Overview
Candida spp., although rare Central Nervous System (CNS) pathogens, can infect both the meninges and the parenchymal brain tissue. In practice, the majority of cases of CNS candidiasis are associated with disseminated or invasive candidiasis (IC). On this page we will focus on the discussion of this form of infection and will refer to it as IC-related CNS Candidiasis. Another form of candidal CNS infection is the one occurring as a postoperative complication of neurosurgical procedures, especially ventriculo-peritoneal (VP) shunt placement. Because of the unique characteristics of this patient population, we have a separate discussion neurosurgery-related CNS candidiasis.
About half of patients dying with invasive candidiasis have evidence of central nervous system involvement [1082, 1355, 1376, 1602, 1724]. A variety of histopathologic and clinical patterns have been described. In approximate order of frequency, the relevant patterns are:
- Candidal Meningitis
Candida meningitis is the most frequent clinical manifestation of IC-related CNS Candidiasis. It is much more common in neonates than in adults. As it will be discussed later, among adults the picture usually has a chronic and indolent course, while in neonates it is usually an acute process [708, 2340].Case reports represent most of the literature on Candida meningitis in adults [206, 559, 582, 877, 2029, 2116, 2340]. Bayer et al. reviewed the first 28 cases published in the English literature [206]. Later, Voice et al. reviewed all cases of candidal meningitis in which the symptoms lasted at least 1 month [2340]. However, case reports do not provide data on incidence. A better perspective probably can be obtained by analyzing autopsy series. In one where Candida was found to be the most frequent cause of cerebral fungal infection, none of the 19 cases had meningeal involvement [1725]. The series by Lipton et al. reviewed the autopsies of 28 patients dying from invasive candidiasis and found that 13 of them (46%) had evidence of CNS involvement. Meningeal disease was seen in only 3 cases [1355]. When combining their experience with other similar published reports, Lipton concluded that in less than 15% of cases, invasive candidiasis will have meningeal involvement [1355].
Among neonates, on the other hand, Candida meningitis is one of the most common manifestations of neonatal invasive candidiasis [164, 433, 708]. Up to 64 percent of neonates dying with invasive candidiasis have CNS involvement and more than 2/3 of these babies have positive <AHREF=”../../../educatio/abbreviations.php#CSF”>CSF cultures at some point during their disease [708].
- Scattered Brain Microabscesses
Scattered brain microabscesses with little or no meningeal involvement have been consistently found in between 18 to 52% of patients dying with invasive candidiasis [1082, 1355, 1376, 1602, 1724, 1950]. Also, Candida spp. have been found to be the second most common agent causing this sort of brain microabscess [1748]. - Candida Brain Abscesses
Very few cases of Candida brain abscesses have been reported in the literature. Most have been secondary to a primary source of candidiasis, including previous untreated episodes of candidemia [254, 341, 751, 992]. One case of a candidal CNS fungus ball has been reported [1355]. Interestingly, a recent series from Fred Hutchinson Cancer Research Center, reported that Candida spp. were the second most common cause of brain abscesses in patients undergoing marrow transplantation [963]. - Vasculitis, Thrombosis and Infarction
Histopathologic confirmation of vascular involvement in cases of CNS-candidiasis was well described by Lipton et al. Cases with evidence of vasculitis, thrombosis, intraluminal proliferation of Candida spp. and small vessel invasion were all described in this series [1355]. Several case reports of cerebrovascular complications related to candidal meningitis, similar to the ones described in the setting of acute bacterial or chronic tuberculous meningitis, have also been published [645, 906, 1861, 2217]. Clinical presentations include basilar artery thrombosis and subarachnoid hemorrhages resulting from rupture of mycotic aneurysm or arteritis with vascular invasion.
Risk factors
IC-related CNS candidiasis is associated with all the (A):usual risk factors for invasive candidiasis.
IC-related CNS Candidiasis and Candida spp.
C. albicans is responsible for the majority of cases, with isolated cases implicating C. tropicalis and C. parapsilosis.
| Reference | N | Neonates | ||||
|---|---|---|---|---|---|---|
| [708] | 25 | 84 | 0 | 12 | 4 | 0 |
| [433] | 17 | 100 | 0 | 0 | 0 | 0 |
| Adults | ||||||
| [1355] | 13 | 92 | 0 | 0 | 8 | 0 |
| Mixed | ||||||
| [582] | 27(2) | 91 | 0 | 0 | 0 | 9(3) |
| [206](1) | 28 | 90 | 0 | 0 | 0 | 10(3) |
| [2340](4) | 18 | 89 | 5.5 | 5.5 | 0 | 0 |
- Two patients with VP-shunt related Candida meningitis are excluded
- Twelve children (50% of them neonates) and 15 adults; cultures available in 22 cases
- No identification was supplied for the organisms
- All cases on this report were classified as having “chronic candida meningitis”
Clinical Manifestations
Candidal meningitis
The manifestations differ between adults and neonates. In adults, the most frequent findings were fever, headache, nuchal rigidity, altered mental status, confusion, and disorientation [206, 2340]. Another relevant and common feature of cases in adults is the prolonged interval between onset of symptoms and diagnosis. Bayer et al described a mean time of 17 weeks, while Voice et al. reported an average delay of 5.3 months [206, 2340]. Indeed, some authors have proposed that this entity be referred to as chronic candidal meningitis [2340]. Voice et al. summarized eighteen such cases published in the literature up to 1993 [2340]. Such an indolent course is certainly, quite unlike the usual course of bacterial infections. It is, however, reminiscent of the indolent course sometimes seen in cases of N/A(L):cryptococcal meningitis or meningeal tuberculosis. Four additional cases (a liver transplant patient and 3 intravenous drug users) have since been published [559, 1867]. These cases represent one end of the spectrum of this disease. We speculate that because of the rarity of the syndrome and the difficulties to make the diagnosis in the initial stages, they all have a trend towards chronicity. This includes candidal meningitis in patients with HIV/AIDS.
