United States

The symptoms of Cerebral Autosomal Disorder Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) do not typically manifest until midlife, but it has been diagnosed in a few children. Although she appeared healthy as a young child, BV had a heterozygous NOTCH3 gene mutation, and she experienced previously undetected strokes in the left frontal area. At 4 years 9 months, BV exhibited sudden onset aphasia and left hemiparesis, and she was found to have had acute ischemic strokes involving the right anterior cerebral artery (ACA) and left middle cerebral artery (MCA) territories. Extensive vascular disease involving the internal carotid arteries, right ACA, and left MCA was also observed. Within days, BV experienced new strokes in the right centrum semiovale, left interior frontal white matter, and right parietal lobe. She underwent encephaloduroarteriosynangiosis (EDAS) procedures in the left brain hemisphere at 5 years 0 months and in the right brain hemisphere at 5 years 3 months. BV experienced brain edema following the second procedure, and she was diagnosed with an acute ischemic stroke in the right MCA area affecting the majority of the temporal, parietal, and occipital lobes approximately 1 week following that procedure. BV had neuropsychological evaluations at 5 years 1 month, 5 years 10 months, and 7 years 1 month. At the time of her first evaluation, BV&#39;s visuospatial processing was average, but her verbal abilities were generally low average. She also exhibited severe inattention and impulsivity. After revascularization surgery and additional strokes, BV&#39;s language processing was stable, but her visuospatial processing had declined and was generally low average to mildly impaired. BV&#39;s cognitive functioning had remained generally stable with some areas of modest development at the time of her third neuropsychological evaluation at 7 years of age.

IPSO 2021

Neuropsychological function across time in a child with NOTCH3 mutation and CADASIL

moyamoya & other arteriopathy

**[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>. 



The symptoms of Cerebral Autosomal Disorder Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) do not typically manifest until midlife, but it has been diagnosed in a few children. Although she appeared healthy as a young child, BV had a heterozygous NOTCH3 gene mutation, and she experienced previously undetected strokes in the left frontal area. At 4 years 9 months, BV exhibited sudden onset aphasia and left hemiparesis, and she was found to have had acute ischemic strokes involving the right anterior cerebral artery (ACA) and left middle cerebral artery (MCA) territories. Extensive vascular disease involving the internal carotid arteries, right ACA, and left MCA was also observed. Within days, BV experienced new strokes in the right centrum semiovale, left interior frontal white matter, and right parietal lobe. She underwent encephaloduroarteriosynangiosis (EDAS) procedures in the left brain hemisphere at 5 years 0 months and in the right brain hemisphere at 5 years 3 months. BV experienced brain edema following the second procedure, and she was diagnosed with an acute ischemic stroke in the right MCA area affecting the majority of the temporal, parietal, and occipital lobes approximately 1 week following that procedure. BV had neuropsychological evaluations at 5 years 1 month, 5 years 10 months, and 7 years 1 month. At the time of her first evaluation, BV's visuospatial processing was average, but her verbal abilities were generally low average. She also exhibited severe inattention and impulsivity. After revascularization surgery and additional strokes, BV's language processing was stable, but her visuospatial processing had declined and was generally low average to mildly impaired. BV's cognitive functioning had remained generally stable with some areas of modest development at the time of her third neuropsychological evaluation at 7 years of age.

