Assessment of MR blood-oxygen-level-dependent (BOLD) cerebrovascular reactivity under general anesthesia in children with moyamoya.

BACKGROUND: Moyamoya is a progressive, non-atherosclerotic cerebral arteriopathy that may present in childhood and currently has no cure. Early diagnosis is critical to prevent a lifelong risk of neurological morbidity. Blood-oxygen-level-dependent (BOLD) MRI cerebrovascular reactivity (CVR) imaging provides a non-invasive, in vivo measure of autoregulatory capacity and cerebrovascular reserve. However, non-compliant or younger children require general anesthesia to achieve BOLD-CVR imaging. OBJECTIVE: To determine the same-day repeatability of BOLD-CVR imaging under general anesthesia in children with moyamoya. MATERIALS AND METHODS: Twenty-eight examination pairs were included (mean patient age = 7.3 ± 4.0 years). Positive and negatively reacting voxels were averaged over signals and counted over brain tissue and vascular territory. The intraclass correlation coefficient (ICC), Wilcoxon signed-rank test, and Bland-Altman plots were used to assess the variability between the scans. RESULTS: There was excellent-to-good (≥ 0.59) within-day repeatability in 18 out of 28 paired studies (64.3%). Wilcoxon signed-rank tests demonstrated no significant difference in the grey and white matter CVR estimates, between repeat scans (all p-values > 0.05). Bland-Altman plots of differences in mean magnitude of positive and negative and fractional positive and negative CVR estimates illustrated a reasonable degree of agreement between repeat scans and no systematic bias. CONCLUSION: BOLD-CVR imaging provides repeatable assessment of cerebrovascular reserve in children with moyamoya imaged under general anesthesia.

Long-term clinical and radiological trajectories of craniocervical vasculopathy in children with PHACE syndrome.

AIM: To describe the rates of stroke and craniocervical vasculopathy progression in children with posterior fossa malformations, hemangioma, arterial anomalies, coarctation of the aorta/cardiac defects, and eye abnormalities (PHACE) syndrome. METHOD: A single-center, retrospective natural history study of children with PHACE syndrome. Clinical and sequential neuroimaging data were reviewed to study the characteristics and progression of vasculopathy and calculate the rates of arterial ischemic stroke (AIS) and transient ischemic stroke (TIA). Vasculopathy progression was defined as worsening or new vascular findings on follow-up magnetic resonance angiography. RESULTS: Thirty-four children with cerebrovascular abnormalities at the PHACE syndrome diagnosis were studied (age range = 2 to 18 years, 85% females). Median age at the initial diagnosis was 5.5 months (interquartile range = 1-52 months); median age at the last follow-up was 8 years 6 months (range = 2-18 years). Overall, 10 (29%) patients had radiological progression of their vasculopathy, with a cumulative progression-free rate of 73% (95% confidence interval [CI] = 0.57-0.89), and a cumulative TIA-free and AIS-free rate of 87% (95% CI = 0.745-0.99). Vasculopathy was continuously progressive in six patients (18%) at the last follow-up. Three patients (9%) had TIA and all had progressive vasculopathy. One patient had presumed perinatal AIS at the initial PHACE diagnosis, while no other patient experienced an AIS during the follow-up. INTERPRETATION: In children with PHACE syndrome, craniocervical vasculopathy is non-progressive and asymptomatic in the majority of cases. The risk of ischemic stroke in these children is very low. Larger and prospective studies are necessary to confirm these findings.

Mechanical Thrombectomy for Pediatric Arterial Ischemic Stroke from Acute M2 Occlusion.

Pediatric large-vessel occlusion has a poor natural history. Recent retrospective studies have demonstrated the potential benefits, feasibility, and safety profile of mechanical thrombectomy in children. However, the role of thrombectomy in pediatric M2 occlusions remains uncertain. In this clinical report, we present a multicenter series of 6 pediatric patients with acute M2 occlusion (female = 1, male = 5; age range, 0.9-16.0 years, mean = 9.2). All 6 patients having undergone thrombectomy had excellent clinical outcomes (pediatric mRS = 0-1) at 3 months and final available follow-up (median, 12 months; range, 3-72 months). Factors relevant to treatment decision-making in pediatric M2 occlusions are discussed, including the important role of multidisciplinary team discussions during acute management.

