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Stroke in Pediatric Bacterial Meningitis: Population-Based Epidemiology

  • Mary Dunbar
    Affiliations
    Department of Community Health Services, University of Calgary, Calgary, Alberta, Canada

    Calgary Pediatric Stroke Program, University of Calgary, Calgary, Alberta, Canada
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  • Hely Shah
    Affiliations
    Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
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  • Siddharth Shinde
    Affiliations
    Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
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  • Joseph Vayalumkal
    Affiliations
    Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
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  • Otto G. Vanderkooi
    Affiliations
    Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada

    Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
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  • Xing-Chang Wei
    Affiliations
    Department of Radiology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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  • Adam Kirton
    Correspondence
    Communications should be addressed to: Dr. Adam Kirton, Alberta Children's Hospital 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada.
    Affiliations
    Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada

    Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada

    Department of Radiology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

    Department of Community Health Services, University of Calgary, Calgary, Alberta, Canada

    Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada

    Hotchkiss Brain Institute, Calgary, Alberta, Canada

    Calgary Pediatric Stroke Program, University of Calgary, Calgary, Alberta, Canada
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      Abstract

      Background

      Bacterial meningitis is a severe infection of the nervous system with a high complication rate including stroke. The purpose of this study is to assess the incidence, risk factors, patterns, and outcomes in pediatric meningitis complicated by stroke.

      Methods

      The study design was a population-based, 10-year retrospective (2002 to 2012) cohort study set in Southern Alberta, Canada. The inclusion criteria were: (1) age from newborn to 18 years, (2) brain magnetic resonance imaging (MRI) including diffusion-weighted imaging during admission, and (3) laboratory confirmed acute bacterial meningitis. The main outcomes were demographics, clinical presentations, risk factors, laboratory findings, radiographic findings, and neurological outcomes.

      Findings

      Forty-three patients had confirmed bacterial meningitis and diffusion MRI (9 neonates (21%), 89% male; 22 infants aged one month to one year (51%), 50% male; and 12 children older than one year (28%), 58% male, median age four years (interquartile range 7.9 years). Ischemic stroke was confirmed in 16/43 (37%), often multifocal (94%). Patients with stroke were significantly more likely to have seizures (P = 0.025), otitis media (P = 0.029), and multiple presentations to hospital (P = 0.013). Mortality was 25% in children with stroke compared with 4% in those without (P = 0.067). Survivors with stroke were more likely to have neurological deficits at follow-up (69% versus 26%, P = 0.019).

      Conclusions

      More than one-third of children with acute bacterial meningitis and clinically indicated MRI had ischemic stroke. Stroke was associated with clinical factors including duration of illness, seizures, and causative organisms. Stroke was associated with higher mortality and morbidity, warranting consideration of increased MRI screening and new approaches to treatment.

