, Durisala N, Ho EC| title=Reversible hearing loss following cryptococcal meningitis: case study. | journal=J Laryngol Otol | year= 2016 | volume= 130 | issue= 7 | pages= 691-5 | pmid=27210482 | doi=10.1017/S002221511600801X | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27210482  }} </ref> The mortality associated with [[fungal meningitis]] is high. Better prognosis is associated with early diagnosis, early initiation of the treatment and compliance of patients with medications.


==Diagnosis==
==Diagnosis==
===History and Symptoms===
===History and Symptoms===
Fungal meningitis can occur in two main clinical pictures: subacute [[meningitis]] and chronic [[meningitis]]. Chronic [[meningitis]] is characterized by the presence of symptoms for more than four weeks. Symptoms include [[headache]], low grade [[fever]], fatigue, weight loss and sometimes focal neurological deficits.
Fungal meningitis can occur in two main clinical pictures: subacute meningitis and chronic meningitis. Chronic meningitis is characterized by the presence of symptoms for more than four weeks. Commonly, patients with fungal meningitis have a history of one or more of the following chronic [[sinusitis]], [[Granulocytopenia]], [[Chronic renal failure|chronic renal failure,]] [[Diabetes]], [[Pregnancy]], persons with [[diabetes]], [[IV drug abusers|IV drug abuse]], prolonged [[intravenous]] therapy, exposure history example travel to or residence inendemic regions of the pathogen, immune suppression examples systemic neoplasia, organ transplantation, [[Human Immunodeficiency Virus|Human immunodeficiency virus]] ([[Human Immunodeficiency Virus (HIV)|HIV]]) / [[acquired immunodeficiency syndrome]] ([[AIDS]]), water [[aspiration]] as in a case of Pseudoallescheria boydii and traumatic inoculation as in a case of [[Sporothrix schenckii]].<ref name="pmid26392507">{{cite journal| author=Morgand M, Rammaert B, Poirée S, Bougnoux ME, Tran H, Kania R et al.| title=Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole. | journal=Antimicrob Agents Chemother | year= 2015 | volume= 59 | issue= 12 | pages= 7857-61 | pmid=26392507 | doi=10.1128/AAC.01506-15 | pmc=4649149 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26392507  }} </ref><ref name="pmid17921648">{{cite journal| author=Shankar SK, Mahadevan A, Sundaram C, Sarkar C, Chacko G, Lanjewar DN et al.| title=Pathobiology of fungal infections of the central nervous system with special reference to the Indian scenario. | journal=Neurol India | year= 2007 | volume= 55 | issue= 3 | pages= 198-215 | pmid=17921648 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17921648  }} </ref><ref name="pmid12751260">{{cite journal| author=Chiller TM, Galgiani JN, Stevens DA| title=Coccidioidomycosis. | journal=Infect Dis Clin North Am | year= 2003 | volume= 17 | issue= 1 | pages= 41-57, viii | pmid=12751260 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12751260  }} </ref><ref name="pmid11429020">{{cite journal| author=Singh N, Husain S| title=Infections of the central nervous system in transplant recipients. | journal=Transpl Infect Dis | year= 2000 | volume= 2 | issue= 3 | pages= 101-11 | pmid=11429020 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11429020  }} </ref><ref name="pmid11229838">{{cite journal| author=Rosenstein NE, Emery KW, Werner SB, Kao A, Johnson R, Rogers D et al.| title=Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995-1996. | journal=Clin Infect Dis | year= 2001 | volume= 32 | issue= 5 | pages= 708-15 | pmid=11229838 | doi=10.1086/319203 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11229838  }} </ref><ref name="pmid11051295">{{cite journal| author=Gottfredsson M, Perfect JR| title=Fungal meningitis. | journal=Semin Neurol | year= 2000 | volume= 20 | issue= 3 | pages= 307-22 | pmid=11051295 | doi=10.1055/s-2000-9394 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11051295  }} </ref><ref name="pmid480580">{{cite journal| author=Fraser DW, Ward JI, Ajello L, Plikaytis BD| title=Aspergillosis and other systemic mycoses. The growing problem. | journal=JAMA | year= 1979 | volume= 242 | issue= 15 | pages= 1631-5 | pmid=480580 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=480580  }} </ref><ref name="pmid7004196">{{cite journal| author=Perfect JR, Lang SD, Durack DT| title=Chronic cryptococcal meningitis: a new experimental model in rabbits. | journal=Am J Pathol | year= 1980 | volume= 101 | issue= 1 | pages= 177-94 | pmid=7004196 | doi= | pmc=1903580 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7004196  }} </ref><ref name="pmid3992427">{{cite journal| author=Perfect JR, Durack DT| title=Chemotactic activity of cerebrospinal fluid in experimental cryptococcal meningitis. | journal=Sabouraudia | year= 1985 | volume= 23 | issue= 1 | pages= 37-45 | pmid=3992427 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3992427  }} </ref><ref name="pmid3899932">{{cite journal| author=Perfect JR, Durack DT| title=Effects of cyclosporine in experimental cryptococcal meningitis. | journal=Infect Immun | year= 1985 | volume= 50 | issue= 1 | pages= 22-6 | pmid=3899932 | doi= | pmc=262129 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3899932  }} </ref><ref name="pmid3275587">{{cite journal| author=Mody CH, Toews GB, Lipscomb MF| title=Cyclosporin A inhibits the growth of Cryptococcus neoformans in a murine model. | journal=Infect Immun | year= 1988 | volume= 56 | issue= 1 | pages= 7-12 | pmid=3275587 | doi= | pmc=259224 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3275587  }} </ref>On presentation patients may have the following symptoms, [[Headache]], [[Neck stiffness]], [[fever]], [[Fatigue]], [[Night sweats]], [[cranial nerves]] involvement,<ref name=":0" /> [[Hydrocephalus]], c[[Cranial neuropathy|ranial neuropathy]], [[Radiculopathy]] and cognitive and personality changes.<ref name=":0">Roos KL, Tyler KL. Chapter 381. Meningitis, Encephalitis, Brain Abscess, and Empyema. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J,  eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.</ref>
 
