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There are limited treatment options for individuals with drug-resistant idiopathic generalized epilepsy (IGE). Small, limited case series suggest that centromedian thalamus deep brain stimulation (CM-DBS) may be an effective treatment option. The optimal CM-DBS target for IGE is underexamined. Here, we present a retrospective analysis of CM-DBS targeting and efficacy for five patients with drug-resistant IGE. Volume of tissue activated (VTA) overlap with CM nucleus was performed using an open-source toolbox. Median follow-up time was 13 months. Median convulsive seizure frequency reduction was 66%. One patient had only absence seizures, with >99% reduction in absence seizure frequency. Four patients had electrode contacts positioned within the CM nucleus target, all of whom had >50% reduction in primary semiology seizure, with 85% median seizure reduction (p = .004, paired-sample t test). Volumetric "sweet-spot" mapping revealed that best outcomes were correlated with stimulation of the middle ventral CM nucleus. Connectivity strength between the sweet-spot region and central peri-Rolandic cortex was increased significantly relative to other cortical regions (p = 8.6 × 10 -4 , Mann-Whitney U test). Our findings indicate that CM-DBS can be an effective treatment for patients with IGE, highlight the importance of accurate targeting and targeting analysis, and within the context of prior work, suggest that ideal CM-DBS targets may be syndrome specific., (© 2024 International League Against Epilepsy.)

Objective: Although >30% of epilepsy patients have drug-resistant epilepsy (DRE), typically those with generalized or multifocal disease have not traditionally been considered surgical candidates. Responsive neurostimulation (RNS) of the centromedian (CM) region of the thalamus now appears to be a promising therapeutic option for this patient population. We present outcomes following CM RNS for 13 patients with idiopathic generalized epilepsy (IGE) and eight with multifocal onsets that rapidly generalize to bilateral tonic-clonic (focal to bilateral tonic-clonic [FBTC]) seizures., Methods: A retrospective review of all patients undergoing bilateral CM RNS by the senior author through July 2022 were reviewed. Electrodes were localized and volumes of tissue activation were modeled in Lead-DBS. Changes in patient seizure frequency were extracted from electronic medical records., Results: Twenty-one patients with DRE underwent bilateral CM RNS implantation. For 17 patients with at least 1 year of postimplantation follow-up, average seizure reduction from preoperative baseline was 82.6% (SD = 19.0%, median = 91.7%), with 18% of patients Engel class 1, 29% Engel class 2, 53% Engel class 3, and 0% Engel class 4. There was a trend for average seizure reduction to be greater for patients with nonlesional FBTC seizures than for other patients. For patients achieving at least Engel class 3 outcome, median time to worthwhile seizure reduction was 203.5 days (interquartile range = 110.5-343.75 days). Patients with IGE with myoclonic seizures had a significantly shorter time to worthwhile seizure reduction than other patients. The surgical targeting strategy evolved after the first four subjects to achieve greater anatomic accuracy., Significance: Patients with both primary and rapidly generalized epilepsy who underwent CM RNS experienced substantial seizure relief. Subsets of these patient populations may particularly benefit from CM RNS. The refinement of lead targeting, tuning of RNS system parameters, and patient selection are ongoing areas of investigation., (© 2024 International League Against Epilepsy.)

Background: Vagus nerve stimulation (VNS) at low frequencies (≤30 Hz) has been an established treatment for drug-resistant epilepsy (DRE) for over 25 years., Objective: To examine the initial safety and efficacy performance of an investigational, high-frequency (≥250 Hz) VNS paradigm herein called "Microburst VNS" (μVNS). μVNS consists of short, high-frequency bursts of electrical pulses believed to preferentially modulate certain brain regions., Methods: Thirty-three (33) participants were enrolled into an exploratory feasibility study, 21 with focal-onset seizures and 12 with generalized-onset seizures. Participants were titrated to a personalized target dose of μVNS using an investigational fMRI protocol. Participants were then followed for up to 12 months, with visits every 3 months, and monitored for side-effects at all time points. This study was registered as NCT03446664 on February 27th, 2018., Results: The device was well-tolerated. Reported adverse events were consistent with typical low frequency VNS outcomes and tended to diminish in severity over time, including dysphonia, cough, dyspnea, and implant site pain. After 12 months of μVNS, the mean seizure frequency reduction for all seizures was 61.3% (median reduction: 70.4%; 90% CI of median: 48.9%-83.3%). The 12-month responder rate (≥50% reduction) was 63.3% (90% CI: 46.7%-77.9%) and the super-responder rate (≥80% reduction) was 40% (90% CI: 25.0%-56.6%). Participants with focal-onset seizures appeared to benefit similarly to participants with generalized-onset seizures (mean reduction in seizures at 12 months: 62.6% focal [n = 19], versus 59.0% generalized [n = 11])., Conclusion: Overall, μVNS appears to be safe and potentially a promising therapeutic alternative to traditional VNS. It merits further investigation in randomized controlled trials which will help determine the impact of investigational variables and which patients are most suitable for this novel therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CD, PA, LK, and The Microburst Study Group were investigators for the Microburst Feasibility Study, and they or their institutions received funding from LivaNova PLC or its subsidiaries to conduct the research. JS received compensation from LivaNova USA Inc to design the fMRI titration protocol for the study. RV, AK, MJ, and KN are employees of LivaNova USA Inc and hold stock or stock options with the company. No authors were compensated for time spent writing this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Intracranial neuromodulation is an evolving therapy for patients with drug-resistant epilepsy (DRE). Deep brain stimulation (DBS) is now available as a therapy for patients with DRE and focal-onset seizures in select health care systems; however, there remains a substantial need of efficacy data before DBS can be more widely adopted into routine clinical practice. This review and commentary focuses on a particular shifting paradigm: DBS as a therapy for children with generalized-onset seizures., Competing Interests: Disclosure R.J. Piper has nothing to disclose. G.M. Ibrahim has received research funding as well as consulting and advisory fees from LivaNova, United Kingdom. M.M. Tisdall has received honoraria from Medtronic, sponsorship from Renishaw, and research funding from the Oakgrove Foundation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: This article describes our findings while treating patients with refractory generalized epilepsy with combined vagus nerve stimulation (VNS) and centro-median deep brain stimulation (CMDBS)., Materials and Methods: A total of 11 consecutive patients with refractory generalized epilepsy (ten with Lennox-Gastaut syndrome) previously submitted to VNS and who subsequently underwent CMDBS were retrospectively studied. The VNS final parameters were 2 to 2.5 mA, 30 Hz, and 500 μs, cycling mode, 30 seconds "on" and 5 minutes "off" for all patients. The CMDBS final parameters were 4 to 5 V, 130 Hz, and 300 μs, bipolar, continuous stimulation in all patients., Results: There were eight male participants, ranging in age from eight to 49 years (mean 19 years). Follow-up time after VNS ranged from 18 to 132 months (mean 52 months) and from an additional 18 to 164 months (mean 42 months) during combined VNS-CMDBS. All patients had daily seizures. Atypical absences were noted in eight patients, tonic seizures in seven, bilateral tonic-clonic seizures in four, atonic seizures in three, and myoclonic seizures in two patients. Four patients were initially considered responders to VNS. All these patients also had an additional >50% seizure frequency reduction during combined VNS-CMDBS. Seven patients were not responders to VNS, and of those, four had an additional >50% seizure frequency reduction during combined VNS-CMDBS. Eight patients had an additional >50% reduction in seizure frequency when moved from VNS alone to VNS-CMDBS therapy. There were two nonresponders during combined VNS-CMDBS therapy, and both were nonresponders to VNS alone. Nine patients were considered responders during VNS-CMDBS combined therapy compared with baseline., Discussion: This study showed that combined VNS-CMDBS therapy was able to double the number of responders compared with VNS alone in a cohort of patients with refractory generalized epilepsy. We believe these data represent the first evidence that combined neuromodulation may be useful in this quite homogeneous patient population., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: To explore a novel scoring system to evaluate the efficacy of vagus nerve stimulation (VNS) in children with drug-resistant generalized epilepsy (DRGE) aged six and younger., Basic Procedures: The data of twelve children with DRGE under the age of 6 years who accepted VNS and have been followed up for at least 3 years were retrospectively reviewed. The outcome was evaluated with the McHugh Classification System and a novel scoring system we proposed., Main Findings: Based on the McHugh Classification System, the total response rate was 91.67% (11/12) and the rate of Grade I was 41.67% (5/12). A novel scoring system involving seizure frequency, seizure duration and quality of life (QOL) was proposed, by which the outcome was scored from -3 to 11 and graded from IV to I. Based on the novel scoring system, the total response rate was 91.67% (11/12) and the rate of Grade I was 33.33% (4/12). The incidence of complication was 16.67% (2/12). The efficacy of VNS appeared a gradually improving trend with plateau or fluctuation over time. Shorter course of epilepsy prior to VNS may be related to better outcome., Principal Conclusions: VNS could effectively reduce the seizure frequency and improve the QOL of children with DRGE aged six and younger. The novel scoring system was comprehensive and feasible to evaluate the efficacy of VNS. The time pattern of the long-term efficacy of VNS requires further investigation., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objective: Refractory idiopathic generalised epilepsy (IGE; also known as genetic generalised epilepsy) is a clinical challenge due to limited available therapeutic options. While vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant focal epilepsy, there is limited evidence supporting its efficacy for refractory IGE., Methods: We conducted a single-centre retrospective analysis of adult IGE patients treated with VNS between January 2003 and January 2022. We analysed the efficacy, safety, tolerability, stimulation parameters and potential clinical features of VNS response in this IGE cohort., Results: Twenty-three IGE patients were implanted with VNS between January 2003 and January 2022. Twenty-two patients (95.65%) were female. The median baseline seizure frequency was 30 per month (interquartile range [IQR]= 140), including generalised tonic-clonic seizures (GTCS), absences, myoclonus, and eyelid myoclonia with/without absences. The median number of baseline anti-seizure medications (ASM) was three (IQR= 2). Patients had previously failed a median of six ASM (IQR= 5). At the end of the study period, VNS therapy remained active in 17 patients (73.9%). amongst patients who continued VNS, thirteen (56.5% of the overall cohort) were considered responders (≥50% seizure frequency reduction). Amongst the clinical variables analysed, only psychiatric comorbidity correlated with poorer seizure outcomes, but was non-significant after applying the Bonferroni correction. Although 16 patients reported side-effects, none resulted in the discontinuation of VNS therapy., Significance: Over half of the patients with refractory IGE experienced a positive response to VNS therapy. VNS represents a viable treatment option for patients with refractory IGE, particularly for females, when other therapeutic options have been exhausted., Competing Interests: Conflicts of interest JPC served as a speaker and received travel expenses from Angelini Pharma. PBM served on an advisory board for Angelini Pharma and received travel expenses from UCB Pharma. AV, COD, NC, BL, BSG, PE, RG, GM, DJC, CPD, KJS, HEN, RDK, and DOB reported no conflicts of interest. Over the last three years, PWW has served as a speaker for Angelini Pharma, and ND has served as a paid advisor and/or speaker for Angelini Pharma, Eisai, Radius Pharma, and UNEEG Medical., (Copyright © 2023. Published by Elsevier Ltd.)