      Keywords

      Introduction

      Bacterial meningitis is a severe infection with high morbidity and mortality that is most common in the first year of life.
      • Brouwer M.C.
      • Tunkel A.R.
      • van de Beek D.
      Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis.
      Advances in immunization and critical care have reduced the incidence and improved survival,
      • Buchholz G.
      • Koedel U.
      • Pfister H.-W.
      • Kastenbauer S.
      • Klein M.
      Dramatic reduction of mortality in pneumococcal meningitis.
      but there is still a high rate of adverse outcome which may be attributable to cerebrovascular complications and stroke.
      Amongst patients with bacterial meningitis, stroke may complicate 17% to 43% of cases.
      • Pryde K.
      • Walker W.T.
      • Hollingsworth C.
      • et al.
      Stroke in paediatric pneumococcal meningitis: a cross-sectional population-based study.
      • Chang C.J.
      • Chang W.N.
      • Huang L.T.
      • et al.
      Cerebral infarction in perinatal and childhood bacterial meningitis.
      • Jan W.
      • Zimmerman R.A.
      • Bilaniuk L.T.
      • Hunter J.V.
      • Simon E.M.
      • Haselgrove J.
      Diffusion-weighted imaging in acute bacterial meningitisin infancy.
      • Stovring J.
      • Snyder R.D.
      Computed tomography in childhood bacterial meningitis.
      Few data exist in the pediatric population. Only two studies have compared children with and without stroke in bacterial meningitis, both of which were limited by modest, nonpopulation-based samples and lack of routine diffusion-weighted MRI.
      • Pryde K.
      • Walker W.T.
      • Hollingsworth C.
      • et al.
      Stroke in paediatric pneumococcal meningitis: a cross-sectional population-based study.
      • Chang C.J.
      • Chang W.N.
      • Huang L.T.
      • et al.
      Cerebral infarction in perinatal and childhood bacterial meningitis.
      To date, no study has utilized diffusion MRI to identify and characterize cerebral infarction in neonatal and childhood meningitis compared with those without stroke. The utility of diffusion MRI includes improved sensitivity for infarct detection, especially in neonates where clinical examination has limited ability to identify stroke and cerebrovascular complications.
      • Jan W.
      • Zimmerman R.A.
      • Bilaniuk L.T.
      • Hunter J.V.
      • Simon E.M.
      • Haselgrove J.
      Diffusion-weighted imaging in acute bacterial meningitisin infancy.
      • Jaremko J.L.
      • Moon A.S.
      • Kumbla S.
      Patterns of complications of neonatal and infant meningitis on MRI by organism: a 10 year review.
      Although more established in adults,
      • Lucas M.J.
      • Brouwer M.C.
      • van de Beek D.
      Neurological sequelae of bacterial meningitis.
      meningitis can lead to both large and small vessel cerebral arteritis, conferring a risk of arterial ischemic stroke.
      • Igarashi M.
      • Gilmartin R.C.
      • Gerald B.
      • Wilburn F.
      • Jabbour J.T.
      Cerebral arteritis and bacterial meningitis.
      Adult studies have identified risk factors for cerebral infarction in bacterial meningitis including older age, compromised immunity, lower level of consciousness at admission, increased inflammatory markers, and seizures.
      • Schut E.S.
      • Lucas M.J.
      • Brouwer M.C.
      • Vergouwen M.D.I.
      • van der Ende A.
      • van de Beek D.
      Cerebral infarction in adults with bacterial meningitis.
      • Bodilsen J.
      • Dalager-Pedersen M.
      • Schønheyder H.C.
      • Nielsen H.
      Stroke in community-acquired bacterial meningitis: a Danish population-based study.
      • Klein M.
      • Koedel U.
      • Pfefferkorn T.
      • Zeller G.
      • Woehrl B.
      • Pfister H.-W.
      Arterial cerebrovascular complications in 94 adults with acute bacterial meningitis.
      • Katchanov J.
      • Heuschmann P.U.
      • Endres M.
      • Weber J.R.
      Cerebral infarction in bacterial meningitis: predictive factors and outcome.
      Although clinical trials do not exist, agents to potentially mitigate this risk including anti-inflammatory (e.g. corticosteroids) and antithrombotic (e.g. aspirin or heparins) medications are readily available and likely safe.
      • Boelman C.
      • Shroff M.
      • Yau I.
      • et al.
      Antithrombotic therapy for secondary stroke prevention in bacterial meningitis in children.
      An improved understanding of risk factors and imaging biomarkers of meningitis-associated stroke in children is required to advance strategies to improve outcomes.
      We conducted a population-based, retrospective cohort study of pediatric patients with bacterial meningitis who underwent acute diffusion MRI to identify risk factors, imaging patterns, and clinical outcome characteristics of bacterial meningitis-associated stroke.

      Methods

      Study design and populations

      This was a population-based, 10-year retrospective, cohort study designed to capture all neonates and children diagnosed with bacterial meningitis in Southern Alberta, Canada (approximately 2.2 million persons). Methods were approved by the Conjoint Health Research Ethics Board of the University of Calgary.

      Case ascertainment

      Screening began from the year 2002 when diffusion MRI became routinely available and ended in 2012 as an institutional MRI screening protocol for meningitis was introduced in 2013. A rigorous approach defined a population-based sample where a single tertiary care pediatric center, regional laboratory, and universal health care combined to assure near 100% case ascertainment.
      Inclusion criteria were: (1) age at diagnosis from newborn (including prematurity) to 18 years, (2) brain MRI including diffusion imaging during admission, and (3) confirmed acute bacterial meningitis. Definitive diagnosis required a clinical diagnosis of bacterial meningitis AND either (1) cerebrospinal fluid (CSF) culture positive for a pathogenic organism OR the combination of CSF pleocytosis (white blood cell count greater than 50 × 106 cells/L) with concomitant positive blood culture for a pathogenic organism. Excluded were cases with: viral, fungal or tuberculous meningitis, clinically or microbiologically suspected contaminant in CSF culture, shunt infection without evidence of clinical meningitis, wound infection related to myelomeningocele or trauma, or incomplete clinical or imaging data. It is possible that the requirement for MRI with diffusion-weighted imaging (DWI) may cause some of the most acutely unwell patients to be omitted, as they may have only received a CT.
      Potential cases were first identified from the Calgary Lab Services database where all positive CSF cultures from the population-base were reviewed. Next, systematic screening of International Classification of Disease 9 and 10 (ICD) codes consistent with bacterial meningitis were applied by skilled coding experts to the Alberta Children's Hospital records as described previously,
      • Cole L.
      • Dewey D.
      • Letourneau N.
      • et al.
      Clinical characteristics, risk factors, and outcomes associated with neonatal hemorrhagic stroke: a population-based case-control study.
      enabling capture of patients transferred after CSF was collected outside the regional laboratory catchment area.

      Chart review

      Using standardized data capture forms, clinical history, physical examination findings, and laboratory values were extracted. All follow-up records were reviewed to estimate neurological outcomes which were extrapolated to the pediatric stroke outcome measure (PSOM). The PSOM is the standard measure in this population and has been validated across all childhood stroke age groups.
      • Kitchen L.
      • Westmacott R.
      • Friefeld S.
      • et al.
      The pediatric stroke outcome measure: a validation and reliability study.
      For analysis, PSOM scores were dichotomized into good (PSOM < 1) versus poor outcome (PSOM ≥ 1).

