NEWS & VIEWS EPILEPSY
Responsive neurostimulation —modulating the epileptic brain Elinor Ben-Menachem and Gregory L. Krauss
Responsive neurostimulation (RNS) is an exciting new approach to treating refractory epilepsy. A recent 2 year follow-up study indicates that long-term RNS treatment is safe, and that efficacy improves with time. Although several issues remain to be resolved, RNS is a welcome new arrival in the armamentarium of epilepsy treatments. Ben-Menachem, E. & Krauss, G. L. Nat. Rev. Neurol. 10, 247–248 (2014); published online 22 April 2014; doi:10.1038/nrneurol.2014.69
Over the past few years, responsive neuro stimulation (RNS) has emerged as a promising approach for the treatment of medically intractable epilepsy (Box 1). Unlike indirect ‘modulatory’ stimulation therapies for epilepsy—for example, cere bellar, thalamic1 or vagus nerve stimula tion (VNS)2—RNS detects seizures directly with implanted intracranial electrodes, then ‘counter-stimulates’ via a small digital processor–stimulator placed in a skull cas sette. RNS was recently approved by the FDA on the basis of a pivotal study involv ing 191 patients with refractory focal epilepsy.3 The study was somewhat compli cated by a large decrease in seizure activ ity even before the implanted device was switched on, but nevertheless demonstrated moderate efficacy for RNS compared with sham stimulation in a treatment-resistant epilepsy population. A newly published follow-up study by Christianne Heck and colleagues has examined the safety and effectiveness of the RNS® System (NeuroPace®, Inc., Mountain View, CA, USA) in 187 patients after approximately 2 years of therapy.4 The patients had highly refractory epilepsy; 34% had previously tried VNS and 32% had undergone resective epilepsy surgery. 55% of the cohort had RNS for two seizure foci, and 45% had one identified focus. Efficacy of the device increased gradually over 2 years of treatment, and the median seizure reduction for patients completing 2 years of RNS treatment was 53%, with 54% of patients experiencing more than 50% seizure reduction. A total of 9% of the
participants were seizure-free for the last 3 months of the study. The RNS device was relatively well tolerated—3.7% of patients had implant site infections, 6% had lead revisions or damage, and 2.1% percent had haemorrhages during initial implantation. The rationale for direct stimulation to interrupt seizures evolved largely from models of cortical networks, which showed that excitation could interrupt progression of synchronized neuronal firing.5 Rather than using animal models of epilepsy, RNS was developed directly in humans in three
steps. First, ‘open-loop’ stimulation was investigated in patients who had depth and subdural electrodes placed for presurgical seizure localization. Individual patients were found to have very stereotyped seizure patterns on intracranial recordings, thereby permitting accurate seizure detec tion and responsive stimulation within several hundred milliseconds of seizure onset. Second, preliminary evidence from open-loop stimulation suggested that direct stimulation over seizure-onset areas was feasible and could potentially terminate seizures in some patients.6 This idea was explored using a fully implanted ‘closedloop’ system in a feasibility and safety study in 65 patients.7 Once implanted, the device seemed to be safe and well tolerated— patients were not aware of stimulations. RNS was then investigated in a randomized ‘sham’-stimulation-controlled study in 191 patients.3 The Heck et al. report is the 2 year extension study of patients evaluated in the ‘sham’ stimulation-controlled study.4 Previous neurostimulator therapies, such as VNS and anterior thalamic nucleus stimulation (approved in Europe only), functioned solely as neuromodulators for drug-resistant epilepsy. Efficacy results
