Fungal Infections of the Central Nervous System
Fungal infections that affect the central nervous system (CNS) usually cause chronic meningitis or brain abscess. Most clinically significant fungal infections involve patients with altered immune function, although immunocompetent hosts can also become infected. Fungal infections are often overlooked as a cause of CNS disease, and delays in diagnosis from 2 months to 11 years have been reported.1 No consistent guidelines regarding the neurosurgical management of these infections have been established because of their infrequent occurrence. This chapter focuses on the medical and surgical management of these uncommon entities.
Incidence and Demographics
The incidence of fungal infections involving the CNS has increased in recent years because of the growing number of patients with compromised immune systems. This is in large part due to the increased use of immunosuppressive agents, which are commonly given to treat inflammatory conditions, malignancies, and acquired immunodeficiency syndrome (AIDS). They are also given to transplant recipients.
The most common causes of fungal meningitis are Cryptococcus neoformans and Cryptococcus gattii. C. neoformans is found throughout the world in soil contaminated by bird feces and in fruits, vegetables, and dairy products.2 In contrast, C. gattii is endemic in Australia and can be isolated from eucalyptus trees.
The incidence of fungal brain abscess has increased because of the administration of corticosteroids, immunosuppressive agents, and broad-spectrum antibiotics.3 Many cases of fungal brain abscess remain undiagnosed until autopsy. Fungal brain abscess is due to Aspergillus species in 18 to 28% of patients.4 Aspergillus meningitis rarely occurs because of the large size of the hyphae ( Fig. 6.1 ) at body temperature, which are unable to infiltrate the microvasculature of the meninges.4
Some fungal infections are associated with specific geographic locations. Coccidioidomycosis is found in the southwestern United States, particularly in Arizona and California′s San Joaquin Valley. Histoplasmosis is found throughout the United States except for the Rocky Mountain states and the Pacific Northwest and is endemic in the valleys of the Ohio, Mississippi, St. Lawrence, and Rio Grande Rivers. Histo-plasma capsulatum is the most common fungus causing pulmonary infections.4 Blastomyces dermatitidis is found throughout the southern and central United States, and young men are most often infected because of greater environmental exposure to the fungus.5
Etiology and Pathogenesis
Candida species are normal flora for the mucosa of the genital and gastrointestinal tracts.5 Common clinical manifestations of infection due to Candida species are thrush and vulvovaginitis. Of all the Candida species identified, only 10 have been found to cause human disease, with Candida albicans, Candida krusei, and Torulopsis glabrata the most frequently identified agents.4 These thin-walled oval organisms reproduce in the yeast form, and true hyphae are usually found only in active infection.4 Systemic candidiasis results when organisms enter the bloodstream after penetrating the mucosal surface following surgery, with intravenous drug use, or in the presence of an indwelling intravenous catheter. Nearly half of patients with systemic disease develop CNS involvement, although the incidence reaches nearly 80% in the presence of endocarditis.4 CNS infection with Candida species is nosocomial in 95% of patients, but infection after neurosurgery is rare.1
The most common etiologic agents for fungal brain abscess at autopsy are Candida species, which can cause microabscesses, macroabscesses, noncaseating granulomas, and glial nodules located at the gray–white junction.3 Other infectious CNS manifestations associated with Candida species are mycotic aneurysms, vasculitis leading to vessel thrombosis and infarction, and intraventricular fungal balls.1 Patients at risk for Candida species brain abscess are premature infants with a low birth weight and those who have cancer, neutropenia, diabetes mellitus, chronic granulomatous disease, or thermal injuries. Also at risk are patients who have a central venous catheter or who have received chemotherapy, antimicrobial therapy, corticosteroids, or immunosuppressive therapy following a bone marrow or solid-organ transplant.3,4
The fungal species C. neoformans forms the only known encapsulated yeast that is pathogenic to humans.4–6 The polysaccharide capsule is responsible for the virulence of the organism because it inhibits phagocytosis and antigen presentation.4,5 This organism reproduces by budding. The primary site of entry of C. neoformans into the host is through the lungs by the inhalation of infected soil or dust. Hematogenous dissemination of the organism to the CNS occurs most often in immunocompromised patients or in the face of overwhelming exposure in immunocompetent individuals. CNS involvement is in the form of meningoencephalitis ( Fig. 6.2 ) in 90% of patients with disseminated disease.4 Defective Tlymphocyte function is the primary predisposing factor for cryptococcosis and is associated with AIDS, hematologic malignancies, collagen vascular diseases, immunosuppression following organ transplant, and corticosteroid use.4,5 Early in the AIDS epidemic, 6 to 8% of patients developed cryptococcal meningoencephalitis.7 Because of the presence of global immune dysfunction, AIDS patients do not develop a significant inflammatory response, necrotizing granulomas do not form, and lymphocyte-mediated activation of macrophages is impaired.8 The widespread CNS involvement that is seen in AIDS patients with cryptococcal meningoencephalitis is due to the inability of the microglia and astrocytes within the brain to contain the infection. C. neoformans can replicate and survive within human microglia.1
Coccidioides immitis forms nonseptate hyphae that become airborne and are inhaled as arthroconidia in infected dust. Disease due to C. immitis is usually restricted to the lungs and causes flulike symptoms, although dissemination can occur through lymphatic and hematogenous routes, leading to caseous granulomas. One-third to one-half of patients with disseminated coccidioidomycosis develop CNS involvement, usually 4 to 12 weeks after the pulmonary infection.4 Basilar leptomeningitis with cerebrospinal fluid (CSF) obstruction leading to hydrocephalus is the most common form of CNS involvement in coccidioidomycosis. Other CNS infectious processes due to C. immitis are encephalitis, multiple miliary granulomas, and solitary brain abscess. Vasculitis of the small and medium-size arteries due to C. immitis can result in cerebral ischemia and infarction of the deep white matter and basal ganglia or the formation of mycotic aneurysms. The spinal meninges can also be involved, resulting in paraplegia from occlusion of the anterior spinal artery or necrotizing meningomyelitis.4
H. capsulatum is found in soil contaminated by bird feces. This fungus is present in the mycelial form in the wild but converts to a budding yeast form at human body temperature.4 Infection with H. capsulatum is contracted by inhaling contaminated dust and is usually limited to the lungs. Acute disease manifests as fever, hypoxia, and pulmonary infiltrates, with severity dependent on the size of the infectious inoculum. The normal immune response in an immunocompetent individual is the formation of caseating granulomas, which calcify and restrict disease to the lungs. Disseminated disease is uncommon in immunocompetent individuals and is usually associated with immunosuppression following organ transplant or AIDS. Systemic disease is characterized by anemia, splenomegaly, leukopenia, cachexia, and fever.5 Involvement of the CNS occurs in 10 to 20% of disseminated cases through hematogenous spread.4 The two primary modes of CNS involvement are (1) basilar leptomeningitis with multiple cranial neuropathies, hydrocephalus, and seizures and (2) intraparenchymal mass lesions ranging from multiple miliary granulomas to large histoplasmomas, with symptomatology referable to their location in the brain. Spinal histoplasmomas can cause myelopathy but the infection is usually clinically silent.1
B. dermatitidis is found in soil and decaying wood in its hyphal form; however, in infected tissue it forms spherical yeasts.4 Conidia are initially inhaled in the lungs in most cases of blastomycosis, although the disease can be contracted via exposed areas of the skin that will develop subcutaneous nodules and can ulcerate.5 The genitourinary tract and the skull can become infected with B. dermatitidis. The CNS is infected in fewer than 5% of cases of disseminated disease by hematogenous spread or through direct extension of cranial or vertebral osteomyelitis.4,6 Intracerebral blastomycomas and chronic meningitis are the most common forms of CNS involvement.
