United States

Introduction: Immunomediated encephalitis has been studied with great interest in recent years. So far, etiology is not known, but it could be stowed by viral infections. Most cases have normal neuroimaging. Our patient presented an associated ischemic stroke. Since our patient presented the two pathologies, related in time, we wondered what the relationship between them might be. Clinical case: Patient of 2 years, without perinatological history to highlight, that after a febrile picture presents clonic focal crises of upper right limb, continuous, difficult to manage and ipsilateral hemiparesis. MRI shows ischemic stroke in the territory of the middle cerebral artery and left anterior choroid artery. A week it presents hemorrhagic reformation, with good evolution.At 30 days from the onset of symptoms, it presents sensory alteration and adds abnormal movements. Anti-NMDA encephalitis is confirmed: it had qualitative antibodies in Cerebrospinal Fluid and plasma. MRI chronic evolution of known injury. Electroencephalogram with typical pattern of anti-NMDA encephalitis. It required first- and second-line treatment. After 6 months, there is clinical improvement. At the moment the child is 7ys and go to regular school, he has a mild hemiparesis. Discussion: We wondered if there was any relationship between these two pathologies. Is it an ischemic stroke that has evolved into an NMDA anti-NMDA encephalitis or an anti-NMDA encephalitis that has had an associated ischemic brain injury? And although they seemed far away, they have several pathophysiological mechanisms that relate them. In both pathologies, the brain receptor involved in cell damage is GluN1 NMDA. We can&#39;t confirm theories with any complete tests.

IPSO 2021

Ischemic Stroke and immune encephalitis: Which came first?

arterial ischemic stroke

**[Download Full Agenda](https://drive.google.com/file/d/1Dm9lJyTfJrvd7-StaHFmUmhXC-J_UgTj/view?usp=sharing)**

Dear IPSO Virtual Conference Attendees:

Welcome to IPSO’s first-ever conference! We are delighted to bring together experts from <u>multiple disciplines</u> and <u>six continents</u> to provide a diverse perspective on pediatric cerebrovascular disease.  

A few quick words about what to expect.  Two important goals of this conference are to (1) foster a sense of community and (2) identify global priorities for our field. Hence, the program includes short presentations on an array of clinical controversies and dedicates more time to panel discussions with a live chat function so that everyone can participate. We are excited to announce IPSO is able to offer 8.75 CME units for the virtual conference. If you would like to claim CME credits, please email  <membership@internationalpediatricstroke.org>. 

We want to hear from you!  Planning for the [IPSO Founding Members’ Congress](https://internationalpediatricstroke.org/2022-congress/) in Vienna, April 24-26, 2022, will commence as soon as the Virtual Conference ends. Let us know your priorities through the live chat function, via email, or by submitting a symposium idea. Based on your input, the Scientific Program Committee will select the topics that we will address in greater depth when we meet again in the spring.

We hope you find the Virtual Conference both interesting and educational, and hope to see you in person in Vienna, or at another IPSO meeting in the future.  

Warm regards,

Heather Fullerton, IPSO President

Adam Kirton, IPSO Vice-President

Lori Jordan, IPSO Secretary & Treasurer


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*Header Photo Credit: Helen Carlson, Ph.D, Alberta Children's Hospital*

To access IPSO 2021, you must pre-register for the conference.  Instructions on how to access the event will be provided directly to attendees and included on the IPSO 2021 conference website. [Register now](https://internationalpediatricstroke.org/2021-congress/registration/).

Welcome to the first IPSO Virtual Conference. The mission of the virtual conference is to unify the global community of professionals engaged in research and clinical care for children with cerebrovascular diseases, and chart a path forward for multinational, multidisciplinary efforts.  Please go here to access the virtual conference platform- <a href="https://underline.io/events/157/reception">Reception page</a>. 



