Reducing epilepsy diagnostic and treatment gaps: Standardized paediatric epilepsy training courses for health care professionals.

AIM: To evaluate improvement in knowledge and clinical behaviour among healthcare professionals after attendance at paediatric epilepsy training (PET) courses. METHOD: Since 2005, 1-day PET courses have taught evidence-based paediatric epilepsy management to doctors and nurses in low-, middle-, and high-income countries. A cohort study was performed of 7528 participants attending 252 1-day PET courses between 2005 and 2020 in 17 low-, middle-, and high-income countries, and which gathered data from participants immediately after the course and then 6 months later. Training outcomes were measured prospectively in three domains (reaction, learning, and behaviour) using a mixed-methods approach involving a feedback questionnaire, a knowledge quiz before and after the course, and a 6-month survey. RESULTS: Ninety-eight per cent (7217 of 7395) of participants rated the course as excellent or good. Participants demonstrated knowledge gain, answering a significantly higher proportion of questions correctly after the course compared to before the course (88% [47 883 of 54 196], correct answers/all quiz answers, vs 75% [40 424 of 54 196]; p < 0.001). Most survey responders reported that the course had improved their epilepsy diagnosis and management (73% [311 of 425]), clinical service (68% [290 of 427]), and local epilepsy training (68% [290 of 427]). INTERPRETATION: This was the largest evaluation of a global epilepsy training course. Participants reported high course satisfaction, showed knowledge gain, and described improvements in clinical behaviour 6 months later. PET supports the global reduction in the epilepsy 'treatment gap' as promoted by the World Health Organization.

Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study.

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.

Functional neurological disorder in children and young people: Incidence, clinical features, and prognosis.

AIM: To report incidence, demographic and clinical characteristics, and symptom outcome of functional neurological disorder (FND) in children. METHOD: Children diagnosed with FND at a regional children's hospital were prospectively recruited by weekly active surveillance for 36 months. Demographic, clinical, and follow-up data were retrospectively extracted by review of electronic records. Descriptive statistical analyses were used. RESULTS: Ninety-seven children (age range 5-15 years) met the case definition of FND (annual incidence 18.3 per 100 000 children). Children with FND were likely to be female (n = 68 [70%]) and older (median 13 years) with no difference in the Scottish Index of Multiple Deprivation (marker of socioeconomic status) compared with the general childhood population. Functional motor (41%) and sensory (41%) symptoms were most common; other somatic symptoms such as headache (31%) and pain (27%) were frequent. Self-reported psychiatric symptoms and infection/inflammation were the most common predisposing and precipitating factors respectively. At a median of 15 months follow-up, 49% of 75 children reported improvement or resolution of FND symptoms with no prognostic factors found. INTERPRETATION: At this regional centre, FND in children had a higher incidence than previously reported and a less optimistic outcome than in some other studies.

Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study.

OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.

Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants.

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216-263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251-357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139-233), χ2 odds ratio = 1.7 (95% CI 1.3-2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations.

Are you tuned in? The challenges of seizure identification in children with intellectual disability - A potential for video-based care-pathway.

This qualitative study explores the challenges parents/carers face in seizure identification in children with coexisting epilepsy and intellectual disability (ID). Semi-structured interviews with parents/carers provided ten hours of data, transcribed verbatim for data analysis. Themes and subthemes were identified and grouped to reflect the findings. The importance of knowing the child's usual behavior and recognizing changes to this was a consistent theme. All participants reported that being 'in tune' with their child helped in seizure recognition. Participants felt that the healthcare professionals (HCP) were poor at recognizing seizures in their children at times. They had mixed thoughts on the difficulty the presence of an ID contributes to seizure recognition. The severity of ID and the seizure type were the two main variables discussed. The study concludes that knowing the child well and understanding the usual behavior of the child is crucial to seizure recognition. A video-based care pathway with videos of both usual behavior and seizure activity available to the HCP to classify the events correctly may be potentially beneficial to improve patient care.

