Increasing prevalence of cerebral palsy in children born very preterm in Denmark.

AIM: To analyse the rising prevalence of cerebral palsy (CP) in children born preterm in Denmark. METHOD: We included all live-born children born preterm in Denmark from 1997 to 2013. The prevalence of CP in children born preterm was categorized by gestational age and correlated with neonatal mortality and changes in clinical factors. RESULTS: Among 70 876 children, 824 (1.2%) had CP. The overall CP prevalence in children born preterm decreased substantially until 2001, from when it increased annually by 2.8% (95% confidence interval 0.6-5.0). When categorized, the prevalence only increased significantly in children born very preterm (gestational weeks 28-31). Neonatal mortality rates decreased steadily at all gestational ages during the entire study period. Clinical factors that changed during the study period were increasing numbers of high-risk pregnancies, maternal obesity, emergency caesarean sections, neonatal admissions, and usage of assisted ventilation. INTERPRETATION: The increasing prevalence of CP in children born preterm was driven by the subgroup born very preterm and matched their decrease in neonatal mortality. In similar population studies, decreased mortality was not followed by increased CP prevalence. An increase in clinical risk factors was unlikely to explain our findings, but more active neonatal life support may have played a role.

Impact of a National Follow-Up Program on the Age at Diagnosis for Cerebral Palsy.

BACKGROUND: The Danish National Cerebral Palsy Follow-up Program (CPOP) is a nationwide program offering standardized treatment to all children with cerebral palsy (CP) since 2004. We aimed to establish if its implementation had a positive impact on the diagnostic age of CP. METHODS: Children with validated CP diagnoses were identified from the Danish Cerebral Palsy Registry and the CPOP. We then compared the age at diagnosis and the clinical features of children with CP born in 2000 to 2003 with those born in 2010 to 2013. Differences in time to diagnosis were compared using log-rank test. RESULTS: The age at diagnosis was not different in the two periods (P = 0.23), with identical overall median diagnostic ages at 13.0 months. The number of children with severe motor disability decreased markedly from 47.5% in 2000 to 2003 to 32.0% in 2010 to 2013 (P < 0.001). There was increased usage of cerebral magnetic resonance imaging; however, this was not associated with lower diagnostic age. CONCLUSIONS: The diagnostic age of CP did not change after the implementation of a nationwide follow-up program, offering standardized and early assessments. However, central clinical aspects also changed significantly between the periods compared, which possibly affected the diagnostic age.

Acetaminophen treatment in children and adults with spinal muscular atrophy: a lower tolerance and higher risk of hepatotoxicity.

Acute liver failure has been reported sporadically in patients with spinal muscular atrophy (SMA) and other neuromuscular disorders with low skeletal muscle mass receiving recommended dosages of acetaminophen. It is suggested that low skeletal muscle mass may add to the risk of toxicity. We aimed to describe the pharmacokinetics and safety of acetaminophen in patients with SMA. We analyzed acetaminophen metabolites and liver biomarkers in plasma from SMA patients and healthy controls (HC) every hour for six or eight hours on day 1 and day 3 of treatment with therapeutic doses of acetaminophen. Twelve patients with SMA (six adults and six children) and 11 HC participated in the study. Adult patients with SMA had significantly lower clearance of acetaminophen compared to HC (14.1 L/h vs. 21.5 L/h). Formation clearance of acetaminophen metabolites, glucuronide, sulfate, and oxidative metabolites were two-fold lower in the patients compared to HC. The liver transaminases and microRNAs increased nine-fold in one adult SMA patient after two days of treatment. The other patients and HC did not develop abnormal liver biomarkers. In this study, patients with SMA had lower clearance and slower metabolism of acetaminophen, and one patient developed liver involvement. We recommend giving 15 mg/kg/dose to SMA adults (with a maximum of 4000 mg/day) and monitoring standard liver biomarkers 48 h after first-time treatment of acetaminophen.

