Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

OBJECTIVE: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS: Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE: Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

CDKL5 deficiency disorder and other infantile-onset genetic epilepsies.

AIM: To differentiate phenotypic features of individuals with CDKL5 deficiency disorder (CDD) from those of individuals with other infantile-onset epilepsies. METHOD: We performed a retrospective cohort study and ascertained individuals with CDD and comparison individuals with infantile-onset epilepsy who had epilepsy gene panel testing. We reviewed records, updated variant classifications, and compared phenotypic features. Wilcoxon rank-sum tests and χ2 or Fisher's exact tests were performed for between-cohort comparisons. RESULTS: We identified 137 individuals with CDD (110 females, 80.3%; median age at last follow-up 3 year 11 months) and 313 individuals with infantile-onset epilepsies (156 females, 49.8%; median age at last follow-up 5 years 2 months; 35% with genetic diagnosis). Features reported significantly more frequently in the CDD group than in the comparison cohort included developmental and epileptic encephalopathy (81% vs 66%), treatment-resistant epilepsy (95% vs 71%), sequential seizures (46% vs 6%), epileptic spasms (66% vs 42%, with hypsarrhythmia in 30% vs 48%), regression (52% vs 29%), evolution to Lennox-Gastaut syndrome (23% vs 5%), diffuse hypotonia (72% vs 36%), stereotypies (69% vs 11%), paroxysmal movement disorders (29% vs 17%), cerebral visual impairment (94% vs 28%), and failure to thrive (38% vs 22%). INTERPRETATION: CDD, compared with other suspected or confirmed genetic epilepsies presenting in the first year of life, is more often characterized by a combination of treatment-resistant epilepsy, developmental and epileptic encephalopathy, sequential seizures, spasms without hypsarrhythmia, diffuse hypotonia, paroxysmal movement disorders, cerebral visual impairment, and failure to thrive. Defining core phenotypic characteristics will improve precision diagnosis and treatment.

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first-line therapies.

OBJECTIVE: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. METHODS: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. RESULTS: We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p < .0001). Fourteen-day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p = .0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p < .0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD. SIGNIFICANCE: Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed.

Continuous electroencephalography (cEEG) in infants with congenital heart disease (CHD).

BACKGROUND: Neonates with congenital heart disease (CHD) undergoing cardiopulmonary bypass (CPB) surgery have increased risk of impaired neurodevelopmental outcomes secondary to brain injury. This study aims to characterize pre- and post-operative continuous EEG (cEEG) patterns to detect abnormal cerebral activity in infants with CHD and investigate whether an association exists between the degree of encephalopathy in pre- and post-operative cEEG. METHODS: This retrospective cohort study conducted between 2010 and 2018 at a tertiary hospital in Cleveland, OH included infants with CHD with cEEG monitoring, who underwent CPB surgery within first 6 months of life. RESULTS: Study included 77 patients, of which 61% were males who were operated at median age 6 days. Pre-operatively, 69% and 87% had normal cEEG and sleep-wake cycles, respectively. Post-operatively, 80% had abnormal cEEG. Longer circulatory arrest time and CPB were associated with lack of continuity (p 0.011), excessive discontinuity (p 0.007) and prolonged inter-burst interval (IBI) duration (p value < 0.001). A significant association existed between severity of encephalopathy in immediate and 24-h post-operative period (p value < 0.001). CONCLUSIONS: More than 80% of neonates with CHD have abnormal post-operative EEG. Longer circulatory arrest time and CPB were associated with lack of continuity, excessive discontinuity, and prolonged IBI duration on post-operative EEG. IMPACT: This study shows that majority of neonates with congenital heart disease (CHD) have normal pre-operative EEG with a continuous background and normal sleep-wake cycles. Also, 80% of neonates had abnormal post-operative EEG. Longer duration of arrest time and bypass time was associated with lack of continuity, excessive discontinuity, and prolonged IBI duration during post-operative EEG monitoring. These findings will help clinicians when counseling parents in the intensive care unit, risk stratification, and long-term neurodevelopmental monitoring in these high-risk patients.

Influences on the trajectory and subsequent outcomes in CDKL5 deficiency disorder.

