Fungal Infections of the Central Nervous System

Pathogens

Fungi that cause CNS infection can be divided into two general groups. The first group consists of primary pathogens including Cryptococcus neoformans / gattii , Coccidioides immitis / posadasii , Blastomyces dermatitidis , Paracoccidioides brasiliensis , Sporothrix schenckii , Histoplasma capsulatum , Talaromyces marneffei, Pseudallescheria boydii ( Scedosporium apiospermum ), and the dematiaceous molds. CNS involvement by these fungi can occur in patients with apparently intact immune systems and, at even higher rates, in immunosuppressed patients. The second group consists of secondary opportunists that cause CNS infection almost exclusively in patients with defective host defenses; this group includes Candida species, Aspergillus species, and mucormycosis caused by fungi in the order Mucorales. Finally, some fungi for which only a few case reports of CNS involvement exist are mostly common in the environment and include Alternaria , Rhodotorula , Aureobasidium , Arthrographis , Acremonium , Clavispora , Blastoschizomyces , Trichosporon , Sepedonium , Bipolaris , Schizophyllum , Paecilomyces , Pneumocystis , and Ustilago . Such cases generally have some unique feature in the medical history, such as direct trauma or CNS penetration, that explains the presence of the fungus in the CNS. Two prime examples are the fungal meningitis outbreaks of 2002 with Exophiala (Wangiella) dermatitidis and of 2012 with Exserohilum rostratum ; both were associated with injection of compounded, preservative-free corticosteroids.

Some of the key characteristics of the more common CNS fungal infections are listed in Table 45-1 .

Host Factors

Geographic factors are important for certain CNS fungal infections. Several groups of fungi are not geographically restricted and have worldwide distribution including Candida albicans and other Candida species, Aspergillus species, and C. neoformans / C. gattii . However, other mycoses such as histoplasmosis, blastomycosis, coccidioidomycosis, talaromycosis (penicillinosis), and paracoccidioidomycosis are largely confined to certain geographic areas, although these lines are blurred with modern travel. It is therefore essential that clinicians evaluating patients with possible fungal infections acquire an accurate travel history.

The CNS is an immunologically sequestered site, with anatomic barriers that exclude not only invading microorganisms but also some components of the immune system. Host defenses normally are highly effective in excluding fungi from the CNS, but certain conditions can lead to failure of these protective functions. Some of these conditions are obvious, such as trauma or the presence of indwelling catheters that allow direct inoculation of fungi into the CNS, immaturity of the blood–brain barrier in neonates, and a high-grade fungemia. In most cases, the fungus enters via the respiratory tract and seeds the CNS hematogenously, but other extracranial origins of CNS infection have been identified such as abscesses, mycotic aneurysms, and meningitis, which can arise from septic emboli associated with endocarditis. Rhinocerebral mucormycosis involves both vascular invasion and direct neural sheath extension into the CNS.

The most important risk factor for the development of CNS fungal infections is suppression of the host immune system, whether due to an underlying disease or to immunosuppressive drugs. Both the etiology of these CNS infections and their responses to therapy depend on the type of immune suppression. For instance, administration of immunosuppressive drugs such as systemic corticosteroids is a leading risk factor for development of CNS fungal infections with C. neoformans/gattii and Aspergillus species. Neutropenia due to cancer chemotherapy is associated with CNS infections caused by Aspergillus and Candida species, and treatment with the iron chelator deferoxamine predisposes to rhinocerebral mucormycosis. Several specific underlying diseases are associated with an increased incidence of CNS fungal infections. For instance, the most important of these associations is the link between the acquired immunodeficiency syndrome (AIDS) and cryptococcal meningitis. Prior to the advent of antiretroviral therapy (ART), rates reported from several cities ranged between 24 and 66 per 1,000 AIDS patients in the United States, but this incidence has been reduced with effective ART. Cryptococcal meningitis continues to occur early, in some patients who have either not received or have stopped antiretroviral drugs, or later, as viral resistance develops to ART. In 2009, the US Centers for Disease Control estimated that worldwide there were 1 million cases per year of cryptococcosis, with over 600,000 deaths, which made it the most deadly invasive fungal infection in the world. With widespread ART availability, the yearly incidence has now been estimated at 270,000, with 180,000 deaths. Cryptococcal meningitis accounts for approximately 8 percent of all invasive mycoses among transplant recipients. There have also been several reports of patients infected with human immunodeficiency virus (HIV) who have contracted CNS infections with Aspergillus species and the use of high-dose ibrutinib for cancer therapy has been associated with Aspergillus and cryptococcal CNS infections. Mold infections have been manifested predominantly as cerebral mass lesions, although cerebral infarctions, meningitis, and spinal cord involvement have also been observed. Patients with advanced HIV infection may also present with disseminated and CNS histoplasmosis, talaromycosis, coccidioidomycosis, blastomycosis, or sporotrichosis.

