Fungal infections of the central nervous system (CNS) are rare in the general population and are invariably secondary to primary focus elsewhere, usually in the lung or intestine. Except for people with longstanding diabetes, they are most frequently encountered in immunocompromised patients such as those with acquired immunodeficiency syndrome or after organ transplantation. Due to the lack of inflammatory response, neuroradiological findings are often nonspecific and are frequently mistaken for tuberculous meningitis, pyogenic abscess or brain tumor. Intracranial fungal infections are being identified more frequently due to the increased incidence of AIDS patients, better radiological investigations, more sensitive microbiological techniques and better critical care of moribund patients. Although almost any fungus may cause encephalitis, cryptococcal meningoencephalitis is most frequently seen, followed by aspergillosis and candidiasis. The biology, epidemiology and imaging features of the common fungal infections of the CNS will be reviewed. The radiographic appearance alone is often not specific, but the combination of the appropriate clinical setting along with computed tomography or magnetic resonance may help to suggest the correct diagnosis.

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Cryptococcal meningitis has emerged as a leading cause of infectious morbidity and mortality in patients with AIDS. Among the human immunodeficiency virus (HIV)-seropositive subjects, cryptococcal meningitis is the second most common cause of opportunistic neuro-infection. Current trends are changing due to the marked improvement of quality and length of life produced by highly active antiretroviral therapy (HAART). The introduction of generic HAART in India has resulted in an increase in the number of individuals getting treatment for HIV infection, as the cost of highly active antiretroviral therapy (HAART) has decreased 20- fold. Cryptococcal meningitis occurs in non-HIV patients who are immunodeficient due to diabetes, cancer, solid organ transplants, chemotherapeutic drugs, hematological malignancies etc and rarely in healthy individuals with no obvious predisposing factors. Diagnosis of cryptococcal meningitis is fairly straightforward once the diagnosis is considered in the differential diagnosis of chronic meningitis. Treatment of a patient with cryptococcal infection is a challenge for both the physician and the patient, but rewarding, as many would recover with timely and adequate antifungal therapy.

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Fungal infections of the central nervous system (CNS) were considered rare until the 1970s. This is no longer true in recent years due to widespread use of corticosteroids, cytotoxic drugs and antibiotics. Immunocompromised patients with underlying malignancy, organ transplantations and acquired immune deficiency syndrome are all candidates for acquiring fungal infections either in meninges or brain. A considerable number of cases of CNS fungal infections even in immunocompetent hosts have been reported. A vast array of fungi may cause infection in the CNS, but barring a few, most of them are anecdotal case reports. Cryptococcus neoformans , Candida albicans, Coccidioides immitis. Histoplasma capsulatum are common causes of fungal meningitis; Aspergillus spp., Candida spp., Zygomycetes and some of the melanized fungi are known to cause mass lesions in brain. Few fungi like C. neoformans, Cladophialophora bantiana, Exophiala dermatitidis, Ramichloridium mackenzie, Ochroconis gallopava are considered as true neurotropic fungi. Most of the fungi causing CNS infection are saprobes with worldwide distribution; a few are geographically restricted like Coccidioides immitis . The infections reach the CNS either by the hematogenous route or by direct extension from colonized sinuses or ear canal or by direct inoculation during neurosurgical procedures.

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Ubiquitously present fungi in the environment find a nidus in the human body and adopt its metabolic machinery to be in symbiosis or become pathogenic. Immunocompromised states like human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS), systemic neoplasia and organ transplantation have enhanced the frequency of fungal infections. High-risk behavior, IV drug abuse and air travel have led to the emergence of new fungal infections hitherto geographically localized. The pathology in the central nervous system (CNS) is dictated largely by the size of the fungus - the yeast forms, by virtue of their small size enter the microcirculation to cause meningitis and microabscesses, while hyphal forms invade the vasculature to manifest as large pale or hemorrhagic infarcts. The growth kinetics of fungi, the antigenic character of the capsule. the proteases secreted by the mycelial forms and the biochemical milieu in the host also determine clinical manifestations. A hospital-based analysis of the available information from India suggests that in the non-HIV patient population, hyphal forms like Aspergillosis and Zygomycosis are the most common pathogens, while yeast forms like Cryptococcus and Candida are the prime pathogens in cases of HIV/AIDS, the altered macrophage function acting in synergy with suppressed cell-mediated immunity. In Northeastern states, systemic infection by Penicillium marneffei is reported in association with HIV though CNS involvement is not recorded. Although fungal infections of the CNS are reported from various hospitals in India, studies are limited by non-availability of relevant microbiological studies and the reported prevalence data is biased by the surgical practices, availability of postmortem and microbiology and laboratory support. Detailed clinical and mycological investigations related to the interaction between the fungus and host environment is a fertile area of research to understand the basic pathogenetic mechanisms.