Association Between Thrombectomy and Functional Outcomes in Pediatric Patients With Acute Ischemic Stroke From Large Vessel Occlusion.

Importance: Pediatric large vessel occlusion (LVO) stroke has a poor natural history. However, uptake of mechanical thrombectomy is hindered by a lack of clinical trial data in children. A randomized clinical trial is not feasible due to small sample sizes and absence of equipoise. Objective: To evaluate whether pediatric patients with acute LVO stroke who undergo thrombectomy have better clinical outcomes than matched patients managed conservatively. Design, Setting, and Participants: This matched case-control study used pooled stroke registry data from 5 tertiary referral hospitals in Australia and Canada from January 2011 to April 2022. Patients were aged 1 month to younger than 18 years with acute LVO stroke. Pooled data identified 31 thrombectomy patients and 46 control patients. Five patients undergoing thrombectomy with basilar artery occlusion were excluded due to insufficient controls. Using a hierarchal matching system (site of occlusion, age group, side of occlusion, and sex), deidentified consensus matching of patients and controls was undertaken while blinded to clinical outcome. Data were analyzed from July to November 2022. Exposure: In the case cohort, mechanical thrombectomy was undertaken for management of acute LVO stroke. The control cohort received medical treatment only. Main Outcomes and Measures: The primary outcome was the functional clinical status 3 months following stroke, measured by the pediatric modified Rankin Scale (mRS). Clinical outcomes were compared between groups using ordinal regression analysis. Results: Of 52 included patients, 31 (60%) were male, and the mean (SD) age was 10.3 (4.4) years. Matching was achieved for 26 children undergoing thrombectomy with 26 controls. There was no significant difference between groups for site or side of occlusion, age, sex, etiology, thrombolysis status, baseline Alberta Stroke Programme Early CT Score, or time since last seen well to presentation. Patients undergoing thrombectomy had superior clinical outcomes than control patients at 3 months on the pediatric mRS (odds ratio, 3.76; 95% CI, 1.32-10.67; P = .01). These superior outcomes were maintained at final follow-up (odds ratio, 3.65; 95% CI, 1.25-10.68; P = .02). Conclusions and Relevance: In the absence of a randomized clinical trial, this case-control study demonstrates better clinical outcomes with thrombectomy than medical management alone for pediatric patients aged 2 to 18 years with anterior circulation LVO stroke.

Cerebral Venous Sinus Thrombosis in Preterm Infants.

BACKGROUND: Neonatal cerebral venous sinus thrombosis (CVST) can lead to brain injury and neurodevelopmental impairments. Previous studies of neonatal CVST have focused on term infants, and studies of preterm infants are lacking. In this study, we examined the clinical and radiological features, treatment and outcome of CVST in preterm infants. METHODS: This was a retrospective, consecutive cohort study of preterm infants (gestational age <37 weeks) with radiologically confirmed CVST. All magnetic resonance imaging/MRV and CT/CTV scans were re-reviewed to study thrombus characteristics and pattern of brain injury. Outcome was assessed by the validated pediatric stroke outcome measure at the most recent clinic visit. RESULTS: Twenty-six preterm infants with CVST were studied. Of these, 65% were moderate-late preterm (32-37 weeks), 27% very preterm (28-32 weeks), and 8% extreme preterm (<28 weeks). Most (73%) were symptomatic at presentation with seizures or abnormal exam. Transverse (85%) and superior sagittal (42%) sinuses were common sites of thrombosis. Parenchymal brain injury was predominantly periventricular (35%) and deep white matter (31%) in location. Intraventricular hemorrhage occurred in 46%. Most infants (69%) were treated with anticoagulation. No treated infant (including eleven with pretreatment hemorrhage) had new or worsening post-treatment hemorrhage. Outcomes ranged from no deficits (50%), mild-moderate (25%), and severe (25%) impairment. CONCLUSIONS: In our sample of preterm infants with CVST, more than one-quarter were asymptomatic. White matter brain lesions predominated and one-half had neurological deficits at follow-up. Anticoagulation of preterm CVST in this small cohort appeared to be safe. Larger studies of preterm CVST are needed.

