J. de Gans

Declining incidence of AIDS dementia complex after introduction of zidovudine treatment

OBJECTIVE--To assess the incidence of the AIDS dementia complex and the presence of HIV I p24 antigen in cerebrospinal fluid in relation to zidovudine treatment. DESIGN--Retrospective study of a consecutive series of patients with AIDS from 1982 to 1988. SETTING--An academic centre for AIDS. PATIENTS--196 Patients with AIDS and neurological symptoms examined from 1982 to 1988. INTERVENTIONS--Zidovudine treatment, which was introduced to The Netherlands on 1 May 1987 for patients with severe symptoms of HIV infection (Centers for Disease Control groups IVA, B, C, and D). MAIN OUTCOME MEASURES--Diagnosis of AIDS dementia complex and presence of HIV I p24 antigen in cerebrospinal fluid. RESULTS--The AIDS dementia complex was diagnosed in 40 of the 196 (20%) patients with AIDS. Thirty eight of 107 patients with AIDS (36%) not taking zidovudine developed the AIDS dementia complex compared with two of the 89 (2%) taking the drug (p less than 0.00001). The incidence of the AIDS dementia complex increased to 53% in the first half of 1987, after the introduction of zidovudine in May 1987, decreasing to 10% in the second half of 1987 and to 3% in 1988. Dementia was diagnosed before definition of the AIDS dementia complex (1986) according to DSM-III criteria and there was good agreement between diagnosis before and after 1986. Sixteen of 61 samples of cerebrospinal fluid (26%) from patients with AIDS (10 with the AIDS dementia complex) not taking zidovudine were positive for HIV I p24 antigen, whereas none of 37 cerebrospinal fluid samples from patients with AIDS (two with the AIDS dementia complex) taking zidovudine were positive. CONCLUSIONS--The incidence of AIDS dementia complex in patients with AIDS declined after the introduction of systematic treatment with zidovudine; the AIDS dementia complex might be prevented by inhibiting viral replication in the central nervous system.

Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos.

Abstract We carried out a meta-analysis of 22 trials to determine ¶the comparative placebo effect of ¶(a) subcutaneous vs. oral and (b) in-hospital vs. at-home administration in the treatment of migraine. The headache relief rates were combined from the placebo arms of these randomised clinical trials assessing the value of sumatriptan in acute treatment of migraine. The main outcome measure was the proportion of patients reclassified from severe or moderate headache severity to no or mild headache severity 2 h after the beginning of treatment. In the oral regimen 222 of 865 patients (25.7%) reported no or mild headache severity after 2 h, compared to 279 of ¶862 patients (32.4%) of those receiving subcutaneous placebo (6.7% difference; 95% CI 2.4–11.0%). Adjusting for treatment setting and severity of headache at baseline did not change the observed difference. After placebo treatment at home 285 ¶of 1054 patients (27.0%) reported no or mild headache severity after 2 h, compared to 216 of 673 patients (32.1%) among those receiving placebo in hospital (5.1% difference; 95% CI 0.6–9.5%). When adjusted for route of administration and severity of headache at baseline, the difference in relief rates between home and hospital setting disappeared. These findings indicate that subcutaneous administration enhances the placebo effect of acute treatment of migraine. Future trials of antimigraine drugs assessing the relative efficacy of various routes of administration should use a double-dummy technique. The interpreting of placebo-controlled trial results must therefore consider that the effect in the drug arm of the trial depends in part on the route of administration.

Lumbar puncture and the risk of herniation: when should we first perform CT?

Abstract Death following lumbar puncture (LP) is feared by physicians. Many opinions are found in literature on the question whether computed cranial tomography (CT) should be performed before LP, to prevent herniation. These opinions are mainly based on retrospective studies and pathophysiological reasoning.In this review the difficulties in the decision whether we should perform CT before LP are discussed. It is explained that the concept of “raised intracranial pressure” is confusing, and that the less ambiguous terms “brain shift” and “raised CSF pressure” should be used instead. Brain shift is a contraindication to LP, whether CSF pressure is raised or not, and whether papilloedema is present or not. Subsequently, recommendations are offered for indications to perform CT before LP, grouped according to the safety and clinical utility of LP.

