A quantitative cross-sectional study of the burden of caring for patients with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex-associated epilepsy in Japan.

INTRODUCTION: Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)-associated epilepsy are rare conditions associated with severe childhood-onset epilepsy. Caregivers play a critical role in the patients' care and may experience significant psychosocial and socioeconomic burden. This cross-sectional study determined the burden of caring for patients with these rare epilepsy conditions in Japan. METHODS: A quantitative online survey was used to assess patients' and caregivers' characteristics and the caregivers' emotional state, among others. Several validated questionnaires were used: the Hospital Anxiety and Depression Scale (HADS; 0-21 score) assessed the caregivers' emotional wellbeing, the Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM; 0-100 score) assessed the health-related quality of life (HRQoL) of the caregivers and their families, and the Work Productivity and Activity Impairment General Health (WPAI:GH; 0-100 % score) questionnaire assessed work productivity. RESULTS: A total of 36 caregivers responded (median [interquartile range (IQR)] age 43.5 [39.5, 48.3] years; 33/36 [92 %] female; 13/36 [36 %] working part-time and 13/36 [36 %] not working). Participants cared for 7/36 (19 %), 19/36 (53 %), and 10/36 (28 %) patients with LGS, DS, and TSC, respectively (median [IQR] age, 11.0 [6.8, 16.3] years; age at first seizure, 0 [0, 0] years). Patients received a median (IQR) of 4 (3, 5) treatment drug types. Patients experienced median (IQR) 3.0 (0, 21.0) epileptic seizures in the previous week; 28/36 (78 %) had severe intellectual disabilities, and 34/36 (94 %) had developmental delays. Caregivers reported stress (17/36 [47 %]), sleep problems (13/36 [36 %]), and anxiety (12/36 [33 %]). They spent a median (IQR) of 50.0 (17.5, 70.0) hours caregiving in the previous week, with 3.0 (1.0, 11.0) hours of seizure-specific care. Caregivers reported that their lives would be easier with a median (IQR) of 1.5 (0, 5.0) hours fewer per week caring for patients during/following seizures. Median HADS scores were 9.5 ('suspected anxiety diagnosis') and 7.5 ('no depression') for caregivers, and PedsQL FIM Total median score was 60.1, indicating HRQoL impairment for the caregiver and their family. WPAI:GH scores for paid workers indicated important work impairment. Higher caregiving hours (≥ 21 h vs. < 21 h in the previous week) resulted in higher caregiver burden as indicated by the HADS Total score (p = 0.0062) and PedsQL FIM Total score (p = 0.0007). CONCLUSIONS: Caregivers of patients with LGS, DS, or TSC in Japan experience a significant time burden, reduced HRQoL, and high level of work/activity impairment. Caregivers provide round-the-clock care to patients and rely on family and specialized caring services to help manage the increased caregiving time, which tends to be associated with greater emotional burden and HRQoL impact.

A systematic literature review on the global epidemiology of Dravet syndrome and Lennox-Gastaut syndrome: Prevalence, incidence, diagnosis, and mortality.

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5-28, prevalence = 5.8-60.8; DS: incidence proportion = 2.2-6.5, prevalence = 1.2-6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6-9.2 years; LGS, 2-15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person-years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.

Natural history of rare diseases using natural language processing of narrative unstructured electronic health records: The example of Dravet syndrome.

OBJECTIVE: The increasing implementation of electronic health records allows the use of advanced text-mining methods for establishing new patient phenotypes and stratification, and for revealing outcome correlations. In this study, we aimed to explore the electronic narrative clinical reports of a cohort of patients with Dravet syndrome (DS) longitudinally followed at our center, to identify the capacity of this methodology to retrace natural history of DS during the early years. METHODS: We used a document-based clinical data warehouse employing natural language processing to recognize the phenotype concepts in the narrative medical reports. We included patients with DS who have a medical report produced before the age of 2 years and a follow-up after the age of 3 years ("DS cohort," 56 individuals). We selected two control populations, a "general control cohort" (275 individuals) and a "neurological control cohort" (281 individuals), with similar characteristics in terms of gender, number of reports, and age at last report. To find concepts specifically associated with DS, we performed a phenome-wide association study using Cox regression, comparing the reports of the three cohorts. We then performed a qualitative analysis of the surviving concepts based on their median age at first appearance. RESULTS: A total of 76 concepts were prevalent in the reports of children with DS. Concepts appearing during the first 2 years were mostly related with the epilepsy features at the onset of DS (convulsive and prolonged seizures triggered by fever, often requiring in-hospital care). Subsequently, concepts related to new types of seizures and to drug resistance appeared. A series of non-seizure-related concepts emerged after the age of 2-3 years, referring to the nonseizure comorbidities classically associated with DS. SIGNIFICANCE: The extraction of clinical terms by narrative reports of children with DS allows outlining the known natural history of this rare disease in early childhood. This original model of "longitudinal phenotyping" could be applied to other rare and very rare conditions with poor natural history description.

