Lauren A. Beslow, MD, MSCE,a​ Michael M. Dowling, MD, PhD,b​ Sahar M.A. Hassanein, MBBS, PhD,c​ John K. Lynch, DO,d​ DimitriosMortality Zafeiriou, MD, PhD,​e LisaAfter R. Sun, MD,f​ Ilona Pediatric Kopyta, PhD,g​ Luigi Titomanlio, MD,h​ Anneli Kolk, MD,i​ Anthony Chan, MBBS,​j Jose Biller, MD,k​ Eric F. Grabowski, MD, ScD,​l Abdalla A. Abdalla, MD,m​ Mark T. Mackay, MBBS,Arterial PhD,​n Gabrielle deVeber, Ischemic MD, MSc,​o on behalf of theStroke International Pediatric Stroke Study Investigators

OBJECTIVES: abstract

Cerebrovascular disease is among the top 10 causes of death in US children, but risk factors for mortality are poorly understood. Within an international registry, we METHODS: identify predictors of– in-hospital mortality after pediatric– arterial ischemic stroke (AIS). Neonates (0 28 days) and children (29 days <19 years) with AIS were enrolled from January 2003 to July 2014 in a multinational stroke registry. Death during hospitalization and cause of death were ascertained from medical records. Logistic RESULTS: regression was used to analyze associations between risk factors and in-hospital mortality. Fourteen of 915 neonates (1.5%) and 70 of 2273 children (3.1%) died during hospitalization. Of 48 cases with reported causes of death, 31 (64.6%) were stroke- – related, with remaining deaths attributed to medical disease. In multivariable analysis, P – P congenital heart disease (odds ratio [OR]: 3.88; 95% confidence interval [CI]: 1.23 12.29; – P = .021), posterior plus anterior circulation stroke (OR: 5.36; 95% CI: 1.70 16.85; = .004), and stroke presentation without seizures (OR: 3.95; 95% CI: 1.26 12.37; = .019) were – P – P associated with in-hospital mortality for neonates. Hispanic ethnicity (OR: 3.12; 95% CI: – P 1.56 6.24; = .001), congenital heart disease (OR: 3.14; 95% CI: 1.75 5.61; < .001), and posterior plus anterior circulation stroke (OR: 2.71; 95% CI: 1.40 5.25; = .003) were CONCLUSIONS: associated with in-hospital mortality for children. In-hospital mortality occurred in 2.6% of pediatric AIS cases. Most deaths were attributable to stroke. Risk factors for in-hospital mortality included congenital heart disease and posterior plus anterior circulation stroke. Presentation without seizures and Hispanic ethnicity were also associated with mortality for neonates and children, respectively. Awareness and study of risk factors for mortality represent opportunities to increase survival.

WHAT’S KNOWN ON THIS SUBJECT: Stroke is among the top 10 causes of death among children according a Division of Neurology, Children’s Hospital of Philadelphia, and Departments of Neurology and Pediatrics, to administrative data in the United States, with Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; bDepartments of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, Texas; cDepartment of differences in mortality possibly associated with Pediatrics, Ain Shams University, Cairo, Egypt; dSection on Stroke Diagnostics and Therapeutics, National geographic location, sex, and race. Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; eDivision of Child Neurology and Developmental Pediatrics, Aristotle University of Thessaloniki, Thessaloniki, Greece; fDepartment WHAT THIS STUDY ADDS: In this study, we add to our of Neurology, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland; gDepartment of understanding of mortality rates among neonates Pediatric Neurology, School of Medicine, Medical University of Silesia, Katowice, Poland; hPediatric Emergency and children with arterial ischemic stroke and i Département, Hôpital Robert Debré, Paris, France; Department of Neuropsychology, University of Tartu, Tartu, identify both demographic and stroke-related risk Estonia; jDepartment of Pediatrics, McMaster Children’s Hospital, McMaster University, Hamilton, Canada; kDepartment of Neurology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; lDepartment factors for in-hospital mortality. of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts; mDepartment of Neurosciences, Al Jalila Children’s Hospital, Dubai, United Arab Emirates; nDepartment of Neurology, The Royal Children’s Hospital, Melbourne, Australia; and oDivision of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada To cite: Beslow LA, Dowling MM, Hassanein SMA, et al. Mortality After Pediatric Arterial Ischemic Stroke. Pediatrics. 2018;141(5):e20174146

Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018:e20174146 ARTICLE ∼ 8 Childhood arterial ischemic mortality. We explored potential oxygenation, or other). Information stroke (AIS) affects 1.2– to 2.4 risk factors for mortality in a large regarding withdrawal of care per 100000 children1 per3 year in multinational cohort of children and included whether withdrawal was developed countries. ‍‍ In one study, neonates with AIS. entirely or in part due to stroke researchers used death certificates METHODS deficit severity or to an underlying from children in the United medical illness. Cause of death was States between 1979 and 1998 to Subjects and Study Design then classified as due to stroke, demonstrate a decline in mortality due to a combination of underlying due to all stroke subtypes4 during that medical disease and stroke, or due to period, including in AIS. This finding The International Pediatric Stroke underlying medical disease. Statistical Analysis was supported by the Global Burden Study (IPSS) is a multinational cohort of Disease Study, which revealed study of children aged 0 to <19 years a global trend toward a decrease with AIS or cerebral sinovenous in mortality among children with thrombosis. IPSS participation was Descriptive statistics included approved by the institutional review ischemic5 stroke between 1990 and counts and percentages for 2013. However, in 2015, childhood board of each contributing center. categorical variables, means cerebrovascular disease remained Informed consent and assent, when with SD for normally distributed among the top 10 causes of death appropriate, was obtained for each – continuous variables, and medians enrolled subject. This study is a among children6 in the United States with interquartile range (IQR) for (1 19 years),​ demonstrating retrospective analysis of the IPSS nonnormally distributed continuous that despite overall decreases registry and includes children >28 variables. A nonparametric test in mortality, stroke remains an days to <19 years and neonates 0 to of trend was used to determine important cause of pediatric deaths. 28 days of life diagnosed with AIS whether mortality changed during between January 1, 2003, and July the study period. Logistic regression Given differing stroke definitions 31, 2014. Subjects with concomitant was used to analyze associations and case ascertainment methods cerebral sinovenous thrombosis were between possible risk factors and among studies, risk factors for Dataexcluded. Abstraction odds of in-hospital mortality. The mortality remain poorly understood. following factors were hypothesized In the United States, Black race and “ ” to be associated with mortality: age living in certain geographic regions Enrolling institutions recorded at stroke, congenital heart disease, (southeastern stroke belt states) medical, laboratory, and imaging clinical stroke severity (Pediatric have been reported as mortality 4,7​ data on a standardized IPSS data National Institutes of Health Stroke risk factors after childhood AIS. ‍ 9 collection form that included Scale [PedNIHSS] score),​ Black race, Geographic region was also demographics, clinical presentation, Hispanic ethnicity, and birth in a low- important in the Global Burden of stroke risk factors, imaging results, or middle- income (LAMI) country. Disease Study; an estimated 4043 laboratory data, treatment, and Only variables with <15% missing children aged 0 to 19 years died of outcome at discharge (normal, data were evaluated, with the ischemic stroke in 2013 globally (0.2 – death, neurologic deficit). Race and exception of the PedNIHSS because per 100000), with 3948 deaths in ethnicity were based on National it has previously been validated as developing countries (30 60-fold 10 Institutes of Health definitions a predictor of functional outcome. higher mortality than in developed 5 and assigned by the enrolling LAMI countries were defined by countries). 11 investigator. For those who died the World Bank. Subjects from 3 The Global Burden of Disease Study during hospitalization, centers were countries (Chile, Estonia, and Poland) also showed a trend toward higher recontacted to obtain date of death whose LAMI status changed to high mortality among male children5 with and cause of death. Causes of death income during the study period were ischemic stroke globally,​ a finding included those directly related to assigned LAMI status on the basis of not present in a previous4 report stroke (brain death, herniation, whether the birth country was LAMI from the United States. The authors hemorrhagic transformation, at the date of stroke ictus. Sites from “ ” of most reports on mortality after intracerebral hemorrhage, or other) the United States were categorized pediatric AIS have not examined or those related to an underlying as stroke belt states if located in specific stroke risk factors or stroke medical illness (treatment-related, the South versus other5 regions as severity; however, recent work from surgery- and/or procedure- in previous work. Multivariable Chile revealed that cardiac disease related, complication, disease Plogistic regression adjusted for and chronic head and/or neck progression, ventricular assist possible risk factors that reached the conditions were associated with device, extracorporeal membrane < .05 level in univariable analyses Downloaded from www.aappublications.org/news by guest on September 25, 2021 2 BESLOW et al TABLE 1 LAMI Country Status (N = 3188), Race and Ethnicity (N = 2567) n/N (%) LAMI countrya 447/3188 (14.0) White 1475/2567 (57.4) Hispanic 396/2567 (15.4) Blackb 196/2567 (7.6) East Indian, South Asian 174/2567 (6.8) Other 167/2576 (6.5) Southeast Asian 83/2576 (3.2) North American First 38/2567 (1.5) Nations Middle Eastern 34/2576 (1.3) Pacific Islander 4/2576 (0.2) a Argentina, Brazil, Chile, Egypt, Estonia, China, Georgia, India, Malaysia, Poland, Romania, Serbia, Thailand. b Black, African American, African Canadian, African, Caribbean. FIGURE 1 In-hospital deaths by year (neonates and children). Percent indicates the mortality rate in study year. a Enrollment through July 31, 2014. with the exception of the PedNIHSS score because too few subjects had this score recorded. Neonatal and childhood stroke cases were analyzed (3.1%) died. Among children, there associated with in-hospital mortality. separately because of differences was no increased risk of death with In children, neither seizures at P ≤ – P in underlying stroke risk factors. increasing age (OR: 0.97 per 1 year presentation nor residence in stroke A value of .05 was considered of age; 95% CI: 0.93 1.01; = .16). belt states versus other US regions statistically significant. Stata Version When age at AIS was categorized as was associated with mortality. previously defined by the National 12.0 (Stata Corp, College Station, TX) 6 Cause of death was available in 9 of Center for Health Statistics,​ 34 of was used for all analyses. 14 neonates (64.3%, Table 4) and 1332 patients who were <1 year old RESULTS 39 of 70 children (55.7%, Table 5). died (2.6%), 19 of 643 patients who Number of days from stroke onset were 1 to 4 years old died (3.0%), 9 to death was available in 9 of 14 of 480 patients who were 5 to 9 years – neonates (64.3%; median 26 days, In total, 915 neonates (541 male old died (1.9%), 14 of 432 patients IQR 15 65 days) and in 40 of 70 patients, 59.1%) and 2273 children who were 10 to 14 years old died – (1322 male patients, 58.2%) with children (57.1%; median 11 days, (3.2%), and 8 of 301 patients who AIS from 87 hospitals in 24 countries P IQR 5 26.5 days). Of 48 cases with were 15 to <19 years old died (2.7%), were included. Median age of reported causes of death, 31 (64.6%) – = .82, test of trend. Univariable the children was 5.7 years (IQR were stroke-related or due to stroke mortality risk factors for neonates 1.6 12.3 years). Race and ethnicity plus medical causes, with remaining and children are found in Tables 2 information, available for 2567 of deaths attributed to medical disease. and 3, respectively. In multivariable 3188 participants (80.5%), and LAMI analysis for neonates, congenital DISCUSSION data are presented in Table 1. – P heart disease (OR: 3.88; 95% CI: 1.23 12.22; = .021), posterior plus Eighty-four of 3188 (2.6%) subjects – P died during the hospitalization. anterior circulation stroke (OR: 5.36; In this multinational cohort, 2.6% 95% CI: 1.70 16.85; = .004), and In-hospital mortality during each – of pediatric patients with AIS died study year is presentedP in Fig 1. Pstroke presentation without seizures during hospitalization, and nearly Stroke deaths did not differ by year (OR: 3.95; 95% CI: 1.26 12.37; 65% of deaths with a known cause of stroke ictus, = .11, test of trend. = .019) were associated with were related to the stroke and/or in-hospital mortality. In multivariable The average yearly in-hospital – subsequent deficits. Risk factors for mortality was 2.7 deaths per analysisP among children, Hispanic in-hospital mortality in neonates and ethnicity (OR: 3.12; 95% CI: 1.56 100 stroke admissions. Children – children included congenital heart were more likely to die during P6.24; = .001), congenital heart disease and stroke in the posterior hospitalization than neonates (odds disease (OR: 3.14; 95% CI: 1.75 5.61; plus anterior circulations, with the – P < .001), and posterior plus anterior ratio [OR]: 2.04; 95% confidence – P additional risk factor of Hispanic interval [CI]: 1.15 3.65; = .015); circulation stroke (OR: 2.71; 95% ethnicity for children. Also, neonates 14 neonates (1.5%) and 70 children CI: 1.40 5.25; = .003) remained presenting without seizures had Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 3 TABLE 2 Univariable Predictors of In-Hospital Mortality in Neonates (0–28 Days), 14 Total Deaths and 915 Total Neonates Risk Factor N With Mortality/N With Variable N With Mortality/N Without Variable OR 95% CI P Male sex 12/541 2/374 4.22 0.94–18.96 .06 LAMI country 3/112 11/803 1.98 0.54–7.21 .30 Southern United States (versus Western, 2/67 3/284 2.88 0.47–17.60 .25 Northeastern, Midwestern United States) Hispanic ethnicity 3/125 11/790 1.74 0.49–6.33 .40 Black race 0/30 14/885 1 NA NA Presentation without seizure 8/243 6/652 3.67 1.26–10.67 .017a Sickle cell anemiab 0/0 14/915 NA NA NA Prothrombotic abnormality 2/94 12/821 1.47 0.32–6.65 .62 Congenital heart disease 6/125 7/707 5.04 1.67–15.26 .004a Arteriopathy (vasculopathy) 0/16 10/770 1 NA NA Anterior and posterior circulation (reference 7/104 Anterior only 7/632; posterior only 0/71 6.44 2.21–18.77 .001a group isolated anterior circulation) NA, not applicable. a Also statistically significant in multivariable analysis. b No neonate was diagnosed with sickle cell anemia.

