Candidiasis of the nervous system

Pooja Raibagkar MD

Infectious Disorders

Updated 02.09.2024
Released 06.13.2005
Expires For CME 02.09.2027

Candidiasis of the nervous system

Author: Pooja Raibagkar MD

See Contributor Disclosures

Editor: Christina M Marra MD

Candidiasis of the nervous system

In This Article

Quick Link

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 nonalbicans 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 central nervous system. Diagnosis is often made from biopsy specimens or culture. Candida meningitis responds best to intravenous amphotericin B and oral flucytosine. The prevalence of multidrug-resistant Candida auris has increased among patients with coronavirus disease 2019 (COVID-19). On 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 (33). 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 (55).

Clinical manifestations

Presentation and course

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

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 (62). Typically, the onset of meningitis evolves subacutely over several days to weeks with fever, headache, meningismus, and diminished consciousness (52). More acute manifestations are often indistinguishable from bacterial meningitis (61). 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 Candida glabrata are known to become progressively obtunded over weeks to months (55).

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 (18). Fever and convulsions can be the only clinical manifestations in children suffering from CNS candidiasis less than 1 year old (69). 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 (52). Generally, the infection appears in patients with advanced infection at an average CD4 count of 135/mm3. (06).

Candidal abscesses are less common than meningitis. Candida species (spp) accounted for 6% of all cases of brain abscess in a national-wide study in Turkey (31). 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 (52). 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 oftentimes detected only at autopsy.

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 (22) or permanent neurologic deficit (05). 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 (11). In these patients with spinal disease, a preceding fungemia weeks to months before is often reported (44). Candida albicans may cause a severe myelitis (28). Syringomyelia is an extraordinary and particularly late manifestation of spinal arachnoiditis after Candida meningitis (49). Polyradiculopathy is reported in several patients (54). Candida spp are the most common cause (78%) of fungal spinal epidural abscess manifested as focal spinal pain, neurologic deficits, and fever (70). It is still rare but has been reported in an immunocompetent incarcerated patient exposed to intermittent corticosteroid use (10).

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 (52; 50).

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 (58). Delay in the diagnosis and institution of therapy are 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 overall mortality of 20% to 50% (66) and mortality of CNS involvement may approach 90% (24). About 11% to 27% of patients end up with serious sequelae (30). Higher morbidity especially pertains to children who often develop psychomotor retardation and aqueductal stenosis with hydrocephalus (34). When patients who have microabscesses have been treated, results have not been favorable. Macroabscesses, however, respond favorably to antifungal therapy.

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 epidural 10 cm linear collection of pus. Microscopic examination and culture revealed C albicans.

Biological basis

	• Although Candida albicans remains the most likely pathogen, infections with nonalbicans species are 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 World Health Organization in 2022 (66). Candida auris has emerged as a global threat due to its multidrug resistance and ability to persist on healthcare surfaces in spite of the use of disinfectants (59; 51). 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, less than 10 are of clinical importance (40). C albicans is the most common species involved in systemic candidiasis and neurocandidiasis in United states (60). The prevalence of C albicans is decreasing with rising frequency of nonalbicans species over the past decade (77%), especially among patients with underlying malignant diseases or hematopoietic stem cell transplant (24). These consist mainly of C glabrata and C parapsilosis, with lesser frequency of C tropicalis, C krusei, C stellatoidea, C pseudotropicalis, C guilliermondii, and C viswanathii (60).

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, and injection drug use (27; 56; 69). Commonly, the fungus spreads through the blood stream from contaminated intravenous lines or breaches in the gut (03). 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 (07). CNS invasion after cranial surgery and even lumbar puncture is also reported by the same authors.

There are several forms of candidiasis affecting the CNS (55). Candida meningitis is a chronic process that is 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 (48). 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 (52). Cerebral infarcts often occur in the basal ganglia. Cerebral mycotic aneurysms are usually associated with Candida endocarditis. Mycotic aneurysms caused by C albicans and C parapsilosis are both reported. Candida parapsilosis has shown trend of increasing invasive disease in last 10 years (66). 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).

