Candida infections of the central nervous system

INTRODUCTION — Candida infections of the central nervous system (CNS) most often involve the meninges. However, intracranial abscesses can occur either as an isolated phenomenon or associated with meningitis [1,2]. The abscesses are usually small microabscesses, multiple, and associated with disseminated infection in immunocompromised hosts [3].

Candida meningitis can occur as a manifestation of disseminated candidiasis, which most often occurs in premature neonates [4-6], in the presence of ventricular drainage devices [7-10], and as isolated chronic meningitis [3,11,12]. In addition to hematogenous spread [4,5,13], Candida can enter the CNS at the time of craniotomy [7] or through a ventricular shunt [7-10].

The clinical features, diagnosis, and treatment of Candida meningitis and other CNS infections will be reviewed here. An overview of Candida infections is presented separately. Candidemia and invasive candidiasis are also discussed separately. (See "Overview of Candida infections" and "Candidemia in adults: Epidemiology, microbiology, and pathogenesis" and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Management of candidemia and invasive candidiasis in adults" and "Candidemia and invasive candidiasis in children: Clinical manifestations and diagnosis" and "Candidemia and invasive candidiasis in children: Management" and "Epidemiology and risk factors for Candida infection in neonates" and "Treatment of Candida infection in neonates".)

EPIDEMIOLOGY — Candida meningitis occurs most often in preterm neonates and following neurosurgical procedures [4,5,7-10,14]. In addition, patients who develop CNS infections are often immunocompromised [3,12,13]. Increased risk for development of CNS candidiasis has been described for patients who have a deficiency of the lectin receptor adaptor molecule CARD9, especially neonates and young children [15]. (See "Epidemiology and risk factors for Candida infection in neonates" and "Candidemia and invasive candidiasis in children: Clinical manifestations and diagnosis", section on 'Risk factors' and "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)

MICROBIOLOGY — Candida CNS infections are almost always due to C. albicans [3,4] but can occur with other species, such as C. parapsilosis and C. tropicalis [9,13]. C. glabrata is a rare cause of CNS infection [4,9]. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis", section on 'Epidemiology'.)

CLINICAL FEATURES — The symptoms of Candida meningitis may be the same as in patients with acute bacterial meningitis (eg, fever, stiff neck, altered mental status, headache). Less commonly, symptoms may be subacute to chronic as may be seen with tuberculous or cryptococcal meningitis. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Tuberculous meningitis: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)

Fever may be the only manifestation in patients who are neutropenic, and signs of sepsis and multiorgan failure often predominate in neonates. Patients with multiple cerebral microabscesses can develop a diffuse encephalopathy [3].

In addition, among patients with hematogenous seeding, other signs of dissemination may be seen, such as endophthalmitis, endocarditis, skin lesions, and renal involvement [3,16]. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species" and "Candida endocarditis and suppurative thrombophlebitis" and "Candida infections of the bladder and kidneys".)

Premature neonates — The features of Candida meningitis in premature neonates were evaluated in a 10-year review of 106 patients with systemic candidiasis [4]. The following findings were noted:

●Meningitis developed in 23 patients (22 percent) and was present in 0.4 percent of admissions to the neonatal intensive care unit.

●The median gestational age was 26 weeks and the median age at onset of clinical disease was eight days.

●The children were severely ill with respiratory decompensation, acidosis, and hypotension. A few patients had other signs of disseminated infection such as intracardiac vegetations, endophthalmitis, and hypoechogenic hepatic lesions on ultrasonography.

The clinical manifestations of Candida meningitis in neonates are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of Candida infection in neonates", section on 'Central nervous system infection'.)

CNS shunts and other devices — Drainage-device infection usually occurs within several months of the surgical procedure and probably results from contamination during the procedure rather than hematogenous seeding of the device [7-10]. In a report that included three patients with neurosurgery-related Candida meningitis and that reviewed 15 others that were previously reported, most had received antibiotics and nine had a recent history of bacterial meningitis [7].

Another report evaluated 24 patients with Candida shunt infections, all but one of whom had a ventriculoperitoneal shunt [8]. The major predisposing factors were recent bacterial meningitis, neurosurgery other than shunt placement, and abdominal complications, such as intestinal perforation.

