Surgical revascularizations for pediatric moyamoya: a systematic review, meta-analysis, and meta-regression analysis.

INTRODUCTION: There is no clear consensus regarding the technique of surgical revascularization for moyamoya disease and syndrome (MMD/MMS) in the pediatric population. Previous meta-analyses have attempted to address this gap in literature but with methodological limitations that affect the reliability of their pooled estimates. This meta-analysis aimed to report an accurate and transparent comparison between studies of indirect (IB), direct (DB), and combined bypasses (CB) in pediatric patients with MMD/MMS. METHODS: In accordance with PRISMA guidelines, systematic searches of Medline, Embase, and Cochrane Central were undertaken from database inception to 7 October 2022. Perioperative adverse events were the primary outcome measure. Secondary outcomes were rates of long-term revascularization, stroke recurrence, morbidity, and mortality. RESULTS: Thirty-seven studies reporting 2460 patients and 4432 hemispheres were included in the meta-analysis. The overall pooled mean age was 8.6 years (95% CI: 7.7; 9.5), and 45.0% were male. Pooled proportions of perioperative adverse events were similar between the DB/CB and IB groups except for wound complication which was higher in the former group (RR = 2.54 (95% CI: 1.82; 3.55)). Proportions of post-surgical Matsushima Grade A/B revascularization favored DB/CB over IB (RR = 1.12 (95% CI 1.02; 1.24)). There was no significant difference in stroke recurrence, morbidity, and mortality. After meta-regression analysis, year of publication and age were significant predictors of outcomes. CONCLUSIONS: IB, DB/CB are relatively effective and safe revascularization options for pediatric MMD/MMS. Low-quality GRADE evidence suggests that DB/CB was associated with better long-term angiographic revascularization outcomes when compared with IB, although this did not translate to long-term stroke and mortality benefits.

Predictors of motor outcome after childhood arterial ischemic stroke.

AIM: To identify clinical and radiological predictors of long-term motor outcome after childhood-onset arterial ischemic stroke (AIS) in the middle cerebral artery (MCA) territory. METHOD: Medical records of 69 children (36 females, 33 males; median age at index AIS 3y 3mo, range: 1mo-16y) who presented to Great Ormond Street Hospital with first AIS in the MCA territory were reviewed retrospectively. Cases were categorized using the Childhood AIS Standardized Classification and Diagnostic Evaluation (CASCADE). Magnetic resonance imaging (MRI) and angiography were evaluated. An Alberta Stroke Program Early Computed Tomography Score (ASPECTS) was calculated on MRI. The Recurrence and Recovery Questionnaire assessed motor outcome and was dichotomized into good/poor. RESULTS: Eventual motor outcome was good in 49 children and poor in 20. There were no acute radiological predictors of eventual motor outcome. At follow-up, CASCADE 3A (i.e. moyamoya) and Wallerian degeneration were significantly associated with poor motor outcome. In the multivariate analysis, younger age and CASCADE 3A predicted poor motor outcome. INTERPRETATION: In the context of recommendations regarding unproven and potentially high-risk hyperacute therapies for childhood AIS, prediction of outcome could usefully contribute to risk/benefit analysis. Unfortunately, paradigms used in adults, such as ASPECTS, are not useful in children in the acute/early subacute phase of AIS. What this paper adds Adult paradigms, such as the Alberta Stroke Program Early Computed Tomography Score system, are not useful for predicting outcome in children. Younger children tend to have a poorer long-term prognosis than older children. Moyamoya is associated with poor prognosis.

Management of haemorrhagic stroke secondary to arteriovenous malformations in childhood.

AIMS: The aim of this study is to describe the outcome and management of all children who have presented with haemorrhagic stroke (HS) secondary to an arteriovenous malformation (AVM) at a single UK centre over a 13-year period. METHODS: All children with HS managed at our institution (2005-2018) were identified and those with underlying AVMs were studied. Clinical and imaging data were obtained from medical records. Outcome was scored using the Recovery and Recurrence Questionnaire. RESULTS: Ninety-three children (median age 8.8 years; 56 males; 8 neonates) presented with both global and focal features (28 had Glasgow Coma Score < 8). Haemorrhage was intraparenchymal in 72; prior risk factors present in 14. An underlying vascular lesion was identified in 68/93, most commonly AVM (n = 48). A systemic cause was found in 10, cerebral venous thrombosis in three, and 9 remain unidentified despite neuroradiological investigation. Median follow-up was 2.4 years, six died, and one was lost to follow-up. Outcome was rated as good in 60/86. Of the 48 AVMs, 3 were Spetzler-Martin (SM) grade 1, 21 SM 2, 21 SM3 and 3 SM4. One patient was treated conservatively as the AVM was too high risk to treat. At follow-up, 19 with AVM were angiographically cured, all with low SM grade and with the use of a single modality in 9 cases (all low SM grade). CONCLUSION: Although children with acute HS are extremely unwell at presentation, supportive care results in a good outcome in the majority. Complete obliteration for childhood AVMs is challenging even with low-grade lesions with multimodal treatment.

