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.

Transitioning from paediatric to adult care in epilepsy: A qualitative study of adolescent experiences.

OBJECTIVE: Transition into adulthood and adult medical care is an important step in the life of young people with epilepsy. We aimed to gain a better insight into the lived experience of the transition to adulthood and adult medical care in epilepsy in Sweden, to improve future transitional care. METHODS: A cross-sectional observational study with digital focus-group meetings and interviews with young people with epilepsy (16-22 years, n = 37) prior to, or after the transfer to adult care, or their primary caregivers if they had intellectual disability. We used reflexive thematic analysis to analyse the experiences and expectations on the transition to adulthood and adult medical care. RESULTS: The results of the thematic analysis included four key areas during transition to adulthood and adult care for young persons with epilepsy: (I) worries on coming changes and future, (II) transfers are not smooth and adult care is less integrated, (III) epilepsy is part of a bigger picture, and (IV) parental roles change. In those with intellectual disability, parents experienced a stressful process and had to increase their efforts to coordinate all care contacts in adult care. Here, epilepsy was often experienced as a minor part of a more complex disease picture, where neurodevelopmental issues were often the primary concern. SIGNIFICANCE: Transition in epilepsy is often complex due to the large burden of co-occurring disease, specifically intellectual disability and neuropsychiatric diagnoses. Transfer to adult care is experienced as unplanned and participants experience uncertainty, indicating a need for an improved transition process. As effective interventions are known in other chronic diseases, future studies should focus on the evaluation of how these approaches can be feasible and effective in young people with epilepsy.

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.

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.

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.

Epilepsy surgery in patients with hypothalamic hamartomas - Population-based two-year and long-term outcomes.

OBJECTIVE: Hypothalamic hamartomas are benign lesions associated with drug resistant epilepsy. Surgical treatment has become an increasingly utilised approach with promising results. This study aims to evaluate seizure outcome and complications after surgery in a population-based series of patients with intractable epilepsy and hypothalamic hamartoma. METHODS: All patients with hypothalamic hamartoma treated with epilepsy surgery in Sweden since 1995 with at least two years of follow-up were included. Preoperative, two-, five- and ten-year prospective longitudinal data were collected from The Swedish National Epilepsy Surgery Register. Data included seizure types and frequency, duration of epilepsy, clinical characteristics, neurological deficits, cognitive level and complications. In a subgroup from Gothenburg, we also analysed data not included in the register such as classification of hamartomas, surgical procedures and gelastic seizures. RESULTS: Eighteen patients were operated on during the period 1995-2020. The median age at epilepsy onset was 6 months and age at surgery 13 years. Four were seizure free and another four had ≥75% reduction in seizure frequency at the two-year follow-up. Two of the 13 patients with a long-term follow-up (five or ten years) were seizure-free and four had ≥75% reduction in seizure frequency. Three had an increased seizure frequency. No major complications were seen. Five had minor complications. In the Gothenburg subgroup all had open pterional disconnection or intraventricular endoscopic disconnection. Six of 12 were free from gelastic seizures at the two-year follow-up and six of eight at the long-term follow-up. CONCLUSION: This study supports surgical treatment of hypothalamic hamartomas as a safe method with a low risk of permanent complications. The seizure reduction seems to be persistent over time.

Method considerations and study protocol for a Nordic multi-centre prospective study on outcomes in rare paediatric epilepsy surgery subgroups.

Epilepsy surgery is a therapeutic option for selected children with drug-resistant epilepsy. Children who are surgical candidates have a high prevalence of neurodevelopmental comorbidities. There is a lack of adequately sized prospective studies in a number of rare surgical subgroups, especially of outcome domains such as cognitive level and health-related quality-of-life. In this article, we describe method considerations and a study protocol for a Nordic population-based multi-centre follow-up programme covering seizure as well as non-seizure outcomes in children aged <4 years undergoing resective epilepsy surgery and children aged ≤18 years undergoing hemispherotomy, callosotomy or surgery for hypothalamic hamartoma.

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.

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.

Caregiver reported seizure precipitants and measures to prevent seizures in children with Dravet syndrome.

