Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV

INTRODUCTION — Cryptococcus neoformans meningoencephalitis is the most frequently encountered manifestation of cryptococcosis. The term "meningoencephalitis" is more appropriate than "meningitis" since histopathologic examination has demonstrated that the brain parenchyma is almost always involved.

Cryptococcal meningoencephalitis is an important opportunistic infection in immunosuppressed patients. Issues related to patients with human immunodeficiency virus (HIV) are discussed in detail separately. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention" and "Clinical management and monitoring during antifungal therapy for cryptococcal meningoencephalitis in persons with HIV".)

The pathogenesis, clinical manifestations, and diagnosis of cryptococcal meningoencephalitis in patients without HIV will be reviewed here. Other issues related to C. neoformans infection are discussed separately. Cryptococcus gattii infection is also presented separately. (See "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV" and "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus gattii infection: Treatment".)

PATHOGENESIS — C. neoformans causes infection following inhalation through the respiratory tract. The organism disseminates hematogenously and has a propensity to localize to the central nervous system (CNS). The basis for the tropism for the CNS is uncertain, but several hypotheses have been proposed:

●The cerebrospinal fluid (CSF) is a favorable growth medium for the organism as it lacks the factors present in serum that inhibit cryptococcal growth [1]. In the serum, the organism activates the alternative complement pathway, but complement activity in the CSF is very low [2].

●Dopamine levels in the CNS may promote cryptococcal virulence by serving as a substrate for melanin production by the organism [3]. (See "Microbiology and epidemiology of Cryptococcus neoformans infection".)

●Production of mannitol by the organism may contribute to brain edema and inhibit phagocyte function [4].

●C. neoformans appears to evade the host innate immune system and invade through the blood-brain barrier [5].

The inflammatory response in the brain is generally milder than that seen in bacterial meningoencephalitis. The inflammatory cell infiltrate is predominantly comprised of mononuclear cells with occasional polymorphonuclear leukocytes. In general, involvement of the brain is diffuse, but localized infection (ie, cryptococcoma) can also occur.

EPIDEMIOLOGY — Most patients with cryptococcal meningitis are immunocompromised. The most common forms of immunosuppression, other than HIV, include glucocorticoid therapy, solid organ transplantation, cancer (particularly hematologic malignancy), and other conditions such as sarcoidosis and hepatic failure. Other risk factors include the use of the tyrosine kinase inhibitor, ibrutinib [6], and the development of anti-granulocyte-macrophage colony stimulating factor (anti-GM-CSF) antibodies [7]. Although many patients have risk factors for disease, in a multicenter retrospective study of 157 cases of central nervous system (CNS) cryptococcosis in patients without HIV, 30 percent had no apparent underlying condition [8].

Additional information on the epidemiology of cryptococcal infection is discussed in detail separately. (See "Microbiology and epidemiology of Cryptococcus neoformans infection".)

CLINICAL MANIFESTATIONS — Clinical presentation of cryptococcal meningoencephalitis in patients without HIV is variable. Some patients have symptoms for up to several months prior to diagnosis, whereas others present with an acute illness of only a few days. Most patients present with signs and symptoms of subacute meningoencephalitis; fever is observed in approximately 50 percent of cases [8-10]. Typically, headache, lethargy, personality changes, and memory loss develop over two to four weeks. Patients may also present with disseminated disease. (See "Cryptococcus neoformans infection outside the central nervous system".)

Among solid organ transplant recipients, cryptococcal infection occurs in an average of 2.8 percent of patients [11,12]. The median time to disease onset is 21 months after transplantation; 68 percent of cases occur >1 year after transplantation. Central nervous system (CNS) involvement and disseminated infection have been documented in 52 to 61 percent of patients with cryptococcal infection [11,13]. Approximately 25 percent of transplant recipients with C. neoformans disease have fungemia [11,14].

DIAGNOSIS — Diagnosis of cryptococcal meningoencephalitis can be challenging because of the subacute onset of symptoms and nonspecific presentation. The disease should be suspected in any immunocompromised patient with fever, headache, and signs or symptoms referable to the central nervous system (CNS). C. neoformans should also be considered in immunocompetent individuals presenting with subacute to chronic meningitis. A lumbar puncture is necessary to definitively diagnose cryptococcal meningoencephalitis, although this procedure should be delayed in the setting of focal neurologic signs, papilledema, or impaired mentation pending the results of radiographic imaging.