Based on host characteristics a study group from France divided CNS candidiasis into three clinical entities: i) CNS micro-abscesses from hematogenous dissemination in patients requiring repeated lumbar punctures, such as hematological malignancies, which has a high mortality rate; ii) CNS vascular lesions in Candida infective endocarditis; and iii) localized candidiasis with macro-abscesses and meningitis, often accompanied with intracranial hypertension, elevated CSF Candida biomarkers, and low mortality rate, but frequent sequalea (07).

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 (29). Spinal disease most often occurs in patients with complex multisystem disorders after a prolonged period of hospitalization.

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 in correct clinical settings.
	• Rapid nonculture diagnostic assays such as BioFire 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.

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 (34). Microabscesses observed by MR usually disappear completely after systemic treatment (52). The CT scan in patients with Candida meningitis is usually normal except for hydrocephalus that occurs in approximately 20% of cases (24; 57). Rarely, there can be associated meningeal enhancement. Cranial MR also reveals infarcts occurring in patients with Candida meningitis. Imaging studies following treatment reveal the residual complications, including cerebral atrophy (34). Calcifications around previous sites of infection are also frequent residual findings (12).

Similar to other causes of osteomyelitis, plain radiographic films illustrate end-plate irregularities with destruction of vertebral bodies and disc space narrowing (44). MRI is the imaging modality of choice with high sensitivity and negative predictive value. Radionuclide studies may be considered in patients who cannot get MRI or CT due to hardware to provide early evidence of disease (21).

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% (52). Candida meningitis is caused by C albicans in about 90% of patients (30). Other species less frequently responsible are C glabrata, C tropicalis, or C parpsilosis (30). 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 (48).

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 (53).

A chronic meningitis with CSF neutrophilic predominance and hypoglycorrhachia is frequent in Candida meningitis and is often difficult to confirm (54). Isolation of Candida species is difficult because of the low concentration of organisms in the CSF (52). 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 (54). 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.

Positive Candida albicans germ tube specific antibodies, or CAGTA, proved to be the only protective factor associated with ICU mortality; however, its current role is limited due to low sensitivity and specificity (71; 65). Mannan is an immunodominant antigen on cell walls of C albicans. Sensitivity and specificity of mannan/antimannan antibody combined assay in serum for diagnosis of invasive candidiasis is 83% and 86%, respectively, but it is only approved in Europe; sensitivity is lower (approximately 60%) when mannan and antimannan IgG assay is used individually (46). β-D-glucan can help identify invasive candidiasis days to weeks prior to positive blood culture and shorten the time for initiation for appropriate treatment. Although serum β-D-glucan has approximately an 80% sensitivity and specificity diagnosis for invasive candidiasis (09), 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 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 help 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 (52). An altered CSF formula often persists for months, especially an elevated protein, and does not necessarily imply a need to prolong treatment (54).

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 (67). 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 (23).

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. There can be giant multinucleated cells forming granuloma and thromboembolic infarcts with fungus invasion of necrotic tissue and blood vessels (07).

Management

	• Early identification and treatment initiation with a multidisciplinary approach is key to 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 (56). 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 (36; 19).

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). 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 (24). 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 due to frequent development of side effects (46; 39). Flucytosine weakens nucleic acid synthesis by 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 (32). Additionally, if there is development of nephrotoxicity, the dose needs to be modified (02). 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 administration of this drug during prolonged periods of immunosuppression (52) and with infection by species of Candida other than C albicans (52). Less frequently, treatment failure is associated with interactions of fluconazole with other drugs such as antiepileptic agents (13).

In a study, 4 years of fluconazole prophylaxis significantly reduced the incidence of invasive candidiasis and its death rates in low birth weight infants, without any fluconazole-resistant Candida species (26). Other azole agents and echinocandins have a limited role in CNS candidiasis. Voriconazole could be considered in rare cases of susceptible C glabrata infection or as a step-down treatment for C krusei due to excellent CSF concentrations (63). 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 (20). 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 (14).

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; 30).

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 in not recommended to be used in children (39).

