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Complications and outcome of bacterial meningitis

Lucas, M.J.

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39833 Lucas, Marjolein Cover en uitn kaart.indd 1 26-04-16 12:39

Complications and outcomeof bacterial meningitis

Marjolein J. Lucas

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Cover design Ferdinand van Nispen tot Pannerden, Citroenvlinder DTP&Vormgeving, my-thesis.nlLay out Ferdinand van Nispen tot Pannerden, Citroenvlinder DTP&Vormgeving, my-thesis.nlPrinted by GVO drukkers & vormgevers B.V., Ede, the Netherlands

ISBN 978-94-6332-024-5

Financial support by the Dutch Heart Foundation for the publication of this thesis is gratefully acknowledged.Printing of this thesis was financially supported by the department of Neurology of the Academic Medical Center, University of Amsterdam, Pfizer BV, Chipsoft, de Nederlandse Meningitis Stichting and TAKE2Development.

© 2016, Marjolein J. Lucas All rights reserved. No parts of this thesis may be reproduced or transmitted in any form or by any means, without permission of the author.

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Complications and outcomeof bacterial meningitis

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. D.C. van den Boom

ten overstaan van een door het College voor Promoties ingestelde

commissie, in het openbaar te verdedigen in de Agnietenkapel

op vrijdag 17 juni 2016, te 12.00 uur

doorMarjolein José Lucas

geboren te Rotterdam

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Promotiecommissie:

Promotor: Prof. dr. D. van de Beek, Universiteit van AmsterdamCo-promotor: Dr. M.C. Brouwer, Universiteit van Amsterdam

Overige leden: Prof. dr. A.M. van Furth, Vrije Universiteit Prof. dr. P. Portegies, Universiteit van Amsterdam Prof. dr. J.M. Prins, Universiteit van Amsterdam Prof. dr. Y.B.W.E.M. Roos, Universiteit van Amsterdam Prof. dr. J. Stam, Universiteit van Amsterdam Prof. dr. C.M.J.E. Vandenbroucke-Grauls, Vrije Universiteit

Faculteit der Geneeskunde

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Contents

Chapter 1 Introduction 7

Chapter 2 Community-acquired bacterial meningitis in 13 adults in the Netherlands, 2006-14: a prospective cohort study Lancet Infectious Diseases 2015, published online

Chapter 3 Cerebral infarction in adults with bacterial meningitis 37 Neurocritical Care 2012; 16: 421–427

Chapter 4 Delayed cerebral thrombosis in bacterial meningitis: 51 a prospective cohort study Intensive Care Medicine 2013; 39: 866-71

Chapter 5 Endocarditis in adults with bacterial meningitis 63 Circulation 2013; 127: 2056-62

Chapter 6 Group A Streptococcal meningitis in adults 79 Journal of Infection 2015; 71: 37-42

Chapter 7 Outcome in patients with bacterial meningitis 93 presenting with a minimal Glasgow Coma Scale score Neurology: Neuroimmunology & Neuroinflammation 2014; 1: e9

Chapter 8 General discussion: neurological sequelae of 109 bacterial meningitis Submitted

Summary 131Samenvatting (Dutch) 137Dankwoord (Dutch) 143Curriculum vitae 149Portfolio 153List of publications 157

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CHAPTER 1

INTRODUCTION

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Introduction

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1Bacterial meningitis is a serious infection of the central nervous system. During bacterial meningitis bacteria enter the subarachnoid space and brain parenchyma via the bloodstream or by direct invasion through the external barrier, such as the ear or sinuses. Invasion of bacteria triggers the release of cytokines, which induce a cascade of inflammatory reactions, resulting in severe inflammation of the meninges surrounding the brain and the spinal cord, leading to a life threatening disease.1

In 1975 the Netherlands reference laboratory was established to monitor the epidemiology of bacterial meningitis. This laboratory collects cerebrospinal fluid (CSF) and blood isolates from approximately 90% of all patients with bacterial meningitis in the Netherlands. Data from this laboratory showed a change in epidemiology of bacterial meningitis in the past 25 years due to the implementation of vaccination against Haemophilus influenzae type B, Neisseria meningitidis group C and most recently, the pneumococcal conjugate vaccines. Due to these vaccines the incidence of bacterial meningitis in the Netherlands had reduced and meningitis is now predominantly a disease occurring in adults.2 Currently, the estimated incidence of bacterial meningitis is 0.94-2.6 per 100.000 adults per year in developed countries and can be up to 10 times higher in less developed countries. The predominant causative pathogens beyond the neonatal age are Streptococcus pneumoniae and N. meningitidis, responsible for 80-85% of bacterial meningitis cases in Europe and the United States.3-6

Following the introduction of adjunctive dexamethasone treatment, outcome and clinical course of bacterial meningitis has improved. Nevertheless, a large proportion of patients develop neurological and systemic complications; especially cerebrovascular complications are common in patients with bacterial meningitis. These complications lead to high mortality and morbidity rates, with mortality rates up to 30% for pneumococcal meningitis and 10% for meningococcal meningitis.6

To define the clinical characteristics of bacterial meningitis in adults following the introduction of different vaccines and adjunctive dexamethasone treatment, two prospective nationwide cohort studies were performed in the Netherlands. The first cohort study was performed between 1998 and 2002, another ongoing study started in 2006. We collected data on patient’s history, symptoms and signs on admission, laboratory findings at admission, clinical course, treatment, outcome and neurologic findings at discharge.

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In this thesis we describe the clinical characteristics, complications and outcome of community-acquired bacterial meningitis patients from these nationwide cohort studies. In chapter 2 we describe the changing incidence of adult bacterial meningitis from 2006 to 2014, including clinical features, prognostic factors and microbiological characteristics of pathogens. Cerebrovascular complications are common in bacterial meningitis, particularly in patients with pneumococcal meningitis. The inflammatory response in bacterial meningitis results in activation of coagulation and inhibition of fibrinolysis, leading to cerebral infarction. Chapter 3 describes the clinical features and prognostic factors of cerebral infarction in bacterial meningitis identified in our prospective nationwide cohort study from 1998-2002. In chapter 4, a rare but devastating cerebrovascular complication of bacterial meningitis is described; delayed cerebral thrombosis. Patients with delayed cerebral thrombosis made good initial recovery, followed by sudden deterioration after 7-42 days caused by multiple cerebral infarctions.

Bacterial meningitis patients often present with another focus of infection outside the central nervous system such as pneumonia, sinusitis, or otitis.3, 7 In chapter 5 we describe an uncommon focus of bacterial meningitis; infective endocarditis. Endocarditis may precede or complicate bacterial meningitis, and was associated with a high rate of unfavorable outcome. Group A streptococcus (GAS) has been described as an uncommon cause of bacterial meningitis. In chapter 6 we show a doubling in cases with GAS meningitis in our prospective nationwide cohort study in the Netherlands in 2013. We found that GAS meningitis occurs in patients with preceding sinusitis and mastoiditis, and is associated with severe intracranial and systemic complications leading to a high mortality rate.

Many patients with bacterial meningitis have an abnormal conscious state upon presentation, and 15-20% is comatose. An abnormal conscious state is known as a strong predictor for poor disease outcome.6 Chapter 7 describes a small minority of bacterial meningitis patients presenting with a minimal score on the Glasgow Coma Scale. Although the majority of these patients have an unfavorable outcome and many patients died, 1 out of 5 of these severely ill patients will make a full recovery. In chapter 8 we conclude with a general discussion, which gives an overview of occurrence and impact of neurological sequelae after pneumococcal and meningococcal meningitis in adults and children. We conclude that early identification of neurological sequelae is very important for children to prevent further developmental delay, and for adults to achieve a successful return in society after bacterial meningitis.

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1References

1. Koedel U, Scheld WM, Pfister HW. Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect Dis 2002; 2: 721-36.

2. Tunkel AR. Bacterial Meningitis. Philadelphia: Lippincott, Williams & Wilkins; 2001. 3. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF. Community-acquired bacterial meningitis in

adults. N Engl J Med 2006; 354: 44-53.4. van de Beek D. Progress and challenges in bacterial meningitis. Lancet 2012; 380: 1623-4.5. Schuchat A, Robinson K, Wenger JD et al. Bacterial meningitis in the United States in 1995. Active

Surveillance Team. N Engl J Med 1997; 337: 970-6.6. Bijlsma MW, Brouwer MC, Kasanmoentalib ES et al. Community-acquired bacterial meningitis in

adults in the Netherlands, 2006-14: a prospective cohort study. Lancet Infect Dis. 2015; pii: S1473-3099(15)00430-2.

7. van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351: 1849-59.

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CHAPTER 2

COMMUNITY-ACQUIRED BACTERIAL MENINGITIS IN ADULTS

IN THE NETHERLANDS, 2006-14: A PROSPECTIVE COHORT STUDY

Merijn W. Bijlsma, Matthijs C. Brouwer*, E. Soemirien Kasanmoentalib*, Anne T. Kloek*, Marjolein J. Lucas*, Michael W. Tanck*,

Arie van der Ende*, Diederik van de Beek*authors contributed equally

Lancet Infectious Diseases 2015; published online

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Abstract

Background We studied causative pathogens, clinical characteristics, and outcome of adult community-acquired bacterial meningitis after the introduction of adjunctive dexamethasone treatment and nationwide implementation of paediatric conjugate vaccines.

Methods In this cohort study, we prospectively assessed adults (age >16 years) with community-acquired bacterial meningitis in the Netherlands, identified through the National Reference Laboratory for Bacterial Meningitis or individual physicians between Jan 1, 2006, and July 1, 2014. We identified independent predictors of an unfavorable outcome (Glasgow Outcome Scale score 1-4) by logistic regression.

Findings We assessed 1412 episodes of community-acquired bacterial meningitis. Incidence declined from 1.72 cases per 100.000 adults per year in 2007-08, to 0.94 per 100.000 per year in 2013-14. Streptococcus pneumoniae caused 1017 (72%) of 1412 episodes. Rates of adult bacterial meningitis decreased most sharply among pneumococcal serotypes included in paediatric conjugate vaccine, and in meningococcal meningitis. We found no evidence of serotype or serogroup replacement. The overall case fatality rate was 244 (17%) of 1412 episodes and unfavorable outcome occurred in 531 (38%) of 1412 episodes. Predictors of unfavorable outcome were advanced age, absence of otitis or sinusitis, alcoholism, tachycardia, lower score on the Glasgow Coma Scale, cranial nerve palsy, a cerebrospinal fluid white cell count lower than 1000 cells per μL, a positive blood culture, and a high serum C-reactive protein concentration. Adjunctive dexamethasone was administered for 1234 (89%) of 1384 assessed episodes. The multivariable adjusted odds ratio of dexamethasone treatment for unfavorable outcome was 0.54 (95% CI 0.39-0.73).

Interpretation The incidence of adult bacterial meningitis has decreased substantially, which is partly explained by herd protection by paediatric conjugate vaccines. Adjunctive dexamethasone treatment was associated with substantially improved outcome.

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Community-acquired bacterial meningitis

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2

Introduction

Bacterial meningitis is associated with substantial mortality and morbidity.1 The epidemiology and treatment of bacterial meningitis has changed over the past 15 years.2, 3 The routine use of protein-polysaccharide conjugate vaccines in childhood against common causative pathogens of bacterial meningitis has reduced the overall incidence, affecting the distributions of causative pathogens and the age groups most often affected.2, 4 The introduction of new treatments, such as dexamethasone as adjunctive treatment, might have affected national outcomes of bacterial meningitis.5, 6 In 2006, we started a prospective cohort study to identify and characterize host genetic traits and bacterial genetic factors controlling occurrence and outcome of bacterial meningitis (MeninGene).7-19 Here, we report data from this study, including the incidence, causative pathogens, clinical features, and prognostic factors in adults with community-acquired bacterial meningitis in the Netherlands from 2006 to 2014.

Methods

Study populationWe identified adults (patients older than age 16 years) who had bacterial meningitis in the Netherlands between Jan 1, 2006, and July 1, 2014, and who were listed in the database of the Netherlands Reference Laboratory for Bacterial Meningitis. This laboratory receives cerebrospinal fluid and blood samples from roughly 85% of all patients with bacterial meningitis in the Netherlands (population 16.9 million).20, 21 The laboratory provided daily updates of the names of hospitals where patients with bacterial meningitis have been admitted in the preceding 2-6 days, and the names of the attending physicians, usually neurologists. Physicians were informed about the study by telephone. Physicians could also contact investigators at any time to include patients, without preceding report of the reference laboratory. Subsequently, patients or their legal representatives received written information about the study and were asked to give written informed consent for participation. Online case record forms were used to collect data on patient’s history, symptoms and signs on admission, laboratory findings at admission, clinical course, outcome and neurological findings at discharge, and treatment. Before the study, all Dutch neurologists received information about the study, which was followed up by periodic reminders.

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We defined bacterial meningitis as a bacterial pathogen cultured in cerebrospinal fluid, or the combination of a positive PCR or antigen test in cerebrospinal fluid for Streptococcus pneumoniae or Neisseria meningitidis with at least one specific cerebrospinal fluid finding predictive of bacterial meningitis (according to the criteria of Spanos and colleagues:22 glucose concentration <340 mg/L [1.9 mmol/L], cerebrospinal fluid glucose: blood glucose ratio <0.23, protein concentration >2200 mg/L, white cell count >2000 cells per μL, or >1180 poly morphonuclear leucocytes per μL). We excluded episodes of hospital-acquired meningitis, defined as bacterial meningitis that occurred while in hospital or within 1 week after discharge.23 We also excluded patients with head trauma or neurosurgery in the previous month, or those with a neurosurgical device or missing outcome.

ProceduresNeurological examinations were done at admission and at discharge. Outcome was scored by the Glasgow Outcome Scale score:24 1=death, 2=vegetative state (unable to interact with the environment), 3=severe disability (unable to live independently but can follow commands), 4=moderate disability (capable of living independently but unable to return to work or school), and 5=mild or no disability (able to return to work or school). A favorable outcome was defined as a score of 5, and an unfavorable outcome as a score of 1-4.

Statistical analysisWe calculated the incidence of community-acquired meningitis as the number of new episodes per epidemiological year (July 1-June 30) per 100.000 adult patients (>16 years old on Jan 1). We tested bacterial susceptibility as previously described.25

N. meningitidis was considered susceptible to penicillin if the minimum inhibitory concentration (MIC) was 0.06 μg/mL or less. Reduced susceptibility was defined as a MIC of 0.06-1.0 μg/mL before 2010, and 0.06-0.25 μg/mL after 2010. Penicillin resistance was defined as a MIC of more than 1.0 μg/mL before 2010, and more than 0.25 μg/mL after 2010. S. pneumoniae was considered to be sensitive to penicillin if the MIC was 0.06 μg/mL or less and resistant if MIC was more than 0.06 μg/mL. We did meningococcal serogrouping and multi locus sequence typing, and pneumococcal serotyping, as previously described.21, 26, 27

Categorical variables are expressed as counts (percentage) and we compared frequency distributions with the Fisher exact test. Continuous variables are

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expressed as median (IQR). We tested differences with the independent t test for normally distributed variables or the Mann-Whitney U test otherwise. We tested trends in the incidence of pneumococcal serotypes with linear regression using incidence per 100.000 adults as the dependent variable and epidemiological year as the independent variable. We chose possible predictors of an unfavorable outcome on the basis of previous research, pathophysiological interest, and availability early in the course of the illness. We investigated the association between these predictors and outcomes with logistic regression, providing odds ratios (OR’s) and 95% CI’s. We assessed the linearity of the association between continuous predictors and outcome with the Hosmer-Lemeshow goodness of fit test and by visual inspection. If there was no linear relationship, the continuous predictor was categorized for further analyses. We estimated both univariable crude OR’s and multivariable OR’s corrected for all other variables in the model. We used multiple imputation for missing data in the multivariable analysis. We used all predictors together to impute missing values using the Mice package (version 2.22). We combined the coefficients of 60 rounds of imputation to obtain the final estimates for the multivariable model. The statistical tests were two-tailed, and we deemed p values of less than 0.05 as statistically significant. We did the imputation and all statistical analyses in R (version 3.0.1).

Role of the funding sourceThe sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Research in context

Evidence before this studyWe searched PubMed for the terms “bacterial meningitis” and “community-acquired infections” or “immunity, herd” or “dexamethasone/therapeutic use”. Serogroup A and C meningococcal conjugate vaccination reduces carriage and disease in both vaccinated and unvaccinated populations. The importance of herd protection has also become clear in meningitis due to Haemophilus influenzae type B and invasive pneumococcal disease. Serotype replacement by pneumococcal

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serotypes not included in the vaccine has been shown by several studies. In 2004, clinical features and prognostic factors for community-acquired bacterial meningitis were described in 696 Dutch adults. The mortality associated with bacterial meningitis was high, and the strongest risk factors for an unfavorable outcome were those that are indicative of systemic compromise, a low level of consciousness, and infection with Streptococcus pneumoniae. A randomized controlled study showed that adjunctive treatment with corticosteroids decreased the rate of unfavorable outcome and mortality in adults with community-acquired bacterial meningitis. In a meta-analysis of individual patient data from five clinical trials in bacterial meningitis, adjunctive dexamethasone did not significantly reduce death or neurological disability. A recent Cochrane review showed that corticosteroids were associated with decreased hearing loss and neurological sequelae.

Added value of this studyOur cohort study shows the epidemiology, clinical practice, prognostic factors, and outcome in adults with community-acquired bacterial meningitis. After the introduction of conjugate vaccines in children, the incidence of serogroup C meningococcal meningitis and vaccine type pneumococcal meningitis has declined substantially in non-immunized adults. Contrary to previous publications, we found no evidence of pneumococcal serotype replacement. Outcome has improved substantially after the introduction of adjunctive dexamethasone treatment, and was associated with better outcome in both pneumococcal and non-pneumococcal episodes.

Implications of all the available evidenceProgress has been made in the prevention and treatment of community-acquired bacterial meningitis. Herd protection is a major part of the effectiveness of conjugate vaccines and can protect those with poor immunological response to vaccination - e.g., infants and elderly people. The development of vaccines covering more pneumococcal serotypes, new potent anti-inflammatory treatments, immediate start of treatment, and aggressive supportive care might further improve the prognosis of patients with bacterial meningitis.

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Figure 1. Selection of patients.

Results

1887 episodes of bacterial meningitis were identified, 1736 (92%) by the reference laboratory and 151 (8%) by physicians (Figure 1). 240 (13%) of 1887 episodes were excluded from the cohort and 235 (12%) met exclusion criteria, resulting in 1412 (75%) episodes in 1391 patients (Figure 1).

Median age was 61 years (Table 1). A history of splenectomy or cerebrospinal fluid leak was present in 71 (5%) of 1374 episodes. For 457 (33%) of 1380 episodes, the patient had used immunosuppressive drugs or had a history of cancer, diabetes, HIV, or alcoholism. Extra-meningeal foci of infection (otitis, sinusitis, pneumonia, or endocarditis) were present in 598 (42%) of 1412 episodes, and were more likely

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to occur in episodes of pneumococcal meningitis (518 [51%] of 1008) than in meningococcal meningitis (nine [6%] of 150) or listeria meningitis (eight [11%] of 74). Headache, neck stiffness, fever, and a change in mental status were common symptoms at presentation (Table 1). The classic triad of fever, altered mental status, and neck stiffness was present in 563 (41%) of 1389 episodes. Rash was noted in 116 (8%) of 1412 episodes, of which 70 (60%) episodes were meningococcal meningitis and 34 (29%) were pneumococcal meningitis. The rash was petechial or consisted of purpura or ecchymosis in 69 (99%) of the 70 meningococcal cases and in 25 (74%) of 34 pneumococcal cases with a rash.

At least one specific cerebrospinal fluid finding predictive of bacterial meningitis was present in 1229 (96%) of 1277 episodes with data available. Cranial imaging was done on admission for 1206 (86%) of 1402 episodes with data available and abnormalities were recorded in 561 (47%) of 1206 episodes, most commonly sinusitis or mastoiditis (386 [34%] of 1125 episodes in which otitis or sinusitis was evaluated), brain edema (118 [10%] of 1165 episodes), and hydrocephalus (58 [5%] of 1177 episodes). Cranial imaging preceded lumbar puncture in 936 (86%) of 1092 episodes with neuro-imaging data available. Treatment was started before imaging in 304 (36%) of 855 episodes for which we had data.

Table 1. Characteristics of the study population.a

DataAge 61 (47-69)Men 707/1412 (50%)History of meningitis 93/1396 (7%)Symptoms <24 h 636/1353 (47%)Seizures 98/1353 (7%)Pretreatment with antibiotics 152/1377 (11%)Otitis or sinusitis 480/1404 (34%)Pneumonia 122/1347 (9%)Endocarditis 17/1346 (1%)Cerebrospinal fluid leak 39/1374 (3%)Immunosuppressive drugs 107/1391 (8%)History of splenectomy 32/1412 (2%)History of cancer 173/1407 (12%)Diabetes 171/1394 (12%)HIV positive 12/1412 (1%)Alcoholism 82/1412 (6%)

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Table 1. Characteristics of the study population.a (Continued)

DataSymptoms and signs on presentation Headache 1015/1223 (83%) Nausea 713/1159 (62%) Neck stiffness 977/1322 (74%) Rash 116/1412 (8%) Heart rate (beats/min)b 100 (84-112) Systolic blood pressure (mm Hg)c 142 (125-163) Diastolic blood pressure (mm Hg)c 80 (69-90) Body temperature (°C) 38.9 (37.9-39.6) ≥38°C 1033/1391 (74%) Score on Glasgow Coma Scale 11 (9-14) <14 (altered mental status) 996/1403 (71%) <8 (coma) 185/1403 (13%) Triad fever, neck stiff ness, or altered mental status 563/1389 (41%) Cranial nerve palsy 109/1245 (9%) Aphasia, hemiparesis, or monoparesis 268/1221 (22%)Indices of CSF inflammation Opening pressure >400 mm water 253/480 (53%) White cell count (cells per μL) 2310 (547-6840) <100 149/1352 (11%) 100-999 316/1352 (23%) ≥999 887/1352 (66%) Protein (g/L)d 3.9 (2.3-6.0) CSF: blood glucose ratioe 0.04 (0.0-0.3)Positive Gram stain 1057/1245 (85%)Positive blood culture 927/1243 (75%)Blood chemical tests C-reactive protein (mg/L) 194 (87-311) <40 162/1353 (12%) >80 1040/1353 (77%) Thrombocyte count (per μL) 199 (151-253) <150 322/1345 (24%)Clinical course Seizures 185/1353 (14%) Pneumonia 221/1311 (17%) Cardiorespiratory failure 530/1412 (38%)Score on Glasgow Outcome Scale 1 (death) 244/1412 (17%) 2 (vegetative state) 2/1412 (<1%) 3 (severe disability) 64/1412 (5%) 4 (moderate disability) 221/1412 (16%) 5 (mild or no disability) 881/1412 (62%)

a Data are number / number evaluated (%) or median (interquartile range). b Evaluated in 1363 episodes.c Evaluated in 1381 episodes. d Evaluated in 1344 episodes. e Evaluated in 1309 episodes.

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The most common pathogen was S. pneumoniae, accounting for 1017 (72%) of 1412 isolates identified (Figure 2, Table 2). Pneumococcal serotype was available for 930 (91%) of 1017 episodes. Serotypes included those covered by the seven-valent, ten-valent, and 13-valent conjugate vaccines (Figure 2, Table 2). 763 (82%) of 930 episodes were due to a pneumococcal serotype included in the 23-valent polysaccharide vaccine. In patients aged older than 65 years, 79 (22%) of 359 episodes were of serotypes covered by the seven-valent vaccine, 129 (36%) were of serotypes covered by the ten-valent vaccine, 181 (50%) were of serotypes covered by the 13-valent vaccine, and 283 (79%) were of serotypes covered by the 23-valent vaccine.

The incidence of community-acquired bacterial meningitis was highest in 2007-08, with 1.72 cases per 100.000 adults per year, and subsequently declined to 0.94 per 100 000 adults per year in 2013-14 (Figure 2). There was a reduction in both the absolute number of pneumococcal cases per year and the proportion of cases caused by the seven-valent vaccine serotypes (Figure 2). The incidence of pneumococcal serotypes included in the seven-valent vaccine decreased from 0.42 per 100.000 adults per year in 2006, to 0.02 in 2013. There was no evidence of serotype replacement. The mean incidence of pneumococcal serotypes not included in the seven-valent vaccine was 0.68 per 100.000 adults per year excluding missing serotypes, and 0.76 per 100.000 adults per year including missing serotypes. The mean incidence of pneumococcal serotypes not included in the ten-valent vaccine was 0.55 per 100.000 adults per year excluding missing serotypes, and 0.63 including missing serotypes. There was no increasing trend in the incidence of non-seven-valent serotypes (β -0.01, p=0.45) or non-ten-valent serotypes (β 0.004, p=0.69) during the observation period.

N. meningitidis was responsible for 150 (11%) of 1412 episodes (Table 2). Meningococcal clonal complex by multilocus sequence typing was available for 119 (79%) of 150 episodes and the most common clonal complexes were ST-41/44 (42 [35%] of 119 episodes), ST-32 (28 [24%] of 119 episodes), and ST-269 (12 [10%] of 119 episodes). Patients with meningococcal meningitis were generally younger (median age 32 years, IQR 19-54) than were patients with other causative bacteria (median 61 years, IQR 46-71; p<0.0001).

Gram staining of cerebrospinal fluid yielded a positive result in 848 (92%) of 919 episodes of pneumococcal meningitis, 109 (83%) of 132 episodes of meningococcal meningitis, and 24 (41%) of 59 episodes of listeria meningitis in which Gram staining was done. Gram stain results led to a change in antimicrobial

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treatment for 560 (43%) of 1316 episodes. Blood cultures were positive for 927 (75%) of 1243 episodes in which cultures were done. Penicillin susceptibility was tested in 928 (91%) of 1017 episodes of pneumococcal meningitis; 15 (2%) of 928 pneumococcal isolates showed penicillin resistance, and three (20%) of these 15 isolates showed reduced susceptibility to ceftriaxone. Antibiotic susceptibility was tested for 134 (89%) of 150 episodes of meningococcal meningitis; 16 (12%) isolates showed intermediate penicillin resistance, all were susceptible to ceftriaxone and rifampicin.

Initial antibiotic treatment included a combination of amoxicillin with a third-generation cephalosporin in 459 (36%) of 1273 episodes. Monotherapy was started with a third-generation cephalosporin in 365 (29%) of 1273 episodes, and with either penicillin or amoxicillin in 259 (20%) of 1273 episodes. Other regimens were used in 190 (15%) of 1273 episodes. Initial antimicrobial treatment was appropriate for the pathogen cultured in 1247 (98%) of 1273 episodes; eight (11%) of 74 patients with listeria meningitis were initially treated with cephalosporin alone. Adjunctive dexamethasone was administered for 1234 (89%) of 1384 assessed episodes. Dexamethasone 10 mg intravenously, every 6 h for 4 days, was started before or with the first dose of parenteral antibiotics in 1075 (78%) of 1384 episodes.5, 28

The overall case fatality rate was 244 (17%) of 1412 episodes and varied with the causative organism: 179 (18%) in 1017 episodes of pneumococcal meningitis, five (3%) in 150 episodes of meningococcal meningitis, and 26 (35%) in 74 episodes of listeria meningitis. An unfavorable outcome occurred in 531 (38%) of 1412 episodes: 413 (41%) of 1017 episodes of pneumococcal meningitis, 19 (13%) of 150 episodes of meningococcal meningitis, and 40 (54%) of 74 episodes of listeria meningitis. The appendix shows characteristics of listeria meningitis episodes. In a multivariable analysis, several characteristics were associated with an unfavorable outcome in bacterial meningitis due to any pathogen: older age, absence of otitis or sinusitis, alcoholism, tachycardia, lower score on the Glasgow Coma Scale, cranial nerve palsy, a cerebrospinal fluid white blood cell count of less than 1000 cells per μL, a positive blood culture, and a high serum C-reactive protein concentration (Table 3).

Pneumococcal serotype was not associated with outcome after correcting for multiple testing, neither with use of serotype 7F as a reference category, nor in dichotomized analyses between high-virulence and low-virulence serotypes or between serotypes included in conjugate vaccines versus those not included (data not shown).29, 30

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Chapter 2

24

The proportion of patients with unfavorable outcome was lower in those treated with adjunctive dexamethasone according to guideline recommendations (10 mg four times per day for 4 days) than those who did not receive it according to guideline recommendations (360 [34%] of 1075 vs. 157 [51%] of 309; p<0.0001). In a multivariable analysis including all baseline variables, the adjusted OR of dexamethasone treatment for unfavorable outcome was 0.54 (95% CI 0.39-0.73) and the adjusted OR for death was 0.46 (0.32-0.66). The adjusted OR for the association between dexamethasone treatment and unfavorable outcome was 0.55 (0.38-0.80) in patients with pneumococcal meningitis and 0.44 (0.23-0.85) for patients with meningitis caused by other pathogens. Hearing loss at discharge was present in 144 (16%) of 902 surviving patients and was not significantly affected by dexamethasone use (OR 1.32, 95% CI 0.80-2.23; p=0.30).

