A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: Functional characterization and targeted treatment.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) are ligand-gated cationic channels formed from combinations of GluA1-4 subunits. Pathogenic variants of GRIA1-4 have been described in patients with developmental delay, intellectual disability, autism spectrum disorder, and seizures, with GRIA2 variants typically causing AMPAR loss of function. Here, we identify a novel, heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V, NM_001083619.1) in a 1-year-old boy with epilepsy, developmental delay, and failure to thrive. We made patch-clamp recordings to compare the functional and pharmacological properties of variant and wild-type receptors expressed in HEK293 cells, with and without the transmembrane AMPAR regulatory protein γ2. This showed GluA2 A643V-containing AMPARs to exhibit a novel gain of function, with greatly slowed deactivation, markedly reduced desensitization, and increased glutamate sensitivity. Perampanel, an antiseizure AMPAR negative allosteric modulator, was able to fully block GluA2 A643V/γ2 currents, suggesting potential therapeutic efficacy. The subsequent introduction of perampanel to the patient's treatment regimen was associated with a marked reduction in seizure burden, a resolution of failure to thrive, and clear developmental gains. Our study reveals that GRIA2 disorder can be caused by a gain-of-function variant, and both predicts and suggests the therapeutic efficacy of perampanel. Perampanel may prove beneficial for patients with other gain-of-function GRIA variants.

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.

Levetiracetam Prophylaxis for Children Admitted With Traumatic Brain Injury.

BACKGROUND: Prophylactic antiseizure medications (ASMs) for pediatric traumatic brain injury (TBI) are understudied. We evaluated clinical and radiographic features that inform prescription of ASMs for pediatric TBI. We hypothesized that despite a lack of evidence, levetiracetam is the preferred prophylactic ASM but that prophylaxis is inconsistently prescribed. METHODS: This retrospective study assessed children admitted with TBI from January 1, 2017, to December 31, 2019. TBI severity was defined using Glasgow Coma Scale (GCS) scores. Two independent neuroradiologists reviewed initial head computed tomography and brain magnetic resonance imaging. Fisher exact tests and descriptive and regression analyses were conducted. RESULTS: Among 167 children with TBI, 44 (26%) received ASM prophylaxis. All 44 (100%) received levetiracetam. Prophylaxis was more commonly prescribed for younger children, those with neurosurgical intervention, and abnormal neuroimaging (particularly intraparenchymal hematoma) (odds ratio = 10.3, confidence interval 1.8 to 58.9), or GCS ≤12. Six children (13.6%), all on ASM, developed early posttraumatic seizures (EPTSs). Of children with GCS ≤12, four of 17 (23.5%) on levetiracetam prophylaxis developed EPTSs, higher than the reported rate for phenytoin. CONCLUSIONS: Although some studies suggest it may be inferior to phenytoin, levetiracetam was exclusively used for EPTS prophylaxis. Intraparenchymal hematoma >1 cm was the single neuroimaging feature associated with ASM prophylaxis regardless of the GCS score. Yet these trends are not equivalent to optimal evidence-based management. We still observed important variability in neuroimaging characteristics and TBI severity for children on prophylaxis. Thus, further study of ASM prophylaxis and prevention of pediatric EPTSs is warranted.