Neurostimulation For Epilepsy Research Articles

QUality of life and Economic evaluation after neuroSTimulation for Epilepsy (QUESTE) in adolescents and adults with drug-resistant epilepsy: protocol for a multicentre, prospective observational cohort study in The Netherlands

IntroductionEpilepsy is one of the most common chronic neurological disorders. Antiseizure medication (ASM) is the first choice of treatment, however, 30% of epilepsy patients are drug-resistant. For these patients, neuromodulation...

Mechanisms of Neurostimulation for Epilepsy.

This review discusses the use of neurostimulation therapies for epilepsy treatment, including vagal nerve stimulation, responsive neurostimulation, and deep brain stimulation. Different therapeutic strategies and their underlying mechanisms are explored, with a focus on optimizing parameters for seizure reduction. The review also highlights the paradigm shift toward a more diverse and multimodal approach to deep brain neuromodulation.

Practical considerations in epilepsy neurostimulation.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Systematic Review and Meta-Analysis of Responsive Neurostimulation in Epilepsy

Neuromodulatory implants provide promising alternatives for patients with drug-resistant epilepsy (DRE) in whom resective or ablative surgery is not an option. Responsive neurostimulation (RNS) operates a unique "closed-loop" system of electrocorticography-triggered stimulation for seizure control. A comprehensive review of the current literature would be valuable to guide clinical decision-making regarding RNS. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols, a systematic PubMed literature review was performed to identify appropriate studies involving patients undergoing RNS for DRE. Full texts of included studies were analyzed and extracted data regarding demographics, seizure reduction rate, responder rate (defined as patients with >50% seizure reduction), and complications were compiled for comprehensive statistical analysis. A total of 313 studies were screened, and 17 studies were included in the final review, representative of 541 patients. Mean seizure reduction rate was 68% (95% confidence interval 61%-76%), and the mean responder rate was 68% (95% confidence interval 60%-75%). Complications occurred in 102 of 541 patients, for a complication rate of 18.9%. A strong publication bias toward greater seizure reduction rate and increased responder rate was demonstrated among included literature. A meta-analysis of recent RNS for DRE literature demonstrates seizure reduction and responder rates comparable with other neuromodulatory implants for epilepsy, demonstrating both the value of this intervention and the need for further research to delineate the optimal patient populations. This analysis also demonstrates a strong publication bias toward positive primary outcomes, highlighting the limitations of current literature. Currently, RNS data are optimistic for the treatment of DRE but should be interpreted cautiously.

Fractional-order model predictive control as a framework for electrical neurostimulation in epilepsy

Objective. Electrical neurostimulation is an increasingly adopted therapeutic methodology for neurological conditions such as epilepsy. Electrical neurostimulation devices are commonly characterized by their limited sensing, actuating, and computational capabilities. However, the sensing mechanisms are often used only for their detection potential (e.g. to detect seizures), which automatically and dynamically trigger the actuation capabilities, but ultimately deploy prespecified stimulation doses that resulted from a period of manual (and empirical) calibration. The potential information contained in the measurements acquired by the sensing mechanisms is, therefore, considerably underutilized, given that this type of stimulation strategy only entails an event-triggered relationship between the sensors and actuators of the device. Such stimulation strategies are suboptimal in general and lack theoretical guarantees regarding their performance. Approach. In order to leverage the aforementioned information, harvested during normal sensing-actuating operation, we must consider a real-time feedback (closed-loop) strategy. More precisely, the stimulation signal itself should automatically adapt based upon the state of the neurophysiological system at hand, estimated from data collected in real-time through sensors in the device. Main results. In this work, we propose a model-based approach for (real-time) closed-loop electrical neurostimulation, in which the evolution of the system is captured by a fractional-order system (FOS). More precisely, we propose a model predictive control (MPC) approach with an underlying FOS predictive model, due to the ability of fractional-order dynamics to more accurately capture the long-term dependence present in biological systems, compared to the standard linear time-invariant models. Furthermore, MPC offers, by design, an additional layer of robustness to compensate for system-model mismatch, which the more traditional strategies lack. To establish the potential of our framework, we focus on epileptic seizure mitigation by computational simulation of our proposed strategy upon seizure-like events. Lastly, we provide evidence of the effectiveness of our method on seizures simulated by commonly adopted models in the neuroscience and medical community present in the literature, as well as real seizure data as obtained from subjects with epilepsy. Significance Our study thus paves the way for the development and implementation of robust real-time closed-loop electrical neurostimulation which can then be used for the construction of more effective devices for epileptic seizure mitigation.

Different modalities of invasive neurostimulation for epilepsy.

