Publications by authors named "Jakob Christensen"

127 Publications

Exploring the prevalence and profile of epilepsy across Europe using a standard retrospective chart review: Challenges and opportunities.

Epilepsia 2021 Sep 2. Epub 2021 Sep 2.

Temple Street Children's University Hospital, Dublin, Ireland.

Objective: This study aimed to determine the prevalence of epilepsy in four European countries (Austria, Denmark, Ireland, and Romania) employing a standard methodology. The study was conducted under the auspices of ESBACE (European Study on the Burden and Care of Epilepsy).

Methods: All hospitals and general practitioners serving a region of at least 50 000 persons in each country were asked to identify patients living in the region who had a diagnosis of epilepsy or experienced a single unprovoked seizure. Medical records were accessed, where available, to complete a standardized case report form. Data were sought on seizure frequency, seizure type, investigations, etiology, comorbidities, and use of antiseizure medication. Cases were validated in each country, and the degree of certainty was graded as definite, probable, or suspect cases.

Results: From a total population of 237 757 in the four countries, 1988 (.8%) patients were identified as potential cases of epilepsy. Due to legal and ethical issues in the individual countries, medical records were available for only 1208 patients, and among these, 113 had insufficient clinical information. The remaining 1095 cases were classified as either definite (n = 706, 64.5%), probable (n = 191, 17.4%), suspect (n = 153, 14.0%), or not epilepsy (n = 45, 4.1%).

Significance: Although a precise prevalence estimate could not be generated from these data, the study found a high validity of epilepsy classification among evaluated cases (95.9%). More generally, this study highlights the significant challenges facing epidemiological research methodologies that are reliant on patient consent and retrospective chart review, largely due to the introduction of data protection legislation during the study period. Documentation of the epilepsy diagnosis was, in some cases, relatively low, indicating a need for improved guidelines for assessment, follow-up, and documentation. This study highlights the need to address the concerns and requirements of recruitment sites to engage in epidemiological research.
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http://dx.doi.org/10.1111/epi.17057DOI Listing
September 2021

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications.

Brain 2021 Aug 25. Epub 2021 Aug 25.

National Centre for Rare Epilepsy-Related Disorders, Oslo University Hospital, 0001 Oslo, Norway.

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1-3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human NaV1.6 channels and whole-cell patch-clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1-3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no (11) or unclassifiable (6) epilepsy; only three had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.
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http://dx.doi.org/10.1093/brain/awab321DOI Listing
August 2021

Psychiatric Disorders in Children and Adolescents With Psychogenic Nonepileptic Seizures.

Neurology 2021 08 24;97(5):e464-e475. Epub 2021 May 24.

From Psychiatry (A.S.H., A.-E.C., M.R.-D., R.E.N.), Aalborg University Hospital; Department of Clinical Medicine (A.S.H., R.E.N.), Aalborg University; Department of Child and Adolescent Psychiatry (C.U.R.), Research Unit, and Department of Neurology (J.C.), Aarhus University Hospital; and Department of Clinical Medicine (C.U.R., J.C.), Aarhus University, Denmark.

Objective: Knowledge regarding psychiatric disorders in children and adolescents with psychogenic nonepileptic seizures (PNES) is limited. This study outlines the spectrum and risk of psychiatric disorders in childhood-onset PNES.

Methods: We performed a nationwide matched cohort study of children and adolescents with PNES 5 to 17 years of age at the time of diagnosis between January 1, 1996, and December 31, 2014. Two matched comparison groups were included: children and adolescents with epilepsy (ES) and children and adolescents without PNES or epilepsy, called healthy controls (HC). Outcomes were prevalent psychiatric disorders before index (i.e., date of diagnosis or corresponding date for HC) and incident psychiatric disorders 2 years after index. Relative risks (RRs) were calculated and adjusted for potential confounders.

Results: We included 384 children and adolescents with validated PNES, 1,152 with ES, and 1,920 HC. Among the cases of PNES, 153 (39.8%) had prevalent psychiatric disorders and 150 (39.1%) had incident psychiatric disorders. Compared to the ES and HC groups, children and adolescents with PNES had elevated risks of both prevalent psychiatric disorders (adjusted RR 1.87, 95% confidence interval [CI] 1.59-2.21, adjusted RR 5.54, 95% CI 4.50-6.81) and incident psychiatric disorders (adjusted RR 2.33, 95% CI 1.92-2.83, adjusted RR 8.37, 95% CI 6.31-11.11). A wide spectrum of specific psychiatric disorders displayed elevated RRs.

Conclusions: Children and adolescents with PNES are at higher risk of a wide range of psychiatric disorders compared to children and adolescents with ES and HC. A careful psychiatric evaluation is warranted to optimize and individualize treatment.
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http://dx.doi.org/10.1212/WNL.0000000000012270DOI Listing
August 2021

Birth characteristics and risk of febrile seizures.

Acta Neurol Scand 2021 Jul 6;144(1):51-57. Epub 2021 Apr 6.

Department of Economics and Business Economics, National Centre for Register-Based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.

Objective: Febrile seizure is a common childhood disorder that affects 2-5% of all children, and is associated with later development of epilepsy and psychiatric disorders. This study determines how the incidence of febrile seizures correlates with birth characteristics, age, sex and brain development.

Methods: This is a cohort study of all children born Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). The Danish National Patient Register was used to identify children with febrile seizures up to 5 years of age. Follow-up ended on 31 December 2016 when all cohort members had potentially reached 5 years of age.

Results: In total, 75,593 (3.59%, 95% CI: 3.57-3.62%) were diagnosed with febrile seizures. Incidence peaked at 16.7 months of age (median: 16.7 months, interquartile range: 12.5-24.0). The 5-year cumulative incidence of febrile seizures increased with decreasing birth weight (<1500 g; 5.42% (95% CI: 4.98-5.88% vs. 3,000-4,000 g; 3.53% (95% CI: 3.50-3.56%)) and with decreasing gestational age at birth (31-32 weeks; 5.90% (95% CI: 5.40-6.44%) vs. 39-40 weeks; 3.56% (95% CI: 3.53-3.60)). Lower gestational age at birth was associated with higher age at onset of a first febrile seizure; an association that essentially disappeared when correcting for age from conception.

