Assessing Communication Impairments in a Rare Neurodevelopmental Disorder: The SCN2A Clinical Trials Readiness Study.

Background and Objectives: SCN2A-related disorders (SCN2A-RDs) entail severe impairments in multiple domains that could serve as nonseizure outcomes in clinical trials. This study evaluated the fitness for purpose of several clinical instruments with both standardized and alternative scoring and with some measures used out of their intended age range for assessing communication in SCN2A-affected participants. Methods: Parents of SCN2A-affected children were recruited through FamilieSCN2A Foundation outreach for a combined cross-sectional and longitudinal study. They completed assessments of their children at study entry and 6 and 12 months later. Assessments included the Vineland Adaptive Behavior Scale (VABS-3), Adaptive Behavior Assessment System (ABAS), Communication Matrix, and Communication and Symbolic Behavior Scale (CSBS). Analyses examined floor and ceiling effects, inter-rater and test-retest reliability, discrimination among different levels of functional impairment, and sensitivity to clinical aspects of SCN2A-RDs. Results: Of 65 participants (28 females, median age 6.4 years, IQR 4.1-10.5), 56 (86%) had epilepsy. Eleven (17%) used speech as their primary communication mode; 84% were considered ineffective communicators. The mean Vineland composite standardized score (SS) was 34 (IQR 26-46). Cross-sectionally, standardized scores decreased with increasing age. There were substantial floor effects for receptive (75%) and expressive (83%) communication. SSs discriminated poorly between verbal vs nonverbal and communicative vs noncommunicative participants and were not sensitive to features reflecting epilepsy severity (e.g., epileptic spasms and number of current medications). By contrast, Vineland growth scale value (GSV) and ABAS, Matrix, and CSBS raw scores had minimal floor effects; most increased with age. These alternative scores distinguished clearly between participants with different levels of communication and were sensitive to aspects of epilepsy severity. Longitudinally, SSs decreased, but other scores remained relatively stable over a year. Discussion: SCN2A-RD is characterized by severe-to-profound impairment with a SS <4 SDs of the norm-referenced mean. Owing to severe floor effects and their insensitivity to markers of communication function, age-standardized scores (e.g., Vineland SS) are not fit for purpose in clinical trials or other settings for evaluating nonseizure outcomes such as communication. GSVs and alternative scoring and assessments have much better measurement profiles in all these regards and should be considered in future precision medicine trials for SCN2A-RDs and other similar rare diseases.

Novel approaches to measuring cognition in individuals with severe to profound functional impairment: A pilot study in SCN2A-related disorder.

Valid clinical outcome assessments with the ability to capture meaningful aspects of neurodevelopment for individuals with neurogenetic conditions associated with profound functional impairments are lacking, yet critical for clinical care and clinical trial readiness. The purpose of this pilot study was to examine and compare the initial psychometric properties of a series of commonly used standardized and norm-referenced measures of cognition and adaptive functioning as well as alternative measures of neurobehavioral functioning designed to capture responsivity (i.e., alertness, awareness, responsivity to the environment) in those with acquired brain injuries in a sample of individuals with severe to profound functional impairment associated with a neurogenetic etiology. Ten individuals (median age = 7.5 years, IQR = 4.8-11.5, range 4-21; n = 8 male) with severe to profound functional impairment associated with SCN2A-Related Disorder and their parents were included in this study. Parents completed the Vineland Adaptive Behavior Scales, Third Edition Comprehensive Interview (Vineland-3) and the Developmental Profile, Fourth Edition Cognitive Scale (DP-4) and their children completed the Bayley Scales of Infant and Toddler Development Cognitive Scale (Bayley-4; given out of the standardized age-range) and two measures of responsivity, the Coma Recovery Scale, Pediatric and the Rappaport Coma/Near Coma Scale. Results demonstrated exceptionally low skills (median Vineland-3 Adaptive Behavior Composite = 35.5) and frequent floor effects across norm-referenced measures (i.e., Vineland-3, DP-4, Bayley-4); however, raw scores yielded more range and variability and no absolute floor effects. There were also no floor effects on measures of responsivity and findings suggest that these alternative tools may capture more variability in some aspects of neurobehavioral functioning that are critical to higher order cognitive functions, particularly for those with mental-ages below a 12 month-level. Initial evidence of construct validity of all measures in this population was shown. Findings support ongoing investigation of measures of responsivity and identified areas of potential measure modification that may improve applicability for individuals with severe to profound functional impairment associated with neurogenetic as opposed to acquired etiologies.

