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Objective: Recessive LAMC3 mutations are recognized to cause epilepsy with cortical malformations characterized by polymicrogyria and pachygyria. The objective of this study was to describe the clinical picture and epilepsy phenotype of four patients with a previously undescribed LAMC3 variant., Methods: All epilepsy patients treated in Kuopio Epilepsy Center (located in Kuopio, Finland) are offered the possibility to participate in a scientific study investigating biomarkers in epilepsy (Epibiomarker study). We have collected a comprehensive database of the study population, and are currently re-evaluating our database regarding the patients with developmental and/or epileptic encephalopathy (DEE). If the etiology of epilepsy remains unknown in the clinical setting, we are performing whole exome sequencing to recognize the genetic causes., Results: Among our study population of 323 DEE patients we recognized three patients with similar homozygous LAMC3 c.1866del (p.(Phe623Serfs*10)) frameshift variant and one patient with a compound heterozygous mutation where the same frameshift variant was combined with an intronic LAMC3 c.4231-12C>G variant on another allele. All these patients have severe epilepsy and either bilateral agyria-pachygyria or bilateral polymicrogyria in their clinical MRI scanning. Cortical malformations involve the occipital lobes in all our patients. Epilepsy phenotype is variable as two of our patients have DEE with epileptic spasms progressing to Lennox-Gastaut syndrome and intellectual disability. The other two patients have focal epilepsy without marked cognitive deficit. The four patients are unrelated. LAMC3 c.1866del p.(Phe623Serfs*10) frameshift variant is enriched in the Finnish population., Significance: Only a few patients with epilepsy caused by LAMC3 homozygous or compound heterozygous mutations have been described in the literature. To our knowledge, the variants discovered in our patients have not previously been published. Clinical phenotype appears to be more varied than previously assumed and patients with a milder phenotype and normal cognition have probably remained unrecognized., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The aim of this study was to develop a feasible method for the detection of negative myoclonus (NM) through long-term home measurements in patients with progressive myoclonus epilepsy type 1., Methods: The number and duration of silent periods (SP) associated with NM were detected during a 48 h home recording using wearable surface electromyography (EMG) sensors., Results: A newly developed algorithm was able to find short (50-69 ms), intermediate (70-100 ms), and long (101- 500 ms) SPs from EMG data. Negative myoclonus assessed by the algorithm correlated significantly with the video-recorded and physician-evaluated unified myoclonus rating scale (UMRS) scores of NM and action myoclonus. Silent period duration, number, and their combination, correlated strongly and significantly also with the Singer score, which assesses functional status and ambulation., Conclusions: Negative myoclonus can be determined objectively using long-term EMG measurements in home environment. With long-term measurements, we can acquire more reliable quantified information about NM as a symptom, compared to short evaluation at the clinic., Significance: As measured using SPs, NM may be a clinically useful measure for monitoring disease progression or assessing antimyoclonic drug effects objectively., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.S. Declarations of interest: none. L.S. Declarations of interest: none. J.H. Declarations of interest: none. K.S. has received speaker’s honorarium by Jazz Pharma. R.K. has received speaker’s honoraria from Eisai, Jazz Pharmaceuticals, Orion, and UCB and honoraria for membership of the advisory boards/consultation of Angelini Pharma, Eisai, Jazz Pharmaceuticals, Orion and UCB. E.M. Declarations of interest: none. P.A.K. is a co-founder in Adamant Health Ltd. He is an inventor in patent applications WO2019166557A1 and WO2020174122A1. S.M.R. is a co-founder in Adamant Health Ltd that develops EMG-based analysis software. She is an inventor in patent applications WO2019166557A1 and WO2020174122A1., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. The polygenic risk score for intelligence was lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Although a striking female preponderance has been consistently reported in epilepsy with eyelid myoclonia (EEM), no study has specifically explored the variability of clinical presentation according to sex in this syndrome. Here, we aimed to investigate sex-specific electroclinical differences and prognostic determinants in EEM. Data from 267 EEM patients were retrospectively analyzed by the EEM Study Group, and a dedicated multivariable logistic regression analysis was developed separately for each sex. We found that females with EEM showed a significantly higher rate of persistence of photosensitivity and eye closure sensitivity at the last visit, along with a higher prevalence of migraine with/without aura, whereas males with EEM presented a higher rate of borderline intellectual functioning/intellectual disability. In female patients, multivariable logistic regression analysis revealed age at epilepsy onset, eyelid myoclonia status epilepticus, psychiatric comorbidities, and catamenial seizures as significant predictors of drug resistance. In male patients, a history of febrile seizures was the only predictor of drug resistance. Hence, our study reveals sex-specific differences in terms of both electroclinical features and prognostic factors. Our findings support the importance of a sex-based personalized approach in epilepsy care and research, especially in genetic generalized epilepsies., (© 2023 International League Against Epilepsy.)

