Candidiasis of the nervous system

Pooja Raibagkar MD

Infectious Disorders

Updated 04.28.2025
Released 06.13.2005
Expires For CME 04.28.2028

Candidiasis of the nervous system

Author: Pooja Raibagkar MD

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Editor: Christina M Marra MD

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Candidiasis of the nervous system

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Introduction

Overview

Candida became a common central nervous system pathogen in the 1960s with the advent of chemotherapeutic agents, glucocorticoids, and injection drug use. Although Candida albicans continues to be the most common pathogen overall, there has been an increasing trend towards non-albicans species in the last 10 years. Meningitis is the most common form of central nervous system (CNS) infection. The clinical symptoms are highly variable. Careful examination of the ocular fundus and the skin may provide clues to suspect Candida infection. Premature infants requiring neurosurgical interventions are at increased risk of both disseminated and CNS candidiasis. In some specific clinical situations, such as bone marrow transplant recipients or severe burn patients, Candida is the leading cause of CNS infection. Mortality is almost 90% when disseminated candidiasis involves the central nervous system. Diagnosis is often made from biopsy specimens or culture. Candida meningitis responds best to intravenous amphotericin B and oral flucytosine. On the World Health Organization’s first fungal pathogen priority list, published in late 2022, Candida albicans and C. auris are among the pathogens of critical importance, which will enhance much-needed public awareness, innovation, and research in this direction.

Key points

	• CNS candidiasis is a leading cause of mortality among invasive candidiasis infections.
	• Neonates, patients with neurosurgical intervention, and immunosuppressed patients, including those with neutropenia, primary immunodeficiency disorders, diabetes, extensive wounds, hematologic malignancy, people living with HIV (PLWH), organ transplant recipients, and intravenous drug users are susceptible to disseminated infection and, therefore, CNS invasion.

Historical note and terminology

The history of candidiasis dates to the 4th century BC when Hippocrates described oral aphtha (thrush) in two patients. In 1861, Zenker discovered a Candida-like organism in brain lesions. A brain abscess caused by Candida species was initially reported in 1895 (31). In 1933, Smith and Sano identified the first case of Candida meningitis, but it was not until 1943 that Candida was successfully cultured from a cerebral lesion. Candida remained a relatively uncommon CNS pathogen until the 1960s when use of chemotherapeutic agents, glucocorticoids, and intravenous heroin rendered increasing numbers of patients susceptible to Candida infections (54). Candida auris, identified in 2009, was isolated from the ear canal of a patient; by 2019, the CDC classified it as an urgent threat, and in 2022, the WHO placed it in the “critical” group of human fungal pathogens; Candida auris is considered one of the first pathogens in humans to have emerged due to climate change (37).

Many of the Candida species have been reclassified in recent years based on extensive phylogenetic studies into clades that better fit the definition of a genus. Candida glabrata, Candida bracarensis, and Candida nivariensis form part of the Nakaseomyces clade, and, hence, are called Nakaseomyces glabrata, Nakaseomyces bracarensis, and Nakaseomyces nivariensis, respectively. Candida krusei now belongs to the Pichia clade and is called P. kudriavzevii. It is also important to note that both Nakaseomyces and Pichia clades now include species that have decreased susceptibility and intrinsic resistance to azole antifungal drugs (28).

Clinical manifestations

Presentation and course

• The most common neurologic manifestation includes meningitis, with less common forms being micro- or macro-abscesses, granuloma, mycotic aneurysm, vasculitis, strokes, pachymeningitis, myelitis, and arachnoiditis.

Meningitis. Meningitis is the most common form of CNS infection caused by Candida (44). The clinical symptoms are highly variable and range from acute to chronic forms (60). Typically, the onset of meningitis evolves subacutely over several days to weeks with fever, headache, meningismus, and diminished consciousness (51). More acute manifestations are often indistinguishable from bacterial meningitis (59). Focal neurologic signs, cranial nerve deficits, papilledema, and seizures are infrequent. A chronic form of Candida meningitis mimics tuberculous or cryptococcal meningitis. Patients infected with the species Nakaseomyces glabrata are known to become progressively obtunded over weeks to months (54).

