Perinatal Ischemic Stroke Research Articles

Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain.

BackgroundPerinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE-5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation.MethodsIschemia was induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or sildenafil intraperitoneal (i.p.) injections. Blood flow (BF) velocities were measured by ultrasound imaging with sequential Doppler recordings and laser speckle contrast imaging. Animals were euthanized, and brain tissues were obtained at 72 h or 8 days after pMCAo. Expression of M1- and M2-like microglia/macrophage markers were analyzed.ResultsAlthough sildenafil (10 mg/kg) treatment potently increased cGMP concentrations, it did not influence early collateral recruitment nor did it reduce mean infarct volumes 72 h after pMCAo. Nevertheless, it provided a significant dose-dependent reduction of mean lesion extent 8 days after pMCAo. Suggesting a mechanism involving modulation of the inflammatory response, sildenafil significantly decreased microglial density at 72 h and 8 days after pMCAo. Gene expression profiles indicated that sildenafil treatment also modulates M1- (ptgs2, CD32 and CD86) and M2-like (CD206, Arg-1 and Lgals3) microglia/macrophages in the late phase after pMCAo. Accordingly, the number of COX-2+ microglia/macrophages significantly increased in the penumbra at 72 h after pMCAo but was significantly decreased 8 days after ischemia in sildenafil-treated animals.ConclusionsOur findings argue that anti-inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after pMCAo in neonatal mice. We propose that sildenafil treatment could represent a potential strategy for neonatal ischemic stroke treatment/recovery.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0560-4) contains supplementary material, which is available to authorized users.

Language learning and brain reorganization in a 3.5-year-old child with left perinatal stroke revealed using structural and functional connectivity

Brain imaging methods have contributed to shed light on the possible mechanisms of recovery and cortical reorganization after early brain insult. The idea that a functional left hemisphere is crucial for achieving a normalized pattern of language development after left perinatal stroke is still under debate. We report the case of a 3.5-year-old boy born at term with a perinatal ischemic stroke of the left middle cerebral artery, affecting mainly the supramarginal gyrus, superior parietal and insular cortex extending to the precentral and postcentral gyri. Neurocognitive development was assessed at 25 and 42 months of age. Language outcomes were more extensively evaluated at the latter age with measures on receptive vocabulary, phonological whole-word production and linguistic complexity in spontaneous speech. Word learning abilities were assessed using a fast-mapping task to assess immediate and delayed recall of newly mapped words. Functional and structural imaging data as well as a measure of intrinsic connectivity were also acquired. While cognitive, motor and language levels from the Bayley Scales fell within the average range at 25 months, language scores were below at 42 months. Receptive vocabulary fell within normal limits but whole word production was delayed and the child had limited spontaneous speech. Critically, the child showed clear difficulties in both the immediate and delayed recall of the novel words, significantly differing from an age-matched control group. Neuroimaging data revealed spared classical cortical language areas but an affected left dorsal white-matter pathway together with right lateralized functional activations. In the framework of the model for Social Communication and Language Development, these data confirm the important role of the left arcuate fasciculus in understanding and producing morpho-syntactic elements in sentences beyond two word combinations and, most importantly, in learning novel word-referent associations, a building block of language acquisition.

Abstract 29: Common Thrombophilias are not Associated With Specific Perinatal Stroke Diseases

