Review Article Pathobiology of fungal infections of the central nervous system with special reference to the Indian scenario S. K. Shankar, A. Mahadevan, C. Sundaram*, Chitra Sarkar^, Geeta Chacko#, D. N. Lanjewar§, Vani Santosh, T. C. Yasha, V. V. Radhakrishnan† Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, *Department of Pathology, Nizam’s Institute of Medical Sciences, Hyderabad, ^Department of Pathology, All India Institute of Medical Sciences, New Delhi, #Department of Pathology, Christian Medical College, Vellore, §Department of Pathology, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, †Department of Pathology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvanathapuram, India Ubiquitously present fungi in the environment Þ nd a nidus Key words: Aspergillosis, central nervous system, cryptococcosis, in the human body and adopt its metabolic machinery to be dimorphic fungi, mycotic infections, pathogenesis, penicilliosis, in symbiosis or become pathogenic. Immunocompromised pheohyphomycosis, zygomycosis states like human immunodeÞ ciency virus (HIV) / acquired immunodeÞ ciency syndrome (AIDS), systemic neoplasia and organ transplantation have enhanced the frequency of fungal Fungi are ubiquitous in nature, but the distribution infections. High-risk behavior, IV drug abuse and air travel of fungal infections in a community depends on the have led to the emergence of new fungal infections hitherto environment, the climatic conditions, socioeconomic geographically localized. The pathology in the central status of the human hosts, their habits and genetic nervous system (CNS) is dictated largely by the size of the factors. The ability of fungi to adapt to the elevated body fungus - the yeast forms, by virtue of their small size enter the temperature and reduced redox state of the tissues and microcirculation to cause meningitis and microabscesses, overcome defense mechanisms of the human host alone while hyphal forms invade the vasculature to manifest as can cause disease of varying severity. In the soil they are large pale or hemorrhagic infarcts. The growth kinetics of saprophytes producing mycelia and airborne conidia. fungi, the antigenic character of the capsule. the proteases Normally fungal infections are of low virulence and secreted by the mycelial forms and the biochemical milieu confined to local infections. In immunocompromised in the host also determine clinical manifestations. A hospital- states, however, the same fungus tends to produce based analysis of the available information from India invasive infection with devastating consequences. suggests that in the non-HIV patient population, hyphal forms Certain body sites like the brain and meninges are like Aspergillosis and Zygomycosis are the(www.medknow.com). most common preferentially invaded by specific groups of fungi pathogens, while yeast forms like Cryptococcus and Candida like Cryptococcus, Candida species. Patients with the are the prime pathogens in cases of HIV/AIDS, the altered acquired immunodeficiency syndrome (AIDS) appear to macrophage function acting in synergy with suppressed be more prone to infections by Candida, Cryptococcus, cell-mediated immunity.a site In Northeastern hosted states, by systemic Medknow Publications This PDF is available for freeNocardia, download Histoplasma andfrom Pneumocystis carinii while infection by Penicillium marneffei is reported in association aspergillosis is uncommon. In cases of hematological with HIV though CNS involvement is not recorded. Although malignancies, solid organ transplantation, renal failure fungal infections of the CNS are reported from various or autoimmune disorders with prolonged steroid hospitals in India, studies are limited by non-availability of therapy, candidiasis and aspergillosis are common. This relevant microbiological studies and the reported prevalence reflects the preferential selectivity of the fungus for host data is biased by the surgical practices, availability of metabolic state and immune status favorable for survival postmortem and microbiology and laboratory support. and growth. A wide variety of fungi now isolated Detailed clinical and mycological investigations related to the from neutropenic patients like Pheohyphomycetes, interaction between the fungus and host environment is a Trichosporum and Penicillium marneffei were not fertile area of research to understand the basic pathogenetic recognized as human pathogens before. Some of the mechanisms. fungi like coccidioidomycosis and histoplasmosis show S. K. Shankar Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, India. E-mail: [email protected] 198 Neurology India | July-September 2007 | Vol 55 | Issue 3 Shankar, et al.: Pathobiology of fungal infections of CNS gender preference, the chronic progressive disease antigen. The fungal antigens are highly cross-reactive being more common in males. In pregnant women the with even quite unrelated fungal antigens.