      Imaging

      All neuroimaging was obtained on a clinical basis on Siemens 1.5T MRI scanners (Magnetom Sonata before or Avanto after September 2006) in accordance with institutional protocols that included diffusion-weighted imaging (b = 0, 500, 1000) and apparent diffusion coefficient maps. Image analysis was performed by two neuroimaging experts (AK, XW) who were not aware of clinical variables. The primary imaging outcome was the presence of acute ischemic stroke, defined as one or more areas of restricted diffusion (hyperintense on DWI, hypointense on apparent diffusion coefficient) in a focal vascular territory. Arterial lesions were classified as arterial ischemic strokes and infarcts in conjunction with cerebral sinovenous thrombosis were classified as venous. Additional imaging outcomes collected were stroke location, structures affected, anterior or posterior circulation, vascular territory (small, large), and laterality based on reported criteria.
      • Aviv R.I.
      • Benseler S.M.
      • Silverman E.D.
      • et al.
      MR imaging and angiography of primary CNS vasculitis of childhood.
      MR venography and arteriography were evaluated. Imaging diagnosis of other complications of meningitis was also recorded: abscess, empyema, extra-axial collections, and hydrocephalus.

      Analysis

      Categorization of patterns and their association with organism, and categorical comparisons of stroke (yes/no), organisms, and proportions were evaluated using Chi-Square or Fisher's exact test. Ordinal data and continuous variables were represented with medians and interquartile ranges (IQR) and significance tested with Wilcoxon rank sum tests due to non-normal distribution of data and low numbers of subjects. Correlation between variables was determined by calculating the coefficient of correlation. Correction for multiple comparisons was not performed.

      Results

      Population

      There were 487 positive CSF cultures evaluated, 62 of which were included. Reasons for exclusion of positive CSF cultures included contamination, patients with shunts without evidence of meningitis, many of whom had multiple samples drawn. ICD-10 codes identified 469 potential patients, of whom 66 were confirmed. Finally, 21 patients had positive blood cultures and CSF leukocytosis, of which 19 were included. There were a total of 93 unique cases of confirmed bacterial meningitis (Fig 1). This included 25 neonates (26%, 64% male), 37 infants aged one month to one year (40%, 57% male), and 34 children greater than one year (37%, 50% male, median age 5.7 years, IQR 6.7 years). Government statistics estimated an average pediatric population of Southern Alberta during the study of approximately 390,000.

      Office of Statistics and Information. Distribution of population by age and sex, Alberta. open.alberta.ca. https://open.alberta.ca/opendata/distribution-of-population-by-age-and-sex-alberta#detailed. Accessed September 1, 2017.

      Our 93 cases over 10 years translates into an estimated incidence of bacterial meningitis of 2.37/100,000 children per year.
      Fig 1
      FIGURE 1Selection criteria. Patients were identified based on positive cerebrospinal fluid cultures (+CSF Cx), ICD-10 discharge codes (ICD-10), and positive blood cultures with at least 50 CSF WBC (+BCx + CSF >50 WBC). The Venn diagram illustrates the overlap of patients found by each method.
      Cerebral imaging of any kind was performed on 71 of 93 patients (76%) (Fig 1). The final study population consisted of 43 patients with diffusion MRI (Fig 1). The age and sex of the study population are summarized in Table 1. The median age of children was 4.0 years, IQR 7.9 years. The entire age range was 26 weeks gestational age to 13.3 years. The proportion of males in the neonatal group was higher than expected (p = 0.023) (Fig 2).

      Urquijo C.R., Milan A. Female population. Statistics Canada. http://www.statcan.gc.ca/pub/89-503-x/2010001/article/11475-eng.htm. Published May 30, 2015. Accessed September 1, 2017.

