Evidence of varicella zoster virus (VZV) reactivation in children with arterial ischemic stroke: Results of the VIPS II Study.

Background: Varicella zoster virus (VZV) has been associated with focal cerebral arteriopathy (FCA) and arterial ischemic stroke (AIS) in childhood. The Vascular effects of Infection in Pediatric Stroke (VIPS) II study aimed to examine this relationship in the modern era when most children in North America and Australia receive VZV vaccination with live, attenuated virus. Methods: This 22-center prospective cohort study enrolled 205 children (28 days-18 years) with AIS (2017-2022), collected baseline [hyperacute (≤72 hours; n=194) and acute (4-6 days; n=181)] and convalescent (1-6 weeks; n=74) serum samples. Sites enrolled 95 stroke-free controls with single serum samples. A virology research laboratory measured VZV IgM and IgG titers by an in-house enzyme-linked immunosorbent assay (ELISA). Baseline IgG seropositivity indicated prior exposure (vaccination/infection) and elevated IgM titers indicated recent reactivation. Results: Median (IQR) age was 11.6 (5.5-15.6) years for cases and 11.8 (6.8-15.3) years for controls. Baseline serologies indicated prior VZV exposure in 198 cases (97%) and all controls. Parents of cases reported VZV vaccination in 160 (78%) and remote chicken pox in three (1.4%). Twenty cases (9.8%) and three controls (3.1%) had serologic evidence of recent VZV reactivation (p=0.06); all had remote VZV exposure (vaccination in 19 cases and all controls) and all were asymptomatic. Recent VZV reactivation was seen in similar proportions in arteriopathic, cardioembolic, and idiopathic stroke. Of 32 cases of FCA, 4 (12.5%) had recent VZV reactivation, versus no cases of arterial dissection (n=10) or moyamoya (n=16). Conclusions: Serologic evidence of recent VZV reactivation (≈1-6 weeks prior to stroke) was present in one in 10 cases of childhood AIS, including those without arteriopathy. Clinically silent VZV reactivation may be a childhood stroke trigger despite widespread vaccination. These cases could represent waning immunity with reactivation of either vaccine virus or wild-type virus after an unrecognized secondary VZV infection.

Cow's Milk Anemia in Childhood Manifesting as Severe Cerebral Venous Sinus Thrombosis.

We describe a series of 7 toddler-aged children with iron deficiency anemia from excessive cow's milk consumption who presented with cerebral venous sinus thrombosis and no other identifiable risk factors for thrombosis. The deep venous system was involved in 6 patients, 6 had venous infarcts, and 5 have significant neurocognitive sequelae.

Thrombophilia screening in the routine clinical care of children with arterial ischemic stroke.

BACKGROUND: Current guidelines recommend thrombophilia evaluation in childhood arterial ischemic stroke, but the impact of screening on management is unknown. The objective of the current study is to report the incidence of thrombophilia identified as part of routine clinical care in the context of available literature reports, and to describe the impact of a diagnosis of thrombophilia on patient management. METHODS: We conducted a single-institution retrospective chart review for all children with arterial ischemic stroke occurring between January 1, 2009 and January 1, 2021. We collected thrombophilia screening results, stroke etiology, and management. We also reviewed the literature of thrombophilia testing in childhood arterial ischemic stroke published prior to June 30, 2022. Meta-analysis methods were used to assess prevalence rates. RESULTS: Among children with thrombophilia testing performed, 5% (six of 122 patients) were factor V Leiden heterozygous, 1% (one of 102 patients) were prothrombin gene mutation heterozygous, 1% (one of 122) had protein S deficiency, 20% (23/116 patients) had elevated lipoprotein(a), 3% (three of 110 patients) had elevated homocysteine levels, and 9% (10/112) had elevated antiphospholipid antibodies, only two of whom had persistently elevated levels. There was no change in stroke therapy due to these results. Literature review revealed a wide range of prevalence for most thrombophilia traits, with high cross-study heterogeneity in most cases. CONCLUSIONS: The rates of thrombophilia in our cohort were consistent with that expected in the general population. The identification of thrombophilia did not alter stroke care. However, some of the results were actionable, prompting evaluation for lipid disorders and patient-specific counseling on cardiovascular risk and risk for venous thrombosis.

