Clinical effectiveness of the psychological therapy Mental Health Intervention for Children with Epilepsy in addition to usual care compared with assessment-enhanced usual care alone: a multicentre, randomised controlled clinical trial in the UK.

BACKGROUND: Mental health difficulties are common in children and young people with chronic health conditions, but many of those in need do not access evidence-based psychological treatments. The study aim was to evaluate the clinical effectiveness of integrated mental health treatment for children and young people with epilepsy, a common chronic health condition known to be associated with a particularly high rate of co-occurring mental health difficulties. METHODS: We conducted a parallel group, multicentre, open-label, randomised controlled trial of participants aged 3-18 years, attending epilepsy clinics across England and Northern Ireland who met diagnostic criteria for a common mental health disorder. Participants were randomised (1:1; using an independent web-based system) to receive the Mental Health Intervention for Children with Epilepsy (MICE) in addition to usual care, or assessment-enhanced usual care alone (control). Children and young people in both groups received a full diagnostic mental health assessment. MICE was a modular psychological intervention designed to treat common mental health conditions in children and young people using evidence-based approaches such as cognitive behaviour therapy and behavioural parenting strategies. Usual care for mental health disorders varied by site but typically included referral to appropriate services. Participants, along with their caregivers, and clinicians were not masked to treatment allocation but statisticians were masked until the point of analysis. The primary outcome, analysed by modified intention-to-treat, was the parent-report Strengths and Difficulties Questionnaire (SDQ) at 6 months post-randomisation. The study is complete and registered with ISRCTN (57823197). FINDINGS: 1401 young people were potentially deemed eligible for study inclusion. Following the exclusion of 531 young people, 870 participants were assessed for eligibility and completed the SDQ, and 480 caregivers provided consent for study inclusion between May 20, 2019, and Jan 31, 2022. Between Aug 28, 2019, and Feb 21, 2022, 334 participants (mean ages 10·5 years [SD 3·6] in the MICE group vs 10·3 [4·0] in control group at baseline) were randomly assigned to an intervention using minimisation balanced by age, primary mental health disorder, diagnosis of intellectual disability, and autistic spectrum disorder at baseline. 168 (50%) of the participants were female and 166 (50%) were male. 166 participants were randomly assigned to the MICE group and 168 were randomly assigned to the control group. At 6 months, the mean SDQ difficulties for the 148 participants in the MICE group was 17·6 (SD 6·3) and 19·6 (6·1) for the 148 participants in the control group. The adjusted effect of MICE was -1·7 (95% CI -2·8 to -0·5; p=0·0040; Cohen's d, 0·3). 14 (8%) patients in the MICE group experienced at least one serious adverse event compared with 24 (14%) in the control group. 68% percent of serious adverse events (50 events) were admission due to seizures. INTERPRETATION: MICE was superior to assessment-enhanced usual care in improving symptoms of emotional and behavioural difficulties in young people with epilepsy and common mental health disorders. The trial therefore shows that mental health comorbidities can be effectively and safely treated by a variety of clinicians, utilising an integrated intervention across ages and in the context of intellectual disability and autism. The evidence from this trial suggests that such a model should be fully embedded in epilepsy services and serves as a model for other chronic health conditions in young people. FUNDING: UK National Institute for Health Research Programme Grants for Applied Research programme and Epilepsy Research UK Endeavour Project Grant.

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.

Caregiver perceptions of the impact of Dravet syndrome on the family, current supports and hopes and fears for the future: A qualitative study.

