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Abstract Introduction The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). Methods In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. Discussion This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. Trial registration Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Background and Objectives: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice., Methods: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes., Results: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years ( p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years ( p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported., Discussion: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation., Classification of Evidence: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy., Trial Registration Information: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: No international guideline is available for minimum safety measures at epilepsy monitoring units (EMUs), although recommendations for preferred practices exist. These are mostly based on expert opinion, without evidence of effectiveness. We do not apply all of these preferred practices at our EMU setting. We audited adverse events and diagnostic utility at our EMU over one year., Methods: From May 2018 to May 2019, we prospectively collected data concerning adverse events and diagnostic utility of all EMU admissions (noninvasive video-electroencephalogram (EEG) recordings); during these admissions, individuals can be ambulant within their EMU room., Results: There were 1062 admissions comprising 1518 EMU days. In 2% of the admissions, a complication occurred, mostly a fall without injury (n = 6). In almost half of the falls, this was from the bed. Complications occurred most often during admissions for presurgical evaluation. Antiseizure medication (ASM) was tapered in 86% of presurgical cases, but no serious injury occurred, and occurring seizures were effectively treated with intranasal midazolam if needed., Conclusions: The overall adverse event rate was low. Falls are the most common adverse event comparable with previously published fall rates at other EMUs where people are restricted to their bed. We showed that restricted ambulation at a well-monitored EMU is not necessary and possibly unwanted. No serious injury due to tapering of ASM occurred, and intranasal midazolam was shown to be effective as acute seizure treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Studies in rodents suggest that flumazenil is a P-glycoprotein substrate at the blood-brain barrier. This study aimed to assess whether [ 11 C]flumazenil is a P-glycoprotein substrate in humans and to what extent increased P-glycoprotein function in epilepsy may confound interpretation of clinical [ 11 C]flumazenil studies used to assess gamma-aminobutyric acid A receptors. Nine drug-resistant patients with epilepsy and mesial temporal sclerosis were scanned twice using [ 11 C]flumazenil before and after partial P-glycoprotein blockade with tariquidar. Volume of distribution, nondisplaceable binding potential, and the ratio of rate constants of [ 11 C]flumazenil transport across the blood-brain barrier (K 1 /k 2 ) were derived for whole brain and several regions. All parameters were compared between pre- and post-tariquidar scans. Regional results were compared between mesial temporal sclerosis and contralateral sides. Tariquidar significantly increased global K 1 /k 2 (+23%) and volume of distribution (+10%), but not nondisplaceable binding potential. At the mesial temporal sclerosis side volume of distribution and nondisplaceable binding potential were lower in hippocampus (both ∼-19%) and amygdala (both ∼-16%), but K 1 /k 2 did not differ, suggesting that only regional gamma-aminobutyric acid A receptor density is altered in epilepsy. In conclusion, although [ 11 C]flumazenil appears to be a (weak) P-glycoprotein substrate in humans, this does not seem to affect its role as a tracer for assessing gamma-aminobutyric acid A receptor density., (© The Author(s) 2015.)

TNF-alpha, IL-12p35, IL-12p40, IL-4, IL-10, TGF-beta1, CCR3, CXCR3, CCR5, Fas and FasL mRNA levels in PBMC of 25 multiple sclerosis (MS) patients were quantified at baseline by real-time PCR according to a post-hoc study design. The baseline values of the different markers were analysed with respect to their correlation with the increase in disability over a period of 10 years. High levels of Fas mRNA were associated with a favourable disease course in relapsing-remitting (RR) MS (R2 = 0.74, P = 0.0001, n = 13), as measured by the Expanded Disability Status Scale (EDSS); high levels of FasL mRNA were associated with relatively mild disease progression (R2 = 0.86, P = 0.0001, n =12) in secondary progressive (SP) MS. These findings suggest that Fas-mediated apoptosis plays a major role in the mechanism underlying long-term disease progression in MS.: