Epilepsy & Behavior 34 (2014) 25–28
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Editorial
Responsive neurostimulation in epilepsy therapy: Some answers, lingering questions☆ 1. Introduction In November 2013, the Food and Drug Administration (FDA) granted a premarket approval for the RNS System (NeuroPace, Inc.) of closedloop, responsive stimulation for the treatment of drug-resistant focal epilepsy. The decision followed a favorable vote by the FDA's Neurological Devices Panel, an advisory board one of the authors (JEC) was a member of, in February 2013 [1]. The RNS System was designed to detect focal electrographic seizures in selected brain regions sampled with intracranial electrodes and respond by delivering electrical stimulation to those regions aimed at terminating the seizures [2]. The panel's endorsement of the device was primarily based on recently published results [3] and updates [1] from the RNS Pivotal Study, a multicenter, prospective, randomized, double-blind, sham stimulation-controlled trial, which assessed the safety and efficacy of the RNS System as adjunctive therapy of seizures from ≤ 2 seizure foci in adults with focal epilepsy that had failed to improve with ≥2 antiepileptic drug trials. During the study, 191 patients with an average of ≥3 disabling simple partial, complex partial, or secondarily generalized seizures/month over a 12-week baseline period (BP) had the stimulator implanted. These were patients with severe forms of epilepsy: 32% had failed therapeutic epilepsy surgery, 34% had been implanted with a vagal nerve stimulator (VNS, which was removed prior to implanted with a), 59% had undergone intracranial monitoring, 55% had two seizure foci, and 50% had mesial temporal lobe epilepsy, of whom 73% had bitemporal epilepsy. The RNS System placement required a craniectomy. The device was connected to one or two of up to four intracranial quadripolar electrode leads consisting of subdural strips, no more than two depth electrodes, or a combination of depth and subdural electrodes localized to 1–2 epileptogenic region(s) previously defined by standard presurgical evaluation [3]. The RNS System was equipped with three computationally efficient algorithms (half-wave, line length, and area) for early seizure detection; two individual detectors could be configured for any two electrode channels [2]. After detection, one to five stimulation therapies, each consisting of two independently programmable bursts, could be delivered sequentially according to several electrode configurations dictated by the spread of the seizure onset. All enrolled patients could undergo modification of the seizure detection parameters
☆ Submission declaration: The work described has not been published previously and is not under consideration for publication elsewhere. The publication is approved by all authors, and it will not be published elsewhere, including electronically in the same form, in English, or in any other language without the written consent of the copyright holder. The views are solely those of the authors and not reflecting the views of the University of Texas or the Veterans Administration. The copyright of this manuscript cannot be transferred to the publisher as US laws require this to be in the public domain.
http://dx.doi.org/10.1016/j.yebeh.2014.02.014 1525-5050/Published by Elsevier Inc.
following device implantation. The subjects were randomized to sham (no stimulation, n = 94) and treatment (n = 97) groups one month after the implant. Following randomization, the subjects assigned to the treatment group began stimulation therapy. Stimulus parameters were adjusted weekly during a four-week optimization period (OP) based on self-reported seizure recurrence, occurrence of side effects to stimulation, and review of the electrocorticogram (ECOG) stored by the RNS System. Because of implant constraints, ECOG was not recorded continuously. The ECOG epochs stored for review included detections of abnormal electrical activity representing presumed ictal discharges, responsive stimulation treatment bursts and their effects on the electrographic ictus, and stimulation-related afterdischarges. A 12-week blinded evaluation period (BEP) followed, during which the treatment group continued to receive responsive stimulation, and the sham group did not. All subjects were assessed in monthly clinic visits, and their seizures were logged on a daily basis. All subjects, whether assigned to treatment or sham, were then able to receive stimulation during an 84-week open-label period (OLP) [3]. 2. RNS System clinical safety and efficacy: results and analysis 2.1. Safety The study met its primary safety endpoint, which required that the rate of serious adverse effects (SAEs) not exceed the prespecified SAE rate of historical comparators for the first four (seizure-related acute implantation of intracranial electrodes and epilepsy resective surgery) and 12 weeks (deep brain stimulation for treatment of movement disorders) after the implant [1]. There was no statistically significant difference in SAEs between the treatment and sham groups during combined OP and BEP. There was also no difference in mood and neuropsychological status. The most nonserious adverse effects were implant site pain and headache. When all patients enrolled in RNS System trials (Feasibility, Pivotal, and Long-term Treatment studies) were pooled (n = 256), there were a total of seven deaths due to SUDEP, which reflects a rate below the corresponding prespecified comparator (9.3/1000 patientyears). One death was due to status epilepticus (SE). Overall, in the pooled population, implant site infection was reported in 6.3% of the patients, premature battery depletion in 4.3%, medical device removal in 4.3%, intracranial hemorrhage not related to seizures in 2.7%, device lead damage in 3.1%, and revision in 2.7% [1]. There were no study withdrawals because of an adverse effect related to a change in seizures. Serious adverse effects due to increased seizure frequency or severity or a new seizure type occurred in 16% of the patients. Episodes of SE occurred in 3.9% of the subjects, with three episodes considered related to the device. One patient experienced nine SE episodes. The rate of
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adverse effects due to changes in seizures and that of SE episodes did not exceed those reported in antiepileptic drug trials of refractory focal epilepsy or as would be expected in patients with severe focalonset seizures [1]. 