BACKGROUND: Dravet syndrome (DS) is a Developmental and Epileptic Encephalopathy (DEE) with onset typically in infancy. Seizures are pharmaco-resistant, and neurodevelopment is compromised in almost all children. There is limited data on the impact of the condition on the family, support needs and hopes and fears in Sweden. METHODS: Interviews were undertaken with the caregivers of 36 of 48 (75%) living children with DS in Sweden focusing on the perceived impact on the family, current supports and hopes and fears for the future. Data from the interviews were analyzed by two raters using reflexive thematic analysis. RESULTS: The analysis revealed seven main themes focusing on the perceived negative impact the disease has on caregivers and family functioning. These negative impacts concerned: caregiver sleep (e.g., frequent night waking), siblings (e.g., gets less attention/time), social life (e.g., limited vacations), family finances (e.g., limited career progression), parental health (both mental and physical) and need for constant supervision (e.g., child's need for constant supervision for fear of seizures). Another theme concerned the impact on family relationships. Whilst some caregivers perceived the impact to be negative (e.g., limited time for each other) others felt that having a child with DS lead to stronger relationships and more 'teamwork'. With respect to supports, the caregivers identified a number of areas where they felt the family could access appropriate supports. Themes regarding supports included: support from the wider family and friends, support from DS support groups (online or in-person), support from the child's hospital or disability service and respite care (e.g., child was looked after on weekends or had paid carers in the home). Regarding hopes and fears for the future, responses focused mainly on fears, including concerns about premature death of the child, transition to adult healthcare services and care arrangements for child when parents are dead. Hopes for the future included better treatment for epilepsy and associated neurodevelopmental problems and finding a cure for DS. CONCLUSIONS: Caregivers of children with DS report that the disease can have a very comprehensive negative impact on caregiver and family functioning. Identifying and providing the supports to ameliorate these negative impacts is vital to optimize caregiver and family wellbeing and quality of life.

Diagnosis, epilepsy treatment and supports for neurodevelopment in children with Dravet Syndrome: Caregiver reported experiences and needs.

BACKGROUND: Dravet syndrome is a rare infantile onset epilepsy syndrome encompassing treatment resistant epilepsy and neurodevelopmental difficulties. There is limited data regarding caregiver experiences of diagnosis, treatment and supports for the associated neurodevelopmental problems. METHOD: Semi-structured interviews were conducted with caregivers of 36/48 children (75% of total population in Sweden) with Dravet syndrome. Data was analysed using thematic analysis. RESULTS: Regarding the diagnostic experience, themes were: Delays in diagnostic process, genetic testing not optimal, communication of Dravet syndrome diagnosis and support and information soon after diagnosis. Caregivers felt that delays in diagnosis and testing could have been avoided whilst experiences of communication of diagnosis and support after diagnosis varied. In terms of treatment for seizures, the themes were: Satisfied with treatment, emergency treatment, treatment with antiseizure medications, strategies to control seizures via temperature regulation/avoidance of infections and use of equipment and aids. Caregivers were in the main accepting that seizures in Dravet syndrome are very difficult to treat and that seizure freedom is often an unachievable goal. Many felt frustrated that they were expected to take responsibility with respect to choice of medication. They often employed strategies (e.g., avoidance of physical activity) to reduce seizures or their impact. In terms of supports for neurodevelopmental problems, the themes were: Struggled to access support, lack of integrated healthcare and satisfaction with school. Many caregivers felt that accessing necessary supports for their children and developmental and behavioural needs was a struggle and that the provision of support often lacked integration e.g., lack of collaboration between child's disability service and school. Caregivers also expressed a desire that there would be better knowledge of Dravet syndrome in emergency departments and schools, that care would be better integrated and that there would be more supports for assessment and interventions regarding the associated neurodevelopmental problems. CONCLUSION: The responses of caregivers of children with Dravet syndrome highlight the need for supports from diagnosis for both epilepsy and neurodevelopmental problems. Good examples of provision were identified but parents often felt they lacked support and support often came from providers who lacked knowledge of the syndrome. Collaboration between medical, disability and school services was often lacking.

Autism and attention-deficit/hyperactivity disorder in children with Dravet syndrome: A population-based study.

AIM: To identify on a population basis the prevalence of autism and attention-deficit/hyperactivity disorder (ADHD) in children with Dravet syndrome and factors associated with symptoms of autism and ADHD. METHOD: Forty-one of 48 children with Dravet syndrome living in Sweden, born between 1st January 2000 and 31st December 2018 underwent assessment including measures of autism and ADHD. Diagnoses of autism and ADHD were made with respect to DSM-5 criteria. Factors associated with features of autism and ADHD were analysed via regression. RESULTS: Twenty-five of the 41 children fulfilled DSM-5 criteria for autism spectrum disorder and 12 of 37 children considered for an ADHD diagnosis fulfilled DSM-5 criteria for ADHD. Severe intellectual disability was significantly associated with a greater degree of autistic features (p < 0.001) and a DSM-5 diagnosis of autism spectrum disorder (p = 0.029). Younger children had significantly more features of ADHD (p = 0.004) and features of inattention were significantly more common than features of hyperactivity/impulsivity (p < 0.001). INTERPRETATION: Children with Dravet syndrome often have significant features of autism and ADHD, primarily inattentive type. Screening for autism and ADHD should be routine in children with Dravet syndrome.

