Health care utilization and mortality for people with epilepsy during COVID-19: A population study.

OBJECTIVE: This study was undertaken to characterize changes in health care utilization and mortality for people with epilepsy (PWE) during the COVID-19 pandemic. METHODS: We performed a retrospective study using linked, individual-level, population-scale anonymized health data from the Secure Anonymised Information Linkage databank. We identified PWE living in Wales during the study "pandemic period" (January 1, 2020-June 30, 2021) and during a "prepandemic" period (January 1, 2016-December 31, 2019). We compared prepandemic health care utilization, status epilepticus, and mortality rates with corresponding pandemic rates for PWE and people without epilepsy (PWOE). We performed subgroup analyses on children (<18 years old), older people (>65 years old), those with intellectual disability, and those living in the most deprived areas. We used Poisson models to calculate adjusted rate ratios (RRs). RESULTS: We identified 27 279 PWE who had significantly higher rates of hospital (50.3 visits/1000 patient months), emergency department (55.7), and outpatient attendance (172.4) when compared to PWOE (corresponding figures: 25.7, 25.2, and 87.0) in the prepandemic period. Hospital and epilepsy-related hospital admissions, and emergency department and outpatient attendances all reduced significantly for PWE (and all subgroups) during the pandemic period. RRs [95% confidence intervals (CIs)] for pandemic versus prepandemic periods were .70 [.69-.72], .77 [.73-.81], .78 [.77-.79], and .80 [.79-.81]. The corresponding rates also reduced for PWOE. New epilepsy diagnosis rates decreased during the pandemic compared with the prepandemic period (2.3/100 000/month cf. 3.1/100 000/month, RR = .73, 95% CI = .68-.78). Both all-cause deaths and deaths with epilepsy recorded on the death certificate increased for PWE during the pandemic (RR = 1.07, 95% CI = .997-1.145 and RR = 2.44, 95% CI = 2.12-2.81). When removing COVID deaths, RRs were .88 (95% CI = .81-.95) and 1.29 (95% CI = 1.08-1.53). Status epilepticus rates did not change significantly during the pandemic (RR = .95, 95% CI = .78-1.15). SIGNIFICANCE: All-cause non-COVID deaths did not increase but non-COVID deaths associated with epilepsy did increase for PWE during the COVID-19 pandemic. The longer term effects of the decrease in new epilepsy diagnoses and health care utilization and increase in deaths associated with epilepsy need further research.

Epilepsy and the risk of COVID-19-related hospitalization and death: A population study.

OBJECTIVE: People with epilepsy (PWE) may be at an increased risk of severe COVID-19. It is important to characterize this risk to inform PWE and for future health and care planning. We assessed whether PWE were at higher risk of being hospitalized with, or dying from, COVID-19. METHODS: We performed a retrospective cohort study using linked, population-scale, anonymized electronic health records from the SAIL (Secure Anonymised Information Linkage) databank. This includes hospital admission and demographic data for the complete Welsh population (3.1 million) and primary care records for 86% of the population. We identified 27 279 PWE living in Wales during the study period (March 1, 2020 to June 30, 2021). Controls were identified using exact 5:1 matching (sex, age, and socioeconomic status). We defined COVID-19 deaths as having International Classification of Diseases, 10th Revision (ICD-10) codes for COVID-19 on death certificates or occurring within 28 days of a positive SARS-CoV-2 polymerase chain reaction (PCR) test. COVID-19 hospitalizations were defined as having a COVID-19 ICD-10 code for the reason for admission or occurring within 28 days of a positive SARS-CoV-2 PCR test. We recorded COVID-19 vaccinations and comorbidities known to increase the risk of COVID-19 hospitalization and death. We used Cox proportional hazard models to calculate hazard ratios. RESULTS: There were 158 (.58%) COVID-19 deaths and 933 (3.4%) COVID-19 hospitalizations in PWE, and 370 (.27%) deaths and 1871 (1.4%) hospitalizations in controls. Hazard ratios for COVID-19 death and hospitalization in PWE compared to controls were 2.15 (95% confidence interval [CI] = 1.78-2.59) and 2.15 (95% CI = 1.94-2.37), respectively. Adjusted hazard ratios (adjusted for comorbidities) for death and hospitalization were 1.32 (95% CI = 1.08-1.62) and 1.60 (95% CI = 1.44-1.78). SIGNIFICANCE: PWE are at increased risk of being hospitalized with, and dying from, COVID-19 when compared to age-, sex-, and deprivation-matched controls, even when adjusting for comorbidities. This may have implications for prioritizing future COVID-19 treatments and vaccinations for PWE.

Case-control study developing Scottish Epilepsy Deaths Study Score to predict epilepsy-related death.