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy., Competing Interests: Declaration of Competing Interest None. The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Neuromodulation in epilepsy is a proven treatment for people with drug-resistant focal epilepsy. Dual device therapies are increasingly utilized in people with drug-resistant epilepsy. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) target the thalamus involving the primary neurobiological network in patients with genetic generalized epilepsy (GGE). We report a novel case of combined neuromodulation in a patient with drug-resistant GGE who achieved a partial response with seizure reduction after VNS implantation yet following VNS-DBS polyneurostimulation gradually achieved prolonged seizure freedom. We speculate that by combining the indirect activating effects of VNS with the direct inhibitory effects of DBS, this may provide synergy to thalamic modulated networks. We hypothesize a "rational polytherapy" may exist in some patients with GGE undergoing dual neuromodulation., (© 2023 International League Against Epilepsy.)

Objective: There are three neurostimulation devices available to treat generalized epilepsy: vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). However, the choice between them is unclear due to lack of head-to-head comparisons. A systematic comparison of neurostimulation outcomes in generalized epilepsy has not been performed previously. The goal of this meta-analysis was to determine whether one of these devices is better than the others to treat generalized epilepsy., Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review of PubMed, Embase, and Web of Science was performed for studies reporting seizure outcomes following VNS, RNS, and DBS implantation in generalized drug-resistant epilepsy between the first pivotal trial study for each modality through August 2022. Specific search criteria were used for VNS ("vagus", "vagal", or "VNS" in the title and "epilepsy" or "seizure"), DBS ("deep brain stimulation", "DBS", "anterior thalamic nucleus", "centromedian nucleus", or "thalamic stimulation" in the title and "epilepsy" or "seizure"), and RNS ("responsive neurostimulation" or "RNS" in the title and "epilepsy" or "seizure"). From 4409 articles identified, 319 underwent full-text reviews, and 20 studies were included. Data were pooled using a random-effects model using the meta package in R., Results: Sufficient data for meta-analysis were available from seven studies for VNS (n = 510) and nine studies for DBS (n = 87). Data from RNS (five studies, n = 18) were insufficient for meta-analysis. The mean (SD) follow-up durations were as follows: VNS, 39.1 (23.4) months; DBS, 23.1 (19.6) months; and RNS, 22.3 (10.6) months. Meta-analysis showed seizure reductions of 48.3% (95% confidence interval [CI] = 38.7%-57.9%) for VNS and 64.8% (95% CI = 54.4%-75.2%) for DBS (p = .02)., Significance: Our meta-analysis indicates that the use of DBS may lead to greater seizure reduction than VNS in generalized epilepsy. Results from RNS use are promising, but further research is required., (© 2023 International League Against Epilepsy.)

Introduction: Stimulation of the thalamus is gaining favor in the treatment of medically refractory multifocal and generalized epilepsy. Implanted brain stimulators capable of recording ambulatory local field potentials (LFPs) have recently been introduced, but there is little information to guide their use in thalamic stimulation for epilepsy. This study sought to assess the feasibility of chronically recording ambulatory interictal LFP from the thalamus in patients with epilepsy., Methods: In this pilot study, ambulatory LFP was recorded from patients who underwent sensing-enabled deep brain stimulation (DBS, 2 participants) or responsive neurostimulation (RNS, 3 participants) targeting the anterior nucleus of the thalamus (ANT, 2 electrodes), centromedian nucleus (CM, 7 electrodes), or medial pulvinar (PuM, 1 electrode) for multifocal or generalized epilepsy. Time-domain and frequency-domain LFP was investigated for epileptiform discharges, spectral peaks, circadian variation, and peri-ictal patterns., Results: Thalamic interictal discharges were visible on ambulatory recordings from both DBS and RNS. At-home interictal frequency-domain data could be extracted from both devices. Spectral peaks were noted at 10-15 Hz in CM, 6-11 Hz in ANT, and 19-24 Hz in PuM but varied in prominence and were not visible in all electrodes. In CM, 10-15 Hz power exhibited circadian variation and was attenuated by eye opening., Conclusion: Chronic ambulatory recording of thalamic LFP is feasible. Common spectral peaks can be observed but vary between electrodes and across neural states. DBS and RNS devices provide a wealth of complementary data that have the potential to better inform thalamic stimulation for epilepsy., (© 2023 S. Karger AG, Basel.)

