The Genetic Landscape of Ischemic Stroke in Children - Current Knowledge and Future Perspectives.

Stroke in childhood has multiple etiologies, which are mostly distinct from those in adults. Genetic discoveries over the last decade pointed to monogenic disorders as a rare but significant cause of ischemic stroke in children and young adults, including small vessel and arterial ischemic stroke. These discoveries contributed to the understanding that stroke in children may be a sign of an underlying genetic disease. The identification of these diseases requires a detailed medical and family history collection, a careful clinical evaluation for the detection of systemic symptoms and signs, and neuroimaging assessment. Establishing an accurate etiological diagnosis and understanding the genetic risk factors for stroke are essential steps to decipher the underlying mechanisms, optimize the design of tailored prevention strategies, and facilitate the identification of novel therapeutic targets in some cases. Despite the increasing recognition of monogenic causes of stroke, genetic disorders remain understudied and therefore under-recognized in children with stroke. Increased awareness among healthcare providers is essential to facilitate accurate diagnosis in a timely manner. In this review, we provide a summary of the main single-gene disorders which may present as ischemic stroke in childhood and describe their clinical manifestations. We provide a set of practical suggestions for the diagnostic work up of these uncommon causes of stroke, based upon the stroke subtype and imaging characteristics that may suggest a monogenic diagnosis of ischemic stroke in children. Current hurdles in the genetic analyses of children with ischemic stroke as well as future prospectives are discussed.

Pediatric Moyamoya Biomarkers: Narrowing the Knowledge Gap.

Moyamoya is a progressive cerebrovascular disorder that leads to stenosis of the arteries in the distal internal carotid, proximal middle cerebral and proximal anterior cerebral arteries of the circle of Willis. Typically a network of collaterals form to bypass the stenosis and maintain cerebral blood flow. As moyamoya progresses it affects the anterior circulation more commonly than posterior circulation, and cerebral blood flow becomes increasingly reliant on external carotid supply. Children with moyamoya are at increased risk for ischemic symptoms including stroke and transient ischemic attacks (TIA). In addition, cognitive decline may occur over time, even in the absence of clinical stroke. Standard of care for stroke prevention in children with symptomatic moyamoya is revascularization surgery. Treatment of children with asymptomatic moyamoya with revascularization surgery however remains more controversial. Therefore, biomarkers are needed to assist with not only diagnosis but also with determining ischemic risk and identifying best surgical candidates. In this review we will discuss the current knowledge as well as gaps in research in relation to pediatric moyamoya biomarkers including neurologic presentation, cognitive, neuroimaging, genetic and biologic biomarkers of disease severity and ischemic risk.

Fronto-Parietal and White Matter Haemodynamics Predict Cognitive Outcome in Children with Moyamoya Independent of Stroke.

Moyamoya disease is a major arteriopathy characterised by progressive steno-occlusion of the arteries of the circle of Willis. Studies in adults with moyamoya suggest an association between abnormal fronto-parietal and white matter regional haemodynamics and cognitive impairments, even in the absence of focal infarction. However, these associations have not been investigated in children with moyamoya. We examined the relationship between regional haemodynamics and ratings of intellectual ability and executive function, using hypercapnic challenge blood oxygen level-dependent magnetic resonance imaging of cerebrovascular reactivity in a consecutive cohort of children with confirmed moyamoya. Thirty children were included in the final analysis (mean age: 12.55 ± 3.03 years, 17 females, 15 idiopathic moyamoya and 15 syndromic moyamoya). Frontal haemodynamics were abnormal in all regardless of stroke history and comorbidity, but occipital lobe haemodynamics were also abnormal in children with syndromic moyamoya. Executive function deficits were noted in both idiopathic and syndromic moyamoya, whereas intellectual ability was impaired in syndromic moyamoya, even in the absence of stroke. Analysis of the relative effect of regional abnormal haemodynamics on cognitive outcomes demonstrated that executive dysfunction was predominantly explained by right parietal and white matter haemodynamics independent of stroke and comorbidity, while posterior circulation haemodynamics predicted intellectual ability. These results suggest that parietal and posterior haemodynamics play a compensatory role in overcoming frontal vulnerability and cognitive impairment.

