Cryptococcal meningitis has an indistinct clinical syndrome. Most cases evolve subacutely, like other fungal infections and tuberculosis. In most cases, headaches, fever, and stiff neck are lacking altogether, and the patient presents with symptoms of gradually increasing intracranial pressure because of hydrocephalus (papilledema is present in half such patients) or with a confusional state, dementia, cerebellar ataxia, or spastic paraparesis, usually without other focal neurologic deficit. A few cases have had an explosive onset, rendering the patient quite ill in a day. Large series of affected patients indicate that 20 to 40 percent of patients have no fever when first examined (the figure applies to patients without HIV). Cranial-nerve palsies are infrequent. Rarely, a granulomatous lesion forms in one 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 caused by 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, it 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. As already emphasized, patients with HIV are particularly vulnerable to cryptococcal infection; estimates are that 6 to 12 percent of HIV patients are subject to meningoencephalitis with the organism.
The spinal fluid shows a variable lymphocytic pleocytosis, usually fewer than 50 cells/mm3, but there may be few or no cells in a patient with HIV (two-thirds have 5 or fewer cells/mm3). The initial CSF formula may display polymorphonuclear cells but it rapidly changes to a lymphocytic predominance. The glucose is reduced in three-fourths of cases (again, it may be normal in HIV patients) and the protein may reach high levels.
Specific diagnosis in developed regions depends on finding C. neoformans antigens in the CSF. The organism may be seen as spherical cells, 5 to 15 μm in diameter, which retain Gram stain and are surrounded by a thick, refractile capsule. India ink 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 of the dye fail to penetrate the capsule, leaving a wide halo around the doubly refractile wall of the organism. Large volumes of CSF (20 to 40 mL) may be needed to find the organism, but in others they are prolific. The search for these organisms is particularly important in HIV patients, in whom the CSF values for cells, glucose, and proteins may be entirely normal but difficulties interpreting the India ink preparation have led to its being used less often.
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 approximately 90 percent reliability in HIV patients and slightly less in others (Chuck and Sande). In most cases the organisms grow readily in Sabouraud glucose agar at room temperature and at 37°C (98.6°F), but these results may not appear for days. Newer enzyme-linked immunoadsorption tests are being used.