Introduction: Immunomediated encephalitis has been studied with great interest in recent years. So far, etiology is not known, but it could be stowed by viral infections. Most cases have normal neuroimaging. Our patient presented an associated ischemic stroke. Since our patient presented the two pathologies, related in time, we wondered what the relationship between them might be. Clinical case: Patient of 2 years, without perinatological history to highlight, that after a febrile picture presents clonic focal crises of upper right limb, continuous, difficult to manage and ipsilateral hemiparesis. MRI shows ischemic stroke in the territory of the middle cerebral artery and left anterior choroid artery. A week it presents hemorrhagic reformation, with good evolution.At 30 days from the onset of symptoms, it presents sensory alteration and adds abnormal movements. Anti-NMDA encephalitis is confirmed: it had qualitative antibodies in Cerebrospinal Fluid and plasma. MRI chronic evolution of known injury. Electroencephalogram with typical pattern of anti-NMDA encephalitis. It required first- and second-line treatment. After 6 months, there is clinical improvement. At the moment the child is 7ys and go to regular school, he has a mild hemiparesis. Discussion: We wondered if there was any relationship between these two pathologies. Is it an ischemic stroke that has evolved into an NMDA anti-NMDA encephalitis or an anti-NMDA encephalitis that has had an associated ischemic brain injury? And although they seemed far away, they have several pathophysiological mechanisms that relate them. In both pathologies, the brain receptor involved in cell damage is GluN1 NMDA. We can't confirm theories with any complete tests.

poster

Background: Perinatal stroke occurs secondary to a focal disruption of blood flow in the brain occurring between 20 weeks' gestation and the 28th day of life. Current literature has associated perinatal stroke with adverse attention outcomes. Despite this, when parents of children with perinatal stroke were surveyed, very few recalled conversations with their clinician regarding their child's attentional outcome. There is therefore a need to evaluate the University Hospital Southampton (UHS) neurodevelopmental protocol to follow up attention outcomes in perinatal stroke. Aims: Firstly to evaluate adherence to the UHS neurodevelopmental protocol. Secondly, to evaluate the use of neuroimaging data and clinical data regarding neonatal seizures and post-natal epilepsy to identify children at risk of attention difficulties. Methodology: We conducted a service evaluation to determine whether the attention problem score from the Child Behavior Checklist (CBCL), was available from the parent reported questionnaire administered at the 2-year follow-up appointment. Neuroimaging data were analysed to identify cortical, white matter, basal ganglia, and thalamic involvement and to quantify infarct size. Presence of neonatal seizures and post-natal epilepsy were extracted from clinical notes. Chi-square was used to compare proportions. Results: CBCL data were only available for 35/63 patients. Reasons for missing CBCL data included patients not attending follow up, not returning questionnaires and inadequate data handling meaning data were not stored correctly. 13/35 children had attention scores in the borderline or clinical range. Basal ganglia and thalamic involvement (p=0.015), neonatal seizures (p=0.028) and post-natal epilepsy (p=0.042) were associated with borderline or clinically significant attention scores. Post-natal epilepsy predicted the highest relative risk of adverse attention outcomes. Conclusion: These clinical predictors could be used to identify children at high risk for attention difficulties to encourage parental adherence to the neurodevelopmental protocol, ensuring a complete clinical dataset and providing information to enable appropriate therapy and education.

A service evaluation of the University Hospital Southampton neurodevelopmental protocol to follow up and identify attention outcomes in children with perinatal stroke

Introduction Neurogenesis occurs after perinatal brain injury as a result of gene expression changes. DNA methylation and demethylation is one mechanism by which gene expression is regulated. Recent work has elucidated a role for Gadd45 proteins in mediating gene demethylation. Hypothesis We hypothesize that Gadd45 is responsible for active demethylation after perinatal hypoxia/ischemia and promotes neurogenesis as part of the regenerative response to injury. Methods We induced perinatal HI in 10 day old C57BL/6 pups by ligation of the right common carotid artery followed by exposure to hypoxia (8% O2/92% N2) for 45 minutes. The pups were sacrificed at 4 or 24 hours for molecular biology or immunohistochemistry. We used quantitative RT-PCR to study gene expression of Gadd45 family and TET family proteins. We evaluated targeted gene methylation status with methylation specific PCR and in situ DNA modifications using immonhistochemistry. Neurogenesis was quantified by 5-ethinyl-2'-deoxyuridine (EdU) incorporation in wild type and Gadd45b knockout mice. Results Gadd45 family mRNA is rapidly upregulated by 14-fold in the subventricular zone (SVZ) by 4 hours following perinatal HI, and remains upregulated at 24 hours. Small transient increases in expression were seen for Gadd45a and Gadd45g at 4 hours. There is no significant change in the expression of TET mRNA. Preliminary suggest specific demethylation of the BDNF promoter by 24 hours. Immunohistochemistry revealed increased expression of 5-hydroxymethylcytosine specifically within the SVZ progenitor cells, and neurogenesis was reduced in Gadd45-/- mice. Conclusion Perinatal HI induces upregulation of Gadd45b, which may contribute to demethylation of growth promoting genes in the neurogenic niche, driving the neurogenic response to perinatal hypoxic-ischemic brain injury.