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Craniocerebral aspergillosis is a rare but dangerous variety of central nervous system infections. Surgery is being widely recognized as the cornerstone of management. Due to the rarity of the disease, difficulty and delay in diagnosis and poor outcome, there is very little in the literature regarding the various surgical strategies that may be adopted in these patients. Early aggressive surgery followed by chemotherapy offers the best chances. Surgical planning would depend upon the type and location of the disease process as well as the condition of the patient. Perioperative care holds immense importance and knowledge of possible complications is essential. Aspergillosis of the central nervous system is difficult to diagnose and equally difficult to treat. Surgery remains the cornerstone of management followed by systemic antifungal medications. Results are better in immunocompetent patients as compared to those who are immunocompromised.

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Fungal infections of the central nervous system (CNS) are being increasingly diagnosed both in immunocompromised and immunocompetent individuals. Sinocranial aspergillosis is more frequently described from countries with temperate climates, more often in otherwise immunocompetent individuals. The clinical syndromes with which fungal infections of the CNS can present are protean and can involve most part of the neuroaxis. Certain clinical syndromes are specific for certain fungal infections. The rhinocerebral form is the most common presenting syndrome with zygomycosis and skull-base syndromes are often the presenting clinical syndromes in patients with sinocranial aspergillosis. Subacute and chronic meningitis in patients with HIV infection is more likely to be due to cryptococcal infection. Early recognition of the clinical syndromes in an appropriate clinical setting is the first step towards achieving total cure in some of these infections.

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Multiple factors influence the outcome of fungal infection of the central nervous system (CNS). The host and the pathogen in concert with drug delivery across the blood-brain barrier and drug activity are key factors in outcome. Drug costs can be prohibitively expensive. Drug toxicity with standard antifungal agents such as amphotericin B (infusion rate toxicity) can be reduced using simple techniques such as slower infusion and appropriate saline loading. Continuous infusion can allow relatively large doses of amphotericin B (up to 2 mg/kg/day, remaining below 0.08 mg/kg/hour) to be given with toxicity profiles comparable to expensive lipid formulations of amphotericin B. Dedicated peripherally inserted central catheters can remain in situ for weeks to months and are safe and relatively inexpensive. Correction of metabolic pathology in the case of mucormycosis and resolution of neutropenia are essential to effective treatment of filamentous fungal infections such as Mucor, Aspergillus and Scedosporium . The pharmacology and pharmacokinetics of the current major antifungal agents used to treat fungal infections of the CNS are reviewed. Tables that provide information about achievable CNS drug levels, antifungal susceptibilities and the likelihood of intrinsic drug resistance of significant fungal pathogens have been included to help the clinician with therapy. Treatment recommendations for Cryptococcal and Candida meningitis and for rhinocerebral infection with Mucor and Aspergillus have been included.

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Background : Central nervous system (CNS) cladosporiosis is a rare infection caused by Cladophialophora bantiana. It has varied presentation and poor outcome. Most of the available data in the literature are reviews of individual case reports. Objective : To describe the clinical, radiological and mycological features of 10 cases of C. bantiana managed at a single tertiary center. To analyze the various treatment options, factors associated with outcome, and to review the relevant literature. Materials and Methods: This is a retrospective study of 10 patients with CNS cladosporiosis managed at National Institute of Mental Health and Neurosciences from 1979 to 2006. It is a descriptive study. The case records were reviewed for clinical presentation, radiological features, management and outcome. Only those patients in whom the fungus could be isolated on culture were included in the study. Results : The age of the patients ranged from three to 42 years. Nine patients presented with features of space-occupying lesion and one patient with chronic meningitis. There were no specific clinical or radiological features. None of patients had impaired immune status. This infection presented as two pathomorphological forms - diffuse meningoencephalitis and focal abscesses. Burr hole tapping and excision are the surgical options. Both patients with burr hole tapping required excision of abscess subsequently. Two out of seven patients with abscess expired compared to all three patients with diffuse meningoencephalitis who expired. Recurrences occurred in four of the five patients following excision of the abscess. Combination antifungal treatment had better result than monotherapy. The outcome was poor with survival of only 50%. Conclusions : Thorough microbiological examination is required to diagnose CNS infection caused by C. bantiana . The outcome is better in patients with abscess. Excision of the abscess followed by combination antifungal therapy results in better outcome. Close follow-up is required due to high risk of recurrence.