The initial treatment of Candida brain abscess (05), epidural abscess (04), and intramedullary abscess (37) is with amphotericin B and flucytosine (61). 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, recent evidence favors these agents over amphotericin B (21; 46). Surgery is indicated in patients with neurologic deficits, spinal instability, large abscesses, or persistent or worsening symptoms during therapy.

A strong progress in fungal vaccine research is being made. However, mounting a protective immune response in immune-compromised individual remains one of many challenges (64).

Outcomes

Flucytosine treatment needs close monitoring for liver- and bone marrow–related toxicity (46). Mortality approaches 10% in neurosurgical procedure-related candida chronic meningitis (42; 08).

References

01: Akhtar N, Wani AK, Tripathi SK, et al. The role of SARS-CoV-2 immunosuppression and the therapy used to manage COVID-19 disease in the emergence of opportunistic fungal infections: A review. Curr Res Biotechnol 2022;4:337-49. PMID 35942233
02: Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009;53(1):24-34. PMID 18955533
03: Berger JR. Fungal disease. In: Johnson RT, Griffin JW, McArthur JC, editors. Current therapy in neurologic disease. 6th edition. C.V. Mosby, 2002:146-50.
04: Bonomo RA, Strauss M, Blinkhorn R, Salata RA. Torulopsis (Candida) glabrata: a new pathogen found in spinal epidural abscess. Clin Infect Dis 1996;22(3):588-9. PMID 8852996
05: Burgert SJ, Classen DC, Burke JP, Blatter DD. Candidal brain abscess associated with vascular invasion: a devastating complication of vascular catheter-related candidemia. Clin Infect Dis 1995;21(1):202-5. PMID 7578733
06: Casado JL, Quereda C, Oliva J, et al. Candidal meningitis in HIV-infected patients: analysis of 14 cases. Clin Infect Dis 1997;25(3):673-6. PMID 9314460
07: Chaussade H, Cazals X, Desoubeaux G, et al. Central nervous system candidiasis beyond neonates: lessons from a nationwide study. Med Mycol 2021;59(3):266-77. PMID 32577733
08: Chen M, Chen C, Yang Q, Zhan R. Candida meningitis in neurosurgical patients: a single-institute study of nine cases over 7 years. Epidemiol Infect 2020;148:e148. PMID 32438931
09: Clancy CJ, Nguyen MH. Diagnosing Invasive Candidiasis. J Clin Microbio 2018;56(5):e01909-17. PMID 29444828
10: Crane JK. Intrathecal spinal abscesses due to Candida albicans in an immunocompetent man. BMJ Case Rep 2018:bcr2017223326. PMID 29588297
11: Curran MP, Lenke LG. Torulopsis glabrata spinal osteomyelitis involving two contiguous vertebrae: a case report. Spine 1996;21:866-70. PMID 8779020
12: Dejonge MH. Radiological case of the month. Candida meningitis in a low birth weight infant. Arch Pediatr Adolesc Med 1997;151(8):845-6. PMID 9265890
13: Denning JE, Baily GC, Hood SV. Azole resistance in Candida. Eur J Clin Microbiol Infect Dis 1997;16:261-80. PMID 9177959
14: De Rose DU, Bersani I, Ronchetti MP, et al. Plasma and cerebrospinal fluid concentrations of micafungin administered at high doses in critically ill infants with systemic candidiasis: a pooled analysis of tow studies. Pharmaceuticals (Basel) 2023;16(3):472. PMID 36986569
15: Dong Z, Fan C, Hou W, et al. Vaginal exposure to Candida albicans during early gestation results in adverse pregnancy outcomes via inhibiting placental development. Front Microbiol 2022;12:816161. PMID 35281308
16: Drummond RA, Lionakis MS. Candidiasis of the central nervous system in neonates and children with primary immunodeficiency. Curr Fungal Infect Rep 2018;12(2):92-7. PMID 30393511