This study aimed to develop a risk prediction model for epilepsy-related death in adults. In this age- and sex-matched case-control study, we compared adults (aged ≥16 years) who had epilepsy-related death between 2009 and 2016 to living adults with epilepsy in Scotland. Cases were identified from validated administrative national datasets linked to mortality records. ICD-10 cause-of-death coding was used to define epilepsy-related death. Controls were recruited from a research database and epilepsy clinics. Clinical data from medical records were abstracted and used to undertake univariable and multivariable conditional logistic regression to develop a risk prediction model consisting of four variables chosen a priori. A weighted sum of the factors present was taken to create a risk index-the Scottish Epilepsy Deaths Study Score. Odds ratios were estimated with 95% confidence intervals (CIs). Here, 224 deceased cases (mean age 48 years, 114 male) and 224 matched living controls were compared. In univariable analysis, predictors of epilepsy-related death were recent epilepsy-related accident and emergency attendance (odds ratio 5.1, 95% CI 3.2-8.3), living in deprived areas (odds ratio 2.5, 95% CI 1.6-4.0), developmental epilepsy (odds ratio 3.1, 95% CI 1.7-5.7), raised Charlson Comorbidity Index score (odds ratio 2.5, 95% CI 1.2-5.2), alcohol abuse (odds ratio 4.4, 95% CI 2.2-9.2), absent recent neurology review (odds ratio 3.8, 95% CI 2.4-6.1) and generalized epilepsy (odds ratio 1.9, 95% CI 1.2-3.0). Scottish Epilepsy Deaths Study Score model variables were derived from the first four listed before, with Charlson Comorbidity Index ≥2 given 1 point, living in the two most deprived areas given 2 points, having an inherited or congenital aetiology or risk factor for developing epilepsy given 2 points and recent epilepsy-related accident and emergency attendance given 3 points. Compared to having a Scottish Epilepsy Deaths Study Score of 0, those with a Scottish Epilepsy Deaths Study Score of 1 remained low risk, with odds ratio 1.6 (95% CI 0.5-4.8). Those with a Scottish Epilepsy Deaths Study Score of 2-3 had moderate risk, with odds ratio 2.8 (95% CI 1.3-6.2). Those with a Scottish Epilepsy Deaths Study Score of 4-5 and 6-8 were high risk, with odds ratio 14.4 (95% CI 5.9-35.2) and 24.0 (95% CI 8.1-71.2), respectively. The Scottish Epilepsy Deaths Study Score may be a helpful tool for identifying adults at high risk of epilepsy-related death and requires external validation.

Socioeconomic status in adulthood of children with and without a history of seizures: A retrospective cohort study.

OBJECTIVE: Compare adulthood socioeconomic status for children with and without a history of seizures. METHODS: Retrospective cohort study using Aberdeen Children of the Nineteen Fifties (ACONF) data comprising children born 1950-1956 attending primary school 1962-1964, with follow-up data collected in 2001. Adulthood socioeconomic status was based on registrar general measure of occupational social class and categorised as high or low. We adjusted for potentially confounding variables including childhood socioeconomic status, behavioural issues (Rutter A/B scores), biological sex, school test scores, educational attainment, parental engagement with education, peer-status in school, and alcohol use in adulthood. A multivariate binary logistic regression was performed to estimate the adjusted association between children with a history of seizures of any type (for example febrile seizures, or provoked seizures of any other etiology or seizures in the context of epilepsy) or severity and adult socioeconomic status. Multiple imputation using the Monte-Carlo-Markov-Chain method accounted for missing data. RESULTS: Pooled estimates (N = 2,208) comparing children with a history of seizures (n = 81) and children without a history of seizures (n = 2,127) found no differences between these cohorts in terms of adulthood socioeconomic status in both unadjusted (Odds Ratio (OR) 1.45 [95 % CI 0.71-2.96], p = 0.31) and adjusted (1.02 [0.46, 2.24], p = 0.96) analyses. Compared to males, females were at increased odds of having a lower socioeconomic status in adulthood (1.56 [1.13-2.17], p = 0.01).Compared to those with low educational attainment, those with moderate (0.32 [0.21, 0.48], p < 0.001) and high (0.12 [0.07, 0.20], p < 0.001) educational attainment were at reduced odds of having a lower socioeconomic status in adulthood. CONCLUSION: Cognitive problems in childhood (using educational attainment and scores on primary school tests proxy markers for cognition) rather than a history of seizures per se, were associated with lower SES in a population of adults born 1950-56 in Aberdeen. This relationship may be different depending on the time in history and nation/region of study. Given the changes in health, education and social support in the management of children with seizures over time, it would be of interest to investigate outcomes in a contemporary cohort. Such studies should ideally have validated diagnoses of seizures, details on seizure characteristics such as seizure type and severity, and a large sample size using national data.

UK research priority setting for childhood neurological conditions.