Accelerometer and Survey Assessed Physical Activity in Children With Epilepsy: A Case-Controlled Study.

PURPOSE: Anecdotal evidence suggests that children with epilepsy (CWE) are limited in the frequency of their daily physical activity (PA). However, there is limited research utilizing device-based measures of PA. We compared levels of PA and sedentary behavior in CWE (11-15 y) and age- and gender-matched healthy controls. METHOD: Participants (n = 60 CWE [25 males, 35 females] and n = 49 controls [25 males, 24 females]) wore a Actigraph accelerometer (GT3X or GT3X+) for 7 consecutive days during waking hours and self-reported their PA and sedentary behaviors. CWE were compared with control children on time spent in different intensities of PA and on self-reported PA and sedentary behavior. Factors associated with PA were analyzed using linear regression. RESULTS: CWE spent less time in accelerometer assessed light (189.15 vs 215.01 min/d, P < .05) and vigorous PA (35.14 vs 44.28 min/d, P < .05) on weekdays compared with controls. There were no significant differences between CWE and control participants in accelerometer assessed time spent sedentary or time spent in PA on weekends. Among CWE, older children engaged in more reported sedentary behavior and younger children spent more time in most domains of PA (P < .05). Furthermore, CWE reported less PA than controls (P = .006). Sixteen percent of controls met World Health Organization PA guidelines compared with 10% of CWE. There was a positive relationship between accelerometer assessed PA and quality of life for CWE. CONCLUSION: CWE spent less time in light and moderate to vigorous PA on weekdays. Further research is needed to understand reasons for these differences.

Scoping review and expert-based consensus recommendations for assessment and management of psychogenic non-epileptic (functional) seizures (PNES) in children: A report from the Pediatric Psychiatric Issues Task Force of the International League Against Epilepsy.

Limited guidance exists regarding the assessment and management of psychogenic non-epileptic seizures (PNES) in children. Our aim was to develop consensus-based recommendations to fill this gap. The members of the International League Against Epilepsy (ILAE) Task Force on Pediatric Psychiatric Issues conducted a scoping review adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-SR) standards. This was supplemented with a Delphi process sent to pediatric PNES experts. Consensus was defined as ≥80% agreement. The systematic search identified 77 studies, the majority (55%) of which were retrospective (only one randomized clinical trial). The primary means of PNES identification was video electroencephalography (vEEG) in 84% of studies. Better outcome was associated with access to counseling/psychological intervention. Children with PNES have more frequent psychiatric disorders than controls. The Delphi resulted in 22 recommendations: Assessment-There was consensus on the importance of (1) taking a comprehensive developmental history; (2) obtaining a description of the events; (3) asking about potential stressors; (4) the need to use vEEG if available parent, self, and school reports and video recordings can contribute to a "probable" diagnosis; and (5) that invasive provocation techniques or deceit should not be employed. Management-There was consensus about the (1) need for a professional with expertise in epilepsy to remain involved for a period after PNES diagnosis; (2) provision of appropriate educational materials to the child and caregivers; and (3) that the decision on treatment modality for PNES in children should consider the child's age, cognitive ability, and family factors. Comorbidities-There was consensus that all children with PNES should be screened for mental health and neurodevelopmental difficulties. Recommendations to facilitate the assessment and management of PNES in children were developed. Future directions to fill knowledge gaps were proposed.

Supporting Attention in Children with Epilepsy (SPACE): Pilot of a psychoeducational intervention.