Children's understanding of epilepsy: A qualitative study.

PURPOSE: To use a qualitative research approach to determine children's understandings of epilepsy and their epilepsy treatment. METHODS: Children aged 7-16 years with physician-confirmed active epilepsy (i.e., having had an epileptic seizure in the past year and or currently taking antiepileptic drugs (AEDs), and not known to have an intellectual disability, were invited to participate. Children had semi-structured interviews separately on two occasions. Between the first and second interviews, an observation of a routine epilepsy clinic appointment of individual children was conducted, and was then discussed during the second interview. Participatory research tools were used in both child interviews to facilitate discussions. Interviews were audio recorded and transcribed, pseudonymized and entered into NVivo (version 12, QSR International). Data were analyzed using a thematic approach. RESULTS: Twenty-three children of mean age 10.1 years (range 8-14), mean duration of epilepsy of 4.6 years (range 2-10) were enrolled. Twelve were 12 female; 7 had focal, 14 had generalized, and 2 had combined epilepsy; 20 were on monotherapy; and 16 had tried previous AEDs. All had an initial (first) interview; 20 were observed during a clinic appointment and had a second interview. Five broad themes emerged: understanding of epilepsy; understanding of seizures; understanding of medication; understanding of children's role in clinical appointments; influences on children's understanding. Children spoke about what epilepsy meant by describing the physical sensations of having a seizure or through the act of taking medication. Children described the role they had, or felt they should have, but reported challenges in being meaningfully involved in clinical appointments. While healthcare professionals were initial information nodes, epilepsy information from parents appeared to be more significant for children. CONCLUSIONS: The perspectives of children with epilepsy are valuable for clinicians to understand; assumptions should not be made that children's views can be accessed via parents. Clinicians need to be constantly aware of children's views and ways of understanding and communicating about their epilepsy. To support this, the research - drawing on children's words, meanings, and stories - was used to inform an easily accessible, gender-neutral, animation about epilepsy that provides information about the condition, seizures, and medication (https://youtu.be/MO7xXL2ZXP8).

Pilot project of psychological services integrated into a pediatric epilepsy clinic: Psychology Adding Value - Epilepsy Screening (PAVES).

RATIONALE: Children and young people with epilepsy (CYPwE) are particularly vulnerable to developing social, emotional, behavioral, and learning difficulties, which, if not identified or addressed at an early stage, can impact adversely on quality of life and long-term psychosocial outcomes. This paper describes the development of a screening protocol and a pathway of early, 'stepped' intervention, which aims to address this issue, together with initial outcomes. METHODS: The Strengths and Difficulties Questionnaire (SDQ) was completed by CYPwE and their parents prior to routine epilepsy clinic appointments. A traffic light system was devised to indicate the reported level of concern and a potential route through the early intervention pathway. RESULTS: Of those CYPwE screened, 53% were found to be experiencing elevated levels of mental health difficulties, which had not previously been identified, and had the opportunity to access an appropriate early intervention. Initial feedback on the PAVES pathway has been positive, with high levels of feasibility and acceptability indicated by young people, parents, and clinicians. CONCLUSIONS: The PAVES approach enables mental health difficulties to be identified and appropriate intervention accessed at an early stage, potentially improving long-term psychosocial outcomes for CYPwE. In addition, if found to be effective in larger trials, PAVES has potential to be adapted and generalized to other populations.

Epidemiology and outcome of status epilepticus in children: a Scottish population cohort study.