Box 1 | Responsive neurostimulation: key facts Development phase The responsive neurostimulation (RNS) approach was developed in three phases: ■■ Open-loop stimulation exploration during intracranial seizure monitoring6 ■■ Closed-loop safety and feasibility study, n = 65 (2004–2007)7 ■■ Double blind, randomized ‘sham stimulation’ controlled study, n = 191 (2006–2011)3 and open extension treatment, n = 1874 The RNS® System The RNS®System7 was developed by NeuroPace®, Inc. (Mountain View, CA, USA), and was approved in 2013 by the FDA, with possible European commercialization in 2015 ■■ MRI, electroconvulsive therapy and deep brain stimulation are contraindicated in patients implanted with this device ■■ Stimulator and/or battery replacement required every 2.8–3.5 years FDA indications: ■■ Adjunctive therapy in individuals 18 years or older ■■ Partial-onset seizures from no more than two foci ■■ Refractory to two or more antiepileptic medications Optimal treatment candidates: ■■ Two seizure foci, or ■■ Seizure foci located in non-resectable zones (for example, perisylvian language and motor areas) Additional treatment and selection issues ■■ Possible modulatory effect of repeated daily stimulation, leading to delayed treatment responses ■■ Optimal subgroups uncertain: bilateral hippocampal seizures, localized neocortical foci, others? ■■ Optimal electrode configurations and stimulation settings are in development
NATURE REVIEWS | NEUROLOGY
VOLUME 10 | MAY 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
‘‘
Efficacy of the device increased gradually over 2 years of treatment…
’’
from numerous case studies and longterm follow-up studies of VNS showed a responder rate (50% seizure reduction or more) of about 43–58% of patients, with 4–6% seizure freedom after 2 years of treat ment in patients with focal-onset seizures.2,8 Bilateral anterior temporal lobe stimula tion was approved in Europe in 2010, but not in the USA. In a double-blind trial involving 110 patients, the responder effi cacy rate in the 2 year follow-up was 54%, with 12% (14 patients) becoming seizurefree for at least 6 months. 9 From these data, we can conclude that the efficacy of RNS compares favourably with that of the existing neurostimulation therapies for refractory epilepsy. An unusual finding in both the RNS and the anterior thalamus stimulation trials was that patients had marked decreases in seizures immediately following device implantation, prior to commencement of stimulation therapy. However, patients ran domly assigned to stimulation had stable reductions in seizure frequency during the study period, whereas sham-treated patients slowly returned towards baseline. Patients receiving RNS exhibited further gradual decreases in seizure frequency after 1 year and 2 years of therapy, although this is beyond the controlled study period. These findings suggest that the effects of RNS might be partially modulatory rather than solely attributable to direct interruption of seizures. In the 2 year RNS trial, patients averaged 5.9 min of stimulation per day: patients typically had several hundred to several thousand electrographic spike bursts per day that were similar to ictal-onset pat terns and, therefore, triggered RNS. This repetitive cortical stimulation in epilepto genic zones could be at least partly respon sible for the late modulatory responses observed in patients receiving RNS.
MAY 2014 | VOLUME 10
The RNS pivotal trial3 and 2 year followup4 are milestones in the development of neurostimulators, because this therapy was devised not to modulate neural networks as with VNS and deep brain stimulation, but to provide stimulation to the seizure focus at the moment when a seizure starts to evolve. The RNS device also collects large volumes of intracranial EEG data that can be downloaded with telemetry—this resource will provide immense benefit in terms of assessing patterns of epileptogenic activity over time. Despite US approval, RNS is still in early development, and several issues remain to be resolved. For example, most of the trial participants had standard stimulation set tings during long-term therapy. However, up to eight electrodes can be linked in bipolar or unipolar (to the skull cassette) stimula tion pairings, and it is possible that inno vative transcortical electrodes or unique stimulation sequences might be helpful to treat seizures due to specific pathologies in various brain regions.