A variety of situations alter the clinical presentation. In newborns and especially, premature babies, respiratory distress is a common manifestation of Candida meningitis and is indistinguishable from that seen in bacterial meningitis or sepsis. Prognosis is grave (17). Fever and convulsions can be the only clinical manifestations in children suffering from CNS candidiasis less than 1 year old (67). Hydrocephalus results from obstruction of cerebrospinal fluid pathways. In people living with HIV (PLWH), Candida meningitis typically has a subacute evolution with headache and fever (51). Generally, the infection appears in patients with advanced infection at an average CD4 count of 135/mm3. (05).

Candidal brain abscess. Candidal abscesses are less common than meningitis. Candida species (spp) accounted for 6% of all cases of brain abscess in a nationwide study in Turkey (29). The clinical picture consists of fever, altered level of consciousness, seizures, headaches, and focal manifestations depending on the size and site of the abscess (Fennelly and Slenker 2013). Signs of systemic infection are infrequent. Microabscesses are those under 3 mm in diameter. These occur in adults and present with a diffuse encephalopathy (51). Focal signs are infrequent, poorly expressed, and fluctuating. Papilledema and meningeal signs are not encountered. In these patients, systemic candidiasis is common, but neurologic involvement is often detected only at autopsy.

Rare manifestations of CNS candidiasis. There are several additional infrequent forms of CNS candidiasis. Vascular complications include invasion of the arteries at the base of the brain that produce transitory (21) or permanent neurologic deficit (04). Infectious, or “mycotic,” aneurysms may rupture, resulting in subarachnoid hemorrhage or subdural hematoma. Candida pachymeningitis results in cranial nerve palsies. Patients with osteomyelitis complain of back pain and demonstrate variable neurologic signs and symptoms (10). In these patients with spinal disease, a preceding fungemia weeks to months before is often reported (44). Candida albicans may cause a severe myelitis (25). Syringomyelia is an extraordinary and particularly late manifestation of spinal arachnoiditis after Candida meningitis (48). Polyradiculopathy is reported in several patients (53). Candida spp are the most common cause (78%) of fungal spinal epidural abscess manifested as focal spinal pain, neurologic deficits, and fever (68). It is still rare but has been reported in an immunocompetent incarcerated patient exposed to intermittent corticosteroid use (09).

In addition, hematogenous spread often involves other organs, which may cause manifestations pertaining to renal, skin, cardiac (endocarditis), and eye (endophthalmitis and subretinal abscess) involvement (51; 49).

Prognosis and complications

For patients with Candida meningitis, a delay in diagnosis of more than 2 weeks after onset of symptoms, CSF glucose levels below 35 mg/dL, development of intracranial hypertension, and focal neurologic deficits are associated with a grave prognosis (57). Delay in the diagnosis and institution of therapy is attributed to several factors, among which are a subacute course, lack of clinical findings, variable spinal fluid formula, negative CSF cultures, slow in vitro growth of Candida, and misinterpretation of positive cultures as contaminants. Invasive candidiasis has an overall mortality of 20% to 50% (64) and mortality of CNS involvement may approach 90% (23). About 11% to 27% of patients end up with serious sequelae (27). Higher morbidity especially pertains to children who often develop psychomotor retardation and aqueductal stenosis with hydrocephalus (32). When patients who have microabscesses have been treated, results have not been favorable, especially in immunocompromised hosts; macroabscesses, however, respond favorably to antifungal therapy (51).

Clinical vignette

A 57-year-old woman with a history of alcohol use disorder was admitted with fever and pleuritic chest pain. Right-sided pneumonia was found. Subsequently, the patient became hypotensive and obtunded. Respiratory distress ensued. Initial therapy consisted of empiric intravenous antibiotics. Blood cultures were positive for Streptococcus pneumoniae. The hospital course was complicated by a cardiac arrest, upper gastrointestinal bleeding, Klebsiella superinfections, acute tubular necrosis, and subarachnoid hemorrhage. Seventeen days after admission, fever, confusion, and nuchal rigidity appeared. A lumbar puncture disclosed cloudy fluid with 1900 white blood cells/mm3 (100% neutrophils). CSF glucose was 119 mg/dL (blood glucose 135 mg/dL), and protein was 129 mg/dL. Gram stain and cultures were negative. On the presumption of a gram-negative meningitis, systemic and intrathecal antibiotics were administered. A later lumbar puncture showed 1900 polymorphonuclear leukocytes. Blood cultures were positive for Candida albicans. Intravenous amphotericin B was given, but 4 days later, the patient died. At necropsy, examination of the spinal cord showed an epidural 10 cm linear collection of pus. Microscopic examination and culture revealed the presence of C. albicans.