AIM: To describe the epidemiology and outcomes of convulsive status epilepticus (CSE) since the introduction of buccal midazolam and the change in International League Against Epilepsy definition of CSE to include seizures of at least 5 minutes. METHOD: All children presenting to paediatric emergency departments with CSE (2011-2017) in Lothian, Scotland, were identified. Data, collated from electronic health records, included patient demographics, clinical characteristics, acute seizure management, and adverse outcomes (for example admission to intensive care). RESULTS: Six hundred and sixty-five children were admitted with CSE who had 1228 seizure episodes (381 males, 284 females; median age 3y 8mo; age range 0-20y 11mo). CSE accounted for 0.38% (95% confidence interval 0.34-0.42) of annual attendances at emergency departments. Annual prevalence was 0.8 per 1000 children aged 0 to 14 years. Thirty-four per cent of children had recurrent CSE. Sixty-nine per cent of seizures lasted 5 to 29 minutes (median duration 10min). Buccal midazolam was given to 30% of children with CSE and had no effect on need for ventilatory support. Seventy per cent of children with CSE required hospital admission. Four per cent resulted in adverse outcome and there were only two deaths. Recurrent seizures, longer duration, and unprovoked seizures increased the odds of adverse outcome. INTERPRETATION: Adverse outcomes have decreased and the use of buccal midazolam is promising. Identifying high-risk groups provides an opportunity for early intervention. These data form the basis for an extensive evaluation of acute seizure management and monitoring long-term outcomes. What this paper adds The annual prevalence of convulsive status epilepticus in Lothian, Scotland, was 0.8 per 1000 children. There was a decrease in case-fatality proportion from 3-9% to 0.2%. Use of buccal midazolam has increased, with no increase in adverse outcomes.

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort.

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

Analysis of EEG networks and their correlation with cognitive impairment in preschool children with epilepsy.

OBJECTIVE: Cognitive impairment (CI) is common in children with epilepsy and can have devastating effects on their quality of life. Early identification of CI is a priority to improve outcomes, but the current gold standard of detection with psychometric assessment is resource intensive and not always available. This paper proposes exploiting network analysis techniques to characterize routine clinical electroencephalography (EEG) to help identify CI in children with early-onset epilepsy (CWEOE) (0-5 years old). METHODS: Functional networks from routinely acquired EEGs of 51 newly diagnosed CWEOE were analyzed. Combinations of connectivity metrics with subnetwork analysis identified significant correlations between network properties and cognition scores via rank correlation analysis (Kendall's τ). Predictive properties were investigated using a cross-validated classification model with healthy cognition, mild/moderate CI, and severe CI classes. RESULTS: Network analysis revealed phase-dependent connectivity having higher sensitivity to CI and significant functional network changes across EEG frequencies. Nearly 70.5% of CWEOE were aptly classified as having healthy cognition, mild/moderate CI, or severe CI using network features. These features predicted CI classes 55% better than chance and halved misclassification penalties. CONCLUSIONS: Cognitive impairment in CWEOE can be detected with sensitivity at 85% (in identifying mild/moderate or severe CI) and specificity of 84%, by network analysis. SIGNIFICANCE: This study outlines a data-driven methodology for identifying candidate biomarkers of CI in CWEOE from network features. Following additional replication, the proposed method and its use of routinely acquired EEG forms an attractive proposition for supporting clinical assessment of CI.

Neurobehavioral problems in children with early-onset epilepsy: A population-based study.

