Global modified‐Delphi consensus on comorbidities and prognosis of SCN8A‐related epilepsy and/or neurodevelopmental disorders

Abstract

ObjectivesWe aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A‐related disorders.MethodsA core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified‐Delphi process. Twenty‐eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified‐Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%–79% fully or partially agree, <10% disagree.ResultsConsensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non‐seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep‐related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE.SignificanceSignificant comorbidities are present in most phenotypes of SCN8A‐related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long‐term management for patients with these comorbidities and provide the basis for future evidence‐based studies on optimal treatments of SCN8A‐related disorders. Identifying the prognosis of patients with SCN8A‐related disorders will also improve care and quality‐of‐life for patients and their caregivers.

Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A‐related epilepsy and/or neurodevelopmental disorders

“…Areas where consensus was not gained relating to loss of function (LOF)/gain of function (GOF) have relevant citations. Consensus on comorbidities and prognosis from Conecker 22 are included. ASD, autism spectrum disorder; ASM, antiseizure medication; CBD, cannabidiol; DD, developmental delay; DEE, developmental epileptic encephalopathy; GI, gastrointestinal; GTCS, bilateral/generalized tonic-clonic seizures; IS, infantile spasms; KD, ketogenic diet; NDD, neurodevelopmental delay; NPO, nothing by mouth; OT, occupational therapy; PT, physical therapy; SCB, sodium channel blocker; SeL(F)IE, self-limited (familial) infantile epilepsy; SUDEP, sudden unexpected death in epilepsy; Sz, seizure; WGS, whole genome sequencing.…”

“…However, there were some limitations to this study, attributed largely to the rare and highly heterogeneous nature of SCN8A, which limits the exposure of many clinicians to the full spectrum of the disorder. Clinicians had limited experience outside of the severe DEE phenotype (see Table S3 in Conecker 22 ), possibly due to less severe cases of SCN8A not requiring the higher level of care provided at tertiary centers and potential underdiagnosis. Limitations were also present in the caregiver group, where we had a limited number of respondents for each phenotype due to the heterogeneity of the disorder.…”

“…The first round covered the following areas: Round 2 primarily focused on identifying consensus on estimated levels of severity and prognosis for comorbidities across the five phenotypes 22 and clarified consensus on EEG/MRI findings, importance of early diagnosis, and treatments based on function of variants.…”

“…Round 3 consisted of clarifying questions pertaining to comorbidities, 22 overall prognosis (epilepsy, development, and cognition), 22 and optimal first-line treatments based on phenotypes.…”

“…In this paper, we discuss results related to phenotypes, diagnosis, and treatment of SCN8A-related disorders, with comorbidities and prognosis included in a companion paper. 22 2 | MATERIALS AND METHODS 2.1 | Leadership Team and Core Panel A Leadership Team, consisting of two project cochairs (a clinician and a caregiver), an experienced process guide (clinician), and two analysts (a caregiver and an independent researcher) provided project oversight, construction and analysis of surveys, and synthesis of results (Figure 1; Table S1 outlines the affiliation, roles, and experience of the entire team).…”