Fungal Infections of the Central Nervous System




Keywords

fungal, meningitis, abscess, immunosuppression, Cryptococcus , Coccidiomycosis, Candida

 


Recognition of fungal infections of the central nervous system (CNS) is increasing in frequency due to the growing population of immunocompromised patients and improvements in diagnostic techniques. Published information on the diagnosis and treatment of these diverse infections ranges from extensive to nonexistent. Therefore, a comprehensive survey of the literature coupled with clinical experience informs the diagnosis, pathophysiology, and management of these potentially life-threatening infections. Major recent references are cited here, and earlier references can be found in the previous edition of this work.




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 , Pseudallescheria boydii ( Scedosporium apiospermum ), and the dematiaceous molds. CNS involvement by these fungi occurs 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 , Schizo- phyllum , Paecilomyces , Pneumocystis , and Ustilago . Such cases generally have some feature of the history, such as direct trauma or CNS penetration, that explains the presence of the fungus in the CNS. Two 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 46-1 .



Table 46-1

Features of Common Fungal Infections of the Central Nervous System






































































































Pathogen Risk Factors CSF Cultures Positive CSF Serologies Major Pathologic Manifestations
Meningitis Infarct Abscess or Mass
Aspergillus spp. Neutropenia, corticosteroids Rare None + ++++ ++
Blastomyces dermatitidis None known Rare Ab + ++
Candida spp. Neutropenia, corticosteroids, CSF shunts, polymorphonuclear leukocyte defects, prematurity 50% None ++ +++
Coccidioides immitis AIDS, corticosteroids 25–45% Ab ++++ + +
Cryptococcus neoformans AIDS, corticosteroids 75–85% An ++++ + ++
Dematiaceous fungi None Rare None + ++++
Histoplasma capsulatum AIDS, corticosteroids 50% Ab/An +++ + +
Paracoccidioides brasiliensis None Rare None ++ +
Pseudallescheria boydii Corticosteroids, aspiration Rare None ++ ++
Sporothrix schenckii Alcohol, AIDS? Rare Ab ++
Zygomycetes (Mucorales) Diabetes, deferoxamine, intravenous drug use Rare None + ++++ +++

Ab, antibody test; An, antigen test; AIDS, acquired immunodeficiency syndrome; CSF, cerebrospinal fluid.




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 Cryptococcus neoformans / C. gattii . However, certain mycoses such as histoplasmosis, blastomycosis, coccidioidomycosis, 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 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 this protective function. Some of these conditions are obvious, such as trauma or the presence of indwelling catheters that allow direct inoculation of organisms 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 vascular invasion and direct 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 response 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 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 underlying diseases are associated with an increased incidence of CNS fungal infections. The most important of these associations is the link between the acquired immuno-deficiency syndrome (AIDS) and cryptococcal meningitis. Prior to the advent of antiretroviral therapy (ART), rates reported from several cities ranged between 24 and 66 per 1000 AIDS patients, but this incidence has been reduced with effective ART. Cryptococcal meningitis continues to occur early, in some patients who have not received 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, making it the most deadly invasive fungal infection in the world today. 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. These infections have predominantly been manifest 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, penicillinosis, coccidioidomycosis, blastomycosis, or sportrichosis.


Patients who undergo organ transplantation and receive concomitant immunosuppression are at significant risk of CNS fungal infection. The most common fungal pathogens in this setting are C. neoformans , Aspergillus species, and Candida species. Infection with C. neoformans in organ transplant recipients is usually manifested as chronic meningitis occurring 6 months or more after 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 with Candida species, with substantial implications for survival and neuro-development 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 brain abscesses. With CSF leaks, the initial infection may be bacterial, but during the use of broad-spectrum antibacterial drugs, superinfection with Candida can occur.


CNS fungal infections can be occasionally associated 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 Exserohilum rostratum contamination of injectable corticosteroids around the spine emphasizes how fungi can aggressively establish disease and travel through tissue with direct inoculation.


