Norwegian population-based study of effectiveness of vagus nerve stimulation in patients with developmental and epileptic encephalopathies.

OBJECTIVE: Evaluate the long-term efficacy of vagus nerve stimulation (VNS) in patients with developmental and epileptic encephalopathies (DEE) compared with epilepsy patients without intellectual disability (ID). METHODS: Long-term outcomes from a Norwegian VNS quality registry are reported in 105 patients with DEEs (Lennox-Gastaut syndrome [LGS] n = 62; Dravet n = 16; Rett n = 9; other syndromes n = 18) were compared with 212 epilepsy patients without ID, with median follow-up of 88 and 72 months, respectively. Total seizure reduction was evaluated at 6, 12, 24, 36, and 60 months. Effect on different seizure types was evaluated at baseline and last observation carried forward (LOCF). RESULTS: Median monthly seizure frequency at LOCF was reduced by 42.2% (p < 0.001) in patients with DEE and by 55.8% (p < 0.001) in patients without ID. In DEE patients, ≥50% seizure reduction at 6 and 24 months were 17.1% and 37.1%, respectively, and 33.5% and 48.6% for patients without ID. Seizure reduction ≥75% at 60 months occurred in 14.3% of DEE patients and 23.1% of patients without ID. Highest median reduction was for atonic seizures, most notably 64.6% for LGS patients. A better effect was seen at 2 years among DEE patients with unchanged medication compared with those with changed medication (54.5% vs. 35.6% responders, p = 0.078). More DEE patients were reported to have greater improvement in ictal or postictal severity (43.8% vs. 28.3%, p = 0.006) and alertness (62.9% vs. 31.6%, p < 0.001) than patients without ID. For both groups, use of the magnet reduced seizure severity. Hoarseness was the most common adverse effect in both groups. In addition, DEE patients were frequently reported to have sleep disturbance, general discomfort, or abdominal problems. SIGNIFICANCE: Our data indicate that VNS is very effective for atonic seizures. Patients without ID had best overall seizure reduction, however, patients with DEE had higher retention rates probably due to other positive effects. PLAIN LANGUAGE SUMMARY: DEE refers to a group of patients with severe epilepsy and intellectual disability. Many of these patients have restricted lifestyles with frequent seizures. VNS is a treatment option for patients who do not respond well to medicines, either because of insufficient effect or serious adverse effects. Our study shows that VNS is well tolerated in this patient group and leads to a reduction in all seizure types, most notably for seizures leading to fall. Many patients experience other positive effects like shorter and milder seizures, as well as improvement in alertness.

Pharmacokinetic Variability of Sulthiame: The Impact of Age, Drug-Drug Interactions, and Biochemical Markers of Toxicity in Patients with Epilepsy.

PURPOSE: Sulthiame is an antiseizure medication increasingly used for epilepsy. The aim of this study was to investigate the pharmacokinetic variability of sulthiame in children and adults with epilepsy with respect to age, comedication, dose, serum concentration, and biochemical markers of toxicity in a clinical setting. METHOD: Retrospective quantitative data from the therapeutic drug monitoring (TDM) database at the Section for Clinical Pharmacology, the National Center for Epilepsy, Norway (2015-2021), were used. RESULTS: TDM data from 326 patients (127 female/199 male) were included [mean age, 11.4 (range 2-44) years; mean weight, 41 (range 14-109) kg]. Interindividual pharmacokinetic variability in the concentration/(dose/body weight) (C/(D/kg)) ratio was 16-fold; intraindividual variability was up to 8-fold (coefficient of variation = 10%-78%). Young children (younger than 6 years) had a significantly lower C/(D/kg) ratio than older age groups ( P < 0.05). Various comedications did not significantly affect the C/(D/kg) ratio, possibly owing to the small sample size. However, CYP2C19-mediated inhibition by sulthiame was indicated because patients using clobazam and sulthiame (n = 28) had a 3.5-fold higher N-desmethylclobazam C/(D/kg) ratio than those using neutral comedication (n = 45; P < 0.001). Patients with pH values below the adjusted normal range (7.32-7.42; n = 15) had a 33% higher sulthiame concentration than those with normal pH values (n = 22; P < 0.05). Blood gas measurements, especially pH, may serve as markers of toxicity and can be used in combination with clinical data when toxicity is suspected. CONCLUSIONS: This study revealed the extensive intraindividual and interindividual pharmacokinetic variability of sulthiame, with age as a contributing factor. Sulthiame has clinically relevant interactions with clobazam. The use of TDM and pH as a biochemical marker may contribute to individualized and safe sulthiame treatment.