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Rhodotorula species have been reported as a causative agent of opportunistic mycoses in immunocompromised hosts. We report a case of sepsis and meningoencephalitis caused by Rhodotorula glutinis in a 20-year-old female patient with systemic lupus erythematosus (SLE), which was diagnosed at autopsy. The patient presented with longstanding fever. She was diagnosed with SLE after admission to the hospital and died on day 5 of the hospital stay. Autopsy was performed to confirm the presence of infection. Sepsis and meningoencephalitis due to Rhodotorula glutinis was confirmed by postmortem blood cultures and histopathological examination of biopsies taken from the brain at autopsy. Infection by Rhodotorula spp. is rare but can be fatal in immunocompromised hosts. Infections by such uncommon yeasts may often be difficult to diagnose, especially in the setting of febrile neutropenia. This report also emphasizes the value of autopsy as a powerful educational tool.

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Fungal infections of the central nervous system (CNS) evoke humoral and cellular immune responses with the scope to enable the host to eliminate the pathogen. Immunopathogenesis of CNS fungal infections remains incompletely understood, with most of our understanding coming from studies on experimentally infected animals. However, activation of brain resident cells combined with relative expression of immunoenhancing and immunosuppressing cytokines and chemokines may play a determinant role and partially explain immunopathogenesis of CNS fungal infections.

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Background: Intracranial fungal masses (IFMs, granulomas and abscesses) are uncommon lesions, infrequently encountered by neurosurgeons. There is no conclusive evidence on the ideal surgical management of these lesions. Aims: To summarize the recent literature on the prevalence, presentation, surgical management and outcome of patients with IFMs. Materials and Methods: The recent published literature was searched using standard search engines (PubMed and Google) for articles reporting on the databases and surgical management of IFMs. A special effort was made to include publications from Indian centers. Results: Intracranial fungal masses were rarely seen even in major neurosurgical centers in India with a prevalence of around one to two per year. While most patients with IFM have immunosuppressed states, nearly 50% of patients with IFMs (especially in India) have no obvious predisposing causes and are apparently immunocompetent. The clinical presentation could be categorized into three groups: 1. Involvement of the cranial nerves 1 to 6 with orbital and nasal symptoms. 2. Focal neurological deficits due to involvement of any part of the neuraxis; and 3. "Stroke-like" presentation with sudden onset of hemiparesis. Based on the presence or absence of radiological evidence of paranasal sinus disease, IFMs were classified into two types: 1. Rhinocerebral type; 2. Purely intracranial type that was further divided into a. intracerebral or b. extracerebral forms. Aspergillus species was the commonest fungal organism causing IFMs but a number of other fungi have been reported to cause IFMs. Surgery for IFMs can be of different types, namely 1. Stereotactic procedures; 2. Craniotomy; 3. Shunt surgery; and 4. Treatment of fungal aneurysms. Generally, radical surgery is advocated for IFMs but there is no unanimity regarding the radicality of the excision especially for the rhinocerebral form of the disease. Surgery should always be followed by antifungal therapy for prolonged periods. Mortality and morbidity in patients with IFMs is very high and ranges from 40-92%. Immunosuppressed patients with IFMs and those in whom the diagnosis is delayed have the highest mortality rates, with immunocompetent patients with the rhinocerebral form of the disease having the best outcome. Conclusions: There should be a high index of suspicion for IFMs not only in patients with known risk factors for the development of fungal infections but also in immunocompetent patients in India. Intraoperative pathological diagnosis should be obtained in any patient suspected to have an IFM and tissue should be processed for fungal cultures. Prompt diagnosis, radical and safe surgery and aggressive and prolonged treatment with anti-fungal agents may lead to a better outcome especially in immunocompetent patients.

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Two patients with cerebrovascular aspergillosis, in the form of arteritis, thrombosis and bland infarcts are reported. One patient had systemic lupus erythematosus with disseminated aspergillosis in lungs, kidneys and brain. The other patient was immunocompetent and had sphenoid sinusitis. Both the patients were diagnosed at autopsy only, despite extensive imaging and laboratory studies. High index of clinical suspicion and early aggressive antifungal therapy are required since definite diagnostic modalities are not available.

