Landscape of childhood epilepsies - A multi-ethnic population-based study.

OBJECTIVE: To describe the clinical features of childhood epilepsy in Qatar. METHODS: A retrospective cross-sectional chart review analysis was conducted at the only tertiary pediatric hospital in Qatar in 1422 patients with epilepsy followed between November 2016 and October 2019. RESULTS: 55% (781) were males and 70% were non-Qatari. Age of epilepsy onset was in the neonatal period in 9% (114/1207 patients). In the non-neonatal cohort, mean age of onset was 4 yrs 9mos ( ± 1.4mos). Focal epilepsy was the predominant epilepsy type in 45% (594/1314 patients) versus generalized epilepsy in 37% and combined focal/generalized epilepsy in 12%. Etiology was unknown in most children (782/1363, 57%) whereas structural and genetic causes represented 23% and 11% of cases respectively. No differences in epilepsy type and etiology were found between different ethnic groups. Children with genetic or structural epilepsies had an earlier epilepsy onset compared to those with unknown etiologies. At the last follow up, only 36% of patients were seizure-free and 12% (170/1422) had a history of status epilepticus. Medically refractory epilepsy was found in 37% (527/1407) of patients, with the most common etiologies being unknown (36%) and structural (37%). Neurodevelopmental co-morbidities were present in most patients (62%), with global developmental delay (47%) and learning/school difficulties (22%) being the most prevalent. 94% of patients with somatic co-morbidities had concomitant neurodevelopmental co-morbidities. Risk factors associated with an increased risk of co-morbidities and intractable epilepsy included early age of epilepsy onset (< 2 years of age); etiology; antenatal risk factors; history of previous central nervous system infection; history of status epilepticus and a family history of consanguinity and epilepsy. SIGNIFICANCE: This large multi-ethnic population-based study confirms that the prevalence, incidence and clinical features of epilepsy in Qatar is in accordance with other epidemiologic studies and highlights risk factors for the development of co-morbidities and medically-intractable epilepsy.

PGAP3 Associated with Hyperphosphatasia with Mental Retardation Plays a Novel Role in Brain Morphogenesis and Neuronal Wiring at Early Development.

Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C>T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene's novel role in brain morphogenesis and neuronal wiring.

Neurophysiologic intraoperative monitoring in pediatrics.

Neurophysiologic intraoperative monitoring, using somatosensory, brainstem auditory, and visual evoked potentials, transcranial electric motor stimulation, and electromyography, is typically used during complex surgeries involving the motor and sensory cortex, brainstem, cranial nerves, spinal cord, nerve root, peripheral roots, brachial plexus, lumbar plexus, and peripheral nerves. The particular type of surgery and the neurologic structures at risk determine the type of monitoring chosen. Although many methods are the same in adult and pediatric patients, some differences in the pediatric population will be discussed here. In general, monitoring consists of two types. The first involves monitoring data which is obtained on an ongoing basis, with comparisons to data obtained at the outset of surgery (baseline). The second form of monitoring involves mapping neural structures, so that a neural structure in the field is identified accurately, to avoid injuring it, or to demonstrate its degree of neurophysiologic function or impairment. In this paper we discuss both forms of monitoring and their general applications, including unique features or modifications needed in the pediatric population.

Role of methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism in pediatric cerebrovascular disorders.

Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation (MTHFR TT) has been linked to an increased risk for stroke, coronary artery disease, and migraine headaches. The authors analyzed the potential link between MTHFR 677C>T homozygosity and childhood stroke. A true association might facilitate screening, recurrence risk stratification, and treatment in patients with cerebrovascular disease. They performed a retrospective chart review of children tested for the MTHFR 677C>/T mutation; 533 patients underwent MTHFR testing, and 8% were homozygous for the MTHFR 677C>T mutation. There was no difference in the cohort compared with the prevalence in the general population. This suggests that the MTHFR 677 C>T polymorphism played a minimal role or no role in stroke risk. However, the data suggest that the MTHFR TT genotype may influence migraine susceptibility in children because there was a higher proportion of migraine patients (28.6%) with the MTHFR TT homozygous genotype.

Antithrombotic treatment in neonatal cerebral sinovenous thrombosis: results of the International Pediatric Stroke Study.

OBJECTIVE: To identify predictors of antithrombotic treatment in neonates with cerebral sinovenous thrombosis (CSVT) in a large multinational study. STUDY DESIGN: Neonates with CSVT from 10 countries were enrolled in the International Pediatric Stroke Study from 2003 through 2007. Term neonates with CSVT who presented with neurologic symptoms or signs of systemic illness and neuroimaging evidence of thrombus or flow interruption within cerebral venous system were included. RESULTS: Of 341 neonates enrolled, 84 had isolated CSVT. Neuroimaging findings, available in 67/84 neonates, included venous ischemic infarction in 5, hemorrhagic infarction or other intracranial hemorrhage in 13, both infarction and hemorrhage in 26, and no parenchymal lesions in 23. Treatment data, available in 81/84 neonates, included antithrombotic medications in 52% (n = 43), comprising heparin (n = 14), low molecular weight heparin (n = 34), warfarin (n = 1), and aspirin (n = 2). By univariate logistic regression analysis, deep venous system thrombosis (P = .05) and location in the United States (P = .001) predicted nontreatment. Presence of infarction, hemorrhage, dehydration, systemic illness, and age did not predict treatment or nontreatment. In multivariate analysis only geographic location remained significant. CONCLUSIONS: In neonatal CSVT, regional antithrombotic treatment practices demonstrate considerable variability and uncertainty about indications for antithrombotic therapy. Additional studies are warranted.