Background: Deep brain stimulation (DBS) of the centromedian nucleus (CM) is an effective therapeutic option for select patients with generalized epilepsy. However, several studies suggest that success varies with active contact location within the CM and the exact target remains undefined., Objective: To quantify the association between active contact location and outcomes across all published series of CM DBS., Methods: A literature search using PRISMA criteria was performed to identify all studies that reported active contact locations PLUS outcomes following DBS of the CM for epilepsy. Patient, disease, treatment, and outcome data were extracted for statistical analysis. Active contact locations were analyzed on a common reference frame and weighted by percent seizure reduction at last follow-up., Results: From 184 studies that were screened for review, 3 studies comprising 47 patients met criteria for inclusion and were analyzed. At time of surgery, mean duration of epilepsy was 18 years. Pooled rates of atonic, atypical absence, generalized tonic-clonic, myoclonic, and tonic epilepsies were 38%, 74%, 68%, 14%, and 60%, respectively. Indirect targeting was used in all these studies. After a mean follow-up duration of 2.3 years, 87% of patients were deemed to be responders with mean seizure reduction of 73% (95% CI: [64%-81%]). Optimal location of the active contact was found to be at the dorsal border of the CM., Conclusions: Success following DBS of the CM for epilepsy varies by active contact location, even within the CM. Our findings suggest that stimulation within the dorsal region of the CM improves outcomes. Additional studies are needed to further refine these findings., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: We designed a prospective, individual-controlled study to evaluate the effect of cardiac-based VNS (cbVNS) in a cohort of patients with generalized epilepsy (GE)., Materials and Methods: Twenty patients were included. They were followed up for six months under regular VNS (rVNS) and subsequently for six months during cbVNS. Stimulation parameters were 500 μsec, 30 Hz, and up to 2.5 mA. Seizure frequency was documented after two, four, and six months during the rVNS and cbVNS phases. Patients with at least 50% seizure frequency reduction were considered responders. The total and relative amount of stimulation cycles generated by both rVNS and cbVNS activation were documented. Findings during rVNS were compared to baseline and cbVNS data were compared to those during rVNS., Results: There was a significant decrease in mean seizure frequency (61% [95% CI, 48-74]; p < 0.001) during the rVNS phase compared to baseline. There was no additional significant (16% [95% CI, 4-35]; p = 0.097) mean seizure frequency reduction during cbVNS compared to the rVNS phase. Fifteen patients (75%) were considered responders after rVNS. Four patients (20%) were considered responders after six months of cbVNS. During the cbVNS phase, the mean total number of cycles/day was 346, 354, and 333 for months two, four, and six, respectively; the cycles generated by rVNS were 142, 138, and 146 for months two, four, and six, respectively; and cycles generated by cbVNS were 204, 215, and 186 for months two, four, and six, respectively. There was no relationship between the mean total number of cycles (-6[95% CI, -85 to 72]; p = 0.431), the mean number of auto-stimulation cycles (27[95% CI,-112 to 166]; p = 0.139), the mean number of regular cycles (-33[95% CI,-123 to 57]; p = 0.122), or the mean percentage of auto-stimulation cycles (13[95% CI,19- 45]; p = 0.109) and outcome during the cbVNS phase. Eight patients showed some decrease in seizure frequency during cbVNS., Conclusions: rVNS was effective in reducing seizure frequency in patients with generalized epilepsy, but activation of the cbVNS feature did not add significantly to rVNS efficacy. On the other hand, although not statistically significant, 40% of the patients showed some reduction in seizure frequency, which might prove useful at an individual level., (© 2020 International Neuromodulation Society.)

We describe a multicenter experience with VNS implantation in pediatric patients with epileptic encephalopathy. Our goal was to assess VNS efficacy and identify potential predictors of favorable outcome. This was a retrospective study. Inclusion criteria were: ≤18 years at the time of VNS implantation and at least one year of follow-up. All patients were non-candidates for excisional procedures. Favorable clinical outcome and effective VNS therapy were defined as seizure reduction >50%. Outcome data were reviewed at one, two, three and five years after VNS implantation. Fisher's exact test, Kaplan-Meier and multiple logistic regression analysis were employed. Twenty-seven patients met inclusion criteria. Responder rate (seizure frequency reduction ≥ 50%) at one-year follow-up was 25.9%, and 15.3% at last follow-up visit. The only variable significantly predicting favorable outcome was time to VNS implantation, with the best outcome achieved when VNS implantation was performed within five years of seizure onset (overall response rate of 83.3% at one year of follow-up and 100% at five years). In total, 63% of patients evidenced improved QOL at last follow-up visit. Only one patient exited the study due to an adverse event at two years from implantation. Early VNS implantation within five years of seizure onset was the only predictor of favorable clinical outcome in pediatric patients with epileptic encephalopathy. Improved QOL and a very low incidence of adverse events were observed.