Gadd45b modulates neurogenesis following perinatal hypoxic-ischemic brain injury

Background and Aims: Subpial hemorrhages (sPH) were first described in infants in 1972, but they remain underrecognized on neuroimaging and the clinical implications of sPH are poorly understood. The aim of this study is to describe the etiologies, risk factors, clinical presentations, and imaging findings of sPH in neonates. Methods: Institutional Neonatal Intensive Care Unit database was queried for presence of sPH. All infants recorded to have intracranial hemorrhage on brain MRI were reviewed by a pediatric neuroradiologist. Through retrospective chart review, data on pregnancy/birth history, comorbidities, and clinical concerns that led to imaging were collected. Results: Twenty-six infants with sPH were identified: 13 (50%) were preterm, 11 (42%) had low birthweight. Comorbidities included hypoxic-ischemic encephalopathy (n=1, 42%), birth trauma (n=6, 23%), cardiopulmonary disease (n=6, 23%), coagulopathy (n=6, 23%), ventricular shunt (n=3, 12%), severe congenital brain anomalies (n=1, 4%), and chromosomal anomaly (n=1, 4%). MRI acquisition was at a median of 5 days of life (range 1 to 41 days). sPH frequently accompanied intraparenchymal (n=17, 65%), subdural (n=16, 62%), intraventricular (n=13, 50%), and subarachnoid hemorrhage (n=8, 31%). In addition, 7 children (27%) had ischemic stroke. All children with sPH had either another form of hemorrhage, ischemic stroke, or both. In addition, 9 patients (34%) had follow-up MRIs. Development of adjacent encephalomalacia was consistently demonstrated in children with large subpial hemorrhages. Sixteen infants with sPH (62%) had clinical and/or electrographic seizures. Conclusions: sPH are associated with multiple comorbid medical conditions, other types of intracranial hemorrhage, and ischemic strokes. Further studies to evaluate long-term clinical implications of subpial hemorrhages are needed.

A new kind of bleed: Subpial hemorrhages in the neonatal intensive care unit

Introduction: In children, perinatal stroke is the most common type. Long-term morbidities can be high, and include motor, cognitive and behavioral domains. While some studies point to poorer global, motor and adaptive outcomes in presumed perinatal compared to acute perinatal stroke, few have studied specific cognitive functions in a developmentally homogenous sample. We aimed to assess cognitive outcomes in a homogenous sample regarding age, time since injury, and development. We predicted that delay in diagnosis and hence intervention may have an impact on long-term cognitive outcome. Hypothesis: Preschoolers with presumed perinatal stroke demonstrate poorer cognitive function than those with acute neonatal stroke. Methods: Children age 4;0-5;11 years (n=63, Acute Perinatal=39, Presumed Perinatal=24) underwent comprehensive neuropsychological assessment as part of standard care. Cognitive function was assessed with age-appropriate standardized tests of general cognitive ability, language, visual-spatial, memory, and motor functions. Parents completed ratings of executive and behavioral function. Data from initial evaluations at a single time point were analyzed retrospectively. Cognitive and behavioral function of the overall sample were compared to population means, as well as between acute and presumed perinatal subgroups. Results: Compared to population means, the perinatal group demonstrated poorer processing speed, auditory memory, visual-spatial and visual-motor skills (pFDR<.01-.05), and increased problems with executive functions (pFDR<.01; flexibility, emerging metacognition) and adaptive skills reported by parents/teachers. Further, the presumed perinatal stroke group showed reduced verbal ability (knowledge, reasoning, naming), and processing speed than the acute perinatal group (ps<.01-.05). Stroke location and maternal education were significant contributors. Conclusions: Perinatal stroke causes diminished cognitive and behavioral function in preschoolers and kindergartners. We found cognitive differences (verbal, processing speed) in children with presumed versus acute perinatal stroke. Findings will be further explored for predictors of outcome in an ongoing study; they underscore the importance of early diagnosis and intervention to improve long-term cognitive and psychosocial function.

