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Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive developmental and epileptic encephalopathy caused by pathogenic variants in the ALDH7A1 gene (PDE-ALDH7A1), which mainly has its onset in neonates and infants. Early diagnosis and treatment are crucial to prevent severe neurological sequelae or death. Sensitive, specific, and stable biomarkers for diagnostic evaluations and follow-up examinations are essential to optimize outcomes. However, most of the known biomarkers for PDE lack these criteria. Additionally, there is little discussion regarding the interdependence of biomarkers in the PDE-ALDH7A1 metabolite profile. Therefore, the aim of this study was to understand the underlying mechanisms in PDE-ALDH7A1 and to discover new biomarkers in the plasma of patients using global metabolomics. Plasma samples from 9 patients with genetically confirmed PDE-ALDH7A1 and 22 carefully selected control individuals were analyzed by ultra high performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HRMS). Two novel and reliable pyridoxine-independent diagnostic markers, 6-hydroxy-2-aminocaproic acid (HACA) and an isomer of C9H11NO4, were identified. Furthermore, a possible reaction mechanism is proposed for HACA. This study demonstrates the capability of global metabolomics in disease screening to detect established and novel biomarkers.

Purpose Cutaneous adverse drug reactions (cADRs) are a major cause of lamotrigine (LTG) discontinuation. Remarkable variation in their reported incidence suggests confounders and diverse terms and definitions. The aim of this study was to identify immunological cADRs and to throw light on classification and differential diagnoses in children and adults. Methods Hospital records of 2683 patients with epilepsy (1897 adults, 786 children) were retrospectively screened. Of these, 403 patients (236 adults, 167 children) with first time exposure to LTG were reviewed. Skin reactions were categorized into possible or probable cADRs due to LTG hypersensitivity, and other skin reactions (OSRs) unlikely to be caused by this mechanism. Results 29 of 403 patients (7.2%) reported emergent skin symptoms within 3 months of treatment with LTG of which 20 (5%: 5.9% adults, 3.6% children) were categorized as possible or probable cADRs. Concomitant infection appeared to be present in several cases, particularly in children. OSRs were found in 4.2% of the children using LTG, compared to 0.8% of the adults (p = 0.04). Conclusions Rash during the early phase of LTG treatment is not always drug hypersensitivity. Whenever skin symptoms occur, other potential causes should receive attention to avoid needless discontinuation, particularly in children. However, when early symptoms and signs of severe cADRs are suspected, LTG should promptly be discontinued.

Objective ADCK3-related disease is a mitochondrial disorder associated with an abnormality of coenzyme Q10 metabolism. Ataxia and epilepsy are common, and the phenotype overlaps with other mitochondrial encephalopathies, particularly POLG-related disease. CoQ10 supplementation may be beneficial. We have noted a remarkable epileptiform pattern in ADCK3-related encephalopathy, and since EEG studies in this rare condition are limited, we wished to assess the evolution of EEG characteristics in patients with this disorder. Methods All EEG recordings of the four known patients from Mid-Norway were systematically reviewed. EEG graphoelements were classified according to the standardized computer-based organized reporting of EEG (SCORE) and international glossary terms. The evolution of EEG features was assessed. A total of 96 recordings spanning over 15-32 years were available, with a mean of 24 per patient (range: 17-28). Altogether, 50 digital recordings were reviewed, including four long-term and 46 selected paper segments. Results In three patients, EEG showed prominent bilateral asynchronous and synchronous epileptiform discharges in occipital and posterior-temporal regions. This intense activity included multiple epileptiform graphoelements, which occurred continuously, nearly continuously or in prolonged runs. The findings remained stable over many years. Significance Although the number of patients is small, we suggest that interictal EEG findings of continuous/nearly continuous bi-occipital spike-waves may serve as a biomarker for this potentially treatable condition. This peculiar EEG pattern might help to differentiate ADCK3-related disease from the more common POLG-related disease, which is usually characterized by lateralized or focal slowing with more sporadic epileptiform elements of similar topography.

We aimed to assess the impact of POLG disease on mental health and quality of life in 15 patients using the Symptom Checklist-90-R (SCL-90-R) and Short-Form 36 Health Survey (RAND-36). We found increased scores in all nine subscales of SCL-90-R, particularly phobic anxiety, depression and somatization. Further, patients reported considerably lower scores in all RAND-36 domains. This study revealed a global decline in mental health and poor quality of life in patients with POLG disease and highlights the need for increased awareness and systematic assessment in order to improve their quality of life and mental health. © 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license.

