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A 30-year-old AIDS-patient with cryptococcal meningitis developed subacute bilateral visual loss associated with high cerebrospinal fluid (CSF) pressure. With immediate CSF drainage the blindness was reversible. The importance of prompt CSF drainage in AIDS-related cryptococcal meningitis with visual failure is stressed.
Eighteen consecutive AIDS patients with a first episode of cryptococcal meningitis were enrolled in the study to evaluate the efficacy and tolerability of amphotericin B with or without flucytosine followed by fluconazole as primary therapy for cryptococcal meningitis in patients with AIDS. The treatment consisted of intravenous amphotericin B 0.6 mg/kg daily with or without flucytosine (150 mg/kg d in four divided doses) for 2 weeks which was then followed by oral fluconazole 400 mg daily for 8 weeks. After completion of primary therapy, all patients received a maintenance dose of oral fluconazole 200 mg daily. The primary therapy was successful in 17 (94%) of the 18 patients. The median length of time to the first negative cerebrospinal fluid culture for Cryptococcus neoformans in the 17 patients with successful treatment was 3 (range 2 to 6) weeks. No patient had to discontinue the treatment due to adverse drug reactions. During a mean observation period of 26.94 weeks, no relapse case was documented among the 17 patients. Our results indicate that this regimen as primary therapy for cryptococcal meningitis in AIDS patients is effective and well tolerated.
A 50 year old man with AIDS, cryptococcal meningitis and a normal CT-scan developed impaired consciousness and even deep coma associated with very high CSF pressure. After lumbar CSF drainage consciousness improved dramatically. We conclude that in patients with cryptococcal meningitis who have impaired consciousness and a normal CT scan, CSF drainage to improve the level of consciousness should be considered.
OBJECTIVE: To evaluate the treatment of serious and uncontrollable intracranial hypertension in patients with acquired immunodeficiency syndrome who developed cryptococcal meningitis. METHODS: All cases of cryptococcal meningitis with elevated pressure and acquired immunodeficiency syndrome were reviewed in detail and described. RESULTS: Cerebrospinal fluid shunting dramatically improved these critically ill patients and was much more successful than serial lumbar punctures or the use of high-dose dexamethasone. CONCLUSION: Patients with acquired immunodeficiency syndrome who develop cryptococcal meningitis and who suffer serious visual loss or ocular palsies with elevated pressures should be considered for cerebrospinal fluid shunting at an early stage.
Eighteen cases of confirmed AIDS with cryptococcal meningitis in Bata Regional Hospital, Equatorial Guinea from January 1997 to November 1999 were analysed. The associated morbidity and mortality rates were very high. Contributory factors were the failure to note the occurrence of AIDS with cryptococcal meningitis, late presentation, serious illness and severe complications, and delayed and inadequate therapy.
BACKGROUND: The risks associated with implanting a cerebrospinal fluid (CSF) shunt in immunocompromised patients with ongoing CSF infection have historically discouraged surgeons from implanting CSF shunts in patients with HIV and cryptococcal meningitis. However, this patient population often requires frequent lumbar punctures to manage elevated intracranial pressure (ICP) secondary to cryptococcal infection. To date, only 7 cases of ventriculoperitoneal (VP) shunting for the treatment of intracranial hypertension in patients with HIV-associated cryptococcal meningitis have been reported. Few of these reports have included outcomes more than 3 months postsurgery. It remains unclear if VP shunts are an effective long-term treatment of intracranial hypertension in this patient population. CASE DESCRIPTIONS: Two patients with HIV/AIDS (CD4 counts of 8 and 81 cells/mm(3)) presented with altered mental status, visual changes, florid cryptococcal meningitis, and elevated ICP (>500 mm CSF) without evidence of hydrocephalus on computed tomography scan. Both patients experienced rapid reversal of symptoms with external lumbar CSF drainage, and remained lumbar drain-dependent after 2 weeks of amphotericin B and flucytosine therapy. Despite evidence of unresolved cryptococcal meningitis, each patient underwent implantation of a VP shunt without complication and was discharged on lifetime fluconazole therapy. They remained asymptomatic at 12 and 16 months after surgery without evidence of shunt infection or malfunction. CONCLUSION: Patients with intracranial hypertension and HIV-associated cryptococcal meningitis who cannot tolerate cessation of external lumbar CSF drainage or frequent lumbar punctures may be considered for VP shunt placement despite severe immunosuppression and persistent CSF cryptococcal infection.
The treatment of non-acquired immunodeficiency syndrome (AIDS) cryptococcal meningitis has not been well defined as yet. The current recommendation is amphotericin B with or without flucytosine. However, due to the many side effects of these drugs, fluconazole is becoming an attractive alternative in patients who cannot tolerate amphotericin B and flucytosine. This case study demonstrates the successful use of fluconazole in a patient with underlying diabetes mellitus and cryptococcal meningitis.
