Article
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Perinatal arterial ischaemic stroke (PAIS) affects between 1:2300 and 1:4000 births, so most paediatricians and neonatologists will see a number of cases during their working life. The exact cause of PAIS in an individual usually is unknown, and discussion may occur about whether prothrombotic investigations, aspirin or anticoagulation are needed. The causes, investigation and treatment of PAIS are completely different from stroke in the older paediatric and adult group. Outcome tends to be good, although cerebral palsy may be seen in up to 30% of cases, epilepsy in 15–25% and cognitive problems may also occur. Fortunately, EEG and MRI can help identify those children with PAIS at the highest risk of neuro-developmental difficulties. This paper reviews what we know about the potential mechanisms causing PAIS, what investigations are necessary, and the likely outcome for the child.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... To explore spatial variations in the venous pulsatility characteristics, vessels were considered according to the local feeding arterial territory in which they lay, i.e., anterior, leftmiddle, right-middle, or posterior cerebral artery. Feeding arteries from the four vascular territories were clearly separable in the TOF image and four regions were manually drawn at the level of the pcMRI slice, making reference to literature example arterial territory maps such as those found in Mut et al. (2014) and Hart et al. (2018). Vessel clusters lying within each region were labeled accordingly. ...
Article
Full-text available
Phase contrast MRI (pcMRI) has been used to investigate flow pulsatility in cerebral arteries, larger cerebral veins, and the cerebrospinal fluid (CSF). Such measurements of intracranial pulsatility and compliance are beginning to inform understanding of the pathophysiology of conditions including normal pressure hydrocephalus, multiple sclerosis, and dementias. We demonstrate the presence of flow pulsatility in small cerebral cortical veins, for the first time using pcMRI at 7 T, with the aim of improving our understanding of the hemodynamics of this little-studied vascular compartment. A method for establishing where venous flow is pulsatile is introduced, revealing significant pulsatility in 116 out of 146 veins, across eight healthy participants, assessed in parietal and frontal regions. Distributions of pulsatility index (PI) and pulse waveform delay were characterized, indicating a small, but statistically significant (p < 0.05), delay of 59 ± 41 ms in cortical veins with respect to the superior sagittal sinus, but no differences between veins draining different arterial supply territories. Measurements of pulsatility in smaller cortical veins, a hitherto unstudied compartment closer to the capillary bed, could lead to a better understanding of intracranial compliance and cerebrovascular (patho)physiology.
... Neonatal strokes are different from strokes seen in older children and adults 11 . In babies, the brain is immature with greater capacity for plasticity in response to brain injury and hence greater potential for recovery 12 . ...
Preprint
Full-text available
Background Neonatal stroke is a devastating condition that causes brain injury in babies and often leads to lifelong neurological impairment. Recent, prospective whole population studies of neonatal stroke are lacking. Neonatal strokes are different from those seen in older children and adults. A better understanding of the aetiology, current management and outcomes of neonatal stroke could reduce the burden of this rare condition. Most healthcare professionals see only a few cases of neonatal stroke in their careers, so population-based prospective studies are needed. Objectives To explore the incidence and two-year outcomes of neonatal stroke across an entire population in the UK and the Republic of Ireland. Population Any infant presenting with neonatal stroke in the first 90 days of life. Design Active national surveillance study using a purpose-built integrated case notification-data collection online platform. Methods Over a 13-month period, British and Irish clinicians will notify any cases of neonatal stroke electronically via the online platform monthly. Clinicians will complete a primary questionnaire via the platform detailing clinical information, demographic details and investigations, including neuroimaging for detailed analysis and classification. An outcome questionnaire will be sent at two years of age via the platform. Appropriate ethical and regulatory approvals have been received from England, Wales, Scotland, Northern Ireland and the Republic of Ireland. Conclusion The neonatal stroke study represents the first multinational population surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, overcoming the challenges of setting up the study. Synopsis Study question The neonatal stroke active surveillance study aims to explore the incidence and two-year outcome of neonatal stroke in the UK and Ireland. What is already known? Neonatal stroke is a rare but often devastating condition with lifelong consequences including cerebral palsy, epilepsy and cognitive delay. There are no contemporary, prospective multinational population studies on the presentation and outcomes of neonatal stroke. Whilst often the aetiology is multifactorial further information on underlying aetiology may help to identify potential future preventative treatments leading to improved outcomes. What does this study add? International collaboration is required to understand the epidemiology, management and outcomes of rare diseases or conditions. This is the first multinational surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, presenting practical and ethical challenges. The study will describe the burden of neonatal stroke while providing parents/carers and healthcare professionals with up-to-date information about the condition including the two-year outcomes.
