The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Efficacy of IV Valproic Acid and Oral Valproic Acid Tapers for the Treatment of Pediatric Headaches in the Emergency Department.

Background and Objectives: Pediatric headaches, including migraine, are a common reason for emergency department (ED) presentation. IV valproic acid (VPA) followed by oral VPA tapers are often used to abort pediatric headache and reduce recurrence, though limited data exist regarding this approach. This study evaluated the effectiveness of IV VPA and oral VPA tapers for the treatment of acute pediatric headaches in the ED in preventing return encounters. Methods: This is a retrospective cohort study of patients aged 5-21 years presenting to a tertiary-care pediatric ED from 2010 to 2016 who received IV VPA for headache or migraine. Primary outcomes were ED disposition, percent pain reduction (initial vs 2-hour patient-reported pain score [10-point scale]), and return for acute headache treatment within 1 month. Results: A total of 486 ED encounters were included with a median patient age of 15 years; most of them were females (76%, 369/486). Of available pain scores within 2 hours of IV VPA administration, 41% (173/425) had ≥50% pain reduction. Fifty-two percent (254/486) were discharged without additional treatment, 14% (69/486) were discharged after additional treatment, and 33% (163/486) were admitted to the hospital. Initial pain score, number of preceding home treatments, and number of preceding ED treatments were not associated with ED disposition. Oral VPA tapers were prescribed in 39% (94/253) of encounters when the patient was discharged after IV VPA. Oral VPA tapers produced a transient decrease in recurrence at 72 hours, which was no longer present at 1 week nor 1 month. There was no difference in the time to recurrence or total number of return visits within 1 month. Discussion: IV VPA was efficacious in treating pediatric headaches evaluated in the ED, with nearly two-thirds of patients discharged home after administration. Oral VPA tapers did not reduce total headache recurrence nor time to recurrence. Given the limited benefit of oral VPA tapers, this practice should be re-examined. Classification of Evidence: This study provides Class IV evidence that for children with headache seen in the ED, IV VPA reduces head pain and Class III evidence that following this with an oral VPA taper is of no benefit.

Neuroimaging for Pediatric Non-First-Time Seizures in the Emergency Department.

Background and Objectives: Neuroimaging is often part of the workup for a pediatric patient presenting with a seizure to an emergency department (ED). We aim to evaluate when neuroimaging in the ED for children with a non-first-time seizure, or nonindex seizure (NIS), is associated with an acute change in management (ACM). Methods: This is a retrospective cohort study of all pediatric patients presenting to an ED from 2008 to 2018 with a NIS, excluding repeat febrile seizures, who underwent neuroimaging. Clinical characteristics were extracted from the electronic medical record. The primary outcome was new abnormal neuroimaging resulting in an ACM, defined as admission to the hospital, neurosurgical intervention, or new nonseizure medication administration. Results: We identified 492 encounters. Neuroimaging revealed new findings in 21% of encounters and led to ACMs in 5% of encounters. ACMs included admissions, neurosurgical interventions, and nonseizure medication changes. Factors associated with ACM included new seizure type (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.3-8.0), new focal examination finding (OR 3.0, 95% CI 1.3-7.1), altered mental status (OR 2.9, 95% CI 1.2-7.0), and a history of only provoked seizures (OR 2.8, 95% CI 1.0-7.5). Patients with 2 risk factors had an OR of 6.9 (95% CI 1.8-26.5) for an ACM, and those with 3-4 risk factors had an OR of 45.8 (95% CI 9.8-213.2). The negative predictive value for ACM in a patient with no risk factors was 98.6% (95% CI 95.9-99.5). Discussion: Patients with a NIS who have abnormal neuroimaging associated with an ACM present with unique risk factors. Prospectively validating these factors may allow for a prediction tool for NIS in EDs where reduced exposure to ionizing radiation, sedation, and resource utilization are critically important.