Candidal Meningitis

Candidal meningitis is rare in children. In one study, 2% of all positive CSF cultures were fungal organisms, and Candida spp. accounted for 94.5% of the fungal isolates. Risk factors for positive CSF Candida cultures in neonates included antimicrobial therapy, umbilical or peripherally inserted central catheterization, total parenteral nutrition, intubation, abdominal surgery, and prematurity. In many cases of neonatal candidiasis, concurrent meningitis was not discovered until autopsy. Extremely low-birth-weight infants with Candida sepsis or meningitis have an increased risk of death or neurodevelopmental impairment. Risk factors in children beyond the neonatal period included concurrent bacterial infection, chronic systemic or CNS disease, and the presence of central venous catheters.

Children with human immunodeficiency virus (HIV) infection are at risk for acquiring disseminated Candida infections, including meningitis. In one study, 27% of HIV-infected patients with disseminated Candida infections had CNS involvement. Nearly all HIV-infected patients who develop Candida infection do so as a result of nosocomial infection. Predisposing factors include oral candidiasis, central venous catheters, prolonged antibiotic therapy, and total parenteral nutrition. Simultaneous pulmonary disease, particularly viral, bacterial, or Pneumocystis jiroveci pneumonias, exists in most HIV-infected patients with disseminated Candida infection. Most patients are febrile for more than 14 days, with peak temperatures of greater than 39°C (102.2°F) before the diagnosis is established.

Myeloperoxidase deficiency is also associated with the risk of developing infection. A mutation in CARD9, a molecule that receives signals from several antifungal pattern-recognition receptors, is associated with chronic mucocutaneous candidiasis and meningitis.

Infections caused by Candida spp. in very-low-birth-weight newborns can be difficult to diagnose because of the broad range of symptoms. Most infants with disseminated candidiasis with meningitis present with respiratory distress and a supplemental oxygen requirement, and most progress to require mechanical ventilation. Candida usually is identified in endotracheal washings, urine, and blood in patients with Candida meningitis. Infants have symptoms on average 11 days before the diagnosis is made. Ophthalmologic examinations are very important in identifying disseminated Candida infections. Marked abdominal distention occurs commonly in disseminated Candida infections in very-low-birth-weight infants and frequently is associated with guaiac-positive stools. Most patients have temperature instability, elevated white blood cell counts, and feeding intolerance. Hepatomegaly may indicate systemic infection.

Antifungal resistance in Candida spp. is a concern. Clinical breakpoints for antifungal agents against common Candida species have been published. Isolates of C. glabrata and C. krusei resistant to AmB exist. C. lusitaniae has intrinsic resistance to AmB and has been reported as a cause of meningitis. C. krusei demonstrates near uniform azole resistance, particularly in immunocompromised patients receiving suppressive azole therapy. Isolates from patients with meningitis due to C. glabrata or any Candida spp. who are slow to clear infection, or in whom unexpected relapse occurs, should undergo antifungal susceptibility evaluation.

For nonneonates the initial therapy of Candida meningitis is with liposomal AmB alone or in combination with oral flucytosine (FCYT). Once the patient has responded, fluconazole (FCZ) is recommended if susceptible. Therapy should continue until signs, symptoms, and CSF abnormalities have resolved. In neonates, AmB deoxycholate is recommended initially. Alternatively, liposomal AmB may be used. Once the neonate has responded to initial therapy FCZ may be used. FCYT may be considered as salvage therapy for neonates who have not responded to AmB therapy. However, it is difficult to use in neonates and low-birth-weight infants because of the immaturity of their gastrointestinal tracts and the risk for developing necrotizing enterocolitis. AmB deoxycholate for children and neonates should begin at the desired daily dose and not be preceded by smaller test doses. The use of FCYT requires careful monitoring and adjustment of dosage based on serum determinations.

Voriconazole (VCZ) has excellent penetration of the CNS and is active against most Candida isolates causing CNS infections; however, the clinical experience with VCZ in neonates is too limited to recommend its use at this time. Caspofungin and the other echinocandins do not achieve adequate CSF concentrations but do achieve appropriate brain parenchyma concentrations and have been successfully used for therapy.