Caregiver reported behavior, sleep and quality of life in children with Dravet syndrome: A population-based study.

OBJECTIVE: The aim of this population-based study was to assess behavior, sleep, and quality of life, and explore factors associated with these in children with Dravet syndrome. METHODS: The Developmental Behavior Checklist, the Insomnia Severity Index, and a global question regarding quality of life from the Epilepsy and Learning Disabilities Quality of Life scale were completed by primary caregivers of 42/48 Swedish children with Dravet syndrome, born 2000-2018. Factors associated with problems with insomnia, behavior and quality of life were analyzed using multivariable linear regression. RESULTS: Scores indicating significant behavioral problems were seen in 29/40 (72 %) children, scores indicating moderate or severe clinical insomnia in 18/42 (43 %) and scores indicating poor or very poor quality of life in 7/41 (17 %). On multivariable analysis, autistic symptoms were significantly associated with behavioral problems (p = 0.013), side-effects of anti-seizure medications (ASMs) were associated with insomnia (p = 0.038), whilst insomnia was significantly associated with poor quality of life (p = 0.016). SIGNIFICANCE: Dravet syndrome in children is associated with significant problems with behavior, sleep and quality of life. There is a need to optimize treatment via ASMs and develop and evaluate interventions to treat behavioral and sleep difficulties to optimize outcomes.

SCN1A Gene Mutations in Indian Children With Epilepsy: Single Center Experience.

OBJECTIVE: To study prevalence of SCN1A gene mutations in complex seizure disorders. METHODS: Retrospective laboratory based study on samples sent for molecular diagnosis in complex seizure disorders. Exome sequencing was performed. Phenotype- genotype correlation was done for patients showing variants in SCN1A gene. RESULTS: 364 samples were evaluated; of which, 54% were of children below 5 years of age. SCN1A mutations were seen in 50 samples of patients with complex seizure disorders; 44 variants were identified. Types of seizure disorders commonly associated were Dravet syndrome and genetic epilepsy with febrile seizures. CONCLUSIONS: SCN1A mutations are common in complex seizure disorders, especially Dravet syndrome. Early identification of SCN1A gene in etiology is important for selection of correct antiepileptic and counselling.

The ketogenic diet for Dravet syndrome: A multicenter retrospective study.

OBJECTIVE: The ketogenic diet (KD) is one of the main treatments for drug-resistant epilepsy. However, there have been few multicenter reports on the use of the KD for the treatment of Dravet syndrome (DS). The aim of this study was to analyze the efficacy and safety of this approach based on a large number of multicenter cases. METHODS: This was a retrospective, multicenter cohort study from 14 centers in China. All patients were treated with the KD. We compared the effects of KD intervention time, age, and other factors. RESULTS: From March 2014 to March 2020, we treated 114 patients with DS with the KD. The male-to-female ratio was 67:47. The KD median initiation age was 3 y and 4 mo, and the median number of antiseizure medications (ASMs) was 2.4. KD therapy was the first choice for three patients. Exactly 10.5% of the patients started KD therapy after failure of the first ASM therapy, with 35.1% after failure of the second, 44.7% after the third, and 7% after the fourth or more. After KD therapy for 1, 3, 6, and 12 mo, the seizure-free rates were 14%, 32.5%, 30.7%, and 19.3%, respectively; KD efficacy (≥50% reduction in seizure frequency) were 57.9%, 76.3%, 59.6%, and 43%, respectively; the retention rates were 97.4%, 93%, 71.9%, and 46.5%, respectively; and the rates of adverse events were 25.2%, 19.9%, 11%, and 5.7%, respectively. CONCLUSIONS: Real-world, multicenter data analysis showed that the KD is effective for patients with DS and has a low incidence of side effects.