Figure 2. Incidence of community-acquired bacterial meningitis in the Netherlands for 2006-14.

(A) Incidence rate per 100.000 adults per year of all episodes reported to the Netherlands Reference Laboratory for Bacterial Meningitis. (B) Incidence rate with 95% CI’s of all included episodes of community-acquired meningitis per 100.000 adults per year. Not all patients could be included in the first months of the study because of pending ethical approval in several hospitals. Routine vaccination against S. pneumoniae at 2 months, 3 months, 4 months, and 11 months of age with the seven-valent conjugate vaccine was started in 2006, and replaced by a ten-valent conjugate vaccine in 2011. Children aged 1-19 years were offered a single meningococcal serogroup C vaccination in 2002, and routine vaccination at 14 months was subsequently introduced.

39833_Lucas.indd 24 22-04-16 18:18


25

2

Table 2. Typing and subtyping of causative pathogens.

DataStreptococcus pneumoniaea 1017/1412 (72%) 7F 110/930 (12%) 3 106/930 (11%) 8 78/930 (8%) 22F 68/930 (7%) 23F 44/930 (5%) 19A 40/930 (4%) 19F 34/930 (4%) 39 other serotypesb 450/930 (48%)Neisseria meningitidis 150/1412 (11%) Serogroup B 113/137 (82%) Serogroup Y 10/137 (7%) Serogroup C 10/137 (7%) Other serogroups 4/137 (3%)Listeria monocytogenes 74/1412 (5%)Haemophilus influenzae 47/1412 (3%)Streptococcus pyogenes 24/1412 (2%)Streptococcus agalactiae 21/1412 (1%)Other streptococcal speciesc 35/1412 (2%)Staphylococcus aureus 21/1412 (1%)Otherd 23/1412 (2%)

a Of the 930 episodes with an identified pneumococcal serotype, 193 episodes were due to serotypes included in the seven-valent pneumococcal conjugate vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F) and 329 episodes were due to serotypes included in the ten-valent vaccine (1, 5 and 7F, in addition to serotypes included in the seven valent vaccine). b Serotype (number): 10A (30), 23B (30), 4 (28), 12F (27), 6B (25), 14 (23), 18C (23), 1 (23), 9N (21), 11A (20), 23A (20), 6A (18), 24F (17), 33F (17), 9V (16), 15B (15), 6C (12), 35F (10), 16F (10), 15A (8), 17F (8), 15C (6), 31 (6), 38 (6), 18B (4), 20 (4), 37 (4), 5 (3), 34 (3), 35B (3), 22A (2), 7A (1), 7B (1), 10B (1), 13 (1), 24B (1), 25A (1), 27 (1), 28F (1). c Streptococcus suis (n=7), Streptococcus salivarius (n=5), Streptococcus mitis (n=4), Streptococcus anginosus (n=3), Streptococcus dysgalactiae subspecies equisimilis (n=3), Streptococcus intermedius (n=3), Streptococcus equi subspecies zooepidemicus (n=2), Streptococcus parasanguinis (n=2), Streptococcus constellatus subspecies constellatus (n=1), Streptococcus gallolyticus subspecies gallolyticus (n=1), Streptococcus gallolyticus subspecies pasteurianus (n=1), Streptococcus gordonii (n=1), Streptococcus oralis (n=1), Streptococcus sanguinis (n=1) d Escherichia coli (n=10), Capnocytophaga canimorsus (n=3), Klebsiella pneumoniae (n=3), Haemophilus parainfluenzae (n=2), Aggregatibacter aphrophilus (n=1), Campylobacter fetus (n=1), Nocardia farcinica (n=1), Pseudomonas aeruginosa (n=1), Salmonella enterica (n=1).

39833_Lucas.indd 25 22-04-16 18:18

Chapter 2

26

Tabl

e 3.

Fac

tors

ass

ocia

ted

with

an

unfa

vora

ble

outc

ome.a

Favo

rabl

e ou

tcom

e(n

=881

)U

nfav

orab

le o

utco

me

(n=5

31)

Uni

vari

able

odd

s rat

iofo

r unf

avor

able

out

com

e(9

5% C

I)

Mul

tivar

iate

odd

s rat

iofo

r unf

avor

able

Out

com

e(9

5% C

I)

P va

lue

of m

ulti-

vari

able

ana

lysi

s

Age

58

(42-

67)

64 (5

5-75

)…

……

16-3

919

4/88

1 (2

2%)

43/5

13 (8

%)

Refe

renc

eRe

fere

nce

…40

-70

542/

881

(62%

)29

7/51

3 (5

6%)

2.47

(1.7

3-3.

54)

1.55

(1.0

2-2.

35)

0.04

1>7

014

5/88

1 (1

7%)

191/

513

(3%

6)5.

94 (4

.01-

8.81

)3.

04 (1

.89-

4.89

)<0

.000

1Sy

mpt

oms <

24 h

428/

855

(50%

)20

8/49

8 (4

2%)

0.72

(0.5

7-0.

90)

0.84

(0.6

5-1.

10)

0.22

Seiz

ures

48

/857

(6%

)50

/496

(10%

)1.

89 (1

.22-

2.92

)1.

50 (0

.85-

2.63

)0.

16Pr

e-tr

eate

d an

tibio

tics

97/8

58 (1

1%)

55/5

19 (1

1%)

0.93

(0.6

4-1.

34)

1.10

(0.7

2-1.

68)

0.65

Otit

is or

sinu

sitis

338/

876

(39%

)14

2/52

8 (2

7%)

0.59

(0.4

6-0.

75)

0.74

(0.5

5-0.

99)

0.04

1Pn

eum

onia

54/8

60 (6

%)

68/4

87 (1

4%)

2.42

(1.6

3-3.

60)

1.36

(0.8

1-2.

27)

0.23

Imm

unos

uppr

essiv

e dr

ugs

57/8

70 (7

%)

50/5

21 (1

0%)

1.51

(1.0

0-2.

29)

1.02

(0.6

2-1.

67)

0.94

Hist

ory

of sp

lene

ctom

y15

/881

(2%

)17

/531

(3%

)1.

91 (0

.89-

4.14

)1.

08 (0

.47-

2.48

)0.

85H

istor

y of

can

cer

83/8

81 (9

%)

90/5

26 (1

7%)

1.98

(1.4

2-2.

77)

1.17

(0.8

0-1.

72)

0.42

Dia

bete

s94

/874

(11%

)77

/520

(15%

)1.

44 (1

.03-

2.02

)1.

38 (0

.93-

2.04

)0.

11H

IV p

ositi

ve9/

881

(1%

)3/

531

(1%

)0.

55 (0

.10-

2.22

)0.

62 (0

.14-

2.63

)0.

51A

lcoh

olism

34/8

81 (4

%)

48/5

31 (9

%)

2.47

(1.5

4-4.

02)

1.98

(1.1

5-3.

41)

0.01

3H

eada

che

716/

819

(87%

)29

9/40

4 (7

4%)

0.41

(0.3

0-0.

56)

0.71

(0.4

9-1.

01)

0.05

8N

ause

a 49

5/76

2 (6

5%)

218/

397

(55%

)0.

66 (0

.51-

0.85

)0.

86 (0

.63-

1.16

)0.

32N

eck

stiff

ness

63

6/83

7 (7

6%)

341/

485

(70%

)0.

75 (0

.58-

0.97

)0.

82 (0

.54-

1.25

)0.

36Ra

sh

85/8

81 (1

0%)

31/5

31 (6

%)

0.58

(0.3

7-0.

90)

0.88

(0.5

3-1.

46)

0.63

Hea

rt ra

te (

beat

s/m

in)b

98 (8

2-11

0)10

2 (8

9-12

0)1.

18 (1

.12-

1.24

)1.

10 (1

.03-

1.17

)0.

0030

Dia

stol

ic b

lood

pre

ssur

e (m

mH

g)c

79 (6

8-88

)80

(70-

92)

1.10

(1.0

3-1.

17)

1.03

(0.9

5-1.

11)

0.51

Tem

pera

ture

(°C

)d39

.0 (3

8.0-

39.7

)38

.8 (3

7.6-

39.5

)0.

87 (0

.81-

0.95

)0.

89 (0

.79-

1.01

)0.

070

Scor

e on

Gla

sgow

Com

a Sc

alee

12 (9

-14)

10 (8

-13)

0.85

(0.8

2-0.

88)

0.91

(0.8

7-0.

96)

0.00

085

Tria

d of

feve

r, ne

ck st

iffne

ss a

nd

Gla

sgow

Com

a Sc

ale

scor

e <

1435

4/85

1 (4

2%)

209/

496

(42%

)1.

02 (0

.81-

1.29

)1.

03 (0

.68-

1.56

)0.

88

39833_Lucas.indd 26 22-04-16 18:18


27

2

Tabl

e 3.

Fac

tors

ass

ocia

ted

with

an

unfa

vora

ble

outc

ome.a

(Con

tinue

d)

Favo

rabl

e ou

tcom

e(n

=881

)U

nfav

orab

le o

utco

me

(n=5

31)

Uni

vari

able

odd

s rat

iofo

r unf

avor

able

out

com

e(9

5% C

I)

Mul

tivar

iate

odd

s rat

iofo

r unf

avor

able

Out

com

e(9

5% C

I)

P va

lue

of m

ulti-

vari

able

ana

lysi

s

Apha

sia, h

emip

ares

is or

m

onop

ares

is14

8/54

7 (2

7%)

120/

257

(47%

)2.

36 (1

.71-

3.25

)1.

15 (0

.83-

1.58

)0.

40

Cra

nial

ner

ve p

alsy

43

/747

(5%

)60

/449

(13%

)2.

68 (1

.74-

4.14

)2.

55 (1

.59-

4.09

)0.

0001

3C

ereb

rosp

inal

flui

d w

hite

cell

coun

t (c

ells

per μ

L)

3183

(950

-798

3)11

86 (2

49-5

010)

……

…

<

100

60/8

46 (7

%)

89/5

06 (1

8%)

3.61

(2.5

0-5.

22)

2.10

(1.3

4-3.

29)

0.00

12

100

-999

157/

846

(19%

)15

9/50

6 (3

1%)

2.47

(1.8

7-3.

25)

2.04

(1.4

6-2.

84)

<0.0

001

1

000-

1000

047

0/84

6 (5

6%)

193/

506

(38%

)Re

fere

nce

Refe

renc

e…

>

1000

0 15

9/84

6 (1

9%)

65/5

06 (1

3%)

1.00

(0.7

1-1.

39)

0.81

(0.5

6-1.

19)

0.29

CSF

pro

tein

( g/

L)f

3.5

(2.1

-5.7

)4.

5 (2

.7-6

.5)

1.08

(1.0

4-1.

11)

1.03

(0.9

9-1.

07)

0.13

CSF

: blo

od g

luco

se ra

tiog

0.1

(0-0

.3)

0.01

(0-0

.1)

……

…

<0.

2556

0/82

5 (6

8%)

407/

484

(84%

)1.

53 (0

.88-

2.64

)1.

28 (0

.63-

2.58

)0.

49

0.2

5-0.

522

3/82

5(27

%)

57/4

84 (1

2%)

0.54

(0.2

9-0.

98)

0.71

(0.3

4-1.

50)

0.36

>

0.5

42/8

25 (5

%)

20/4

84 (4

%)

Refe

renc

eRe

fere

nce

…Po

sitiv

e bl

ood

cultu

re55

0/77

7 (7

1%)

377/

466

(81%

)1.

75 (1

.31-

2.34

)1.

44 (1

.02-

2.05

)0.

040

Thro

mbo

cyte

coun

t20

7 (1

60-2

57)

185

(135

-237

)…

……

<

150

163/

845

(19%

)15

9/50

0 (3

2%)

1.94

(1.5

0-2.

50)

1.32

(0.9

6-1.

81)

0.08

8

150

-450

664/

845

(79%

)33

4/50

0 (6

7%)

Refe

renc

eRe

fere

nce

…

>45

018

/845

(2%

)7/

500

(1%

)0.

77 (0

.32-

1.87

)0.

46 (0

.17-

1.26

)0.

13C

-rea

ctiv

e pr

otei

n (m

g/L)

h16

2 (7

2-27

2)24

9 (1

34-3

70)

1.04

(1.0

3-1.

05)

1.02

(1.0

1-1.

03)

<0.0

001

a Th

e st

udy

incl

uded

141

2 ep

isode

s of c

omm

unity

-acq

uire

d m

enin

gitis

in 1

391

patie

nts;

data

are

num

ber /

num

ber e

valu

ated

(%) o

r med

ian

(inte

rqua

rtile

rang

e), u

nles

s st

ated

oth

erw

ise. Th

e m

ultiv

aria

ble

anal

ysis

used

an

impu

ted

data

set

with

60

impu

tatio

n ro

unds

, all

varia

bles

in t

he t

able

wer

e en

tere

d in

the

mul

tivar

iabl

e lo

gist

ic

regr

essio

n m

odel

sim

ulta

neou

sly. C

SF=c

ereb

rosp

inal

flui

d.b

Eval

uate

d in

136

3 ep

isode

s; od

ds r

atio

is fo

r an

incr

ease

of t

en b

eats

per

min

. c Ev

alua

ted

in 1

381

episo

des;

odds

rat

io is

for

a 10

mm

Hg

incr

ease

. d Ev

alua

ted

in 1

391

episo

des.

e Ev

alua

ted

in 1

403

episo

des;

odds

ratio

is fo

r a o

ne p

oint

incr

ease

. f Eval

uate

d in

134

4 ep

isode

s. g Ev

alua

ted

in 1

309

episo

des.

h Eva

luat

ed in

135

3 ep

isode

s; od

ds

ratio

is fo

r a 1

0 m

g/L

incr

ease

.

39833_Lucas.indd 27 22-04-16 18:18

Chapter 2

28

Discussion

Our findings show that the incidence of adult bacterial meningitis has decreased since the introduction of conjugate vaccines, primarily because of falls in pneumococcal and meningococcal meningitis. Incidence decreased most sharply among pneumococcal serotypes included in the seven-valent and ten-valent conjugate vaccines; these vaccines were introduced in the Netherlands in 2006 and 2011. A surveillance study4 of 17.4 million people in the USA during 1998-2007, showed a similar effect of herd protection in adults. Our study included 16.8 million people, and by contrast with the US study, we observed no serotype replacement of non-vaccine serotypes. This difference between studies might only partly be explained by age differences. The US study showed that serotype replacement was age dependent, with an increase of 90% in children aged younger than 5 years, 61% at any age, and 18% in patients older than 65 years.4 Dutch surveillance data has shown evidence of serotype replacement,31, 32 but only for all invasive pneumococcal disease combined, and not in the subgroup of patients with meningitis. Pneumococcal meningitis due to non-vaccine types did not increase during the observation period in adults or children aged 0-16 years (data not shown). The incidence of adult meningitis due to non-seven-valent or non-ten-valent serotypes in 2006-13 was not higher than in 1998-2002.1

Serogroup C meningococcal meningitis virtually disappeared after routine vaccination against this bacterium in 2002.33 Herd protection was responsible for more than 36% of the effect of meningococcal conjugate serogroup C vaccine and lasted for more than 10 years.34 Serogroup B meningococcal meningitis has probably decreased because of a natural fluctuation in incidence.21

The relative contribution of pneumococcal meningitis to adult bacterial meningitis has increased and has led to a change in population characteristics of those with bacterial meningitis. Patients with bacterial meningitis are older and more likely to have risk factors for pneumococcal meningitis, such as otitis, sinusitis, and an immunocompromised state, than were patients in 1998-2002.1 For the subgroup of pneumococcal meningitis, the proportions of patients with an unfavorable outcome or death have decreased substantially over this period (unfavorable outcome from 50% to 41%, absolute risk reduction -9%, 95% CI -7 to -11; death from 30% to 18%, absolute risk reduction -12%, 95% CI -10 to -14).1 The strongest risk factors for an unfavorable outcome were those that suggested systemic compromise, a low level of consciousness, and infection with S. pneumoniae.

39833_Lucas.indd 28 22-04-16 18:18


29

2

Dexamethasone treatment has been used widely as adjunctive treatment for adults with bacterial meningitis. In our study, it was administered to about 90% of patients, irrespective of the causative pathogen. Dexamethasone treatment was independently associated with favorable outcome and increased survival in patients with both pneumococcal and non-pneumococcal meningitis. These findings are consistent with the results of a Cochrane review.35 We previously wrote that it seems unlikely that a study could have enough power to prove or disprove an effect of adjunctive dexamethasone treatment on meningococcal meningitis.18 The use of observational data precludes making strong conclusions about treatment effects, but the present findings in combination with a randomized study in the same population,5 and meta-analysis of randomized clinical trials35, 36

showing a similar effect, suggest that implementation of dexamethasone treatment has improved the prognosis of bacterial meningitis, both pneumococcal and non-pneumococcal.

A history of meningitis was reported for 7% of episodes. This proportion is similar to previous studies.37, 38 Causes of recurrent meningitis are cerebrospinal fluid leakage and immunodeficiency, which should carefully be assessed in patients with recurrent meningitis.37-39 Because of the large number of patients with a history of meningitis in our cohort, physicians could consider vaccinating against the most common causes of bacterial meningitis in their region in any patient with bacterial meningitis.

Our study has several limitations. Patients who underwent lumbar puncture and who had a positive cerebrospinal fluid culture were over-represented. 11-22% of patients with bacterial meningitis have negative cerebrospinal fluid cultures.40 Lumbar puncture might be postponed in patients with coagulation disorders or severe septic shock, which can result in negative cerebrospinal fluid cultures. Additionally, patients with bacterial meningitis who have space-occupying lesions on CT might not undergo lumbar puncture. Another limitation of our study was that we had little information about comorbidity and the timing of systemic and neurological complications. The vaccination status of patients was also not available. Theoretically, decreased incidence rates among serotypes included in the seven-valent vaccine could be, at least partly, due to vaccination of Dutch adults. However, in the Netherlands, routine pneumococcal vaccination for adults is not advised by the Health Council of the Netherlands, with the exception of high-risk groups (e.g., those with hyposplenia or asplenia, sickle cell disease, and cerebrospinal fluid leakage). Based on sales records from Dutch pharmacies,

39833_Lucas.indd 29 22-04-16 18:18

Chapter 2

30

pneumococcal vaccine coverage is low among adults aged older than 65 years in the Netherlands.32 Finally, antibiotic resistance among pneumococcal isolates was rare. Adding dexamethasone has the potential to reduce cerebrospinal fluid penetration of vancomycin, a drug that has become the standard empirical antimicrobial treatment for pneumococcal strains that, on the basis of local epidemiology, are likely to be highly resistant to penicillin or cephalosporin.41 Although a prospective multicenter observational study42 has shown that appropriate concentrations of vancomycin in cerebrospinal fluid can be achieved even when concomitant steroids are used, some experts have advised the addition of rifampicin to vancomycin and ceftriaxone or cefotaxime regimens in areas with high rates of pneumococcal drug resistance.3, 41

Our findings show the substantial improvement in the prognosis of pneumococcal meningitis over the past two decades and the effect of paediatric conjugate vaccines on adult bacterial meningitis. Herd protection is a major part of the effectiveness of conjugate vaccines and can protect those with poor immunological response to vaccination - e.g., infants and elderly people. The development of vaccines covering more pneumococcal serotypes, new potent anti-inflammatory treatments,14 starting treatment immediately after blood cultures are obtained, and aggressive supportive care might further improve the prognosis of patients with bacterial meningitis.

39833_Lucas.indd 30 22-04-16 18:18


31

2

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2 McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet 2012; 380: 1703-11.

3 van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012; 380: 1693-702.

4 Thigpen MC, Whitney CG, Messonnier NE et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med 2011; 364: 2016-25.

5 de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347: 1549-56.

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13 Adriani KS, Brouwer MC, van der Ende A, van de Beek D. Bacterial meningitis in adults after splenectomy and hyposplenic states. Mayo Clin Proc 2013; 88: 571-78.

14 Woehrl B, Brouwer MC, Murr C et al. Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis. J Clin Invest 2011; 121: 3943-53.

15 Brouwer MC, Meijers JC, Baas F et al. Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis. Acta Neuropathol 2014; 127: 553-64.

16 Mook-Kanamori BB, Valls Seron M, Geldhoff M et al Thrombin-activatable fibrinolysis inhibitor influences disease severity in humans and mice with pneumococcal meningitis. J Thromb Haemost 2015; 13: 2076-86.

17 Piet JR, Geldhoff M, van Schaik BD et al. Streptococcus pneumoniae arginine synthesis genes promote growth and virulence in pneumococcal meningitis. J Infect Dis 2014; 209: 1781-91.

18 Heckenberg SG, Brouwer MC, van der Ende A, van de Beek D. Adjunctive dexamethasone in adults with meningococcal meningitis. Neurology 2012; 79: 1563-69.

19 Koopmans MM, Brouwer MC, Bijlsma MW et al. Listeria monocytogenes sequence type 6 and increased rate of unfavorable outcome in meningitis: epidemiologic cohort study. Clin Infect Dis 2013; 57: 247-53.

20 Spanjaard L, Bol P, Ekker W, Zanen HC. The incidence of bacterial meningitis in the Netherlands—a comparison of three registration systems, 1977-1982. J Infect 1985; 11: 259-68.

21 Bijlsma MW, Bekker V, Brouwer MC, Spanjaard L, van de Beek D, van der Ende A. Epidemiology of invasive meningococcal disease in the Netherlands, 1960-2012: an analysis of national surveillance data. Lancet Infect Dis 2014; 14: 805-12.

22 Spanos A, Harrell FE Jr, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989; 262: 2700-07.

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23 van de Beek D, Drake JM, Tunkel AR. Nosocomial bacterial meningitis. N Engl J Med 2010; 362: 146-54.24 Jennett B, Teasdale G. Management of head injuries. 2 edn. Philadelphia: F A Davis, 1981.25 van de Beek D, de Gans J, Spanjaard L, Vermeulen M, Dankert J. Antibiotic guidelines and antibiotic

use in adult bacterial meningitis in the Netherlands. J Antimicrob Chemother 2002; 49: 661-66.26 Spanjaard L, Bol P, Zanen HC. Non-neonatal meningitis due to less common bacterial pathogens, the

Netherlands, 1975-83. J Hyg (Lond) 1986; 97: 219-28.27 Mulder CJ, Zanen HC. A study of 280 cases of neonatal meningitis in the Netherlands. J Infect 1984; 9:

177-84.28 van de Beek D, Brouwer MC, de Gans J et al. Richtlijn bacteriële meningitis. Utrecht: Nederlandse

Vereniging voor Neurologie, 2013.29 Harboe ZB, Thomsen RW, Riis A et al. Pneumococcal serotypes and mortality following invasive

pneumococcal disease: a population-based cohort study. PLoS Med 2009; 6: e1000081.30 Jansen AG, Rodenburg GD, van der Ende A et al. Invasive pneumococcal disease among adults:

associations among serotypes, disease characteristics, and outcome. Clin Infect Dis 2009; 49: e23-29.31 van Deursen AM, van Mens SP, Sanders EA et al. Invasive pneumococcal disease and 7-valent

pneumococcal conjugate vaccine, the Netherlands. Emerg Infect Dis 2012; 18: 1729-37.32 Rodenburg GD, de Greeff SC, Jansen AG et al. Effects of pneumococcal conjugate vaccine 2 years after

its introduction, the Netherlands. Emerg Infect Dis 2010; 16: 816-23.33 Kaaijk P, van der Ende A, Berbers G, van den Dobbelsteen GP, Rots NY. Is a single dose of meningococcal

serogroup C conjugate vaccine sufficient for protection? Experience from the Netherlands. BMC Infect Dis 2012; 12: 35.

34 Bijlsma MW, Brouwer MC, Spanjaard L, van de Beek D, van der Ende A. A decade of herd protection after introduction of meningococcal serogroup C conjugate vaccination. Clin Infect Dis 2014; 59: 1216-21.

35 Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2015; 9: CD004405.

36 van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis 2004; 4: 139-43.

37 Durand ML, Calderwood SB, Weber DJ et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993; 328: 21-28.

38 Adriani KS, van de Beek D, Brouwer MC, Spanjaard L, de Gans J. Community-acquired recurrent bacterial meningitis in adults. Clin Infect Dis 2007; 45: e46-51.

39 Tebruegge M, Curtis N. Epidemiology, etiology, pathogenesis, and diagnosis of recurrent bacterial meningitis. Clin Microbiol Rev 2008; 21: 519-37.

40 Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev 2010; 23: 467-92.

41 van de Beek D, de Gans J, Tunkel AR, Wijdicks EF. Community-acquired bacterial meningitis in adults. N Engl J Med 2006; 354: 44-53.

42 Ricard JD, Wolff M, Lacherade JC et al. Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective multicenter observational study. Clin Infect Dis 2007; 44: 250-55.

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Supplementary table

Supplemental table 1. Clinical characteristics of patients with L. monocytogenes meningitis compared to meningitis due to other pathogens.a

Characteristic L. monocytogenes meningitis (n=74)

Meningitis due to other pathogens (n=1338)

P value

Age 69 (62-76) 60 (46-69) <0.0001Men 49/74 (66%) 658/1338 (49%) 0.006Otitis or sinusitis 2/74 (3%) 478/1330 (36%) <0.0001Immunosuppressive drugs 34/74 (46%) 73/1317 (6%) <0.0001History of cancer 21/74 (28%) 152/1333 (11%) 0.0001Diabetes mellitus 11/74 (15%) 160/1320 (12%) 0.47Alcoholism 7/74 (10%) 75/1338 (6%) 0.19Heart rate (beats/min) 96 (86-110) 100 (84-112) 0.70Score on Glasgow Coma Scale 12 (10-14) 11 (9-14) 0.03Cranial nerve palsy 6/67 (9%) 97/1172 (8%) 0.82C-reactive protein 116 (55-184) 201 (91-317) <0.0001CSF white cell count (cells/mm3) 720 (356-1499) 2560 (581-7307) <0.0001CSF protein (g/L) 2.6 (1.8-3.7) 4.0 (2.3-6.1) <0.0001Positive blood culture 44/68 (65%) 883/1175 (75%) 0.06Any adjunctive dexamethasone 50/73 (69%) 1184/1311 (90%) <0.0001Adjunctive dexamethasone according to guideline recommendation

37/73 (51%) 1038/1311 (79%) <0.0001

Unfavorable outcome 40/74 (54%) 491/1338 (37%) 0.004Death 26/74 (35%) 218/1338 (16%) 0.0002

a Data are number / number evaluated (%) or median (interquartile range), statistical tests: Fisher exact for categorical and Mann-Whitney U Test for continuous data.

Appendix 1. Local investigators (participating hospitals)

P. Admiraal (Gemini Ziekenhuis), J.C. Baart (Ziekenhuisgroep Twente), R.J. Beukers (Medisch Centrum Alkmaar), H.P. Bienfait (Gelre Ziekenhuizen), H.J. Bökkerink (Zkh Nij Smellinghe), A.E. Bollen (Wilhelmina Ziekenhuis Assen), H.M. Bos (St. Anna Ziekenhuis), D. Broere (Westfries Gasthuis), M.H. Christiaans (Diakonessenhuis Utrecht), S.F.T.M. de Bruijn (Haga Ziekenhuis), K. de Gans (Groene Hart Ziekenhuis), R.J. de Graaf (Amphia Ziekenhuis), L. de Lau (Slotervaart Ziekenhuis), M.C. de Rijk (Catharina Ziekenhuis), P. de Roos (Ziekenhuis Rivierenland), J.P. de Ruiter (Streekziekenhuis Koningin Beatrix), R.F. Duyff (Zkh de Tjongerschans), J.L.A. Eekhof (Diaconessenhuis Leiden), J.