Biological basis

	• Although Candida albicans remains the most likely pathogen, infections with non-albicans species have been increasingly recognized in the last decade, especially in healthcare facilities, in patients with malignancy, and transplant recipients.
	• CNS invasion occurs via the hematogenous route, local spread from nearby structures, or after neurosurgical procedures or lumbar puncture.

Etiology and pathogenesis

Candida albicans and Candida auris are part of the critical importance group in the first fungal priority pathogen list (FPPL) developed by the World Health Organization in 2022 (64). Candida auris has emerged as a global threat due to its multidrug resistance and ability to adhere to human skin and inanimate objects and to persist on healthcare surfaces in spite of the use of disinfectants (37). The source is from the skin, oropharynx, gut, and vaginal flora where the microorganism is normally found. Although there are approximately 350 species of Candida, six are of clinical importance (40; 34). C. albicans is the most common species involved in systemic candidiasis and neurocandidiasis in United states (58). The prevalence of C. albicans is decreasing with rising frequency of non-albicans species over the past decade (77%), especially among patients with underlying malignant diseases or hematopoietic stem cell transplant (23). These consist mainly of Nakaseomyces glabrata (formerly Candida glabrata) and C. parapsilosis, with lesser frequency of C. tropicalis, Pichia kudriavzevii (formerly Candida krusei), C. stellatoidea, C. pseudotropicalis, C. guilliermondii, and C. viswanathii (58).

Risk factors for developing candidiasis include prematurity, severe COVID19 infection, CARD9 (caspase recruitment domain-containing protein 9) deficiency, central lines, intensive care unit admission, administration of antibiotics, HIV infection, cancer, chemotherapy, steroids, diabetes mellitus, neurosurgery, placement of prosthetic material, severe burns, intravenous drug use, and mutations in immune-related genes (55; 67; 34). Commonly, the fungus spreads through the bloodstream from contaminated intravenous lines or breaches in the gut (02). Involvement of the CNS usually results from hematogenous dissemination (45), but direct invasion may occur from the oral cavity, orbit, or middle ear (44). An extracranial focus of infection is identified in more than 70% of patients with CNS disease (06). CNS invasion after cranial surgery and even lumbar puncture is also reported (06).

There are several forms of candidiasis affecting the CNS (54). Candida meningitis is a chronic process associated with dense exudates at the base of the brain. When candidemia is prolonged, seeding of the CNS is widespread. Consequent microabscesses are commonly found at the gray-white junction, basal ganglia, and cerebellum (47). They consist of foci of necrosis surrounded by polymorphonuclear leukocytes or noncaseating granulomas with giant cells that contain hyphae. Vascular invasion of the arterial lumen is found in 23% of patients with CNS candidiasis at autopsy (51). Cerebral infarcts often occur in the basal ganglia. Cerebral mycotic aneurysms are usually associated with Candida endocarditis. Mycotic aneurysms caused by both C. albicans and C. parapsilosis have been reported. C. parapsilosis has shown a trend of increasing invasive disease in the last 10 years (64). Like L. monocytogenes, C. albicans uses clathrin-dependent endocytosis for invasion as well as other proteins for internalization, such as dynamin, cortactin, and E-cadherin (41). Discovery of the C. auris-specific adhesin surface colonization factor (scf1) has provided crucial understanding of this adhesin in biofilm formation, colonization of skin and medical devices, and virulence during invasive infections (37).

