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Background: Early and effective treatment of central nervous system (CNS) inflammatory disorders is vital to reduce neurologic morbidity and improve long-term outcomes in affected children. Rituximab is a B-cell-depleting monoclonal antibody whose off-label use for these disorders is funded in the province of Alberta, Canada, by the Short-Term Exceptional Drug Therapy (STEDT) program. This study describes the use of rituximab for pediatric CNS inflammatory disorders in Alberta., Methods: Rituximab applications for CNS inflammatory indications in patients <18 years of age were identified from the STEDT database between January 1, 2012, and December 31, 2019. Patient information was linked to other provincial datasets including the Discharge Abstract Database, Pharmaceutical Information Network, and Provincial Laboratory data. Analysis was descriptive., Results: Fifty-one unique rituximab applications were identified, of which 50 were approved. New applications increased from one in 2012 to a high of 12 in 2018. The most common indication was autoimmune encephalitis without a specified antibody ( n = 16, 31%). Most children were approved for a two-dose ( n = 33, 66%) or four-dose ( n = 16, 32%) induction regimen. Physician-reported outcomes were available for 24 patients, of whom 14 (58%) were felt to have fully met outcome targets., Conclusion: The use of rituximab for pediatric CNS inflammatory disorders has increased, particularly for the indication of autoimmune encephalitis. This study identified significant heterogeneity in dosing practices and laboratory monitoring. Standardized protocols for the use of rituximab in these disorders and more robust outcome reporting will help better define the safety and efficacy of rituximab in this population.

Purpose: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1 -related neurodevelopmental disorder., Methods: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated., Results: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder., Conclusion: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Perinatal arterial ischemic stroke (PAIS) underlies approximately 10% of infantile spasms (IS). We aim to identify patterns of brain injury in ischemic stroke that may predispose infants to infantile spasms., Methods: Sixty-four perinatal arterial ischemic stroke patients were identified meeting the following inclusion criteria: term birth, magnetic resonance imaging (MRI) showing ischemic stroke or encephalomalacia in an arterial distribution, and follow-up records. Patients who developed infantile spasms (PAIS-IS) were analyzed descriptively for ischemic stroke injury patterns and were compared to a seizure-free control group (PAIS-only). Stroke injury was scored using the modified pediatric ASPECTS (modASPECTS)., Results: The PAIS-IS (n = 9) group had significantly higher modASPECTS than the PAIS-only (n = 16) group ( P = .002, Mann-Whitney). A greater proportion of PAIS-IS patients had injury to deep cerebral structures (67%) than PAIS-only (25%)., Conclusion: Infarct size was significantly associated with infantile spasms development. Results support theories implicating deep cerebral structures in infantile spasms pathogenesis. This may help identify perinatal arterial ischemic stroke patients at risk of infantile spasms, facilitating more timely diagnosis.