Nienke Wagenaar, MD,​a Miriam Martinez-Biarge, MD,​b Niek E. van der Aa, MD, PhD,a​ Ingrid C. van Haastert, MA, PhD,​a FlorisNeurodevelopment Groenendaal, MD, PhD,​a Manon J.N.L. Benders, MD, PhD, After​a Frances M. Cowan, Perinatal MD, PhD,b​ Linda S. de Vries, MD, PhDa Arterial Ischemic Stroke BACKGROUND AND OBJECTIVES: abstract ∼ Perinatal arterial ischemic stroke (PAIS) leads to cerebral palsy in 30% of affected children and has other neurologic sequelae. Authors of most outcome studies focus on middle cerebral artery (MCA) stroke without differentiating between site and extent of affected tissue. Our aim with this study was to report outcomes after different METHODS: n PAIS subtypes. n Between 1990 and 2015, 188 term infants from 2 centers (London [ = 79] and Utrecht [ = 109]) had PAIS on their neonatal MRI. Scans were reevaluated to classify stroke territory and determine specific tissue involvement. At 18 to 93 (median 41.7) months, adverse neurodevelopmental outcomes were recorded as 1 or more of cerebral palsy, RESULTS: cognitive deficit, language delay, epilepsy, behavioral problems, or visual field defect. The MCA territory was most often involved (90%), with posterior or anterior cerebral artery territory strokes occurring in 9% and 1%, respectively. Three infants died, and 24 had scans unavailable for reevaluation or were lost to follow-up. Of 161 infants seen, 54% had an adverse outcome. Outcomes were the same between centers. Main branch MCA stroke resulted in 100% adverse outcome, whereas other stroke subtypes had adverse outcomes in only 29% to 57%. The most important outcome predictors were involvement of CONCLUSIONS: the corticospinal tracts and basal ganglia. Although neurodevelopmental outcome was adverse in at least 1 domain with main branch MCA stroke, in other PAIS subtypes outcome was favorable in 43% to 71% of children. Site and tissue involvement is most important in determining the outcome in PAIS.

WHAT’S KNOWN ON THIS SUBJECT: Perinatal arterial ischemic stroke often leads to adverse aDepartment of Neonatology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; and bDepartment of Paediatrics, Imperial College London, London, United Kingdom neurodevelopmental outcomes. Authors of most outcome studies do not differentiate between site Dr Wagenaar is the main author and drafted the manuscript, contributed to data acquisition and and extent of affected tissue in their association interpretation, and was responsible for communication with all coauthors; Drs Martinez-Biarge with neurodevelopmental outcome. and van Haastert contributed to data acquisition and interpretation and revised the manuscript for intellectual content; Drs van der Aa, Groenendaal, and Benders contributed to the analysis and WHAT THIS STUDY ADDS: With this study, we interpretation of the data and read the manuscript critically for intellectual content; Drs Cowan describe neurodevelopmental outcomes in different and de Vries contributed to the study design, coordination and supervision of data collection and perinatal arterial ischemic stroke subtypes in a analysis, and drafting and critically reviewing the manuscript; and all authors have seen and large and international cohort. Several MRI-based approved the final manuscript as submitted and take full responsibility for the manuscript. risk factors are provided that contribute to the DOI: https://​doi.​org/​10.​1542/​peds.​2017-​4164 prediction of neurodevelopmental outcomes in Accepted for publication May 30, 2018 individual patients with perinatal stroke. Address correspondence to Linda S. de Vries, MD, PhD, Wilhelmina Children’s Hospital, University Medical Centre Utrecht, KE 04.123.1, PO Box 85090, 3508 AB Utrecht, Netherlands. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics To cite: Wagenaar N, Martinez-Biarge M, van der Aa NE, et al. Neurodevelopment After Perinatal Arterial Ischemic Stroke. Pediatrics. 2018;142(3):e20174164

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number 3, September 2018:e20174164 ARTICLE Perinatal arterial ischemic stroke different subtypes of PAIS in term Best, Netherlands, or Picker (PAIS) is an important cause of infants, taking into account its lesion System, Cleveland, OH) by using long-lasting1,2​ neurodevelopmental site and involvement of well-defined a scanning protocol including at problems. ‍ With increased use of important brain structures. least T1-weighted, T2-weighted, neuroimaging techniques, especially METHODS and diffusion-weighted imaging MRI, the incidence from hospital- (DWI). In general, infants were ∼ based studies is now considered to sedated to minimize movement be 1 in 2300 to 5000 live-born term3,4​ The neonates in this study comprised artifacts. Because we included infants neonates with a low mortality rate. ‍ 2 cohorts of term newborn infants over a long time period, the MRI protocol was not always the same; Adverse consequences of PAIS who were admitted to the NICU or ’ imaging details have been reported include cerebral palsy (CP), usually referred for neurologic assessment to 6,9,​ 16​ Queen Charlotte s or Hammersmith Evaluationpreviously .of‍ ‍MRI Data of a hemiparetic