Cryptococcal meningitis

Diagnostic workup
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By Joseph R Berger MD

Radiology. CT imaging is insensitive to cryptococcal meningitis, revealing nonspecific atrophy or no abnormalities in most instances (Post et al 1985; Popovich et al 1990; Tien et al 1991). On rare occasion, unusual manifestations may be observed, such as CT demonstration of large, ring-enhancing, intraparenchymal lesions with intralesional calcification (Awasthi et al 2001). MRI is more sensitive than CT. In a study of 62 HIV-seropositive patients with cryptococcal meningoencephalitis, baseline imaging was abnormal in 53% of CT scans but in 92% of MRIs (Charlier et al 2008). Despite its increased sensitivity, MRI may still substantially underestimate the lesion burden found on pathologic examination (Mathews et al 1992).

Contrast enhanced imaging with MRI may reveal meningeal enhancement but appears to do so less frequently than in non-HIV-infected patients with cryptococcal meningitis. In one study comparing cryptococcal meningitis in HIV and non-HIV populations, normal brain imaging was observed in 44% of the former versus 13% of the latter (Lee 2011). Parenchymal cryptococcomas may appear as enhancing mass lesions within the parenchyma (Zuger et al 1986; Tien et al 1991; Andreula et al 1993). On diffusion-weighted MR imaging, cryptococcomas show a hypointense central cavity, which on apparent diffusion coefficient maps is hyperintense; these features mimic necrotic brain tumors rather than pyogenic brain abscesses (Ho 2005). Miliary nodular enhancing leptomeningeal lesions have been noted uncommonly (Tien et al 1991). In the absence of pathological confirmation, it is difficult to exclude the possibility of concurrent opportunistic pathology accounting for enhancing mass lesions (Mathews et al 1992). In immunocompetent individuals, multiple cystic lesions in the basal ganglia with marked ring enhancement (in contradistinction to the typical absence of contrast enhancement in the immunosuppressed individual) has been described (Saigal et al 2005).

Nonenhancing foci (which may be numerous in the basal ganglia and midbrain, displaying signal intensities similar to CSF) represent dilated Virchow-Robin spaces. On pathologic examination these may be filled with clusters of cryptococci and mucinous secretions. These collections have been referred to as gelatinous pseudocysts by some authors (Popovich et al 1990; Tien et al 1991; Mathews et al 1992; Andreula et al 1993).

Cerebrospinal fluid. Identification of cryptococcus in the CSF is the gold standard for establishing the diagnosis. In contrast to non-HIV-infected individuals with cryptococcal meningitis, CSF abnormalities may be subtle in AIDS patients. The opening pressure is elevated in about two thirds and may exceed 500 mm of water. Animal studies suggest that C neoformans strain differences, such as the expression of glucorunoxylomannan, influences the degree of inflammation and the elevation of intracranial pressure (Fries 2005). The CSF is typically clear, although on occasion, may be cloudy. Pleocytosis is lacking or modest in most instances; however, occasionally vigorous mixed inflammatory responses are seen. Hypoglycorrhachia and elevated protein levels are found in up to three fourths of cases.

India ink stains will disclose cryptococci in 50% of non-AIDS patients and in as many as 80% of those with AIDS (Perfect et al 1983). The India ink is positive in 70% to 94% of patients with positive CSF cultures. Cryptococcal antigen latex agglutination is a reliable test of the presence of the organism in the CSF as it is positive in more than 90% of patients with meningitis (Kovacs et al 1985; Zuger et al 1986; Chuck and Sande 1989; Clark et a 1990; Saag et al 1992; Rozenbaum and Goncalves 1994) and is a valuable test while awaiting fungal cultures (Snow and Dismukes 1975). Falsely negative cryptococcal antigen tests may occur and do not appear to be due to a prozone phenomena or interference from bound antibody or protein (Currie et al 1993). Like the India ink test, high titer CSF cryptococcal antigen (greater than 2:2034) is seen more commonly in the AIDS patient than the non-AIDS patient with cryptococcal meningitis. With rare exception, such as the occasional patient with parenchymal cryptococcomas and no meningitis who has sterile CSF, cryptococci are cultured from CSF in virtually all patients with meningitis (Zuger et al 1986). The yield is improved when large volumes of CSF (10 to 30 mL) are removed and cultured. Neither India ink nor CSF cryptococcal antigen studies are reliable measures to assess the adequacy of therapy. CSF fungal cultures are definitive in this regard.

As mentioned, other CSF parameters are frequently abnormal as well. The CSF leukocyte count varies considerably. With rare exception, lymphocytes predominate. White cell counts rarely exceed 800 cells/cu mm (Rippon 1988). Low numbers may occur in the setting of AIDS or corticosteroid administration. The number of cryptococci may exceed the number of leukocytes. A quantitative assessment of the number of viable yeast may yield between 103 and 107 colony-forming units of yeasts per mL of CSF (Perfect et al 1983). CSF protein levels are high and may exceed 1 g/dL, but are typically in the range of 40 to 600 mg/dL. In those instances where the protein is excessive, a subarachnoid block should be considered. Hypoglycorrhachia may also be seen.

Serologic studies. Cryptococcal antigen titers in serum are usually elevated in patients with cryptococcal meningitis, in some cases even when antigen titers in CSF are negative (Chuck and Sande 1989). The level of serum cryptococcal antigen and changes in response to therapy do not appear to reliably reflect CSF responses (Eng et al 1986; Clark et al 1990; Powderly et al 1992). On at least one occasion, blood culture was diagnostic and CSF negative for Cryptococcus in the presence of cryptococcal meningoencephalitis (Sivasangeetha et al 2007).

Serum cryptococcal antigen titers may reflect disease disseminated to other organs; this occurs in conjunction with meningitis in up to one half of cases. Titers above 1:8 suggest disseminated cryptococcosis. Most common sites for extrameningeal infection are the lungs, blood, urine, and bone marrow, but virtually any organ may be involved (Kovacs et al 1985; Larsen et al 1989; Clark et al 1990; Rozenbaum and Goncalves 1994).

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited