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Fungal infections of the CNS may arise without obvious predisposing cause, but frequently they complicate some other disease process such as AIDS, organ transplantation, severe burns, leukemia, lymphoma or other malignancy, diabetes, collagen vascular disease, or prolonged corticosteroid therapy The factors operative in these clinical situations are not fully understood, but interference with the body s normal ora and impaired T-cell and humoral responses are the most obvious ones Thus fungal infections tend to occur in patients with leukopenia, inadequate T-lymphocyte function, or insuf cient antibodies Infections related to impairment of the body s protective mechanisms are referred to as opportunistic and include not only fungal infections but also those due to certain bacteria (Pseudomonas and other gram-negative organisms,
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L monocytogenes), protozoa (Toxoplasma), and viruses (cytomegalovirus, herpes simplex, and varicella zoster) It follows that these types of infection should always be considered and sought in the aforementioned clinical situations Fungal meningitis develops insidiously, as a rule, over a period of several days or weeks, similar to tuberculous meningitis; the symptoms and signs are also much the same as with tuberculous infection Involvement of several cranial nerves, arteritis with thrombosis and infarction of brain, multiple cortical and subcortical microabscesses, and hydrocephalus frequently complicate the course of fungal meningitis, just as they do in all chronic meningitides Often the patient is afebrile or has only intermittent fever The spinal uid changes in fungal meningitis are also like those of tuberculous meningitis Pressure is elevated to a varying extent, pleocytosis is moderate, and lymphocytes predominate Exceptionally, in acute cases, a pleocytosis above 1000 per cubic millimeter and a predominant polymorphonuclear response are observed On the other hand, in patients with AIDS or with leukopenia for other reasons, the pleocytosis may be minimal or even absent Glucose is subnormal and protein is elevated, sometimes to very high levels The speci c diagnosis can best be made from smears of the CSF sediment and from cultures and also by demonstrating antigens of the organism by immunodiffusion, latex particle agglutination, or comparable antigen recognition tests The CSF examination should also include a search for tubercle bacilli and abnormal white cells because of the not infrequent concurrence of fungal infection and tuberculosis, leukemia, or lymphoma Some of the special features of the more common fungal infections are indicated below Cryptococcosis (Torulosis, European Blastomycosis) Cryptococcosis (formerly called torulosis) is one of the more frequent fungal infections of the CNS The cryptococcus is a common soil fungus found in the roosting sites of birds, especially pigeons Usually the respiratory tract is the portal of entry, less often the skin and mucous membranes The pathologic changes are those of a granulomatous meningitis; in addition, there may be small granulomas and cysts within the cerebral cortex, and sometimes large granulomas and cystic nodules form deep in the brain (cryptococcomas) The cortical cysts contain a gelatinous material and large numbers of organisms; the solid granulomatous nodules are composed of broblasts, giant cells, aggregates of organisms, and areas of necrosis Cryptococcal meningitis has a number of distinctive clinical features Most cases are acquired outside the hospital and evolve subacutely, like other fungal infections or tuberculosis A few of our cases have had an explosive onset, rendering the patient quite ill in a day In the majority of patients, the early complaints are headache, nausea, and vomiting; mental changes are present in about half In other cases, however, headaches, fever, and stiff neck are lacking altogether, and the patient presents with symptoms of gradually increasing intracranial pressure due to hydrocephalus (papilledema is present in half such patients) or with a confusional state, dementia, cerebellar ataxia, or spastic paraparesis, usually without other focal neurologic de cit Furthermore, large series of affected patients indicate that 20 to 40 percent of patients have no fever when rst examined (the gure applies to patients without AIDS); we suspect that more frequent measurement of temperature would give a greater incidence of fever Cranial nerve palsies are infrequent ndings Rarely, a granulomatous lesion forms in one
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part of the brain, and the only clue to the etiology of the cerebral mass is a lung lesion and an abnormality of the CSF Meningovascular lesions, presenting as small deep strokes in an identical manner to meningovascular syphilis, may be superimposed on the clinical picture A pure motor hemiplegia, like that due to a hypertensive lacune, has been the most common type of stroke in our experience The course of the disease is quite variable It may be fatal within a few weeks if untreated More often, the course is steadily progressive over a period of several weeks or months; in a few patients, it may be remarkably indolent, lasting for years, during which there may be periods of clinical improvement and normalization of the CSF Lymphoma, Hodgkin disease, leukemia, carcinoma, tuberculosis, and other debilitating diseases that alter the immune responses are predisposing factors in as many as half the patients Patients with AIDS are particularly vulnerable to cryptococcal infection; estimates are that 6 to 12 percent of AIDS patients are subject to life-threatening meningoencephalitis with the organism The spinal uid shows a variable lymphocytic pleocytosis, usually less than 50 cells per cubic millimeter, but it should be emphasized that there may be few or no cells in a patient with AIDS (two-thirds have 5 or fewer cells per cubic millimeter) The initial CSF formula may display polymorphonuclear cells, but it rapidly changes to a lymphocytic predominance The glucose is reduced in three-quarters of cases (again, it may be normal in AIDS patients) and the protein may reach high levels Speci c diagnosis depends upon nding Cryptococcus neoformans or its antigens in the CSF These are spherical cells, 5 to 15 m in diameter, which retain Gram s stain and are surrounded by a thick, refractile capsule Large volumes of CSF (20 to 40 mL) may be needed to nd the organism in some cases, but in others they are proli c Indiaink preparations are distinctive and diagnostic in experienced hands (debris and talc particles from the gloves used in lumbar puncture may be mistaken for the organism), but the rate of positive tests under the best circumstance is 75 percent The carbon particles fail to penetrate the capsule, leaving a wide halo around the doubly refractile wall of the organism The search for these organisms is particularly important in AIDS patients, in whom the CSF values for cells, glucose, and proteins may be entirely normal A latex agglutination test for the cryptococcal polysaccharide antigen in the CSF is now widely available and gives rapid results The latter test, if negative, excludes cryptococcal meningitis with about a 90 percent reliability in AIDS patients and slightly less in others (see Chuck and Sande) In most cases the organisms grow readily in Sabouraud glucose agar at room temperature and at 37 C, but these results may not appear for days Newer enzyme-linked immunoadsorption tests are being evaluated The principal diseases to be considered in differential diagnosis are tuberculous meningitis (distinguished by fever, distinctive pulmonary lesions, low serum sodium due to inappropriate secretion of ADH, and organisms in CSF); granulomatous cerebral vasculitis (normal glucose values in CSF); multifocal leukoencephalopathy (negative CSF); unidenti able forms of viral meningoencephalitis (normal CSF glucose values); sarcoidosis; and lymphomatosis or carcinomatosis of meninges (neoplastic cells in CSF) Treatment In patients without AIDS, this consists of intravenous administration of amphotericin B, given in a dose of 05 to 07 mg/ kg/day Intrathecal administration of the drug in addition to the intravenous route appears not to be essential Administration of the
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