Conclusions: The risk of febrile seizures increased with decreasing birth weight and gestational age at birth. The association between low gestational age at birth and age at first febrile seizure suggests that onset of febrile seizures is associated with the stage of brain development.
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http://dx.doi.org/10.1111/ane.13420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178233PMC
July 2021

Social outcome and psychiatric comorbidity of generalized epilepsies - A case-control study.

Epilepsia 2021 May 18;62(5):1158-1169. Epub 2021 Mar 18.

Department of Neurology, Odense University Hospital, Odense, Denmark.

Objective: To investigate social outcome and psychiatric comorbidity of patients with idiopathic/genetic generalized epilepsies (IGEs) and its subtypes (epilepsy with generalized tonic-clonic seizures alone [EGTCS], juvenile absence epilepsy [JAE], and juvenile myoclonic epilepsy [JME]).

Methods: A cohort of 402 adult patients with IGE from the Danish island Funen was matched with 4020 randomly selected geography-, age-, and sex-matched controls via the Danish Civil Registration System. Based on register data, we compared social status measured by cohabitant status, educational attainment, income, affiliation to labor market, and psychiatric comorbidity.

Results: As compared to controls, patients with IGE had similar cohabitant status but fewer children (no children: 59.0% vs 50.9%), and lower educational level (primary school only: 46.0% vs 37.3%), employment rate (outside of workforce: 56.7% vs 46.5%), and income (low income: 32.6% vs 24.9%) (P < 0.001 for all comparisons). Having IGE was associated with higher a proportion of psychiatric comorbidity (IGE, 22.6%; controls, 13.0%) (P < 0.001). Seizure-free patients did not differ from controls; patients with persistent seizures had lower incomes and employment rates. In the IGE subgroup analyses, JME was associated with worse social status in all parameters studied (eg, 65.9% of JME patients were outside the workforce vs 44.5% of matched controls; P < 0.001), whereas no adverse social status was identified in patients with EGTCS and JAE.

Significance: Patients with IGE in general and JME in particular have poorer social status and more psychiatric comorbidity than matched population controls without epilepsy. Poor seizure control was associated with social status and may contribute to negative socioeconomic consequences associated with IGE.
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http://dx.doi.org/10.1111/epi.16870DOI Listing
May 2021

Repeated traumatic brain injury and risk of epilepsy: a Danish nationwide cohort study.

Brain 2021 04;144(3):875-884

National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus BSS, Aarhus University, Denmark.

Traumatic brain injury is associated with increased risk of epilepsy, but the importance of repeated traumatic brain injuries has not yet been established. We performed a nationwide population-based cohort study of 2 476 905 individuals born in Denmark between 1977 and 2016. We estimated hazard ratios (HRs) and the cumulative incidence of epilepsy following traumatic brain injury using Cox and competing risk regression, respectively. To estimate the cumulative incidence of epilepsy in the population without traumatic brain injury, we matched 10 controls for each subject with traumatic brain injury on year of birth, sex, and date of brain insult in the index person. In the cohort, traumatic brain injury was sustained by 167 051 subjects (71 162 females and 95 889 males), and 37 200 individuals developed epilepsy (17 905 females and 19 295 males). Compared with subjects without traumatic brain injury, the relative risk of epilepsy increased after a first traumatic brain injury [HR 2.04, 95% confidence interval (CI) 1.96-2.13] and even more after a second traumatic brain injury (HR 4.45, 95% CI 4.09-4.84). The risk increased with the severity of the first and the second traumatic brain injury, most notably after severe traumatic brain injuries. Females were more likely than males to develop epilepsy after mild traumatic brain injury (HR 2.13, 95% CI 2.00-2.28 versus HR 1.77, 95% CI 1.66-1.88; P < 0.0001); in contrast, males were more likely than females to develop epilepsy after severe traumatic brain injury (HR 5.00, 95% CI 4.31-5.80 versus 3.21, 95% CI 2.56-4.03; P = 0.0012). The risk remained increased for decades after the traumatic brain injury. This knowledge may inform efforts to prevent the development of post-traumatic epilepsy.
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http://dx.doi.org/10.1093/brain/awaa448DOI Listing
April 2021

Epilepsy risk in offspring of affected parents; a cohort study of the "maternal effect" in epilepsy.

Ann Clin Transl Neurol 2021 01 29;8(1):153-162. Epub 2020 Nov 29.

National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus BSS, Aarhus University, Aarhus, Denmark.

Objective: To assess whether the risk of epilepsy is higher in offspring of mothers with epilepsy than in offspring of fathers with epilepsy.

Methods: In a prospective population-based register study, we considered all singletons born in Denmark between 1981 and 2016 (N = 1,754,742). From the Danish National Patient Register since 1977, we identified epilepsy diagnoses in all study participants and their family members. Cox regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CI), adjusted for relevant confounders.

Results: We included 1,754,742 individuals contributing > 30 million person-years of follow-up. The incidence rate of epilepsy in offspring of unaffected parents was 78.8 (95% CI: 77.8-79.8) per 100,000 person-years, while the corresponding rate in offspring with an affected father was 172 per 100,000 person-years (95% CI: 156-187) and in offspring with an affected mother was 260 per 100,000 person-years (95% CI: 243-277). Having an affected mother was associated with a 1.45-fold (95% CI: 1.30-1.63) higher risk of epilepsy in the offspring, compared to having an affected father. This maternal effect was found both in male (HR = 1.39, 95% CI: 1.19-1.62) and female offspring (HR = 1.53, 95% CI: 1.30-1.80), and across various ages at onset in the offspring. The maternal effect was also found in familial epilepsies (i.e. where the affected parent had an affected sibling; HR = 1.50, 95% CI: 1.04-2.16).

Interpretation: We found a clear maternal effect on offspring risk of epilepsy in this nationwide cohort study.
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http://dx.doi.org/10.1002/acn3.51258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818075PMC
January 2021

Systemic lupus erythematosus during pregnancy is not associated with school performance in offspring - A Danish population-based study.

