Responsive Neurostimulation (RNS) for the treatment of epilepsy Daniel Friedman, MD Assistant Professor NYU Comprehensive Epilepsy Center April 27, 2014

The RNS™ System Cranially implanted battery powered responsive neurostimulator Connected to 2 leads (depth and/or subdural) with 4 electrode contacts each

Figure 3 The NeuroPace Responsive Neurostimulator (RNS®) System (Mountain View, CA) Stacey WC and Litt B (2008) Technology Insight: neuroengineering and epilepsy—designing devices for seizure control Nat Clin Pract Neurol 10.1038/ncpneuro0750

The RNS® System: Responsive Stimulation Patient Data Management System (PDMS) Neurostimulator and Leads Programmer Patients are provided a Wand and Remote Monitor to use at home to transfer information from the Neurostimulator to the PDMS through the internet. Remote Monitor 4

RNS® System Indication The RNS® System is an adjunctive therapy for: >18 years of age partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci refractory to two or more antiepileptic medications have frequent and disabling seizures (motor partial seizures, complex partial seizures and/or secondarily generalized seizures) [insert script]   5

The RNS™ System Neurostimulator detects and stimulates abnormal brain electrical activity with implanted electrodes Programmer sets detection and stimulation parameters Programmer and Patient Data Transmitter send ECoG data to web-based repository for review

RNS® System: Responsive Stimulation Physician identifies electrocortico-graphic activity to be detected Detection and stimulation settings programmed, then adjusted as needed Varied seizure patterns require individualized settings Here are examples of detections and stimulations in 3 different patients. This is the type of data the physician can review on the programmer or the PDMS. The physician programs the Neurostimulator to detect and briefly stimulate specific electrocorticographic activity of interest. The arrows indicate the detection, followed by the stimulation. The physician reviews these recordings, determines if the stimulation is having the desired effect, and then adjusts detection and stimulation based on the patient’s clinical response.

Patient Data Management System Caution: InvestigationalDevice. Limited by US Law to Investigational Use Only.Caution: investigational device. Limited by US law to investigational use only.

Single Patient Seizure Plot: 2009-2014 Red: disabling seizures, Green: auras; Black: total seizures

The NeuroPace Responsive Neurostimulator (RNS®) System Trial 191 patients; 32 centers Randomized to Treatment vs. Sham group for 3 months Need to know localization of epileptic brain tissue 1- 2 foci 3 or more disabling seizures per month

Study Design Morrell M J Neurology 2011;77:1295-1304

The NeuroPace Responsive Neurostimulator (RNS®) System TRIAL RESULTS Overall: 38% Seizure Reduction in Active Treatment 17% Seizure Reduction in Sham Treatment

Other outcomes Improved quality of life in treated group No difference in memory function between treated and sham groups

Safety Bleeding in the brain in 2.3% Infection of scalp/soft tissue in 5.3% (4 pts had to have device removed); no brain infection Other rarer side effects included pain, abnormal sensations related to stimulation and worsening seizures

- Those with 1 focus were more likely to be seizure-free Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial At the end of 2years of treatment, 9% were seizure free during the last 3 mo - Those with 1 focus were more likely to be seizure-free ~7% had worsening of seizures Many had improvement in cognitive functioning Seizure frequency percent change by subject: most recent 3 months. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. Epilepsia Volume 55, Issue 3, pages 432-441, 22 FEB 2014 DOI: 10.1111/epi.12534 http://onlinelibrary.wiley.com/doi/10.1111/epi.12534/full#epi12534-fig-0005

Treatment with RNS – Patient perspective Localize seizure onset regions using EEG, MRI, PET, MEG, SPECT and/or intracranial EEG RNS leads and stimulator implanted & recording activated Patient uploads data daily Post-op visit 10-14 days Data reviewed, detectors adjusted if necessary, stimulation activated Follow up visits ~ 1-3 months Data reviewed, detectors and stimulation parameters adjusted Patient continues to upload data every 1-7 days Long term follow-up, every 3 months Continue to upload data Monitor battery/device function Adjust parameters as necessary Battery change about every 2 years, may be longer/shorter