Impact of COVID-19 public health measures on myelin oligodendrocyte glycoprotein IgG-associated disorders in children.

BACKGROUND: Despite better characterization of the spectrum of MOG-IgG-associated disorders (MOGAD) in children, the role of infection in its pathophysiology remains unclear. The goal of this study was to evaluate if public health measures put in place to prevent the spread of SARS-CoV-2 in March 2020 in Ontario (Canada) have been associated with a change in the incidence of MOGAD and other neuroinflammatory disorders in children. METHODOLOGY: We reviewed a single-centre cohort of children referred for a suspicion of neuroinflammatory disorder between January 2015 and March 2021. Age, date, sex, diagnosis, MOG-IgG antibodies status and detected pathogens at presentation were identified. Comparative statistical analysis was performed based on diagnosis between years and seasons using Pearson's Chi-squared test or Fisher's exact test for categorical variables and using ANOVA or Kruskal-Wallis test for continuous variables, as appropriate. We compared the post-lockdown period (March 17th, 2020, to March 31st, 2021) to previous calendar years (2015 to 2019) alone and to previous calendar years and the pre-lockdown 2020 period (January 1st, 2020, to March 16th, 2020). A p-value of < 0.05 was considered significant. Post-hoc pairwise comparisons between the post-lockdown period and previous years were performed on significant results. A false discovery rate adjustment with an adjusted p-value (q-value) < 0.05 was computed. We hypothesized that the number of new MOGAD would be significantly lower in the post-lockdown period compared to previous years due to decreased regional pathogen transmission. RESULTS: Among 491 referred cases, we identified 415 new cases of neuroinflammatory disorder between January 2015 and March 2021. The number of new neuroinflammatory disorder diagnoses did not change between years. We noted significantly fewer new MOGAD diagnoses in 2020 compared to previous years, with no MOGAD patients presenting in 2020 after the spring lockdown (q=0.0009). In addition, there were significantly fewer parainfectious neuroinflammatory cases (q=0.04) and pathogen detected (q=0.04) in the post-lockdown period. The number of new multiple sclerosis (MS) and aquaporin-4 neuromyelitis optica spectrum disorders (AQP4-NMOSD) cases remained stable despite the lockdown (q=0.185 and 0.693 respectively). INTERPRETATION: Enhanced population-based infection control strategies may have a role in modulating the incidence of MOGAD and parainfectious neuroinflammatory disorders, but not MS or AQP4-NMOSD.

Distinct Clinical and Radiographic Phenotypes in Pediatric Patients With Moyamoya.

BACKGROUND: Given the expanding evidence of clinico-radiological differences between moyamoya disease (MMD) and moyamoya syndrome (MMS), we compared the clinical and radiographic features of childhood MMD and MMS to identify predictors of ischemic event recurrence. METHODS: We reviewed a pediatric moyamoya cohort followed between 2003 and 2019. Clinical and radiographic characteristics at diagnosis and follow-up were abstracted. Comparisons between MMD and MMS as well as between MMD and two MMS subgroups (neurofibromatosis [MMS-NF1] and sickle cell disease [MMS-SCD]) were performed. RESULTS: A total of 111 patients were identified. Patients with MMD presented commonly with transient ischemic attacks (TIAs) (35 % MMD versus 13% MMS-NF1 versus 9.5% MMS-SCD; P = 0.047). Symptomatic stroke presentation (MMD 37% versus MMS-NF1 4% versus 33%; P = 0.0147) and bilateral disease at diagnosis (MMD 73% versus MMS-NF1 22 % versus MMS-SCD 67%; P = 0.0002) were uncommon in MMS-NF1. TIA recurrence was common in MMD (hazard ratio 2.86; P = 0.001). The ivy sign was absent on neuroimaging in a majority of patients with MMS-SCD (MMD 67% versus MMS-NF1 52% versus MMS-SCD 9.5%; P = 0.0002). Predictors of poor motor outcome included early age at diagnosis (odds ratio [OR] 8.45; P = 0.0014), symptomatic stroke presentation (OR 6.6; P = 0.019), and advanced Suzuki stage (OR 3.59; P = 0.019). CONCLUSIONS: Moyamoya exhibits different phenotypes based on underlying etiologies. Frequent TIAs is a common phenotype of MMD and symptomatic stroke presentation a common feature of MMD and MMS-SCD, whereas unilateral disease and low infarct burden are common in MMS-NF1. In addition, absence of ivy sign is a common phenotype in MMS-SCD.