Cross-sectional study of a United Kingdom cohort of neonatal vein of galen malformation.

OBJECTIVE: Describe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation identified before 28 days of life. METHODS: Neonates with angiographically confirmed vein of Galen malformation presenting to 1 of 2 UK treatment centers (2006-2016) were included; those surviving were invited to participate in neurocognitive assessment. Results in each domain were dichotomized into "good" and "poor" categories. Cross-sectional and angiographic brain imaging studies were systematically interrogated. Logistic regression was used to explore potential outcome predictors. RESULTS: Of 85 children with neonatal vein of Galen malformation, 51 had survived. Thirty-four participated in neurocognitive assessment. Outcomes were approximately evenly split between "good" and "poor" categories across all domains, namely, neurological status, general cognition, neuromotor skills, adaptive behavior, and emotional and behavioral development. Important predictors of poor cognitive outcome were initial Bicêtre score ≤ 12 and presence of brain injury, specifically white matter injury, on initial imaging; in multivariate analysis, only Bicêtre score ≤ 12 remained significant. INTERPRETATION: Despite modern supportive and endovascular treatment, more than one-third of unselected newborns with vein of Galen malformation did not survive. Outcome was good in around half of survivors. The importance of white matter injury suggests that abnormalities of venous as well as arterial circulation are important in the pathophysiology of brain injury. Ann Neurol 2018;84:547-555.

Seeking normality: Parents' experiences of childhood stroke.

BACKGROUND: Incidence of paediatric stroke has been estimated to range from 1.2 to 13 per 100,000 children under 18 years of age. It is a significant cause of long-term morbidity in children with long-term impacts on physical, cognitive, psychological, and social outcomes. However, little is known about the experiences of parents caring for a child with stroke. Such information is needed to inform the development of child- and family-centred care. METHODS: We conducted in-depth interviews with parents of children with stroke. Participants were purposively sampled from three regional specialist services in England, based on the age of the child at stroke onset and time since first stroke. Interviews used a topic guide and were audio recorded and transcribed in full. Thematic analysis was conducted to develop an account that reflected patients' experiences from their own perspectives. RESULTS: Twelve parents participated with five children classified as having no to mild deficits and seven with moderate to severe deficits. Parents were concerned about the effects of stroke on the child's psychological, cognitive, and social well-being. Significant impacts on parents own well-being and on the family were reported. Although most experienced good quality acute care, meeting the child's needs after hospital discharge was problematic, with low levels of awareness of paediatric stroke among professionals and difficulties accessing relevant information and services. Meeting special education needs was variable. Parents were proactive in seeking to establish a sense of normality for the child and themselves. CONCLUSIONS: The findings illuminate a wider picture of paediatric stroke than indicated by clinical outcomes alone. Parents' experiences varied according to the child's needs but also family's situation and geographical location. Particular attention should be paid to co-ordinating services to meet multiple needs after discharge from hospital.

Rates and Risk Factors for Arterial Ischemic Stroke Recurrence in Children.