17: Fennelly AM, Slenker AK, Murphy LC et al. Candida cerebral abscesses: a case report and review of literature. Med Mycol 2013;51(7):779-84. PMID 23651179
18: Fernandez M, Moylett EH, Noyola DE, et al. Candidal meningitis in neonates: a 10 year review. Clin Infect Dis 2000;31:458-63. PMID 10987705
19: Fisher MC, Alastruey-Izquierdo A, Berman J, et al. Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol 2022;20(9):557-71. PMID 34352028
20: Fly JH, Kapoor S, Bobo K, Stulz JS. Updates in the pharmacologic prophylaxis and treatment of invasive candidiasis in the pediatric and neonatal intensive care units: updates in the pharmacologic prophylaxis. Curr Treat Options Infect Dis 2022;14(2):15-34. PMID 36329878
21: Gamaletsou MN, Kontoyiannis DP, Sipsas NV, et al. Candida osteomyelitis: analysis of 207 pediatric and adult cases (1970-2011). Clin Infect Dis 2012;55(10):1338-51. PMID 22911646
22: Germain M, Gourdeau M, Hebert J. Case report: familial chronic mucocutaneous candidiasis complicated by deep Candida infection. Am J Med Sci 1994;307:282-3. PMID 8160723
23: Gheshlaghi M, Helweg-Larsen J. Fatal chronic meningitis caused by Candida dubliniensis after liver transplantation. Med Mycol Case Rep 2019;27:22-4. PMID 31890490
24: Goralska K, Blaszkowska J, Dzikowiec M. Neuroinfections caused by fungi. Infection 2018;46(4):443-59. PMID 29785613
25: Habibzadeh A, Lankarani KB, Farjam M, et al. Prevalence of fungal drug resistance in COVID-19 infection: a global meta-analysis. Curr Fungal Infect Rep 2022;16(4):154-64. PMID 35990407
26: Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole-resistant Candida species. Pediatrics 2008;121(4):703-10. PMID 18381534
27: Herbst M, Gazendam R, Reimnitz D, et al. Chronic Candida albicans meningitis in a 4-year-old girl with a homozygous mutation in the CARD9 gene (Q295X). Pediatr Infect Dis J 2015;34(9):999-1002. PMID 25933095
28: Ho K, Williams A, Gronseth G, Aldrich M. Spinal cord swelling and candidiasis. Neuroradiology 1982;24:117-8. PMID 7177372
29: Jeantin L, Plu I, Amador M, et al. Pearls & oy-sters: spinal cord candidiasis linked to CARD9 deficiency masquerading as a longitudinally extensive transverse myelitis. Neurology 2022;99(11):475-9. PMID 35794021
30: Kelly L, Walsh J, Skally M, et al. Candida meningitis/ventriculitis over a decade. Increased morbidity and length of stay a concern. Br J Neurosurg 2023;37(2):227-30. PMID 35361033
31: Korkmaz S, Korkmaz D. Brain abscess incidence and microbial etiology in Turkey: a nationanwide cross-sectional study. Eur Rev Med Pharmacol Sci 2023;27(20):9703-9. PMID 37916333
32: Kunka ME, Cady EA, Woo HC, et al. Flucytosin pharmacokinetics in a critically ill patients receiving continuous renal replacement therapy. Case Rep Crit Care 2015;2015:927496. PMID 26246919
33: Kwon-Chung KJ, Bennett JE, editors. Medical mycology. Philadelphia: Lea & Febiger, 1992:280-336.
34: Lai PH, Lin SM, Pan HB, Yang CF. Disseminated miliary cerebral candidiasis. AJNR Am J Neuroradiol 1997;18(7):1303-6. PMID 9282859
35: Lanternier F, Mahdaviani SA, Barbati E, et al. Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both. J Allergy Clin Immunol 2015;135(6):1558-68. PMID 25702837
36: Lee Y, Puumala E, Robbins N, Cowen LE. Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond. Chem Rev 2021;121(6):3390-411. PMID 32441527
37: Lindner A, Becker G, Warmuth-Metz M, Schalke BC, Bogdahn U, Toyka KV. Magnetic resonance image findings of spinal intramedullary abscess caused by Candida albicans: case report. Neurosurgery 1995;36(2):411-2. PMID 7731525