Objective: Continuous spikes and waves during sleep (CSWS) is an epileptic encephalopathy characterized by generalised epileptiform activity and neurocognitive dysfunction. Causes and outcome are diverse and treatment is mainly empirical., Methods: Retrospective descriptive analysis of clinical and EEG data of children with CSWS diagnosed between 1998 and 2018 at the University Hospital Heidelberg., Results: Ninety-five children were included with a median age at diagnosis of 5.4 years. A structural/metabolic aetiology was found in 43.2%, genetic alterations in 17.9%, while it remained unknown in 38.9%. The proportion of patients with genetic aetiology increased from 10.3% (1998-2007) to 22.8% (2008-2018). On average, each patient received 5 different treatments. CSWS was refractory in >70% of cases, steroids and neurosurgery were most effective. No difference was observed between children with CSWS or Near-CSWS (Spike-Wave-Index 40-85%)., Conclusions: Our cohort confirms CSWS as an age-dependent epileptic encephalopathy. Structural brain abnormalities were most frequent, but genetic causes are increasingly identified. More specific criteria for the diagnosis and treatment goals should be elaborated and implemented based on evidence., Significance: This study is the largest monocentric observational study on treatment effects in children with CSWS, providing data for diagnostic and therapeutic decisions., Competing Interests: Declaration of competing interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background and Importance: At least 25% of patients with idiopathic generalized epilepsy do not obtain adequate seizure control with medication. This report describes the first use of responsive neurostimulation (RNS), bilaterally targeting the centromedian/ventrolateral (CM/VL) region in a patient with drug-refractory Jeavons syndrome (eyelid myoclonia with absences)., Clinical Presentation: A patient, diagnosed with eyelid myoclonia with absences (EMA) and refractory to medication, was offered RNS treatment in the CM/VL region of the thalamus. Stimulation was triggered by thalamic neural activity having morphological, spectral, and synchronous features that corresponded to 3- to 5-Hz spike-wave discharges recorded on prior scalp electroencephalography., Conclusion: RNS decreased daily absence seizures from a mean of 60 to ≤10 and maintained the patient's level of consciousness during the occurring episodes. This therapy should be evaluated further for its potential to treat patients with pharmaco-refractory generalized epilepsy., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: For patients with generalized epilepsy who do not respond to antiseizure medications, the therapeutic options are limited. Vagus nerve stimulation (VNS) is a treatment mainly approved for therapy-resistant focal epilepsy. There is limited information on the use of VNS on generalized epilepsies, including Lennox-Gastaut Syndrome (LGS) and genetic generalized epilepsy (GGE)., Methods: We identified patients with a diagnosis of generalized epilepsy (including LGS and GGE), who underwent VNS implantation at the London Health Sciences Centre and Western University, London, Ontario, since this treatment became available in Canada in 1997 until July 2018. We assessed response to the treatment, including admissions to hospital and complications., Results: A total of 46 patients were included in this study with a history of therapy-resistant generalized epilepsy. The mean age at implantation was 24 years (interquartile range [IQR] = 17.8-31 years), significantly younger in the LGS group (p = 0.02) and 50% (n = 23) were female. The most common etiologies were GGE in 37% (n = 17) and LGS in 63% (n = 29). Median follow-up since VNS implantation was 63 months (IQR: 31-112.8 months). Of the LGS group 41.7% (n = 12) of patients had an overall seizure reduction of 50% or more, and 64.7% (n = 11) in the GGE group without statistical significance between the groups. The best response in seizure reduction was seen in generalized tonic-clonic seizures, with a significant reduction in the GGE group (p = 0.043). There was a reduction of seizure-related hospital admissions from 91.3% (N = 42) preimplantation, to 43.5% (N = 20) postimplantation (p < 0.05). The frequency of side effects due to the stimulation was almost equal in both groups (62.1% in LGS and 64.7% in GGE)., Conclusions: Vagus nerve stimulation should be considered as a treatment in patients with therapy-resistant generalized epilepsy, especially in cases with GGE., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: We report on the seizure frequency and attention outcome during thalamic centromedian stimulation (CM-DBS) in patients with refractory generalized epilepsy (GE)., Methods: Twenty consecutive patients with GE who were submitted to CM-DBS and had at least one year of follow-up were prospectively studied. The CM was targeted bilaterally. Stimulation intensity was ramped up (bipolar, continuous, 130 Hz; 300μsec) until 4.5 V or until side effects developed. Contacts` position was determined on postoperative volumetric MRI scans. Attention was qualitatively evaluated using the SNAP-IV (Swanson, Nolan, and Pelham) questionnaire. Patients were considered responders during CM-DBS if an at least 50% seizure frequency reduction was obtained compared to baseline., Results: Median age was 15.5 years (13 males). Median follow-up time was 2.55 years. EEG disclosed generalized spike-and wave discharges in all patients. MRI was normal in 10 patients, showed diffuse atrophy in 6 patients, and showed abnormalities in 4 patients (3 patients had bilateral cortical development abnormalities and one had unilateral hemispheric atrophy). Patients presented with daily multiple seizure types (8 to 66 per day; median: 37), including tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic seizures. Mean DBS intensity was 4.3 V. An insertional effect was noted in 14 patients. CM-DBS was able to significantly reduce the frequency of tonic (p < 0.001), atypical absence seizures (p < 0.001), atonic seizures (p = 0.001) and bilateral generalized tonic-clonic seizures (p = 0.004). One patient became seizure-free. Ninety percent of the patients were considered responders (>50% seizure frequency reduction). All patients showed some improvement in attention. The mean number of items in which improvement was noted in the SNAP-IV questionnaire was 4.8. There was a significant relationship between overall seizure frequency reduction and improvement of attention (p = 0.033)., Discussion: This prospective, open label study included a large, homogeneous cohort and provided evidence on the efficacy of CM-DBS in reducing the seizure burden and increasing attention in patients with refractory generalized epilepsy., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

To characterize the clinical phenotype of Sunflower syndrome. Sunflower syndrome is a rare photosensitive epilepsy syndrome characterized by highly stereotyped seizures, photosensitivity, and heliotropism. We retrospectively reviewed the medical records of patients seen in the Massachusetts General Hospital for Children (MGHfC) pediatric epilepsy program with a history of Sunflower syndrome. Twenty-four patients were identified; 18 were female. At the time of initial MGHfC evaluation, patients' ages ranged from 6.4 to 25 years, with a median age of 11.5 years. All patients presented with hand-waving episodes (HWEs), although one patient no longer demonstrates this, but now has eye blinking episodes on exposure to light. Four have associated eye fluttering as a component of their most prevalent light-induced seizures. The average age at onset of HWEs was six years. Seventeen developed other symptoms prior to the onset of HWEs. The most prevalent symptom was an attraction to light and possible absence seizures. Light-induced seizures were generally refractory to broad-spectrum antiepileptic drugs (AEDs). Only three patients had a reduction of HWEs with the use of AEDs. Several non-pharmacological strategies reduced seizure frequency, however, efficacy varied. These non-pharmacological strategies included avoiding stimulus, focusing on other tasks, and occupying or restraining the hand that was involved in hand-waving. The use of tinted glasses reduced seizure frequency in 17 patients, however, no patient achieved seizure freedom. Twenty-two patients had available EEGs, 20 of which showed interictal epileptiform discharges. Additionally, many of the patients experienced a negative impact on their self-concept due to anxiety, depression, or negative interactions with peers. Sunflower syndrome is a generalized, pharmacoresistant epilepsy with childhood onset and remains poorly understood. To improve clinical care and scientific understanding, long-term prospective research exploring the natural history, etiology, and effective treatments for Sunflower syndrome should be conducted. [Published with video sequence].

