Closed-Loop Brain Stimulation for Drug-Resistant Epilepsy: Towards an Evidence-Based Approach to Personalized Medicine

Sisterson, Nathaniel D; Wozny, Thomas A.; Kokkinos, Vasileios; Constantino, Alexander C; Richardson, R. Mark

doi:10.1007/s13311-018-00682-4

Cited by 85 publications

(83 citation statements)

References 35 publications

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“…However, the favorable clinical outcomes we observed suggest either that this concern is negligible when seizure onset is synchronous over large cortical territories or that early therapy delivery during seizures is less critical than previously thought. We cannot exclude the possibility that stimulation in the middle of the regional SOZ or other approaches to optimizing stimulation parameters might result in even better outcomes. Indeed, an emerging mechanistic conception of seizure generation involves specific synchronizing and desynchronizing nodes that regulate the epileptic network in a “push‐pull control mechanism.” It follows that modulation of these critical nodes, which may exist outside of the SOZ, could influence activity in the wider epileptic network.…”

Section: Discussionmentioning

confidence: 99%

Responsive neurostimulation for regional neocortical epilepsy

et al. 2019

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Objective Surgical resection of seizure‐producing brain tissue is a gold standard treatment for drug‐resistant focal epilepsy. However, several patient‐specific factors can preclude resective surgery, including a spatially extensive (“regional”) seizure‐onset zone (SOZ). For such patients, responsive neurostimulation (RNS) represents a potential treatment, but its efficacy has not been investigated in this population. Methods We performed a multicenter retrospective cohort study of patients (N = 30) with drug‐resistant focal epilepsy and a regional neocortical SOZ delineated by intracranial monitoring who were treated with the RNS System for at least 6 months. RNS System leads were placed at least 1‐cm apart over the SOZ, and most patients were treated with a lead‐to‐lead stimulation pathway. Five patients underwent partial resection of the SOZ concurrent with RNS System implantation. We assessed change in seizure frequency relative to preimplant baseline and evaluated correlation between clinical outcome and stimulation parameters. Results Median follow‐up duration was 21.5 months (range 6‐52). Median reduction in clinical seizure frequency was 75.5% (interquartile range [IQR] 40%‐93.9%). There was no significant difference in outcome between patients treated with and without concurrent partial resection. Most patients were treated with low charge densities (1‐2.5 µC/cm2), but charge density, interlead distance, and duration of treatment were not significantly correlated with outcome. Significance RNS is a feasible and effective treatment in patients with drug‐resistant regional neocortical seizures. Prospective studies in larger cohorts are necessary to determine optimal lead configuration and stimulation parameters, although our results suggest that lead‐to‐lead stimulation and low charge density may be effective in some patients.

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Section: Discussionmentioning

confidence: 99%

Responsive neurostimulation for regional neocortical epilepsy

et al. 2019

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“…All patients met International League Against Epilepsy criteria for focal epilepsy 24,25 and underwent diagnostic intracranial recording, followed by multidisciplinary recommendation for closed-loop neurostimulation therapy using the RNS System. All patients implanted with the RNS System between January 28, 2015, and June 6, 2017, at our center were included in this study.…”

Section: Patientsmentioning

confidence: 99%

Association of Closed-Loop Brain Stimulation Neurophysiological Features With Seizure Control Among Patients With Focal Epilepsy