... To explore spatial variations in the venous pulsatility characteristics, vessels were considered according to the local feeding arterial territory in which they lay, i.e. anterior, left-middle, rightmiddle or posterior cerebral artery. Feeding arteries from the four vascular territories were clearly separable in the TOF image and four regions were manually drawn at the level of the pcMRI slice, making reference to literature example arterial territory maps such as those found in Mut et al. (2014) and Hart et al. (2018). Vessel clusters lying within each region were labeled accordingly. ...
Preprint
Full-text available
Phase contrast MRI has been used to investigate flow pulsatility in cerebral arteries, larger cerebral veins and the cerebrospinal fluid. Such measurements of intracranial pulsatility and compliance are beginning to inform understanding of the pathophysiology of conditions including normal pressure hydrocephalus, multiple sclerosis and dementias. We demonstrate the presence of flow pulsatility in small cerebral cortical veins, for the first time using phase contrast MRI at 7 Tesla, with the aim of improving our understanding of the haemodynamics of this little-studied vascular compartment. An automated method for establishing where venous flow is pulsatile is introduced, revealing significant pulsatility in 116 out of 146 veins, across 8 healthy participants, assessed in parietal and frontal regions. Distributions of pulsatility index and pulse waveform delay were characterized, indicating a small, but statistically significant (p<0.05), delay of 59±41 ms in cortical veins with respect to the superior sagittal sinus, but no differences between veins draining different arterial supply territories. Measurements of pulsatility in smaller cortical veins, a hitherto unstudied compartment closer to the capillary bed, could lead to a better understanding of intracranial compliance and cerebrovascular (patho)physiology.
... Although previous studies have identified several risk factors, their interdependence and role in the causal pathway of PAIS are poorly understood. [5][6][7][8][9][10][11][12] Most available studies are either small, often restricted to term infants, lack an adequate comparison group, or do not control for interdependencies between potential risk factors. ...
Article
AIM: To identify maternal, obstetric, and neonatal risk factors related to perinatal arterial ischaemic stroke (PAIS) diagnosed within 28 days after birth and to understand the underlying pathophysiology. METHOD: For case and control ascertainment, we used active surveillance in 345 paediatric hospitals and a population-based perinatal database for quality assurance of hospital care. We analysed complete cases of PAIS using logistic regression. Multivariate analysis was guided by a directed acyclic graph. RESULTS: After exclusion of records with missing data, we analysed 134 individuals with PAIS and 576 comparison individuals. In univariate analysis, male sex, preterm birth (<37wk gestational age), small for gestational age (SGA), low umbilical artery pH (<7.1), low 5-minute-Apgar score (<7), multiple pregnancies, hypoxia, intubation/mask ventilation, nulliparity, Caesarean section, vaginal-operative delivery, chorioamnionitis, and oligohydramnios were associated with an increased risk. Mutual adjustment yielded male sex (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.20–2.73), multiple birth (OR 3.22; 95% CI 1.21–8.58), chorioamnionitis (OR 9.89; 95% CI 2.88–33.94), preterm birth (OR 1.86; 95% CI 1.01–3.43), and SGA (OR 3.05; 95% CI 1.76–5.28) as independent risk factors. INTERPRETATION: We confirmed the increased risk in males and the role of chorioamnionitis and SGA for PAIS, pointing to the importance of inflammatory processes and fetal–placental insufficiency. Multiple birth and preterm birth were additional risk factors.
Article
Full-text available
Neonatal stroke is a devastating condition that causes brain injury in babies and often leads to lifelong neurological impairment. Recent prospective population studies of neonatal stroke are lacking. Neonatal strokes are different from those in older children and adults. A better understanding of its aetiology, current management, and outcomes could reduce the burden of this rare condition. The study aims to explore the incidence and 2 year outcomes of neonatal stroke across an entire population in the UK and Republic of Ireland. This is an active national surveillance study using a purpose-built integrated case notification-data collection online platform. Over a 13 month period, with a potential 6 month extension, clinicians will notify neonatal stroke cases presenting in the first 90 days of life electronically via the online platform monthly. Clinicians will complete a primary questionnaire via the platform detailing clinical information, including neuroimaging, for analysis and classification. An outcome questionnaire will be sent at 2 years of age via the platform. Appropriate ethics and regulatory approvals have been received. The neonatal stroke study represents the first multinational population surveillance study delivered via a purpose-built integrated case notification-data collection online platform and data safe haven, overcoming the challenges of setting up the study.
