Central Nervous System Fungal Infections

Jundishapur Journal of Microbiology (2010); 3(2): 41-47 41

Review article

Central nervous system fungal infections; a review article Majid Zarrin1, Ali Zarei Mahmoudabadi1,2 1Department of Medical Mycoparasitology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 2Infectious and Tropical Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

How to cite this article: Zarrin M, Zarei Mahmoudabadi A. Central nervous system fungal infections; a review article. Jundishapur J Microbiol. 2010; 3(2): 41-7.

Received: April 2010 Accepted: April 2010

Abstract Central nervous system (CNS) fungal infections have a high rate of morbidity and mortality that increased during last three decades. CNS fungal infections present a diagnostic and therapeutic challenge. High numbers of organ transplants, chemotherapy patients, intensive care unit hospitalizations, immunocompromised patients and haematological malignancies increase morbidity and mortality. Several fungi including, saprophytic fungi, melanized fungi, dimorphic fungi, yeast and yeasts-likes cause CNS fungal infections. New antifungal, posaconazole, voriconazole and echinocandins as well as traditionally antifungal, amphotericine B, flucytosine and itraconazole were used for CNS fungal infection therapy.

Keywords: CNS fungal infection, Candida, Cryptococcus, Saprophytic fungi, Dimorphic fungi

Introduction encephalitis, stroke, parenchymal brain, or Infections of the central nervous system myelopathy [1-2]. A diversity of fungi lead (CNS) with fungi can cause devastating to CNS infection which can be a meningitis consequences. Although several fungi may or space-occupying lesion. cause infection in normal humans, most of Acute or neutrophilic meningitis has them are opportunistic and influence been most frequently seen in Candida immunocompromised hosts. With the meningitis, whereas Cryptococcus exception of Candida albicans, that is a neoformans typically causes the chronic normal flora of the human mucus, most lymphocytic meningitis and Coccidioides fungal elements get into the body through immitis causes the granulomatous breathing or skin scrapes. Invasion of the meningitis. Although meningitis is the most CNS with fungi can cause one or more the frequent symptom of CNS fungal symptoms such as acute or chronic infections, the filamentous fungi cause meningitis, abscesses or granuloma, granuloma or brain abscess more often than

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Jundishapur Journal of Microbiology (2010); 3(2): 41-47 42 meningitis. Haematogenous dissemination the reducing of the cryptococcosis could follow the primary fungal infection, incidence related to AIDS. Cryptococcoma with following involvement of CNS. or brain mass lesions because of C. Seldom, trauma or local injuries pare the neoformans are very less frequent in way to CNS infection [3]. A mechanical comparison to meningitis caused by barrier protects the CNS from fungal serotype A and D. In contrast, serotype B, invasion. Though, in proper conditions the common in non-immunocompromise hosts, CNS is infected by a haematogenous route. frequently causes a pseudotumor mass in In addition, the CNS infection can occur brain. Rarely, a mass lesion could occur after the anatomic barrier is infringed with a without meningitis [9]. The majority of trauma, surgery or by spreading to cryptococcoses begin as a primary paranasal sinus or canal of ear. pulmonary infection. Approximately 5-10% of HIV infected hosts develop the Causative Fungi cryptococcal meningitis as an AIDS Cryptococcus neoformans important disease and approximately 40% There are two varieties of C. neoformans of cases first manifest the disease [10-11]. var. neoformans (Serotype A and D) and var. gatti (Serotype B and C). Serotype A is Candida species distributed worldwide and is most Candida species live as normal flora of the associated with pigeon droppings [4]. mucous membrane and skin. C. albicans is Serotype D is isolated in Europe with the most frequent cause of meningitis and heterogeneous distribution and serotype B abscess of brain among Candida species. is originally associated with vicinity of Other less common pathogens species are Eucalyptus trees [5]. The etiological place C. tropicalis, C. parapsilosis, C. lusitaniae, of serotype C has not been identified. C. glabrata and C. krusei. In infants Molecular epidemiology of C. neoformans meningitis is more common than in older reveals genetic variation among different patients. Occasionally, Candida meningitis isolates. could happen in a healthy human [12]. The most prevalent agent which caused Autopsies of disseminated candidiasis chronic fungal meningitis is C. neoformans patients revealed a high occurrence of brain var. neoformans and 90% of infections abscesses (50% of patients) [13]. The happen in immunocompromised patients progress of mass lesion or meningitis in [6]. Moreover in places where C. brain caused by Candida is related to neoformans var. gatti is endemic, the factors which control the local proliferation commonest isolate from AIDS patients is C. and facilitate Candida access to the CNS. neoformans var. neoformans. There is not In newborns, candidiasis of CNS is an any report of transmission from animal to infection of the compromised or premature human and human transmission is rarely child. Candida meningitis associated to reported. C. neoformans make a capsular neurosurgery was also described. Direct antigen, glycoronoxylomannan, in huge inoculation into the CNS throughout quantities, that is stable to heat, resistant to surgery happened in 72% patients [14]. pronase and has 24 hours half life [7]. After IV therapeutic management or Cryptococcus has higher incidence throughout open heart surgery, Candida among AIDS patients in Africa and colonizing in the muco-cutaneous as normal Southeast Asia than in the USA [8]. In the flora can invade the CNS by infection of developed countries, the beginning of blood stream [15]. Broad different strong antiretroviral treatments has resulted conditions such as long term antibiotics,