poster

Reperfusion therapy (thrombolysis) is widely used in adults, but the extrapolation of the method to children is impossible because of the age-related features of the hemostasis system and metabolism in children. Aim. Еvaluate the efficacy and safety of thrombolysis in children with arterial ischemic stroke (AIS). Materials: From March 2018 to November 2019, ten children with stroke underwent thrombolysis. Criteria recommended by Thrombolysis in Pediatric Stroke were taken as criteria for selecting patients for thrombolysis. Ten children from 3.5 to 16 years old (average age -10.3g) were included. Results: Patients with stroke had: thrombophilia-2, autoimmune hemolytic anemia-1, polyangiitis-1, Epstein-Barr virus infection-1, transient nocturnal hemoglobinuria with aplastic anemia-1, arteropahty-2, Kavasaki disease -2. The severity of stroke was from 9 to 24 points by PedNIHSS (average -15.8b). The stroke was confirmed by MRI-angiography. The time of start of thrombolysis was from 4 to 10 hours (average 6.3 hours). Thrombolysis in all cases was carried out by the recombinant human tissue plasminogen activator - alteplase. None of our patients had any complications (hemorrhage). MRI control of the efficacy of thrombolysis was carried out after 6-8 hours. In 5 cases, the effect was pronounced: the change on the PedNIHSS scale: from 9 to 2b, from 22 to 8, from 9 to 4, from 10 to 2, from 15 to 6; in five - ineffective: 1- with the infection, two with progressive arteriopathy, one - with polyangiitis, one- transient nocturnal hemoglobinuria with aplastic anemia. A child with polyangiitis and AIS in the basilar artery was thromboextracted after ineffective thrombolysis. Conclusion: In our center, we considered as potential candidates for thrombolysis of all children with AIS who arrived at the clinic no later than 12 hours from the onset of the disease. In our observation, the effectiveness of thrombolysis depended on the etiology of AIS.

Thrombolysis in children and adolescents with ischemic stroke. Experience of the Primary Pediatric Stroke Center in Moscow

We evaluated 22 children presenting with "posterior circulation" symptoms with provocative digital catheter angiography with neck rotation and observed "dynamic arterial compression" (DAC) involving the V3 segment where C1 rotates on C2 in 10 children. 17 (14M) presented with stroke, 12 had vertebral artery (VA) dissection, with 3 having "presumed dissection" as stroke mechanism. DAC of the VA was found in 10 (9M), all with observed VA dissection. These 10 were treated with surgical fusion at C1/C2. None had recurrent stroke post op. The 7 without DAC were not treated surgically. AIS etiologies: dissection 2, presumed dissection 3, basilar artery occlusion 1, cardioembolic 1. We presume that in 4 of these 7, supraphysiologic rotation from trauma led to VA dissection but they were not surgically treated as there was no DAC under "normal" degrees of rotation. In 3/7, one VA was either occluded or was unable to be catheterized so could not be assessed. 5 other children (4M) presented with posterior circulation symptoms but did not have AIS. Provocative angiography and did not demonstrate DAC. Etiologies: post-concussion syndrome, opiate ingestion, MELAS, vertebral pseudoaneurysm, and psychogenic. Our observations, particularly of bilateral VA dissection at V3 in 3 children, with high incidence of DAC at this same region suggests that DAC may lead to VA dissection. Our observation of children without DAC demonstrates that such compression is not normal physiology. DAC may be an age or stage of growth-related RF for VA dissection. Other factors, such as arterial wall composition (collagen vascular genetic variants) and hypercoagulable states may also contribute. Our protocol for suspected posterior circulation stroke includes c-spine immobilization, evaluation by provocative digital catheter angiography, with strong consideration for surgical intervention in those demonstrating DAC.

Is Cupid at risk of Bowhunter's Syndrome? Vertebral artery compression with neck rotation in children with posterior circulation symptoms