Immune Reconstitution Syndrome


While host immunity is critical in the eradication of CNS infections, immunologic recovery can also be detrimental and contribute towards worsening disease expression. This entity of overstimulation of the immune system has been called immune reconstitution syndrome (IRS) or immune reconstitution inflammatory syndrome (IRIS) and has been described during ART, in transplant recipients, and even in apparently normal hosts with cryptococcal meningitis. For example, upon initiation of ART during management of HIV-related cryptococcal meningitis, HIV RNA levels decline rapidly and there is repopulation of the host with memory and naïve CD4 + lymphocytes; within 4 to 6 weeks, an immunologic shift occurs from a Th2 to a Th1 response. IRIS may be manifested by headaches, fever, CSF lymphocytosis, increased intracranial pressure, and evidence of increased inflammation on neuroimaging without evidence of viable yeasts in the CSF. The pathologic finding is that of granuloma formation. Patients who initiated ART within 30 to 60 days of treatment for C. neoformans infection are significantly more likely to develop IRIS than those who initiated ART at a later time. This observation has led to controversy about when to start ART during the management of cryptococcal meningitis—present guidelines give a generous range of between 2 and 10 weeks for ART initiation after the start of antifungal therapy.


Similarly, in solid organ transplant recipients with cryptococcosis, IRIS was observed in 5 percent of patients within 1 to 2 months after initiation of antifungal therapy and was more common in those receiving potent immunosuppressive regimens and those with graft loss. IRIS can occur in any patient in whom there is a rapid shift in immune reactivity. Since the appearance of IRIS in fungal CNS infections is commonly misconstrued as a treatment failure or relapse of infection that leads to unwarranted or inappropriate changes in specific therapy, its clinical recognition is important. IRIS should be considered when treatment appears to have controlled fungal disease by culture or biomarker data but new signs of inflammation develop clinically or on imaging studies.


Recognition of IRIS is important to the clinical management of CNS fungal infections because overabundance of inflammation leads to clinical worsening. Corticosteroid therapy may be considered to reduce inflammation and cerebral edema.




Cryptococcus Neoformans and Gattii


The encapsulated yeast C. neoformans is the most common cause of fungal meningitis. 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. In less-developed countries lacking access to ART, cryptococcal meningitis continues to occur frequently.


This ubiquitous encapsulated saprophytic yeast occupies a wide environmental niche. It is found worldwide in bird excreta, soil, animals, and even humans. 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 until host defenses become weakened. The reason this yeast has a particular tendency to spread to the CNS remains imprecisely explained. 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.


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 divided into several species: C. neoformans var. grubii or neoformans (serotypes A and D), and C. gattii (serotypes B and C). All serotypes can cause meningitis, but there is some geographic variation in the distribution of disease; most patients with cryptococcal meningitis in the United States and Europe have been infected with either serotype A or D. 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 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. Probably less than 10 percent of patients with cryptococcal meningitis have no known underlying disease. 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. Lymphocyte functions are abnormal in most patients with disseminated cryptococcosis. Most patients with HIV infection have CD4 counts below 100/μl. Recent studies have attempted to determine genetic susceptibility to cryptococcosis. Most patients with AIDS and cryptococcosis present with a particularly high burden of 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 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 yeast and a quantitative deficiency in the inflammatory response indicates an impaired immune system and can lead to a poor prognosis despite 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. Recently, an inexpensive and simple lateral flow assay has been developed and it compares favorably to the other antigen tests. Although cases occasionally are difficult to diagnose, with the proper use of CSF culture, India ink studies, and polysaccharide antigen 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


Coccidioides immitis and Coccidioides 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 (CFA) in the CSF. CFA titers are positive in approximately 70 percent of patients at initial diagnosis, and in almost all patients as meningitis progresses.


It is likely that genetic susceptibility plays an important role as a risk factor for meningitis. 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. 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. Lifelong triazole therapy for meningitis is required because of the extremely high rate of relapse.




Histoplasma Capsulatum


Histoplasma 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 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 and solid organ transplant 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 assay CSF serologies. There are occasional serologic cross-reactions with other fungi, which can cause diagnostic confusion. 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.




Blastomyces Dermatitidis


Blastomyces dermatitidis is a dimorphic fungus 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 without evidence of extraneural disease. CSF cultures are rarely positive, and a chronic neutrophilic pleocytosis is a common finding in blastomycotic meningitis. CNS involvement occasionally presents with a mass lesion (blastomycoma) in the brain parenchyma.


Immunocompromised patients are at increased risk of 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


Paracoccidioides 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.


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.




Sporothrix Schenckii


Sporothrix schenckii is a worldwide saprophyte of vegetation, notably sphagnum moss. Sporothricosis presents as a chronic infection of skin and the subcutaneous lymphatic system, developing after a primary inoculation such as a rose-thorn puncture. 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, and most do not have overt extraneural disease at presentation. Diagnosis of this infection with low fungal burden in the CNS can be extremely difficult using traditional culture methods. To reduce delays of up to 6 to 7 months, a test for Sporothrix antibodies in the CSF should be performed.