BACKGROUND AND PURPOSE: Recurrent ischemic events are common in children with arterial ischemic stroke (AIS) and put patients at risk for further neurological impairment. This study sought to identify rates and risk factors for recurrent AIS or transient ischemic attack in a cohort of children seen after index AIS and uniformly investigated and managed using contemporary clinical guidelines. METHODS: Case note and radiology review of children >28 days and <18 years of age who presented to Great Ormond Street Hospital from 2005 to 2015 with index AIS. Demographic characteristics, medical history, index AIS features, radiological findings, and neurological outcome were examined. Recurrence was identified from clinical records and coded as AIS (if there was associated new cerebral infarction) or transient ischemic attack. RESULTS: Eighty-four children (43 girls; median age at index AIS, 4.1 years) were identified. Cumulative AIS recurrence was 5% at 1 month, 10% at 3 months, 12% at 6 months, 12% at 12 months, and 15% at 60 months after index event. Factors that independently predicted AIS recurrence were referral to Great Ormond Street Hospital from outside the catchment area, a prior relevant diagnosis, bilateral arteriopathy, and AIS CASCADE category 3A or 3B (Childhood AIS Standardized Classification and Diagnostic Evaluation). Multiple infarcts and evidence of mature, as well as acute, infarcts on first brain imaging, although independently associated with AIS recurrence, were also associated with bilateral arteriopathy. Only CASCADE categories 3A and 3B (bilateral cerebral arteriopathy with or without collaterals) remained significant in multivariate analysis. AIS recurrence was not associated with poor neurological outcome. CONCLUSIONS: AIS recurrence remains a significant problem, despite the wide use of antithrombotic medications. AIS subtypes should direct clinicians and future trials to use stratified management strategies and durations of treatment. Bilateral cerebral arteriopathies are especially sinister, and consensus criteria should be developed to improve consistency of management.

Presentation, course, and outcome of postneonatal presentations of vein of Galen malformation: a large, single-institution case series.

AIM: To describe presentation, clinical course, and outcome in postneonatal presentations of vein of Galen malformation (VGM). METHOD: Children older than 28 days presenting with VGM (from 2006-2016) were included. Notes/scans were reviewed. Outcome was dichotomized into 'good' or 'poor' using the Recovery and Recurrence Questionnaire. Logistic regression was performed to explore relationships between clinico-radiological features and outcome. RESULTS: Thirty-one children (18 males, 13 females) were included, presenting at a median age of 9.6 months (range 1.2mo-11y 7mo), most commonly with macrocrania (n=24) and prominent facial veins (n=9). Seven had evidence of cardiac failure. VGM morphology was choroidal in 19. Hydrocephalus (n=24) and loss of white matter volume (n=15) were the most common imaging abnormalities. Twenty-nine patients underwent glue embolization (median two per child). Angiographic shunt closure was achieved in 21 out of 28 survivors. Three children died of intracranial haemorrhage (1y, 6y, and 30d after embolization). Ten patients underwent neurosurgical procedures; to treat haemorrhage in four, and hydrocephalus in the rest. Outcome was categorized as good in 20 out of 28 survivors, but this was not predictable on the basis of the variables listed above. INTERPRETATION: Postneonatally presenting VGM has distinctive clinico-radiological features, attributable to venous hypertension. Endovascular treatment is associated with good outcomes, but more specific prognostic prediction was not possible within this cohort. WHAT THIS PAPER ADDS: Clinical and radiological features in older children with vein of Galen malformation relate to venous hypertension. Outcome is good in most cases with endovascular therapy. Mortality is low but is related to intracranial haemorrhage.

Cerebral vasculopathy in childhood neurofibromatosis type 2: cause for concern?

Unlike adult neurofibromatosis type 2 (NF2), which presents with symptoms related to bilateral vestibular schwannomas, children with NF2 most frequently present with ocular, dermatological, and neurological symptoms. Arteriopathy, a well-established feature in neurofibromatosis type 1, is not a widely recognized feature of NF2. Here we report three children with NF2 with cerebral arteriopathy and/or arterial ischaemic stroke. Bevacizumab, a vascular endothethial growth factor inhibitor, is an established treatment for rapidly growing vestibular schwannomas; however, it carries a risk of both ischaemic and haemorrhagic stroke. Thus, the role of screening and risk to benefit ratio of bevacizumab in NF2 merit further consideration. WHAT THIS PAPER ADDS: Children with neurofibromatosis type 2 (NF2) may be at increased risk of cerebral vasculopathy and arterial ischaemic stroke. Targeted magnetic resonance angiography should be performed in children with NF2 who are being considered for bevacizumab therapy.

Outcome and recurrence 1 year after pediatric arterial ischemic stroke in a population-based cohort.