Objective: Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1., Methods: TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed., Results: The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006)., Significance: Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Transcranial magnetic stimulation (TMS)-evoked EEG potentials (TEPs) have been used to study the excitability of different cortical areas (CAs) in humans. Characterising the interhemispheric symmetry of TMS-EEG may provide further understanding of structure-function association in physiological and pathological conditions. We hypothesise that, in keeping with the underlying cytoarchitectonics, TEPs in contralateral homologous CAs share similar, symmetric spectral features, whilst ipsilateral TEPs from different CAs diverge in their waveshape and frequency content. We performed single-pulse (<1 Hz) navigated monophasic TMS, combined with high-density EEG with active electrodes, in 10 healthy participants. We targeted two bilateral CAs: premotor and motor. We compared frequency power bands, computed Pearson correlation coefficient (R) and Correlated Component Analysis (CorrCA) to detect divergences, as well as common components across TEPs. The main frequency of TEPs was faster in premotor than in motor CAs (p < .05) across all participants. Frequencies were not different between contralateral homologous CAs, whilst, despite closer proximity, there was a significant difference between ipsilateral premotor and motor CAs (p > .5), with frequency decreasing from anterior to posterior CAs. Correlation was high between contralateral homologous CAs and low between ipsilateral CAs. When applying CorrCA, specific components were shared by contralateral homologous TEPs. We show physiological symmetry of TEP spectral features between contralateral homologous CAs, whilst ipsilateral premotor and motor TEPs differ despite lower geometrical distance. Our findings support the role of TEPs as biomarker of local cortical properties and provide a first reference dataset for TMS-EEG studies in asymmetric brain disorders., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome., Methods: In this multicenter retrospective cohort study, we included 267 EEM patients from 9 countries. Data about electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia over body regions other than eyelids (body-MYO)., Results: Kernel density estimation revealed a trimodal distribution of AEO and Fisher-Jenks optimization disclosed three EEM subgroups: early-onset (EO-EEM), intermediate-onset (IO-EEM) and late-onset subgroup (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome., Significance: Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians towards a more accurate classification and prognostic profiling of EEM patients., (This article is protected by copyright. All rights reserved.)

Mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures is associated with common variation at rs7587026, located in the promoter region of SCN1A. We sought to explore possible underlying mechanisms. SCN1A expression was analysed in hippocampal biopsy specimens of individuals with mesial temporal lobe epilepsy with hippocampal sclerosis who underwent surgical treatment, and hippocampal neuronal cell loss was quantitatively assessed using immunohistochemistry. In healthy individuals, hippocampal volume was measured using MRI. Analyses were performed stratified by rs7587026 type. To study the functional consequences of increased SCN1A expression, we generated, using transposon-mediated bacterial artificial chromosome transgenesis, a zebrafish line expressing exogenous scn1a, and performed EEG analysis on larval optic tecta at 4 day post-fertilization. Finally, we used an in vitro promoter analysis to study whether the genetic motif containing rs7587026 influences promoter activity. Hippocampal SCN1A expression differed by rs7587026 genotype (Kruskal-Wallis test P = 0.004). Individuals homozygous for the minor allele showed significantly increased expression compared to those homozygous for the major allele (Dunn's test P = 0.003), and to heterozygotes (Dunn's test P = 0.035). No statistically significant differences in hippocampal neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, individuals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippocampal volume compared to major allele homozygotes (Cohen's D = - 0.28, P = 0.02), and to heterozygotes (Cohen's D = - 0.36, P = 0.009). Compared to wild type, scn1lab-overexpressing zebrafish larvae exhibited more frequent spontaneous seizures [one-way ANOVA F(4,54) = 6.95 (P < 0.001)]. The number of EEG discharges correlated with the level of scn1lab overexpression [one-way ANOVA F(4,15) = 10.75 (P < 0.001]. Finally, we showed that a 50 bp promoter motif containing rs7587026 exerts a strong regulatory role on SCN1A expression, though we could not directly link this to rs7587026 itself. Our results develop the mechanistic link between rs7587026 and mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures. Furthermore, we propose that quantitative precision may be important when increasing SCN1A expression in current strategies aiming to treat seizures in conditions involving SCN1A haploinsufficiency, such as Dravet syndrome., (© 2022. The Author(s).)

