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The lack of ideal measurement of treatment efficacy is a well acknowledged problem in the epilepsy community, both in clinical care and clinical trials. Whilst still the current gold-standard, self-reported seizure frequency significantly underestimates the true number of seizures and does not account for any other at least equally important outcome parameters, such as neurodevelopment and cognition. With the rise of disease modifying treatments, the need for more reliable endpoints in practice and clinical trials becomes more pressing. In this paper we assembled an expert panel to discuss the nature of these needs, current limitations, and obstacles based on a survey amongst these experts who were queried about the most important issues regarding the use of electroencephalography (EEG) parameters as endpoints in clinical drug and device development.A structured survey was sent to a group of experts in the design and conduct of epilepsy trials in adults and children. This was followed by a virtual in-person meeting discussing the results of the trial and identifying a list of most important issues.Six clinical trialists and 5 individuals from pharmaceutical companies returned the survey containing 14 questions, and 8 clinical trialists and 10 pharma-representatives attended the meeting. Three main issues were identified (1) lack of accuracy of seizure diaries due to nocturnal seizures, subtle motor seizures, impairment of consciousness and lack of awareness of the seizure by the patient (2) inter-rater variability of EEG assessment (3) lack of standardization regarding definition(s) of seizures (clinical and electrographic), EEG recording methods and EEG data management. Recommended solutions included (1) validation of EEG parameters as biomarkers and use of wearables (2) development of a manual that describes EEG rating criteria, protocol for validation by 1 central reader and use of a resolution of disagreements reporting template (3) standardization of EEG recording, data management and reporting.Current developments in research and technology seem promising to advance the use of EEG parameters as potential endpoints and offer partial solutions to the current needs. However, continuous, focused and collaborative efforts of all stakeholders (academia, industry and regulatory agencies) are needed to formulate guidelines, validate emerging technologies and approve them for use in trials. It is the intent of this opinion "position paper" to stimulate those efforts.

Several emergencies were admitted less frequently to the hospital during the coronavirus disease 2019 (COVID‐19) pandemic. To investigate whether this also occurred with status epilepticus (SE) we compared admissions due to first SE from March to April 2020 (“Time of COVID,” TOC) with January to February 2020 (“pre‐COVID,” preCOV). We also compared admission numbers in TOC and preCOV with the respective 2‐month periods in 2018 and 2019 in a retrospective cohort analysis. Two investigators independently searched the hospital patient database for various forms of SE. There was no significant change in the 2‐month incidences of first SE in the city of Salzburg from preCOV of 6.1 (95% confidence interval [CI] 2.9‐12.3) to TOC of 6.9/100 000 adults (95% CI 3.4‐13.3). Admission numbers did not differ significantly from previous years. Estimated adjusted incidence was in line with a recent 5‐year epidemiological study in Salzburg. However, a trend toward less‐frequent nonconvulsive SE (NCSE) and loss of female predominance were indirect hints of underdiagnosing SE. In contrast to other medical conditions, SE most often presents clinically with impaired consciousness, which may promote admission to emergency departments even in times of lock‐down. Further research of medical support of women and patients with NCSE during pandemic‐related restrictions is warranted.

Summary Objective In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic–clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population‐based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome. Methods We conducted a retrospective population‐based incidence study of all adult patients with SE residing in the city of Salzburg between January 2011 and December 2015. Patients with hypoxic encephalopathy were excluded. SE was defined and classified according to the ILAE 2015. Results We identified 221 patients with a median age of 69 years (range 20‐99 years). The age‐ and sex‐adjusted incidence of a first episode of SE, NCSE, and SE with prominent motor phenomena (including CSE) was 36.1 (95% confidence interval [CI] 26.2‐48.5), 12.1 (95% CI 6.8‐20.0), and 24.0 (95% CI 16.0‐34.5; including CSE 15.8 [95% CI 9.4‐24.8]) per 100 000 adults per year, respectively. None of the patients whose SE ended with or consisted of only bilateral tonic–clonic activity died. In all other clinical presentations, case fatality was lower in awake patients (8.2%) compared with patients with impaired consciousness (33%). Significance This first population‐based study using the ILAE 2015 definition and classification of SE found an increase of incidence of 10% compared to previous definitions. We also provide epidemiologic evidence that different patterns of status evolution and LOCs have strong prognostic implications.