Importance: Randomized clinical trials have shown the efficacy of thrombectomy of large intracranial vessel occlusions in adults; however, any association of therapy with clinical outcomes in children is unknown. OBJECTIVE: To evaluate the use of endovascular recanalization in pediatric patients with arterial ischemic stroke. DESIGN: This retrospective, multicenter cohort study, conducted from January 1, 2000, to December 31, 2018, analyzed the databases from 27 stroke centers in Europe and the United States. Included were all pediatric patients (<18 years) with ischemic stroke who underwent endovascular recanalization. RESULTS: Seventy-three children from 27 participating stroke centers were included. Median age was 11.3 years (interquartile range [IQR], 7.0-15.0); 37 patients (51%) were boys, and 36 patients (49%) were girls. Sixty-three children (86%) received treatment for anterior circulation occlusion and 10 patients (14%) received treatment for posterior circulation occlusion; 16 patients (22%) received concomitant intravenous thrombolysis. Neurologic outcome improved from a median PedNIHSS score of 14.0 (IQR, 9.2-20.0) at admission to 4.0 (IQR, 2.0-7.3) at day 7. Median mRS score was 1.0 (IQR, 0-1.6) at 6 months and 1.0 (IQR, 0-1.0) at 24 months. One patient (1%) developed a postinterventional bleeding complication and 4 patients (5%) developed transient peri-interventional vasospasm. The proportion of symptomatic intracerebral hemorrhage events in the HERMES meta-analysis of trials with adults was 2.79 (95% CI, 0.42-6.66) and in Save ChildS was 1.37 (95% CI, 0.03-7.40). CONCLUSIONS: The results of this study suggest that the safety profile of thrombectomy in childhood stroke does not differ from the safety profile in randomized clinical trials for adults; most of the treated children had favorable neurologic outcomes. This study may support clinicians' practice of off-label thrombectomy in childhood stroke in the absence of high-level evidence.

Feasibility, safety, and outcome of endovascular recanalization in childhood stroke: The Save ChildS Study

Idiopathic intracranial hypertension (IIH) is a pathologic elevation of the intracranial pressure (ICP) that can lead to blindness, cognitive decline, debilitating headaches, and distressing pulsatile tinnitus (PT). IIH most commonly affects overweight women of childbearing age, and has an incidence of 20 in 100,000 in this patient cohort, and is becoming even more prevalent with the increasing obesity epidemic. We are also noticing a rise in childhood IIH as the childhood obesity epidemic similarly increases. MRI/MRV imaging demonstrates focal stenoses of the transverse dural venous sinus (TS) in up to 93% of patients with IIH versus 6.8% of asymptomatic control subjects. TS stenoses are critical to the pathophysiology of IIH. While the inciting event of IIH is unknown, it is apparent that TS stenoses are a critical part of a positive feedback loop, and disrupting TS stenoses with venous sinus stenting (VSS) can break the vicious cycle and cure IIH. The aim of this presentation is to review the pathophysiology underlying IIH and the role VSS can play in treating IIH patients. The indications of VSS, success rates, complications rates and revision surgery rates are reviewed in the context of other available surgical therapies including shunting, optic nerve sheath fenestration, and bariatric surgery.

Venous sinus stenting for idiopathic intracranial hypertension

Introduction: Pediatric AIS has a high recurrence rate of 10-25%. We observed a high rate of early recurrence or extension of stroke on repeat MRI performed within 2 weeks of index stroke and hypothesized that early radiographic extension of stroke or recurrent stroke would predict late clinical recurrence. Methods: IRB approved retrospective chart review of children ages 1 week to 18 years with AIS in our institutional pediatric stroke database who had repeat MRI within two weeks of initial acute presentation. Results: 67 patients had early repeat MRI. 24 (35.9%) had early extension or new stroke on repeat MRI. Of these, 6 (25%) had late clinical recurrence while only 1/47 (2.3%) who did not have early recurrence/extension went on to have late recurrence. 15/23 (66%) of patients with early change on MRI had early recurrence, 8/23 had extension. Neither was more predictive of late recurrence. 4/67 (5.9 %) had hemorrhagic conversion (one was symptomatic -headache). Radiographic extension or new stroke on early repeat MRI was significantly associated with late recurrence (p=0.0036). Using logistic regression, early extension/recurrence was found to be predictive of late recurrence, (OR 13.99, 95%CI 1.57-124). Conclusion: Children with AIS have a high rate of ongoing early, clinically silent, ischemic injury despite antithrombotic therapy, which is associated with late clinical recurrence. This early imaging finding may serve as a biomarker that might prove useful as an endpoint in clinical trials comparing early antithrombotic therapies or to identify patients at higher risk of subsequent recurrent overt stroke who might benefit from intensified therapy. Given the high rate of early and late recurrence and low hemorrhage rates from current antithrombotic therapies, more aggressive therapy with dual antithrombotic agents should be investigated.