Article
Full-text available
The aim of this study was to identify prognostic factors in newborns with cerebral infarction. Antenatal and perinatal factors and early clinical, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings were compared with neurodevelopmental outcome in 24 children with evidence of cerebral infarction on neonatal MRI. Out of 24 infants, 19 had an infarction in the territory of a major cerebral vessel and 5 in the borderzone between cerebral arteries. Neuromotor outcome was normal in 17 and abnormal in 7 infants. Of these 7 infants, 5 infants showed a definite hemiplegia, whereas the other 2 showed some asymmetry of tone or function but no definite hemiplegia. None of the adverse antenatal or perinatal factors was significantly associated with abnormal outcome. Neonatal clinical examination was also not always predictive of the outcome. The extent of the lesion on MRI was a better predictor. In particular, it was the concomitant involvement of hemisphere, internal capsule and basal ganglia that was always associated with an abnormal outcome whereas the involvement of only one or two of the three tended to be associated with a normal outcome. EEG was also very helpful. Abnormal background activity either unilateral or bilateral was found in 6 infants and 5 out of 6 developed hemiplegia. In contrast, the presence of seizure activity in presence of a normal background was not related to abnormal outcome. Early MRI and EEG can help to identify the infants with cerebral infarction who are likely to develop hemiplegia.
Article
Full-text available
To evaluate the diagnostic accuracy of cranial ultrasound (CUS) for detection of neonatal arterial territory cerebral infarction in term infants. CUS scans from term infants with neonatal magnetic resonance imaging (MRI) evidence of neonatal infarction were reviewed. The scans were grouped by acquisition time after birth: 1-3 days (early) or 4-14 days (late). Brain MRI showed infarction in the territory of the middle cerebral artery in 43 of 47 infants, anterior cerebral artery in one, and posterior cerebral artery in three. Twelve of the 47 had minor changes on MRI in the white matter in the contralateral hemisphere, and four infants had bilateral infarctions. The early CUS scans were abnormal in 68% of the infants; the late CUS scans were abnormal in 87%. The late CUS scans were correct for laterality and site of lesion in 25/47 (53%) infants. In six infants with smaller lesions of the cortical middle cerebral artery branch or lesions in the posterior cerebral artery territory, the CUS scans were persistently normal. Normal early CUS scans do not exclude a diagnosis of neonatal stroke, although most scans are abnormal. CUS scans performed after day 3 were abnormal in 87% of infants. CUS scan findings were accurate for lesion laterality and site in 53%, and, in 34%, the scans showed abnormality strongly suggestive of infarction but not always site specific. For optimal prognostic information, infants with clinical histories or CUS scan findings suggestive of infarction should have a neonatal brain MRI scan.
Article
The aim of the present study was to perform a meta-analysis of published data to determine the significance of clinical factors and exposures to the risk of perinatal arterial ischaemic stroke (PAIS) and provide guidance for clinical diagnosis and treatment. A comprehensive literature search of the PubMed, Embase, MEDLINE and Cochrane Library databases for relevant observational studies (cohort/case-control) from March 1984 to March 2016 was undertaken. Two review authors independently examined the full text records to determine which studies met the inclusion criteria and evaluated risk factors for PAIS. Risk ratios, odds ratios and 95% confidence intervals were estimated. A total of 11 studies were included in the analyses. Intrapartum fever >38°C, pre-eclampsia, oligohydramnios, primiparity, forceps delivery, vacuum delivery, fetal heart rate abnormalities, abnormal cardiotocography tracing, cord abnormalities, birth asphyxia, emergency caesarean section, tight nuchal cord, meconium-stained amniotic fluid, umbilical arterial pH <7.10, Apgar score at 5 min <7, resuscitation at birth, hypoglycaemia, male gender and small for gestational age were identified as risk factors for PAIS. This systemic review and meta-analysis provides a preliminary evidence-based assessment of the risk factors for PAIS. Patients with any of the risk factors identified in this analysis should be given careful consideration to ensure the prevention of PAIS. Future studies focusing on the combined effects of multiple prenatal, perinatal and neonatal risk factors for PAIS are warranted.