OBJECTIVE: The aim of this population-based, cross-sectional study was to describe caregiver-reported seizure precipitants, measures taken to prevent seizures and rescue therapies in children with Dravet Syndrome (DS). METHODS: In a population-based study, caregivers of 42/48 Swedish children with DS born between 2000 and 2018 were interviewed. Frequency of precipitants, preventive measures, and rescue therapies were compared between children born 2000-2009 and 2010-2018 and between `severe´ and `less severe´ epilepsy. RESULTS: All children had experienced precipitants. Preventive measures were employed in all. Seizures had been provoked by a median of seven (range 2-11) out of 13 factors. A median of eight (range 1-17) preventive measures out of 19 were reported. The most common precipitants were fever (n=42, 100%), and afebrile infections (n=39/42, 93%). Afebrile infections (p=0.014) and reduced ambient temperature (p=0.006) were more common precipitants in younger children, and bright light in children with severe epilepsy (p=0.013). The most common factors avoided were warm weather (n=35/42, 83%) and physical activity (n=27/42, 64%). It was more common to avoid strong emotions (p=0.035) and reduced temperature (p=0.002) in younger children, and to avoid infections (p=0.024) and crowds (p=0.046) in children with 'severe' epilepsy. Many children (n=28/42, 67%) or their siblings (n=16/34, 47% of individuals with siblings) had stayed home to avoid infections in school/day-care. Use of emergency medicines was more frequent in younger children (p=0.006) and in children with 'severe' epilepsy (p=0.007). SIGNIFICANCE: Caregiver-reported seizure precipitants are common in DS. Caregivers employ a range of measures to avoid seizures, restricting family life.

Dravet syndrome in children-A population-based study.

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

[Stereoelectroencephalography - a safe and effective procedure for epilepsy surgery evaluation]. / Stereo-EEG ­ en effektiv metod för att utreda svårbehandlad epilepsi.

In this paper, we report our experiences from the first 30 patients investigated with stereoelectroencephalography (SEEG) at Sahlgrenska University Hospital, Gothenburg, Sweden. Clinical, neurophysiological, and imaging data were reviewed. Twelve children and 18 adults with drug-resistant epilepsy underwent 33 SEEG procedures. 53% of the patients had normal brain MRI. In total, 347 SEEG electrodes were implanted (median 12 per patient). Twenty patients subsequently had resective surgery based on SEEG findings. Focal cortical dysplasia was found in all cases. In 45% of the patients, vicinity of eloquent cortex limited resections. Epilepsy surgery based on SEEG resulted in seizure freedom in 58% of the cases. Minor complications were seen in eight patients, all of which resolved without sequelae. No major complications were seen. SEEG is a safe and effective method to delineate cortical areas involved in seizure generation.

Endocrine and metabolic aspects of narcolepsy type 1 in children.

STUDY OBJECTIVES: To study whether the onset of narcolepsy type 1 (NT1) in children and adolescents affects BMI, specific metabolic risk factors, the onset of puberty, longitudinal growth or other endocrine functions. METHODS: A population-based study, comprising 34 patients, was performed with a clinical evaluation, an assessment of puberty and growth, actigraphy and blood samples at fasting, from patients and controls, to evaluate pituitary function, growth factors, thyroid gland, gonads, insulin sensitivity, appetite regulation and blood lipids. RESULTS: In the post-H1N1 vaccination (PHV) narcolepsy group, the median BMI SDS was higher 6-12 months after the onset of narcolepsy (p < 0.01), but it was no different 10 years after the onset of narcolepsy (p = 0.91), compared with 12-24 months before the onset of narcolepsy. There was a correlation between an increase in BMI and a decrease in total energy expenditure (R = -0.74). In the nPHV group, weight and BMI changes were smaller and no significant changes were recorded. Early puberty was more common in patients with puberty onset after narcolepsy onset (n = 16/19) compared with patients with puberty onset before narcolepsy onset (n = 3/11, p = 0.02). There was no significant change in height SDS during the studied period. Although they were within normal ranges, both median HDL and median TSH levels were significantly lower in NT1 patients, compared with controls. CONCLUSIONS: We found a high prevalence of large BMI gain in the period immediately after the onset of narcolepsy, which had almost normalized at the long-term follow-up. The onset of narcolepsy led to early puberty in both sexes. Linear growth was not affected. We did not find any strong indicators of metabolic disturbances.

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies.

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.

'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.

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.

Cortical excitability measured with transcranial magnetic stimulation in children with epilepsy before and after antiepileptic drugs.