2.2. Efficacy Similar to reports from the anterior thalamic stimulation trial [4], an important “surgical” or implant-related effect was apparent, in that there was approximately a 30% median percent reduction in seizure frequency following device implantation in both treatment and sham groups and prior to the initiation of stimulation in the treatment group [1]. The implant-related effect in the sham group largely resolved by the fifth month after implantation, mostly due to very high seizure frequencies in two subjects at the end of the BEP relative to baseline. In contrast, subjects in the treatment group maintained a postimplant seizure improvement throughout the BEP [1,3]. The positive implantrelated clinical effect seemed to extend to quality-of-life changes: both the treatment and the sham group experienced statistically significant and clinically meaningful improvements in the overall and subscale scores derived with QOLIE-89 inventory at the end of the BEP compared with the BP, although the difference between groups was not significant [1]. Improvements in quality of life continued to increase during the OLP when all subjects could receive stimulation. This suggests that the stimulation itself improved quality of life in most patients but that the BEP may have been too short to detect significant stimulation-related effects above those offered by the implant or sham. The stimulation treatment effect was estimated in the primary efficacy analysis by the difference between the reduction in mean seizure frequency noted in the treatment (37.9%, 95% confidence interval = 27.7–46.7%) and that noted in the sham (17.3%, 95% confidence interval = 2.3–29.9%) group during the BEP relative to the BP [1]. The treatment effect was statistically significant (p b 0.012) when several modifications to the generalized estimating equation model prespecified by the sponsor and agreed by the FDA were applied post hoc to improve data fitting. These modifications were as follows: monthly instead of daily seizure counts, negative binomial instead of Poisson distribution of the seizure counts, and inclusion of several clinical covariates used in randomization [1]. The treatment effect was not significantly dependent on seizure onset (mesial temporal vs. other), number of seizure foci (unifocal vs. bifocal), and prior epilepsy surgery vs. no surgery [1]. Most benefit from stimulation was gained by subjects with a high number of seizures at baseline (≥84 seizures/month). The greatest reduction was noted in disabling simple partial motor seizures, with less decreases noted in complex partial and secondarily generalized seizures [1]. Additional efficacy measures during the BEP relative to the BP demonstrated a positive trend in treatment vs. sham subjects: responder rate (percent of subjects with ≥ 50% reduction in seizures, 29% vs. 27%), change in mean seizure frequency (− 11.4 vs. − 5.3 seizures/ month from baseline 33.8 vs. 35.2), median percent change in seizures (− 28% vs. − 19%), change in days with seizures (− 19% vs. − 18% from baseline 10.7 vs. 10.6 days/month), and mean change in a seizure severity score [1]. None of the differences between groups for these secondary outcomes was statistically significant. With the exception of the responder rate, however, the study protocol did not specify whether the trial was adequately powered to detect significant differences. Overall, 76% and 70% of the subjects in the treatment and sham groups, respectively, reported a decrease in the number of seizures in the BEP relative to the BP. A total of 2.1% of the treatment subjects and none of the sham subjects were seizure-free during the BEP. Conversely, 20% and 19% reported no change or ≤50% increase in seizure frequency, and 4% and 11% reported a ≥50% increase in seizures frequency in the treatment and sham groups, respectively [1]. During the OLP, all subjects could receive stimulation and were allowed changes in antiepileptic medications but were not disclosed
their prior assignments to either the treatment or the sham group. Similar to other neurostimulation modalities (VNS, anterior thalamic), the efficacy of RNS appeared to improve over time above that noted during the BEP. The proportion of responders (≥50% reduction in seizures) was 43.6% at one year and 54.6% at two years. The median percentage seizure reduction was 44% at one year and 53% at two years. During the OLP, the subjects previously assigned to the sham group experienced seizure reduction that approached the extent seen in those initially treated with stimulation [1]. The device's retention rate was high: 92% of implanted subjects completed the entire two-year study. Moreover, high patient satisfaction with the device was reflected in that 93% decided to replace their stimulator at the end of battery service (≤3 years). Overall, the results of the RNS Pivotal Study support the application in the clinical realm of a very attractive concept that seizures can be terminated by concurrently applied electricity. This concept is grounded in observation and solid experimental evidence (reviewed in [2,5]). The RNS System is reasonably safe when compared with other neuroinvasive procedures. The device has a high retention rate by the patients in the study, suggesting in part that the neurosurgical risk may be balanced overall by the absence of drug-related adverse effects, which could complicate the alternative of an exclusive use of pharmacologic therapy and comparatively higher antiepileptic drug doses. Efficacy results are encouraging if mixed. A direct comparison between the RNS Pivotal and VNS trials is difficult given different trial designs. Nevertheless, it is reassuring that the RNS System showed a trend towards greater seizure frequency decrease than VNS E03 and E05 trials during the blinded periods (37.9% vs. 24.5% and 27.9%, respectively) and comparable responder rates during the blind (29% vs. 31% and 23.4%, respectively) and at one year (43.6% vs. 35% in the E05 trial). However, RNS System use did not lead to a significant difference in responder rates between the treatment vs. sham (29% vs. 27%) groups during the blinded period. This suggests that combined with effectiveness at reducing seizures skewed towards patients with high baseline seizure counts, the blinded period in the pivotal trial may have been too short to allow for significant results in patients with rarer seizures. Alternatively, these findings may be partly explained by highly variable device effectiveness in individual subjects associated with different baseline seizure frequencies reflecting various degrees of disease severity. Furthermore, it is important that long-term improvement be measured against the natural history of the disease [6,7]. Based on the trial, a set of candidates to benefit most from responsive neurostimulation is identified: patients with severe refractory focal epilepsy, especially those with very frequent disabling seizures; those who are not candidates for epilepsy surgery; and those refusing surgery or in whom surgery did not have a satisfactory result. 3. RNS Pivotal trial and beyond: concerning rational electrotherapy The RNS System trial results reviewed above invite several questions about how the RNS System can be used clinically on a case-by-case basis in future practice. First, did the RNS System work the way it was intended to? In other words, to what extent was the reduction in seizures attributed to the activation of responsive stimulation during the trial due to immediate, seizure-aborting or mitigating effects of stimulation or to longer-term presumed neuromodulatory influences on seizure initiation or propagation? These questions are important because the rational use of the device is based on the idea of immediate cessation of seizures by stimulation; as such, adjusting the detection and stimulation parameters during the trial was based mainly on a short-term, weekly-to-monthly sequential feedback of seizure recurrence. That responsive neurostimulation is able to abort seizures recorded electrographically has been demonstrated in small pilot studies (reviewed in [2]), but no adequate pivotal trial data to support it were pooled and released. Using the device without large-scale trial data to verify its operational premise may invite untoward outcomes in the future. Such an outcome may be merely a lack of efficacy at the cost of
Editorial