Intellectual functioning and adaptive behaviour in children with Dravet syndrome: A population-based study.

AIM: To identify, on a population basis, the prevalence of intellectual disability in children with Dravet syndrome, profiles on a measure of adaptive behaviour, and factors associated with intellectual functioning and adaptive behaviour. METHOD: Forty-two out of 48 children with Dravet syndrome living in Sweden, born between 1st January 2000 and 31st December 2018, underwent assessment of intellectual functioning and adaptive behaviour. Factors associated with level of intellectual functioning and adaptive behaviour were analysed. RESULTS: Eight-six per cent (n = 36) of the children fulfilled DSM-5 criteria for intellectual disability (29% [n = 12] mild intellectual disability, 24% [n = 10] moderate intellectual disability, 33% [n = 14] severe intellectual disability, 0% profound intellectual disability) and 93% (n = 39) had an adaptive behaviour composite more than two standard deviations below the mean. Communication was a significant weakness compared with daily living skills (p < 0.001; mean difference 95% confidence interval [CI] -8.193 to -4.092) and socialization (p = 0.001; mean difference 95% CI 6.511 to -1.775) on the Vineland Adaptive Behavior Scales, Second Edition. The only factors significantly associated with both decreased adaptive behaviour and presence of severe intellectual disability was the presence of increased autistic symptoms and younger age. INTERPRETATION: Children with Dravet syndrome have a very high level of intellectual disability and almost all have significant deficits in adaptive behaviour. Greater deficits in adaptive behaviour and greater severity of intellectual disability are associated with the presence of increased autistic symptoms, highlighting the need for comprehensive neurodevelopmental assessment for all affected children. WHAT THIS PAPER ADDS: Eighty-six per cent (n = 36) of children with Dravet syndrome fulfilled criteria for intellectual disability. Ninety-three per cent (n = 39) of children with Dravet syndrome had significant deficits in adaptive behaviour. Communication was a significant weakness on a measure of adaptive behaviour. Increased autistic symptoms were associated with greater deficits in cognition/adaptive behaviour. Older age and earlier status epilepticus were associated with decreased adaptive behaviour.

Anesthetic considerations in Dravet syndrome.

We describe a two-year-old boy with Dravet syndrome, a severe genetic epilepsy, who developed a generalized tonic-clonic seizure immediately following an intravenous bolus of lidocaine given for propofol pain amelioration during induction of anesthesia for emergency gastroscopy. Although lidocaine has not specifically been reported as potentiating seizures in Dravet syndrome, it is well-established that sodium channel blockers can worsen seizures in this population.

Prevalence and healthcare resource utilization of patients with Dravet syndrome: Retrospective linkage cohort study.

PURPOSE: Prevalence, demography, antiseizure medication (ASM) usage, healthcare resource utilization (HCRU), and mortality of Dravet syndrome (DS) in the UK were investigated using primary and secondary care data in this retrospective cohort study. METHODS: Patients with confirmed DS were anonymously identified from the UK Clinical Practice Research Datalink (CPRD) GOLD database (01/01/1987-31/10/2018) using the DS Read Codes (F25G.11 or F25G.00). Probable DS was identified using the International Classification of Diseases-10/Read Code for epilepsy plus stiripentol or potassium bromide prescription. CPRD data were linked to the Hospital Episode Statistics database and Office for National Statistics to calculate HCRU and mortality. RESULTS: The prevalence of confirmed (n = 32; 1.1/100,000) and probable (n = 22; 0.6/100,000) DS in 2017 was 1.5/100,000. Most patients with DS (confirmed, n = 22/28; probable, n = 8/14) were aged <18 years in 2017. Mean (standard deviation) ASM usage was 5.5 (2.7) in confirmed DS and 7.6 (3.8) in probable DS, over 3.4 (3.5) years and 10.0 (6.2) years of follow-up, respectively. HCRU (per patient-year) was similarly high in patients with confirmed and probable DS; mainly consisting of general practitioner consultations (mean, 4.8-7.9), outpatient visits (5.6-8.3), hospital admissions (0.9-4), and emergency department visits (0.3-2.3). Fewer than five deaths were recorded in patients with confirmed and probable DS. CONCLUSION: Using linked national healthcare databases, our study showed that the UK prevalence of DS recorded in primary care was low, and most cases were in patients aged <18 years. HCRU and ASM usage were similarly high in confirmed or probable DS.

