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Aim: To investigate reasons for the declining prevalence of cerebral palsy (CP) in children born at term in Denmark by evaluating obstetric and neonatal factors associated with CP, and their changes over time., Method: In this cohort study, we included 987 495 children (504 600 [51.1%] males and 482 895 [48.9%] females) born after 37 completed gestational weeks during birth years 1997 to 2013. Risk ratios of CP for each factor were calculated with log-binominal regression analyses. Significant factors were evaluated concerning their development in prevalence over time., Results: In the antenatal period, there were significant associations with an increased risk of CP and high maternal body mass index (BMI), smoking during pregnancy, nulliparity, male sex, gestational age, and low birthweight. In the study period, fewer females smoked during pregnancy and fewer children were born post-term, dropping from 22.6% to 11.4% and 9.4% to 2.5% respectively. Conversely, the proportion of females with high BMI increased. Most significant risk factors were found in the neonatal period, with an increase in children with diagnosed birth defects and children admitted to neonatal care., Interpretation: Reasons for the declining prevalence of CP appear to be multifactorial and likely include the decline in maternal smoking and children born post-term along with centralization and advances in neonatal treatment., (© 2021 Mac Keith Press.)

Background: Cerebral palsy (CP) is the most common severe motor disability and a manifestation of early brain damage., Aims: To analyze if abnormal levels of first-trimester biomarkers were associated with CP. Furthermore, to investigate their clinical applicability in early predicting of CP., Study Design: Nationwide cohort study., Subjects: We included 258.057 singleton live births, born during 2008-2013 with completed first-trimester assessments., Outcome Measures: Data on beta subunit of human chorionic gonadotropin (beta-hCG), pregnancy-associated plasma protein-A (PAPP-A), nuchal translucency thickness, and biparietal diameter (BPD) were converted to multiple of the medians (MoM). Associations were analyzed by comparing mean and extreme levels between pregnancies with and without CP. All CP diagnoses were validated by trained neuropediatricians. Logistic regression was used to create an early prediction model., Results: The mean beta-hCG value was significantly lower in pregnancies with CP (0.96MoM [95% CI 0.91-1.02] vs 1.04MoM [1.04-1.04], p = 0.01) and the mean PAPP-A value tended to be lower (0.96MoM [0.91-1.01] vs 1.01MoM [1.00-1.01], p = 0.07). Moreover, fetuses that developed CP more likely had a BPD measurement below the fifth percentile (7.5% vs 5%, p = 0.045). The final prediction model had poor discrimination., Conclusions: Pregnancies with CP tend to have lower values of beta-hCG and PAPP-A in the first trimester, however, the associations are mediated differently. Nonetheless, abnormal levels of the most common first-trimester biomarkers only have weak associations with CP; resulting in inadequate predictive abilities when included in an early prediction model., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Chronic diseases in children can impact their parents; this may be overlooked in a clinical setting. Our aim was to investigate associations of chronic diseases in children with their parents' employment, health care utilization, mental health, and mortality. In a matched cohort study using nationwide and population-based data in Denmark, we included parents to children (< 18 years) with acute disseminated encephalomyelitis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis/juvenile idiopathic arthritis during 2008-2015. The reference group was parents to unaffected children. Outcomes were parental employment (early retirement, cash benefits, income), health care utilization (e.g., general practitioner, or hospital visits), mental health (visits to psychiatry/psychology clinics, antidepressant drug redemptions), and mortality. We included 13,769 parents with a chronically ill child and 138,606 control parents. Annual income was unaffected for two-parent families after the child's disease onset, but two-parent families had increased hazard of early retirement of 25% (95% CI = 1.01-1.54; p = 0.04). Parents with a chronically ill child had (a) increased rate of antidepressant drug redemptions or psychology/psychiatry visits (hazard ratio 1.37; 95% CI = 1.28-1.46 at 1-year follow-up); (b) increased health care utilization, with an increased marginal mean in primary care of 1% (95% CI = 1.00-1.02; p = 0.005), hospital-affiliated visits of 19% (95% CI = 1.14-1.24; p < 0.0001), and hospital admissions of 14% (95% CI = 1.09-1.20; p < 0.0001); and (c) 69% increased mortality hazard (95% CI = 1.30-2.18; p < 0.0001) in parents younger than 50 years with no comorbidities, albeit small in absolute numbers., Conclusion: Pediatric chronic diseases were negatively associated with parental employment, mental health, and mortality, and increased health care utilization., What Is Known: • Studies on the impact of pediatric chronic diseases on parental health are qualitative. • Knowledge is unavailable regarding the impact on parental work, health care utilization, and mortality., What Is New: • Among 13,769 parents with a chronically ill child and 138,606 control parents, parents with a chronically ill child had 37% increased antidepressant drug redemptions, and these parents <50 years without comorbidities had 69% increased mortality hazard. • Medical doctors should consider the parental health condition and societal challenges related to having child with a chronic disease., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle., Methods: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls., Results: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally., Conclusions: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure., Impact: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Folate prevents neural tube defects and may play a role in some neurodevelopmental disorders., Objectives: We investigated whether higher intakes of periconceptional or midpregnancy folate, as recommended, were associated with a reduced risk of offspring cerebral palsy (CP)., Methods: We included participants from the Nordic collaboration cohort consisting of mother-child dyads in the Danish National Birth Cohort and the Norwegian Mother, Father, and Child Cohort Study [combined as MOthers and BAbies in Norway and Denmark (MOBAND-CP)]. A total of 190,989 live-born children surviving the first year of life were included. Missing covariate data were multiply imputed. Our exposures were defined as any or no folic acid supplementation in gestational weeks (GWs) -4 to 8 (periconceptional), 9 to 12, and -4 to 12, and supplemental, dietary, and total folate during midpregnancy (GWs 22-25). CP overall and the unilateral and bilateral spastic subtypes, as well as CP with low or moderate/high gross motor function impairments, were our outcomes of interest., Results: Periconceptional folic acid supplementation was not associated with CP [adjusted odds ratio (aOR), 1.02; 95% CI: 0.82-1.28]. However, supplementation in GWs 9 to 12 was associated with a reduced risk of CP (aOR, 0.74; 95% CI: 0.57-0.96), and inverse associations