Incidence and prevalence of psychogenic nonepileptic seizures in a Norwegian county: A 10-year population-based study.

OBJECTIVE: This study was undertaken to measure the incidence and prevalence of active psychogenic nonepileptic seizures (PNES) in a Norwegian county. METHODS: Using the Norwegian patient registry, we identified patients in Møre and Romsdal County in Norway diagnosed with F44.5 (conversion disorder with seizures or convulsions) or R56.8 (convulsions, not elsewhere classified) in the period January 2010 to January 2020. A review of the patients' medical records and an assessment of diagnostic validity were performed. PNES were diagnosed according to the recommendations by the International League Against Epilepsy Nonepileptic Seizures Task Force. Point prevalence of PNES on January 1, 2020 and incidence rates for the period 2010-2019 were determined. RESULTS: Based on PNES within the past 5 years, we found a PNES prevalence of 23.8/100 000 (95% confidence interval [CI] = 17.9-29.6), including all levels of diagnostic certainty. For the highest level of diagnostic certainty (video-electroencephalographically confirmed), the prevalence was 10.6/100 000 (95% CI = 6.7-14.5). The highest prevalence was found in the age group 15-19 years, at 59.5/100 000 (95% CI = 22.6-96.3). The mean annual incidence rate between 2010 and 2019 was 3.1/100 000/year (95% CI = 2.4-3.7). SIGNIFICANCE: We report for the first time a population-based estimate of the prevalence of PNES. Our findings suggest that the prevalence of PNES is within the range of estimates from non-population-based data. We found a strikingly high prevalence of PNES in the 15-19-year age group.

Short-term Seizure Outcomes in Childhood Epilepsy.

BACKGROUND AND OBJECTIVES: Seizure freedom is the optimal response to antiepileptic treatment. In previous studies, it has been shown that between 61% and 71% of children with epilepsy achieve seizure freedom, whereas 7% to 20% have drug-resistant epilepsy. The definition of drug resistance has not been consistent across studies, and there is a lack of contemporary population-based data. We used data from a large nationwide child cohort to provide such information, implementing the current standard definition of drug resistance. METHODS: The study was based on the Norwegian Mother and Child Cohort Study. Potential epilepsy cases were identified through registry linkages and parental questionnaires. Medical record reviews and parental interviews were used to collect clinical information and to classify seizures, epilepsies, and etiologies. RESULTS: The cohort included 112 745 eligible children aged 3 to 13 years (median age 7 years) at end of follow-up. Of these, 600 were epilepsy cases with at least 1 year of follow-up since epilepsy onset (median follow-up time: 5.8 years). There were 178 (30%) who had developed drug-resistant epilepsy, 353 (59%) who had been seizure free for ≥1 year, and 69 (12%) with intermediate seizure outcomes. Having an identified cause of epilepsy (genetic, structural, metabolic, or infectious) was associated with unsatisfactory seizure outcome (48% drug resistance) and influenced the relative risk associated with other prognostic factors. Sociodemographic characteristics were not associated with short-term seizure outcomes. CONCLUSIONS: Drug resistance occurs in 3 out of 10 children with epilepsy, whereas 6 out of 10 become seizure free. Having an identified cause of epilepsy is associated with poor response to treatment.

Seizures, syndromes, and etiologies in childhood epilepsy: The International League Against Epilepsy 1981, 1989, and 2017 classifications used in a population-based cohort.

