Perinatal Arterial Stroke Research Articles

Perinatal Stroke as It is: Updates, Insights and Challenges

Perinatal stroke comprises a heterogeneous group of focal cerebrovascular injuries that occur between 20 weeks of gestation and 28 days of postnatal life. Perinatal stroke is a leading cause of life-long disability, causing most cases of hemiparetic cerebral palsy. The intent of this article was to provide a comprehensive review of the 6 different types of perinatal stroke based on neuroimaging and clinical presentation, highlighting their similarities and distinctions in etiology and outcome, and further discuss a neuroimaging pathway for suspected perinatal stroke and follow-up imaging.Learning Objective: To provide an update on the current knowledge of the role of neuroimaging in diagnosis and long-term prognosis of perinatal stroke diseases and to understand the microglial role in perinatal arterial stroke

Ultrasound in the Diagnosis of Perinatal Ischemic Strokes (Literature Review with Their Own Clinical Observations)

The issues of early diagnosis of perinatal arterial stroke (PAII) continue to be discussed in the domestic and foreign literature. Along with MRI, the ultrasound method allows to identify foci of ischemia of different localization and sizes in newborns. During ultrasound, we identified 29 cases of PAIA of different localization in children of different gestational and postnatal age. Analysis of our own and published data showed that up to 32 weeks of gestational development, AII develops in the lenticular-striar basin, and later in the cortical-subcortical region. Diagnostic capabilities of ultrasound in PAII can be significantly expanded by using ultrasound duplex scanning of brain vessels. Our observations showed that the nature of changes in Doppler parameters depends on the localization of the affected vascular basin and on the duration of cerebrovascular disorders

Developmental neuroplasticity of the white matter connectome in children with perinatal stroke.

To employ diffusion imaging connectome methods to explore network development in the contralesional hemisphere of children with perinatal stroke and its relationship to clinical function. We hypothesized alterations in global efficiency of the intact hemisphere would correlate with clinical disability. Children with unilateral perinatal arterial (n = 26) or venous (n = 27) stroke and typically developing controls (n = 32) underwent 3T diffusion and T1 anatomical MRI and completed established motor assessments. A validated atlas coregistered to whole-brain tractography for each individual was used to estimate connectivity between 47 regions. Graph theory metrics (assortativity, hierarchical coefficient of regression, global and local efficiency, and small worldness) were calculated for the left hemisphere of controls and the intact contralesioned hemisphere of both stroke groups. Validated clinical motor assessments were then correlated with connectivity outcomes. Global efficiency was higher in arterial strokes compared to venous strokes (p < 0.001) and controls (p < 0.001) and was inversely associated with all motor assessments (all p < 0.012). Additional graph theory metrics including assortativity, hierarchical coefficient of regression, and local efficiency also demonstrated consistent differences in the intact hemisphere associated with clinical function. The structural connectome of the contralesional hemisphere is altered after perinatal stroke and correlates with clinical function. Connectomics represents a powerful tool to understand whole brain developmental plasticity in children with disease-specific cerebral palsy.

Abstract TP103: Neonatal Stroke Alters Communication of Microglial Cells With Microglia-Derived Exosomes and Microvesicles

Inflammation modulates brain injury after perinatal arterial stroke. We previously demonstrated that microglial cells play an important role in protecting neonatal brain from acute stroke by phagocytosing dying neurons, attenuating cytokine accumulation and by protecting neurovascular integrity. Microglia may modulate injury in neonatal stroke via crosstalk between cells via other mechanisms, such as by releasing extracellular vesicles from microglia (MEV), including exosomes (MExo) and microvesicles (MMV). Aim: Elucidate the mechanisms of MEV communication with brain cells in injured neonatal brain and role of these vesicles in protection. Methods: Transient middle cerebral artery occlusion (tMCAO) was performed in postnatal day 9 (P9). Microglial cells were isolated by CD11b-conjugated beads from ischemic and contralateral cortex 24h after reperfusion and plated at same density for 96h. MEV were isolated by multi-step centrifugation (MMV) and ultra-centrifugation (MExo) and labeled with MiniClaret dye. Uptake of MEV from contralateral/ injured cortex by Iba1 + -cells from contralateral and injured regions was determined 10, 30 &amp; 120min. Images co-stained with flotillin-1, which is strongly expressed in MMV but not in MExo, were analyzed using Volocity ® . Results: The uptake of MEV from injured cortex by microglia from injured cortex was significantly higher than uptake of contralateral-MEV by microglia from uninjured cortex (5-fold at 10min; p&lt;0.0001) regardless of time. Uptake of MEV from injured regions by microglia from contralateral cortex and contralateral-MEV by microglia from injured cortex were low. While the number of ipsilateral and contralateral flotillin-1 + -MMV was similar, uptake of flotillin-1 - -MExo and ratio of ipsilateral MExo/MEV were significantly increase. Summary: Our data demonstrate selective enhancement of microglial communication with MEV from activated microglia after acute neonatal stroke as well as distinct MEV-subtype-dependent mechanisms of communication in injured brain. This mechanism could provide a better understanding of the role of microglia on the severity of neonatal stroke. Support: AHA17IRG33430004, RO1NS44025, RO1HL139685