were indicated for both the unilateral (aOR, 0.68; 95% CI: 0.46-1.02) and bilateral (aOR, 0.70; 95% CI: 0.49-1.02) spastic subtypes, although the associations were not statistically significant. Supplemental or dietary folate in midpregnancy alone were not associated with CP. Strong inverse associations were observed with low gross motor function impairment (aOR, 0.49; 95% CI: 0.29-0.83), while for unilateral CP the aOR was 0.63 (95% CI: 0.34-1.22) for intakes of ≥500 compared to ≤199 dietary folate equivalents/day during midpregnancy., Conclusions: Our findings suggest that folate intakes in GWs 9 to 12 and midpregnancy were associated with lower risks of CP, while no association was observed for periconceptional supplementation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Aim: Children with dyskinetic cerebral palsy (CP) are often severely affected and effective treatment is difficult, due to different underlying disease mechanisms. Comprehensive systematic movement disorder evaluations were carried out on patients with this disorder., Methods: Patients born from 1995 to 2007 were identified from the Danish Cerebral Palsy Register and referrals to the neuropaediatric centre, Rigshospitalet, Copenhagen. They were classified by gross motor function, manual functional ability, communication ability, dystonia and spasticity. Electromyography was carried out on the upper and lower limbs. Magnetic resonance imaging scans were revised, and aetiological searches for underlying genetic disorders were performed., Results: We investigated 25 patients with dyskinetic CP at a mean age of 11.7 years. Dystonia, spasticity and rigidity were found in the upper limbs of 21, four and six children, respectively, and in the lower limbs of 18, 18 and three children. The mean total Burke-Fahn-Marsden score for dystonia was 45.02, and the mean Disability Impairment Scale level was 38% for dystonia and 13% for choreoathetosis. Sustained electromyography activity was observed in 20/25 children. Stretching increased electromyography activity more in children with spasticity. There were 10 re-classifications., Conclusion: The children had heterogenic characteristics, and 40% were reclassified after systematic movement disorder evaluation., (© 2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Aim: To quantify and analyse the prevalence and clinical features of cerebral palsy (CP) in Denmark for birth years 2008-2013 and compare results with previous periods., Method: A nationwide register-based study covering all children with a confirmed diagnosis of CP born in Denmark. Information about CP subtype, aetiology and severity was collected from the Cerebral Palsy Follow-up Program and supplemented from medical files. Data from the Danish Medical Birth Register was included, and the results were compared to previous data from the Danish National Cerebral Palsy Register. Prevalence per 1000 live births and proportions were analysed using the Cochran-Armitage test for trend., Results: The period covered 368,618 live births and 636 children with CP, making the overall prevalence for the period 1.73 per 1000 live births. This was significantly lower than the prevalence of 1.99 for the previous period 1999-2007 (p = 0.004). The decline in prevalence between the two periods was mainly due to a decrease in children with bilateral spastic and dyskinetic CP born after 37 gestational weeks. The decline in prevalence was accompanied by a smaller proportion of children with associated impairment., Conclusion: We found a decrease in prevalence and severity in CP among Danish children. The decline was most pronounced in children born after 37 gestational weeks with severe subtypes of CP. National guidelines that recommend induction of labour before the completion of week 42 and therapeutic hypothermia for term neonates with hypoxic-ischaemic encephalopathy, may have contributed to the decline., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest on the submitted paper., (Copyright © 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objectives: Young adults with cerebral palsy (CP) face potential challenges. The transition to young adulthood is characterized by significant changes in roles and responsibilities. Furthermore, young adults with chronic conditions face a transfer from pediatric care to adult healthcare. This study explores how living with CP affects young adults in general, and specifically which psychosocial, medical and healthcare needs are particularly important during this phase of life., Methods: A qualitative study with data from individual, semi-structured, in-depth interviews with six young adults with CP (ages 21-31 years) were transcribed verbatim and analyzed. The participants were selected to provide a maximum variation in age, gender, Gross Motor Function Classification System score and educational background. A descriptive thematic analysis was used to explore patterns and identify themes., Results: Three themes were identified: "Being a Young Adult", "Development in Physical Disability and New Challenges in Adulthood" and "Navigating the Healthcare System". The three themes emerged from 15 sub-themes. Our findings emphasized that young adults with CP faced psychosocial challenges in social relationships, participation in education and work settings and striving towards independence. The transition to young adulthood led to a series of new challenges that the young adults were not prepared for. Medical challenges included managing CP-related physical and cognitive symptoms and navigating adult health care services, where new physicians with insufficient knowledge regarding CP were encountered., Conclusion: The young adults with CP were not prepared for the challenges and changes they faced during their transition into adulthood. They felt that they had been abandoned by the healthcare system and lacked a medical home. Better transitional care is urgently needed to prepare them for the challenges in young adulthood., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Cerebral palsy (CP) is the most common neuro-motor disability in young children. Disruptions of maternal hormone function during pregnancy have been linked to CP risk. We investigated whether prenatal exposure to pesticide compounds with endocrine-disrupting action affect CP risk. We conducted a case-control study of 3905 CP cases and 39,377 controls born between 1998 and 2010 in California to mothers who lived in proximity (within 2 km) to any agricultural pesticide application recorded in the California Pesticide Use Reporting (PUR) system. We focused on 23 pesticides considered endocrine disruptors that are frequently used, and we found that exposure to any of the 23 pesticides in the first trimester was associated with elevated CP risks in female offspring (OR = 1.19; 95% CI: 1.05-1.35) but not males (OR = 0.99; 95% CI: 0.89-1.09) compared to the unexposed offspring. Positive associations were estimated for 15 pesticides suspected to affect the estrogen and 7 pesticides suspected to affect the thyroid hormone system. Our study suggests that first trimester exposure to pesticides that are suspected endocrine disruptors are associated with CP risk in female offspring. Pesticide exposures in early pregnancy may have sex-specific influences on the neuro-motor development of the fetus by interfering with endocrine systems.