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Engelsman (Spaarne Ziekenhuis), R.H. Enting (UMC Groningen), B. Feenstra (Zkh. Lievensberg), E. Geiger (Beatrix ziekenhuis Gorinchem), P. Groot (St. Jansdal Ziekenhuis Harderwijk), W.J.H.M. Grosveld (Reinier de Graaf Gasthuis), G. Hageman (Medisch Spectrum Twente), S.G.B. Heckenberg (Kennemer Gasthuis), D. Herderscheê (Tergooi ziekenhuizen), W. Hoefnagels (Zorgsaam Ziekenhuis), R.S. Holscher (Antonius Ziekenhuis Sneek), E.M. Hoogerwaard (Rijnstate Ziekenhuis), U.W. Huisman (Van Wheel Bethesda), B.C. Jacobs (Erasmus Medisch Centrum), C. Jansen (Gelderse Vallei Ziekenhuis), K Jellema (Medisch centrum Haaglanden), H. Kerkhoff (Albert Schweizer Zkh), E.J.W. Keuter (Diaconessenhuis Meppel), J.G.M. Knibbeler (Ropke-Zweers ziekenhuis), A.J.M. Kok (Elkerliek Ziekenhuis ), N.D. Kruyt (LUMC), M.J.H. Langedijk (Refaja ziekenhuis), M. Liedorp (Havenziekenhuis), H.J.M.M. Lohmann (Deventer ziekenhuis), H. Lövenich (St Jans Gasthuis Weert), N.K. Maliepaard (Waterland Ziekenhuis), D.S.M. Molenaar (Ziekenhuis Amstelland), W.G.H. Oerlemans (Meander Medisch Centrum), E.W. Peters (Admiraal de Ruyter ziekenhuis), P.H.M. Pop (Viecurie Ziekenhuis), P. Portegies (OLVG), B. Post (UMC St Radboud), F.M. Reesink (Ommelander Ziekenhuis Groep), J.C. Reijneveld (Vumc), A.M.G. Sas (Vlietland ziekenhuis), R. Saxena (Maasstad Ziekenhuis), P.R. Schiphof (Ziekenhuis Bernhoven), J.P. Schipper (Bethesda Ziekenhuis), A. Schreuder (Atrium Medisch Centrum), A. Schuitemaker (Hofpoort ziekenhuis), E.S. Schut (Martini Ziekenhuis), T.H. Sie (Rode Kruis Ziekenhuis), A.L. Strikwerda (t lange land ziekenhuis), G.A. Sulter (Ziekenhuis de Sionsberg ), R.J.J. Tans (MC groep), M. Te Linteloo (Franciscus Ziekenhuis), L.L. Teunissen (Sint Antonius Ziekenhuis), M.T. Tonk (Ziekenhuis Bronovo), J.T.H. van Asseldonk (Elisabeth-TweeSteden Ziekenhuis), C.J.W. van de Vlasakker (Slingeland ziekenhuis), J. van de Vlekkert (Flevoziekenhuis), J.S.P. van den Berg (Isala Klinieken), M.M. van der Graaff (Boven-IJ Ziekenhuis), G.W. van Dijk (Canisius-Wilhelmina Ziekenhuis), M.P.J. van Goor (Laurentius Ziekenhuis), B. van Harten (Medisch Centrum Leeuwarden), R.J. van Oostenbrugge (Academisch ziekenhuis Maastricht), N.P. van Orshoven (Orbis Medisch Centrum), L. van Winsen (Maasziekenhuis), M.D.I. Vergouwen (UMC Utrecht), F.H. Vermeij (Sint Franciscus Gasthuis), H.F. Visee (Jeroen Bosch Ziekenhuis), L.J.J.C. Wagener-Schimmel (Maxima Medisch Centrum), A.D. Wijnhoud (IJsselland Ziekenhuis), R.J.W. Witteveen (Rijnland Ziekenhuis), E.J. Wouda (St. Lucas Andreas Ziekenhuis), E.V. Zuilen (Scheper ziekenhuis).

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CHAPTER 3

CEREBRAL INFARCTION IN ADULTS WITH BACTERIAL MENINGITIS

Marjolein J. Lucas*, Ewout S. Schut*, Matthijs C. Brouwer, Mervyn D. I. Vergouwen, Arie van der Ende, Diederik van de Beek

*authors contributed equally

Neurocritical Care 2012; 16: 421-427

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Abstract

Background To evaluate clinical features and prognostic factors of cerebral infarctions in adults with community-acquired bacterial meningitis.

Methods An observational cross-sectional study, including 696 patients of whom 174 had cerebral infarction, from a prospective nationwide cohort of community-acquired bacterial meningitis (period 1998-2002), confirmed by culture of cerebral spinal fluid (CSF) in patients aged over 16 years. Two investigators independently determined the presence of infarction.

Results Cerebral infarction occurred in 174 episodes (25%), with a high interrater agreement for determining the presence of cerebral infarction (kappa 0.95). Cerebral infarctions occurred in 128 of 352 patients (36%) with pneumococcal meningitis, in 22 of 257 (9%) with meningococcal meningitis and in 24 of 87 patients (28%) with meningitis caused by other bacteria. Patients with infarctions were older (p<0.001) and often presented with predisposing conditions, such as otitis and/or sinusitis (p=0.001) or an immunocompromised state (p=0.003) compared to those without infarction. Patients with infarctions presented with lower scores on the Glasgow Coma Scale (p<0.001), lower CSF white cell counts (p=0.001), and higher serum erythrocyte sedimentation rate (ESR) (p<0.001). Unfavorable outcome occurred in 108 (62%) patients with infarctions. In a multivariate analysis, infarction was related with unfavorable outcome (odds ratio 3.37; 95% confidence interval 2.19-5.21; p<0.001). We identified lower CSF white cell counts and high ESR to be independent risk factors for cerebral infarction.

Conclusion Cerebral infarction is a common and severe complication in adults with community-acquired bacterial meningitis. Preventing cerebral infarctions will be important in reducing the high morbidity and mortality rate in adults with community-acquired bacterial meningitis.

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Cerebral infarction in bacterial meningitis

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Introduction

Bacterial meningitis is a serious and life-threatening disease. Streptococcus pneumoniae and Neisseria meningitidis are the predominant causative pathogens in adults, causing 80-85% of all cases, with mortality rates up to 30% for pneumococcal meningitis and 10% for meningococcal meningitis.1-4 Cerebrovascular complications are particularly common in pneumococcal meningitis, with reported rates of 10-29%.2, 5, 6 Few cohort studies on cerebral infarctions in bacterial meningitis have been published.5, 7, 8 We performed a nationwide prospective cohort study on clinical features and prognostic factors of 696 episodes of community-acquired bacterial meningitis in adults.3 Here we report the features and prognostic factors of cerebral infarction in bacterial meningitis identified in this cohort.

Methods

The Dutch Meningitis Cohort Study, a prospective nationwide observational cohort study in the Netherlands, included 696 episodes of community-acquired bacterial meningitis, confirmed by culture of cerebrospinal fluid (CSF) in adults. Inclusion and exclusion criteria are described more extensively elsewhere.3 In summary, all patients were aged over 16 years and were listed in the database of the Netherlands Reference Laboratory for Bacterial Meningitis from October 1998 to April 2002. This laboratory receives CSF isolates from approximately 90% of all patients with bacterial meningitis. Informed consent was obtained from all participating patients or their legally authorized representatives. Patients using immunosuppressive drugs, with asplenia, diabetes mellitus, alcoholism, or infection with human immunodeficiency virus (HIV) were considered immunocompromised.

This study is an observational case-control study on cerebral infarction. Clinical data, including specific queries about cerebral infarction, had been prospectively collected by means of a case record form. Two clinicians independently reviewed all case record forms and classified patients as having no cerebral infarction, probable cerebral infarction or definite cerebral infarction (ES, MDV). Interrater agreement was assessed by calculation of the kappa coefficient. Differences in classification were resolved by discussion. Definite cerebral infarction was defined as focal neurologic signs on admission or during the course of the disease, diagnosed

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by a neurologist, with a lesion consistent with recent infarction visualized on cranial computed tomography (CT). Probable cerebral infarction was defined as mono- or hemiparesis, central facial weakness, ataxia, or aphasia on admission or during clinical course, which could not be explained by epileptic seizures or other neurological complications, without confirmation by cranial CT. In these patients CT scanning was either not performed, or was performed but did not show lesions that could explain the patient’s clinical condition.

On admission and at discharge, all patients underwent a neurologic examination performed by a neurologist, and outcome was graded according to the Glasgow Outcome Scale. This is a well-validated measurement scale with scores varying from 1 (indicating death) to 5 (good recovery). A favorable outcome was defined as a score of 5, and an unfavorable outcome as a score of 1-4. We categorized the cause of death in patients who died within 14 days after admission, since death within this period is likely to be caused by direct consequences of the meningitis.3, 9 Two clinicians independently classified the cause of death into systemic causes (e.g., septic shock, respiratory failure, multiple-organ dysfunction, and cardiac ischemia) or neurologic causes (e.g., brain herniation, cerebrovascular complications, intractable seizures, and withdrawal of care because of poor neurologic prognosis). Interrater agreement was assessed by calculation of the kappa coefficient.6 Differences were resolved by discussion.

Population description was done with medians and interquartile ranges. The Mann-Whitney U test was used to identify differences between episodes with and without cerebral infarction with respect to continuous variables, and the v2 test was used to compare categorical variables. The analyses were performed for definite cerebral infarctions (confirmed by cranial CT) and all cerebral infarctions. We used logistic regression to examine the association between potential predictors and cerebral infarction. Odds ratios (OR) and 95% confidence intervals (CI) were used to quantify the strength of these associations. Based on previous research and pathophysiologic interest, nine potentially relevant predictors were chosen. We evaluated whether the prognostic value of these risk factors could be attributed to the causative pathogen, by adjusting the analysis with the inclusion of this variable into the prognostic model. Statistical analyses were performed using PASW software, version 18 (SPSS Institute) and p values <0.05 were considered significant.

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Results

From 1998 to 2002, 696 episodes of community-acquired bacterial meningitis were included in 671 patients. CSF culture yielded S. pneumoniae in 352 episodes (51%), N. meningitidis in 257 episodes (37%), and other bacteria in 87 episodes (13%). In 174 of 696 episodes (25%) patients were classified as having cerebral infarctions. The kappa for interrater agreement on determining cerebral infarction was high (0.95). Infarctions were classified as definite in 60 of 696 episodes (9%) and probable in 114 of 696 episodes (16%).

Of 174 patients with cerebral infarctions 80 patients (46%) presented with focal neurologic signs on admission, consisting of monoparesis in 15 episodes (9%), hemiparesis in 42 episodes (25%), quadriparesis in seven episodes (4%), aphasia in 59 episodes (48%), and ataxia in ten episodes (9%). In the other 94 patients, symptoms of infarction developed during clinical course.

Patients with cerebral infarctions were older than patients without cerebral infarctions (median age, 61 years [IQR 47-72] vs. 48 [IQR 28-64], p<0.001; Table 1). The proportion of females among patients with cerebral infarctions was higher than among patients without cerebral infarctions (59 vs. 48%, p=0.013). Patients with infarctions presented more often with predisposing conditions, such as otitis and/or sinusitis (35 vs. 22%, p=0.001) or an immunocompromised state (24 vs. 14%, p=0.003). They presented with lower levels of consciousness (median score on the Glasgow Coma Scale, 10 [IQR 8-13] vs. 12 [IQR 9-15]; p<0.001), and were therefore more likely to present with the classic triad of symptoms, consisting of fever, neck stiffness, and a change in mental status (52 vs. 41%; p=0.015). Patients with infarctions had higher median systolic blood pressures (150 [IQR 130-170] vs. 135 [IQR 120-157]; p<0.001) and presented less often with skin rash (9 vs. 31%; p<0.001).

Cranial imaging was performed in 124 of 174 patients with infarctions (71%); all 124 patients underwent CT. Cerebral infarctions were diagnosed by cranial CT in 60 of 174 patients. On admission, CT confirmed clinical suspicion of infarction in only 23 of 80 patients (29%) with infarctions presenting with focal neurologic signs. Sixty-four of 114 patients with probable cerebral infarctions had normal CT (56%). Other abnormalities on cranial imaging were: sinusitis/otitis (62 episodes, 9%), cerebral edema (48 episodes, 7%), hydrocephalus (14 episodes, 2%), and cerebritis/empyema which by themselves could not fully account for the clinical focal deficits (25 episodes, 4%). These abnormalities were either seen in combination with cerebral infarction on CT or could not explain the focal neurologic signs.

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Table 1. Clinical and laboratory characteristics and outcome in patients with and without cerebral infarctions complicating bacterial meningitis.a

Characteristic Cerebral infarctions (n=174)

No cerebral infarction (n=522)

P value

Age 61 (47-72) 48 (28-64) <0.001Female 102/174 (59%) 249/522 (48%) 0.01Predisposing conditions Otitis/sinusitis 60/174 (35%) 116/522 (22%) 0.001 Immunocompromised stateb 41/174 (24%) 73/522 (14%) 0.003 Diabetes Mellitus 18/171 (11%) 28/519 (5%) 0.02 Pneumoniae 25/174 (14%) 58/522 (11%) 0.25Symptoms on presentation Headache 122/150 (81%) 422/476 (89%) 0.02 Nausea 104/143 (73%) 345/467 (74%) 0.785 Rash 16/171 (9%) 160/512 (31%) <0.001 Triad of fever, neck stiffness, and change in mental status

90/174 (52%) 215/522 (41%) 0.02

Systolic blood pressure (mm Hg)c 150 (130-170) 135 (120-157) <0.001 Heart rate (beats/min)d 100 (84-120) 98 (80-110) 0.070Focal neurologic signs on admission Monoparesis 15/165 (9%) 1/512 (0.2%) <0.001 Hemiparesis 42/168 (25%) 7/514 (1.4%) <0.001 Quadriparesis 7/171 (4%) 6/514 (1%) 0.015 Ataxia 10/115 (9%) 8/434 (2%) <0.001Score on Glasgow Coma Scale Median 10 (8-13) 12 (9-15) <0.001 <14 (indicating change in mental status) 145/172 (84%) 332/522 (63%) <0.001 <8 (indicating coma) 39/172 (23%) 57/522 (11%) <0.001Blood chemistry testse

Leukocyte count (cells/mm3) 17 (13-22) 19 (13-23) 0.111 ESR (mm/h) 51 (30-77) 36 (16-66) <0.001 Thrombocyte count (platelets/mm³) 181 (132-233) 185 (142-241) 0.20 C-reactive proteine (mg/L) 234 (125-357) 206 (128-293) 0.05Indexes of inflammation in the CSFf

CSF opening pressure (cm H2O) 40 (27-50) 36 (24-50) 0.336 Leukocyte count Median (cells/mm³) 1877 (356-6031) 3339 (947-9122) 0.001 <1000/mm³ 62/165 (38%) 122/480 (25%) 0.003 Protein (g/L) 4.8 (3.0-6.7) 4.0 (2.1-6.9) 0.40 CSF: blood glucose ratio (mg/dL) 0.05 (0.01-0.20) 0.08 (0.01-0.31) 0.23CSF culture Streptococcus pneumoniae 128/174 (74%) 224/522 (43%) <0.001 Neisseria meningitidis 22/174 (13%) 235/522 (45%) <0.001 Other 24/174 (14%) 63/522 (12%) 0.551

a Data are number / number evaluated (%) or median (interquartile range). b Immunocompromised state is defined as the use of immunosuppressive drugs, presence of asplenia, diabetes mellitus, alcoholism, or infection with HIV. c Blood pressure was determined in 670 patients. d Heart rate was determined in 652 patients. e Blood leukocyte counts were determined in 690 patients, erythrocyte sedimentation rate (ESR) in 549 patients, thrombocyte count in 653 patients, C-reactive protein levels in 392 patients. f CSF opening pressure was determined in 216 patients, CSF leukocyte count in 645 patients, CSF protein level in 634 patients and CSF: blood to glucose ratio in 617 patients.

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Lumbar puncture was performed in all episodes and showed lower median CSF white blood cell (WBC) counts in patients with infarctions as compared with patients without cerebral infarctions (1877 per mm3 [IQR 356-6031] vs. 339 [IQR 947-9122]; p=0.001). Patients with infarctions also had lower median CSF: blood glucose ratio (0.05 [IQR 0.01-0.20] vs. 0.08 [IQR 0.01-0.31]; p=0.023), higher C-reactive protein levels (234 mg/L [IQR 125-357] vs. 206 [IQR 128-293]; p=0.05) and erythrocyte sedimentation rates (51 mm/h [51 [IQR 30-77] vs. 36 [IQR 128-293]; p<0.001). CSF culture yielded S. pneumoniae in 74% of episodes complicated by cerebral infarction and in 43% of episodes without cerebral infarction (p<0.001).

Table 2. Complications and outcome in patients with and without cerebral infarctions complicating bacterial meningitis.

Characteristic Cerebral infarctions (n=174)

No cerebral infarction (n=522)

P value

Systemic complications Cardiorespiratory failure 75/174 (43%) 126/522 (24%) <0.001 Hyponatraemiaa 52/161 (32%) 134/499 (27%) 0.182 Fever during admission 154/168 (92%) 451/503 (90%) 0.450Persistent feverb 30/158 (19%) 54/460 (12%) 0.043Recurrent feverc 52/154 (34%) 109/449 (24%) 0.016Neurologic complications Impairment of consciousness 101/174 (58%) 175/522 (34%) <0.001 Hearing impairment 50/174 (29%) 94/522 (18%) 0.002 Seizures 49/173 (28%) 58/514 (11%) <0.001 Glasgow Outcome Scale score 1 (death) 55/174 (32%) 88/522 (17%) <0.001 2 (vegetative state) 2/174 (1%) 1/522 (0,2%) 0.095 3 (severe disability) 16/174 (9%) 8/522 (2%) <0.001 4 (moderate disability) 35/174 (20%) 32/522 (6%) <0.001 5 (mild or no disability) 66/174 (38%) 393/522 (75%) <0.001Cause of deathd

Systemic 25/55 (45%) 54/88 (61%) 0.06 Neurologic 30/55 (55%) 34/88 (39%) 0.06

a Hyponatremia was defined as a serum sodium level <135 mmol/L. b Persistent fever is defined as fever that continued longer than 10 days after initiation of appropriate antibiotic therapy. c Recurrent fever is defined as a (rectal) temperature of 38 ºC or higher occurring after at least one afebrile day during the course of hospitalization. d Evaluated in patients who died within 2 weeks after admission.

Patients with cerebral infarction had higher proportions of systemic and neurologic complications (Table 2): cardiorespiratory failure in 43%, impairment of consciousness in 58%, and seizures in 28%. There was a higher rate of unfavorable outcome in patients with cerebral infarctions: 108 of 174 (62%)

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patients with cerebral infarctions compared to 129 of 522 (25%) patients without cerebral infarctions (p<0.001). Overall, 55 of 174 (32%) patients with cerebral infarctions died, compared to 88 of 522 (17%) patients without cerebral infarction (p<0.001). The majority (55%) of patients with cerebral infarctions died due to a neurologic cause, whereas death was due to a systemic cause in most patients without infarctions (61%; p=0.06). The kappa for the classification of cause of death was 0.60. Death occurred in 45% of patients with definite cerebral infarction and in 25% of patients with probable cerebral infarction.

Table 3. Multivariate analysis of factors associated with cerebral infarction.a

Characteristic All patients Odds ratio (95% CI)

P value Adjusted for bacterial cause Odds ratio (95% CI)

P value

Age 1.02 (1.01-1.03) 0.001 1.02 (1.00-1.03) 0.012Predisposing conditions Otitis/sinusitis 1.58 (0.98-2.54) 0.061 1.13 (0.67-1.91) 0.638 Immunocompromised stateb 1.52 (0.89-2.58) 0.124 1.42 (0.83-2.44) 0.197 Pneumoniae 1.08 (0.57-2.06) 0.806 1.23 (0.64-2.36) 0.540Clinical characteristics on admission Score on Glasgow Coma Scale 0.92 (0.86-0.99) 0.029 0.94 (0.87-1.01) 0.097 Heart rate 1.00 (0.99-1.01) 0.852 1.00 (0.99-1.01) 0.837Laboratory features ESR (mm/h) 1.13 (1.01-1.26) 0.033 1.14 (1.02-1.27) 0.025 CSF white cell count <1000/mm³ 1.67 (1.04-2.67) 0.035 1.56 (0.97-2.53) 0.069CSF culture Streptococcus pneumoniae 2.25 (1.34-3.77) 0.002

a OR’s are calculated for 1 year increments for age, per 20 mm per hour for erythrocyte sedimentation rate (ESR), per 100.000 per mm3 and per one-point decrease on the Glasgow Coma Scale. b Immunocompromised state is defined as the use of immunosuppressive drugs, presence of asplenia, diabetes mellitus, alcoholism, or infection with HIV.

In the multivariate analysis, advanced age, a low score on Glasgow Coma Scale on admission, a high erythrocyte sedimentation rate and a CSF leukocyte count below 1000 cells/mm3 were identified as risk factors for cerebral infarction (Table 3). After correction for bacterial cause, advanced age and high erythrocyte sedimentation rate remained independent risk factors for cerebral infarctions. Cerebral infarction was independently related with unfavorable outcome (OR 3.37; 95% CI 2.19-5.21; p<0.001; Table 4).

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Table 4. Factors associated with unfavorable outcome in multivariate analysis.a

Characteristic Odds ratio (95% CI) P valueAge 1.02 (1.01-1.03) 0.001Score on Glasgow Coma Scale 0.86 (0.80-0.92) <0.001CSF leukocyte count <1000/mm3 4.55 (2.95-7.04) <0.001Streptococcus pneumoniae 2.63 (1.71-4.04) <0.001Cerebral infarction 3.37 (2.19-5.21) <0.001

a OR’s are calculated in 1 year increments for age and per one-point decrease on the Glasgow Coma Scale.

Discussion

Our study shows that cerebral infarction is a common and severe complication, occurring in 25% of adults with bacterial meningitis, resulting in a high mortality rate (32%). Cerebral infarction was independently related with unfavorable outcome. This high incidence of cerebrovascular complications is in agreement with results reported by others.2, 4, 8

In a multivariate analysis we identified advanced age, a decreased level of consciousness, parameters of systemic inflammation, and infection with S. pneumoniae as factors predicting the development of cerebral infarction. First, advanced age is a well-known general risk factor for cerebral infarction.10 The higher incidence of atherosclerosis in the elderly may predispose for cerebral infarction during bacterial meningitis. Second, a decreased level of consciousness has previously been described as a major marker for severity of cerebral inflammation in bacterial meningitis.11 Apparently, the severity of inflammation is directly related to the risk of cerebral infarction. Third, a low CSF WBC and a high ESR on admission have both been described as markers of the inflammatory response in the systemic compartment and sepsis.12 Our results are in line with those of a retrospective study in 68 meningitis patients describing a decreased level of consciousness and low CSF white blood cell count to be risk factors for cerebral infarctions in a univariate analysis.7 However, only six patients in this previous study had cerebral infarctions, limiting the power of the study to correct for possible confounders.

Cerebral infarctions in bacterial meningitis have previously been attributed to cerebral vasculitis, after autopsy studies in the 1950s and 1960s described inflammatory infiltrations of cerebral arteries and veins.13-15 Clinical studies have described segmental arterial narrowing on cerebral angiography in

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patients with ischemic stroke complicating bacterial meningitis.2, 16 However, cerebral infarctions have also been described in patients with a normal cerebral angiography and abnormal angiographies have been described in patients with no clinical signs of vasculitis.8 Vasospasm has also been implicated in the pathogenesis of ischemic stroke in bacterial meningitis. A transcranial Doppler ultrasonography study in 22 bacterial meningitis patients showed increased cerebral blood flow velocities in 18 patients, of which two had definite cerebral infarctions.17 This increased cerebral blood flow was attributed to vasospasm, although arterial narrowing due to other causes (e.g., vasculitis, arterial thrombosis) will cause a similar increase in cerebral blood flow. In recent years accumulating data shows that severe infection result in activation of the coagulation pathway.6, 18 Activation of the coagulation cascade and inhibition of the fibrinolysis pathway were also shown in patients with bacterial meningitis, especially in patients who have cerebral infarctions as a complication.5, 19 A recent autopsy study showed that fibrin thrombi and cerebral infarctions were mostly present in the absence of inflammatory vessel wall infiltrates suggesting that diffuse cerebral intravascular coagulation might be an additional mechanism causing ischemic stroke in pneumococcal meningitis.5, 20

Several therapies have been evaluated to decrease the rate of cerebral infarctions in bacterial meningitis patients. A small trial performed in 1976-1977 evaluated heparin therapy in 15 bacterial meningitis patients and showed increased mortality in the seven patients treated with heparin.21 Activated protein C (APC) is an endogenous protein that promotes fibrinolysis and inhibits thrombosis and inflammation, that has shown to benefit patients with severe sepsis.22 However, the 128 patients with bacterial meningitis included in a retrospective analysis of 4096 patients included in APC trials had a high rate of intracranial hemorrhage.23 Therefore, heparin and APC are contra-indicated in bacterial meningitis patients. Antiplatelet agents to prevent stroke have only been studied in tuberculous meningitis.24 In this trial 118 patients with tuberculous meningitis were randomized to aspirin or placebo treatment. Aspirin resulted in an absolute risk reduction of stroke of 19.1% and a significant reduction in mortality compared to placebo (22 vs. 43%). Potential targets for new therapies may be identified by genetic association studies. Recently, a meta-analysis showed a strong association of genetic variation in the plasminogen activator inhibitor 1 gene with vascular complications and mortality in meningococcal disease (including meningitis and sepsis cases).2 Targeting adjunctive treatment to patients with a genetically

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increased risk for vascular complications may provide benefits while limiting the risks in the whole population of bacterial meningitis patients.25

The study was performed nationwide and was descriptive by nature. As a result patients did not receive cranial imaging according to a pre-specified protocol, and cerebral infarctions were diagnosed clinically and/or by the absence of abnormalities on cranial imaging, which is common in the acute phase of cerebral infarctions. Since stroke was more common in individuals with sinusitis or otitis, the possibility that many of the ‘‘probable’’ strokes actually had cerebritis from contiguous spread of infection cannot be excluded. Although infarctions were considered arterial in most cases, our data does not allow a clear distinction between venous and arterial infarctions, since no vascular imaging studies were performed and results of post-mortem examinations, if performed, were not available. The use of diffusion-weighted MRI could result in a higher proportion of neuro-imaging confirmed cerebral infarctions in adults with bacterial meningitis. A further limitation of our study was that only patients with positive CSF cultures were included. Negative CSF cultures are estimated to occur in 11-30% of patients with bacterial meningitis.3, 4, 25, 26 However, no significant differences in clinical presentation have been reported between patients with culture-positive bacterial meningitis and patients with culture-negative bacterial meningitis.4, 26, 27 In addition, the successful implementation of dexamethasone in the Netherlands has led to a significant reduction of mortality and unfavorable outcome in patients with pneumococcal meningitis.28, 29 Most patients in our current study did not receive steroid therapy and therefore the rate of cerebral infarction may be higher than in patients treated with dexamethasone.28, 30 Finally, the epidemiology of bacterial meningitis has changed as a result of the widespread use of conjugate vaccines.1 The rates of bacterial meningitis have decreased since 1998, but the disease still often results in death.31 S. pneumoniae is now the most common etiological agent of bacterial meningitis in the United States and Europe, accounting for approximately two thirds of adult cases in the United States and the Netherlands.29,

31 Our study showed that this group in particular is at risk for cerebral infarction. In conclusion, we found that cerebral infarction is a common and severe

complication in adults with community-acquired bacterial meningitis. Preventing cerebral infarctions will be important in reducing the high morbidity and mortality rate in adults with community-acquired bacterial meningitis.

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References

1. Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev 2010; 23: 467-92.

2. Kastenbauer S, Pfister HW. Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Brain 2003; 126: 1015-25.


4. Durand ML, Calderwood SB, Weber DJ et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993; 328: 21-8.

5. Vergouwen MD, Schut ES, Troost D, van de Beek D. Diffuse cerebral intravascular coagulation and cerebral infarction in pneumococcal meningitis. Neurocrit Care 2010; 13: 217-27.

6. Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, de Gans J. Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series. Lancet Neurol 2006; 5: 123-9.

7. Katchanov J, Heuschmann PU, Endres M, Weber JR. Cerebral infarction in bacterial meningitis: predictive factors and outcome. J Neurol 2010; 257: 716-20.

8. Pfister HW, Borasio GD, Dirnagl U, Bauer M, Einhaupl KM. Cerebrovascular complications of bacterial meningitis in adults. Neurology 1992; 42: 1497-504.

9. McMillan DA, Lin CY, Aronin SI, Quagliarello VJ. Community-acquired bacterial meningitis in adults: categorization of causes and timing of death. Clin Infect Dis 2001; 33: 969-75.

10. Grau AJ, Weimar C, Buggle F et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke. Stroke 2001; 32: 2559-66.

11. Roine I, Peltola H, Fernandez J et al. Influence of admission findings on death and neurological outcome from childhood bacterial meningitis. Clin Infect Dis 2008; 46: 1248-52.

12. Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, de Gans J. Attenuated cerebrospinal fluid leukocyte count and sepsis in adults with pneumococcal meningitis: a prospective cohort study. BMC Infect Dis 2006; 6: 149.