Article
Perinatal stroke causes cerebral palsy and lifelong disability. Specific diseases are definable, but mechanisms are poorly understood. Evidence suggests possible associations between arterial perinatal stroke and prothrombotic disorders, but population-based, controlled, disease-specific studies are limited. Understanding thrombophilia in perinatal stroke informs pathogenesis models and clinical management. We conducted a population-based, prospective, case-control study to determine the association of specific perinatal stroke diseases with known thrombophilias. Children with idiopathic magnetic resonance imaging-classified neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), or fetal periventricular venous infarction (PVI) were recruited. Standardized thrombophilia evaluations were performed after 12 months of age on stroke cases and controls, including quantified proteins C and S, antithrombin, factors VIII/IX/XI, fibrinogen, lipoprotein(a), homocysteine, lupus anticoagulant, anticardiolipin antibodies and genotyping of factor V Leiden (FVL), factor II G20210A (FII), and methylenetetrahydrofolate reductase C677T. A total of 212 children were studied: 46 with NAIS, 34 with APPIS, 55 with PVI, and 77 controls (male, 53%; median age, 4.8 years). Of 14 parameters, no differences were observed in 12, including all common thrombophilias. Mean prothrombin time was shorter in arterial strokes (P < .001). Rates of antiphospholipid antibodies were low, comparable to those in controls, and resolved on repeat testing. FVL and FII rates were comparable to population norms. Total number of possible abnormalities did not differ between cases and controls. Our prospective, population-based, controlled, disease-specific study suggests minimal association between perinatal stroke and thrombophilia. This does not exclude the possibility of disordered coagulation at the time of stroke but suggests testing in childhood is not indicated.
Article
Background: Children with perinatal arterial ischemic stroke (PAIS) are at risk for later neurocognitive and behavioral deficits, yet the clinical predictors of these outcomes are understudied. We examined the influence of clinical and infarct characteristics on attention and executive functioning in children following PAIS. Methods: Forty children born at term (≥37 weeks' gestation) with PAIS (28 with neonatal arterial ischemic stroke and 12 with presumed PAIS) underwent a comprehensive neuropsychological battery at age three to 16 years (median age 7.2 years; 58% male) to assess attention and executive functioning. Parents also completed questionnaires regarding real-world functioning. Clinical variables including perinatal stroke subtype, infarct characteristics (location, laterality, and volume), and the presence of comorbid epilepsy were ascertained from the medical record. Results: Presumed PAIS, larger infarct volume, and comorbid epilepsy negatively influenced the performance on attention and executive functioning measures. These clinical variables were also associated with greater functional problems on parent reports, including a higher frequency of attention-deficit/hyperactivity disorder symptoms and greater difficulties in some subdomains of executive functioning. Infarct location and laterality were not associated with performance measures or parental report of functioning. Conclusion: Although all children with PAIS are at risk for later deficits in attention and executive functioning, those with presumed PAIS, larger infarct size, and comorbid epilepsy appear to be the most vulnerable. As they approach and reach school age, these children should undergo neuropsychological assessment to ensure timely implementation of therapeutic interventions and behavioral strategies.
Article
Objective: To investigate risk factors for neonatal arterial ischemic stroke (NAIS), and compare them with those present in term controls and infants with hypoxic-ischemic encephalopathy (HIE). Study design: Antepartum and intrapartum data were collected at presentation from 79 infants with NAIS and compared with 239 controls and 405 infants with HIE. The relationships between risk factors and NAIS were explored using univariable and multivariable regression. Results: Compared with controls, infants with NAIS more frequently had a family history of seizures/neurologic diseases, primiparous mothers, and male sex. Mothers of infants with NAIS experienced more intrapartum complications: prolonged rupture of membranes (21% vs 2%), fever (14% vs 3%), thick meconium (25% vs 7%), prolonged second stage (31% vs 13%), tight nuchal cord (15% vs 6%), and abnorm8al cardiotocography (67% vs 21%). Male sex (OR 2.8), family history of seizures (OR 6.5) or neurologic diseases (OR 4.9), and ≥1 (OR 5.8) and ≥2 (OR 21.8) intrapartum complications were independently associated with NAIS. Infants with NAIS and HIE experienced similar rates though different patterns of intrapartum complications. Maternal fever, prolonged rupture of membranes, prolonged second stage, tight nuchal cord, and failed ventouse delivery were more common in NAIS; thick meconium, sentinel events, and shoulder dystocia were more frequent in HIE. Abnormal cardiotocography occurred in 67% of NAIS and 77.5% of infants with HIE. One infant with NAIS and no infant with HIE was delivered by elective cesarean (10% of controls). Conclusions: NAIS is multifactorial in origin and shares risk factors in common with HIE. Intrapartum events may play a more significant role in the pathogenesis of NAIS than previously recognized.