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Introduction: Rhinocerebral mycosis is a rapidly progressive fatal opportunistic infection, predominantly affecting people in an immunocompromised state. Aggressive surgical therapy, with repeated debridement in combination with intravenous amphotericin B can lead to a high rate of cure. Aim: To determine the predictors of mortality in rhinocerebral mycosis. Materials and Methods: The demographic data, clinical features, radiological (MRI/CT) findings, treatment details of patients with a diagnosis of rhinocerebral mycosis confirmed on histopathology were analyzed retrospectively. The outcome was assessed as alive and dead. Univariate analysis with odds ratio (OR) was employed in data analysis. Chi-square test was used for P value. Results: There were 38 patients. The age range was 7-82 (mean 48.68) years; 30 (79%) were males. Craniofacial pain was the most common initial presenting symptom, noted in 29 (76.3%). Rhino-orbital involvement was noted in 24 (63.2%) and 12 (31.6%) had associated focal neurological deficits. Immunocompromised state was noted in 24 (63.2%). Eighteen (47.4%) patients died. The predictors for mortality: odds ratio (95% CI) were 2.45 (1.01-3.89) for elderly age, 5.67 (4.13-7.21) for intracranial extension, 2.6 (1.26-3.94) for immunocompromised state, 2.62 (1.25-3.99) for infection with zygomycosis and 2.33 (1.01-3.65) for anemia. Conclusion: Rhinocerebral mycosis is associated with high mortality in spite of aggressive therapy. Intracranial extension with focal neurological deficits is a major predictor of mortality in rhinocerebral mycosis.

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Background: Intracranial fungal granulomas occur by extension from contiguous structures or by hematogenous dissemination from lungs. Isolated granulomas without any obvious source of infection are extremely uncommon. Objective: To describe isolated intracerebral Aspergillus spp. granuloma without any obvious source of infection. Materials and Methods: We analyzed clinical, radiological and pathological features of isolated intracerebral aspergillus granulomas diagnosed in our institution between 1986 and 2006. The chest X-ray and paranasal sinus (PNS) X-rays were reviewed. Fungal stainings were done on histological sections. Results: We identified eight patients with Aspergillus spp. intracerebral granulomas (six males, two females). There were no predisposing risk factors. The chest and PNS X-rays were normal. On computerized tomography all were heterogeneously enhancing lesions with perilesional edema. Pre or perioperative diagnosis was never made. Histological studies revealed granulomas with minimal fibrosis and giant cells and septate hyphae of Aspergillus spp. on fungal stains. Two patients died of postoperative complications and two patients relapsed. Conclusion: Isolated intracerebral aspergillus granulomas are rare and pose a diagnostic challenge. Fungal granulomas should be considered in the differential diagnosis of intracerebral inflammatory pathologies.

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While fungal infections of the central nervous system (CNS) are relatively rare, fungal pathogens are increasingly being recognized as an important etiology of CNS infections, particularly amongst the growing immunocompromized population. In this paper we aim to provide a practical approach to the diagnosis of fungal infections of the CNS, review some of the diagnostic methods currently available and discuss diagnosis of certain pathogens of particular interest to the practicing neurologist.

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Fungal infections of the central nervous system (CNS) usually present as subacute meningitis. Other manifestations include mass effect and focal neurological deficits. ^[1] Cerebrospinal fluid (CSF) examination and biopsy of the lesion are helpful in disclosing the organism involved. Aspergillosis presents as brain abscess or granuloma with predominant neutrophils in CSF. Voriconazole is a broad spectrum triazole antifungal agent. It can be given orally and has lesser adverse effects We report a 69-years-old diabetic male, with aspergilloma of para-nasal sinus invading the CNS, who responded well to voriconazole treatment. He discontinued the medication by himself as it was costly. Within a month of stopping the medication, he developed features of subacute meningitis. However he showed clinical improvement after the medication was restarted. The case is reported for the clinical evidence of antifungal activity of voriconazole against aspergillosis.

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Opportunistic fungal infections are major causes of morbidity and mortality in the immunocompromized. Fungi have evolved complex and coordinated mechanisms to survive in the environment and the mammalian host. Fungi must adapt to "stressors" in the host, including nutrient scarcity, pH and reactive oxygen and nitrogen intermediates, in addition to evading host immunity. Knowledge of the immunopathogenesis of fungal infections has paved the way to promising strategies for immunotherapy. These include strategies that increase phagocyte number, activate innate host defense pathways in phagocytes and dendritic cells and stimulate antigen-specific immunity (e.g., vaccines). Immunotherapy must be tailored to specific immunocompromized states. Our review focuses on cryptococcosis and coccidioidomycosis because of the propensity of these diseases to involve the central nervous system (CNS). The CNS has long been considered "immunologically privileged" in the sense of being isolated from normal immune surveillance. This notion is only partially accurate. Immune-based therapies for fungal CNS disease are at an exploratory level and merit further evaluation in clinical trials.

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