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Cryptococcal meningitis.

Cryptococcal meningitis is a common opportunistic infection in AIDS patients, particularly in Southeast Asia and Africa. Cases also occur in patients with other forms of immunosupression and in apparently immunocompetent individuals. Mortality from HIV-associated cryptococcal meningitis remains high (10-30%), even in developed countries, because of the inadequacy of current antifungal drugs and the complication of raised intracranial pressure. In cohorts of HIV-infected patients from sub-Saharan Africa, cryptococcosis has accounted for 13-44% of all deaths. Optimal current therapy is with amphotericin B 0.7-1 mg/kg/day plus flucytosine 100 mg/kg/day for 2 weeks, followed by fluconazole 400 mg/day for 8 weeks and 200 mg/day thereafter. Saline loading reduces amphotericin B nephrotoxicity. If there is no contraindication on CT head scan, repeat lumbar puncture with drainage of cerebrospinal fluid (CSF) is recommended for patients with very raised CSF opening pressure. Expansion of antiretroviral programmes raises the prospect of transforming the long-term prognosis of these patients, provided that they survive the acute phase of the illness. Studies are needed to define more fungicidal drug regimens and to improve the treatment of raised intracranial pressure.

AIDS-Related Opportunistic Infections↗

Early mycological treatment failure in AIDS-associated cryptococcal meningitis.

Cryptococcal meningitis causes significant morbidity and mortality in persons with AIDS. Of 236 AIDS patients treated with amphotericin B plus flucytosine, 29 (12%) died within 2 weeks and 62 (26%) died before 10 weeks. Just 129 (55%) of 236 patients were alive with negative cerebrospinal fluid (CSF) cultures at 10 weeks. Multivariate analyses identified that titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, together with dose of amphotericin B, had the strongest joint association with failure to achieve negative CSF cultures by day 14. Among patients with similar CSF cryptococcal antigen titers, CD4 cell counts, and serum albumin levels, the odds of failure at week 10 for those without negative CSF cultures by day 14 was five times that for those with negative CSF cultures by day 14 (odds ratio, 5.0; 95% confidence interval, 2.2-10.9). Prognosis is dismal for patients with AIDS-related cryptococcal meningitis. Multivariate analyses identified three components that, along with initial treatment, have the strongest joint association with early outcome. Clearly, more effective initial therapy and patient management strategies that address immune function and nutritional status are needed to improve outcomes of this disease.

AIDS-Related Opportunistic Infections↗

Granulocyte colony stimulating factor therapy of experimental cryptococcal meningitis.

Cryptococcal meningitis was induced in mice using intracerebral injection of Cryptococcus neoformans. Beginning either 3 days before or 1 day after infection, mice were treated with human recombinant granulocyte colony stimulating factor (hGCSF). In high doses hGCSF reduced the brain tissue burden of C. neoformans but had no effect on survival. The effect of hGCSF was dependent on size of the infecting dose and time of administration. A large innocula of C. neoformans, or when hGCSF was initiated after infection, there was no added benefit. Some groups of mice also received low doses of fluconazole beginning 1 day after infection. Fluconazole both prolonged survival and reduced brain tissue counts of C. neoformans. Combined cytokine/fluconazole therapy was superior to either agent given alone. These studies suggest that hGCSF can add to the efficacy of fluconazole therapy in murine cryptococcosis, and suggest that polymorphonuclear leucocytes contribute to host defence in cryptococcal meningitis. The relative potency of fluconazole appears greater than hGCSF.

Animals↗

[Effect of implantation of an Ommaya reservoir on prognosis for cryptococcal meningitis].