===Physical Examination===
===Physical Examination===
As in the case of any disease, a complete physical exam must be done on the patient looking for positive and negative symptoms. The clinical presentation of [[fungal meningitis]] is usually obscure as are the findings on physical exam. The pertinent findings are low grade [[fever]] and possible neurological signs like focal [[weakness]], loss of sensation and [[cranial nerves]] involvement.
As in the case of any disease, a complete physical exam must be done on the patient looking for positive and negative symptoms. The clinical presentation of [[fungal meningitis]] is usually obscure as are the findings on physical exam. The pertinent findings are low grade [[fever]] and possible [[neurological]] signs like focal [[weakness]], loss of sensation and [[cranial nerves]] involvement.
Physical exam findings, including presence of rashes, [[lymphadenopathy]], [[hepatomegaly]], pulmonary disease, ocular pathology (eg, [[endophthalmitis]], vitritis, [[chorioretinitis]], [[uveitis]], optic nerve involvement), and cranial nerve (CN) palsies, may narrow the differential. [[Papilledema]] and [[Abducens nerve palsy|abducens nerve pals]]<nowiki/>y suggest the presence of [[increased intracranial pressure]] (ICP).  [[Kernig's sign]] and [[brudzinski's sign]] are not typically present in [[fungal meningitis]].
 
===Laboratory Findings===
===Laboratory Findings===
A lumbar puncture is essential for the diagnosis of [[fungal meningitis]] and initiation of the appropriate treatment. The [[cerebrospinal fluid]] (CSF) of a patient having bacterial meningitis is distinguished by the presence of lymphocytosis, low glucose level and high proteins level. Specific CSF stains and cultures as well as serologies help in determining the specific nature of the causative [[fungi]].
A lumbar puncture is essential for the diagnosis of fungal meningitis and initiation of the appropriate treatment. The [[cerebrospinal fluid]] ([[CSF]]) of a patient having fungal meningitis is distinguished by the presence of [[lymphocytosis]], low [[glucose]] level and high proteins level. Specific [[CSF]] stains and cultures as well as serologies help in determining the specific nature of the causative [[fungi]].
Biopsy of skin lesions, chest radiography, [[ophthalmologic]] examination, computed tomography or MRI of the [[brain]], in addition to cultures of [[CSF]], [[blood]], and [[sputum]], may provide essential diagnostic clues.
 
===CT===
===CT===
The diagnosis of [[fungal meningitis]] mainly relies on the results of the [[cerebrospinal fluid]] (CSF) analysis, stain and culture. The role of imaging is to rule out other differential diagnosis of the initial presentation. In addition, brain imaging must be done when the patient has signs of increased [[intracranial pressure]] to prevent brain herniation.
The diagnosis of [[fungal meningitis]] mainly relies on the results of the [[cerebrospinal fluid]] ([[CSF]]) analysis, stain and culture. The role of imaging is to rule out other differential diagnosis of the initial presentation. In addition, brain imaging must be done when the patient has signs of increased [[intracranial pressure]] to prevent brain herniation.
 
