Current Literature Responsive Neurostimulation: The Hope and the ...

Current Literature In Clinical Science

Responsive Neurostimulation: The Hope and the Challenges

Two-Year Seizure Reduction in Adults With Medically Intractable Partial Onset Epilepsy Treated With Responsive Neurostimulation: Final Results of the RNS System Pivotal Trial. Heck C, King-Stephens D, Massey A, Nair D, Jobst B, Barkley G, Salanova V, Cole A, Smith M, Gwinn R, Skidmore C, Van Ness P, Bergey G, Park Y, Miller I, Geller E, Rutecki P, Zimmerman R, Spencer D, Goldman A, Edwards J, Leiphart J, Wharen R, Fessler J, Fountain N, Worrell G, Gross R, Eisenschenk S, Duckrow R, Hirsch L, Bazil C, O’Donovan C, Sun F, Courtney T, Seale C, Morrell M. Epilepsia 2014;55:432–441.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial- onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

Commentary The quest for palliating pharmacoresistant focal epilepsy with neurostimulation has been ongoing for decades. Multiple structures within and outside the brain have been stimulated to achieve better seizure control with varying degrees of success, including the cerebellum (1), three separate thalamic nuclei (subthalamic nucleus, centromedian nucleus, and anterior thalamic nucleus [2–4]), the corpus callosum, the vagus nerve (5, 6), and more recently, the hippocampus (7). The paper chosen for this commentary highlights responsive neurostimulation (RNS), the most recent “success story” in this field. The results of this massive, multicenter, randomized clinical trial are obvious and straightforward: An initial response seen 5 months postimplantation (41.5% seizure reduction in the Treatment arm compared to a 9.4% reduction in the Sham group) continued to improve during a subsequent open-label phase where both Treatment and Sham received stimulation. Epilepsy Currents, Vol. 14, No. 5 (September/October) 2014 pp. 270–271 © American Epilepsy Society

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Two years after implantation, around half the patients (55%, to be exact) achieved a 50% or greater reduction in seizure frequency. Intracranial hemorrhages and infections each occurred in about 2% of implanted patients, neither mood nor cognitive function worsened, and quality of life improved. Following these positive results, RNS is now the only FDA approved neurostimulation treatment besides vagus nerve stimulation (VNS). This availability introduces a much-needed innovative option for patients with intractable focal epilepsy. It also obligates us—the epilepsy community—to pursue questions aimed at better understanding, targeting, and optimizing treatment outcomes with this new technology, as well as better defining its place within the current therapeutic armamentarium. The most evident initial question is to define the target patient population. “Potential” candidates could be those mirroring the cohort included in the study: adult patients with intractable focal epilepsy who are not candidates for the potentially curative option of resective epilepsy surgery, and/ or who have already failed the palliative option of VNS. Yet, the current study was neither powered nor designed to identify specific predictors of a favorable response to responsive

Responsive Neurostimulation

stimulation, so the “ideal” candidates remain to be defined. The reported results provide two insights in this regard: 1) patients with mesial temporal lobe epilepsy (MTLE) had similar response to those with non-MTLE, reinforcing the notion that RNS use needs not to be limited nor preferentially provided to patients with MTLE, and 2) younger patients with more than one ictal onset zone seemed least likely to become seizurefree with this intervention, supporting the potentially preferential effectiveness of RNS to treat limited and well-defined epileptic foci. A welcome next step would be to push investigations to further identify predictors of a successful response, starting by evaluating seizure outcomes in relation to variables already available within the main study dataset, such as prior use of invasive EEG (potentially then better informing the placement of stimulating electrodes) or prior initial response to VNS therapy (potentially then correlating with a stimulationsensitive epilepsy). A second opportunity for advancement lies in better defining ideal stimulation parameters with increased availability and use of the RNS technology. As stimulation targets vary from the neocortex to the hippocampus, and from lesional or malformed brain tissue to grossly normal brain, the inherent electrophysiology and, therefore, the stimulation parameters necessary to interrupt or prevent ictal discharges in these very different targets is expected to vary (2). Systematic efforts to refine criteria for stimulation parameters targeting specific anatomo-functional networks may be helpful. The third task to consider is the most challenging but also the most impactful responsibility: that is, defining the role of RNS in the current therapeutic landscape. In the absence of any direct comparisons of RNS with the other available neurostimulation treatment option (VNS), we can rely only on objective data derived from each modality’s randomized clinical trial data for guidance. Acknowledging that such comparisons of historical data are not fair but also recognizing that an ideal direct prospective comparison of VNS to RNS will be difficult if not impossible—given radical differences in the procedures themselves likely negating patients’ willingness for randomization—one needs to at least review the data. On one hand, two randomized double-blind clinical trials investigated the efficacy of VNS, titled EO3 and EO5 (5, 6): both had randomized patients receiving either typical VNS (denoted “high”) or an active, low-frequency control VNS (denoted “low”). Both studies required patients to have ≥6 seizures per month, be ≥12 years old, use at most 3 AEDs, and have medically refractory seizures. Both assessed their outcomes after approximately 3 months of treatment, showing significant benefit in the “high frequency” group with 24.5% and 27.9% respective reductions in seizure frequency compared with patient baselines and a significant proportion of patients experiencing a reduction of ≥50% in their seizures at the same 3-month time point (23.4% and 31%, respectively). After 1 year, patients in the EO5 open-label phase of the study had a 45% reduction in seizure frequency, and 35% had a reduction of ≥50% in seizures. The responder