Current state of hemispherectomy and callosotomy for pediatric refractory epilepsy in Denmark.

OBJECTIVE: To evaluate outcomes from hemispherectomy and callosotomy related to the need for anti-seizure medication (ASM), seizure frequency, and cognition. METHODS: A review of the medical charts of all Danish pediatric patients who underwent hemispherectomy or callosotomy from January 1996 to December 2019 for preoperative and postoperative ASM use, seizure frequency, and cognitive data. RESULTS: The median age of epilepsy onset was two years (interquartile range (IQR): 0.0-5.3) for the hemispherectomy patients (n = 16) and one year (IQR: 0.6-1.7) for callosotomy patients (n = 5). Median time from onset to final surgery was 3.4 years for hemispherectomy and 10.2 years for callosotomy, while the median follow-up time was 6.9 years and 9.0 years, respectively. Preoperatively, all patients had daily seizures and were treated with ≥ 2 ASM. Hemispherectomy resulted in a reduction in seizure frequency in 87.5 % of patients, with 78.6 % achieving seizure freedom. Furthermore, 81.3 % experienced a reduction in ASM use and 56.3 % stopped all ASM. Median IQ/developmental quotient (IQ/DQ) was low preoperatively (44.0 [IQR: 40.0-55.0]) and remained unchanged postoperatively (IQ change: 0.0 [IQR: -10.0-+4.0]). Callosotomy resulted in a seizure reduction of 86-99 % in four patients, and ASM could be reduced in three patients. Median IQ/DQ was 20.0 preoperatively (IQR: 20.0-30.0) and remained unchanged postoperatively (IQ change: 0.0 [IQR: 0.0]). CONCLUSION: Hemispherectomy and callosotomy result in a substantial reduction in seizure frequency and ASM use without deterioration of IQ. Extensive epilepsy surgery should be considered early in children with drug-resistant epilepsy.

Cerebral Palsy - Early Diagnosis and Intervention Trial: protocol for the prospective multicentre CP-EDIT study with focus on diagnosis, prognostic factors, and intervention.

BACKGROUND: Early diagnosis of cerebral palsy (CP) is important to enable intervention at a time when neuroplasticity is at its highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that an early-diagnosis set-up can lower diagnostic age in high-risk infants. The aim of the current study is to lower diagnostic age of CP regardless of neonatal risk factors. Additionally, we want to investigate if an early intervention program added to standard care is superior to standard care alone. METHODS: The current multicentre study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing the feasibility of an early diagnosis set-up and the GO-PLAY early intervention. CP-EDIT is a prospective cohort study, consecutively assessing approximately 500 infants at risk of CP. We will systematically collect data at inclusion (age 3-11 months) and follow a subset of participants (n = 300) with CP or at high risk of CP until the age of two years. The GO-PLAY early intervention will be tested in 80 infants with CP or high risk of CP. Focus is on eight areas related to implementation and perspectives of the families: early cerebral magnetic resonance imaging (MRI), early genetic testing, implementation of the General Movements Assessment method, analysis of the GO-PLAY early intervention, parental perspective of early intervention and early diagnosis, early prediction of CP, and comparative analysis of the Hand Assessment for Infants, Hammersmith Infant Neurological Examination, MRI, and the General Movements method. DISCUSSION: Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in clinical care in Denmark. Additionally, there is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. Most studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy. The current study aims at improving care of patients with CP even before they have an established diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov ID 22013292 (reg. date 31/MAR/2023) for the CP-EDIT cohort and ID 22041835 (reg. date 31/MAR/2023) for the GO-PLAY trial.

The Positive Predictive Value of Pediatric Stroke Diagnoses in Administrative Data: A Retrospective Validation Study.