AIM: To evaluate cortical excitability with transcranial magnetic stimulation (TMS) in children with new-onset epilepsy before and after antiepileptic drugs (AEDs). METHOD: Fifty-five drug-naïve patients (29 females, 26 males; 3-18y), with new-onset epilepsy were recruited from 1st May 2014 to 31st October 2017 at the Child Neurology Department, Queen Silvia's Children's Hospital, Gothenburg, Sweden. We performed TMS in 48 children (23 females, 25 males; mean [SD] age 10y [3y], range 4-15y) with epilepsy (27 generalized and 21 focal) before and after the introduction of AEDs. We used single- and paired-pulse TMS. We used single-pulse TMS to record resting motor thresholds (RMTs), stimulus-response curves, and cortical silent periods (CSPs). We used paired-pulse TMS to record intracortical inhibition and facilitation at short, long, and intermediate intervals. RESULTS: There were no differences in cortical excitability between children with generalized and focal epilepsy at baseline. After AED treatment, RMTs increased (p=0.001), especially in children receiving sodium valproate (p=0.005). CSPs decreased after sodium valproate was administered (p=0.050). As in previous studies, we noted a negative correlation between RMT and age in our study cohort. Paired-pulse TMS could not be performed in most children because high RMTs made suprathreshold stimulation impossible. INTERPRETATION: Cortical excitability as measured with RMT decreased after the introduction of AEDs. This was seen in children with both generalized and focal epilepsy who were treated with sodium valproate, although it was most prominent in children with generalized epilepsy. We suggest that TMS might be used as a prognostic tool to predict AED efficacy. WHAT THIS PAPER ADDS: Resting motor threshold (RMT) correlated negatively with age in children with epilepsy. No differences in cortical excitability were noted between patients with generalized and focal epilepsy. Treatment with antiepileptic drugs decreased cortical excitability as measured with transcranial magnetic stimulation (TMS). Decreased cortical excitability with increased RMT was recorded, especially after sodium valproate treatment. Paired-pulse TMS was difficult to perform because of high RMTs in children.

Medición de la excitabilidad cortical con estimulación magnética transcraneal en niños con epilepsia antes y después de los fármacos antiepilépticos OBJETIVO: Evaluar la excitabilidad cortical con estimulación magnética transcraneal (EMT) en niños con epilepsia de nueva aparición antes y después del uso de un fármaco antiepiléptico (FAE). MÉTODO: Cincuenta y cinco pacientes sin tratamiento previo (29 mujeres, 26 varones; de 3-18 años), con epilepsia de nueva aparición fueron reclutados del 1 de mayo de 2014 al 31 de octubre de 2017 en el Departamento de Neurología Infantil del Hospital de Niños Queen Silvia, en Gotemburgo, Suecia. Se realizó EMT en 48 niños (23 mujeres, 25 varones; media [DE] de 10 años [3 años], rango 4-15 años) con epilepsia (27 generalizada y 21 focal) antes y después de la introducción de los FAE. Usamos EMT de pulso único y de pulso emparejado. Utilizamos EMT de pulso único para registrar umbrales motores en reposo (UMR), curvas de estímulo-respuesta y períodos silenciosos corticales (PSC). Usamos EMT de pulso emparejado para registrar la inhibición y la facilitación intracorticales a intervalos cortos, largos e intermedios. RESULTADOS: No hubo diferencias en la excitabilidad cortical entre niños con epilepsia generalizada y focal al inicio. Después del tratamiento con FAE, los UMR aumentaron (p.0,001), especialmente en niños que recibieron valproato de sodio (p.0,005). Los PSC disminuyeron después de la administración del valproato sódico (p.0,050). Como en estudios anteriores, observamos una correlación negativa entre UMR y edad en nuestra cohorte de estudio. La EMT de pulso emparejado no se pudo realizar en la mayoría de los niños porque los UMR altos hacían imposible la estimulación supraumbral. INTERPRETACIÓN: La excitabilidad cortical medida con UMR disminuyó después de la introducción de los FAE. Esto se vio en niños con epilepsia generalizada y focal que fueron tratados con valproato de sodio, fue más prominente en niños con epilepsia generalizada. Sugerimos que EMT podría utilizarse como una herramienta de pronóstico para predecir la eficacia de la FAE.