Background: Perinatal stroke causes cerebral palsy and lifelong disability. Specific diseases are definable, including arterial and venous ischemic injuries, but pathophysiological mechanisms are poorly understood. Thrombophilia has long been considered a potential contributor but population-based, controlled, disease-specific studies are limited. Hypothesis: Thrombophilia is uncommon in children with perinatal stroke. Methods: Subjects were recruited from the Alberta Perinatal Stroke Project, a population-based cohort with MRI-classified perinatal strokes: neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), and fetal periventricular venous infarction (PVI). Standardized thrombophilia evaluations were performed prospectively (2008-2015) after 12 months of age on stroke cases and matched controls. Measures included protein C and S, antithrombin III, factors VIII/IX/XI, fibrinogen, lipoprotein a, lupus anticoagulant, and antiphospholipid antibodies. Groups were compared (ANOVA, chi-square), corrected for multiple comparisons. Results: A total of 252 children were studied (58 NAIS, 48 APPIS, 69 PVI, 77 controls). Of 14 parameters, no differences were observed in 12 including all common thrombophilias. Prothrombin times were shorter in arterial strokes compared to controls (p<0.001). Factor XI levels were higher in arterial and PVI strokes compared to controls (p=0.004). Rates of genetic thrombophilias including factor V Leiden, prothrombin gene, and MTHFR were low and comparable to population rates. Conclusion: 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.

Ischemic Perinatal Stroke

Ischemic strokes are more common in the perinatal period than at any other time of life. Several risk factors for perinatal stroke have been identified but the impact of or interactions between the risk factors are not well understood. To date, there are no reliable predictors of ischemic stroke on which to base prevention or treatment interventions. Studies in the last decade focusing specifically on IPS have improved the knowledge base for perinatal stroke but there are many areas that still need clarification, such as risk factors contributing to IPS and which of these might be utilized as predictive markers for newborns with increased risk. This article provides a review of what is currently known of the prevalence, potential risks, pathophysiology, diagnosis, treatment, and outcome of ischemic perinatal stroke.

Long-term Neuropsychological Outcome and Quality of Life in Perinatal Ischemic Stroke

Background: Perinatal arterial ischemic stroke is an established risk factor for neuromotor and cognitive sequelae, but little is known about long-term neuropsychological implications. We aimed to evaluate long-term neuropsychological outcome and its effect on life quality in children with history of perinatal arterial ischemic stroke. Methods: Seventeen children with history of perinatal arterial ischemic stroke, selected from the institutional cerebrovascular registry, were recruited for this study. Outcome was investigated using a battery of standardized neuropsychological tests and PedsQL questionnaire. A neuropsychological composite score (Cognitive Index) was calculated taking into account impaired performances. Results: 47% of the patients had impaired Cognitive Index. Neuropsychological functions involved included: language, visuo-motor and executive functions, visual selective attention, with sustained attention as the most affected (59% of patients). Impairment in Cognitive Index was significantly associated with poor quality of life as perceived by parents. Conclusion: In conclusion, minor impairments, such as neuropsychological deficits, can frequently occur in children with history of perinatal arterial ischemic stroke and may affect quality of life.

Outcome of hemiplegic cerebral palsy born at term depends on its etiology

ObjectivesTo elucidate the etiology and its relationship to the outcomes of hemiplegic cerebral palsy (HCP). Participants and methodsMR images and outcomes of 156 children with HCP born at term and older than three years were investigated in two major centers for cerebral palsy in Japan. Etiologies were classified into perinatal ischemic stroke (PIS), cerebral dysgenesis (CD), and others. PIS was divided into periventricular venous infarction (PVI) and two types of arterial infarction; middle cerebral artery infarction (MCAI) and deep gray matter infarction (DGMI). Initial signs and the time of presentation were investigated among the three types of PIS. As functional outcomes, laterality of paresis, age at initial walk, affected hand’s function, intellectual development, and occurrence of epilepsy were compared among all the four types. ResultsEtiology: PIS was found in 106 children (68%), while CD accounted for 28 (18%). Among PIS, venous infarction was more common than arterial infarction (62:44). Outcomes: PVI revealed later presentation of motor asymmetry and more involvement of lower extremity as the initial sign among PIS groups. Only MCAI showed right-side predominance in laterality of paresis. DGMI related to better intellectual development and PVI showed lower occurrence of epilepsy, while there was no significant difference in affected hand’s function among the four groups. PIS groups showed significantly earlier attainment of independent walk, better intellectual development, and lower occurrence of epilepsy than CD. ConclusionsPVI was the most common cause of HCP born at term, and the etiology closely related to the initial signs of hemiplegia and overall outcomes.