Genetic or idiopathic generalized epilepsies (IGEs) account for 15-20% of all epilepsies. These syndromes have always been considered as good prognosis forms of epilepsy over time; however, for some patients, there is a need to maintain antiseizure drugs (ASD) for a long-time. Drug resistance is not uncommon (7-15%). Lifestyle remains essential and is an integral part of the treatment. Comorbidities such as obstructive sleep apnea syndrome must be considered and treated. A highly underestimated condition is the risk of sudden unexpected death in epilepsy (SUDEP). Very few data are available about the prevalence of SUDEP in IGE, but patients with generalized tonic-clonic seizures (GTCS) are exposed to this risk. IGEs are also characterized by a specific pharmalogical sensisitivity but may be aggravated by ASDs. Historically, the treatment of IGEs has relied mostly on valproate but this drug should be avoided in women of childbearing potential. Women with IGE not treated with valproate are more likely to have unsatisfactory seizure control. Female gender appears now as a new risk factor for drug-resistance. Finally, aside from the typical forms, there are epilepsies that fulfill most of the criteria of IGE, but that have an unusual history with GTCS, absences, falls, and drug resistance. Patients do not have psychomotor regression, brain magnetic resonance imaging is normal. EEG shows generalized fast rhythms during NREM sleep. These patients with refractory generalized epilepsy with sleep-related fast activities do not belong to a well-established syndromic category. These cases are considered "intermediary" between IGE and epileptic encephalopathies., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Aim: Knowledge about cardiac stress related to seizures in electroconvulsive therapy (ECT) and spontaneously occurring generalized convulsive seizures (GCS) is limited. The aim of the present study was to analyze cardiac function and circulating markers of cardiac stress in the early postictal period after ECT and GCS., Methods: Patients undergoing ECT in the Department of Psychiatry, Psychotherapy and Psychosomatics and patients undergoing diagnostic video-EEG monitoring (VEM) in the Department of Neurology were prospectively enrolled between November 2017 and November 2018. Cardiac function was examined twice using transthoracic echocardiography within 60 min and >4 h after ECT or GCS. Established blood markers (troponin T high-sensitive, N-terminal pro brain natriuretic peptide) of cardiac stress or injury were collected within 30 min, 4 to 6 h, and 24 h after ECT or GCS. In the ECT group, the troponin T values were also correlated with periprocedural heart rate and blood pressure values. Because of organizational or technical reasons, the measurement was not performed in all patients., Results: Twenty patients undergoing ECT and 6 patients with epilepsy with a GCS during VEM were included. Postictal echocardiography showed no wall motion disorders and no change in left ventricular and right ventricular functions. Four of 17 patients displayed a transient increase in high-sensitive cardiac troponin T 4-6 h after the seizure (3 patients with ECT-induced seizure). None of these 4 patients had signs of an acute cardiac event, and periprocedural blood pressure or heart rate peaks during ECT did not significantly differ in patients with and without troponin T elevation., Conclusions: Signs of mild cardiac stress can occur in some patients following ECT or GCS without clinical complications, probably related to excessive catecholamine release during the seizure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Vagus nerve stimulaton (VNS) has been used for adjunctive treatment of drug-resistant epilepsy for more than 25 years. The true efficacy has been debated, as blinded randomized controlled trials are unavailable. The aim of this study was to evaluate the patient-reported perceived benefit of VNS and to compare clinical characteristics of patients with and without benefit., Methods: Observational study of all 43 adult patients receiving VNS for >2 years at one single center. Mean duration of treatment was 9 years. At inclusion, a semi-structured interview on VNS effectiveness was performed. In patients without benefit, the VNS was turned off. The outcome was evaluated after an observation period of one year., Results: 21 patients (49%) reported no clear benefit and stopped VNS. Only one of them resumed treatment within one year. Patients without benefit had received more new antiepileptic drugs (AEDs) during VNS treatment than those reporting benefit (p = 0.05). Other differences between the two groups were not found. Ten patients (23%) had been seizure free >1 year at inclusion (5 in the benefit and 5 in the non-benefit group). Seizure control was attributed to the response of another new treatment in the majority of these patients., Conclusion: Half of the patients had not perceived clear benefit from VNS, and all but one terminated VNS without worsening of seizures within one year. The true outcome of long-term VNS is difficult to assess in real-world practice. The effect may be overestimated due to confounding factors, particularly the common introduction of novel AEDs and the natural course of the disorder. Patients without perceived benefit from long-term VNS should not routinely remain on treatment and be subject to undue generator re-implantations., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Responsive neurostimulation (RNS) has emerged as an adjunctive treatment modality for patients with intractable focal epilepsy who are not surgical candidates or have more than one ictal onset focus. We report a 34-year-old patient with intractable, childhood-onset, genetic generalized epilepsy (GGE) with tonic, atonic, myoclonic and absence seizures treated with RNS. Strip electrodes over the right posterior frontal cortex and depth electrodes placed in the right anterior nucleus were used for event detection and responsive stimulation. Two-year follow-up revealed 90-95% clinical seizure reduction. This case suggests that refractory GGE may be effectively treated with RNS targeting thalamocortical networks., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Objective: Vagus Nerve Stimulation (VNS) is a neuromodulation device approved for the treatment of medically refractory epilepsy. Worldwide, only 35 cases of pregnancies that has been described. This study aims to continue to increase the limited knowledge of the use of VNS during pregnancy., Methods: We interrogated the database of the Epilepsy program at Western University (1998-2018), and identified those patients who were implanted with VNS and became pregnant., Results: From 114 patients implanted with VNS in our centre, four patients had a total of seven pregnancies. This is the first report with one woman implanted with VNS having three pregnancies. Three patients had genetic generalized epilepsy and one focal epilepsy due to periventricular nodular heterotopia. The median duration since implantation was 3.17 years (IQR: 1.33-4.33) and the output was 2.75 mA (IQR: 1.5-3.5). No modifications in stimulation settings were made in any patient during pregnancy. Three patients had obstetric complications, requiring c-sections. All babies were healthy, except one with intellectual disabilities of unclear severity., Conclusion: Our small sample suggests VNS could increase the obstetrical complications, but is likely safe for the fetus. However, a larger sample size should be collected to determine safety and potential teratogenicity of VNS., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background: Epilepsy and migraine are paroxysmal neurological conditions associated with disturbances of cortical excitability. No useful biomarkers to monitor disease activity in these conditions are available. Phase clustering was previously described in electroencephalographic (EEG) responses to photic stimulation and may be a potential epilepsy biomarker., Objective: The objective of this study was to investigate EEG phase clustering in response to transcranial magnetic stimulation (TMS), compare it with photic stimulation in controls, and explore its potential as a biomarker of genetic generalized epilepsy or migraine with aura., Methods: People with (possible) juvenile myoclonic epilepsy (JME), migraine with aura, and healthy controls underwent single-pulse TMS with concomitant EEG recording during the interictal period. We compared phase clustering after TMS with photic stimulation across the groups using permutation-based testing., Results: We included eight people with (possible) JME (five off medication, three on), 10 with migraine with aura, and 37 controls. The TMS and photic phase clustering spectra showed significant differences between those with epilepsy without medication and controls. Two phase clustering-based indices successfully captured these differences between groups. One participant was tested multiple times. In this case, the phase clustering-based indices were inversely correlated with the dose of antiepileptic medication. Phase clustering did not differ between people with migraine and controls., Conclusion: We present methods to quantify phase clustering using TMS-EEG and show its potential value as a measure of brain network activity in genetic generalized epilepsy. Our results suggest that the higher propensity to phase clustering is not shared between genetic generalized epilepsy and migraine., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose of Review: To summarize recent developments in therapeutic options, both medical and surgical, for patients with drug-resistant generalized epilepsy syndromes, which continue to be a multifaceted challenge for patients and physicians., Recent Findings: Newer generation pharmaceutical options are now available, such as brivaracetam, rufinamide, lacosamide, perampanel, and cannabidiol. Less restrictive dietary options appear to be nearly as effective as classic ketogenic diet for amelioration of seizures. The latest implantable devices include responsive neurostimulation and deep brain stimulation. Corpus callosotomy is an effective treatment for some seizure types, and newer and less invasive approaches are being explored. Resective surgical options have demonstrated success in carefully selected patients despite generalized electrographic findings on electroencephalogram. The current literature reflects a widening range of clinical experience with newer anticonvulsant medications including cannabinoids, dietary therapies, surgical approaches, and neurostimulation devices for patients with intractable generalized epilepsy.

Genetic epileptic encephalopathies are a rather wide spectrum of childhood epilepsies with onset of epilepsy in the first 1.5-2 years of life, regression or delayed psychomotor and speech development and 'massive' epileptiform activity on electroencephalogram (EEG). The review discusses the difficulties of choosing the optimal method of genetic examination, problems with the interpretation of the results obtained, the formulation of the diagnosis, the determination of the prognosis of the course and targeted therapy. It is emphasized that the interpretation of the identified genetic variants is not an easy task, requiring close interaction between specialists in molecular genetics, bioinformatics, neurology and clinical genetics. The possibilities of targeted treatment of genetic epileptic encephalopathies are still limited, but knowledge of the genetic cause of epilepsy allows making a more informed choice of the treatment.

Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long-interval intracortical inhibition (LICI) response on TMD (F(1, 46) = 4.69, p = 0.04), but not seizure control (F(2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = -2.12; T (50) = -2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = -2.12; T (50) = -2.47, p = 0.04) and Fatigue (MD = -3.42; T (50) = -2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted., (Published by Elsevier Inc.)