Patient-advocate-led global coalition adapting fit-for-purpose outcomes measures to assure meaningful inclusion of DEEs in clinical trials.

Existing clinical tools that measure non-seizure outcomes lack the range and granularity needed to capture skills in developmental and epileptic encephalopathy (DEE)-affected individuals who also fall in the severe to profound range of intellectual disability. This effectively excludes those with severe impairments from clinical trials, impeding the ability of sponsors to evaluate disease-modifying therapies (DMTs). The Inchstone Project, an international, patient advocate-led collaboration, brings together leading researchers, clinicians, pharmaceutical companies, and advocates to develop an adapted, validated assessment battery within 5 years. The goal is to support trials of DMTs for the DEEs by providing sufficiently sensitive measurement tools to demonstrate therapeutic efficacy. An initial pilot study administered 7 established assessments to 10 individuals affected by SCN2A-DEE, identifying specific limitations of existing measures and areas for improvement. It was clear that most tools do not account for challenges throughout the DEE population, including vision impairments, significant motor impairments and profound intellectual disability, which need to be accounted for in creating a 'fit-for-purpose' battery for the DEE population. Several novel assessments, including two measures of responsivity developed for use in monitoring recovery after acquired brain injury as well as individualized Goal Attainment Scaling, showed promise in this group. The team also completed a DEE-wide survey with over 270 caregivers documenting their children's abilities and priorities for their improvement from new treatments. The Inchstone team is using this information to evaluate how existing tools might be updated to better capture what is most important to families and measure their child's small but important improvements over time. These efforts are building a coherent picture across multiple DEEs of what domains, or concepts of interest, have the greatest impact on most patients and families. The Inchstone team is on course to adapt non-seizure outcome measures that are (1) sufficiently sensitive to measure small increments of meaningful change ('Inchstones') and (2) applicable to multiple DEE conditions.

DEE-P Connection's Inchstone project is adapting assessment tools to measure the smallest developmental changes in those affected by developmental and epileptic encephalopathies (DEEs) - severe epilepsy and related developmental disorders. More sensitive measures will allow profoundly impacted individuals to be effectively included in clinical trials and result in better DEE treatments. Caregivers of children with DEEs understand firsthand that clinical tools intended to measure non-seizure outcomes, like communication and motor skills, were not designed for and don't work for their children. More sensitive tools are needed to measure the small changes that occur in DEEs. The limitations of existing measurement tools for DEEs have significant consequences: - Non-seizure responses to new therapies cannot be measured without tools designed specifically for individuals with severe to profound intellectual disability.- If a response cannot be measured in a trial, a potentially beneficial impact will be missed and a therapy, having failed to demonstrate an effect, may not gain regulatory approval.- DEE-affected individuals are less likely to benefit from the wave of new disease-modifying therapies providing hope for many other rare genetic diseases. DEE-P Connections, a patient advocacy organization supporting families caring for those severely affected by DEEs, launched The Inchstone Project to address this problem. This team science research collaborative unites researchers, pharmaceutical companies, advocates and others around a shared vision of adapting existing tools to reliably capture the small but important changes in skills in those severely affected by DEEs. To better understand these gaps, the Inchstone team conducted a pilot study with 10 children with SCN2A DEE. The team administered multiple assessments to explore how to adapt the tools to better capture the abilities and growth of this population. The team also completed a comprehensive DEE-wide survey with over 270 caregivers documenting their children's abilities and priorities for their improvement from new treatments, helping to document how existing tools may be updated to better capture what's most important to families and measure their children's small but important improvements over time. The Inchstone Project is on course to assure those profoundly impacted by DEEs are meaningfully included in clinical trials by establishing trusted and reliable non-seizure measurement tools.

Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Infants, Children, and Adolescents with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. The International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy, and their representatives to develop minimum sets of standardized outcomes and outcome measurement methods for clinical practice. Using modified Delphi consensus methods with consecutive rounds of online voting over 12 months, a core set of outcomes and corresponding measurement tool packages to capture the outcomes were identified for infants, children, and adolescents with epilepsy. Consensus methods identified 20 core outcomes. In addition to the outcomes identified for the ICHOM Epilepsy adult standard set, behavioral, motor, and cognitive/language development outcomes were voted as essential for all infants and children with epilepsy. The proposed set of outcomes and measurement methods will facilitate the implementation of the use of patient-centered outcomes in daily practice.

Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Adults with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. Therefore, the International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy and their representatives to develop minimum sets of standardized outcomes and outcomes measurement methods for clinical practice that support patient-clinician decision-making and quality improvement. Consensus methods identified 20 core outcomes. Measurement tools were recommended based on their evidence of strong clinical measurement properties, feasibility, and cross-cultural applicability. The essential outcomes included many non-seizure outcomes: anxiety, depression, suicidality, memory and attention, sleep quality, functional status, and the social impact of epilepsy. The proposed set will facilitate the implementation of the use of patient-centered outcomes in daily practice, ensuring holistic care. They also encourage harmonization of outcome measurement, and if widely implemented should reduce the heterogeneity of outcome measurement, accelerate comparative research, and facilitate quality improvement efforts.

Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel Nav1.2 are rare, with clinically heterogeneous expressions that include epilepsy, autism and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relationship to channel function, 81 patients (36 female, 44%, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their Nav1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal onset, n = 27; infant onset, n = 18; and later onset n = 24; and autism without seizures, n = 12) was strongly correlated with a non-seizure severity index (P = 0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (P = 0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland Adaptive Behavior composite score of 49.5 (>3 standard deviations below the norm-referenced mean of the test). Epileptic spasms were significantly more common in infant-onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (P = 0.007). Primary phenotype was also strongly correlated with variant function (P < 0.0001); gain-of-function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy and to severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups, representing: (i) primarily later-onset epilepsy with moderate loss-of-function variants and low severity indices; (ii) mostly infant-onset epilepsy with moderate loss-of-function variants but higher severity indices; and (iii) late-onset and autism only, with the lowest severity indices (mostly zero) and severe/complete loss-of-function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relationship between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on Nav1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance towards clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

FDA Patient-Focused Drug Development Guidances: Considerations for Trial Readiness in Rare Developmental and Epileptic Encephalopathies

Developmental and epileptic encephalopathies (DEE) are rare, often monogenic neurodevelopmental conditions. Most affected individuals have refractory seizures. All have multiple severe impairments which can be as life-limiting as or more limiting than the seizures themselves. Mechanism- and gene-targeted therapies for these individually rare, genetic conditions hold hope for treatment, amelioration of disease expression, and even cure. The near absence of fit-for-purpose (FFP) clinical outcome assessments (COA) to establish the benefits for nonseizure outcomes of these new therapies in clinical trials poses significant challenges to drug development. The Food and Drug Administration Patient-Focused Drug Development guidance series provides direction for how to overcome these challenges and to ensure FFP measures are available for trials. The goal is to have measures that address outcomes of importance to patients and caregivers, reliably and accurately measure the outcome in the spectrum of abilities for the target disease, and are sensitive to meaningful change over time. The guidances identify 3 primary strategies: (1) directly adopting and implementing available outcome measures; (2) creating measures de novo; and (3) a middle path of adapting or modifying existing measures. Emphasized throughout the guidances is the indispensable and extensive role of the patient or caregiver to assuring the goal of having fit measures is achieved. This review specifically considers the difficulties of adopting available COAs in severely impaired patient groups and ways to adapt or modify existing COAs to be FFP as encouraged in the guidances. Adaptations include alternative scoring, use of assessments in out-of-intended age ranges, and modifications for individuals with sensory or motor impairments. Some additional considerations that may facilitate achieving adequate clinical outcome measures, especially for rare diseases, include use of personalized endpoints, merging of existing COAs, and developing a consortium of rare DEE advocates and researchers to ensure fitness of adapted COAs across multiple rare disease groups. The FDA guidances help ensure that clinical trials targeting nonseizure outcomes, especially in severely impaired populations, will have adequately valid and sensitive outcome measures. This in turn will strengthen the ability of trials to provide informative tests of whether treatments provide meaningful therapeutic efficacy.

Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey.

PURPOSE: Plant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients. METHODS: The BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales. RESULTS: A total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1-73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51-80%). However, improvements in nonseizure outcomes (18-56%) were also reported in patients who either had no change or worsening of seizure frequency. CONCLUSIONS: This survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.

What does better look like in individuals with severe neurodevelopmental impairments? A qualitative descriptive study on SCN2A-related developmental and epileptic encephalopathy.

PURPOSE: There are limited psychometric data on outcome measures for children with Developmental Epileptic Encephalopathies (DEEs), beyond measuring seizures, and no data to describe meaningful change. This study aimed to explore parent perceptions of important differences in functional abilities that would guide their participation in clinical trials. METHODS: This was a descriptive qualitative study. Semi-structured one-on-one interviews were conducted with 10 families (15 parent participants) with a child with a SCN2A-DEE [8 male, median (range) age 7.5 (4.5-21)] years. Questions and probes sought to understand the child's functioning across four domains: gross motor, fine motor, communication, and activities of daily living. Additional probing questions sought to identify the smallest differences in the child's functioning for each domain that would be important to achieve, if enrolling in a traditional therapy clinical trial or in a gene therapy trial. Data were analyzed with directed content analysis. RESULTS: Expressed meaningful differences appeared to describe smaller developmental steps for children with more limited developmental skills and more complex developmental steps for children with less limited skills and were different for different clinical trial scenarios. Individual meaningful changes were described as important for the child's quality of life and to facilitate day-to-day caring. CONCLUSION: Meaningful change thresholds have not been evaluated in the DEE literature. This study was a preliminary qualitative approach to inform future studies that will aim to determine quantitative values of change, applicable to groups and within-person, to inform interpretation of specific clinical outcome assessments in individuals with a DEE.

Epilepsy in childhood and school performance: a nation-wide cohort study.

Childhood epilepsy has been linked to poor academic performance, but large-scale studies are lacking. In this nation-wide study of school-aged children, we examined the association between childhood epilepsy and school performance in standardized tests according to phenotypic and treatment-related characteristics. We performed a matched register-based cohort study of children born in Denmark (1997-2009) who participated in the Danish National School Test Programme between 2010 and 2019. We used population and health registers to identify children with epilepsy and a randomly sampled sex- and age-matched reference cohort without epilepsy (ratio 1:10). Norm-based test scores from language and mathematics reflecting performance as a percentile of the nation-wide distribution of scores (scale 1-100) were used to assess academic performance. Adjusted differences in mean standardized scores between children with and without epilepsy were estimated using linear regression models. Among 582 840 children participating in the School Test Programme, we identified 4659 (0.8%) children with epilepsy (52.8% males) and 46 590 matched reference children. Median age at epilepsy onset was 7.5 years (interquartile range: 4.0-10.6). Childhood epilepsy was associated with poorer school performance overall (mean score = 48.2 versus references = 56.7; adjusted difference = -6.7, 95% CI: -7.4 to -6.0), and worse performance was found in all epilepsy subgroups, including in 3534 children with uncomplicated epilepsy (i.e. no other pre-existing neurologic or intellectual disabilities and no identified possible cause for epilepsy; adjusted difference = -6.0, 95% CI: -6.8 to -5.2). No major variation by sex, age or subject was observed, but larger score differences were seen in children using antiseizure medication at time of testing (e.g. valproate monotherapy, adjusted difference = -9.3, 95% CI: -11.5 to -7.0 and lamotrigine monotherapy, adjusted difference = -13.1, 95% CI: -15.0 to -11.3) and in children with psychiatric comorbidity, especially epilepsy with comorbid intellectual disability (adjusted difference = -27.0, 95% CI: -30.0 to -23.9) and epilepsy with comorbid attention deficit/hyperactivity disorder (adjusted difference = -15.7, 95% CI: -19.0 to -12.4). Children with epilepsy scored significantly lower than their unaffected siblings (adjusted difference = -6.2, 95% CI: -7.1 to -5.4). In conclusion, childhood epilepsy was associated with impaired academic performance throughout schooling, which suggest that there is a widespread need for educational support of children with epilepsy, even when the child has no other comorbidities and when the epilepsy appears well-managed.