Presumed perinatal ischemic stroke: A review.

The risk of stroke is actually highest during the perinatal period. However, some newborn infants may have no signs indicative of the need of brain imaging, or brain images taken may not be sensitive enough to diagnose ischemic injuries; so, the diagnosis of stroke may be delayed several months or years. The neurological picture in patients with perinatal stroke detected through neuroimaging months or years after the neonatal period is called presumed perinatal ischemic stroke. Although a presumed perinatal ischemic stroke is just a confirmation of the existence of an important level of underdiagnosis in relation to perinatal stroke, establishing the extent of this condition has allowed to improve knowledge on perinatal ischemic vascular disease.

Accidente cerebrovascular isquémico presuntamente perinatal. Revisión

The risk of stroke is actually highest during the perinatal period. However, some newborn infants may have no signs indicative of the need of brain imaging, or brain images taken may not be sensitive enough to diagnose ischemic injuries; so, the diagnosis of stroke may be delayed several months or years. The neurological picture in patients with perinatal stroke detected through neuroimaging months or years after the neonatal period is called presumed perinatal ischemic stroke. Although a presumed perinatal ischemic stroke is just a confirmation of the existence of an important level of underdiagnosis in relation to perinatal stroke, establishing the extent of this condition has allowed to improve knowledge on perinatal ischemic vascular disease.

Functional independence in 3.5 years old children with neonatal arterial ischemic stroke

Perinatal ischemic stroke is one of the most common type of stroke in children and the most important cause of unilateral Cerebral Palsy. The object of the study was to find the factors related to lesser functional independence at 3.5 years old, in a population of children with neonatal arterial ischemic stroke. It was a French multicentric cohort study (AVCnn cohort), in a population of term born children with neonatal arterial ischemic stroke. 100 newborns were included between November 2003 and October 2006, in 39 French hospital centers. At 3.5 years old, their functional independence was assessed by the Wee-FIM scale. The Wee-FIM stars were compared to healthy children of same age in general population and with the following factors: cerebral palsy, epilepsy, stroke side and mother studies level. 80 children fulfilled the Wee-FIM scale at 3.5 years old. The motor condition at 7 years old was known in 69 children (42 boys and 27 girls): 23 had cerebral palsy and 7 were epileptic. The AVC was in the right hemisphere in 26% of cases and in the left hemisphere in 74% of cases. 70% of the mothers were graduated more than Bachelor Degree. Functional independence was weaker in the AVCnn cohort than in healthy children of same age in general population, except for alimentation. The most affected fields were bladder control, bath and shower transfers, expression and comprehension. Epilepsy seems to be the most pejorative factor on independence, and even more if associated to cerebral palsy. The most impacted fields were then: dressing, toilet use, sphincters control, and transfers. Stroke side and mother studies level were not associated to significant variation of functional independence. There is a delay in all functional independence fields in children with neonatal arterial ischemic stroke. Functional independence, assessed by the Wee-FIM scale, seems to be most of all impacted by the presence of epilepsy.

Arterial ischemic perinatal stroke

Stroke is more common in the newborn period than at any other time in childhood and carries the risk of significant long-term neurodevelopmental morbidity. Arterial ischemic stroke may present acutely in the neonatal period, or may come to attention later when the child develops a hemiparesis or symptomatic epilepsy syndrome. Case-control and hospital-based cohort studies have revealed many factors associated with arterial ischemic perinatal stroke (IPS), including congenital heart disease, placental pathology, and thrombophilia. Since both motor and cognitive abnormalities may result, supportive care of the individual with arterial IPS requires a multidisciplinary approach and must extend beyond the acute illness phase. Herein we review the epidemiology, presentation, risk factors, suggested diagnostic approach, treatment, and outcomes of arterial IPS.

P202 – 2912: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms A1298C and C677T as genetic risk factors for perinatal and childhood arterial ischemic stroke?