Objective To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. Results We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Interpretation Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Purpose: To study the prevalence and directionality of comorbid epilepsy and psychosis in Norway. Methods: The Norwegian Prescription Database (NorPD) provided individual-based information on all antiseizure medications (ASMs) and antipsychotic drugs (APDs) dispensed during 2004–2017. Subjects were ≥18 years of age at the end of the study period. Diagnosis-specific reimbursement codes from the 10th revision of the International Classification of Diseases/2nd edition of the International Classification of Primary Care (ICD-10/ICPC-2) combined with ATC codes were used as indicators of diagnosis. Subjects had collected ASMs for epilepsy or APDs for psychosis at least four times, at least once issued with an ICD-10 code from the specialist healthcare service. Directionality was analyzed in subjects receiving both treatments. To reduce prevalent comorbidity bias, we employed a four-year comorbidity-free period (2004–2007). The use of specific ASMs and APDs was analyzed. Results: A total of 31,289 subjects had collected an ASM for epilepsy at least four times, 28,889 an APD for psychosis. Both the prevalence of treatment for epilepsy and of treatment for psychosis was 0.8%. Further, 891 subjects had been treated for both conditions; 2.8% with epilepsy had been treated for psychosis, and 3.1% with psychosis had been treated for epilepsy. Among 558 subjects included in the analyses of directionality, 56% had collected the first APD before an ASM, whereas 41% had collected an ASM first. During the last year prior to comorbidity onset, levetiracetam, topiramate, or zonisamide had been used for epilepsy by approximately 40%, whereas olanzapine and quetiapine were most used in patients with psychosis, and clozapine in 13%. Conclusion: The proportion of patients with prior antipsychotic treatment at onset of epilepsy is higher than previously acknowledged, as demonstrated in this nation-wide study. Apart from a shared neurobiological susceptibility, the bidirectionality of epilepsy and psychosis may be influenced by various environmental factors, including the interaction of pharmacodynamic effects. APDs may facilitate seizures; ASMs may induce psychiatric symptoms. In patients with combined treatment, these potential drug effects should receive ample attention, along with the psychosocial consequences of the disorders. A prudent multi-professional approach is required.

Brivaracetam (BRV) is one of our latest antiseizure medications (ASMs). It is an analogue of levetiracetam with limited real-life experience. The purpose of this study was to evaluate clinical experience with BRV with focus on efficacy, tolerability and pharmacokinetic variability among adult patients with difficult-to-treat epilepsy.We retrospectively collected clinical and laboratory data from patients aged 18 years who initiated treatment with BRV during 2016-2019 and were followed for one year or cessation of BRV.The study cohort consisted of 120 adults with drug-resistant epilepsy. Serum concentrations of BRV were available in 72 patients. After one-year follow-up, the retention rate of BRV was 52%. Fifty-seven patients (48%) were responders (50 reduction of seizure frequency), of whom six became seizure free. Adverse effects were reported in 78 patients (65%); 37 (31%) experienced psychiatric problems like increased irritability, anxiety and depressive symptoms. The mean daily BRV dose was 159 mg (SD 80 mg) and the mean serum concentration 5.4 μmol/L (SD 4.1 μmol/L). In 24 patients, BRV replaced levetiracetam. Pharmacokinetic variability between patients was considerable; 14-fold variation in concentration/dose (C/D)-ratios. Concomitant use of enzyme-inducing ASMs decreased the C/D-ratio by 48%. There were no significant differences in serum concentrations between responders vs. non-responders, or those who experienced adverse effects or not.After 1 year of treatment with BRV, we found a responder rate of 48% in adult patients with difficult-to-treat epilepsy. The drug was largely well tolerated, but one third experienced psychiatric adverse effects. The combination of clinical and pharmacokinetic data provides insight into factors contributing to efficacy and tolerability of new ASMs.

Purpose To report the clinical outcome of nicotine exposure in patients with autosomal dominant sleep-related hypermotor epilepsy (ADSHE), along with serum concentrations of the major nicotine metabolite cotinine. Methods We recruited 17 ADSHE patients with CHRNA4 mutations (12 with p.S280F and 5 with p.L291 dup). Clinical characteristics were collected from hospital records. A telephone interview was performed on the use and seizure-reducing effect of nicotine applying a six-point rating scale from “none” to very good“. Serum concentrations of cotinine were measured in 14 nicotine users. Results All patients but one had ever used nicotine. Nine had used snuff; seven were current users. Eleven had used transdermal nicotine; nine were current users. Seven reported long-lasting seizure control, all used nicotine, four transdermal nicotine and three snuff. In 78% of patients using continuous transdermal nicotine, the effect was rated as good or very good. Cotinine concentrations were 453 ± 196 (mean ± SD) nmol/l in seven patients using transdermal nicotine only vs. 1241 ± 494 nmol/l in seven using other forms of nicotine. No correlation with seizure control was found. Three patients experienced improvement with transdermal delivery compared to snuff. Conclusion This is the hitherto largest observational study supporting a favorable effect of nicotine in this specific seizure disorder. Better seizure control from transdermal nicotine compared to only day-time consumption suggests benefit from exposure throughout the night. According to current clinical experience, patients with uncontrolled ADSHE harboring relevant mutations should be offered precision treatment with transdermal nicotine.