cranial surgery, device maintenance, and operation. For example, a patient may experience no initial overall clinical seizure reduction after the device was implanted and the first adjustments of detection and stimulation parameters have been made, despite examples of individual seizures recorded on ECOG that were indeed aborted after stimulation. In such case, should serial changes in parameters be performed to improve clinical seizure control in a reasonable amount of time, with the inherent trial-and-error risks, or could a neuromodulatory effect be bet on to improve seizure outcome? What parameter adjustments, if any, and in which domain, detection or stimulation or both, have most consistently resulted in positive outcomes after an initial limited treatment response and may most likely be of benefit in this case? Crucial to answering such questions is understanding the link between the clinical and electrographic activity changes associated with the device. A step to this end is establishing the relationship between the rate of clinical seizures logged during the trial and a treatment marker, such as the rate of ictal discharges recorded on ECOG. It is natural yet not proven to think that while such marker does not capture all stimulation treatment effects, including seizure duration, intensity, and spread, it is indeed linked to the prespecified outcome, i.e., clinical seizure rate changes. The RNS Pivotal trial, however, did not provide electrographic metrics such as determining the device's seizure detection sensitivity and specificity nor did it provide electrographic surrogate outcomes, such as the effect of stimulation on the rate of seizures captured by ECOG. Such determinations are not trivial. Calculating the sensitivity and specificity of the detection tools would require the recording of all clinical events or subclinical seizures, including the ones not detected by the device. Assuming that lead implantation was accurate enough to detect all electrographic ictal discharges in each subject, such recordings would require long-term continuous ECOG epochs stored by the RNS System available for offline review, a feat not included in the trial but recently reported in a groundbreaking first-in-man study [5]. In addition, calculating treatment metrics is complicated by the need of both early seizure detection and early stimulation for the device to be effective in most cases [2]. Such a short window of opportunity (several seconds) confounds detection specificity calculations, since stimulation therapy may be applied to self-limited, nonevolving interictal activity appearing quasi-identical to a would-be seizure discharge terminated by stimulation. Nevertheless, we believe that no effort should be spared towards an evaluation of ECOG measures of detection and stimulation. In parallel with continued research on the biophysics of electrical stimulation at multiple neural scales [8], acute clinical trials set in the EMU [9] or involving continuous long-term portable ECOG recordings are necessary to assess rigorously the performance of the RNS System. These trials could be designed to include the statistical framework adopted by prior studies evaluating individual detection features adopted by the RNS System and stimulation treatments [9]. Applying the full (combined) detection module of the device to a large-scale, publicly available ECOG database [10] may define better its ability to recognize a wide range of ictal patterns characterizing focal epilepsy. Working towards the release of an extracranial version of the device made available to EMUs nationwide for training and trial during phase II monitoring may complement such studies in providing a large body of data of its short-term use and may guide lead implantation for subsequent longterm operation according to current specifications. On a shorter time span, the disclosure of gathered ECOG data by the sponsor during the pivotal trial would also allow partial yet informative answers as to how the device performs. Potentially useful measures of detection accuracy include the difference and correlation between the number of daily definite ictal patterns (subclinical and clinical seizures recorded on ECOG and scored by expert reviews) that were detected but not terminated by stimulation (failed and suboptimal stimulations) and the number of daily clinical events recorded in the seizure log; for an individual subject, a consistently null or positive difference and high correlation over time would indicate a robust and clinically useful
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level of detection. Stimulation efficacy could be estimated by comparing the number of ictal patterns detected during a period when the stimulation was off with the number of electrographic seizures detected but not aborted by stimulation during periods when stimulation was enabled. A comparatively high value of the latter does not necessarily imply ineffective stimulation, as it may be due to an increase in subclinical seizures at the expense of clinically overt ones or occur with incidental increases in ictogenicity in some patients during the onstimulation periods; a relatively low number of seizures stimulated but not aborted, however, would confirm a positive electrographic response to stimulation. Charting the number of detections–stimulations of epileptiform activity across time could help measure fluctuations in ictogenic potential and, by doing so, would help uncover potential long-term neuromodulatory influences in addition to immediate seizure-aborting effects associated with stimulation. As such, a consistently downward trend in the number of epileptiform patterns detected over time would support a gradual antiepileptogenic effect on epileptic networks that may explain in part the progressive improvement in seizure counts reported with long-term RNS use, similarly observed with other neurostimulation modalities (VNS, anterior thalamic). Although these and similar measures applied to ECOG data may generate a limited number of easy-to-interpret data patterns, they can offer important clues about how the RNS System works. Second, have a few stimulus selection and optimization strategies crystalized to a degree necessary for clinical application in individual patients? Can such strategies be devised? Allowing stimulus location to vary by targeting various supratentorial structures with intracranial electrodes tuned to individual epileptic networks, the RNS System has afforded unprecedented degrees of freedom in selecting stimulation attributes, even when compared with other stimulation devices, such as VNS or anterior thalamic. In addition, the RNS Pivotal trial has proposed a wide range of parameter values open for optimization for a number of sequential stimulations, independently programmable bursts, and electrode configurations, to include current frequency (1 to 333 Hz), amplitude (0.5 to 12 mA), pulse width per phase (40 to 1000 μs), and burst duration (10 to 5000 ms). During the trial, except for 1-Hz pulse frequency and 1000-μs pulse duration, the full range of stimulus options was used, but how these options were selected is unclear. Although a set of initial stimulation settings was recommended, an optimization strategy for stimulation parameters was not prespecified. In contrast, such road map guiding stimulation changes was included in the protocol of a previous short-term, EMU-based, closed-loop stimulation trial [9] or that of the VNS E03 trial, which included stepwise current increments to tolerable levels [11]. This wide range of stimulus selection adds to the high variability of electrographic phenotypes that RNS is intended to detect and respond to [8]. Optimization across that many parameter options based on pure empiricism is not practical. Without rational stimulus optimization strategies, the multitude of sources of operational