      Sixteen patients had diffusion MRI confirmation of ischemic stroke (37%) of the 43 with DWI imaging. The demographics of those with and without stroke were not significantly different (Table 2).
      Table 1Age and Sex. Sex and Age Distribution of the 43 Patients With Bacterial Meningitis and MRI With DWI
      Number (% of total)% Male
      Neonates (<28 days)9 (21%)89%
      Infants (28 days-1 year)22 (51%)50%
      Children (>1 year)12 (28%58%
      Fig 2
      FIGURE 2Meningitis demographics. Sex of study population divided by age from birth at presentation. Star = P value < 0.05 for test of proportion of male patients = 0.512.
      Table 2Population Demographics. Patient Populations of Those With and Without Stroke in Bacterial Meningitis. n = Number of Patients with Positive Result/Number of Patients With Available Information. P Values Determined by Fisher's Exact Test or Wilcoxon Rank-Sum Test
      StrokeNo StrokeP Value
      n%n%
      Demographics
       Total number1627
       Male11/1668.8%15/2755.6%0.52
       <35 weeks post conceptual age at diagnosis1/156.7%2/267.7%1
       <28 days old at diagnosis3/1618.8%6/2722.2%1
       1 month 1 year at diagnosis6/1640.0%7/2626.9%0.51
       >1 year at diagnosis4/1526.7%8/2630.8/%1
       History of prematurity (<35 weeks GA)3/1520.0%7/2626.9%0.72
       Shunt predating presentation1/166.3%1/273.7%1
       Pre-existing medical condition3/1618.8%6/2524.0%1
       Presented from community15/1693.8%23/2785.2%0.64
       Presented from NICU1/166.3%4/2714.8%0.64
      Presentation
       Duration of symptoms (median days, IQR)3.5(5)2(1)0.086
       Number of presentations (median, IQR)2(2)1(0)0.013
       Triage to first antibiotics (median min, IQR)124(182)273(398)0.35
       Decreased LOC at admission10/1566.7%9/2437.5%0.19
       Fever >48 hours at admission9/1560.0%6/2326.1%0.049
       Meningismus10/1190.9%6/1346.2%0.11
       Seizures before or during admission13/1681.3%11/2544.0%0.025
       New focal signs during admission4/1625.0%3/2611.5%0.40
       Hyponatremia6/1540%5/2123.8%0.27
      Laboratory values
       Serum WBC on admission (median, IQR)7.8(11.1)6.5(8.1)0.75
       Serum Hb on admission (median, IQR)105(38)112(34)0.82
       CSF WBC on admission (median, IQR)261(474)784(2261)0.14
       CRP at admission (median, IQR)237(232.9)155.5(63.3)0.11
       Number of patients with CSF glucose <0.59/1464.3%11/2055.0%0.73
       MRI findings
       Time between MRI and CSF (median days, IQR)3.65(4.35)1.75(4.8)0.09
       Changes consistent with sinusitis1/166.3%5/2420.8%0.37
       Changes consistent with otitis5/1631.3%1/244.2%0.029
       Changes consistent with mastoiditis5/1631.3%2/248.3%0.077
      Course and treatment
       PICU admission10/1662.5%15/2657.7%1
       PICU admission duration (median days, IQR)3(28.5)4(4)0.34
       Hospital admission duration (median days, IQR)29.9(73.5)13.89(11)0.013
       ASA5/1533.3%0/140.042
       Heparin4/1526.7%1/224.5%0.14
       Steroids3/1225%1/214.8%0.13
       Need for vasopressors2/1414.3%3/837.5%0.33
      Outcome
       Death4/1625%1/254%0.067
       Follow-up duration (median years, IQR)6.7(7.9)4.8(4.9)0.67
       Epilepsy at follow-up3/1323.1%3/1816.7%0.68
       Normal neurological exam5/1631.3%14/1973.7%0.019
       Motor deficit7/1546.7%4/1526.7%0.45
       Cognitive deficit5/1241.7%2/922.2%0.64
       Behavioral deficit1/119.1%1/128.3%1
       Speech deficit4/1233.3%1/137.7%0.16
       Hearing loss2/1020.0%3/1717.6%1

      Clinical presentation

      More stroke patients had fever for more than 48 hours at presentation compared with those without stroke (60% versus 26%, P = 0.049). The median number of presentations to the hospital for a patient with stroke was two (IQR 2) and significantly more than one (IQR 0) for those without (P = 0.013). Seizure before or during admission was more common in stroke patients (81% versus 44%, OR 5.5 (1.3 to 24.3), P = 0.025). The proportion of patients with decreased level of consciousness, meningismus, hyponatremia, and new focal neurological signs during admission all appeared higher in the stroke group but did not reach significance.

      Microbiology

      Group B Streptococcus (GBS) and Escherichia coli were associated with neonates and infants under 90 days old while Streptococcus pneumoniae accounted for 53% of the children older than one month, of whom 44% had stroke. GBS was the responsible organism in three (33%) of the neonatal cases, but also affected an additional three infants with late presentation. One neonate and two older infants with GBS had stroke (50%). There were five individuals with Haemophilus influenza, one of whom had stroke (20%), and four cases of E. coli, one of whom had stroke (25%) (Supplementary Fig 1).

      Laboratory

      Serum and CSF white blood cell counts did not differ significantly between groups with and without stroke (Table 2). Twenty patients had CSF glucose that was undetectably low (<0.5 mmol/L), nine of whom had stroke (P = 0.728).