Cognitive outcomes in preschoolers with presumed vs. acute perinatal stroke

Objective Perinatal intracranial hemorrhage (pICH) is a rare event that occurs during the fetal/neonatal period with potentially devastating neurological outcome. However, the etiology of pICH is frequently hard to depict. We investigated the role of rare genetic variations in unexplained cases of pICH. Methods We performed whole-exome sequencing (WES) in fetuses and term neonates with otherwise unexplained pICH and their parents. Variant causality was determined according to the American College of Medical Genetics and Genomics (ACMG) criteria, consistency between suggested genes and phenotypes, and mode of inheritance. Results Twenty-six probands (25 families) were included in the study (9 with a prenatal diagnosis and 17 with a postnatal diagnosis). Intraventricular hemorrhage (IVH) was the most common type of hemorrhage (n = 16, 62%), followed by subpial (n = 4, 15%), subdural (n = 4, 15%), and parenchymal (n = 2, 8%) hemorrhage. Causative/likely causative variants were found in 4 subjects from 3 of the 25 families (12%) involving genes related to the brain microenvironment (COL4A1, COL4A2, and TREX-1). Additionally, potentially causative variants were detected in genes related to coagulation (GP1BA, F11, Von Willebrand factor [VWF], FGA, and F7; n = 4, 16%). A potential candidate gene for phenotypic expansion related to microtubular function (DNAH5) was identified in 1 case (4%). Fifty-five percent of the variants were inherited from an asymptomatic parent. Overall, these findings showed a monogenic cause for pICH in 12% to 32% of the families. Interpretation Our findings reveal a clinically significant diagnostic yield of WES in apparently idiopathic pICH and support the use of WES in the evaluation of these cases

Whole-exome sequencing analysis in antenatal and perinatal intracerebral hemorrhage

Introduction: Adenosine deaminase 2 (ADA2) deficiency is a rare genetic cause of pediatric cerebrovascular disease typically associated with polyarteritis nodosa-like multi-systemic vasculitis. Patients usually present with strokes around age 2, after presenting with a livedo reticularis rash, systemic signs of inflammation and immunodeficiency. We present a now 2-year-old female, who initially presented at 5 months of age, then showed recurrent cerebral infarcts at 8 months of age, after which she was found to have a compound heterozygous pathogenic mutation involving the ADA2 gene. We highlight the importance of identifying ADA2 mutations in recurrent idiopathic strokes even in infancy and despite lack of accompanying systemic features, given available preventative immunotherapies. Case: A previously healthy 5-month-old female initially presented with altered mental status without focal deficits and was found to have bi-thalamic infarcts with a non-yielding work up (vessel imaging, hypercoagulable studies, echocardiogram). She re-presented at 8 months of age with sudden left sided weakness with acute infarcts of the right corona radiata and internal capsule; early chronic infarcts of the right basal ganglia and the deep right periatrial white matter, likely representing a third ischemic event. Cerebral angiography was without signs of vasculitis. Whole exome sequencing sent given recurrent idiopathic strokes, identified a compound heterozygous pathogenic mutation in the ADA2 gene. She is maintained on etanercept with no recurrent infarcts but with residual mild left hemiparesis. Discussion: ADA2 deficiency represents a rare cause for pediatric stroke, but one that is easily identifiable with genetic testing and preventable with immunosuppression. With less than 75 reported cases, our patient is one of the youngest, and to our knowledge only to have ischemic strokes in the absence of systemic symptoms thus far. Consider early genetic testing for ADA2 mutations in infantile stoke, despite lack of systemic manifestations.