Objective The knowledge of arterial ischemic stroke (AIS) risk factors is still insufficient. Most frequently reported risk factors are cerebral arteriopathies, cardiac diseases, vascular malformations, infections, and traumas. Because of multifactorial etiology AIS might possibly have a multigenic inheritance pattern. The potential genetic risk factor for AIS could be the decreased activity of methylenetetrahydrofolate reductase (MTHFR), which is caused by common polymorphisms C677T (rs1801133) and A1298C (rs1801131). The aim of the study is to examine the role of these two MTHFR polymorphisms in searching for genetic determinants in arterial ischemic stroke. Methods 78 randomly selected pediatric stroke patients, 50 with perinatal and 28 with childhood stroke, participated in the study. Population-based control-group for perinatal stroke consisted of 150 and for childhood stroke of 84 healthy individuals. DNA testing for MTHFR C677T and A1298C mutations was performed, genotypes were determined by PCR using specific primers. Association analysis (p-values with Fisher exact test, odds ratios with 95% confidence intervals) was performed using Terminal software. Results The 677T allele carrier status (p=0.9, OR=1.0) did not show relevance as a genetic risk factor for perinatal stroke. An interesting observation was the fact that minor allele frequency of A1298C was higher in healthy controls than in patients with either perinatal (p=0.08, OR=0.63) or childhood (p=0.14, OR=0.6) AIS. On the other hand, minor allele frequency of C677T demonstrated a weak association with childhood AIS (p=0.09, OR=1.7, 95% CI: 0.9–3.2). Conclusion Our data support the hypothesis that functional MTHFR polymorphism C677T may represent a genetic risk factor for childhood AIS, representing 1.7-times higher risk. The A1298C polymorphism was not found as genetic risk factor for perinatal nor for childhood stroke.

Comparison of Hypercoagulable Evaluation in Perinatal and Pediatric Ischemic Stroke (P2.261)

Comparison of Hypercoagulable Evaluation in Perinatal and Pediatric Ischemic Stroke (P2.261)

A Case of Neonatal Cerebral Infarction associated with Mutation in homozygousMTHFRC677T Gene

C677T mutation in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) predisposes to hyperhomocysteinemia in vivo and is known to be one of the causes of perinatal ischemic stroke. As MTHFR plays a role in the metabolism of homocysteine, C677T mutation may account for reduced enzymatic activity resulting in hyperhomocysteinemia. This may be prevented by introducing activity-enhancing coenzymes such as folic acid, vitamin B6, and B12. Though C677T mutation is known as a significant risk factor for cerebral infarction, reported cases of cerebral infarction among affected neonates are scarce. This report describes a case of a neonate homozygous for C677T mutation who had a perinatal ischemic stroke, born in a mother whose folic acid and nutritional consumption had been reduced during pregnancy.

Pediatric stroke and transcranial direct current stimulation: methods for rational individualized dose optimization.

Background: Transcranial direct current stimulation (tDCS) has been investigated mainly in adults and doses may not be appropriate in pediatric applications. In perinatal stroke where potential applications are promising, rational adaptation of dosage for children remains under investigation.Objective: Construct child-specific tDCS dosing parameters through case study within a perinatal stroke tDCS safety and feasibility trial.Methods: 10-year-old subject with a diagnosis of presumed perinatal ischemic stroke and hemiparesis was identified. T1 magnetic resonance imaging (MRI) scans used to derive computerized model for current flow and electrode positions. Workflow using modeling results and consideration of dosage in previous clinical trials was incorporated. Prior ad hoc adult montages vs. de novo optimized montages provided distinct risk benefit analysis. Approximating adult dose required consideration of changes in both peak brain current flow and distribution which further tradeoff between maximizing efficacy and adding safety factors. Electrode size, position, current intensity, compliance voltage, and duration were controlled independently in this process.Results: Brain electric fields modeled and compared to values previously predicted models (Datta et al., 2011; Minhas et al., 2012). Approximating conservative brain current flow patterns and intensities used in previous adult trials for comparable indications, the optimal current intensity established was 0.7 mA for 10 min with a tDCS C3/C4 montage. Specifically 0.7 mA produced comparable peak brain current intensity of an average adult receiving 1.0 mA. Electrode size of 5 × 7 cm2 with 1.0 mA and low-voltage tDCS was employed to maximize tolerability. Safety and feasibility confirmed with subject tolerating the session well and no serious adverse events.Conclusion: Rational approaches to dose customization, with steps informed by computational modeling, may improve guidance for pediatric stroke tDCS trials.