13. Cairns H, Russell DS. Cerebral arteritis and phlebitis in pneumococcal meningitis. J Pathol Bacteriol 1946; 58: 649-65.

14. Buchan GC, Alvord EC Jr. Diffuse necrosis of subcortical white matter associated with bacterial meningitis. Neurology 1969; 19: 1-9.

15. Swartz MN, Dodge PR. Bacterial meningitis - a review of selected aspects. General clinical features, special problems and unusual meningeal reaction mimicking bacterial meningitis. N Engl J Med 1965; 272: 842-8.

16. Weisfelt M, de Gans J, van der Poll T, van de Beek D. Pneumococcal meningitis in adults: new approaches to management and prevention. Lancet Neurol 2006; 5: 332-42.

17. Ries S, Schminke U, Fassbender K, Daffertshofer M, Steinke W, Hennerici M. Cerebrovascular involvement in the acute phase of bacterial meningitis. J Neurol 1997; 244: 51-5.

18. Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109: 2698-704.

19. Weisfelt M, Determann RM, de Gans J et al. Procoagulant and fibrinolytic activity in cerebrospinal fluid from adults with bacterial meningitis. J Infect 2007; 54: 545-50.

20. Schut ES, Brouwer MC, de Gans J, Florquin S, Troost D, van de Beek D. Delayed cerebral thrombosis after initial good recovery from pneumococcal meningitis. Neurology 2009; 73: 1988-95.

21. Macfarlane JT, Cleland PG, Attai ED, Greenwood BM. Failure of heparin to alter the outcome of pneumococcal meningitis. Br Med J 1977; 2: 1522.

22. Laterre PF. Clinical trials in severe sepsis with drotrecogin alfa (activated). Crit Care 2007; 11(Suppl 5): S5.23. Vincent JL, Nadel S, Kutsogiannis DJ et al. Drotrecogin alfa (activated) in patients with severe sepsis

presenting with purpura fulminans, meningitis, or meningococcal disease: a retrospective analysis of patients enrolled in recent clinical studies. Crit Care 2005; 9: R331-43.

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24. Misra UK, Kalita J, Nair PP. Role of aspirin in tuberculous meningitis: a randomised open-label placebo controlled trial. J Neurol Sc 2010; 293: 12-7.

25. Brouwer MC, Read RC, van de Beek D. Host genetics and outcome in meningococcal disease: a systematic review and metaanalysis. Lancet Infect Dis 2010; 10: 262-74.

26. Sigurdardottir B, Bjornsson OM, Jonsdottir KE, Erlendsdottir H, Gudmundsson S. Acute bacterial meningitis in adults: a 20-year overview. Arch Intern Med 1997; 157: 425-30.

27. Tunkel AR. Bacterial meningitis. Philadelphia: Lippincott, Williams & Wilkins; 2001. 28. de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347:

1549-56. 29. Brouwer MC, Heckenberg SG, de Gans J, Spanjaard L, Reitsma JB, van de Beek D. Nationwide


30. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis 2004; 4: 139-43.

31. Thigpen MC, Whitney CG, Messonnier NE et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med 2011; 364: 2016-25.

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CHAPTER 4

DELAYED CEREBRAL THROMBOSIS IN BACTERIAL MENINGITIS:

A PROSPECTIVE COHORT STUDY

Marjolein J. Lucas, Matthijs C. Brouwer, Diederik van de Beek

Intensive Care Medicine 2013; 39: 866-71

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Abstract

Background To study the incidence and clinical characteristics of delayed cerebral thrombosis in bacterial meningitis patients.

Methods We assessed the incidence and clinical characteristics of delayed cerebral thrombosis in adults with cerebrospinal fluid (CSF) culture proven community-acquired bacterial meningitis included in a prospective nationwide study in the Netherlands performed from 2006 to 2012.

Results Delayed cerebral thrombosis occurred in 11 of 1032 episodes (1.1%). CSF culture yielded Streptococcus pneumoniae in ten patients and Listeria monocytogenes in one. Adjunctive dexamethasone therapy was administered before or with the first dose of antibiotics in 9 of 11 patients; two patients were initially not treated with dexamethasone. All patients made good initial recovery, followed by sudden deterioration after 7-42 days. Cranial imaging studies showed multiple cerebral infarctions in all patients. The outcome was unfavorable in all but one patient. In an explorative analysis, patients with delayed cerebral thrombosis had eightfold higher complement C5a CSF concentrations on the diagnostic lumbar puncture as compared in those without delayed cerebral thrombosis (p=0.04).

Conclusion Delayed cerebral thrombosis is a rare but devastating complication of bacterial meningitis. Adjunctive dexamethasone therapy seems to predispose patients with bacterial meningitis to this complication. We found some evidence that this thrombotic complication is associated with activation of the complement system.

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Introduction

Cerebrovascular complications are common in patients with bacterial meningitis with reported rates between 10 and 36%.1-4 In 2009 we reported six patients with a delayed cerebral thrombosis complicating pneumococcal meningitis who suddenly deteriorated 7-19 days after excellent initial recovery.5 All patients with delayed cerebral thrombosis were treated with adjunctive dexamethasone, suggesting a causal relationship with this newly introduced therapy. We then analyzed the incidence, causative pathogens, relation with adjunctive dexamethasone, and outcome of delayed cerebral thrombosis in adult community-acquired bacterial meningitis patients included in a prospective nationwide cohort study.6

Methods

In a nationwide cohort study in the Netherlands we prospectively included episodes of community-acquired bacterial meningitis confirmed by culture of cerebrospinal fluid (CSF) in adults between 2006 and 2012.7, 8 Inclusion and exclusion criteria are described elsewhere.9 Patients were classified as having delayed cerebral thrombosis if they made good initial recovery with sudden deterioration after the first week of admission caused by cerebral infarctions. Outcome was graded according to the Glasgow Outcome Scale.10 A favorable outcome was defined as a score of 5 and an unfavorable outcome as a score of 1-4. CSF was obtained from the diagnostic lumbar puncture in a subset of patients and analyzed for levels of C3a, C5a, sC5b-9, IL1-b, IL-6, TNF-alpha, and PAI-1 using the Microvue C5a and sC5b-9 Quidel ELISA kits and Milliplex Luminex assays. The Mann-Whitney U test was used to identify differences between groups with SPSS 18.0, and a p value <0.05 was regarded as significant. The study was approved by the ethics committee of the Academic Medical Center, Amsterdam, the Netherlands.

Results

From 2006 to 2012, 1032 episodes of community-acquired bacterial meningitis were included in the cohort. CSF culture yielded Streptococcus pneumoniae in 741 episodes (72%), N. meningitidis in 112 episodes (11%), and other bacteria

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in 179 episodes (17%). Delayed cerebral thrombosis occurred in 11 patients (1.1%; Table 1). Two of these patients have been reported previously.5 CSF culture yielded S. pneumoniae in ten patients and Listeria monocytogenes in one patient. On admission cranial CT was performed in nine patients and did not show cerebral infarctions. Adjunctive dexamethasone therapy was administered before or with the first dose of antibiotics in 9 of 11 patients (82%). All nine received dexamethasone 10 mg four times daily, eight patients for 4 days and one patient for 6 days.

Table 1. Initial presentation of patients developing delayed cerebral thrombosis complicating bacterial meningitis.a

Characteristic Current case series(n=11)

Other cases in literature(n=7)

Total(n=18)

Age 55 (51-66) 52 (41-59) 54 (45-64)Female 7/11 (64%) 1/7 (14%) 8/18 (44%)Predisposing conditions Otitis/sinusitis 5/11 (45%) 2/7 (28%) 7/18 (39%) Immunocompromised stateb 3/11 (27%) 1/7 (14%) 4/18 (22%)Symptoms on presentation Headache 6/11 (55%) 5/7 (71%) 11/18 (61%) Triad of fever, neck stiffness, and change in mental status

6/11 (55%) 7/7 (100%) 13/18 (72%)

Focal neurologic signs on admission 1/11 (9%) 1/7 (14%) 2/18 (11%)Score on Glasgow Coma Scalec 11 (9-14) 10 (9-13) 11 (9-14) <14 (change in mental status) 8/11 (73%) 4/5 (80%) 13/18 (72%) <8 (indicating coma) 1/11 (9%) 0 1/18 (5%)Initial CSF indexes of inflammationd,e

Leukocyte count (/mm³) 1843 (217-2610) 1374 (109-9743) 1776 (131-2155) Protein (g/L) 5.1 (3.1-6.9) 5.6 (2.4-7.4) 5.3 (3.0-6.4) CSF: blood glucose ratio 0.02 (0-0.04) Not reported 0.02 (0-0.04)CSF culture Streptococcus pneumoniaef 10/11 (91%) 7/7 (100%) 17/18 (95%) Listeria monocytogenesg 1/11 (9%) 0 1/18 (5%)Initially treated with adjunctive dexamethasone

9/11 (82%) 6/7 (86%) 15/18 (83%)

Abnormal cranial CT/MRIh 4/9 (44%) 3/6 (50%) 7/15 (47%)

a Data are number / number evaluated (%) or median (interquartile range). b Immunocompromised state is defined as the use of immunosuppressive drugs, presence of asplenia, diabetes mellitus, alcoholism, or infection with HIV. c Score on GCS was determined in all patients included in the current series and in 5 patients in the literature. d CSF leukocyte counts, CSF protein level and CSF: blood to glucose ratio were determined in 10 patients included in the current studies. e CSF leukocyte counts were determined in 5 and CSF protein levels in 6 patients in the literature. f Serotype 3 in 3 patients, serotype 6B, 7F, 8, 9V, 10A and 18C each in 1 patient. g Serotype 4b. h Sinusitis in 3, and an old vascular lesion, edema of the right parietal lobe and combined mastoiditis and pneumatocephalus each in 1 patient.

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Table 2. Clinical characteristics at time of deterioration of patients with delayed cerebral thrombosis complicating bacterial meningitis.a

Characteristic Current case series(n=11)

Other cases in literature(n=7)

Total(n=18)

Days between admission and deterioration

13 (9-20) 11 (7-20) 12 (8-20)

Symptoms and signs Fever 3/11 (27%) 6/7 (86%) 9/18 (50%) Headache 1/11 (9%) 4/7 (57%) 5/18 (28%) Impairment of consciousness 8/11 (73%) 6/7 (86%) 14/18 (78%) Hemiparesis 9/11 (82%) 3/7 (43%) 12/18 (67%) Seizures 3/11 (27%) 1/7 (14%) 4/18 (22%)CSF indexes of inflammationb,c

Leukocyte count (/mm³) 1090 (48-1880) 166 (28-3216) 500 (47-1816) Protein (g/L) 1.7 (1.3-2.4) 3.0 (1.5-7.1) 1.7 (1.5-2.9) Glucose concentration (mg/dL) 45 (29-52) 39 (13-63) 45 (29-53)CSF culture negative 7/7 (100%) 5/5 (100%) 12/12 (100%)Infarctions on cranial CT/MRI 11/11 (100%) 7/7 (100%) 18/18 (100%)Therapy after secondary deterioration High-dose corticosteroids 6/11 (54%) 6/7 (86%) 12/18 (67%) Prolonged or restarted antibiotics 4/11 (36%) 5/7 (71%) 9/18 (50%)Glasgow Outcome Scale score 1 (death) 3/11 (27%) 3/7 (43%) 6/18 (33%) 3 (severe disability) 7/11 (64%) 4/7 (57%) 11/18 (61%) 5 (mild or no disability) 1/11 (9%) 0 1/18 (5%)Neurologic sequelae Hemiparesis 7/8 (64%) 2/4 (50%) 9/12 (75%) Apathy 3/8 (37%) 2/4 (50%) 5/12 (42%) Cognitive impairment 3/8 (37%) 0 3/12 (25%)

a Data are number / number evaluated (%) or median (interquartile range). b CSF leukocyte counts were determined in 6 patients and CSF protein and glucose concentrations were determined in 7 patients included in the current studies. c CSF leukocyte counts and CSF protein and glucose concentrations were determined in 5 patients in the literature.

All patients made an excellent initial recovery in the 1st week of admission. They were either ready for discharge or discharged. Seven to 42 days after admission (median 13 days, IQR 9-20), they suddenly deteriorated with impaired consciousness, focal neurologic abnormalities, and seizures (Table 2). Neuro-imaging showed multiple infarctions in the posterior and anterior cerebral circulation in all patients (Figure 1). Echocardiography was performed in seven patients, and endocarditis was ruled out in all. Lumbar puncture was repeated after clinical deterioration in seven patients and showed persistent or recurrent inflammation and negative cultures in all. Six of 11 patients (55%) received high-dose corticosteroids after secondary deterioration. Antibiotic treatment was prolonged or restarted after clinical

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deterioration in four patients. The outcomes were poor: three patients died, seven remained severely disabled, and only one patient had a good recovery (Table 2). Of the six patients treated with corticosteroids on deterioration, four survived, and one of them had a favorable outcome.

Figure 1. Neuro-imaging results in 11 patients with delayed cerebral thrombosis complicating bacterial meningitis.

We analyzed CSF markers of inflammation, coagulation, and fibrinolysis in three bacterial meningitis patients with and 296 without delayed cerebral thrombosis. Concentrations of C5a (median, 76.1 vs. 9.5 ng/mL; p=0.041) and sC5b-9 (median, 9.614 vs. 1.810 ng/mL; p=0.011) were higher in patients who would develop delayed cerebral thrombosis later during the clinical course (Figure 2). We identified seven additional patients with delayed cerebral thrombosis in the literature: we described four of these cases in the 2009 publication5 and added three

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cases published after this study.11-13 Combining our patients and those reported in the literature, we found that all but 1 patient had pneumococcal meningitis, and 15 (83%) were initially treated with adjunctive dexamethasone therapy (Tables 1, 2). Before clinical deterioration all 18 patients were awake and fully conscious. The outcomes were poor, with 6 patients dying, 11 surviving with severe disability, and only 1 patient with mild or no disability.

Figure 2. CSF levels of C5a and sC5b-9 on diagnostic CSF puncture in bacterial meningitis patients without or with delayed cerebral thrombosis (DCT) complicating the clinical course. Line represents median; dots represent levels in individual patients.

Discussion

Delayed cerebral thrombosis is a rare but devastating complication of bacterial meningitis found in 1% of cases. Dexamethasone therapy seemed to predispose patients to this complication, as delayed cerebral thrombosis was not identified in two cohort studies performed before the introduction of dexamethasone.9, 14 The current case series, however, shows that this complication also occurred in patients who were not treated with dexamethasone. Adjunctive dexamethasone treatment has been shown to decrease mortality in community-acquired bacterial meningitis in adults8, 15-18 and has been implemented on a large scale in patients with pneumococcal meningitis.8, 19 We reported a decline in mortality from 30 to 20% after the introduction of adjunctive dexamethasone therapy in the Netherlands.8 Importantly, this beneficial effect of dexamethasone was reached notwithstanding the devastating outcome of the current 11 patients with delayed

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cerebral thrombosis. Therefore, the risk of delayed cerebral thrombosis should not be a ground to withhold dexamethasone.

In an exploratory analysis we found that patients with delayed cerebral thrombosis had significantly higher complement C5a and C5b-9 CSF concentrations on admission. A previous study showed that C5 fragment levels in CSF of patients with bacterial meningitis correlated with disease severity and poor outcome.7 The mechanism of delayed cerebral thrombosis might be partly complement-mediated through C5a. Interaction of the complement system with coagulation and fibrinolysis was shown to be mediated by C5a in several thrombotic disorders.20-24

Although the characteristics of the interaction of steroids and the complement system have not been elucidated, an initial inhibitory effect of dexamethasone on complement activation may explain a rebound effect of a C5a-mediated inflammatory reaction in delayed cerebral thrombosis patients. In light of this explanation, some authors suggest a gradual withdrawal of dexamethasone rather than the abruptly terminated 4-day course.13 However, as the 4-day regimen had been shown to be effective in randomized clinical trials and a meta-analysis, this regimen should not be changed without substantial evidence of equal or increased benefit.8, 15, 16 Another explanation may be that high-dose glucocorticosteroids can tip the balance toward sustained coagulation and platelet aggregation by influencing the tissue factor/factor VII pathway, which is also activated and upregulated by C5a.21

This study has several limitations. First, not all patients in the cohort that clinically deteriorated received cranial imaging. In some cases the prognosis was determined by co-morbid conditions, and therefore no further investigations were performed. This could have led to an underestimation of the incidence of delayed cerebral thrombosis. A further limitation of our study was that patients with negative CSF cultures were not included, comprising 11-30% of patients.9,

25-27 However, no significant differences in clinical presentation have been reported between patients with culture-positive bacterial meningitis and culture-negative bacterial meningitis.

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References


2. Vergouwen MD, Schut ES, Troost D, Van De Beek D. Diffuse cerebral intravascular coagulation and cerebral infarction in pneumococcal meningitis. Neurocrit Care 2010; 13: 217-227.

3. Weisfelt M, Van De Beek D, Spanjaard L, Reitsma JB, De Gans J. Clinical features, complications, and outcome in adults with pneumococcal meningitis: a prospective case series. Lancet Neurol 2006; 5: 123-129.

4. Schut ES, Lucas MJ, Brouwer MC, Vergouwen MD, Van Der Ende A, Van De Beek D. Cerebral infarction in adults with bacterial meningitis. Neurocrit Care 2012; 16: 421-427.

5. Schut ES, Brouwer MC, De Gans J, Florquin S, Troost D, Van De Beek D. Delayed cerebral thrombosis after initial good recovery from pneumococcal meningitis. Neurology 2009; 73: 1988-1995.

6. Lucas MJ, Brouwer MC, Van De Beek D. Delayed cerebral thrombosis in bacterial meningitis: a prospective cohort study. In: Proceedings of the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, 9-12 September 2012 (abstract L1-1223).

7. Woehrl B, Brouwer MC, Murr C, Heckenberg SG, Baas F, Pfister HW et al . Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis. J Clin Invest 2011; 121: 3943-3953.

8. Brouwer MC, Heckenberg SG, De Gans J, Spanjaard L, Reitsma JB, Van De Beek D. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology 2010; 75: 1533-1539.

9. Van De Beek D, De Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351: 1849-1859.

10. Jennett B, Teasdale G, Braakman R, Minderhoud J, Knill-Jones R. Predicting outcome in individual patients after severe head injury. Lancet 1976; 1: 1031-1034.

11. Kawaguchi T, Ogawa Y, Inoue T, Tominaga T. Cerebral arteritis with extremely late onset secondary to bacterial meningitis - case report. Neurol Med Chir 2011; 51: 302-305.

12. Kato Y, Takeda H, Dembo T, Tanahashi N. Delayed recurrent ischemic stroke after initial good recovery from pneumococcal meningitis. Intern Med 2012; 51: 647-650.

13. Cm Rice, Ramamoorthi M, Renowden SA, Heywood P, Whone AL, Scolding NJ. Cerebral ischaemia in the context of improving, steroid-treated pneumococcal meningitis. QJM 2012; 105: 473-475.

14. Klein M, Koedel U, Kastenbauer S, Pfister HW, Van De Beek D, Schut ES et al. Delayed cerebral thrombosis after initial good recovery from pneumococcal meningitis: past as prologue: delayed stroke as a parainfectious process of bacterial meningitis? Neurology 2010; 75: 193-194.

15. De Gans J, Van De Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347: 1549-1556.

16. Brouwer MC, Mcintyre P, De Gans J, Prasad K, Van De Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2010; 9: Cd004405.

17. Van De Beek D, De Gans J, Tunkel AR, Wijdicks EF. Community acquired bacterial meningitis in adults. N Engl J Med 2006; 354: 44-53.

18. Van De Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012; 380: 1693-1702.

19. Korshin A, Koster-Rasmussen R, Meyer CN. Adjunctive steroid treatment: local guidelines and patient outcome in adult bacterial meningitis. Scand J Infect Dis 2007; 39: 963-968.

20. Ritis K, Doumas M, Mastellos D, Micheli A, Giaglis S, Magotti P et al. A novel C5a receptor-tissue factor Cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 2006; 177: 4794-4802.

21. Kourtzelis I, Markiewski MM, Doumas M, Rafail S, Kambas K, Mitroulis I et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 2010; 116: 631-639.

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22. Huber-Lang M, Sarma JV, Rittirsch D, Schreiber H, Weiss M, Flierl M et al. Changes in the novel orphan, C5a receptor (C5l2), during experimental sepsis and sepsis in humans. J Immunol 2005; 174: 1104-1110.

23. Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8: 776-787.

24. Kambas K, MM Markiewski, Pneumatikos IA, Rafail SS, Theodorou V, Konstantonis D et al. C5a and TNF-alpha up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome. J Immunol 2008; 180: 7368-7375.

25. Durand Ml, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS Jr et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993; 328: 21-28.

26. Brouwer MC, Read RC, Van De Beek D. Host genetics and outcome in meningococcal disease: a systematic review and meta-analysis. Lancet Infect Dis 2010; 10: 262-274.

27. Sigurdardottir B, Bjornsson OM, Jonsdottir KE, Erlendsdottir H, Gudmundsson S. Acute bacterial meningitis in adults. A 20-year overview. Arch Intern Med 1997; 157: 425-430.

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ENDOCARDITIS IN ADULTS WITH BACTERIAL MENINGITIS

Marjolein J. Lucas, Matthijs C. Brouwer, Arie van der Ende, Diederik van de Beek

Circulation 2013; 127: 2056-62

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Abstract

Background Endocarditis may precede or complicate bacterial meningitis, but the incidence and impact of endocarditis in bacterial meningitis are unknown.

Methods and results We assessed the incidence and clinical characteristics of patients with meningitis and endocarditis from a nationwide cohort study of adults with community-acquired bacterial meningitis in the Netherlands from 2006 to 2012. Endocarditis was identified in 24 of 1025 episodes (2%) of bacterial meningitis. Cultures yielded Streptococcus pneumoniae in 13 patients, Staphylococcus aureus in 8 patients, and Streptococcus agalactiae, Streptococcus pyogenes, and Streptococcus salivarius in 1 patient each. Clues leading to the diagnosis of endocarditis were cardiac murmurs, persistent or recurrent fever, a history of heart valve disease, and S. aureus as the causative pathogen of bacterial meningitis. Treatment consisted of prolonged antibiotic therapy in all patients and surgical valve replacement in 10 patients (42%). Two patients were treated with oral anticoagulants, and both developed life-threatening intracerebral hemorrhage. Systemic (70%) and neurological (54%) complications occurred frequently, leading to a high proportion of patients with unfavorable outcome (63%). Seven of 24 patients (29%) with meningitis and endocarditis died.

Conclusion Endocarditis is an uncommon coexisting condition in bacterial meningitis but is associated with a high rate of unfavorable outcome.

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Clinical Perspective

Bacterial meningitis is a serious and life-threatening disease. The predominant causative pathogen is Streptococcus pneumoniae, causing two thirds of cases. Mortality rates associated with bacterial meningitis are high, and neurological and systemic complications occur in a large proportion of patients. One of the potential complications is endocarditis. Endocarditis may precede or complicate bacterial meningitis, but the incidence and impact of endocarditis in bacterial meningitis were unknown. In a large, prospective, nationwide cohort study of adults with community-acquired bacterial meningitis, we analyzed the incidence and clinical characteristics of patients with meningitis and endocarditis. We found that although endocarditis is an uncommon coexisting condition in bacterial meningitis, it is associated with a high rate of unfavorable outcome. The most common causative pathogens were S. pneumoniae and Staphylococcus aureus. Clues leading to the diagnosis of endocarditis were cardiac murmurs, persistent or recurrent fever, preexisting heart valve disease, secondary clinical deterioration, S. aureus as the causative pathogen, atrial flutter, and splinter hemorrhages. This study indicates that cardiologic consultation should be a priority in patients with community-acquired meningitis presenting with clues for endocarditis. Because about half of patients with pneumococcal meningitis have either persistent or recurrent fever, many future patients with pneumococcal meningitis will need ancillary investigations to rule out or to establish endocarditis. In most patients, endocarditis was diagnosed during hospitalization or even after discharge, so early detection of endocarditis in patients with bacterial meningitis may lower the rate of complications and unfavorable outcome.

Introduction

Bacterial meningitis is a life-threatening disease that is associated with considerable mortality and morbidity.1-3 To prevent death and long-term disabling sequelae caused by bacterial meningitis, conjugate vaccines were developed.4 Vaccination resulted in a sharp decrease in meningococcal disease occurrence and a moderate decrease in pneumococcal meningitis.4 Currently, Streptococcus pneumoniae is responsible for 70% of the cases in Europe and the United States.5 Bacterial meningitis is often related to other foci of infection outside the central

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nervous system such as pneumonia, sinusitis, or otitis.1, 2, 5, 6 An uncommon focus of bacterial meningitis is infective endocarditis.7 Endocarditis may precede or complicate bacterial meningitis, but the impact of coexisting endocarditis for patients with meningitis is unknown. We investigated the incidence, clinical features, treatment, and outcome of patients with both bacterial meningitis and endocarditis identified in a nationwide cohort study of adults with community-acquired bacterial meningitis.

Methods

In a prospective nationwide observational cohort study in the Netherlands, we included episodes of community-acquired bacterial meningitis confirmed by culture of cerebrospinal fluid (CSF) in adults. Methods have been described in detail previously.6 In summary, all patients were ≥16 years of age and were listed in the database of the Netherlands Reference Laboratory for Bacterial Meningitis from January 2006 to March 2012. This laboratory receives CSF isolates from ≈90% of all patients with bacterial meningitis in the Netherlands. Patients with negative CSF cultures, hospital-associated meningitis, or a neurosurgical device and patients who underwent a neurosurgical operation within 1 month before bacterial meningitis onset were excluded. Patients using immunosuppressive drugs and those with asplenia, diabetes mellitus, alcoholism, or infection with HIV were considered immunocompromised. Informed consent was obtained from all participating patients or their legally authorized representatives.

Clinical data were prospectively collected by means of an online case record form. The presence of endocarditis was scored as a standard question in the case record form. The diagnosis of endocarditis was confirmed by reanalysis of the results of cardiologic analyses and echocardiography, which were collected retrospectively. Endocarditis was defined as heart valve vegetation identified by echocardiography or autopsy or the fulfillment of the Duke criteria for infective endocarditis.8, 9 At discharge, all patients underwent a neurological examination performed by a neurologist, and outcome was graded according to the Glasgow Outcome Scale. This is a well-validated measurement scale with scores varying from 1 to 5.10 A favorable outcome was defined as a score of 5; an unfavorable outcome, as a score of 1 to 4.

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The Mann-Whitney U test was used to evaluate differences between bacterial meningitis patients with and without endocarditis with respect to continuous variables, and the χ2 test and Fisher exact test were used to compare categorical variables. Statistical analyses were performed with IBM SPSS Statistics, version 19, and values of p<0.05 were considered significant. The study was approved by the ethics committee of the Academic Medical Center, Amsterdam, the Netherlands.

Results

From January 2006 to March 2012, 1025 episodes of community-acquired bacterial meningitis were included in the cohort, and endocarditis was identified in 24 of these patients (2.3%). Nine patients (38%) were female, and the median age was 63 years (quartiles 1-3, 50-71 years; Table 1). Causative organisms were S. pneumoniae in 13 patients, Staphylococcus aureus in 8 patients, and Streptococcus agalactiae, Streptococcus pyogenes, and Streptococcus salivarius in 1 patient each. Patients with endocarditis were more likely to have S. aureus as the causative pathogen compared with patients without endocarditis (8 of 24 [33%] versus 6 of 1001 [1%]; p<0.001; Table 2).

Endocarditis was identified on admission in 3 patients (12%; all had pneumococcal meningitis), during hospitalization in 19 patients (79%; median time between admission and detection, 8 days [minimum-maximum values, 2-57 days]), or after discharge (2 patients with pneumococcal meningitis, 8%). Both patients with endocarditis diagnosed after discharge had malaise, night sweats, and recurrent fever. Median time between admission and detection was shorter among patients with S. aureus meningitis compared with those with S. pneumoniae meningitis (21 patients diagnosed after admission: 3 days [quartiles 1-3, 3-8 days] versus 16 days [quartiles 1-3, 9-39 days]; p=0.015).