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 sporothricosis has also been described in patients with AIDS.




Penicillium Marneffei


Penicillium marneffei is a dimorphic fungus that is found in the geographic range of bamboo rats, and has become a common cause of opportunistic infection in HIV-infected patients in parts of Southeast Asia. Pathophysiologically, the infection appears similar to histoplasmosis but it has a unique predisposition for producing skin lesions. In one series, 3 of 20 CSF samples were positive for this fungus during disseminated disease. Around 10 percent of patients with disseminated penicilliosis also have concomitant cryptococcal meningitis.




Candida Species


Candida species form part of the normal human microbial flora and rarely cause invasive disease unless host defenses are impaired. The yeast can gain access to the bloodstream and then the CNS via contaminated intravenous catheters or through illicit intravenous drug use. Neonates, neutropenic patients, and those recovering from major surgery are particularly susceptible to invasive candidiasis, including CNS involvement. The placement of foreign bodies in the CNS, such as drug wafer implants, can provide an entry for Candida infections. Based on autopsy studies, Candida species are the most common fungi to invade the CNS in the setting of malignancy, and their ability to transverse the immature blood–brain barrier is a dreaded complication of fungemia in neonates with associated neurodevelopmental morbidity. Candida may cause meningitis, ventriculitis, or parenchymal lesions such as abscesses or granulomas. C. albicans is the species implicated in most CNS infections, but other species such as Candida tropicalis , Candida lusitaniae , and Candida parapsilosis occasionally produce CNS disease.


In the normal host, Candida rarely causes deep-seated infections. Factors that can encourage spread of Candida from mucosal surfaces to deeper tissues, such as the subarachnoid space, include prematurity, broad-spectrum antibacterial therapy, hyperalimentation, malignancy, indwelling catheters, treatment with corticosteroids, neutropenia, abdominal surgery, diabetes mellitus, burns, and intravenous drug use. Candida invades brain tissue more commonly than the subarachnoid space.


Candida meningitis has been reported in both congenital and acquired immunodeficiency syndromes, emphasizing the importance of the host response. For example, patients with chronic granulomatous disease of childhood and myeloperoxidase deficiency may present with Candida meningitis. Several cases of Candida meningitis have been reported in patients with the global immune defects caused by severe combined immune deficiency (SCID) and the specific innate immunity defects of chronic mucocutaneous candidiasis. Therefore, a specific underlying immune deficiency should be considered in any case of spontaneously occurring Candida meningitis, especially in children. Patients with AIDS frequently have mucocutaneous forms of candidiasis such as thrush and esophagitis, but involvement of the CNS has been reported rarely in these patients. Candida meningitis has been described as a superinfection of the CNS in patients recovering from bacterial meningitis. Candida infection can involve the brain and subarachnoid space by direct extension through trauma, ventriculostomy placement, or ventricular shunts, particularly in the presence of antibacterial use. Candida uncommonly can also invade from adjacent paranasal sinuses or bone. The infection may produce intracranial extension through an arteritis and even lead to subarachnoid hemorrhage.


The CSF in Candida meningitis can show a predominance of either mononuclear or neutrophilic cells. Only approximately half of routine CSF cultures yield the fungus, despite the fact that Candida organisms are easy to grow in the laboratory; a large CSF volume is needed to optimize culture, and better methods of CSF detection need to be validated to detect fungal products such as arabinitol or antigens such as beta- d -glucan or mannan. The clinical significance of a positive culture for Candida from CSF obtained through an indwelling device such as a ventriculostomy tube may not be clear as the fungus is a frequent contaminant; if a positive culture is found and CSF parameters are normal, another CSF specimen should be obtained from a lumbar puncture. In the absence of symptoms or an abnormal CSF profile, and with a negative follow-up culture, further treatment is probably unnecessary but the device should be removed and, when necessary, replaced.




Aspergillus Species


Aspergillus species are ubiquitous in the environment and can be found in the air of most buildings, including hospitals. Both neutrophils and macrophages provide important host defense mechanisms directed against the spores and hyphae of Aspergillus . CNS infection with Aspergillus species can develop by direct extension from the paranasal sinuses by direct inoculation after head trauma, following surgery, or by hematogenous spread in immunocompromised hosts, particularly those with prolonged neutropenia. This fungus accounts for approximately 5 percent of CNS fungal infections. A clinically important characteristic of Aspergillus infections is their predilection to invade arteries, causing thromboses and cerebral infarction or mycotic aneurysm. Less commonly, meningitis and meningoencephalitis can occur, and rhinocerebral disease similar to mucormycosis has been described.