Background: Jeavons syndrome is an underreported epileptic syndrome characterized by eyelid myoclonia, eyelid closure-induced seizures or electroencephalography paroxysms, and photosensitivity. Drug-resistant epilepsy is common, but the prognostic factors and clinical course leading to drug resistance have not been well characterized., Methods: We identified 30 patients who met the diagnostic criteria of Jeavons syndrome at a single institution between January 1, 2000 and December 15, 2016. Criteria for Jeavons syndrome included all of the following: (1) eyelid myoclonia with or without absences, (2) eye-closure-induced seizures or electroencephalography paroxysms, and (3) seizure onset after 12 months of age. We reviewed and described the epilepsy history, antiepileptic drug trials, and response to treatments., Results: Mean age at seizure onset was 7.3 years, and 80% were female. Absence seizures (63%) and generalized tonic-clonic seizures (23%) were most common at onset. Diagnosis was delayed by an average of 9.6 years. After a median follow-up of two years, 80% of patients had drug resistant epilepsy and 70% experienced generalized tonic-clonic seizures. Generalized tonic-clonic seizures and seizure types other than absence seizures increased the risk of drug-resistant epilepsy (P values 0.049 and 0.03, respectively). Valproic acid, lamotrigine, ethosuximide, and levetiracetam were the most effective in reducing seizures by more than 50%., Conclusions: The diagnosis of Jeavons syndrome is often delayed. Generalized tonic-clonic seizures and seizure types other than absence seizures may be predictors of drug-resistant epilepsy among patients with Jeavons syndrome., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To describe the response to vagus nerve stimulator (VNS) in otherwise neurotypical children with medically intractable primary generalized epilepsy., Methods: Retrospective chart review of patients who underwent vagus nerve stimulator surgery between January 2011 and December 2015., Results: Eleven patients were identified. Median follow-up duration was 2.5 years (1.2-8.4 years). Prior to vagus nerve stimulator surgery, all patients had at least 1 seizure per week, and 7/11 (64%) had daily seizures. At 1-year follow-up after vagus nerve stimulator, 7/11 (64%) reported improved seizure frequency and 6/11 (55%) reported fewer than 1 seizure per month. Three patients (27%) reported complications related to vagus nerve stimulator surgery, and no patients required device removal., Significance: In children with medically intractable primary generalized epilepsy, vagus nerve stimulator is well tolerated and appears to lead to improvement in seizure frequency. Improvement was not attributable to epilepsy classification, age at vagus nerve stimulator implantation, output current, duty cycle, or follow-up duration.

Approximately 30% of individuals with epilepsy are refractory to antiepileptic drugs and currently approved neuromodulatory approaches fall short of providing seizure freedom for many individuals with limited utility for generalized seizures. Here, we expand on previous findings and investigate whether ventral pallidum deep brain stimulation (VP-DBS) can be efficacious for various acute seizure phenotypes. For rats administered pilocarpine, we found that VP-DBS (50 Hz) decreased generalized stage 4/5 seizure median frequency from 9 to 6 and total duration from 1667 to 264 s even after generalized seizures emerged. The transition to brainstem seizures was prevented in almost all animals. VP-DBS immediately after rats exhibited their first partial forebrain stage 3 seizure did not affect the frequency of partial seizures but reduced median partial seizure duration from 271 to 54 s. Stimulation after partial seizures also reduced the occurrence and duration of secondarily generalized stage 4/5 seizures. VP-DBS prior to pilocarpine administration prevented the appearance of partial seizures in almost all animals. Lastly, VP-DBS delayed the onset of generalized tonic-clonic seizures (GTCSs) from 111 to 823 s in rats administered another chemoconvulsant, pentylenetetrazol (PTZ, 90 mg/kg). In this particular rat seizure model, stimulating electrodes placed more laterally in both VP hemispheres and more posterior in the left VP hemisphere provided greatest efficacy for GTCSs. In conclusion, our findings posit that VP-DBS can serve as an effective novel neuromodulatory approach for a variety of acute seizure phenotypes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Neuropeptide Y (NPY) is an important 36 amino acid peptide that is abundantly expressed in the mammalian CNS and is known to be an endogenous modulator of seizure activity, including in rat models of Genetic Generalised Epilepsy (GGE) with absence seizures. Studies have shown that viral-mediated "gene therapy" with overexpression of NPY in the hippocampus can suppress seizures in acquired epilepsy animal models. This study investigated whether NPY gene delivery to the thalamus or somatosensory cortex, using recombinant adeno-associated viral vector (rAAV), could produce sustained seizure suppression in the GAERS model of GGE with absence seizures. Three cohorts of GAERS were injected bilaterally into the thalamus (short term n = 14 and long term n = 8) or the somatosensory cortex (n = 26) with rAAV-NPY or rAAV-empty. EEG recordings were acquired weekly post-treatment and seizure expression was quantified. Anxiety levels were tested using elevated plus maze and open field test. NPY and NPY receptor mRNA and protein expression were evaluated using quantitative PCR, immunohistochemistry and immunofluorescence. Viral overexpression of human NPY in the thalamus and somatosensory cortex in GAERS significantly reduced the time spent in seizure activity and number of seizures, whereas seizure duration was only reduced after thalamic NPY overexpression. Human and rat NPY and rat Y2 receptor mRNA expression was significantly increased in the somatosensory cortex. NPY overexpression in the thalamus was observed in rAAV-NPY treated rats compared to controls in the long term cohort. No effect was observed on anxiety behaviour. We conclude that virally-mediated human NPY overexpression in the thalamus or somatosensory cortex produces sustained anti-epileptic effects in GAERS. NPY gene therapy may represent a novel approach for the treatment of patients with genetic generalised epilepsies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: We examined the yield from EMFIT bed alarms and staff response time to generalised seizure in a medium term residential assessment unit for epilepsy., Methods: The Scottish Epilpesy Centre (SEC) has a Video Observation System (VOS) that provides continuous recording of all patient spaces (external and internal) and allows retention of clinically relevant events. A retrospective audit of daily EMFIT test records, nursing seizure record sheets (seizure type and EMFIT alert status), clinical incident reporting systems and the VOS database of retained clinical events was conducted for an 9 month period from April 1st 2016 till December 31st 2016. All generalized tonic clonic seizures (GTCS) were noted by patient, time and location and staff response time to GTCS was calculated., Results: There were 85 people admitted during the audit period who had 61 GTCS. 50 events were in bed and EMFIT alert status was recorded. On 8 occasions the EMFIT did not alert: 5 events were not of sufficient duration or frequency, in 2 the patient fell from the bed early and 1 event the alarm did not trigger. The average response time to GTCS was 23s. The longest response time was 69s (range, 0-69s, sd 15.76.)., Conclusions: The EMFIT bed alarm appears to be a valuable adjunct to safety systems. Within the novel environment of the SEC it is possible to maintain a response time to GTCS that is comparable to hospital based UK video telemetry units., (Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Since the approval of Vagal Nerve Stimulation (VNS) Therapy for medically refractory focal epilepsies in 1997, it has been also reported to be effective for a wide range of generalized seizures types and epilepsy syndromes. Instead of conventional VNS Therapy delivered at 20-30Hz signal frequencies, this study evaluates efficacy and tolerability of high-frequency burst VNS in a natural animal model for genetic generalized epilepsy (GGE), the epileptic baboon., Methods: Two female baboons (B1 P.h. Hamadryas and B2 P.h. Anubis x Cynocephalus) were selected because of frequently witnessed generalized tonic-clonic seizures (GTCS) for VNS implantation. High-frequency burst VNS Therapy was initiated after a 4-5 week baseline; different VNS settings (0.25, 2 or 2.5mA, 300Hz, 4 vs 7 pulses, 0.5-2.5s interburst interval, and intermittent stimulation for 1-2 vs for 24h per day) were tested over the subsequent 19 weeks, which included a 4-6 week wash-out period. GTCS frequencies were quantified for each setting, while seizure duration and postictal recovery times were compared to baseline. Scalp EEG studies were performed at almost every setting, including intermittent light stimulation (ILS) to evaluate photosensitivity. Pre-ILS ictal and interictal discharge rates, as well as ILS responses were compared between trials. The Novel Object test was used to assess potential treatment effects on behavior., Results: High-frequency burst VNS Therapy reduced GTCS frequencies at all treatment settings in both baboons, except when output currents were reduced (0.25mA) or intermittent stimulation was restricted (to 1-2h/day). Seizure duration and postictal recovery times were unchanged. Scalp EEG studies did not demonstrate treatment-related decrease of ictal or interictal epileptic discharges or photosensitivity, but continuous treatment for 120-180s during ILS appeared to reduce photoparoxysmal responses. High-frequency burst VNS Therapy was well-tolerated by both baboons, without cardiac or behavioral changes. Repetitive muscle contractions involving the neck and left shoulder girdle were observed intermittently, most commonly at 0.5 interburst intervals, but these were transient, resolving with a few cycles of stimulation and not noted in wakefulness., Conclusions: This preclinical pilot study demonstrates efficacy and tolerability of high-frequency burst VNS Therapy in the baboon model of GGE. The muscle contractions may be due to aberrant propagation of the stimulus along the vagal nerve or to the ansa cervicalis, but can be reduced by minimal adjustment of current output or stimulus duration., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The onset of generalized seizures is a long debated subject in epilepsy. The relative roles of cortex and thalamus in initiating and maintaining the different seizure types are unclear., Objective: The purpose of the study is to estimate whether the cortex or the centromedian thalamic nucleus is leading in initiating and maintaining seizures in humans., Methods: We report human ictal recordings with simultaneous thalamic and cortical electrodes from three patients without anesthesia being assessed for deep brain stimulation (DBS). Patients 1 and 2 had idiopathic generalized epilepsy whereas patient 3 had frontal lobe epilepsy. Visual inspection was combined with nonlinear correlation analysis., Results: In patient 1, seizure onset was bilateral cortical and the belated onset of leading thalamic discharges was associated with an increase in rhythmicity of discharges, both in thalamus and cortex. In patient 2, we observed bilateral independent interictal discharges restricted to the thalamus. However, ictal onset was diffuse, with discharges larger in the cortex even though they were led by the thalamus. In patient 3, seizure onset was largely restricted to frontal structures, with belated lagging thalamic involvement., Conclusion: In human generalized seizures, the thalamus may become involved early or late in the seizure but, once it becomes involved, it leads the cortex. In contrast, in human frontal seizures the thalamus gets involved late in the seizure and, once it becomes involved, it lags behind the cortex. In addition, the centromedian nucleus of the thalamus is capable of autonomous epileptogenesis as suggested by the presence of independent focal unilateral epileptiform discharges restricted to thalamic structures. The thalamus may also be responsible for maintaining the rhythmicity of ictal discharges.