The symptoms and signs associated with Candida ventricular drainage device infections are similar to those seen with the more common bacterial infections of these devices [7,8]. In addition to fever, shunt malfunction can result in manifestations of increased intracranial pressure, such as headache, nausea, vomiting, and mental status changes. (See "Infections of cerebrospinal fluid shunts".)

Among children, the CNS shunt is typically implanted in premature babies because of hydrocephalus. In a series of 48 CNS shunt infections in children, 8 (17 percent) were due to Candida spp [9]. The onset of infection ranged from one month to one year after shunt insertion. The clinical manifestations were subtle and slowly progressive.

Devices such as carmustine biopolymer wafers implanted to deliver chemotherapy to brain tumors and deep brain stimulators for the treatment of Parkinson disease and other movement disorders have been reported rarely to be infected with Candida spp [17-19].

Chronic meningitis — Chronic Candida meningitis occurs uncommonly and clinically resembles meningitis caused by tuberculosis or cryptococcosis. Patients can have illness for weeks to months before the diagnosis is made. In a review of 18 cases, headache, fever, and nuchal rigidity were the most common findings, but vomiting, confusion, visual disturbances, and cranial nerve palsies also were seen [11]. Five of the patients (28 percent) had no underlying illness or risk factor for candidiasis that were known.

In a review of 14 human immunodeficiency virus (HIV)-infected patients (median CD4 cell count 135/microL) with Candida meningitis [12], the major clinical features were headache and fever in the absence of focal neurologic symptoms.

DIAGNOSIS — The possible presence of CNS Candida infection should be suspected in patients with neurologic symptoms who have one or more of the following [3]:

●Isolation of Candida from the cerebrospinal fluid (CSF).

●Isolation of Candida from another normally sterile site in patients who have pleocytosis on CSF analysis. Finding Candida species in blood cultures is helpful, but candidemia may not be documented in patients with Candida meningitis.

●Lack of adequate response of presumed bacterial or mycobacterial meningitis to appropriate therapy.

CSF analysis — Lumbar puncture to obtain CSF for culture and analysis is essential for establishing the diagnosis. The overall rate of culture positivity is approximately 80 percent [3]. A positive CSF culture should not be considered a contaminant, particularly in immunocompromised patients; this is true even if other pathogens are identified [3].

In a review of neonatal infection, Candida was isolated from the CSF in 17 of 23 patients (74 percent) [4]. The initial CSF analysis was not always helpful. Twelve patients had a normal CSF white cell count. The mean CSF glucose concentration was 95 mg/dL (5.3 mmol/L), with only five patients having a glucose concentration below 45 mg/dL (2.5 mmol/L), and the mean CSF protein concentration was 214 mg/dL. The Gram stain was negative for yeast in all patients, and eight of the neonates had sterile blood cultures. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states".)

The CSF findings are also variable in patients with neurosurgery-related Candida meningitis. Some have a neutrophilic pleocytosis similar to that seen in bacterial meningitis [7], whereas others have a lymphocytic predominance [8].

The diagnosis is more difficult in patients with chronic meningitis because the organism is present in low numbers and the yield of standard cultures of CSF is poor. In the above review of 18 cases, the following findings were noted [11]:

●CSF analysis showed a mononuclear or neutrophilic pleocytosis, an elevated protein concentration, and reduced glucose concentration.

●The CSF smear was positive in only three patients.

●The initial cultures were positive in eight patients. Use of special techniques resulted in the growth of Candida species in four patients, but the cultures remained negative in three.

In patients with chronic Candida meningitis, large-volume (10 to 20 mL) spinal taps are often required to obtain sufficient CSF for culture. The microbiology laboratory should be asked to culture the entire sample or to filter the sample through a Millipore filter and culture the filter on appropriate media. (See "Approach to the patient with chronic meningitis", section on 'CSF examination and other laboratory testing'.)

1,3-beta-D-glucan, a cell wall component of many fungi, is detected by the beta-D-glucan assay. The serum beta-D-glucan assay may be positive in patients with a variety of invasive fungal infections, including invasive candidiasis. Based upon a case report of Candida meningitis and experience with an outbreak of fungal meningitis related to injection of mold-contaminated methylprednisolone, the beta-D-glucan assay may also be useful in testing CSF as an adjunct to CSF cultures in patients with chronic Candida meningitis [20,21]. Importantly, this test can be positive in the setting of many different fungal infections, and cut-offs to define positivity in CSF are not defined. Test results must therefore be interpreted with caution. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults", section on 'Beta-D-glucan assay'.)