type, cognitive n ’ dysfunction, epilepsy, and language, Hospital in London, United Kingdom visual, and behavioral problems, ( = 79) or the Wilhelmina Children s Hospital of the University Medical which are reported1 to occur in 50% n Neonatologists experienced in to 75% of infants. Several groups Center in Utrecht (UMCU), the neonatal brain MRI (F.C. and L.dV.) have described MRI parameters that Netherlands ( = 117) between reevaluated each (of both centers) October 1990 and January 2015. help in predicting5,6​ adverse outcome MRI scan. The lesions were assessed after PAIS. ‍ More specifically, the All infants had acute symptoms in 3 planes, if possible. On the basis development of CP mainly depends in the first week after birth, most of shape, extent, and localization of on involvement of the corticospinal often (hemi) convulsions, but in a the area of signal intensity changes, few infants their symptoms were tracts (CSTs) at the level of the – all infants were classified to 1 of the less neurologically specific. All had posterior limb of the internal 2,capsule7​ 11 stroke subtypes shown in Fig 1 on (PLIC) or cerebral peduncles. ‍ ‍ PAIS confirmed on their neonatal the basis of their most predominant Visual field defects occur most often MRI. Eight infants were excludedn stroke pattern. when PAIS clearly involves the optic because of congenital syndromes 12,13​ Classification was mostly based on radiation. ‍ withn known adverse outcome ( = 4) vascular territory of specific named nor other significant brain lesions PAIS most often occurs in the arteries that resulted in characteristic ( = 4), resulting in a ntotal cohort of 15 territory of the middle cerebral = 187 infants. Infants who died in infarctions as described by Govaert. artery (MCA), and most studies on However, we felt that consistency of the neonatal periodn ( = 3), whose outcome are focused on main branch involvement of particular anatomic 1,14​ neonatal MRI nscan could not be MCA stroke. ‍ Because occlusion reevaluated ( = 4), or who were lost structures was more important, of the proximal segment (M1) of the to follow-up ( = 20) were excluded and the involvement of specific MCA will lead to infarction of the from further analyses (Supplemental anatomic hallmarks was also used for entire MCA region, including the Table 7). This resulted in a total study classification. A hemispheric lesion in basal ganglia and CST, development cohort of 161 term neonates. the MCA territory located posterior of unilateral CP can be reliably to the central sulcus was attributed predicted. However, often only Informed verbal parental consent to the posterior branch of the MCA, more distal MCA segments or the was obtained to perform an whereas involvement anterior to the anterior cerebral artery (ACA) or MRI for clinical purposes. The central sulcus was attributed to the posterior cerebral artery (PCA) Institutional Review Board of the anterior branch. When the full central are involved resulting in relatively UMCU approved the use of MRI data sulcus was involved, but not regions for anonymous data analysis and characteristic lesion patterns15 that more anterior or posterior, this was can be recognized on MRI. Authors waived the requirement to obtain attributed to the middle branch MCA. of most studies on outcome in PAIS written informed consent. In London, If the anterior or posterior areas and do not differentiate between these neonatal MRI scans were performed middle branch MCA were involved, lesion patterns involving various after obtaining written informed the most predominant branch sites and extent of affected tissue. consent and permission to use these was chosen, and central sulcus We hypothesized that outcome scansMRI and clinical data for research. involvement was noted separately. of PAIS primarily depends on Involvement of the central sulcus the brain area that is affected by region was best assessed in the the stroke. Therefore, our aim In both centers, MRI was performed parasagittal plane. Where >1 MCA with this study was to report on on a 1.0, 1.5, or 3T whole-body branch artery was involved this was neurodevelopmental outcomes of system (Philips Medical Systems, also noted separately as multiple Downloaded from www.aappublications.org/news by guest on September 24, 2021 2 WAGENAAR et al FIGURE 1 Classification of stroke territory subtypes. Stroke subtypes were classified on the basis of the following infarction territories: main MCA (complete MCA infarction); anterior MCA branch (partial MCA infarction anterior to the central sulcus); middle MCA branch (partial MCA infarction involving the central sulcus); posterior MCA branch (partial MCA infarction posterior to the central sulcus); cortical MCA branch (superficial MCA infarction involving only the cortex, without involvement of the striatum); perforator branch (perforator stroke involving only the deep gray matter [thalamus and/or basal ganglia]); PCA or ACA (non-MCA infarction). In these examples, CST involvement is seen in the main MCA stroke and the anterior and posterior MCA branch strokes. Secondary network injury to the thalamus is seen with the main branch and the anterior MCA stroke.