et al. 2019

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IMPORTANCE A bidirectional brain-computer interface that performs neurostimulation has been shown to improve seizure control in patients with refractory epilepsy, but the therapeutic mechanism is unknown. OBJECTIVE To investigate whether electrographic effects of responsive neurostimulation (RNS), identified in electrocorticographic (ECOG) recordings from the device, are associated with patient outcomes. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of ECOG recordings and accompanying clinical meta-data from 11 consecutive patients with focal epilepsy who were implanted with a neurostimulation system between January 28, 2015, and June 6, 2017, with 22 to 112 weeks of follow-up. Recorded ECOG data were obtained from the manufacturer; additional system-generated meta-data, including recording and detection settings, were collected directly from the manufacturer's management system using an in-house, custom-built platform. Electrographic seizure patterns were identified in RNS recordings and evaluated in the time-frequency domain, which was locked to the onset of the seizure pattern.MAIN OUTCOMES AND MEASURES Patterns of electrophysiological modulation were identified and then classified according to their latency of onset in relation to triggered stimulation events. Seizure control after RNS implantation was assessed by 3 main variables: mean frequency of seizure occurrence, estimated mean severity of seizures, and mean duration of seizures. Overall seizure outcomes were evaluated by the extended Personal Impact of Epilepsy Scale questionnaires, a patient-reported outcome measure of 3 domains (seizure characteristics, medication adverse effects, and quality of life), with a range of possible scores from 0 to 300 in which lower scores indicate worse status, and the Engel scale, which comprises 4 classes (I-IV) in which lower numbers indicate greater improvement. RESULTS Electrocorticographic data from 11 patients (8 female; mean [range] age, 35 [19-65] years; mean [range] duration of epilepsy, 19 [5-37] years) were analyzed. Two main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network were discovered: direct and indirect effects. Direct effects included ictal inhibition and early frequency modulation but were not associated with improved clinical outcomes (odds ratio [OR], 0.67; 95% CI, 0.06-7.35; P > .99). Only indirect effects-those occurring remote from triggered stimulation-were associated with improved clinical outcomes (OR, infinity; 95% CI, -infinity to infinity; P = .02). These indirect effects included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation. CONCLUSIONS AND RELEVANCE These findings suggest that RNS effectiveness may be explained by long-term, stimulation-induced modulation of seizure network activity rather than by direct effects on each detected seizure.

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“…Neumann and colleagues [15] then go to the next level by providing detailed insight into factors that affect the development of intelligent, adaptive DBS that can deliver highly individualized treatment to patients with movement disorders. Along the same lines, Sisterson et al [16] review the evolution of closed-loop brain stimulation for epilepsy, proposing an evidencebased solution for individualizing therapy that is driven by a bottom-up informatics approach. Focusing on pediatrics, Ibrahim and colleagues [17] address neuromodulatory strategies for the treatment of intractable epilepsy in children, including putative mechanisms of action and biomarkers for treatment success.…”

Section: Brain-computer Interfaces For Restoring Movement Seizure Comentioning

confidence: 99%

A New Era for Surgical Neurotherapeutics

Richardson

Abel

2019

Neurotherapeutics

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Surgical interventions now have the potential to outperform traditional drug treatments in the management of many different neurological disorders. For example, in epilepsy, despite the introduction of more than a dozen new anti-epileptic medications over the past two decades, the overall rates of seizure freedom are unchanged [1,2], whereas responsive neurostimulation is now known to confer significant improvements in seizure reduction and quality of life in these same medically refractory patients [3,4]. Thus, modern neurosurgical techniques and devices, having low morbidity and, in many cases, excellent efficacy, are increasingly seen as part of a normal spectrum of treatment that includes medications, rather than existing in a separate dimension. In this issue of Neurotherapeutics, an international group of expert authors describe this new era for therapies delivered via neurosurgery, in which advances in neuroscience, computational biology, and imaging are driving both the evolution of traditional strategies and the initiation of novel approaches.

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Closed-Loop Brain Stimulation for Drug-Resistant Epilepsy: Towards an Evidence-Based Approach to Personalized Medicine

Cited by 85 publications

References 35 publications

Responsive neurostimulation for regional neocortical epilepsy

Responsive neurostimulation for regional neocortical epilepsy

Association of Closed-Loop Brain Stimulation Neurophysiological Features With Seizure Control Among Patients With Focal Epilepsy

A New Era for Surgical Neurotherapeutics

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