Cryptococcosis

Cryptococcosis is a systemic fungal infection, and meningitis is its most serious manifestation. Cryptococcal meningitis was rare in the United States in the pre-HIV era; however, due to HIV it has become the most common cause of fungal meningitis in immunocompromised patients, infecting 2% to 9% of adults with AIDS. In the United States and worldwide it remains an uncommon finding in pediatric patients. In adult studies, progressively severe headaches without the presence of fever were common manifestations. Patients frequently have few symptoms but can present with nausea, dizziness, and irritability. Nuchal rigidity is usually absent. Cranial nerve palsies are found in approximately one-fifth of adult patients. Diplopia is one of the most common manifestations. Papilledema is seen in nearly one-third of patients. Patients with coexistent AIDS frequently have very few symptoms.

Pediatric patients with cryptococcal meningitis usually have signs and symptoms not referable to the CNS. In a report of 13 U.S. children with AIDS diagnosed with extrapulmonary cryptococcosis, meningitis was found in 62% and was the most common form of extrapulmonary disease. In eight U.S. children with acute lymphoblastic leukemia (ALL) who developed extrapulmonary cryptococcosis, 63% had meningitis. Fever was the most common symptom, occurring in 60%. Headache was present in only 40% and an equal percentage were asymptomatic. In the latter, LPs performed as part of their routine management revealed unexpected growth of C. neoformans on culture. Treatment in this series of ALL patients included AmB (intravenous, intrathecal, or both), alone or combined with oral FCYT. Relapse was a major complication, occurring in 60% of patients thought to have been treated successfully. Relapses occurred within 2 to 6 months of completing therapy. Treatment of the relapses generally included combination therapy of AmB and FCYT, with the occasional use of intrathecal AmB.

An 18-year review of cases of Cryptococcus infection in Colombia identified only 41 cases (2.6%) among 1578 cases in a national database. Neurocryptococcosis accounted for 87.8% of presentations. Ten children had HIV infection, 11 had other risk factors, and 19 had no identifiable risk factor. The most frequent signs and symptoms were headache (78.1%), fever (68.8%), nausea and vomiting (65.6%), and confusion (50%). Meningeal signs, alteration of vision, and seizures and other neurologic signs were found in 28.1%, 28.1%, and 18.8%, respectively. AmB alone or in combination with FCZ, FCYT, itraconazole (ITZ), or caspofungin was used for treatment in the majority of patients.

Illnesses predisposing to cryptococcal meningitis include systemic lupus erythematosus treated with corticosteroids alone or in combination with azathioprine, chronic mucocutaneous candidiasis, and hyper-IgE syndrome. Zoonotic transmission has occurred.

Direct examination of the CSF using the India ink test can provide an immediate presumptive diagnosis. The sensitivity of this test varies, but in studies of adult patients with AIDS, positive results approached 75%. Other useful stains include silver, periodic acid–Schiff, and mucicarmine. Gram stain of CSF is insensitive and unreliable.

Diagnosis of cryptococcal meningitis is aided by serologic tests. The most common is the cryptococcal capsular polysaccharide antigen test, which can be performed on serum, CSF, or other sterile body fluids. Its sensitivity is nearly 100% for the serum of patients who are HIV positive. The CSF antigen test in some studies seems to be less sensitive (91%). In patients not infected with HIV, the sensitivity of the serologic test in the CSF approaches 90%. False-positive results caused by cross-reactions of antigens in disseminated infections with Trichosporon beigelii have been reported. Culture remains the gold standard for establishing the diagnosis and monitoring of therapy.