Objective: To elucidate the effects of single and paired-pulse TMS on seizure activity at electrographic and clinical levels in people with and without epilepsy., Methods: A cohort of 35 people with epilepsy, two people with alternating hemiplegia of childhood (AHC) with no epilepsy, and 16 healthy individuals underwent single or paired-pulse TMS combined with EEG. Clinical records and subject interviews were used to examine seizure frequency four weeks before and after TMS., Results: There were no significant differences in seizure frequency in any subject after TMS exposure. There was no occurrence of seizures in healthy individuals, and no worsening of hemiplegic attacks in people with AHC., Conclusions: No significant changes in seizure activity were found before or after TMS., Significance: This study adds evidence on the safety of TMS in people with and without epilepsy with follow-up of four weeks after TMS., (© 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.)

Background and Objectives: Eyelid myoclonia (EM) with absences (EMA) is a generalized epilepsy syndrome with a prognosis and clinical characteristics that are still partially undefined. We investigated electroclinical endophenotypes and long-term seizure outcome in a large cohort of patients with EMA., Methods: In this multicenter retrospective study, patients with EMA with ≥5 years of follow-up were included. We investigated prognostic patterns and sustained terminal remission (STR), along with their prognostic factors. Moreover, a 2-step cluster analysis was used to investigate the presence of distinct EMA endophenotypes., Results: We included 172 patients with a median age at onset of 7 years (interquartile range [IQR] 5-10 years) and a median follow-up duration of 14 years (IQR 8.25-23.75 years). Sixty-six patients (38.4%) displayed a nonremission pattern, whereas remission and relapse patterns were encountered in 56 (32.6%) and 50 (29.1%) participants. Early epilepsy onset, history of febrile seizures (FS), and EM status epilepticus significantly predicted a nonremission pattern according to multinomial logistic regression analysis. STR was achieved by 68 (39.5%) patients with a mean latency of 14.05 years (SD ±12.47 years). Early epilepsy onset, psychiatric comorbid conditions, and a history of FS and generalized tonic-clonic seizures were associated with a lower probability of achieving STR according to a Cox regression proportional hazards model. Antiseizure medication (ASM) withdrawal was attempted in 62 of 172 patients, and seizures recurred in 74.2%. Cluster analysis revealed 2 distinct clusters with 86 patients each. Cluster 2, which we defined as EMA-plus, was characterized by an earlier age at epilepsy onset, higher rate of intellectual disability, EM status epilepticus, generalized paroxysmal fast activity, self-induced seizures, FS, and poor ASM response, whereas cluster 1, the EMA-only cluster, was characterized by a higher rate of seizure remission and more favorable neuropsychiatric outcome., Discussion: Early epilepsy onset was the most relevant prognostic factor for poor treatment response. A long latency between epilepsy onset and ASM response was observed, suggesting the effect of age-related brain changes in EMA remission. Last, our cluster analysis showed a clear-cut distinction of patients with EMA into an EMA-plus insidious subphenotype and an EMA-only benign cluster that strongly differed in terms of remission rates and cognitive outcomes., (© 2022 American Academy of Neurology.)