lesions. Small punctate lesions were involvement (Fig 2) for the purposes appointments. We only used data “ ” not considered part of the spectrum of this study. from after 12 months until 7 years. of multiple lesions. Often with hemispheric strokes, Cognitive development was signal changes were also seen determined by using the Magnetic resonance images were also in the thalami, particularly the “ ” developmental quotient of the evaluated for involvement of specific pulvinar, that are likely secondary Griffiths Mental Development regions we considered likely to be to network injury rather than part 17 Scale (GMDS), calculated by of major importance in predicting of the primary stroke. Examples of using all subscale scores except outcome (ie, the CST, the central primary thalamic stroke (perforator locomotion, the Bayley Scales of sulcus region, thalami, and basal stroke) and secondary network 2,8​ Infant and Toddler Development, ganglia, as described previously ‍ ), injury to the thalamus are shown in Third Edition (BSITD-III), or the mainly by visual inspection of the ‍Fig 1 (anterior MCA). Bilateral lesions Wechsler –Preschool and Primary were described as bilateral stroke DWI from MRI scans done in the MRI Scale of Intelligence second or third when stroke lesions were equally z 18 20 from the first week and from T1- and edition. ‍ ‍ For all cognitive tests, severe or as smaller contralateral T2-weighted images7 when the MRI scores were calculated to allow lesions when 1 region of stroke was acquired later. Involvement comparison of the data for statistical predominated. z − of the CSTs has been described Neurodevelopmental Outcome analyses. Cognitive delay was defined 11 − previously. Only when the middle as a score below 1, corresponding part of PLIC and cerebral peduncle to 1 SD. Language delay was defined − were affected, carrying the main Neurodevelopmental outcome was as a language score on the GMDS motor tracts, was this classified as determined during routine follow-up of < 1 SD, >15 points on the Dutch Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number 3, September 2018 3 FIGURE 2 Classification of cerebral peduncle involvement. Involvement of the cerebral peduncle was only scored when the full (A and E) or middle third of the cerebral peduncle was involved (B and F), as described by Kirton et al.11 Lateral (C and G) or median (D and H) peduncle abnormalities were not defined as “cerebral peduncle involvement” in our analyses. Involvement of the PLIC was only scored when the full (I) or middle (J) part of the PLIC was involved and not when there was only anterior (K) or posterior (L) PLIC involvement.

21 language screening instrument,​ or a UMCU cohort, parents completed24 pediatric ophthalmologist specialized diagnosis of speech and/or language the Child Behavior Checklist. in assessing visual field defects disorders. Only behavioral assessments after in infancy in Utrecht. An adverse 2 years of age were taken into outcome was defined as the presence CP was diagnosed by using criteria22 from the European CP Network,​ account. Postneonatal epilepsy of 1 or more of the following: CP, and severity was determined by was classified as (recurrence of) cognitive deficit, language delay, seizures diagnosed on EEG for epilepsy, behavioral problems, or using the Gross Motor23 Function Classification System. Behavioral which regular medication was Statisticalvisual field Analysesdefect at latest follow-up. problems were asked about at each given. Visual field defects included clinic visit, and, when appropriate, hemianopia and quadrantanopia, children were referred to a clinical diagnosed by a specialized visual Descriptive statistics are summarized psychologist; additionally, in the development unit in London or as percentages of the available study Downloaded from www.aappublications.org/news by guest on September 24, 2021 4 WAGENAAR et al TABLE 1 General Characteristics of the Study Population Characteristics Total, N = 161 5 infants (3%), who had an MRI in Gestational age, median (IQR) 40.3 (39.0–41.1) the second week after birth without Birth wt, median (IQR) 3440 (3040–3700) DWI abnormalities and T1- or Birth wt z score <−1 SD, n (%) 41 (26) Head circumference at birth, median (IQR) 34.8 (33.5–36.0) T2-weighted imaging of insufficient Male sex, n (%) 103 (64) quality to assess the CST. Infants that Apgar score at 1 min, median (IQR) 7 (5–9) were lost to follow-up (Supplemental Apgar score at 5 min, median (IQR) 9 (7–10) Table 7) did not differ in terms of Seizures, n (%) 142 (88) stroke pattern classification, basal Postnatal d at first seizures, median (IQR) 1 (0–2) Hypoglycemia,a​ n (%) 28 (17) ganglia and thalami (BGT), or CST Postnatal d at MRI, median (IQR) 5 (3.5–7) Clinicalinvolvement. Characteristics per Stroke MRI >7 d after