Pediatric Stroke-Are We Asking the Right Questions? The 2022 Sidney Carter Award Lecture.

Over the past few decades, robust clinical and research collaborations among pediatric stroke researchers have informed and improved the care of children with stroke. Risk factors and presentation of childhood stroke have been described, and the acute and chronic burden of childhood stroke has been better delineated. Nevertheless, high-quality data for the treatment of children with stroke is dwarfed by that available for adult stroke, and it is therefore tempting to extend research questions and treatment trials from adults to children. A trial designed to answer a question about stroke in adults may yield useful information about stroke in childhood, but a trial that incorporates the unique neurodevelopmental and etiologic aspects of childhood stroke is more likely to truly advance care. Research questions and study design in childhood stroke must capture the complexity of stroke mechanisms and medical comorbidities in children who suffer stroke, the impact on the developing nervous system, and the role of normal and aberrant neurodevelopment in recovery.

Acute Hospital Management of Pediatric Stroke.

The field of pediatric stroke has historically been hampered by limited evidence and small patient cohorts. However the landscape of childhood stroke is rapidly changing due in part to increasing awareness of the importance of pediatric stroke and the emergence of dedicated pediatric stroke centers, care pathways, and alert systems. Acute pediatric stroke management hinges on timely diagnosis confirmed by neuroimaging, appropriate consideration of recanalization therapies, implementation of neuroprotective measures, and attention to secondary prevention. Because pediatric stroke is highly heterogenous in etiology, management strategies must be individualized. Determining a child's underlying stroke etiology is essential to appropriately tailoring hyperacute stroke management and determining best approach to secondary prevention. Herein, we review the methods of recognition, diagnosis, management, current knowledge gaps and promising research for pediatric stroke.

Why Would a Child Have a Stroke?

Identifying the etiology of childhood arterial ischemic stroke helps prevent stroke recurrence. In addition, stroke may herald a serious underlying condition requiring treatment, such as acquired heart disease, malignancy, or autoimmune disorder. Evidence-based guidelines exist for adults to identify and treat common risk factors for primary and secondary stroke, including hypertension, diabetes, elevated lipids, atrial fibrillation, and sleep apnea, which are rarely relevant in children. However, guidelines do not exist in pediatrics. Identifying the cause of childhood stroke may be straightforward or may require extensive clinical and neuroimaging expertise, serial evaluations, and reassessment based on the evolving clinical picture. Risk factors may be present but not necessarily causative, or not causative until a triggering event such as infection or anemia occurs. Herein, we describe strategies to determine stroke etiology, including challenges and potential pitfalls.

Hemorrhagic Transformation Following Childhood Cardioembolic Stroke Is Not Increased in Anticoagulated Patients.

OBJECTIVE: To characterize the risk of hemorrhagic transformation following cardioembolic stroke in childhood, and whether anticoagulation impacts that risk. METHODS: Ninety-five children (1 month-18 years) with cardioembolic arterial ischemic stroke between January 1, 2009, and December 31, 2019, at 2 institutions were identified for retrospective chart review. Neuroimaging was reviewed to assess for hemorrhagic transformation. RESULTS: There were 11 cases of hemorrhagic transformation; 8 occurred within 2 days of stroke diagnosis. Risk of hemorrhagic transformation did not differ in patients with and without anticoagulation use (15% vs 9%, estimated risk difference 5%; CI -9%, 19%). Stroke size did not predict hemorrhagic transformation (OR 1.004, 95% CI 0.997, 1.010). Risk of hemorrhagic transformation was higher in strokes that occurred in the inpatient compared with the outpatient setting (16% vs 6%). CONCLUSION: Hemorrhagic transformation occurred in 11% of pediatric cardioembolic ischemic stroke, usually within 2 days of stroke diagnosis, and was not associated with anticoagulation or stroke size.

Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA.

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K-RAS-MAPK pathway (Padia et al., Laryngoscope Investig Otolaryngol 4: 170-173 [2019]). Activating pathogenic variants in the gene PIK3CA, which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., Pediatr Dev Pathol 16: 51 [2013]; Luks et al., J Pediatr 166: 1048-1054.e1-5 [2015]; Al-Olabi et al., J Clin Invest 128: 1496-1508 [2018]). These vascular malformations are part of the PIK3CA-related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic PIK3CA pathogenic variants (Keppler-Noreuil et al., Am J Med Genet A 167A: 287-295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet-Dechaume-Blanc syndrome, and Wyburn-Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., Interv Neuroradiol 7: 5-17 [2001]; Krings et al., Neuroimaging Clin N Am 17: 245-258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., Am J Neuroradiol 39: 2103-2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene PIK3CA We propose that CVMS be recognized as part of the PIK3CA-related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.

Focal Cerebral Arteriopathy of Childhood: Clinical and Imaging Correlates.

Background and Purpose: Focal cerebral arteriopathy (FCA) of childhood with unilateral stenosis of the anterior circulation is reported to account for up to one-quarter of childhood arterial ischemic stroke, with stroke recurrence in 25% of cases. Limited knowledge regarding pathophysiology and outcome results in inconsistent treatment of FCA. Methods: Children with arterial ischemic stroke due to FCA between January 1, 2009, and January 1, 2019, were retrospectively identified at our institution which serves the US Pacific Northwest region. Electronic health record data, including neuroimaging studies, were reviewed, and the Pediatric Stroke Outcome Measure at 1 year was determined as the primary clinical end point. Results: Fifteen children were diagnosed with FCA, accounting for 19% of children with cerebral arteriopathies (n=77). Among children with FCA, the median age at the time of stroke was 6.8 years (Q1­Q3, 1.9­14.0 years). Four (20%) patients had worsening stroke, 3 of whom had concurrent infection. Three (20%) FCA cases were treated with steroids, one of whom had worsening stroke. Median Pediatric Stroke Outcome Measure at 1 year was 1.0 (Q1­Q3, 0.6­2.0). Variability in arteriopathy severity was observed within many patients. Patients with more severe arteriopathy using the Focal Cerebral Arteriopathy Severity Score had larger strokes and were more likely to have worsening stroke. The most common long-term neurological deficit was hemiparesis, which was present in 11 (73%) patients and associated with middle cerebral artery arteriopathy and infarcts. Conclusions: FCA may be less common than previously reported. Neuroimaging in FCA can help identify patients at greater risk for worsening stroke.

Pediatric Thrombectomy: Design and Workflow Lessons From Two Experienced Centers.

Endovascular thrombectomy has played a major role in advancing adult stroke care and may serve a similar role in pediatric stroke care. However, there is a need to develop better evidence and infrastructure for pediatric stroke care. In this work, we review 2 experienced pediatric endovascular thrombectomy programs and examine key design features in both care environments, including a formalized protocol and workflow, integration with an adult endovascular thrombectomy workflow, simplification and automation of workflow steps, pediatric adaptations of stroke imaging, advocacy of pediatric stroke care, and collaboration between providers, among others. These essential features transcend any single hospital environment and may provide an important foundation for other pediatric centers that aim to enhance the care of children with stroke.