[5,8] In deep dissemination rate is equal to or exceeds that in males, tissue mycosis, the antigen of the infective yeast is quite reflecting the hormonal influence on the growth of different from that found in cultures with spores and fungi. Worldwide travel has increased the exposure of mycelium. Both humoral and cell-mediated immunity many communities to formally geographically limited take part to contain the fungus and a high degree of fungal infections. overlap in immune response is exhibited. The immunity Fungi like Blastomyces dermatitides, Paracoccidioides against fungi is not long-lasting unlike in bacteria and brasiliensis, Pseudoallescheria boydii and Coccidioides viruses, the antigenic potential being variable, highly immitis are capable of eliciting disease in the absence nonspecific and relatively poor to elicit response. This of known predisposing factors and are hence labeled makes the host prone for reinfection by the same fungus pathogenic fungi. It is essential to realize that any fungus at the previously infected site, despite healing of the is potentially a central nervous system (CNS) pathogen existing infection in the individual. and patients with fungal infections have some degree of Nonspecific (innate) defense mechanisms to fungal immunosuppression. Classification as pathogenic and infections include skin and mucosa behaving as opportunistic fungi is more for ease of understanding of mechanical barriers and cytokines facilitating emigration the pathology as overlap in pathogenesis and invasive of phagocytic cells (polymorphs and macrophages) to patterns exists in both forms. ingest and destroy the microbes. Neutrophils, the The morphology and size of the organism determine first line of defense against microbes are short-lived the evolution and phenotype of CNS lesions. The small cells that have powerful antifungal and bactericidal yeast forms, up to 20 µm in diameter (Blastomyces, mechanisms. Macrophages are long-lived and form the Coccidioides, Paracoccidioides, Sporotrichum, first line of defense against inhaled microbial pathogens, Histoplasma, Cryptococcus and Candida) reach the small like Aspergillus spores. T lymphocytes in conjunction arterioles and capillaries producing leptomeningitis with macrophages are important in conferring specific and subpial ischemic lesions as they have access resistance to fungal infection. to the microcirculation from which they seed the Fatal fugal infections are uncommon among subarachnoid space. Intermediate-sized pseudohyphae patients with intact immunological defense and are such as those of Candida occlude small vessels in the caused by restricted number of ‘pathogenic’ fungi. microcirculation to produce local areas of tissue necrosis In immunocompromised patients, the protective that transform into abscesses. The large hyphal forms mechanisms are deficient or absent making them of variable size (Septate-Aspergillus, Cephalosporium, prone to infections from saprophytic fungi that are Cladosporium etc; non-septate-Zygomyces) obstruct generally nonpathogenic in immunocompetent hosts. large and intermediate size arteries and occasionally Disseminated and progressive infection caused by veins, giving rise to large infarcts. Routine histology, Penicilliosis marneffei is an emerging opportunistic special stains and morphological characteristics indicate infection in AIDS patients and is endemic in Southeast the type of fungus, but speciation needs culturing and Asia and Southern China. biochemical characterization. Tissue fungal(www.medknow.com). infection The following presentation centers more on the burden of less than 10³ CFU/gm of tissue usually proves patholobiology of common fungal infections of CNS to be histologically negative.[1] relevant to India while rare and emerging fungi invading The phenomenon of resistance to fungal infection the brain are dealt with briefly. Though fungal infections is poorly understoodThis PDFa andsite most is hosted availableof the data availableby forMedknow is freeof the download nervous Publications system from are reported from various extrapolation from animal models. Immunity to fungal centers in India [Table 1], the studies are limited by infections is related to the tissue reaction elicited by the non-availability of relevant mycological studies. The fungi and their products.[2-4] Unlike superficial fungi, prevalence data of fungal infections from various centers the deep mycosis has diverse antigens