Background: This retrospective cohort study aimed to examine the positive predictive value (PPV) of pediatric stroke diagnoses in the Danish National Registry of Patients (DNRP) and the impact of different stroke definitions on the PPV. Methods: We included children registered with a stroke or stroke-related diagnosis in the DNRP between January 2017 through December 2020. Two assessors reviewed medical records and validated cases according to the American Heart and American Stroke Association (AHA/ASA) stroke definition. The level of interrater agreement was examined using kappa statistics. Validation by the AHA/ASA definition was compared with validation according to the definition in the International Classification of Disease 11th version (ICD-11) and the World Health Organization's definition. Results: Stroke was confirmed in 120 of 309 included children, yielding an overall PPV of 0.39 (95% CI: 0.33-0.45). PPV varied across stroke subtypes from 0.83 (95% CI: 0.71-0.92) for ischemic stroke (AIS), 0.57 (95% CI: 0.37-0.76) for unspecified stroke, 0.42 (95% CI: 0.33-0.52) for intracerebral hemorrhage (ICH) to 0.31 (95% CI: 0.55-0.98) and 0.07 (95% CI: 0.01-0.22) for cerebral venous thrombosis and subarachnoid hemorrhage (SAH), respectively. Most non-confirmed ICH and SAH diagnoses were in children with traumatic intracranial hemorrhages (36 and 66% respectively). Among 70 confirmed AIS cases, 25 (36%) were identified in non-AIS code groups. PPV varied significantly across stroke definitions with the highest for the AHA/ASA definition (PPV = 0.39, 95% CI: 0.34-0.45) and the lowest for the WHO definition (PPV = 0.29, 95% CI: 0.24-0.34). Correspondingly, the incidence of pediatric AIS per 100.000 person-years changed from 1.5 for the AHA/ASA definition to 1.2 for ICD-11 and 1.0 for the WHO-definition. The overall interrater agreement was considered excellent (κ=0.85). Conclusion: After validation, stroke was confirmed in only half of the children registered in the DNRP with a stroke-specific diagnosis. Non-validated administrative data should be used with caution in pediatric stroke research. Pediatric stroke incidence rates may vary markedly depending on which stroke definition is used.

Acute triage of childhood stroke in Denmark.

OBJECTIVE: This 2-year observational study aimed to test the feasibility of implementing a pediatric stroke triage-setup that connected frontline providers with vascular neurologists and to examine final diagnoses in children triaged for suspected stroke. METHODS: Prospective, consecutive registration of children with suspected stroke triaged by a team of vascular neurologists from Jan 1st, 2020 and through Dec 2021, Eastern Denmark (census 530,000 children). Based on the provided clinical information, the children were triaged to either assessment at the Comprehensive Stroke Center (CSC) in Copenhagen or to a pediatric department. All included children were retrospectively followed-up for clinical presentations and final diagnosis. RESULTS: A total of 163 children with 166 suspected stroke events were triaged by the vascular neurologists. Cerebrovascular disease was present in 15 (9.0%) suspected stroke events; one child had intracerebral hemorrhage, one had subarachnoid hemorrhage, two children presented with three TIA events and nine children presented with 10 ischemic stroke events. Two children with ischemic stroke were eligible for acute revascularization treatment of which both were triaged to the CSC. The sensitivity of the triage by acute revascularization indication was 1.00 (95% confidence interval (95% CI): 0.15-1.00) and specificity 0.65 (95% CI: 0.57-0.73). Non-stroke neurological emergencies were present in 34 (20.5%) children, including seizures in 18 (10.8%) and acute demyelinating disorders in 7 (4.2%). CONCLUSION: Implementing regional triage-setup that connected frontline providers to vascular neurologists was feasible; this system was activated for the majority of children with ischemic stroke according to an expected incidence and led to identification of children eligible for revascularization treatments.

Mortality patterns in a Danish nationwide cohort of persons with intellectual disabilities.