AIM: To identify research priorities regarding the effectiveness of interventions for children and young people (CYP) with childhood neurological conditions (CNCs). These include common conditions such as epilepsies and cerebral palsy, as well as many rare conditions. METHOD: The National Institute for Health and Care Research (NIHR) and the James Lind Alliance (JLA) champion and facilitate priority setting partnerships (PSPs) between patients, caregivers, and clinicians (stakeholders) to identify the most important unanswered questions for research (uncertainties). A NIHR-JLA and British Paediatric Neurology Association collaboration used the JLA PSP methodology. This consisted of two surveys to stakeholders: survey 1 (to identify uncertainties) and survey 2 (a prioritization survey). The final top 10 priorities were agreed by consensus in a stakeholder workshop. RESULTS: One hundred and thirty-two charities and partner organizations were invited to participate. In survey 1, 701 participants (70% non-clinicians, including CYP and parent and caregivers) submitted 1800 uncertainties from which 44 uncertainties were identified for prioritization in survey 2; from these, 1451 participants (83% non-clinicians) selected their top 10 priorities. An unweighted amalgamated score across participant roles was used to select 26. In the final workshop, 14 health care professionals, 11 parent and caregivers, and two CYP ranked the 26 questions to finalize the top 10 priorities. Ten top priority questions were identified regarding interventions to treat CYP with CNCs and their associated comorbidities, for example, sleep, emotional well-being, and distressing symptoms. INTERPRETATION: The results of this study will inform research into the effectiveness of interventions for children with neurological conditions.

Using Critical Success Index or Gilbert Skill Score as composite measures of positive predictive value and sensitivity in diagnostic accuracy studies: Weather forecasting informing epilepsy research.

The Critical Success Index (CSI) and Gilbert Skill score (GS) are verification measures that are commonly used to check the accuracy of weather forecasting. In this article, we propose that they can also be used to simplify the joint interpretation of positive predictive value (PPV) and sensitivity estimates across diagnostic accuracy studies of epilepsy data. This is because CSI and GS each provide a single measure that takes the weather forecasting equivalent of PPV and sensitivity into account. We have re-analysed data from our recent systematic review of diagnostic accuracy studies of administrative epilepsy data using CSI and GS. We summarise the results and benefits of this approach.

Screening for anxiety, depression and suicidality by epilepsy specialists in adult services in Scotland.

OBJECTIVE: Clinical guidelines recommend screening people with epilepsy (PWE) regularly for mental distress, but it is unclear how guidelines are implemented. We surveyed epilepsy specialists in adult Scottish services to determine approaches used to screen for anxiety, depression, and suicidality; the perceived difficulty of screening; factors associated with intention to screen; and treatment decisions made following positive screens. METHODS: An anonymous email-based questionnaire survey of epilepsy nurses and epilepsy neurology specialists (n = 38) was conducted. RESULTS: Two in every three specialists used a systematic screening approach; a third did not. Clinical interview was employed more often than standardized questionnaire. Clinicians reported positive attitudes towards screening but found screening difficult to implement. Intention to screen was associated with favorable attitude, perceived control, and social norm. Pharmacological and non-pharmacological interventions were proposed equally often for those screening positive for anxiety or depression. CONCLUSION: Routine screening for mental distress is carried out in Scottish epilepsy treatment settings but is not universal. Attention should be paid to clinician factors associated with screening, such as intention to screen and resulting treatment decisions. These factors are potentially modifiable, offering a means of closing the gap between guideline recommendations and clinical practice.

Questionnaire-based screening for mental distress in epilepsy: Outline and feasibility of an outpatient screening and intervention pathway.

OBJECTIVE: Mental distress is present in a significant proportion of people with epilepsy (PWE), with a negative impact across life domains. It is underdiagnosed and under-treated despite guidelines recommending screening for its presence (e.g., SIGN, 2015). We describe a tertiary-care epilepsy mental distress screening and treatment pathway, with a preliminary investigation of its feasibility. METHODS: We selected psychometric screening instruments for depression, anxiety, quality of life (QOL), and suicidality, establishing treatment options matched to instrument scores on the Patient Health Questionnaire 9 (PHQ-9), along 'traffic light' lines. We determined feasibility outcomes including recruitment and retention rates, resources required to run the pathway, and level of psychological need. We undertook a preliminary investigation of change in distress scores over a 9-month interval and determined PWE engagement and the perceived usefulness of pathway treatment options. RESULTS: Two-thirds of eligible PWE were included in the pathway with an 88% retention rate. At the initial screen, 45.8% of PWE required either an 'Amber-2' intervention (for moderate distress) or a 'Red' one (for severe distress). The equivalent figure at the 9-month re-screen was 36.8%, reflective of an improvement in depression and QOL scores. Online charity-delivered well-being sessions and neuropsychology were rated highly for engagement and perceived usefulness, but computerized cognitive behavioral therapy was not. The resources required to run the pathway were modest. CONCLUSION: Outpatient mental distress screening and intervention are feasible in PWE. The challenge is to optimize methods for screening in busy clinics and to determine the best (and most acceptable) interventions for screening positive PWE.