Presentation and course of AIDS dementia complex: 10 years of follow-up in Amsterdam, The Netherlands

ObjectiveTo assess the clinical presentation and course of the AIDS dementia complex (ADC). DesignRetrospective study of a consecutive series of symptomatic HIV-1 -infected patients [Centers for Disease Control and Prevention (CDC) stages IVA, B, C and D] evaluated for neurological symptoms between 1982 and 1992. SettingAn academic referral centre for AIDS. PatientsA total of 536 symptomatic HIV-1-infected patients evaluated for neurological symptoms between 1982 and 1992. InterventionsZidovudine treatment, which was introduced in The Netherlands on 1 May 1987 for patients with severe symptoms of HIV infection (CDC stages IVA, B, C and D). Main outcome measuresDiagnosis of ADC and CD4 cell count, clinical features, neuropsychological abnormalities, computed tomography (CT) and magnetic resonance imaging (MRI) abnormalities, cerebrospinal fluid (CSF) findings and course in patients with ADC. ResultsADC was diagnosed in 40 out of 536 (7.5%) immunosuppressed, neuroiogically symptomatic HIV-1-infected patients in CDC stage IV, and was the AIDS-defining illness in six. The mean CD4 cell count of the 40 patients with ADC was 109 χ 106/1. Neuropsychological abnormalities in 15 out of 17 patients tested were in accordance with subcortical dementia. On CT scan of the brain, 70% showed no or only mild cortical atrophy. MRI was more sensitive than CT scan for detecting white matter abnormalities (73 versus 35%; P = 0.02). CSF examination showed mononuclear pleocytosis in 25%, protein level increase in 55%, and HIV-1 p24 core protein in 38% (13 out of 34). The mean survival was 6.7 months in the 40 ADC patients, but 4 months in 20 patients who had never used zidovudine, compared with 14.8 months in 10 patients who started zidovudine after they were classified as having ADC (P < 0.001). Three of these 10 patients improved remarkably, and two slightly, after starting zidovudine. ADC developed after discontinuation of zidovudine in nine patients. Only one patient developed ADC while receiving 600 mg zidovudine. ConclusionsMRI is more sensitive than CT for detecting white matter abnormalities. To date, there is no specific or sensitive CSF marker for ADC. Zidovudine may improve symptoms and prolong survival in patients with ADC, which rarely developed with continued zidovudine use in our study.

Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis

Background: In this nationwide prospective cohort study, we evaluated the implementation of adjunctive dexamethasone therapy in Dutch adults with pneumococcal meningitis. Methods: From March 2006 through January 2009, all Dutch patients over 16 years old with community-acquired pneumococcal meningitis were prospectively evaluated. Outcome was classified as unfavorable (defined by a Glasgow Outcome Scale score of 1 to 4 points at discharge) or favorable (a score of 5). Clinical characteristics and outcome were compared with a similar nationwide cohort of 352 patients with pneumococcal meningitis from a previous period before guidelines recommended dexamethasone therapy (1998–2002). A multivariable prognostic model was used to adjust for differences in case mix between the 2 cohorts. Results: We evaluated 357 episodes with pneumococcal meningitis in 2006–2009. Characteristics on admission were comparable with the earlier cohort (1998–2002). Dexamethasone was started with or before the first dose of antibiotics in 84% of episodes in 2006–2009 and 3% in 1998–2002. At discharge, unfavorable outcome was present in 39% in 2006–2009 and 50% in 1998–2002 (odds ratio [OR] 0.63; 95% confidence interval [CI] 0.46–0.86; p = 0.002). Rates of death (20% vs 30%; p = 0.001) and hearing loss (12% vs 22%; p = 0.001) were lower in 2006–2009. Differences in outcome remained after adjusting for differences in case mix between cohorts. Conclusions: Dexamethasone therapy has been implemented on a large scale as adjunctive treatment of adults with pneumococcal meningitis in the Netherlands. The prognosis of pneumococcal meningitis on a national level has substantially improved after the introduction of adjunctive dexamethasone therapy. Classification of evidence: This study provides Class III evidence that dexamethasone (10 mg IV, given every 6 hours for 4 days started before or with the first dose of parenteral antibiotics) reduced the proportion of patients with unfavorable outcomes (Glasgow Outcome Scale score of 1 to 4) in the 2006–2009 cohort, as compared to the 1998–2002 cohort (39% vs 50%; OR 0.63; 95% CI 0.46–0.86; p = 0.002). Mortality rate (20% vs 30%; absolute risk difference 10%; 95% CI 4%–17%; p = 0.001) was also lower in 2006–2009.

