United States

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.

IPSO 2021

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

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


![](https://assets.underline.io/uploads/markdown_image/1/image/1c71a0aebc49947c923a7920d9f28857.jpg)



  
    
  


  



*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>. 



poster

Novel Oral Anticoagulants (NOACs) for pediatric stroke prevention - Marcela Torres

Controversies in sickle cell disease - Fenella Kirkham

Controversies in sickle cell disease - Pat McGann

Lessons & challenges from the pandemic - Lauren Beslow

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.

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

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