‘‘
Rather than using animal models of epilepsy, RNS was developed directly in humans in three steps
’’
In addition, optimal treatment subgroups remain to be explored. In the current trial, a subgroup of patients exhibited a dramatic reduction in seizure frequency, but another small group showed worsening. On the basis of the available data, patients with bilateral hippocampal seizures seem to be an optimal treatment group. Patients in whom RNS therapy failed often had electrodes that were determined to be distant from seizureonset zones, highlighting the importance of accurate identification of the seizure focus or foci. RNS heralds the dawn of a new era for the treatment of patients with refractory epi lepsy. It will be exciting to see whether intra cranial EEG and ‘responsive’ stimulation
sequences can be further developed and used to more effectively treat patients with various focal epilepsies in specific brain areas, for example, bilateral periventricular nodule syndrome, focal c ortical dysplasia and insular seizures.10 Sahlgrenska Academy, Göteborg University, Sahlgrenska University Hospital, 41345 Göteborg, Sweden (E.B.‑M.). Johns Hopkins University, Meyer 2‑147, 600 North Wolfe Street, Baltimore, MD 21287, USA (G.L.K.). Correspondence to: E.B.‑M. [email protected] Competing interests The authors declare no competing interests. 1.
Krauss, G. L. & Koubeissi, M. Z. Cerebellar and thalamic stimulation treatment for epilepsy. Acta Neurochir. Suppl. 97, 347–356 (2007). 2. Morris, G. L. 3rd et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Epilepsy Curr. 13, 297–303 (2013). 3. Morrell, M. J. & RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77, 1295–1304 (2011). 4. Heck, C. N. et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia 55, 432–441 (2014). 5. Anderson, W. S., Kudela, P., Weinberg, S., Bergey, G. K. & Franaszczuk, P. J. Phasedependent stimulation effects on bursting activity in a neural network cortical simulation. Epilepsy Res. 84, 42–55 (2009). 6. Kossoff, E. H. et al. Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia 45, 1560–1567 (2004). 7. RNS®System clinical summary. NeuroPace®, Inc. [online], http://www.neuropace.com/ product/pdfs/RNS‑300M_Clinical_Summary_ EN.pdf (2013). 8. Kuba, R. et al. Vagus nerve stimulation: longitudinal follow-up of patients treated for 5 years. Seizure 18, 269–274 (2009). 9. Fisher, R. et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 5, 899–908 (2010). 10. Smith, J. R. et al. Closed-loop stimulation in the control of focal epilepsy of insular origin. Stereotact. Funct. Neurosurg. 88, 281–287 (2010).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
Responsive neurostimulation —modulating the epileptic brain Elinor Ben-Menachem and Gregory L. Krauss
Responsive neurostimulation (RNS) is an exciting new approach to treating refractory epilepsy. A recent 2 year follow-up study indicates that long-term RNS treatment is safe, and that efficacy improves with time. Although several issues remain to be resolved, RNS is a welcome new arrival in the armamentarium of epilepsy treatments. Ben-Menachem, E. & Krauss, G. L. Nat. Rev. Neurol. 10, 247–248 (2014); published online 22 April 2014; doi:10.1038/nrneurol.2014.69
Over the past few years, responsive neuro stimulation (RNS) has emerged as a promising approach for the treatment of medically intractable epilepsy (Box 1). Unlike indirect ‘modulatory’ stimulation therapies for epilepsy—for example, cere bellar, thalamic1 or vagus nerve stimula tion (VNS)2—RNS detects seizures directly with implanted intracranial electrodes, then ‘counter-stimulates’ via a small digital processor–stimulator placed in a skull cas sette. RNS was recently approved by the FDA on the basis of a pivotal study involv ing 191 patients with refractory focal epilepsy.3 The study was somewhat compli cated by a large decrease in seizure activ ity even before the implanted device was switched on, but nevertheless demonstrated moderate efficacy for RNS compared with sham stimulation in a treatment-resistant epilepsy population. A newly published follow-up study by Christianne Heck and colleagues has examined the safety and effectiveness of the RNS® System (NeuroPace®, Inc., Mountain View, CA, USA) in 187 patients after approximately 2 years of therapy.4 The patients had highly refractory epilepsy; 34% had previously tried VNS and 32% had undergone resective epilepsy surgery. 55% of the cohort had RNS for two seizure foci, and 45% had one identified focus. Efficacy of the device increased gradually over 2 years of treatment, and the median seizure reduction for patients completing 2 years of RNS treatment was 53%, with 54% of patients experiencing more than 50% seizure reduction. A total of 9% of the
