Jan de Gans

Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series

BACKGROUND Bacterial meningitis is a grave disease of high incidence, especially in less developed countries. Here, we describe its clinical presentation, spectrum of complications, prognostic factors, and outcome in adults with pneumococcal meningitis. METHODS From October, 1998, to April, 2002, we assessed 352 episodes of community-acquired pneumococcal meningitis, confirmed by culture of cerebrospinal fluid (CSF), which occurred in patients older than 16 years. Predictors for an unfavourable outcome (Glasgow outcome scale score 1-4) were identified by logistic regression with multiple imputation techniques. FINDINGS 245 (70%) episodes of pneumococcal meningitis were associated with an underlying disorder. Cranial CT was done for 85% of episodes and revealed underlying disorders in 17% (50/299) and meningitis-associated intracranial complications in 39% (117/299). Independent predictors for an unfavourable outcome were a low score on the Glasgow coma scale, cranial nerve palsies, a raised erythrocyte sedimentation rate, a CSF leucocyte count less than 1000 cells per mm(3), and a high CSF protein concentration on admission. Overall in-hospital mortality was 30%. Prevalence of neurological and systemic complications did not differ between patients aged younger than 60 years and those aged 60 years and older; however, systemic complications were the cause of death in 59% (32/54) of fatal episodes in patients aged 60 years and older, whereas neurological complications were the cause of death in 65% (20/31) of fatal episodes in younger patients. INTERPRETATION Pneumococcal meningitis is associated with high mortality and morbidity rates in adults. Whereas neurological complications are the leading cause of death in younger patients, elderly patients die predominantly from systemic complications.

Steroids in adults with acute bacterial meningitis: a systematic review

Bacterial meningitis is uncommon but causes significant mortality and morbidity, despite optimum antibiotic therapy. A clinical trial in 301 patients showed a beneficial effect of adjunctive steroid treatment in adults with acute community-acquired pneumococcal meningitis, but data on other organisms or adverse events are sparse. This led us to do a quantitative systematic review of adjunctive steroid therapy in adults with acute bacterial meningitis. Five trials involving 623 patients were included (pneumococcal meningitis=234, meningococcal meningitis=232, others=127, unknown=30). Overall, treatment with steroids was associated with a significant reduction in mortality (relative risk 0.6, 95% CI 0.4-0.8, p=0.002) and in neurological sequelae (0.6, 0.4-1, p=0.05), and with a reduction of case-fatality in pneumococcal meningitis of 21% (0.5, 0.3-0.8, p=0.001). In meningococcal meningitis, mortality (0.9, 0.3-2.1) and neurological sequelae (0.5, 0.1-1.7) were both reduced, but not significantly. Adverse events, recorded in 391 cases, were equally divided between the treatment and placebo groups (1, 0.5-2), with gastrointestinal bleeding in 1% of steroid-treated and 4% of other patients. Since treatment with steroids reduces both mortality and neurological sequelae in adults with bacterial meningitis, without detectable adverse effects, routine steroid therapy with the first dose of antibiotics is justified in most adult patients in whom acute community-acquired bacterial meningitis is suspected.

Host genetic susceptibility to pneumococcal and meningococcal disease: a systematic review and meta-analysis

Streptococcus pneumoniae and Neisseria meningitidis can cause sepsis and meningitis. Several risk factors for pneumococcal and meningococcal disease have been identified, but the cause of basic differences in susceptibility between individuals and populations is unknown. Single-nucleotide polymorphisms are thought to explain interindividual differences in susceptibility. New technologies provide the opportunity to study the genetic basis of susceptibility to these diseases. In recent years, several studies have been published on these polymorphisms in pneumococcal and meningococcal disease, many with apparently conflicting results. Herein we provide a systematic overview of all polymorphisms studied for a relation with susceptibility to pneumococcal and meningococcal disease. We also propose an initiative to pool genetic data on pneumococcal and meningococcal meningitis in one biobank.

Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data

Summary Background Dexamethasone improves outcome for some patients with bacterial meningitis, but not others. We aimed to identify which patients are most likely to benefit from dexamethasone treatment. Methods We did a meta-analysis of individual patient data from the randomised, double-blind, placebo-controlled trials of dexamethasone for bacterial meningitis in patients of all ages for which raw data were available. The pre-determined outcome measures were death at the time of first follow-up, death or severe neurological sequelae at 1 month follow-up, death or any neurological sequelae at first follow-up, and death or severe bilateral hearing loss at first follow-up. Combined odds ratios (ORs) and tests for heterogeneity were calculated using conventional Mantel-Haenszel statistics. We also did exploratory analysis of hearing loss among survivors and other exploratory subgroup analyses by use of logistic regression. Findings Data from 2029 patients from five trials were included in the analysis (833 [41·0%] aged <15 years). HIV infection was confirmed or likely in 580 (28·6%) patients and bacterial meningitis was confirmed in 1639 (80·8%). Dexamethasone was not associated with a significant reduction in death (270 of 1019 [26·5%] on dexamethasone vs 275 of 1010 [27·2%] on placebo; OR 0·97, 95% CI 0·79–1·19), death or severe neurological sequelae or bilateral severe deafness (42·3% vs 44·3%; 0·92, 0·76–1·11), death or any neurological sequelae or any hearing loss (54·2% vs 57·4%; 0·89, 0·74–1·07), or death or severe bilateral hearing loss (36·4% vs 38·9%; 0·89, 0·73–1·69). However, dexamethasone seemed to reduce hearing loss among survivors (24·1% vs 29·5%; 0·77, 0·60–0·99, p=0·04). Dexamethasone had no effect in any of the prespecified subgroups, including specific causative organisms, pre-dexamethasone antibiotic treatment, HIV status, or age. Pooling of the mortality data with those of all other published trials did not significantly change the results. Interpretation Adjunctive dexamethasone in the treatment of acute bacterial meningitis does not seem to significantly reduce death or neurological disability. There were no significant treatment effects in any of the prespecified subgroups. The benefit of adjunctive dexamethasone for all or any subgroup of patients with bacterial meningitis thus remains unproven. Funding Wellcome Trust UK.

Cognitive Impairment in Adults with Good Recovery after Bacterial Meningitis

Adults without neurologic sequelae after bacterial meningitis are supposed to live without restrictions. Neuropsychological outcome was assessed in 51 adults from a prospective cohort with good recovery, defined as Glasgow Outcome Scale score 5, after pneumococcal or meningococcal meningitis. Patients who recovered well after pneumococcal meningitis showed cognitive slowness (P=.001). A cognitive disorder was found in 27% of these patients. Patients who previously had meningococcal meningitis were not significantly different from control subjects. Scores on general health and quality of life questionnaires revealed lower scores for patients with meningitis, which were related to cognitive slowing (R, -0.46 to -0.38). In conclusion, adults surviving pneumococcal meningitis were at significant risk of neuropsychological abnormalities, even if they were clinically well recovered.

Community-Acquired Listeria monocytogenes Meningitis in Adults

BACKGROUND Listeria monocytogenes is the third most common cause of bacterial meningitis. METHODS We prospectively evaluated 30 episodes of community-acquired L. monocytogenes meningitis, confirmed by culture of cerebrospinal fluid specimens, in a nationwide study in The Netherlands. Outcome was graded using the Glasgow outcome score; an unfavorable outcome was defined as a score of 1-4. RESULTS We found 30 episodes of L. monocytogenes meningitis. All patients were immunocompromised or > 50 years old. In 19 (63%) of 30 patients, symptoms were present for > 24 h; in 8 patients (27%), symptoms were present for > or = 4 days. The classic triad of fever, neck stiffness, and change in mental status was present in 13 (43%) of 30 patients. An individual cerebrospinal fluid indicator of bacterial meningitis was present in 23 (77%) of 30 cases. Gram staining of cerebrospinal fluid samples revealed the causative organism in 7 (28%) of 25 cases. The initial antimicrobial therapy was amoxicillin based for 21 (70%) of 30 patients. The coverage of initial antimicrobial therapy was microbiologically inadequate for 9 (30%) of the patients. The mortality rate was 17% (5 of 30), and 8 (27%) of 30 patients experienced an unfavorable outcome. Inadequate initial antimicrobial therapy was not related to outcome. CONCLUSIONS In contrast with previous reports, we found that patients with meningitis due to L. monocytogenes do not present with atypical clinical features; however, typical cerebrospinal fluid findings predictive for bacterial meningitis might be absent. A high proportion of patients received initial antimicrobial therapy that did not cover L. monocytogenes.