Use of alteplase in childhood arterial ischaemic stroke: a multicentre, observational, cohort study.

BACKGROUND: The safety and efficacy of thrombolysis after acute stroke in children have not been established. Our aim was to describe current practices and results of the use of alteplase for acute arterial ischaemic stroke in children enrolled in an international pediatric stroke registry and to compare current practices with those published in case reports and with guidelines for the use of alteplase for adult stroke. METHODS: In this multicentre observational cohort study, we analysed the clinical features, the dosing and timing of treatment, and the short-term outcome in children treated with alteplase for acute arterial ischaemic stroke who were enrolled in the International Pediatric Stroke Study (IPSS) between January, 2003, and July, 2007. The findings from the IPSS were compared with published case reports for clinical features, adherence to adult guidelines for alteplase, and outcomes. FINDINGS: Of 687 children with acute arterial ischaemic stroke enrolled in the IPSS, 15 (2%) received alteplase: nine received intravenous alteplase and six received intra-arterial alteplase. The median time to treatment from stroke onset was 3.3 h (range 2.0-52.0 h) for intravenous alteplase and 4.5 h (3.8-24.0 h) for intra-arterial alteplase. Two patients died (one owing to massive infarction and brain herniation, and one owing to brainstem infarction). At discharge from hospital, one patient was healthy and 12 patients had neurological deficits. Intracranial haemorrhage after alteplase occurred in four of 15 patients, although none of the bleeding events was judged to be acutely symptomatic. When compared with ten patients reported in published articles who were given intravenous alteplase, the nine patients in the IPSS cohort were mostly younger, waited longer for treatment, and had worse outcomes, which suggests there is a publication bias towards short treatment intervals from symptom onset and favourable outcomes. INTERPRETATION: Children with acute stroke received alteplase infrequently and at time intervals that often deviated from adult guidelines. Although no alteplase-related deaths or symptomatic intracranial haemorrhage was reported, poor neurological outcome was common. Clinical trials to evaluate the dose and the safety and efficacy of alteplase are needed in childhood stroke.

Intraoperative neurophysiologic monitoring in 80 patients with Chiari I malformation: role of duraplasty.

Neurophysiologic intraoperative monitoring of the brainstem auditory evoked potentials (BAEPs) is a widely used method to assess the functional integrity of the central auditory system during surgery involving the brainstem or the cranial nerves. The purpose of this study is to describe our experience with neurophysiologic intraoperative monitoring of BAEPs during posterior fossa decompression (PFD) surgery for the management of Chiari I malformation. Although suboccipital craniectomy is the standard surgical technique applied in all cases undergoing PFD, the role of dural patch grafting (duraplasty) remains controversial. In most cases, the PFD was supplemented by duraplasty only when the Chiari I malformation was complicated by the presence of syringomyelia. Our study reviewed the intraoperative BAEP changes during the different surgical stages of Chiari repair and correlated these with clinical and radiological findings present. Our data revealed that for both groups of patients, with or without associated syringomyelia, the predominant improvement in central conduction in most cases occurred during the period of bony decompression without significant additional improvement after the duraplasty procedure.

The cost of pediatric stroke care and rehabilitation.

BACKGROUND AND PURPOSE: There is little data regarding the cost of pediatric stroke care or the elements that contribute to these costs. We examined costs for poststroke care during the first year after diagnosis and compared these costs with the volume of the cerebral infarct and the level of neurological and functional outcome. METHODS: We identified 39 children who sustained nontraumatic ischemic or hemorrhagic strokes and confirmed the diagnoses by review of medical and radiology records. Medical costs were tabulated for the year after the diagnosis of stroke. Cerebral infarct volumes were measured from MRI or CT scans. Neurological outcome was assessed by telephone with a modification of the Pediatric Stroke Outcome Measure (PSOM), and functional outcomes were assessed with a standardized quality-of-life measure. RESULTS: The median cost for poststroke care during the year after diagnosis was $42,338 for the entire group. The cost for stroke care was higher for hemorrhagic stroke than for ischemic stroke. Cost had a significant positive correlation with neurological impairment. The modified PSOM score positively correlated with impairments of physical, emotional, social, and school function. CONCLUSIONS: The cost of stroke care may be one measure of stroke severity, with more extensive strokes resulting in greater medical costs. In addition, stroke appears to impair children's social ability along with their neurological function.