Objective: The European Union–funded E-PILEPSY network (now continuing within the European Reference Network for rare and complex epilepsies [EpiCARE]) aims to harmonize and optimize presurgical diagnostic procedures by creating and implementing evidence-based guidelines across Europe. The present study evaluates the current evidence on the diagnostic accuracy of long-term video-electroencephalographic monitoring (LTM) in identifying the epileptogenic zone in epilepsy surgery candidates. Methods: MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched for relevant articles. First, we used random-effects meta-analytical models to calculate pooled estimates of sensitivity and specificity with respect to postsurgical seizure freedom. In a second phase, we analyzed individual patient data in an exploratory fashion, assessing diagnostic accuracy within lesional and nonlesional temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE) patients. We also evaluated seizure freedom rate in the presence of “localizing” or “nonlocalizing” LTM within each group. The quality of evidence was assessed using the QUADAS-2 tool and the GRADE approach. Results: Ninety-four studies were eligible. Forty-four were included in sensitivity meta-analysis and 34 in specificity meta-analysis. Pooled sensitivity was 0.70 (95% confidence interval [CI] = 0.60-0.80) and specificity was 0.40 (95% CI = 0.27-0.54). Subgroup analysis was based on individual data of 534 patients (41% men). In lesional TLE patients, sensitivity was 0.85 (95% CI = 0.81-0.89) and specificity was −0.19 (95% CI = 0.13-0.28). In lesional ETLE patients, a sensitivity of 0.47 (95% CI = 0.36-0.58) and specificity of 0.35 (95% CI = 0.21-0.53) were observed. In lesional TLE, if LTM was localizing and concordant with resection site, the seizure freedom rate was 247 of 333 (74%), whereas in lesional ETLE it was 34 of 56 (61%). The quality of evidence was assigned as “very low.”. Significance: Long-term video-electroencephalographic monitoring is associated with moderate sensitivity and low specificity in identification of the epileptogenic zone. Sensitivity is remarkably higher in lesional TLE compared to lesional ETLE. Substantial heterogeneity across the studies indicates the need for improved design and quality of reporting.

Background Neuronal ceroid lipofuscinosis (NCL) is a hereditary lysosomal storage disease with progressive brain neurodegeneration. Mutations in ceroid lipofuscinosis neuronal protein 5 (CLN5) cause CLN5 disease, a severe condition characterized by seizures, visual failure, motor decline, and progressive cognitive deterioration. This study aimed to identify causative gene variants in Pakistani consanguineous families diagnosed with NCL. Methods After a thorough clinical and neuroradiological characterization, whole exome sequencing (WES) was performed in 3 patients from 2 unrelated families. Segregation analysis was subsequently performed through Sanger sequencing Analysis WES led to the identification of the 2 novel homozygous variants c.925_926del, (p.Leu309AlafsTer4) and c.477 T > C, (p.Cys159Arg). Conclusion In this study, we report two novel CLN5 cases in the Punjab region of Pakistan. Our observations will help clinicians observe and compare common and unique clinical features of NCL patients, further improving our current understanding of NCL., Highlights • Neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease. • It is characterized by progressive brain neurodegeneration. • WES was performed in 3 patients from 2 unrelated Pakistani families. • WES led to the identification of the 2 novel homozygous variants. • We report a novel CLN5 case in the Punjab region of Pakistan.

Brivaracetam (BRV) is a high-affinity synaptic vesicle glycoprotein 2A ligand that is structurally related to levetiracetam (LEV). Compared to LEV, its affinity to the ligand is >10%-30% higher. Due to its more lipophilic characteristics, it might have a quicker penetration across the blood-brain barrier and potentially also a stronger anticonvulsant effect. Thus, we aimed to explore its usefulness in the treatment of status epilepticus (SE). We retrospectively assessed treatment response and adverse events in adjunctive treatment with intravenous BRV in patients with SE from January 2016 to July 2017 at our institution. Seven patients aged median 68 years (range = 29-79) were treated with intravenous BRV. Three patients had SE with coma and four without. SE arose de novo in two patients; etiology was remote symptomatic in four patients and progressive symptomatic in one patient. The most frequent etiology was remote vascular in two patients. BRV was administered after median four antiepileptic drugs (range = 2-11). Time of treatment initiation ranged from 0.5 hours to 105 days (median = 10.5 hours). Immediate clinical and electrophysiological improvement was observed in two patients (29%). Median loading dose was 100 mg intravenously over 15 minutes (range = 50-200 mg), titrated up to a median dose of 100 mg/d (range = 100-300). Median Glasgow Outcome Scale score was 3 (range = 3-5), with an improvement in 86% of patients compared to admission. We observed no adverse events regarding cardiorespiratory function. BRV might have potential as a novel antiepileptic drug in early stages of SE. Its potential may lie its ability to cross the blood-brain barrier more quickly than LEV and its favorable safety profile. Prospective studies for the use of BRV in SE are required.

