CNS fungal infections: A review

Highlights

• CNS fungal diseases have become increasingly common due to immunosuppressive therapies, transplantation, and HIV/AIDS.

• Several therapies increasingly employed for neurological conditions may predispose to fungal disease.

• CNS fungal disorders may present in variegate fashion and are often difficult to diagnosis and treat.

• Clinical, laboratory and radiographic features of these infections are valuable in establishing their diagnosis.

Introduction

Fungal infections of the central nervous system (CNS), though rare, have become increasingly common in the past several decades [1]. This is largely the consequence of increased use of immunosuppressive therapies, wider availability of stem cell and organ transplantation, and the spread of HIV/AIDS. Despite their clinical presentation, they are associated with potentially devastating health outcomes. There are currently more than 100,000 fungal species that have been recognized, but only a couple of hundred have been demonstrated to be pathogenic and only 10–15% of those result in neurological disease [1]. Pathogenic fungi capable of causing clinical disease in otherwise normal individuals have a restricted geographic distribution occurring chiefly in North America. These fungi include Blastomycetes, Coccidioides, Paracoccidioides, Histoplasma, and Sporothrix. Opportunistic fungi are found worldwide. Examples of the latter include Aspergillus, Candida, Cryptococcus, and Rhizopus. Sources of the various fungi can be found in Table 1.

The three main categories of fungal pathogens that affect the CNS include yeasts, dimorphic fungi, and molds [1]. The major morphological form of the fungus dictates the predominant clinical syndrome associated with the fungal infection; however, there is a great deal of overlap that may be observed in these syndromes caused by these fungi. Fungi that grow as small pseudomycetes (yeasts), e.g., cryptococcus, blastomycosis, histoplasmosis, coccidiomycosis, and sporotrichosis, primarily cause a leptomeningitis. Those growing as large pseudomycetes, e.g., candida, typically produce cerebral abscesses or granulomas. Those growing large branched hyphae, e.g., the septate mycetes, e.g., aspergillosis, or non-septate mycetes, e.g., zygomycosis, have a propensity to invade blood vessels causing stroke as well as invasion of orbits, sinuses, and cranial bone (Table 2).

Typically, fungi seed the CNS after it has been inhaled as an aerosol and has established infection in the lungs and/or lymph nodes. Occasionally, after inhalation, the site of initial infection is the paranasal sinuses. Hematogenous dissemination from the lungs follows with systemic infection and CNS involvement. The CNS may also be involved by direct spread from paranasal sinuses, orbits or other facial sites.

Both within the United States and worldwide, cryptoccocus is the most common clinically recognized cause of fungal meningitis accounting for about 70% of overall fungal infections, followed by coccidoimycosis (16.4%), candidiasis (7.6%), and histoplasmosis (6%) [2]. In some autopsy series candida is the most common histologically confirmed fungal infection of the brain and may remain undiagnosed during life [3]. Infection by these organisms depends largely on the geographic distribution and immune status of the patient. The most common risk factors for fungal infection include HIV/AIDs, organ transplantation, immunosuppression with chemotherapy or corticosteroids, and hematologic malignancy [2] (Table 3).

The growing use of immunosuppressants and biologic agents to treat neurologic diseases make our patient population potentially more susceptible to fungal infections. For instance, use of anti-tumor necrosis factor (TNF) therapies such as methotrexate and infliximab for treatment of neuro-sarcoidosis has been associated with fungal infections. Such infections include histoplasmosis, coccidiomycosis, candidiasis, cryptococcosis, and aspergillosis [4]. TNF-α plays a crucial role in the formation/maintenance of granulomas as well as macrophage activation making hosts susceptible to fungal infections. Eculizimab, approved for treatment of myasthenia gravis and neuromyelitis optica spectrum disorder, can increased the risk of fungal infections such as aspergillosis and candidiasis due to its inhibition of terminal complement activation [5].

Immunosenescence is also a factor that contributes to the risk of fungal infection [6,7]. For instance, patients over 65 years of age are more likely to be hospitalized for Coccidioides infections compared to younger populations. With age comes a reduction in naïve CD4+ and CD8+ T cells as well as decreased CD28 expression. The loss of CD28 expression increases risk of infection as these cells play a pivotal role in recognition and defense against intracellular pathogens. Moreover, the less functional T-cells are prone to produce type 2 cytokines leading to an increased Th2 response and decreased Th1 response. Th1 cells are responsible for production of interferon (IFN) gamma, which is critical for the stimulation of neutrophils to fight fungi. Though the number of natural killer cells increases, their ability to activate cytotoxic receptors is decreased.

Although these fungi often infect immunocompromised individuals, there are a growing number of cases being identified in immunocompetent individuals, such as infection with Cryptoccocus, Coccidioides, Histoplasma or Aspergillus [2]. Ideally, a definitive diagnosis of CNS fungal infection involves biopsy and visualization of the organism on histopathologic staining. However, there are a number of ancillary tests to aid in the diagnosis, which vary in sensitivity and specificity (Table 4).