Most intracranial infections with Aspergillus occur in neutropenic patients. The risk of disseminated aspergillosis with subsequent brain parenchymal involvement or meningitis increases with the duration of neutropenia. Most infections manifest as brain parenchymal lesions, but spinal cord lesions may also develop. Occasionally, Aspergillus infection involves the vertebrae and eventually the subarachnoid space. Patients with chronic granulomatous disease of childhood with its lack of an oxidative burst by phagocytes are particularly susceptible to this type of infection. The pulmonary alveolar macrophage may be most important in initial control of this ubiquitous fungus in the lungs, but polymorphonuclear leukocytes are probably crucial in defense against CNS invasion.


Diagnosis can be delayed because of insensitivity of cultures, and both CSF polymerase chain reaction and galactomannan antigen tests on CSF are helpful in diagnosing CNS involvement.




Mucormycosis


Fungi of the order Mucorales are widespread in the environment, and infection is usually due to inhalation of spores. The genus Rhizopus is responsible for most human infections. CNS infection in compromised hosts can occur by direct extension from the paranasal sinuses, through hematogenous spread such as with illicit intravenous drug use, or by spread along nerve roots. Mucormycosis commonly is associated with invasion of arteries and thrombosis, with resulting tissue infarction. Presentation involving invasion of the subarachnoid space occurs occasionally, but disease limited to the meninges is unusual. In a large review of 929 cases with mucormycosis, 283 patients had CNS infection, of which 69 percent was rhinocerebral, 16 percent was localized cerebral infection, and 15 percent had hematogenous dissemination from other organs.


Patients with diabetes mellitus (with or without ketoacidosis) or malignancy or those receiving immunosuppressive drugs or prolonged voriconazole therapy are at risk of this disseminated infection. There have been reports of disseminated mucormycosis, including brain involvement, in patients on dialysis receiving the iron chelator deferoxamine; this agent may interfere with the antifungal activity of transferrin, thus allowing for dissemination of the mold. A different iron chelator, deferasirox, cannot be used as a siderophore by the fungus and actually has been evaluated as a treatment of mucormycosis as it competes for essential iron supplies with the fungus.




Pseudallescheria Boydii


Pseudallescheria boydii has a worldwide distribution in soil and contaminated water. This fungus is also known as Monosporium apiospermum or Scedosporium apiospermum when it is in the asexual state. Although rare, CNS infection can result in brain abscesses or chronic neutrophilic meningitis. Classically, CNS infection is associated with aspiration of contaminated water during trauma, or near-drowning in fresh water. Presumably, the fungus penetrates through the cribiform plate during water immersion or establishes a pulmonary focus with later dissemination to the CNS, producing meningitis or brain abscesses. Other risk factors for infection include corticosteroid use and diabetes.




Phaeohyphomycosis


The dematiaceous fungi are a group of common environmental molds that have brown pigment in their walls; diverse genera are linked by their ability to produce melanin. This group of fungi has occasionally caused CNS infection, and for certain species it appears that there is some neurotropism. Cladosporium trichoides , also known as Xylohypha bantiana and finally renamed as Cladophialophora bantianum , is the most common isolate of this class of fungi found in CNS infections, which usually manifest as a brain abscess, although meningitis has been described. Meningitis caused by other species of these “black molds” is also occasionally reported, such as with Rhinocladiella mackenzei .


CNS infections with these organisms have been caused by contaminated corticosteroid injections around the spine. In 2002, Exophiala dermatitidis produced four cases of meningitis from contaminated corticosteroids injected epidurally for pain management. Patients presented with headaches, altered mental states, and focal neurologic findings approximately 1 to 3 months after the injections. A larger outbreak of Exserohilum rostratum infection in 2012 and 2013 involved over 500 cases; clinical presentations ranged from meningitis with or without stroke to parameningeal infections (e.g., epidural abscess, arachnoiditis with cauda equina syndrome, and vertebral osteomyelitis).


Most patients diagnosed with brain abscesses due to one of the dematiaceous fungi have no apparent underlying immune defect, but immunosuppressed patients may be at special risk. The portal of entry for these fungi is not known in most cases, but because of a predilection for abscess formation in the frontal and parietal lobes, at least some of these infections may result from direct extension through the sinuses.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Aug 12, 2019 | Posted by in NEUROLOGY | Comments Off on Fungal Infections of the Central Nervous System

Full access? Get Clinical Tree

Get Clinical Tree app for offline access