uncertainty may render RNS use in common practice ineffective and, in selected cases, potentially deleterious given the costs of device implantation. The challenges to stimulation optimization design are many. A selected stimulus parameter set must be tried on a minimum number of events for proper statistical validation of its effects, which may not be realized during relatively short optimization and blinded evaluation periods [8]. Such longer periods may be necessary for improved optimization, but they are difficult to implement. Without electrographic metrics and surrogate treatment markers, such as those discussed in the prior paragraph, defining the immediate seizureaborting effects of stimulation and the timeline of an appropriate optimization schedule is not possible. Optimal stimulation parameters may vary considerably among patients and targeted networks. In addition, defining a dose–response relationship between stimulus attribute values and seizure occurrence, presently not required by the FDA for medical device approval, or defining reasonable assumptions of it is necessary for rational optimization strategies. Such a dose–response curve may not be smooth or monotonous and is also likely to vary among
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subjects. While challenges of an effective, rational stimulation selection and optimization strategy briefly exposed here seem daunting, several short- and medium-term measures may be of benefit. First, we encourage the release by the RNS pivotal trial team of outcome data stratified according to whether preimplant intracranial extraoperative monitoring was performed to characterize the epileptic foci and determine the location of future stimulation delivery. Based on these data, recommendations as to whether such monitoring restricted to NAEC level-4 epilepsy centers is needed before device implantation can be made. Second, the publication of subject-specific outcome data together with individual optimized stimulus parameter sets (i.e., in many cases, the latest set to be selected for a subject and active at the last follow-up during the OLP or during the Long-term Treatment study) may offer a narrower “useful” parameter range. While not necessarily optimal in the strictest sense, these parameter sets may serve as reasonable initial optimization choices in the future common use of the device. In this way, optimizing the RNS System use is simplified, avoiding excessive trial and error and “effectiveness minima” resulting from myriad theoretical parameter combinations. Third, we propose the creation of a publicly available, longitudinal RNS registry. Such a registry would contain data from the RNS pivotal and other clinical trials and also from less rigorous clinical reports and single cases. Retrospective observations would include stimulation parameter sets sequentially uploaded during optimization, along with outcome data on seizure control and potential side effects. A potential model registry would be the NINDS supported International Epilepsy Electrophysiology Portal (www.ieeg.org). Built along similar proposals [12], the registry would assist both researchers and clinical epileptologists in summing up the role of the RNS System in refractory focal epilepsy and improve its use for the benefit of patients with most severe forms of epilepsy. The academic community must collaborate to understand the optimal parameters of RNS rather than repeating the same history with VNS, where we still are not certain about optimal stimulation parameters or preimplantation predictors for greater efficacy despite almost 17 years of clinical experience. 4. FDA regulatory framework: proposed changes The measures proposed here subscribe to the larger call for tightening of the FDA regulatory standards for therapeutic medical devices requiring a premarket approval application to complement a departure from the “black box” view of devices prevalent nowadays. We agree that for neurostimulation devices, as for therapeutic drugs, detailed data on mechanisms of action are often not needed for good use and may be expensive to accrue. However, when mechanistic presumptions directly affect device operation, we believe that these should be adequately evaluated. In addition, a more stringent application to characterizing the effects of device parameter choices is needed. At present, the FDA regulatory process examines the evidence of safety and efficacy of the stimulation devices as a whole, without limiting the range of parameters available to that for which such evidence is adequate. As long as some stimulation parameters are used in a regulatory trial, even if only once and briefly, they could be included in the marketed version of the device. Therapeutic devices should be released with limited range of parameters for clinical use reflecting those parameters for which safety and efficacy data clearly exist (i.e., used by the majority of patients within pivotal trials with positive efficacy and safety data). In conclusion, future FDA approval standards should require data on
surrogate neurophysiological markers and electrographic treatment metrics and characterization of responses in treatment groups stratified based on narrower stimulation parameter ranges. The advent of the RNS System as a clinical tool in the treatment of severe focal epilepsy is one of the most exciting new development since the VNS was approved in 1997. Undertaking steps to improve what we know about how it works will facilitate its due implementation in clinical practice.
Disclosure Dr. Cavazos owns 4% of shares of Brain Sentinel (AKA: LGCH, Inc.), a start-up company developing a convulsion-alerting device based on EMG recordings.
References [1] http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Medical Devices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/ucm340251. htm. [Accessed on April 9, 2013]. [2] Sun FT, Morrell MJ, Wharen Jr RE. Responsive cortical stimulation for the treatment of epilepsy. Neurotherapeutics 2008;5(1):68–74. [3] Morrell MJ, RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011;77(13): 1295–304. [4] Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, et al. SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51(5):899–908. [5] Cook MJ, O'Brien TJ, Berkovic SF, Murphy M, Morokoff A, Fabinyi G, et al. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. Lancet Neurol 2013;12(6):563–71. [6] Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA, et al. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol 2007;62(4):382–9. [7] Choi H, Heiman GA, Munger Clary H, Etienne M, Resor SR, Hauser WA, et al. Seizure remission in adults with long-standing intractable epilepsy: an extended follow-up. Epilepsy Res 2011;93(2–3):115–9. [8] Sunderam S, Gluckman B, Reato D, Bikson M. Toward rational design of electrical stimulation strategies for epilepsy control. Epilepsy Behav 2010;17(1):6–22. [9] Osorio I, Frei MG, Sunderam S, Giftakis J, Bhavaraju NC, Schaffner SF, et al. Automated seizure abatement in humans using electrical stimulation. Ann Neurol 2005;57(2): 258–68. [10] Klatt J, Feldwisch-Drentrup H, Ihle M, Navarro V, Neufang M, Teixeira C, et al. The EPILEPSIAE database: an extensive electroencephalography database of epilepsy patients. Epilepsia 2012;53(9):1669–76. [11] The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 1995;45(2):224–30. [12] Synofzik M, Fins JJ, Schlaepfer TE. A neuromodulation experience registry for deep brain stimulation studies in psychiatric research: rationale and recommendations for implementation. Brain Stimul 2012;5(4):653–5.