Lupus 2021 Feb 16;30(2):228-237. Epub 2020 Nov 16.

Department of Public Health, Aarhus University, Aarhus, Denmark.

Introduction: Systemic lupus erythematosus (SLE) in pregnancy is considered a risk factor for a range of adverse outcomes in the offspring. Studies have indicated increased risk of neurodevelopmental disorders such as autism spectrum disorders, dyslexia and ADHD. However, the overall long-term cognitive development of children born to women with SLE has scarcely been examined. In this study, we compare test scores from the Danish National School Tests of children born to women SLE with children of the background population.

Methods: We included all singleton children born in Denmark between 1995 and 2008, who were listed in the Danish National School Test Register (n=738,862). Children born to women with SLE were identified through linkage of national healthcare registers. We assessed the children's performance in the national school tests between 2nd and 8th grade, in reading and mathematics. Information on the mothers' redeemed prescriptions in pregnancy was included in stratified analyses. Differences of mean test scores were derived from linear regressions and compared according to maternal SLE status, and predefined categories of medication exposures.

Results: In total, 312 (0.04%) children were born to mothers with SLE. There were no differences in performance in neither reading nor mathematics tests between those born to mothers with SLE and children born to mothers without SLE. When stratifying on medication exposures among children whose mothers had SLE, there was a non-significant tendency towards poorer results among those exposed to hydroxychloroquine and/or immunosuppressants (n=31), compared to those not exposed to these medications. A similar tendency was observed among children whose mothers received hydroxychloroquine for non-SLE reasons (n=1,235).

Conclusion: This study indicates no major harmful effect on the child's neurocognitive development from exposure to SLE, hydroxychloroquine and/or immunosuppressants, as measured by school performance.
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http://dx.doi.org/10.1177/0961203320973076DOI Listing
February 2021

Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Intellectual Disability and Delayed Childhood Milestones.

JAMA Netw Open 2020 11 2;3(11):e2025570. Epub 2020 Nov 2.

Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.

Importance: There is concern about neurodevelopmental outcomes associated with prenatal exposure to valproate and other antiepileptic drugs (AEDs) among children of mothers with or without epilepsy.

Objective: To study the risk of intellectual disability and delayed development in childhood milestones among children of women who used valproate or other AEDs during pregnancy.

Design, Setting, And Participants: This population-based cohort study analyzed information on use of AEDs from the Danish National Prescription Registry and register diagnoses from the Danish Psychiatric Central Research Register and Danish National Patient Registry. The study included all live-born singletons in Denmark from January 1, 1997, to December 31, 2011. Data were analyzed in April 2020.

Exposures: Prenatal exposure to maternal valproate and other AEDs.

Main Outcomes And Measures: The main measures were adjusted Cox regression estimates of hazard ratios (aHRs) for intellectual disability and a combined outcome of intellectual disability with delayed childhood milestones.

Results: A total of 913 302 children (468 708 [51.3%] boys; mean [SD] age, 10.3 [4.4] years and median [interquartile range] age, 10.1 [6.5-14.0] years at final follow-up) were identified and contributed more than 10.2 million person-years of observation, including 580 children exposed to valproate (302 [51.3%] boys). At end of follow-up, 6958 children (0.8%) were identified as having intellectual disability and 14 967 children (1.6%) were identified as having intellectual disability with delayed childhood milestones. Compared with offspring not exposed to valproate prenatally, offspring of women who used valproate during pregnancy had increased risk of intellectual disability (aHR, 4.48; 95% CI, 2.97-6.76) and intellectual disability with delayed childhood milestones (aHR, 6.07; 95% CI, 4.67-7.89). Among mothers with epilepsy, offspring exposed prenatally to valproate had increased risk of intellectual disability (aHR, 1.95; 95% CI, 1.21-3.14) and intellectual disability with delayed childhood milestones (aHR, 3.07; 95% CI, 2.24-4.20) compared with offspring without prenatal exposure. Compared with offspring without prenatal exposure to AEDs, increased risk of intellectual disability was identified in children with prenatal exposure to maternal monotherapy use of carbamazepine (aHR, 3.84; 95% CI, 2.32-6.38), clonazepam (aHR, 2.41; 95% CI, 1.09-5.35), and oxcarbazepine (aHR, 3.70; 95% CI, 2.11-6.51) but not lamotrigine (aHR, 1.33; 95% CI, 0.71-2.48).

Conclusions And Relevance: These findings suggest that prenatal exposure to valproate was associated with increased risk of intellectual disability and delayed childhood milestones. Statistically significant associations were also found for prenatal exposure to other AEDs. These findings suggest that women of childbearing potential may need to be counseled on use of AEDs.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.25570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656282PMC
November 2020

Rivaroxaban Plasma Levels and Levetiracetam.

Ann Intern Med 2020 11;173(9):771

Aarhus University Hospital, Aarhus, Denmark (M.H., J.C., L.P.N.).

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http://dx.doi.org/10.7326/L20-1064DOI Listing
November 2020

Triphasic Waves Are Generated by Widespread Bilateral Cortical Networks.

J Clin Neurophysiol 2021 Sep;38(5):415-419

Departments of Clinical Neurophysiology and.

Purpose: Triphasic waves (TWs) have been observed in the EEG recorded in patients with various types of encephalopathy, yet their genesis and significance is still debated. The aim of this study was to elucidate the localization of the cortical generators of TWs using EEG source imaging.

Methods: In 20 consecutive patients who had encephalopathy with TWs, EEG source imaging of the first negative and the positive phases of the TW was performed. Three different approaches were used: equivalent current dipoles, a distributed source model, and a recently described spatial filtration method for visualizing EEG in source space.

Results: Equivalent current dipole models failed to provide valid solutions. The distributed source model and the spatial filtration method suggested that TWs were generated by large, bilateral cortical networks, invariably involving the anterior frontal and the temporo-polar areas.

Conclusions: Source imaging localized TWs to anterior frontal and temporo-frontal structures. Involvement of these regions is consistent with the typical pathophysiological changes of altered consciousness and cognitive changes observed in patients with TW encephalopathy.
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http://dx.doi.org/10.1097/WNP.0000000000000770DOI Listing
September 2021

Stigma surrounding functional seizures.

