Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper.

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed.

Short- and long-interval intracortical inhibition in EPM1 is related to genotype.

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.

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

When is it time for palliative and end-of-life care in status epilepticus?

Status epilepticus (SE) is a neurological emergency characterized by high rates of short-term and long-term morbidity and mortality. Status epilepticus seems to be a marker of the severity of other underlying conditions rather than a determinant of death on its own. Careful diagnosis and acute treatment of complications and causes of death to SE or its underlying etiology will enable the differentiation of SE patients that would benefit from different levels of treatment intensity. All SE patients should be treated actively with first- and second-line drugs as early as possible. For cases in which seizures continue after second-line treatment, the current guidelines fail to offer possibilities other than the active path with general anesthesia and intensive care unit (ICU) care. However, the intensity of care should be evaluated before starting ICU care or in unclear cases with the time-limited trial at ICU. There are now multiple possibilities for specialty palliative SE care that include sequential and add-on use of second-line drugs and palliative sedation at the ward. If ICU care is prolonged, the patient's status needs to be constantly re-evaluated and communicated to the family. When patients exhibit multiple predictors of mortality and poor functional outcomes, they should be allowed to have a natural death in a peaceful environment without unnecessarily prolonged suffering. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

The burden of chronic drug-refractory focal onset epilepsy: Can it be prevented?

Despite the many therapeutic options for epilepsy available today, a third of patients still have poorly controlled epilepsy. Over the years, their transition through lines of treatment exposes them to increased risk of disease progression, mortality, morbidity, mental distress, and not least significantly impaired quality of life (QoL). The present review explores the multiple factors contributing to the impairment of health-related QoL in PWE-including both seizure-related and non seizure-related. The analysis aims to identify potential areas of intervention and strategies for a more holistic approach to epilepsy care and inform policy-makers and healthcare providers in their approach to this condition.

Adult onset epilepsy incidence in Finland over 34 years: A nationwide registry study.

BACKGROUND AND PURPOSE: The incidence of epilepsy is decreasing among the working-aged in high-income countries, but previous studies have reported conflicting results in Finland. METHODS: A nationwide population-based cross-sectional analysis was made of annual epilepsy drug reimbursement rights frequency data from the Social Insurance Institution of Finland, the national authority, between 1986 and 2019. All persons at least 20 years of age living in Finland during the study period were included. RESULTS: Based on the analysis of 77,939 new reimbursement rights, crude incidence was 57.4/100,000 (95% confidence interval [CI] = 57.0-57.8) person-years, and age-standardized (to the European Standard Population 2013) incidence was 51.6/100,000 person-years. Both crude (r = 0.62, p = 0.00009) and standardized (r = 0.65, p = 0.00003) incidence increased over time. Incidence increased in both men (from 66.4 to 71.6/100,000, r = 0.51, p = 0.002) and women (from 51.5 to 55.3/100,000, r = 0.68, p < 0.00001). The mean male to female incidence rate ratio was 1.28 (95% CI = 1.26-1.30, range = 1.15-1.41), but decreased during the study period (r = -0.47, p = 0.006). Incidence decreased in those 20-59 years old but increased in all older age groups. This development was similar between sexes. CONCLUSIONS: The incidence of adult onset epilepsy in Finland increased in people older than 60 years and decreased in the 20-59-year age group during the study period. These trends were similar between sexes. Therefore, etiological epilepsy trends in the elderly need to be studied further to plan public health measures to prevent epilepsy in this age group.

Comorbidities in patients with Unverricht-Lundborg disease (EPM1).

BACKGROUND: Unverricht-Lundborg disease (EPM1) typically leads to accumulating disability. Disability may also be caused by comorbidities but there are no data available on these. AIMS OF THE STUDY: To investigate the frequency of comorbidities in EPM1. METHODS: Comorbidity data of a previously described cohort of 135 Finnish patients with EPM1 were retrieved from neurological, surgical (including subspecialities), internal medicine (including subspecialities) and intensive care patient charts of the treating hospitals. RESULTS: Mean follow-up time was 31.4 years (SD 12.4 years, range 6.8-57.8 years), during which at least one comorbidity was observed in 107 patients (79%) and three or more in 53 (39%). The most common diagnostic categories were external injuries, mental and behavioural disorders and endocrine, nutritional and metabolic diseases. The most common single comorbid diagnosis was a fracture of the ankle (in 19% of all patients). The second most common single comorbid diagnosis in the cohort was diabetes (in 13% of all patients), and the third was depression, recorded for 13% of the cohort. Malignancies and cardiovascular end-organ damage were rare, whereas phimosis/paraphimosis appeared more common than in general population. CONCLUSIONS: Patients with EPM1 often have comorbidities. Trauma and mental health risks should be especially followed and acted upon. Further studies are needed to more accurately comorbidity risks, characteristics and patient needs.