CARD9 deficiency has been speculated to cause CNS-invasive fungal disease by impaired Th17 cell differentiation, decreased pro-inflammatory cytokine production, and defective neutrophil accumulation in the CNS (70). Based on host characteristics a study group from France divided CNS candidiasis into three clinical entities: (1) CNS micro-abscesses from hematogenous dissemination in patients requiring therapeutic lumbar punctures, such as in hematological malignancies, which has a high mortality rate; (2) CNS vascular lesions in Candida infective endocarditis; and (3) localized candidiasis with macro-abscesses and meningitis, often accompanied with intracranial hypertension, elevated CSF Candida biomarkers, and low mortality rate, but frequent sequelae (06).

Spinal involvement occurs in the form of vertebral osteomyelitis, usually of the thoracic or lumbar spine (44). Epidural abscesses are encountered in the cervical and thoracic spine. A spinal cord involvement in the form of longitudinally extensive transverse myelitis by spinal cord candidiasis linked to CARD9 deficiency is reported (26). Spinal disease most often occurs in patients with complex multisystem disorders after a prolonged period of hospitalization.

Epidemiology

• Conditions interfering with the normal function of host immune function play an important role in the development of disseminated and CNS candidiasis.

Risk factors, including geographical region, healthcare system, patient demographics, and environmental conditions, play important roles in determining the incidence and prevalence of invasive candidiasis (34). All the features predisposing to systemic candidiasis also favor the development of CNS candidiasis (51).

Table 1. Risk Factors for Central Nervous System Candidiasis

Risk factors for CNS candidiasis due to invasive candidiasis
	Hematological or oncological malignancy
	Infective endocarditis
	Neonates, especially preterm infants
	Long-term ICU admission
	Solid organ transplantation
	Severe burns
	Broad-spectrum antibiotic use
Risk factors for localized CNS disease without evidence of candidemia or local invasive candidiasis
	Diabetes mellitus
	Intravenous drug use
	Neurosurgery
Risk factors for CNS candidiasis related to intrinsic or acquired disimmune states
	Genetic susceptibility to invasive candidiasis by variation in immune-related genes
	Chronic granulomatous disease
	Neutrophilic myeloperoxidase deficiency
	Altered T lymphocytes in chronic mucocutaneous candidiasis
	Severe combined immunodeficiency
	Specific IgA deficiency
	Caspase recruitment domain-containing protein 9 (CARD9) deficiency
	People living with human immunodeficiency virus
	Immunosuppressive treatment, including corticosteroids

According to a nationwide study conducted in France, hematological malignancy and infective endocarditis were primarily responsible for disseminated infection, whereas CARD9 deficiency, diabetes mellitus, injection drug use, and neurosurgery accounted for localized CNS disease without evidence of candidemia or another location of invasive candidiasis (06). There is an increased incidence of both disseminated and CNS candidiasis in newborns, especially premature infants. CNS involvement is seen in up to 60% of invasive candidiasis pediatric cases (15). In some specific clinical situations, such as bone marrow transplant recipients or severe burn patients, Candida is a leading cause of CNS infection (66). Disimmune states contributing to CNS candidiasis include chronic granulomatous disease, neutrophilic myeloperoxidase deficiency, altered T lymphocytes in chronic mucocutaneous candidiasis, severe combined immunodeficiency, specific IgA deficiency, or CARD9 deficiency (33; 06). Although meningitis and abscesses occur in PLWH, the most common complication in PLWH is oral and pharyngeal candidiasis. These forms of candidiasis, however, are rarely invasive.

Diagnostic workup

	• The gold standard for diagnosis of CNS candidiasis is culture. However, nonculture diagnostic tests, tissue histopathology neuroimaging, and CSF analysis may further aid diagnosis in the correct clinical setting.
	• Rapid nonculture diagnostic assays such as BioFire BCID and T2Candida offer rapid diagnosis and early initiation of antifungal treatment while awaiting culture results.
	• rRNA PCR of spinal fluid and metagenomic next generation sequencing are emerging techniques considered in diagnostically challenging cases.
	• Concurrent endophthalmitis, retinal exudates, and dermatological infection are often signs of widespread infection.