Efficient organisation of the contralateral hemisphere connectome is associated with improvement in intelligence quotient after paediatric epilepsy surgery.

OBJECTIVE: Aims of epilepsy surgery in childhood include optimising seizure control and facilitating cognitive development. Predicting which children will improve cognitively is challenging. We investigated the association of the pre-operative structural connectome of the contralateral non-operated hemisphere with improvement in intelligence quotient (IQ) post-operatively. METHODS: Consecutive children who had undergone unilateral resective procedures for epilepsy at a single centre were retrospectively identified. We included those with pre-operative volume T1-weighted non-contrast brain magnetic resonance imaging (MRI), no visible contralateral MRI abnormalities, and both pre-operative and two years post-operative IQ assessment. The MRI of the hemisphere contralateral to the side of resection was anatomically parcellated into 34 cortical regions and the covariance of cortical thickness between regions was used to create binary and weighted group connectomes. RESULTS: Eleven patients with a post-operative IQ increase of at least 10 points at two years were compared with twenty-four patients with no change in IQ score. Children who gained at least 10 IQ points post-operatively had a more efficiently structured contralateral hemisphere connectome with higher global efficiency (0.74) compared to those whose IQ did not change at two years (0.58, p = 0.014). This was consistent across thresholds and both binary and weighted networks. There were no statistically significant group differences in age, sex, age at onset of epilepsy, pre-operative IQ, mean cortical thickness, side or site of procedure, two year post-operative Engel scores or use of anti-seizure medications between the two groups. CONCLUSIONS: Surgical procedures to reduce or stop seizures may allow children with an efficiently structured contralateral hemisphere to achieve their cognitive potential.

The association of structural connectome efficiency with cognition in children with epilepsy.

OBJECTIVE: Cognitive impairment is common in children with epilepsy (CWE), but understanding the underlying pathological processes is challenging. We aimed to investigate the association of structural brain network organisation with cognition. METHODS: This was a retrospective cohort study of CWE without structural brain abnormalities, comparing whole brain network characteristics between those with cognitive impairment and those with intact cognition. We created structural whole-brain connectomes from anatomical and diffusion tensor magnetic resonance imaging using the number of streamlines and tract-averaged fractional anisotropy. We assessed the differences in average path length and global network efficiency between children with cognitive impairment and those without,using multivariable analyses to account for possible clinical group differences. RESULTS: Twenty-eight CWE and cognitive impairment had lower whole brain network global efficiency compared with 34 children with intact cognition (0.54, standard deviation (SD):0.003 vs. 0.56, SD:0.002, p < 0.001), which is equivalent to longer normalized network average path lengths (1.14, SD:0.05 vs. 1.10, SD:0.02, p = 0.003). In multivariable logistic regression cognitive impairment was not significantly associated with age of onset, duration of epilepsy, or number of antiseizure medications, but was independently associated with daily seizures (p = 0.04) and normalized average path length (p = 0.007). CONCLUSIONS: Higher structural network average path length and lower global network efficiency may be imaging biomarkers of cognitive impairment in epilepsy. Understanding what leads to changes in structural connectivity could aid identification of modifiable risk factors for cognitive impairment. These findings are only applicable to the specific cohort studied, and further confirmation in other cohorts is required.

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.

Language function following preterm birth: prediction using machine learning.

BACKGROUND: Preterm birth can lead to impaired language development. This study aimed to predict language outcomes at 2 years corrected gestational age (CGA) for children born preterm. METHODS: We analysed data from 89 preterm neonates (median GA 29 weeks) who underwent diffusion MRI (dMRI) at term-equivalent age and language assessment at 2 years CGA using the Bayley-III. Feature selection and a random forests classifier were used to differentiate typical versus delayed (Bayley-III language composite score <85) language development. RESULTS: The model achieved balanced accuracy: 91%, sensitivity: 86%, and specificity: 96%. The probability of language delay at 2 years CGA is increased with: increasing values of peak width of skeletonized fractional anisotropy (PSFA), radial diffusivity (PSRD), and axial diffusivity (PSAD) derived from dMRI; among twins; and after an incomplete course of, or no exposure to, antenatal corticosteroids. Female sex and breastfeeding during the neonatal period reduced the risk of language delay. CONCLUSIONS: The combination of perinatal clinical information and MRI features leads to accurate prediction of preterm infants who are likely to develop language deficits in early childhood. This model could potentially enable stratification of preterm children at risk of language dysfunction who may benefit from targeted early interventions. IMPACT: A combination of clinical perinatal factors and neonatal DTI measures of white matter microstructure leads to accurate prediction of language outcome at 2 years corrected gestational age following preterm birth. A model that comprises clinical and MRI features that has potential to be scalable across centres. It offers a basis for enhancing the power and generalizability of diagnostic and prognostic studies of neurodevelopmental disorders associated with language impairment. Early identification of infants who are at risk of language delay, facilitating targeted early interventions and support services, which could improve the quality of life for children born preterm.