Octavian V. Lie Jose E. Cavazos⁎ Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA San Antonio VA Epilepsy Center of Excellence, San Antonio, TX, USA ⁎Corresponding author at: Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. E-mail address: [email protected] (J.E. Cavazos). 27 November 2013 Available online xxxx
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Editorial
Responsive neurostimulation in epilepsy therapy: Some answers, lingering questions☆ 1. Introduction In November 2013, the Food and Drug Administration (FDA) granted a premarket approval for the RNS System (NeuroPace, Inc.) of closedloop, responsive stimulation for the treatment of drug-resistant focal epilepsy. The decision followed a favorable vote by the FDA's Neurological Devices Panel, an advisory board one of the authors (JEC) was a member of, in February 2013 [1]. The RNS System was designed to detect focal electrographic seizures in selected brain regions sampled with intracranial electrodes and respond by delivering electrical stimulation to those regions aimed at terminating the seizures [2]. The panel's endorsement of the device was primarily based on recently published results [3] and updates [1] from the RNS Pivotal Study, a multicenter, prospective, randomized, double-blind, sham stimulation-controlled trial, which assessed the safety and efficacy of the RNS System as adjunctive therapy of seizures from ≤ 2 seizure foci in adults with focal epilepsy that had failed to improve with ≥2 antiepileptic drug trials. During the study, 191 patients with an average of ≥3 disabling simple partial, complex partial, or secondarily generalized seizures/month over a 12-week baseline period (BP) had the stimulator implanted. These were patients with severe forms of epilepsy: 32% had failed therapeutic epilepsy surgery, 34% had been implanted with a vagal nerve stimulator (VNS, which was removed prior to implanted with a), 59% had undergone intracranial monitoring, 55% had two seizure foci, and 50% had mesial temporal lobe epilepsy, of whom 73% had bitemporal epilepsy. The RNS System placement required a craniectomy. The device was connected to one or two of up to four intracranial quadripolar electrode leads consisting of subdural strips, no more than two depth electrodes, or a combination of depth and subdural electrodes localized to 1–2 epileptogenic region(s) previously defined by standard presurgical evaluation [3]. The RNS System was equipped with three computationally efficient algorithms (half-wave, line length, and area) for early seizure detection; two individual detectors could be configured for any two electrode channels [2]. After detection, one to five stimulation therapies, each consisting of two independently programmable bursts, could be delivered sequentially according to several electrode configurations dictated by the spread of the seizure onset. All enrolled patients could undergo modification of the seizure detection parameters
☆ Submission declaration: The work described has not been published previously and is not under consideration for publication elsewhere. The publication is approved by all authors, and it will not be published elsewhere, including electronically in the same form, in English, or in any other language without the written consent of the copyright holder. The views are solely those of the authors and not reflecting the views of the University of Texas or the Veterans Administration. The copyright of this manuscript cannot be transferred to the publisher as US laws require this to be in the public domain.
http://dx.doi.org/10.1016/j.yebeh.2014.02.014 1525-5050/Published by Elsevier Inc.
following device implantation. The subjects were randomized to sham (no stimulation, n = 94) and treatment (n = 97) groups one month after the implant. Following randomization, the subjects assigned to the treatment group began stimulation therapy. Stimulus parameters were adjusted weekly during a four-week optimization period (OP) based on self-reported seizure recurrence, occurrence of side effects to stimulation, and review of the electrocorticogram (ECOG) stored by the RNS System. Because of implant constraints, ECOG was not recorded continuously. The ECOG epochs stored for review included detections of abnormal electrical activity representing presumed ictal discharges, responsive stimulation treatment bursts and their effects on the electrographic ictus, and stimulation-related afterdischarges. A 12-week blinded evaluation period (BEP) followed, during which the treatment group continued to receive responsive stimulation, and the sham group did not. All subjects were assessed in monthly clinic visits, and their seizures were logged on a daily basis. All subjects, whether assigned to treatment or sham, were then able to receive stimulation during an 84-week open-label period (OLP) [3]. 2. RNS System clinical safety and efficacy: results and analysis 2.1. Safety The study met its primary safety endpoint, which required that the rate of serious adverse effects (SAEs) not exceed the prespecified SAE rate of historical comparators for the first four (seizure-related acute implantation of intracranial electrodes and epilepsy resective surgery) and 12 weeks (deep brain stimulation for treatment of movement disorders) after the implant [1]. There was no statistically significant difference in SAEs between the treatment and sham groups during combined OP and BEP. There was also no difference in mood and neuropsychological status. The most nonserious adverse effects were implant site pain and headache. When all patients enrolled in RNS System trials (Feasibility, Pivotal, and Long-term Treatment studies) were pooled (n = 256), there were a total of seven deaths due to SUDEP, which reflects a rate below the corresponding prespecified comparator (9.3/1000 patientyears). One death was due to status epilepticus (SE). Overall, in the pooled population, implant site infection was reported in 6.3% of the patients, premature battery depletion in 4.3%, medical device removal in 4.3%, intracranial hemorrhage not related to seizures in 2.7%, device lead damage in 3.1%, and revision in 2.7% [1]. There were no study withdrawals because of an adverse effect related to a change in seizures. Serious adverse effects due to increased seizure frequency or severity or a new seizure type occurred in 16% of the patients. Episodes of SE occurred in 3.9% of the subjects, with three episodes considered related to the device. One patient experienced nine SE episodes. The rate of
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adverse effects due to changes in seizures and that of SE episodes did not exceed those reported in antiepileptic drug trials of refractory focal epilepsy or as would be expected in patients with severe focalonset seizures [1]. 