Jundishapur Journal of Microbiology (2010); 3(2): 41-47 43 steroids, immunosuppressive and predisposing factors than on gender, race, chemotherapeutic agents, neutropenia and age or geography. Zygomycetes thrive in a AIDS promote haematogenous highly acid condition that has rich dissemination [15-17]. carbohydrate. Therefore a diabetic ketoacidosis person has a more risk of Aspergillus species defective phagocyte function and offers an Aspergillus is ubiquitous saprophyte environment for quick invasion [25]. In organism in soil, water and decaying addition, Zygomycetes proliferate in vegetation. This fungus enters the body neutropenic patients whose serum iron through the respiratory tract and paranasal concentration is increased by deferoxamine sinuses [18]. The invasion to CNS is [26]. Although these fungi have been followed by direct inoculation into a region considerated opportunistic, the cerebral anatomically near to the brain or by the forms of the disease has been recorded in haematogenous seeding. In addition to previously healthy individuals [27]. primary infection of lungs, haematogenous dissemination is also initiated by direct Melanized fungi inoculation into bloodstream via the middle Infections of CNS with pigmented fungi are ear, paranasal sinuses, eye, and mastoid or dramatically reported in recent years [28]. as a result of open-heart operation [19]. Exophiala dermatitidis, Ramichloridium Occurrence of Aspergillus infection can mackenzie and Cladosporium bantiana, spread to infant CNS [20]. mainly cause the primary cerebral Aspergillus fumigatus is recognized as infections. Secondary cerebral phaeohypho- the most frequent species to cause invasive mycosis arises from extension of an infection. A. flavus is considered as the infected site and haematogenously spreads agent of a great part of infections in to brain [29]. E. dermatitidis has been paranasal sinus [21]. Although A. terreus is described as the major neurotropic fungi of an unusual cause of CNS invasion, it is East Asia though it is isolated worldwide in amphotericin B resistance and consequently environment. related with high death [22]. Meningitis is Melanin has been recognized as a rare in aspergillosis. Abscesses of brain are virulence factor in several fungi and widely common in disseminated aspergillosis [13]. researched in C. neoformans and Wangiella Extended neutropenia and use of high-dose dermatiditis [30-31]. An uncommon of corticosteroids are the main predisposing symptom of brain involvement is formation factors in patients with solid organ of abscess without meningitis. Otherwise, transplant and cancers [13,23]. Though, the meningitis can be the only symptom [32]. infection could happen in an The infections are frequently reported in immunocompetent human [24]. apparently immunocompetent hosts [28]. Clinical managing of patients with primary Zygomycetes CNS caused melanized fungi is difficult CNS zygomycosis is a worldwide fungal because of their weak response to infection caused by class Zygomycetes such antifungals and death rates is high despite as the Genera Rhizopus, Rhizomucor, of immune response. Absidia, Mucor, Cunninghamella, Apophysomyces and Saksenaes. Other fungi Zygomycosis is an opportunistic fungal Among dimorphic fungi C. immitis and infection and the distribution of its different Histoplasma capulatum are the frequent clinical types is more according to organisms causing infections of the CNS. A