TABLE 3 Univariable Predictors of In-Hospital Mortality in Children (29 Days–<19 Years), 70 Total Deaths and 2273 Total Children Risk Factor N With Mortality/N With Variable N With Mortality/N Without Variable OR 95% CI P Male 42/1322 28/951 1.08 0.67–1.76 .75 LAMI country 22/335 48/1938 2.77 1.65–4.65 <.001 Southern United States (versus Western, 12/355 21/767 1.24 0.60–2.56 .55 Northeastern, Midwestern United States) Hispanic ethnicity 22/271 48/2002 3.60 2.14–6.06 <.001a Black race 3/166 67/2107 0.56 0.17–1.80 .33 Presentation without seizure 45/1570 24/632 0.75 0.45–1.24 .26 Sickle cell anemia 0/98 70/2175 NA NA NA Prothrombotic disorder 3/173 67/2100 0.54 0.17–1.72 .29 Congenital heart disease 28/397 42/1784 3.15 1.93–5.14 <.001a Arteriopathy (vasculopathy) 11/679 52/1383 0.42 0.22–0.81 .01 Anterior and posterior circulation (reference 18/221 Anterior only 34/1298; posterior only 3.30 1.83–5.95 <.001a group isolated anterior circulation) 11/434 PedNIHSS median (IQR) 20.5 (12.5–28) of 12 with PedNIHSS 6.5 (3–12) of 342 with PedNIHSS scores 1.13b 1.08–1.19 <.001 scores who died who did not die NA, not applicable. a Also statistically significant in multivariable analysis. b OR for PedNIHSS is per 1-point increase in score.

TABLE 4 Causes of Death Among Neonates Stroke-Related (N = 2) Stroke-Related Plus Medical Cause (N = 4) Medical Cause (N = 3) Care withdrawn because of deficits (2) Congenital heart disease plus support withdrawn because of Air leak syndrome related to congenital heart disease stroke-related deficits (2) (1) Pneumothorax plus support withdrawn because of stroke- Acute renal failure (1) related deficits (2) Neurologic respiratory arrest plus severity of underlying Meningitis (1) disease (1)

– an increased risk of in-hospital cohort of childhood stroke (age >28 Canadian cohort of 1129 pediatric mortality. A major strength of the days 19 years), 4 of 124 ischemic12 AIS patients presenting13 between IPSS registry and the current report stroke patients (3.2%) died,​ 1992 and 2001. In that study, 35 is that children from 24 countries, which is similar to our finding of of 74 in-hospital deaths13 (47.3%) including 13 LAMI nations, were an in-hospital mortality rate of were stroke-related. Although included. 3.1% among children. The overall not directly comparable because in-hospital mortality rate of 2.6% we in-hospital mortality was not In a previous cross-sectional analysis report is lower than the in-hospital reported, our in-hospital mortality of critical care usage in a California mortality rate of 6.5% reported in a rate appears lower than the mortality Downloaded from www.aappublications.org/news by guest on September 25, 2021 4 BESLOW et al TABLE 5 Causes of Death Among Children Stroke-Related (N = 14) Stroke-Related Plus Medical Cause (N = 11) Medical Cause (N = 14) Brain death (6)a,​b Congenital heart disease plus support withdrawn due to Bronchopneumonia (1) stroke-related deficits (9) Herniation (6)a,​c,​d Severe pertussis, support withdrawn due to medical severity Congenital heart disease (7) and stroke-related deficits (1) Hemorrhagic transformation (4)b,​d Human immunodeficiency and unspecified stroke-related Acquired cardiomyopathy (2) cause (1) Care withdrawn because of deficits Chronic renal failure and renal transplant rejection (4)c,​d (1) Neurologic respiratory failure (1) Malaria (1) Tuberculosis meningitis (1) Juvenile idiopathic arthritis with acquired pulmonary hypertension leading to fatal arrhythmia (1) a One child with brain death after herniation. b One child with brain death after hemorrhagic transformation. c One child with herniation leading to withdrawal of care. d Two children with herniation after hemorrhagic transformation leading to withdrawal of care.