Epileptic Spasms Predict Poor Epilepsy Outcomes After Perinatal Stroke.

Perinatal stroke is a significant cause of severe epilepsy, including epileptic spasms. Although epileptic spasms due to underlying structural lesion often respond poorly to treatment and evolve into drug-resistant epilepsy, outcomes are not uniformly poor, and predictors of outcomes are not well described. We performed a single-institution retrospective review of epileptic spasms following perinatal stroke to determine if outcome depended on vascular subtype. We identified 24 children with epileptic spasms due to perinatal ischemic stroke: 11 cases of perinatal arterial stroke and 13 cases of perinatal venous infarct. Initial response to treatment was similar between groups; however, although children with perinatal arterial stroke who responded to epileptic spasms therapy had high rates of seizure freedom, many children with perinatal venous infarct, regardless of initial response, had residual drug-resistant epilepsy. We consider whether the mechanism for epileptogenesis may be different between arterial and venous strokes, and whether these 2 groups should be monitored for epileptic spasms, and subsequent epilepsy, differently.

The Role of Mitochondrial and Endoplasmic Reticulum Reactive Oxygen Species Production in Models of Perinatal Brain Injury.

Significance: Perinatal brain injury is caused by hypoxia-ischemia (HI) in term neonates, perinatal arterial stroke, and infection/inflammation leading to devastating long-term neurodevelopmental deficits. Therapeutic hypothermia is the only currently available treatment but is not successful in more than 50% of term neonates suffering from hypoxic-ischemic encephalopathy. Thus, there is an urgent unmet need for alternative or adjunct therapies. Reactive oxygen species (ROS) are important for physiological signaling, however, their overproduction/accumulation from mitochondria and endoplasmic reticulum (ER) during HI aggravate cell death. Recent Advances and Critical Issues: Mechanisms underlying ER stress-associated ROS production have been primarily elucidated using either non-neuronal cells or adult neurodegenerative experimental models. Findings from mature brain cannot be simply transferred to the immature brain. Therefore, age-specific studies investigating ER stress modulators may help investigate ER stress-associated ROS pathways in the immature brain. New therapeutics such as mitochondrial site-specific ROS inhibitors that selectively inhibit superoxide (O2•-)/hydrogen peroxide (H2O2) production are currently being developed. Future Directions: Because ER stress and oxidative stress accentuate each other, a combinatorial therapy utilizing both antioxidants and ER stress inhibitors may prove to be more protective against perinatal brain injury. Moreover, multiple relevant targets need to be identified for targeting ROS before they are formed. The role of organelle-specific ROS in brain repair needs investigation. Antioxid. Redox Signal. 31, 643-663.

Perinatal Arterial Stroke: A Multi-site RCT of Intensive Infant Rehabilitation (I-ACQUIRE)

Perinatal Arterial Stroke: A Multi-site RCT of Intensive Infant Rehabilitation (I-ACQUIRE)

Chapter 4 - Fetal and neonatal neuroimaging

Magnetic resonance imaging (MRI) can provide detail of the soft tissues of the fetal and neonatal brain that cannot be obtained by any other imaging modality. Conventional T1 and T2 weighted sequences provide anatomic detail of the normally developing brain and can demonstrate lesions, including those associated with preterm birth, hypoxic ischemic encephalopathy, perinatal arterial stroke, infections, and congenital malformations. Specialized imaging techniques can be used to assess cerebral vasculature (magnetic resonance angiography and venography), cerebral metabolism (magnetic resonance spectroscopy), cerebral perfusion (arterial spin labeling), and function (functional MRI). A wealth of quantitative tools, most of which were originally developed for the adult brain, can be applied to study the developing brain in utero and postnatally including measures of tissue microstructure obtained from diffusion MRI, morphometric studies to measure whole brain and regional tissue volumes, and automated approaches to study cortical folding. In this chapter, we aim to describe different imaging approaches for the fetal and neonatal brain, and to discuss their use in a range of clinical applications.