We conducted a retrospective, multicenter study evaluating the safety of discontinuing maintenance therapy for cryptococcal meningitis after immune reconstitution. Inclusion criteria were a previous definitive diagnosis of cryptococcal meningitis, a CD4 cell count of >100 cells/microL while receiving highly active antiretroviral therapy (HAART), and the subsequent discontinuation of maintenance therapy for cryptococcal meningitis. The primary end point was relapse of cryptococcal disease. As of July 2002, 100 patients were enrolled. When maintenance therapy was discontinued, the median CD4 cell count was 259 cells/microL and the median plasma virus load was <2.30 log10 copies/mL, and serum cryptococcal antigen was undetectable in 56 patients. During a median follow-up period of 28.4 months (range, 6.7-64.5; 262 person-years), 4 events were observed (incidence, 1.53 events per 100 person-years; 95% confidence interval, 0.42-3.92). Three of these patients had a CD4 cell count of >100 cells/microL and a positive serum cryptococcal antigen test result during the recurrent episode. In conclusion, discontinuation of maintenance therapy for cryptococcal meningitis is safe if the CD4 cell count increases to >100 cells/microL while receiving HAART. Recurrent cryptococcal infection should be suspected in patients whose serum cryptococcal antigen test results revert back to positive after discontinuation of maintenance therapy.
To evaluate whether oral fluconazole reduces the risk of a first episode of cryptococcal meningitis in HIV-infected patients, we conducted a case-control study of patients cared for in a university teaching hospital and two urban HIV-outpatient clinics. Cases consisted of HIV-infected patients with CD4 cell counts less than 250/microL who developed a first episode of cryptococcal meningitis between July 1, 1990, and June 30, 1993. For each case (n = 18), 4 control subjects were chosen from HIV-infected patients (CD4 count < 250/microL) whose cerebrospinal fluid was negative for cryptococcal antigen and culture, and who were matched by age, sex, and time of lumbar puncture. There were no significant differences between cases and controls in age, sex, insurance status, mean CD4 count, history of oral candidosis, presence of a previous AIDS-defining illness, the number of visits to the HIV-outpatient clinic, or use of antiretroviral therapy. In the 6 months before lumbar puncture, 2 of 18 cases (11%) and 26 of 72 controls (36%) were exposed to fluconazole, a finding that gives a matched odds ratio (adjusted for race, route of HIV infection, and CD4 count) of 0.08 (95% CI 0.01-0.84; p = 0.035) and indicates a 92% protective efficacy. We conclude that fluconazole reduces the risk of a first episode of cryptococcal meningitis in HIV-infected patients with a CD4 count less than 250/microL. Although the optimum dose and duration of fluconazole could not be determined, our results suggest that less than daily use was effective in the prevention of cryptococcal meningitis.
Hydrocephalus can be associated with increased morbidity and mortality in cryptococcal meningitis if left untreated. Both ventriculoperitoneal and ventriculoatrial shunting have been used in persons with cryptococcosis complicated by hydrocephalus, but the indications for and complications, success, and timing of these interventions are not well known. To this end, we reviewed the clinical courses of 10 non-human immunodeficiency virus-infected patients with hydrocephalus secondary to cryptococcal meningitis who underwent shunting procedures. Nine of 10 patients who underwent shunting had noticeable improvement in dementia and gait. Two patients required late revision of their shunts. Shunt placement in eight patients with acute infection did not disseminate cryptococcal infection into the peritoneum or bloodstream, nor did shunting provide a nidus from which Cryptococcus organisms proved difficult to eradicate. Shunting procedures are a safe and effective therapy for hydrocephalus in patients with cryptococcal meningitis and need not be delayed until patients are mycologically cured.
PURPOSE: To describe an unusual, favorable visual outcome in a patient with lupus erythematosus and cryptococcal meningitis and to present bilateral superior oblique muscle paresis. METHODS: Case report. A 15-year-old girl with lupus erythematosus and cryptococcal meningitis had bilateral superior oblique paresis, bilateral optic nerve head swelling, and increased intracranial pressure. She developed a visual acuity of no light perception in the right eye. RESULTS: Treatment with oral fluconazole, acetazolamide, and dexamethasone, as well as repeated lumbar punctures to reduce intracranial pressure, was followed by recovery to a visual acuity of 20/20 in both eyes and normal ocular motility. CONCLUSION: With appropriate treatment, visual loss associated with cryptococcal meningitis may have a favorable outcome.