Objective: In patients with Genetic Generalized Epilepsy (GGE), transcranial magnetic stimulation (TMS) can induce epileptiform discharges (EDs) of varying duration. We hypothesized that (a) the ED duration is determined by the dynamic states of critical network nodes (brain areas) at the early post-TMS period, and (b) brain connectivity changes before, during and after the ED, as well as within the ED., Methods: EEG recordings from two GGE patients were analyzed. For hypothesis (a), the characteristics of the brain dynamics at the early ED stage are measured with univariate and multivariate EEG measures and the dependence of the ED duration on these measures is evaluated. For hypothesis (b), effective connectivity measures are combined with network indices so as to quantify the brain network characteristics and identify changes in brain connectivity., Results: A number of measures combined with specific channels computed on the first EEG segment post-TMS correlate with the ED duration. In addition, brain connectivity is altered from pre-ED to ED and post-ED and statistically significant changes were also detected across stages within the ED., Conclusion: ED duration is not purely stochastic, but depends on the dynamics of the post-TMS brain state. The brain network dynamics is significantly altered in the course of EDs.

The brain-computer interface (BCI) is an exciting advance in neuroscience and engineering. In a motor BCI, electrical recordings from the motor cortex of paralysed humans are decoded by a computer and used to drive robotic arms or to restore movement in a paralysed hand by stimulating the muscles in the forearm. Simultaneously integrating a BCI with the sensory cortex will further enhance dexterity and fine control. BCIs are also being developed to: provide ambulation for paraplegic patients through controlling robotic exoskeletons; restore vision in people with acquired blindness; detect and control epileptic seizures; and improve control of movement disorders and memory enhancement. High-fidelity connectivity with small groups of neurons requires microelectrode placement in the cerebral cortex. Electrodes placed on the cortical surface are less invasive but produce inferior fidelity. Scalp surface recording using electroencephalography is much less precise. BCI technology is still in an early phase of development and awaits further technical improvements and larger multicentre clinical trials before wider clinical application and impact on the care of people with disabilities. There are also many ethical challenges to explore as this technology evolves.

Background: Epilepsy is a common neurological disorder, with over 80 % of cases found in low- and middle-income countries (LMICs). Studies from high-income countries find a significant economic burden associated with epilepsy, yet few studies from LMICs, where out-of-pocket costs for general healthcare can be substantial, have assessed out-of-pocket costs and health care utilization for outpatient epilepsy care., Methods: Within an established health and socio-demographic surveillance system in rural South Africa, a questionnaire to assess self-reported health care utilization and time spent traveling to and waiting to be seen at health facilities was administered to 250 individuals, previously diagnosed with active convulsive epilepsy. Epilepsy patients' out-of-pocket, medical and non-medical costs and frequency of outpatient care visits during the previous 12-months were determined., Results: Within the last year, 132 (53 %) individuals reported consulting at a clinic, 162 (65 %) at a hospital and 34 (14 %) with traditional healers for epilepsy care. Sixty-seven percent of individuals reported previously consulting with both biomedical caregivers and traditional healers. Direct outpatient, median costs per visit varied significantly (p < 0.001) between hospital (2010 International dollar ($) 9.08; IQR: $6.41-$12.83) and clinic consultations ($1.74; IQR: $0-$5.58). Traditional healer fees per visit were found to cost $52.36 (IQR: $34.90-$87.26) per visit. Average annual outpatient, clinic and hospital out-of-pocket costs totaled $58.41. Traveling to and from and waiting to be seen by the caregiver at the hospital took significantly longer than at the clinic., Conclusions: Rural South Africans with epilepsy consult with both biomedical caregivers and traditional healers for both epilepsy and non-epilepsy care. Traditional healers were the most expensive mode of care, though utilized less often. While higher out-of-pocket costs were incurred at hospital visits, more people with ACE visited hospitals than clinics for epilepsy care. Promoting increased use and effective care at clinics and reducing travel and waiting times could substantially reduce the out-of-pocket costs of outpatient epilepsy care.

Introduction: Pharmacological treatment of epilepsy in some patients is ineffective and alternative methods of treatment are need. These include neurofeedback (EEG biofeedback, NF). The aim of this study was to evaluate the clinical and neurophysiological effectiveness of NF in children with epilepsy with primary generalized seizures., Material and Methods: The study involved a group of 63 children with primary generalized seizures, aged 6-16 years, including 39 girls and 24 boys. As the efficacy of pharmacotherapy was not satisfactory for them, they have been referred to Neuromedica Institute in Krakow for NF treatment. The evaluation of preliminary clinical and neurophysiological parameters was performed. Individual NF therapy protocols were elaborated and trainings were conducted for 0.5-4 years. Individual therapy protocols were prepared by biofeedback specialist and trainings were conducted by biofeedback therapists. The same specialist also made a comparison of selected elements of the EEG in children before and after NF therapy., Results: The children enrolled into the study were diagnosed with epilepsy at the age of 6 months to the age of 16 years Tonic-clonic seizures and absence seizures were the most often seizure types in the examined group. Seizures occurred in 19 children every day. In 33/63 children clinical manifestation of seizures and EEG pattern when taken together allow the specific epilepsy syndrome diagnosis in 7 cases. In 27 children two or more antiepileptic drugs were used, and in 36 monotherapy was used. NF therapy had a significant impact on the clinical condition of the children, causing subsidence of seizures in most of them. In 23/63 children antiepileptic treatment was withdrawn and in 15 reduction of treatment was achieved. The impact of the NF therapy on the EEG parameters was beneficial, both in terms of the background activity and other parameters. Paroxysmal EEG pattern subsided in the vast majority of children (63 to 16) including a continuous paroxysmal activity from 12 to 4, interrupted from 51 to 12 and generalized from 63 to 21, with reduced susceptibility to photostimulation from 31 to 18 and hyperventilation from 39 to 17., Conclusions: In half of children with primary generalized epilepsy with a characteristic EEG pattern specific epilepsy syndrome was diagnosed. In half of children subsidence of epileptic graphoelements in EEG was observed after NF therapy. In % of children paroxysmal bioelectric pattern subsided and sensitivity of EEG to hyperventilation and photostimulation decreased significantly. NF therapy had a positive impact on all the parameters of background bioelectrical activity. In 1/3 of children treated with NF pharmacotherapy of epilepsy was discontinued and in 1/4 reduced.