rate among Chilean children8 with AIS, and hemorrhagic stroke, we did not with 415% in the work by Fullerton among whom 26.5% died. demonstrate an increased risk of et al,​ so our cohort could have been in-hospital mortality in southern underpowered to demonstrate a Geographic, sex, and racial disparities states among the neonatal or difference. Although Black race in childhood stroke mortality 1,have5,​ 7​ childhood stroke groups. was not a risk factor for in-hospital been found in several studies. ‍ ‍ mortality in the current study, an In the Global Burden of Disease Black race was not a risk factor for interesting finding was that Hispanic Study, there was excess mortality in in-hospital mortality in the current ethnicity was a risk factor for children with ischemic stroke from cohort, whereas Black race was a in-hospital mortality among children developing nations compared with mortality4 risk factor in previous with AIS, even when controlling for those from developed countries as work. Several reasons could account LAMI country status. The reasons well as a trend toward increased5 for these differences, including for this finding are not known, but mortality in male patients. Although enrollment period.4 The study by similar results have been found in living in a LAMI country was a Fullerton et al included subjects childhood intracerebral16,17​ hemorrhage risk factor for death in children in from 1979 to 1998, whereas our and in adult stroke. ‍ Among 1172 children with spontaneous univariable analysis, living in a LAMI cohort presented between 2003 and ’ country was not a risk factor for 2014. In 1998, the landmark Stroke intracerebral hemorrhage from neonatal mortality or for childhood Prevention Trial14 in Sickle Cell Anemia the Kids Inpatient Database, 150 mortality in multivariable analysis. was published,​ and subsequent (12.8%) died, and Hispanic16 ethnicity However, it is possible that the work has shown that ischemic stroke was a risk factor for death. Among lack of association between LAMI mortality decreased among Black adults with ischemic stroke in the countries and mortality in this cohort children in the time period between United States, stroke mortality rates have increased among Hispanics was because only 14% of participantsP 1998 and 2007 compared15 with 18 were from LAMI countries. Although between 1988 and 1997. Therefore, since 2013. In future research not statistically significant, the access to improved preventive stroke efforts, investigators should value for in-hospital mortality for measures like transfusion therapy explore whether ethnic differences male sex among neonates with stroke in children with sickle cell disease in mortality rates are related to was .06. Given that only 14 deaths may be in part responsible for the disparities in care. occurred among neonatal stroke lack of association between Black subjects, it is possible that male sex race and in-hospital mortality in Previous outcome studies have been would emerge as a risk factor for the current cohort. However,4 in the primarily small single-site studies, in-hospital mortality among neonates work by Fullerton et al,​ the excess studies from large administrative if the sample size were larger. In 7 mortality risk among Black children data sets in which examining contrast to work by Fullerton et al,​ was not fully explained by sickle cell individual data was not possible, which revealed that stroke in the anemia, and the authors concluded or have assessed predictors of southern United States compared that other factors could play a combined neurologic and mortality with other United States regions was role. In the current study, 6.8% of outcomes. Therefore, few previous a risk for mortality for both ischemic participants were Black, compared studies have examined risk factors Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 5 for mortality. We found that stroke for infarct volume quantification. (eg, cyanotic vs acyanotic lesions) cause was associated with mortality. Despite this limitation, our results or specific procedures or support Congenital heart disease was a suggest that increased stroke devices were related to mortality. risk factor for in-hospital mortality severity is a risk factor for mortality. Mortality cause was not available among neonates and children. Among Both neonates and children with in nearly 43% of the subjects who those with congenital heart disease, strokes that affected the posterior died, so it is difficult to draw firm the cause of death was stroke- and anterior circulations were conclusions about reasons for related or in part stroke-related in at increased risk for mortality death. However, among those for 65.2% of cases, indicating that the compared with those with isolated whom cause of death was known, strokes themselves are an important anterior circulation stroke, a the stroke itself was the cause or cause of mortality in this group. Our finding that