A cardiology consult was requested in 22 patients. Reasons for consulting a cardiologist were cardiac murmur (10 patients), persistent or recurrent fever (6 patients), preexisting heart valve disease (3 patients), secondary clinical deterioration (3 patients), S. aureus as the causative pathogen (3 patients), atrial flutter (2 patients), splinter hemorrhages (1 patient), or a combination of factors (2 factors in 7 patients, 3 factors in 1 patient). In 3 patients, no clear reason was reported for consulting a cardiologist. Two patients were not seen by a cardiologist: 1 patient died a few hours after admission, and the other patient had no clinical

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suspicion of endocarditis (the diagnosis was made during autopsy). Endocarditis was confirmed by echocardiography in 21 patients (transesophageal in 16 patients and transthoracic in 5 patients) and by autopsy in 1 patient. Eight patients had aortic valve endocarditis; 9 patients had mitral valve endocarditis; and 1 patient had tricuspid valve endocarditis. Four patients had involvement of 2 valves (aortic and mitral valve endocarditis in 2 patients, aortic and tricuspid valve endocarditis in 1 patient, mitral and tricuspid valve endocarditis in 1 patient). Two patients fulfilled the Duke criteria for endocarditis without a positive echocardiogram. In 1 of these patients, no echocardiography was performed because the patient died a few hours after admission. In the other patient, 1 transesophageal and 2 transthoracic echocardiographies were performed without clear findings of endocarditis. Blood cultures were positive on admission in all patients with endocarditis. Typical endocarditic skin lesions were reported in 6 patients (25%) and occurred more often in patients with S. aureus meningitis compared with patients with S. pneumoniae meningitis (4 of 8 [50%] versus 1 of 13 [8%]; p=0.05).

Patients often had predisposing conditions for infective endocarditis. Immunocompromised state was identified in 8 patients, alcohol abuse in 4, and heart valve disease in 3; 1 patient had an intracardiac device.11 Five patients (21%) presented with the triad of meningitis, endocarditis, and pneumonia caused by S. pneumonia, known as the Austrian syndrome. The majority of patients had a subacute presentation (18 of 24 [75%], defined as signs and symptoms >24 hours). Cranial computed tomography was performed on admission in 23 patients and showed abnormalities in 7 patients: cerebral infarction in 7 patients, brain edema in 2 patients, and mastoid opacification and cerebral aneurysm in 1 patient each.

The proportion of patients with at least 1 individual CSF finding predictive of bacterial meningitis (glucose level <34 mg/dL [1.9 mmol/L], ratio of CSF glucose to blood glucose <0.23, protein level >220 mg/dL, or leukocyte count >2000 per 1 mm3)12 was lower in patients with endocarditis compared with those without endocarditis (14 of 24 [58%] versus 877 of 1001 [88%]; p<0.001). Endocarditis patients with S. aureus meningitis were less likely to have at least 1 individual CSF finding predictive of bacterial meningitis as described above compared with endocarditis patients with pneumococcal meningitis (1 of 8 [13%] versus 12 of 13 [92%]; p=0.001). CSF Gram staining was performed in 21 patients and showed bacteria in 14 patients (67%).

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Table 1. Presenting symptoms of 24 bacterial meningitis patients with endocarditis.a

Clinical characteristics Values Clinical characteristics ValuesAge 63 (50-71) Focal neurologic deficits 7/24 (29%)Female 9/24 (38%) Aphasia 4/24 (17%)Predisposing conditions for endocarditis

Paresis 4/24 (17%)

Immunocompromised stateb 8/24 (33%) Blood chemistry testsg

Alcoholism 4/23 (17%) Leukocyte count (cells/mm3) 14 (11-25) Heart valve replacement 3/24 (13%) C-reactive protein (mg/L) 277 (194-349) Intracardiac device 1/24 (4%) ESR (mm/h) 44 (24-71)Antibiotic pretreatment 0/24 Indexes of inflammation in CSFh

Symptoms and signs on admission Leukocyte count (cells/mm3) 1184 (183-12400) Duration of symptoms >24 h 17/22 (77%) Protein (g/L) 1.4 (0.9-4.5) Headache 12/17 (71%) CSF: blood glucose ratio 0.2 (0-0.5) Nausea 9/18 (50%) CSF culture Temperature ≥38°C 17/22 (71%) Streptococcus pneumoniae 13/24 (54%) Triad of fever, neck stiffness, and change in mental status

10/24 (42%) Staphylococcus aureus 8/24 (33%)

Neck stiffness 20/24 (83%) Other bacteriai 3/24 (13%) Seizures 1/24 (4%) Abnormal cranial CT/MRI 7/23 (30%) Splinter hemorrhagesc 6 Generalized edema 1/23 (4%) Cardiac murmurc 10 Hypodensity consistent with

new infarction 3/23 (13%)

Systolic blood pressure (mmHg)d 130 (118-165) Old vascular lesion 2/23 (9%) Heart rate (beats/min)e 116 (90-130) Mastoid opacification 1/23 (4%) Signs of septic shockf 10/23 (43%) Cerebral aneurysm 1/23 (4%) Score on Glasgow Coma Scale 11 (9-14) Austrian syndrome 5/24 (21%) <14 (indicating change in mental status)

17/24 (71%) Time to endocarditis diagnosis (days) (median, minimum-maximum values)j

9 (2-57)

<8 (indicating coma) 4/24 (17%)

a Data are number / number evaluated (%) or median (interquartile range) unless otherwise stated. b Immunocompromised state is defined as the use of immunosuppressive drugs, presence of asplenia, diabetes mellitus, alcoholism, or infection with HIV. c Denominator unknown, not scored in the case record form. d Blood pressure was determined in 23 patients. e Heart rate was determined in 23 patients. f Defined as diastolic blood pressure <60 mmHg, systolic blood pressure ≤90 mmHg and/or heart rate ≥120/min. g Blood leukocyte count was determined in 24 patients, C-reactive protein was determined in 23 patients, ESR was determined in 15 patients. h CSF leukocyte count, protein level and glucose ratio were determined in 23 patients. i Streptococcus agalactiae, Streptococcus pyogenes and Streptococcus salivarius. j Determined in 21 patients in who endocarditis was not identified on presentation.

All patients received microbiologically adequate initial antimicrobial therapy. The median duration of antimicrobial treatment in surviving patients with endocarditis was 49 days (minimum-maximum values, 28-166 days; Table 3). Adjunctive dexamethasone therapy was administered before or with the first dose of antibiotics in 17 of 24 patients (71%), and all patients received dexamethasone

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10 mg 4 times daily for 4 days. Two patients received adjunctive dexamethasone after the first dose of antibiotics, and the remaining 5 patients were not treated with adjunctive corticosteroid therapy.

Table 2. Clinical and outcome characteristics of bacterial meningitis patients with and without endocarditis.a

Characteristic Endocarditis (n=24) No endocarditis (n=1001) P valueAge 63 (50-71) 60 (45-69) 0.30Female 9 (38%) 502 (50%) 0.22Predisposing conditions 9/24 (38%) 570/1001 (57%) 0.06 Immunocompromised stateb 8/24 (33%) 250/1001 (25%) 0.35 Alcoholism 4/23 (17%) 52/954 (6%) 0.04 Otitis/sinusitis 1/24 (4%) 332/998 (33%) 0.001 Pneumonia 6/24 (25%) 150/977 (15%) 0.20Positive blood culture 24/24 (100%) 658/879 (75%) 0.005Positive CSF Gram stain 14/21 (67%) 781/910 (86%) 0.02CSF indexes of inflammationc

Protein (g/L) 1.4 (0.9-4.5) 3.9 (2.4-6.0) 0.04CSF culture Streptococcus pneumoniae 13 (54%) 725 (72%) 0.05 Staphylococcus aureus 8 (33%) 6 (1%) <0.001Systemic complications Respiratory failure 13/23 (57%) 247/966 (26%) 0.001 Circulatory shock 9/23 (39%) 100/956 (11%) <0.001 Arthritis 4/22 (18%) 27/948 (3%) 0.004 Pneumonia 7/23 (30%) 161/923 (17%) 0.20Neurologic complications Cerebral infarction 9/24 (38%) 222/1000 (22%) 0.08 Intracerebral hemorrhage 3/24 (13%) 18/1000 (2%) 0.01Glasgow Outcome Scale score 0.017d

1 (death) 7/24 (29%) 179/1001 (18%) 2 (vegetative state) 1/24 (4%) 0 3 (severely disabled) 2/24 (8%) 45/1001 (5%) 4 (moderately disabled) 5/24 (21%) 159/1001 (16%) 5 (mild or no disability) 9/24 (38%) 615/1001 (61%)

a Data are number / number evaluated (%) or median (interquartile range) unless otherwise stated. b Immunocompromised state is defined as the use of immunosuppressive drugs, presence of asplenia, diabetes mellitus, alcoholism, or infection with HIV. c CSF protein count was determined in 23 patients with endocarditis and in 950 patients without endocarditis. d p value based on all 5 categories (Mann-Whitney U test).

The majority of patients developed complications during the clinical course (Table 3). The proportion of patients with respiratory failure (13 of 23 [57%] versus 247 of 966 [25%]; p=0.001), circulatory shock (9 of 23 [39%] versus 100 of 956 [11%]; p<0.001), and arthritis (4 of 22 [18%] versus 27 of 948 [3%]; p=0.004) was higher

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among patients with endocarditis compared with those without endocarditis. Two patients with endocarditis developed spondylodiscitis and a psoas abscess (S. aureus and S. pneumoniae in 1 patient each). Patients with endocarditis were more likely to develop cerebral infarctions (9 of 24 [38%] versus 222 of 1000 [22%]; p=0.08) and intracerebral hemorrhages (3 of 24 [13%] versus 18 of 1000 [2%]; p=0.01) compared with patients without endocarditis.

Table 3. Complications and outcome of 24 bacterial meningitis patients with endocarditis.a

Clinical characteristics ValuesSystemic complications 16/23 (70%)Spondylodiscitis 2/24Psoas abscess 2/24Respiratory failure 13/23 (57%)Persistent fever 8/22 (36%)Arthritis 4/22 (18%)Pneumonia 7/23 (30%)Neurologic complications 13/24 (54%)Focal neurologic deficits 3/22 (14%)Hearing impairment 3/18 (17%)Cerebral infarction 9/24 (38%)Intracerebral hemorrhage 3/24 (13%)Brain abscess 1/24 (4%)Duration antibiotic treatment (days, minimum-maximum values) 49 (28-166)Days between admission and discharge (days) 55 (39-80)SurgeryValve replacement 10/24 (42%)Mechanical valve 6 (25%)Tissue valve 4 (17%)Removal of ICD 1 (4%)Days between diagnosis and surgery (days, minimum-maximum values) 9 (1-45)Glasgow Outcome Scale score 1 (death) 7/24 (29%) 2 (vegetative state) 1/24 (4%) 3 (severe disability) 2/24 (8%) 4 (moderate disability) 5/24 (21%) 5 (mild or no disability) 9/24 (38%)Neurologic sequelae 8/17 (47%) Cognitive impairment 3/17 (18%) Paresis 3/17 (18%) Aphasia 2/17 (12%) Hearing loss 2/17 (12%)

a Data are number / number evaluated (%) or median (interquartile range) unless otherwise stated.

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Two patients were treated with oral anticoagulants because of a history of heart valve replacement (both aortic and mitral valve replacement with mechanic valves in both patients), and both developed intracerebral hemorrhages. Cranial imaging was performed during admission in 20 patients and was abnormal in 9 patients. New abnormalities, not present on admission, were found 5 patients and consisted of cerebral infarction in 4 patients, intracerebral hemorrhage in 3 patients, and a brain abscess in 1 patient.

Seven of 24 patients (29%) with endocarditis died (median time after admission, 25 days; minimum-maximum values, 1-72 days). Unfavorable outcome occurred in 15 of 24 patients with endocarditis (63%) compared with 386 of 1001 meningitis patients without endocarditis (39%; p=0.019). Neurological sequelae were present on discharge in 8 of 17 survivors (47%), consisting of cognitive impairment in 3 (18%), hemiparesis in 3 (18%), aphasia in 2 (12%), and hearing loss in 2 patients (12%).

Cardiac surgery was performed in 11 of 24 patients (6 patients with S. aureus and 5 patients with S. pneumoniae meningitis) and consisted of a valve replacement in 10 patients (6 mechanical valves and 4 biotissue valves [3 animal tissues and 1 allograft]) and removal of an intracardiac device (an implantable cardioverter-defibrillator) in 1 patient. Echocardiographic and surgical data in 10 patients who underwent valve surgery are presented in Table 4. Mitral valve surgery was performed in 5 patients: 4 patients received a valve replacement (3 biotissue valves and 1 mechanical valve) and 1 patient received a valve repair. Four of these 5 patients with mitral valve surgery had large vegetations on the mitral valve with echocardiography; 1 patient also had an abscess on this valve; and the mitral valve was perforated in 2 patients. Aortic valve replacement was done in 6 patients (1 biotissue valve and 5 mechanical valves): 5 patients had large vegetations, and the aortic valve was completely destroyed in 1 patient.

Table 4. Echocardiographic and surgical data in 10 patients who underwent valve surgery.

Echocardiographic information Surgical information5 patients with mitral valve involvementa

Large vegetations (n=4)Abscess (n=1)Perforation (n=2)

Replacement (n=4)Repair (n=1)Mechanical valve (n=1) Biotissue valve (n=3)

6 patients with aortic valve involvementa

Large vegetations (n=5)Destruction (n=1)

Replacement (n=6)Mechanical valve (n=5) Biotissue valve (n=1)

a One patient had both mitral and aortic valve involvement.

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The median time to cardiac surgery after diagnosis was 9 days (minimum-maximum values, 1-45 days). In 6 of 10 patients, surgery was performed after completion of the course of antibiotics for the meningitis. There was no difference in outcome between patients who were completely treated or partially treated for meningitis before cardiac surgery was performed.

Nine of 10 patients who received valve replacement (90%) survived compared with 8 of 14 patients without valve replacement (57%; p=0.17). One patient had a recurrence of prosthetic valve endocarditis 30 days after surgery, prompting surgical replacement of the prosthetic valve. Another patient underwent replacement of the prosthetic valve 5 months after surgery because the prosthetic device dehisced.

Discussion

Endocarditis is an uncommon coexisting condition in bacterial meningitis identified in 2% of patients, but it is associated with high rates of unfavorable outcome (63%). The most common causative pathogens were S. pneumoniae and S. aureus, and clues leading to the diagnosis of endocarditis were cardiac murmurs, persistent or recurrent fever, a history of heart valve disease, and S. aureus as the causative pathogen of bacterial meningitis. Therefore, cardiologic consultation should be a priority in patients with community-acquired meningitis presenting with clues for endocarditis. Because about half of patients with pneumococcal meningitis have either persistent or recurrent fever,13 many future patients with pneumococcal meningitis will need ancillary investigations to rule out or to establish endocarditis. The general recommendation for antibiotic treatment duration in patients with endocarditis and meningitis is 4 to 6 weeks, which is substantially longer than the standard 10 to 14 days for meningitis patients without endocarditis.14 Even longer courses of antibiotics are advised if the patient undergoes cardiac surgery.

Several studies suggest that combined antibiotic and surgical therapy for infective endocarditis reduces the risk of death resulting from any cause, especially among patients who have congestive heart failure, perivalvular invasive disease, or uncontrolled infection despite maximal antimicrobial therapy.15 In our series, although not significant and confounded by indication, patients who underwent valve replacement had better survival compared with those without surgery (90% versus 57%; p=0.17). The timing and indications for surgical intervention in infective endocarditis remain controversial.16 A randomized, controlled trial of 76

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patients with infective endocarditis showed that early valve surgery performed within 48 hours after diagnosis reduces the risk of death resulting from any cause or embolic events by reducing the risk of systemic embolism.16 In our 10 patients with valve replacement, surgery was performed a median of 9 days after diagnosis (minimum-maximum values, 1-45 days); only 3 patients underwent valve replacement within 48 hours.

Time between admission and detection of endocarditis was substantially shorter for patients with S. aureus meningitis compared with those with S. pneumoniae meningitis (3 versus 16 days). Previous studies have shown that patients with S. aureus meningitis almost uniformly present with a primary infection focus, most commonly pneumonia or endocarditis.17 This suggests that, in case of S. aureus infection, endocarditis precedes bacterial meningitis and that, in bacterial meningitis caused by S. pneumonia, endocarditis is a complication. In case of S. aureus infection, meningitis is caused by septic emboli originating from cardiac valve vegetations. Our finding that fewer patients with S. aureus infection had individual CSF findings predictive of bacterial meningitis compared with patients with pneumococcal infection is in line with this hypothesis.

Ischemic stroke is a common complication in all patients with bacterial meningitis, occurring in 22% of bacterial meningitis patients without endocarditis in our study. In a previous study, we showed that cerebral infarction was present in 25% of 696 patients with bacterial meningitis.18 Ischemic stroke is also a major complication in endocarditis patients; in a previous cohort study of 1437 patients, 15.2% developed cerebral infarctions.19 In patients with both bacterial meningitis and endocarditis, there seems to be an additional risk at developing ischemic stroke; 9 of 24 patients (38%) with both bacterial meningitis and endocarditis developed cerebral infarctions in our study.

Pneumococcal meningitis patients more often present with typical clinical and CSF characteristics of bacterial meningitis, and the possibility of endocarditis is perhaps considered only after the development of complications indicative of endocarditis. Early detection of endocarditis in pneumococcal meningitis patients may lower the rate of complications and unfavorable outcome. Five of 13 patients with pneumococcal meningitis had coexisting endocarditis and pneumonia, also known as the Austrian syndrome.7, 20 All patients with the Austrian syndrome had an unfavorable outcome, reflecting the severity of this condition. Whether the primary focus of infection is the meningitis or endocarditis remains difficult to distinguish because initial complaints of endocarditis can be nonspecific.

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Patients with meningitis and endocarditis should not be treated with anticoagulant therapy. Intracranial hemorrhage is a rare but devastating complication in patients with bacterial meningitis, with high rates of mortality and unfavorable outcome (65% and 95%, respectively).21 A previous study showed a 5-fold increased risk of developing intracranial hemorrhage in patients with bacterial meningitis using anticoagulant therapy.21 Patients with S. aureus meningitis and endocarditis are at even higher risk of intracerebral hemorrhage compared with other bacterial meningitis patients using anticoagulant therapy.15,

21 In these patients, discontinuation of anticoagulant therapy should be considered until the patient has recovered from the acute phase of the bacterial meningitis episode.

This study has several limitations. First, several clinical characteristics of endocarditis patients were not scored in the case record form (e.g., cardiac murmur, skin lesion, dental focus), which makes it difficult to determine their relevance in the diagnosis of endocarditis in meningitis patients. Furthermore, in patients with severe bacterial meningitis who died in the first days of admission, endocarditis may have been missed. This could have led to an underestimation of the incidence of endocarditis. Therefore, the provided incidence figures should be regarded as the minimal values. A further limitation of our study was that only patients with positive CSF cultures were included. Negative CSF cultures are estimated to occur in 11% to 30% of patients with bacterial meningitis.22, 23 However, no significant differences in clinical presentation have been reported between patients with culture-positive bacterial meningitis and culture-negative bacterial meningitis. The design of our study, a prospective cohort study, precludes firm conclusions about the mechanisms explaining the association between meningitis and endocarditis; we did not have standard baseline (on admission) echocardiographic data of all our patients.

Conclusions

Endocarditis should be considered in patients with S. aureus meningitis, a history of heart valve disease, or cardiac murmurs and in patients with clinical deterioration or persistent/ recurrent fever during admission. Endocarditis in meningitis patients is associated with a high rate of neurological and systemic complications and requires prolonged antibiotic treatment and cardiac surgery in

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a selection of patients. Anticoagulant therapy is contraindicated in the acute phase of meningitis because the risk of intracranial hemorrhages is high. Despite optimal antibiotic treatment, 63% of patients die or have long-term neurological sequelae.

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Staphylococcus aureus meningitis in adults. Scand J Infect Dis 2009; 41: 375-377.18. Schut ES, Lucas MJ, Brouwer MC, Vergouwen MD, van der Ende A, van de Beek D. Cerebral infarction

in adults with bacterial meningitis. Neurocrit Care 2012; 16: 421-427.19. Dickerman SA, Abrutyn E, Barsic B, Bouza E, Cecchi E, Moreno A et al. The relationship between the

initiation of antimicrobial therapy and the incidence of stroke in infective endocarditis: an analysis from the ICE Prospective Cohort Study (ICEPCS). Am Heart J 2007; 154: 1086-1094.

20. Aronin SI, Mukherjee SK, West JC, Cooney EL. Review of pneumococcal endocarditis in adults in the penicillin era. Clin Infect Dis 1998; 26: 165-171.

21. Mook-Kanamori BB, Fritz D, Brouwer MC, van der Ende A, van de Beek D. Intracerebral hemorrhages in adults with community associated bacterial meningitis in adults: should we reconsider anticoagulant therapy? PLoS One 2012; 7: e45271.

22. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS Jr et al. Acute bacterial meningitis in adults: a review of 493 episodes. N Engl J Med 1993; 328: 21-28.

23. Sigurdardóttir B, Björnsson OM, Jónsdóttir KE, Erlendsdóttir H, Gudmundsson S. Acute bacterial meningitis in adults: a 20-year overview. Arch Intern Med 1997; 157: 425-430.

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GROUP A STREPTOCOCCAL MENINGITIS IN ADULTS

Marjolein J. Lucas, Matthijs C. Brouwer, Sandra Bovenkerk, Wing Kit Man, Arie van der Ende, Diederik van de Beek

Journal of Infection 2015; 71: 37-42

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Abstract

Background We report on the incidence, clinical characteristics, and bacterial genotype of group A streptococcal (GAS) meningitis in the Netherlands.

Methods We assessed the incidence, clinical characteristics, and outcome of patients with GAS meningitis from a nationwide cohort study of adults with community-acquired bacterial meningitis in the Netherlands from 2006 to 2013.

Results GAS was identified in 26 of 1322 patients with community-acquired bacterial meningitis (2%); 9 cases (35%) occurred in the first four months of 2013. GAS meningitis was often preceded by otitis or sinusitis (24 of 26 [92%]) and a high proportion of patients developed complications during clinical course (19 of 26 [73%]). Subdural empyema occurred in 8 of 26 patients (35%). Nine patients underwent mastoidectomy and in 5 patients neurosurgical evacuation of the subdural empyema was performed. Five of 26 patients (19%) died and 11 of 21 surviving patients had neurologic sequelae (52%). Infection with the emm1 and cc28 GAS genotype was associated with subdural empyema (both 4 of 6 [67%] vs. 2 of 14 [14%]; p=0.037).

Conclusion GAS meningitis is an uncommon but severe disease. Patients are at risk for empyema, which is associated with infection with the emm1 and cc28 genotype.

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Introduction

Periodic increases in group A streptococcus (GAS) or Streptococcus pyogenes invasive disease have been reported for several European countries over the past decades.1, 2 Studies suggest that viral infections such as influenza may contribute to these periodic increases of disease.3, 4 GAS are differentiated on bases of antigenic variation of the emm gene encoded M protein, which is therefore an epidemiological marker, but is also considered a virulence factor.5, 6 Bacterial virulence genotypes, i.e., emm1 positive isolates, have been suggested to play a role in periodic increased GAS invasive disease. Emm1 and emm3 genotypes have been associated with severe GAS infections such as streptococcal toxic shock syndrome.7, 8

GAS has been described as an uncommon cause of bacterial meningitis, and was previously identified in 0.2-1% of adult cases.9, 10 We report on the incidence, clinical characteristics, and bacterial genotype of GAS meningitis in a prospective nationwide cohort study in the Netherlands performed from 2006 to 2013.

Material and methods

In a prospective nationwide observational cohort study in the Netherlands we included episodes of community-acquired bacterial meningitis confirmed by culture of cerebrospinal fluid in adults. Methods have been described in detail previously.11 In summary, all patients were 16 years of age or older and were listed in the database of the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM) from January 2006 to July 2013. This laboratory receives cerebrospinal fluid (CSF) isolates from approximately 90% of all patients with bacterial meningitis in the Netherlands. The NRLBM provided daily updates of the names of the hospitals where patients with bacterial meningitis had been admitted in the preceding 2-6 days and the names of physicians. Physicians were contacted, and informed consent was obtained from all participating patients or their legally authorized representatives. Physicians could also contact the investigators without report of the NRLBM for inclusion of patients. Episodes reported by physicians with negative CSF cultures could also be included if blood cultures showed GAS and CSF analysis showed at least one individual predictor of bacterial meningitis defined as a glucose level of less than 34 mg/dL

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[1.9 mmol/L], a ratio of CSF glucose to blood glucose of less than 0.23, a protein level of more than 220 mg/dL, or a leukocyte count of more than 2000/mL,12 and the clinical presentation was compatible with bacterial meningitis. Patients with hospital-associated meningitis, a neurosurgical device or patients who underwent a neurosurgical operation within one month before bacterial meningitis onset were excluded. Patients using immunosuppressive drugs, with asplenia, diabetes mellitus, alcoholism, or infection with human immunodeficiency virus (HIV) were considered immunocompromised. The presence of otitis and sinusitis as predisposing factor was based on cranial imaging findings of mastoid or sinus opacification on admission, or a clinical diagnosis by the admitting physician. At discharge, all patients underwent a neurologic examination performed by a neurologist, and outcome was graded according to the Glasgow Outcome Scale. This is a well-validated measurement scale with scores varying from 1 to 5.13 A favorable outcome was defined as a score of 5, and an unfavorable outcome as a score of 1-4. The study was approved by the ethics committee of the Academic Medical Center, Amsterdam, The Netherlands.

We performed multilocus sequence typing (MLST) and emm genotyping. MLST uses the nucleotide sequences of internal fragments of seven selected housekeeping genes to allocate unique allelic types to each of these genes. To identify clonal complexes, i.e. groups of related genotypes (ST), isolates were grouped with all isolates present in the S. pyogenes database using the eBURST algorithm14 with the software provided by the MLST website.15 Clonal complexes consisted of sequence types that shared 6 of 7 alleles with at least 1 other sequence type in the complex and named after the putative founder (i.e. the ST that has the greatest number of single-locus variants) of the group or after the most frequent ST of the group. Sequence types that did not group with other sequence types in the database were defined as singletons. The emm genotype was determined according to the emm genotypic typing scheme encoding M and M-like proteins including >150 different emm types.16, 17

We evaluated the disease occurrence with the occurrence of influenza using the database of the Dutch national institute for health care research.17 The Mann-Whitney U test was used to evaluate differences between GAS meningitis patients with and without subdural empyema with respect to continuous variables, and the chi-squared test and the Fisher’s exact test were used to compare categorical variables. Statistical analyses were performed using IBM SPSS Statistics, version 19 and p values <0.05 were considered significant.

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Results

From January 2006 to July 2013, 1824 episodes of community-acquired bacterial meningitis were identified of which 1322 were included in the cohort (Figure 1). During the study period GAS was identified in 26 patients; in 22 the bacterium was cultured from CSF and in 4 the bacterium was cultured from blood in patients with typical CSF abnormalities but negative cultures.12 Nine of 26 cases (35%) occurred in the first four months of 2013 (Figure 2).

Figure 1. Flowchart of patients included in the cohort.

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Figure 2. Incidence of GAS meningitis per 10 million adults in the Netherlands.

The median age of the 26 patients was 45 years (interquartile range [IQR] 35-58; Table 1) and 16 were female (61%). Preceding otitis or sinusitis was present in 24 of 26 patients (92%). The classical triad of fever, altered mental status and neck stiffness was present in 7 of 22 patients (32%). On admission cranial computed tomography (CT) was performed in all patients and was abnormal in 21 patients (81%): 24 had mastoid or sinus opacification (92%), 8 had pneumatocephalus (31%), 6 had generalized brain edema (23%), 4 had subdural empyema (15%), and 3 patients had cerebritis (12%; Figure 3). Lumbar puncture was performed in all patients and CSF examination showed a median leukocyte count of 842/mm3 (IQR 517-2716/mm3), a median protein count of 2.1 g/L (IQR 1.5-4.8 g/L) and a median CSF to blood glucose ratio of 0.4 mg/dL (IQR 0.3-0.5). CSF Gram staining was performed in 18 patients and showed bacteria in 13 patients (72%). Blood cultures were positive in 19 of 26 patients (73%).

All patients received microbiologically adequate initial antimicrobial therapy. Six patients were treated with combination therapy including clindamycin. Adjunctive dexamethasone therapy was administered before or with the first dose of antibiotics in 22 of 24 patients (92%); 21 patients received dexamethasone according to protocol (10 mg 4 times daily for 4 days), and 1 patient received dexamethasone 10 mg 4 times daily for 6 days.