Fungal infection can involve the brain in 10 to 50% of patients with invasive aspergillosis. The primary site of infection is usually the lungs.4 In immunocompetent individuals, a local immediate hypersensitivity reaction in the lungs leads to the formation of granulomas that contain the organism.4 Dissemination to the brain is either through the bloodstream or by direct extension from the paranasal sinuses.1 Risk factors for Aspergillus species infection of the brain include neutropenia from a hematologic malignancy, hepatic disease, Cushing syndrome, AIDS, diabetes mellitus, chronic granulomatous disease, intravenous drug use, organ transplant, bone marrow and stem cell transplant, chronic corticosteroid use, malnutrition, chronic pulmonary disease, and prior craniotomy.3,4,9 Of the 350 different Aspergillus species, Aspergillus fumigatus and Aspergillus flavus, acting as opportunistic pathogens, cause most infections in humans.4
Aspergillus species have a predilection for invading blood vessel walls ( Fig. 6.3 ) in medium-size to large arteries, where they destroy the internal elastic layer, causing thrombosis, vascular occlusion, and subsequent cerebral infarction in the distribution of the artery. The resulting necrotic brain parenchyma serves as an ideal environment for fungal proliferation, leading to the formation of a brain abscess that can reach several centimeters in diameter. In addition to causing brain abscesses, Aspergillus species can cause mycotic aneurysms ( Fig. 6.4 ) to form through their effect on the wall of the blood vessel, which is usually an anterior or middle cerebral artery. Rupture of these intracranial aneurysms can result in intracerebral hematomas ( Fig. 6.5 ) or subarachnoid hemorrhage.4 Direct extension of Aspergillus species from the paranasal sinuses ( Fig. 6.6 ) or orbits can lead to a solitary frontal lobe brain abscess adjacent to the site of intracranial entry.
Organisms of the genera Rhizopus, Absidia, and Mucor (family Mucoraceae) cause mucormycosis. The Mucor mold is found worldwide in rotting organic matter. The nonseptate hyphae branch at right angles. The fungal spores become airborne as infected dust and can be cultured from the nose and throat of healthy individuals. This fungal infection enters the skin after trauma or a burn.4 Like Aspergillus species, this fungus frequently involves medium-size and large blood vessels, resulting in thrombosis and widespread necrosis of the mucosa and skull base, which creates an ideal environment for growth and dissemination.
Mucormycosis is an aggressive fungal infection that can involve the brain through hematogenous spread or after head trauma, but it typically results from direct extension of an infection involving the face or nasopharynx ( Fig. 6.7 ). Predisposing conditions for mucormycosis are the following: diabetes mellitus (70% of patients, usually with ketoacidosis); acidemia from sepsis, dehydration, diarrhea, or renal failure; intravenous drug abuse; hematologic malignancy; renal transplant; and the use of deferoxamine for iron overload.3,10 Intravenous drug abusers are at risk for cerebral mucormycosis via direct inoculation of the blood stream with fungus from contaminated needles. Normal hosts account for fewer than 5% of cases of CNS mucormycosis. Rhizopus arrhizus is one of the most common of the Mucor species causing brain abscess and belongs to the order Mucorales. R. arrhizus and Rhizopus oryzae are responsible for 95% of infections in humans.5
Scedosporium apiospermum is the asexual form of Pseudallescheria boydii. It can enter the CNS by direct extension from trauma or infected sinuses, by hematogenous dissemination from a pulmonary focus, or by an intravenous catheter. Normal hosts or immunocompromised individuals with neutropenia or cellular immunodeficiency can develop CNS infection from Scedosporium species.11 Brain abscess is the most common CNS manifestation of Scedosporium species infection, although meningitis and ventriculitis can occur.
Other fungi that have been reported to cause brain abscess include Cladophialophora bantiana, Bipolaris hawaiiensis, Bipolaris spicifera, Exophiala (Wangiella) dermatitidis, Ochroconis gallopava (Dactylaria constricta var. gallopava), Ramichloridium mackenziei, Curvularia pallescens, and Acrophialophora fusispora.3
Presentation
Clinical Features
Chronic meningitis usually presents with the onset of indolent symptoms of at least 4 weeks’ duration.12 It is necessary to distinguish this entity from recurrent aseptic meningitis and persistent encephalitis. Determining the date of the onset of symptoms and the timing of symptom development can be important in confirming the diagnosis of chronic meningitis. Symptoms associated with chronic meningitis can wax and wane for weeks to months. Early symptoms may include headache, nausea, decreased memory and comprehension, decreased vision, double vision, vomiting, confusion, unsteady gait, and cranial nerve palsies. A dementia-like picture can be present in the face of hydrocephalus. With worsening cerebral edema, papilledema and brainstem compression with upper motor neuron signs, increased deep tendon reflexes, and Cheyne-Stokes respiration can develop.