rate improved to 43.2% at 2 years (5). On the other hand, the RNS clinical trial randomized patients to Active versus Sham stimulation, included slightly older patients (18–70 years), with partial seizures, medically refractory epilepsy (failure of ≥2 AEDs), 3 or more seizures per month (on average), and an EEG workup (scalp or invasive) showing 1 to 2 epileptogenic regions. Over a similar 3-month follow-up period, stimulated patients reported a decrease in seizure frequency of 37.9% (slightly higher than that reported in E03 and E05), with 29% of patients reporting a decrease in seizures of ≥50% (within the range of the blinded phase responder rates reported for E03 and E05 above). The 1-year responder rate is 43% with RNS, improving to 55% at 2 years (about a 10% point then higher than that reported with VNS). An ongoing long-term follow-up RNS study will inform us about the sustainability of this response. So, given the relatively comparable nature of these numbers, we are even more so obligated to face the initial two challenges highlighted earlier: Identify the patients who would preferentially benefit from RNS and identify how best to treat them with the stimulation. Patients with intractable focal epilepsy are eagerly awaiting new treatment options. Efforts to develop innovative therapies like the RNS will always be commended and needed. by Lara Jehi, MD References 1. Fountas KN, Kapsalaki E, Hadjigeorgiou G. Cerebellar stimulation in the management of medically intractable epilepsy: A systematic and critical review. Neurosurg Focus 2010;29:E8. 2. Fisher RS. Deep brain stimulation for epilepsy. Handb Clin Neurol 2013;116:217–234. 3. Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, Oommen K, Osorio I, Nazzaro J, Labar D, Kaplitt M, Sperling M, Sandok E, Neal J, Handforth A, Stern J, DeSalles A, Chung S, Shetter A, Bergen D, Bakay R, Henderson J, French J, Baltuch G, Rosenfeld W, Youkilis A, Marks W, Garcia P, Barbaro N, Fountain N, Bazil C, Goodman R, McKhann G, Babu Krishnamurthy K, Papavassiliou S, Epstein C, Pollard J, Tonder L, Grebin J, Coffey R, Graves N; SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51:899–908. 4. Velasco F, Velasco AL, Velasco M, Jimenez F, Carrillo-Ruiz JD, Castro G. Deep brain stimulation for treatment of the epilepsies: The centromedian thalamic target. Acta Neurochir Suppl 2007;97:337–342. 5. Morris GL III, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology 1999;53:1731–1735. 6. DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B, Reed R, Collins S, Tecoma E, Morris GL, Vaughn B, Naritoku DK, Henry T, Labar D, Gilmartin R, Labiner D, Osorio I, Ristanovic R, Jones J, Murphy J, Ney G, Wheless J, Lewis P, Heck C. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia 2000;41:1195–1200. 7. Tellez-Zenteno JF, Wiebe S. Hippocampal stimulation in the treatment of epilepsy. Neurosurg Clin N Am 2011;22:465–75, vi.

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