PURPOSE: Neurobehavioral problems (i.e., cognitive impairment/behavior problems) are a major challenge in childhood epilepsy. Yet there are limited data in children with early-onset epilepsy (CWEOE; onset ≤4 years), the period in which the incidence of childhood epilepsy is highest. This study aimed to determine the prevalence, spectrum, and risk factors for neurobehavioral problems CWEOE. METHODS: This prospective, population-based, case-controlled study identified children with newly diagnosed early-onset epilepsy in South East Scotland using active multisource capture-recapture surveillance (May 2013 - June 2015). The CWEOE and controls completed an age-appropriate neurobehavioral assessment battery across seven domains: general cognitive ability (GCA), adaptive behavior, externalizing, internalizing, executive functioning, social functioning, and Autism Spectrum Disorder (ASD) risk. RESULTS: Fifty-nine CWEOE were identified with an ascertainment of 98% (95% confidence interval [CI] 94, 103). Forty-six (78% [95% CI 65.9, 86.6]) CWEOE (27 male, median age 25.5, range 1-59, months) and 37 controls (18 male, median age 31.5, range 3-59, months) consented for study entry. The CWEOE were similar to controls in gender, age, prematurity, and family history of psychopathology, but not socioeconomic status (Fisher's exact test [FET] < .001). Neurobehavioral assessments were carried out a median of 2.97 (Interquartile range [IQR] 1.51-4.95) months post epilepsy diagnosis. More CWEOE (63% [95% CI 48.6, 75.5]) had neurobehavioral problems compared with controls (27% [95% CI 15.4, 43.0]); p < 0.01. This observation was independent of socioeconomic status. Multidimensional problems were prevalent in CWEOE with 43% having two or more different domain-level problems; GCA impairment, adaptive behavior, internalizing, social functioning, and ASD risk were particularly marked. Risk factors varied by domain. DISCUSSION: This novel study using comprehensive psychometric assessments found that neurobehavioral problems in CWEOE were detectable, common, and multidimensional. The degree of cooccurrence implies that problems are the norm, and multidimensional screening should be considered at epilepsy onset. The findings could aid policy development on health and educational provision in CWEOE.

Acquired neuromyotonia in children with CASPR2 and LGI1 antibodies.

Acquired neuromyotonia is a form of peripheral nerve hyperexcitability. In adults, pathogenic antibodies that target the extracellular domains of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) have been reported. We describe three paediatric patients with acquired neuromyotonia and CASPR2 and LGI1 serum antibodies. They all presented with acute-onset myokymia and pain in the lower limbs; one patient also had muscle weakness. Electromyography was suggestive of peripheral nerve hyperexcitability. Two patients improved without immunotherapy; one treated patient remained immunotherapy-dependent. Although not fatal, acquired paediatric neuromyotonia can be disabling. It is amenable to symptomatic treatment or may undergo spontaneous recovery. More severe cases may require rational immunotherapy. WHAT THIS PAPER ADDS: The symptoms of neuromyotonia may resolve spontaneously or may require sodium channel blockers. Patients with debilitating symptoms who are refractory to symptomatic therapy may require immunotherapy.

NEUROMIOTONÍA ADQUIRIDA EN NIÑOS CON ANTICUERPOS CASPR2 Y LGI1: La neuromiotonía adquirida es una forma de hiperexcitabilidad de los nervios periféricos. En algunos adultos, se han notificado anticuerpos patógenos que se dirigen a los dominios extracelulares de la proteína 1 inactivada por glioma rico en leucina (LGI1) y la proteína 2 asociada a contactina (CASPR2). Describimos tres pacientes pediátricos con neuromiotonía adquirida y anticuerpos séricos CASPR2 y LGI1. Todos presentaban mioquimia de inicio agudo y dolor en las extremidades inferiores; un paciente también tenía debilidad muscular. La electromiografía sugirió hiperexcitabilidad del nervio periférico. Dos pacientes mejoraron sin inmunoterapia; un paciente tratado permaneció dependiente de la inmunoterapia. Aunque no es fatal, la neuromiotonía pediátrica adquirida puede ser incapacitante. Es susceptible de tratamiento sintomático o puede sufrir una recuperación espontánea. Los casos más graves pueden requerir inmunoterapia racional.