Measuring the inch stones for progress: Gross motor function in the developmental and epileptic encephalopathies.

OBJECTIVE: Developmental and epileptic encephalopathies (DEE) entail moderate to profound impairments in gross motor skills and mobility, which are poorly quantified with clinical outcomes assessments (COA) used in neuro-typical populations. We studied the motor domain of the Adaptive Behavior Assessment System-3 for ages 0-5 years (ABAS) used outside of its intended age range with a focus on raw scores. METHODS: In a cross-sectional survey, 117 parents of children with a variety of DEEs (ages 1-35 years, median = 9) completed the motor domain section of the ABAS. Floor and ceiling effects and associations with epilepsy-related factors were assessed with appropriate parametric and nonparametric statistical techniques. The sensitivity of the ABAS and additional measures of mobility borrowed from the cerebral palsy literature (Functional Activities Questionnaire (FAQ-22) walking level (FAQ-WL)) to different levels of the Functional Mobility Scale was determined. RESULTS: ABAS motor scores corresponded to a median age equivalent of 20.5 months (Inter-Quartile Range (IQR) 8-34). Most raw scores corresponded to standardized scores > 2 standard deviations below the ABAS standardization sample mean. ABAS raw scores demonstrated minimal floor and ceiling effects (<5%). In linear regression models, scores increased with age under 6 years (p < 0.0001) but flattened out thereafter. Scores varied substantially by DEE group (p < 0.001) and decreased with higher convulsive seizure frequency (<0.0001) and number of seizure medications (p < 0.001). ABAS and other motor scores were sensitive to important differences in mobility as represented by the FMS at 5 yards. Further, they correlated with declines in mobility function from 5 to 500 yards. SIGNIFICANCE: An out-of-range COA with raw scores may provide a measure of motor ability and mobility sensitive within the range of moderate to profound impairment seen in patients with DEE. This approach could shorten the time to appropriate COA development and ensure timely clinical trial readiness for novel therapies for rare DEEs.

Epilepsy and COVID 2021.

Coronavirus 19 (COVID-19) has infected over 400 million people worldwide. Although COVID-19 causes predominantly respiratory symptoms, it can affect other organs including the brain, producing neurological symptoms. People with epilepsy (PWE) have been particularly impacted during the pandemic with decreased access to care, increased stress, and worsening seizures in up to 22% of them probably due to multiple factors. COVID-19 vaccines were produced in a record short time and have yielded outstanding protection with very rare serious side effects. Studies have found that COVID-19 vaccination does not increase seizures in the majority of PWE. COVID-19 does not produce a pathognomonic EEG or seizure phenotype, but rather 1 that can be seen in other types of encephalopathy. COVID-19 infection and its complications can lead to seizures, status epilepticus and post-COVID inflammatory syndrome with potential multi-organ damage in people without pre-existing epilepsy. The lack of access to care during the pandemic has forced patients and doctors to rapidly implement telemedicine. The use of phone videos and smart telemedicine are helping to treat patients during this pandemic and are becoming standard of care. Investment in infrastructure is important to make sure patients can have access to care even during a pandemic.

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.

Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures: Genetic test results. Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

Staring Spells: How to Distinguish Epileptic Seizures from Nonepileptic Staring.