Pediatr Res 2020 11 28;88(5):684-685. Epub 2020 Jul 28.

Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

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http://dx.doi.org/10.1038/s41390-020-1095-zDOI Listing
November 2020

Effectiveness and tolerability of adjunctive brivaracetam in patients with focal seizures: Second interim analysis of 6-month data from a prospective observational study in Europe.

Epilepsy Res 2020 09 9;165:106329. Epub 2020 Apr 9.

School of Medicine, University of Glasgow, Glasgow, G12 8QQ, United Kingdom. Electronic address:

Brivaracetam (BRV) is indicated for adjunctive treatment of focal (partial-onset) seizures with or without secondary generalisation in patients 4 years of age and older in the European Union (EU). An ongoing 12-month, prospective, non-interventional post-marketing study (EP0077; NCT02687711) is collecting real-world information on patients receiving treatment with adjunctive BRV in Europe. In this study, BRV is prescribed according to routine clinical practice and the EU Summary of Product Characteristics. This second interim analysis assessed effectiveness, tolerability and health-related quality of life outcomes for up to 6 months of treatment. At the cut-off date (13 April 2018), 266 patients from five countries had attended Visit 1, 24.1 % (64/266) had completed the study, 37.6 % (100/266) were ongoing, and 38.3 % (102/266) had discontinued. In total, 261 patients had at least one dose of BRV and were included in the analyses. Patients had a mean time since epilepsy diagnosis of 23.2 years, a mean of eight lifetime AEDs (sum of AEDs discontinued prior to study entry and concomitant at study entry), and a median of five focal seizures per 28 days during the 3-month retrospective Baseline. 66.3 % of patients initiated BRV at a dose within the recommended starting range (50-100 mg/day) and 87.1 % of patients received BRV modal doses within the recommended dose range (50-200 mg/day) during the study. Retention rates were 79.1 % (N = 239) at 3 months and 62.1 % (N = 211) at 6 months. The 50 % responder rates for focal seizures were 46.8 % (N = 139) at 3 months and 53.6 % (N = 97) at 6 months. The proportions of patients who were seizure-free were 10.7 % (21/196) and 7.5 % (15/199) at 3 and 6 months of treatment, respectively. Median percent reductions in focal seizure frequency per 28 days from Baseline to 3 and 6 months were 34.6 % (N = 139) and 53.3 % (N = 97), respectively. Overall, 44.2 % of patients had an improvement and 15.4 % had a worsening in Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 total score from Baseline to 6 months (N = 52). At least one treatment-emergent adverse event (TEAE) was reported in 51.0 % (133/261) of patients, and 34.5 % (90/261) of patients had drug-related TEAEs. The most common drug-related TEAEs (≥5% of patients) were drug ineffective (7.7 %), seizure (6.5 %), and fatigue (6.1 %). In this 6-month interim analysis, BRV showed effectiveness when used in clinical practice in five European countries. BRV was well tolerated, and no new safety signals were observed.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106329DOI Listing
September 2020

Methanol-Assisted Autocatalysis in Catalytic Methanol Synthesis.

Angew Chem Int Ed Engl 2020 Oct 13;59(41):18189-18193. Epub 2020 Aug 13.

Department of Chemical and Biochemical Engineering, Technical University of Denmark, Søltofts Plads B229, 2800 Kgs., Lyngby, Denmark.

Catalytic methanol synthesis is one of the major processes in the chemical industry and may grow in importance, as methanol produced from CO and sustainably derived H are envisioned to play an important role as energy carriers in a future low-CO -emission society. However, despite the widespread use, the reaction mechanism and the nature of the active sites are not fully understood. Here we report that methanol synthesis at commercially applied conditions using the industrial Cu/ZnO/Al O catalyst is dominated by a methanol-assisted autocatalytic reaction mechanism. We propose that the presence of methanol enables the hydrogenation of surface formate via methyl formate. Autocatalytic acceleration of the reaction is also observed for Cu supported on SiO although with low absolute activity, but not for Cu/Al O catalysts. The results illustrate an important example of autocatalysis in heterogeneous catalysis and pave the way for further understanding, improvements, and process optimization of industrial methanol synthesis.
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http://dx.doi.org/10.1002/anie.202006921DOI Listing
October 2020

Cumulative incidence and relative risk of sleep problems among children and adolescents with newly diagnosed neurodevelopmental disorders: A nationwide register-based study.

J Sleep Res 2021 06 21;30(3):e13122. Epub 2020 Jun 21.

National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.

We estimated the absolute and relative risk of sleep problems in children and adolescents with newly diagnosed neurodevelopmental disorders. This was a population-based cohort study of individuals born in Denmark in 1993-2014 and followed in nationwide registers in 2011-2016. We estimated the 5-year cumulative incidence of sleep problems in incident cases of attention-deficit/hyperactivity disorder (ADHD; n = 12,844), autism spectrum disorder (ASD; n = 8,073), oppositional defiant disorder/conduct disorder (ODD/CD; n = 2,234) and epilepsy (n = 3,709). Hazard ratios (HRs) for sleep problems were estimated by Cox regression. The 5-year risk of sleep problems was highest in ADHD (29.2%; 95% CI, 28.4-30.1), ASD (24.2%; 95% CI, 23.1-25.3) and ODD/CD (27.1% 95% CI, 25.0%-29.2%) and lowest in epilepsy (11.3%; 95% CI, 10.2%-12.6%). For ADHD and ASD, sleep problems were more common in females than in males. Furthermore, sleep problems were predicted by high parental socioeconomic status and varied with the geographical region of residence, suggesting that different clinical practices exist across Denmark and that sleep problems may be more likely to go undetected in families of lower socioeconomic position. Compared with individuals without these disorders, the likelihood of sleep problems was increased in individuals with ADHD (HR, 33.81; 95% CI, 32.78-34.87), ASD (HR, 16.77; 95% CI, 16.15-17.41), ODD/CD (HR, 14.73; 95% CI, 13.88-15.64) and epilepsy (HR, 6.01; 95% CI, 5.67-6.37). After mutual adjustment for comorbidity, HRs were attenuated, especially in ASD, ODD/CD and epilepsy when adjusted for ADHD, suggesting that the increased risk of sleep problems in individuals with ASD, ODD/CD and epilepsy is driven largely by comorbid ADHD.
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http://dx.doi.org/10.1111/jsr.13122DOI Listing
June 2021

Incidence rates and characteristics of pediatric onset psychogenic nonepileptic seizures.