NEUROMIOTONIA ADQUIRIDA EM CRIANÇAS COM ANTICORPOS PRCAS2 E GIL1: A neuromiotonia adquirida é uma forma de hiperexcitabilidade nervosa periférica. Em alguns adultos, anticorpos patogênicos que visam os domínios extracelulares da proteína glioma-inativada rica em leucina1 (GIL1) e da proteína contactina-associada 2 (PRCAS2) foram reportados. Descrevemos três pacientes pediátricos com neuromiotonia adquirida e anticorpos séricos PRCAS2 e GIL1 CASPR2. Todos apresentaram miocimia de início agudo e dor nos membros inferiores; um paciente também teve fraqueza muscular. A eletromiografia foi sugestiva de hiperexcitabilidade nervosa periférica. Dois pacientes melhoraram sem imunoterapia; um paciente tratado permaneceu imunoterapia-dependente. Embora não seja fatal, a neuromiotomia pediátrica aguda pode ser incapacitante. É responsiva a tratamento sintomático e pode apresentar recuperação espontânea. Casos mais severaos podem requerer imunoterapia racional.

Cognitive impairment in early onset epilepsy is associated with reduced left thalamic volume.

OBJECTIVE: The objective of this study was to investigate whether reduction of thalamic volumes in children with early onset epilepsy (CWEOE) is associated with cognitive impairment. METHODS: This is a nested case-control study including a prospectively recruited cohort of 76 children with newly-diagnosed early onset epilepsy (onset <5years age) and 14 healthy controls presenting to hospitals within NHS Lothian and Fife. Quantitative volumetric analysis of subcortical structures was performed using volumetric T1-weighted magnetic resonance imaging (MRI) and correlated with the results of formal neurocognitive and clinical assessment. False discovery rate was used to correct for multiple comparisons as appropriate with q<0.05 used to define statistical significance. RESULTS: Age, gender, and intracranial volume (ICV)-adjusted left thalamic volumes were significantly reduced in CWEOE with cognitive impairment compared to CWEOE without impairment (5295mm3 vs 6418mm3, q=0.008) or healthy controls (5295mm3 vs 6410mm3, q<0.001). The differences in left thalamic volume remained if gray matter or cortical/cerebellar volumes were used as covariates rather than ICV (q<0.05). The degree of volume reduction correlated with the severity of cognitive impairment (q=0.048). SIGNIFICANCE: Reduced left thalamic volume may be a biomarker for cognitive impairment in CWEOE and could help inform the need for further formal cognitive evaluations and interventions.

Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases.

OBJECTIVE: The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation. METHOD: Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained. RESULTS: Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases. SIGNIFICANCE: Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males.

Observational pilot study of reported symptoms of obstructive sleep apnoea in children with epilepsy.

AIM: To estimate symptoms of obstructive sleep apnoea (OSA) and excessive daytime sleepiness (EDS) in children with epilepsy (CWE) compared with those in a typically developing comparison group. CWE are known to have poor sleep, with increased rates of OSA suggested. METHOD: The Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire (PSQ-SRBD) was used to estimate OSA symptoms, with scores ≤0.33 known to be highly sensitive and specific for OSA. The Epworth Sleepiness Scale (ESS) was used to assess EDS, with scores of 10 or above considered abnormal. RESULTS: Thirty-three CWE (21 males, 12 females) were studied (median age [interquartile range {IQR}] 9y [5-12]), along with 42 comparison children (20 males, 22 females; median age [IQR] 6y [4-8.5]). Fifty-five per cent of CWE scored 0.33 or higher on the PSQ-SRBD compared with 7% in the comparison group (p<0.001), and 30% of CWE had an abnormal ESS compared with 5% controls (p=0.003). Within the CWE cohort, PSQ-SRDB and ESS appeared higher in those taking antiepileptic drugs (AEDs); although PSQ-SRBD score for CWE not on AEDs was higher than in the comparison group. INTERPRETATION: This study suggests higher rates of symptoms of OSA and EDS in CWE compared with typically developing children. AEDs may be a confounding factor, but do not alone account for the associations seen. Further studies including polysomnography to verify the presence (rather than suggestion by questionnaire) of OSA are warranted.

Socioeconomic deprivation is an independent risk factor for behavioral problems in children with epilepsy.