OBJECTIVE: The study investigated the effect of seizure and medication burden at initial contact with the International CDKL5 Disorder Database on subsequent development and clinical severity and compared quality of life among those whose development progressed, remained stable, or regressed between baseline and follow-up. METHODS: The effects of seizure and medication burden at baseline (high or low) on the CDKL5 Disorder Severity Scores and CDKL5 Developmental Score (CDS) at follow-up were assessed using linear and negative binomial regressions, respectively, with adjustment for age at baseline, gender, and follow-up duration with and without genotype. Seizure and medication burden were defined by average daily seizure count (high, ≥5/day; low, <5/day) and number of antiseizure medications (high, ≥3/day; low, <3/day), respectively. The effects of change in CDS over time (improved, stable, or deteriorated) on Quality of Life Inventory-Disability (QI-Disability) total and domain scores at follow-up were assessed in those aged at least 3 years at follow-up using linear regression models with adjustment for baseline CDS, gender, and follow-up duration. RESULTS: The expected follow-up CDS was lower for individuals with high compared to low seizure burden at baseline (ß = -.49, 95% confidence interval [CI] = -.84 to -.13). The average total QI-Disability score was 5.6 (95% CI = -.2 to 11.5) points higher among those with improved compared with stable or deteriorating CDS and 8.5 (95% CI = 3.1-13.8) points lower for those with deteriorating compared to stable or improved CDS. SIGNIFICANCE: Our finding that later development showed slight improvement in those with better earlier seizure control even after adjustment for genotype suggests that the trajectory for an individual child is not necessarily predetermined and could possibly be influenced by optimal seizure management. This has implications for children's quality of life.

Treatment Practices and Outcomes in Continuous Spike and Wave during Slow Wave Sleep: A Multicenter Collaboration.

OBJECTIVES: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US. STUDY DESIGN: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables. RESULTS: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs. CONCLUSIONS: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.

Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability: A systematic review and meta-analysis.

OBJECTIVE: Clinical genetic sequencing is frequently utilized to diagnose individuals with neurodevelopmental disorders (NDDs). Here we perform a meta-analysis and systematic review of the success rate (diagnostic yield) of clinical sequencing through next-generation sequencing (NGS) across NDDs. We compare the genetic testing yield across NDD subtypes and sequencing technology. METHODS: We performed a systematic review of the PubMed literature until May 2020. We included clinical sequencing studies that utilized NGS in individuals with epilepsy, autism spectrum disorder (ASD), or intellectual disability (ID). Data were extracted, reviewed, and categorized according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two investigators performed clinical evaluation and grouping following the International League Against Epilepsy (ILAE) guidelines. Pooled rates of the diagnostic yield and 95% confidence intervals were estimated with a random-effects model. RESULTS: We identified 103 studies (epilepsy, N = 72; ASD, N = 14; ID, N = 21) across 32,331 individuals. Targeted gene panel sequencing was used in 73, and exome sequencing in 36 cohorts. Given highly selected patient cohorts, the diagnostic yield was 17.1% for ASD, 24% for epilepsy, and 28.2% for ID (23.7% overall). The highest diagnostic yield for epilepsy subtypes was observed in individuals with ID (27.9%) and early onset seizures (36.8%). The diagnostic yield for exome sequencing was higher than for panel sequencing, even though not statistically significant (27.2% vs 22.6%, P = .071). We observed that clinical sequencing studies are performed predominantly in countries with a high Inequality-adjusted Human Development Index (IHDI) (countries with sequencing studies: IHDI median = 0.84, interquartile range [IQR] = 0.09 vs countries without sequencing studies: IHDI median = 0.56, IQR = 0.3). No studies from Africa, India, or Latin America were identified, indicating potential barriers to genetic testing. SIGNIFICANCE: This meta-analysis and systematic review provides a comprehensive overview of clinical sequencing studies of NDDs and will help guide policymaking and steer decision-making in patient management.

Digital conversations about suicide among teenagers and adults with epilepsy: A big-data, machine learning analysis.