Successful Pediatric Mechanical Thrombectomy for HeartMate 3-Related Intracranial Thromboembolism.

Thromboembolic events post left ventricular assist devices (LVAD) implantation remain a major cause of morbidity and mortality. Mechanical thrombectomy for the treatment of pediatric intracranial thromboembolic events have been reported in LVADs, but never following HeartMate 3 (HM3) implantation. We present the case of an 8-year-old, 26.5 kg male with dilated cardiomyopathy and decompensated heart failure who presented with extensive intracranial thromboembolism in the early postoperative period following HM3 implantation and underwent successful mechanical thrombectomy with a favorable neurological outcome.

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.

Rotational Vertebrobasilar Insufficiency: Is There a Physiological Spectrum? Phase-Contrast Magnetic Resonance Imaging Quantification in Healthy Volunteers.

BACKGROUND: Some cases of cerebral ischemia have been attributed to dynamic flow limitation in neck vessels. It however remains unknown whether this represents the extreme end of a physiological response. METHODS: Eighteen healthy volunteers were recruited to this prospective study. Cervical blood flow (ml/min/m2) was assessed using phase-contrast MRI, and cerebral perfusion ratios were assessed using arterial spin labeling perfusion at neutral position, predefined head rotations, as well as flexion and extension. Inter-reader agreements were assessed using intraclass correlation coefficient. RESULTS: The mean age was 38.6 ± 10.8 (range = 22-56) years, for five male participants and 13 females. The means for height and weight were 168 cm and 73.2 kg, respectively. There were no significant differences in individual arterial blood flow with change in head position (P > 0.05). Similarly, the repeated-measures analysis of variance test demonstrated no significant difference in perfusion ratios in relation to head position movement (P > 0.05). Inter-reader agreement was excellent (intraclass correlation coefficient = 0.97). CONCLUSIONS: There is neither significant change in either individual cervical arterial blood flow nor cerebral perfusion within the normal physiological/anatomical range of motion in healthy individuals. It is therefore reasonable to conclude that any such hemodynamic change identified in a patient with ischemic stroke be considered causative.

Hemorrhagic transformation and stroke recurrence in children with cardiac disease receiving antithrombotic therapy for secondary stroke prevention.

BACKGROUND: Antithrombotic therapy is currently recommended for stroke prevention in pediatric cardioembolic stroke where the recurrence risk is high; however, safety concerns remain. The primary objective of this study was to evaluate clinical and radiographic predictors of hemorrhagic transformation and stroke recurrence in children with cardiac disease to ascertain the safety and failure rates for secondary stroke prevention. METHODS: This was a single-center, retrospective analysis of a prospectively enrolled cohort of children with radiologically confirmed cardioembolic stroke from January 2003 to December 2017 treated with institutional guidelines. RESULTS: Eighty-two children met inclusion criteria (male 44 [54%]; neonates 23 [28%]; median age 0.43 years [0.08-4.23]). Hemorrhagic transformation occurred in 20 (24%) with the majority (75% of 20) being petechial and asymptomatic. One death (1%) was reported from hemorrhagic transformation. Four children (5%) had major extracranial hemorrhage. Most (95%) received antithrombic therapy, with anticoagulation being favored (82%). Greater stroke volume was associated with hemorrhagic transformation using the pediatric Alberta Stroke Program Early CT Score (6.1 ± 3.3 vs. 3.5 ± 2.3; p = .006). Stroke recurred in 11 (13%) children at a median 32 days (5.5-93) from the index event and the majority (90%) were on treatment at the time of recurrence. Children with univentricular physiology were less likely to have hemorrhagic transformation (RR 0.31; 95% CI 0.09-0.96, p = .04); however, they had higher rates of recurrent stroke before final palliative repair. CONCLUSIONS: In spite of the 24% hemorrhagic transformation rate, antithrombotic therapy has a positive risk-balance in certain cardioembolic stroke subgroups, particularly in those with single-ventricle physiology, when accounting for stroke volume.

Childhood arterial ischemic stroke due to mineralizing angiopathy: an 18-year single-center experience.