Summary Objective Safety in epilepsy monitoring units (EMUs) has become an increasing concern because adverse events occur in up to 10% of patients undergoing long‐term video EEG in EMUs. The aim of this study was to assess the effectiveness of a specific safety protocol in an EMU. Methods We retrospectively assessed the adverse event rates in a group without (group 1, 84‐month period, Innsbruck, Austria) and a group with (group 2, 33‐month period, Salzburg, Austria) personalized safety measures utilizing a standardized protocol for long‐term epilepsy monitoring in high‐risk patients. Differences in adverse event rates during and after long‐term video EEG between the two groups were calculated and compared. Results In group 1, 44/507 (9%, 95% confidence interval [CI] 6.5–11.5%) patients experienced 53 adverse events: 20/507 (4%, 95% CI 2.6–6.0%) patients had psychiatric events, 15/507 (3%, 95% CI 1.8–4.8%) patients sustained a total of 19 injuries during seizures, and 10/507 (2%, 95% CI 1.1–3.6%) patients had 13 episodes of status epilepticus; one adverse event was treatment‐related (valproic acid–induced encephalopathy; 1/507, 0.2%, 95% CI 0.0–1.1%). By using the new safety protocol in group 2, the adverse event rate was only 5% (95% CI 3.4–7.6%; 30 adverse events in 26/491; 45% reduction; p = 0.036), in contrast. These events included 13 psychiatric complications in 13/491 (2%, 95% CI 1.6–4.5%, p = 0.252) patients, 12 seizure‐related injuries in 9/491 (2%, 95% CI 1.0–3.4%, p = 0.250) patients, and 5 episodes of status epilepticus in 4/491 (1%, 95% CI 0.3–2.1%, p = 0.120) patients. Significance Implementation of personalized safety measures in high‐risk patients resulted in a clinically relevant reduction of adverse events in the EMU. Safety protocols are a valid tool to reduce the occurrence of adverse events in EMUs.

The non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) - receptor antagonist perampanel (PER) was approved in 2015 for treatment of primary generalized tonic-clonic seizures (pGTCS). The aim of this narrative review is to summarize available data on pharmacological properties, efficacy and tolerability of PER in pGTCs.Data sources included MEDLINE, EMBASE, Google Scholar and ClinicalTrials.gov, conference proceedings of the ILAE congresses and the most recent conference proceedings of the American Epilepsy Society (2013 to 2015).A placebo-controlled clinical phase III study including 164 patients (≥ 12 years) with pGTCS in idiopathic generalized epilepsies (IGE) demonstrated efficacy of PER in reducing pGTCS with good tolerability profile, and without aggravating absence seizures or myoclonic seizures. Dizziness, the main adverse event (AE), can be avoided by bedtime administration. Psychiatric AEs ranging from mild depression to aggression and suicidal attempts should be especially monitored in patients with a history of psychiatric disorders. Co-administration of enzyme inducing antiepileptic drugs (AEDs) might decrease PER plasma levels and make dose adjustment necessary. A reduced efficacy of progesterone-containing oral contraceptives should be considered when administering PER to young women. There is lack of evidence on PER treatment in pregnancy. Although no teratogenic effects were observed in animal models, PER is not recommended for women of childbearing age without contraception.

OBJECTIVES: Total anomalous pulmonary venous connection (TAPVC) occurs as isolated cases, in combination with single ventricle physiology, and may be complicated by pulmonary venous obstruction. We sought to identify potential risk factors for long-term mortality and reoperations. METHODS: Data from 193 consecutive patients who had undergone repair of TAPVC between 1974 and 2011 were analysed using multivariate Cox regression. Mean follow-up time was 15.0 ± 11.0 years, 95% complete. RESULTS: Survival was 82.7 ± 2.9% at 20 years. Single ventricle physiology (5.9% of the patients, P< 0.001) emerged as the only significant risk factor for mortality in multivariate analyses. Freedom from cardiac reoperation was 82.2 ± 3.3% at 20 years. Single ventricle physiology (P< 0.001) was the only risk factor for cardiac reoperations in multivariate analyses. Freedom from reoperations for pulmonary venous obstruction was 90.4 ± 2.5% at 20 years. An age at operation of ≤30 days (52.8% of the patients, P= 0.007) was the only risk factor for reoperations for pulmonary venous obstruction in univariate analyses. In patients with isolated TAPVC (n= 177), preoperative pulmonary venous obstruction (53.7% of the patients, P= 0.030) and deep hypothermic circulatory arrest (78.5% of the patients, P= 0.017) emerged as risk factors for mortality in univariate analyses. An age at operation of ≤30 days (53.7% of the patients, P= 0.022) was the only risk factor for reoperations for pulmonary venous obstruction in univariate analyses. CONCLUSIONS: Survival into the third decade without reoperations is excellent in patients with isolated TAPVC without preoperative pulmonary venous obstruction, irrespective of the type of anomalous connection. In contrast, survival of patients with TAPVC and single ventricle physiology is among the poorest of all congenital heart defects. Reoperations for pulmonary venous obstruction are rare and are predominantly required in patients who were operated on as neonates. Survival may be improved by using a strategy of low-flow cardiopulmonary bypass.