Itraconazole compared with amphotericin B plus flucytosine in Aids patients with cryptococcal meningitis

ObjectiveWe conducted a comparison of itraconazole versus amphotericin B plus flucytosine in the initial treatment of cryptococcal meningitis in patients with AIDS and established the efficacy of itraconazole as maintenance treatment. DesignThe trial was a prospective, randomized, and non-blinded study.Setting: The study was performed at an academic centre for AIDS, Amsterdam, The Netherlands. Patients, participantsTwenty-eight HIV-1-seropositive men with a presumptive diagnosis of cryptococcal meningitis, randomized between 5 February 1987 and 1 January 1990, were included for analysis. InterventionsOral itraconazole (200 mg twice daily), versus amphotericin B (0.3 mg/kg daily) intravenously plus oral flucytosine (150 mg/kg daily) was administered for 6 weeks followed by maintenance therapy with oral itraconazole (200 mg daily) to all patients. Main outcome measuresOutcome measures were a complete or partial response, recrudescence and relapse. ResultsA complete response was observed in five out of the 12 patients who completed 6 weeks of initial treatment with itraconazole versus all 10 patients who completed treatment with amphotericin B plus flucytosine (P = 0.009). A partial response was observed in seven out of the 14 patients assigned to itraconazole. During maintenance therapy, recrudescence (n = 6) or relapse (n = 1) occurred in seven out of the 12 patients initially assigned to itraconazole, whereas two relapses occurred among nine patients initially treated with amphotericin B plus flucytosine (P = 0.22); recurrence of clinical symptoms was significantly related to a positive cerebrospinal fluid culture at 6 weeks (P = 0.003). ConclusionItraconazole is less effective compared with amphotericin B plus flucytosine in achieving a complete response in initial therapy in AIDS patients with cryptococcal meningitis.

Seizures in adults with bacterial meningitis

Objective: To evaluate the occurrence and prognostic relevance of seizures in adults with community-acquired bacterial meningitis. Methods: An observational cross-sectional study, in which patients with seizures are selected from a prospective nationwide cohort of 696 episodes of community-acquired bacterial meningitis, confirmed by culture of CSF in patients aged >16 years. We retrospectively collected data on EEGs. Results: Seizures occurred in 121 of 696 episodes (17%). Death occurred in 41% of patients with seizures compared to 16% of patients without seizures (p < 0.001). The median number of seizures was 2 (interquartile range [IQR] 1 to 4). The median time between admission and the first seizure was 1 day (IQR 0 to 3). Patients with in-hospital seizures were more likely to have a CSF leukocyte count below 1,000 cells/mm3 (36% vs 25%; p = 0.01), had higher median CSF protein levels (4.8 g/L [IQR 3.4 to 7.6] vs 4.1 g/L [IQR 2.1 to 6.8]), and higher median erythrocyte sedimentation rate (46 mm/hour [IQR 31 to 72] vs 36 mm/hour [IQR 18 to 69]; p = 0.02) than patients without in-hospital seizures. Focal cerebral abnormalities developed more often in patients with in-hospital seizures than in those without (41% vs 14%; p < 0.001). In a multivariate analysis, seizures were significantly more likely in patients with predisposing conditions, tachycardia, a low Glasgow Coma Scale score on admission, infection with Streptococcus pneumoniae, and focal cerebral abnormalities. Neuroimaging was performed on admission in 70% of episodes with prehospital seizures, with CT revealing a focal lesion in 32% of those episodes. Antiepileptic drugs were administered in 82% of patients with seizures and EEG was performed in 31% of episodes; a status epilepticus was recorded in five patients. Conclusions: Seizures occur frequently in adults with community-acquired bacterial meningitis. Seizures are associated with severe CNS and systemic inflammation, structural CNS lesions, pneumococcal meningitis, and predisposing conditions. The high associated mortality rate warrants a low threshold for starting anticonvulsant therapy in those with clinical suspicion of a seizure.