Treatment of cryptococcal meningitis is prolonged and, in immunocompromised patients, frequently requires lifelong maintenance therapy. Practice guidelines have been published for children. For HIV-negative, non–transplant recipient children, AmB deoxycholate plus FCYT should be given for at least 2 weeks as induction therapy if no neurologic complications are present and CSF culture performed at 2 weeks of therapy is negative. Liposomal AmB or AmB lipid complex may be substituted for AmB deoxycholate in those intolerant to the latter. In patients with neurologic complications, consideration for extension of the induction phase to 4 to 6 weeks using a lipid formulation of AmB for the final 4 weeks of therapy should be made. Consolidation using oral FCZ for 8 weeks follows, and, on completion, maintenance therapy with FCZ should be started and continued for 6 to 12 months.

For HIV-infected children, induction therapy consisting of AmB plus FCYT for 2 weeks followed by consolidation with FCZ for 8 weeks is recommended. For patients intolerant of AmB, the use of lipid formulations of AmB should be considered. The combination of AmB plus FCYT results in rapid sterilization of the CSF and was associated with improved survival. FCZ is used for maintenance therapy for 1 year or longer. Most experts would not discontinue maintenance therapy for children younger than 6 years. Based on adult data, for children 6 years and older receiving highly active antiretroviral therapy with a CD4 cell count of 100 cells/µL or greater and low or undetectable viral RNA level for 3 months or more, maintenance therapy may be discontinued after a minimum of 1 year but should be restarted if the CD4 cell count falls below 100 cells/µL.

In patients with renal compromise associated with AmB, FCYT levels must be monitored carefully. The dose of FCYT should be reduced based on glomerular filtration rate, and continuing doses should be adjusted to maintain serum FCYT levels of 25 to 60 µg/mL. Serum cryptococcal antigens are not useful in monitoring response to therapy, and the use of CSF cryptococcal antigens to monitor response to therapy also is controversial. Therapy is best judged to be successful by the demonstration of sterility of CSF fungal cultures.

Histoplasmosis

Infection with Histoplasma capsulatum, usually a benign and self-limited disease, is endemic in many parts of the United States. Disseminated disease, including meningitis, is a rare occurrence in children. Case reports of adults generally describe immunocompromised individuals. Clinical presentations vary widely in the manifestation of meningitis. In these cases, 39% presented with meningitis associated with acute dissemination, 25% presented with single histoplasmoma that manifested as symptomatic mass lesions alone or with dissemination, 25% presented with chronic meningitis without evidence of dissemination, and the remaining patients presented with meningitis as a manifestation of recurrent disease. Rarely embolization to the brain caused by Histoplasma endocarditis has been associated with meningitis.

Meningitis occurring in patients with AIDS has become common in endemic areas. In one report, disseminated histoplasmosis caused 8% of the AIDS-defining illnesses in children. The duration of symptoms varies. In patients without AIDS, the symptoms generally last longer than 6 months and can last 7 years. In patients with AIDS, symptoms usually manifest more acutely and within a much shorter time frame. In one series, neurologic findings occurred in all but 6% of the patients. The most common signs and symptoms include depressed consciousness (29%), headaches (24%), confusion (22%), cranial nerve deficits (19%), other focal deficits (16%), seizures (14%), personality changes (12%), and ataxia (11%). Findings such as meningismus, Babinski sign, or papilledema were seen in less than 8%. In adult patients without AIDS, the death rate is approximately 12%, with a relapse rate of 44%. In adult patients with AIDS, the death rate is 100% in some series.

Diagnosis can be aided by serologic testing. High levels of anti– H. capsulatum antibodies were detected in the serum of 70%. CSF serology was helpful in 75% of patients who were tested. Culture of the CSF was positive for fewer than half of the cases in one review. In a second series in patients with AIDS, cultures of blood, bone marrow, respiratory secretions, and brain or meninges were positive in 49%, 53%, 58%, and 75%, respectively. Ten to 25% of patients with disseminated disease lack a positive antibody response. Serology may be false positive in patients with other fungal diseases or tuberculosis. The antibody response to acute Histoplasma infection may remain elevated for years. The use of Histoplasma antigen is a useful test in immunocompromised patients with disseminated Histoplasma .