OBJECTIVE: To determine the nature of staring spells and factors distinguishing epileptic from nonepileptic staring spells, we studied the clinical and demographic features of children with staring spells referred to a regional new-onset seizure clinic. STUDY DESIGN: Our retrospective chart review encompassed 2818 consecutive patients evaluated in the new-onset seizure clinic between September 22, 2015, and March 19, 2018. We identified 121 patients with newly presenting staring spells. RESULTS: Sixty-two of 121 (51%) children were diagnosed with nonepileptic staring spells and 59 (49%) with epileptic seizures (24 with absence epilepsy, 35 with focal epilepsy). Patients with nonepileptic staring spells were younger (4.8 vs 7.1 years, P = .001) and more likely to have developmental delay (P = .005) than the seizure group. There was an 8.9-month delay on average from the onset of staring spells to the new-onset seizure clinic visit. The emergency department was a referral source for 80% (28/35) of focal seizures. In children with focal seizures, the staring spells typically lasted >1minute (29/35, 83%), whereas only 19 of 62 (31%) of children with nonepileptic staring spells had events lasting this long (P = .04). All children had a routine electroencephalography (EEG) on the day of new-onset seizure clinic visit. EEG was diagnostic in 100% (24/24) of absence seizures and 51% (18/35) of focal seizures. CONCLUSIONS: In children presenting with staring spells, the differential diagnosis of epileptic staring spells vs nonepileptic staring spells can be made by history and routine EEG. Staring was as likely to be epileptic as nonepileptic spells. Younger children with developmental delay were more likely to have nonepileptic events. Our simple approach based on event duration, postictal symptoms, and EEG allowed identification of epileptic staring on first visit to new-onset seizure clinic but requires validation in future prospective studies including long-term video EEG monitoring and follow-up.

Genetic Testing and Hospital Length of Stay in Neonates With Epilepsy.

BACKGROUND: We evaluated changes in genetic testing for neonatal-onset epilepsy and associated short-term outcomes over an 8-year period among a cohort of patients in the neonatal intensive care unit (NICU) at a single institution before and after the introduction of sponsored genetic epilepsy testing in January 2018. METHODS: Our primary outcome was a change in length of stay (LOS) after 2018. We also ascertained severity of illness with the Neonatal Sequential Organ Failure Assessment (nSOFA), type and result of genetic testing, turnaround time to molecular diagnosis (TAT), LOS, antiseizure medications (ASMs), and use of technology at discharge. We compared outcomes using nonparametric tests and difference-in-difference analysis. RESULTS: Fifty-three infants with genetic testing were included; 20 infants were tested after 2018. A total of 4160 infants in the NICU without genetic testing were used as reference. In the genetic testing group, LOS was 25 days (interquartile range [IQR] 5, 49) pre-2018 and 19 days (IQR 6, 19) post-2018 (P < 0.001 when compared with the reference population in the difference-in-difference analysis). TAT decreased from 51 days to 17 days after 2018 (P = 0.003). ASM number decreased from 4 (IQR 2, 5) to 2 post-2018 (IQR 1, 3) (P = 0.02). Over the same time periods there was no significant change in birth weight, maximum nSOFA score, or technology dependence. CONCLUSIONS: In this cohort, changes in genetic testing for neonatal-onset epilepsy were associated with shorter LOS that was not explained by changes in severity of illness, birth weight, or the average LOS in the NICU over time. Validation of these results in a larger, multicenter sample size is warranted.

COVID-19 vaccine in patients with Dravet syndrome: Observations and real-world experiences.

OBJECTIVE: Vaccination against the SARS-CoV-2 virus is a primary tool to combat the COVID-19 pandemic. However, vaccination is a common seizure trigger in individuals with Dravet syndrome (DS). Information surrounding COVID-19 vaccine side effects in patients with DS would aid caregivers and providers in decisions for and management of COVID-19 vaccination. METHODS: A survey was emailed to the Dravet Syndrome Foundation's Family Network and posted to the Dravet Parent & Caregiver Support Group on Facebook between May and August 2021. Deidentified information obtained included demographics and vaccination status for individuals with DS. Vaccine type, side effects, preventative measures, and changes in seizure activity following COVID-19 vaccination were recorded. For unvaccinated individuals, caregivers were asked about intent to vaccinate and reasons for their decision. RESULTS: Of 278 survey responses, 120 represented vaccinated individuals with DS (median age = 19.5 years), with 50% reporting no side effects from COVID-19 vaccination. Increased seizures following COVID-19 vaccination were reported in 16 individuals, but none had status epilepticus. Of the 158 individuals who had not received a COVID-19 vaccination, 37 were older than 12 years (i.e., eligible at time of study), and only six of these caregivers indicated intent to seek vaccination. The remaining 121 responses were caregivers to children younger than 12 years, 60 of whom indicated they would not seek COVID-19 vaccination when their child with DS became eligible. Reasons for vaccine hesitancy were fear of increased seizure activity and concerns about vaccine safety. SIGNIFICANCE: These results indicate COVID-19 vaccination is well tolerated by individuals with DS. One main reason for vaccine hesitancy was fear of increased seizure activity, which occurred in only 13% of vaccinated individuals, and none had status epilepticus. This study provides critical and reassuring insights for caregivers and health care providers making decisions about the safety of COVID-19 vaccinations for individuals with DS.