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Table 1. Presenting symptoms of 26 patients with GAS meningitis.a

Characteristic n/N (%) Characteristic n/N (%)Age 45 (35-58) CSF examinationc

Female 16 (61%) Leukocyte count (cells/mm³) 842 (517-2716)Predisposing conditions <1000/mm³ 12/23 (52%) Otitis 21/26 (81%) Protein (g/L) 2.1 (1.5-4.8) Sinusitis 7/26 (27%) CSF: blood glucose ratio (mg/dL) 0.4 (0.3-0.5) Diabetes mellitus 2/26 (8%) Cranial CT / MRI on admissionSymptoms on presentation Abnormal 21/26 (81%) Headache 20/22 (91%) Generalized edema 6/26 (23%) Nausea 11/18 (61%) Hydrocephalus 2/26 (8%) Triad of fever, neck stiffness, and change in mental status

7/22 (32%) Recent infarction 1/26 (4%)

Focal neurologic signs on admission 12/25 (48%) Sinus or mastoid opacification 24/26 (92%) Hemiparesis 5 Mastoid abscess 1/26 (4%) Cranial nerve palsy 5 Intracranial air 8/26 (31%) Aphasia 4 Subdural empyema 4/26 (15%)Score on Glasgow Coma Scaleb 11 (10-14) Cerebritis 3/26 (12%) <14 (altered mental status) 16/25 (64%) <8 (coma) 3/25 (12%)

a Continuous data are displayed as median (interquartile range). b Score on GCS was determined in 25 patients. c CSF leukocyte counts, CSF protein level and CSF: blood to glucose ratio were determined in 23 patients.

The majority of patients developed systemic (54%) or neurological (65%) complications (Table 2). Toxic shock syndrome and diffuse intravascular coagulation occurred each in 1 patient (4%). Nine patients (35%) had subdural empyema, which was identified on admission in 4 patients and during hospitalization in 5 patients, with a median of 2 days (range 2-4 days) after admission. Cranial CT on admission did not show empyema in these patients. Cerebral abscess and cerebral sinus thrombosis occurred each in 2 patients. Either ENT or neurosurgery was performed in 12 patients (46%). Five of 9 patients with subdural empyema underwent neurosurgical evacuation through craniotomy; all of these patients had midline shift on CT or MRI (median shift 7.5 mm, range 3-8 mm). One patient died before neurosurgical evacuation could have been performed. In three patients neurosurgical evacuation was not required because of small empyema size and spontaneous recovery. One patient with hydrocephalus received external ventricular drainage.

Unfavorable functional outcome occurred in 8 patients (31%). Five (19%) died after a median of 2 days (range 2-6 days) and causes of death were brain herniation in 3 patients, cardiac arrest and toxic shock syndrome each in one patient.

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Neurologic sequelae on discharge were present in 11 of 21 survivors (52%). Most common sequelae were cognitive impairment, peripheral facial nerve palsy and hearing loss, each occurring in 3 patients (14%).

Figure 3. Cranial CT scans of different patients with GAS meningitis. a. sinus and mastoid opacification; b. mastoid opacification and intracranial air; c. subdural empyema; d. cerebral abscess.

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Table 2. Complications and outcome of 26 patients with GAS meningitis.

Characteristic n/N (%) Characteristic n/N (%)Systemic complications Surgery 12/26 (46%) Respiratory failure 10/25 (40%) Mastoidectomy 6 Circulatory shock 6/24 (25%) Mastoid drainage 3 Persistent fevera 3/24 (13%) Evacuation of empyema 5 Pneumonia 1/25 (4%) Glasgow Outcome Scale score Hyponatremia 2/22 (9%) 1 (death) 5 (19%) Toxic shock syndrome 1 2 (vegetative state) 0

3 (severe disability) 1 (4%)Neurological complications 4 (moderate disability) 2 (8%) Cerebral infarction 2/24 (8%) 5 (mild or no disability) 18/26 (70%) Cerebral abscess 2/24 (8%) Neurologic sequelae 11/21 (52%) Subdural empyema 5/24 (21%) Paresis 1/21 (5%) Hydrocephalus 1/24 (4%) Aphasia 1/21 (5%) Hearing impairment 6/24 (25%) Hearing loss 3/21 (14%) Seizures 2/25 (8%) Cognitive impairment 3/21 (14%) Cavernous sinus thrombosis 1/24 (4%) Facial nerve palsy 3/21 (14%) Sigmoid sinus thrombosis 1/24 (4%) Blindness 1/21 (5%)

a Defined as temperature >38.0 °C for more than 10 consecutive days.

Twenty of 26 bacterial strains (73%) were available for genotyping; all were isolated from CSF. MLST analysis of 20 isolates showed 13 unique sequence types (ST) belonging to 9 clonal complexes and one singleton (Table 3). The most prevalent clonal complexes (cc) were cc28 (6 episodes, 30%), cc382 and cc99 (each 2 episodes, 10%). There was no association between clonal complexes and outcome, but numbers were low.

Table 3. Emm typing and multi locus sequence typing of 20 GAS CSF isolates.

Emm type No (%) Clonal complex No (%)emm1.0 6 (30%) cc15 2 (11%)emm3.1 1 (5%) cc25 1 (5%)emm3.41 1 (5%) cc28 6 (32%)emm4.0 1 (5%) cc382 3 (16%)emm5.1 1 (5%) cc39 1 (5%)emm5.64 1 (5%) cc407 1 (5%)emm5.75 1 (5%) cc62 1 (5%)emm6.0 2 (10%) cc99 3 (16%)emm6.4 1 (5%) cc42 1 (5%)emm18.0 1 (5%) singleton 1 (5%)emm44.0 1 (5%)emm87.0 1 (5%)emm89.0 1 (5%)emm123.1 1 (5%)

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Fourteen different emm types were identified. The most prevalent emm type was emm1, which was identified in 6 of 20 episodes (30%). All 6 isolates within this emm1 type belonged to ST28. Three of these cases occurred in 2013, while the remaining three occurred in 2006, 2007 and 2011, respectively. GAS belonging to other clonal complexes occurred only once a year or less. Emm6.0 was identified in 2 patients (10%). The other emm types were emm3.1; emm3.41; emm4.0; emm5.1; emm5.64; emm5.75; emm6.4; emm18.0; emm44.0; emm87.0; emm89.0 and emm123.1, identified in one episode each. Patients with emm1 and cc28 were more likely to develop subdural empyema (4 of 6 [67%]) compared to other clonal complexes and emm types (2 of 14 [14%]) (Fisher’s exact p=0.037).

Discussion

Our study shows that GAS meningitis is an uncommon disease that occurs in patients with preceding sinusitis and mastoiditis, which is associated with high rate of severe intracranial complications (empyema and brain abscess) and systemic complications (respiratory failure and circulatory shock) leading to a high case fatality rate.

In 2013, we notified a doubling in cases with GAS meningitis in our prospective nationwide surveillance study in the Netherlands. Several temporal increases of invasive GAS infections in other Western countries have been associated to either bacterial genotype or (seasonal) influenza patterns.1, 2 We found that the number of cases caused by cc28 GAS doubled in 2013, although numbers are still low. During 2012-2013, the influenza season in the Netherlands was substantially longer as compared to previous years.17 The prolonged influenza season may have been the major contributing factor to the observed rate of GAS meningitis in 2013.4, 18 Indeed, the incidence of GAS meningitis cases has declined in 2014 (unpublished data).

A new finding is the high rate of subdural empyema (35%) associated with GAS meningitis. Subdural empyema rarely complicates bacterial meningitis, occurring in about 3% of adults with community-acquired bacterial meningitis.19 In a retrospective study over the period 1987-2000, none of the 41 patients with GAS meningitis developed empyema.20 The development of subdural empyema was associated with bacterial genotype (cc28/emm1 genotype). Although such association has not been reported previously, a surveillance study from Ireland

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noted that patients with invasive GAS disease by emm1-type strains had more severe illness as compared to all other emm types.18 The most prevalent emm type was emm1, identified in 30% of episodes, which is concordant with the proportion of emm1 identified in the surveillance study from Ireland (48.6%).18 The mechanism by which the cc28/emm1 bacterial genotype influences the occurrence of empyema remains to be elucidated.

Other important complications that may occur in GAS meningitis are cerebral abscess and sinus thrombosis. Brain abscess remains a challenging clinical problem with substantial case fatality rates21 and needs to be treated with prolonged antibiotic therapy. Cerebral sinus thrombosis complicates bacterial meningitis by continuous spread of infection from the sinuses, nose or ear, also indicated by the high rate of pneumatocephalus. As the majority of patients with GAS meningitis present with otitis or sinusitis, consultation of an ear, nose and throat specialist is warranted in all cases.

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References

1. Lamagni TL, Darenberg J, Luca-Harari B, Siljander T, Efstratiou A, Henriques-Normark B et al. Epidemiology of severe Streptococcus pyogenes disease in Europe. J Clin Microbiol 2008; 46: 2359-67.

2. Darenberg J, Henriques-Normark B, Lepp T, Tegmark-Wisell K, Tegnell A, Widgren K. Increased incidence of invasive group A streptococcal infections in Sweden, January 2012-February 2013. Euro Surveill 2013; 18: 20443.

3. van de Beek D, Hensen EF, Spanjaard L, de Gans J, Enting RH, Dankert J. Meropenem susceptibility of Neisseria meningitidis and Streptococcus pneumoniae from meningitis patients in The Netherlands. J Antimicrob Chemother 1997; 40: 895e7.

4. Zakikhany K, Degail MA, Lamagni T, Waight P, Guy R, Zhao H et al. Increase in invasive Streptococcus pyogenes and Streptococcus pneumoniae infections in England, December 2010 to January 2011. Euro Surveill 2011; 16.

5. Beall B, Facklam R, Thompson T. Sequencing emm-specific PCR products for routine and accurate typing of group A streptococci. J Clin Microbiol 1996; 34: 953-8.

6. Facklam R, Beall B, Efstratiou A, Fischetti V, Johnson D, Kaplan E et al. Emm typing and validation of provisional M types for group A streptococci. Emerg Infect Dis 1999; 5: 247-53.

7. Luca-Harari B, Darenberg J, Neal S, Siljander T, Strakova L, Tanna A et al. Clinical and microbiological characteristics of severe Streptococcus pyogenes disease in Europe. J Clin Microbiol 2009; 47: 1155-65.

8. Davies HD, McGeer A, Schwartz B, Green K, Cann D, Simor AE et al. Invasive group A streptococcal infections in Ontario, Canada. Ontario group A streptococcal study group. N Engl J Med 1996; 335: 547-54.

9. Schlech III WF, Ward JI, Band JD, Hightower A, Fraser DW, Broome CV. Bacterial meningitis in the United States, 1978 through 1981. The National Bacterial Meningitis Surveillance Study. JAMA 1985; 253: 1749-54.

10. Bruun T, Kittang BR, Mylvaganam H, Lund-Johansen M, Skrede S. Clinical, microbiological and molecular characteristics of six cases of group A streptococcal meningitis in western Norway. Scand J Infect Dis 2010; 42: 665-71.

11. Brouwer MC, Heckenberg SG, de Gans J, Spanjaard L, Reitsma JB, van de Beek D. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology 2010; 75: 1533-9.

12. Spanos A, Harrell Jr FE, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations. JAMA 1989; 262: 2700-7.


14. MLST multilocus sequence typing database. Available at: http://eburst.mlst.net, [accessed 01.08.14].15. Feil EJ, Li BC, Aanensen DM, Hanage WP, Spratt BG. eBURST: inferring patterns of evolutionary

descent among clusters of related bacterial genotypes from multilocus sequence typing data. J Bacteriol 2004; 186: 1518-30.

16. Enright MC, Spratt BG, Kalia A, Cross JH, Bessen DE. Multilocus sequence typing of Streptococcus pyogenes and the relationships between emm type and clone. Infect Immun 2001; 69: 2416-27.

17. NIVEL-Netherlands institute for health services research. Available at: http://www.nivel.nl, [accessed 01.05.14].

18. Meehan M, Murchan S, Bergin S, Flanagan O, Cunney R. Increased incidence of invasive group A streptococcal disease in Ireland, 2012 to 2013. Euro Surveill 2013; 18.

19. Jim KK, Brouwer MC, van der Ende A, van de Beek D. Subdural empyema in bacterial meningitis. Neurology 2012; 79: 2133-9.

20. van de Beek D, de Gans J, Spanjaard L, Sela S, Vermeulen M, Dankert J. Group a streptococcal meningitis in adults: report of 41 cases and a review of the literature. Clin Infect Dis 2002; 34: e32-6.

21. Brouwer MC, Tunkel AR, van de Beek D. Brain abscess. N Engl J Med 2014; 371: 1758.

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CHAPTER 7

OUTCOME IN PATIENTS WITH BACTERIAL MENINGITIS

PRESENTING WITH A MINIMAL GLASGOW COMA SCALE SCORE

Marjolein J. Lucas, Matthijs C. Brouwer, Arie van der Ende, Diederik van de Beek

Neurology: Neuroimmunology & Neuroinflammation 2014; 1: e9

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Abstract

Background In bacterial meningitis, a decreased level of consciousness is predictive for unfavorable outcome, but the clinical features and outcome in patients presenting with a minimal score on the Glasgow Coma Scale are unknown.

Methods We assessed the incidence, clinical characteristics, and outcome of patients with bacterial meningitis presenting with a minimal score on the Glasgow Coma Scale from a nationwide cohort study of adults with community-acquired bacterial meningitis in the Netherlands from 2006 to 2012.

Results Thirty of 1083 patients (3%) presented with a score of 3 on the Glasgow Coma Scale. In 22 of 30 patients (73%), the minimal Glasgow Coma Scale score could be explained by use of sedative medication or complications resulting from meningitis such as seizures, cerebral edema, and hydrocephalus. Systemic (86%) and neurologic (47%) complications occurred frequently, leading to a high proportion of patients with unfavorable outcome (77%). However, 12 of 30 patients (40%) survived and 7 patients (23%) had a good functional outcome, defined as a score of 5 on the Glasgow Outcome Scale. Patients presenting with a minimal Glasgow Coma Scale score on admission and bilaterally absent pupillary light responses, bilaterally absent corneal reflexes, or signs of septic shock on admission all died.

Conclusion Patients with community-acquired bacterial meningitis rarely present with a minimal score on the Glasgow Coma Scale, but this condition is associated with high rates of morbidity and mortality. However, 1 out of 5 of these severely ill patients will make a full recovery, stressing the continued need for aggressive supportive care in these patients.

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Introduction

Bacterial meningitis is a serious and life-threatening disease.1 Streptococcus pneumoniae and Neisseria meningitidis are the predominant causative pathogens of this disease in adults,2 causing 80-85% of all cases, with high associated morbidity and mortality rates.3-5 Many patients with bacterial meningitis present with an abnormal conscious state, and 15-20% of patients are comatose upon presentation.5 An abnormal conscious state, in most studies graded by the Glasgow Coma Scale, is a strong predictor for poor disease outcome in bacterial meningitis.5, 6 The exact cause of an abnormal conscious state in bacterial meningitis remains unclear, but it is likely caused by a complex interaction between severe brain inflammation, raised intracranial pressure (ICP), and resulting complications such as hydrocephalus, cerebral (micro)infarctions, or epileptic seizures.7-9 The evaluation of patients with an abnormal conscious state in bacterial meningitis might further be complicated by the use of antiepileptic or sedative medication.

The clinical features and outcome of the most severely ill patients, those who present with a score on the Glasgow Coma Scale of 3, are unknown. The time frame for concluding that neurologic damage is irreversible in these patients is unclear. In this study we analyzed the incidence, clinical characteristics, complications, and outcome of patients with bacterial meningitis presenting with a minimal Glasgow Coma Scale score.

Methods

In a prospective nationwide observational cohort study in the Netherlands, we included episodes of community-acquired bacterial meningitis confirmed by culture of CSF in adults. Methods of the MeninGene Study have been described in detail elsewhere.5, 10 In summary, all patients were 16 years of age or older and were listed in the database of the Netherlands Reference Laboratory for Bacterial Meningitis from January 2006 to March 2012. This laboratory receives CSF isolates from approximately 90% of all patients with bacterial meningitis in the Netherlands. Patients with negative CSF cultures, hospital-acquired meningitis, a neurosurgical device, or who underwent a neurosurgical operation within 1 month before bacterial meningitis onset were excluded. Patients using immunosuppressive drugs and those with asplenia, diabetes mellitus,

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alcoholism, or infection with human immunodeficiency virus were considered immunocompromised. Informed consent was obtained from all participating patients or, in case of decreased consciousness, from their legally authorized representatives. Clinical data, including specific queries about the Glasgow Coma Scale score on admission, had been prospectively collected by means of an online case record form. The Glasgow Coma Scale grades coma severity according to 3 categories of responsiveness: eye opening, motor responses, and verbal responses, with scores ranging from 3 to 15.11 Information about brainstem reflexes including pupillary light responses, respiratory drive, EEG data, intubation, and sedative medication at the time of presentation was not a standard part of the case record form. These data were all collected retrospectively by reanalyzing correspondence from ambulance and emergency departments.

At discharge, all patients underwent a neurologic examination performed by a neurologist, and outcome was graded according to the Glasgow Outcome Scale. This is a well-validated measurement scale with scores varying from 1 to 5.12 A favorable outcome was defined as a score of 5 and an unfavorable outcome as a score of 1-4. Two clinicians independently classified the cause of death. The interrater agreement (k) for cause of death was 0.73. Differences were resolved by discussion.

The study was approved by the ethics committee of the Academic Medical Center, Amsterdam, the Netherlands.

Results

From 2006 to 2012, 1083 episodes of community-acquired bacterial meningitis were included in the cohort. Thirty of 1083 patients (3%) presented with a Glasgow Coma Scale score of 3 on admission (Figure 1). Fifteen patients (50%) were female and the median age was 65 years (interquartile range 49-76 years; Table 1). Fifteen patients (50%) had one or more predisposing conditions for bacterial meningitis, consisting of otitis/sinusitis in 8, immunocompromised state in 6, and pneumonia in 2.

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Figure 1. Distribution of scores on Glasgow Coma Scale for adults presenting with community-acquired bacterial meningitis.

Data on pupillary light responses could be retrieved for 25 of 30 patients (83%). Pupillary light responses were bilaterally present in 15 patients (60%), unilaterally absent in 2 (8%), and bilaterally absent in 8 (32%; Table 1). Anisocoria was noted in 6 of 20 patients (30%). Data on corneal reflexes could be retrieved for 9 patients, and corneal reflexes were bilaterally absent in 7 (including 4 patients with bilaterally absent pupillary light responses), unilaterally absent in 1, and bilaterally present in 1. One patient had an absent respiratory drive at time of presentation and died the next day. Of 30 patients, 13 (43%) were intubated prior to neurologic examination; 5 of these 13 patients (39%) received sedative drugs, 2 of whom also received muscle relaxant drugs. The remaining patients did not receive sedative medication prior to initial neurologic examination. Eight of 23 patients (35%) with a minimal Glasgow Coma Scale score presented with neck stiffness, 10 of 30 patients (33%) presented with seizures, and 9 of 26 patients (34%) had signs of septic shock at time of presentation.

Seizures consisted of tonic-clonic seizures in all 10 patients; 4 patients received benzodiazepines to stop the seizures and 1 patient received sedative drugs and muscle relaxant drugs prior to intubation. One patient had prolonged seizures despite benzodiazepines; it is unknown how the prolonged seizures were treated in this patient.

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Cranial CT on admission was performed in 27 of 30 patients (90%) and was abnormal in 67% (Table 1; Figure 2). In 22 of 30 patients (73%), the minimal Glasgow Coma Scale score could be explained either by complications resulting from the meningitis (seizures in 10, hydrocephalus in 5, and cerebral edema in 7) or by sedative medication (5 patients). In the other 8 patients, the minimal score on the Glasgow Coma Scale was explained by a direct effect of the meningitis (defined as a combination of severe brain inflammation and raised ICP).

Cranial imaging was repeated during admission in 16 patients (all patients underwent CT scan, 1 patient underwent CT and MRI scan) and was abnormal in 10 patients (63%). New abnormalities not present on admission were found in 2 patients and consisted of cerebral infarctions in both.

Table 1. Clinical characteristics of 30 patients with bacterial meningitis presenting with a minimal coma score.a

Characteristics n/N (%) Characteristics n/N (%)Age 65 (49-76) Abnormal cranial CT 18/27 (67%)Female 15/30 (50%) Generalized edema 8/27 (30%)Predisposing conditions 15/30 (50%) Hydrocephalus 5/27 (19%) Otitis/sinusitis 8/30 (27%) Presumed recent infarction 1/27 (4%) Immunocompromised state 6/30 (20%) Subdural empyema / effusion 2/27 (7%) Pneumonia 2/24 (8%) Mastoid opacification 7/27 (26%)

Sinus opacification 4/27 (15%)Duration of symptoms >24 h 14/26 (54%) Blood chemistry testsd

Symptoms and signs on admission Leukocyte count (cells/mm3) 15 (10-20) Bilaterally absent pupillary light reflex

8/25 (32%) ESR (mm/h) 12 (5-60)

Bilaterally absent corneal reflex 7/9 (78%) C-reactive proteine (mg/L) 221 (110-327) Temperature ≥38°C 21/29 (70%) Indexes of inflammation in the

CSFe

Neck stiffness 8/23 (35%) Leukocyte count median (cells/mm3)

2240 (160-10750)

Seizures 10/30 (34%) Leukocytes <1000 cells/mm3 10/27 (37%) Systolic blood pressureb 130 (120-159) Protein 5.5 (3.3-7.2) Heart rate (beats/min)b 102 (98-140) CSF: blood glucose ratio 0.01 (0-0.13) Signs of septic shockc 9/26 (35%) CSF culture

Streptococcus pneumoniae 26/30 (87%)Adjunctive dexamethasone 25/29 (86%)

a Data are number / number evaluated (%) or median (interquartile range). b Systolic blood pressure and heart rate was determined in 27 patients. c Defined as diastolic blood pressure <60 mm Hg, systolic blood pressure ≤90 mm Hg, or heart rate ≥120 bpm. d Leukocyte count was determined in 30 patients, ESR in 9 patients, and C-reactive protein levels in 30 patients. e CSF leukocyte count was determined 27 patients, CSF protein levels in 28 patients and CSF: blood glucose ratio was determined in 29 patients.

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Twenty-nine of the 30 patients (97%) had at least one individual CSF finding predictive of bacterial meningitis (glucose level <34 mg/dL [1.9 mmol/L], ratio of CSF glucose to blood glucose <0.23, protein level >220 mg/dL, or leukocyte count >2000/mm3).13 Ten of 27 patients (37%) had a CSF leukocyte count below 1000 cells/mm3, which has previously been associated with poor outcome.5 CSF cultures grew S. pneumoniae in 26 patients (87%) and Haemophilus influenzae, Salmonella enterica, Streptococcus pyogenes, and Staphylococcus aureus in 1 patient each. Initial antibiotic treatment was microbiologically adequate in all patients and 25 of 29 patients (86%) received adjunctive dexamethasone on admission.14 The clinical characteristics, results of cranial imaging, and CSF analysis were similar when considering only patients who did not receive sedative medication (Supplementary Table e-1).

Table 2. Complications and outcome of 30 bacterial meningitis patients presenting with a minimal coma score.a

Characteristic n/N (%) Characteristic n/N (%)Systemic complications Time to deathb 2 (1-22) Respiratory failure 15/25 (60%) Causes of death Pneumonia 6/26 (23%) Extensive neurological damage due

to meningitis6/18 (33%)

Hyponatremia 4/27 (15%) Withdrawal of treatment 2/18 (11%)Neurologic complications Brain herniation on CT 4/18 (22%) Cerebral infarction 3/30 (10%) Multi-organ failure 2/18 (11%) Subdural empyema 2/30 (7%) Septic shock 2/18 (11%) Hearing impairment 4/30 (13%) Cardiac arrest 1/18 (6%) Seizures 7/30 (23%) Delayed cerebral thrombosis 1/18 (6%)Outcome Neurologic sequelae 5/12 (42%) GOS 1 18/30 (60%) Cognitive impairment 4 GOS 2 0 Poor general condition 2 GOS 3 2/30 (7%) Bilateral hearing loss 1 GOS 4 3/30 (10%) Hemiparesis 1 GOS 5 7/30 (23%)

a Data are number / number evaluated (%) or median (interquartile range). b Data concerning 18 deceased patients.

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Figure 2. Spectrum of abnormal CT scanning of patients with bacterial meningitis presenting with a minimal Glasgow Coma Scale score; (A) Generalized cerebral edema with signs of pseudo- subarachnoid hemorrhage; (B) subdural empyema; (C) generalized cerebral edema indicating severe cerebral inflammation; (D) hydrocephalus.

The majority of patients (87%; Table 2) developed complications during the clinical course. Systemic complications consisted of respiratory failure (15 of 25 [60%]), pneumonia (6 of 26 [23%]), and hyponatremia (4 of 27 [15%]). Neurologic complications consisted of seizures (7 of 30 [23%]), hearing impairment (4 of 30

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[13%]), cerebral infarction (3 of 30 [10%]), and subdural empyema (2 of 30 [7%]). EEG was performed in 5 patients during the clinical course. Four of these patients had an isoelectric EEG (1 to 3 days after admission) and treatment was withdrawn resulting in immediate death. In 1 patient, the EEG was performed on the eleventh day showing severe cortical dysfunction (with some residual cerebral activity). Care was withdrawn and the patient subsequently died of multi-organ failure. One patient with hydrocephalus was treated with external ventricular drainage on the day of admission but died 3 days later. Four patients with hydrocephalus were not treated with external ventricular drainage because of other poor prognostic factors (multi-organ failure, clinically brain dead) or because the hydrocephalus was mild and spontaneously resolved on follow-up imaging. None of the patients were treated with continuous ICP measuring or ICP-directed treatment.

Table 3. Clinical characteristics of bacterial meningitis patients presenting with a minimal coma score with good outcome and with poor outcome.a

Characteristic Good outcomeb (n=10) Poor outcomec (n=20)Symptoms and signs on admissionSeizures 3/10 (30%) 7/20 (35%)Sedation 2/10 (20%) 3/20 (15%)Septic shock 0/6 9/20 (45%)Abnormal cranial CT 5/9 (56%) 13/18 (72%)Generalized edema 2/9 (22%) 6/18 (33%)Hydrocephalus 1/9 (11%) 4/18 (22%)Indexes of inflammation in the CSFd

Leukocytes <1000 cells/mm3 1/10 (10%) 9/17 (53%)Protein (g/L) 5.5 (2.7-7.1) 5.4 (3.9-8.2)CSF cultureStreptococcus pneumoniae 9/10 (90%) 17/20 (85%)Adjunctive dexamethasone 10/10 (100%) 15/19 (79%)

a Data are number / number evaluated (%) or median (interquartile range). b Good outcome is defined as GOS 4-5. c Poor outcome is defined as GOS 1-3. d CSF leukocyte count was determined 27 patients and CSF protein level in 28 patients.

Twelve of the 30 patients (40%) survived and 7 patients (23%) had a good functional outcome, defined as a score of 5 on the Glasgow Outcome Scale. Neurologic sequelae were present on discharge in 5 of 12 survivors (42%) and consisted of cognitive impairment in 4, poor general condition in 2, and bilateral hearing loss and hemiparesis in 1 patient each; 3 surviving patients with sequelae were scored as moderately disabled on the Glasgow Outcome Scale and 2 as severely disabled requiring nursing home admission. All 11 patients presenting with either

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bilaterally absent pupillary light responses or bilaterally absent corneal reflexes died (Table 3). Furthermore, all 9 patients with signs of septic shock on admission died; septic shock was defined as diastolic blood pressure <60 mm Hg, systolic blood pressure ≤90 mm Hg, or heart rate ≥120 beats per minute. The mortality rate and frequency of sequelae were similar when considering only patients who did not receive sedative medication on admission (Supplementary Table e-2).

The causes of death in the 18 deceased patients were as follows: extensive neurologic damage due to meningitis (6 patients), acute brain herniation shown on cranial imaging (4 patients), withdrawal of care because of poor neurologic prognosis (2 patients; care was withdrawn 2 and 3 days after admission), multi-organ failure or septic shock (2 patients each), and cardiac arrest or delayed cerebral thrombosis (1 patient each).15 Autopsy was performed in 3 patients showing severe brain damage in all patients. In 1 patient venous sinus thrombosis was identified that was not diagnosed prior to autopsy.

Discussion

Our study shows that a small minority of patients with community-acquired bacterial meningitis present with a minimal score on the Glasgow Coma Scale (3%). Although the majority of these patients had an unfavorable outcome (77%) and many patients died (60%), the number of patients who recovered completely was substantial. We could not identify clinical parameters predictive for favorable outcome, for example epileptic seizures or sedative drugs. However, patients presenting with a minimal Glasgow Coma Scale score on admission and bilaterally absent pupillary light responses, bilaterally absent corneal reflexes, or signs of septic shock on admission all died. Physicians confronted with a patient with bacterial meningitis presenting with a minimal Glasgow Coma Scale score should be aware that at least 1 out of 5 patients will make a full recovery.