Pediatr Res 2020 11 11;88(5):796-803. Epub 2020 May 11.

Unit for Psychiatric Research, Psychiatry, Aalborg University Hospital, Aalborg, Denmark.

Background: Pediatric onset psychogenic nonepileptic seizures (PNES) is a highly disabling disorder and potentially misdiagnosed as epilepsy. Still, knowledge regarding PNES in children and adolescents is limited and data on both incidence and characteristics are scarce. This study investigated the incidence rate (IR) and clinical characteristics of pediatric onset PNES, including possible differences when having comorbid epilepsy.

Methods: A population-based study of children and adolescents aged 5-17 years with an incident diagnosis of PNES in the Danish healthcare registries between 1996 and 2014. In total, 386 children and adolescents were included after assessment of diagnostic validity using medical record data.

Results: The IR increased during the study period with the maximum IR observed in 2014 (7.4 per 100,000 person-years). A history of both neurologic and psychiatric problems as well as negative life events was identified. Comorbid epilepsy was confirmed for 55 cases (14.2%) and was associated with intellectual disabilities, school support and prolonged delay in PNES diagnosis.

Conclusions: PNES are increasingly diagnosed in children and adolescents, and the clinical profile of both neurologic and psychiatric health problems underscores the need for collaborative pediatric and mental healthcare. These findings provide important information for future healthcare planning in this area.

Impact: This nationwide study is the first to report population-based incidence rates of pediatric onset PNES documenting markedly increasing incidence rates between 1996 and 2014. A history of both neurologic and psychiatric problems as well as negative life events was identified for pediatric onset PNES. Comorbid epileptic seizures were associated with intellectual disabilities, school support and prolonged delay in PNES diagnosis. The clinical profile of both neurologic and psychiatric health problems underscores the need for collaborative pediatric and mental healthcare. The increasing number of children and adolescents diagnosed with PNES is important information for future healthcare planning in this area.
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http://dx.doi.org/10.1038/s41390-020-0945-zDOI Listing
November 2020

Seizure detection using heart rate variability: A prospective validation study.

Epilepsia 2020 11 7;61 Suppl 1:S41-S46. Epub 2020 May 7.

Department of Neurophysiology, Aarhus University Hospital, Aarhus, Denmark.

Although several validated seizure detection algorithms are available for convulsive seizures, detection of nonconvulsive seizures remains challenging. In this phase 2 study, we have validated a predefined seizure detection algorithm based on heart rate variability (HRV) using patient-specific cutoff values. The validation data set was independent from the previously published data set. Electrocardiography (ECG) was recorded using a wearable device (ePatch) in prospectively recruited patients. The diagnostic gold standard was inferred from video-EEG monitoring. Because HRV-based seizure detection is suitable only for patients with marked ictal autonomic changes, we defined responders as the patients who had a>50 beats/min ictal change in heart rate. Eleven of the 19 included patients with seizures (57.9%) fulfilled this criterion. In this group, the algorithm detected 20 of the 23 seizures (sensitivity: 87.0%). The algorithm detected all but one of the 10 recorded convulsive seizures and all of the 8 focal impaired awareness seizures, and it missed 2 of the 4 focal aware seizures. The median sensitivity per patient was 100% (in nine patients all seizures were detected). The false alarm rate was 0.9/24 h (0.22/night). Our results suggest that HRV-based seizure detection has high performance in patients with marked autonomic changes.
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http://dx.doi.org/10.1111/epi.16511DOI Listing
November 2020

Association of Rheumatoid Arthritis in Pregnancy With School Performance of Offspring: A Danish Nationwide Register-Based Study.

Arthritis Care Res (Hoboken) 2021 07;73(7):975-982

Aarhus University, Aarhus, Denmark.

Objective: To examine the overall cognitive development of children exposed to maternal rheumatoid arthritis (RA) in utero by comparing their school test scores to those of their peers.

Methods: Children born in Denmark during 1995-2008 and listed in the National School Test Register were included (n = 738,862). Children exposed to maternal RA were identified through linkage of national registers. In separate analyses, exposure was subdivided according to maternal serostatus. Preclinical maternal RA was included as a separate exposure. The Danish national school tests are mandatory standardized tests. Results from all reading tests (grades 2, 4, 6, and 8) and mathematics tests (grades 3 and 6) from 2010-2017 were included. Test scores were compared according to maternal RA exposure for each test separately using linear regressions.

Results: We identified 934 children exposed to maternal RA in utero. There were no differences in reading test scores between maternal RA exposed and unexposed children. RA exposed children scored poorer in both mathematics tests (adjusted differences of mean score -0.14 SD (95% confidence interval [95% CI] -0.23, -0.06) and -0.16 SD (95% CI -0.26, -0.07). There was no appreciable difference between children by maternal RA serostatus. Children exposed to preclinical RA (n = 589) showed the same pattern of performance as children exposed to RA.

Conclusion: RA-exposed children scored slightly poorer in mathematics tests but performed as well as their unexposed peers in the reading tests. The results do not suggest that RA in pregnancy has a major impact on offspring school performance.
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http://dx.doi.org/10.1002/acr.24223DOI Listing
July 2021

Limited Clinical Application and Concerns of Bias in Long-term Risk of Epilepsy, Psychiatric Disorders, and Mortality Following Febrile Seizures-Reply.

JAMA Pediatr 2020 07;174(7):730-732

National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark.

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http://dx.doi.org/10.1001/jamapediatrics.2020.0046DOI Listing
July 2020

Accidental deaths in young people with epilepsy and psychiatric comorbidity-A Danish nationwide cohort study.

Epilepsia 2020 03 18;61(3):479-488. Epub 2020 Feb 18.

Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.