Treatment with liposomal AmB given over 4 to 6 weeks, followed by ITZ for a minimum of 1 year and until CSF abnormalities have resolved, including Histoplasma antigen levels, is currently recommended. The liposomal form provides higher CNS levels than the deoxycholate form. However, none of the AmB formulations achieves detectable concentrations in the CSF. The use of intrathecal AmB is not recommended for H. capsulatum meningitis. A trial comparing AmB with liposomal AmB (AmBisome, LAmB) as induction therapy showed that the agents had similar efficacy for treating disseminated histoplasmosis. Determination of ITZ serum trough blood levels should be performed to ensure appropriate drug levels.

Patients with AIDS for whom induction therapy was successful must remain on an anti- Histoplasma agent indefinitely. A few cases of children with disseminated histoplasmosis and AIDS have been reported, but none with meningitis; in these children, antifungal therapy must be continued indefinitely. A case report demonstrated that ketoconazole was ineffective for preventing recurrence of nonmeningeal disseminated disease. Because of its poor CNS penetration, it is likely to be ineffective for prophylaxis of meningitis. In patients with AIDS, some success has been achieved with the use of ITZ for suppressive therapy in disseminated disease. However, few data exist on its use for suppressive therapy for meningitis or CNS disease caused by Histoplasma . For maintenance therapy, FCZ (high dose), ITZ, or intravenous AmB are available. In a case report, FCZ was effective in an adult with disease refractory to AmB therapy.

Coccidioidomycosis

C. immitis ( Coccidioides posadasii in Texas and Central and South America) meningitis is a more common cause of chronic meningitis than is Histoplasma . The incidence of coccidioidomycosis has increased substantially in the past two decades.

The rate of hospitalization for coccidioidal meningitis in California increased approximately twofold from 2001 to 2011. Over the 12-year period, 13% of hospitalizations for coccidioidomycosis were due to meningitis. Approximately 1% of children with symptomatic pulmonary disease develop disseminated disease. Of patients with disseminated coccidioidomycosis, 15% to 20% develop meningitis. History of exposure is a crucial factor in diagnosing this disease and relies on careful questioning regarding travel to or residence in an endemic area. Exposure of wounds to colonized soil has been implicated in at least one pediatric case. An association between facial cutaneous coccidioidomycosis and meningitis has been described. Coccidioidomycosis in infancy was described more than 40 years ago. Infants usually have severe disease with high mortality rates and morbidity.

CSF shows a mononuclear pleocytosis with an elevated protein and decreased glucose concentration. Elevated CSF pressures may herald the development of hydrocephalus. Diagnosis is made easier by the availability of reliable serologic tests. Complement-fixing antibodies appear in the CSF only in patients with meningitis and provide a sensitivity of 76%. Sensitivity was increased to 96% when the complement-fixation test was incubated at 4°C. Based on pooling five studies, Coccidioides can be cultured from the CSF of 76% of patients with meningitis but was seen on direct CSF examination in only 8%. Experts in the field consider that the rate of positive CSF cultures is much lower (approximately 33%) and that visualization of the organism in CSF by direct examination rarely occurs.

If untreated, Coccidioides meningitis is uniformly fatal. FCZ is the drug of choice for treatment of meningitis and has a success rate of 79%. It is also used for sustaining remission. Practice guidelines exist for the treatment of coccidioidomycosis in adults. Therapy with oral FCZ is preferred; 9 to 12 months have been shown effective in adults, but no controlled studies in pediatric patients have been published. If treatment is begun with azole therapy, it should be continued for life.

ITZ is reported to be effective for the treatment of Coccidioides meningitis. Because of its variable oral bioavailability, monitoring for adequate serum drug levels is recommended. Adult patients with Coccidioides meningitis had high relapse rates (40–50%), which rendered them dependent on lifelong therapy with ITZ.

Clinical trials with large numbers of children do not exist for the azoles; some authorities consider intravenous and intrathecal AmB to be the standard therapy for coccidioidal meningitis. It also is recommended for patients who do not respond to FCZ or ITZ treatment. Some experts initially use a combination of oral azole with intrathecal AmB with the thought that responses are more prompt with this approach. AmB can be administered intrathecally into the lumbar area or cisterna magna or by using an Ommaya reservoir.

The initial dose of AmB administered into the CSF is 0.025 mg. The dose is increased by doubling until a maintenance dose of 0.1 to 0.5 mg is attained. After this dose has been achieved, therapy can be given every other day, alternating with intravenous administration of AmB. Therapy is continued until the child’s condition has stabilized, at which point intrathecal therapy gradually can be stretched out to every 3 weeks. This program is continued until the CSF indices are normal and culture results have been negative for at least 1 year.

Use of VCZ has been successful in two case reports, and other similar anecdotal references have been reported at referral centers. VCZ, posaconazole, or VCZ plus caspofungin have been used for salvage therapy alone or in combination with liposomal AmB.

Blastomycosis

Blastomyces dermatitidis is an uncommon cause of chronic meningitis and is difficult to diagnose premortem unless the patient has other signs of systemic blastomycosis. When systemic blastomycosis occurs, it can involve the CNS in 5% to 10% of cases. A review of CNS cases of blastomycosis revealed that approximately 23% were not associated with extraneural disease. Common extraneural sites include bone, genitourinary tract, and skin. Previously blastomycosis most often affected immunocompetent patients. Fifty-five percent of cases of CNS blastomycosis involve individuals with immunosuppressive conditions. Patients with AIDS are at high risk for developing chronic infection. Because of the difficulty in diagnosing Blastomyces meningitis and its similarities to tuberculous meningitis, patients usually are treated for presumptive tuberculous meningitis. Although meningitis is the most common form of CNS blastomycosis, solitary mass lesions also can occur. A review of 22 cases treated from 1990 to 2008 demonstrated a mortality rate of 18%.

Examination of CSF obtained by LP usually is negative. However, the yield from ventricular fluid seems to be higher. Diagnosis relies on the characteristic histopathologic appearance in tissues and occasionally on culture of ventricular CSF. Culture isolation of Blastomyces from the CSF is possible in approximately half of cases. Testing for the presence of B. dermatitidis antigen may yield better results. In one report, all CSF samples tested using a commercially available assay were found to be positive. Blastomycosis meningitis is associated with a pleocytosis that may be lymphocytic or neutrophilic in nature. The CSF protein is elevated in the majority of cases. Meningitis caused by B. dermatitidis frequently has a neutrophilic predominance. Seeking Blastomyces from other sources, including sputum and urine, is indicated. In a study of AIDS patients, examination of sputum was useful for establishing the diagnosis of disseminated blastomycosis.

Treatment of CNS blastomycosis relies on the administration of the lipid formulation of AmB for 4 to 6 weeks, followed by oral azole therapy (i.e., FCZ, ITZ, VCZ) for a minimum of 12 months or until CSF abnormalities have resolved. For children, no specific recommendations exist for the treatment of CNS disease, although for children with severe blastomycosis AmB deoxycholate or a lipid formulation of amphotericin is recommended for initial therapy. ITZ is recommended as follow-up therapy for 12 months. A review favors the use of VCZ as the azole of choice after initial therapy with lipid formulation of amphotericin. Azoles should not be considered for primary treatment of CNS blastomycosis. Children respond less satisfactorily to oral azole therapy than do adults. Although only a few published reports exist supporting the use of lipid formulations of AmB to treat CNS blastomycosis, these drugs are preferred because of the need of prolonged duration of therapy in these patients. Experimental animal data exist demonstrating superior penetration of liposomal AmB compared with lipid complex or the deoxycholate formulations of amphotericin.