38: Marra CM, Rohatgi S, Bloom AK, Kahle KT, Haj AK. Case 25-2022: A 25-year-old woman with headache and blurred vision. N Engl J Med 2022;387(7):641-50. PMID 36070713
39: McCarthy MW, Kalasauskas D, Petraitis V, Petraitene R, Walsh TJ. Fungal infections of the central nervous system in children. J Pediatric Infect Dis Soc 2017;6(3):e123-33. PMID 28903523
40: McCarty TP, White CM, Pappas PG. Candidemia and invasive candidiasis. Infect Dis Clin North Am 2021;35(2):389-413. PMID 34016283
41: Moreno-Ruiz E, Galan-Diez M, Zhu W, et al. Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism. Cell Microbiol 2009;11(8):1179-89. PMID 19416270
42: Nguyen MH, Yu VL. Meningitis caused by Candida species: an emerging problem in neurosurgical patients. Clin Infect Dis 1995;21(2):323-7. PMID 8562739
43: O'Brien D, Stevens NT, Lim CH, et al. Candida infection of the central nervous system following neurosurgery: a 12-year review. Acta Neurochir (Wien) 2011;153(6):1347-50. PMID 21431456
44: Osenbach RK, Zeidman SM. Infections in Neurosurgical Surgery: Diagnosis and Management. Philadelphia: Lippincott-Raven, 1999;10:124-6.
45: Panackal AA, Williamson PR. Fungal Infections of the central nervous system. Continuum (Minneap Minn) 2015;21(6 Neuroinfectious Disease):1662-78. PMID 26633781
46: Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of Candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62(4):e1-50. PMID 26679628
47: Pelz RK, Hendrix CW, Swoboba SM, et al. Double blind placebo controlled trial of fluconazole to prevent candida infection in critically ill surgical patients. Ann Surg 2001;233:542-8. PMID 11303137
48: Pendlebury WW, Perl DP, Munoz DG. Multiple microabscesses in the central nervous system: a clinicopathologic study. J Neuropathol Exp Neurol 1989;48:290-300. PMID 2649643
49: Phanthumchinda K, Kaoropthum S. Syringomyelia associated with post-meningitic spinal arachnoiditis due to Candida tropicalis. Postgrad Med J 1991;67:767-9. PMID 1754530
50: Ramamurthy S, Joseph J, Dave VP. Candida Albicans sub-retinal abscess following COVID-19. Indian J Ophthalmol 2022;70(10):3707-9. PMID 36190078
51: Rhodes J, Fisher MC. Global epidemiology of emerging Candida auris. Curr Opin Microbiol 2019;52:84-9. PMID 31279224
52: Sanchez-Portocarrero J, Perez-Cecilia E, Corral O, et al. The central nervous system and infection by Candida species. Diagn Microbiol Infect Dis 2000;37:169-79. PMID 10904190
53: Sanchez-Portocarrero J, Perez-Cecilia E, Roca V, et al. Candida albicans meningitis in 2 parenteral drug addicts. Review of the literature. Enferm Infecc Microbiol Clin 1993;11(5):244-9. PMID 8324020
54: Sarmiento R, Holubka J, Khatib R. Case report: Candida meningitis with an intradural filling defect 1 year after candidemia. Am J Med Sci 1994;307:115-8. PMID 8141137
55: Scheld WM, Whitley RJ, Marra CM. Infections of the central nervous system. 3rd edition. Philadelphia, Lippincott Williams & Wilkins, 2004;39:697-725.
56: Schwartz S, Kontoyiannis DP, Harrison T, Ruhnke M. Advances in the diagnosis and treatment of fungal infections of the CNS. Lancet Neurol 2018;17(4):362-72. PMID 29477506
57: Sharma R, Bell D, Foster T. Neurocandidiasis. Radiopaedia.org. Accessed Jan 35, 2024.
58: Shoham S, Nucci M, Walsh TJ. Chapter 88 - Mucocutaneous and deeply invasive candidiasis. In: Guerrant RL, Walker DH, Weller PF. Tropical infectious diseases: principles, pathogens and practice. 3rd edition. W.B. Saunders, 2011:589-96.
59: Spivak ES, Hanson KE. Candida auris: an emerging fungal pathogen. J Clin Microbiol 2018;56(2). PMID 29167291