Mineralizing angiopathy is a unique, age-specific stroke syndrome characterized by basal ganglia infarction and lenticulostriate calcification after minor head injury in early childhood. There is limited understanding of the pathophysiology, course, and clinical outcome of this syndrome. We describe the clinical and radiographical phenotype of a single-center, consecutively enrolled cohort of children with mineralizing angiopathy from January 2002 to January 2020 and provide a comparative analysis to previously published literature. Fourteen children were identified. Previously unreported findings include: stroke onset in eight children older than 18 months; presence of basal ganglia hemorrhage in four; multifocal basal ganglia infarcts in three; presence of additional non-basal ganglia calcifications in three; and presence of thrombophilia in one. Seven children had moderate-to-severe neurological deficits. There was no symptomatic stroke recurrence (mean follow-up 3y 7mo, SD 1y 7mo). Our expanded phenotype highlights distinct characteristics of mineralizing angiopathy in children and has the potential to inform future research. What this paper adds Children with mineralizing angiopathy are often misdiagnosed as having a limb fracture despite normal x-rays. A magnetic resonance imaging-only approach may miss this entity. Non-contrast computed tomography, in addition to MRI is recommended to identify calcifications in idiopathic arterial ischemic stroke. Most children have moderate-to-severe neurological sequela.

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.

Swallowing, Oral Motor, Motor Speech, and Language Impairments Following Acute Pediatric Ischemic Stroke.

BACKGROUND AND PURPOSE: Following adult stroke, dysphagia, dysarthria, and aphasia are common sequelae. Little is known about these impairments in pediatric stroke. We assessed frequencies, co-occurrence and associations of dysphagia, oral motor, motor speech, language impairment, and caregiver burden in pediatric stroke. METHODS: Consecutive acute patients from term birth-18 years, hospitalized for arterial ischemic stroke (AIS), and cerebral sinovenous thrombosis, from January 2013 to November 2018 were included. Two raters reviewed patient charts to detect documentation of in-hospital dysphagia, oral motor dysfunction, motor speech and language impairment, and caregiver burden, using a priori operational definitions for notation and assessment findings. Other variables abstracted included demographics, preexisting conditions, stroke characteristics, and discharge disposition. Impairment frequencies were obtained by univariate and bivariate analysis and associations by simple logistic regression. RESULTS: A total of 173 patients were stratified into neonates (N=67, mean age 2.9 days, 54 AIS, 15 cerebral sinovenous thrombosis) and children (N=106, mean age 6.5 years, 73 AIS, 35 cerebral sinovenous thrombosis). Derived frequencies of impairments included dysphagia (39% neonates, 41% children); oral motor (6% neonates, 41% children); motor speech (37% children); and language (31% children). Common overlapping impairments included oral motor and motor speech (24%) and dysphagia and motor speech (23%) in children. Associations were found only in children between stroke type (AIS over cerebral sinovenous thrombosis) and AIS severity (more severe deficit at presentation) for all impairments except feeding impairment alone. Caregiver burden was present in 58% patients. CONCLUSIONS: For the first time, we systematically report the frequencies and associations of dysphagia, oral motor, motor speech, and language impairment during acute presentation of pediatric stroke, ranging from 30% to 40% for each impairment. Further research is needed to determine long-term effects of these impairments and to design standardized age-specific assessment protocols for early recognition following stroke.

Neurologic complications of pediatric congenital heart disease.

Improved medical management and surgical outcomes have significantly decreased mortality in children with congenital heart disease; however, with increased survival, there is a greater lifetime exposure to neurologic complications with serious long-term neurodevelopmental consequences. Thus, recent focus has shifted to recognition and reduction of these extracardiac comorbidities. Vascular and infective complications, such as arterial ischemic stroke, infective endocarditis, and localization-related epilepsy are some of the most common neurologic comorbidities of congenital heart disease. In addition, it is now well recognized that congenital heart disease has an impact on overall brain development and contributes to adverse neurodevelopmental outcomes across multiple domains. The goal of this chapter is to summarize the most common neurologic comorbidities of congenital heart disease and its management.

Bow hunter syndrome: A rare yet important etiology of posterior circulation stroke.