PURPOSE: Children with epilepsy are at high risk for impairing symptoms of attention deficit hyperactivity disorder (ADHD), especially difficulties with attention. There is limited evidence regarding the use of psychological interventions for children with epilepsy and attention difficulties. We developed and piloted a novel psychoeducational intervention -Supporting Attention in Children with Epilepsy (SPACE). METHODS: Eligible children with epilepsy (8-13 years) and difficulties with attention underwent a comprehensive psychological assessment and took part in a single-arm trial of the SPACE intervention. The first three sessions of SPACE took place in groups of 3-5 children and two psychologists. The final three sessions involved one psychologist meeting the child and parent(s). The child's teacher joined for one of the final three sessions. The first group of participants participated in the intervention in person. Subsequent groups took part online due to COVID-19-related restrictions. Measures of ADHD -inattention symptoms (parent and teacher), executive functioning (child, parent, and teacher), and epilepsy-specific and general Health-Related Quality of Life (HRQOL) (child and parent) were administered before and three months after completing the intervention. RESULTS: Twenty-seven children with epilepsy expressed an interest in participating. Sixteen children met eligibility criteria and participated in a single-arm pilot of the intervention. All 16 participants completed the intervention. Pre- and post-intervention data were available for 15 of the 16 children. Improvement in function was noted on all measures and reached statistical significance for child ratings of executive functioning (p = 0.030) and HRQOL (p = 0.043), and parent-rated child HRQOL (p < 0.001). Qualitative feedback regarding content and acceptability was positive. CONCLUSION: A psychoeducational intervention for children with epilepsy and difficulties with attention can lead to improved executive functioning and HRQOL. Such an intervention may be a useful first-line intervention for children with epilepsy at risk for or diagnosed with ADHD and/or be used in combination with pharmacological treatment with children with epilepsy and ADHD. However, more robustly designed studies are needed.

Perceived impact of epilepsy on sleep: Views of children with epilepsy, parents and school staff.

OBJECTIVE: To gain an understanding of the views of school-aged children with epilepsy, their parents, and school staff regarding the impact of epilepsy on sleep. METHODS: As part of the What I Need in School (WINS) study, school-aged children (n = 18) with 'active epilepsy' (taking Anti-Seizure Medications, ASMs, for epilepsy), their parents (n = 68) and school staff (n = 56) were interviewed or completed bespoke questionnaires. Questions focussed on the potential impact of epilepsy on the child's sleep or tiredness in school and the potential impact of sleep/tiredness on learning and behavior. RESULTS: Fifty-six percent of children believed that epilepsy affects their sleep while 65% of parents believed that their child had more difficulties with sleep than other children of their age. Seventy-eight percent of parents believed that their child's difficulties were due to epilepsy and 95% believed that their child's difficulties impacted their learning and behavior. Fifty-four percent of school staff believed that the child with epilepsy they supported was more tired/fatigued than their peers, and 86% of school staff believed that the child's increased tiredness affected their learning/behavior. Parents of children with intellectual disabilitiy were significantly more likely to indicate that they felt that their child had more sleep difficulties than other children (p = 0.016). Regarding the impact on their sleep, participating children felt that epilepsy contributed to difficulties in falling and staying asleep and daytime tiredness. Their parents reported a range of potential sleep difficulties and potential impacts on the child's learning and behavior. Parental reported difficulties included daytime tiredness, difficulty falling and staying asleep, and the impact of nocturnal seizures. In terms of impact, parents felt that sleep difficulties impacted negatively cognition and emotional-behavioral functioning. Additionally, parents reported that ASMs and medication for ADHD can contribute to sleep difficulties. School staff felt that many of the children appeared tired/fatigued during the day and this could lead to less engagement with classroom activities, impact attention and processing speed negatively, and contribute to behavioral and emotional difficulties. CONCLUSION: The majority of children and parents who responded believed that epilepsy affects the child's sleep. Most parents and school staff also believed that the child's sleep difficulties/excess tiredness were due to the child's epilepsy and that the difficulties significantly impacted the child's learning and behavior. There is a need to better understand the role epilepsy plays in sleep difficulties and associated learning and behavioral impairments. There is also a need to develop interventions to reduce the subsequent impact on child learning and behavior.

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.

Parental experiences of having a child with CLN3 disease (juvenile Batten disease) and how these experiences relate to family resilience.