Higher-Quality Data Collection Is Critical to Establish the Safety and Efficacy of Pediatric Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Because children often have lifelong morbidity after stroke, there is considerable enthusiasm to pursue mechanical thrombectomy in childhood stroke based on literature reports. However, current published data may reflect inconsistent reporting and publication bias, which limit the ability to assess safety and efficacy of mechanical thrombectomy in childhood stroke. METHODS: This retrospective cohort study compared reporting quality and clinical outcomes for mechanical thrombectomy between a trial-derived cohort of 42 children treated with mechanical thrombectomy for acute stroke at study sites and 133 patients reported in the literature. National Institutes of Health Stroke Scale at baseline, 24 hours after mechanical thrombectomy, and at discharge were compared between study site patients and literature patients. Odds ratios (ORs) were used to compare reporting frequencies. Proportional odds logistic regression was used to compare outcomes. RESULTS: Premechanical thrombectomy National Institutes of Health Stroke Scale was available in 93% of study patients compared with 74% of patients in the literature (OR, 4.42 [95% CI, 1.47-19.89]). Postmechanical thrombectomy National Institutes of Health Stroke Scale was available in 69% of study patients compared with 29% of literature cases at 24 hours (OR, 5.48 [95% CI, 2.62-12.06]), and 64% of study patients compared with 32% of cases at discharge (OR, 3.85 [95% CI, 1.87-8.19]). For study sites, median scores were 12 at baseline, 9 at 24 hours, and 5 at discharge. Median scores in case reports were 15 at baseline, 4 at 24 hours, and 3 at discharge. ORs for differences in outcomes between groups were 5.97 (95% CI, 2.28-15.59) at 24 hours and 3.68 (95% CI, 1.45-9.34) at discharge. CONCLUSIONS: Study site patients had higher rates of National Institutes of Health Stroke Scale reporting and worse short-term outcomes compared with literature reports. Rigorous data collection is needed before treatment guidelines for pediatric mechanical thrombectomy can be developed.

Deep medullary vein engorgement and superficial medullary vein engorgement: two patterns of perinatal venous stroke.

Perinatal venous stroke has classically been attributed to cerebral sinovenous thrombosis with resultant congestion or thrombosis of the small veins draining the cerebrum. Advances in brain MRI, in particular susceptibility-weighted imaging, have enabled the visualization of the engorged small intracerebral veins, and the spectrum of perinatal venous stroke has expanded to include isolated congestion or thrombosis of the deep medullary veins and the superficial intracerebral veins. Congestion or thrombosis of the deep medullary veins or the superficial intracerebral veins can result in vasogenic edema, cytotoxic edema or hemorrhage in the territory of disrupted venous flow. Deep medullary vein engorgement and superficial medullary vein engorgement have characteristic findings on MRI and should be differentiated from neonatal hemorrhagic stroke.

Forehead location and large segmental pattern of facial port-wine stains predict risk of Sturge-Weber syndrome.

BACKGROUND: Children with forehead port-wine stains (PWSs) are at risk of Sturge-Weber syndrome (SWS). However, most will not develop neurologic manifestations. OBJECTIVE: To identify children at greatest risk of SWS. METHOD: In this retrospective cohort study of children with a forehead PWS, PWSs were classified as "large segmental" (half or more of a contiguous area of the hemiforehead or median pattern) or "trace/small segmental" (less than half of the hemiforehead). The outcome measure was a diagnosis of SWS. RESULTS: Ninety-six children had a forehead PWS. Fifty-one had a large segmental PWS, and 45 had a trace/small segmental PWS. All 21 children with SWS had large segmental forehead PWSs. Large segmental forehead PWSs had a higher specificity (0.71 vs 0.27, P < .0001) and a higher positive predictive value (0.41 vs 0.22, P < .0001) for SWS than any forehead involvement by a PWS. LIMITATIONS: Retrospective study at a referral center. CONCLUSION: Children with large segmental forehead PWSs are at highest risk of SWS.

Spectrum of cerebral arteriopathies in children with arterial ischemic stroke.