Objective: The objective of this study was to investigate the accident-related mortality among people younger than 55 years of age with epilepsy compared with the general population and to study how psychiatric comorbidity influences this risk.

Methods: This is a population-based cohort study of individuals born in Denmark between 1960 and 2015 (n = 3, 665 616). Persons diagnosed with epilepsy and psychiatric disorders were identified in the Danish National Patient Register and the Danish Central Psychiatric Central Register. We estimated the hazard ratio (HR) with 95% confidence intervals (CIs) of accidental death in people with epilepsy compared with persons without epilepsy.

Results: We identified 61 330 persons (1.7%) diagnosed with epilepsy. Median age at end of follow-up was 27.8 years. In people with epilepsy, 5253 died during follow-up, 480 (9%) of whom died from accidents. Among people without epilepsy, 52 588 died during follow-up, of whom 1280 (2.4%) died from accidents. People with epilepsy had a 3.7-fold (95% CI 3.4-4.1) increased risk of accidental death compared with persons without epilepsy. When we adjusted for psychiatric disorders, the risk remained significantly elevated in people with epilepsy compared to people without epilepsy (adjusted HR [aHR] 2.44, 95% CI 2.22-2.69). When stratifying the analyses on epilepsy and psychiatric disorders, people with epilepsy and psychiatric disorders had an aHR of 4.95 (95% CI 3.82-6.41) when compared with persons without epilepsy and psychiatric disorders.

Significance: The risk of accidental death was increased in people with epilepsy and was particularly high among people with epilepsy with psychiatric comorbidity. The findings highlight the need for awareness and prevention strategies in people with epilepsy, especially in people with comorbid psychiatric disorders.
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http://dx.doi.org/10.1111/epi.16453DOI Listing
March 2020

Risk of febrile seizures among children conceived following fertility treatment: A cohort study.

Paediatr Perinat Epidemiol 2020 03 6;34(2):114-121. Epub 2020 Feb 6.

Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.

Background: Studies have shown that fertility treatment in mothers is associated with neurological problems in children. However, knowledge about any association between maternal use of fertility treatment and febrile seizures in children is lacking.

Objective: To determine whether maternal use of fertility treatment is associated with febrile seizures in children.

Methods: All liveborn children in Denmark during 1996-2012 (n = 1 065 901) were linked with the Danish Infertility Cohort and the Danish national registers and were followed from one year of age until the first episode of a febrile seizure, death, emigration, loss to follow-up, or end of follow-up (December 2015). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders.

Results: Approximately 16% children (n = 172 140) were conceived by infertile women, and approximately 3% (n = 34 082) were diagnosed with febrile seizures during follow-up. Compared with children conceived by fertile women, children conceived following any fertility treatment (HR 1.11, 95% CI 1.06, 1.16), following specific fertility treatment, for example IVF (HR 1.15, 95% CI 1.05, 1.25), ICSI (HR 1.20, 95% CI 1.10, 1.32), and following fertility drugs (HR 1.06, 95% CI 1.00, 1.11) had slight increase in risk of febrile seizures, after adjusting for calendar year of birth, parental age, education, parity status, and maternal smoking during pregnancy. The associations were unchanged when children conceived naturally by infertile women were used as the reference group.

Conclusions: Children conceived following fertility treatment had slightly increased relative risk for febrile seizures.
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http://dx.doi.org/10.1111/ppe.12653DOI Listing
March 2020

Sociodemographic, personal, and disease-related determinants of referral to patient-reported outcome-based follow-up of remote outpatients: a prospective cohort study.

Qual Life Res 2020 May 3;29(5):1335-1347. Epub 2020 Jan 3.

AmbuFlex/WestChronic, Occupational Medicine, University Research Clinic, Aarhus University, Gl. Landevej 61, 7400, Herning, Denmark.

Purpose: We examined the association between sociodemographic, personal, and disease-related determinants and referral to a new model of health care that uses patient-reported outcomes (PRO) measures for remote outpatient follow-up (PRO-based follow-up).

Methods: We conducted a prospective cohort study among outpatients with epilepsy at the Department of Neurology at Aarhus University Hospital, Denmark. Included were all persons aged ≥ 15 years visiting the department for the first time during the period from May 2016 to May 2018. Patients received a questionnaire containing questions about health literacy, self-efficacy, patient activation, well-being, and general health. We also collected data regarding sociodemographic status, labour market affiliation, and co-morbidity from nationwide registers. Associations were analysed as time-to-event using the pseudo-value approach. Missing data were handled using multiple imputations.

Results: A total of 802 eligible patients were included in the register-based analyses and 411 patients (51%) responded to the questionnaire. The results based on data from registers indicated that patients were less likely to be referred to PRO-based follow-up if they lived alone, had low education or household income, received temporary or permanent social benefits, or if they had a psychiatric diagnosis. The results based on data from the questionnaire indicated that patients were less likely to be referred to PRO-based follow-up if they reported low levels of health literacy, self-efficacy, patient activation, well-being, or general health.

Conclusion: Both self-reported and register-based analyses indicated that socioeconomically advantaged patients were referred more often to PRO-based follow-up than socioeconomically disadvantaged patients.
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http://dx.doi.org/10.1007/s11136-019-02407-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190685PMC
May 2020

[Diagnosis, monitoring and treatment of tuberous sclerosis complex].

Ugeskr Laeger 2019 Nov;181(45)

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.
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November 2019

[Diagnosis, monitoring and treatment of tuberous sclerosis complex].

Ugeskr Laeger 2019 Nov;181(45)

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.
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November 2019

Trend of antidepressants before, during, and after pregnancy across two decades-A population-based study.

Brain Behav 2019 11 15;9(11):e01441. Epub 2019 Oct 15.

Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.

Introduction: Factors that influence antidepressant (AD) prescription and use during pregnancy are multiple including, in particular, the balance between the potential risk of untreated depression and the potential risk of AD treatment. Surveillance of temporal trends of AD use might identify areas requiring further research. We studied the use of ADs before, during, and after pregnancy using national data across two decades in Denmark.