Stimulant and non-stimulant drug therapy for people with attention deficit hyperactivity disorder and epilepsy.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) can co-occur in up to 40% of people with epilepsy. There is debate about the efficacy and tolerability of stimulant and non-stimulant drugs used to treat people with ADHD and co-occurring epilepsy. OBJECTIVES: To assess the effect of stimulant and non-stimulant drugs on children and adults with ADHD and co-occurring epilepsy in terms of seizure frequency and drug withdrawal rates (primary objectives), as well as seizure severity, ADHD symptoms, cognitive state, general behaviour, quality of life, and adverse effects profile (secondary objectives). SEARCH METHODS: We searched the following databases on 12 October 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 9 October 2020), CINAHL Plus (EBSCOhost, 1937 onwards). There were no language restrictions. CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy.  SELECTION CRITERIA: We included randomised controlled trials of stimulant and non-stimulant drugs for people of any age, gender or ethnicity with ADHD and co-occurring epilepsy. DATA COLLECTION AND ANALYSIS: We selected articles and extracted data according to predefined criteria. We conducted primary analysis on an intention-to-treat basis. We presented outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), except for individual adverse effects where we quoted 99% CIs. We conducted best- and worst-case sensitivity analyses to deal with missing data. We carried out a risk of bias assessment for each included study using the Cochrane risk of bias tool and assessed the overall certainty of evidence using the GRADE approach. MAIN RESULTS: We identified two studies that matched our inclusion criteria: a USA study compared different doses of the stimulant drug osmotic-release oral system methylphenidate (OROS-MPH) with a placebo in 33 children (mean age 10.5 ± 3.0 years), and an Iranian study compared the non-stimulant drug omega-3 taken in conjunction with risperidone and usual anti-seizure medication (ASM) with risperidone and ASM only in 61 children (mean age 9.24 ± 0.15 years). All children were diagnosed with epilepsy and ADHD according to International League Against Epilepsy and Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria, respectively. We assessed both studies to be at low risk of detection and reporting biases, but assessments varied from low to high risk of bias for all other domains. OROS-MPH No participant taking OROS-MPH experienced significant worsening of epilepsy, defined as: 1. a doubling of the highest 14-day or highest two-day seizure rate observed during the 12 months before the trial; 2. a generalised tonic-clonic seizure if none had been experienced in the previous two years; or 3. a clinically meaningful intensification in seizure duration or severity (33 participants, 1 study; low-certainty evidence). However, higher doses of OROS-MPH predicted an increased daily risk of a seizure (P < 0.001; 33 participants, 1 study; low-certainty evidence). OROS-MPH had a larger proportion of participants receiving 'much improved' or 'very much improved' scores for ADHD symptoms on the Clinical Global Impressions for ADHD-Improvement tool (33 participants, 1 study; low-certainty evidence). OROS-MPH also had a larger proportion of people withdrawing from treatment (RR 2.80; 95% CI 1.14 to 6.89; 33 participants, 1 study; moderate-certainty evidence). Omega-3 Omega-3 with risperidone and ASM were associated with a reduction in mean seizure frequency by 6.6 seizures per month (95% CI 4.24 to 8.96; 56 participants, 1 study; low-certainty evidence) and an increase in the proportion of people achieving 50% or greater reduction in monthly seizure frequency (RR 2.79, 95% CI 0.84 to 9.24; 56 participants, 1 study; low-certainty evidence) compared to people on risperidone and ASM alone. Omega-3 with risperidone and ASM also had a smaller proportion of people withdrawing from treatment (RR 0.65, 95% CI 0.12 to 3.59; 61 participants, 1 study; low-certainty evidence) but a larger proportion of people experiencing adverse drug events (RR 1.40, 95% CI 0.44 to 4.42; 56 participants, 1 study; low-certainty evidence) compared to people on risperidone and ASM alone. AUTHORS' CONCLUSIONS: In children with a dual-diagnosis of epilepsy and ADHD, there is some evidence that use of the stimulant drug OROS-MPH is not associated with significant worsening of epilepsy, but higher doses of it may be associated with increased daily risk of seizures; the evidence is of low-certainty. OROS-MPH is also associated with improvement in ADHD symptoms. However, this treatment was also associated with a large proportion of treatment withdrawal compared to placebo. In relation to the non-stimulant drug omega-3, there is some evidence for reduction in seizure frequency in children who are also on risperidone and ASM, compared to children who are on risperidone and ASM alone. Evidence is inconclusive whether omega-3 increases or decreases the risk of adverse drug events. We identified only two studies - one each for OROS-MPH and omega-3 - with low to high risk of bias. We assessed the overall certainty of evidence for the outcomes of both OROS-MPH and omega-3 as low to moderate. More studies are needed. Future studies should include: 1. adult participants; 2. a wider variety of stimulant and non-stimulant drugs, such as amphetamines and atomoxetine, respectively; and 3. additional important outcomes, such as seizure-related hospitalisations and quality of life. Clusters of studies which assess the same drug - and those that build upon the evidence base presented in this review on OROS-MPH and omega-3 - are needed to allow for meta-analysis of outcomes.