Jundishapur Journal of Microbiology (2010); 3(2): 41-47 44 frequent cause of meningitis is C. immitis culture examination of CNS biopsy and which is geographically limited to CSF. Grocott's methenamine silver (GMS) Southwest United States and South America staining is usually used for biopsy staining. countries [13,33]. Coccidial meningitis Causative agents have several morphology happens in 30-50% of patients with and size based on disease type. Branched disseminated infection. The infection can septate hyphae indicate Aspergillus, occur in an immunocomponent human. Cephalosporium and Penicillium whereas Patients with HIV positive, solid organ non-septate hyphae were seen in CNS transplant, treated by steroids and infection due to Zygomycetes. Melanized pregnancy are at a high risk of fungi including; Cladosporium, Exophiala, dissemination [13]. Wangiella are presented as dematiaceous Histoplasmosis caused by H. elements [38,39]. Yeast forms (up to 20m capsulatum is endemic in the United States, in diameter) were usually seen in CNS South America, Southeast Asia and Africa caused by Blastomyces dermatitidis, [13]. This dimorphic fungus can cause Candida species, C. neoformans, H. meningitis in 5-25% of AIDS patients capsulatum, Sporotrichum and which is similar to non-AIDS patients [34]. Paracoccidioides. The presence of spherule CNS infections may involve the patients indicates CNS infection with C. immitis who have solid organ transplantation and [40]. patients treated with steroids. CNS histoplasmosis has been identified in 10- Treatment 20% of disseminated hosts [34]. A high rate of morbidity and mortality of Occasionally, brain abscesses are presented patients with fungal infections of CNS are [35]. caused by several factors, such as organ CNS localization in blastomycosis can transplant, chemotherapy, ICU occur in 5% of immunocompetent humans hospitalization, immunocompromised and 40% of cases who suffers from patients and haematological malignancies. progressive HIV. Meninges are infrequent The treatment of fungal CNS infection is sites and abscesses of brain are also rare influenced by multiple factors including, the [36]. CNS infections in host, the pathogen and its drug paracoccidioidomycosis, penicilliosis susceptibility, drug delivery across the because of Penicililum marneffei are very blood-brain barrier and drug activity in the unusual. Cerebral infections by CNS, brain and spinal cord [39]. Peudoallesheria boydii are very rare. This Amphotericin B is a polyene antibiotic that fungus causes meningoencephalitis and binds to ergosterols in the cell wall of fungi microabsecesses. Maduralla mycetomatis and increased cell permeability. K+ leakage involves the CNS rarely. The fungus infects due to this permeability causes cell death the brain after local trauma. There are a few [41]. Amphotericin B and/or flucytosine in reports of brain abscesses because of combination are recommended for CNS Fusarium [37]. infections especially caused by Candida and C. neoformans [42-44]. Diagnostic tests Fluconazole as intravenous or oral CNS clinical manifestations, neuroimaging preparations has more activity against (CT or MRI) and CSF cytochemical yeasts (Candida and Cryptococcus) than characteristics are main criteria of filamentous fungi and is widely distributed diagnosis. In addition, diagnosis is also throughout body tissues, including the CSF. made by fungal tests including direct and

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