60: Toda M, Williams SR, Berkow EL, et al. Population-based active surveillance for culture-confirmed candidemia — four sites, United States, 2012–2016. MMWR Surveill Summ 2019;68(No. SS-8):1-15. PMID 31557145
61: Vasquez JA, Sobel JD. Candidiasis. In: Dismukes WE, Pappas PG, Sobel JD, editors. Clinical Mycology. Oxford, NY: Oxford University Press, 2003:143-87.
62: Voice RA, Bradley SF, Sangeorzan JA, Kauffman CA. Chronic candidal meningitis: an uncommon manifestation of candidiasis. Clin Infect Dis 1994;19(1):60-6. PMID 7948559
63: Walsh TJ, Karlsson MO, Darol T, et al. Pharmacokinetics and safety of voriconazole in children after single and multiple dose administration. Antimicrob Agent Chemother 2004;48:2166-72.
64: Wang XJ, Sui X, Yan L, Wang Y, Cao YB, Jiang YY. Vaccines in the treatment of invasive candidiasis. Virulence 2015;6(4):309-15. PMID 25559739
65: Wei S, Wu T, Wu Y, Ming D, Zhu X. Diagnostic accuracy of Candida albicans germ tube antibody for invasive candidiasis: systematic review and meta-analysis. Diagn Microbiol Infect Dis 2019;93(4):339-45. PMID 30552034
66: World Health Organization. WHO fungal priority pathogens list to guide research, development and public health action. Geneva: World Health Organization, 2022. Licence: CC BY-NC-SA 3.0 IGO.
67: Wilson MR, O'Donovan BD, Gelfand JM et al. Chronic meningitis investigated via metagenomic next-generation sequencing. JAMA Neurol 2018;75(8):947-55. PMID 29710329
68: Winkelman MD, Galloway PG. Central nervous system complications of thermal burns. A postmortem study of 139 patients. Medicine (Baltimore) 1992;71(5):271-83. PMID 1522803
69: Xiao H, Miao Y, Liu L, et al. Clinical characteristics of central nervous system candidiasis due to Candida albicans in children: a single-center experience. BMC Infect Dis 2022;22(1):945. PMID 36526986
70: Yang H, Shah A, Nelson S, Schwab JH. Fungal spinal epidural abscess: a case series of nine patients. Spine J 2019;19(3):516-22. PMID 30121322
71: Zaragoza R, Peman J, Quindos G, et al. Clinical significance of the detection of Candida albicans germ tube-specific antibodies in critically ill patients. Clin Microbiol Infect 2009;15(6):592-5. PMID 19438621

Contributors

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 Concord Hospital has no relevant financial relationship to disclose.
See Profile

Editor

Christina M Marra MD

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

Former Authors

Amar Sawar MD, Niranjan Singh MD, John B Selhorst MD, Aarti Jerath BA, Chandan Reddy MD, and Nivedita 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

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

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

Also Relevant

Brain abscess
Viral meningitis

Clinical Categories

Infectious Disorders

Web References

Clinical Trials

NIH: Meningitis

Alerts and Advisories

FDA approves REZZAYO™ (rezafungin for injection) for candidemia and invasive candidiasis

Candidiasis of the nervous system

Candidiasis of the nervous system

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Genital herpes: neurologic complications

Zika virus: neurologic complications

Gram-negative bacillary meningitis

Pneumococcal meningitis

HTLV-1 associated myelopathy

Infective endocarditis

Japanese encephalitis

Candidiasis of the nervous system

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Genital herpes: neurologic complications

Zika virus: neurologic complications

Gram-negative bacillary meningitis

Pneumococcal meningitis

HTLV-1 associated myelopathy

Infective endocarditis

Japanese encephalitis

This is an article preview.
Start a Free Account
to access the full version.