Imaging biomarker of recurrent stroke in children: Early radiographic recurrence or extension predicts late recurrence

Introduction: Moyamoya disease (MMD) in children commonly presents as cerebral ischemia (80%) rather than hemorrhage (20%) as well as headaches, seizures, involuntary movements and progressive decline in intellectual ability. We present a pediatric patient with MMD presenting with worsening migraines, anxiety, fatigue and nonspecific subcortical signal abnormalities on brain imaging. Case: A 7-year-old French-Canadian girl presented with a 2-year history of monthly, bifrontal headaches, associated with nausea, vomiting, photo- and phonophobia. An initial brain-MRI at 5 years of age showed non-specific subtle bifrontal subcortical millimetric white matter hyperintensities on T2/FLAIR, a finding often seen in pediatric migraine patients. She was treated with daily Vitamin B2 and NSAIDs as-needed, with a good initial response. At 7 years of age, her headaches occurred 3-4 times/month. She also complained of increasing anxiety, fatigue as well as 2-3 episodes of paroxysmal confusion, right-handed clumsiness, and expressive aphasia lasting minutes, triggered by stress or crying. The patient nevertheless continued to have a normal development and exam. A repeat MRI at 6-years-of-age showed mild progression of the bifrontal subcortical white matter hyperintensities. An MRI at 7-years-of-age showed further progression of the same signal changes, with prominent tortuous signal voids within the deep grey matter, mostly the basal ganglia and non-visibility of the M1 and M2 segments of the MCA bilaterally, confirming the diagnosis of MMD. Discussion: Approximately 90% of pediatric patients with MMD are diagnosed solely after a cerebral ischemic infarct. Early symptoms and neuroimaging can often be subtle or misleading. The worsening of migraine-like headaches, along with anxiety, fatigue, and paroxysmal self-resolving episodes of aphasia should prompt re-investigation. Conventional angiography is the gold-standard imaging modalities for the diagnosis of MMD. Conventional nonquantitative brain-MRI, while limited, may provide useful clues to obtain an early diagnosis in patients, such as in our case. It allows visualization of late sequelae of previous strokes, including silent strokes, appearing as T2/FLAIR hyperintensities, brain atrophy and ventriculomegaly. Abnormal vasculature can appear as multiple tortuous flow voids in deep structures on T1 and T2 sequences. The "ivy sign", due to leptomeningeal engorgement, can be seen on postcontrast-MRI or FLAIR-MRI.

Subclinical pediatric moyamoya disease preceded by non-specific brain-MRI signal changes, anxiety, fatigue and recurrent migraines