Impacts of Perinatal Induced Photothrombotic Stroke on Sensorimotor Performance in Adult Rats

Perinatal ischemic stroke is a leading cerebrovascular disorder occurring in infants around the time of birth associated with long term comorbidities including motor, cognitive and behavioral deficits. We sought to determine the impact of perinatal induced stroke on locomotion, behavior and motor function in rats. A photothrombotic model of ischemic stroke was used in rat at postnatal day 7. Presently, we induced two lesions of different extents, to assess the consequences of stroke on motor function, locomotion and possible correlations to morphological changes. Behavioral tests sensitive to sensorimotor changes were used; locomotion expressed as distance moved in the open field was monitored and histological changes were also assessed. Outcomes depicted two kinds of lesions of different shapes and sizes, relative to laser illumination. Motor performance of rats submitted to stroke was poor when compared to controls; a difference in motor performance was also noted between rats with small and large lesions. Correlations were observed between: motor performance and exposition time; volume ratio and exposition time; and in the rotarod between motor performance and volume ratio. Outcomes demonstrate that photothrombotic cerebral ischemic stroke induced in early postnatal period and tested in adulthood, indeed influenced functional performance governed by the affected brain regions.

The Pediatric Stroke Recurrence and Recovery Questionnaire

We developed the Recurrence and Recovery Questionnaire (RRQ) by converting the Pediatric Stroke Outcome Measure (PSOM) to a questionnaire for telephone interview and sought to validate the RRQ in a large cohort. We analyzed parents' RRQ responses and same-day PSOM assessments for 232 children who had arterial ischemic stroke, cerebral sinovenous thrombosis, or presumed perinatal ischemic stroke. We assessed the agreement and consistency of the PSOM and RRQ, and we identified conditions that contributed to differences between the 2 measures. We tested selected factors as predictors of differences between the total PSOM and total RRQ (tPSOM and tRRQ) scores. Median PSOM score was 1.5 and median RRQ score was 1.5. There was good agreement between tPSOM and tRRQ, and RRQ was a reliable estimator of PSOM at the total and component level. Preexisting neurologic deficits or chronic illnesses increased the difference between the tPSOM and tRRQ; the chronic illness effect was confirmed with univariate analysis. The RRQ can characterize poststroke function when a child cannot return for examination. While the RRQ is not identical to the PSOM, the 2 measures likely assess closely related aspects of recovery. The RRQ is particularly useful when assessing outcomes of large cohorts, and will be useful in performing long-term follow-up studies of pediatric stroke.

Pathophysiological role of inflammatory molecules in paediatric ischaemic brain injury

Ischaemic stroke is one of the major causes of death and lifelong disability also in the paediatric population. Strong scientific effort has been put to clarify the pathophysiology of this disease in adults. However, only few studies have been performed in children. Preliminary results indicate that pathophysiological processes might differently affect the poststroke neuronal injury in neonates as compared to children. During the neural development, selective molecular mechanisms might be differently triggered by an ischaemic insult, thus potentially resulting in defined postischaemic clinical outcomes. Basic research studies in neonatal animal models of cerebral ischaemia have recently shown a potential role of soluble inflammatory molecules (such as cytokines, chemokines and oxidants) as pivotal players of neuronal injury in both perinatal and childhood ischaemic stroke. Although larger clinical trials are still needed to confirm these preliminary results, the potential benefits of selective treatments targeting inflammation in perinatal asphyxia encephalopathy might represent a promising investigation field in the near future. In this review, we will update evidence on the pathophysiological role of soluble inflammatory mediators in neonatal and childhood ischaemic stroke. Recent evidence on potential anti-inflammatory treatments to improve paediatric stroke prognosis will be discussed.