Progressive Worsening of Gait and Motor Abnormalities in Older Adults With Dravet Syndrome.

BACKGROUND AND OBJECTIVES: Relative to the pediatric population, there is limited information about Dravet syndrome (DS) in adults. In addition to some of the gait abnormalities reported in children with DS (such as crouch gait and ataxia), adults with this condition have other gait and motor disturbances. Our primary objective was to examine gait and motor manifestations in adults with DS. METHODS: This study includes a prospective arm where 6 patients (mean age, 32 years) were examined through a modified version of the Unified Parkinson's Disease Rating Scale (mUPDRS) in 2014 and again in 2019. mUPDRS scores were assigned to gait, resting tremors, facial expression, arising from a chair, posture, and body bradykinesia. The cross-sectional arm includes mUPDRS testing in patients who were not evaluated in 2014 and an instrumental gait analysis (IGA). These cross-sectional tests were done in the 2019-2020 period. The IGA was performed using ProtoKinetics software with a gait mat built with sensors and 2 cameras capturing the sagittal and coronal planes. The IGA was performed in a group of 17 patients with DS (mean age, 31 years); the control group consisted of 81 healthy individuals, whose mean age was 62 years. Regression analyses were performed for the IGA and mUPDRS data. RESULTS: Five out of 6 participants evaluated prospectively over 5 years experienced worsening of their parkinsonian manifestations, including gait. Two patients (47 and 51 years of age) who were initially ambulatory could no longer walk 5 years later. The cross-sectional analysis of mUPDRS in a larger group of adults showed that worse scores for arising from a chair (p = 0.04), body bradykinesia (p = 0.01), and gait (p = 0.0003) were positively associated with age. The IGA cross-sectional arm revealed that all 17 adults with DS had abnormal gait measures in all domains tested. This group of patients performed worse than the healthy and older control group. DISCUSSION: Although seizures may decrease in older adults with DS, this prospective and cross-sectional study showed that their motor symptoms and gait become progressively worse as they age.

Inequities in Therapy for Infantile Spasms: A Call to Action.

OBJECTIVE: The aim of this study was to determine whether selection of treatment for children with infantile spasms (IS) varies by race/ethnicity. METHODS: The prospective US National Infantile Spasms Consortium database includes children with IS treated from 2012 to 2018. We examined the relationship between race/ethnicity and receipt of standard IS therapy (prednisolone, adrenocorticotropic hormone, vigabatrin), adjusting for demographic and clinical variables using logistic regression. Our primary outcome was treatment course, which considered therapy prescribed for the first and, when needed, the second IS treatment together. RESULTS: Of 555 children, 324 (58%) were non-Hispanic white, 55 (10%) non-Hispanic Black, 24 (4%) non-Hispanic Asian, 80 (14%) Hispanic, and 72 (13%) other/unknown. Most (398, 72%) received a standard treatment course. Insurance type, geographic location, history of prematurity, prior seizures, developmental delay or regression, abnormal head circumference, hypsarrhythmia, and IS etiologies were associated with standard therapy. In adjusted models, non-Hispanic Black children had lower odds of receiving a standard treatment course compared with non-Hispanic white children (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.20-0.89; p = 0.02). Adjusted models also showed that children with public (vs. private) insurance had lower odds of receiving standard therapy for treatment 1 (OR, 0.42; CI, 0.21-0.84; p = 0.01). INTERPRETATION: Non-Hispanic Black children were more often treated with non-standard IS therapies than non-Hispanic white children. Likewise, children with public (vs. private) insurance were less likely to receive standard therapies. Investigating drivers of inequities, and understanding the impact of racism on treatment decisions, are critical next steps to improve care for patients with IS. ANN NEUROL 2022;92:32-44.