Methods: We included 1,232,233 pregnancies leading to live birth in Denmark between 1 January 1997 and 31 December 2016. Information on redemption of AD prescriptions was obtained from the Danish National Prescription Register.

Results: We identified 29,504 (2.4%) pregnancies having at least one AD prescription (96,232 AD prescriptions) during pregnancy. The majority redeemed more than one prescription (69.7%) often for a single kind of AD (83.5%), and in 94% of the AD-exposed pregnancies, the estimated duration of treatment was 1 month or longer. Prescription of ADs during pregnancy increased steadily from 0.4% in 1997 to 4.6% in 2011, but decreased thereafter to 3.1% in 2016. The proportion of pregnancies with ADs in 2011 was 6.05-fold higher than that in 1997. The temporal trends in AD prescription in the years before and after pregnancy were similar to the trend during pregnancy. The decreasing use of ADs during pregnancy after 2011 was mainly driven by a decrease in the use of selective serotonin reuptake inhibitors (SSRIs), especially citalopram, the main type of SSRIs used in Denmark.

Conclusion: Prescription of ADs during pregnancy in Denmark increased steadily from 1997 to 2011 but decreased sharply thereafter. More research is needed to show whether the same trend exists in other populations, like women of reproductive age, men of reproductive age, and old people, and other countries. We also need to find explanation for the decreasing trend in recent years and potential risk for untreated depression.
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http://dx.doi.org/10.1002/brb3.1441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851806PMC
November 2019

Evaluation of Long-term Risk of Epilepsy, Psychiatric Disorders, and Mortality Among Children With Recurrent Febrile Seizures: A National Cohort Study in Denmark.

JAMA Pediatr 2019 12;173(12):1164-1170

National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark.

Importance: Febrile seizures occur in 2% to 5% of children between the ages of 3 months and 5 years. Many affected children experience recurrent febrile seizures. However, little is known about the association between recurrent febrile seizures and subsequent prognosis.

Objective: To estimate the risk of recurrent febrile seizures and whether there is an association over long-term follow-up between recurrent febrile seizures and epilepsy, psychiatric disorders, and death in a large, nationwide, population-based cohort in Denmark.

Design, Setting, And Participants: This population-based cohort study evaluated data from all singleton children born in Denmark between January 1, 1977, and December 31, 2011, who were identified through the Danish Civil Registration System. Children born in Denmark who were alive and residing in Denmark at age 3 months were included (N = 2 103 232). The study was conducted from September 1, 2017, to June 1, 2019.

Exposures: Hospital contacts with children who developed febrile seizures between age 3 months and 5 years.

Main Outcomes And Measures: Children diagnosed with epilepsy were identified in the Danish National Patient Register and children diagnosed with psychiatric disorders were identified in the Psychiatric Central Research Register. Competing risk regression and Cox proportional hazards regression were used to estimate the cumulative and relative risk of febrile seizures, recurrent febrile seizures, epilepsy, psychiatric disorders, and death.

Results: Of the 2 103 232 children (1 024 049 [48.7%] girls) in the study population, a total of 75 593 children (3.6%) were diagnosed with a first febrile seizure between 1977 and 2016. Febrile seizures were more common in boys (3.9%; 95% CI, 3.9%-4.0%) than in girls (3.3%; 95% CI, 3.2%-3.3%), corresponding to a 21% relative risk difference (hazard ratio, 1.21; 95% CI, 1.19-1.22). However, the risks of recurrent febrile seizures, epilepsy, psychiatric disorders, and death were similar in boys and girls. The risk of (recurrent) febrile seizures increased with the number of febrile seizures: 3.6% at birth, 22.7% (95% CI, 22.4%-23.0%) after the first febrile seizure, 35.6% (95% CI, (34.9%-36.3%) after the second febrile seizure, and 43.5% (95% CI, (42.3%-44.7%) after the third febrile seizure. The risk of epilepsy increased progressively with the number of hospital admissions with febrile seizures. The 30-year cumulative risk of epilepsy was 2.2% (95% CI, (2.1%-2.2%) at birth compared with 15.8% (95% CI, 14.6%-16.9%) after the third febrile seizure, while the corresponding estimates for risk of psychiatric disorders were 17.2% (95% CI, 17.2%-17.3%) at birth and 29.1% (95% CI, 27.2%-31.0%) after the third febrile seizure. Mortality was increased among children with recurrent febrile seizures (1.0%; 95% CI, 0.9%-1.0% at birth vs 1.9%; 95% CI, 1.4%-2.7% after the third febrile seizure), although this risk was associated primarily with children who later developed epilepsy.

Conclusions And Relevance: A history of recurrent febrile seizures appears to be associated with a risk of epilepsy and psychiatric disorders, but increased mortality was found only in individuals who later developed epilepsy.
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http://dx.doi.org/10.1001/jamapediatrics.2019.3343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784760PMC
December 2019

Enhancement of cranial nerves, conus medullaris, and nerve roots in POLG mitochondrial disease.

Neurol Genet 2019 Oct 6;5(5):e360. Epub 2019 Sep 6.

Department of Neurology (M.B., J.C.), Aarhus University Hospital; Centre for Rare Diseases (M.B.), Department of Pediatrics, Aarhus University Hospital; Department of Radiology (Y.Y.), Aalborg University Hospital; and Danish Epilepsy Centre (A.B.), Dianalund, Denmark.

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http://dx.doi.org/10.1212/NXG.0000000000000360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745717PMC
October 2019

Seizure detection based on heart rate variability using a wearable electrocardiography device.

Epilepsia 2019 10 20;60(10):2105-2113. Epub 2019 Sep 20.

Department of Neurophysiology, Aarhus University Hospital, Aarhus, Denmark.

Objective: To assess the feasibility and accuracy of seizure detection based on heart rate variability (HRV) using a wearable electrocardiography (ECG) device. Noninvasive devices for detection of convulsive seizures (generalized tonic-clonic and focal to bilateral tonic-clonic seizures) have been validated in phase 2 and 3 studies. However, detection of nonconvulsive seizures still needs further research, since currently available methods have either low sensitivity or an extremely high false alarm rate (FAR).