BACKGROUND: CLN3 disease is a neurodegenerative condition presenting in the first decade of life typically leading to death in the third decade. The earliest symptom is rapidly progressive visual impairment followed by intellectual and motor impairments, epilepsy and behavioural disturbances. There are limited data on how the condition affects the family system or the role of family resilience in paediatric neurodegenerative diseases. METHODS: Semi-structured interviews were conducted with eight parents (five mothers and three fathers) of five children with CLN3. Interview questions focused on the experience of having a child with CLN3, its impact on the family system as well as the concept of family resilience. Data were analysed via thematic analysis. RESULTS: The thematic analysis resulted in four main themes. The theme 'recurring losses' included the feeling of losing a healthy child, the child's loss of abilities and loss of relationships. The theme 'disruption to the family system' included that siblings could be 'side-lined', the potential negative impact on romantic relationships and difficulties finding time to oneself. The theme 'Society is not developed for a progressive disease' highlighted the difficulties parents faced with respect to contacts with the health and/or social insurance system. The paediatric health care system was seen as supportive, but the adult health care system was not seen as fit for the purpose. Regarding family resilience, parents felt that the disease forced them to reconsider what was important in life. Several parents described that they learned to value small moments of joy and create deep connections through involvement in family routines and rituals. CONCLUSIONS: CLN3 places a very significant burden on the family system including parental feelings of loss, impact on family relationships and lack of understanding within the health/social insurance systems. The concept of family resilience may be useful in understanding the experiences of families affected by paediatric neurodegenerative conditions.

Epilepsy in schools: Views on educational and therapeutic provision, understanding of epilepsy and seizure management.

OBJECTIVE: To gain an understanding of the views of young people with epilepsy, their parents and school staff regarding educational and therapeutic provision, understanding of epilepsy and seizure management in schools. METHODS: School-aged children (n = 20) with 'active epilepsy' (taking Anti-Seizure Medications (ASMs) for epilepsy), their parents (n = 68), and school staff (n = 56) were interviewed or completed bespoke questionnaires. In addition, all participating children underwent psychological assessment including measures of behavior and cognition. RESULTS: Only 15% of participating children had received psychological support despite 60% scoring within the at-risk range on a measure of behavioral and emotional difficulties. More than half of the responding children reported that some of their teachers and friends did not know that they had epilepsy. A significant minority of parents (32%) did not feel that the child's transition from preschool to primary, or primary to secondary school was managed well. Knowledge of the child's epilepsy was felt to be significantly better in special schools than mainstream schools according to both parents and school staff. Staff in special schools perceived they were more knowledgeable about the child's ASMs and changes to ASMs than staff in mainstream schools. Staff in special schools were significantly more likely to have received training on general aspects of epilepsy, seizure management, and impacts on learning and/or behavior. Parental interviews indicated difficulties accessing educational and therapeutic supports. Parents often felt that they had to drive the process to gain supports themselves. They also reported limited professional support, and inadequate communication between themselves and the school and school staff and medical/therapeutic professionals regarding their child's needs. Parents would like more school staff to recognize the impacts of epilepsy on learning and behavior and to support their child more holistically. Many parents wanted more resources for assessment and therapeutic provision in relation to their child's learning, behavior, and emotions. CONCLUSION: Knowledge of epilepsy is felt by parents and staff to be significantly better in special schools compared with mainstream schools. Parents highlighted the need for increased knowledge of the impacts of epilepsy on learning and behavior and perceived a need for more resources for assessment of these difficulties.

Feasibility of telephone-delivered therapy for common mental health difficulties embedded in pediatric epilepsy clinics.