Neuroimaging — Computed tomography (CT) can detect hydrocephalus, which is particularly common in patients with infected CNS shunts [8,9]. However, the CT scan is often normal and may not detect microabscesses [3,13,22]. In comparison, magnetic resonance imaging (MRI) can detect microabscesses, which appear as multiple, small, enhanced ring lesions, sometimes with a hemorrhagic component [23]. When such lesions are seen, MRI is also used to monitor the response to antifungal therapy. (See 'Duration' below.)

TREATMENT

Antifungal therapy — The standard initial therapy for Candida meningitis has been amphotericin B combined with flucytosine [24]. Amphotericin B is used because of its fungicidal activity against almost all Candida species, even though drug levels in the cerebrospinal fluid (CSF) and brain are low [25,26]. Flucytosine is added because of its anti-candidal activity and excellent penetration into CSF and brain tissue [26].

For the treatment of Candida CNS infections in adults, we recommend a lipid formulation of amphotericin B (5 mg/kg intravenously [IV] once daily) with or without flucytosine (table 1). Liposomal amphotericin B (AmBisome) is preferred because it appears to give higher concentrations in the brain compared with other lipid formulations or amphotericin B deoxycholate [24,25].

In neonates, amphotericin B deoxycholate (1.0 mg/kg IV once daily) is the formulation used. Neonates tolerate the deoxycholate formulation better than adults, and there is little experience using the lipid formulations in this group [4,27]. Flucytosine is not recommended because adverse effects are frequent in neonates [28].

Therapy with an amphotericin B formulation with or without flucytosine should continue for several weeks until clinical improvement as well as improvement in the CSF profile has occurred. We favor repeating the lumbar puncture weekly until the white blood cell count decreases and the culture no longer yields Candida.

Flucytosine (5-FC) is given at a dose of 25 mg/kg orally four times per day in patients with normal renal function. Careful attention to serum levels is warranted to avoid bone marrow toxicity, particularly in patients with renal dysfunction. When available, monitoring of serum 5-FC concentrations is recommended after three to five doses of therapy, and should be obtained two hours after a dose has been administered. The target peak concentration is between 50 and 80 mcg/mL; concentrations >100 mcg/mL should be avoided. Serum drug concentrations should be repeated if renal function worsens or if leukopenia or thrombocytopenia occurs. With decreasing renal function (often due to amphotericin B), toxicity is more common and patients must be monitored particularly carefully. If amphotericin B–induced nephrotoxicity occurs, the dose of flucytosine should be reduced.

All patients receiving flucytosine should undergo regular monitoring of complete blood counts (CBC). In settings in which serum flucytosine concentrations are not available, CBC monitoring two to three times per week provides an indirect method of screening for excessive dosing. An otherwise unexplained reduction in the neutrophil or platelet count may reflect flucytosine toxicity and the dose should be reduced immediately. (See "Pharmacology of flucytosine (5-FC)", section on 'Serum concentration monitoring' and "Amphotericin B nephrotoxicity".)

Fluconazole has excellent CNS penetration and is active against most Candida isolates causing CNS infections [29]. However, treatment outcomes have varied with the use of fluconazole alone or in combination with flucytosine [9-11,30]. In patients infected with a fluconazole-susceptible Candida spp, we recommend that oral fluconazole be used as step-down therapy after an initial several-week course of liposomal amphotericin B with or without flucytosine [11,24]. In adult patients with a normal serum creatinine, oral fluconazole should be given at a dose of 400 to 800 mg (6 to 12 mg/kg) daily. Since fluconazole is highly bioavailable, oral therapy is appropriate for most patients. Intravenous therapy (at the same dose) should be given to patients who are unable to take oral medications, who are not expected to have good gastrointestinal absorption, or who are severely ill.