Aim: To compare the prevalence of mental disorders (MDs) in a cohort of children and adolescents with and without cerebral palsy (CP) and to explore whether there is an association between MDs and the Gross Motor Function Classification System (GMFCS) level., Method: A register-linkage follow-up study of 10- to 16-year children with CP (identified in the Danish National Cerebral Palsy Registry, n = 893), and 2627 children without CP, matched by gender and age. Information on MDs was obtained from the National Patient Registry in Denmark and based on ICD-10-codes. Conditional logistic regression was performed in order to compare the prevalence of MDs., Results: The prevalence of MDs was significantly higher in children and adolescents with CP (22.4%, CI 19.8-25.2%) compared with controls (6.3%, CI 5.5-7.3%). Intellectual disability was statistically significantly associated with motor function (odds ratio (OR) 4.55, CI 2.81-7.36 for GMFCS levels IV-V compared to GMFCS level I), but there were no statistically significant association between motor function and autism spectrum disorders, ADHD or affective disorders., Interpretation: Our findings emphasize that follow-up of children with CP should include screening for both cognitive dysfunction and other mental disorders. The motor function does not predict the risk of other mental disorders than intellectual disability in children and adolescents with CP., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest. The first author was supported by funding from the Ludvig and Sara Elsass Foundation. The Foundation had no influence on the interpretation of the results., (Copyright © 2020. Published by Elsevier Ltd.)

Aim: We aimed at describing clinical findings in children with dyskinetic as compared to bilateral spastic cerebral palsy (CP)., Methods: Data were extracted from the Danish nationwide CP register. Participants were born in 1999-2007 and were 5-6 years at ascertainment., Results: The total number of CP cases was 1165 of which 92 had dyskinetic and 540 bilateral spastic CP. Prevalence of dyskinetic CP was 0.16 per 1000 live births. In participants with dyskinetic compared to bilateral spastic CP, there was more frequently an Apgar level less than five at five minutes (22.7% vs. 11.2%) and neonatal seizures (43.5% vs. 28.5%), but less respiratory deficiency, hyperbilirubinaemia and sepsis. Impairment based on gross motor function classification was more severe in dyskinetic CP (level III-V 90.0% vs. 66.0%). In dyskinetic CP, there was a high rate of reduced developmental quotient (68.1%), visual impairment (39.3%) and epilepsy (51.6%). Basal ganglia lesions were more prevalent in dyskinetic compared to bilateral spastic CP (27.7% vs. 12.8%)., Conclusion: Cases of dyskinetic CP had overlapping clinical features with cases of bilateral spastic CP, but differed significantly in several perinatal risk factors. The children with dyskinetic CP had experienced more peri- or neonatal adverse events, and neurodevelopmental impairment was severe., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Children of immigrants in Denmark have excess risk for some of the most well-established risk factors for cerebral palsy (CP)., Objectives: To study differences in risk of CP between children of immigrants and children of Danish-born mothers, and explore whether socioeconomic status drives any potential association., Methods: A register-based cohort study including 1,274,616 children born in Denmark between 1981 and 2007. Of these, 2807 had a validated CP diagnosis in the Danish CP Register. We estimated the risk of CP as odds ratios (OR) using logistic regression and assessed mediation through socioeconomic status using natural effect models., Results: In children of Danish-born mothers, 2.2/1000 had CP overall and the prevalence was similar for children of immigrants. However, children of immigrants had lower risk of unilateral spastic CP than children of Danish native-born mothers; OR = 0.59 (95% CI:0.38-0.91) for Western and OR = 0.79 (95% CI:0.61-1.03) for Non-Western immigrants. By contrast, the risk of bilateral spastic CP was higher in children of Non-Western immigrants (OR = 1.27 (95% CI:1.05-1.53)), especially from Turkey and Pakistan compared with children of Danish native-born mothers. The mediation analysis revealed an indirect effect (through maternal educational level and household income) with an OR of 1.06 (95% CI:0.99-1.14) for children of Non-Western immigrants., Conclusions: While children of immigrants had lower risk of unilateral spastic CP than children of Danish-born mothers, the risk of bilateral spastic CP was increased in children of Non-Western immigrants. Socioeconomic status did not appear to be a significant contributor to the increased risk of bilateral spastic CP., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the diagnostic accuracy and clinical utility of electromagnetic source imaging (EMSI) in presurgical evaluation of patients with epilepsy., Methods: We prospectively recorded magnetoencephalography (MEG) simultaneously with EEG and performed EMSI, comprising electric source imaging, magnetic source imaging, and analysis of combined MEG-EEG datasets, using 2 different software packages. As reference standard for irritative zone (IZ) and seizure onset zone (SOZ), we used intracranial recordings and for localization accuracy, outcome 1 year after operation., Results: We included 141 consecutive patients. EMSI showed localized epileptiform discharges in 94 patients (67%). Most of the epileptiform discharge clusters (72%) were identified by both modalities, 15% only by EEG, and 14% only by MEG. Agreement was substantial between inverse solutions and moderate between software packages. EMSI provided new information that changed the management plan in 34% of the patients, and these changes were useful in 80%. Depending on the method, EMSI had a concordance of 53% to 89% with IZ and 35% to 73% with SOZ. Localization accuracy of EMSI was between 44% and 57%, which was not significantly different from MRI (49%-76%) and PET (54%-85%). Combined EMSI achieved significantly higher odds ratio compared to electric source imaging and magnetic source imaging., Conclusion: EMSI has accuracy similar to established imaging methods and provides clinically useful, new information in 34% of the patients., Classification of Evidence: This study provides Class IV evidence that EMSI had a concordance of 53%-89% and 35%-73% (depending on analysis) for the localization of epileptic focus as compared with intracranial recordings-IZ and SOZ, respectively., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants., Results: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign., Conclusion: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Background: Glucocorticoids are widely used in the treatment of several pediatric diseases with undisputed disease-related benefits. Perinatal exposure to high levels of glucocorticoids can have long-term adverse cerebral effects. In adults, glucocorticoid treatment has been associated with smaller volumes of subcortical grey matter structures. Recently, we observed smaller total brain volumes in children and adolescents treated with glucocorticoid during childhood compared to healthy controls. The possible long-term effects of glucocorticoid treatment during childhood on subcortical brain volume and microstructure remain unknown., Method: We examined 30 children and adolescents, who had previously been treated with glucocorticoids for nephrotic syndrome or rheumatic disease, and 30 healthy volunteers. Patients and healthy control groups were matched by age, gender, and level of parent education. Participants underwent 3 T magnetic resonance (MR) brain imaging. T1-weighted and diffusion-weighted images were acquired. Volume and mean diffusivity (MD) measures were extracted for hippocampus, amygdala, nucleus accumbens, caudate nucleus and putamen. Multiple linear regression analyses were used to assess differences between patients and controls, and to evaluate possible dose-response relationships. A priori, we expected patients to display lower hippocampal and amygdala volumes., Results: While children previously treated with glucocorticoids displayed smaller right hippocampal volumes than controls, this difference did not survive correction for multiple comparisons. Furthermore, patients as compared to controls showed lower right hippocampal MD, which remained when correcting for global changes in MD. The longer the time between the glucocorticoid treatment termination and MR-scan, the more right hippocampal MD values resembled that of healthy controls. Patient and controls did not differ in amygdala volume or MD. Analyses of the nucleus accumbens, caudate nucleus and putamen only revealed smaller putamen volumes in patients compared to controls, which remained significant when controlling for total brain volume., Conclusion: The results suggest that extra-cerebral diseases during childhood treated with glucocorticoids may be associated with reduced subcortical grey matter volumes and lower right hippocampal mean diffusivity later in life. Our findings warrant replication and elaboration in larger, preferably prospective and longitudinal studies. Such studies may also allow disentangling disease-specific effects from possible glucocorticoid treatment effects., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To analyse trends in prevalence and severity of cerebral palsy (CP) in Denmark in birth years 1999-2007 and compare with previous periods., Method: Data has been collected uniformly in the Danish cerebral palsy national register nationwide since 1995. Rates in the time periods 1999-2001, 2002-2004 and 2005-2007 covering 585,393 births were analysed by gestational age and subtypes., Results: Total number of CP cases in the period was 1165. The overall prevalence of CP decreased significantly from 2.1 in 1999-2001 to 1.8 in 2005-2007 per 1000 livebirths (p = 0.022). The decline was only significant for children born at term (p = 0.007) but not for the preterm (p = 0.44). The decline in children born at term was based on a decrease in bilateral spastic CP (n = 117 in years 1999-2001 and n = 59 in 2005-2007). Multidisciplinary obstetric skills training with neonatal resuscitation in Denmark was initiated in 2003 and timely associated with the decrease. The prevalence of unilateral spastic CP the prevalence did not change, but in the two last time periods more children had a right-sided than left-sided unilateral spastic CP., Conclusion: The decline in rate of CP seen in 2005-2007 as compared to 1999-2001 was mainly based on fewer cases of severe spastic CP in term infants. We hypothesize that improved neonatal resuscitation in the delivery room may be partly responsible for the decrease. In premature children the decline was not significant in this time period, but has been dramatically decreasing in the years before the time period here analysed., (Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the accuracy of automated EEG source imaging (ESI) in localizing epileptogenic zone., Methods: Long-term EEG, recorded with the standard 25-electrode array of the IFCN, from 41 consecutive patients with focal epilepsy who underwent resective surgery, were analyzed blinded to the surgical outcome. The automated analysis comprised spike-detection, clustering and source imaging at the half-rising time and at the peak of each spike-cluster, using individual head-models with six tissue-layers and a distributed source model (sLORETA). The fully automated approach presented ESI of the cluster with the highest number of spikes, at the half-rising time. In addition, a physician involved in the presurgical evaluation of the patients, evaluated the automated ESI results (up to four clusters per patient) in clinical context and selected the dominant cluster and the analysis time-point (semi-automated approach). The reference standard was location of the resected area and outcome one year after operation., Results: Accuracy was 61% (95% CI: 45-76%) for the fully automated approach and 78% (95% CI: 62-89%) for the semi-automated approach., Conclusion: Automated ESI has an accuracy similar to previously reported neuroimaging methods., Significance: Automated ESI will contribute to increased utilization of source imaging in the presurgical evaluation of patients with epilepsy., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Accurate localization of the epileptic focus is essential for surgical treatment of patients with drug-resistant epilepsy. Electric source imaging (ESI) is increasingly used in pre-surgical evaluation. However, most previous studies have analysed interictal (II) discharges. Prospective studies comparing the feasibility and accuracy of II and ictal (IC) ESI are lacking., Methods: We prospectively analysed long-term video-electroencephalography recordings (LTM) of patients admitted for pre-surgical evaluation. We performed ESI of II and IC signals using two methods, i.e. equivalent current dipole (ECD) and a distributed source model (DSM). LTM recordings employed the standard 25-electrode array (including inferior temporal electrodes). An age-matched template head model was used for source analysis. Results were compared with intracranial recordings, conventional neuroimaging methods [magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)] and outcome at 1 year after surgery., Results: A total of 87 consecutive patients were analysed. ECD gave a significantly higher proportion of patients with localized focal abnormalities (94%) compared with MRI (70%), PET (66%) and SPECT (64%). Agreement between the ESI methods and intracranial recording was moderate to substantial (k = 0.56-0.79). A total of 54 patients were operated (47 patients more than 1 year ago) and 62% of them became seizure-free. The localization accuracy of II-ESI was 51% for DSM and 57% for ECD, and that for IC-ESI was 51% for DSM and 62% for ECD. The differences between the ESI methods were not significant. Differences in localization accuracy between ESI and MRI (55%), PET (33%) and SPECT (40%) were not significant., Conclusions: The II-ESI and IC-ESI of LTM data have high feasibility and their localization accuracy is similar to that of conventional neuroimaging methods., (© 2018 EAN.)