Purpose: Vagus nerve stimulaton (VNS) has been used for adjunctive treatment of drug-resistant epilepsy for more than 25 years. The true efficacy has been debated, as blinded randomized controlled trials are unavailable. The aim of this study was to evaluate the patient-reported perceived benefit of VNS and to compare clinical characteristics of patients with and without benefit. Methods: Observational study of all 43 adult patients receiving VNS for > 2 years at one single center. Mean duration of treatment was 9 years. At inclusion, a semi-structured interview on VNS effectiveness was performed. In patients without benefit, the VNS was turned off. The outcome was evaluated after an observation period of one year. Results: 21 patients (49%) reported no clear benefit and stopped VNS. Only one of them resumed treatment within one year. Patients without benefit had received more new antiepileptic drugs (AEDs) during VNS treatment than those reporting benefit (p = 0.05). Other differences between the two groups were not found. Ten patients (23%) had been seizure free > 1 year at inclusion (5 in the benefit and 5 in the non-benefit group). Seizure control was attributed to the response of another new treatment in the majority of these patients. Conclusion: Half of the patients had not perceived clear benefit from VNS, and all but one terminated VNS without worsening of seizures within one year. The true outcome of long-term VNS is difficult to assess in realworld practice. The effect may be overestimated due to confounding factors, particularly the common introduction of novel AEDs and the natural course of the disorder. Patients without perceived benefit from longterm VNS should not routinely remain on treatment and be subject to undue generator re-implantations. Open Archive under an Elsevier User License. Articles published under an Elsevier user license are protected by copyright. Users may access, download, copy, translate, text and data mine (but may not redistribute, display or adapt) the articles for non-commercial purposes provided that users: • Cite the article using an appropriate bibliographic citation (i.e. author(s), journal, article title, volume, issue, page numbers, DOI and the link to the definitive published version on ScienceDirect) • Maintain the integrity of the article • Retain copyright notices and links to these terms and conditions so it is clear to other users what can and cannot be done with the article • Ensure that, for any content in the article that is identified as belonging to a third party, any re-use complies with the copyright policies of that third party • Any translations, for which a prior translation agreement with Elsevier has not been established, must prominently display the statement: "This is an unofficial translation of an article that appeared in an Elsevier publication. Elsevier has not endorsed this translation."

We present pharmacokinetic data during pregnancy and lactation for brivaracetam, lacosamide and perampanel based on two case studies. Patient 1 used brivaracetam as monotherapy and gave birth to twins. Patient 2 used a combination of brivaracetam, lacosamide and perampanel. In both patients, serum drug concentrations were monitored throughout the pregnancies. Drug concentrations were also analysed in umbilical cord blood at birth, in serum from the offspring and in breastmilk after five days and 3-11 weeks. There were minor changes in concentration/dose-ratios for brivaracetam and lacosamide. The mean milk/serum ratios for brivaracetam and lacosamide were 0.71 and 0.83, respectively, five days and 3-5 weeks after delivery. The perampanel serum concentration increased by up to 80% in Patient 2 during the last part of gestation. The mean milk/serum-ratio for perampanel was 0.13, unchanged from five days to five weeks after delivery. Whereas serum concentrations of brivaracetam and lacosamide remained fairly stable throughout pregnancy, perampanel concentrations seemed to steadily increase towards the end. The distribution to milk was considerable for brivaracetam and lacosamide and low for perampanel. More studies on mother-infant pairs are warranted to confirm these results in larger groups.

Since 1993, fifteen new anti-epileptic drugs have entered the market. But while the potential for personalised treatment has never been greater, the proportion of patients achieving seizure freedom is no higher than it was before.

Ictal visual hallucinations may have occipital as well as temporal lobe origin. We report a patient with clustering of focal aware seizures with visual hallucinations. Ictal EEG findings and seizure semiology with alternating contralateral elementary visual phenomena and non-lateralizing experiential hallucinations (visual scenes, memory flashbacks, spatial distortion) corresponded to a lesion in the posterior part of the right parahippocampal gyrus. This area is part of the hippocampal-parahippocampal system for mapping allocentric space. Within this system, the parahippocampal cortex encodes information about visual environmental scenes in concert with functionally defined neurons relevant for episodic memory and spatial cognitive processes (place, grid, border and head direction cells, as well as neurons tracking the passage of time). These functions are tightly linked to visual exploration. We suggest that the hippocampal-parahippocampal spatial navigation system is a crucial part of the networks responsible for the semiology of experiential seizures with complex visual hallucinations and elements of recall., Highlights • Ictal visual hallucinations may have occipital or temporal lobe origin. • In temporal lobe epilepsy, they may be experiential and non-lateralized. • In the present patient, such seizures were related to a parahippocampal lesion. • This area overlaps with the spatial representation systems of the brain. • A more precise outline of the substrate for experiential seizures is suggested.

Background Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. Methods A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries. Results We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset—onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. Conclusion Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Objective Lacosamide (LCM) is an antiepileptic drug (AED) with insufficient clinical experience in patients with intellectual disability (ID). They often have more severe epilepsy with comorbidities. The objective was to evaluate the efficacy and tolerability of lacosamide (LCM) in patients with refractory epilepsy with and without ID in a real‐life setting, taking drug monitoring (TDM) data into account therapeutic. Methods Retrospectively, we identified 344 patients using LCM from the TDM service covering the majority of the country, at the National Center for Epilepsy in Norway (2013‐2018). Clinical and TDM data were available for 132 patients. Results Forty‐four of the 132 patients (33%) had ID. The retention rate was significantly higher in the ID vs the non‐ID group after 1 year (84% vs 68%, P < .05). By combining clinical and TDM data, we demonstrated that 37/38 responding patients had serum concentrations above the lower limit of the reference range (>10 µmol/L), and 16/17 with lower concentrations were non‐responders. Mean serum concentration/dose ratios were similar in both groups, 0.06 and 0.07 µmol/L/mg. There were no significant differences regarding efficacy and tolerability. The risk of LCM withdrawal was significantly higher when LCM was added to sodium channel blockers, even if the latter was discontinued. Significance Lacosamide was generally well tolerated in patients with drug‐resistant epilepsy, where one third had ID, and in these patients the retention rate was higher. The combination of clinical and TDM data could possibly facilitate LCM therapy in these vulnerable patients. This article will not be available due to copyright restrictions. (c) 2019 by Wiley.