Background: Resting-state functional magnetic resonance imaging (rsfMRI) reflects spontaneous activation of cortical networks. After stroke, these networks reorganize, both due to structural lesion and reorganization of functional connectivity (FC)., Objective: We studied FC in chronic phase occipital stroke patients with homonymous visual field defects before and after repetitive transorbital alternating current stimulation (rtACS)., Methods: This spin-off study, embedded in the randomized, sham-controlled REVIS trial, comprised 16 chronic occipital stroke patients with visual field defect and 12 healthy control subjects. The patients underwent rsfMRI at baseline, after two weeks of rtACS or sham treatment, and after two months of treatment-free follow-up, whereas the control subjects were measured once. We used a multivariate regression connectivity model to determine mutual prediction accuracy between 74 cortical regions of interest. Additionally, the model parameters were included into a graph to analyze average path length, centrality eigenvector, centrality degree, and clustering of the network. The patients and controls at baseline and the two treatment groups were compared with multilevel modeling., Results: Before treatment, the patients and controls had similar whole-network prediction accuracy and network parameters, whereas centrality eigenvector differed in perilesional regions, indicating local modification in connectivity. In line with behavioral results, neither prediction accuracy nor any network parameter changed systematically as a result of rtACS rehabilitation compared to sham., Conclusions: Whole-network FC showed no difference between occipital stroke patients and healthy population, congruent with the peripheral location of the visual network in relation to the high-density cortical core. rtACS treatment in the given setting did not affect FC.

Background: Although described as non-progressive, alternating hemiplegia of childhood (AHC) can display a sudden deterioration, anecdotally reported mainly in childhood. Outcome in adulthood is uncertain., Objectives: Aim of this study is to describe the long-term follow-up of neurological function in adults with AHC., Methods: Seven adults with AHC were included in this retrospective single-center study. Clinical history and previous investigation data were gathered from the review of medical records. Video-documented neurological examination was performed at the last follow-up visit in four out of the seven reported indivisuals., Results: Over a median follow-up of 16 years, neurological outcome and trajectories were heterogeneous. All individuals showed new neurological signs or symptoms. Three experienced a serious irreversible neurological deterioration after prolonged quadriplegic episodes and/or status epilepticus in their second or third decade. One patient died at age 29., Conclusions: This video-series suggests that AHC in adulthood is not stationary; larger cohorts are needed to identify genotype-phenotype correlations and clinically useful outcome predictors., Competing Interests: The authors report no sources of funding and no conflicts of interest., (© 2021 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

We report new genetic diagnoses of Dravet syndrome in a group of adults with complex epilepsy of unknown cause, under follow-up at a tertiary epilepsy center. Individuals with epilepsy and other features of unknown cause from our unit underwent whole-genome sequencing through the 100 000 Genomes Project. Virtual gene panels were applied to frequency-filtered variants based on phenotype summary. Of 1078 individuals recruited, 8 (0.74%) were identified to have a pathogenic or likely pathogenic variant in SCN1A. Variant types were as follows: nonsense (stopgain) in five (62.5%) and missense in three (37.5%). Detailed review of childhood history confirmed a phenotype compatible with Dravet syndrome. Median age at genetic diagnosis was 44.5 years (range 28-52 years). Tonic-clonic seizures were ongoing in all despite polytherapy including valproate. All had a history of fever sensitivity and myoclonic seizures, which were ongoing in two (25%) and three (37.5%) individuals, respectively. Salient features of Dravet syndrome may be less apparent in adulthood, making clinical diagnosis difficult. Regardless of age, benefits of a genetic diagnosis include access to syndrome-specific treatment options, avoidance of harmful drugs, and monitoring for common complications., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To develop and test wearable monitoring of surface electromyography and motion for detection and quantification of positive and negative myoclonus in patients with progressive myoclonic epilepsy type 1 (EPM1)., Methods: Surface electromyography and three-dimensional acceleration were measured from 23 EPM1 patients from the biceps brachii (BB) of the dominant and the extensor digitorum communis (EDC) of the non-dominant arm for 48 hours. The patients self-reported the degree of myoclonus in a diary once an hour. Severity of myoclonus with action was evaluated by using video-recorded Unified Myoclonus Rating Scale (UMRS). Correlations of monitored parameters were quantified with the UMRS scores and the self-reported degrees of myoclonus., Results: The monitoring-based myoclonus index correlated significantly (p < 0.001) with