first symptoms or birth, n (%) 22 (14) Subtype Side of stroke lesion, n (%) Right 51 (32) Left 103 (64) Bilateral 7 (4) Infants with cortical MCA infarction ± Lesion subtype, n (%) were born at significantly later ± P Main MCA 31 (19) gestational age (mean 40.7 1.3 vs Anterior MCA branch 17 (11) 40.0 1.4 weeks; < .03) compared Middle MCA branch 21 (13) Posterior MCA branch 28 (17) with other subtypes. Cortical MCA branch 21 (13) Hypoglycemia was more often Perforator branch 27 (17) found in infants with PCA infarction PCA or ACA 16 (10) P compared with the other subtypes a Hypoglycemia was defined as a blood glucose <2 mmol/L. (58% vs 16%; < .0001) and more often in main branchP MCA strokes compared with other subtypes cohort or as median and interquartile There were no differences in infant (36% vs 16%; < .02), whereas the range (IQR) where appropriate. clinical parameters between the 2 incidence of hypoglycemia wasP not Stroke subtypes and other imaging centers, so results are reported for significantly different between PCA χ features were compared with the total cohort. In Utrecht, 30 infants and main branch MCA stroke ( > .1). t 2 – outcome Uparameters by using received erythropoietin as part of an25 Seizures at presentation were tests, independent tests, or Mann intervention study or off-label use. less common inP perforator stroke Whitney tests (for nonparametric These infants did not differ in stroke compared with the other subtypes variables). Binary logistic regression patterns and also had equal rates (62% vs 94%; < .0001). Also, analysis was performed to determine of adverse outcome (unpublished perforator stroke was lessP often independent MRI predictors for data N.W., N.A., F.G., M.B. and L.dV.) left sided compared with the other adverse outcome, which were and were therefore not reported subtypes (48% vs 71%; < .03). expressed as odds ratios (ORs) with MRIseparately. Findings Other characteristics from Table 95% confidence intervals (CIs). 1 were not significantly different These regression analyses were Neurodevelopmentalbetween stroke subtypes. Outcome – performed for the total cohort and MRI was performed at a median also separately for those without of 5 (IQR: 3.5 7) days after birth. main MCA branch infarction. The MCA was most commonly All infants were seen between 12 Statistical analyses were performed involved, and most often affected months and 7 years with a median were the main branch, posterior, age of 41.7 months when last seen Pwith SPSS, version 21 (IBM SPSS Statistics, IBM Corporation). and perforator branches (19%, (Table 3). There were no differences values <.05 were considered to 17%, and 17%, respectively) and in outcomes between centers. At be statistically significant. less often the anterior, middle, or 1 their latest follow-up, 49 infants of the cortical branches (11%, 13%, (30%) had developed CP; Gross RESULTS and 13%, respectively). PCA stroke Motor Function Classification System was found in 14 cases (9%) and levels were determined for 40 infants ACA stroke in 2 cases (1%). Clinical with 90% at level I, 8% at level II, The total study cohort consisted of characteristics are given in Table 1 and 3% at level IV (1 child with ’ 161 term neonates born at a median and details of involvement of specific bilateral main branch MCA). There of 40.3 weeks gestation and a regions in Table 2. Involvement of were no infants in this study who median birth weight of 3440 g (Table 1). the CST could not be determined in were first diagnosed with CP beyond Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number 3, September 2018 5 TABLE 2 MRI Features per Stroke Territory Subtype Total, n = 161 Main MCA, Anterior MCA Middle MCA Posterior MCA Cortical MCA Perforator PCA or ACA, n = 31 Branch, n = 17 Branch, n = 21 Branch, n = 28 Branch, n = 21 Branch, n = 27 n = 16 CST involvement PLIC alone 28 (18) 0 (0) 8 (47) 5 (24) 9 (32) 0 (0) 6 (26) 0 (0) PLIC and 46 (30) 28 (100) 3 (18) 6 (29) 4 (14) 0 (0) 2 (9) 0 (0) peduncle Basal ganglia and/or thalamic involvement BG alone 25 (16) 1 (3) 5 (29) 1 (5) 1 (4) 0 (0) 17 (63) 0 (0) Thalamus 17 (11) 0 (0) 1 (6) 3 (14) 2 (7) 0 (0) 8 (30) 3 (21) alone BGT 41 (26) 30 (97) 2 (12) 1 (5) 6 (21) 0 (0) 2 (7) 0 (0) Central sulcus 68 (43) 31 (100) 7 (41) 21 (100) 9 (35) 0 (0) 0 (0) 0 (0) involvement Bilateral lesions Smaller 26 (18) 10 (39) 1 (6) 1 (5) 5 (19) 4 (19) 2 (8) 3 (21) lesions Bilateral 7 (5) 2 (8) 1 (6) 1 (5) 0 (0) 0 (0) 2 (8) 1 (7) stroke Multiple lesions 58 (39) 12 (46) 5 (31) 6 (30) 12 (46) 7 (33) 7 (28) 9 (64) Neonatal magnetic resonance images were reevaluated for involvement of the CSTs at the peduncle and the PLIC (n = 156), basal ganglia (n = 159), and central sulcus region (n = 157). In 148 infants, we could assess the presence of multiple and/or bilateral lesions. BG, basal ganglia.