The Brain-Immune Connection: ADA2 deficiency is a preventable cause of pediatric stroke

Case description 16 years old female with JD was admitted for stroke with symptoms of sudden onset right-sided hemiparesis, diplopia, dysarthria & difficulty word finding. On examination,was alert, oriented & neurologically intact except dysarthric speech, ataxic gait, bilateral dysmetria & dysdiadokinesia. MRI brain showed patchy asymmetric areas of T2/FLAIR hyperintensities without diffusion restriction involving pons, bilateral middle cerebellar peduncles & hemispheres. Initially started on immunosuppressive therapy (Steroids, Methotrexate & Cellcept) with concerns for cerebral vasculitis but due to worsening symptoms, imaging findings further investigation revealed positive JC Virus in her CSF fluid. Thus diagnosed with PML. Subsequently was treated with plasmapheresis. After 6 months of treatment & rehab she continues to show improvement. She is now able to sit without support & her speech is more clear. Recent JC virus results show 333 copies/ml (down from 2,900 at time of diagnosis). Recent MRI shows some improvement as well. Discussion: Active replication of JC virus in the brain leads to the development of PML, characterized by focal areas of demyelination and necrosis of glial cells(3). Diagnosis of PML is based clinically, neuroimaging & detection of JC virus in CSF. Most commonly reported neurological features are mono- and hemiparesis (50%), apathy (46%), confusion (38%), visual disturbance (29%), and seizures (21%)(2). In the pediatric population less than 50 cases of PML have been reported related to AIDS & less than 10 cases with inherited immunodeficiency. To our knowledge this is the first PML case reported in a pediatric patient with Juvenile Dermatomyositis (JD) and subsequent immunosuppression(1). References: 1.ReAngelini L, et al. Progressive multifocal leukoencephalopathy in a child with hyperimmunoglobulin E recurrent infection syndrome and review of the literature. Neuropediatrics. 2001;32(5):250-255. doi:10.1055/s-2001-19119 2.Shitrit D, et al. Progressive multifocal leukoencephalopathy in transplant recipients. Transpl Int. 2005;17(11):658-665. doi:10.1007/s00147-004-0779-3 3.Burke MT, et al. Progressive multifocal leukoencephalopathy with gastrointestinal disease in a pediatric kidney transplant recipient. Pediatr Transplant. 2013;17(5):E119-E124. doi:10.1111/petr.12107 Images: Asymmetric T2/FLAIR hyperintense signal within the right cerebellar peduncle the extensive cerebral hemisphere without evidence of diffusion restriction

Progressive multifocal leukoencephalopathy in a child with juvenile dermatomyositis presented as stroke

Introduction: Pediatric stroke is one of the leading causes of morbidity and mortality worldwide. Given the paucity of literature on etiology and presentation of childhood stroke in India, the clinico-etiological profile study would give better insights into understanding, treating and preventing childhood stroke among the Indian population. Methods: This is a Retro-prospective cohort study conducted at Narayana health city, Bangalore over a 6months period. 76 children in the age group of 0-18yrs diagnosed as arterial ischemic stroke clinically and radiologically, were included. Data was collected from hospital database and at OPD visits, analyzed and compared with available Indian and international data. Results: Our study found that most common causes for pediatric stroke were: cardio-embolic (28%), cryptogenic (27%), arteriopathy (17%) and infections (15%). There was a definite male preponderance (66%) and most of them presented at 0-5yrs age (52%). Clinically, common presenting features were hemiparesis (63%), seizures (53%), facial paresis (26%), encephalopathy (22%), fever (17%), headache (9%). 57% of patients had single cerebral hemispheric involvement. Multiple vascular territories were involved in 30%. Nine children had recurrence (11%) of which, four had Moya Moya Disease, two had cardioembolic stroke, one had vertebral artery dissection, one had propionic aciduria and one Prothrombin gene mutation. Most of them were managed conservatively (95%). Four children (7%) underwent interventions: STA-MCA bypass with EDAMS, vertebral artery coiling and 2 mechanical thrombectomy. Conclusions: Our study found the cardio-embolic phenomena as the commonest cause of AIS in India. Rarer causes of stroke were also identified. 27% remained cryptogenic despite exhaustive evaluation. A definite male preponderance was noted. Further multi-centric studies with larger sample size would confirm these findings and shed light on common causes, modes of diagnosis, preventive and curative treatment specific to Indian pediatric population.