ANTECEDENTES: El trastorno por déficit de atención e hiperactividad (TDAH) puede concurrir en hasta el 40% de las personas con epilepsia. Existe un debate sobre la eficacia y la tolerabilidad de los fármacos estimulantes y no estimulantes utilizados para tratar a las personas con TDAH y epilepsia concurrente. OBJETIVOS: Evaluar el efecto de los fármacos estimulantes y no estimulantes en niños y adultos con TDAH y epilepsia concurrente, en cuanto a la frecuencia de las crisis epilépticas y las tasas de retiro del fármaco (objetivos principales), así como la gravedad de las crisis epilépticas, los síntomas del TDAH, el estado cognitivo, el comportamiento general, la calidad de vida y el perfil de efectos adversos (objetivos secundarios). MÉTODOS DE BÚSQUEDA: El 12 de octubre de 2020 se realizaron búsquedas en las siguientes bases de datos: Registro Cochrane de Estudios (CRS Web), MEDLINE (Ovid, 1946 hasta el 9 de octubre de 2020), CINAHL Plus (EBSCOhost, 1937 en adelante). No hubo restricciones de idioma. El CRS Web incluye ensayos controlados aleatorizados o cuasialeatorizados de PubMed, Embase, ClinicalTrials.gov, la Plataforma de registros internacionales de ensayos clínicos (ICTRP) de la Organización Mundial de la Salud, el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials; CENTRAL) y los registros especializados de los Grupos Cochrane de Revisión, incluido el de Epilepsia. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados aleatorizados de fármacos estimulantes y no estimulantes para personas de cualquier edad, sexo o etnia con TDAH y epilepsia concurrente. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se seleccionaron los artículos y se extrajeron los datos según criterios predefinidos. El análisis principal se realizó por intención de tratar. Los desenlaces se presentaron como razones de riesgos (RR) con intervalos de confianza (IC) del 95%, excepto en el caso de los efectos adversos individuales, en los que se citaron los IC del 99%. Se realizaron análisis de sensibilidad en el mejor y peor de los casos para lidiar con los datos faltantes. Se realizó una evaluación del riesgo de sesgo para cada estudio incluido mediante la herramienta Cochrane de riesgo de sesgo y la certeza general de la evidencia se evaluó mediante el método GRADE. RESULTADOS PRINCIPALES: Se identificaron dos estudios que cumplieron con los criterios de inclusión: un estudio de EE.UU. comparó diferentes dosis del fármaco estimulante metilfenidato con un sistema oral de liberación osmótica (OROS­MPH) con un placebo en 33 niños (media de edad 10,5 ± 3,0 años), y un estudio iraní comparó el fármaco no estimulante omega­3 tomado junto con la risperidona y la medicación anticonvulsiva (MAC) habitual con la risperidona y la MAH solamente en 61 niños (media de edad 9,24 ± 0,15 años). Todos los niños tenían un diagnóstico de epilepsia y TDAH según los criterios de la International League Against Epilepsy y del Diagnostic and Statistical Manual of Mental Disorders, cuarta edición, respectivamente. Se consideró que ambos estudios tenían un riesgo de sesgo de detección y de notificación bajos, pero las evaluaciones variaron de riesgo de sesgo bajo a alto en todos los demás dominios. OROS­MPH Ningún participante de los que recibieron OROS­MPH presentó un empeoramiento significativo de la epilepsia, definido como: 1. una duplicación de la tasa más alta de convulsiones en 14 días o en dos días, observada durante los 12 meses anteriores al ensayo; 2. una convulsión tónico­clónica generalizada si no se había experimentado ninguna en los dos años anteriores; o 3. una intensificación clínicamente significativa de la duración o la gravedad de las convulsiones (33 participantes, un estudio; evidencia de certeza baja). Sin embargo, las dosis más altas de OROS­MPH predijeron un mayor riesgo diario de presentar una convulsión (p < 0,001; 33 participantes, un estudio; evidencia de certeza baja). Con el OROS­MPH hubo una mayor proporción de participantes que recibieron puntuaciones de "mucha mejoría" o "muchísima mejoría" en los síntomas del TDAH según la herramienta Clinical Global Impressions for ADHD­Improvement (33 participantes, un estudio; evidencia de certeza baja). Con el OROS­MPH también hubo una mayor proporción de personas que se retiraron del tratamiento (RR 2,80; IC del 95%: 1,14 a 6,89; 33 participantes, un estudio; evidencia de certeza moderada). Omega­3 El omega­3 con la risperidona y la MAC se asociaron con una reducción de la frecuencia media de las crisis epilépticas en 6,6 crisis epilépticas por mes (IC del 95%: 4,24 a 8,96; 56 participantes, un estudio; evidencia de certeza baja) y un aumento de la proporción de personas que lograron una reducción del 50% o más en la frecuencia mensual de las crisis epilépticas (RR: 2,79; IC del 95%: 0,84 a 9,24; 56 participantes, un estudio; evidencia de certeza baja) en comparación con las personas que recibieron risperidona y MAC solamente. Con el omega­3 con risperidona y MAC también hubo una menor proporción de personas que se retiraron del tratamiento (RR 0,65; IC del 95%: 0,12 a 3,59; 61 participantes, un estudio; evidencia de certeza baja), pero una mayor proporción de personas que presentaron eventos adversos al fármaco (RR 1,40; IC del 95%: 0,44 a 4,42; 56 participantes, un estudio; evidencia de certeza baja) en comparación con las personas que recibieron risperidona y MAC solamente. CONCLUSIONES DE LOS AUTORES: En los niños con un doble diagnóstico de epilepsia y TDAH, hay alguna evidencia de que el uso del fármaco estimulante OROS­MPH no se asocia con un empeoramiento significativo de la epilepsia, pero las dosis más altas podrían estar asociadas con un mayor riesgo diario de crisis epilépticas; la evidencia es de certeza baja. OROS­MPH también se asocia con una mejoría de los síntomas del TDAH. Sin embargo, este tratamiento también se asoció con una gran proporción de retiro del tratamiento en comparación con el placebo. En relación con el fármaco no estimulante omega­3, existe alguna evidencia de una reducción de la frecuencia de las convulsiones en los niños que también recibieron risperidona y MAC, en comparación con los niños que sólo recibieron risperidona y MAC. La evidencia no es concluyentes en cuanto a si los omega­3 aumentan o disminuyen el riesgo de experimentar efectos adversos de los medicamentos. Sólo se identificaron dos estudios (uno con OROS­MPH y otro con omega­3) con un riesgo de sesgo bajo a alto. La certeza general de la evidencia para los desenlaces de OROS­MPH y omega­3 se consideró baja a moderada. Se necesitan más estudios. Los estudios futuros deberían incluir: 1. participantes adultos; 2. una mayor variedad de fármacos estimulantes y no estimulantes, como las anfetaminas y la atomoxetina, respectivamente; y 3. desenlaces adicionales importantes, como las hospitalizaciones relacionadas con las convulsiones y la calidad de vida. Se necesitan grupos de estudios que evalúen el mismo fármaco (y estén desarrollados sobre evidencia presentada en esta revisión acerca de OROS­MPH y omega­3) para poder realizar un metanálisis de los desenlaces.