Aspergillosis

CNS infections with Aspergillus fumigatus and other Aspergillus spp. are associated with a high mortality rate. In a review containing 47 cases of Aspergillus meningitis alone the overall case fatality rate was 64.5%, a significant number of whom were immunocompromised. The same report contained 15 cases of chronic meningitis and 5 cases of spinal arachnoiditis, among whom the mortality rates were 47% and 40%, respectively. Conditions placing patients at risk include neurosurgical procedures, spinal anesthesia, organ and bone marrow transplantation, malignancies, diabetes, and AIDS. Some early reports of CNS aspergillosis were in infants who appeared to be normal. Modes of acquisition include extension from a contiguous focus, intravenous drug abuse, hematogenous spread, and iatrogenic introduction. In addition to brain abscesses, manifestations of Aspergillus spp. CNS infection include meningoencephalitis, isolated spinal cord lesions, aqueductal stenosis, and mycotic aneurysms. Magnetic resonance imaging is superior to computed tomography for the delineation of CNS lesions.

The diagnosis of meningitis is difficult. In one review, premortem diagnosis was made in only 45% of cases of Aspergillus meningitis. Premortem diagnosis was greater in chronic Aspergillus meningitis and spinal arachnoiditis, 73% and 100%, respectively. CSF antigen-based assays (galactomannan and 1,3,β-D-glucan) demonstrated a sensitivity of 86.7% compared to 31% positivity for culture in one review.

Recommendations for therapy of CNS Aspergillus infections for children are similar to adults. Published guidelines for treatment of adults recommend the use of VCZ. For those intolerant to or who fail to respond to VCZ, therapy with ITZ, posaconazole, or lipid formulations of AmB should be attempted. ITZ and VCZ have been used successfully in case reports.

Sporotrichosis

Although primarily a lymphocutaneous disease, S. schenckii has been reported to cause meningitis. Recent cases have occurred in adults with AIDS as an underlying risk factor. Meningeal seeding may occur through hematogenous spread from the lungs. Meningeal involvement produces CSF indices and abnormalities similar to those seen with the other fungal meningitides. CSF fungal culture is insensitive for the diagnosis of Sporothrix meningitis. The use of S. schenckii antibody in the CSF has been effective in diagnosing meningitis in patients without other overt signs of this infection.

Treatment is very difficult. Practice guidelines for adults recommend AmB given as a lipid formulation for 4 to 6 weeks as initial therapy. No preference for AmB deoxycholate over a lipid formulation is provided. Step-down therapy using ITZ is recommended once response to initial therapy occurs and should be continued for at least 12 months. Monitoring of serum levels is recommended to ensure adequate drug exposure. For patients with immunosuppressive diseases or conditions, ITZ suppressive therapy is recommended.

Mucormycosis

Meningitis caused by Mucor spp. or other Zygomycetes usually occurs as a result of direct extension from paranasal sinus disease. Infection with these organisms most commonly is seen in the immunocompromised host and particularly in patients with diabetes mellitus or patients receiving high doses of corticosteroids. Patients (particularly dialysis patients) undergoing chelation therapy with deferoxamine are at risk for developing infection. The association with deferoxamine therapy is seen with Cunninghamella . Mucor spp. have been reported as a cause of CNS disease in children, but very rarely. Treatment employs AmB deoxycholate or lipid formulations. Improved survival has been seen among cancer patients with mucormycosis of the head and neck with treatment using liposomal AmB. Surgical excision of rhinocerebral infection is recommended along with antifungal therapy. Isavuconazole, a broad-spectrum azole antifungal, has recently been approved by the U.S. Food and Drug Administration for the treatment of invasive mucormycosis and aspergillosis. A comparison of isavuconazole to VZC demonstrated that it had fewer adverse effects than VCZ.

Other Fungal Infections

Acremonium spp. are common soil fungi that may cause chronic meningitis in humans. Xylohypha bantiana, an uncommon dematiaceous fungus, caused a fungal brain abscess in an adolescent girl; this report increases the number of cases reported in the literature to nearly 40. Cerebral chromoblastomycosis also has been reported. Other fungal organisms causing CNS infection include Paracoccidioides brasiliensis (i.e., South American blastomycosis), Prototheca wickerhamii, Blastoschizomyces capitatus, Rhodotorula spp., Pseudallescheria boydii, A. mansoni, C. lusitaniae, B. spicifera, and C. parapsilosis.