Arterial Ischemic Stroke in an Adolescent With Presumed Perinatal Ischemic Stroke

The risk of recurrent ischemic stroke after presumed perinatal stroke and the risk factors for such recurrence are rarely reported. Here, we present an adolescent with a history of presumed perinatal stroke who presented with arterial ischemic stroke recurrence at the age of 15 years. Hereditary thrombophilia screening performed at the time of his stroke recurrence demonstrated protein S deficiency. No evidence-based consensus guidelines on thrombophilia screening in children with presumed perinatal stroke exist, nor has the role of secondary prophylaxis been addressed. There is a risk of stroke recurrence after presumed perinatal stroke, and routine thrombophilia screening may identify those children who are at higher risk for recurrence and who might therefore benefit from secondary prophylaxis. Clear guidelines should be developed to standardize investigations and management of children with presumed perinatal ischemic stroke.

Risk Factors and Presentations of Periventricular Venous Infarction vs Arterial Presumed Perinatal Ischemic Stroke

To determine whether clinical presentations and risk factor profiles differ between periventricular venous infarction (PVI) and arterial presumed perinatal ischemic stroke (APPIS). Retrospective cohort study. A total of 59 children with presumed perinatal ischemic stroke (PPIS) from the SickKids Children's Stroke Program who were carried to term (63% boys). Single tertiary care center subspecialty program. Participants had validated magnetic resonance imaging classification to define PVI and APPIS subgroups. Clinical presentations, times to parental and physician concern, age at diagnosis, and standardized risk factor evaluations including maternal, fetal, obstetrical, neonatal, and prothrombotic variables. Patients with PVI and APPIS were compared using chi(2) or Fisher exact tests and Wilcoxon rank sum or Mann-Whitney U tests. A total of 12 children (20%) had PVI and 47 (80%) had APPIS. Median parental concern was 5 months, with delays to physician concern (7 months) and diagnosis (12 months). Delays were longer in PVI cases compared with APPIS (P = .002). Most presented with asymmetrical motor development but children with APPIS were more likely to present with seizures or nonmotor delays (P = .01). Children with APPIS were more likely to have acute perinatal risk factors (66% vs 17%; P = .002) including fetal distress, emergency caesarian section, or neonatal resuscitation. Cardiac evaluations were unremarkable. Prothrombotic abnormalities were common (44%) including protein S deficiency, lupus anticoagulant, and elevated factor IX but were comparable between APPIS and PVI subgroups. Diagnosis of PPIS is often delayed. The association of acute perinatal risk factors with APPIS compared with PVI supports distinct timing of these diseases. Prospective, case-control risk factor studies of PPIS subtypes are required to develop prevention strategies.

Lipoprotein (a), Birth Weight and Neonatal Stroke

Background: Elevated lipoprotein (Lp) (a) is the most common genetically determined risk factor found in babies with perinatal ischemic stroke. The influence of maternal Lp(a) has not been studied extensively to date. Objectives: To investigate the role of Lp(a) in our population of neonates with stroke. Methods: In a prospective uncontrolled cohort of term-born children with neonatal arterial ischemic stroke, Lp(a) levels were investigated in 69 mothers and 69 children. Paternal Lp(a) was not explored. Results: An increased Lp(a) level was found in 26 mothers [38%; 95% confidence interval (CI) 28–50%] and in 15 children (22%; 95% CI 13–33%). Both rates were higher than the reference range reported in the general Caucasian population (10% in adults and 5% in children). Additionally, there was a correlation between maternal and infantile Lp(a) levels (p < 0.0001) and between elevated maternal Lp(a) level and lower birth weight (p = 0.027). Conclusions: Elevated maternal Lp(a) is apparently a risk factor for neonatal arterial ischemic stroke. We speculate that the pathological mechanism of this relation may be mediated through a dysfunction of the placental vascularization.