===MRI===
The diagnosis of [[fungal meningitis]] mainly relies on the results of the [[cerebrospinal fluid]] ([[CSF]]) analysis, stain and culture. The role of imaging is to rule out other differential diagnosis of the initial presentation. In addition, brain imaging must be done when the patient has signs of increased [[intracranial pressure]] to prevent brain herniation. Also, [[MRI]] can detect meningeal enhancement, [[tumors]] and para-meningeal infections ([[brain abscess]]).<ref name=":0" />
 


==Treatment==
==Treatment==
Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose [[antifungals]]. In addition, frequent lumbar punctures are recommended in order to relieve the increased [[intracranial pressure]]<ref name="pmid15838017">{{cite journal| author=Bicanic T, Harrison TS| title=Cryptococcal meningitis. | journal=Br Med Bull | year= 2004 | volume= 72 | issue=  | pages= 99-118 | pmid=15838017 | doi=10.1093/bmb/ldh043 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15838017  }} </ref>.
Fungal meningitis, such as [[Cryptococcal Meningitis|cryptococcal]] meningitis, is treated with long courses of high dose [[antifungals]]. In addition, frequent [[lumbar puncture]]<nowiki/>s are recommended in order to relieve the increased [[intracranial pressure]]<ref name="pmid15838017">{{cite journal| author=Bicanic T, Harrison TS| title=Cryptococcal meningitis. | journal=Br Med Bull | year= 2004 | volume= 72 | issue=  | pages= 99-118 | pmid=15838017 | doi=10.1093/bmb/ldh043 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15838017  }} </ref>.


==References==
==References==
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[[Category:Neurology]]
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[[Category:Disease]]
[[Category:Disease]]
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Latest revision as of 21:48, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby; Prince Tano Djan, BSc, MBChB [2]

Overview

Fungal meningitis results from the infection of the meninges by fungi, most commonly cryptococcus. While cryptococcal meningitis occurs worldwide, other fungal meningitis are endemic to specific regions of the world.[1] Fungal meningitis usually affects immunocompromised patients like HIV patients and transplant recipients on chronic immunosuppression medications. The course of the disease is progressive and may lead to complications if a high dose long term treatment with antifungals are not initiated.[2]

Historical perspective

The first report of human cryptococcosis was published by Busse and Busckhe more than 100 years ago; 10 years later, it was identified as the cause of human meningitis. Cryptococcus neoformans, an encapsulated basidiomycetous yeast, represents one of the most common CNS pathogens encountered in clinical practice today. In 1661, Thomas Willis first described the inflammation of meninges and an epidemic of meningitis. In 1891, Heinrich Quincke provided an early analysis of CSF by introducing a new technique of lumbar puncture. Some specific historical feature usually surround the outbreak of rare causes of fungal meningitis. For example, outbreaks of fungal meningitis in 2002 with Exophiala dermatitidis and more recently in 2012 with Exserohilum rostratum were associated with contamination of compounded corticosteroids with resultant severe complications.[3][4][5] The 1980s witnessed an increase in the number of cases of cryptococcus meningitis in the United States and certain African countries largely due to HIV infection

Classification

Fungal meningitis is usually classified according to the causative organism if identified. It may also be additionally classified according to the severity and duration of the disease as mild, moderate, severe, acute, subacute, chronic and recurrent fungal meningitis.[6][7][8][9][10][11][12][13][14]

Pathophysiology

The pathophysiology of fungal meningitis is not very well studied however, it is known to have a lot of similarities with bacterial meningitis. Fungal meningitis usually occurs in immunocompromised patients. The initial step in fungal meningitis is the pulmonary exposure to the fungi by the inhalation of airborne fungal spores. The pulmonary infection is usually self limited and maybe asymptomatic. Fungal infections are not contagious so they do not spread from one person to another.With an associated impaired immune response the fungus may disseminate. For instance in cryptococcal infection, the fungus may remain dormant in the lungs until the immune system weakens and then can reactivate and disseminate to the CNS. Cryptococcus has predilection for CNS dessimination. Although this remains unclear, the presence of a receptor on glial cells for a ligand on the organism has been suggested to enhance its invasion.[15] Cryptococcal meningitis is most common due to the virulence factors of the organism that enhancing invasion of the blood brain barrier. These factors include: polysaccharide capsule which makes the organism withstand phagocytosis and host immune system, melanin production, ability to thrive at mammalian body temperatures, urease production and phospholipase production.[16][17][18][19][20][21][22][23][24] Once the fungi cross the blood brain barrier they cause an inflammation of the meninges and arachnoid space. The inflammation promotes cytokine release mainly tumor necrosis factor (TNF), interleukin 1, interleukin 2 , interleukin 6, interleukin 12, colony-stimulating factors, and interferon-λ.[25][26][27] The cytokines lead to modulation of host system resuting in fever, increase in the permeability of the blood brain barrier and subsequent cerebral edema and increase in the intracranial pressure. The increase in the permeability of the blood brain barrier is the cause of the observed elevation of the protein level in the cerebral spinal fluid.[28]