BACKGROUND: Mental and physical health treatment should be delivered together for children and young people with epilepsy. Training healthcare professionals (HCPs) in epilepsy services to deliver mental health interventions is an important way to facilitate integrated care. OBJECTIVE: To determine the feasibility of remotely delivered assessment and psychological treatment for mental health difficulties delivered by HCPs in pediatric epilepsy clinics with limited formal training in psychological interventions. We hypothesized that it would be (i) feasible to train HCPs to deliver the psychological intervention and (ii) that participants receiving the psychological therapy would report reductions in symptoms of mental health difficulties including anxiety, depression, and behavior difficulties and improve quality of life. METHODS: Thirty-four children and young people with epilepsy who had impairing symptoms of a common mental health difficulty (anxiety, depression, disruptive behavior, and/or trauma) were allocated to receive 6 months of a modular cognitive behavioral intervention delivered by a HCP with limited formal psychological therapy experience. Thirteen HCPs were trained in delivery of the intervention. Healthcare professional competence was assessed in a two-stage process. Parent-reported measures of mental health symptoms and quality of life were completed at baseline and following the intervention. Paired t-tests were used to analyze changes in symptoms over time. RESULTS: All thirteen HCPs who participated in the training were considered competent in therapeutic delivery by the end of the training period. Twenty-three patients completed pre- and post-intervention measures and were included in the analysis. There were statistically significant improvements in: symptoms of mental health problems (p = 0.01; Cohen's d = 0.62), total impact of mental health problems (p = 0.03; Cohen's d = 0.52), anxiety and depression symptoms (p = 0.02; Cohen's d = 0.57) and quality of life (p = 0.01; Cohen's d = 0.57). CONCLUSION: A modular cognitive behavioral treatment delivered over the telephone by HCPs with limited experience of psychological therapy was feasible and effective in treating mental health problems in children and young people with epilepsy. Health-related Quality of Life also improved over the duration of treatment. A randomized controlled trial (RCT) is needed to demonstrate efficacy of the intervention.

Use of Multiple Ion Fragmentation Methods to Identify Protein Cross-Links and Facilitate Comparison of Data Interpretation Algorithms.

Multiple ion fragmentation methods involving collision-induced dissociation (CID), higher-energy collisional dissociation (HCD) with regular and very high energy settings, and electron-transfer dissociation with supplementary HCD (EThcD) are implemented to improve the confidence of cross-link identifications. Three different S. cerevisiae proteasome samples cross-linked by diethyl suberthioimidate (DEST) or bis(sulfosuccinimidyl)suberate (BS3) are analyzed. Two approaches are introduced to combine interpretations from the above four methods. Working with cleavable cross-linkers such as DEST, the first approach searches for cross-link diagnostic ions and consistency among the best interpretations derived from all four MS2 spectra associated with each precursor ion. Better agreement leads to a more definitive identification. Compatible with both cleavable and noncleavable cross-linkers such as BS3, the second approach multiplies scoring metrics from a number of fragmentation experiments to derive an overall best match. This significantly increases the scoring gap between the target and decoy matches. The validity of cross-links fragmented by HCD alone and identified by Kojak, MeroX, pLink, and Xi was evaluated using multiple fragmentation data. Possible ways to improve the identification credibility are discussed. Data are available via ProteomeXchange with identifier PXD018310.

Physical activity in people with epilepsy: A systematic review.

This study aimed to systematically review studies focusing on levels of physical activity (PA) in people with epilepsy (PWE) compared with non-epilepsy controls, and identify factors associated with PA in PWE. Intervention studies were also reviewed to consider the effects of psychological interventions on levels of PA, and the effects of PA-based interventions on seizure activity, psychiatric comorbidity, and health-related quality of life (HRQoL). PRISMA guidelines were followed. Searches were conducted using PubMed, Cochrane Controlled Register of Trials, PsycINFO, and Embase. Forty-six studies met inclusion criteria, including case-control, cross-sectional, and intervention studies. Assessment measures included questionnaires, activity trackers, and measures of physiological fitness. Twelve of 22 (54.5%) case-control studies utilizing self-report questionnaire measures reported that PWE were performing lower levels of PA, less likely to be engaging in PA, or less likely to meet PA guidelines than controls. The remaining studies did not find a difference between PWE and controls. Eight of 12 (67%) case-control studies utilizing exercise/fitness tests reported that PWE performed significantly poorer than controls, whereas in two studies PWE performed better than controls. One of three studies investigating the relationship between PA and seizure frequency found that increased self-reported PA was associated with having fewer seizures, whereas two did not find a significant relationship. All seven cross-sectional studies that included measures of HRQoL and depression/anxiety found a positive relationship between levels of PA and HRQoL/reduced levels of depression and anxiety. All four studies that used PA-based interventions demonstrated improvements in levels of PA and increased HRQoL. Study quality was almost universally low. In conclusion, there is some evidence that PWE engage in less PA than peers, and that interventions can improve PA levels and HRQoL. However, there is a need for more robust study designs to better understand PA in individuals with epilepsy.