Delayed cerebral thrombosis after initial good recovery from pneumococcal meningitis.

Objective: To report an unusual clinical course in 6 patients with community-acquired acute bacterial meningitis and to compare clinical features with cases reported in the literature. Methods: Case series from Dutch hospitals from 2003 to 2008. Results: Five out of six patients were male, age ranged from 30 to 73 years (mean age, 47 years). All patients had pneumococcal meningitis, received adjunctive dexamethasone treatment on admission, and made a good or excellent initial recovery. After 7 to 19 days, patients suddenly deteriorated, developing headache, fever, a decreased level of consciousness, brainstem signs, or hemiparesis. Imaging studies showed infarctions involving the thalamus or brainstem in all patients. Repeated lumbar puncture showed a pleocytosis, but CSF cultures were sterile. Five patients were treated with high-dose steroids on deterioration. Outcome was poor: 4 patients died and 2 remained disabled. Autopsies, performed in 2 patients, showed infarctions predominantly involving the posterior circulation territory, thrombosis in penetrating arteries, but no evidence of vasculitis. We identified 5 meningitis cases with delayed vasculopathy in the literature, but these patients did not exactly resemble the clinical course of our patients. Conclusions: Delayed cerebral thrombosis may occur in patients with excellent recovery from pneumococcal meningitis. All patients were treated initially with adjunctive dexamethasone therapy, suggesting a dexamethasone-associated effect. Pathology suggests an immunologic reaction targeting cerebral blood vessels.

Meningitis due to viridans streptococci in adults

Abstract Seven patients are reported with meningitis due to viridans streptococci. These patients represented 5% of culture-proven cases of bacterial meningitis in adults participating in a prospective multicentre clinical trial evaluating the use of dexamethasone. Meningitis was iatrogenic in three patients: one patient had been treated with endoscopic sclerotherapy for oesophageal varices, and two patients had undergone thermocoagulation of the gasserian ganglion for trigeminal neuralgia in the previous days.

Dexamethasone treatment in adults with pneumococcal meningitis: risk factors for death

In experimental meningitis, adjunctive treatment with steroids reduces cerebrospinal fluid inflammation and thereby improves neurological outcome. On the basis of these findings, several clinical trials have assessed treatment with adjunctive steroids in bacterial meningitis, with conflicting results. Recently, the results of the European Dexamethasone Study showed a beneficial effect of adjunctive dexamethasone in adults with bacterial meningitis. In that study, the effect of dexamethasone on outcome was most striking in patients with pneumococcal meningitis. The aim of the present study was to further evaluate the effect of dexamethasone in adults with pneumococcal meningitis by performing a post hoc analysis of the European Dexamethasone Study. In a multivariate analysis, tachycardia (p=0.02), advanced age (p=0.03), low score on the Glasgow Coma Scale (p=0.03), positive blood culture (p=0.04), and absence of dexamethasone therapy (p=0.05) were independent predictors for death. Patients who were treated with adjunctive dexamethasone were less likely to develop both systemic and neurological complications during hospitalisation, compared with patients who received placebo. In conclusion, independent risk factors for death in pneumococcal meningitis are tachycardia, advanced age, low level of consciousness, bacteraemia, and absence of dexamethasone therapy. Treatment with adjunctive dexamethasone in adults with pneumococcal meningitis reduces both systemic and neurological complications.