Cryptococcal meningitis

Pathogenesis and pathophysiology
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By Joseph R Berger MD

Human infection is usually acquired by inhalation of spores. The initial pulmonary infection is generally asymptomatic, although a self-limited pneumonia resolving over several weeks to months in the absence of treatment may be seen. Containment of the infection to the lungs is the consequence of both cell-mediated and humoral immunity (Eisenman et al 2007). Pulmonary cryptococcosis includes the constellation of fever, cough, pleuritic pain, malaise, and weight loss. Occasionally, the cough is productive of blood-tinged sputum. The disease often affects both lungs and examination reveals diminished breath sounds, dullness to percussion, and, on occasion, a friction rub. Pulmonary infection generally resolves in its entirety, although the infection may persist as a mediastinal mass (Rippon 1988). Chest radiographs show variable patterns depending on the severity of the disease, the duration of the infection, and the host response.

Typically, the spread of C neoformans is limited to the lung and lymph nodes, but hematogenous dissemination may result in the seeding of other organs. The latter is particularly likely in the setting of immunosuppression. Alternatively, the organism may become reactivated from the sites of initial infection years later. Factors influencing dissemination include the polysaccharide capsule and secreted enzymes including laccase, phospholipase B, and urease (Eisenman et al 2007). Resistance to infection is primarily dependent on cell-mediated immunity, although clinical infection occurs in both apparently normal and immunocompromised individuals (Dismukes 1992). Most cases of cryptococcal meningitis are observed in individuals with underlying impairment in cell-mediated immunity (Schimpff and Bennett 1975), chiefly, in the setting of AIDS, lymphoreticular malignancies, sarcoidosis, connective tissue diseases, bone marrow and organ transplantation, and corticosteroid therapy. Humoral responses are generated by cryptococcal infection and may play a role in control of infection. Anticryptococcal immunoglobulins may be detected in the CSF of patients with cryptococcal meningitis (Porter et al 1977); however, the absence of cryptococcal infection in persons with congenital or acquired humoral abnormalities indicates that this is of limited importance (Gupta et al 1987).

To a large degree, the tissue involved determines the nature of the pathological response to cryptococcal infection. In general, 2 types of histologic pattern occur with cryptococcal infection: (1) gelatinous and (2) granulomatous (Baker and Haugen 1955). Both types may coexist in the same lesion. The gelatinous lesions are characterized by masses of organisms and mucoid degeneration of the affected tissue. Granulomatous lesions are characterized by the presence of histiocytes, giant cells, lymphocytes, and variable degrees of a fibroblastic response.

Mouse studies indicate that Cryptococcus neoformans crosses the blood brain barrier by transcellular migration across brain endothelial cells (Chang 2004) and then proliferates in the subarachnoid space resulting in leptomeningeal opacification with a gelatinous appearance. In HIV-infected individuals, the inflammatory response may be sparse and discrete, resulting in focal collections of macrophages and formation of giant cells. Focal granulomas composed of macrophages, lymphocytes, giant cells, and fungi may be seen. In cryptococcal meningitis, an exudate typically predominates at the base of the brain. This leptomeningeal exudate is usually gray-yellow in color and may extend over the surface of the cerebral and cerebellar hemispheres, although it predominates in the basal meninges. Extension into the ventricles and perivascular space is observed, and hydrocephalus may develop. Inflammation is usually, but not invariably, minimal. The organisms extend along Virchow-Robin spaces where clusters of fungi may distend the perivascular space into adjacent parenchyma. This pathological process may also affect the spinal cord and nerve roots giving rise to myeloradiculitis (Murai et al 2006). Intracerebral abscesses and cryptococcomas may be found in some cases. Mucicarmine staining demonstrates the capsule of the organism (Lang et al 1990; Vinters and Anders 1990). Tubercles averaging 2 to 3 mm in diameter may occur along blood vessels. A collection of yeast that distorts without destroying the brain and exhibits little or no surrounding inflammation or gliosis is referred to as a “gelatinous pseudocyst” (Garcia et al 1985). Typically, these lesions have been present for a relatively short period of time. Localized granulomatous lesions are referred to as “cryptococcomas,” “torulomas,” or “cryptococcal granulomas” (Selby and Lopes 1973). Although these lesions are chiefly observed in the cerebral hemispheres, they have also been reported in the cerebellum (Kanaly 2007) and spinal cord (Shen 2006). Persons with these lesions generally exhibit focal neurologic findings and have had the infection for a period of weeks or months.

Another cause of focal neurologic findings in the setting of cryptococcal meningitis is cerebrovascular disease (Saul et al 1986; Yu et al 1989; Tornero Estebanez et al 1992; Goel et al 1999; Kalita et al 1999; Lan et al 2001), which occurs as a consequence of perivascular granulomatous infiltration or from vascular occlusion at the time of brain herniation. Multiple ischemic insults can be observed, although this is distinctly unusual (Rosario et al 2012). Persons with AIDS have a higher incidence of parenchymal brain lesions and involvement of extracranial sites, as well as concomitant opportunistic infection (most often Pneumocystis carinii pneumonia) in 15% to 35% (Tantisiriwat and Powderly 2001).

Cryptococcus is cleared by neutrophils and macrophages in a process that is mediated by complement, interferon, and T lymphocyte-derived lymphokines. Animal experiments reveal a critical role of interferon-γ for control of cryptococcal CNS infection and suggest that anti-CD40 and IL-2 therapy can be protective (Zhou et al 2007). The large polysaccharide capsule appears to be a virulence factor, inhibiting phagocytosis and leukocyte migration and activating the alternative complement pathway. One of the capsule’s defense mechanisms is the ability to produce a toxic polysaccharide that kills the engulfing macrophage (Steenbergen et al 2001). Survival in mammalian hosts is encouraged by the stimulation of capsular production by the physiologic concentrations of CO2 and by the low ferric iron concentrations found in the lung.

Cryptococcus has a particular affinity for the CNS, perhaps due to the absence of complement and soluble anticryptococcal factors present in serum and a diminished inflammatory response to the agent in brain tissue. A receptor on CNS cells for a ligand on the yeast has been proposed (Jimenez-Lucho et al 1990; Merkel and Scofield 1993) but has yet to be identified. Specific phenotypes of C neoformans appear to have a predilection for invasion of the nervous system. These include melanin production, the ability to thrive at body temperature, and the presence of a polysaccharide capsule (Kwon-Chung and Rhodes 1986; Chang and Kwon-Chung 1994). In vitro experiments reveal that C neoformans causes marked alterations in the cytoskeleton of human brain endothelial cells resulting in swelling of mitochondria and endoplasmic reticulum, membrane ruffling, and irregular nuclear morphology with a resultant disruption of the blood-brain barrier (Chen 2003). Elaboration of urease is also believed to be important in the disruption of the blood-brain barrier (Eisenman et al 2007).

In This Article

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