In most patients with intellectual disability (ID), the etiology is unknown, but lately several de novo variants have been associated with ID. One of the involved genes, CUX2, has twice been reported to be affected by a de novo variant c.1768G>A; p.(Glu590Lys) in patients with ID or epileptic encephalopathy. CUX2 is expressed primarily in nervous tissues where it may act as a transcription factor involved in neural specification. Here we describe a third case who was diagnosed with epilepsy including general and myoclonic seizures, moderate to severe cognitive disability, and infantile autism. The patient was heterozygous for the c.1768G>A; p.(Glu590Lys) variant in CUX2 identified by whole exome sequencing. These findings strongly suggest a causal impact of this variant and add to our understanding of a subset of patients with ID, seizures, and autism spectrum disorder as well as suggest an important role for the CUX2 gene in human brain function.

Background: We investigated whether the risk of cerebral palsy (CP) in the child varies by parents' socioeconomic status, in Denmark and Norway., Methods: We included almost 1.3 million children born in Demark during 1981-2007 and 2.4 million children born in Norway during 1967-2007, registered in the Medical Birth registries. Data on births were linked to Statistics Denmark and Norway to retrieve information on parents' education and relationship status and, in Denmark, also income. CP diagnoses were obtained from linkage with national registries. We used multivariate log-binominal regression models to estimate relative risk (RR) of CP according to parental socioeconomic status., Results: There was a strong trend of decreasing risk of CP with additional education of both the mother and the father. These trends were nearly identical for the two parents, with a one-third reduction in risk for those with the highest education compared with parents with the lowest education. When both parents had high education, risk of CP was further reduced (RR 0.58, 0.53-0.63). Women with partners had a reduction in risk (RR 0.79, 0.74-0.85) compared with single mothers overall. Risk patterns were stable over time, across countries and within spastic bilateral and unilateral CP. Household income was not associated with risk of CP., Conclusions: Risk of CP in two Scandinavian countries was lower among educated parents and mothers with a partner, but unrelated to income. Factors underlying this stable association with education are unknown, but could include differences in potentially modifiable lifestyle factors and health behaviours.

Background: Cerebral palsy is the most frequent motor disability in childhood, but little is known about its etiology. It has been suggested that cerebral palsy risk may be increased by prenatal thyroid hormone disturbances. The objective of this study was to investigate whether maternal thyroid disorder is associated with increased risk of cerebral palsy., Methods: A population-based cohort study using two study populations. 1) 1,270,079 children born in Denmark 1979-2007 identified in nationwide registers, and 2) 192,918 children born 1996-2009 recruited into the Danish National Birth Cohort and The Norwegian Mother and Child Cohort study, combined in the MOthers and BAbies in Norway and Denmark (MOBAND) collaboration cohort. Register-based and self-reported information on maternal thyroid disorder was studied in relation to risk of cerebral palsy and its unilateral and bilateral spastic subtypes using multiple logistic regression. Children were followed from the age of 1 year to the age of 6 years, and cerebral palsy was identified in nationwide registers with verified diagnoses., Results: In register data, hypothyroidism was recognized in 12,929 (1.0%), hyperthyroidism in 9943 (0.8%), and unclassifiable thyroid disorder in 753 (< 0.1%) of the mothers. The odds ratio for an association between maternal thyroid disorder and bilateral spastic cerebral palsy was 1.0 (95% CI: 0.7-1.5). Maternal thyroid disorder identified during pregnancy was associated with elevated risk of unilateral spastic cerebral palsy (odds ratio 3.1 (95% CI: 1.2-8.4)). In MOBAND, 3042 (1.6%) of the mothers reported a thyroid disorder in pregnancy, which was not associated with cerebral palsy overall (odds ratio 1.2 (95% CI: 0.6-2.4))., Conclusions: Maternal thyroid disorder overall was not related to bilateral spastic cerebral palsy, but maternal thyroid disorder identified in pregnancy was associated with increased risk of unilateral spastic cerebral palsy. These findings should be replicated in studies making use of maternal blood samples.

BackgroundPerinatal exposure to glucocorticoids and elevated endogenous glucocorticoid levels during childhood can have detrimental effects on the developing brain. Here, we examined the impact of glucocorticoid treatment during childhood on brain volumes.MethodsA total of 30 children and adolescents with rheumatic or nephrotic disease previously treated with glucocorticoids and 30 controls matched on age, sex, and parent education underwent magnetic resonance imaging (MRI) of the brain. Total cortical gray and white matter, brain, intracranial volume, and total cortical thickness and surface area were derived from MRI scans.ResultsPatients had significantly smaller gray and white matter and total brain volumes relative to healthy controls. Brain volume differences disappeared when accounting for intracranial volume, as patients had relatively smaller intracranial volumes. Group differences were mainly driven by the children with rheumatic disease. Total cortical thickness and cortical surface area did not significantly differ between groups. We found no significant associations between glucocorticoid-treatment variables and volumetric measures.ConclusionObserved smaller total brain, cortical gray, and white matter volumes in children and adolescents previously treated with glucocorticoids compared with that in healthy controls may reflect both developmental and degenerative processes. Prospective longitudinal studies are warranted to clarify whether findings are related to treatment or disease.

Surgery is the only treatment option with the potential to cure epilepsy. This review is a description of the multidisciplinary and multimodal presurgical evaluation process and the outcome of the Danish epilepsy surgery programme. The outcome aligns with international results and serious complications to surgery are very rare. The annual number of operations per capita compares to neighbouring countries and is equally distributed across Denmark. In accordance with international recommendations, Danish drug-resistant patients should be referred to epilepsy surgery evaluation at an early stage of the disease.