the UMRS scores (ρ = 0.883 for BB and ρ = 0.823 for EDC) and with the self-reported myoclonus degrees (ρ = 0.483 for BB and ρ = 0.443 for EDC). Ten patients were assessed as probably having negative myoclonus in UMRS, while our algorithm detected that in twelve patients., Conclusions: Wearable monitoring was able to detect both positive and negative myoclonus in EPM1 patients., Significance: Our method is suitable for quantifying objective, real-life treatment effects at home and progression of myoclonus., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.M.R. is a co-founder in Adamant Health Ltd that develops EMG-based analysis software. J.H. Declarations of interest: none. K.S. Declarations of interest: none. L.S. Declarations of interest: none. P.A.K. is a co-founder in Adamant Health Ltd. E.M. Declarations of interest: none. R.K. is a medical advisor of Adamant Health Ltd. RK has received grants from the Academy of Finland and Saastamoinen Foundation, speaker’s honoraria from Eisai, Omamedica, Orion, Sandoz, Sanofi and UCB and honoraria for membership of the advisory boards/consultation of Eisai, Marinus Pharmaceuticals, Orion and UCB., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We describe real-world experience with cannabidiol (CBD) in adults with Dravet Syndrome (DS) via GW Pharma early access programme at two UK neurology centres. Adults with genetically-confirmed DS had CBD added to existing therapy, titrated up to 20 mg/kg, as tolerated. The primary outcome measure was percentage reduction in convulsive seizures. Secondary outcome measures included changes in myoclonic seizures, and in cognition and quality of life as assessed by the Caregiver Global Impression of Change (CGIC), and incidence of adverse events (AEs). 18 adults (7 female; median age 27.5 years; range 20-51) were included. Median follow-up was 176 days. In one, another antiseizure drug, clobazam, was introduced during the programme. 3/17 (17.6%) had >30% reduction in convulsive seizures (range: 87.5-100%). AEs occurred in all, the most common being transaminitis (52.9%). Behavioural AEs led to discontinuation in 3/18 (16.7%), including a seizure-free responder. In 7/18, CBD was stopped due to lack of effect. 8/18 continue on treatment. Improvements in CGIC were reported in 41.2% and 47.1% by physicians and families, respectively. 17.6% achieved sufficient reduction in convulsive seizure frequency to qualify for NHS funding. AEs led to withdrawal in only 16.7%. Close monitoring and dose adjustments of other antiseizure drugs were necessary., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: The term 'precision medicine' describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy., Methods: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management., Results: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%)., Significance: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach., Competing Interests: Competing interests: PS has received speaker fees and participated at advisory boards for Biomarin, Zogenyx, GW Pharmaceuticals, and has received research funding from ENECTA BV, GW Pharmaceuticals, Kolfarma srl., and Eisai., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

In this cohort study, we aim to compare outcomes from coronavirus disease 2019 (COVID-19) in people with severe epilepsy and other co-morbidities living in long-term care facilities which all implemented early preventative measures, but different levels of surveillance. During 25-week observation period (16 March-6 September 2020), we included 404 residents (118 children), and 1643 caregivers. We compare strategies for infection prevention, control, and containment, and related outcomes, across four UK long-term care facilities. Strategies included early on-site enhancement of preventative and infection control measures, early identification and isolation of symptomatic cases, contact tracing, mass surveillance of asymptomatic cases and contacts. We measured infection rate among vulnerable people living in the facilities and their caregivers, with asymptomatic and symptomatic cases, including fatality rate. We report 38 individuals (17 residents) who tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive, with outbreaks amongst residents in two facilities. At Chalfont Centre for Epilepsy (CCE), 10/98 residents tested positive: two symptomatic (one died), eight asymptomatic on weekly enhanced surveillance; 2/275 caregivers tested positive: one symptomatic, one asymptomatic. At St Elizabeth's (STE), 7/146 residents tested positive: four symptomatic (one died), one positive during hospital admission for symptoms unrelated to COVID-19, two asymptomatic on one-off testing of all 146 residents; 106/601 symptomatic caregivers were tested, 13 positive. In addition, during two cycles of systematically testing all asymptomatic carers, four tested positive. At The Meath (TM), 8/80 residents were symptomatic but none tested; 26/250 caregivers were tested, two positive. At Young Epilepsy (YE), 8/80 children were tested, all negative; 22/517 caregivers were tested, one positive. Infection outbreaks in long-term care facilities for vulnerable people with epilepsy can be quickly contained, but only if asymptomatic individuals are identified through enhanced surveillance at resident and caregiver level. We observed a low rate of morbidity and mortality, which