Patients who undergo organ transplantation and receive concomitant immunosuppression are at a significant risk of CNS fungal infection. The most common fungal pathogens in this setting are C. neoformans/C. gattii , Aspergillus species, and Candida species. Infection with C. neoformans in organ transplant recipients is usually manifested as a chronic or subacute meningitis occurring 6 months or more after organ transplantation. Infections with Aspergillus and Candida species usually occur within the first 2 months after organ transplantation, and CNS involvement is usually manifested by brain abscesses. CNS aspergillosis may be underdiagnosed in organ transplant recipients; in one series of 44 brains from liver transplant recipients examined at autopsy, 9 cases of cerebral aspergillosis were identified, of which only 2 were diagnosed before death.

Other high-risk underlying diseases or conditions associated with CNS fungal infection include malignancies, diabetes mellitus, and prematurity. Poorly controlled diabetic patients with or without ketoacidosis are at increased risk of rhinocerebral mucormycosis. Premature infants are at risk of disseminated infections and specifically of meningoencephalitis with Candida species, which has substantial implications for survival and for neurodevelopment issues with CNS involvement.

Infections that arise from direct inoculation of fungi into the CNS are usually seen after head trauma or neurosurgical procedures or as complications of implanted cerebrospinal fluid (CSF) shunts. In patients who have open head injuries, fungi that are ubiquitous in the environment may contaminate the wounds, leading to meningitis and focal fungal brain abscesses. With CSF leaks, the initial infection may be bacterial, but during the use of prolonged broad-spectrum antibacterial drugs, superinfection with Candida can occur.

CNS fungal infections can be associated occasionally with the presence of a CSF-diverting shunt. The most common fungus associated with CSF shunt infections is C. albicans . It appears that infection occurs as a result of either contamination of the shunt apparatus during insertion or subsequent manipulation, or through hematogenous spread. Among the published cases of CSF shunt infections with C. albicans , an association exists with recent antibacterial therapy and colonization with Candida species at other body sites. Other fungi that have caused CNS infection in the setting of a CSF shunt include C. neoformans , Trichosporon beigelii , Candida glabrata , and Candida tropicalis . There is some controversy concerning the origin of cryptococcal shunt infections. In many of the patients with CSF shunts who were subsequently found to have C. neoformans infection, the shunts were originally placed for either idiopathic hydrocephalus or chronic culture-negative meningitis; these patients probably had chronic CNS cryptococcal infection before their shunts were inserted.

There are rare reports of fungal infection associated with neurosurgical procedures; among these, Aspergillus and Candida species account for most cases. In some of these patients, infection was attributed to direct extension of the fungus from the paranasal sinuses, and in others it was thought that fungi were introduced with devices inserted during the operative procedure. Many of these patients have additional predisposing conditions such as prior treatment with antibacterial agents or high-dose corticosteroids. The dramatic outbreak of over 500 patients with meningitis, arachnoiditis, and epidural abscesses due to E. rostratum contamination of injectable corticosteroids around the spine emphasizes how fungi can aggressively establish disease. They travel through tissue after direct inoculation and are helped by immunosuppression, such as with corticosteroids.