Background: It has been debated whether mild analgesics, mainly paracetamol, adversely affect aspects of neurodevelopment. We examined whether mother's use of paracetamol, aspirin or ibuprofen in pregnancy is associated with increased risk of cerebral palsy (CP) in the child., Method: We included 185 617 mother-child pairs from the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study. We created harmonized definitions of analgesic use in pregnancy, as well as indications for analgesic use and other potential confounders. Children with CP were identified in nationwide registers. We estimated the average causal effect of analgesics on risk of CP using marginal structural models with stabilized inverse probability weights., Results: Paracetamol use was reported in 49% of all pregnancies, aspirin in 3% and ibuprofen in 4%. Prenatal exposure to paracetamol ever in pregnancy was associated with increased risk of overall CP [adjusted odds ratio (aOR) 1.3, 95% confidence interval (CI): 1.0-1.7] and unilateral spastic CP (aOR 1.5, 95% CI: 1.0-2.2). The association appeared to be driven by an increased risk of unilateral spastic CP in children exposed in second trimester (aOR 1.6, 95% CI: 1.0-2.5). Children ever prenatally exposed to aspirin in pregnancy had an elevated risk of bilateral spastic CP (aOR 2.4, 95% CI: 1.1-5.3) compared with unexposed., Conclusion: We observed an increased risk of spastic CP in children prenatally exposed to paracetamol and aspirin. Although we controlled for several important indications for analgesic use, we cannot exclude the possibility of confounding by underlying diseases., (© The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Heightened levels of glucocorticoids in children and adolescents have previously been linked to prolonged changes in the diurnal regulation of the stress-hormone cortisol, a glucocorticoid regulated by the hypothalamic-pituitary-adrenal-axis (HPA-axis). To address this question, we examined the salivary cortisol awakening response (CAR) and daily cortisol output in 36 children and adolescents (25 girls/11 boys) aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder and 36 healthy controls. Patients and controls did not significantly differ in the CAR or diurnal cortisol output; however, sex-dependent group differences were observed. Specifically, female patients had a higher CAR relative to female controls, while male patients had higher daily cortisol levels compared to male controls. Notably, CAR in female patients and daily cortisol levels in male patients showed a positive linear relationship with the mean daily glucocorticoid doses administered during treatment. The observed dose-response associations suggest that glucocorticoid therapy during childhood and adolescence might trigger long-term changes in HPA-axis regulation, which may differ for males and females., (© 2017 Wiley Periodicals, Inc.)

Objective: Prenatal exposure to psychotropic drugs may affect the trajectories of brain development. In a register study, we investigated whether such exposure is associated with long-term impaired cognitive abilities., Method: Individuals born in Denmark in 1995-2008 were included. As proxies for cognitive impairment, requiring special needs education, attending special needs school, diagnoses of neurological/mental disorder, missed final examinations, and low school grade average were used. We accounted for maternal confounders., Results: We identified 868 159 individuals of whom 13 983 (1.6%) were prenatally exposed. The adjusted odds ratio (OR) was 0.97[0.92-1.02] for requiring special needs education, 1.28[1.14-1.43] for attending special needs school, 1.32[1.20-1.46] for a neurological/mental disorder diagnosis, 1.37[1.22-1.54] for missing the final examinations, and 1.13[0.82-1.55] for obtaining a low school grade average. Exposure to psycholeptics (primarily antipsychotics and sedatives) was correlated with significantly increased risk for four outcomes. The highest was the risk of missing the primary school examinations (OR: 1.51[1.29-1.76]). The overall highest risk concerned the presence of a neurological/mental disorder after prenatal exposure to psychoanaleptics (primarily antidepressants) (OR: 1.86[1.24-2.78)., Conclusion: Prenatal exposure to psychotropic drugs affects proxy outcomes of cognitive disabilities at school age. Exposure to psycholeptics carries the largest risk. The role of psychoanaleptics is currently unclear., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We describe a case of a child suffering from alternating hemiplegia with a heterozygous p. E815K pathogenic variant of ATP1A3. The patient started to present abnormal eye movements in the first days of life, followed by the appearance at 2 months of dystonic episodes, and later on, by recurrent episodes of alternating hemiplegia more often on the right side. A severe epilepsy started at the age of 2 years with episodes of status epilepticus since the onset which frequently recurred, requiring admission to the intensive care unit. MRI showed bilateral mesial temporal sclerosis and a left-sided ischaemic lesion. Interictal EEG showed bilateral abnormalities, whereas postictal EEG after status epilepticus showed overt slowing on the left side, suggesting a predominant involvement of ictal activity of the left hemisphere. We hypothesize that in our patient, the left hemisphere might have been more prominently affected by the pathogenetic abnormalities underlying alternating hemiplegia of childhood, rendering it more prone to early ischaemic lesions and recurrent unilateral status epilepticus. We speculate whether alternating hemiplegia of childhood shares some common pathophysiological mechanisms with familial hemiplegic migraine that may be associated with a pathogenic variant of ATP1A2.

Purpose: Epilepsy surgery is performed based on the assumption that medical refractory epilepsy will continue. Rarely seizure freedom occurs before surgery is performed, while the patient is being evaluated as an epilepsy surgery candidate. The aim of this study was to describe the number of children withdrawn from an epilepsy surgery programme due to unexpected seizure improvement., Methods: We retrospectively studied 173 children under 18 years with medical refractory epilepsy referred for epilepsy surgery between 1996 and 2010. Medical records were reviewed in 2012 and 2015., Results: At the first evaluation point in 2012, 13 patients were withdrawn from the epilepsy surgery programme due to unexpected marked improvement. In 2015, 6 of them were still seizure free. They had unexpected seizure freedom due to change in AED treatment (n=3) or after a febrile episode (n=3). The mean number of years they had had seizures was 3.4 years (range 0.6-6.2 years) and the number of seizures at inclusion was 209 per month (range 6-750 per month). The duration of follow-up was 6.6 years after inclusion into the epilepsy surgery programme (range 4.0-13.0 years). The aetiology of the epilepsy for these patients was heterotopia (n=1), focal cortical dysplasia (n=3), infarction (n=1) and unknown, with normal MRI (n=1). They all had an IQ in the normal range. Two of the remaining 7 children were operated later., Conclusion: Unexpected seizure control may occur during epilepsy surgery evaluation., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Although epilepsy surgery is a recognized treatment option for drug-resistant epilepsies since several decades, the management of antiepileptic drugs (AEDs) after successful surgery still remains one of the most difficult and unsolved therapeutic challenges. Indeed, no systematic controlled trials have been specifically conducted so far and no consensus or standardized guidelines regarding postsurgical drug discontinuation policy and procedures are available., Methods: In this paper, we aim to provide an updated overview on the present knowledge on this topic, which is based mainly on retrospective studies reporting practices used in individual centers., Results: Currently available data suggest that: 1) rate of seizure recurrence appears to be higher in patients undergoing early (before 6 months or 9 months according to different studies) AED withdrawal; 2) seizures that recur during AED tapering are easier to control than unprovoked postoperative seizure relapses; 3) there is no evidence to support negative long-term implications on seizure outcomes in patients who attempted AED withdrawal. In the pediatric age group, shorter intervals from surgery to AED reduction and to complete AED discontinuation predict seizure relapse during or after AED reduction/withdrawal. However, this does not correlate with the chances of regaining seizure freedom after drug reintroduction., Conclusion: Carefully conducted prospective longitudinal studies and randomized controlled trials are warranted to establish the correct post-surgical pharmacologic treatment and to identify the best candidates for AEDs discontinuation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B . Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