Cerebrospinal fluid — Lumbar puncture with measurement of the opening pressure and careful evaluation of the cerebrospinal fluid (CSF) with India ink, polymerase chain reaction (PCR) CSF testing, and/or cryptococcal antigen testing should suggest the diagnosis in most cases. Culture nearly always establishes the diagnosis.

●The opening pressure may be markedly elevated. Almost 70 percent of acquired immunodeficiency syndrome (AIDS) patients with cryptococcal meningoencephalitis have opening pressures >200 mmH₂0 on the initial lumbar puncture [9]. Increased intracranial pressure is observed less frequently in patients without HIV.

●Cell counts of the CSF are characteristically low in HIV-associated infection (0 to 50 cells/microL), and higher in non-HIV-associated cases (20 to 200 cells/microL). Mononuclear cells predominate in patients with cryptococcal meningoencephalitis (50 to 80 percent).

●Low glucose levels and elevated protein levels are frequently observed. Inflammatory cell counts have a lymphocytic predominance. Some patients present with normal CSF protein and glucose values [15].

●Examination of the CSF with India ink demonstrates encapsulated yeast forms in approximately 75 percent of patients with HIV and in 50 percent of patients without HIV [16,17]. Gram stain is usually not sufficient since the organisms stain poorly and can be confused with host cells (picture 1A-C).

The diagnosis of cryptococcal meningoencephalitis is established by culturing the organism from the CSF. Cultures are positive in about 90 percent of patients without HIV. C. neoformans usually takes three to five days to grow in the laboratory. At least 3 to 5 mL of CSF should be used for culture; the yield may be increased by culturing more than 15 mL of CSF [16,18].

Cryptococcal antigen — Cryptococcal antigen testing is a useful tool in the diagnosis of cryptococcal meningoencephalitis. Antigen testing can be collected in the CSF or the serum and can be quantified by evaluating serial dilutions. The height of the antigen titer generally correlates with the burden of organisms. However, serial measurement of antigen titers is not a reliable indicator of response to therapy.

●In the CSF − CSF cryptococcal antigen should be sent in addition to CSF culture when cryptococcal meningoencephalitis is suspected. Antigen test results are generally available soon after the lumbar puncture is performed and can help make the diagnosis before the culture results are complete. The antigen test is very sensitive and specific in the CSF. In a study of five antigen tests (four latex agglutination assays and one enzyme-linked immunoassay), all had sensitivities ranging from 93 to 100 percent and specificities of 93 to 98 percent compared with culture [19]. More recently, a lateral flow assay has been developed for cryptococcal antigen detection, which is inexpensive, easy to perform, and accurate [20]. False-positive CSF cryptococcal antigen results have been reported rarely following exposure of samples to disinfectants or soap or after samples were placed into an anaerobic transport vial [21-23]. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Cryptococcal antigen (CrAg)'.)

●In the serum − If a lumbar puncture cannot be performed expediently, serum cryptococcal antigen testing can be helpful to support the diagnosis if positive. However, it cannot be reliably used to rule out cryptococcal meningoencephalitis in patients without HIV. Because patients without HIV tend to have a lower cryptococcal burden, the sensitivity of serum antigen testing is lower than in patients with HIV [24]. False-negative serum cryptococcal antigen tests can also occur with samples that contain a large amount of antigen (the prozone phenomenon) if the laboratory is using a latex agglutination assay and doesn't pretreat the sample with pronase [19]. Among organ transplant recipients, patients with CNS or disseminated cryptococcosis are more likely to have a positive serum cryptococcal antigen result than patients with limited pulmonary disease [14]. False-positive serum cryptococcal antigen tests can occur in the setting of infections due to the fungus Trichosporon asahii (formerly Trichosporon beigelii) or the bacterial genera Stomatococcus or Capnocytophaga [25-27]. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Cryptococcal antigen (CrAg)'.)

Cryptococcal PCR — A multiplex polymerase chain reaction (PCR) assay has been found to be useful for the diagnosis of cryptococcal meningitis in patients with HIV infection (>90 percent sensitivity and specificity) [28]. However, with the lower burden of CSF yeasts in many patients without HIV, this test may be less sensitive [29,30]. Additional information about the use of this test in patients with HIV is presented elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Cryptococcal PCR'.)

