Fungal meningitis

Cryptococcus neoformans and Cryptococcus gattii are environmental saprophytes, found as budding yeasts in clinical specimens.[48] C neoformans is found worldwide and has been isolated from soil contaminated by birds, especially pigeon excreta. C neoformans (serotypes A and D) usually causes infection in immunocompromised individuals. In contrast, C gattii (serotypes B and C) predominantly causes infection in apparently immunocompetent individuals, and is found primarily in tropical and subtropical regions, notably Australia and Papua New Guinea. C gattii has been found in association with several species of eucalyptus trees.

Histoplasma capsulatum is a thermally dimorphic fungus that exists as a mold in the environment, and as small intracellular yeasts in clinical specimens.[8]H capsulatum contaminates soil and has been isolated from poultry house litter, caves, and areas harboring bats and bird roosts.

Coccidioides species are also thermally dimorphic fungi.[28][29]Coccidioides immitis and Coccidioides posadii cause clinically indistinguishable disease. In the soil of the semiarid and desert endemic areas, septate hyphae give rise to thick-walled, airborne arthroconidia. In susceptible hosts, multinucleate spherules develop, which mature and rupture, releasing endospores that give rise to further spherules.

Candida species are part of the normal human flora, causing disease only when the skin or mucosal barriers to infection and/or protective immune responses are impaired. Candida albicans is to date the most commonly recognized cause of candidal meningitis, although other, nonalbicans Candida species may be increasing as causes of neurocandidiasis.[49][50][51]

Aspergillus meningitis is rare. Invasive Aspergillus disease of paranasal sinuses may cause hypertrophic cranial pachymeningitis. Rare cases of spinal arachnoiditis and meningitis have been reported after diskitis from epidural corticosteroid injection or spinal anesthesia as an iatrogenic complication in immunocompetent subjects.[52][53] Acute and chronic meningitis as well as meningoencephalitis have been reported in case studies of which nearly half did not have known cause of immunosuppression.[54]

Mucormycosis (zygomycosis) is an aggressive and lethal mycosis that may complicate sinus infection in immunosuppressed patients leading to local angioinvasion, tissue necrosis, and spread to orbits, cavernous sinus, and brain; chronic meningitis is rarely reported with focal intracerebral mucormycosis.[46]

With the notable exception of Candida species, many fungal pathogens are thought to be acquired through inhalation. Meningeal involvement, either isolated or associated with widely disseminated infection, results from hematogenous dissemination from the lungs. This may occur either following primary infection, or after a period of controlled, latent infection, when host immunity is compromised. Protection from Cryptococcus neoformans and the endemic mycoses is associated with an active granulomatous inflammatory response, and depends on intact cell-mediated immunity involving both CD4 and CD8 T cells (Th1 pattern of cytokine release).[55]

Cryptococcal infection is probably acquired through the inhalation of small yeasts or basidiospores. The primary pulmonary infection is often asymptomatic. Reactivation of latent infection may be important in HIV-associated cryptococcal meningitis.[56] The organism has a particular predilection for dissemination to the brain. This may relate to the production of melanin (that may interfere with oxidative killing by phagocytes) from L-dopa in the brain by a cryptococcal laccase enzyme.[57]

In histoplasmosis, hematogenous dissemination may occur throughout the reticuloendothelial system via parasitized macrophages. There are numerous reports of histoplasmosis in patients who have not returned to endemic areas for many years. This suggests the importance of reactivation of latent infection. In endemic areas, the relative importance of reactivation versus progressive primary infection is less clear.[58]

Coccidioidal meningitis occurs in approximately half of individuals with disseminated disease. Following the initial primary infection, dissemination to the brain, when it occurs, typically takes weeks to months. In high-risk, symptomatic populations, the dissemination rate may be >15%.[11]

Candidal meningitis may occur as a complication of candidemia, especially in neonates and premature infants. It is also associated with head trauma and neurosurgical procedures. In contrast to cryptococcosis and the endemic mycoses, the major risk factor for invasive candidiasis in adults is neutropenia.[55]

Primary and secondary fungal pathogens

There is no formal classification of fungal meningitides.

Fungal meningitides are commonly classified according to the etiologic agent involved. Fungal pathogens that cause meningitis may be classified into primary and secondary pathogens, although this distinction is not clear cut. Cryptococcal meningitis is the most common type of fungal meningitis.

Primary pathogens are capable of causing disease in apparently immunocompetent patients, although most frequently cause disease in immunosuppressed individuals.

Primary pathogens include:

Cryptococcus neoformans
Coccidioides immitis
Histoplasma capsulatum.

Secondary or opportunistic pathogens that occur in the setting of obvious immune dysfunction or of anatomic abnormalities include:

Candida
Aspergillus
Other molds (e.g., Fusarium).

Pathophysiology

Classification

Primary and secondary fungal pathogens