Mortality disparities among persons with intellectual disability are important to guide health-care practices. The objective was to evaluate mortality patterns of persons with intellectual disability in a nationwide study from 1976 to 2020. This study establishes a Danish nationwide cohort of persons with intellectual disability and age- and sex-matched reference cohort through linkage between several registers. We established a cohort of 79,114 persons with intellectual disability. Standardized mortality ratios were increased for persons with intellectual disability, most pronounced among younger persons and among females. Life expectancies were markedly lower; among persons with intellectual disability 63.6 years among females and 59.8 years among males in 2016-2020 compared to 82.4 and 78.7 years among females and males in the reference cohort. Life expectancies decreased with severity of intellectual disability. This study reports the establishment of a nationwide Danish cohort of persons with intellectual disability.

Breast Cancer Screening Among Women With Intellectual Disability in Denmark.

Importance: Breast cancer-specific mortality is increased among women with intellectual disability (ID), and knowledge about participation in breast cancer screening in this group is needed. Objective: To examine participation in the Danish national breast cancer screening program among women with ID compared with women without ID. Design, Setting, and Participants: This dynamic population-based cohort study assessed participation in the Danish national breast cancer screening program initiated in 2007, targeting women aged 50 to 69 years with a screening interval of 2 years. In all, 6357 women with ID born between 1941 and 1967 and eligible for the screening program were identified in national registers. Women entered the study between January 1, 2007, and December 31, 2017. Subsequently, 273 women were excluded due to a history of carcinoma in situ or breast cancer, and 489 due to registration errors in registers. Each woman was individually age-matched with 10 women without ID (reference group). All women were followed up until March 31, 2021, or censoring (due to death, carcinoma in situ, or breast cancer). Data were analyzed from December 1, 2021, to June 31, 2022. Exposures: Intellectual disability was defined as being registered with an ID diagnosis or a diagnosis most likely leading to ID or residing at an institution for persons with ID. Main Outcomes and Measures: Participation in breast cancer screening (fully, partly, and never). Results: A total of 5595 women with ID and 49 423 age-matched women in the reference group were included in the analysis. Of these, 2747 women with ID (49%) and 24 723 in the reference group (50%) were 50 years of age at study entry; for those older than 50 years, the median age was 51 years (IQR, 50-58 years) in both groups. In all, 1425 women with ID (25%) were fully screened according to guidelines for the Danish breast cancer screening program compared with 30 480 women in the reference group (62%). Women with ID had nearly 5 times higher odds of never being screened compared with the reference group (odds ratio, 4.90 [95% CI, 4.60-5.22]). In all, 2498 women with ID (45%) and 6573 in the reference group (13%) were never screened. The proportion of never-screened women increased with severity of ID, from 834 of 2287 (36%) among women with mild ID to 173 of 212 (82%) among women with profound ID. Conclusions and Relevance: The findings of this cohort study suggest that women with ID are markedly less likely to participate in breast cancer screening compared with women without ID. These findings further suggest a need for tailored guidelines and approaches for breast cancer screening in this group of women.

The magnitude rather than the rate of decline in fetal growth is a stronger risk factor for perinatal mortality in term infants.