Épidémiologie des accidents vasculaires cérébraux en pédiatrie

Incidence of perinatal arterial stroke (ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage) occurring between 20 weeks of gestation and postnatal day 28 ranges between 20 and 65 cases per 100,000 living births. In children aged 29days to 18 years old, the total incidence is 1.3 to 4.3 for 100,000 per year. In France, almost 450children are hospitalized for a stroke each year, among them approximately half have an intracerebral hemorrhage.

Abstract TP406: Ipsilesional Myelination is Impaired in Children With Perinatal Arterial Stroke

Introduction: Stroke is a leading cause of perinatal brain injury and cerebral palsy. Current therapeutic efforts focus on optimizing developmental curves but the biological processes dictating these outcomes are poorly understood. Alterations in myelination are recognized as a major determinant of outcome in preterm brain injury but are unexplored in perinatal stroke (PS). Hypothesis: Ipsilesional delays in myelination occur in children with PS and are associated with poor developmental outcome. Methods: Participants were identified through the Alberta Perinatal Stroke Project, a population-based research cohort. Inclusion criteria were: 1) MRI-confirmed, unilateral arterial PS, 2) T1-weighted MRI &gt;6mo, 3) absence of other neurological disorders, 4) neurological outcome (Pediatric Stroke Outcome Measure, PSOM), and 5) motor assessments (Assisting Hand Assessment, AHA; Melbourne Assessment). FreeSurfer software measured hemispheric asymmetry in myelination intensity. A second method using ImageJ validated the detection of myelination asymmetry. Overall PSOM scores were classified as poor (&gt;1) or not. Repeated measures ANOVA compared perilesional, ipsilesional remote, and contralesional homologous regions. Myelination ratios for stroke cases were compared to typically developing controls (t-test), PSOM scores (t-test), and motor assessments (Pearson’s correlation). Results: Nineteen arterial stroke cases (mean age: 13.73±4.0yo) and 27 controls (mean age: 12.52±3.7yo) were studied. Stroke cases showed a greater degree of asymmetry with lower myelination in the lesioned hemisphere, compared to controls (p&lt;0.001). Myelination in perilesional regions was decreased compared to ipsilesional remote (p&lt;0.001) and contralesional homologous areas (p&lt;0.001). Ipsilesional remote regions were decreased compared to homologous regions on the contralesional hemisphere (p=0.009). Contralesional myelination was also less than controls (p&lt;0.001). Myelination ratios were not associated with PSOM, AHA, or Melbourne scores (p=0.144, 0.218, 0.366 respectively). Conclusion: Myelination of uninjured brain in the lesioned hemisphere is altered in children with PS. Further study is required to determine clinical significance.

Different response to antiepileptic drugs according to the type of epileptic events in a neonatal ischemia-reperfusion model

Perinatal arterial stroke is the most frequent form of cerebral infarction in children. Neonatal seizures are the most frequent symptom during the neonatal period. The current management of perinatal stroke is based on supportive care. It is currently unknown if treatment of the seizures modifies the outcome, and no clinical studies have focused on seizures during neonatal stroke. We studied the effect of phenobarbital and levetiracetam on an ischemic-reperfusion stroke model in P7 rats using prolonged electroencephalographic recordings and a histologic analysis of the brain (24h after injury). The following two types of epileptic events were observed: 1) bursts of high amplitude spikes during ischemia and the first hours of reperfusion and 2) organized seizures consisting in discharges of a 1–2Hz spike-and-wave. Both phenobarbital and levetiracetam decreased the total duration of the bursts of high amplitude spikes. Phenobarbital also delayed the start of seizures without changing the total duration of epileptic discharges. The markedly limited efficacy of the antiepileptic drugs studied in our neonatal stroke rat model is frequently observed in human neonatal seizures. Both drugs did not modify the stroke volume, which suggests that the modification of the quantity of bursts of high amplitude spikes does not influence the infarct size. In the absence of a reduction in seizure burden by the antiepileptic drugs, we increased the seizure burden and stroke volume by combining our neonatal stroke model with a lithium-pilocarpine-induced status epilepticus. Our data suggest that the reduction of burst of spikes did not influence the stroke volume. The presence of organized seizure with a pattern close to what is observed in human newborns seems related to the presence of the infarct. Further research is required to determine the relationship between seizure burden and infarct volume.