Imaging findings. MRI is the imaging modality of choice with high sensitivity and negative predictive value. Macroabscesses have a variable CT density that becomes a nodular or ring-enhanced hyperdensity after the addition of contrast. However, MRI scanning frequently discloses widespread, small, ring-enhancing lesions with a hemorrhagic component (32). Microabscesses observed by MR usually disappear completely after systemic treatment (51). The CT scan in patients with Candida meningitis is usually normal except for hydrocephalus that occurs in approximately 20% of cases (23; 56). Rarely, meningeal enhancement may be associated. Cranial MR also reveals infarcts occurring in patients with Candida meningitis. Imaging studies following treatment reveal the residual complications, including cerebral atrophy (32). Calcifications around previous sites of infection are frequent residual findings in neonates, presumably as a result of calcification of parenchymal granulomas (11; 17).

Similar to other causes of osteomyelitis, plain radiographic films in individuals with Candida osteomyelitis illustrate end-plate irregularities with destruction of vertebral bodies and disc space narrowing (44). Radionuclide studies may be considered in patients who cannot get MRI or CT due to hardware to provide early evidence of disease (20).

Spinal fluid findings. In Candida meningitis, a pleocytosis approximates 600 white cells/mm3, and a neutrophilic or monocytic predominance is present. CSF protein is usually elevated. The fungus is identified by staining techniques in nearly 40% of cases and by culture in about 80% (51). Candida meningitis is caused by C. albicans in about 90% of patients (27). Other species less frequently responsible are Nakaseomyces glabrata, C. tropicalis, or C. parpsilosis (27). In exceptional cases, the CSF is completely normal, but stains or culture show the presence of a Candida species. Patients with Candida microabscesses generally have a normal spinal fluid formula, and gram staining and culture of CSF are also usually unrevealing (47).

Importantly, several clinical situations alter the CSF profile. The pleocytosis and protein concentrations in postsurgical Candida CNS infection tend to be in the range of 1 to 1000/mm3 (mean 276) with neutrophilic predominance and 42 to 666 g/dl (mean 155), respectively (43). In PLWH, pleocytosis is mostly lymphocytic (52).

A chronic meningitis with CSF neutrophilic predominance and hypoglycorrhachia is frequent in Candida meningitis, and the cause is often difficult to confirm (53). Isolation of Candida species is difficult because of the low concentration of organisms in the CSF (51). Therefore, repeated lumbar punctures with large samples of spinal fluid may be needed to increase the yield of positive cultures. A minimum of 5 mL and, more ideally, a sample of 15 mL are recommended (53). The ventricular CSF profile may be normal when lumbar CSF is abnormal (38). Smaller available amounts limit the identification of CNS candidiasis in the neonate. For positive cultures, contamination is not a reasonable consideration if risk factors for invasive candidiasis are present. Additionally, the presence of more than one pathogen in the CSF is not infrequent because of the clinical conditions in which Candida meningitis commonly appears. Multiple pathogens in the spinal fluid occur in neonates, postsurgical patients, individuals with shunt infections, and immunocompromised patients.

Serology findings. Positive C. albicans germ tube specific antibodies, or CAGTA, proved to be the only protective factor associated with ICU mortality; however, its role is limited due to low sensitivity and specificity (69; 63). Mannan is an immunodominant antigen on the cell walls of C. albicans. Sensitivity and specificity of mannan/antimannan antibody combined assay in serum for diagnosis of invasive candidiasis is 89% and 63%, respectively, but it is only approved in Europe; sensitivity is lower (approximately 60%) when mannan and antimannan IgG assay is used individually (46; 34). Beta-D-glucan can help identify invasive candidiasis days to weeks before a positive blood culture and shorten the time for initiation of appropriate treatment. Although serum beta-D-glucan has approximately an 80% sensitivity and specificity for diagnosis of invasive candidiasis (08), its use in CNS infection is not established, and this test can be negative in Candida meningitis when the CSF concentration is elevated (38).

Nonculture-based techniques. Nonculture-based U.S. Food and Drug Administration (FDA)-approved techniques include matrix-assisted laser desorption/ionization time of flight (MALDI-TOF), peptide nucleic acid fluorescent in situ hybridization (PNA-FISH), the β-D glucan (Fungitell) assay, the T2Candida assay, and the BioFire Filmarray blood culture identification (BCID) panel. These tests aid in clinical decision-making for early intervention while culture results are still pending (40). Once appropriate antifungal treatment is initiated, the spinal fluid becomes sterile in about 1 week (51). An altered CSF formula often persists for months, especially an elevated protein, and does not necessarily imply a need to prolong treatment (53).