Cryptococcus neoformans and gattii

The encapsulated yeast C. neoformans is the most common cause of fungal meningitis worldwide. The first report of cryptococcal infection in humans was provided by Busse and Buschke in 1894 in a patient with bone infection and probable disseminated disease. The first case of meningeal cryptococcal infection was reported 10 years later, in 1905, and cryptococcosis emerged as a significant CNS infection during the twentieth century. The number of infections with C. neoformans rose dramatically in the United States and certain African countries following the onset of the AIDS epidemic. It peaked at approximately a million cases per year, but even with the advent of widespread ART it is estimated that there are approximately 270,000 cases per year, with over 180,000 deaths.

This ubiquitous encapsulated saprophytic yeast occupies a wide environmental niche. It is found worldwide in bird excreta, soil, animals, and even humans. A large outbreak of C. gattii infections in the Pacific Northwest was associated with trees. It is likely that most infections occur after inhalation of small yeasts or basidiospores, leading to a primary pneumonia or a primary lung–lymph node complex in which the yeasts remain dormant for long periods in the host, until the host defenses become weakened. The reason that this yeast has a particular tendency to spread to the CNS remains imprecisely explained. It is likely that Cryptococcus travels by three mechanisms across the blood–brain or blood–CSF barrier: (1) transcytosis; (2) paracellular; and (3) the Trojan Horse method. Ligands on C. neoformans such as the hyaluronic acid antigen (CPS1) have been associated with the CD44 receptor on brain endothelial cells, perhaps allowing for transcytosis through the blood–brain barrier. Another cryptococcal mechanism for transcytosis is to use the secreted yeast metalloprotease encoded by the MPR1 gene. On the paracellular front, the UREl gene and its encoded protein help control trafficking of the yeast directly through the blood–brain barrier. Finally, multiple experiments have shown Cryptococcus to travel across the blood–brain barrier within mononuclear cells (Trojan Horse effect). It is anticipated that not only are there multiple mechanisms for CNS targeting but that many cryptococcal genes are involved in the efficient movement of Cryptococcus into the brain.

CNS infection usually manifests as a meningitis or meningoencephalitis, although mass lesions or torulomas may be seen. There are four serotypes (A to D) based on the type of capsular polysaccharide, which are then divided into several species: C. neoformans var. grubii or neoformans (serotypes A and D), and C. gattii (serotypes B and C). Furthermore, C . neoformans has been divided into multiple genotypes or subspecies of VNI, VNII, VNB (I and II), VNIII, and VNIV; C. gattii has been divided into five cryptic species (VGI–V). All serotypes can cause meningitis, but there is some geographic variation in their distribution for disease; for example, most patients with cryptococcal meningitis in the United States and Europe have been infected with either the serotype A or D strains. Infections with C. gattii are found more commonly in southern California, Southeast Asia, and Australia; this distribution reflects the natural distribution of certain Eucalyptus trees that are likely one of the environmental yeast repositories. A recent outbreak of C. gattii infections on Vancouver Island showed that there are other trees, such as firs and oaks, that can contain this fungus, perhaps related to ecologic evolution in the setting of global climate change. Despite earlier reports that many patients with cryptococcal meningitis had no known immune deficiency, recent experience suggests that a much higher proportion of patients have some identifiable form of immunosuppression. About 10 percent of patients with cryptococcal meningitis have no known underlying disease but a series of host-altered genes linked with an increased genetic susceptibility to cryptococcosis have been identified. However, most cases occur in those with known defective cell-mediated immunity due to corticosteroid treatment, reticuloendothelial malignancy, organ transplantation, sarcoidosis, collagen vascular diseases, or AIDS. Use of new anticancer agents such as ibrutinib (kinase inhibitor) can be associated with rapid development of cryptococcal and Aspergillus brain infections. Lymphocyte functions are abnormal in most patients with disseminated cryptococcosis. Patients with HIV infection have severe lymphocytopenia with CD4 counts below 100/μL. Most patients with AIDS and cryptococcal meningitis present with a particularly high burden of CSF yeasts. India ink examinations of the CSF are positive in over 80 percent of patients, and extraordinarily high titers of cryptococcal polysaccharide antigen in CSF and serum are common, with quantitative viable CSF yeast counts that can exceed 10 ⁶ colony-forming units (CFU)/mL of CSF. The response of some of these patients to infection includes a paucity of CSF leukocytes; approximately two-thirds of patients with AIDS and cryptococcal meningitis have fewer than 20 leukocytes/mm ³ in their CSF on presentation. This combination of a high burden of yeasts and a quantitative deficiency in the inflammatory response indicates an impaired immune system and can lead to a poor prognosis despite administration of fungicidal therapy.