      Neuroimaging

      Of the 71 patients with acute imaging, 15 underwent a CT, six an ultrasound, two a CT and an ultrasound, four an MRI without DWI, and one an MRI on a separate admission. The remaining 43 comprise the study population with MRI and DWI. Of the 28 patients with acute imaging excluded from the study due to lack of MRI with DWI, one (4%) was found to have stroke (venous sinus thrombosis and brainstem infarction), the remainder had no evidence of stroke. Thus there does not seem to have been significant selection bias introduced by the requirement for MRI with DWI. The median duration between presentation and MRI for patients with stroke was 1.75 days (IQR 4.8, range 0 to 17 days) compared with 3.65 days (IQR 4.35, range 0 to 80 days) for patients without stroke (P = 0.09).
      Fourteen of the sixteen stroke patients had arterial ischemic infarction, most (75%) in the bilateral anterior circulation in small-to-medium sized, perforating arterial territories (Fig 3). Seven patients had associated hemorrhage though all were petechial transformation with no hematoma formation. The median number of infarcted areas per patient was six (range one to 15). S. pneumoniae was typically associated with frontal infarction and deeper perforating areas including the basal ganglia and splenium of the corpus callosum (Fig 3A-F). GBS affected predominantly deep perforating arteries in the basal ganglia (Fig 3H-J). Gram negative infections were associated with severe, bilateral thalamic or brainstem infarction, both of which were fatal (Fig 3K and L).
      Fig 3
      FIGURE 3Stroke Imaging. Images are axial MRI diffusion-weighted images (b = 1000) unless otherwise stated. Areas of acute infarction appear “bright”. A-I; Streptococcus pneumonia with multifocal, deep and superficial multiple areas of infarction. A = patient 27 coronal, B = patient 36, C = patient 22, D = patient 21, E = patient 10, F = patient 19, G: Streptococcus, not pneumonia, patient 33, sequence demonstrates progressive infarction over 19 days. G2: 4 days after initial imaging, G3: 19 days after initial imaging. H-J: Group B Streptococcus. H = patient 4, I = patient 14 coronal, J = patient 16. K: E. coli, patient 2. K2: axial T2-weighted MRI demonstrating diffuse encephalomalacia due to extensive infarction. L = gram negative bacilli, patient 25.
      Eleven patients (26%) had MR angiography, seven of whom had stroke. Four (9%) demonstrated signs of large vessel arteriopathy consisting of irregular stenosis of major branches of the circle of Willis. One patient demonstrated progression of both arteriopathy and stroke recurrence over three MRI assessments across 19 days (Fig 3G). In another patient, there was progression of arterial stenosis but no new infarcts. MR venography was completed in 15 subjects (35%). Cerebral sinovenous thrombosis was diagnosed in four, two of which had venous infarction.
      The images of the 71 patients with cerebral imaging of any kind during their admission were reviewed for additional nonstroke complications. Two had definitive abscess while another was considered probable (4%). Seven (10%) were suspected to have empyema, 28 (40%) had extra-axial collections, and 13 (19%) developed early hydrocephalus.

      Course in hospital

      The majority of children in both groups (63% stroke, 58% without) were admitted to intensive care. Median length of hospital stay was 29.9 days (IQR 73.5) for stroke patients, significantly longer than 13.9 days (IQR 11) for those without (P = 0.013) (Table 2). Five of the children with stroke (31%) were treated with ASA for stroke prevention. Heparin was given to one patient with cerebral venous sinus thrombosis, and three patients for femoral clot. Steroids were given to four children, three with stroke and one without.

      Outcomes

      Follow-up information was available for all 16 stroke patients (Supplementary Table 1) and 24 of 27 without stroke. The mean duration of follow-up was 6.7 years (range four months to 10.5 years) and 4.8 years (range one month to 12 years) respectively. Four stroke patients died (25%) compared with one in the nonstroke group (4%) (P = 0.067). Children with stroke were less likely to have a normal neurological examination at discharge (21% versus 76%, P = 0.002) and at follow-up (31% versus 74%, P = 0.019). Type of deficits did not differ between groups. Epilepsy was present at follow-up for three of 13 stroke patients for whom information was available (23.1%), compared with three of 18 without stroke (16.7%) (P = 0.66).
      PSOM scores were available for 40 patients (93%) (Table 2). There was a strong correlation between PSOM score and the number of areas infarcted (coefficient of correlation 0.78, P = 0.007). Patients with a good outcome (PSOM < 1) had fewer areas of infarct (median 4, IQR 5.5) compared with those with poor outcome (PSOM ≥ 1) (median 11, IQR 7) (P = 0.0061). All subjects with bilateral thalamic or bilateral brainstem infarcts had a severe outcome or death. Among patients with stroke, no additional clinical factors were associated with outcome.

      Discussion

      We provide population-based data describing the clinical, imaging, and microbiologic factors associated with bacterial meningitis and stroke in children. Our results confirm that stroke is common and serious complication with increased morbidity and mortality.
      Our estimate of the incidence of pediatric bacterial meningitis in Southern Alberta was 2.37/100,000 children/year, slightly lower than previous estimates in Canada of 3.5/100,000.

      Public Health Agency of Canada. Bacterial meningitis in Canada:Hospitalizations (1994-2001). Canada.ca. https://www.canada.ca/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2005-31/bacterial-meningitis-canada-hospitalizations-1994-2001.html. Published January 12, 2005. Accessed September 1, 2017.