participants were seizure-free for the last 3 months of the study. The RNS device was relatively well tolerated—3.7% of patients had implant site infections, 6% had lead revisions or damage, and 2.1% percent had haemorrhages during initial implantation. The rationale for direct stimulation to interrupt seizures evolved largely from models of cortical networks, which showed that excitation could interrupt progression of synchronized neuronal firing.5 Rather than using animal models of epilepsy, RNS was developed directly in humans in three
steps. First, ‘open-loop’ stimulation was investigated in patients who had depth and subdural electrodes placed for presurgical seizure localization. Individual patients were found to have very stereotyped seizure patterns on intracranial recordings, thereby permitting accurate seizure detec tion and responsive stimulation within several hundred milliseconds of seizure onset. Second, preliminary evidence from open-loop stimulation suggested that direct stimulation over seizure-onset areas was feasible and could potentially terminate seizures in some patients.6 This idea was explored using a fully implanted ‘closedloop’ system in a feasibility and safety study in 65 patients.7 Once implanted, the device seemed to be safe and well tolerated— patients were not aware of stimulations. RNS was then investigated in a randomized ‘sham’-stimulation-controlled study in 191 patients.3 The Heck et al. report is the 2 year extension study of patients evaluated in the ‘sham’ stimulation-controlled study.4 Previous neurostimulator therapies, such as VNS and anterior thalamic nucleus stimulation (approved in Europe only), functioned solely as neuromodulators for drug-resistant epilepsy. Efficacy results
Box 1 | Responsive neurostimulation: key facts Development phase The responsive neurostimulation (RNS) approach was developed in three phases: ■■ Open-loop stimulation exploration during intracranial seizure monitoring6 ■■ Closed-loop safety and feasibility study, n = 65 (2004–2007)7 ■■ Double blind, randomized ‘sham stimulation’ controlled study, n = 191 (2006–2011)3 and open extension treatment, n = 1874 The RNS® System The RNS®System7 was developed by NeuroPace®, Inc. (Mountain View, CA, USA), and was approved in 2013 by the FDA, with possible European commercialization in 2015 ■■ MRI, electroconvulsive therapy and deep brain stimulation are contraindicated in patients implanted with this device ■■ Stimulator and/or battery replacement required every 2.8–3.5 years FDA indications: ■■ Adjunctive therapy in individuals 18 years or older ■■ Partial-onset seizures from no more than two foci ■■ Refractory to two or more antiepileptic medications Optimal treatment candidates: ■■ Two seizure foci, or ■■ Seizure foci located in non-resectable zones (for example, perisylvian language and motor areas) Additional treatment and selection issues ■■ Possible modulatory effect of repeated daily stimulation, leading to delayed treatment responses ■■ Optimal subgroups uncertain: bilateral hippocampal seizures, localized neocortical foci, others? ■■ Optimal electrode configurations and stimulation settings are in development
NATURE REVIEWS | NEUROLOGY
VOLUME 10 | MAY 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS
‘‘
Efficacy of the device increased gradually over 2 years of treatment…
’’
from numerous case studies and longterm follow-up studies of VNS showed a responder rate (50% seizure reduction or more) of about 43–58% of patients, with 4–6% seizure freedom after 2 years of treat ment in patients with focal-onset seizures.2,8 Bilateral anterior temporal lobe stimula tion was approved in Europe in 2010, but not in the USA. In a double-blind trial involving 110 patients, the responder effi cacy rate in the 2 year follow-up was 54%, with 12% (14 patients) becoming seizurefree for at least 6 months. 9 From these data, we can conclude that the efficacy of RNS compares favourably with that of the existing neurostimulation therapies for refractory epilepsy. An unusual finding in both the RNS and the anterior thalamus stimulation trials was that patients had marked decreases in seizures immediately following device implantation, prior to commencement of stimulation therapy. However, patients ran domly assigned to stimulation had stable reductions in seizure frequency during the study period, whereas sham-treated patients slowly returned towards baseline. Patients receiving RNS exhibited further gradual decreases in seizure frequency after 1 year and 2 years of therapy, although this is beyond the controlled study period. These findings suggest that the effects of RNS might be partially modulatory rather than solely attributable to direct interruption of seizures. In the 2 year RNS trial, patients averaged 5.9 min of stimulation per day: patients typically had several hundred to several thousand electrographic spike bursts per day that were similar to ictal-onset pat terns and, therefore, triggered RNS. This repetitive cortical stimulation in epilepto genic zones could be at least partly respon sible for the late modulatory responses observed in patients receiving RNS.