OBJECTIVE: Digital media conversations can provide important insight into the concerns and struggles of people with epilepsy (PWE) outside of formal clinical settings and help generate useful information for treatment planning. Our study aimed to explore the big data from open-source digital conversations among PWE with regard to suicidality, specifically comparing teenagers and adults, using machine learning technology. METHODS: Advanced machine-learning empowered methodology was used to mine and structure open-source digital conversations of self-identifying teenagers and adults who endorsed suffering from epilepsy and engaged in conversation about suicide. The search was limited to 12 months and included only conversations originating from US internet protocol (IP) addresses. Natural language processing and text analytics were employed to develop a thematic analysis. RESULTS: A total of 222 000 unique conversations about epilepsy, including 9000 (4%) related to suicide, were posted during the study period. The suicide-related conversations were posted by 7.8% of teenagers and 3.2% of adults in the study. Several critical differences were noted between teenagers and adults. A higher percentage of teenagers are: fearful of "the unknown" due to seizures (63% vs 12% adults), concerned about social consequences of seizures (30% vs 21%), and seek emotional support (29% vs 19%). In contrast, a significantly higher percentage of adults show a defeatist ("given up") attitude compared to teenagers (42% vs 4%). There were important differences in the author's determined sentiments behind the conversations among teenagers and adults. SIGNIFICANCE: In this first of its kind big data analysis of nearly a quarter-million digital conversations about epilepsy using machine learning, we found that teenagers engage in an online conversation about suicide more often than adults. There are some key differences in the attitudes and concerns, which may have implications for the treatment of younger patients with epilepsy.

Screening for suicidality and its relation to undiagnosed psychiatric comorbidities in children and youth with epilepsy.

INTRODUCTION: Depression and anxiety are the most common psychiatric comorbidities in children and youth with epilepsy (CYE) and known to contribute to suicidality among them. However, not much is known about suicidality in CYE without established psychiatric comorbidities. Our research aimed to fill this knowledge gap and correlate this latent suicidality with screening tests for depression and anxiety. METHOD: After Institutional Review Board (IRB) approval, CYE who attended the epilepsy clinic or underwent testing in the pediatric epilepsy monitoring unit at the Cleveland Clinic and lacked established psychiatric diagnosis were enrolled. They filled out self-reported, validated scales for screening of depression, anxiety, and suicidality (Center for Epidemiological Studies Depression Scale for Children [CES-DC], Screen for Child Anxiety Related Emotional Disorders [SCARED], and Ask Suicide-Screening Questions [ASQ], respectively). Univariate descriptive statistics along with χ2 test of association and independent Student's t-test were performed for statistical analysis. RESULTS: A total of 119 (54.6% females) CYE were included in the study. Close to a third (30.2%) of CYE were positive for anxiety on SCARED, and 41.2% were positive for depression based on CSE-DC scoring. A total of 13 (10.9%) CYE indicated suicidality by answering at least one positive response on ASQ. The SCARED had a low positive correlation with the ASQ (r = 0.32) but a moderate positive correlation with the CES-DC (r = 0.64). CONCLUSION: We found that a small but significant 11% of CYE without any established psychiatric diagnosis expressed suicidality on a self-reported questionnaire. This highlights the importance of using psychiatry screening tests in all CYE. Future research using a larger, diversified cohort is needed to confirm our findings.

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development.

OBJECTIVE: The cyclin-dependent kinase like 5 (CDKL5) gene is a known cause of early onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure-free periods and cortical visual impairment (CVI), (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones. METHODS: This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving seven primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit. RESULTS: Ninety-two patients with CDD were seen during the enrollment period. Eighteen were male (19%); median age at last visit was 5 years (interquartile range = 2.0-11.0). Eighty-one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor-tonic-spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty-three percent of patients experienced a seizure-free period ranging from 1 to >12 months, but only 6% were still seizure-free at the last visit. CVI was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. CVI was correlated with reduced milestone achievement after adjusting for age at last visit and a history of hypsarrhythmia. SIGNIFICANCE: The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. CVI is a common feature in CDD and is correlated with achieving fewer milestones.

Variation of the prevalence of pediatric polypharmacy: A scoping review.