AIM: The aim of this study was to examine whether socioeconomic deprivation in children with epilepsy (CWE) increases risk for behavioral problems independent of seizure factors. METHODS: A cross-sectional study was done in which parents of children attending a specialist epilepsy clinic were invited to complete a child behavior checklist (CBCL) questionnaire about their child. Medical and sociodemographic data on CWE were obtained through their pediatric neurologists. Home postal code was used to obtain quintiles of Scottish Index of Multiple Deprivation 2012 (SIMD2012) scores for individuals. Lower (1-3) quintiles correspond to higher socioeconomic deprivation. Regression analysis was used to investigate whether a lower quintile was an independent risk factor for scores >63 (significant behavioral problem). RESULTS: Parents of 87 children (42 male, mean age of 10.5years) were enrolled. Fifty-nine percent had total scores >63. A higher proportion of children from quintiles 1-3 compared to those from quintiles 4-5 had externalizing (49% vs. 25%, p=0.02) and total (54% vs. 30%, p=0.02) scores >63. Adjusted OR of quintiles 1-3 vs. 4-5 for scores >63=14.8, 95% CI=3.0, 68.0. Fewer children with scores >63 and from quintiles 1-3 were known to the child and adolescent mental health service (CAMHS) compared to those in quintiles 4-5 (p=0.01). INTERPRETATION: Socioeconomic deprivation was an independent risk factor for behavioral problems in CWE. Children with epilepsy and behavioral problems who lived in socioeconomically deprived areas received less help.

Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum.

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

A case-control study to investigate the prevalence of obstructive sleep apnea and the utility of the PSQ-SRBD questionnaire in children and young people with epilepsy.

STUDY OBJECTIVES: Epilepsy and obstructive sleep apnea syndrome (OSAS) are each relatively common in children. OSAS may affect cognition, such that recognition of OSAS is important for children and young people with epilepsy (CYPWE). Published pilot data reported 55% CYPWE had symptoms suggestive of OSAS, compared with 7% typically developing controls. The primary aim of this study was to ascertain OSAS prevalence by polysomnography (PSG) in CYPWE, with secondary aims being to evaluate the utility of sleep questionnaires in CYPWE. METHODS: Children and young people with epilepsy and age- and sex-matched typically developing controls were studied. A single night of level I attended PSG was undertaken, along with questionnaires [Pediatric Sleep Questionnaire (PSQ-SRBD), Pittsburgh Sleep Quality Index (PSQI) and the childhood and adolescent Epworth Sleepiness Scale (ESS-CHAD)]. OSAS was defined as obstructive apnea-hypopnea index (oAHI) of ≥ 1 event/h. RESULTS: Polysomnography was performed in 72 children including 48 CYPWE (60% male) and 24 controls (54% male). Mean age (11 years) was similar for CYPWE and controls, p= 0.42; with slightly higher BMI z scores (0.7 v 0.1, p=0.03) noted in CYPWE. Mean oAHI was 0.61 in CYPWE versus 0.42 (controls), p=0.62. Despite higher PSQ-SRBD scores in CYPWE (0.38 v 0.12, p<0.001), no difference in OSAS prevalence (10% vs. 4%, p=0.78) was found. Children and young people with epilepsy had higher ESS-CHAD (6 vs. 3.5, p=0.01) and PSQI (5 vs. 3.3, p=0.02) scores indicating greater levels of daytime sleepiness and poorer sleep quality. CONCLUSIONS: The study found no evidence for increased OSAS prevalence in CYPWE, whilst the utility of the PSQ-SRBD in predicting OSAS appears limited for CYPWE. Children and young people with epilepsy are, however demonstrably sleepier with poorer sleep quality. The cause for these findings remains unclear. CLINICAL TRIAL REGISTRATION: Investigation of Sleep Quality and Prevalence of Sleep-disordered Breathing in Children and Young People With Epilepsy; https://www.clinicaltrials.gov/study/NCT03103841.