Article
Objectives: To evaluate the epileptic, academic, and developmental status at age 7 years in a large population of term-born children who sustained neonatal arterial ischemic stroke (NAIS), and to assess the co-occurrence of these outcomes. Study design: A cohort study including 100 term newborns with NAIS was designed. Two infants died during the neonatal period, 13 families were lost to follow-up, and 5 families declined to participate in this evaluation. Thus, 80 families completed the 7-year clinical assessment. Epileptic status, schooling, motor abilities, global intellectual functioning, spoken language, and parental opinions were recorded. Principal component analysis was applied. Results: Rates of impaired language, cerebral palsy, low academic skills, active epilepsy, and global intellectual deficiency were 49%, 32%, 28%, 11%, and 8%, respectively. All were highly correlated. Eventually, 59% of children were affected by at least 1 of the aforementioned conditions. In 30% of cases, the viewpoints of health practitioners and parents did not match. Conclusion: The prevalence of severe disabilities at 7 years after NAIS is low, but most children exhibit some impairment in developmental profile. Trial registration: ClinicalTrials.gov (NCT02511249), Programme Hospitalier de Recherche Clinique Régional (0308052), Programme Hospitalier de Recherche Clinique Interrégional (1008026), and EudraCT (2010-A00329-30).
The incidence of perinatal arterial ischaemic stroke (PAIS) is about 1 in 2300 live births. Evidence about the aetiology is still lacking. The aim of this study was to identify maternal, perinatal and neonatal risk factors for symptomatic PAIS in full-term infants. Each full-term infant with PAIS was matched to three healthy controls for gestational age, date of birth and hospital of birth. Antenatal and perinatal risk factors were studied using univariate and multivariate conditional logistic regression analysis. Fifty-two infants were diagnosed with PAIS. Significant risk factors in the univariate analysis (p<0.05) were nulliparity (64% vs 47%), maternal fever (>38°C) during delivery (10% vs 1%), fetal heart rate decelerations (63% vs 16%), meconium-stained amniotic fluid (44% vs 17%), emergency caesarean section (35 vs 2%), Apgar score (1 min) ≤3 (29% vs 1%), Apgar score (5 min) <7 (25% vs 1%), umbilical artery pH <7.10 (56% vs 10%), hypoglycaemia <2.0 mmol/l (29% vs 3%) and early-onset sepsis/meningitis (14% vs 2%). In the multivariate analysis, maternal fever (OR 10.2; 95% CI 1.3 to 78.5), Apgar score (5 min) <7 (OR 18.1; 95% CI 3.4 to 96.8), hypoglycaemia <2.0 mmol/l (OR 13.0; 95% CI 3.2 to 52.6) and early-onset sepsis/meningitis (OR 5.8; 95% CI 1.1 to 31.9) were significantly associated with PAIS. Maternal fever during delivery and early-onset sepsis/meningitis were found to be involved with PAIS as was previously noted. Apgar score (5 min) <7 and hypoglycaemia were found to be important risk factors in term PAIS.
Article
This study aimed to investigate the maternal, pre- and perinatal, and prothrombotic factors with congenital hemiparesis due to presumed perinatal stroke (PPS). Prothrombotic risk factors including protein C and S, antithrombin III, lipoprotein (a), homocystein, factor VIII levels; anticardiolipin antibodies and lupus anticoagulant; methylenetetrahydrofolate reductase mutations, factor V Leiden, prothrombin G20210A mutations were investigated. Arterial ischemic stroke was detected in 60% and periventricular venous infarction in 40%. At least one prothrombotic risk factor was present in 69%, two in 17%, and three or more in 8.5% of cases. The most common combination was methylenetetrahydrofolate reductase C677T and factor V Leiden heterozygosity. The etiology and pathogenesis of PPS is still unclear. According to this study, most of the patients with PPS might have one or more prothrombotic risk factors and certain prenatal risk factors including intrauterine growth retardation, twin gestation and preeclampsia might be related to PPS.
Mechanisms of perinatal arterial ischemic stroke
  • Mechanism
  • D Risk Factors For Pais Fern Andez-L Opez
  • N Natarajan
  • S Ashwal
MECHANISM AND RISK FACTORS FOR PAIS Fern andez-L opez D, Natarajan N, Ashwal S, et al. Mechanisms of perinatal arterial ischemic stroke. J Cerebr Blood Flow Metabol 2014; 34: 921e32.