OBJECTIVE: The study provides updated information about the distribution of seizures, epilepsies, and etiologies of epilepsy in the general child population, and compares the old and new classification systems from the International League Against Epilepsy (ILAE). METHODS: The study platform was the Norwegian Mother and Child Cohort Study. Cases of epilepsy were identified through registry linkages and sequential parental questionnaires. Epilepsy diagnoses were validated using a standardized protocol, and seizures, epilepsies, and etiologies were classified according to the old (ILAE 1981/1989) and new (ILAE 2017) classifications. Information was collected through medical record reviews and/or parental telephone interviews. RESULTS: The study population included 112,744 children aged 3-13 years at the end of follow-up on December 31, 2012. Of these, there were 606 children with epilepsy (CWE). Distribution of seizure types varied by age of onset. Multiple seizure types were common with early onset. Focal epilepsies were the most common, occurring in 317 per 100,000 children in the study population and in 59% of CWE. Generalized epilepsies were found in 190 per 100,000 (35% of CWE). CWE with onset during the first 2 years of life had an even distribution of focal and generalized epilepsies, whereas focal epilepsies became dominant at later ages of onset. A definite cause of epilepsy had been demonstrated in 33% of CWE. The ILAE 1989 classification allowed for a broad syndrome category in 93% of CWE and a defined epileptic syndrome in 37%. With the ILAE 2017 classification, 41% of CWE had a defined epileptic syndrome and 63% had either a defined syndrome or structural-metabolic etiology. SIGNIFICANCE: The distribution of seizures and epilepsies is strongly dependent on age of onset. Despite diagnostic advances, the causes of epilepsy are still unknown in two-thirds of CWE. The ILAE 2017 classifications allow for a higher precision of diagnoses, but at the expense of leaving more epilepsies classifiable only at the mode of onset level.

Incidence and Prevalence of Childhood Epilepsy: A Nationwide Cohort Study.

BACKGROUND AND OBJECTIVES: Epilepsy affects 0.5% to 1% of children and is the most frequent chronic neurologic condition in childhood. Incidence rates appear to be declining in high-income countries. The validity of epilepsy diagnoses from different data sources varies, and contemporary population-based incidence studies are needed. METHODS: The study was based on the Norwegian Mother and Child Cohort Study. Potential epilepsy cases were identified through registry linkages and parental questionnaires. Cases were validated through medical record reviews and telephone interviews of parents. RESULTS: The study population included 112 744 children aged 3 to 13 years (mean 7.4 years) at end of registry follow-up (December 31, 2012). Of these, 896 had registry recordings and/or questionnaire reports of epilepsy. After validation, 587 (66%) met the criteria for an epilepsy diagnosis. The incidence rate of epilepsy was 144 per 100 000 person-years in the first year of life and 58 per 100 000 for ages 1 to 10 years. The cumulative incidence of epilepsy was 0.66% at age 10 years, with 0.62% having active epilepsy. The 309 children (34%) with erroneous reports of epilepsy from the registry and/or the questionnaires had mostly been evaluated for nonepileptic paroxysmal events, or they had undergone electroencephalography examinations because of other developmental or neurocognitive difficulties. CONCLUSIONS: Approximately 1 out of 150 children is diagnosed with epilepsy during the first 10 years of life, with the highest incidence rate observed during infancy. Validation of epilepsy diagnoses in administrative data and cohort studies is crucial because reported diagnoses may not meet diagnostic criteria for epilepsy.

Comorbidity and Childhood Epilepsy: A Nationwide Registry Study.