Impaired social attention detected through eye movements in children with early-onset epilepsy.

OBJECTIVES: Children with early-onset epilepsy (CWEOE; epilepsy onset before 5 years) exhibit impaired social functioning, but social attention has not yet been examined. In this study we sought to explore visual attention via eye tracking as a component of social attention and examine its relationship with social functioning and Autism Spectrum Disorder (ASD) risk scores. METHODS: Forty-seven CWEOE (3-63 months) and 41 controls (3-61 months) completed two eye-tracking tasks: (1) preference for social versus nonsocial naturalistic scenes, and (2) face region preference task. ASD risk was measured via the Modified Checklist for Autism in Toddlers or Conners Early Childhood Total Score. Social functioning was assessed via the Greenspan Social-Emotional Growth Chart, or Infant-Toddler Social & Emotional Assessment Competence Scale, or Conners Early Childhood Social Functioning Scale, depending on age. Fixation preferences for social scenes and eyes were compared between groups and evaluated by age and social functioning scores. RESULTS: Regression analysis revealed that CWEOE viewed the social scene to a significantly less degree than controls. The greatest difference was found between the youngest CWEOE and controls. Fixation duration was independently and significantly related to social functioning scores. There were no significant differences between CWEOE and controls in the face scanning task, and there was no significant relationship between either task and ASD risk scores. SIGNIFICANCE: CWEOE exhibit task-specific atypical social attention early in the course of the disease. This may be an early marker of impaired social development, and it suggests abnormal social brain development.