Patients with cryptococcal meningitis may present with a wide spectrum of CNS findings, ranging from symptoms of headaches with or without fever to subacute dementia developing over months. The latex agglutination test and enzyme-linked immunosorbent assay are both sensitive (>90%) and specific (>90%) if proper controls are used. An inexpensive and simple lateral flow assay (LFA) has been developed and it compares favorably to the other antigen tests.

The recent addition of the BioFire PCR Film Assay uses multiplex PCR for major CNS pathogens and includes C. neoformans . Two aspects to this test need to be discussed. First, false negatives occur with low burden of yeasts, so pelleting CSF before PCR testing may be necessary. Second, a positive PCR test supports the fact that viable yeasts are present and might be used in deciding between relapse of infection and IRIS. Although cases occasionally are difficult to diagnose, with the proper use of CSF culture, India ink studies, polysaccharide antigen, and PCR tests, the only limiting factor in the diagnosis of CNS cryptococcosis is usually failure to perform a lumbar puncture because the diagnosis is not considered.

Coccidioides immitis and posadasii

C. immitis and C. posadasii are dimorphic fungi with a natural habitat in semiarid soil, which explains their geographic distribution in the southwestern United States and in parts of Mexico and South America. Because many tourists travel through these areas and may become infected, clinicians outside the organism’s natural habitat occasionally encounter coccidioidomycosis. Inhalation of the arthrospores leads to a primary pulmonary infection. Most patients remain asymptomatic, and fewer than 0.2 percent of primary infections disseminate outside the lung. Occasionally, the fungus reaches the meninges, either by hematogenous spread or direct extension from osteomyelitis of the skull or vertebrae; seeding of the CNS usually occurs a few months after the primary infection.

Symptoms of chronic meningitis are most common. There are cases in which brain involvement occurs without meningitis, but this presentation is unusual. Spinal arachnoiditis with obstructive hydrocephalus and cerebral vasculitis with infarcts and abscesses also have been reported. It appears that patients with coccidioidomycosis involving the facial skin are at higher risk of meningitis than those with skin involvement at more distant body sites.

Diagnosis may be confirmed by culture of the fungus from the CSF, but in endemic areas it is diagnosed in many patients on the basis of a CSF pleocytosis (which demonstrates eosinophilia in up to 70% of cases) and the presence of complement-fixing antibodies (CFAs) in the CSF. CFA titers are positive in approximately 70 percent of patients at initial diagnosis, and in almost all patients as meningitis progresses. A new Coccidioides antigen test of CSF can also frequently detect CNS involvement.

It is likely that genetic susceptibility plays an important role as a risk factor for meningitis. For instance, meningitis appears to develop at greater rates in Blacks, Filipinos, and possibly other ethnic groups such as Hispanics compared to Whites.

Most patients who contract CNS infection with Coccidioides have no apparent underlying disease, but immunosuppressed patients are at greater risk of CNS involvement after primary infection. Corticosteroid treatment has been associated with more severe manifestations of primary infection, as well as with reactivation of latent disease and dissemination to the CNS. There have also been many reported cases of CNS infection with Coccidioides in patients with AIDS and in transplant recipients. The natural history of coccidioidal meningitis is such that patients whose only detected extrapulmonary site of infection is the CNS live significantly longer than those with more diffuse disease. White blood cell count in the CSF decreases during the course of both treated and untreated infection, and therefore cannot be used to gauge response to therapy. Unfortunately, lifelong triazole therapy for meningitis is required because of the extremely high rate of relapse after initial induction antifungal therapy.

Histoplasma capsulatum

H. capsulatum is a dimorphic fungus endemic in certain areas of the Ohio and central Mississippi River Valley in the United States as well as in Latin America. It can be found in bird and bat guano, and in soil contaminated with this guano. Outbreaks of the disease have been attributed to disturbance of contaminated soil, allowing the conidia to become airborne and inhaled. Asymptomatic infection in endemic areas is very common; skin test data indicate that up to 69 percent of the population show evidence of prior infection in certain endemic areas. Most infected individuals have minimal symptoms, and dissemination occurs only rarely. When dissemination does occur, between 10 and 25 percent of patients develop CNS involvement. Although granulomas and other brain parenchymal lesions have been described, most patients with CNS lesions present with meningitis.