Extraneural cultures — The diagnosis of cryptococcal meningoencephalitis is occasionally made by recovering C. neoformans from an extraneural site before CNS disease is suspected. This is especially true in patients with HIV infection who have a high likelihood of extraneural disease involving the respiratory tract, urinary tract, or bloodstream at the same time as CNS infection. As an example, blood cultures have been positive for cryptococci in approximately two-thirds of HIV-associated cases of meningoencephalitis [18].

Therefore, lumbar puncture should be considered for patients with positive serum cryptococcal antigen or extraneural culture to rule out CNS involvement. Immunocompetent individuals with only pulmonary involvement who have no CNS signs or symptoms may not require a lumbar puncture prior to treatment. (See "Cryptococcus neoformans infection outside the central nervous system".)

Radiography — Radiographic imaging of the brain with computed tomography (CT) or magnetic resonance imaging (MRI) prior to lumbar puncture is important in the setting of focal neurologic signs, papilledema, or impaired mentation. MRI is more effective than CT for identifying CNS cryptococcal lesions [31].

Radiographic images frequently show no abnormality or cerebral atrophy without obstruction or other pathology [32]. Less commonly, hydrocephalus may be seen. Mass lesions are seen in about 10 percent of patients with CNS cryptococcal infections [9]. Acute and subacute cerebral infarcts have also been described [10,33].

Some brain lesions persist radiographically for long periods even in those who have had a good clinical response to therapy [32]. Lesions that develop surrounding edema during effective therapy are typically due to an immunologic response associated with control of infection, the so-called immune reconstitution inflammatory syndrome [33]. (See "Immune reconstitution inflammatory syndrome", section on 'IRIS associated with preexisting cryptococcal infection'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cryptococcosis".)

SUMMARY AND RECOMMENDATIONS

●Definitions and pathogenesis

•Cryptococcus neoformans meningoencephalitis is the most frequently encountered manifestation of cryptococcosis. The term "meningoencephalitis" is more appropriate than "meningitis" since histopathological examination has demonstrated that the brain parenchyma is almost always involved. (See 'Introduction' above.)

•C. neoformans causes infection following inhalation through the respiratory tract. The organism disseminates hematogenously and has a propensity to localize to the central nervous system. The inflammatory response in the brain is generally milder than that seen in bacterial meningoencephalitis. The inflammatory cell infiltrate is predominantly comprised of mononuclear cells with occasional polymorphonuclear leukocytes. In general, involvement of the brain is diffuse, but localized infection (ie, cryptococcoma) can also occur. (See 'Pathogenesis' above.)

●Epidemiology – Most patients with cryptococcal meningitis are immunocompromised. The most common forms of immunosuppression other than HIV include glucocorticoid therapy, solid organ transplantation, cancer (particularly hematologic malignancy), and other conditions such as sarcoidosis and hepatic failure. (See 'Epidemiology' above.)

●Clinical manifestations – Clinical presentation is variable. Some patients have symptoms for up to several months prior to diagnosis, whereas others present with an acute illness of only a few days. Fever is observed in approximately 50 percent of cases. Typically, headache, lethargy, personality changes, and memory loss develop over two to four weeks. Patients may also present with disseminated disease (eg, >1 noncontiguous site). (See 'Clinical manifestations' above.)

●Diagnosis

•Cerebrospinal fluid (CSF) testing – A lumbar puncture is necessary for diagnosis of cryptococcal meningoencephalitis. The opening pressure should be measured, along with India ink evaluation, cryptococcal antigen testing, fungal culture, and routine spinal fluid studies. The diagnosis is established definitively by culturing the organism from the spinal fluid. (See 'Cerebrospinal fluid' above.)

•Serum cryptococcal antigen – Serum cryptococcal antigen testing is useful for evaluation of patients without HIV infection, although a negative result cannot be used to rule out cryptococcal meningoencephalitis. The height of the antigen titer generally correlates with the burden of organisms, although serial measurement of antigen titers is not a reliable indicator of response to therapy. (See 'Cryptococcal antigen' above.)

•Radiography – Radiographic imaging of the brain with CT or MRI prior to lumbar puncture is important in the setting of focal neurologic signs, papilledema, or impaired mentation. Radiographic images frequently show no abnormality or cerebral atrophy without obstruction or other pathology. Less commonly, hydrocephalus may be seen. Mass lesions are seen in about 10 percent of patients with central nervous system cryptococcal infections. (See 'Radiography' above.)