Neuro-imaging showed that 1 out of 4 patients with bacterial meningitis presenting with a minimal score on the Glasgow Coma Scale have cerebral abnormalities such as hydrocephalus or subdural empyema, which may require emergency neurosurgery. Hydrocephalus and empyema rarely complicate bacterial meningitis (3-5% of patients) but have been associated with high rates of death and unfavorable outcome.16-18 Early identification and subsequent neurosurgical treatment of these complications may improve prognosis. Therefore, immediate

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cranial imaging should be a priority in patients with a minimal score on the Glasgow Coma Scale on admission to rule out treatable conditions. Because of the risk of increasing brain shift due to lumbar puncture, cranial imaging should precede lumbar puncture in all patients with a minimal Glasgow Coma Scale score to rule out space-occupying lesions causing brain shift.8 Antibiotic therapy and adjunctive dexamethasone therapy if indicated should be started before sending the patient to the imaging room. Although some authors have advocated the use of continuous ICP measuring and ICP lowering by use of CSF drainage and medication, the benefit of ICP management in these patients is still unclear.19, 20

The abnormal conscious state could be explained by potentially reversible causes, such as seizures, sedative medication, or muscle relaxants, in a subgroup of patients (47%). However, these patients had similar outcomes compared to the other patients, suggesting that seizures and the need for intubation are markers of disease severity rather than indicators of a reversible cause of an abnormal conscious state. A minimal score on the Glasgow Coma Scale was preceded by epileptic seizures in 33% of patients and 5 patients received antiepileptic or sedative medication as treatment for seizures. Epilepsy has previously been described in 17% of patients with bacterial meningitis.21 If no clear explanation for a minimal coma score other than severe inflammation can be found, an EEG should be performed. This is also true for those patients with a waxing and waning level of consciousness. In 9 patients, signs of septic shock were present on admission and likely contributed to the minimal Glasgow Coma Scale score. Three of them also had seizures and one received sedative medication; in the other 5 patients, there was no explanation for the minimal coma score other than septic shock. Stabilization of hemodynamics is of the utmost importance early during sepsis and should have priority in patients with meningitis with concomitant sepsis. Despite aggressive management of the patients with sepsis included in our study, all patients with signs of septic shock on admission eventually died.

This study has several limitations. First, several clinical characteristics of patients with a minimal Glasgow Coma Scale score on admission were not routinely captured in the case record form (for example, brainstem reflexes, anisocoria, sedative medication), but these data were collected retrospectively. Furthermore, patients with a minimal score on the Glasgow Coma Scale may have been missed: patients with bacterial meningitis presenting with a minimal coma score may have severe brain edema, prohibiting a lumbar puncture. Another reason to withhold a lumbar puncture may be diffuse intravascular coagulation, which may occur

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due to concomitant sepsis. In patients with meningitis with predominant signs of septic shock, meningitis may be missed because the typical sign of meningitis, neck stiffness, is often absent in comatose patients. All these factors may have led to an underestimation of the incidence of a minimal Glasgow Coma Scale score in patients with bacterial meningitis. Furthermore, this is an observational study, and all treatment decisions (for instance to place CSF catheters, operate for subdural empyema, or use ICP management) were at the discretion of the treating physician. Therefore, treatments between patients were different, which is likely to have influenced outcome. This implies our study cannot be used to determine treatment effects, but it does reflect clinical practice as it currently is in the Netherlands. Finally, only patients with positive CSF cultures were included. Negative CSF cultures are estimated to occur in 11-20% of patients with bacterial meningitis.22-24 However, the clinical presentation of patients with culture-positive bacterial meningitis and patients with culture-negative bacterial meningitis was reported to be similar.

Patients with community-acquired bacterial meningitis rarely present with a minimal score on the Glasgow Coma Scale, but this condition is associated with high rates of morbidity and mortality. However, 1 out of 5 of these severely ill patients will make a full recovery, stressing the continued need for aggressive supportive care.

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References

1. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012; 380: 1693-1702.

2. McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet 2012; 380: 1703-1711.




6. Weisfelt M, van de Beek D, Spanjaard L, Reitsma JB, de Gans J. A risk score for unfavorable outcome in adults with bacterial meningitis. Ann Neurol 2008; 63: 90-97.

7. van de Beek D, Weisfelt M, de Gans J, Tunkel AR, Wijdicks EF. Drug Insight: adjunctive therapies in adults with bacterial meningitis. Nat Clin Pract Neurol 2006; 2: 504-516.


9. Mook-Kanamori BB, Geldhoff M, van der Poll T, van de Beek D. Pathogenesis and pathophysiology of pneumococcal meningitis. Clin Microbiol Rev 2011; 24: 557-591.

10. van de Beek D. Progress and challenges in bacterial meningitis. Lancet 2012; 380: 1623-1624.11. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;

2: 81-84.12. Jennett B, Teasdale G, Braakman R, Minderhoud J, Knill-Jones R. Predicting outcome in individual

patients after severe head injury. Lancet 1976; 1: 1031-1034.13. Spanos A, Harrell FE Jr, Durack DT. Differential diagnosis of acute meningitis. An analysis of the

predictive value of initial observations. JAMA 1989; 262:2700-2707.14. van de Beek D, de Gans J, Spanjaard L, Vermeulen M, Dankert J. Antibiotic guidelines and antibiotic

use in adult bacterial meningitis in The Netherlands. J Antimicrob Chemother 2002; 49: 661-666.15. Schut ES, Lucas MJ, Brouwer MC, Vergouwen MD, van der Ende A, van de Beek D. Cerebral infarction

in adults with bacterial meningitis. Neurocrit Care 2012; 16: 421-427.16. Kasanmoentalib ES, Brouwer MC, van der Ende A, van de Beek D. Hydrocephalus in adults with

community-acquired bacterial meningitis. Neurology 2010; 75: 918-923.17. Jim KK, Brouwer MC, van der Ende A, van de Beek D. Cerebral abscesses in patients with bacterial

meningitis. J Infect 2012; 64: 236-238.18. Jim KK, Brouwer MC, van der Ende A, van de Beek D. Subdural empyema in bacterial meningitis.

Neurology 2012; 79: 2133-2139.19. Lindvall P, Ahlm C, Ericsson M, Gothefors L, Naredi S, Koskinen LO. Reducing intracranial pressure

may increase survival among patients with bacterial meningitis. Clin Infect Dis 2004; 38: 384-390.20. Abulhasan YB, Al-Jehani H, Valiquette MA et al. Lumbar drainage for the treatment of severe bacterial

meningitis. Neurocrit Care 2013; 19:199-205.21. Zoons E, Weisfelt M, de Gans J et al. Seizures in adults with bacterial meningitis. Neurology 2008; 70:

2109-2115.22. Durand ML, Calderwood SB, Weber DJ et al. Acute bacterial meningitis in adults. A review of 493

episodes. N Engl J Med 1993; 328: 21-28.23. Sigurdardottir B, Bjornsson OM, Jonsdottir KE, Erlendsdottir H, Gudmundsson S. Acute bacterial

meningitis in adults. A 20-year overview. Arch Intern Med 1997; 157: 425-430.24. Brouwer MC, Thwaites GE, Tunkel AR, van de Beek D. Dilemmas in the diagnosis of acute community-

acquired bacterial meningitis. Lancet 2012; 380: 1684-1692.

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Supplementary tables

Table e-1. Clinical characteristics of 25 patients with bacterial meningitis presenting with a minimal coma score who did not receive sedative medication.a

Characteristics n/N (%) Characteristics n/N (%)Age (years) 65 (59-76) Abnormal cranial CT 14/22 (64%)Female 12/25 (48%) Generalized edema 5/22 (23%)Predisposing conditions 12/25 (48%) Hydrocephalus 5/22 (23%) Otitis/sinusitis 5/25 (20%) Presumed recent infarction 1/21 (5%) Immunocompromised state 4/25 (16%) Subdural empyema/effusion 1/22 (5%) Pneumonia 2/19 (11%) Mastoid opacification 5/22 (23%)Duration of symptoms >24 h 11/22 (52%) Sinus opacification 1/22 (5%)Symptoms and signs on admission Blood chemistry testsd

Bilaterally absent pupillary 7/21 (33%) Leukocyte count (cells/mm3) 14 (8-18)light reflex ESR (mm/h) 22 (5-61) Bilaterally absent corneal reflex 5/6 (83%) C-reactive proteine (mg/L) 219 (100-345) Temperature ≥38°C 19/21 (90%) Indexes of inflammation in the

CSFe

Neck stiffness 7/19 (37%) Leukocyte count median 1620 (94-10913) Seizures 9/25 (36%) (cells/mm3)

Systolic blood pressureb 131 (118-159) Leukocytes <1000 cells/mm3 10/22 (45%) Heart rate (beats/min)b 102 (98-140) Protein 5.4 (3.3-6.1) Signs of septic shockc 9/26 (35%) CSF: blood glucose ratio 0.01 (0-0.15)

CSF culture Streptococcus pneumoniae 21/25 (84%)Adjunctive dexamethasone 20/24 (83%)

a Data are number / number evaluated (%) or median (interquartile range). b Systolic blood pressure and heart rate was determined in 22 patients. c Defined as diastolic blood pressure <60 mm Hg, systolic blood pressure ≤90 mm Hg, or heart rate ≥120 bpm. d Leukocyte count was determined in 25 patients, ESR in 8 patient, and C-reactive protein levels in 25 patients. e CSF leukocyte count was determined 22 patients, CSF protein levels in 23 patients and CSF: blood glucose ratio was determined in 24 patients.

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Table e-2. Complications and outcome of 25 bacterial meningitis patients presenting with a minimal coma score, who did not receive sedative medication.a

Characteristic n/N (%) Characteristic n/N (%)Systemic complications Time to death 1 (1-15) Respiratory failure 13/21 (62%) Causes of death Pneumonia 5/23 (22%) Extensive neurological 6 (40%) Hyponatremia 3/23 (13%) damage due to meningitisNeurologic complications Withdrawal of treatment 2 (13%) Cerebral infarction 3/25 (12%) Brain herniation on CT 2 (13%) Subdural empyema 0 Multi-organ failure 1 (7%) Hearing impairment 3/25 (12%) Septic shock 2 (13%) Seizures 7/25 (28%) Cardiac arrest 1 (7%)Outcome Delayed cerebral thrombosis 1 (7%) GOS 1 15/25 (60%) Neurologic sequelae 4/10 (40%) GOS 2 0 Cognitive impairment 2 GOS 3 2/25 (8%) Poor general condition 1 GOS 4 2/25 (8%) Bilateral hearing loss 1 GOS 5 6/25 (24%) Hemiparesis 1

a Data are number / number evaluated (%) or median (interquartile range).

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GENERAL DISCUSSION

Adapted from:NEUROLOGICAL SEQUELAE OF

BACTERIAL MENINGITIS

Marjolein J. Lucas, Matthijs C. Brouwer, Diederik van de Beek

Submitted

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Abstract

Background We reported on occurrence and impact of neurological sequelae after bacterial meningitis.

Methods We reviewed occurrence of neurological sequelae in children and adults after pneumococcal and meningococcal meningitis.

Results Most frequently reported sequelae are focal neurological deficits, hearing loss, cognitive impairment and epilepsy. Adults with pneumococcal meningitis have the highest risk of developing focal neurological deficits, which are most commonly caused by cerebral infarction, but can also be due to cerebritis, subdural empyema, cerebral abscess or intracerebral bleeding. Focal deficits may improve during clinical course and even after discharge, but a proportion of patients will have persisting focal neurological deficits that often interfere in patient’s daily life. Hearing loss occurs in a high proportion of patients with pneumococcal meningitis and has been associated with co-existing otitis. Children and adults recovering from bacterial meningitis without apparent neurological deficits are at risk for long-term cognitive deficits. Early identification of neurological sequelae is important for children to prevent additional developmental delay, and for adults to achieve successful return in society after the disease.

Conclusion Neurological sequelae occur in a substantial amount of patients following bacterial meningitis. Most frequently reported sequelae are focal neurological deficits, hearing loss, cognitive impairment and epilepsy.

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Introduction

The estimated incidence of bacterial meningitis is 0.8-2.6 per 100.000 adults per year in developed countries and can be up to 10 times higher in less developed countries.1-5 Despite the implementation of effective antibiotic therapy, adjunctive dexamethasone therapy and modern intensive care facilities, associated mortality and morbidity rates remain high.1, 3 Predominant causative pathogens beyond the neonatal age are Streptococcus pneumonia and Neisseria meningitidis, responsible for 70-80% and 10-20% of bacterial meningitis cases in Europe and the United States.1, 6 Reported case fatality rates vary with age of the patient, causative pathogen and country income status.6 Meningitis caused by S. pneumoniae has the highest case fatality rates, ranging from 20-37% in high-income countries and up to 51% for low-income countries.6 Case fatality rates for meningococcal meningitis are much lower, ranging between 3-10% for high- and low-income countries.7, 8 Neurological sequelae have been estimated to occur in a substantial number of surviving patients: about half of survivors suffer from focal neurological deficits, including hearing loss, epilepsy and cognitive impairment.9-13 Costs associated with post-meningitis sequelae have an important economic impact on health care systems.14 We reviewed occurrence and impact of neurological sequelae after pneumococcal and meningococcal meningitis.

Methods

For this qualitative review of neurological sequelae after bacterial meningitis we searched PubMed using Entrez for studies on neurological sequelae after pneumococcal and meningococcal meningitis, by use of the terms “Streptococcus pneumoniae”, “Neisseria meningitidis”, “meningitis”, “sequelae”, “cognitive impairment”, “hearing loss”, “hydrocephalus”, “seizures”, “epilepsy”, “vision loss”, “outcome” and “long-term follow-up”. Studies were eligible for inclusion if the sequelae were reported per causative pathogen and if sequelae were reported separately for children and adults. We limited the review to bacterial meningitis caused by S. pneumoniae and N. meningitidis, as these are currently the most common pathogens of bacterial meningitis.1, 6 Sequelae among children and adults were evaluated separately.

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Focal neurological deficits

Focal neurological deficits after bacterial meningitis are most commonly caused by cerebrovascular accidents,15 but may also be due to other cerebral pathologies, such as subdural empyema,16 cerebral abscess,17 or intracerebral bleeding.18 Invasion of bacteria in the subarachnoid space and brain parenchyma triggers the release of cytokines resulting in severe inflammation.19 This inflammatory response goes hand in hand with activation of coagulation and inhibition of fibrinolysis, which may result in thrombosis, infarction and hemorrhage.15, 20, 21 Focal neurologic deficits due to cerebral infarction may be present on admission (early), develop during clinical course (intermediate), or after initial good recovery (late; i.e., delayed cerebral thrombosis).15, 22 Cerebral infarctions occur in one of four bacterial meningitis patients;15 focal neurological deficits are present on admission in half of these patients, the other half develop symptoms of infarction during clinical course. Delayed cerebral thrombosis is identified in about 1% of bacterial meningitis patients and mainly occurs in patients with pneumococcal meningitis.22 Patients with delayed cerebral thrombosis develop headache and focal neurological deficits after initial good recovery, which is most commonly followed by coma, caused by multiple cerebral infarctions.22

Children In a nationwide prospective cohort study including 45 children with pneumococcal meningitis in Denmark, focal neurological deficits (including aphasia, ataxia or paresis) were identified in only one child (3%).23 An Australian study retrospectively analyzed clinical outcome of 57 children aged below 5 years with pneumococcal meningitis and found that focal neurological deficits (motor impairment) were present in 8 children (14%) at discharge. In 7 of them, matching cerebral lesions were identified by neuro-imaging: cerebral infarction in five children, cerebral vasculitis and cerebral abscess in one child each.24

In low-income countries, cohort studies specifically on pneumococcal meningitis are lacking and data could be derived from clinical trials only. In a double-blind, placebo controlled trial among 238 children with pneumococcal meningitis in Malawi, focal neurological deficits after discharge were subdivided in hemiplegia, cerebral palsy, speech disorder and motor delay, and were identified in 3 (1%), 15 (6%), 2 (1%) and 9 (4%) patients, respectively.25 Adjunctive dexamethasone treatment was given in 55% of children, and did not affect the proportion of neurological sequelae. In this clinical trial, focal neurological deficits

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occurred less often after meningococcal meningitis as compared to pneumococcal meningitis: a speech disorder was identified in two of 67 (3%) children, and one child had cerebral palsy.25 In Brazil, a prospective cohort study of 81 children with meningococcal meningitis described focal neurological deficits in 3%.10 In a study among 157 children after an epidemic of group A meningococcal meningitis in rural West Africa, 2% had focal neurological deficits during follow-up 6 to 12 months after meningococcal meningitis.9 Interestingly, among children surviving meningitis, studies showed no difference in occurrence of focal neurological deficits between high-resource countries and low-resource countries.

Adults A prospective nationwide cohort study in the Netherlands including 696 adults with culture-proven community-acquired bacterial meningitis from 1998 to 2002 described cerebral infarction in 25% of adults with bacterial meningitis.15

Cerebral infarction was defined as focal neurologic signs on admission or during the course, with or without a lesion consistent with recent infarction visualized on cranial computed tomography (CT). About half of these patients presented with focal neurological deficits on admission and in the other half focal deficits developed during clinical course. Causative pathogens in this cohort study were S. pneumoniae in 352 episodes (51%), N. meningitidis in 257 episodes (37%), and other bacteria in 87 episodes (13%). Cerebral infarctions occurred in 128 of 352 adult patients (36%) with pneumococcal meningitis. Multivariate analysis identified advanced age, a decreased level of consciousness, parameters of systemic inflammation, and infection with S. pneumonia as predictive for the development of cerebral infarction.15 This study, however, was performed prior to routine use of adjunctive dexamethasone therapy.15

In a Dutch nationwide prospective cohort study from 2006 to 2009, 357 adult patients with pneumococcal meningitis were evaluated after the implementation of adjunctive dexamethasone therapy. In this study dexamethasone was started with or before the first dose of antibiotics in 84% of episodes and focal neurological deficits were present in 11% of surviving patients at discharge.26 In the Danish cohort study 142 adults with pneumococcal meningitis were included and focal neurological deficits were present in 22%. Sixteen percent of patients included in this cohort were treated with adjunctive dexamethasone and neurological sequelae occurred significantly less frequent in patients treated with corticosteroids compared to those who were not treated with corticosteroids (13% vs. 47%, p=0.004).23 In low-resource countries, studies systematically reporting

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the occurrence of focal neurological sequelae specifically among adults with pneumococcal meningitis are lacking.

Focal neurological deficits are less common in adults after meningococcal meningitis. In the Dutch prospective cohort study, cerebral infarction occurred in 22 of 257 (9%) patients with meningococcal meningitis, either on admission or during clinical course.15 This study reported focal neurological deficits at discharge in 2% of meningococcal meningitis survivors. This study was performed before the routine use of adjunctive dexamethasone therapy, but similar rates have been reported after the implementation of adjunctive dexamethasone therapy.27 In studies performed in low-resource countries data are scarce. In a prospective study in Ethiopia, including 243 adults with presumed meningococcal meningitis of which 77% was CSF culture or Gram proven, nine patients (4%) developed neurologic sequelae: 4 hemiplegia, 3 nerve deafness, 2 cranial nerve palsies.28

Management Focal neurological deficits are most commonly caused by cerebral infarction. A cardio-embolic cause should be ruled out by echocardiography, since endocarditis is a severe coexisting condition in bacterial meningitis identified in 2% of patients. Patients with both bacterial meningitis and endocarditis seem to have an additional risk at developing ischemic stroke.29

Another important cause of focal deficits is the development of subdural empyema and this should be considered in patients with rapid deterioration, particularly in those with Group A streptococcal meningitis or with preceding otitis or sinusitis. Contrast-enhanced CT shows hypodense collections, but sometimes subdural empyema at the convexity can be missed on CT and MRI scan may be required if there is a high clinical suspicion.16 In a proportion of these patients neurosurgical evacuation of the empyema may be indicated. General recommendations are to prolong antibiotic treatment in patients with empyema; for 3-4 weeks if an empyema has been evacuated, and even longer if the patient is conservatively treated.16 Because of the increased risk of empyema in patients with otitis or sinusitis, consultation of an ear, nose, and throat specialist is warranted early on admission in all bacterial meningitis patients to remove these foci of infection.30 If focal neurologic deficits occur after initial good recovery, delayed cerebral thrombosis should be suspected. In these cases, immediate high-dose steroids was suggested to be beneficial and antibiotic therapy should be prolonged or restarted until repeated CSF cultures remain negative.22, 31

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Focal neurological deficits may improve over time. The Australian study among children with pneumococcal meningitis assessed long-term outcome (19±20 months after discharge) in 40 of 57 patients. Motor impairment was present in 8% of children at long-term follow-up, compared to 14% of children at discharge.24 Persisting focal neurological deficits will often interfere in patient’s daily life. Therefore, consulting a rehabilitation specialist, speech therapist or occupational therapist is indicated for these patients after bacterial meningitis.

Hearing loss

Cochlear involvement may result from direct spread of bacterial products and inflammatory mediators from the meninges, cerebrospinal fluid, perilymphatic system, the vestibulocochlear nerve, or via the bloodstream following bacteremia or sepsis.19 Sensoneurinal hearing impairment is thought to develop during the first few days of the illness and can be transient or permanent.32-34 Otitis has been identified as the main risk factor for hearing loss after pneumococcal meningitis.23,

35 Other risk factors for hearing loss are advanced age, presence of comorbidity, severity of meningitis (defined by the need for assisted ventilation or signs of septic shock), low CSF glucose level and a high CSF protein level.36

Children In a prospective multicenter study in the US among 151 children surviving pneumococcal meningitis, 48 (32%) had unilateral (n=26) or bilateral (n=22) moderate to severe hearing loss at discharge. Severe hearing impairment was defined as the absence of an observable response at ≥70 dBnHL (decibel above normal adults hearing level) and moderate impairment was defined as no response at 50 to 60 dBnHL. Twelve children required a hearing aid and/or cochlear implant.37 Twenty-two percent of children received adjunctive dexamethasone treatment before or within 1 hour after the first dose of antibiotics, there was no reduction is the occurrence of hearing loss in this group. Another study among 102 Bangladeshi children with pneumococcal meningitis reported profound hearing loss in 25%. These children were screened for hearing loss by means of otoacoustic emission testing. Children with hearing loss >40 dB underwent testing by means of auditory brainstem response and tympanometry. Hearing loss was classified as mild (26-40 dB), moderate (41-60 dB), severe (61-80 dB), or profound (>80 dB) in accordance with the International Classification of Impairments, Activities, and

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Participation. Short-term follow-up (after 1 month) was performed in 51 children and revealed profound hearing loss in 33%. Long-term follow-up (after 6-24 months) was performed in the other 52 children and revealed profound hearing loss in 18%. The lower rate of hearing loss in the long-term follow-up group was explained by the recovery of transient hearing impairment.11 In a twenty-year surveillance study of invasive pneumococcal disease in England, sensorineural hearing impairment was identified in seven (14%) of 51 children who had auditory assessment after pneumococcal meningitis.38 A study conducted in Angola among 82 children surviving pneumococcal meningitis described hearing loss (≥60 dB threshold) in 30% of children. Hearing was tested by brainstem-evoked response audiometry on day 7 of hospitalization.39

Hearing loss is a less common complication in patients after meningococcal meningitis in developed countries. In a large nationwide cohort study in the Netherlands among 578 children who survived bacterial meningitis, hearing loss occurred in 20 of 495 children (4%) after meningococcal meningitis. Hearing loss was evaluated within 6 months after bacterial meningitis in two thirds of patients; the other patients were evaluated after this follow-up period had ended. They either underwent a formal hearing assessment, consisting of auditory brainstem response, audiogram, tested at an audiology center or by an otorhinolaryngologist, or their hearing was screened using distraction methods at the children’s health clinic. Hearing loss was defined as a perceptive loss of >25 dB.40 In two African studies hearing loss after meningococcal meningitis was more common. In an Angolan study hearing loss occurred in 19% of 351 meningococcal meningitis patients, measured on day 7 of hospitalization.39 In a randomized controlled trial performed in Malawi hearing loss was identified in 23% of 67 children with meningococcal meningitis.25

Adults In adults with pneumococcal meningitis, hearing loss is also a common sequel. A Dutch study analyzed hearing loss in 531 adults surviving pneumococcal meningitis included in two prospective nationwide cohort studies in the Netherlands, and reported hearing loss in 22%. Audiological examination was performed in 82 patients. Combining the clinical and audiology data, any hearing loss (mild to severe) was present on discharge in 116 episodes. In this study, 45% of patient was treated with the standard regimen of dexamethasone (10 mg four times daily, started with or before the first doses of antibiotics). The proportion of patients with hearing loss treated with or without dexamethasone was similar

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(48 of 240 [20%] vs. 68 of 291 [23%]; p=0.35). The proportion of patients with severe hearing loss treated with or without dexamethasone was also similar (20 of 240 [8%] vs. 35 of 291 [12%]; p=0.16).35 In a nationwide study among 240 survivors of pneumococcal meningitis in Denmark who were tested by use of audiometry, hearing loss was found in 99 of 144 adult patients (69%). In this study all survivors of pneumococcal meningitis were tested, while most other studies only performed audiometric testing for patients clinically suspected of hearing loss. Thirty-eight percent of patients, who were not suspected of hearing loss at clinical bedside evaluation, were found to have hearing loss when tested by audiometry.36 In two Dutch prospective nationwide cohort studies on community-acquired meningococcal meningitis in adults, hearing loss was described in 19 of 237 patients (8%) from 1998-2002 vs. 3 of 96 patients (3%) from 2006-2011, respectively before and after the implementation of adjunctive dexamethasone therapy.27

Few studies have reported the rate of hearing loss after pneumococcal and meningococcal meningitis in low-resource countries. In a randomized placebo-controlled trial among adults in Malawi, hearing loss was detected in 40% of patients after pneumococcal meningitis, tested after 40 days.41

Management Early identification of hearing loss is essential for the acquisition of normal speech and language and for educational and social development in children.42 Therefore, hearing evaluation should be performed in all surviving patients as part of the routine follow-up after bacterial meningitis, also in patients who are not clinically suspected of hearing loss. It is important to identify hearing loss on time, because ossification of the cochlea may occur within weeks after bacterial meningitis and can make cochlear implantation difficult or even impossible.42 An MRI scan should be performed urgently to identify signs of ossification and early cochlear implantation is recommended if ossification is present.43

Seizures

Cortical inflammation is described to be the main mechanism of seizures in bacterial meningitis. Seizures may also be associated with underlying cerebral pathologies, such as hydrocephalus, edema, subdural empyema, or cerebral infarction.

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Children In a study in Malawi among 598 children with bacterial meningitis, almost half (48%) had a history of seizures upon presentation. Forty-one percent received anticonvulsant therapy during hospitalization. In this study 200 patients died; 61% of those had a history of seizures upon presentation.25 In an Australian study on 94 children with pneumococcal meningitis, almost half (48%) had at least one seizure during admission. Seizures occurred before admission in 23% and 13% of patients developed a seizure disorder, defined as at least one seizure post discharge.44 A Greek follow-up study on pneumococcal meningitis in children described a seizure disorder in 7 of 47 (15%) children, defined as recurrent episodes of seizures after discharge. Follow-up assessment was performed 4 to 23 years (mean 12 +/- 6 years) after discharge.45 The previous mentioned study among 102 children with pneumococcal meningitis in Angola showed that 63% of patients had seizures at home prior to admission, 45% at presentation and 58% during admission.39 The same study described a relatively low proportion of seizures after meningococcal meningitis; of 42 patients, 33% had seizures at home prior to admission, 17% upon presentation and 17% during admission.39 In a study from Gambia, seizures during admission occurred in 19% of 89 children with meningococcal meningitis.46 In a prospective study in Brazil among 81 children diagnosed with meningococcal meningitis, sixty-eight survivors were followed-up 35 months after discharge, and seizures were identified in only one of 68 patients (2%).10

Adults An observational cross-sectional study of 696 adults with community-acquired bacterial meningitis analyzed the occurrence of both pre-hospital and in-hospital seizures. CSF culture yielded S. pneumoniae in 352 episodes (51%), N. meningitidis in 257 episodes (37%), and other bacteria in 87 episodes (13%). Pre-hospital seizures were described in 25 of 352 pneumococcal meningitis patients (7%), in-hospital seizures were described in 85 of 352 pneumococcal meningitis episodes (24%). Seizures occurred less often in meningococcal meningitis; 4 of 257 patients with meningococcal meningitis (2%) presented with pre-hospital seizures and 12 (5%) developed seizures during admission. The overall median time between admission and first seizure was 1 day (interquartile range 0-3) and 75% of seizures occurred before or within 48 hours of admission. Bacterial meningitis patients with seizures were more likely to have abnormalities on neuro-imaging; the most common intracranial complication in bacterial meningitis patients with seizures is cerebral infarction, occurring in 20% of patients.47 Seizures during the acute phase of bacterial meningitis were furthermore related to a low level

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of consciousness on admission, a leukocyte count below 1000 cells/mm3, low glucose and high protein levels in the cerebrospinal fluid and infection with S. pneumoniae.48 Seventeen percent of patients received adjunctive dexamethasone.