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.

Brief update on hemodynamic responses in animal models of neonatal stroke and hypoxia–ischemia

Perinatal arterial stroke is a cerebrovascular event occurring around the time of birth, with pathological or radiological evidence of focal arterial infarction mainly affecting the middle cerebral arterial territory, with an incidence of 1 in 2500 term births (Badve et al., 2012). Perinatal hypoxia–ischemia (HI) is a major cause of acute mortality, with an incidence of 2–4 per 1000 full term births (Vannucci, 2000). Perinatal brain injury induced by stroke and/or HI has been associated with permanent neuropsychological handicaps, including mental retardation, cerebral palsy, epilepsy or learning disability. No therapeutic method is available for perinatal encephalopathy apart from initiating hypothermia within 6 h after birth, but only 1 infant in 6 benefits (Azzopardi et al., 2009 and Gonzalez and Ferriero, 2009). Although these studies provide proof of concept that in this context cell death is both delayed and preventable, the protection is limited and there is still no treatment available for perinatal stroke or brain injury occurring in preterm and term infants. Clinical presentations (cause, severity, magnitude, and deteriorating speed), and inherent potentials (adaptation, preconditioning-tolerance, and intolerance) against an HI or ischemic insult are different from one infant to another. Consequently, it is incumbent on scientists in the field of neonatal brain injury to address the questions of therapeutic efficacy of an array of potential therapies in several developmentally appropriate models. Towards that end, a number of new models of neonatal HI and stroke have been introduced recently, the last being that reported by Tsuji et al. (2013). These models have been designed in the rat and mouse brain and most of them present a great variability in the lesion size and brain areas damaged, whereas this last reported model in the mouse is highly reproducible with a selective cortical infarction.

Hypoxia-Ischemia and Infection Associated with Symptomatic Perinatal Arterial Stroke in Full-Term Infants

Background: The incidence of perinatal arterial stroke (PAS) 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 factors predictive of symptomatic PAS in full-term infants.Methods: Each full-term infant with PAS was matched to three healthy controls for gestational age (< 7 days), date (< 7 days) and hospital of birth. Ante- and perinatal risk factors were studied using univariate and multivariate conditional logistic regression analysis.Results: Fifty-four infants were diagnosed with PAS. Primipara (65% vs 46%), maternal fever (> 38 °C) (9% vs 1%), fetal heart rate decelerations (63% vs 15%), emergency caesarean section (33 vs 2%), Apgar Score (1 min) ≤ 3 (28% vs 1%), Apgar Score (5 min) < 7 (24% vs 1%), umbilical artery pH < 7.0 (21% vs 2%), hypoglycaemia < 2.0 mmol/L (28% vs 3%) and early onset sepsis/meningitis (13% vs 2%) were significant risk factors in the univariate analysis.In the multivariate analysis maternal fever (OR 11.0; 95% CI 1.4 - 85.6), Apgar Score (5 min) < 7 (OR 17.1; 95% CI 3.0 - 96.8), hypoglycaemia < 2.0 mmol/L (OR 13.8; 95% CI 3.4 - 54.2) and early onset sepsis/meningitis (OR 7.0; 95% CI 1.4 - 35.5) were significantly associated with PAS.Conclusion: Fetal distress, maternal fever during delivery and early onset sepsis/meningitis were associated with PAS similar to previous studies. Hypoglycaemia was also associated with PAS, which was previously noted in the preterm infant.

Rhepo for Reduction of Perinatal Arterial Stroke: A Feasibility and Safety Study

Background: Perinatal Arterial Stroke (PAS) occurs in 1 per 2600 newborns. No causative therapy is available. Experimental studies in a neonatal stroke model suggest neuroprotective effect of recombinant erythropoietine (rhEPO). We therefore performed a feasibilty and safety study of rhEPO in neonates with PAS. Patients: 17 neonates with MRI-proven PAS were included, and treated with 3 subsequent doses of rhEPO of 1000 IU/kg: immediately after MRI-diagnosis of PAS and at 24 and 48 hrs after the first dose. MRI/MRA was repeated one week and 3 months after the diagnosis of PAS. During the first weeks hemodynamic, coagulation and hematologic parameters (red cell, white cell and platelet counts), liver and renal function, and Le/Ri regional cerebral saturation (rScO2) with NIRS were monitored. Results: HR, blood pressure and coagulation were always in the normal range, as were liver and renal functions. The table summarizes red, white and platelet counts (median and ranges). Hct's were always in the normal range. Slightly higher rScO2-values were detected at the infarction side.(day1-3: 0.69[0.56-0.95] vs 0.63[0.54-0.85]). Table Conclusion: Treatment with rhEPO (1000 IU/kg daily for 3 d) in neonates with PAS had no effect on red and white cell production or on platelets or coagulation. Cerebral oxygenation was higher on the infarction side. rhEPO therapy seems to be safe, but its effectivity remains to be confirmed.

Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor

Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia–ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.

The Role of Hypoxia-Ischemia in Term Newborns with Arterial Stroke

The role of generalized hypoxia-ischemia in the genesis of perinatal focal arterial stroke remains puzzling. Animal studies have demonstrated that hypoxia-ischemia may alter blood flow through the ductus venosus, thereby increasing the risk for placental emboli entering the cerebral circulation. A retrospective review was performed of clinical records of all term newborns admitted to a tertiary perinatal center between January 1995 and May 2007 with acute arterial stroke on neuroimaging during the first week of life. Newborns were classified into 2 groups on the basis of neuroimaging abnormalities: stroke alone, or stroke and nonfocal hypoxic-ischemic brain injury. A total of 62 newborns had focal or multifocal stroke, 36 with stroke alone and 26 with stroke with nonfocal hypoxia-ischemia. Multiple risk factors for hypoxia-ischemia occurred in most newborns in both groups. These data indicate that hypoxia-ischemia may play a role in the genesis of stroke in the term newborn with or without evidence of nonfocal hypoxic-ischemic brain injury on neuroimaging.

Neonatal arterial ischaemic stroke: obstetric issues

Perinatal arterial ischaemic stroke (PAIS) is increasingly recognised as an important cause of neurological morbidity in children. The aetiology remains unclear although perinatal risk factors have been identified from limited case series. Risk factors for PAIS in term infants are different from those in preterm infants. Maternal primiparity, infertility, cocaine use, prothrombotic disorders, prolonged rupture of membranes, abnormal cardiotocograph, instrumental deliveries and emergency caesarean sections are reported risk factors in term infants. Uncomplicated vaginal delivery and prelabour caesarean section are uncommon in cases of PAIS. The presence of multiple risk factors increases the odds of developing PAIS. For preterm babies, fetal heart abnormalities, twin-twin transfusion and hypoglycaemia are recognised risk factors. Larger cohort studies are required to elucidate further the multifactorial pathway to perinatal arterial stroke.

Perinatal Arterial Stroke in the Preterm Infant

In term infants there has been an increasing awareness of stroke as part of the differential diagnosis of neonatal seizures and other neurological symptoms. The etiological factors responsible for perinatal cerebral infarction, the clinical presentation, and long-term consequences are diverse. Most perinatal arterial ischemic stroke studies looking at maternal, perinatal, and infant characteristics exclude preterm infants from the population studied. More than 10 years ago, it had already been described that perinatal stroke is not only a disorder of term or near-term infants, however, data about preterm infants suffering from stroke are scarce. It is not clear whether this is due to a lower incidence, a lack of awareness, or a different (sub)clinical presentation. In this review the differences between preterm and full-term infants in incidence, clinical presentation, neuro-imaging findings, vascular distribution, and risk factors are described.

Language Organisation in Left Perinatal Stroke

Right-hemispheric organisation of language has been observed following early left-sided brain lesions. The role of the site of damage is still controversial, as other aspects influence the pattern of speech organisation including timing of the lesion and the presence of epilepsy. We studied a group of 10 term-born children homogeneous for timing/type of lesion and clinical picture. All subjects had left perinatal arterial stroke, right hemiplegia, normal cognitive functions and no or easily controlled epileptic seizures. In half the patients, the lesion clearly involved Broca's area, in the other half it was remote from it. Language lateralization was explored by an fMRI covert rhyme generation task. Eight of 10 subjects showed a right lateralisation of language, including all five patients with a damaged left Broca and 3/5 of those without it. Group analysis in patients with right hemispheric organisation showed brain activations homotopic to those found in the left hemisphere of a matched control group. Our findings confirm that, at the end of gestation, the human brain exhibits extraordinary (re-)organisational capabilities. Language organisation in the right hemisphere is favoured by the presence of destructive lesions of the left Broca's area at birth, and occurs in brain regions homotopic to those usually involved in language processing.