Purpose To investigate the change in zonisamide (ZNS) serum concentration and its consequences in pregnant women with epilepsy. Methods Six hospitals in Norway and Denmark screened their records for women who had been using ZNS during pregnancy. Absolute serum concentrations as well as concentration/dose (CD)-ratios were compared to non-pregnant values. Descriptive data on seizure control and obstetrical data were also collected. Results 144 serum concentrations from 23 pregnancies in 15 individual women with epilepsy were included (six on monotherapy). The mean ZNS serum concentration fell to a minimum of 58.6 ± 15.1%, while the C/D-ratio fell to as low as 55.1 ± 15.3% of the non-pregnant-value. The lowest values were seen in gestational months six to nine, and the individual nadir varied considerably (range: 24–81% of the non-pregnant value). Four out of ten previously seizure-free patients experienced breakthrough seizures. Gestational age, weight at birth and head circumference of the newborns were within the reference ranges. Conclusions ZNS serum concentrations may fall by over 40% during pregnancy, with large interindividual variability. In some patients, this may lead to worsened seizure control. These findings are in line with reports on other AEDs and suggest that regular therapeutic drug monitoring and dose adjustments may be useful.

Purpose The aim of this study was to investigate the association between alcohol use and seizures in acutely hospitalized patients. We wished to study the extent of the problem as well as the clinical characteristics of people with various forms of alcohol-related seizures, including their drinking pattern. Method After admission, a semi-structured interview took place with 134 consecutive patients (epilepsy 92, single seizures 42). Alcohol use was assessed by the Alcohol Use Disorders Identification Test (AUDIT) and by the number of alcohol units consumed during 6 days prior to the seizure. Sleep time was recorded during the previous 3 days and nights. A follow-up telephone interview covering the same weekdays was performed on a seizure-free day at least 4 weeks later. Results 28% of patients had AUDIT scores ≥8 (hazardous drinking); 22% in epilepsy, 43% in single seizures (p = .012). Non-focal seizures were increased in single seizures, suggesting a withdrawal mechanism. In the 58 epilepsy patients with social drinking (excluded hazardous drinking or excessive binging), the alcohol intake was not different prior to seizure compared to follow-up, downgrading the role of modest alcohol intake as a seizure precipitant in epilepsy. On the other hand, a high percentage of binge drinkers had epilepsy (57%), and in the subgroup of Idiopathic Generalized Epilepsy (IGE) even social drinking was associated with seizures. Seizures peaked on Sundays and Mondays. Less sleep prior to the seizure was associated with hazardous drinking. Conclusion Alcohol is a major seizure precipitant in the context of hazardous drinking and withdrawal. In people with epilepsy, occasional binge drinking is associated with loss of seizure control. Social drinking is an uncommon cause of seizure breakthrough in predominantly focal epilepsy, but caution is warranted in IGE. Alcohol intake prior to a seizure is often accompanied by other triggers, such as sleep loss. Alcohol alone should not always be blamed.

Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p

Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED), still insufficiently studied regarding pharmacokinetic variability, efficacy and tolerability. The purpose of this study was to evaluate therapeutic drug monitoring (TDM) data in Norway and relate pharmacokinetic variability to clinical efficacy and tolerability in a long-term clinical setting in patients with refractory epilepsy.This retrospective observational study included TDM-data from the main laboratories and population data from the Norwegian Prescription Database in Norway, in addition to clinical data from medical records of adult patients using ESL for up to three years, whenever possible.TDM-data from 168 patients were utilized for assessment of pharmacokinetic variability, consisting of 71% of the total number of patients in Norway using ESL, 2011-14. Median daily dose of ESL was 800mg (range 400-1600mg), and median serum concentration of ESL was 53μmol/L (range 13-132μmol/L). Inter-patient variability of ESL was extensive, with 25-fold variability in concentration/dose ratios. Additional clinical data were available from 104 adult patients out of the 168, all with drug resistant focal epilepsy. After 1, 2 and 3 years follow-up, the retention rate of ESL was 83%, 72% and 64%, respectively. ESL was generally well tolerated as add-on treatment, but sedation, cognitive impairment and hyponatremia were reported. Hyponatremia (sodium137mmol/L) was present in 36% of the patients, and lead to discontinuation in three.Pharmacokinetic variability of ESL was extensive and the demonstration of usefulness of TDM requires further studies. In patients with drug resistant focal Epilepsy, the high retention rate indicated good efficacy and tolerability. Hyponatremia was observed in one third of the patients. The present results point to a need for individualization of treatment and TDM may be useful.