Management Seizures in the acute phase of bacterial meningitis should be treated with antiepileptic medication. If the patient has been seizure-free for three months after the acute phase, antiepileptic treatment could be discontinued. The occurrence of seizures during acute bacterial meningitis is strongly associated with the development of late seizures. Late unprovoked seizures and epilepsy are described as long-term sequelae of bacterial meningitis, and the risk appears to be highest after pneumococcal meningitis.49-51 The majority of late seizures occurs within 5 years after bacterial meningitis and tends to be recurrent.49, 52 Late seizures after the acute phase of bacterial meningitis should be considered symptomatic, and therefore long-term antiepileptic treatment is indicated in these patients. Seizures are an important cause of deteriorating consciousness in bacterial meningitis patients. A rare but treatable cause of the deterioration of consciousness during admission is a non-convulsive status epilepticus. If seizures have occurred during admission and the patient does not regain consciousness, an EEG is indicated to rule out a non-convulsive status epilepticus.

Hydrocephalus

Communicating hydrocephalus is the most common form of hydrocephalus in bacterial meningitis patients and results from impaired resorption of cerebrospinal fluid through the arachnoid granulations caused by the high protein and leukocyte content of the cerebrospinal fluid.53-55 Acute obstructive hydrocephalus is rarely reported in bacterial meningitis patients, and these rare cases usually occur in younger children.

Children In a prospective study in 103 children surviving pneumococcal meningitis, 22 (21%) had evidence of hydrocephalus on cranial CT or MRI at the time of hospital discharge. Eight patients (8%) required placement of a ventriculoperitoneal shunt.37 In a retrospective cohort study in Denmark of bacterial meningitis patients above 14 years of age, hydrocephalus was identified in 3 of 83 episodes with pneumococcal meningitis (4%).56 A randomized controlled

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trial among 238 children with pneumococcal meningitis in Malawi identified hydrocephalus in one patient only. In the same study, no hydrocephalus was identified in any of the meningococcal meningitis patients at all. In this African study no CT scans of the brain were performed, so hydrocephalus could only be detected in children in whom the fontanel was patent. Cranial ultrasound was performed in 51% of 299 children with a patent fontanel.25

Adults In another prospective nationwide cohort study from Dutch hospitals, hydrocephalus was diagnosed in 14 of 366 adults with pneumococcal meningitis (4%). Hydrocephalus was present on admission in 69% of patients, was associated with a high rate of unfavorable outcome (69%) and half of patients died.57 In this study hydrocephalus was diagnosed in 2 of 70 adults with meningococcal meningitis (3%).57

Management In patients with mild hydrocephalus without clinical deterioration, spontaneous resolution may occur and invasive procedures are not recommended. In patients with communicating hydrocephalus, a lumbar puncture allows measurement of the cerebrospinal pressure. Repeated lumbar puncture may reduce intracranial pressure effectively. Caution should be attempted with regard to evolving brain shift and the risk for brain herniation in these patients. In patients with obstructive hydrocephalus or brain shift, either due to a space-occupying lesion or diffuse brain edema, an external ventricular CSF catheter should be placed.52

Cognitive impairment

Bacterial toxins, cytotoxic products of the inflammatory response and parenchymal damage in bacterial meningitis lead to neuronal damage. The hippocampus is the most vulnerable area for neuronal damage and this results in hippocampal atrophy, as seen on MRI scans in bacterial meningitis survivors.58 Children who recovered from bacterial meningitis are at great risk for long-term cognitive deficits, consisting of learning difficulties and cognitive slowness resulting in poor school performance.12

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Children A Dutch cohort study of 680 school-age meningitis survivors and 304 age matched controls showed that 22% of children surviving pneumococcal meningitis underachieved at school, compared to 5% of controls. Of the children surviving pneumococcal meningitis, 12% repeated a class twice, compared to 8% of children in the reference group and 12% was referred to a special-needs school. In this study, parents completed questionnaires on educational, behavioral and general health problems, on average 6.2 years after meningitis episode.12 A follow-up study on the short- and long-term impact of pneumococcal meningitis among 102 Bangladeshi children, aged 2-59 months, found high rates of cognitive delay that affected ability to learn, language development and social relationships. Half of the patients were followed up 30 to 40 days after discharge, the other half 6 to 24 months after discharge and in both groups 41% of the children had significant deficits in cognitive development, defined as a score of <70 on the Mental Development Index of the Bailey Scales of Infant Development or the Stanfort-Binet Intelligence Scale.11 In a 20-year surveillance study of invasive pneumococcal disease in England, 10% of children showed global developmental delay after pneumococcal meningitis.38A nationwide population based cohort study examined educational achievement and economic self-sufficiency in adults who had bacterial meningitis in childhood. When comparing 455 patients with had a history of pneumococcal meningitis with individuals from the comparison cohort, completion of high school was reached in 10% less in the meningitis group and higher education was reached in 9% less.59 Cognitive deficits after bacterial meningitis in low-recourse countries have barely been studied. The randomized study among children in Malawi described behavior problems in 4 of 238 (2%) pneumococcal meningitis patients and global developmental delay also in 4 patients (2%).25

In a nationwide Danish population based cohort study, 1338 persons had a history of childhood meningococcal meningitis; 11% fewer persons had completed high school and 8% fewer had attained a higher education compared with individuals from the comparison cohort.59 The aforementioned Dutch cohort study showed that 20% of children surviving meningococcal meningitis underachieved at school, 18% repeated a class twice, and 12% was referred to a special-needs school.12 The study among children in Malawi described behavior problems in 2 of 67 (3%) patients after meningococcal meningitis, and global delay was only seen in one patient after meningococcal meningitis (1%).25

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Adults Adults may also suffer from cognitive deficit after bacterial meningitis. Cognitive impairment occurred in 32% of adult patients in a Dutch study involving 155 survivors of bacterial meningitis (79 after pneumococcal and 76 after meningococcal meningitis) and 72 healthy controls.60 The proportion of cognitive impairment was similar for survivors of pneumococcal and meningococcal meningitis. The median time between onset of meningitis and cognitive testing in this follow-up study was 49.5 months (range 5-164 months). Four cognitive domains were tested with a battery of standardised neuropsychological tests: intelligence, memory, attention, executive functioning, and reaction speed. Cognitive impairment consisted mainly of mental slowness and mild memory impairments. Patients reported significant improvement in physical impairment in the years after meningitis, while cognitive outcome was not related to time. One third of patients in this study received adjunctive dexamethasone treatment; the use of dexamethasone was not associated with cognitive impairment.60

Management Early identification of cognitive impairment following bacterial meningitis is important and therefore neuropsychological testing should be performed when there are indications for cognitive dysfunction. In children there may be an indication for special attention at school or a different school type to prevent (further) developmental delay. In adults, cognitive impairments may hinder the patients in returning to their job or fulfilling their role in family life. Recognition of neuropsychological sequelae and providing support for the patient are important steps in patient management to achieve a successful return in society.

Visual impairment

Visual impairment is an uncommon complication of bacterial meningitis. Possible causes of visual impairment in bacterial meningitis patients consist of endophthalmitis, herpes reactivation or optic nerve lesions caused by the meningeal inflammatory process. Visual impairment can also be caused by cerebral infarction and cavernous sinus thrombosis. In a study among 102 Bangladeshi children after pneumococcal meningitis, vision loss occurred in 8% of 51 children evaluated 30 to 40 days after discharge. The other 51 children were evaluated 6 to 24 months after discharge and vision loss was present in 4% of these patients. In this study, children were screened for high-grade vision impairment or blindness

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during neurological examination. Those who showed any abnormality during screening were referred to a trained paediatric ophthalmologist for testing of visual acuity and funduscopic examination. Vision loss was noted if visual acuity was <6/60.11 In a Greek a study among 47 children after pneumococcal meningitis, vision loss was found in 2% of children, 12 years after discharge.45 In a study on 102 patients, both children and adults, 6 to 12 months after an epidemic of group A meningococcal meningitis in West Africa, vision loss was reported to occur in 10% of patients. Visual acuity was tested by recognition of the position of hands drawn on a board that was placed 5 meter distant from the subject.9

Future directions

Implementation of dexamethasone treatment has improved the prognosis of both pneumococcal and non-pneumococcal meningitis in developed countries and reduces sequelae after meningitis. Findings of a randomized study61 and meta-analyses of randomized clinical trials62, 63 support the use of dexamethasone in high-income countries. In a Cochrane meta-analysis, the effect of dexamethasone was primarily found on reduction of long-term neurological sequelae and hearing loss. In a nationwide prospective cohort study in the Netherlands from 2006 to 2014, dexamethasone treatment was independently associated with increased proportion of patients with complete recovery and increased survival in patients with both pneumococcal and non-pneumococcal meningitis. The Cochrane meta-analysis showed adjuvant therapy with dexamethasone did not reduce mortality or morbidity in low-resource countries with a high prevalence of HIV.25, 41

It is important to recognize neurological sequelae after bacterial meningitis. To achieve this, all bacterial meningitis patients should be subjected to standardized follow-up. Patients and their family members should always be informed about the nature and frequency of neurological sequelae following bacterial meningitis, such as cognitive slowness, difficulty with concentration and hearing loss. Hearing evaluation should be performed in all surviving patients before discharge. In patients with no hearing loss during initial testing, follow-up testing may be indicated. Neuropsychological testing is not routinely indicated, but should be performed with a low threshold if cognitive deficits are suspected. To achieve successful return in society and to prevent developmental delay in children, referral to a psychologist or rehabilitation physician may be indicated.

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It may be important to detect underlying causes of cerebral infarctions in bacterial meningitis patients, as cerebral infarction occurs frequently and it is the main determinant of focal neurological deficits. For example, a specific genotype causing lower plasminogen activator inhibitor-1 (PAI-1) levels was found to be to be associated with an increase in cerebrovascular complications and unfavorable outcome in pneumococcal meningitis.64 In line with this, new therapies could be developed focused on specific complications. In all patients with focal neurological deficits, cranial imaging should be performed to rule out hydrocephalus, subdural empyema, cerebral abscess or cerebral infarction, as these complications often require specific treatment.

Conclusions

Neurological sequelae occur in a substantial amount of patients following bacterial meningitis, both in adults and children. Most frequently reported sequelae consist of focal neurological deficits, hearing loss, cognitive impairment and epilepsy. Hearing loss after meningococcal meningitis is found to be more common in low-resource countries. Early identification of neurological sequelae, especially cognitive impairment and hearing loss, is important for children to prevent (further) developmental delay, and for adults to achieve a successful return in society after bacterial meningitis. For low-resource countries, where the meningitis burden is highest, prospective population-based cohort studies are needed to evaluate the rate and impact of neurological sequelae after pneumococcal and meningococcal meningitis, in children and adults.

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Table 1. Neurologic sequelae of bacterial meningitis.

Sequelae Pneumococcal meningitis Meningococcal meningitis ReferencesFocal deficits Children 3-14% 2-3% 9, 10, 23, 24, 25 Adults 11-36% 2-9% 15, 23, 26, 28Hearing loss Children 14-32% 4-23% 11, 25, 37, 38, 39, 40 Adults 22-69% 3-40% 27, 35, 36, 41Seizures Children 15-63% 2-33% 10, 39, 44, 45, 46 Adults 31% 6% 47Hydrocephalus Children 0-21% - 25, 37, 56 Adults 4% 3% 57Cognitive impairment Children 2-41% 1-20% 11, 12, 25, 38, 59 Adults 32% 32% 60

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52. Pomeroy SL, Holmes SJ, DODGE PR, Feigin RD. Seizures and other neurologic sequelae of bacterial meningitis in children. N Engl J Med 1990; 323: 1651-7.

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60. Hoogman M, van de Beek D, Weisfelt M, de Gans J, Schmand B. Cognitive outcome in adults after bacterial meningitis. J Neurol Neurosurg Psychiatry 2007; 78: 1092-6.

61. de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347: 1549-56.

62. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. The Cochrane database of systematic reviews 2015; 9: CD004405.

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Bacterial meningitis is a life-threatening disease. The estimated incidence of bacterial meningitis is 0.94-2.6 per 100.000 adults per year in developed countries and can be up to 10 times higher in less developed countries. Streptococcus pneumoniae and Neisseria meningitidis are the predominant causative pathogens in adults, causing 80-85% of all cases. Despite the implementation of effective antibiotic therapy, adjunctive dexamethasone therapy and modern intensive care facilities, mortality and morbidity rates remain high. Neurological and systemic complications occur in a large proportion of patients and survivors of bacterial meningitis are at high risk of long-term neurological sequelae. In this thesis we describe the clinical characteristics, complications and outcome of community-acquired bacterial meningitis patients from two nationwide prospective cohort studies in the Netherlands.

In chapter 2 we describe the incidence, clinical features, prognostic factors and microbiological characteristics of 1412 bacterial meningitis patients, from 2006 to 2014. Following the introduction of conjugate vaccines, the incidence of adult bacterial meningitis has decreased and prognosis of patients with pneumococcal meningitis has improved substantially. Rates of bacterial meningitis decreased most sharply among pneumococcal serotypes included in the conjugate vaccine, and in meningococcal meningitis.

Cerebrovascular complications are common in patients with bacterial meningitis. In chapter 3 we describe clinical features and prognostic factors of cerebral infarctions in adults with community-acquired bacterial meningitis. Cerebral infarction occurred in 25% of 696 bacterial meningitis episodes and in 36% of patients with pneumococcal meningitis. In a multivariate analysis we identified advanced age, a decreased level of consciousness, parameters of systemic inflammation, and infection with S. pneumoniae as factors predicting the development of cerebral infarction. Unfavorable outcome occurred in 62%, and 32% of patients with cerebral infarction died. Chapter 4 describes 11 bacterial meningitis patients with good initial recovery, followed by sudden deterioration after 7-42 days caused by multiple cerebral infarctions. This rare but devastating complication of bacterial meningitis seemed to be related to adjunctive dexamethasone therapy and is potentially associated with activation of the complement system.

In chapter 5 we describe the incidence and clinical characteristics of adult patients with meningitis and endocarditis from 2006 to 2012. Endocarditis was identified in 24 of 1025 episodes (2%) of bacterial meningitis and was associated

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Summary

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with a high rate of unfavorable outcome (63%). Cultures yielded Streptococcus pneumoniae in 13 patients, Staphylococcus aureus in 8 patients, and Streptococcus agalactiae, Streptococcus pyogenes, and Streptococcus salivarius in 1 patient each. Clues leading to the diagnosis of endocarditis were cardiac murmurs, persistent or recurrent fever, a history of heart valve disease, and S. aureus as the causative pathogen of bacterial meningitis. This study indicates that cardiologic consultation should be a priority in patients with community-acquired meningitis presenting with clues for endocarditis.

In chapter 6 we report on the incidence, clinical characteristics, outcome and bacterial genotype of group A streptococcal (GAS) meningitis in the Netherlands from 2006 to 2013. GAS was identified in 2% of patients with community-acquired bacterial meningitis. We observed an increase of group A streptococcal meningitis in 2013, which may be influenced by the prolonged influenza season in 2012-2013. GAS meningitis was often preceded by otitis or sinusitis (92%) and a high proportion of patients developed complications during clinical course (73%). Subdural empyema occurred in 35% of patients, and was associated with bacterial genotype (cc28/emm1 genotype).

In Chapter 7 we describe the incidence, clinical characteristics and outcome of patients with bacterial meningitis presenting with a minimal score on the Glasgow Coma Scale, from 2006 to 2012. Thirty of 1083 patients (3%) presented with a score of 3 on the Glasgow Coma Scale. Systemic (86%) and neurologic (47%) complications occurred frequently, leading to a high proportion of patients with unfavorable outcome (77%). However, 40% survived and 23% of patients had a good functional outcome, stressing the continued need for aggressive supportive care.

In chapter 8 we conclude with an overview of occurrence and impact of neurological sequelae after pneumococcal and meningococcal meningitis in adults and children. Long-term neurological sequelae occur in a substantial number of surviving patients. Most frequently reported sequelae are focal neurological deficits, hearing loss, cognitive impairment and epilepsy. Early identification of neurological sequelae is very important for children to prevent further developmental delay, and for adults to achieve a successful return in society after bacterial meningitis.

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SAMENVATTING

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Bacteriële meningitis, ook bekend als hersenvliesontsteking, is een levensbedreigende infectieziekte. De incidentie bedraagt ongeveer 0.94-2.6 per 100.000 volwassenen per jaar in de Westerse wereld, en is ongeveer 10 keer zo hoog in ontwikkelingslanden. De belangrijkste verwekkers zijn Streptococcus pneumoniae (pneumokok) en Neisseria meningitidis (meningokok), die in ongeveer 80-85% van de patiënten gevonden worden. Ondanks behandeling met antibiotica en dexamethason blijft de morbiditeit en mortaliteit van deze aandoening hoog. Een groot gedeelte van de patiënten ontwikkelt complicaties en patiënten die de ziekte overleven hebben een aanzienlijke kans op blijvende restverschijnselen. In dit proefschrift beschrijven we de klinische kenmerken, complicaties en uitkomst van patiënten met bacteriële meningitis uit twee grote landelijke cohort studies.

In hoofdstuk 2 beschrijven we de incidentie, klinische kenmerken, prognostische factoren en de microbiologische karakteristieken van 1412 patiënten tussen 2006 en 2014. Na de invoering van verschillende vaccinaties is de incidentie van bacteriële meningitis sterk gedaald en de prognose van patiënten met pneumokokken meningitis verbeterd. De daling is het sterkst onder pneumokokken serotypes die in vaccins worden gebruikt en meningokokken meningitis.

Cerebrovasculaire complicaties komen vaak voor bij patiënten met bacteriële meningitis. In hoofdstuk 3 beschrijven we de klinische kenmerken en prognostische factoren van bacteriële meningitis patiënten met herseninfarcten. Herseninfarcten kwamen voor bij 25% van de 696 bacteriële meningitis patiënten, en bij 36% van de patiënten met pneumokokken meningitis. We hebben aangetoond dat een hoge leeftijd, een verlaagd bewustzijn, tekenen van een systemische ontsteking en Streptococcus pneumoniae als verwekker, risicofactoren zijn voor het ontwikkelen van herseninfarcten. In deze studie had 62% van de patiënten met een herseninfarct een slechte uitkomst en 32% is overleden. In hoofdstuk 4 beschrijven we 11 bacteriële meningitis patiënten die in de eerste instantie goed opknapten, maar na 7-42 dagen plotseling verslechterden, wat veroorzaakt werd door meerdere herseninfarcten. Deze zeldzame, maar ernstige complicatie is mogelijk gerelateerd aan de behandeling met dexamethason en de activatie van het complement systeem.

In hoofdstuk 5 beschrijven we patiënten met bacteriële meningitis en endocarditis (hartklep ontsteking) tussen 2006 en 2012. Endocarditis werd gevonden bij 24 van de 1025 patiënten met bacteriële meningitis, en was geassocieerd met een slechte uitkomst (63%). De verwekkers waren

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Samenvatting

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Streptococcus pneumoniae (13 patiënten), Staphylococcus aureus (8 patiënten), en Streptococcus agalactiae, Streptococcus pyogenes en Streptococcus salivarius (elk 1 patiënt). Aanwijzingen die naar de diagnose endocarditis leidden waren een hartruis, aanhoudende of terugkerende koorts, een hartklepaandoening in de voorgeschiedenis en Staphylococcus aureus als verwekker van de meningitis. Deze studie laat zien dat een consult van de cardioloog van groot belang is bij patiënten die zich presenteren met aanwijzingen voor endocarditis.

In hoofdstuk 6 rapporteren we de incidentie, klinische kenmerken, uitkomst en het bacteriële genotype van groep A streptokokken (GAS) meningitis in Nederland tussen 2006 en 2013. Een groep A streptokok werd bij 2% van de patiënten met bacteriële meningitis gevonden als verwekker. In 2013 hebben we een stijging waargenomen van het aantal groep A streptokokken, wat mogelijk veroorzaakt werd door het verlengde griepseizoen in 2012-2013. GAS meningitis werd vaak voorafgegaan door een oor- of bijholteontsteking (92%) en een groot deel van de patiënten ontwikkelde complicaties tijdens het beloop van de ziekte (73%). Een subduraal empyeem (een ophoping van pus in de ruimte rondom de hersenen) ontstond bij 35% van de patiënten en was geassocieerd met een specifiek bacterieel genotype (cc28/emm1 genotype).

In hoofdstuk 7 beschrijven we de incidentie, klinische kenmerken en uitkomst van bacteriële meningitis patiënten die zich presenteren met een minimale score op de Glasgow Coma Scale, van 2006 tot 2012. Dertig van de 1083 (3%) patiënten presenteerden zich met een minimale coma score op de Glasgow Coma Scale. Systemische (86%) en neurologische (47%) complicaties kwamen zeer vaak voor, en een groot deel van de patiënten had een slechte uitkomst (77%). Desalniettemin heeft 40% het overleefd en 23% van de patiënten had een goede functionele uitkomst, waaruit blijkt dat bij de behandeling van deze patiënten alles op alles moet worden gezet.

In hoofdstuk 8 geven we een overzicht van de meest voorkomende restverschijnselen na een bacteriële meningitis, zowel bij kinderen als volwassenen. Een groot deel van de overlevende patiënten houdt blijvende restverschijnselen, dit zijn bijvoorbeeld focale uitvalsverschijnselen, gehoorverlies, epilepsie en problemen met concentratie en geheugen. Het is van belang om deze restverschijnselen in een vroeg stadium te ontdekken, om een ontwikkelingsachterstand bij kinderen te voorkomen en om volwassenen weer succesvol terug te kunnen laten keren in de maatschappij.

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DANKWOORD

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Graag wil ik een aantal personen in het bijzonder bedanken voor hun bijdrage aan dit proefschrift.

Ten eerste alle bacteriële meningitis patiënten, hun partners en familieleden. Dank voor uw medewerking, zonder u is dit onderzoek niet mogelijk.

Diederik, mijn promotor, toen je een aantal jaar geleden aan me vroeg of ik onderzoek wilde doen twijfelde ik nog. Je hebt me laten zien hoe leuk het kan zijn, met dit proefschrift als resultaat! Bedankt dat je me die kans hebt gegeven. Het was een ontzettend leuke en leerzame tijd. De goede sfeer en onvergetelijke congressen maakten het compleet!

Matthijs, ik ken niemand die zo snel reageert op mailtjes als jij. Het was heel fijn om jou als copromotor te hebben. Zonder jou was dit proefschrift er niet geweest! Heel erg bedankt voor al je hulp, begeleiding en natuurlijk de gezelligheid de afgelopen jaren.

Alle leden van de leescommissie wil ik hartelijk bedanken voor het vakkundig beoordelen van de inhoud van mijn proefschrift.

Dank aan alle medewerkers van het Nederlands Referentie Laboratorium voor Bacteriële Meningitis en alle neurologen en arts-assistenten die het onderzoek mogelijk hebben gemaakt.

En natuurlijk mijn kamergenoten; Merel, Merijn, Anne, Soemirien, Daan, Philip en Joost. Dank voor de gezellig tijd in de meningitiskamer! Maar ook buiten deze kamer hebben we ons goed vermaakt, vele meningitisuitjes (en de ochtenden daaropvolgend) zijn me bijgebleven en ik denk er met veel plezier aan terug!

Mijn lieve paranimfen, Annelot en Charlotte, bedankt dat jullie op deze bijzondere dag aan mijn zijde staan. Annelot, we kennen elkaar vanaf dag één van de geneeskunde opleiding, en hebben sindsdien zoveel dingen samen meegemaakt. Bedankt voor alles. Lieve Charlotte, al hele lange tijd vriendinnen! Dank voor je interesse, steun en alle leuke momenten die we samen hebben!

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Rob, Loura, Hélène en Herman, bedankt voor jullie betrokkenheid en dat jullie zo’n leuke schoonfamilie zijn.

Lieve Irene en Nico, zus en broer. Ik ben trots op jullie! Bedankt voor de gezelligheid en dat we altijd voor elkaar klaar staan.

Lieve pap en mam. Jullie hebben mij alle kansen in het leven gegeven en steunen me onvoorwaardelijk. Ik kan me geen betere ouders wensen. Heel veel dank daarvoor!

Lieve Jurgen. Je bent de meest enthousiaste en positieve persoon die ik ken! Bedankt voor je eeuwige geduld en dat je er altijd voor me bent. Op naar jouw promotie en dan klaar voor al het moois wat komen gaat! Ik heb er zin in!

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CURRICULUM VITAE

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Marjolein José Lucas was born on August 4th 1986 in Rotterdam. In 2004 she finished secondary school at the Vossius Gymnasium in Amsterdam and started her medical studies at the University of Amsterdam. During her studies she did a 3-month clinical internship at Turiani Hospital in Tanzania. In 2007 she participated in a research project on the course of respiratory tract infections in children, at the department of paediatrics and virology at the Academic Medical Center. In 2011 she obtained her medical degree and started working as a neurology resident in the Onze Lieve Vrouwe Gasthuis in Amsterdam, for 6 months. At the end of 2011 she started the PhD project described in this thesis, under supervision of professor dr. D. van de Beek and dr. M.C. Brouwer, at the Department of Neurology at the Academic Medical Center (AMC), University of Amsterdam. In 2014 she started her Neurology training at the Academic Medical Center (prof. dr. Y.B.W.E.M. Roos, prof. dr. I.N. van Schaik, prof. dr. J.H.T.M. Koelman), which she plans to complete in 2020. Marjolein lives together with Jurgen Piet in Amsterdam.

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PORTFOLIO

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1. PhD trainingYear Workload

(ECTS)General coursesPractical Biostatistics 2012 1.1Laboratory animals 2012 3.0BROK (Basiscursus Regelgeving Klinisch Onderzoek) 2013 0.9Specific coursesESCMID Postgraduate Education Course. “Significance of Experimental Models for Studying Bacterial Meningitis and Sepsis”.

2012 1

PresentationsDelayed Cerebral Thrombosis in Bacterial Meningitis. Oral presentation at the 52nd ICAAC conference in San Francisco.

2012 0.5

Outcome in Patients with Bacterial Meningitis Presenting with a Minimal Level of Consciousness. Poster presentation at the 53rd ICAAC conference in Denver, Colorado.

2013 0.5

Klinische uitkomst van bacteriële meningitis patiënten met een minimale comascore bij opname. Oral presentation at Wetenschappelijke vergadering, Nederlandse vereniging voor neurologie.

2013 0.5

(International) conferences51st ICAAC conference in Chicago. 2011 152nd ICAAC conference in San Francisco. 2012 153rd ICAAC conference in Denver, Colorado. 2013 1Wetenschappelijke vergadering, Nederlandse vereniging voor neurologie.

2013 0.5

24th ECCMID, Barcelona, Spain. 2014 1

2.0 TeachingYear Workload

(ECTS)LecturingNeurological infectious diseases. Nurse training at the Amstel Academy.

2012-2013 0.5

3.0 Parameters of esteemYear

GrantsASM Infectious Disease (ID) Fellow Travel Grant, American Society of Microbiology.

2013

Travel Grant ECCMID. 2014

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LIST OF PUBLICATIONS

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List of publications

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Lucas MJ, Brouwer MC, van de Beek D. Neurological sequelae of bacterial meningitis. Submitted.

Bijlsma MW, Brouwer MC, Kasanmoentalib ES, Kloek AT, Lucas MJ, Tanck MW, van der Ende A, van de Beek D. Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. Lancet Infectious Diseases 2015, published online.

Lucas MJ, Brouwer MC, Bovenkerk S, Man WK, van der Ende A, van de Beek D. Group A Streptococcal meningitis in adults. Journal of Infection 2015; 71: 37-42.

Lucas MJ, Brouwer MC, van de Ende A, van de Beek D. Outcome in patients with bacterial meningitis presenting with a minimal Glasgow Coma Scale score. Neurology: Neuroimmunology & Neuroinflammation 2014; 1: e9.

Lucas MJ, Brouwer MC, van der Ende A, van de Beek D. Endocarditis in adults with bacterial meningitis. Circulation 2013; 127: 2056-62.

Lucas MJ, Brouwer MC, van de Beek D. Delayed cerebral thrombosis in bacterial meningitis: a prospective cohort study. Intensive care medicine 2013; 39: 866-71.

Lucas MJ, Schut ES, Brouwer MC, Vergouwen MD, van der Ende A, van de Beek D. Cerebral infarction in adults with bacterial meningitis. Neurocritical Care 2012; 16: 421-7.

Lucas MJ, Brouwer MC, van de Beek D. De diagnostische waarde van nekstijfheid en de tekens van Kernig en Brudzinski bij meningitis. Tijdschrift voor Neurologie en Neurochirurgie. Vol 112 – nr.3 – 2011.

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