      This may relate to our strict inclusion criteria and exclusion of patients with other forms of meningitis such as shunt infections. The incidence of stroke in those with DWI was 37%. A less precise estimate based on the 71 children who received cerebral imaging of any kind is 24%, and if it is assumed that none of the 22 children without cerebral imaging had stroke, the rate of stroke in our cohort of 93 patients with meningitis was 18%. Studies of stroke in infant bacterial meningitis have estimated an incidence ranging from 24%
      • Ouchenir L.
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      while in children with S. pneumoniae meningitis, rates of 45% have been reported.
      • Pryde K.
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      • Hollingsworth C.
      • et al.
      Stroke in paediatric pneumococcal meningitis: a cross-sectional population-based study.
      Similar to our study, these earlier studies were affected by some degree of selection bias with regard to which patients underwent imaging.
      Stroke has been consistently reported in neonatal meningitis,
      • Friede R.L.
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      as compared with our population-based rate of 33%. Half of our neonates with GBS meningitis had stroke in keeping with a series of 14 infants with late onset GBS meningitis and cerebrovascular complications, 11 of which included acute stroke (78%).
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      Males were over-represented in the 93 patients with confirmed meningitis, but only during the first four months of life (67% of cases birth to four months). A male preponderance in meningitis has been reported in some studies
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      A study of 280 cases of neonatal meningitis in The Netherlands.
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      Male neonates may also have an increased incidence of complications due to meningitis
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      International Pediatric Stroke Study Group
      Male predominance in childhood ischemic stroke: findings from the international pediatric stroke study.
      including neonatal arterial strokes,
      • Golomb M.R.
      • Fullerton H.J.
      • Nowak-Göttl U.
      • Deveber G.
      International Pediatric Stroke Study Group
      Male predominance in childhood ischemic stroke: findings from the international pediatric stroke study.
      • Kirton A.
      • Armstrong-Wells J.
      • Chang T.
      • et al.
      Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study.
      though mechanisms are unclear.
      • Normann S.
      • de Veber G.
      • Fobker M.
      • et al.
      Role of endogenous testosterone concentration in pediatric stroke.
      The most common pathogen in non-neonates was S. pneumoniae (53%) where the stroke rate was high at 48%. This rate appears comparable to a prospective Danish study in adults that found S. pneumoniae responsible for 51% of bacterial meningitis with a stroke rate of 36%.
      • Schut E.S.
      • Lucas M.J.
      • Brouwer M.C.
      • Vergouwen M.D.I.
      • van der Ende A.
      • van de Beek D.
      Cerebral infarction in adults with bacterial meningitis.
      Arteriopathy is also prominent in adults with S. pneumoniae meningitis imaged prospectively.
      • Pfister H.W.
      • Feiden W.
      • Einhäupl K.M.
      Spectrum of complications during bacterial meningitis in adults. Results of a prospective clinical study.
      The marked progress in immunization strategies against this organism
      • Tan T.Q.
      Pediatric invasive pneumococcal disease in the United States in the era of pneumococcal conjugate vaccines.
      may represent an important public health advance toward the prevention of stroke in the young. Routine immunizations were also recently shown to be protective against childhood stroke,
      • Fullerton H.J.
      • Hills N.K.
      • Elkind M.S.V.
      • et al.
      Infection, vaccination, and childhood arterial ischemic stroke.
      further highlighting the complexity of relationships between infections, immunity, and stroke. In addition, the advent of vaccines to prevent meningitis decreased the overall incidence of meningitis over the course of the study period.
      • McIntyre P.B.
      • O'Brien K.L.
      • Greenwood B.
      • van de Beek D.
      Effect of vaccines on bacterial meningitis worldwide.
      The pathophysiology of cerebral infarction in bacterial meningitis is not well established. In four of our patients, cerebral arteriopathy was observed, one of which was associated with progressive infarction. In adults with meningitis undergoing systematic transcranial Doppler, cerebral arteriopathy is suggested in 50% to 80%.
      • Ries S.
      • Schminke U.
      • Fassbender K.
      • Daffertshofer M.
      • Steinke W.
      • Hennerici M.
      Cerebrovascular involvement in the acute phase of bacterial meningitis.
      • Müller M.
      • Merkelbach S.
      • Huss G.P.
      • Schimrigk K.
      Clinical relevance and frequency of transient stenoses of the middle and anterior cerebral arteries in bacterial meningitis.
      Arterial irregularity and stenosis in neonatal bacterial meningitis is demonstrable by MR angiography and has been correlated with pathologic evidence of vasculitis.
      • Jan W.
      • Zimmerman R.A.
      • Bilaniuk L.T.
      • Hunter J.V.
      • Simon E.M.
      • Haselgrove J.
      Diffusion-weighted imaging in acute bacterial meningitisin infancy.
      In contrast, other series have shown imaging evidence of vessel narrowing but no vasculitis on pathology, suggesting alternative mechanisms such as vasospasm,