Causes

Fungal meningitis is initially caused by the inhalation of airborne fungal spores. The pulmonary infection is usually self limiting and can be asymptomatic. The most common cause of fungal infection is cryptococcus neoformans which is usually found in soil and bird excreta.[29] Other common causes of fungal meningitis include; Aspergillus spp., Blastomyces dermatitidis, Coccidioides immitis, Candida spp., Histoplasma capsulatum and Sporothrix schenckii.[30][31][32][2][33] Rarely, fungal meningitis may be caused by Xylohypha (formerly Cladosporium) trichoides, Curvularia, Mucor, Arthrographis kalrae, Pneumocystis jirovecii,[34][35] Cryptococcus albidus,[36], Alternaria spp,[37], Rhodotorula spp, [38] Acremonium spp,[39] Dreschlera spp,[40] Malassezia spp,[41] Scedosporium spp,[42] Arthrographis spp,[43] Blastoschizomyces,[44][45] Paecilomyces,[46][47] Aureobasidium,[48] Clavispora,[49] Ustilago,[50] Exophiala (Wangiella)[51] and Exserohilum[5]

Differentiating fungak meningitis from other Conditions

The differential diagnosis of fungal meningitis includes a range of medical conditions that can be broadly classified into infectious and non infectious. The cerebrospinal fluid analysis and radiological findings help distinguishing fungal meningitis from other causes of meningitis example bacterial meningeal infection, protozoal meningeal infection, viral meningeal infection, and non infectious causes.

Epidemiology and Demographics

While cryptococcus and candida infections occur worldwide, other fungal infections tend to cluster in specific geographical regions.[52][2] There is an increasing trend of fungal meningitis. This has been attributed to enlarging population of high-risk immunosuppressed patients, more successful pharmacological immunosuppression and chemotherapies, increase in numbers of patients living with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS), migration of susceptible persons into hyperendemic areas and aging of the population.[2][53] Cryptococcal meningitis occurs worldwide but it is highly prevalent in southeast Asia and southern and east Africa where the prevalence of HIV is high.[28] The incidence of cryptococcal meningitis is almost the same as in meningococcal meningitis[54] with an incidence of one case per 100,000 persons.[54] Prior to the introduction of highly active antiretroviral therapy (HAART) in the United States, yearly incidence rate of cryptococcal meningitis was on ascendancy with incidence of 6600 cases per 100,000 persons with AIDS[55] The incidence has decreased with the advent of HAART [56] although cases are still reported.[57] The worldwide incidence of cryptococcal meningitis is pegged at 1,000,000 annually according to an estimate by Centers for Disease Control and Prevention CDC in 2009[58] with approximately half of these resulting in death.[58] The prevalence of fungal meningitis does not vary with gender.[59] Non-Caucasian race have a higher prediclection to developing fungal meningitis especially coccidioidal meningitis[60] The prevalence of fungal meningitis does not vary with age.[59] The major factor accounting for age predilection has to do with the clinical state of the patient and the immune response. For example candida meningitis may occur in older children[61][62] and in adults with neutropenia, often presenting with brain abscesses rather than meningitis.[63] Children with certain conditions have higher incidence of fungal meningitis example myeloperoxidase deficiency,[64][65] chronic granulomatous disease of childhood[66][67] and chronic mucocutaneous candidiasis.[68]

Screening

It is recommended that patients with CD4 counts ≤ 100 cells/μl, should have routine cryptococcal antigen screening. Patients with positive result are offered preemptive anti-fungal therapy.[69][70]

Risk Factors

Fungal meningitis rarely occurs in otherwise healthy individuals. Co-existing medical conditions, immunosuppression and travel history to areas where specific fungi are endemic are risk factors for fungal meningitis. [30][31][32][2][53][71][72][73]

Natural History, Complications and Prognosis

If left untreated, neurological complications might occur. Fungal meningitis may be complicated by abscesses, bone invasion, fluid collections, neurological deficits, ocular invasion, papilledema, neurodevelopmental delays in children, and seizures[74][75][76][77][78] The mortality associated with fungal meningitis is high. Better prognosis is associated with early diagnosis, early initiation of the treatment and compliance of patients with medications.