Excitabilidade cortical medida com estimulação magnética transcraniana em crianças com epilepsia antes e após drogas antiepilépticas OBJETIVO: Avaliar a excitabilidade cortical com estimulação magnética transcraniana (TMS) em crianças com epilepsia de início recente antes e após drogas antiepilépticas (DAEs). MÉTODO: Cinquenta e cinco pacientes não expostos a drogas (29 do sexo feminino, 26 do sexo masculino; 3-18a), com epilepsia de início recente foram recrutadas de 1 de maio de 2014a a 31 de outubro de 2017 no Departamento de Neurologia Infantil, Hospital Rainha Silvia, Gothenburg, Suécia. Aplicamos TMS em 48 crianças (23 do sexo feminino, 25 do sexo masculino; média [DP] de idade 10a [3a], variação 4-15a) com epilepsia (27 generalizada e 21 focal) antes e após a introdução de DAEs. Usamos TMS de pulso único e pareado. O TMS de pulso único foi usado para registrar os limiares motores de repouso (LMR), curvas de estímulo-resposta, e períodos de silêncio cortical (PSC). Usamos TMS de pulsos pareados para registrar inibição e facilitação intracortical nos intervalos curto, longo e intermediário. RESULTADOS: Não houve diferenças na excitabiildade cortical entre crianças com epilepsia generalizada e focal na linha de base. Após o tratamento com DAE, o LMR aumentou (p=0,001), especialmente em crianças recebendo valproato de sódio (p=0,005). Os PSCs diminuíram após o valproato de sódio ser (p=0,050). Como em estudos prévios, notamos correlação negativa entre LMR e idade em nossa coorte. TMS de pulso pareado não pôde ser realizado na maioria das crianças porque os altos LMRs tornaram a estimulação supra-limiar impossível. INTERPRETAÇÃO: A excitabilidade cortical mensurada por LMR diminuiu após a introdução de DAEs. Isso foi visto em crianças com epilepsia generalizada e focal tratadas com valproato de sódio, embora tenha sido mais proeminente naquelas com epilepsia generalizada. Sugerimos que o TMS pode ser usada como ferramenta prognóstica para predizer a eficácia da DAE.

Potassium citrate and metabolic acidosis in children with epilepsy on the ketogenic diet: a prospective controlled study.

AIM: To investigate if potassium citrate, a mild alkaline compound, can prevent metabolic acidosis in children with epilepsy treated with the ketogenic diet without reducing antiepileptic efficacy. METHOD: In this prospective controlled study, we investigated the frequency of initial uncompensated metabolic acidosis in 51 participants. There were 22 participants with and 29 without potassium citrate supplementation. The ketogenic diet was used as add-on treatment to children with drug resistant epilepsy. We also estimated the proportion of participants with a greater than 50% seizure reduction after 7 months. RESULTS: None of the 22 participants (15 males, seven females; median age 1y 7mo, interquartile range [IQR] 3y 3mo) with, and 10 of 29 (12 males, 17 females; median age 6y 1mo, IQR 4y 8mo) without potassium citrate developed metabolic acidosis (odds ratio=0.04, 95% CI 0.00-0.75 [p<0.01]); median pH 7.32 vs 7.24; [p<0.001]), and median bicarbonate 19.7mmol/L vs 14.0mmol/L (p<0.001). The number of seizures was reduced by more than 50% in 9 of 22 with potassium citrate and 8 of 29 participants without potassium citrate, 7 months after introducing a ketogenic diet (p=0.4). INTERPRETATION: In the ketogenic diet, potassium citrate supplementation can prevent metabolic acidosis, without reducing antiepileptic efficacy. WHAT THIS PAPER ADDS: Citrate supplementation prevents metabolic acidosis in children treated with a ketogenic diet. Efficacy of the ketogenic diet is not affected by supplementation with citrate. Citrate supplementation does not affect beta-hydroxybuturate concentration. Potassium citrate reduces the time needed to reach an optimal ketogenic ratio. This article is commented on by Schoeler on page 8 of this issue.

Cortical mapping of receptive language processing in children using navigated transcranial magnetic stimulation.

We used a stepwise process to develop a new paradigm for preoperative cortical mapping of receptive language in children, using temporary functional blocking with transcranial magnetic stimulation (TMS). The method combines short sentences with a lexical decision task in which children are asked to point at a picture that fits a short sentence delivered aurally. This was first tested with 24 healthy children aged 4-16 years. Next, 75 sentences and 25 slides were presented to five healthy children in a clinical setting without TMS. Responses were registered on a separate computer, and facial expressions and hand movements were filmed for later offline review. Technical adjustments were made to combine these elements with the existing TMS equipment. The audio-recorded sentences were presented before the visual stimuli. Sentence lists were constructed to avoid similar stimuli in a row. Two different baseline lists were used before the TMS registration; the second baseline resulted in faster responses and was chosen as the reference for possible response delays induced by TMS. Protocols for offline reviews were constructed. No response, incorrect response, self-correction, delayed response, and perseveration were considered clear stimulation effects, while poor attention, discomfort, and other events were regarded as unclear. Finally, three children (6:2, 14:0, 14:10 years) with epilepsy and expected to undergo neurosurgery were assessed using TMS (left hemisphere in one; both hemispheres in the other two). In the two assessed bilaterally, TMS effects indicated bilateral language processing. Delayed response was the most common error. This is a first attempt to develop a new TMS paradigm for receptive language mapping, and further evaluation is suggested.