PURPOSE: To examine the range of prevalence of pediatric polypharmacy in literature through a scoping review, focusing on factors that contribute to its heterogeneity in order to improve the design and reporting of quality improvement, pharmacovigilance, and research studies. METHODS: We searched Ovid Medline, PubMed, EMBASE, CINAHL, Ovid PsycINFO, Cochrane CENTRAL, and Web of Science Core Collection databases for studies with concepts of children and polypharmacy, along with a hand search of the bibliographies of six reviews and 30 included studies. We extracted information regarding study design, disease conditions, and prevalence of polypharmacy. RESULTS: Two hundred eighty-four studies reported prevalence of polypharmacy. They were more likely to be conducted in North America (37.7%), published after 2010 (44.4%), cross-sectional (67.3%), in outpatient settings (59.5%). Prevalence ranged from 0.9% to 98.4%, median 39.7% (interquartile range [IQR] 22.0%-54.0%). Studies from Asia reported the highest median prevalence of 45.4% (IQR 27.3%-61.0%) while studies from North America reported the lowest median prevalence of 30.4% (IQR 14.7%-50.2%). Prevalence decreased over time: median 45.6% before 2001, 38.1% during 2001 to 2010, and 34% during 2011 to 2017. Studies involving children under 12 years had a higher median prevalence (46.9%) than adolescent studies (33.7%). Inpatient setting studies had a higher median prevalence (50.3%) than studies in outpatient settings (38.8%). Community level samples, higher number and duration of medications defining polypharmacy, and psychotropic medications were associated with lower prevalence. CONCLUSIONS: The prevalence of pediatric polypharmacy is high and variable. Studies reporting pediatric polypharmacy should account for context, design, polypharmacy definition, and medications evaluated.

Increasing utilization of pediatric epilepsy surgery in the United States between 1997 and 2009.

OBJECTIVE: To examine national trends of pediatric epilepsy surgery usage in the United States between 1997 and 2009. METHODS: We performed a serial cross-sectional study of pediatric epilepsy surgery using triennial data from the Kids' Inpatient Database from 1997 to 2009. The rates of epilepsy surgery for lobectomies, partial lobectomies, and hemispherectomies in each study year were calculated based on the number of prevalent epilepsy cases in the corresponding year. The age-race-sex adjusted rates of surgeries were also estimated. Mann-Kendall trend test was used to test for changes in the rates of surgeries over time. Multivariable regression analysis was also performed to estimate the effect of time, age, race, and sex on the annual incidence of epilepsy surgery. RESULTS: The rates of pediatric epilepsy surgery increased significantly from 0.85 epilepsy surgeries per 1,000 children with epilepsy in 1997 to 1.44 epilepsy surgeries per 1,000 children with epilepsy in 2009. An increment in the rates of epilepsy surgeries was noted across all age groups, in boys and girls, all races, and all payer types. The rate of increase was lowest in blacks and in children with public insurance. The overall number of surgical cases for each study year was lower than 35% of children who were expected to have surgery, based on the estimates from the Connecticut Study of Epilepsy. SIGNIFICANCE: In contrast to adults, pediatric epilepsy surgery numbers have increased significantly in the past decade. However, epilepsy surgery remains an underutilized treatment for children with epilepsy. In addition, black children and those with public insurance continue to face disparities in the receipt of epilepsy surgery.

Pre-operative evaluation in pediatric patients with cortical dysplasia.

INTRODUCTION: Focal cortical dysplasia (FCD) is an important cause of refractory seizures and catastrophic epilepsy in infants and children who had epilepsy surgery. AIMS OF THE REVIEW: This manuscript will discuss age-related unique clinical characteristics in evaluation of infants and young children because the understanding of these age-related features is critical in selecting children who can benefit from epilepsy surgery. In addition, we will review the non-invasive tools available for the presurgical evaluation of children with FCD and their individual contribution to the formulation of the presurgical hypothesis.

Continuous Electroencephalogram (cEEG) Findings and Neurodevelopmental Outcomes in Neonates with Congenital Heart Disease (CHD) at 12-24 Months of Age.