Dravet syndrome in children-A population-based study.

OBJECTIVE: The aim was to describe age at diagnosis, cumulative incidence, SCN1A variants, mortality, seizure types and treatments in children with Dravet Syndrome (DS) in Sweden. METHODS: Children diagnosed with DS, born between January 1st 2000 and December 31st 2018 were included in a population-based study. Clinical data, frequency of seizure types and treatments were collected from caregivers and medical records in 42 children. Age at diagnosis, cumulative incidence and treatment were compared between children born in Sweden 2000-2009 and 2010-2018. RESULTS: We identified 55 children with DS, 53 were born in Sweden. Three children had died of definite, probable, or possible sudden unexpected death in epilepsy, one of acute anoxic brain injury and three of pneumonia or pneumonitis. Median age at death was 4.7 (range 3.3-11) years. In 49/53 children with known SCN1A status, a pathogenic/likely pathogenic variant of SCN1A was detected. In two a SCN1A variant of unknown significance was found. For children born in Sweden 2010-2018, median age at DS diagnosis was lower (1.6 vs 4.5 years, p = 0.001) and cumulative incidence higher (1/33,000 vs 1/46,000 live-born children, p = 0.03), compared to children born in 2000-2009. The most common seizure types were focal to bilateral tonic clonic (n = 41/42) and myoclonic (n = 35/42). Tonic seizures were reported in 25/42 children. Sodium-channel inhibitors had been used in 9/24 children born in 2010-2018 and 17/18 children born in 2000-2009 (p = 0.001). SIGNIFICANCE: A SCN1A variant that could explain the syndrome was found in over 90% of children. Tonic seizures seem to be more frequent than earlier described. Median age at diagnosis was lower, cumulative incidence higher and use of contra-indicated sodium-channel inhibitors less common for children born in 2010-2018 compared with children born in 2000-2009. This could indicate an increased awareness of DS.

Epidemiology, healthcare resource use, and mortality in patients with probable Dravet syndrome: A population-based study on German health insurance data.

OBJECTIVE: Ten-year retrospective study to assess burden of illness in patients with probable Dravet syndrome (DS) identified from German healthcare data. METHODS: In the absence of an International Classification of Diseases code, patients with probable DS were identified using a selection algorithm considering diagnoses and drug prescriptions. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, annual hospitalization rate (AHR) and length of stay (LOS), medication use, and mortality. RESULTS: In the final study year, 64 patients with probable DS (mean [range] age: 33.2 [3-82] years; male: 48%) were identified. Prevalence: 4.7 per 100,000 people. During the study, 160 patients with probable DS were identified and followed up for 1,261 patient-years. Mean cost of healthcare was €11,048 per patient-year (PPY), mostly attributable to inpatient care (47%), medication (26%), and services and devices (19%). Annual healthcare costs were significantly greater for those with prescribed rescue medication (15% of patient-years) vs. without (€16,123 vs. €10,125 PPY, p < 0.001). Mean (standard deviation [SD]) AHR and LOS were 1.1 (1.7) and 17.5 (33.5) days PPY. AHR was significantly greater in patients with prescribed rescue medication vs. without (1.6 [2.0] vs. 1.0 [1.6] PPY, p < 0.001). Mean (SD) number of antiseizure medications prescribed was 2.6 (1.2) PPY and 5.0 (2.5) over the entire observable time for each patient. Mortality rate was significantly higher for probable DS vs. matched controls (11.88% [19 events] vs. 1.19% [172 events], p < 0.001). CONCLUSION: Probable DS is associated with substantial healthcare costs in Germany.

Dravet syndrome: Effects on informal caregivers' mental health and quality of life - A systematic review.