Diagnosis

History and Symptoms

Fungal meningitis can occur in two main clinical pictures: subacute meningitis and chronic meningitis. Chronic meningitis is characterized by the presence of symptoms for more than four weeks. Commonly, patients with fungal meningitis have a history of one or more of the following chronic sinusitis, Granulocytopenia, chronic renal failure, Diabetes, Pregnancy, persons with diabetes, IV drug abuse, prolonged intravenous therapy, exposure history example travel to or residence inendemic regions of the pathogen, immune suppression examples systemic neoplasia, organ transplantation, Human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS), water aspiration as in a case of Pseudoallescheria boydii and traumatic inoculation as in a case of Sporothrix schenckii.[13][52][30][31][32][2][53][71][72][73][79]On presentation patients may have the following symptoms, Headache, Neck stiffness, fever, Fatigue, Night sweats, cranial nerves involvement,[28] Hydrocephalus, cranial neuropathy, Radiculopathy and cognitive and personality changes.[28]

Physical Examination

As in the case of any disease, a complete physical exam must be done on the patient looking for positive and negative symptoms. The clinical presentation of fungal meningitis is usually obscure as are the findings on physical exam. The pertinent findings are low grade fever and possible neurological signs like focal weakness, loss of sensation and cranial nerves involvement. Physical exam findings, including presence of rashes, lymphadenopathy, hepatomegaly, pulmonary disease, ocular pathology (eg, endophthalmitis, vitritis, chorioretinitis, uveitis, optic nerve involvement), and cranial nerve (CN) palsies, may narrow the differential. Papilledema and abducens nerve palsy suggest the presence of increased intracranial pressure (ICP). Kernig's sign and brudzinski's sign are not typically present in fungal meningitis.

Laboratory Findings

A lumbar puncture is essential for the diagnosis of fungal meningitis and initiation of the appropriate treatment. The cerebrospinal fluid (CSF) of a patient having fungal meningitis is distinguished by the presence of lymphocytosis, low glucose level and high proteins level. Specific CSF stains and cultures as well as serologies help in determining the specific nature of the causative fungi. Biopsy of skin lesions, chest radiography, ophthalmologic examination, computed tomography or MRI of the brain, in addition to cultures of CSF, blood, and sputum, may provide essential diagnostic clues.

CT

The diagnosis of fungal meningitis mainly relies on the results of the cerebrospinal fluid (CSF) analysis, stain and culture. The role of imaging is to rule out other differential diagnosis of the initial presentation. In addition, brain imaging must be done when the patient has signs of increased intracranial pressure to prevent brain herniation.

MRI

The diagnosis of fungal meningitis mainly relies on the results of the cerebrospinal fluid (CSF) analysis, stain and culture. The role of imaging is to rule out other differential diagnosis of the initial presentation. In addition, brain imaging must be done when the patient has signs of increased intracranial pressure to prevent brain herniation. Also, MRI can detect meningeal enhancement, tumors and para-meningeal infections (brain abscess).[28]


Treatment

Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose antifungals. In addition, frequent lumbar punctures are recommended in order to relieve the increased intracranial pressure[80].