Epilepsy affects 1% of the general population, about one-third of which is pharmacologically resistant. Uncontrolled seizures are associated with an increased risk of traumatic injury and sudden unexpected death of epilepsy. There is a considerable psychological and financial burden on caregivers of patients with epilepsy, particularly among pediatric patients. Epilepsy surgery, when indicated, is the most promising cure for epilepsy. However, when surgery is contraindicated or refused by the patient, neurostimulation is an alternative palliative approach, albeit with a lower chance of entirely curing patients of seizures. There are many options for neurostimulation. The three most commonly used invasive neurostimulation procedures that consistently show evidence of being safe and efficacious are vagal nerve stimulation, responsive neuro stimulation, or anterior thalamic nucleus deep brain stimulation. The goal of this review is to summarize the current evidence supporting the use of these three techniques, which are approved by most regulatory bodies, and discuss different factors that may enable epilepsy surgeons to choose the most appropriate modality for each patient.

Responsive Neurostimulation in Epilepsy: Wall to Block Seizures or Bridge to Resection?

Mesial Temporal Resection Following Long-Term Ambulatory Intracranial EEG Monitoring With a Direct Brain-Responsive Neurostimulation System Hirsch LJ, Mirro EA, Salanova V, Witt TC, Drees CN, Brown MG, Lee RW, Sadler TL, Felton EA, Rutecki P, Shin HW, Hadar E, Hegde M, Rao VR, Mnatsakanyan L, Madhavan DS, Zakaria TJ, Liu AA, Heck CN, Greenwood JE, Bigelow JK, Nair DR, Alexopoulos AV, Mackow M, Edwards JC, Sotudeh N, Kuzniecky RI, Gwinn RP, Doherty MJ, Geller EB, Morrell MJ. Epilepsia. 2020;61(3):408-420. doi: 10.1111/epi.16442Objective:To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator (RNS) system.Methods:We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS system using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS system chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3 months before MTL resection.Results:We identified 157 patients treated with the RNS system with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five (16%) patients subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine (38%) patients had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; 8 of 9 continued RNS system treatment. Fifteen (62%) patients had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS system treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with 8 of 15 seizure-free. For those with more than 1 year of follow-up (N = 21), 15 (71%) patients were seizure-free during the most recent year, including all 8 patients with unilateral onsets and 7 (54%) of 13 patients with bilateral onsets.Significance:Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

Noninvasive Brain Stimulation in Epilepsy.

Neurostimulation in epilepsy is a long standing established concept, and through experimental and clinical uses, our understanding of neurostimulation and neuromodulation has grown substantially. Noninvasive brain stimulation techniques use electromagnetic principles to noninvasively modulate brain activity in a spatiotemporally targeted manner. This review focused on the two predominant forms of noninvasive neurostimulation: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, and their current applications in the diagnosis and management of epilepsy. A number of small randomized sham-controlled studies suggest that both TMS and transcranial direct current stimulation may have a beneficial effect in decreasing seizure frequency in patients with medically refractory epilepsy, without significant side effects. Small pilot studies also suggest that TMS in combination with EEG may be used to develop quantitative biomarkers of cortical hyperexcitability in patients with epilepsy. Furthermore, TMS is already Food and Drug Administration-cleared for presurgical mapping of eloquent cortex, and preliminary studies suggest that navigated TMS represents a highly valuable clinical supplement for preoperative functional planning. Transcranial magnetic stimulation and transcranial direct current stimulation have shown great potential benefit for patients with epilepsy; however, further large multicenter randomized sham-controlled studies are needed to better optimize stimulation settings and protocols, define mechanisms of action, assess long-term effects, and clearly define roles and determine efficacy.

Sleep disruption is not observed with brain-responsive neurostimulation for epilepsy.

ObjectiveNeurostimulation devices that deliver electrical impulses to the nervous system are widely used to treat seizures in patients with medically refractory epilepsy, but the effects of these therapies on sleep are incompletely understood. Vagus nerve stimulation can contribute to obstructive sleep apnea, and thalamic deep brain stimulation can cause sleep disruption. A device for brain‐responsive neurostimulation (RNS® System, NeuroPace, Inc) is well tolerated in clinical trials, but potential effects on sleep are unknown.MethodsSix adults with medically refractory focal epilepsy treated for at least six months with the RNS System underwent a single night of polysomnography (PSG). RNS System lead locations included mesial temporal and neocortical targets. Sleep stages and arousals were scored according to standard guidelines. Stimulations delivered by the RNS System in response to detections of epileptiform activity were identified by artifacts on scalp electroencephalography.ResultsOne subject was excluded for technical reasons related to unreliable identification of stimulation artifact on EEG during PSG. In the remaining five subjects, PSG showed fragmented sleep with frequent arousals. Arousal histograms aligned to stimulations revealed a significant peak in arousals just before stimulation. In one of these subjects, the arousal peak began before stimulation and extended ~1 seconds after stimulation. A peak in arousals occurring only after stimulation was not observed.SignificanceIn this small cohort of patients, brain‐responsive neurostimulation does not appear to disrupt sleep. If confirmed in larger studies, this could represent a potential clinical advantage of brain‐responsive neurostimulation over other neurostimulation modalities.