BACKGROUND: Prenatal diagnosis of an infant suspected of having fetal growth restriction is important because of its strong association with perinatal mortality and morbidity. The current Delphi consensus criteria include a decline of >50th percentiles in fetal growth when diagnosing late fetal growth restriction; however, the evidence underpinning this criterion is limited. OBJECTIVE: This study aimed to analyze the relationships among the magnitude of decline in fetal growth and stillbirth, perinatal mortality, and adverse neonatal outcomes. STUDY DESIGN: This cohort study of 15,861 pregnancies was conducted at the Mater Mother's Hospital in Brisbane, Australia. The decline in fetal growth was calculated as a drop in either estimated fetal weight or abdominal circumference percentiles between 2 ultrasound scans performed after 18 weeks of gestation. Relationships between declining fetal growth and the outcomes were, firstly, analyzed as a continuous variable and, if significant, further assessed with the rate of decline and different magnitudes of decline, compared to the referent category (change in growth of ±10 percentiles between scans). The 3 categories of growth decline were >10th to <25th percentiles, ≤25th to <50th percentiles, and ≥50th percentiles. Associations were analyzed by logistic regressions. The primary study outcomes were stillbirth and perinatal mortality (composite of stillbirth and neonatal death). The secondary outcomes were birth of a small-for-gestational-age infant (birthweight of <10th percentile for gestation), emergency cesarean delivery for nonreassuring fetal status, and composite severe neonatal morbidity. RESULTS: The risks of stillbirth and perinatal mortality increased significantly by 2.6% (0.4%-4.6%) and 2.8% (1.0%-4.5%), respectively, per 1 percentile decline in fetal growth. In addition, the odds of stillbirth (adjusted odds ratio, 3.68 (1.32-10.24) and perinatal mortality (4.44) (1.82-10.84)) compared to the referent group were significantly increased only when the decline was ≥50th percentiles, regardless of birthweight. Furthermore, none of the primary outcomes were significantly associated with the rate of growth decline. The risk of a small-for-gestational-age infant increased by 2.4% (2.2%-2.7%) for every percentile decline. Conversely, reduced fetal growth was not associated with emergency cesarean delivery for nonreassuring fetal status or severe neonatal morbidity. CONCLUSION: Our results supported the use of a ≥50th percentile decline in fetal growth as a criterion for identifying infants at risk of late fetal growth restriction. This cutoff also identified fetuses at high risk of perinatal mortality, regardless of birthweight and rate of growth decline. Our findings may guide obstetrical practice by alerting clinicians to the importance of incorporating the magnitude of fetal growth decline into antenatal counseling and decisions regarding the timing of birth.

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype−phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype−phenotype correlations and improve prognostic outcomes.

[Treatment of status epilepticus in children and adults].

This review finds that, in children and adults with epilepsy, there are several treatment options. Multiple antiseizure medications are available and in case of drug-resistant epilepsy, a non-pharmacological approach is recommended, including epilepsy surgery, vagus nerve stimulation, or ketogenic diet treatment. The aim of the treatment is to avoid further seizures, but also to avoid negative cognitive, psychological, and social consequences of epilepsy.

Causes and Risk Factors of Pediatric Spontaneous Intracranial Hemorrhage-A Systematic Review.

Previous studies suggest that the most common cause of spontaneous intracerebral hemorrhage in children and adolescents is arteriovenous malformations (AVMs). However, an update containing recently published data on pediatric spontaneous intracranial hemorrhages is lacking. The aim of this study is to systematically analyze the published data on the etiologies and risk factors of pediatric spontaneous intracranial hemorrhage. This systematic review was performed in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A search in PubMed, Embase, Scopus, Web of Science and Cochrane Library was conducted aiming for articles published in year 2000 and later, containing data on etiology and risk factors of spontaneous intracranial hemorrhages in unselected cohorts of patients aged between 1 month and 18 years. As a result, forty studies were eligible for data extraction and final analysis. These included 7931 children and adolescents with 4009 reported etiologies and risk factors. A marked variety of reported etiologies and risk factors among studies was observed. Vascular etiologies were the most frequently reported cause of pediatric spontaneous intracranial hemorrhages (n = 1727, 43.08% of all identified etiologies or risk factors), with AVMs being the most common vascular cause (n = 1226, 70.99% of all vascular causes). Hematological and systemic causes, brain tumors, intracranial infections and cardiac causes were less commonly encountered risk factors and etiologies.

First-trimester biomarkers and the risk of cerebral palsy.

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.

[Challenges and advances in paediatric arterial ischaemic stroke].

Neurological sequelae occur in more than 50% of children with arterial ischemic stroke. Early recognition and treatment are essential in improving outcome. However, diagnostic delay in paediatric stroke often extends beyond 24 hours, and children rarely access hyperacute recanalisation therapies. This review describes clinical presentations, risk factors and treatment of paediatric ischaemic stroke. Additionally, we share our experience from a systematic paediatric stroke pathway implemented in Eastern Denmark since 2017.