Objective Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is characterized by hypermotor seizures and may be caused by gain-of-function mutations affecting the nicotinic acetylcholine receptor (nAChR). Benefit from nicotine consumption has been reported in adult patients with this disorder. For the first time, the effect of transdermal nicotine is evaluated in children. Methods Transdermal nicotine was applied to three boys, two aged 10 years (7 mg/24 h) and one six years (3.5 mg/24 h). Autosomal dominant sleep-related hypermotor epilepsy was caused by the p.S280F-CHRNA4 (cholinergic receptor, nicotinic, alpha polypeptide 4) mutation. The children suffered from frequent, persistent nocturnal seizures and had developed educational and psychosocial problems. Seizure frequency and cognitive and behavioral parameters were assessed before and after treatment. Results A striking seizure reduction was reported soon after treatment onset. Hypermotor seizures disappeared; only sporadic arousals, sometimes with minor motor elements, were observed. Psychometric testing documented improvement in cognitive domains such as visuospatial ability, processing speed, memory, and some areas of executive functions. Significance Nicotine appears to be a mechanistic treatment for this specific disorder, probably because of desensitization of the mutated receptors. It may control seizures resistant to conventional drugs for epilepsy and impact socioeducational function in children. This mode of precision therapy should receive more attention and should be available to more patients with uncontrolled CHRNA4-related ADSHE across the age span. © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Purpose Juvenile neuronal ceroid lipofuscinosis (CLN3 disease) is the most common neurodegenerative disorder in childhood with survival until young adult age. Visual loss is followed by epilepsy, cognitive, neuropsychiatric, and motor symptoms. We have studied the evolution of electroencephalographic (EEG) and seizure characteristics. Methods Twenty-four patients were recruited via the Norwegian CLN3 disease parent association. Parents were interviewed. Medical records and EEG reports/recordings were collected. Electroencephalographic elements were classified according to Standardized computer-based organized reporting of EEG (SCORE). The evolution of EEG features along with seizure types was assessed by testing the difference in proportions with standardized normal deviate comparing findings below and above 15 years of age. Results Mean age at study or death (n = 12) was 21.2 (10–39) years. Twenty-two patients had experienced seizures; the first was usually bilateral tonic–clonic (TC). Later, focal motor seizures frequently occurred, often with increasing multifocal and polymorphic features. Paroxysmal nonepileptic motor and autonomous symptoms were also suspected in several patients. Distinct myoclonic seizures were uncommon. In four patients, we identified episodes of bradycardia/sinus arrest. Electroencephalography showed progressive slowing of the background activity (p = 0.029). Focal epileptiform discharges were rare and mainly seen at age < 10. Combined multifocal and bilateral epileptiform discharges increased in adolescence (p = 0.002). Conclusion Seizure and EEG characteristics change with time in CLN3 disease. Tonic–clonic seizures are common at onset, and multifocal motor seizures increase with age. In contrast, focal epileptiform abnormalities are more common in childhood, compared to later multifocal and bilateral discharges. This seizure disorder belongs to the combined generalized and focal epilepsies. Paucity of myoclonic seizures does not warrant classification as a classic progressive myoclonic epilepsy. When attacks with only behavior arrest occur, cardiac conduction abnormalities should be considered. © 2019. This is the authors’ accepted and refereed manuscript to the article. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/

The aim of this study was to investigate the association between alcohol use and seizures in acutely hospitalized patients. We wished to study the extent of the problem as well as the clinical characteristics of people with various forms of alcohol-related seizures, including their drinking pattern.After admission, a semi-structured interview took place with 134 consecutive patients (epilepsy 92, single seizures 42). Alcohol use was assessed by the Alcohol Use Disorders Identification Test (AUDIT) and by the number of alcohol units consumed during 6 days prior to the seizure. Sleep time was recorded during the previous 3 days and nights. A follow-up telephone interview covering the same weekdays was performed on a seizure-free day at least 4 weeks later.28% of patients had AUDIT scores ≥8 (hazardous drinking); 22% in epilepsy, 43% in single seizures (p = .012). Non-focal seizures were increased in single seizures, suggesting a withdrawal mechanism. In the 58 epilepsy patients with social drinking (excluded hazardous drinking or excessive binging), the alcohol intake was not different prior to seizure compared to follow-up, downgrading the role of modest alcohol intake as a seizure precipitant in epilepsy. On the other hand, a high percentage of binge drinkers had epilepsy (57%), and in the subgroup of Idiopathic Generalized Epilepsy (IGE) even social drinking was associated with seizures. Seizures peaked on Sundays and Mondays. Less sleep prior to the seizure was associated with hazardous drinking.Alcohol is a major seizure precipitant in the context of hazardous drinking and withdrawal. In people with epilepsy, occasional binge drinking is associated with loss of seizure control. Social drinking is an uncommon cause of seizure breakthrough in predominantly focal epilepsy, but caution is warranted in IGE. Alcohol intake prior to a seizure is often accompanied by other triggers, such as sleep loss. Alcohol alone should not always be blamed.

Purpose Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females. Epilepsy is a major clinical feature, but its long-term course in RTT has not been sufficiently explored. This study addresses the development of the epilepsy in adults with RTT. Methods Available females diagnosed with RTT in Norway were asked to participate. Parents/caregivers were interviewed, the girls/women were examined and their medical records reviewed. Participants were categorized according to age, epilepsy, seizure patterns and mutation severity groups. RTT severity was assessed (epilepsy score excluded). Results 70 females with classic RTT were included. A presumed pathogenic mutation in MECP2 was found in 96%. The presence of active epilepsy (seizures last five years) was similar in all age groups above the age of ten: 11 (65%) in adolescents (11–20 years), 9 (60%) in young adults (21–30 years) and 14 (67%) in participants above 30 years of age. Tonic-clonic seizures within the last year were present in 55, 67 and 64%, and ≥ weekly seizures occurred in 27, 45 and 50% in the respective age groups. Among participants with active epilepsy, 69% had unremitting seizures, whereas 31% had experienced remissions for more than six months during the last five years. In the oldest group (>30 years), only 19% had obtained seizure control for >5 years, and 14% had never experienced seizures. Seizure activity correlated with RTT severity score, whereas the relationship to mutation type remained ambiguous. Conclusion Epilepsy continues to be a major concern in adults with RTT. Two thirds of women above 30 years of age remained with active epilepsy and 50% of them had seizures at least weekly. © 2018. This is the authors’ accepted and refereed manuscript to the article. Locked until 23.06.2019 due to copyright restrictions. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/