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.

Cognitive functioning in progressive myoclonus epilepsy type 1 (Unverricht-Lundborg Disease, EPM1).

OBJECTIVE: The aim of this neuropsychological study of a large cohort of patients with progressive myoclonus epilepsy type 1 (Unverricht-Lundborg disease, EPM1) was to characterize the cognitive function of EPM1 patients and to explore the association between the disability caused by the disease and cognitive performance. METHOD: Sixty-eight genetically verified EPM1 patients homozygous for the expansion mutation in the CSTB gene (37 males and 31 females aged 35 ±â€¯11) participated in a neuropsychological assessment of intellectual ability, verbal memory, and executive and psychomotor function. The clinical evaluation comprised administering (and video-recording) the unified myoclonus rating scale (UMRS) to assess the severity of each patient's myoclonus. Forty-six healthy volunteers (19 males and 27 females aged 32 ±â€¯11) served as the control group for the neuropsychological tests. RESULTS: The cognitive performance of the EPM1 patient group was impaired. Verbal Intelligence Quotient (VIQ) was below the average range (VIQ < 85) in 49% of the patients; further, Performance Intelligence Quotient (PIQ) was below average in 75% of the patients. The patients performed worse than the controls in both immediate and delayed story recall (p = 0.001); however, in the word list learning task, the patients performed only slightly worse than the controls. The one-hour delayed recall of the learned words was similar in both groups, and the percentage of retained words and story contents did not differ between the patients and controls. The patients were impaired in all of the executive function tests as well as in the psychomotor speed tests (p < 0.001 for all). Also, the patients' simple psychomotor speed in the tapping task was significantly slowed in comparison to controls (p < 0.001). CONCLUSION: The patients had impaired performance in the majority of the cognitive measures; they showed the highest level of impairment in all the executive function tests and in the psychomotor speed tests. The measures of these cognitive domains are timed-therefore, it is clear that severe myoclonus limits patients' performance. In contrast, verbal memory, especially delayed recall, was the least affected cognitive domain.

The ENIGMA-Epilepsy working group: Mapping disease from large data sets.

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.

Focal nonmotor versus motor seizures: The impact on diagnostic delay in focal epilepsy.

OBJECTIVE: To test the hypothesis that people with focal epilepsy experience diagnostic delays that may be associated with preventable morbidity, particularly when seizures have only nonmotor symptoms, we compared time to diagnosis, injuries, and motor vehicle accidents (MVAs) in people with focal nonmotor versus focal seizures with motor involvement at epilepsy onset. METHODS: This retrospective study analyzed the enrollment data from the Human Epilepsy Project, which enrolled participants between 2012 and 2017 across 34 sites in the USA, Canada, Europe, and Australia, within 4 months of treatment for focal epilepsy. A total of 447 participants were grouped by initial seizure semiology (focal nonmotor or focal with motor involvement) to compare time to diagnosis and prediagnostic injuries including MVAs. RESULTS: Demographic characteristics were similar between groups. There were 246 participants (55%) with nonmotor seizures and 201 participants (45%) with motor seizures at epilepsy onset. Median time to diagnosis from first seizure was 10 times longer in patients with nonmotor seizures compared to motor seizures at onset (P < .001). The number and severity of injuries were similar between groups. However, 82.6% of MVAs occurred in patients with undiagnosed nonmotor seizures. SIGNIFICANCE: This study identifies reasons for delayed diagnosis and consequences of delay in patients with new onset focal epilepsy, highlighting a treatment gap that is particularly significant in patients who experience nonmotor seizures at epilepsy onset.

Lacosamide in patients with epilepsy of cerebrovascular etiology.

