Fungal meningitis overview
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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 (Wangiella) 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 limited and can be asymptomatic. The most common cause of fungal infection is C. neoformans which is usually found in soil and bird excreta.[29]
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.
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 neoformans.
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.
Natural History, Complications and Prognosis
Fungal meningitis usually presents with progressive symptoms of headache, low grade fever and fatigue. If left untreated, neurological complications might occur.
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. Symptoms include headache, low grade fever, fatigue, weight loss and sometimes focal neurological deficits.
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.
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.
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.
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[30].
References
- ↑ 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.
- ↑ Gottfredsson M, Perfect JR (2000). "Fungal meningitis". Semin Neurol. 20 (3): 307–22. doi:10.1055/s-2000-9394. PMID 11051295.
- ↑
- ↑
- ↑
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Polacheck I, Platt Y, Aronovitch J (1990). "Catecholamines and virulence of Cryptococcus neoformans". Infect Immun. 58 (9): 2919–22. PMC 313587. PMID 2117574.
- ↑ Jacobson ES, Emery HS (1991). "Catecholamine uptake, melanization, and oxygen toxicity in Cryptococcus neoformans". J Bacteriol. 173 (1): 401–3. PMC 207201. PMID 1898925.
- ↑ Jacobson ES, Tinnell SB (1993). "Antioxidant function of fungal melanin". J Bacteriol. 175 (21): 7102–4. PMC 206840. PMID 8226653.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑
- ↑
- ↑
- ↑
- ↑ 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.
- ↑ Bicanic T, Harrison TS (2004). "Cryptococcal meningitis". Br Med Bull. 72: 99–118. doi:10.1093/bmb/ldh043. PMID 15838017.