may indicate that larger ó á contributed to the cause of death in finding supports the conclusions strokes are associated with death. á n 64.6% of cases, a finding consistent of L pez-Espejo and Hern ndez- Also, among children for whom the 12 8 with work by Fox et al in which Ch vez from a Chilean cohort. PedNIHSS was scored ( = 354), the 6 of 11 childhood stroke deaths Both studies indicate that children median score among those who died (54.5%) were due to the stroke itself. with cardiac stroke may warrant was 20.5 compared with 6.5 among Importantly, 12 of 14 stroke-related additional monitoring for neurologic those who survived hospitalization. deaths were due to progression to deterioration. Although not Although these results are not brain death or herniation, indicating significant in multivariable analysis, surprising and are consistent with 17 that malignant cerebral edema is a children with arteriopathic stroke the adult literature,​ children with likely mechanism. It is critical for seemed to have decreased mortality. larger or more clinically severe pediatric intensivists and other strokes may also benefit from Seizures at presentation have been medical personnel to recognize especially vigilant monitoring. associated with– poor outcome and malignant middle cerebral artery more severe stroke in the pediatric syndrome and herniation syndromes 19 22 Another study limitation is that population. ‍‍ In our cohort of because these fatal conditions can be cause of death was not available neonates, presentation without treated with lifesaving and function- for 36 of 84 participants (42.9%) seizures was associated with sparing hemicraniectomy when who died. Cause of death was 22,26​ in-hospital mortality. One possible recognized quickly. ‍ The fact that collected retrospectively, and in explanation for our finding is that the strokes or their direct sequelae some cases additional details neonates who presented with are responsible for more than half were not available. Certain sites seizures may have been diagnosed of pediatric stroke deaths indicates deidentified data and were not and treated more quickly for their that improved stroke recognition, able to relink study identification strokes. Moreover, although seizures earlier supportive care, more rapid 23 numbers to patient names to are associated with cortical strokes,​ intervention, and neuroprotective collect additional information. deep strokes in neonates are treatments are critical for decreasing We also do not have information associated both with nonseizure mortality after stroke in the pediatric about timing of complications like presentations (persistent altered population. hemorrhagic transformation of consciousness, diffuse hypotonia) 13,24​ infarction. Our registry did not CONCLUSIONS and with worse outcomes. ‍ collect information about seizures Children who were critically ill after presentation or EEG results. or moribund after stroke may Electrographic-only seizures are25 In-hospital mortality occurred in not have been included because common in critically ill children,​ 2.6% of pediatric patients with of the reluctance of clinicians to so it is possible that the number AIS in a multinational prospective approach distressed parents for of neonates with seizures was cohort from both LAMI and non- consent. This problem may have underestimated. Finally, although LAMI countries, indicating that been especially true in neonates congenital heart disease was a risk stroke remains an important for whom redirection of care was a factor for death among neonates cause of death in neonates and common mechanism of mortality. and children, the IPSS did not children. We leverage one of the Therefore, we consider our mortality collect information regarding heart largest prospective pediatric rate to be a minimum estimate. lesion type and use of ventricular stroke registries available and Furthermore, additional information assist devices or extracorporeal have confirmed risk factors for is needed on stroke-related deaths membrane oxygenation. Therefore, mortality found in single-site studies after hospitalization. Imaging was we were not able to analyze whether as well as identified risk factors not available for central review or specific congenital heart diseases for in-hospital mortality that have Downloaded from www.aappublications.org/news by guest on September 25, 2021 6 BESLOW et al – not previously been reported. Contributing Members of the MD; Great Ormond Street Hospital: IPSS (2003 2014): Ain Shams Vijeya Ganesan, MD; Hospital Carlos Risk factors for mortality among ’ neonates and children included University: Sahar Hassanein, MD, Van Buren: Lucila Andrade Alveal, congenital heart disease and stroke PhD; Akron Children s Hospital: MD; Hospital Clinico San Borja Abdalla Abdalla, MD; Alberta Arriaran: Monica Troncoso, MD; affecting both the anterior and ’ posterior circulation. Additional risk Children's Hospital: Adam Kirton, Hospital Italiano: Diana Altuna, MD; factors included Hispanic ethnicity MD; All Children s Hospital: Neil Hospital Regional Universitario (among children) and presentation Goldenberg, MD; Aristotle University (Carlos Haya): Patricia Garcia Soler, without seizures (among neonates). of Thessaloniki: Dimitirios Zafeiriou, MD; Hospital Sant Joan de Deu: MD, PhD; Bangkok Hospital: Montri Veronica Gonzalez, MD; The Hospital Physicians including neonatologists, ’ Saengpattrachai, MD; BiLo Charities for Sick Children: Gabrielle deVeber, pediatric intensivists, and hospitalist ’ pediatricians who care for pediatric Children s Cancer Center: Hal MD, Mahendranath Moharir, MD, patients with AIS may use the Crosswell, MD; Boston Children s Nomazulu Dlamini, MD, PhD; Indiana Hospital: Michael Rivkin, MD; British Hemophilia and Thrombosis Center: information in this report to aid ’ ’ recognition of those who may be Columbia Children's Hospital: Bruce Frederico Xavier, MD; Janeway at high risk for deterioration and Bjornson,​MD; Children s Central Children s Health and Rehabilitation: David Buckley, MD; Jaslok Hospital death. Additional studies are needed Hospital: Nana Tatishvili, MD; Clinic ’ for Child Neurology & Psychiatry, and Research Centre: Anaita Hegde, to understand reasons for ethnic ’ disparities and to develop improved University of Belgrade: Vesna MD; John Hunter Children s Hospital: Brankovic-Sreckovic, MD; Children s Christina Miteff, MD; Johns Hopkins neuroprotective strategies for ’ children with severe AIS. Clinic of Tartu University Hospital: Hospital: Ryan Felling, MD, PhD; Life Anneli Kolk, MD; Children s Hospital Memorial Hospital Bucharest: Adrian ’ ACKNOWLEDGMENTS Colorado: Timothy Bernard, MD, Toma, MD; Loma Linda University Jennifer Armstrong, MD; Children s School of Medicine: Stephen ’ Hospital of Eastern Ontario: Peter Ashwal, MD, Chalmer McClure, Humphreys, MD; Children s Hospital MD; Maimonides Medical Center: ’ IPSS Group Original Investigators: of New York: Geoffrey Heyer, Steven Pavlakis, MD; Massachusetts Loma Linda University School of MD, Robert Fryer, MD; Children s General Hospital for Children: Eric ’ Medicine, Loma Linda, California: Hospital of Buffalo: Ann Yeh, MD; Grabowski, MD; McMaster University Steve Ashwal, MD; Hospital for Children s Hospital of Philadelphia: Medical Centre: Anthony Chan, Sick Children, Toronto, Ontario, Rebecca Ichord, MD, Lori Billinghurst, MD; Medical University of Silesia: Canada: Gabrielle deVeber, MD, MD; Children's Hospital of Ilona Kopyta, MD, PhD; Medical ’ ’ MHSc; University of California, Oklahoma: Chaouki Khoury, MD; University of Vienna: Francesco ’ San Francisco, California: Donna ’ Children s Hospital of Pittsburgh: Cardona, MD; Miami Children s Ferriero, MD, Heather Fullerton, MD; Lisa Abraham, MD; Children s Hospital: Marcel Deray, MD; Monroe Children s Hospital of Philadelphia, Hospital of Wisconsin: Harry Carell Jr. Children's Hospital at Philadelphia, Pennsylvania: Rebecca Whelan, MD; Children's Medical Vanderbilt: Lori Jordan, MD, PhD, ’ Ichord, MD; Institute of Child Centre Munster: Ulrike Nowak-Gottl, Juliann Paolicchi, MD; Mother Health, University College London, MD; Children s Memorial Hospital: and Child Health Care Institute: ’ ’ London, United Kingdom: Fenella Mark Wainwright, MD, PhD, John Gordana Kovacevic, MD; Nationwide Kirkham, MB, BChir; National Condie, MD; Children s National Children s Hospital: Warren Lo, MD, Institutes of Health/National Medical Center: Jessica Carpenter, Melissa Chung, MD, JoEllen Lee, CNP; Institute of Neurologic Disorders MD; Charite University Hospital: New York Presbyterian Hospital/ and Stroke, Bethesda, Maryland: Susanne Holzhauer, MD; Chinese Weill Cornell Medical Center: Barry John K. Lynch, DO, MPH; Bristol PLA General Hospital: Yang Guang, Kosofsky, MD, Dana Leifer, MD; New ’ ’ Royal Hospital for Children, Bristol, MD, Li-Ping Zou MD; Cincinnati York University, School of Medicine: United Kingdom: Finbar O Callaghan, Children s Hospital Medical Center: Ruth Nass, MD; Ohio Stroke Registry: MBChB; Maimonides Medical Center, Max Wiznitzer, MD; Oregon Health é J. Michael Taylor, MD; Cleveland Brooklyn, New York: Steve Pavlakis, and Science University: Jenny Wilson, é Clinic Foundation: Neil Friedman, MD; Universit de Sherbrooke MD; Clinica Davila: Luis Conto, MD; MD, Jason Coryell, MD, Carter Wray Fleurimont, Sherbrooke, Qu bec, Columbia University Medical Centre: MD; Phoenix Children's Hospital: ’ Canada: Guillaume Sebire, MD, Sally Sultan, MD, Mitchell Elkind, MD; John Condie, MD; Paediatrics Institute PhD; and Hospital for Sick Children, Cook Children s Hospital: Marcela Hospital Kuala Lumpur: Terrence Toronto, Ontario, Canada: Andrew Torres, MD; Georgetown University Gerard, MD; Pontificia Universidad Willan, MSc, PhD. Medical Center: Nassim Zecavati, Catolica de Chile: Marta Hernandez, Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 7 é ’ ’ MD; Queen