confirmed that preventative measures with isolation of suspected and confirmed COVID-19 residents can reduce resident-to-resident and resident-to-caregiver transmission. Children and young adults appear to have lower infection rates. Even in people with epilepsy and multiple co-morbidities, we observed a high percentage of asymptomatic people suggesting that epilepsy-related factors (anti-seizure medications and seizures) do not necessarily lead to poor outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Occipital strokes often cause permanent homonymous hemianopia leading to significant disability. In previous studies, non-invasive electrical brain stimulation (NIBS) has improved vision after optic nerve damage and in combination with training after stroke., Objective: We explored different NIBS modalities for rehabilitation of hemianopia after chronic stroke., Methods: In a randomized, double-blinded, sham-controlled, three-armed trial, altogether 56 patients with homonymous hemianopia were recruited. The three experiments were: i) repetitive transorbital alternating current stimulation (rtACS, n = 8) vs. rtACS with prior cathodal transcranial direct current stimulation over the intact visual cortex (tDCS/rtACS, n = 8) vs. sham (n = 8); ii) rtACS (n = 9) vs. sham (n = 9); and iii) tDCS of the visual cortex (n = 7) vs. sham (n = 7). Visual functions were evaluated before and after the intervention, and after eight weeks follow-up. The primary outcome was change in visual field assessed by high-resolution and standard perimetries. The individual modalities were compared within each experimental arm., Results: Primary outcomes in Experiments 1 and 2 were negative. Only significant between-group change was observed in Experiment 3, where tDCS increased visual field of the contralesional eye compared to sham. tDCS/rtACS improved dynamic vision, reading, and visual field of the contralesional eye, but was not superior to other groups. rtACS alone increased foveal sensitivity, but was otherwise ineffective. All trial-related procedures were tolerated well., Conclusions: This exploratory trial showed safety but no main effect of NIBS on vision restoration after stroke. However, tDCS and combined tDCS/rtACS induced improvements in visually guided performance that need to be confirmed in larger-sample trials.NCT01418820 (clinicaltrials.gov).

Competing Interests: Competing interests: SMS reports representing the Association of British Neurologists and The Royal College of Physicians (London) at the MHRA Valproate Stakeholders Network, is a member of the scientific advisory board of Dravet Syndrome UK, patron of AHC UK, and has received honoraria or grant funding from UCB, Eisai, Vitaflo and Nutricia. SB has received honoraria from UCB. KS and HMC declare no potential competing interests. FR-G is a committee member of the MHRA Neurology, Pain and Psychiatry Expert Advisory Group and MHRA Sodium Valproate Expert Working Group, and council member of ILAE British branch and has received honoraria from LivaNova.

Advances in genetics may enable a deeper understanding of disease mechanisms and promote a shift to more personalised medicine in the epilepsies. At present, understanding of consequences of genetic variants mainly relies on preclinical functional work; tools for acquiring similar data from the living human brain are needed. Transcranial magnetic stimulation (TMS), in particular paired-pulse TMS protocols which depend on the function of cortical GABAergic interneuron networks, has the potential to become such a tool. For this report, we identified and reviewed 23 publications on TMS studies of cortical excitability and inhibition in 15 different genes or conditions relevant to epilepsy. Reduced short-interval intracortical inhibition (SICI) and reduced cortical silent period (CSP) duration were the most commonly reported findings, suggesting abnormal GABA A - (SICI) or GABA B ergic (CSP) signalling. For several conditions, these findings are plausible based on established evidence of involvement of the GABAergic system; for some others, they may inform future research around such mechanisms. Challenges of TMS include lack of complete understanding of the neural underpinnings of the measures used: hypotheses and analyses should be based on existing clinical and preclinical data. Further pitfalls include gathering sufficient numbers of participants, and the effect of confounding factors, especially medications. TMS-EEG is a unique perturbational technique to study the intrinsic properties of the cortex with excellent temporal resolution; while it has the potential to provide further information of use in interpreting effects of genetic variants, currently the links between measures and neurophysiology are less established. Despite these challenges, TMS is a tool with potential for elucidating the system-level in vivo functional consequences of genetic variants in people carrying genetic changes of interest, providing unique insights., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