BACKGROUND: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy, with predictable negative consequences for informal caregivers' mental health. This systematic review aimed to evaluate the representativeness of depression, anxiety, and burden in these caregivers and assess their quality of life. METHODS: The PRISMA recommendations were followed, and a comprehensive search was conducted on PubMed/MEDLINE, WoS and Scopus databases, without date or language limits. Only observational quantitative studies on adult informal caregivers of patients with DS were considered. RESULTS: Of 876 records found, 21 full-text articles were assessed and only 6 met the inclusion criteria. The latter have mostly a cross-sectional design and include samples composed by 19 to 742 caregivers, mainly mothers/females. Most of the study participants had a Bachelor's degree/higher educational level and were married. An important incidence of depression and anxiety on DS caregivers was reported, with significantly higher levels compared with population norms and with carers of other patients with epilepsy. Depression/anxiety were shown to be significantly associated with caregivers' fatigue and compromised sleep quality. Other important aspects of burden have been identified; however, comparisons between studies were not possible as different scales were used. Caregivers' health-related quality of life is also affected, with mothers reporting a worse perception on this domain. CONCLUSIONS: Mental health and quality of life of DS caregivers are compromised, with mothers bearing an apparently greater burden. Studies using validated instruments for this population to assess the previously considered outcomes are needed, in order to inform the development of preventive strategies and problem-oriented interventions.

Assessing seizure burden in pediatric epilepsy using an electronic medical record-based tool through a common data element approach.

OBJECTIVE: Improvement in epilepsy care requires standardized methods to assess disease severity. We report the results of implementing common data elements (CDEs) to document epilepsy history data in the electronic medical record (EMR) after 12 months of clinical use in outpatient encounters. METHODS: Data regarding seizure frequency were collected during routine clinical encounters using a CDE-based form within our EMR. We extracted CDE data from the EMR and developed measurements for seizure severity and seizure improvement scores. Seizure burden and improvement was evaluated by patient demographic and encounter variables for in-person and telemedicine encounters. RESULTS: We assessed a total of 1696 encounters in 1038 individuals with childhood epilepsies between September 6, 2019 and September 11, 2020 contributed by 32 distinct providers. Childhood absence epilepsy (n = 121), Lennox-Gastaut syndrome (n = 86), and Dravet syndrome (n = 42) were the most common epilepsy syndromes. Overall, 43% (737/1696) of individuals had at least monthly seizures, 17% (296/1696) had a least daily seizures, and 18% (311/1696) were seizure-free for >12 months. Quantification of absolute seizure burden and changes in seizure burden over time differed between epilepsy syndromes, including high and persistent seizure burden in patients with Lennox-Gastaut syndrome. Individuals seen via telemedicine or in-person encounters had comparable seizure frequencies. Individuals identifying as Hispanic/Latino, particularly from postal codes with lower median household incomes, were more likely to have ongoing seizures that worsened over time. SIGNIFICANCE: Standardized documentation of clinical data in childhood epilepsies through CDE can be implemented in routine clinical care at scale and enables assessment of disease burden, including characterization of seizure burden over time. Our data provide insights into heterogeneous patterns of seizure control in common pediatric epilepsy syndromes and will inform future initiatives focusing on patient-centered outcomes in childhood epilepsies, including the impact of telemedicine and health care disparities.

The molecular and phenotypic spectrum of CLCN4-related epilepsy.

OBJECTIVE: This study was undertaken to expand the phenotypic and genetic spectrum of CLCN4-related epilepsy and to investigate genotype-phenotype correlations. METHODS: We systematically reviewed the phenotypic and genetic spectrum of newly diagnosed and previously reported patients with CLCN4-related epilepsy. Three novel variants identified in four patients reported in this study were evaluated through in silico prediction and functional analysis by Western blot, immunofluorescence, and electrophysiological measurements. RESULTS: Epilepsy was diagnosed in 54.55% (24/44) of individuals with CLCN4-related disorders and was drug-resistant in most cases. Of 24 patients, 15 had epileptic encephalopathy and four died at an early age; 69.57% of patients had seizure onset within the first year of life. Myoclonic seizures are the most common seizure type, and 56.25% of patients presented multiple seizure types. Notably, seizure outcome was favorable in individuals with only one seizure type. All patients showed intellectual disability, which was severe in 65.22% of patients. Additional common features included language delay, behavioral disorders, and dysmorphic features. Five patients benefitted from treatment with lamotrigine. Most variants, which were mainly missense (79.17%), were inherited (70.83%). Whereas frameshift, intragenic deletion, or inherited variants were associated with milder phenotypes, missense or de novo variants led to more severe phenotypes. All evaluated CLCN4 variants resulted in loss of function with reduced ClC-4 currents. Nonetheless, genotype-phenotype relationships for CLCN4-related epilepsy are not straightforward, as phenotypic variability was observed in recurrent variants and within single families. SIGNIFICANCE: Pathogenic CLCN4 variants contribute significantly to the genetic etiology of epilepsy. The phenotypic spectrum of CLCN4-related epilepsy includes drug-resistant seizures, cognitive and language impairment, behavioral disorders, and congenital anomalies. Notably, the mutation type and the number of seizure types correlate with the severity of the phenotype, suggesting its use for clinical prognosis. Lamotrigine can be considered a therapeutic option.