Evaluating a multidisciplinary inpatient program for youth with type 1 diabetes mellitus.

Among youth with type 1 diabetes mellitus (T1D), older adolescents demonstrate more dysglycemia and less adherence to disease management. Poor disease management during this time of development can continue into adulthood, perpetuating the economic and health burden to the individual, health care system and society. This study aimed to evaluate the effectiveness of an inpatient multidisciplinary approach to treating youth with T1D. All T1D admissions to the 4 week Chronic Illness Management Program (CIMP) between 1 January 2016 and 31 December 2017 were eligible for inclusion. Data related to physiological and psychosocial outcomes were compared between admission and discharge. Follow-up data, including hemoglobin A1c (HbA1c), psychosocial measures, and health care utilization, were collected at 3, 6, and 12 months after discharge to assess sustained changes. Fifty-seven T1D admissions were included in the sample. There was a significant reduction in mean HbA1c from admission (11.1%/98 mmol/mol) to discharge (9.1%/76 mmol/mol). Patients also demonstrated significant improvements in all psychosocial outcome measures. Improvements in HbA1c were sustained at 3 months follow-up; however, average values returned to baseline by 6 months follow-up. In contrast to preadmission history, the majority of the sample reported reduced crisis health care utilization 1 year after discharge. The inpatient setting provides an intensive treatment model for diabetes management that promotes sustainable behavior change 3 months after discharge. While additional community supports are needed for long-term improvement, this program model may benefit patients who have been unable to manage their diabetes with outpatient treatment and therapy alone.

Intellectual functioning and behavior in Dravet syndrome: A systematic review.

BACKGROUND: Dravet syndrome (DS) is a developmental and epileptic encephalopathy with onset in the first year of life. At onset, the child displays normal development, but during the second year of life, stagnation/slowing of neurodevelopment is seen. In addition to difficulties with intellectual development, many children display behavioral problems including autistic features, and difficulties with attention and hyperactivity. AIM: The aim of the present study was to systematically review studies that have focused on the prevalence of cognitive/developmental quotients (DQs) consistent with intellectual disability (ID), deficits in adaptive behavior, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and behavioral difficulties. A secondary aim was to consider possible factors associated with intellectual and behavioral outcomes in individuals with DS. METHOD: A systematic review using PubMed and Scopus following the Preferred Reporting Items for Systematic Review (PRISMA) guidelines was conducted on the 24th of September 2019. Study quality was rated by two researchers using the National Institutes of Health (NIH) Quality assessment tools. RESULT: Twenty-nine studies met inclusion criteria. The pooled prevalence of ID was 86% (range across studies: 50%-100%). The pooled prevalence for ASD was 31%. The mean level of adaptive behavior was more than 2 standard deviations (SDs) below average. The prevalence of behavioral difficulties on standardized instruments ranged between 37% and 100%. The only factor consistently associated with lower cognitive scores was age with older children having significantly lower cognitive scores than younger children. For behavioral difficulties, the most consistent association was with low health-related quality of life (HRQoL) with better HRQoL associated with fewer behavioral difficulties. Study quality was almost universally poor or fair - 15/29 studies were rated 'poor', 13/29 studies were 'fair', and 1 was 'good'. DISCUSSION: The prevalence of cognitive scores consistent with ID is very high in DS. Many patients also have significant deficits in adaptive behavior highlighting that the majority of patients with DS will meet criteria for ID. The prevalence of ASD would also appear to be higher than the general population but studies show a wide range. Behavioral difficulties are common, but most studies have not used instruments adapted to patients with low intelligence quotient/DQ (IQ/DQ). No study used standardized instruments to assess ADHD. Few studies have used comprehensive statistical methods to evaluate possible factors associated with worse cognitive and behavioral outcome. CONCLUSION: It should be routine to screen for cognitive and behavioral difficulties for all patients with DS. There is a need for more robust studies regarding intellectual and behavioral disorders in patients with DS. These should be large population-based or multinational studies that employ standardized instruments.

'In the best case seizure-free' - Parental hopes and worries before and satisfaction after their child's epilepsy surgery.