For enhancing food waste weighing measurements we established a platform (Restaurant Forum RF) for different kinds of food service businesses. Our aim was to explore food waste data, but also to develop a monitoring system by increasing our knowledge about the relevant processes and possible internal barriers. We studied food waste generation and origin in the outlets and how to avoid overproduction of food and buffet line waste. During 2016-2017, a number of outlets (n = 51) conducted food waste measurements over a period of two weeks. The businesses that participated included schools, day-care centres and work place and student canteens, which present sectors that mainly serve a lunch buffet. According to our results, 17.5% of all prepared food ended up as waste, which can be further divided into kitchen waste (2.2%), serving waste (11.3%) and customer leftovers (3.9%). On average, 449 g of food was prepared per portion and 78 g of this ended up as waste. We also studied the mechanisms of waste generation, best practices for decreasing food waste, how staff experienced weighing measurements and how measurement systems can be utilized in food service business management., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We describe the case of a 35-year-old man with focal epilepsy since age 16. Due to a refractory course, several treatments were tried over the years, including insertion of a deep brain stimulator. At the time of his first assessment at our unit, he had recently been diagnosed with hypertension. An MR scan of brain revealed multiple T2 hyperintense white matter lesions, and evidence of previous haemorrhage in the left basal ganglia and pons. On follow-up imaging, the changes were considered to be in keeping with hypertensive arteriopathy. He was referred for further assessment of his hypertension and was found to have a para-aortic paraganglioma. This was excised 16 months after his initial presentation to us. The surgery was associated with an improvement in his seizure control. This case serves as a reminder of the need to be vigilant about the possibility of coexisting conditions in people with epilepsy., Competing Interests: Competing interests: SMS reports grants from Epilepsy Society and the Muir Maxwell Trust during the conduct of the study; personal fees from UCB, Eisai and Nutricia and grants from Vitaflo, outside the submitted work., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Avoidable food waste is produced in the food service sector, with significant ecological and economical impacts. In order to understand and explain better the complex issue of food waste a qualitative study was conducted on the reasons for its generation in restaurants and catering businesses. Research data were collected during three participatory workshops for personnel from three different catering sector companies in Finland. Based on synthesized qualitative content analysis, eight elements influencing production and reduction of food waste were identified. Results revealed the diversity of managing food waste in the food service sector and how a holistic approach is required to prevent and reduce it. It is crucial to understand that food waste is manageable and should be an integral component of the management system. The model of eight factors provides a framework for recognition and management of food waste in the food service sector., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We carried out a project to map the volume and composition of food waste in the Finnish food service sector. The amount, type and origin of avoidable food waste were investigated in 51 food service outlets, including schools, day-care centres, workplace canteens, petrol stations, restaurants and diners. Food service outlet personnel kept diaries and weighed the food produced and wasted during a one-week or one-day period. For weighing and sorting, the food waste was divided into two categories: originally edible (OE) food waste was separated from originally inedible (OIE) waste, such as vegetable peelings, bones and coffee grounds. In addition, food waste (OE) was divided into three categories in accordance with its origins: kitchen waste, service waste and customer leftovers. According to the results, about 20% of all food handled and prepared in the sector was wasted. The findings also suggest that the main drivers of wasted food are buffet services and overproduction., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Occipital stroke often leads to visual field loss, for which no effective treatment exists. Little is known about the potential of non-invasive electric current stimulation to ameliorate visual functions in patients suffering from unilateral occipital stroke. One reason is the traditional thinking that visual field loss after brain lesions is permanent. Since evidence is available documenting vision restoration by means of vision training or non-invasive electric current stimulation future studies should also consider investigating recovery processes after visual cortical strokes. Here, protocols of repetitive transorbital alternating current stimulation (rtACS) and transcranial direct current stimulation (tDCS) are presented and the European consortium for restoration of vision (REVIS) is introduced. Within the consortium different stimulation approaches will be applied to patients with unilateral occipital strokes resulting in homonymous hemianopic visual field defects. The aim of the study is to evaluate effects of current stimulation of the brain on vision parameters, vision-related quality of life, and physiological parameters that allow concluding about the mechanisms of vision restoration. These include EEG-spectra and coherence