Voriconazole achieves excellent CSF concentrations and is active against most Candida species causing CNS infection. However, clinical experience with voriconazole for Candida CNS infections is limited. It can be useful as step-down therapy, but not initial therapy, for the rare cases of CNS infections due to C. krusei or C. glabrata. Most strains of C. krusei are susceptible to voriconazole. However, voriconazole cannot be used for C. glabrata unless susceptibility testing verifies that the organism is susceptible, as this species is frequently resistant, or can become resistant, to all azoles.

Posaconazole does not achieve adequate CSF levels [24,31], and there is little experience in using this agent for invasive candidiasis. Therefore, posaconazole is not recommended for the treatment of CNS Candida infections.

Data of isavuconazole concentrations in human brain tissue and CSF are scarce [32,33]. In a systematic review of 36 individuals with CNS fungal infections treated with isavuconazole as primary or salvage therapy, 21 (58 percent) had complete or partial clinical response [34]. However, none of the patients had CNS Candida infection. Isavuconazole is not recommended for treatment of Candida CNS infections.

Caspofungin and the other echinocandins do not achieve adequate CSF concentrations to treat Candida meningitis [35]. In a case report, new cerebral abscesses developed in a patient being treated with caspofungin for Candida endocarditis [36]. There are experimental animal studies showing the effectiveness of anidulafungin and micafungin for CNS Candida infections, but the dosages used far exceed those recommended in humans [37,38]. The echinocandins should not be used for CNS candidiasis.

Duration — Antifungal therapy should continue until all abscesses, if seen at presentation, have resolved on magnetic resonance imaging (MRI); the CSF glucose, pleocytosis, protein, and culture have returned to normal; and the patient's symptoms and signs have resolved [24]. It may take weeks to months for the above measures to be accomplished, especially in patients with chronic Candida meningitis.

There are no data available concerning the frequency of testing, but the following approach seems reasonable:

●For patients with cerebral abscesses, MRI should be repeated at two weeks (or earlier if the patient is deteriorating) and then monthly until resolution.

●For patients with acute meningitis, lumbar puncture should be repeated weekly for the first few weeks to be sure that the CSF changes are returning toward normal and that cultures are negative.

●For patients with chronic meningitis, lumbar puncture should be repeated as for acute meningitis. The best parameters to follow are the CSF white cell count and protein and glucose concentrations. Because the organism is present in low numbers and the yield of standard cultures of CSF is poor, a negative CSF culture is not adequate to determine response to therapy [11].

Patients who have cerebral abscesses, are markedly immunocompromised, or have chronic Candida meningitis need longer courses of therapy, and patients who have infected ventricular shunts or implantable CNS devices must have the device removed to achieve cure of the infection [7-9,24].

Removal of CNS devices — Infected ventricular devices should be removed [24]. Other implanted devices, such as deep brain stimulators and carmustine biopolymer wafers used for chemotherapy, should also be removed if possible [17-19]. Systemic antifungal therapy should also be administered to patients with infected ventricular devices, as discussed above. (See 'Antifungal therapy' above.)

If it is not possible to remove a ventricular device, we suggest administering amphotericin B deoxycholate through the device into the ventricle at a dose of 0.01 to 0.5 mg in 2 mL 5% dextrose in water [24]. Toxicity (headache, nausea, vomiting) is a limiting factor. (See "Pharmacology of amphotericin B", section on 'Intrathecal'.)

MORTALITY — Data on mortality comes from the relatively small case series described above. The following illustrate the range of findings in the different settings noted above (neonates, neurosurgery patients, and chronic meningitis):

●In a review of 320 neonates with birth weights <1000 grams, 27 had meningitis, 15 of whom had neurodevelopmental parameters tested at 18 to 22 months of age [28]. In this small cohort, 53.3 percent had neurodevelopmental impairment documented, and 29.6 percent died.

●In two reviews with a total of 40 neurosurgical patients with Candida meningitis, 4 died (10 percent) [7,8]. In one series, 1 of the deaths was in the only patient among the 22 total patients in whom the shunt was not removed [8].

●In the review of 18 patients with chronic Candida meningitis, the overall mortality was 53 percent [11]. However, among the 12 patients who were appropriately treated and followed, only 4 (33 percent) died. A similar mortality (31 percent) has been noted in HIV-infected patients with chronic Candida meningitis [12].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)

SUMMARY AND RECOMMENDATIONS

Epidemiology and clinical features

●Candida infections of the central nervous system (CNS) most often involve the meninges. However, intracranial abscesses can occur either as an isolated phenomenon or associated with meningitis. The abscesses are usually small microabscesses, multiple, and associated with disseminated infection in immunocompromised hosts. (See 'Introduction' above.)

●Candida meningitis can occur as a manifestation of disseminated candidiasis, which most often occurs in premature neonates, in the presence of ventricular drainage devices, and as isolated chronic meningitis. In addition to hematogenous spread, Candida can enter the CNS at the time of craniotomy or through a ventricular shunt. (See 'Introduction' above.)

●As with Candida infections at most other sites, patients who develop CNS infections are usually immunocompromised. Most cases occur in preterm neonates and after neurosurgery. (See 'Epidemiology' above.)

●The symptoms of Candida meningitis can be the same as in patients with acute bacterial meningitis (eg, fever, stiff neck, altered mental status, headache). Fever may be the only manifestation in patients who are neutropenic, whereas signs of sepsis and multiorgan failure often predominate in neonates. Symptoms in patients with chronic Candida meningitis may be subtle and persist for weeks to months prior to diagnosis. Patients with multiple cerebral microabscesses can develop a diffuse encephalopathy. (See 'Clinical features' above.)

●Drainage device infection usually occurs within several months of the surgical procedure and probably results from implantation during the procedure rather than hematogenous seeding of the device. The symptoms and signs associated with Candida ventricular drainage device infections are similar to those seen with the more common bacterial infections of these devices. In addition to fever, shunt malfunction can result in manifestations of increased intracranial pressure, such as headache, nausea, vomiting, and mental status changes. (See 'CNS shunts and other devices' above.)

Diagnosis

●The possible presence of CNS Candida infection should be suspected in patients with neurologic symptoms who have one or more of the following:

•Isolation of Candida from the cerebrospinal fluid (CSF).

•Isolation of Candida from another normally sterile site in patients who have pleocytosis on CSF analysis. Finding Candida species in blood cultures is helpful, but candidemia may not be documented in patients with Candida meningitis.

•Lack of adequate response of presumed bacterial or mycobacterial meningitis to appropriate therapy (see 'Diagnosis' above).

●Lumbar puncture to obtain CSF for culture and analysis is essential for establishing the diagnosis. The beta-D-glucan assay using CSF might be a useful adjunct to CSF culture and analysis. (See 'CSF analysis' above.)

Treatment

●For the treatment of Candida CNS infections in adults, we recommend liposomal amphotericin B (5 mg/kg intravenously [IV] once daily) with or without flucytosine (25 mg/kg orally four times daily) (table 1) (Grade 1C). For neonates, we recommend amphotericin B deoxycholate, 1 mg/kg IV once daily (Grade 1C). (See 'Antifungal therapy' above.)

●Therapy with an amphotericin B formulation with or without flucytosine should continue for at least a few weeks and until the patient has shown clinical improvement as well as improvement in the CSF profile has been noted. We favor repeating the lumbar puncture weekly to ascertain that the white blood cell count is decreasing and that culture no longer yields Candida. In patients infected with a fluconazole-susceptible Candida strain, we recommend that oral fluconazole be used as step-down therapy after the initial course of amphotericin B with or without flucytosine (Grade 1C). (See 'Antifungal therapy' above.)

●Antifungal therapy should continue until all abscesses, if seen at presentation, have resolved on magnetic resonance imaging; the CSF glucose, pleocytosis, protein, and culture have returned to normal; and the patient's symptoms and signs have resolved. It may take weeks to months for the above measures to be accomplished. (See 'Duration' above.)

●Infected ventricular devices should be removed. Other implanted devices, such as deep brain stimulators and carmustine biopolymer wafers used for chemotherapy, should also be removed if possible. Systemic antifungal therapy should be administered to patients with infected ventricular devices, as discussed above. If it is not possible to remove a ventricular device, we suggest administering amphotericin B deoxycholate through the device into the ventricle at a dose of 0.01 to 0.5 mg in 2 mL 5% dextrose in water (Grade 2C). (See 'Removal of CNS devices' above.)