A Review of Neurostimulation for Epilepsy in Pediatrics.

Neurostimulation for epilepsy refers to the application of electricity to affect the central nervous system, with the goal of reducing seizure frequency and severity. We review the available evidence for the use of neurostimulation to treat pediatric epilepsy, including vagus nerve stimulation (VNS), responsive neurostimulation (RNS), deep brain stimulation (DBS), chronic subthreshold cortical stimulation (CSCS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). We consider possible mechanisms of action and safety concerns, and we propose a methodology for selecting between available options. In general, we find neurostimulation is safe and effective, although any high quality evidence applying neurostimulation to pediatrics is lacking. Further research is needed to understand neuromodulatory systems, and to identify biomarkers of response in order to establish optimal stimulation paradigms.

Neuromodulation beyond neurostimulation for epilepsy: scope for focused ultrasound

ABSTRACTIntroduction: Epilepsy is one of the most common neurological disorders and is often difficult to control with medication. Intractable epilepsy often results in compromised quality of life (QOL), neurologic morbidity and even mortality. In carefully selected cases, resective surgery offers the best potential for cure or seizure control. However, a large proportion of patients are not suitable for resective epilepsy surgery. Neuromodulation techniques are increasingly being used to treat such refractory cases. Recently, the FDA approved Magnetic Resonance-guided Focused Ultrasound (MRgFUS) for essential tremor and this novel technology is also being explored in several other neuropsychiatric conditions and neurological disorders, including epilepsy.Area covered: While the literature is scant and scattered, the pertinent literature of the MRgFUS is reviewed with an emphasis on research relevant to its application for epilepsy.Expert opinion: Limited preliminary clinical experiences and research studies with MRgFUS ablation or neuromodulation for epilepsy have shown promising results; however, this procedure remains experimental requiring further investigations. Safe and reversible opening of the blood-brain barrier (BBB) with MRgFUS adds an additional therapeutic avenue by allowing targeted delivery of neurotherapeutics in neurological disorders, potentially including epilepsy. Ongoing clinical trials and research coupled with technological advancements contribute to strengthening the MRgFUS epilepsy field. MRgFUS could be the future technology of choice for ‘ablation’ or ‘sononeuromodulation’, and/or a ‘targeted therapeutics’ for epilepsy.

Putting it all together: Options for intractable epilepsy: An updated algorithm on the use of epilepsy surgery and neurostimulation

For drug-resistant epilepsy, nonpharmacologic treatments should be considered early rather than late. Of the nondrug treatments, only resective surgery can be curative. Neurostimulation is palliative, i.e., not expected to achieve a seizure-free outcome. While resective surgery is the goal, other options are necessary because the majority of patients with drug-resistant epilepsy are not surgical candidates, and others have seizures that fail to improve with surgery or have only partial improvement but not seizure freedom. Neurostimulation modalities include vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS), each with its own advantages, disadvantages, and side effects. In most scenarios, determined by noninvasive evaluation, especially EEG and MRI, several strategies are reasonable. For focal epilepsies, the choices are between resective surgery, with or without intracranial EEG, and all three modalities of neurostimulation. In situations where resective surgery is likely to result in seizure freedom, such as mesiotemporal lobe epilepsy or lesional focal epilepsy, resection (standard, laser, or radiofrequency) is preferred. For difficult cases like extratemporal nonlesional epilepsies, neurostimulation offers a less invasive option than resective surgery. For generalized and multifocal epilepsies, VNS is an option, RNS is not, and DBS has only limited evidence.“This article is part of the Supplement issue Neurostimulation for Epilepsy.”

Cognitive safety of intracranial electrodes for epilepsy.

Two recent articles in Epilepsia have raised concerns about adverse cognitive effects associated with intracranial electrode implantation. However, both studies have important limitations, and their results contrast with studies that report no adverse cognitive effects of intracranial electrodes for diagnosis or neurostimulation in epilepsy. Furthermore, no data are provided on the relative safety of depth electrodes implanted along the longitudinal axis of the hippocampus vs other electrode locations or types of electrodes. Instituting changes in the use of depth electrodes based solely on these 2 studies is not clinically indicated. Further research is needed.