The impact of COVID-19 in Dravet syndrome: A UK survey.

OBJECTIVES: To understand the risks, impact and outcome of COVID-19 in people affected by Dravet Syndrome (DS). MATERIALS AND METHODS: An anonymous cross-sectional online survey was conducted between June 17 and July 13, 2020, addressed to families of people with DS. RESULTS: A total of 116 responses were collected, from families of children (n = 86; 74%) and adults (30; 26%) with DS. The majority (106; 91%) were shielded at the family home during lockdown. Symptoms compatible with COVID-19 were reported in 22 (19%) individuals. Only four individuals with symptoms had a PCR swab test, none of which was positive. Only one symptomatic person had antibody testing (but not swab testing), which was positive. One person had repeatedly positive swab tests whilst in hospital for renal failure, but had no typical symptoms of COVID-19. In 50% of people with DS who developed possible or probable COVID-19 symptoms, seizure worsening was reported, in terms of increased seizure frequency or duration or both. Medical attention was required in 9/22 (41%), all of whom were children. CONCLUSIONS: In this cohort of people with DS, we observed an infection rate, determined by compatible symptoms, of 19%, with no deaths and benign outcome in most cases despite the underlying complex epilepsy although children often required medical attention. Early adoption of preventative measures, including testing of symptomatic individuals, regular surveillance for people living in residential care facilities, and shielding of individuals with comorbidities increasing the risk of severe outcome, may limit the impact of COVID-19.

Photoparoxysmal response and its characteristics in a large EEG database using the SCORE system.

OBJECTIVE: To characterize photoparoxysmal EEG response (PPR) using a standardized protocol of intermittent photic stimulation (IPS) and standardized definitions for PPR, classified into six types. METHODS: Using the SCORE system (Standardized Computer-Based Organized Reporting of EEG) we prospectively built a large database of standardized EEG annotations. In this study, we extracted the features related to PPR from the structured dataset consisting of 10,671 EEG recordings with IPS, from 7,188 patients. RESULTS: The standardized IPS protocol elicited PPR in 375 recordings (3.5%), in 288 patients (4%), with a preponderance among young (11-20 years) and female patients (67%). PPR was persistent in patients with multiple recordings. The most frequent type of PPR was activation of preexisting epileptogenic area (58%), followed by generalized-PPR limited to the stimulus train (22%). We could not find any recording with self-sustained posterior response. Seizures were elicited in 27% of patients with PPR, most often myoclonic seizures and absences, in patients with self-sustained generalized PPR. CONCLUSIONS: The most common type of PPR was accentuation of preexisting epileptogenic area. Self-sustained posterior response could not be documented. Self-sustained generalized-PPR had the highest association with seizures. SIGNIFICANCE: Using standardized stimulation protocol and definitions for PPR types, IPS provides high diagnostic yield.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Sleep in Dravet syndrome: A parent-driven survey.