References

  1. ↑ Bovers M, Hagen F, Kuramae EE, Diaz MR, Spanjaard L, Dromer F; et al. (2006). "Unique hybrids between the fungal pathogens Cryptococcus neoformans and Cryptococcus gattii". FEMS Yeast Res. 6 (4): 599–607. doi:10.1111/j.1567-1364.2006.00082.x. PMID 16696655.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Gottfredsson M, Perfect JR (2000). "Fungal meningitis". Semin Neurol. 20 (3): 307–22. doi:10.1055/s-2000-9394. PMID 11051295.
  3. ↑
  4. ↑
  5. ↑ 5.0 5.1 Pettit AC, Pugh ME (2013). "Index case for the fungal meningitis outbreak, United States". N Engl J Med. 368 (10): 970. doi:10.1056/NEJMc1300630. PMID 23465119.
  6. ↑ Zheng H, Chen Q, Xie Z, Wang D, Li M, Zhang X; et al. (2016). "A retrospective research of HIV-negative cryptococcal meningoencephalitis patients with acute/subacute onset". Eur J Clin Microbiol Infect Dis. 35 (2): 299–303. doi:10.1007/s10096-015-2545-0. PMID 26792138.
  7. ↑ Zunt JR, Baldwin KJ (2012). "Chronic and subacute meningitis". Continuum (Minneap Minn). 18 (6 Infectious Disease): 1290–318. doi:10.1212/01.CON.0000423848.17276.21. PMID 23221842.
  8. ↑ Chimalizeni Y, Tickell D, Connell T (2010). "Evidence behind the WHO guidelines: hospital care for children: what is the most appropriate anti-fungal treatment for acute cryptococcal meningitis in children with HIV?". J Trop Pediatr. 56 (1): 4–12. doi:10.1093/tropej/fmp123. PMID 20097705.
  9. ↑ Malessa R, Krams M, Hengge U, Weiller C, Reinhardt V, Volbracht L; et al. (1994). "Elevation of intracranial pressure in acute AIDS-related cryptococcal meningitis". Clin Investig. 72 (12): 1020–6. PMID 7711408.
  10. ↑ Saag MS, Powderly WG, Cloud GA, Robinson P, Grieco MH, Sharkey PK; 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. 326 (2): 83–9. doi:10.1056/NEJM199201093260202. PMID 1727236.
  11. ↑ Sloan D, Dlamini S, Paul N, Dedicoat M (2008). "Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings". Cochrane Database Syst Rev (4): CD005647. doi:10.1002/14651858.CD005647.pub2. PMID 18843697.
  12. ↑ Witt MD, Lewis RJ, Larsen RA, Milefchik EN, Leal MA, Haubrich RH; et al. (1996). "Identification of patients with acute AIDS-associated cryptococcal meningitis who can be effectively treated with fluconazole: the role of antifungal susceptibility testing". Clin Infect Dis. 22 (2): 322–8. PMID 8838190.
  13. ↑ 13.0 13.1 Morgand M, Rammaert B, Poirée S, Bougnoux ME, Tran H, Kania R; et al. (2015). "Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole". Antimicrob Agents Chemother. 59 (12): 7857–61. doi:10.1128/AAC.01506-15. PMC 4649149. PMID 26392507.
  14. ↑ Banarer M, Cost K, Rychwalski P, Bryant KA (2005). "Chronic lymphocytic meningitis in an adolescent". J Pediatr. 147 (5): 686–90. doi:10.1016/j.jpeds.2005.07.010. PMID 16291364.
  15. ↑
  16. ↑ Granger DL, Perfect JR, Durack DT (1985). "Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide". J Clin Invest. 76 (2): 508–16. doi:10.1172/JCI112000. PMC 423853. PMID 3928681.
  17. ↑ Jong A, Wu CH, Gonzales-Gomez I, Kwon-Chung KJ, Chang YC, Tseng HK; et al. (2012). "Hyaluronic acid receptor CD44 deficiency is associated with decreased Cryptococcus neoformans brain infection". J Biol Chem. 287 (19): 15298–306. doi:10.1074/jbc.M112.353375. PMC 3346080. PMID 22418440.
  18. ↑ Kwon-Chung KJ, Rhodes JC (1986). "Encapsulation and melanin formation as indicators of virulence in Cryptococcus neoformans". Infect Immun. 51 (1): 218–23. PMC 261090. PMID 3079732.
  19. ↑ Polacheck I, Platt Y, Aronovitch J (1990). "Catecholamines and virulence of Cryptococcus neoformans". Infect Immun. 58 (9): 2919–22. PMC 313587. PMID 2117574.
  20. ↑ Jacobson ES, Emery HS (1991). "Catecholamine uptake, melanization, and oxygen toxicity in Cryptococcus neoformans". J Bacteriol. 173 (1): 401–3. PMC 207201. PMID 1898925.
  21. ↑ Jacobson ES, Tinnell SB (1993). "Antioxidant function of fungal melanin". J Bacteriol. 175 (21): 7102–4. PMC 206840. PMID 8226653.
  22. ↑ Chang YC, Kwon-Chung KJ (1994). "Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence". Mol Cell Biol. 14 (7): 4912–9. PMC 358863. PMID 8007987.