OBJECTIVE: Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population-based cohort. METHODS: Children aged 29 days to < 16 years with radiologically confirmed AIS occurring over a 1-year period residing in southern England (population = 5.99 million children) were eligible for inclusion. Outcome was assessed during a home visit using the Pediatric Stroke Outcome Measure (PSOM). Parental impressions of recovery were assessed using the Pediatric Stroke Recurrence and Recovery Questionnaire. PSOM score was estimated via telephone interview or clinician interview whenever home visit was not possible. RESULTS: Ninety-six children with AIS were identified. Two children were lost to follow-up. Nine of 94 (10%) children died before the 12-month follow-up. One child had an AIS recurrence. PSOM scores were available for 78 of 85 living children at follow-up. Thirty-nine of 78 (50%) had a good outcome (total PSOM score < 1), and 39 of 78 (50%) had a poor outcome. Seizures at onset of AIS were associated with a poor outcome (odds ratio = 3.5, 95% confidence interval = 1.16-10.6). Twenty-eight of 73 (38%) children were judged by their carers to have fully recovered. Ten of 84 (12%) children had recurrent seizures, and 17 of 84 (20%) reported recurrent headaches. INTERPRETATION: AIS carries a significant risk of mortality and long-term neurological deficit. However, the rates of mortality, recurrence, and neurological impairment were markedly lower in this study than previously published figures in the United Kingdom. Ann Neurol 2016;79:784-793.

Neuropsychological outcome following childhood stroke - a review.

OBJECTIVES: Childhood stroke is a rare but devastating occurrence. Its infrequency has meant that a clear body of knowledge has not been fully established regarding its impact on neuropsychological outcome. Our aims were (i) to critically review the recent literature on neuropsychological outcome following childhood stroke; (ii) to investigate the factors related to neuropsychological outcome following childhood stroke. METHODS: Literature searches were conducted and revealed 39 relevant papers from the period 1999-2015. RESULTS: The review found that a significant number of children experience difficulties in a wide range of neuropsychological domains, with particular vulnerabilities noted in attention, speed of information processing and executive functioning. There were inconsistent findings regarding the correlates of neuropsychological outcome, which is likely due to methodological limitations of the studies. CONCLUSIONS: This review strongly indicates that childhood stroke can affect a myriad of neuropsychological domains, with attention, speed of processing and executive function particularly vulnerable. Methodological issues, particularly around heterogeneous samples and measurement difficulties, limit the conclusions that can be drawn regarding the predictors of outcome.

Diagnosis of vertebral artery dissection in childhood posterior circulation arterial ischaemic stroke.

AIM: Review a series of children with posterior circulation arterial ischaemic stroke (PCAIS) to identify diagnostic modality and associations in cases of vertebral artery dissection (VAD). METHOD: Retrospective analysis of 30 cases of childhood PCAIS identified from two tertiary centres over 11 years. Clinical and demographic details were recorded. Brain and cerebrovascular imaging were reviewed. Aetiology was classified using the Childhood Arterial Ischaemic Stroke Standardized Classification and Diagnostic Evaluation criteria. Outcome was evaluated using standardized paediatric stroke outcome scores. Logistic regression was used to explore variables associated with diagnosis. RESULTS: Twenty-three patients were male (77%) and 7 were female (23%). VAD was the most commonly identified aetiology, in 15 cases (50%). Aetiology was undetermined in 12 (40%), probable cardioembolism in two, and reversible cerebral vasoconstriction syndrome in one. In those with VAD, diagnosis was made on initial magnetic resonance angiography (MRA) in six (40%). Further cases of VAD were diagnosed with catheter angiography (n=6), computed tomographic angiography (n=1), or follow-up MRA (n=2). Presence of multiple infarcts was associated with a diagnosis of VAD. INTERPRETATION: Endoluminal cerebrovascular imaging increases the rate of diagnosis of VAD in childhood PCAIS and should especially be considered if there are multiple infarcts.

Diagnostic delays in paediatric stroke.

BACKGROUND: Stroke is a major cause of mortality in children. Conditions that mimic stroke also cause severe morbidity and require prompt diagnosis and treatment. We have investigated the time to diagnosis in a cohort of children with stroke. METHODS: A population-based cohort of children with stroke was prospectively identified in the south of England. Case notes, electronic hospital admission databases and radiology records were reviewed. Timing of symptom onset, presentation to hospital, first neuroimaging, first diagnostic neuroimaging and presenting clinical features were recorded. RESULTS: Ninety-six children with an arterial ischaemic stroke (AIS) and 43 with a haemorrhagic stroke (HS) were identified. The median time from symptom onset to diagnostic neuroimaging was 24.3 h in AIS and 2.9 h in HS. The initial imaging modality was CT in 68% of cases of AIS. CT was diagnostic of AIS in 66% of cases. MRI was diagnostic in 100%. If initial neuroimaging was non-diagnostic in AIS, then median time to diagnosis was 44 h. CT was diagnostic in 95% of HS cases. Presentation outside normal working hours resulted in delayed neuroimaging in AIS (13 vs 3 h, p=0.032). Diffuse neurological signs or a Glasgow Coma Scale <9 resulted in more expeditious neuroimaging in both HS and AIS. CONCLUSIONS: The diagnosis of AIS in children is delayed at every stage of the pathway but most profoundly when the first neuroimaging is CT scanning, which is non-diagnostic. MRI should be the initial imaging modality of choice in any suspected case of childhood AIS.