BACKGROUND AND OBJECTIVE: Children with epilepsy are at increased risk of other disorders and difficulties, preceding, cooccurring with, or after the diagnosis of epilepsy. Risk estimates vary, few studies are population-based, and few provide comprehensive assessments of comorbidities. We used nationwide registry data to describe frequencies of medical, neurologic, developmental, and psychiatric conditions occurring before and after children are diagnosed with childhood epilepsy. METHODS: Data were obtained from the Norwegian Patient Registry, which is an administrative database recording International Classification of Diseases, 10th Revision diagnoses from all government-funded specialist health services in Norway (outpatient consultations and hospitalizations). We included data from the years 2008 through 2013 for all children born in Norway between 1996 and 2013 (0-17 years of age at the end of follow-up). Children with epilepsy were compared with the general child population, adjusting for sex and age. We also compared children with complicated epilepsies (ie, epilepsies with additional neurologic and/or developmental disorders) to children with uncomplicated epilepsies. RESULTS: The study population included 1 125 161 children. There were 6635 (0.6%) children with epilepsy. Nearly 80% of children with epilepsy had ≥1 comorbid disorder. All types of disorders were more frequent in children with epilepsy, with additional medical disorders recorded in 55%, neurologic disorders in 41%, and developmental/psychiatric disorders in 43%. Children with complicated epilepsies had the highest overall levels of comorbidity, but the risk of medical and psychiatric comorbidities was also substantial among children with uncomplicated epilepsies. CONCLUSIONS: The overall frequency of comorbid disease is high in children with epilepsy, including children with presumably uncomplicated epilepsies.

Febrile seizures after 2009 influenza A (H1N1) vaccination and infection: a nationwide registry-based study.

BACKGROUND: During the 2009 influenza A (H1N1) pandemic, a monovalent pandemic strain vaccine containing the oil-in-water adjuvant AS03 (Pandemrix®) was offered to the Norwegian population. The coverage among children reached 54%. Our aim was to estimate the risk of febrile seizure in children after exposure to pandemic influenza vaccination or infection. METHODS: The study population comprised 226,889 children born 2006-2009 resident in Norway per October 1st, 2009. Febrile seizure episodes were defined by emergency hospital admissions / emergency outpatient hospital care with International Classification of Diseases, Version 10, codes R56.0 or R56.8. The self-controlled case series method was applied to estimate incidence rate ratios (IRRs) in pre-defined risk periods compared to the background period. The total observation window was ± 180 days from exposure day. Among 113,068 vaccinated children, 656 (0.6%) had at least one febrile seizure episode. RESULTS: The IRR of febrile seizures 1-3 days after vaccination was 2.00 (95% confidence interval [CI]: 1.15-3.51). In the period 4-7 days after vaccination, no increased risk was observed. Among the 8172 children diagnosed with pandemic influenza, 84 (1.0%) had at least one febrile seizure episode. The IRR of febrile seizures on the same day as a diagnosis of influenza was 116.70 (95% CI: 62.81-216.90). In the period 1-3 days after a diagnosis of influenza, a tenfold increased risk was observed (IRR 10.12, 95% CI: 3.82 - 26.82). CONCLUSIONS: In this large population-based study with precise timing of exposures and outcomes, we found a twofold increased risk of febrile seizures 1-3 days after pandemic influenza vaccination. However, we found that pandemic influenza infection was associated with a much stronger increase in risk of febrile seizures.

Differences across counties in the registered prevalence of autism, ADHD, epilepsy and cerebral palsy in Norway.

BACKGROUND: In 2012, we published an overview of the prevalence of developmental disorders and neurological diseases in children in Norway, which was unknown at the time. In this article we will compare diagnostics and treatment across counties and institutions. MATERIAL AND METHOD: The prevalence across counties of autism spectrum disorders, ADHD, epilepsy and cerebral palsy in children aged 0-12 was estimated with the aid of data from the Norwegian Patient Register for the years 2008-11. RESULTS: In the age group 6-12 years, nationwide prevalence amounted to 0.6% for autism spectrum disorders, 2.0% for ADHD, 0.9% for epilepsy and 0.3% for cerebral palsy. In total, 5.0% of all twelve-year-olds were registered with one or more of these diagnoses. The prevalence of autism spectrum disorders and ADHD varied between the counties, from 0.3% to 1.5% for autism spectrum disorders and from 1.1% to 3.5% for ADHD. For epilepsy and cerebral palsy there was little variation between the counties. Diagnostics and treatment of these four conditions are spread over 29 somatic hospitals and 102 units for child and youth psychiatry. INTERPRETATION: The variations across counties in the prevalence of autism spectrum disorders and ADHD are most likely due to variations in diagnostic practices. We ask whether it is appropriate to spread the provision of treatment across such a high number of institutions.