OBJECTIVES: To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE). MATERIALS AND METHODS: Exploratory post hoc analyses of a double-blind, initial monotherapy trial of lacosamide vs carbamazepine-controlled release (carbamazepine-CR) (SP0993; NCT01243177); a double-blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline. RESULTS: In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine-CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine-CR) reported treatment-emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine-CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine-CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure-free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure-free. CONCLUSIONS: These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine-CR.

Cognitive functioning in new-onset juvenile myoclonic epilepsy.

PURPOSE: Juvenile myoclonic epilepsy (JME) is a common genetic generalized epilepsy syndrome. Adult patients with JME have shown a neuropsychological profile suggestive of subtle frontal dysfunction, but studies of cognitive functioning in the early phases of JME are rare. We analyzed the cognitive performance data of 18 patients who had undergone a neuropsychological assessment either at the time of JME diagnosis and before the initiation of an antiepileptic drug (AED) treatment (11 patients) or during the first 6 years after JME diagnosis (seven patients). METHODS: The cognitive performance of the18 patients with JME (mean age: 18.1, range: 15-33 years) and 18 healthy controls (mean age: 18.7, range: 15-25 years) was compared in a retrospective study. The assessed cognitive domains were visuomotor speed, attention, executive function, and verbal memory. RESULTS: The patients with JME and the healthy controls did not differ in any of the assessed cognitive domains. The clinical variables did not correlate to cognitive performance. Furthermore, cognitive performance did not differ between the patients evaluated at the time of diagnosis and before the initiation of AEDs and the patients evaluated during the first 6 years after diagnosis and with an AED treatment. CONCLUSIONS: The cognitive performance of patients with new-onset JME was similar to healthy controls. We could not detect the frontal dysfunction that has been suggested to be associated with JME. Patients were in adolescence or early adulthood with a short duration of epilepsy, which may have contributed to the discovery of no cognitive impairments.

Perampanel for treatment of status epilepticus in Austria, Finland, Germany, and Spain.

OBJECTIVE: Novel treatments are needed to control treatment-resistant status epilepticus (SE). We report a summary of clinical cases where perampanel was used in established SE, refractory SE (RSE), or super-refractory SE (SRSE). METHODS: Medical records were retrospectively reviewed for perampanel administration in SE at five European hospitals between 2011 and 2015. RESULTS: Of 1319 patients identified as experiencing SE, 52 (3.9%) received perampanel. Median latency from SE onset to perampanel initiation was 10 days. Patients with SE had previously failed benzodiazepines (when received) and a median of five other antiepileptic drugs (AEDs). Median initial perampanel dose was 6 mg/d, up-titrated to a median maximum dose of 10 mg/d. Perampanel was the last drug added in 32/52 (61.5%) patients, with response attributed to perampanel in 19/52 (36.5%) patients. A greater proportion of perampanel non-responders had SRSE (51.5%; 17/33) vs perampanel responders (31.6%; 6/19), and had failed a higher mean number of AEDs before initiating perampanel (5.9 vs 5.1, respectively). Most commonly reported adverse effects during perampanel treatment were dizziness (n = 1 [1.9%]) and somnolence (n = 1 [1.9%]). No serious adverse effects were documented, and none led to discontinuation of perampanel. CONCLUSIONS: Perampanel was administered to patients with established SE, RSE, or SRSE at greater initial doses than those administered in clinical practice to patients with epilepsy. The SE cases reported here represent a refractory and heterogeneous population, and rate of seizure cessation attributed to perampanel treatment (36.5%) represents a notable response. These data should be confirmed in a larger patient population.

Management of prolonged epileptic seizures and status epilepticus in palliative care patients.