Objective: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients., Methods: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients., Results: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features., Conclusion: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy., (© 2016 American Academy of Neurology.)

Objective: Reviewing magnetoencephalography (MEG) recordings is time-consuming: signals from the 306 MEG-sensors are typically reviewed divided into six arrays of 51 sensors each, thus browsing each recording six times in order to evaluate all signals. A novel method of reconstructing the MEG signals in source-space was developed using a source-montage of 29 brain-regions and two spatial components to remove magnetocardiographic (MKG) artefacts. Our objective was to evaluate the accuracy of reviewing MEG in source-space., Methods: In 60 consecutive patients with epilepsy, we prospectively evaluated the accuracy of reviewing the MEG signals in source-space as compared to the classical method of reviewing them in sensor-space., Results: All 46 spike-clusters identified in sensor-space were also identified in source-space. Two additional spike-clusters were identified in source-space. As 29 source-channels can be easily displayed simultaneously, MEG recordings had to be browsed only once. Yet, this yielded a global coverage of the recorded signals and enhanced detectability of epileptiform discharges because MKG-artefacts were suppressed and did not impede evaluation in source-space., Conclusions: Our results show that reviewing MEG recordings in source-space is accurate and much more rapid than the classical method of reviewing in sensor-space., Significance: This novel method facilitates the clinical use of MEG., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Cerebral palsy (CP) is often accompanied by psychopathology and learning disability., Aims: (1) to evaluate the prevalence of psychopathology as estimated by the Child Behavior Checklist (CBCL) parental questionnaire in 8- to 15-year-old Danish children with CP and to analyze its association with cognitive ability and families' social characteristics; (2) to examine to what extent children with CP had been evaluated by a child psychiatrist and/or psychologist., Method: The parents of 462 children with CP answered a questionnaire about their child's treatment and the family's characteristics and 446 the CBCL. The cutoff for psychopathology was the Total CBCL score or DSM-oriented scores above the 93rd percentile in an age- and gender-stratified population., Results: The psychopathology screening was positive in 46.2% (CI 41.6-50.8%) against 15.1% in general population. Cognitive disability was associated with an increased prevalence of psychopathology (odds ratio (OR) 2.6, CI 1.4-4.6, for Developmental Quotient of cognitive function (DQ) 50-85 and OR 3.0, CI 1.3-7.0, for DQ<50). Children with CP and a single parent showed increased odds for a positive CBCL screening compared to children living with two parents (OR 2.1, 95% CI 1.1-4.0). Children with DQ 50-85 more often had a psychological evaluation. A positive CBCL screening was strongly associated with a psychiatric assessment (21% vs. 7%, p<0.01)., Conclusion: The high prevalence of emotional and behavioral problems indicates that screening for psychopathology should be a part of multidisciplinary follow-up of CP. The CBCL can be used as a screening instrument in children with CP without severe motor and cognitive disability., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Epilepsy surgery is increasingly used to treat children with medically intractable epilepsy. This study investigates the aetiology and seizure outcome in Danish children operated between 1996 and 2010., Methods: Retrospectively collected data on structural magnetic resonance imaging (MRI) diagnoses, surgical procedures and seizure outcomes classified according to the Engel Classification were used. Changes over time grouped as 1996-2000, 2001-2005 and 2006-2010 were analysed., Results: A total of 95 children underwent epilepsy surgery. Sixty-three operations were performed in Denmark and 50 abroad. In all, 14 children needed reoperation. The median follow-up period was four years. At the latest follow-up, Engel class I (indicating no disabling seizures) was found in 67% of the patients. Cortical dysplasia, mesial temporal sclerosis and tumour were the most common MRI findings. The percentage of tumours operated decreased over time, and frontal lobe resections increased. In the 2006-2010 period, resections with normal MRI were performed, resulting in a less favourable Engel outcome. Persistent, unexpected complications were seen in three of 113 operations., Conclusions: The majority of children who undergo epilepsy surgery have a good, worthwhile seizure outcome. The seizure outcome for Danish children corresponds to that of other epilepsy surgery centres. The clinical criteria for selection of patients changed over time., Funding: none., Trial Registration: The Danish Data Protection Agency approved the project with record number: 2013-41-2459.

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders., (Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.)

Aim: As early intervention is important in cerebral palsy (CP), an early diagnosis is desirable. The aim of this study was to establish the median diagnostic age of CP and to identify predictors of an early diagnosis in a population-based cohort., Method: Using the Danish National Cerebral Palsy Registry (NCPR), we identified 1291 children with CP (764 males, 527 females) born between 1995 and 2003. The date of diagnosis was defined as the day the parents were told that their child was spastic or had CP. We calculated the age of diagnosis and analysed the following predictors: type of CP, degree of motor disability, cerebral ultrasonography results, epilepsy, gestational age, and degree of cognitive impairment., Results: We found the overall median corrected diagnostic age of CP to be 11 months. Early diagnosis was associated with the type of CP, presence of epilepsy, a high degree of motor disability, and abnormalities in the cerebral ultrasonography. The gestational age was not associated with the diagnostic age., Interpretation: The median diagnostic age implies that half of the Danish children with CP will be able to enter an early intervention program before 1 year of age. A late diagnosis was associated with less severe symptoms, and gestational age did not influence the diagnostic age., (© 2015 Mac Keith Press.)

Aim: To analyse the social situation of parents who have a child with cerebral palsy (CP)., Method: This was a population-based longitudinal study with linkage to public registries. Parents of children with CP (n=3671) identified in the Danish CP Registry were compared with 17,983 parents of children without CP. Employment, income, cohabitation status, and presence of additional children were factors analysed during a follow-up period of 28 years. We followed parents from before their child was born and up to the age of 43 years of the child., Results: Mothers of children with CP under the age of 10 were less often employed: odds ratio [OR] of employment at age 5y 0.45 (95% confidence interval [CI] 0.36-0.57), but only 11% left the labour market. Mothers of children without CP had higher incomes: ratio full-time working 1.11 (95% CI 1.07-1.15). The risk of not living together was not increased among parents of children with CP: at age 5 years OR 1.04 (95% CI 0.84-1.28). Parents of children with CP as the first born postponed or more seldom had subsequent children: hazard ratio [HR] 0.75 (95% CI 0.68-0.83)., Interpretation: The Danish welfare system seems to have succeeded in keeping parents in the labour market and living together with their child. Special attention needs to be paid to the financial situation of families with children with CP under 10 years of age., (© 2015 Mac Keith Press.)

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

We report the experiences from the first two years of a paediatric ethical committee at Rigshospitalet. The committee consists of five clinicians (nurses and doctors) and five non-clinicians. Themes of the sixteen reported case were: genetic testing, life-sustaining treatment ("when is enough enough?"), non-consensus between the parents and health personal and between different health personal, controversies to different religious wishes and to optimizing resources of the department versus individual care of a critically ill child. Within paediatrics a need for ethical reflection seems obvious.

Objective: To investigate the association between proportionality of fetal and placental growth measured at birth and the risk for congenital cerebral palsy (CP)., Study Design: We identified all live-born singletons born in Denmark between 1995 and 2003 and followed them from 1 year of age until December 31st, 2008. Information on four indices of fetal growth: ponderal index, head circumference/ abdominal circumference ratio, cephalization index and birth weight/ placenta weight ratio was collected. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). All measurements were evaluated as gestational age and sex specific z-scores and in z-score percentile groups, adjusted for potential confounders, and stratified on gestational age groups (<32, 32-36, 37-38, 39, 40, ≥ 41 weeks)., Results: We identified 503,784 singleton births, of which 983 were confirmed cases of CP. Head/ abdominal circumference ratio (aHR:1.12; 95%CI:1.07-1.16) and cephalization index (aHR:1.14; 95%CI:1.11-1.16) were associated with the risk of CP irrespective of gestational age. Birth weight-placental weight ratio was also associated with CP in the entire cohort (aHR:0.90; 95%CI:0.83-0.97). Ponderal index had a u-shaped association with CP, where both children with low and high ponderal index were at higher risk of CP., Conclusions: CP is associated with disproportions between birth weight, birth length, placental weight and head circumference suggesting pre and perinatal conditions contribute to fetal growth restriction in children with CP.

Purpose: West syndrome (WS) is a severe age-related acute epileptic encephalopathy of infancy characterized by infantile spasms, hypsarrhythmia and psychomotor delay. The aim of this study was to investigate if patients with WS had an altered autonomic output to the heart., Methods: In 23 patients with WS the heart rate variability (HRV) was investigated by examining time- and frequency-domain parameters of HRV at the time of the diagnosis of hypsarrhythmia and compared to 22 age-matched controls. For the WS patients the same dataset was obtained and compared again at the end of the study period, when hypsarrhythmia was no longer present., Results: Compared to controls, patients with WS during hypsarrhythmia had significantly lower SDNN (the standard deviation of the NN interval, i.e. the square root of variance) (19.2 ms; p = 0.007, Mann-Whitney's U-Test) and total power (242 ms(2); p = 0.044, Mann-Whitney's U-Test) in the awake state, indicating an abnormal autonomic output to the heart. Comparing the initial to the final examination demonstrated a significant increase in the HRV parameters SDNN (31.3 ms) and total power (757 ms(2); p = 0.001 and p = 0.013, Wilcoxon Signed Ranked Test). In addition, at the final examination the WS-patients no longer differed significantly from the controls., Conclusion: Our data suggest that the initial reduction in HRV in patients at the time of onset of WS is transient and related to the presence of hypsarrhythmia., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Hemiconvulsion-hemiplegia-epilepsy syndrome is a rare consequence of a status epilepticus in the course of a febrile illness in children under the age of four years. Various degrees of hemiplegia and within a variable interval, subsequent epilepsia follows. Neuroimaging show unilateral cytotoxic oedema at the initial convulsive state, followed by severe chronic atrophy of the affected hemisphere. The aetiology remains unclear. Several mechanisms may contribute to this condition. To improve the outcome, further studies are needed and early diagnosis is essential.

Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a very rare condition caused by a fever-associated status epilepticus causing various degrees of hemiplegia and secondary epilepsy affecting children under the age of four. The aetiology is not fully understood. We report a case of a two-year-old girl with adrenogenital syndrome presenting with HHE syndrome in the course of a bacterial septicaemia.

Objective: Mesial temporal lobe epilepsy (MTLE) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis (HS), which is characterized by pronounced loss of hippocampal pyramidal neurons. microRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE and HS., Methods: miRNA expression was quantified in hippocampal specimens from human patients using miRNA microarray and quantitative real-time polymerase chain reaction RT-PCR, and by RNA-seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of miRNAs in the human hippocampus. The potential effect of miRNAs on targets genes was investigated using the dual luciferase reporter gene assay., Results: miRNA expression profiling showed that 25 miRNAs were up-regulated and 5 were down-regulated in hippocampus biopsies of MTLE/HS patients compared to controls. We showed that miR-204 and miR-218 were significantly down-regulated in MTLE and HS, and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR-204 and miR-218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO1, GRM1, SLC1A2, and GNAI2, as bona fide targets of miR-218. GRM1 was also shown to be a direct target of miR-204., Significance: miR-204 and miR-218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)