OBJECTIVE: To determine that children with arterial ischemic stroke (AIS) due to an identifiable arteriopathy are distinct from those without arteriopathy and that each arteriopathy subtype has unique and recognizable clinical features. METHODS: We report a large, observational, multicenter cohort of children with AIS, age 1 month to 18 years, enrolled in the International Pediatric Stroke Study from 2003 to 2014. Clinical and demographic differences were compared by use of the Fisher exact test, with linear step-up permutation min-p adjustment for multiple comparisons. Exploratory analyses were conducted to evaluate differences between cases of AIS with and without arteriopathy and between arteriopathy subtypes. RESULTS: Of 2,127 children with AIS, 725 (34%) had arteriopathy (median age 7.45 years). Arteriopathy subtypes included dissection (27%), moyamoya (24.5%), focal cerebral arteriopathy-inflammatory subtype (FCA-i; 15%), diffuse cerebral vasculitis (15%), and nonspecific arteriopathy (18.5%). Children with arteriopathic AIS were more likely to present between 6 and 9 years of age (odds ratio [OR] 1.93, p = 0.029) with headache (OR 1.55, p = 0.023), multiple infarctions (OR 2.05, p < 0.001), sickle cell anemia (OR 2.9, p = 0.007), and head/neck trauma (OR 1.93, p = 0.018). Antithrombotic use and stroke recurrence were higher in children with arteriopathy. Among arteriopathy subtypes, dissection was associated with male sex, older age, headache, and anticoagulant use; FCA-i was associated with hemiparesis and single infarcts; moyamoya was associated with seizures and recurrent strokes; and vasculitis was associated with bilateral infarctions. CONCLUSION: Specific clinical profiles are associated with cerebral arteriopathies in children with AIS. These observations may be helpful indicators in guiding early diagnosis and defining subgroups who may benefit most from future therapeutic trials.

MRI Vessel Wall Enhancement and Other Imaging Biomarkers in Pediatric Focal Cerebral Arteriopathy-Inflammatory Subtype.

Background and Purpose- Focal cerebral arteriopathy-inflammatory type (FCA-i) is a common cause of pediatric arterial ischemic stroke characterized angiographically by unifocal and unilateral stenosis/irregularity of the large anterior circulation arteries with a presumed inflammatory cause. Arterial vessel wall enhancement (VWE) on vessel wall magnetic resonance imaging is a potential biomarker of inflammation that may improve diagnosis, guide treatment, and predict outcomes in patients with FCA-i. We hypothesized that patients with FCA-i with more severe or extensive VWE would have worse arteriopathy, larger infarcts, worse clinical outcome, and increased risk for infarct progression/recurrence. Methods- Pediatric patients with arterial ischemic stroke, classified as FCA-i, and who underwent vessel wall imaging were retrospectively identified at our institution. Clinical data were reviewed and the Pediatric Stroke Outcome Measure at 1 year was determined as the primary clinical end point. Neuroimaging studies were assessed for infarct size, arteriopathy severity (Focal Cerebral Arteriopathy Severity Score), and VWE. Results- Nine cases of FCA-i with vessel wall imaging were evaluated, and there was a strong correlation between clinical outcome at 1-year with initial infarct volume (Spearman correlation coefficient rho=0.84; P<0.01) and arteriopathy severity (Focal Cerebral Arteriopathy Severity Score; rho=0.85; P<0.01). Patients with infarct progression/recurrence had worse Focal Cerebral Arteriopathy Severity Score at presentation compared with those without progression/recurrence (median [IQR]; 9.0 [8.0-11.8] and 5.0 [4.0-7.0], respectively; P<0.05). On the contrary, measures of VWE were not correlated with arteriopathy severity, infarct size, clinical outcome, or risk of infarct progression/recurrence. Moreover, not all patients with FCA-i demonstrated VWE. Conclusions- VWE may not be a reliable biomarker for the diagnosis or assessment of FCA-i, and future work is needed to assess the utility of vessel wall imaging in pediatric arterial ischemic stroke and FCA-i.