2.2. Efficacy Similar to reports from the anterior thalamic stimulation trial [4], an important “surgical” or implant-related effect was apparent, in that there was approximately a 30% median percent reduction in seizure frequency following device implantation in both treatment and sham groups and prior to the initiation of stimulation in the treatment group [1]. The implant-related effect in the sham group largely resolved by the fifth month after implantation, mostly due to very high seizure frequencies in two subjects at the end of the BEP relative to baseline. In contrast, subjects in the treatment group maintained a postimplant seizure improvement throughout the BEP [1,3]. The positive implantrelated clinical effect seemed to extend to quality-of-life changes: both the treatment and the sham group experienced statistically significant and clinically meaningful improvements in the overall and subscale scores derived with QOLIE-89 inventory at the end of the BEP compared with the BP, although the difference between groups was not significant [1]. Improvements in quality of life continued to increase during the OLP when all subjects could receive stimulation. This suggests that the stimulation itself improved quality of life in most patients but that the BEP may have been too short to detect significant stimulation-related effects above those offered by the implant or sham. The stimulation treatment effect was estimated in the primary efficacy analysis by the difference between the reduction in mean seizure frequency noted in the treatment (37.9%, 95% confidence interval = 27.7–46.7%) and that noted in the sham (17.3%, 95% confidence interval = 2.3–29.9%) group during the BEP relative to the BP [1]. The treatment effect was statistically significant (p b 0.012) when several modifications to the generalized estimating equation model prespecified by the sponsor and agreed by the FDA were applied post hoc to improve data fitting. These modifications were as follows: monthly instead of daily seizure counts, negative binomial instead of Poisson distribution of the seizure counts, and inclusion of several clinical covariates used in randomization [1]. The treatment effect was not significantly dependent on seizure onset (mesial temporal vs. other), number of seizure foci (unifocal vs. bifocal), and prior epilepsy surgery vs. no surgery [1]. Most benefit from stimulation was gained by subjects with a high number of seizures at baseline (≥84 seizures/month). The greatest reduction was noted in disabling simple partial motor seizures, with less decreases noted in complex partial and secondarily generalized seizures [1]. Additional efficacy measures during the BEP relative to the BP demonstrated a positive trend in treatment vs. sham subjects: responder rate (percent of subjects with ≥ 50% reduction in seizures, 29% vs. 27%), change in mean seizure frequency (− 11.4 vs. − 5.3 seizures/ month from baseline 33.8 vs. 35.2), median percent change in seizures (− 28% vs. − 19%), change in days with seizures (− 19% vs. − 18% from baseline 10.7 vs. 10.6 days/month), and mean change in a seizure severity score [1]. None of the differences between groups for these secondary outcomes was statistically significant. With the exception of the responder rate, however, the study protocol did not specify whether the trial was adequately powered to detect significant differences. Overall, 76% and 70% of the subjects in the treatment and sham groups, respectively, reported a decrease in the number of seizures in the BEP relative to the BP. A total of 2.1% of the treatment subjects and none of the sham subjects were seizure-free during the BEP. Conversely, 20% and 19% reported no change or ≤50% increase in seizure frequency, and 4% and 11% reported a ≥50% increase in seizures frequency in the treatment and sham groups, respectively [1]. During the OLP, all subjects could receive stimulation and were allowed changes in antiepileptic medications but were not disclosed
their prior assignments to either the treatment or the sham group. Similar to other neurostimulation modalities (VNS, anterior thalamic), the efficacy of RNS appeared to improve over time above that noted during the BEP. The proportion of responders (≥50% reduction in seizures) was 43.6% at one year and 54.6% at two years. The median percentage seizure reduction was 44% at one year and 53% at two years. During the OLP, the subjects previously assigned to the sham group experienced seizure reduction that approached the extent seen in those initially treated with stimulation [1]. The device's retention rate was high: 92% of implanted subjects completed the entire two-year study. Moreover, high patient satisfaction with the device was reflected in that 93% decided to replace their stimulator at the end of battery service (≤3 years). Overall, the results of the RNS Pivotal Study support the application in the clinical realm of a very attractive concept that seizures can be terminated by concurrently applied electricity. This concept is grounded in observation and solid experimental evidence (reviewed in [2,5]). The RNS System is reasonably safe when compared with other neuroinvasive procedures. The device has a high retention rate by the patients in the study, suggesting in part that the neurosurgical risk may be balanced overall by the absence of drug-related adverse effects, which could complicate the alternative of an exclusive use of pharmacologic therapy and comparatively higher antiepileptic drug doses. Efficacy results are encouraging if mixed. A direct comparison between the RNS Pivotal and VNS trials is difficult given different trial designs. Nevertheless, it is reassuring that the RNS System showed a trend towards greater seizure frequency decrease than VNS E03 and E05 trials during the blinded periods (37.9% vs. 24.5% and 27.9%, respectively) and comparable responder rates during the blind (29% vs. 31% and 23.4%, respectively) and at one year (43.6% vs. 35% in the E05 trial). However, RNS System use did not lead to a significant difference in responder rates between the treatment vs. sham (29% vs. 27%) groups during the blinded period. This suggests that combined with effectiveness at reducing seizures skewed towards patients with high baseline seizure counts, the blinded period in the pivotal trial may have been too short to allow for significant results in patients with rarer seizures. Alternatively, these findings may be partly explained by highly variable device effectiveness in individual subjects associated with different baseline seizure frequencies reflecting various degrees of disease severity. Furthermore, it is important that long-term improvement be measured against the natural history of the disease [6,7]. Based on the trial, a set of candidates to benefit most from responsive neurostimulation is identified: patients with severe refractory focal epilepsy, especially those with very frequent disabling seizures; those who are not candidates for epilepsy surgery; and those refusing surgery or in whom surgery did not have a satisfactory result. 3. RNS Pivotal trial and beyond: concerning rational electrotherapy The RNS System trial results reviewed above invite several questions about how the RNS System can be used clinically on a case-by-case basis in future practice. First, did the RNS System work the way it was intended to? In other words, to what extent was the reduction in seizures attributed to the activation of responsive stimulation during the trial due to immediate, seizure-aborting or mitigating effects of stimulation or to longer-term presumed neuromodulatory influences on seizure initiation or propagation? These questions are important because the rational use of the device is based on the idea of immediate cessation of seizures by stimulation; as such, adjusting the detection and stimulation parameters during the trial was based mainly on a short-term, weekly-to-monthly sequential feedback of seizure recurrence. That responsive neurostimulation is able to abort seizures recorded electrographically has been demonstrated in small pilot studies (reviewed in [2]), but no adequate pivotal trial data to support it were pooled and released. Using the device without large-scale trial data to verify its operational premise may invite untoward outcomes in the future. Such an outcome may be merely a lack of efficacy at the cost of