Arne Reimers,1,2 Jon Andsnes Berg,3 Margrete Larsen Burns,4 Eylert Brodtkorb,5,6 Svein I Johannessen,6,7 Cecilie Johannessen Landmark4,7,8 1Department of Clinical Pharmacology, St Olavs University Hospital, Trondheim, Norway; 2Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 3Laboratory of Clinical Biochemistry, Section of Clinical Pharmacology, Haukeland University Hospital, Bergen, Norway; 4Department of Pharmacology, Section for Clinical Pharmacology, The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway; 5Department of Neurology and Clinical Neurophysiology, St Olavs University Hospital, Trondheim, Norway; 6Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway; 7The National Center for Epilepsy, Oslo University Hospital, Oslo, Norway; 8Programme for Pharmacy, Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway Background and objective: Laboratories sometimes use different reference ranges for the same antiepileptic drug (AED), particularly for new and poorly investigated drugs. This may contribute to misunderstandings, concerns or inappropriate dose changes, which in turn may affect therapeutic effect, drug safety or treatment adherence. Therefore, the Norwegian Association of Clinical Pharmacology wished to update and harmonize the reference ranges for AEDs and establish national guidelines for Norway. Methods: A working group collected information on the reference ranges used by Norwegian laboratories for all commonly used AEDs. These reference ranges were compared to recent recommendations by the International League Against Epilepsy, current literature, applicable clinical studies, reference ranges used by leading Northern European epilepsy centers outside of Norway, and routine data derived from Norwegian laboratory databases. Results: Reference ranges varied between laboratories for four of 23 available AEDs (lamotrigine, valproate, eslicarbazepine and oxcarbazepine). For four AEDs (brivaracetam, perampanel, stiripentol and sulthiame), reference ranges had not previously been established. In total, 13 reference ranges were either harmonized, updated or newly established. No changes were applied to the remaining 10 AEDs. Conclusion: Updated and harmonized reference ranges are now available for 22 of the 23 AEDs available in Norway. The exception is vigabatrin (reference range not applicable). Revision of reference ranges is an important part of pharmacovigilance of AEDs and must be a continuous process based on current literature and clinical experience. Keywords: antiepileptic drug, serum concentration, reference range, therapeutic drug monitoring

Antiepileptic drugs (AEDs) are effective against seizures, but their use is often limited by adverse effects, among them psychiatric and behavioral ones including aggressive behavior (AB). Knowledge of the incidence, risk factors, and the underlying mechanisms of AB induced by AEDs may help to facilitate management and reduce the risk of such side effects. The exact incidence of AB as an adverse effect of AEDs is difficult to estimate, but frequencies up to 16% have been reported. Primarily, levetiracetam (LEV), perampanel (PER), and topiramate (TPM), which have diverse mechanisms of action, have been associated with AB. Currently, there is no evidence for a specific pharmacological mechanism solely explaining the increased incidence of AB with LEV, PER, and TPM. Serotonin (5-HT) and GABA, and particularly glutamate (via the AMPA receptor), seem to play key roles. Other mechanisms involve hormones, epigenetics, and “alternative psychosis” and related phenomena. Increased individual susceptibility due to an underlying neurological and/or a mental health disorder may further explain why people with epilepsy are at an increased risk of AB when using AEDs. Remarkably, AB may occur with a delay of weeks or months after start of treatment. Information to patients, relatives, and caregivers, as well as sufficient clinical follow-up, is crucial, and there is a need for further research to understand the complex relationship between AED mechanisms of action and the induction/worsening of AB. Copyright © 2018 Cerine C. Hansen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background The genetic understanding of primary familial brain calcification (PFBC) has increased considerably in recent years due to the finding of causal genes like SLC20A2 , PDGFRB and PDGFB . The phenotype of PFBC is complex and has as of yet been poorly delineated. The most common clinical presentations include movement disorders, cognitive symptoms and psychiatric conditions. We report a family including two sisters with brain calcifications due to a variant in SLC20A2 and generalized tonic-clonic seizures as the principal phenotypic trait. Methods The affected siblings underwent whole exome sequencing and candidate variants and cosegregation in the family were validated by Sanger sequencing. Results Both siblings and their asymptomatic father were heterozygous for a variant in SLC20A2 . The siblings also had a variant in CHRNB2 , a known epilepsy gene associated with autosomal dominant frontal lobe epilepsy, which they had inherited from the mother. Conclusions To our knowledge, the reported siblings represent the third and fourth subjects with confirmed SLC20A2 variants exhibiting epilepsy as a phenotypic trait. Our findings support seizures as part of the phenotypic spectrum of SLC20A2- related PFBC. However, the present phenotype may also result from additional genetic influence, such as the identified missense variant in CHRNB2 .

Antiepileptic drugs (AEDs) and hormonal contraceptives may affect each other's metabolism and clinical efficacy. Loss of seizure control and unplanned pregnancy may occur when these compounds are used concomitantly. Although a large number of available preparations yield a plethora of possible drug combinations, most of these drug interactions are predictable and, thus, avoidable. Unfortunately, there is a substantial lack of data regarding the newer AEDs. Detailed understanding of these issues is necessary for those who prescribe AEDs and/or hormonal contraception to women with epilepsy, as well as for those who provide comprehensive care, education and counseling to them, in order to reduce the unacceptably high number of unplanned pregnancies among women with epilepsy.