Introduction Moyamoya disease (MMD) is a malignant cause of childhood stroke characterized by occlusion of the distal internal carotid arteries and branches by neointimal cells staining positive for smooth muscle cell (SMC) markers. ACTA2 encodes smooth muscle α-actin (α-SMA). A subset of ACTA2 mutations that predispose to thoracic aortic aneurysms and dissections including mutations altering arginine 179 are also associated with bilateral MMD-like occlusions. This study aims to elucidate the molecular pathogenesis of this disease to potentially inform the etiology of large vessel disease in stroke patients in the general population. Hypothesis We hypothesize that Acta2SMC-R179C/+ mice have disrupted differentiation of SMCs in cerebrovascular arteries, and thus the cells are primed to proliferate and migrate excessively, leading to MMD-like disease. Methods 
We generated patient-derived ACTA2 R179C and control induced pluripotent stem cell (iPSC) lines, and the Acta2SMC-R179C/+ mouse model, which expresses the Acta2 R179C mutation in SMCs via the SM-22-Cre-Lox system. Phenotypic differences between mutant and WT brains are characterized using micro CT, non-invasive cuff blood pressure measurements, and echocardiography. SMC phenotype is evaluated by protein expression of contractile genes, BrdU ELISA proliferation assay, Transwell migration assay, and immunofluorescence. Results/Anticipated Results: Patient-derived ACTA2 R179C iPSC-derived SMCs from patients show de-differentiation, continued expression of stem cell markers, and increased proliferation and migration. rt-PCR and sequencing of genomic DNA performed in aortic tissue and explanted SMCs confirms the presence of the mutation in the mutant mice and absence in mice with only the floxed allele (WT). Two-dimensional gel confirms presence of mutant α-SMA. Acta2SMC-R179C/+ mice display straightened and narrowed cerebral arteries at 8 weeks of age and hypotension but no aortic disease between 2 and 12 months of age. Explanted SMCs from Acta2SMC-R179C/+ mice exhibit decreased levels of differentiation markers and increased proliferation and migration. Acta2SMC-R179C/+ SMCs also show less robust and disrupted α-SMA filaments. Conclusion Acta2SMC-R179C/+ mice display MMD-like cerebrovascular disease and Acta2SMC-R179C/+ SMCs exhibit stem cell-like characteristics including de-differentiation, increased proliferation and migration.

Characterization of vascular disease in Acta2 SMC-R179C/+ mice

Introduction: Digital subtraction angiography (DSA) is commonly performed post pial synangiosis to establish the degree of neovascularization. However, angiography is invasive, and the risk of ionizing radiation is a concern in children. Our study aimed to identify whether arterial spin labelling (ASL) can predict post-operative angiogram grading. In addition, we aimed to identify whether patients who underwent ASL imaging without DSA had similar postoperative outcomes when compared to patients who received ASL imaging and post-operative DSA. Methods: The medical records of patients undergoing pial synangiosis at a single institution were reviewed during a 10-year period. Results: Twenty-two patients were identified. Twenty-one hemispheres of 13 patients with "ASL only" and 14 hemispheres of 9 patients with "ASL + DSA" were analyzed. Both groups had similar rates of MRI evidence of acute or chronic stroke preoperatively; 61.9% in the ASL only group and 64.3% in the ASL + DSA group. All symptoms improved in frequency after intervention except categories of hemorrhage and non-chronic headaches. We found a significant correlation between revascularization observed on the DSA and the ASL graded by 3 neuroradiologists. The ASL grades in patients with a postoperative Matsushima grade indicating robust neovascularization were significantly higher than the ASL grades of patients with a poor postoperative Matsushima grade. Conclusions: Non-invasive ASL perfusion imaging had an association with post-operative DSA neoangiogenesis following pial synangiosis surgery. There were no significant stroke-risk differences between ASL and ASL + DSA cohorts. Both cohorts show significant improvement in pre-operative symptoms after surgery. Providers may consider obtaining a postoperative ASL MRI imaging in lieu of a catheter angiogram.

Arterial-spin labeling imaging for assessment of neoangiogenesis after pial synangiosis in pediatric moyamoya patients