OBJECTIVE: The objective of this study was to gain a better understanding of parental hopes and worries before and subsequent experiences two years after their child had undergone epilepsy surgery. METHODS: The parents of 107 children and young people who underwent epilepsy surgery at a single center completed surveys focusing on hopes and concerns before surgery and subsequent experiences at two-year follow-up. Responses were analyzed by thematic analysis. RESULTS: Before surgery, parental hopes focus on not only seizure freedom or reduction but also potential improvements in child development and emotional-behavioral functioning. Worries before surgery include not only potential injury or loss of skills but also a concern that the surgical procedure would not lead to an improvement in the child's seizures. The vast majority of parents experienced positive aspects at the two-year follow-up including seizure freedom or reduction but also perceived improvements in behavior, development, and sleep. This suggests that for many, expectations for the surgery were met. A small number of parents reported negative effects of surgery including loss of skills, worsening/lack of improvement in seizure frequency, or negative impact on development. SIGNIFICANCE: For the majority of parents whose children undergo surgery, expectations are met, and fears are not realized. Knowledge of parental hopes and worries before surgery as well as experiences after the operation is useful for improving pre- and postsurgical counseling.

Do behavior and emotions improve after pediatric epilepsy surgery? A systematic review.

OBJECTIVE: The objective was to systematically review studies that have focused on behavioral and emotional functioning before (baseline) and after (follow-up) pediatric epilepsy surgery. METHODS: The systematic review was carried out according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed and EMBASE were searched from inception. Findings are described with respect to (1) changes in behavior and emotions between baseline and follow-up, (2) factors associated with changes in behavior and emotions, and (3) impact of study quality on findings. RESULTS: Fifteen studies met inclusion criteria. The majority of studies employed parent report screening checklists. In these studies, scores were reported to have significantly improved at follow-up on at least one domain in seven studies and not to have changed significantly in two studies. In no studies was a deterioration in behavior noted. In studies that used Diagnostic and Statistical Manual of Mental Disorders (DSM) clinical diagnoses, no significant change was noted in the numbers of children diagnosed at baseline and at follow-up. In total, 21 children lost diagnoses, whereas 16 children developed new diagnoses. A better seizure outcome was associated with improvements in behavioral-emotional functioning at follow-up in three of the four studies where it was considered. In terms of study quality, none of the studies was rated as strong (ie, had no weak ratings on a quality assessment tool). SIGNIFICANCE: There is some evidence of improvement in emotional and behavioral functioning after epilepsy surgery. However, this is confined to scores on parent-reported screening measures of emotional and behavioral symptoms and not clinical diagnoses. Future research should focus on including responses from multiple respondents (child, parent, teacher) when using screening instruments, but also diagnostic interviews. There is a need for long-term follow-up (beyond 2 years) with sufficiently large sample sizes including data from nonsurgery controls to understand factors associated with changes in functioning postsurgery.

Parent-reported symptoms of ADHD in young people with epilepsy before and two years after epilepsy surgery.

The aim was to compare parent-reported symptoms of attention-deficit/hyperactivity disorder (ADHD) before (baseline) and two years after pediatric epilepsy surgery (follow-up). The parents of 107 children who underwent epilepsy surgery completed surveys including the Conners 10-item scale at baseline and follow-up. Changes in scores between baseline and follow-up were compared using paired sample t-test. Factors associated with changes in scores were analyzed using linear regression. Features of ADHD were significantly reduced at follow-up (p < 0.001). Items with the greatest reduction were items focusing on core aspects of the diagnostic criteria for ADHD. Fewer children were in the at-risk range for ADHD on the Conners 10-item scale at follow-up but this did not reach statistical significance (49% vs. 43%; p = 0.481). Factors independently significantly associated with improvement in ADHD symptoms on multivariable analysis were higher baseline scores (p < 0.001), seizure-free status (p = 0.029), and right-sided surgery (p = 0.031). Children who undergo epilepsy surgery have a high rate of ADHD symptoms. Parent-rated symptoms of ADHD improved at 2-year follow-up after epilepsy surgery. All children undergoing epilepsy surgery should undergo assessment for ADHD at baseline and follow-up.