      • Lyons E.L.
      • Leeds N.E.
      The angiographic demonstration of arterial vascular disease in purulent meningitis. Report of a case.
      • Davis D.O.
      • Dilenge D.
      • Schlaepfer W.
      Arterial dilatation in purulent meningitis. Case report.
      which may also underlie “delayed” stroke in meningitis.
      • Wittebole X.
      • Duprez T.
      • Hantson P.
      Delayed cerebral ischaemic injury following apparent recovery from Streptococcus pneumoniae meningitis.
      Arterial clots have also been described in the absence of vasculitis in S. pneumoniae meningitis,
      • Mook-Kanamori B.B.
      • Geldhoff M.
      • van der Poll T.
      • van de Beek D.
      Pathogenesis and pathophysiology of pneumococcal meningitis.
      the mechanisms of which are likely to be multifactorial, with recent in vivo evidence that neutrophil extracellular traps contribute to intravascular coagulation in mouse models of bacteremia.
      • McDonald B.
      • Davis R.
      • Jenne C.N.
      Neutrophil extracellular traps (NETs) promote disseminated intravascular coagulation in sepsis.
      There is evidence that greater host immune reactions may be associated with higher stroke likelihood.
      • Schut E.S.
      • Lucas M.J.
      • Brouwer M.C.
      • Vergouwen M.D.I.
      • van der Ende A.
      • van de Beek D.
      Cerebral infarction in adults with bacterial meningitis.
      • Bodilsen J.
      • Dalager-Pedersen M.
      • Schønheyder H.C.
      • Nielsen H.
      Stroke in community-acquired bacterial meningitis: a Danish population-based study.
      The interaction between organism and host immunity may in part explain why rates of stroke differ between organisms. There is growing evidence that recent herpesvirus infection is associated with pediatric stroke, further suggesting an immune-host response that results in vasculopathy.
      • Elkind M.S.V.
      • Hills N.K.
      • Glaser C.A.
      • et al.
      Herpesvirus infections and childhood arterial ischemic stroke: results of the VIPS study.
      Most patients had multiple areas of infarction, often involving both the basal ganglia and cortex. An Australian study of MRI patterns by organism determined that the majority of patients with streptococcal meningitis had multiple infarcts that were often confluent over multiple vascular territories and involved the basal ganglia.
      • Jaremko J.L.
      • Moon A.S.
      • Kumbla S.
      Patterns of complications of neonatal and infant meningitis on MRI by organism: a 10 year review.
      This appears similar to patterns in neonatal GBS infarction where combined deep and superficial injuries are described.
      • Hernández M.I.
      • Sandoval C.C.
      • Tapia J.L.
      • et al.
      Stroke patterns in neonatal group B streptococcal meningitis.
      In contrast, E. coli meningitis may be more likely to demonstrate diffusion restriction in extra-axial collections and ventriculomegaly.
      • Jaremko J.L.
      • Moon A.S.
      • Kumbla S.
      Patterns of complications of neonatal and infant meningitis on MRI by organism: a 10 year review.
      Such imaging patterns may be useful biomarkers of organism identification (when cultures are not available) or help identify pathophysiological mechanisms that might be targeted with new therapies.
      Possible predictors of stroke risk in children with meningitis have included seizures, focal neurological signs, fever, decreased level of consciousness, and hydrocephalus.
      • Pryde K.
      • Walker W.T.
      • Hollingsworth C.
      • et al.
      Stroke in paediatric pneumococcal meningitis: a cross-sectional population-based study.
      • Chang C.J.
      • Chang W.N.
      • Huang L.T.
      • et al.
      Cerebral infarction in perinatal and childhood bacterial meningitis.
      Similar risk factors are seen in adults in addition to higher erythrocyte sedimentation rate or C-reactive protein.
      • Schut E.S.
      • Lucas M.J.
      • Brouwer M.C.
      • Vergouwen M.D.I.
      • van der Ende A.
      • van de Beek D.
      Cerebral infarction in adults with bacterial meningitis.
      • Bodilsen J.
      • Dalager-Pedersen M.
      • Schønheyder H.C.
      • Nielsen H.
      Stroke in community-acquired bacterial meningitis: a Danish population-based study.
      There have been efforts to predict stroke risk based on transcranial Doppler arterial velocity though a recent study found limited correlations with MR angiogram findings.
      • Klein M.
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      • Pfefferkorn T.
      • Zeller G.
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      Arterial cerebrovascular complications in 94 adults with acute bacterial meningitis.
      In our study, multiple presentations, presence of seizures, evidence of otitis media, and fever greater than 48 hours were significantly associated with stroke. Seizures are the most common presenting symptom of stroke in neonates with any etiology
      • Sreenan C.
      • Bhargava R.
      • Robertson C.M.
      Cerebral infarction in the term newborn: clinical presentation and long-term outcome.
      and are frequently subclinical, suggesting electroencephalogram screening may be useful in this population. There is also evidence that postischemic seizures may be associated with a worse outcome, possibly due to increased excitotoxicity and neuronal death, and thus early detection and treatment may have a positive effect on outcome.
      • Bryndziar T.
      • Sedova P.
      • Kramer N.M.
      • et al.
      Seizures following ischemic stroke: frequency of occurrence and impact on outcome in a long-term population-based study.
      • Xu T.
      • Ou S.
      • Liu X.
      • et al.