Cryptococcal meningitis has a high mortality rate of central nervous infection. The patients usually die of the disease itself, or complications from increased intracranial pressure. Early diagnosis and treatment, including surgical drainage, will improve the results. In this series, twenty-one patients with high intracranial pressure (ICP > 300 mmH2 O) are presented. Fourteen received implantation of Ommaya reservoir to aspirate cerebrospinal fluid (CSF) for relief of symptoms of ICP. Meanwhile 4 of these 14 patients also received intraventricular injection of amphotericin B because of poor response to systemic drugs. Another seven patient received systemic drug therapy only. Survival during therapy occurred in 11 of 14 patients in the surgical group, compared with only 1 of 7 patients treated by drug therapy alone (P = 0.019). In the 14 patients who received implantation of an Ommaya reservoir, there was one complication of CSF leakage when the reservoir ruptured because of repeated aspiration. For patients with cryptococcal meningitis with high ICP, early implantation of an Ommaya reservoir will improve the survival rate.

Adolescent↗

Cryptococcal Meningitis.

Cryptococcal meningitis, often seen in immunocompromised hosts, is also a disease of the immune-competent individual. The diagnosis of cryptococcal meningitis requires a lumbar puncture with measurement of the opening pressure, standard laboratory assessment including cell count, protein and glucose, fungal culture, and cryptococcal polysaccharide antigen. Serum cryptococcal antigen is of great diagnostic value in individuals infected with HIV. Hospital admission for initial therapy with amphotericin B desoxycholate is required. Adjuvant oral therapy with flucytosine for the first 2 weeks of therapy is strongly recommended. If flucytosine is not well tolerated, it may be discontinued with close monitoring and follow-up of cerebrospinal fluid (CSF) response to therapy. Good hydration and appropriate premedication concomitant to the use of amphotericin B are useful interventions preventing side effects. Occasionally, amphotericin B needs to be discontinued due to intolerance or side effects. After CSF sterilization is completed, therapy can be switched to oral fluconazole. Fluconazole is well absorbed orally. There is rarely a need to give intravenous fluconazole.

Journal Article↗

Comparison of D0870 and fluconazole in the treatment of murine cryptococcal meningitis.

Cryptococcal meningitis is a common infection in patients with AIDS. Using a murine cryptococcosis model, we compared treatment with a new triazole, D0870, and fluconazole. Groups of ICR (Institute for Cancer Research) mice were infected intracerebrally with eight different isolates of Cryptococcus neoformans variety neoformans with different in vitro susceptibilities to fluconazole. For survival studies mice were challenged with two to four times LD(50) or six to nine times LD(50). Treatment was given for 10 days. Mice were observed through to day 30. To assess the effect of treatment on fungal tissue burden, mice received a three to five times LD(50) inoculum and treatment for 10 days. They were sacrificed on day 12 and serial dilutions of brain homogenates were cultured. Fluconazole prolonged survival primarily in isolates which were susceptible in vitro. D0870 prolonged survival in all isolates except one, which was also resistant in vitro to D0870 and fluconazole. Both drugs reduced colony counts of all isolates. D0870 warrants further development for use in cryptococcosis, and appears effective for isolates relatively resistant to fluconazole. There is a relative correlation of in vivo and in vitro susceptibility to D0870 as well as fluconazole.

Animals↗

Massive pleural effusions in cryptococcal meningitis.

Cryptococcal infection uncommonly presents with pulmonary manifestations and even more rarely so as massive bilateral effusions. Pleural involvement is usually associated with underlying pulmonary parenchymal lesions and is unusual while on antifungal therapy. We report a patient with cryptococcal meningitis who, while on intravenous 5-flucytosine and amphotericin B, developed life-threatening bilateral massive pleural effusions with evidence of spontaneous resolution, consistent with prior hypothesis of antigenic stimulation as the cause of pleural involvement.

Adult↗

D-mannitol in cerebrospinal fluid of patients with AIDS and cryptococcal meningitis.

Cryptococcal meningitis (CM) is associated with raised intracranial pressure which is linked with serious neurological sequelae. Cryptococcus neoformans produces D-mannitol in vitro and in experimental meningitis in rabbits. Mannitol present in the cerebrospinal fluid (CSF) of CM patients could exacerbate raised intracranial pressure and contribute to neurological damage. To link CSF mannitol to cryptococcal infection, levels of mannitol in the CSF of AIDS patients with CM were measured by gas-liquid chromatography. Mannitol was detected in 19 of 21 samples (range, 1.5 to 26.2 mg/liter), but there was no quantitative correlation between the mannitol concentration and the cryptococcal antigen titer.

AIDS-Related Opportunistic Infections↗

Cerebral infarction in chronic meningitis: a comparison of tuberculous meningitis and cryptococcal meningitis.

Twenty-eight patients with cerebral infarction secondary to chronic meningitis were retrospectively identified at our institution over a period of 5 years. They accounted for 47% (17/36) of tuberculous meningitis (TBM) and 32% (11/34) of cryptococcal meningitis cases. Single infarctions were found in 15 patients and multiple infarctions in 13. The distribution of single infarctions was: basal ganglia 7; internal capsule 3; thalamus 1; cerebellum 1; and cortical infarct 3. Therapeutic outcomes at 3 months were determined using a modified Barthel INDEX: At follow-up of 3 months or more, 10 had good outcomes while the other 18 had poor outcomes. The 18 with poor outcomes included six who died, and 12 who had severe neurological sequelae. TBM and cryptococcal meningitis shared similar clinical features, both being frequently associated with other neurological complications, including hydrocephalus, cranial nerve palsy, and seizures in our patients. However, extracranial involvement, such as spinal and pulmonary involvement, was more commonly found in TBM patients. Cerebral infarction can occur in both the acute stage and later stages of treatment. Mortality and morbidity are high, and early diagnosis and appropriate antimicrobial treatment are essential. If hydrocephalus is demonstrated, early ventricular decompression is needed to prevent further cerebral ischaemia.

Adolescent↗

[Cryptococcal meningitis].

Cryptococcal meningitis is a life-threatening disease. Headache, vomiting, cranial nerve symptoms and mental changes are the most common symptoms, but as many as 15% may have no symptoms referable to the CNS. For chemotherapy four drugs are available: namely amphotericin B, 5-fluorocytosine, miconazole and ketoconazole. Most cases have been treated by combination of amphotericin B and 5-fluorocytosine. The intrathecal administration of amphotericin B should be considered for patients who fail to respond to the usual intravenous therapy. The case is reported of a patient who died due to hydrocephalus, and the CSF-levels of the administered drugs are presented. Some pitfalls of therapy are discussed.

Adult↗

[Cryptococcal meningitis following cryptococcal pneumonia in an immunocompetent].

Cryptococcal meningitis (CM) is common in the immunocompromised (especially due to AIDS), but also occurs in immunocompetent subjects. CM can complicate cryptococcal pneumonia (CP) not only in the immunocompromised but also in the immunocompetent. We describe a healthy 26-year-old man who developed a prolonged lung infection. Diagnosis of cryptococcal pneumonia was established from bronchoscopic washings. He recovered spontaneously, so no antifungal treatment was given. 4 months later he was admitted with cryptococcal meningitis and was treated successfully with amphotericin B. An extensive immunologic study revealed no abnormalities. Since CM can complicate cryptococcal pneumonia, it is recommended that patients with CP be followed, even if recovery is apparently complete.

Adult↗

[Differential diagnosis in patients with tuberculous meningitis and cryptococcal meningitis].

OBJECTIVE: To search for the main differential points in clinical and CSF changes between patients with tuberculous meningitis (TBM) and cryptococcal meningitis (CCM). METHODS: Fifty three cases of TBM and 55 cases of CCM who admitted to hospital from February 1983 to December 1997 were investigated retrospectively. Main symptoms, signs and CSF changes before administration of specific antibiotics were compared. RESULTS: 9%(5/53) TBM and 49% (27/55) CCM patients had headache without fever at the onset. The incidences of symptoms of failing eyesight, hearing loss and paralysis of extremities were 13% (7/53) and 36%(20/55), 2% (1/53) and 16% (9/55), and 19% (10/53) and 0 in TBM and CCM patients respectively. The rate and the degrees of optic papilla edema in CCM patients (66%, 16/36 slight, 13/36 moderate, and 7/36 serious) were significantly higher and more serious than that in TBM (15%, 8/8 slight). The patients with initial CSF pressure over 400 mm H2O were 11% and 90% in TBM and CCM. All but 20 CCM patients had elevation of CSF protein content, and 45% (24/53) TBM and 9%(5/55) CCM were > 2 g/L. CONCLUSIONS: This study shows that the most important differences between TBM and CCM are: headache not accompanied by fever at the onset, failing eyesight, striking elevation of initial CSF pressure, moderately and serious degree of optic papilla edema, normal CSF protein content occurs usually in CCM more than those in TBM patients. On the other hand, striking elevation of CSF protein content (> 2 g/L) occurs usually in TBM patients.

