The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

Resident Workshop Standardizes Patient Handoff and Improves Quality, Confidence, and Knowledge.

OBJECTIVES: Residency programs are required to instruct residents in handoff; however, a handoff curriculum endorsed by the Accreditation Council for Graduate Medical Education does not exist. Although curricula are available, we preferred to use a curriculum that could be taught quickly, was easy to implement, and used a mnemonic that resembled current practices at our institution. We designed and implemented a novel handoff educational workshop intended to improve resident confidence and performance. METHODS: In this observational study, pediatric residents across postgraduate training years during winter 2014-spring 2015 participated in two study segments: a handoff workshop with questionnaires and handoff observations. Co-investigators developed and led an interactive workshop for residents that emphasized a standardized approach using the SIGNOUT mnemonic (see text for definition). The effect of workshop participation on handoff abilities was evaluated using a validated, handoff evaluation tool administered before and after the workshop. Qualitative feedback was obtained from residents using pre- and postworkshop surveys. RESULTS: Forty-three residents participated in the workshop; 41 residents completed handoff observations. Improvements were noted in clinical judgment (P = 0.02) and organization/communication (P = 0.005). Pre- and postworkshop surveys demonstrated self-perceived increases in confidence, comfort, and knowledge (P < 0.001). CONCLUSIONS: Improvements in handoffs, particularly in clinical judgment and organization/communication domains, suggest that a more standardized handoff approach is beneficial, especially for postgraduate year 1 residents. The novel, interactive workshop we developed can be taught quickly, is easy to implement, is appropriate for all resident training levels, and improves resident confidence and skill. This workshop can be implemented by training programs across all disciplines, possibly leading to improved patient safety.

Handoff Tool Improves Transitions from the Operating Room to the Neonatal Intensive Care Unit.

Introduction: Standardized handoffs reduce medical errors and prevent adverse events or near misses. This article describes a quality improvement initiative implementing a unique standardized handoff tool and process to transition from the operating room to the neonatal intensive care unit (NICU) at a level-four regional center with many inpatients requiring surgical intervention. Before this project, there was no standardized handoff tool or process for postsurgical transitions. The primary aim was to achieve 80% compliance with completing a structured postoperative OR to NICU handoff tool within 12 months of implementation. Methods: An interdisciplinary team developed and implemented a standardized NICU postoperative handoff tool and process that requires face-to-face communication, defines team members who should be present, and highlights communication with the family. In addition, the handoff tool compliance and process measures were monitored, evaluated, and audited. Results: Although not consistent, we achieved eighty percent compliance with the outcome measures using the handoff tool. We did not sustain 80% of appropriate providers present at handoff. In addition, insufficient data assess overall parental satisfaction with the surgical experience. Although improved, the process measure of immediate postoperative family updates did not reach the targeted goal. However, the balancing measure of staff experience and satisfaction did improve. Conclusion: Implementing a standardized handoff tool and process with an interdisciplinary and interdepartmental collaboration improves critical patient transitions from the operating room to the NICU.