      Association between seizures after ischemic stroke and stroke outcome: a systematic review and meta-analysis.
      • El-Hayek Y.H.
      • Wu C.
      • Chen R.
      • et al.
      Acute postischemic seizures are associated with increased mortality and brain damage in adult mice.
      Stroke prevention strategies in meningitis are limited. Mechanisms for stroke such as inflammation, vasospasm, and increased coagulation are potential targets for therapy. Inflammation and infection are known risk factors for stroke,
      • Lindsberg P.J.
      • Grau A.J.
      Inflammation and infections as risk factors for ischemic stroke.
      and steroids have been shown to improve outcome in certain meningitis populations.
      • McGill F.
      • Heyderman R.S.
      • Panagiotou S.
      • Tunkel A.R.
      • Solomon T.
      Acute bacterial meningitis in adults.
      A randomized placebo trial of dexamethasone in neonatal meningitis suggested a mortality benefit,
      • Mathur N.B.
      • Garg A.
      • Mishra T.K.
      Role of dexamethasone in neonatal meningitis: a randomized controlled trial.
      however using steroids in meningitis is not generally considered standard of care in children, with the exception of H. influenzae.
      • Brouwer M.C.
      • McIntyre P.
      • Prasad K.
      • van de Beek D.
      Corticosteroids for acute bacterial meningitis.
      Steroids may also be beneficial in certain childhood stroke populations though this remains unproven.
      • Steinlin M.
      • Bigi S.
      • Stojanovski B.
      • et al.
      Focal cerebral arteriopathy: do steroids improve outcome?.
      Vasospasm is another potential mechanism however strategies to treat vasospasm related to other causes (e.g. calcium channel blockers) have not been studied in stroke associated with bacterial meningitis. Finally, hypercoagulability occurs in the setting of meningitis and can possibly be mitigated with heparin, ASA or both. ASA has shown modest benefit in studies of tuberculous meningitis.
      • Schoeman J.F.
      • Janse van Rensburg A.
      • Laubscher J.A.
      • Springer P.
      The role of aspirin in childhood tuberculous meningitis.
      • Misra U.K.
      • Kalita J.
      • Nair P.P.
      Role of aspirin in tuberculous meningitis: a randomized open label placebo controlled trial.
      Heparin has not been studied for primary prevention of stroke in meningitis since an adult study in 1977 demonstrated lack of benefit and possible bleeding risk.
      • MacFarlane J.T.
      • Cleland P.G.
      • Attai E.D.
      • Greenwood B.M.
      Failure of heparin to alter the outcome of pneumococcal meningitis.
      A more recent retrospective pediatric study suggested safety and possible efficacy when used for secondary prevention.
      • Boelman C.
      • Shroff M.
      • Yau I.
      • et al.
      Antithrombotic therapy for secondary stroke prevention in bacterial meningitis in children.
      Antithrombotics were used infrequently in our study but there were no apparent adverse effects. There are currently no therapies recommended for primary stroke prevention in meningitis, however, stroke may be a primary mechanism of long-term morbidity and remains an important target where therapeutic approaches need to be advanced.
      Outcomes in pediatric meningitis complicated by stroke carry high rates of morbidity and mortality. The largest series of 22 cases of pediatric meningitis and stroke at two Canadian centers demonstrated mortality in two (9%), severe disability in two, moderate disability in two, and minimal disability (PSOM total 1 or 2) in the remainder.
      • Boelman C.
      • Shroff M.
      • Yau I.
      • et al.
      Antithrombotic therapy for secondary stroke prevention in bacterial meningitis in children.
      Our study found an overall mortality rate of 5/43 (12%), 80% of whom had stroke. There was also significantly more disability in the children with stroke and those with poor outcomes had more areas of infarct. The early recognition of meningitis and effective primary and secondary prevention of stroke remain important clinical goals.
      Limitations of our study include its retrospective nature. Not every case of meningitis may have been identified though our population-based methods were exhaustive. Our rigorous inclusion criteria for meningitis may have led to an underestimation of meningitis, and our requirement for MRI may have inadvertently omitted the sickest patients who may have died before undergoing head imaging. One patient of the 28 (4%) excluded from the study due to head imaging with a modality other than MRI with DWI was found to have stroke. Some patients received an MRI later in the course of their illness (after seven days from diagnosis) and thus some diffusion changes may not have been recognized if infarction occurred earlier. Complete clinical information was not available for every patient from the chart review, possibly limiting our risk factors analysis.
      In conclusion, more than a third of children with bacterial meningitis warranting MRI have stroke. Risk factors include multiple presentations to hospital, association with otitis media, seizures, and common causative organisms. Stroke was predominantly associated with subtypes of streptococcus in our population and the pattern of infarction frequently involved multiple small-vessel territories and the basal ganglia. Poor outcome was significantly associated with more areas of stroke. Stroke was associated with higher mortality and morbidity, warranting consideration for increased MRI screening and new approaches to treatment.

      Funding

      This work was supported by CIHR [ FDN-143294 ]

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