TABLE 3 Cognitive Developmental Score After the Age of 12 Months per Time Point Age at Testing, mo, GMDS: DQ (Without BSITD-III: Cognitive WPPSI: Total IQ z Score, Median (IQR) z Score <−1 SD, Median (IQR) Locomotor Composite Score, Score, Median (IQR) n (%) Subscore), Median Median (IQR) (IQR) 12–18 mo, n = 83 15.2 (13.0 to 17.6) 98.2 (92.2 to 110.0) — — −0.15 (−0.65 to 0.83) 15 (18) ∼2 y, n = 123a 24.0 (21.1 to 25.0) 98.5 (91.1 to 104.7) 105.0 (95.0 to 113.8) — −0.03 (−0.67 to 17 (13) 0.67)b ∼3–4 y, n = 71 41.1 (36.0 to 42.4) 98.9 (88.6 to 107.5) — — −0.09 (−0.95 to 0.64) 14 (19) ∼5–7 y, n = 64 67.0 (65.0 to 70.0) — — 102.0 (88.0 to 111.0) 0.10 (−0.80 to 0.73) 11 (17) Latest follow-up, n 41.7 (24.6 to 66.0) — — — −0.04c (−0.95 to 37 (23) = 160 0.68)

DQ, developmental quotient; WPPSI, Wechsler Preschool and Primary Scale of Intelligence; —, not applicable. a At ∼2 y, 106 tested with the GMDS, and 28 tested with the BSITD-III. b When tested with both GMDS and BSITD-III, a z score was calculated for the latest test. c z score could not be calculated in 3 infants because of severe delay (<−2 SD).

’

2 years of age. Cognitive test results outcome results from each patient s Infants with language delay had – were available for 157 infants, and 3 last follow-up. increased risk of cognitive delay (OR: − infants could not be tested because of 11.8; 95% CI 4.7 29.2), but excluding severe delay (< 2 SD). This resulted Overall, 50 of 87 (57%) infants those with main MCA branch stroke, z − the odds for cognitive delay were 6.5 in 37 infants (23%) with a cognitive with adverse outcome developed – z − times increased with language delay score < 1 SD and 13 infants (8%) sequelae in multiple domains. Of (95% CI 2.1 20.1). Postneonatal with a cognitive score < 2 SD the 49 infants with CP, 35 (71%)n – had another adverse outcome, most epilepsy also increased the risk for (Table 3). At their latest follow-up, 87 commonly a cognitive deficit ( = cognitive delay (OR: 9.1; 95% CI 3.1 of 161 infants (54%) had an adverse 26.6), but this was only significant in 22; 45%). Visual field defects did not outcome; 38 infants (24%) had 1 or the main MCA branch stroke group. occur in isolation, and most often, MRI Parameters Associated With a combination of adverse outcomes they occurred in combination with Neurodevelopmental Outcome without having CP. More details on CP (13 of 17). Although adverse adverse outcome domains per stroke outcomes commonly co-occurred, subtype are given in Table 4. Further only 4 children were affected in all 6 Analyzing all infarcts together, analyses were performed by using developmental domains. univariate analyses revealed Downloaded from www.aappublications.org/news by guest on September 24, 2021 6 WAGENAAR et al TABLE 4 Adverse Outcome Domains per Stroke Territory Subtypes PAIS Type and Total Main MCA Anterior MCA Middle MCA Posterior MCA Cortical MCA Perforator PCA or ACA Outcomes (No. With (n = 161), (n = 31), Branch Branch Branch Branch Branch (n = 16), n (%) Data) n (%) n (%) (n = 17), n (%) (n = 21), n (%) (n = 28), n (%) (n = 21), n (%) (n = 27), n (%) CP, 49 (30) 31 (100) 2 (12) 4 (19) 6 (21) 0 (0) 4 (15) 2 (13) N = 161 Cognitive deficit, 37 (23) 17 (57) 1 (6) 3 (14) 8 (29) 3 (14) 2 (7) 3 (19) n = 160 Language delay, 34 (23) 15 (58) 4 (25) 2 (10) 5 (20) 3 (17) 3 (11) 2 (17) n = 145 Postneonatal 18 (12) 12 (41) 1 (6) 0 (0) 3 (12) 0 (0) 0 (0) 2 (13) epilepsy, n = 151 Behavioral 31 (25) 10 (37) 4 (31) 1 (6) 6 (25) 2 (13) 3 (17) 5 (42) problems, n = 126 Visual field defect, 17 (18) 12 (48) 0 (0) 0 (0) 2 (14) 0 (0) 0 (0) 3 (27) n = 96 Combination 50 (31) 26 (84) 3 (18) 2 (10) 8 (29) 2 (10) 2 (7) 7 (44) of adverse outcomes, n = 161 Within normal 74 (46) 0 (0) 9 (53) 13 (62) 12 (43) 15 (71) 18 (67) 7 (44) range, n = 161 Number of infants tested per outcome domain are presented in the first column.

TABLE 5 Univariate Associations Between the MRI Parameters and Neurodevelopmental Outcome Domains Involvement on MRI PLIC, Cerebral Basal Ganglia, Thalamus, BGT, Central Sulcus, Bilateral Multiple Lesions, OR (95% CI) Peduncle, OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) Lesions, OR (95% CI) OR (95% CI) OR (95% CI) CP 6.7 (1.2–38.7) 115.6 (35.2– 5.5 (1.6–19.4) NS 102.2 (27.8– 16.7 (6.7–41.6) 2.3 (1.0–5.2) NS 379.4) 376.2) Cognitive NS 6.1 (2.7–13.5) NS NS 5.9 (2.5–14.1) 4.2 (1.9–9.4) NS NS deficit Language delay NS 4.7 (2.0–10.8) NS NS 7.2 (2.7–18.8) 4.1 (1.7–9.4) NS NS Postneonatal NS 11.4 (3.5–37.4) NS NS 11.8 (3.1–44.9) 4.1 (1.4–12.2) 4.4 (1.5–12.9) 2.9 (1.0–8.6) epilepsy Behavioral NS NS NS NS 3.8 (1.5–9.5) NS NS NS problems Visual field NS 8.4 (2.4–28.6) NS NS 7.8 (2.0–30.7) 3.5 (1.0–11.8) NS NS defect Adverse NS 17.7 (5.9–52.9) NS NS 68.6 (8.9–526.5) 4.9 (2.4–9.7) NS NS outcome in any domain NS, nonsignificant.

n associations between with different outcome domains, In the other subgroup ( = 130), CP several MRI parameters and as described in Table 6. Because was still associated with involvement – neurodevelopmental outcome there was involvement of the CST, of the cerebral peduncle (OR: 34.4; domains (Table 5). Involvement of basal ganglia, and central sulcus 95% CI 5.6 208.9) and combined – the cerebral peduncles and combined in all main MCA branch infarcts, BGT involvement (OR: 6.9; 95% CI involvement of the BGT were both multivariable analyses were 1.1 45.1). Adverse cognitive outcome – related to almost all adverse outcome repeated separating all infants with was associated with combined BGT domains with ORs ranging between main MCA branch infarction from involvement (OR: 4.4; 95% CI 1.2 Multivariable3.8 and 115.6 (ModelingTable 5). the others (Table 6). 16.9). Language delay and visual field defects were no longer associated In infants with main MCA branch with MRI features, but postneonatal For the total cohort, several MRI infarction, no specific MRI epilepsy remained associated with – parameters were significantly parameters were associated with involvement of the cerebral peduncle and independently associated different adverse outcome domains. (OR: 9.7; 95% CI 1.0 101.1) and Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number 3, September 2018 7 TABLE 6 Logistic Regression Models for Neurodevelopmental Outcome Domains With Best Fit Outcome Domain MRI Parameters Total Cohort, N = 161 Subgroup (n = 130) Excluding Main Branch MCA Stroke OR 95% CI OR 95% CI CP Cerebral peduncle 63.0 10.7–369.4 34.4 5.6–208.9 BGT 21.0 4.1–106.6 6.9 1.1–45.1 Cognitive deficit BGT 5.9 2.5–14.1 4.4 1.2–16.9 Language delay BGT 7.1 2.7–18.8 NS NS Postneonatal epilepsy Cerebral peduncle 13.9 2.9–67.6 9.7 1.0–101.1 Bilateral lesions 3.6 1.1–11.7 15.9 2.3–110.8 Behavioral problems BGT 3.8 1.5–9.5 8.9 1.9–41.2 Visual field defect BGT 7.8 2.0–30.7 NS NS Adverse outcome in any Cerebral peduncle 4.0 1.1–14.7 NS NS domain BGT 27.9 3.2–244.0 17.1 2.1–141.1 NS, nonsignificant.