OBJECTIVES: To describe and quantify the nature and severity of sleep disruptions in young people with Dravet syndrome (DS) based upon parent report. METHODS: Qualitative review of available pediatric sleep instruments with parent members of the Dravet syndrome Foundation led to the design of a series of questions customized to DS and other severe epilepsies. The questionnaire was administered as part of an on-line survey that reflected specific sleep-related concerns of parents of children with severe epilepsy. RESULTS: 76 parent-respondents completed the survey for their children-participants. Children's median age was 7.5 years (IQR 4.7-15.3); 41 (54 %) were female. The majority of parents (70/76, 93 %) used some method to monitor children while sleeping; co-sleeping was the most common method (45/76, 59 %). Seizures disrupted sleep in 40/76 (53 %); 19(48 %) reported nocturnal seizures 3 or more nights per week. In addition, 58/76 (76 %) also reported non-seizure-related nocturnal awakenings with 30 reporting awakenings 3 or more nights affected per week. SIGNIFICANCE: Young people with Dravet syndrome have frequently disrupted sleep secondary to seizures and other factors. Co-sleeping practices, medication effects, enuresis during seizures and other factors are not considered on standard sleep questionnaires. Current findings highlight the frequency of epilepsy-specific concerns and lay groundwork for sleep measures more appropriate for this population.

Fenfluramine HCl (Fintepla® ) provides long-term clinically meaningful reduction in seizure frequency: Analysis of an ongoing open-label extension study.

OBJECTIVE: Fenfluramine has been shown to provide clinically meaningful and statistically significant reductions in convulsive seizure frequency in children and adolescents (aged 2-18 years) with Dravet syndrome in two randomized, placebo-controlled clinical trials. The objective of this analysis was to assess longer-term safety and efficacy of fenfluramine in patients who completed one of the double-blind studies and entered an open-label extension (OLE) study. METHODS: Patients enrolling in the OLE study initiated fenfluramine at 0.2 mg/kg/d regardless of their treatment assignment in the double-blind study. After 4 weeks, the fenfluramine dose could be titrated based on efficacy and tolerability to maximum of 0.7 mg/kg/d (absolute maximum 27 mg/d) or maximum of 0.4 mg/kg/d (absolute maximum 17 mg/d) in patients receiving concomitant stiripentol. The number and type of seizures were recorded daily in an electronic diary, and safety, including echocardiography, was assessed at Months 1, 2, and 3, and at 3-month intervals thereafter. RESULTS: A total of 232 patients were enrolled as of March 13, 2018. During this analysis period, patients were treated for a median 256 days (range = 46-634 days). Over the entire OLE analysis period, the median decrease in convulsive seizure frequency compared to baseline in the double-blind studies was -66.8% (range = -100% to 234.9%; P < .001). The median reduction in seizure frequency was similar in patients <6 (-75.7%) and ≥6 years old (-64.7%). The most commonly reported adverse events included pyrexia (21.6%), nasopharyngitis (19.4%), and decreased appetite (-15.9%). No valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) was observed. SIGNIFICANCE: Study results demonstrate that fenfluramine provides clinically meaningful (≥50%) seizure frequency reduction over an extended period in patients with Dravet syndrome. No patient developed VHD or PAH, and fenfluramine was generally well tolerated.

Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients.

OBJECTIVE: The aim of this study was to perform a molecular characterization of 17 Argentinean pediatric patients with diagnosis of having epileptic encephalopathies (EEs) of the first year of life without known etiology, applying next-generation sequencing (NGS). METHODS: We included 17 patients with EE with age of onset under 12 months without known etiology after ruling out structural abnormalities, metabolic disorders, and large chromosomal abnormalities. They presented with the following clinical phenotypes: Dravet syndrome (DS; n: 7), epilepsy of infancy with migrating focal seizures (EIMFS; n: 3), West syndrome (WS; n: 2), and undetermined epileptic encephalopathy (UEE; n: 5). Neurologic examinations, seizure semiology, brain magnetic resonance imaging, and standard electroencephalography (EEG) or video-EEG studies were performed in all cases. Using a custom amplicon strategy, we designed an NGS panel to study 47 genes associated with EEs. RESULTS: Pathogenic variants were detected in 8 cases (47%), including seven novel pathogenic variants and one previously reported as being pathogenic. The pathogenic variants were identified in 6 patients with DS (SCN1A gene), one with EIMFS (SCN2A gene), and one with UEE (SLC2A1 gene). Nonrelevant variants were identified in the patients with WS. CONCLUSION: We demonstrated the feasibility of an NGS-gene panel approach for the analysis of patients with EE in our setting. A genetic diagnosis was achieved in nearly 50% of patients, 87% of them presenting with nonpreviously reported variants. The early identification of the underlying causative genetic alteration will be a valuable tool for providing prognostic information and genetic counselling and also to improve therapeutic decisions in Argentinean patients.