Increase in cognitive function is seen in many single-operated pediatric patients after epilepsy surgery.

PURPOSE: The recurrent seizures of pediatric drug-resistant epilepsy (DRE) are known to impair brain development and can lead to a loss in cognitive functioning. Surgery is increasingly being used to treat children with DRE. This study investigates the pre- and postoperative cognitive function in a pediatric epilepsy surgery cohort as well as predictive determinants of change in intelligence quotient (IQ) following surgery. METHODS: A consecutive series of 91 Danish children who underwent focal resective epilepsy surgery between January 1996 and December 2016 were included. All underwent preoperative cognitive evaluation and were reevaluated at 1-year and/or 2-year follow-up. Single-operated and multi-operated patients were examined separately. RESULTS: 79 of 91 patients were single-operated. Single-operated patients received less anti-epileptic drugs (AED) and experienced a decrease in seizure frequency postoperatively, p < 0.001. IQ increased postoperatively (IQ change ± standard deviation: 3.3 ± 14.0), p < 0.05. High preoperative seizure frequency was a significant predictor for decreased IQ, p < 0.01. Multi-operated patients did not experience a reduction in AED treatment. Surgery and continued AED treatment did, however, result in significantly better seizure control, p < 0.01. IQ remained unchanged in multi-operated patients. CONCLUSION: Epilepsy surgery allowed for IQ gains in single-operated patients. Preoperative seizure frequency was a significant predictor of IQ change following surgery. Interactions between other, not included, possible predictors remain to be examined. Single-operated patients had the best cognitive outcome. The inclusion of a non-surgical control group is needed to assess the extent of the beneficial effects of surgery on cognitive ability.

[Infantile spasms].

Infantile spasms (IS) is a severe developmental and epileptic encephalopathy, occurring mainly in children aged 3-18 months. IS have multiple aetiologies, and the treatment differs accordingly. Early diagnosis and treatment may improve the outcome, but many patients are initially misdiagnosed. Evaluation includes seizure semiology, electroencephalography, cerebral magnetic resonance imaging and genetic and metabolic testing. Treatment varies among centres, and initial treatment may include vigabatrin and/or corticosteroids. In recent years, as summarised in this review, knowledge has substantially increased regarding genetic aetiologies and treatment regimens.

Continuing decline in the prevalence of cerebral palsy in Denmark for birth years 2008-2013.

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.

Everolimus as adjunctive treatment in tuberous sclerosis complex-associated epilepsy in children.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant multi-organ disease. In TSC, epilepsy is frequent and often treatment refractory. Dysfunction of the tumour-suppressing hamartin/tuberin complex leads to an over-activated mammalian target of rapamycin (mTOR) signalling pathway and uncontrolled cell growth. Protocolled treatment of TSC-associated epilepsy with the mTOR inhibitor everolimus has recently been approved by The Danish Medicines Council in Denmark. METHODS: Clinical data on the first Danish paediatric patients treated with everolimus for epilepsy and a review of the literature are presented. RESULTS: Four patients met the inclusion criteria and had been treated for more than 12 months. Onset of epilepsy was at a median age of 1.1 years (range: 0.3-3.3 years) and current age was 3.4 years (range: 2.2-7.4 years). The previous median number of antiepileptic drugs was 5.0 (range: 2-10) and the concomitant median number of antiepileptic drugs was 2.5 (range: 1-4). Several other treatment modalities had been or were still being applied, including ketogenic diet (n = 3), vagus nerve stimulation (n = 1) and epilepsy surgery (n = 2). The number of focal seizures was in the 20-160 range per week before everolimus. All patients had a > 50% seizure reduction after 12 months of everolimus treatment. One patient became seizure free. Side effects were mild and self-limiting. CONCLUSIONS: Early data on everolimus as an adjunctive treatment in TSC-associated epilepsy are promising with regards to both effect and tolerability. FUNDING: none. TRIAL REGISTRATION: not relevant.