measures, and visual evoked potentials. The design of stimulation protocols involves an appropriate sham-stimulation condition and sufficient follow-up periods to test whether the effects are stable. This is the first application of non-invasive current stimulation for vision rehabilitation in stroke-related visual field deficits. Positive results of the trials could have far-reaching implications for clinical practice. The ability of non-invasive electrical current brain stimulation to modulate the activity of neuronal networks may have implications for stroke rehabilitation also in the visual domain., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: Do-not-resuscitate orders may be associated with poor outcome in patients with intracerebral hemorrhage because of less active management., Aims: We sought to characterize the practice of issuing do-not-resuscitate orders in intracerebral hemorrhage. We also aimed to identify possible differences in care according to do-not-resuscitate status., Methods: We conducted a retrospective study of all consecutive intracerebral hemorrhage patients admitted to the Meilahti Hospital of the Helsinki University Central Hospital between January 2005 and March 2010. Data obtained from medical records allowed comparison of characteristics of patients and care of do-not-resuscitate and non-do-not-resuscitate patients as well as patients with early (within 24 h) and late (>24 h) do-not-resuscitate decisions. Logistic regression was used to identify factors independently associated with do-not-resuscitate decisions., Results: Of our 1013 patients, a do-not-resuscitate order was issued in 368 (35%), of which 262 (73%) occurred within 24 h from admission. Advanced age (odds ratio 1·06 per year; 95% confidence interval 1·04-1·08), more severe stroke (1·09 per National Institutes of Health Stroke Scale point; 1·06-1·13), and deterioration soon after admission (5·12, 3·33-7·87) had the strongest associations with do-not-resuscitate decisions. Patients with do-not-resuscitate orders received recommended care including stroke unit care (43% vs. 64%; P < 0·001) and prophylaxis for deep venous thrombosis (45% vs. 54%; P = 0·027) less often than non-do-not-resuscitate patients. This was especially the case when the do-not-resuscitate order was issued early., Conclusions: In addition to confirming the role of known intracerebral hemorrhage prognostic factors in do-not-resuscitate decision-making, our results demonstrate that do-not-resuscitate orders led to less active care of intracerebral hemorrhage patients., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

Defects in seven genes encoding sarcomere proteins have been shown to cause hypertrophic cardiomyopathy. To date, only one study reporting defects in the cardiac troponin I gene associated with hypertrophic cardiomyopathy has been published, and the proportion of hypertrophic cardiomyopathy cases caused by defects in this gene is unknown. Therefore, the authors screened 37 unrelated Finnish patients with hypertrophic cardiomyopathy for variants in the cardiac troponin I gene. Exons 1-8 of the troponin I gene were screened with the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method. Five different variants (four intron variants and one silent exon variant) were found. Most variants were also present in control samples and none of the variants co-segregated with the disease in families. The results of the present study indicate that defects in the cardiac troponin I gene do not cause hypertrophic cardiomyopathy in patients from Eastern Finland.

Objectives: The aim of the study was to screen 36 unrelated patients with hypertrophic cardiomyopathy (HCM; 16 familial and 20 sporadic cases) from a genetically homogeneous area in eastern Finland for variants in the cardiac beta-myosin heavy chain (beta-MHC) and alpha-tropomyosin (alpha-TM) genes., Background: Mutations in the beta-MHC and alpha-TM genes have been reported to be responsible for 30% to 40% and less than 5% of familial HCM cases, respectively. However, most genetic studies have included patients from tertiary care centers and are subject to referral bias., Methods: Exons 3-26 and 40 of the beta-MHC gene and the nine exons of the alpha-TM gene were screened with the PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) method. Linkage analyses between familial HCM locus and two intragenic polymorphic markers (MYO I and MYO II) of the beta-MHC gene were performed in 16 familial HCM kindreds., Results: A previously reported Arg719Trp (arginine converted to tryptophan in codon 719) mutation of the beta-MHC gene was found in one proband and two relatives. In addition, a novel Asn696Ser (asparagine converted to serine in codon 696) substitution was found in one HCM patient. No linkage between familial HCM and the beta-MHC gene was observed in 16 familial kindreds. A previously reported Aspl75Asn (aspartic acid converted to asparagine in codon 175) mutation of the alpha-TM gene was found in four probands and 16 relatives. Mutations in the beta-MHC and alpha-TM genes accounted for 6% and 25% familial HCM cases and 3% and 11% of all cases, respectively., Conclusions: Our results indicate that the beta-MHC gene is not the predominant gene for HCM in the Finnish population, whereas HCM caused by the Aspl75Asn mutation of the a-TM gene is more common than previously reported.