OBJECTIVE: This study aims to assess the role of continuous EEG (cEEG) background patterns and duration of cross-clamp time and cardiopulmonary bypass (CPB) in children with congenital heart disease (CHD) undergoing cardiac surgery and its correlation with abnormal neurodevelopmental outcomes at 12-24 months on Bayley Scales of Infant and Toddler Development (BSID-III). METHODS: This retrospective cohort study included infants with CHD and cEEG monitoring, who underwent surgery by 44 weeks gestational age. RESULTS: 34 patients were included, who were operated at median age - 7 days. Longer duration of cross- camp time was associated with poor language composite scores (LCS) (p value = 0.036). A significant association existed between severity of encephalopathy in 24-hour post-operative period and poor LCS (p value = 0.026). CONCLUSION: Majority of neonates with CHD have below average cognitive, language and motor composite scores on BSID-III. Longer duration of cross-clamp time and severity of encephalopathy during 24-hour post-operative EEG monitoring are associated with poor LCS.

CDKL5 Deficiency Disorder: Some Lessons Learned 20 Years After the First Description.

Loss of function variants in the Cyclin-dependent kinase-like 5 gene (CDKL5) causes CDKL5 deficiency disorder (CDD). Most cases of CDD are due to a de novo missense or truncating variants. The CDKL5 gene was discovered in 1998 as part of the genomic mapping of the chromosome Xp22 region that led to the discovery of the serine-threonine kinases STK9. Since then, there have been significant advancements in the description of the disease in humans, the understanding of the pathophysiology, and the management of the disease. There have been many lessons learned since the initial description of the condition in humans in 2003. In this article, we will focus on pathophysiology, clinical manifestations, with particular focus on seizures because of its relevance to the medical practitioners and researchers and guidelines for management. We finalize the manuscript with the voice of the parents and caregivers, as discussed with the 2019 meeting with the Food and Drug Administration.

Modification of a parent-report sleep scale for individuals with CDKL5 deficiency disorder: a psychometric study.

STUDY OBJECTIVES: Sleep difficulties are common in CDKL5 deficiency disorder (CDD), a developmental and epileptic encephalopathy (DEE). This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Daytime Somnolence (DOES) and Sleep Breathing Disorders (SBD) domains of the Sleep Disturbance Scale for Children (SDSC) for CDD. METHODS: A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a US Centers of Excellence clinic or registered with the International CDKL5 Disorder Database. RESULTS: The median age was 10.3 years (range 3.2 - 40.7 years) and 105 (84%) were female. Two of the three SBD items related were not observed by most respondents and analysis was restricted to the DIMS and DOES domains. Using all items in the initial confirmatory factor analysis, two items in the DIMS domain and one item in the DOES domain loaded poorly. After deleting these items and repeating the analysis, item loading (0.524-0.814) and internal consistency (DIMS: 0.78, DOES: 0.76) statistics were good. The square of the inter-domain correlation coefficient was 0.17, less than Average Variance Extracted values for both domains and indicating good discriminant validity. The Tucker-Lewis and Comparative Fit indices were slightly lower than the threshold of >0.9 for establishing goodness of fit. CONCLUSIONS: The modified DIMS and DOES domains from the SDSC could be suitable clinical outcome assessments of insomnia and related impairments in CDD and potentially other DEE conditions.

Healthcare utilization and clinical characteristics of genetic epilepsy in electronic health records.