Responsive neurostimulation for treatment of pediatric drug-resistant epilepsy

Responsive neurostimulation for epilepsy involves an implanted device that delivers direct electrical brain stimulation in response to detection of incipient seizures. Responsive neurostimulation is a safe and effective treatment for adults with drug-resistant epilepsy, but although novel treatments are critically needed for younger patients, responsive neurostimulation is currently not approved for children with drug-resistant epilepsy. Here, we report a 16-year-old patient with seizures arising from eloquent cortex, who was successfully treated with responsive neurostimulation. This case highlights the potential utility of this therapy for pediatric patients and underscores the need for larger studies.

Pilot data on responsive epilepsy neurostimulation, measures of sleep apnea and continuous glucose measurements

ObjectivesTo match responsive neurostimulator (RNS) and polysomnographic data to determine if RNS detections and stimulations correlate with measurements of sleep disordered breathing and continuous glucose measurements (CGM).Materials and methodsIn a patient with an RNS with detection/stimulation leads implanted bi-temporally detection-stimulation counts were matched by time with coinciding polysomnogram and CGM data.ResultsTemporal dispersion of RNS DSC were independent of measures of sleep apnea, hypopnea or glucose.ConclusionHippocampal nighttime responsive neurostimulation therapies did not appear to worsen measures of normal or abnormal sleep.

Deep brain and cortical stimulation for epilepsy.

Deep brain and cortical stimulation for epilepsy.

Commentary: 2016 Epilepsia Basic Science Prize.

Commentary: 2016 Epilepsia Basic Science Prize.

Implantation of Responsive Neurostimulation for Epilepsy Using Intraoperative Computed Tomography: Technical Nuances and Accuracy Assessment.

Implantation of responsive neurostimulation (RNS) system has been previously discussed in the literature but there is a paucity of data on target accuracy and the use of intraoperative imaging. We describe our experience with 8 patients using intraoperative computed tomography (iCT) during implantation of the NeuroPace RNS system. A frame-based system was used. CT images were obtained and merged with preoperative magnetic resonance imaging and metabolic imaging studies to calculate target coordinates. An occipital entry point with a trajectory parallel to the hippocampus was planned. The leads were placed in the parahippocampal white matter circuitry. iCT images were obtained for immediate confirmation of lead accuracy. Images were computationally merged and superimposed on the magnetic resonance images and final coordinates of the distal contact were compared with the intended target. Targeting error was calculated in each axis as well as Euclidean distance. Preoperative and postoperative seizure frequency per month was used to evaluate outcomes. Fifteen occipitotemporal leads were placed in 8 patients. The vector error means in the x, y, and zplaneswere 0.57 mm ± 0.44 mm, 0.71 mm ± 0.84 mm, and 2.23 mm ± 1.43 mm, respectively. The mean Euclidean distance error was 2.63 mm ± 1.32 mm. The z axis was found to have a significantly higher error [F2,42= 12.955; P= 0.001] when compared with the x or y axes. The median preoperative and postoperative seizure frequency per month was 3.4 and 0.78 seizures, respectively. Frame-based stereotactic implantation of the NeuroPace RNS system using iCT is feasible and allows for intraoperative target accuracy confirmation and correction.

Closed loop neurostimulation for epilepsy

Various neurostimulation modalities have emerged in the field of epilepsy. Despite the fact that delivery of an electrical current to the hyperexcitable epileptic brain might, at first, seem contradictory, neurostimulation has become an established therapeutic option with a promising efficacy and adverse effects profile. In “responsive” neurostimulation the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or prevent an upcoming seizure. The design of technology required for responsive stimulation is more challenging compared to devices for open-loop neurostimulation. The achievement of therapeutic success is dependent on adequate sensing and stimulation algorithms and a fast coupling between both. The benefits of delivering current only at the time of an approaching seizure merit further investigation. Current experience with responsive neurostimulation in epilepsy is still limited, but seems promising.

Neurostimulation for epilepsy

Neurostimulation for epilepsy is a rapidly expanding field. Since the introduction of vagus nerve stimulation more than 15 yr ago, there have been new developments in the area, including deep brain stimulation (DBS) and responsive neuro- stimulation. Both of these modalities now have class-I evidence supporting their use. The pivotal trials for DBS and responsive neurostimulation will be summarized. Little is known about the application of these new modalities in pediatric population. Case reports and case series of DBS including pediatric population are summarized.