Background Mitochondria play an important role in iron metabolism and haematopoietic cell homeostasis. Recent studies in mice showed that a mutation in the catalytic subunit of polymerase gamma (POLG) was associated with haematopoietic dysfunction including anaemia. The aim of this study was to analyse the frequency of anaemia in a large cohort of patients with POLG related disease. Methods We conducted a multi-national, retrospective study of 61 patients with confirmed, pathogenic biallelic POLG mutations from six centres, four in Norway and two in the United Kingdom. Clinical, laboratory and genetic data were collected using a structured questionnaire. Anaemia was defined as an abnormally low haemoglobin value adjusted for age and sex. Univariate survival analysis was performed using log-rank test to compare differences in survival time between categories. Results Anaemia occurred in 67% (41/61) of patients and in 23% (14/61) it was already present at clinical presentation. The frequency of anaemia in patients with early onset disease including Alpers syndrome and myocerebrohepatopathy spectrum (MCHS) was high (72%) and 35% (8/23) of these had anaemia at presentation. Survival analysis showed that the presence of anaemia was associated with a significantly worse survival (P = 0.004). Conclusion Our study reveals that anaemia can be a feature of POLG-related disease. Further, we show that its presence is associated with significantly worse prognosis either because anaemia itself is impacting survival or because it reflects the presence of more serious disease. In either case, our data suggests anaemia is a marker for negative prognosis.

Objective In juvenile myoclonic epilepsy (JME), various EEG characteristics have been suggested as poor prognostic signs, but their significance is unclear. The aim of this study was to assess the influence of EEG variables on seizure and psychosocial outcome after a follow-up exceeding 20 years. Methods 396 EEG recordings were available for assessment in 40 patients (42 complete digital, 330 paper segments and 24 written reports only). Mean follow-up was 31 years (range 20–68). The number of EEGs per patient ranged from 2 to 23 (mean 9). Twenty-one patients were in remission for >5 years, whereas 19 had persistent seizures. Favorable psychosocial outcome was found in 14 of 37. EEGs were retrospectively categorized into four main groups; normal, slowing, epileptiform discharges or both slowing and epileptiform discharges, with further sub-classification. Hyperventilation and photoparoxysmal responses were also evaluated. Scoring of EEG findings was blinded to seizure and psychosocial outcome. Results Significant associations were found between poor seizure control and prolonged ≥3s epileptiform runs, p =0.03 (8/19 vs 2/21), long ≥3s photoparoxysmal runs, p =0.04 (6/19 vs 1/21) and long ≥3s hyperventilation-induced epileptiform runs, p =0.02 (5/19 vs 0/21). The strongest association between persistent seizures and EEG was found when all epileptiform runs ≥3s were combined ( p =0.007), with a positive predictive value equal to 79% and a negative predictive value equal to 69%. Fast (4-5c/s) spike-wave runs were also more frequent in patients with persistent seizures compared to the remission group, p =0.04 (9/19 vs 3/21). Other epileptiform elements occurred equally in the two prognostic groups. Psychosocial outcome was not influenced by EEG findings. Prolonged runs within 6 months from first recording did also predict clinical outcome, p =0.03; (8/19 vs 2/21), with a positive predictive value equal to 80% and a negative predictive value equal to 63%. Significance Fast spike-wave runs and prolonged (≥3s) epileptiform runs, including photoparoxysmal and hyperventilation-induced runs were associated with persistent seizures in JME. Focal EEG abnormalities were not associated with clinical outcome. Conceivably, the duration of epileptiform bursts reflects the degree of deficient intracortical inhibition. Prolonged runs may represent an essential predictive feature for poor seizure control in JME.

Lacosamide (LCM) is a new antiepileptic drug (AED). Experience from therapeutic drug monitoring (TDM) in clinical practice is limited. The purpose of this study is to evaluate the pharmacokinetic variability of LCM in relation to efficacy and tolerability in patients with refractory epilepsy in a real-life setting. Variables included age, gender, daily doses and serum concentrations of LCM and other AEDs from the TDM-database at the National Center for Epilepsy in Norway. Clinical data regarding efficacy and tolerability were collected from medical records. The Norwegian Prescription Database (NorPD) was used to include population-based numbers of users. TDM-data from 344 patients were included. The median dose, serum concentration, and concentration/dose (C/D)-ratio of LCM was 350 (range 25–700) mg/day, 19.7 (range 8.1–56.2) µmol/L, and 0.06 (0.02–0.82) µmol/L/mg, respectively. Serum concentrations were reduced by 28% by concomitant use of enzyme inducers and increased by 30% in patients aged >65 years. Efficacy and tolerability were assessed in 227 patients: 29% had >50% seizure reduction (eight seizure free), 30% had no effect, and 44% reported adverse effects. In Norway, there were on average 500 patients per year using LCM in this period based on NorPD. The study demonstrated pharmacokinetic variability and use of TDM of LCM in Norway. Data were collected from multiple sources for improved pharmacovigilance. Serum concentrations were influenced by enzyme inducers and ageing, indicating the usefulness of TDM. Effect and tolerability were favorable within a suggested reference range of 10–40 µmol/L given drug-fasting conditions.