Candidal meningitis in neonates usually presents as part of the syndrome of neonatal invasive candidiasis. Neurologic clinical signs are related to increased intracranial pressure (bulging fontanelle and splitting sutures). Signs of sepsis and progressive clinical deterioration are commonly found [708]. Therefore, a physician dealing with sepsis in a neonate should suspect Candida meningitis if Candida spp. are recovered from the blood, urine, or other site suggestive of heavy colonization. In the series by Faix et. al, 57% of infants with candidal meningitis never received antifungal therapy despite having CSF abnormalities either because the diagnosis was not suspected or Candida was thought to be a contaminant. All these untreated babies died [708].
Scattered microabscesses
Data on the presentation of this form of CNS candidiasis are limited. Autopsy reports of this entity are retrospective in nature, and some of their authors have emphasized lack of good antemortem neurological examinations. Indeed, patients with advanced invasive candidiasis are usually severely ill and in obtunded state that precludes an exhaustive neurologic exam [1724]. Thus, even though up to half of patients with invasive candidiasis can have histopathologic evidence of scattered brain abscesses, it seems that few present with identifiable neurologic symptoms [1082, 1355, 1376, 1602, 1724].
Specific Diagnostic Strategies
Meningeal candidiasis produces alterations in the CSF very similar to those seen in cases of other fungal etiologies (cryptococcosis, histoplasmosis) and cerebral tuberculosis [206, 2340]. Typical abnormalities include CSF pleocytosis between 500 to 600 cells/mm3, lymphocyte or polymorphonuclear preponderance (both are found), moderately low glucose (but only ~60% of cases), and mild increase in protein concentration (mean 123 mg/dl, range 30-260 mg/dl).
The gram stain is positive in only 30% of cases. Difficulties in growing Candida spp. from the CSF have also been reported [433, 1867, 2340]. To resolve this problem, a large volume CSF tap (30 cc or more) should be performed on patients with chronic meningitis that might be fungal. The CSF fluid should be centrifuged and the sediment cultured. Alternatively, the CSF could be filtered with subsequent culture of the filter.
Computerized tomography and MRI may detect parenchymal abscesses or even meningeal inflammation [341, 407, 1095, 2239]. However, the microscopic size of the characteristic lesions may prevent identification with these studies.
Therapies
The general recommendations for treatment of invasive candidiasis form the basis of therapy. Special considerations related to the blood-brain barrier and the pharmacologic characteristics of available antifungal agents include the following:
- Amphotericin B. Despite its excellent fungicidal activity, amphotericin B has the disadvantage of penetrating the blood-brain barrier poorly. However, the benefit of the intravenous use of this agent for the treatment of candidal meningitis has long been noted [206]. Cures after using this agent alone have been reported [708, 1211, 1949]. Intraventricular administration of amphotericin B has been suggested but does not usually seem necessary, especially given the severe risk of complications with this therapy [378].
- 5-fluorocytosine. This agent is characterized by its excellent CNS penetration. However development of resistance when using it alone is often described. Successful results have been frequently achieved when combining this agent with amphotericin B and this therapeutic regimen has been encouraged by many authors [331, 433, 708, 1344, 1644, 2117].
- Fluconazole. Fluconazole achieves good levels in the CSF, but experimental data comparing this drug with amphotericin B have generally shown that fluconazole has lesser efficacy as therapeutic agent for CNS candidiasis [127, 1758]. Adequate dosage of this agent was not able to eradicate Candida spp. from brain parenchyma and pathologic lesions remained [1111]. This might be due to the relatively fungistatic nature of fluconazole in comparison to the fungicidal nature of amphotericin B. Therapeutic failures when using this agent alone have been reported [2340]. But, successful therapy has also been described [494, 957].
Based on these limited data, amphotericin B is considered the first line antifungal agent for the treatment of CNS candidiasis. Intravenous administration of amphotericin B 0.5-0.7 mg/kg/day with or without 5-fluorocytosine is recommended. Duration of treatment should be decided on a case by case modality, based on results of serial CSF cultures.
Difficult Clinical situations
Candidal Meningitis in patients with HIV/AIDS
Despite the high rate of mucosal candidiasis and the immunodeficiency of patients with HIV/AIDS, Candida rarely cause any form of invasive candidiasis and CNS candidiasis is not an exception [1234, 1330]. A recent publication reviewed the 14 cases reported in the English literature after 16 years into the HIV epidemic [392]. Since then only one similar case has been published [1861]. The data in these reports can be summarized as follows:
- Candidal meningitis is an unusual entity among patients with HIV/AIDS.
- HIV/AIDS patients presenting with candidal meningitis will have the (A):usual risk factors for invasive candidiasis. Among these, intravenous drug abuse is the most frequent.
- Candidemia is rarely documented among HIV patients with candidal meningitis.
- A subacute/chronic clinical course is commonly seen in this population.
- Because clinical and laboratory findings are so similar to those seen in tuberculous meningitis, patients are frequently misdiagnosed with this entity. This usually causes a delay in receiving appropriate therapy.