A national study of epilepsy-related deaths in Scotland: Trends, mechanisms, and avoidable deaths.

OBJECTIVE: This study was undertaken to investigate the trends and mechanisms of epilepsy-related deaths in Scotland, highlighting the proportion that were potentially avoidable. METHODS: This was a retrospective observational data-linkage study of administrative data from 2009-2016. We linked nationwide data encompassing mortality records, hospital admissions, outpatient attendance, antiepileptic drug (AED) prescriptions, and regional primary care attendances. Adults (aged ≥16 years) suffering epilepsy-related death were identified for study using International Classification of Diseases, 10th Revision coding combined with AED prescriptions. We reported epilepsy-related mortality rate (MR), age-specific mortality ratios, multiple cause-of-death frequencies, and the proportion of potentially avoidable deaths (identified as those with an underlying cause listed as avoidable by the Office for National Statistics). RESULTS: A total of 1921 epilepsy-related deaths were identified across Scotland; 1185 (62%) decedents were hospitalized for seizures in the years leading up to death, yet only 518 (27%) were seen in a neurology clinic during the same period. MR remained unchanged over time, ranging from 5.9 to 8.7 per 100 000 Scottish population (95% confidence interval [CI] = -.05 to .66 per 100 000 for annual change in MR). Mortality ratios were significantly increased in young adults aged 16-54 years (2.3, 95% CI = 1.8-2.8), peaking at age 16-24 years (5.3, 95% CI = 1.8-8.8). Sudden unexpected death in epilepsy (SUDEP) constituted 30% of the 553 young adult epilepsy-related deaths, with several other non-SUDEP fatal mechanisms identified including aspiration pneumonia, cardiac arrest, AED or narcotic poisoning, drowning, and alcohol dependence. Seventy-six percent of young adult epilepsy-related deaths were potentially avoidable. SIGNIFICANCE: Epilepsy-related deaths are a major public health problem in Scotland, given that they are not reducing, people are dying young, and many deaths are potentially avoidable. SUDEP is only one of several important mechanisms by which epilepsy-related deaths are occurring in young adults. Services may need to be re-evaluated to improve specialist referral following seizure-related hospital admissions.

Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. METHODS: Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. RESULTS: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.

OBJECTIVES: To assess the efficacy and safety profile of add-on cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials. METHODS: Patients received plant-derived, highly purified CBD medicine (Epidiolex® in the USA; Epidyolex® in Europe; 100 mg/ml oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta-analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period. RESULTS: 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62-0.80]; DS, 0.71 [0.60-0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47-0.67]; DS, 0.63 [0.52-0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure-free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam. CONCLUSIONS: Add-on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.

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.

The accuracy of using administrative healthcare data to identify epilepsy cases: A systematic review of validation studies.

Our objective was to undertake a systematic review ascertaining the accuracy of using administrative healthcare data to identify epilepsy cases. We searched MEDLINE and Embase from 01/01/1975 to 03/07/2018 for studies evaluating the diagnostic accuracy of routinely collected healthcare data in identifying epilepsy cases. Any disease coding system in use since the International Classification of Diseases, Ninth Revision (ICD-9) was permissible. Two authors independently screened studies, extracted data, and quality-assessed studies. We assessed positive predictive value (PPV), sensitivity, negative predictive value (NPV), and specificity. The primary analysis was a narrative synthesis of review findings. Thirty studies were included, published between 1989 and 2018. Risks of bias were low, high, and unclear in 4, 14, and 12 studies, respectively. Coding systems included ICD-9, ICD-10, and Read Codes, with or without antiepileptic drugs (AEDs). PPVs included ranges of 5.2%-100% (Canada), 32.7%-96.0% (USA), 47.0%-100% (UK), and 37.0%-88.0% (Norway). Sensitivities included ranges of 22.2%-99.7% (Canada), 12.2%-97.3% (USA), and 79.0%-94.0% (UK). Nineteen studies contained at least one algorithm with a PPV >80%. Sixteen studies contained at least one algorithm with a sensitivity >80%. PPV was highest in algorithms consisting of disease codes (ICD-10 G40-41, ICD-9 345) in combination with one or more AEDs. The addition of symptom codes to this (ICD-10 R56; ICD-9 780.3, 780.39) lowered PPV. Sensitivity was highest in algorithms consisting of symptom codes with one or more AEDs. Although using AEDs alone achieved high sensitivities, the associated PPVs were low. Most NPVs and specificities were >90%. We conclude that it is reasonable to use administrative data to identify people with epilepsy (PWE) in epidemiological research. Studies prioritizing high PPVs should focus on combining disease codes with AEDs. Studies prioritizing high sensitivities should focus on combining symptom codes with AEDs. We caution against the use of AEDs alone to identify PWE.