An emerging modality to detect CSF Candida infection is metagenomic next-generation sequencing. Using this method, C. dubliniensis meningitis was identified in a patient with normal serum β-D-glucan assay and negative culture of a lumbar meningeal biopsy after 20 months of Illness (65). Another case of C. dubliniensis was reported in a liver transplant patient with negative culture and PCR of spinal fluid until the fourth CSF culture grew the offending agent on day 28 of illness, with simultaneous detection by 18s rRNA PCR of the CSF (22).

CSF (1→3)-beta-D-glucan is emerging as an important biomarker for early diagnosis and also a useful indicator of relative burden and therapeutic response, which can guide the duration of therapy. However, it lacks the specificity and requires a better understanding of cutoff values in CSF for the common fungal pathogens causing CNS invasive fungal diseases, including Candida (61).

Histopathology findings. Histopathological analysis shows a wide spectrum of abnormalities, ranging from mild encephalitis to massive destruction of brain tissue. Lesions show perivascular cuffs of lymphocytes and plasma cell infiltrate with diffuse extracellular edema to necrosis; gliosis; and diffuse infiltration of lymphocytes, plasma cells, and macrophages. Giant multinucleated cells can form granuloma and thromboembolic infarcts with fungus invasion of necrotic tissue and blood vessels (06).

Management

	• Early identification and treatment initiation with a multidisciplinary approach are key to the successful management of CNS candidiasis.
	• Initial treatment in the form of liposomal amphotericin B, with or without flucytosine in adults, and amphotericin deoxycholate in neonates is recommended.
	• After an initial positive response, step-down treatment with fluconazole can be considered until all signs, symptoms, and CSF and radiological abnormalities have been resolved.
	• If possible, infected CNS devices should be removed.

Treatment of CNS candidiasis is challenging. It often requires a multidisciplinary approach, prompt initiation of treatment, and reversal of defects in the host immune system (55). Untreated or inadequately treated, the mortality rate approaches 80% (44). Additionally, a higher frequency of resistance to antifungal therapy and greater mortality occur with infections by non-albicans species (35; 18).

In adults, the treatment of choice for Candida meningitis is a combination of liposomal amphotericin B, 5 mg/kg intravenously daily, with or without oral flucytosine 25 mg/kg four times daily (46).

Treatment algorithm for central nervous system candidiasis

Algorithm for key concepts for treatment of CNS candidiasis in adults and neonates. Abbreviations:CNS=central nervous system; CSF=cerebrospinal fluid; IV=intravenous; Rx=treatment. (Contributed by Dr. Pooja Raibagkar.)

Amphotericin B destabilizes fungal cell membranes and increases permeability, leading to cell death. Intravenous liposomal formulation is preferred in adults due to higher CNS availability compared to amphotericin B deoxycholate (23). However, in neonates amphotericin B deoxycholate (1 mg/kg once daily intravenous) is used due to better tolerance, and flucytosine is typically reserved for only salvage therapy if there is no response to initial treatment or due to frequent development of side effects (46; 39). Flucytosine weakens nucleic acid synthesis by the formation of toxic, fluorine pyrimidine antimetabolites. Due to flucytosine’s major side effect of myelosuppression, careful monitoring of serum levels (normal: 25 to 100 mg/L) and frequent monitoring of blood counts is warranted (30). Additionally, if there is development of nephrotoxicity, the dose needs to be modified (01). Flucytosine has a synergistic action with amphotericin and has excellent CSF penetration compared to amphotericin B. With this combination, recovery rates of 88% to 100% are reported (44).

With clinical improvement, step-down therapy with fluconazole 400 to 800 mg (6 to 12 mg/kg) daily orally or intravenously (for those who cannot take oral medications) can be used if the isolate is sensitive to fluconazole.