FIGURE 3 Graphic representation of the logistic regression models for neurodevelopmental outcome domains. Specific brain regions as seen on early MRI increase the odds for CP, epilepsy, and behavioral problems in a subgroup of 130 infants excluding those with main branch MCA stroke. Data are presented as OR with 95% CI.

– – bilateral lesions (OR: 15.9; 95% CI 17.1; 95% CI 2.1 141.1; Table 6; infants with PAIS depends on stroke 2.3 110.8). Behavioral problems Fig 3). territory (the site, extent, and were associated with combined DISCUSSION location of the lesion). To the best – BGT involvement (OR: 8.9; 95% CI of our knowledge, this is the first 1.9 41.2). Combined involvement of study in which is provided a precise the BGT increased the risk of adverse In this study, we have demonstrated overview of a spectrum of different outcome in at least 1 domain (OR: that an adverse outcome in term outcome domains per stroke pattern Downloaded from www.aappublications.org/news by guest on September 24, 2021 8 WAGENAAR et al –

27,34​ 36 in a large cohort of term infants are seen in the middle third of the PAIS. ‍ ‍ ‍ We found that cognitive from 2 centers. Additionally, with cerebral peduncle they are always delay occurred in 23% of all PAIS our study, we highlight the use of associated with the7,9​ development patients but in 57% of those with early neonatal MRI, and especially of hemiplegic CP. ‍ Because pre- a main branch MCA stroke when DWI, to predict neurodevelopmental Wallerian degeneration is the result last seen at a median age of 41 outcome, because outcome is not of anterograde degeneration of the months. Authors of other studies only dependent on stroke territory descending axons of injured cell have reported even higher rates of but also on the involvement of bodies within the infarcted areas, cognitive impairment36,37​ after PAIS at specific brain regions, such as the it was found more often in infants school age. ‍ Because most infants CST. with larger infarctions (affecting were still young when last seen, the complete motor cortex). Infants we did not see a trend over time. It is of great importance to clinicians with other stroke subtypes not Multivariable analysis revealed that and parents to evaluate promptly resulting in involvement of the CST cognitive delay was related to BGT the risk of an adverse outcome in in our cohort did not develop CP. We involvement. However, this seemed patients with PAIS, because early performed multivariable modeling to reflect larger strokes, because intervention strategies, which may separately for those without main BGT involvement was most often attenuate unfavorable development, 26 MCA branch infarction, to determine seen in main and partial branch MCA need to be appropriately focused. individual MRI risk factors for strokes. Other studies have revealed It is also important when possible to adverse outcome in milder subtypes. that larger infarct volume was reassure parents that outcomes are – For these subtypes, involvement of associated with adverse cognitive likely to be good. Several studies on 38 41 the cerebral peduncle was still a risk development in PAIS. ‍ We also neurodevelopment after PAIS are factor for CP and epilepsy, illustrating found that posterior MCA branch available, but authors of these studies the importance of pre-Wallerian and PCA strokes had higher rates of report a wide range of abnormal degeneration in the prediction of cognitive delay compared with other neurodevelopment, mainly because adverse outcome in those with less nonmain MCA subtypes, indicating there is no distinction between 27,28​ widespread stroke. that not only volume but also location specific stroke subtypes. ‍ This of affected tissue plays an important makes risk estimation difficult for Involvement of the BGT increased role in cognitive development. In a the individual child. With our study, the risk for CP, in agreement with 42 8,30,​ 31​ recent study, Stephan-Otto et al we have distinguished several the literature. ‍ ‍ In our cohort, reported that stroke in regions specific PAIS subtypes and described BGT involvement most commonly posterior to the central sulcus, incidence rates per outcome domain occurred with larger infarcts (main close to the arcuate fasciculus, may for them, enabling more personalized and partial MCA branches) and account for language deficits after prediction of long-term development. was most often part of the primary ∼ PAIS. In our cohort, rates of language In the literature, the incidence rate of stroke. But BGT involvement could delay were not higher in posterior CP after PAIS is 30%, comparable also be a manifestation of secondary 6,8,​ 27,​ 28​ compared with anterior MCA branch to our study. ‍ ‍ However, infants injury to connectivity pathways (eg, strokes, but many children were with main MCA branch infarction corticothalamic or corticostriatal too young for detailed speech