Although Histoplasma meningitis can occur in apparently normal hosts, it occurs in immunocompromised populations at a higher rate. Patients with AIDS, solid organ transplant recipients, and those receiving biologics such as anti-TNF therapy are at high risk of development of disseminated disease, usually due to reactivation of latent infection. Because CSF cultures may be positive in only 10 to 30 percent of cases even when large volumes (10 to 20 ml) of CSF are incubated for weeks, it is important to use CSF serologies. There are occasional serologic cross-reactions with other fungi, which can cause diagnostic confusion. However, the Histoplasma CSF polysaccharide antigen has been found to be positive in 40 percent of patients with Histoplasma meningitis and is a reasonable first screening test for this fungus in the CNS.

Blastomyces dermatitidis

B. dermatitidis and recently discovered Blastomyces helicus are dimorphic fungi endemic in Africa and in certain parts of the lower Mississippi River Valley, North Central states, and mid-Atlantic states in the continental United States. It is presumed that spores are inhaled from a source in the soil, but its natural location in the environment has been identified only occasionally. Most individuals have subclinical disease, and dissemination occurs rarely. Disseminated blastomycosis is characterized by granulomatous and suppurating lesions of the lung, bone, and skin. In some series, blastomycosis has been reported to involve the brain in 6 to 33 percent of disseminated cases. Although patients with CNS blastomycosis usually present with evidence of infection at other sites, occasionally meningitis is the initial presentation and there is no evidence of extraneural disease. CSF cultures are rarely positive, and a chronic neutrophilic pleocytosis is a common finding in blastomycotic meningitis. In cases of subacute and chronic meningitis, screening the CSF by Blastomyces antigen testing may be helpful, although the sensitivity and specificity of such testing are not well characterized. CNS involvement occasionally presents with a mass lesion (blastomycoma) within the brain parenchyma.

Immunocompromised patients are at increased risk of disseminated infection with B. dermatitidis . A review of 24 cases of infection with B. dermatitidis in a heterogeneous population of immunocompromised patients showed 6 cases of disseminated disease, including 4 with CNS involvement.

Paracoccidioides brasiliensis

P. brasiliensis is a dimorphic fungus endemic to subtropical areas of Mexico and Central and South America. The lung is the primary location for initial infection; a few patients present with widely disseminated disease that can involve the CNS. Small case series report dissemination in 9 to 27 percent of patients, and the infection reportedly involves the CNS in approximately 13 percent of cases with disseminated disease.

Meningitis is an unusual manifestation of CNS infection with P. brasiliensis , with brain parenchymal involvement more common; patients frequently present with seizures. CNS infection occurs in normal hosts and in those who are immunosuppressed. The host response against this microorganism remains poorly understood but an immunosuppressed individual probably has an increased chance of CNS involvement.

Sporothrix schenckii

S. schenckii and its other species are worldwide saprophytes of vegetation, notably sphagnum moss. Sporothricosis presents as a chronic infection of the skin and the subcutaneous lymphatic system, developing after a primary inoculation such as a rose-thorn puncture or cat scratch. Pulmonary disease from inhalation of spores is uncommon. Dissemination beyond the skin, lung, and joints is rare; only approximately a dozen cases of Sporothrix meningitis have been reported in the literature, and most do not have overt extraneural disease at presentation. Diagnosis of this infection with its low fungal burden in the CNS can be extremely difficult using traditional culture methods. To reduce diagnostic delays of up to 6 to 7 months, a test for Sporothrix antibodies in the CSF should be performed; it may be the only clue to the diagnosis.

Although meningitis with S. schenckii is so uncommon that risk factors cannot be defined accurately, certain patients may be predisposed to dissemination from a local infection including patients with myelodysplastic syndromes, ethanol abusers, or patients taking corticosteroids. Disseminated and CNS sporotrichosis has also been described in patients with AIDS.