A practical approach to acute hemiparesis in children.

Acute hemiparesis in children is a common clinical syndrome presenting to a variety of care settings. The recognition and the differential diagnosis is challenging, particularly in young children. Arterial ischaemic stroke (AIS) is the primary diagnosis to be considered as this requires emergency investigations and management; however, there are several conditions collectively described as 'stroke mimics' that need consideration. Accurate diagnosis is essential for appropriate management. Clinical data combined with neuroimaging are important for accurate diagnosis and management. This review and the accompanying illustrative case vignettes suggest a practical approach to differential diagnosis and management of children presenting with acute hemiparesis.

Are children with acute arterial ischaemic stroke eligible for hyperacute thrombolysis? A retrospective audit from a tertiary UK centre.

AIM: The aim of this study was to evaluate the number of children with acute arterial ischaemic stroke (AIS) who would have been eligible for hyperacute thrombolysis in the authors' unit (Great Ormond Street Hospital, London, UK) and to identify barriers to this treatment. METHOD: We compared the characteristics of children with a diagnosis of acute AIS, identified from neuroimaging databases, seen at our centre between January 2006 and December 2011. The criteria for hyperacute thrombolysis were predefined by us: age ≥8y; imaging-confirmed diagnosis of acute AIS and arrival at our centre within 6 hours of symptom onset; occluded major artery on computed tomography (CT) or magnetic resonance angiography; no contraindications. Factors that precluded therapy were examined. RESULTS: Of a total of 107 children with acute AIS identified on MRI (n=64; 33 females, 31 males; median age 4y, range 1mo-17y) or CT databases (n=43; 14 females, 29 males; median age 1y, range 1mo-15y), none would have been eligible for hyperacute thrombolysis. The major barriers to this were (1) delayed diagnosis, (2) delayed transfer to the tertiary centre, (3) age, and (4) medical comorbidities. Of 107 children, three (2.8%) would have been eligible for thrombolysis if diagnosis and transfer had occurred in a timely manner. An additional 11 children (10.3%) would have been eligible if the age criterion was 28 days or more and if diagnosis and transfer had occurred promptly. INTERPRETATION: Although hyperacute thrombolysis is, as yet, an unproven treatment in childhood AIS, at least a subset of patients could potentially benefit. This audit has identified that clinical factors preclude treatment in a high percentage of children. Furthermore, in our specialist unit, without an emergency department, we identified major logistic barriers that will need to be addressed to enable access to hyperacute therapies. These results could inform future trial design and service delivery.

Chickenpox and risk of stroke: a self-controlled case series analysis.

BACKGROUND: There is good evidence that respiratory and other infections that cause systemic inflammation can trigger strokes; however, the role of specific infections is unclear. Case reports have highlighted chickenpox as a possible risk factor for arterial ischemic stroke, particularly in children, but rigorous studies are needed to determine and quantify any increased risk. METHODS: We used anonymized electronic health records totaling >100 million person-years of observation from 4 UK primary care databases to identify individuals who had documented clinical chickenpox and a stroke or transient ischemic attack (TIA). Self-controlled case series methods were used to quantify any increased risk of first stroke or TIA in the 0-6 and 7-12 months following chickenpox compared to other observed time periods. We analyzed data within each database, and performed meta-analyses to obtain summary age-adjusted incidence ratios (IRs) separately for adults and children. RESULTS: Five hundred sixty eligible individuals (including 60 children) were identified who experienced chickenpox and a stroke or TIA during follow-up. Among children, there was a 4-fold increased risk of stroke in the 0-6 months after chickenpox (summary IR = 4.07; 95% confidence interval [CI], 1.96-8.45; I(2) = 0%). Among adults, there was a less marked increased risk with moderate between-database heterogeneity (random-effects summary IR = 2.13; 95% CI, 1.05-4.36; I(2) = 51%). There was no significant increased risk of stroke in the 7-12 months after chickenpox in children or adults, nor was there evidence of increased risk of TIA in either time period. CONCLUSIONS: Our study provides new evidence that children who experience chickenpox are at increased risk of stroke in the subsequent 6 months.