A6-year-oldgirl presented with acute-onset headache andfluctuating right-sided weakness.HerPedNIHSSwas13. Brain MRI/MRA showed acute pontine arterial ischemic stroke(AIS)and remote right cerebellar and thalamic infarcts.No antecedent trauma or other stroke risk factors were identified. Clinical suspicion of bow hunter syndromewas raised. CTshowed congenital C2-C3 fusion and dynamic angiogramconfirmed the diagnosis. The management challenges of this rare condition are discussed below.

Autonomic dysregulation in children with epilepsy with postictal generalized EEG suppression following generalized convulsive seizures.

OBJECTIVE: Postictal generalized electroencephalographic suppression (PGES) has been associated with sudden unexpected death in epilepsy (SUDEP) in adults. Decreased heart rate variability (HRV) is one clinical marker of SUDEP in adults with epilepsy. The objective of this study was to analyze the characteristics of HRV associated with generalized convulsive seizures (GCS) ±â€¯PGES in children. METHODS: Nine hundred and seventy-seven consecutive children who underwent prolonged scalp video-EEG (vEEG) and 1-lead electrocardiogram (ECG) monitoring at the Hospital for Sick Children, Toronto, Ontario, Canada were reviewed retrospectively from 2009 to 2011. Thirty-five children had GCS captured during their vEEG with or without PGES and met inclusion criteria. Children were subdivided into three age groups and compared with age-matched controls: 3-6 years; 7-12 years; and 13-18 years. Interictal HRV was measured at 5 min during N2 sleep. Preictal HRV was measured at 1 h prior to GCS onset, and postictal HRV was measured at 3 min post-GCS cessation. Low frequency (LF: ms2, 0.04-0.15 Hz) and high frequency (HF: ms2, 0.15-0.4 Hz) bands of heart rate oscillations were analyzed during the interictal and preictal periods. The root mean square of successive differences (RMSSDs) was analyzed during the following time points: interictal; preictal; and postictal. RESULTS: Thirty-five children had GCS: 18 children with PGES [3-6 years (n = 2); 7-12 years (n = 6); 13-18 years (n = 10)] and 17 children without PGES [3-6 years (n = 6); 7-12 years (n = 5); 13-18 years (n = 6)]. Seventeen additional age-matched controls were identified [3-6 years (n = 3); 7-12 years (n = 5); 13-18 years (n = 9)]. Seventy-four GCS were captured consisting of 36 GCS + PGES and 38 GCS - PGES. There was no difference of interictal HRV among children with GCS ±â€¯PGES and controls. The preictal LF and HF in 36 GCS + PGES were significantly higher compared with 38 GCS - PGES (p < 0.01). The postictal RMSSD in 36 GCS + PGES was significantly higher compared with 38 GCS - PGES (p < 0.01). The pre- to postictal RMSSD change was significantly lower in children with GCS + PGES than in those with GCS - PGES (p = 0.035). CONCLUSIONS: In summary, the preictal HRV in GCS + PGES was significantly higher than in children with GCS - PGES. The higher remaining postictal RMSSD in children with GCS + PGES is a potential indicator of autonomic dysregulation. In certain children with epilepsy, autonomic dysregulation may contribute to poor recovery from a GCS with subsequent PGES, thereby contributing to SUDEP. Heart rate variability and autonomic regulation in children with epilepsy should be further studied prospectively in order to better understand the mechanism by which PGES may lead to SUDEP.

A child with a stroke, drug-refractory epilepsy and congenital heart disease: can a hemispherectomy be safely performed between staged cardiac procedures?

BACKGROUND: The safety of hemispherectomy between staged cardiac procedures is unknown and not previously reported. METHOD: Retrospective review of a case with drug-resistant epilepsy due to stroke following bidirectional cavopulmonary connection (BDCPC). RESULTS: This report describes the first case of a successful pediatric peri-insular functional hemispherectomy in the setting of a BDCPC. A discussion of the complex preoperative planning from both a cardiac and neurological perspective is presented. Considerations regarding hemispherectomy and its effects on the cardiac physiology, and perioperative considerations are emphasized in clinical decision making. CONCLUSIONS: A multidisciplinary approach was critical in this child which led to a successful outcome.