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cranial surgery, device maintenance, and operation. For example, a patient may experience no initial overall clinical seizure reduction after the device was implanted and the first adjustments of detection and stimulation parameters have been made, despite examples of individual seizures recorded on ECOG that were indeed aborted after stimulation. In such case, should serial changes in parameters be performed to improve clinical seizure control in a reasonable amount of time, with the inherent trial-and-error risks, or could a neuromodulatory effect be bet on to improve seizure outcome? What parameter adjustments, if any, and in which domain, detection or stimulation or both, have most consistently resulted in positive outcomes after an initial limited treatment response and may most likely be of benefit in this case? Crucial to answering such questions is understanding the link between the clinical and electrographic activity changes associated with the device. A step to this end is establishing the relationship between the rate of clinical seizures logged during the trial and a treatment marker, such as the rate of ictal discharges recorded on ECOG. It is natural yet not proven to think that while such marker does not capture all stimulation treatment effects, including seizure duration, intensity, and spread, it is indeed linked to the prespecified outcome, i.e., clinical seizure rate changes. The RNS Pivotal trial, however, did not provide electrographic metrics such as determining the device's seizure detection sensitivity and specificity nor did it provide electrographic surrogate outcomes, such as the effect of stimulation on the rate of seizures captured by ECOG. Such determinations are not trivial. Calculating the sensitivity and specificity of the detection tools would require the recording of all clinical events or subclinical seizures, including the ones not detected by the device. Assuming that lead implantation was accurate enough to detect all electrographic ictal discharges in each subject, such recordings would require long-term continuous ECOG epochs stored by the RNS System available for offline review, a feat not included in the trial but recently reported in a groundbreaking first-in-man study [5]. In addition, calculating treatment metrics is complicated by the need of both early seizure detection and early stimulation for the device to be effective in most cases [2]. Such a short window of opportunity (several seconds) confounds detection specificity calculations, since stimulation therapy may be applied to self-limited, nonevolving interictal activity appearing quasi-identical to a would-be seizure discharge terminated by stimulation. Nevertheless, we believe that no effort should be spared towards an evaluation of ECOG measures of detection and stimulation. In parallel with continued research on the biophysics of electrical stimulation at multiple neural scales [8], acute clinical trials set in the EMU [9] or involving continuous long-term portable ECOG recordings are necessary to assess rigorously the performance of the RNS System. These trials could be designed to include the statistical framework adopted by prior studies evaluating individual detection features adopted by the RNS System and stimulation treatments [9]. Applying the full (combined) detection module of the device to a large-scale, publicly available ECOG database [10] may define better its ability to recognize a wide range of ictal patterns characterizing focal epilepsy. Working towards the release of an extracranial version of the device made available to EMUs nationwide for training and trial during phase II monitoring may complement such studies in providing a large body of data of its short-term use and may guide lead implantation for subsequent longterm operation according to current specifications. On a shorter time span, the disclosure of gathered ECOG data by the sponsor during the pivotal trial would also allow partial yet informative answers as to how the device performs. Potentially useful measures of detection accuracy include the difference and correlation between the number of daily definite ictal patterns (subclinical and clinical seizures recorded on ECOG and scored by expert reviews) that were detected but not terminated by stimulation (failed and suboptimal stimulations) and the number of daily clinical events recorded in the seizure log; for an individual subject, a consistently null or positive difference and high correlation over time would indicate a robust and clinically useful
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level of detection. Stimulation efficacy could be estimated by comparing the number of ictal patterns detected during a period when the stimulation was off with the number of electrographic seizures detected but not aborted by stimulation during periods when stimulation was enabled. A comparatively high value of the latter does not necessarily imply ineffective stimulation, as it may be due to an increase in subclinical seizures at the expense of clinically overt ones or occur with incidental increases in ictogenicity in some patients during the onstimulation periods; a relatively low number of seizures stimulated but not aborted, however, would confirm a positive electrographic response to stimulation. Charting the number of detections–stimulations of epileptiform activity across time could help measure fluctuations in ictogenic potential and, by doing so, would help uncover potential long-term neuromodulatory influences in addition to immediate seizure-aborting effects associated with stimulation. As such, a consistently downward trend in the number of epileptiform patterns detected over time would support a gradual antiepileptogenic effect on epileptic networks that may explain in part the progressive improvement in seizure counts reported with long-term RNS use, similarly observed with other neurostimulation modalities (VNS, anterior thalamic). Although these and similar measures applied to ECOG data may generate a limited number of easy-to-interpret data patterns, they can offer important clues about how the RNS System works. Second, have a few stimulus selection and optimization strategies crystalized to a degree necessary for clinical application in individual patients? Can such strategies be devised? Allowing stimulus location to vary by targeting various supratentorial structures with intracranial electrodes tuned to individual epileptic networks, the RNS System has afforded unprecedented degrees of freedom in selecting stimulation attributes, even when compared with other stimulation devices, such as VNS or anterior thalamic. In addition, the RNS Pivotal trial has proposed a wide range of parameter values open for optimization for a number of sequential stimulations, independently programmable bursts, and electrode configurations, to include current frequency (1 to 333 Hz), amplitude (0.5 to 12 mA), pulse width per phase (40 to 1000 μs), and burst duration (10 to 5000 ms). During the trial, except for 1-Hz pulse frequency and 1000-μs pulse duration, the full range of stimulus options was used, but how these options were selected is unclear. Although a set of initial stimulation settings was recommended, an optimization strategy for stimulation parameters was not prespecified. In contrast, such road map guiding stimulation changes was included in the protocol of a previous short-term, EMU-based, closed-loop stimulation trial [9] or that of the VNS E03 trial, which included stepwise current increments to tolerable levels [11]. This wide range of stimulus selection adds to the high variability of electrographic phenotypes that RNS is intended to detect and respond to [8]. Optimization across that many parameter options based on pure empiricism is not practical. Without rational stimulus optimization strategies, the multitude of sources of operational uncertainty may render RNS use in common practice ineffective and, in selected cases, potentially deleterious given the costs of device implantation. The challenges to stimulation optimization design are many. A selected stimulus parameter set must be tried on a minimum number of events for proper statistical validation of its effects, which may not be realized during relatively short optimization and blinded evaluation periods [8]. Such longer periods may be necessary for improved optimization, but they are difficult to implement. Without electrographic metrics and surrogate treatment markers, such as those discussed in the prior paragraph, defining the immediate seizureaborting effects of stimulation and the timeline of an appropriate optimization schedule is not possible. Optimal stimulation parameters may vary considerably among patients and targeted networks. In addition, defining a dose–response relationship between stimulus attribute values and seizure occurrence, presently not required by the FDA for medical device approval, or defining reasonable assumptions of it is necessary for rational optimization strategies. Such a dose–response curve may not be smooth or monotonous and is also likely to vary among