Unlabelled: Neurofeedback (EEG biofeedback, NF) is one of the methods of non-pharmacological instrumental therapy. In the treatment of epilepsy it is considered as a complementary method, reducing the number of seizures. The aim of this study was to investigate the effect of NF on the incidence of clinical attacks and bioelectrical activity of the brain in children with epilepsy with partial seizures and secondarily generalized seizures., Material and Methods: The study involved a group of 78 children with partial seizures, additionally 30 of them had second-ry generalized seizures. There were 35 girls and 43 boys ranging in age from 5 to 17.5 years. They were treated with NF in the Neuromedica Institute in Krakow, in the period 2005-2015. Treatment time ranged from 6 months to 3 years. We have evaluated the incidence of seizures before and after NF therapy. Visual analysis of EEG recordings with assessment of background activity, location of focal changes, presence of paroxysmal pattern and epileptic graphoelements., Results: In 41/78 children seizures occurred 1-2 times a month, in 19/78 every day and 9 children were diagnosed with epileptic syndrome. During NF therapy 52/78 children experienced resolution of clinical seizures. NF therapy was ineffective in only one child. In 18 child withdrawal of antiepileptic treatment was achieved and in 22 reduction of drug doses. Epileptic graphoelements occurred in 46/78 children before treatment and in 21/78 children after treatment. Before NF therapy irregular bio-electrical activity was found in 51 children versus 27 children with regular bioelectric activity and in 27 children versus 51 children after the therapy. The amplitude of this activity returned to normal in 19 children, and in 29 children the frequency of background activity. Particularly surprising was to restore synchrony and symmetry of EEG pattern in 44 children (11 children before NF treatment to 55 children after the treatment). Even more significant effect of NF therapy was observed in EEG patterns, abolition of paroxysmal pattern and reduction of continuous, localized and generalized changes. NF therapy also advantageously reduced the number of localized changes and decreased sensitivity of EEG pattern to hyperventilation and photostimulation., Conclusions: During NF therapy in almost all children with epileptic partial seizures and secondarily generalized seizures resolution or reduction of clinical seizures was observed. In nearly 1/4 of children withdrawal of antiepileptic treatment was achieved and in higher number reduction of pharmacotherapy. All parameters of the background EEG bioelectric activity in these children have improved, especially synchrony and symmetry of EEG pattern and paroxysmal changes subsided.

Generalized epilepsy is characterized by recurrent seizures caused by oscillatory neuronal firing throughout thalamocortical networks. Current therapeutic approaches often intervene at the level of the thalamus or cerebral cortex to ameliorate seizures. We review here the therapeutic potential of cerebellar stimulation. The cerebellum forms a prominent ascending input to the thalamus and, whereas stimulation of the foliated cerebellar cortex exerts inconsistent results, stimulation of the centrally located cerebellar nuclei (CN) reliably stops generalized seizures in experimental models. Stimulation of this area indicates that the period of stimulation with respect to the phase of the oscillations in thalamocortical networks can optimize its effect, opening up the possibility of developing on-demand deep brain stimulation (DBS) treatments., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To identify the clinical determinants of occurrence of postictal generalized EEG suppression (PGES) after generalized convulsive seizures (GCS)., Methods: We reviewed the video-EEG recordings of 417 patients included in the REPO2MSE study, a multicenter prospective cohort study of patients with drug-resistant focal epilepsy. According to ictal semiology, we classified GCS into 3 types: tonic-clonic GCS with bilateral and symmetric tonic arm extension (type 1), clonic GCS without tonic arm extension or flexion (type 2), and GCS with unilateral or asymmetric tonic arm extension or flexion (type 3). Association between PGES and person-specific or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures., Results: A total of 99 GCS in 69 patients were included. Occurrence of PGES was independently associated with GCS type (p < 0.001) and lack of early administration of oxygen (p < 0.001). Odds ratio (OR) for GCS type 1 in comparison with GCS type 2 was 66.0 (95% confidence interval [CI 5.4-801.6]). In GCS type 1, risk of PGES was significantly increased when the seizure occurred during sleep (OR 5.0, 95% CI 1.2-20.9) and when oxygen was not administered early (OR 13.4, 95% CI 3.2-55.9)., Conclusion: The risk of PGES dramatically varied as a function of GCS semiologic characteristics. Whatever the type of GCS, occurrence of PGES was prevented by early administration of oxygen., (© 2015 American Academy of Neurology.)

Atonic seizures are debilitating and poorly controlled with antiepileptic medications. Two surgical options are primarily used to treat medically refractory atonic seizures: corpus callosotomy (CC) and vagus nerve stimulation (VNS). However, given the uncertainty regarding relative efficacy and surgical complications, the best approach for affected patients is unclear. The PubMed database was queried for all articles describing the treatment of atonic seizures and drop attacks with either corpus callosotomy or VNS. Rates of seizure freedom, >50% reduction in seizure frequency, and complications were compared across the two patient groups. Patients were significantly more likely to achieve a >50% reduction in seizure frequency with CC versus VNS (85.6% versus 57.6%; RR: 1.5; 95% CI: 1.1-2.1). Adverse events were more common with VNS, though typically mild (e.g., 22% hoarseness and voice changes), compared with CC, where the most common complication was the disconnection syndrome (13.2%). Both CC and VNS are well tolerated for the treatment of refractory atonic seizures. Existing studies suggest that CC is potentially more effective than VNS in reducing seizure frequency, though a direct study comparing these techniques is required before a definitive conclusion can be reached., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Drug-resistant epileptic patients account for 40 % of cases of epilepsy. Consequently, specific therapeutic options could be surgical resection or, if not indicated, deep brain stimulation (DBS). The aim of this study is to review data from patients affected by drug-resistant complex partial epilepsy with or without generalization treated by anterior thalamic nucleus (AN) DBS to evaluate the efficacy and potential future applications of this approach as a standard method for palliative seizure control., Methods: Six patients affected by drug-resistant complex partial seizures underwent AN DBS from March 2007 to February 2011. The preoperative tests consisted of electroencephalography (EEG), video EEG, morphologic and functional magnetic resonance imaging (MRI), non-acute positron emission tomography (PET), neuropsychological evaluation, Liverpool seizure scale, and Quality Of Life In Epilepsy (QOLIE). These tests and a seizure diary were also administered during a follow-up of at least 3 years., Results: The improvement in terms of decrease of seizures was more than 50 % in patients affected by complex partial seizures strictly related to limbic system origin. The amelioration was unsatisfactory for patients having anatomical lesions outside the limbic structures with evidence of late diffusion in limbic areas. One patient died 40 days after surgery for reasons not concerned with DBS., Conclusions: Although the limited number of enrolled patients limits the reliability of data, the results are in accordance with those found in the recent literature and deserve to be considered for further studies regarding real efficacy, indications, stimulation parameters, side effects, and complications.