There are evidences regarding the role of NK cytotoxic activity in the resistance against experimental C. neoformans infection. To assess the status of NK cell activity in human C. neoformans infection, we studied the peripheral blood of twelve patients with cryptococcal meningitis, six patients with CNS disease different to cryptococcal meningitis, and twelve healthy subjects. The number of CD16+cells and the NK cytotoxic activity of peripheral blood mononuclear cells was studied. The in vitro effect of exogenous IL-2 and interferon gamma on such cytotoxic activity was also studied. The number of CD16+ cells was not significantly different in patients compared to controls. However, cryptococcal patients exhibited a significant lower NK activity compared to both control groups (p less than 0.05 in both cases). The low NK activity of cryptococcal patients was fully reconstituted in vitro with the addition of rIL-2 but not with rIFN gamma. In vitro experiments suggest that the low NK activity of cryptococcal meningitis patients is not due to amphotericin B therapy or blockade of NK cells by C. neoformans-derived molecules. The results of this study suggests that patients with cryptococcal meningitis have a defective NK cytotoxic function and may aid to understand the pathogenesis of this disease.
Cryptococcal meningitis was induced in BALB/c mice by intracerebral infection with Cryptococcus neoformans. Drug therapy was initiated 1 day later, with mice receiving amphotericin B (AMB), SCH 39304, combination therapy, or no drug therapy (controls). Most, but not all, combinations showed additive benefits, significantly prolonging survival and reducing organism counts in tissues compared with those in controls and groups which received the drugs independently. Optimum protection was obtained when a single dose of 10 mg of AMB per kg of body weight was combined with a fairly narrow SCH 39304 dose range. AMB antagonism did not occur with any regimen tested. AMB-azole combinations may be reasonable alternatives for patients who fail standard cryptococcosis therapeutic regimens.
Cryptococcal meningitis is a common cause of chronic meningitis in Papua New Guinea, affecting apparently immunocompetent people. The majority of infections are believed to be due to Cryptococcus neoformans var. gattii. We have reviewed the records of 49 Melanesian adults who presented with proven cryptococcal meningitis to the University teaching hospital in Port Moresby, and compare our findings with other published studies of cryptococcal meningitis in the tropics and sub-tropics. None of the patients had an obvious cause of immunosuppression. Visual disturbances and fundoscopic changes of papilloedema or papillitis were particularly common. The in-hospital case fatality rate for patients treated with amphotericin B and flucytosine was 22.4%. Of the fully treated patients, 31% became completely blind before being discharged from hospital. Therapy directly aimed at reducing intracranial pressure may improve outcome.
Persistently elevated intracranial pressure (ICP) is one of the most accurate predictors of a poor prognosis in patients with AIDS-related cryptococcal meningitis. We present a severe case of persistent cryptococcal meningitis in a patient with advanced AIDS, complicated by elevation of ICP. A ventriculoperitoneal shunt was placed that successfully lowered the ICP and alleviated the associated symptoms. The elevated ICP secondary to AIDS-related cryptococcal meningitis should be treated aggressively. Despite the risk of shunt complications, cerebrospinal fluid shunts can be considered in these patients if they do not respond to other treatment.
In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.
Atypical presentations of cryptococcal infection have been described as manifestations of immune reconstitution in HIV-infected patients following introduction of antiretroviral therapy. We describe a patient presenting with cryptococcal meningitis as an immune reconstitution reaction 10 weeks after initiation of anti-retroviral therapy. Subclinical CSF cryptococcal infection was demonstrated and the serum cryptococcal antigen was negative.
OBJECTIVE: Cryptococcus neoformans infections of the central nervous system affect up to ten percent of AIDS patients. Standard therapy with amphotericin B with or without 5-flucytosine has a high rate of failure, relapse, and toxicity. Fluconazole is a new triazole antifungal agent available in both oral and intravenous forms that has shown efficacy in the primary and maintenance treatment of cryptococcal meningitis in AIDS patients. In this open, noncomparative trial, we evaluated the safety and efficacy of intravenous fluconazole followed by oral fluconazole in the treatment of acute cryptococcal meningitis in AIDS patients. METHODS: Thirteen AIDS patients with acute cryptococcal meningitis, or relapse after successful primary therapy, received 400 mg of intravenous fluconazole daily for 12-16 days followed by oral fluconazole 400 mg/d for the duration of primary therapy. If cerebrospinal fluid (CSF) cultures converted to negative within 32 weeks of treatment, the fluconazole dose was decreased to 200 mg/d as maintenance therapy. RESULTS: Fluconazole therapy was successful in six patients (46 percent) and unsuccessful in seven (54 percent). Of the seven patients considered unsuccessful, one demonstrated clinical improvement but remained CSF-culture positive, five were clinical failure and were switched to amphotericin B therapy, and one died after two weeks secondary to cryptococcal meningitis. No patient experienced any adverse reactions necessitating discontinuation of therapy. CONCLUSIONS: In this small group of patients, moderate doses of parenteral and oral fluconazole for acute cryptococcal meningitis in AIDS patients demonstrated failure rates similar to those reported in other studies with fluconazole and with amphotericin B. As there was no difference in initial Karnofsky scores or the severity of disease in treatment successes versus failures, it is difficult to determine who might respond to fluconazole as initial therapy or who should be treated initially with another agent. Further studies and clinical experience are needed.