Background and Aims: There are few retrospective studies describing clinical-radiological features and outcomes of children with Down Syndrome (DS) and Moyamoya (MM). Our aims are to present three cases of DS/MM from our institution, perform a review of the literature to compile similar case reports, determine if there is a clinical-radiological syndrome specific to DS/MM, and determine if this association is related to different outcomes. Methods: Our clinical database was reviewed between 2017-2019 for patients with DS/MM and cross-referenced with our radiology PACS database. We then reviewed the clinical data, imaging, treatment, and outcomes of previously 38-reported cases in English world literature with DS/MM from 1977 to 2018 using PubMed, Ovid, Medline, and Embase. Results: Case 1: Six year-old girl with focal status epilepticus, left MCA infarction and bilateral MM. Case 2: Three year-old boy with right hemiparesis, left MCA infarction and bilateral MM. Case 3: Thirteen year-old boy with right leg monoparesis, MRI-A: left ACA infarction and left ICA-MCA incipient MM. Case 1 & 2: managed with multiple burr holes (MBH). Case 1: surgery was performed 5 days after initial stroke due to rapid progression. Case 3: treated conservatively. On follow-up, all children had minimal deficit and continued on ASA. We reviewed 38 DS/MM cases found in the literature: 30 children presented with hemiparesis and 12 were treated surgically. Conclusions: Our findings are suggestive that DS/MM presentation and severity is variable with relatively good outcomes post-surgery. To our knowledge, Case 1 is the first reported child with DS/MM treated with urgent surgical MBH revascularization.


Stroke in children with moyamoya and down syndrome; 3 cases and review of the literature

Introduction: Moyamoya is a progressive steno-occlusive arteriopathy affecting the distal internal carotid artery and its branches. Associated to an underlying condition such as neurofibromatosis type 1 (MMS-NF1) or sickle cell disease (MMS-SCD), it is called moyamoya syndrome (MMS) while an isolated arteriopathy is referred to as moyamoya disease (MMD). It remains unknown whether the associated condition impacts its evolution. Objective: We hypothesize that MMD presents and evolves differently compared to MMS. Methods: We performed a single-center chart review of patients with moyamoya followed between 2003 and 2019. Clinical and radiographic features at diagnosis were obtained. Subsequent stroke or neurosurgery clinic visits were reviewed to identify ischemic event occurrence. Evidence of disease progression or new infarction was sought on follow up MRI studies. Group comparisons between children with MMD and MMS and between MMD and MMS subgroups (MMS-NF1 and MMS-SCD) were conducted using Pearson's Chi-squared, Fisher's Exact, Mann-Whitney U, or t test, as appropriate. Survival analysis by cerebral hemisphere using Cox regression were conducted to assess ischemic event occurrence, disease progression and silent infarction at follow-up. A false discovery rate (FDR) p-value adjustment for multiple comparisons with a q-value< 0.05 was applied. Results: One hundred and eleven patients were identified (MMD=49; MMS-NF=23; MMS-SCD=21). MMD presented more with TIA than MMS (22.45% vs MMS 4.84%, q=.02), while MMS-NF1 presented less with a stroke compared to the other groups (MMD 46.94% vs MMS-NF1 8.7% vs MMS-SCD 42.86%; q=0.0032). MMS-NF1 had more frequently unilateral disease (MMD 26.53% vs MMS-NF1 78.26% vs MMS-SCD 33.33%; q=.0003) and less infarcts (MMD 67.35% vs MMS-NF 26.09% vs MMS-SCD 80.95%; q=.0008) at diagnosis, while MMS-SCD were less likely to have an ivy sign (MMD67.35% vs MMS-NF1 52.17% vs MMS-SCD 9.52%, q=.0003). At follow-up, MMD patients were more likely to suffer another ischemic event compared to MMS patients (OR 1.92, p=.019), these events were mainly TIA (OR 2.5, p=.004). However, compared to the other groups, MMS-NF1 were less likely to have another TIA (OR 0.43, p=.045). Conclusion: MMS has varying phenotypes. MMS-NF1 tends to be unilateral with a lower burden of infarction at presentation, while an ivy sign is not a common feature of MM-SCD. Compared to MMS-SCD and MMD, MMS-NF1 is less likely to have further ischemic events.


Neuropsychological function across time in a child with NOTCH3 mutation and CADASIL

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Thrombolysis in children and adolescents with ischemic stroke. Experience of the Primary Pediatric Stroke Center in Moscow

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