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subjects. While challenges of an effective, rational stimulation selection and optimization strategy briefly exposed here seem daunting, several short- and medium-term measures may be of benefit. First, we encourage the release by the RNS pivotal trial team of outcome data stratified according to whether preimplant intracranial extraoperative monitoring was performed to characterize the epileptic foci and determine the location of future stimulation delivery. Based on these data, recommendations as to whether such monitoring restricted to NAEC level-4 epilepsy centers is needed before device implantation can be made. Second, the publication of subject-specific outcome data together with individual optimized stimulus parameter sets (i.e., in many cases, the latest set to be selected for a subject and active at the last follow-up during the OLP or during the Long-term Treatment study) may offer a narrower “useful” parameter range. While not necessarily optimal in the strictest sense, these parameter sets may serve as reasonable initial optimization choices in the future common use of the device. In this way, optimizing the RNS System use is simplified, avoiding excessive trial and error and “effectiveness minima” resulting from myriad theoretical parameter combinations. Third, we propose the creation of a publicly available, longitudinal RNS registry. Such a registry would contain data from the RNS pivotal and other clinical trials and also from less rigorous clinical reports and single cases. Retrospective observations would include stimulation parameter sets sequentially uploaded during optimization, along with outcome data on seizure control and potential side effects. A potential model registry would be the NINDS supported International Epilepsy Electrophysiology Portal (www.ieeg.org). Built along similar proposals [12], the registry would assist both researchers and clinical epileptologists in summing up the role of the RNS System in refractory focal epilepsy and improve its use for the benefit of patients with most severe forms of epilepsy. The academic community must collaborate to understand the optimal parameters of RNS rather than repeating the same history with VNS, where we still are not certain about optimal stimulation parameters or preimplantation predictors for greater efficacy despite almost 17 years of clinical experience. 4. FDA regulatory framework: proposed changes The measures proposed here subscribe to the larger call for tightening of the FDA regulatory standards for therapeutic medical devices requiring a premarket approval application to complement a departure from the “black box” view of devices prevalent nowadays. We agree that for neurostimulation devices, as for therapeutic drugs, detailed data on mechanisms of action are often not needed for good use and may be expensive to accrue. However, when mechanistic presumptions directly affect device operation, we believe that these should be adequately evaluated. In addition, a more stringent application to characterizing the effects of device parameter choices is needed. At present, the FDA regulatory process examines the evidence of safety and efficacy of the stimulation devices as a whole, without limiting the range of parameters available to that for which such evidence is adequate. As long as some stimulation parameters are used in a regulatory trial, even if only once and briefly, they could be included in the marketed version of the device. Therapeutic devices should be released with limited range of parameters for clinical use reflecting those parameters for which safety and efficacy data clearly exist (i.e., used by the majority of patients within pivotal trials with positive efficacy and safety data). In conclusion, future FDA approval standards should require data on
surrogate neurophysiological markers and electrographic treatment metrics and characterization of responses in treatment groups stratified based on narrower stimulation parameter ranges. The advent of the RNS System as a clinical tool in the treatment of severe focal epilepsy is one of the most exciting new development since the VNS was approved in 1997. Undertaking steps to improve what we know about how it works will facilitate its due implementation in clinical practice.
Disclosure Dr. Cavazos owns 4% of shares of Brain Sentinel (AKA: LGCH, Inc.), a start-up company developing a convulsion-alerting device based on EMG recordings.
References [1] http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Medical Devices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/ucm340251. htm. [Accessed on April 9, 2013]. [2] Sun FT, Morrell MJ, Wharen Jr RE. Responsive cortical stimulation for the treatment of epilepsy. Neurotherapeutics 2008;5(1):68–74. [3] Morrell MJ, RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011;77(13): 1295–304. [4] Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, et al. SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51(5):899–908. [5] Cook MJ, O'Brien TJ, Berkovic SF, Murphy M, Morokoff A, Fabinyi G, et al. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. Lancet Neurol 2013;12(6):563–71. [6] Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA, et al. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol 2007;62(4):382–9. [7] Choi H, Heiman GA, Munger Clary H, Etienne M, Resor SR, Hauser WA, et al. Seizure remission in adults with long-standing intractable epilepsy: an extended follow-up. Epilepsy Res 2011;93(2–3):115–9. [8] Sunderam S, Gluckman B, Reato D, Bikson M. Toward rational design of electrical stimulation strategies for epilepsy control. Epilepsy Behav 2010;17(1):6–22. [9] Osorio I, Frei MG, Sunderam S, Giftakis J, Bhavaraju NC, Schaffner SF, et al. Automated seizure abatement in humans using electrical stimulation. Ann Neurol 2005;57(2): 258–68. [10] Klatt J, Feldwisch-Drentrup H, Ihle M, Navarro V, Neufang M, Teixeira C, et al. The EPILEPSIAE database: an extensive electroencephalography database of epilepsy patients. Epilepsia 2012;53(9):1669–76. [11] The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 1995;45(2):224–30. [12] Synofzik M, Fins JJ, Schlaepfer TE. A neuromodulation experience registry for deep brain stimulation studies in psychiatric research: rationale and recommendations for implementation. Brain Stimul 2012;5(4):653–5.
Octavian V. Lie Jose E. Cavazos⁎ Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA San Antonio VA Epilepsy Center of Excellence, San Antonio, TX, USA ⁎Corresponding author at: Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. E-mail address: [email protected] (J.E. Cavazos). 27 November 2013 Available online xxxx