A cohort study of clinical and etiological profile of arterial ischemic stroke among Indian pediatric population: A single center experience

The problem of a pediatric stroke has become relevant in recent decades. More than 50% of children with ischemic stroke are diagnosed with arteriopathy. Aim: assessment of the clinical features and course of arteriopathy in children diagnosed with arterial ischemic stroke (AIS). Materials: 72 patients with AIS, who were treated in Moscow primary pediatric stroke center from 2013 to 2018. Boys vs girls - 42 vs 30 (58,4%vs41,6%), the average age 7.6 years. The observation period was from 16 months to 5 years. Results: in 43 children out of 72 were diagnosed the arteriopathy. 30/43 showed signs of unilateral focal stenosis of the distal internal carotid artery (ICA) and / or the middle cerebral artery (CMA) and / or the anterior cerebral artery (PMA) with / without occlusion, The severity of stroke by PedNIHSS in average 7,3. CT was made: CT angiography 28 patients (from 7 days to 4 months from the onset of stroke (1 patient twice), 8 - direct catheter angiography. Arteriopathies in patients with focal cerebral artheropathy were divided: vasculitis- 3, progressive arteriopathy -4, dissection-3, transient cerebral arteriopathy (TCA)- 20. Dynamic MRI study (from 3 to 6 months) showed: a complete restoration of blood flow-5; increase of stenosis -4; decrease of stenosis - 11; without dynamics relatively acute period -3. MR-angiography after 9-12 months: full restoration of blood flow-9; reduction of stenosis (incomplete recovery) -7. Relapse of AIS was observed in 6 patients (11.6%)with artheriopathy during the follow-up period. Conclusion: Modern methods of neuroimaging have significantly improved the diagnosis of childhood stroke, clarifying the nature and extent of cerebral vascular lesions, including artheriopathy, which is very important in determining the management of children and adolescents.

Transient cerebral arteriopathy in children and adolescents, features of clinical manifestations and course

Objectives: The prevalence of cancer among children with ischemic stroke is unknown. This study sought to evaluate cancer-associated childhood ischemic stroke in a multinational pediatric stroke registry. Methods: Children between 29 days and 19 years of age with arterial ischemic stroke (AIS) and/or cerebral sinovenous thrombosis (CSVT) enrolled in the International Pediatric Stroke Study between January 2003 and June 2019 were included. Data including types of cancer, stroke etiology, and stroke treatment were compared between subjects with and without cancer using Wilcoxon rank sum and chi-square tests. Results: Remote or active cancer was present in 99 of 2968 children (3.3%) with AIS and 64 of 596 children (10.7%) with CSVT. Children with cancer were older than children without cancer in both the AIS (9.5 versus 5.7 years, p=0.0001) and CSVT groups (8.2 versus 6.3 years, p=0.014). Among children in whom cancer type was identified, 42 of 88 (48%) AIS cases had brain tumors and 35 (40%) had hematologic malignancies; 45 of 58 (78%) CSVT cases had hematologic malignancies and 8 (14%) had brain tumors. Primary causes most commonly reported in children with cancer-associated AIS included: arteriopathy (n=34, 62%), cardioembolic (n=9, 16%), prothrombotic state (n=4, 7%), and infection (n=4, 7%). The most frequently reported primary cause of CSVT in children with cancer was prothrombotic state (n=38, 83%). Children with cancer were less likely to receive any antithrombotic therapy for AIS (58 % v. 80%, p=0.007) and anticoagulation for CSVT (71% v. 87%, p=0.046), compared with children without cancer. Recurrent AIS (5% v. 2%, p=0.04) and CSVT (5% v. 1%, p=0.006) were more common among children with cancer. CONCLUSION: Cancer is an important risk factor for incident and recurrent childhood stroke. Although multiple risk factors for stroke were noted in children with cancer, presence of cerebral arteriopathy in children with AIS and prothrombotic state in children with CSVT appear to be the most significant underlying mechanisms contributing to increased risk for stroke in this population. Future research investigating the role of stroke prophylaxis in the high-risk subpopulations identified in this study are warranted.

Next from IPSO 2021

A service evaluation of the University Hospital Southampton neurodevelopmental protocol to follow up and identify attention outcomes in children with perinatal stroke

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Cancer-associated stroke in children: Results from the International Pediatric Stroke Study (IPSS)