Adolescent↗

[Simultaneous association of tubercular meningitis and cryptococcal meningitis in an African with human immunodeficiency virus HIV positive serology. University Hospital Center of Bujumbura,Burundi].

The authors report a connection between a meningitis tuberculosis and a meningoencephalitis with cryptococcus in the case of an african VIH+. The diagnostic of a meningitis tuberculosis was retained on an indirect arguments, this of meningoencephalitis of direct arguments (antigen cryptococcus, cultivation on Sabouraud environment). The pulmonary tuberculosis and/or extrapulmonary tuberculosis is current in Central Africa during HIV infection, as well as the crytococcosis during AIDS. But, any observation on neuromeningitis strike of those two infections have been reported up to now.

Adult↗

The association of 25-hydroxyvitamin D deficiency with neuroinflammation and prognosis in HIV-negative cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) in HIV-negative individuals is increasing, yet the role of vitamin D remains unclear. This study investigates serum 25-hydroxyvitamin D [25(OH)D] levels and their clinical implications in HIV-negative CM patients. METHODS: We conducted a retrospective case-control study of 93 HIV-negative CM patients and 191 healthy controls (HCs). Serum 25(OH)D levels, cerebrospinal fluid (CSF) fungal burden, cytokine profiles, the incidence of postinfectious inflammatory response syndrome (PIIRS), and one-year mortality were assessed. Bivariate logistic regression models identified predictors of mortality. RESULTS: CM patients had significantly lower serum 25(OH)D levels than HCs (18.33 vs. 23.69&#xa0;ng/mL, p&#xa0;<&#xa0;0.001), with a higher rate of deficiency (<20&#xa0;ng/mL) in the CM group (59.14% vs. 34.03%, p&#xa0;<&#xa0;0.001). Lower 25(OH)D levels were associated with elevated CSF levels of IL-6 and IL-8 (p&#xa0;<&#xa0;0.05). Deficiency was linked to increased PIIRS incidence (43.64% vs. 21.05%, p&#xa0;=&#xa0;0.028). Bivariate logistic regression showed a protective trend for 25(OH)D levels (OR 0.939, 95% CI 0.877-1.006, p&#xa0;=&#xa0;0.075), although deficiency was not associated with higher mortality. CONCLUSIONS: Serum 25(OH)D deficiency is prevalent in HIV-negative CM patients and linked to neuroinflammation and increased risk of PIIRS. Serum 25(OH)D levels may serve as a useful prognostic marker, although further research is needed.

Humans↗

Possibility of diagnosing meningitis by gas chromatography: cryptococcal meningitis.

Cerebrospinal fluid (CSF) from eight patients with cryptococcal meningitis, from ten patients with viral meningitis, and from four control patients without meningitis were analyzed by electron-capture gas-liquid chromatography (EC-GLC). All cryptococcal specimens had similar EC-GLC profiles, and these differed from those of the controls. Viral EC-GLC patterns were different from those obtained with specimens from the patients with cryptococcal infection and from the controls. In addition, specimens from patients with various types of viral infections gave profiles that differed from each other. Two normal CSFs were inoculated with Cryptococcus neoformans; aliquots of these cultures showed an EC-GLC pattern very similar to that seen in CSF of patients with cryptococcal meningitis. The EC-GLC procedure is rapid, reproducible, and easy to perform and may hold promise as an additional aid in the diagnosis of cryptococcal infection.