or will all develop CP, whereas this networks) particularly in the thalami 17,30,​ 32​ language assessment. It was of percentage ranges between 0% and and best seen on DWI. ‍ The interest that infants with language 21% in other stroke subtypes. With increased risk for CP most likely delay had 6.5 to 10 times increased our data, we provide a firm basis stemmed from the larger stroke risk of cognitive delay, revealing that for informing parents of infants than just the BGT involvement. This language and cognition are closely with main MCA branch infarction is supported by several studies related. However, cognitive delay differently about future prospects revealing that primary stroke lesions might also precede language delay than parents of infants with other restricted to the BGT (ie, perforator or share a common origin, and exact stroke subtypes. stroke) are usually not associated 6,33​ causative mechanisms need to be with adverse motor outcome. ‍ Involvement of the CST on neonatal studied further. Development of In our cohort, only 15% of infants MRI was seen in the majority of postneonatal epilepsy increased the with perforator stroke developed patients with more extensive risk for cognitive delay as described unilateral spastic CP, all related to stroke subtypes, as reported in previously, but this was limited to 8,29​ additional involvement of the PLIC. 43 other studies. ‍ The CST signal infants with main MCA stroke. “ changes are best seen on early DWI Authors of a limited number of ” and have been described as pre- studies reported on long-term This study has several limitations Wallerian degeneration. When they cognitive outcome in infants with inherent to its retrospective design. Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 142, number 3, September 2018 9 36,37​ Infants were only eligible if they were been underdiagnosed. ‍ Long-term personalized planning of therapeutic admitted to the NICU or referred for outcome studies with a prospective interventions, and long-term neurologic assessment, excluding design are needed to determine support for behavioral and cognitive infants with (smaller) infarcts that whether early predictions in PAIS difficulties. may not have caused neonatal patients remain stable over time. ABBREVIATIONS symptoms; also, preterm44 infants Even with this large study, some were not included. However, our subgroups were small, and we strict inclusion criteria resulted in a cannot exclude that some ACA: anterior cerebral artery homogeneous group of term infants associations between brain regions ADC: apparent diffusion with PAIS. This study was focused and outcomes might have been coefficient on DWI from MRI, whereas early significant. BGT: basal ganglia and thalami DWI may not always be possible in CONCLUSIONS BSITD-III: Bayley Scales of Infant all institutions. However, we were and Toddler often able to see signal intensity Development, Third changes in CST on T2-weighted In a large cohort of term- Edition sequence as well, especially when the born infants from 2 centers, CI: confidence interval MRI was done in the second half of we have demonstrated that CP: cerebral palsy the first week. The use of apparent neurodevelopmental outcomes vary CST: corticospinal tract diffusion coefficient (ADC) maps between PAIS subtypes. Although DWI: diffusion-weighted imaging from DWI to assess acute ischemic neurodevelopmental outcome GMDS: Griffiths Mental injury is recommended to avoid T2 was invariably adverse in at least Development Scale shine-through and other artifacts. 1 domain with main branch MCA IQR: interquartile range Because the ADC map was not always stroke, in other PAIS subtypes, MCA: middle cerebral artery available for our cohort, we used outcome was normal in 43% to OR: odds ratio DWI for all infants. When ADC maps 71% of children. With this study, we PAIS: perinatal arterial ischemic were available, they were used to provide clinicians with important stroke verify DWI signal abnormalities, information for more precise risk PCA: posterior cerebral artery as is recommended in clinical evaluation of neurodevelopment PLIC: posterior limb of the practice. Infants that performed well in PAIS patients on the basis of the internal capsule were sometimes discharged from tissue involved, assessed from early UMCU: University Medical Center follow-up, and cognitive, language, MRI allowing better counseling in Utrecht and behavioral problems may have of parents in the neonatal period, 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 24, 2021 Neurodevelopment After Perinatal Arterial Ischemic Stroke Nienke Wagenaar, Miriam Martinez-Biarge, Niek E. van der Aa, Ingrid C. van Haastert, Floris Groenendaal, Manon J.N.L. Benders, Frances M. Cowan and Linda S. de Vries Pediatrics 2018;142; DOI: 10.1542/peds.2017-4164 originally published online August 2, 2018;

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