Methods: In this phase 2 study, we prospectively recruited patients admitted to long-term video-EEG monitoring (LTM). ECG was recorded using a dedicated wearable device. Seizures were automatically detected using HRV parameters computed off-line, blinded to all other data. We compared the performance of 26 automated algorithms with the seizure time-points marked by experts who reviewed the LTM recording. Patients were classified as responders if >66% of their seizures were detected.

Results: We recruited 100 consecutive patients and analyzed 126 seizures (108 nonconvulsive and 18 convulsive) from 43 patients who had seizures during monitoring. The best-performing HRV algorithm combined a measure of sympathetic activity with a measure of how quickly HR changes occurred. The algorithm identified 53.5% of the patients with seizures as responders. Among responders, detection sensitivity was 93.1% (95% CI: 86.6%-99.6%) for all seizures and 90.5% (95% CI: 77.4%-97.3%) for nonconvulsive seizures. FAR was 1.0/24 h (0.11/night). Median seizure detection latency was 30 s. Typically, patients with prominent autonomic nervous system changes were responders: An ictal change of >50 heartbeats per minute predicted who would be responder with a positive predictive value of 87% and a negative predictive value of 90%.

Significance: The automated HRV algorithm, using ECG recorded with a wearable device, has high sensitivity for detecting seizures, including the nonconvulsive ones. FAR was low during the night. This approach is feasible in patients with prominent ictal autonomic changes.
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http://dx.doi.org/10.1111/epi.16343DOI Listing
October 2019

Patient-initiated versus fixed-interval patient-reported outcome-based follow-up in outpatients with epilepsy: a pragmatic randomized controlled trial.

J Patient Rep Outcomes 2019 Sep 13;3(1):61. Epub 2019 Sep 13.

AmbuFlex/WestChronic, Occupational Medicine, University Research Clinic, Aarhus University, Gl. Landevej 61, DK-7400, Herning, Denmark.

Background: The use of patient-reported outcome (PRO) could potentially contribute to the reorganization of the health care system. AmbuFlex is a PRO system used in remote patient monitoring, in which questionnaires are sent to patients at fixed intervals. The PRO data are used by clinicians to decide whether patients need clinical attention. Better self-management and cost-saving follow-up activities may be achieved by letting patients initiate need of contact. We evaluated the effects of patient-initiated PRO-based outpatient follow-up on health care resource utilization, quality of care, and the patient perspective.

Methods: We conducted a parallel two-arm pragmatic randomized controlled trial at the Department of Neurology, Aarhus University Hospital, Denmark. Outpatients with epilepsy (≥ 15 years old), attending fixed-interval PRO-based follow-up with web-based questionnaires, were randomly assigned in a ratio of 0.55:0.45 to either 1) patient-initiated PRO-based follow-up (open access telePRO) or 2) fixed-interval PRO-based follow-up (standard telePRO). The primary outcome was the number of outpatient hospital contacts related to epilepsy retrieved from a regional registry. Hospitals admissions and emergency room visits were also assessed. Secondary self-reported outcomes including general health, well-being, health literacy, self-efficacy, number of seizures, side effects, confidence, safety, and satisfaction were retrieved from questionnaires. Data were analyzed by the intention-to-treat and per-protocol approaches.

Results: Between January 2016 and July 2016, 593 patients were randomized to either open access telePRO (n = 346) or standard telePRO (n = 247). At 18 months, no statistically significant differences were found between the arms regarding number of telephone consultations or outpatient visits. Patients in the open access arm had a slightly lower, statistically significant number of emergency room visits than patients in the standard arm. Self-reported mental well-being in the open access arm was slightly, statistically significantly lower than in the standard arm. Other secondary outcomes did not differ statistically significantly between arms.

Conclusion: This study did not find, as hypothesized, less use of health care resources or improved patient self-management or satisfaction in the patient-initiated PRO-based initiative compared to fixed-interval PRO-based follow-up. Patient-initiated PRO-based follow-up may be used as an alternative to fixed-interval PRO-based follow-up in patients who prefer this approach, but there is insufficient evidence for recommending a system-wide shift to patient-initiated PRO-based follow-up.

Trial Registration: Registered 4 February 2016 with ClinicalTrials.gov: NCT02673580 .
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http://dx.doi.org/10.1186/s41687-019-0151-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744536PMC
September 2019

Selective serotonin reuptake inhibitors and risk of epilepsy after traumatic brain injury - A population based cohort study.

PLoS One 2019 19;14(7):e0219137. Epub 2019 Jul 19.

Research Unit for General Practice and Section for General Medical Practice, Department of Public Health, Aarhus University, Aarhus, Denmark.

Objective: Traumatic brain injury (TBI) is common and associated with a marked increased risk of developing epilepsy. Animal studies indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the risk of epilepsy after TBI. The aim of this study was to investigate whether use of SSRIs modifies the risk of epilepsy after TBI.

Methods: This was a cohort study of 205,715 persons, who suffered a TBI in Denmark from 1996 to 2013. For each person with TBI, we matched 10 reference persons (N = 2,057,150) who were alive on the day of TBI and who had the same age and gender but had no history of TBI. We used a stratified Cox regression to calculate the relative risk of epilepsy after TBI for persons exposed to TBI, SSRI or both after adjustment for income, civil status, medical and neurological comorbidities, severe mental disease, and substance abuse.

Results: The risk of epilepsy was 5.61 times higher for persons who used SSRI at time of TBI (adjusted Hazard Ratio (aHR): 5.61 (95% CI: 4.88; 6.45)), 3.23 times higher for persons who had a TBI but did not use SSRI at time of TBI (aHR: 3.23 (95% CI: 3.12;3.35)), and 1.31 times higher for persons who used SSRI but had no TBI (aHR: 1.31 (95% CI: 1.18; 1.45)) compared to persons unexposed to both TBI and SSRI.

Conclusions: This large population based cohort study showed that people using SSRI at the time of a TBI had higher risk of developing epilepsy compared to people not using SSRI at the time of TBI. The results are in line with those of animal studies and calls for further studies to evaluate whether the association is due to SSRIs or to the underlying disease (e.g. depression or anxiety).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219137PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641473PMC
February 2020
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