Cerebrospinal Fluid↗

Coagglutination (COA) test for the rapid diagnosis of cryptococcal meningitis.

Cryptococcus coagglutination (COA) test reagent was prepared locally and showed no cross reactions with different species of bacteria or yeasts or with 75 control sera including 25 that gave positive results for RA factor. We used the COA test to detect cryptococcus antigen in the CSF and we could confirm the diagnosis of 11 out of 115 suspected cases of fungal meningitis; the titre varied from 4 to 128. A four-fold rise in titre confirmed the diagnostic value and a steady fall in titre in three patients on therapy indicated the prognostic value of the test. The earliest confirmation was in a renal transplant patient on the eighth day after onset of symptoms. The COA test was negative with the CSF of 118 patients with chronic meningitis. Cryptococcal colony forming units (cfu) in CSF varied from 100 to greater than 100,000/ml and correlated well with microscopy and with the COA antigen titre in CSF. Four out of the 11 patients who had cryptococcaemia, had 50,000-100,000 cfu/ml in the CSF. Cryptococcus antigen was detected by COA in the serum of all 11 patients, even in those with only 100 cfu/ml in CSF. In the three post-renal transplant patients, who were being monitored regularly, the diagnosis was made early and all three recovered on antifungal therapy with no relapse to date (1-2 years). All the others, including the two primary CNS infections, succumbed to the disease because they presented late for diagnosis and therapy. The cryptococcus COA test is a simple and specific test that can be used as a rapid test to confirm early diagnosis and permit prompt therapy, which should improve the prognosis in CNS and other forms of systemic cryptococcosis. Moreover, it is reproducible and cost-effective, particularly in countries where the latex and other expensive test reagents are not generally available.

Adolescent↗

[A clinical study of cryptococcal meningitis--sequential changes of cryptococcal antigen titers].

We reviewed the clinical manifestations, sequential changes in cryptococcal antigen titers in serum and cerebrospinal fluid (CSF), and the antifungal drug susceptibility of Cryptococcus neoformans in three patients with cryptococcal meningitis between 1996 and 2000. Cryptococcal antigen titers were measured using the latex agglutination method with Pastrex Cryptococcus (Fuji Mebio, Tokyo) and Serodirect Cryptococcus (Eiken Chemical, Tokyo). The underlying systemic diseases in the three patients were liver cirrhosis, non-Hodgkin's lymphoma associated with miliary tuberculosis, and malignant thymoma associated with systemic lupus erythymatosus. The CSF samples showed positive indian ink staining in two of the three patients and C. neoformans was cultured from all three. The cryptococcal antigen titers in serum were higher than those in the CSF. The serum and CSF cryptococcal antigen titers measured by Serodirect Cryptococcus were higher than those measured by Pastrex Cryptococcus. The maximum titers of antigen in serum and CSF measured by Serodirect Cryptococcus were greater than 1,024 in all three patients. The treatment regimens used for the three patients were amphotericin-B (AMPH-B) and flucytosine (5-FC), fluconazole (FLCZ) and intrathecal AMPH-B, FLCZ and 5-FC, and intrathecal AMPH-B, respectively. The antigen titers in serum and CSF decreased after treatment in all three patients. The antigen titers decreased slowly over 7.3 months in the most seriously ill patient who had non-Hodgkin's lymphoma associated with miliary tuberculosis. The time between the beginning of treatment and CSF cryptococal antigen titers falling to less than 8 was 1.7 to 7.3 months in the three patients, but the serum titers did not decrease to less than 8 during this period. The minimum inhibitory concentration was 0.06-0.25 microgram/ml for AMPH-B, 4-8 micrograms/ml for 5-FC, 2-8 micrograms/ml for FLCZ, 0.125-0.5 microgram/ml for miconazole and 0.03-0.125 microgram/ml for itraconazole. The measurement of sequential changes in cryptococcal antigen titers in serum and CSF was useful for evaluating the response to treatment.

Adult↗