Therapy should be continued until all signs, symptoms, and CSF (negative culture and resolution of pleocytosis with downward trending protein) and radiological abnormalities resolve (46). The resistance of Candida species to fluconazole is mainly associated with the previous long-term administration of this drug, linked to the overexpression of genes encoding lanosterol 14 alpha-demethylase (ERG11) (51; 34) and with infection by species of Candida other than C. albicans (51). Less frequently, treatment failure is associated with interactions of fluconazole with other drugs such as antiepileptic agents (12).

In a study, 4 years of fluconazole prophylaxis significantly reduced the incidence of invasive candidiasis and its associated mortality rates in low-birth-weight infants, without any fluconazole-resistant Candida species (24). Other azole agents and echinocandins have a limited role in treating CNS candidiasis. Voriconazole could be considered in rare cases of susceptible Nakaseomyces glabrata infection or as a step-down treatment for P. kudriavzevii due to excellent CSF concentrations (46). However, posaconazole and echinocandins have no role in CNS candidiasis (46). Micafungin is FDA approved for invasive candidiasis treatment in neonatal intensive care units (NICU) for infants less than 4 months old (19). Although echinocandins are not well studied for neonatal CNS infections, a pooled analysis shows promising results with high values in neonatal CSF reaching therapeutic levels and resolution of meningeal infection (13).

In addition to antifungal therapy, removal of infected CNS devices, including ventriculostomy drains, shunts, stimulators, prosthetic reconstructive devices, and biopolymer wafers that deliver chemotherapy, is highly recommended, if possible, for individuals with CNS Candida infection (46; 27).

Because of the infrequent occurrence of CNS candidiasis in children, experience with dual fungal agents is limited in this population. The treatment regimen should be constantly monitored with serum levels of flucytosine to prevent myelotoxicity. As noted above, flucytosine is not recommended in neonates. Echinocandins only achieve sufficient concentrations in CSF to treat Candida if the blood-brain barrier is breached. They are reserved for refractory cases only in children. Posaconazole is not recommended for use in children (39).

The initial treatment of Candida brain abscess (04), epidural abscess (03), and intramedullary abscess (36) is with amphotericin B and flucytosine (59). Surgical debridement is often necessary in conjunction with antifungal treatment (46).

Although treatment of vertebral Candida osteomyelitis consists primarily of medical therapy with amphotericin B traditionally based on limited information from case reports and case series, there are case reports of successful treatment of osteomyelitis with itraconazole, voriconazole, posaconazole, and caspofungin; therefore, some evidence favors these agents over amphotericin B (20; 46). Surgery is indicated in patients with neurologic deficits, spinal instability, large abscesses, or persistent or worsening symptoms during therapy.

Substantial progress in fungal vaccine research is being made. However, mounting a protective immune response in immune-compromised individuals remains one of many challenges (62).

Outcomes

Invasive candidiasis in healthcare settings is attributed to 30% to 40% mortality with a high level of morbidity, markedly affecting quality of life (34). Flucytosine treatment needs close monitoring for liver- and bone marrow–related toxicity (46). Mortality approaches 10% in neurosurgical procedure-related Candida chronic meningitis (42; 07).

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Pooja Raibagkar MD

Dr. Raibagkar of Lahey Hospital & Medical Center has no relevant financial relationship to disclose.
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Christina M Marra MD

Dr. Marra of the University of Washington School of Medicine has no relevant financial relationships to disclose.
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Former Authors

Amar Sawar MD
Niranjan N Singh MD
John B Selhorst MD
Aarti U Jerath BA
Chandan Reddy MD
Nivedita U Jerath MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Candidiasis of the nervous system

Associated Disorders

chronic granulomatous disease
chronic mucocutaneous candidiasis
HIV/AIDS
IgA deficiency
neutrophilic myeloperoxidase deficiency
- severe combined immunodeficiency

Differential Diagnosis

almost all the infectious diseases of the CNS
bacterial meningitis
Herpes simplex encephalitis
neurotuberculosis
brucellosis cryptococcosis
- aspergillosis
- coccidiomycosis
- histoplasmosis
- cerebral embolisms
- parameningeal suppuration
- chronic subdural hematomas
- borreliosis
- carcinomatous meningitis

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Candidiasis of the nervous system

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Introduction

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Table 1. Risk Factors for Central Nervous System Candidiasis

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