A normal neurologic examination and an absence of fever may be seen in patients with chronic meningitis. Skin lesions may require a biopsy for the diagnosis of cryptococcosis, coccidioidomycosis, blastomycosis, or sporotrichosis. Skin lesions will precede meningeal symptoms in 10% of patients with cryptococcosis.13 Lymphadenopathy may be present with histoplasmosis. Retinal lesions are sometimes present in patients with cryptococcosis or coccidioidomycosis.
Candida meningitis is rare except in patients who are immunosuppressed, have had prior neurosurgery, or have a hematologic malignancy, and in very low birth weight newborns.14 Newborns with Candida meningitis have typically had long intensive care unit stays and have for prolonged periods required indwelling intravenous catheters through which the fungus has access to the bloodstream. Congenital malformations of the intestine or urinary tract that have required surgical repair can also act as a portal for Candida entry into the blood. Hydrocephalus can already be present when Candida meningitis is diagnosed, and CSF shunts that become infected with Candida are at risk for partial or complete obstruction, usually requiring multiple surgical revisions. One retrospective review of pediatric shunt infections found that 17% were Candida-related.15 The etiology of shunt infection due to Candida species was either contamination at the time of placement or hematogenous dissemination from a remote source.4
Patients with cryptococcal meningoencephalitis often have an insidious clinical presentation, leading to a delay in diagnosis. Underlying disease entities that predispose to cryptococcal meningitis are corticosteroid therapy and AIDS. Symptoms associated with raised intracranial pressure due to hydrocephalus, such as headaches, nausea, and vomiting, may be the only complaints.4 Psychosis and confusion can be presenting symptoms. Visual symptoms such as decreased acuity due to papilledema or rapid visual deterioration from neuritis of the optic nerves or chiasm can occur.1
Exposure to Coccidioides species is necessary for infection, which usually begins as a pulmonary process 2 to 4 weeks after exposure. In immunosuppressed patients, coccidioidal meningitis presents as a systemic illness with fever, malaise, headache, cranial nerve findings, and skin lesions. Histoplasma meningitis can occur in immunosuppressed patients who have AIDS, are organ transplant recipients, or are taking corticosteroids or tumor necrosis factor-α inhibitors.16
Fungal abscesses can develop in any part of the brain, and the clinical presentation depends on their location. Headache, seizures, altered level of consciousness, encephalopathy, focal neurologic deficits, meningismus, personality changes, and aphasia can be seen with fungal brain abscess. Nearly a third of bone marrow transplant recipients who have Candida species brain abscesses may have no clinical findings.3 Blastomycomas will be either asymptomatic or cause symptoms related to their location in the brain. Chronic meningitis can also result from B. dermatitidis infection, which presents similarly to tuberculous meningitis and often results in the development of hydrocephalus. The presentation of cranial and spinal epidural blastomycoccal abscesses can be due to the underlying mass effect on the brain or spinal cord. Histoplasmomas can occur throughout the brain and cause symptoms that reflect their location.
Aspergillus species brain abscess can present with a strokelike syndrome due either to vascular occlusion or to hemorrhage that is referable to the area of the brain that is involved. Severely immunocompromised patients can present with relatively non-specific clinical findings, such as altered consciousness or seizure activity, whereas immunocompetent individuals may have headache or focal neurologic findings.3 Rhinocerebral mucormycosis will usually present with findings referable to the eyes or the sinuses, such as headache, facial pain or edema, nasal congestion, and epistaxis.10 Fever and abnormalities involving cranial nerves II through VII are common, and blindness, diplopia, chemosis, proptosis, and ophthalmoplegia can also result from invasion of the orbit, cavernous sinus, and ophthalmic artery. Invasion of the carotid artery with thrombosis and hemiparesis is possible because of the potential for this mold to invade blood vessels. As the infection spreads to adjacent structures, necrotic lesions can involve the nares, turbinates, hard palate, sphenoid sinus, sella turcica, and cribriform plate. Findings in advanced mucormycosis include blindness, diabetes insipidus, carotid artery occlusion, cavernous sinus thrombosis, and bifrontal brain abscess ( Fig. 6.8 ).4,17 Hematogenous dissemination of Mucor species to the basal ganglia in intravenous drug abusers can lead to brain abscess that presents with fever, headache, and a neurologic deficit such as a hemiparesis.3 Scedosporium apiospermum can cause brain abscess in immunocompromised patients or in immunocompetent patients 15 to 30 days after near-drowning.3
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