MAY 2014 | VOLUME 10
The RNS pivotal trial3 and 2 year followup4 are milestones in the development of neurostimulators, because this therapy was devised not to modulate neural networks as with VNS and deep brain stimulation, but to provide stimulation to the seizure focus at the moment when a seizure starts to evolve. The RNS device also collects large volumes of intracranial EEG data that can be downloaded with telemetry—this resource will provide immense benefit in terms of assessing patterns of epileptogenic activity over time. Despite US approval, RNS is still in early development, and several issues remain to be resolved. For example, most of the trial participants had standard stimulation set tings during long-term therapy. However, up to eight electrodes can be linked in bipolar or unipolar (to the skull cassette) stimula tion pairings, and it is possible that inno vative transcortical electrodes or unique stimulation sequences might be helpful to treat seizures due to specific pathologies in various brain regions.
‘‘
Rather than using animal models of epilepsy, RNS was developed directly in humans in three steps
’’
In addition, optimal treatment subgroups remain to be explored. In the current trial, a subgroup of patients exhibited a dramatic reduction in seizure frequency, but another small group showed worsening. On the basis of the available data, patients with bilateral hippocampal seizures seem to be an optimal treatment group. Patients in whom RNS therapy failed often had electrodes that were determined to be distant from seizureonset zones, highlighting the importance of accurate identification of the seizure focus or foci. RNS heralds the dawn of a new era for the treatment of patients with refractory epi lepsy. It will be exciting to see whether intra cranial EEG and ‘responsive’ stimulation
sequences can be further developed and used to more effectively treat patients with various focal epilepsies in specific brain areas, for example, bilateral periventricular nodule syndrome, focal c ortical dysplasia and insular seizures.10 Sahlgrenska Academy, Göteborg University, Sahlgrenska University Hospital, 41345 Göteborg, Sweden (E.B.‑M.). Johns Hopkins University, Meyer 2‑147, 600 North Wolfe Street, Baltimore, MD 21287, USA (G.L.K.). Correspondence to: E.B.‑M. [email protected] Competing interests The authors declare no competing interests. 1.
Krauss, G. L. & Koubeissi, M. Z. Cerebellar and thalamic stimulation treatment for epilepsy. Acta Neurochir. Suppl. 97, 347–356 (2007). 2. Morris, G. L. 3rd et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Epilepsy Curr. 13, 297–303 (2013). 3. Morrell, M. J. & RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77, 1295–1304 (2011). 4. Heck, C. N. et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia 55, 432–441 (2014). 5. Anderson, W. S., Kudela, P., Weinberg, S., Bergey, G. K. & Franaszczuk, P. J. Phasedependent stimulation effects on bursting activity in a neural network cortical simulation. Epilepsy Res. 84, 42–55 (2009). 6. Kossoff, E. H. et al. Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia 45, 1560–1567 (2004). 7. RNS®System clinical summary. NeuroPace®, Inc. [online], http://www.neuropace.com/ product/pdfs/RNS‑300M_Clinical_Summary_ EN.pdf (2013). 8. Kuba, R. et al. Vagus nerve stimulation: longitudinal follow-up of patients treated for 5 years. Seizure 18, 269–274 (2009). 9. Fisher, R. et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 5, 899–908 (2010). 10. Smith, J. R. et al. Closed-loop stimulation in the control of focal epilepsy of insular origin. Stereotact. Funct. Neurosurg. 88, 281–287 (2010).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