  23. ↑ Cox GM, Mukherjee J, Cole GT, Casadevall A, Perfect JR (2000). "Urease as a virulence factor in experimental cryptococcosis". Infect Immun. 68 (2): 443–8. PMC 97161. PMID 10639402.
  24. ↑ Cox GM, McDade HC, Chen SC, Tucker SC, Gottfredsson M, Wright LC; et al. (2001). "Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans". Mol Microbiol. 39 (1): 166–75. PMID 11123698.
  25. ↑
  26. ↑
  27. ↑
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Roos KL, Tyler KL. Chapter 381. Meningitis, Encephalitis, Brain Abscess, and Empyema. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.
  29. ↑ Koroshetz WJ. Chapter 382. Chronic and Recurrent Meningitis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012.
  30. ↑ 30.0 30.1 30.2 Chiller TM, Galgiani JN, Stevens DA (2003). "Coccidioidomycosis". Infect Dis Clin North Am. 17 (1): 41–57, viii. PMID 12751260.
  31. ↑ 31.0 31.1 31.2 Singh N, Husain S (2000). "Infections of the central nervous system in transplant recipients". Transpl Infect Dis. 2 (3): 101–11. PMID 11429020.
  32. ↑ 32.0 32.1 32.2 Rosenstein NE, Emery KW, Werner SB, Kao A, Johnson R, Rogers D; et al. (2001). "Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995-1996". Clin Infect Dis. 32 (5): 708–15. doi:10.1086/319203. PMID 11229838.
  33. ↑ del Brutto OH (2000). "[Central nervous system mycotic infections]". Rev Neurol. 30 (5): 447–59. PMID 10775973.
  34. ↑ Villanueva JL, Cordero E, Caballero-Granado FJ, Regordan C, Becerril B, Pachón J (1997). "Pneumocystis carinii meningoradiculitis in a patient with AIDS". Eur J Clin Microbiol Infect Dis. 16 (12): 940–2. PMID 9495679.
  35. ↑ Baena Luna MR, Muñoz García J, Grancha Bertolín L, Sanz García M (1998). "[Presence of Pneumocystis carinii in cerebrospinal fluid]". An Med Interna. 15 (5): 265–6. PMID 9629775.
  36. ↑ Melo JC, Srinivasan S, Scott ML, Raff MJ (1980). "Cryptococcus albidus meningitis". J Infect. 2 (1): 79–82. PMID 7185917.
  37. ↑ OHASHI Y (1960). "On a rare disease due to Alternaria tenuis Nees (alternariasis)". Tohoku J Exp Med. 72: 78–82. PMID 13730495.
  38. ↑ Shinde RS, Mantur BG, Patil G, Parande MV, Parande AM (2008). "Meningitis due to Rhodotorula glutinis in an HIV infected patient". Indian J Med Microbiol. 26 (4): 375–7. PMID 18974495.
  39. ↑ Fincher RM, Fisher JF, Lovell RD, Newman CL, Espinel-Ingroff A, Shadomy HJ (1991). "Infection due to the fungus Acremonium (cephalosporium)". Medicine (Baltimore). 70 (6): 398–409. PMID 1956281.
  40. ↑ Fuste FJ, Ajello L, Threlkeld R, Henry JE (1973). "Drechslera hawaiiensis: causative agent of a fatal fungal meningo-encephalitis". Sabouraudia. 11 (1): 59–63. PMID 4739938.
  41. ↑ Rosales CM, Jackson MA, Zwick D (2004). "Malassezia furfur meningitis associated with total parenteral nutrition subdural effusion". Pediatr Dev Pathol. 7 (1): 86–90. doi:10.1007/s10024-003-4030-5. PMID 15255040.
  42. ↑ Symoens F, Knoop C, Schrooyen M, Denis O, Estenne M, Nolard N; et al. (2006). "Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient after double-lung transplantation". J Heart Lung Transplant. 25 (5): 603–7. doi:10.1016/j.healun.2005.12.011. PMID 16678041.
  43. ↑ Chin-Hong PV, Sutton DA, Roemer M, Jacobson MA, Aberg JA (2001). "Invasive fungal sinusitis and meningitis due to Arthrographis kalrae in a patient with AIDS". J Clin Microbiol. 39 (2): 804–7. doi:10.1128/JCM.39.2.804-807.2001. PMC 87827. PMID 11158158.
  44. ↑ Girmenia C, Micozzi A, Venditti M, Meloni G, Iori AP, Bastianello S; et al. (1991). "Fluconazole treatment of Blastoschizomyces capitatus meningitis in an allogeneic bone marrow recipient". Eur J Clin Microbiol Infect Dis. 10 (9): 752–6. PMID 1810730.
  45. ↑ Naficy AB, Murray HW (1990). "Isolated meningitis caused by Blastoschizomyces capitatus". J Infect Dis. 161 (5): 1041–2. PMID 2324536.
  46. ↑ Kantarcioğlu AS, Hatemi G, Yücel A, De Hoog GS, Mandel NM (2003). "Paecilomyces variotii central nervous system infection in a patient with cancer". Mycoses. 46 (1–2): 45–50. PMID 12588483.
  47. ↑ Fagerburg R, Suh B, Buckley HR, Lorber B, Karian J (1981). "Cerebrospinal fluid shunt colonization and obstruction by Paecilomyces variotii. Case report". J Neurosurg. 54 (2): 257–60. doi:10.3171/jns.1981.54.2.0257. PMID 7192726.