Summary Background Epilepsy affects around 70 million people worldwide. Psychiatric comorbidity may add to the burden of the disease. We studied substance use disorders and psychotic disorders among people with epilepsy from a population-based perspective. Methods Norwegian specialist health services (hospitals and outpatient clinics) report diagnoses for individual patients to the Norwegian Patient Register. We used information on subjects born in 1930–1994 who were registered with a diagnosis of epilepsy at least once during the five-year period of 2008–2012. We compared the proportion of people with epilepsy registered with substance use disorders (alcohol use disorders or non-alcohol drug use disorders) and psychotic disorders (schizophrenia spectrum disorders or bipolar disorder) with similar figures in the population without epilepsy. We applied chi-square tests and log-binomial regression for analysis. Results Overall, 0.90% of the Norwegian adult population was registered with epilepsy in somatic hospitals during 2008–2012. The total proportion registered with alcohol use disorder was 5.74% among people with epilepsy and 1.29% in the population without epilepsy (age- and sex-adjusted relative risk [RR]: 4.42, 95% confidence interval [CI]: 4.22–4.62). The corresponding figures were 4.32% and 1.22% (RR 3.86 [95% CI: 3.67–4.06] for drug use disorder, 1.72% and 0.60% (RR 2.94 [95% CI: 2.71–3.19]) for schizophrenia spectrum disorders, and 1.50% and 0.68% (RR 2.29 [95% CI: 2.10–2.49]) for bipolar disorder. Conclusion People with epilepsy were more often registered with substance use disorders and psychotic disorders than people without epilepsy. Psychiatric comorbidity requires particular attention in both diagnostic work-up and management of epilepsy, and creates complex medical challenges that require close cooperation between neurologists and psychiatrists. These findings may have implications for the organization and further development of comprehensive epilepsy care.

Purpose The view that juvenile myoclonic epilepsy (JME) is a uniform and life-long disorder is currently being challenged. The aim of this study was to assess the seizure and psychosocial outcome of JME at least 20 years after onset. Methods In 1992, 42 patients with JME were identified. In 2012, 37 agreed to a semi-structured interview. In the remaining five, only medical records were available. Results Of 40 patients with known seizure outcome, 21 were in remission for >5 years. Seven were off antiepileptic drugs (AEDs), four being seizure free for >10 years. Myoclonic seizures (MC) evolving to generalized tonic–clonic seizures (GTC) were associated with seizure persistence ( p =0.013), whereas >1 year between MC and GTC onset was associated with a trend to GTC remission ( p =0.069). Of 19 patients with uncontrolled seizures, eight experienced remission with second generation AEDs. Favorable psychosocial outcome by interview was found in a third, whereas another third had psychiatric comorbidity, seven with substance or alcohol abuse. Psychosocial and seizure outcome did not correlate. Conclusion This study corroborates the heterogeneity of JME in terms of seizure and psychosocial outcome, but without a clear association between the two. It confirms that seizure control may persist after AED withdrawal in some and supports MC evolving to GTC as a predictor of seizure persistence. Moreover, it suggests that newer broad spectrum AEDs may improve the prognosis of JME; their impact should be focus of prospective studies.

BACKGROUND In pregnant women with epilepsy the use of antiepileptic drugs may increase the risk of harming the foetus. For the treating neurologist it may be challenging to find a balance between optimal seizure control and the lowest possible drug dosage. The aim of this study was to assess the prevalence and type of congenital malformations in children exposed to antiepileptic drugs during pregnancy. MATERIAL AND METHOD In Norway we have prospectively followed 813 pregnancies in women with epilepsy as part of an international cohort study. The women had three check-ups during the pregnancy, and the children were followed up twice during their first year of life. RESULTS We found a total of 34 congenital malformations in the children, of which 12 were heart defects, yielding a malformation rate of 4.5%. Six of the malformations (18%) were detected prenatally, 20 (59%) were reported immediately after birth, and eight (24%) were discovered during the child's first year of life. INTERPRETATION Our study shows that 95.5%.of the women included who used antiepileptic drugs during pregnancy gave birth to a healthy child. This Norwegian cohort is too small to evaluate the teratogenic risk associated with the individual drugs.

Purpose High initial serum concentrations increase the risk of cutaneous adverse reactions. Genetic variants of the main metabolizing isoenzyme, uridine diphosphate glucuronosyltransferase (UGT) 1A4 influence the elimination of lamotrigine (LTG). Our aim was to investigate the potential association between the two best studied variants, *2 (P24T) and *3 (L48V), and the occurrence non-bullous skin reactions from LTG. Method The study included 29 patients of Caucasian ethnicity with a history of non-bullous skin reactions from LTG. 184 subjects tolerant to LTG for at least three months were used as controls. UGT1A4 genotyping was performed in all patients and controls by sequencing of the first part of exon 1. Six controls were excluded due to rare genetic variants. Results Two of 29 subjects (7%) with rash from LTG were heterozygous for UGT1A4 *2, compared to 23 of 178 (13%) tolerant controls (p=0.54). Four of 29 subjects (14%) with rash from LTG were heterozygous for UGT1A4 *3 compared to 25 of 178 (14%) tolerant controls (p=0.97). Conclusion It is unlikely that heterozygosity of the UGT1A4 genetic variants *2(P24T) or *3(L48V) influences the risk of non-bullous skin reactions in patients treated with LTG.