Understanding the clinical characteristics and medical treatment of individuals affected by genetic epilepsies is instrumental in guiding selection for genetic testing, defining the phenotype range of these rare disorders, optimizing patient care pathways and pinpointing unaddressed medical need by quantifying healthcare resource utilization. To date, a matched longitudinal cohort study encompassing the entire spectrum of clinical characteristics and medical treatment from childhood through adolescence has not been performed. We identified individuals with genetic and non-genetic epilepsies and onset at ages 0-5 years by linkage across the Cleveland Clinic Health System. We used natural language processing to extract medical terms and procedures from longitudinal electronic health records and tested for cross-sectional and temporal associations with genetic epilepsy. We implemented a two-stage design: in the discovery cohort, individuals were stratified as being 'likely genetic' or 'non-genetic' by a natural language processing algorithm, and controls did not receive genetic testing. The validation cohort consisted of cases with genetic epilepsy confirmed by manual chart review and an independent set of controls who received negative genetic testing. The discovery and validation cohorts consisted of 503 and 344 individuals with genetic epilepsy and matched controls, respectively. The median age at the first encounter was 0.1 years and 7.9 years at the last encounter, and the mean duration of follow-up was 8.2 years. We extracted 188,295 Unified Medical Language System annotations for statistical analysis across 9659 encounters. Individuals with genetic epilepsy received an earlier epilepsy diagnosis and had more frequent and complex encounters with the healthcare system. Notably, the highest enrichment of encounters compared with the non-genetic groups was found during the transition from paediatric to adult care. Our computational approach could validate established comorbidities of genetic epilepsies, such as behavioural abnormality and intellectual disability. We also revealed novel associations for genitourinary abnormalities (odds ratio 1.91, 95% confidence interval: 1.66-2.20, P = 6.16 × 10-19) linked to a spectrum of underrecognized epilepsy-associated genetic disorders. This case-control study leveraged real-world data to identify novel features associated with the likelihood of a genetic aetiology and quantified the healthcare utilization of genetic epilepsies compared with matched controls. Our results strongly recommend early genetic testing to stratify individuals into specialized care paths, thus improving the clinical management of people with genetic epilepsies.

Epilepsy with eyelid myoclonia in the setting of de novo pathogenic variant in ATP1A3.

Mutations in the ATP1A3 gene have been associated with several syndromes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. In this clinical commentary, we report a 2-year-old female patient with de novo pathogenic variant in the ATP1A3 gene associated with an early-onset form of epilepsy with eyelid myoclonia. The patient had frequent eyelid myoclonia occurring 20-30 times per day, without loss of awareness or other motor manifestations. EEG showed generalized polyspikes and spike-and-wave complexes maximal in the bifrontal regions, with prominent eye closure sensitivity. A sequencing-based epilepsy gene panel revealed a de novo pathogenic heterozygous variant in ATP1A3. The patient showed some response to flunarizine and clonazepam. This case highlights the importance of considering ATP1A3 mutations in the differential diagnosis of early-onset epilepsy with eyelid myoclonia and the potential benefit of flunarizine in improving language and coordination development in patients with ATP1A3-related disorders.

Pediatric anti-NMDA-receptor autoimmune encephalitis in siblings: Developmental, Electrophysiologic, and Genetic Implications.

BACKGROUND: Anti-NMDAR encephalitis is a leading cause of autoimmune encephalitis in children. Untreated disease can lead to long-term neurological disability. CASE REPORT: We present siblings with pediatric-onset anti-NMDAR encephalitis. One was treated early, while the other's diagnosis and treatment were delayed by several years. Developmental, electrophysiologic, and genetic implications are discussed. CONCLUSION: Anti-NMDAR encephalitis is a severely debilitating disease that often requires prompt initiation and early escalation in treatment. Delayed treatment may lead to irreversible neurological sequalae. Further studies exploring associations between timing and tier of treatment initiation and longitudinal outcomes are needed.

The development, content and response process validation of a caregiver-reported severity measure for CDKL5 deficiency disorder.

BACKGROUND: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity. METHODS: We conducted cognitive interviews with 15 parent caregivers of 1-39-year-old children with CDD. Caregivers discussed their understanding and concerns regarding appropriateness of both questions and answer options. Item wording and questionnaire structure were adjusted iteratively to ensure questions were understood as intended. RESULTS: The CCSA was refined during three rounds of cognitive interviews into two measures: (1) the CDD Developmental Questionnaire - Caregiver (CDQ-Caregiver) focused on developmental skills, and (2) the CDD Clinical Severity Assessment - Caregiver (CCSA-Caregiver) focused on symptom severity. Branching logic was used to ensure questions were age and skill appropriate. Initial pilot data (n = 11) suggested no floor effects. CONCLUSIONS: This study modified the caregiver portion of the initial CCSA and provided evidence for its content and response process validity.