  48. ↑ Kutleša M, Mlinarić-Missoni E, Hatvani L, Voncina D, Simon S, Lepur D; et al. (2012). "Chronic fungal meningitis caused by Aureobasidium proteae". Diagn Microbiol Infect Dis. 73 (3): 271–2. doi:10.1016/j.diagmicrobio.2012.03.007. PMID 22504065.
  49. ↑ Krcmery V, Mateicka F, Grausova S, Kunova A, Hanzen J (1999). "Invasive infections due to Clavispora lusitaniae". FEMS Immunol Med Microbiol. 23 (1): 75–8. PMID 10030550.
  50. ↑ MOORE M, RUSSELL WO, SACHS E (1946). "Chronic leptomeningitis and ependymitis caused by Ustilago, probably U. zeae (corn smut)". Am J Pathol. 22: 761–77. PMID 20991975.
  51. ↑ Centers for Disease Control and Prevention (CDC) (2002). "Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy--United States, July-November 2002". MMWR Morb Mortal Wkly Rep. 51 (49): 1109–12. PMID 12530707.
  52. ↑ 52.0 52.1 Shankar SK, Mahadevan A, Sundaram C, Sarkar C, Chacko G, Lanjewar DN; et al. (2007). "Pathobiology of fungal infections of the central nervous system with special reference to the Indian scenario". Neurol India. 55 (3): 198–215. PMID 17921648.
  53. ↑ 53.0 53.1 53.2 Fraser DW, Ward JI, Ajello L, Plikaytis BD (1979). "Aspergillosis and other systemic mycoses. The growing problem". JAMA. 242 (15): 1631–5. PMID 480580.
  54. ↑ 54.0 54.1
  55. ↑
  56. ↑
  57. ↑
  58. ↑ 58.0 58.1
  59. ↑ 59.0 59.1
  60. ↑
  61. ↑
  62. ↑
  63. ↑
  64. ↑
  65. ↑
  66. ↑
  67. ↑
  68. ↑
  69. ↑ Cassim N, Schnippel K, Coetzee LM, Glencross DK (2017). "Establishing a cost-per-result of laboratory-based, reflex Cryptococcal antigenaemia screening (CrAg) in HIV+ patients with CD4 counts less than 100 cells/μl using a Lateral Flow Assay (LFA) at a typical busy CD4 laboratory in South Africa". PLoS One. 12 (2): e0171675. doi:10.1371/journal.pone.0171675. PMID 28166254.
  70. ↑ Greene G, Sriruttan C, Le T, Chiller T, Govender NP (2017). "Looking for fungi in all the right places: screening for cryptococcal disease and other AIDS-related mycoses among patients with advanced HIV disease". Curr Opin HIV AIDS. 12 (2): 139–147. doi:10.1097/COH.0000000000000347. PMID 28134711.
  71. ↑ 71.0 71.1 Perfect JR, Lang SD, Durack DT (1980). "Chronic cryptococcal meningitis: a new experimental model in rabbits". Am J Pathol. 101 (1): 177–94. PMC 1903580. PMID 7004196.
  72. ↑ 72.0 72.1 Perfect JR, Durack DT (1985). "Chemotactic activity of cerebrospinal fluid in experimental cryptococcal meningitis". Sabouraudia. 23 (1): 37–45. PMID 3992427.
  73. ↑ 73.0 73.1 Perfect JR, Durack DT (1985). "Effects of cyclosporine in experimental cryptococcal meningitis". Infect Immun. 50 (1): 22–6. PMC 262129. PMID 3899932.
  74. ↑ John Marx. Chapter 107. Central Nervous System Infections. Marx: Rosen's Emergency Medicine, 7th ed. Mosby: Elsevier; 2009.
  75. ↑ Farrugia MK, Fogha EP, Miah AR, Yednock J, Palmer HC, Guilfoose J (2016). "Candida meningitis in an immunocompetent patient detected through (1→3)-beta-d-glucan". Int J Infect Dis. 51: 25–26. doi:10.1016/j.ijid.2016.08.020. PMID 27590564.
  76. ↑ Nyazika TK, Hagen F, Machiridza T, Kutepa M, Masanganise F, Hendrickx M; et al. (2016). "Cryptococcus neoformans population diversity and clinical outcomes of HIV-associated cryptococcal meningitis patients in Zimbabwe". J Med Microbiol. 65 (11): 1281–1288. doi:10.1099/jmm.0.000354. PMID 27638836.
  77. ↑ Leonhard SE, Fritz D, van de Beek D, Brouwer MC (2016). "Cryptococcal meningitis complicating sarcoidosis". Medicine (Baltimore). 95 (35): e4587. doi:10.1097/MD.0000000000004587. PMC 5008555. PMID 27583871.
  78. ↑ Neo WL, Durisala N, Ho EC (2016). "Reversible hearing loss following cryptococcal meningitis: case study". J Laryngol Otol. 130 (7): 691–5. doi:10.1017/S002221511600801X. PMID 27210482.
  79. ↑ Mody CH, Toews GB, Lipscomb MF (1988). "Cyclosporin A inhibits the growth of Cryptococcus neoformans in a murine model". Infect Immun. 56 (1): 7–12. PMC 259224. PMID 3275587.
  80. ↑ Bicanic T, Harrison TS (2004). "Cryptococcal meningitis". Br Med Bull. 72: 99–118. doi:10.1093/bmb/ldh043. PMID 15838017.

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