Prolonged seizures and status epilepticus (SE) are relevant problems in palliative care. Timely recognition and effective early treatment with first- and second-line antiepileptic drugs (AEDs) may prevent unnecessary hospitalizations. Seizures should be recognized and addressed like any other symptom that causes discomfort or reduces quality of life. Use of alternative AED administration routes (buccal, intranasal, or subcutaneous) may offer possibilities for effective and individualized AED therapy, even during the last days of life. In hospice or home care, however, also intravenous treatment is possible via vascular access devices for long-term use. Aggressive unlimited intensive care unit (ICU) treatment of refractory SE in palliative patients is mostly not indicated. At worst, intensive care can be futile and possibly harmful: death in the ICU is often preceded by long and aggressive treatments. Metastatic cancer, old age, high severity of acute illness, overall frailty, poor functional status before hospital admission, and the presence of severe comorbidities all increase the probability of poor outcome of intensive care. When several of these factors are present, consideration of withholding intensive care may be in the patient's best interests. Anticipated outcomes influence patients' preferences. A majority of patients with a limited life expectancy because of an incurable disease would not want aggressive treatment, if the anticipated outcome was survival but with severe functional impairment. Doctors' perceptions about their patients' wishes are often incorrect, and therefore, advance care planning including seizure management should be done early in the course of the disease. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Incidence of the different stages of status epilepticus in Eastern Finland: A population-based study.

OBJECTIVE: The objective of this study was to determine the incidence in Eastern Finland of the different stages of status epilepticus (SE): 1) at the early stage of SE (a prolonged seizure lasting over 5 min);, 2) refractory SE (RSE), and 3) super-refractory SE (SRSE). METHODS: Firstly, we conducted a retrospective study on the incidence and outcome of intensive care unit (ICU)-treated RSE and SRSE in the adult population (≥16 years) in Kuopio University Hospital (KUH)'s special care responsibility area (840,000 inhabitants). Secondly, we conducted a prospective study using the International League Against Epilepsy (ILAE)'s new definition for SE (prolonged seizures lasting over 5 min), in adult (≥16 years) patients in the KUH municipality district (North Savo, 248,000 inhabitants). RESULTS: The retrospective study on ICU-treated RSE and SRSE from 2010 to 2012 identified 75 patients with RSE, of whom 21% were treated as SRSE, resulting in an annual age-adjusted incidence of ICU-treated RSE of 3.0/100,000 (95% confidence interval [CI]: 2.4-3.8) and 0.6/100,000 (95% CI: 0.4-1.0) for SRSE. In the prospective study of early stage SE (seizures lasting over 5 min), we identified 151 consecutive episodes during the 9-month study period in 2015, corresponding to an annual age-adjusted incidence of 81.1/100,000 (95% CI: 75.8-87.0). In this study, 11 seizure episodes became refractory, resulting in an age-adjusted incidence of RSE of 6.0/100,000 (95% CI: 3.4-10.4), of which seven were treated in the ICU [3.8/100,000 (95% CI: 1.8-7.8)], four were treated palliatively [2.2/100,000 (95% CI: 0.82-5.7)], and two evolved to SRSE [1.1/100,000 (95% CI: 0.3-4.3)]. CONCLUSIONS: The new ILAE 2015 definition of SE resulted in a four-fold increase in incidence of SE compared to the earlier 30-min definition reported earlier in Europe. In the epidemiology of RSE, the incidence of ICU-treated RSE, palliatively treated RSE, and SRSE needs to be separated. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures.

Abnormal motor cortical adaptation to external stimulus in Unverricht-Lundborg disease (progressive myoclonus type 1, EPM1).

Unverricht-Lundborg disease (EPM1) is associated with progressive functional and anatomic changes in the thalamus and motor cortex. The neurophysiological mechanisms behind the impaired thalamocortical system were studied through short-term adaptation of the motor cortex to transcranial magnetic stimulation (TMS) via repetition suppression (RS) phenomenon. RS is considered to be related to neural processing of external stimuli. We hypothesized that this neural processing is progressively impaired in EPM1 from adolescence to adulthood. Eight adult patients with EPM1 (age: 40 ± 13 yr), six adolescent patients with EPM1 (age: 16 ± 1 yr), and ten adult controls (age: 35 ± 12 yr) were studied using navigated TMS and RS study protocol including trains of four repeated stimuli with intertrain interval of 20 s and interstimulus interval of 1 s. Changes in RS were investigated from adolescence to adulthood in EPM1 by comparing with adult controls. In controls, the RS was seen as 50-55% reduction in motor response amplitudes to TMS after the first stimulus. RS was mild or missing in EPM1. RS from first to second stimulus within the stimulus trains was significantly stronger in adolescent patients than in adult patients ( P = 0.046). Abnormal RS correlated with the myoclonus severity of the patients. In agreement with our hypothesis, neural processing of external stimuli is progressively impaired in EPM1 possibly due to anatomically impaired thalamocortical system or inhibitory tonus preventing sufficient adaptive reactiveness to stimuli. Our results suggest that RS abnormality might be used as a biomarker in the therapeutic trials for myoclonus. NEW & NOTEWORTHY Unverricht-Lundborg disease (EPM1) is associated with impaired thalamocortical function, which we studied in 8 adult and 6 adolescent patients and in 10 adult controls through repetition suppression (RS) of the motor cortex. We hypothesized that neural processing is progressively impaired in EPM1 from adolescence to adulthood. RS was normal in controls, whereas it was mild or missing in EPM1. Stronger RS was seen in adolescent patients than in adult patients correlating with the myoclonus severity.

Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG1 are not associated with increased risk for valproate-induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy.

OBJECTIVE: Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma (POLG1) increase the risk for liver injury for patients on valproate (VPA) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in POLG1 and determined the occurrence of VPA-induced hepatotoxicity (VHT) or pancreatic toxicity in a cohort of patients with epilepsy. METHODS: Patients with epilepsy (N = 367) were retrospectively identified from medical record files and screened for mutations in POLG1. Patients who had received VPA monotherapy and carried either of the two variants, p.Q1236H or p.E1143G, without other pathogenic mutations in POLG1 (n = 33, variant group) and patients without these variants (n = 28, nonvariant group) were included in the study. Clinical data on epilepsy, characteristics of VPA treatment, risk factors for VHT, laboratory data on liver and pancreas functions, and adverse effects were collected. RESULTS: A total of 122 patients had either the POLG1 p.Q1236H (n = 99) or p.E1143G (n = 24) variant in the heterozygous or homozygous state. Transient liver dysfunction was identified in three (n = 33, 9.1%) variant group patients and in one (n = 28, 3.6%) nonvariant group patient (P = 0.62). Mild to moderate elevations in liver enzymes were encountered in both groups. Furthermore, two patients on VPA polytherapy developed acute pancreatitis, and two pediatric patients with heterozygous p.Q1236H variants and mutations in IQSEC2 and GLDC, respectively, had elevated levels of VPA metabolites in urine, elevated plasma glycine, and/or increased acylglycine excretion. SIGNIFICANCE: POLG1 p.Q1236H and p.E1143G variants could not be identified as statistically significant risk factors for VHT or pancreatic toxicity. We suggest that VPA treatment could be suitable for patients who harbor these common variants in the absence of other pathogenic mutations in POLG1.

Antiepileptic drug treatment of generalized tonic-clonic seizures: An evaluation of regulatory data and five criteria for drug selection.

BACKGROUND: A generalized tonic-clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper. METHODS: Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs). RESULTS: (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs. CONCLUSION: Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices.

Current standards of neuropsychological assessment in epilepsy surgery centers across Europe.

We explored the current practice with respect to the neuropsychological assessment of surgical epilepsy patients in European epilepsy centers, with the aim of harmonizing and establishing common standards. Twenty-six epilepsy centers and members of "E-PILEPSY" (a European pilot network of reference centers in refractory epilepsy and epilepsy surgery), were asked to report the status of neuropsychological assessment in adults and children via two different surveys. There was a consensus among these centers regarding the role of neuropsychology in the presurgical workup. Strong agreement was found on indications (localization, epileptic dysfunctions, adverse drugs effects, and postoperative monitoring) and the domains to be evaluated (memory, attention, executive functions, language, visuospatial skills, intelligence, depression, anxiety, and quality of life). Although 186 different tests are in use throughout these European centers, a core group of tests reflecting a moderate level of agreement could be discerned. Variability exists with regard to indications, protocols, and paradigms for the assessment of hemispheric language dominance. For the tests in use, little published evidence of clinical validity in epilepsy was provided. Participants in the survey reported a need for improvement concerning the validity of the tests, tools for the assessment of everyday functioning and accelerated forgetting, national norms, and test co-normalization. Based on the present survey, we documented a consensus regarding the indications and principles of neuropsychological testing. Despite the variety of tests in use, the survey indicated that there may be a core set of tests chosen based on experience, as well as on published evidence. By combining these findings with the results of an ongoing systematic literature review, we aim for a battery that can be recommended for the use across epilepsy surgical centers in Europe.