Cognitive outcome in adults after bacterial meningitis

Objective: To evaluate cognitive outcome in adult survivors of bacterial meningitis. Methods: Data from three prospective multicentre studies were pooled and reanalysed, involving 155 adults surviving bacterial meningitis (79 after pneumococcal and 76 after meningococcal meningitis) and 72 healthy controls. Results: Cognitive impairment was found in 32% of patients and this proportion was similar for survivors of pneumococcal and meningococcal meningitis. Survivors of pneumococcal meningitis performed worse on memory tasks (p<0.001) and tended to be cognitively slower than survivors of meningococcal meningitis (p = 0.08). We found a diffuse pattern of cognitive impairment in which cognitive speed played the most important role. Cognitive performance was not related to time since meningitis; however, there was a positive association between time since meningitis and self-reported physical impairment (p<0.01). The frequency of cognitive impairment and the numbers of abnormal test results for patients with and without adjunctive dexamethasone were similar. Conclusions: Adult survivors of bacterial meningitis are at risk of cognitive impairment, which consists mainly of cognitive slowness. The loss of cognitive speed is stable over time after bacterial meningitis; however, there is a significant improvement in subjective physical impairment in the years after bacterial meningitis. The use of dexamethasone was not associated with cognitive impairment.

Pneumococcal meningitis in adults: new approaches to management and prevention

Since the virtual eradication of meningitis due to Haemophilus influenzae type B by vaccination in the developed world, pneumococcal meningitis has become the leading cause of bacterial meningitis beyond the neonatal period. Clinical and experimental research has increased our knowledge about the pathophysiology and pathogenesis of the disease over the past decades. Despite the availability of effective antibiotics, supportive care facilities, and recent advances in adjunctive strategies-ie, adjunctive dexamethasone-mortality and morbidity rates associated with pneumococcal meningitis remain unacceptably high. Although preliminary results after the introduction of the pneumococcal conjugate vaccine are promising, the incidence of multidrug-resistant pneumococcal strains is rising worldwide. Here we discuss clinical aspects of pneumococcal meningitis in adults, with focus on pathophysiology, and stress the urgent need for adequate preventive measures and new effective treatments.

Clinical features, outcome, and meningococcal genotype in 258 adults with meningococcal meningitis: a prospective cohort study.

Abstract Meningococcal meningitis remains a life-threatening disease. Neisseria meningitidis is the leading cause of meningitis and septicemia in young adults and is a major cause of endemic bacterial meningitis worldwide. The Meningitis Cohort Study was a Dutch nationwide prospective observational cohort study of adults with community-acquired bacterial meningitis, confirmed by culture of cerebrospinal fluid, from October 1998 to April 2002. Patients underwent a neurologic examination at discharge, and outcome was graded with the Glasgow Outcome Scale. Serogrouping, multi-locus sequence typing, and susceptibility testing of meningococcal isolates were performed. The study identified 258 episodes of meningococcal meningitis in 258 patients. The prevalence of the classical triad of fever, neck stiffness, and change in mental status was low (70/258, 27%). When rash was added to the classical triad, 229 of 258 (89%) patients had at least 2 of 4 signs. Systolic hypotension was associated with rash (22/23 vs. 137/222, p = 0.002) and absence of neck stiffness (6/23 vs. 21/220, p = 0.05). Neuroimaging before lumbar puncture was an important cause of delay of therapy: antibiotics were not initiated before computed tomography (CT) scan in 85% of patients who underwent CT scan before lumbar puncture. Unfavorable outcome occurred in 30 of 258 (12%) patients, including a mortality rate of 7%. Neurologic sequelae occurred in 28 of 238 (12%) patients, particularly hearing loss (8%). Factors associated with sepsis and infection with meningococci of clonal complex 11 (cc11) are related with unfavorable outcome. Abbreviations: cc = clonal complex, CRP = C-reactive protein, CSF = cerebrospinal fluid, CT = computed tomography, ESR = erythrocyte sedimentation rate, GCS = Glasgow Coma Scale, IQR = interquartile range, MLST = multi-locus sequence typing, WBCC = white blood cell count.

Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]

BackgroundThe treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question.DesignGACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage.Conclusion372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients.Trial RegistrationCurrent Controlled TrialsISRCTN45122933