Ischemic sequelae and other vascular diseases.

Although pediatric stroke is associated with higher survival rates compared with adult stroke, a substantial body of evidence indicates significant neuropsychologic morbidity in pediatric stroke survivors. Neuroplasticity does not guarantee good outcome in children. The general trends observed in the literature are reviewed as is the profile observed in common causes of pediatric stroke: congenital heart disease, moyamoya disease, and sickle cell disease. The neuropsychologic profile of pediatric stroke patients is heterogeneous due to the multiplicity of associated causes. Stroke in early infancy and large strokes are associated with cognitive impairment while more limited disorders, such as phasic deficit, are observed in childhood stroke. Executive dysfunction is common in pediatric stroke, but social interaction skills are usually preserved. Congenital heart disease and sickle cell disease are associated with global neuropsychologic dysfunction while cognition is usually preserved in moyamoya. Executive dysregulation is instead more frequently reported in this population. Further study of maladaptive processes after pediatric stroke will allow identification of predictors of functional and neuropsychologic outcomes and permit personalization of care.

Predictive Factors for Epilepsy in Pediatric Patients With Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber syndrome is characterized by a facial port-wine stain associated with either or both a retinal angioma and a cerebral pial angioma. Because a pial angioma may not be evident on the initial imaging studies, individuals at risk for epilepsy are often not identified before their first seizure. The aim of this study is to identify predictive factors predisposing Sturge-Weber patients to epilepsy. METHODS: The medical archives and photography database of our institution were reviewed to identify Sturge-Weber Syndrome patients followed up between 1990 and 2015. Patients without epilepsy were compared with patients with epilepsy based on the location of the port-wine stain, its extent and cerebral imaging. RESULTS: Twenty-four patients were included in the study. Thirteen did not develop epilepsy. Patients with bilateral port-wine stain were at higher risk of epilepsy (P = 0.03). Unilateral port-wine stain did not increase the risk of epilepsy (P = 0.29) regardless of its extent. The presence of developmental venous anomalies on brain imaging was also associated with a higher risk of epilepsy (P = 0.03). CONCLUSIONS: Bilateral facial port-wine stain and cerebral developmental venous anomalies increase the risk of epilepsy in Sturge-Weber syndrome patients. Because they can be detected at birth, they might guide preventive management and follow-up.

Prognostication Value of Descending Corticospinal Tract DWI Signal in Neonatal Cerebral Sinovenous Thrombosis.

BACKGROUND: Descending corticospinal tract diffusion-weighted magnetic resonance imaging (MRI) signal is predictive of poor motor outcome in neonatal and childhood arterial ischemic stroke. However, descending corticospinal tract diffusion-weighted MRI signal has not been documented in the setting of cerebral sinovenous thrombosis, and its role is not understood. OBJECTIVE: We describe a neonate with cerebral sinovenous thrombosis, extensive diffusion restriction, and bilateral descending corticospinal tract diffusion-weighted MRI signal on MRI of the brain. We discuss the underlying mechanisms and implications of these findings in venous ischemia. CONCLUSION: The prognostic value of descending corticospinal tract diffusion-weighted MRI signal differs when observed in cerebral sinovenous thrombosis from when observed in arterial ischemic stroke. Consequently, caution should be exercised in using descending corticospinal tract diffusion-weighted MRI signal to predict outcome in children with cerebral sinovenous thrombosis.