Mary Hospital: Virginia Manish Parakh, MD; Universit de Virginia University: Paola Pergami, é é Wong, MD; Riley Children s Hospital: Sherbrooke Fleurimont, Sherbrooke, MD, PhD; Winnipeg Children s Meredith Golomb, MD; Robert Debr Qu bec, Canada: Guillaume Sebire, Hospital: Mubeen Rafay, MD; Yale ’ Hospital: Luigi Titomanlio, MD; Royal MD, PhD; University of Bern School of Medicine: Lauren A. Children s Hospital: Mark Mackay, Hospital (Inselspital): Maja Steinlin, Beslow, MD. ’ MD, Fiona Newall, Paul Monagle, MD; MD; University of California, San ’ Schneider Children s Hospital: Li Francisco: Heather Fullerton, MD, Thank you to Alexandra Linds for Kan, MD; Seattle Children s Hospital: Christine Fox, MD; University College providing organizational support for ’ ’ Catherine Amlie-Lefond, MD;Sophia London Institute of Child Health, this work. Children s Hospital: Maayke Hunfeld, SOCS: Finbar O Callaghan, MD, PhD; ABBREVIATIONS MD; St Christopher's Hospital for Universidade Estadual de Campinas: ’ Children: Deepti Raybagkar, MD; St Carolina Oliviera, MD; University of Louis Children s Hospital: Michael Rochester Medical Center: Norma B. AIS: arterial ischemic stroke Noetzel, MD, Kristin Guilliams, MD; Lerner, MD, Shalu Narang, MD, Jill ’ CI: confidence interval Stanford University Medical Center: M Cholette, MD; University of Texas IPSS: International Pediatric Jorina Elbers, MD; Stollery Children s San Antonio: Shannon Carpenter, MD, Stroke Study Hospital: Jerome Yager, MD, Amanda Blair, MD; University í IQR: interquartile range Patricia Massicotte, MD; Superiora of Texas Southwestern Medical LAMI: low- and middle- income Sor Mar a Ludovica Childrens Center: Michael Dowling, MD, PhD, ’ OR: odds ratio Hospital: Jose Francisco Vilavedra, Janna Journeycake, MD, Patricia PedNIHSS: Pediatric National MD; Texas Children s Hospital: Plumb RN; The University of Utah Institutes of Health Lisa Nassif El-Hakam, MD; Umaid and Primary Children's Medical Stroke Scale Hospital for Women and Children: Center: Susan Benedict, MD; West Dr Beslow designed the study, designed the data collection instrument regarding cause of death, collected the data, performed all statistical analyses, and drafted the manuscript; Dr Dowling conceptualized the study, designed the study, designed the data collection instrument regarding cause of death, and collected the data; Drs Hassanein, Lynch, Titomanlio, Kolk, Biller, Grabowski, Abdalla, and Mackay designed the data collection instrument regarding cause of death and collected the data; Drs Zafeiriou, Sun, Kopyta, and Chan reviewed the study design, designed the data collection instrument regarding cause of death, and collected the data; Dr deVeber designed the study, designed the data collection instrument regarding cause of death, collected the data, and coordinated and supervised the data collection process and analysis plan; and all authors critically reviewed, revised, and edited the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work. DOI: https://​doi.​org/​10.​1542/​peds.​2017-​4146 Accepted for publication Feb 14, 2018 Address correspondence to Lauren A. Beslow, MD, MSCE, Division of Neurology, Children’s Hospital of Philadelphia, 3501 Civic Center Blvd, 10th Floor, Philadelphia, PA 19104-4399. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 25, 2021 PEDIATRICS Volume 141, number 5, May 2018 9 Mortality After Pediatric Arterial Ischemic Stroke Lauren A. Beslow, Michael M. Dowling, Sahar M.A. Hassanein, John K. Lynch, Dimitrios Zafeiriou, Lisa R. Sun, Ilona Kopyta, Luigi Titomanlio, Anneli Kolk, Anthony Chan, Jose Biller, Eric F. Grabowski, Abdalla A. Abdalla, Mark T. Mackay, Gabrielle deVeber and on behalf of the International Pediatric Stroke Study Investigators Pediatrics originally published online April 25, 2018;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2018/04/23/peds.2 017-4146 References This article cites 23 articles, 7 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2018/04/23/peds.2 017-4146#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Neurology http://www.aappublications.org/cgi/collection/neurology_sub Neurologic Disorders http://www.aappublications.org/cgi/collection/neurologic_disorders_ sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 25, 2021 Mortality After Pediatric Arterial Ischemic Stroke Lauren A. Beslow, Michael M. Dowling, Sahar M.A. Hassanein, John K. Lynch, Dimitrios Zafeiriou, Lisa R. Sun, Ilona Kopyta, Luigi Titomanlio, Anneli Kolk, Anthony Chan, Jose Biller, Eric F. Grabowski, Abdalla A. Abdalla, Mark T. Mackay, Gabrielle deVeber and on behalf of the International Pediatric Stroke Study Investigators Pediatrics originally published online April 25, 2018;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2018/04/23/peds.2017-4146

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2018 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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