RESULTS OF A MULTICENTER DOUBLE BLINDED RANDOMIZED CONTROLLED PIVOTAL INVESTIGATION OF THE RNS™ SYSTEM FOR TREATMENT OF INTRACTABLE PARTIAL EPILEPSY IN ADULTS
Martha J. Morrell and the RNS System Pivotal Investigators
Rationale: The RNS™ System (NeuroPace,Inc.) is an investigational device being evaluated for safety and efficacy in adults with medically intractable partial onset seizures. The RNSTM System includes a cranially implanted programmable responsive neurostimulator connected to depth and/or subdural leads, a physician programmer, a patient remote monitor and a web based interactive data repository. Based on the favorable safety results of a two year Feasibility Investigation, a Pivotal Investigation commenced in December 2005.
Methods: Eligible subjects were 18 to 70 years of age, had an average of 3 disabling partial seizures a month, had failed 2 or more antiepileptic medications (AEDs) and had seizure foci localized to one or 2 regions. Subjects completed a 3 month baseline to determine eligibility based on seizure frequency and were then given the option to have the RNS System Neurostimulator and Leads implanted. The Neurostimulator was programmed to acquire data on seizure detection. One month post-operatively, subjects were randomized 1:1 to receive sham or active responsive stimulation. In order to maintain the blind, physicians responsible for
acquiring data for the primary and secondary safety and efficacy outcomes were blinded to the randomization status. Programming and other device management was the responsibility of a non-blinded treatment physician. Seizure frequency was considered over the 84 days beginning 2 months after implantation. At completion of this blinded efficacy evaluation period (BEP), all subjects were able to receive stimulation until 2 years post-implant, then could transition into a 5 year open label long term treatment trial.
Results: As of May 28, 2009, 191 subjects had been implanted with the RNS System Neurostimulator and Leads across 29 sites. Mean age was 36 years (range 18-67) and 48% were female. The mean age of seizure
onset was 14 years (range 0-54). Subjects were taking 2.8 AEDs (range 0-8). 34% had been previously treated with a VNS and 33% with epilepsy surgery; 16% had been treated with both VNS and surgery. 60% of subjects
had prior intracranial monitoring for localization of the epileptic focus. 46% had ictal onset in mesial temporal structures only, and 82% of these subjects had bilateral mesial temporal ictal onsets. The results of a
safety and efficacy analysis for the BEP will be available after the final subject completes in August 2009.
Conclusion: The RNS™ System is a cranially implanted responsive neurostimulator being evaluated as an adjunctive treatment for adults with intractable partial-onset epilepsy. A multicenter double blind randomized controlled pivotal investigation of the RNS System collected efficacy and safety data on 191 adults with medically intractable partial onset seizures. These subjects had severe epilepsy and many had failed
multiple epilepsy treatments. Nearly half of these subjects had seizures originating in mesial temporal structures, most with bilateral onsets. Efficacy and safety results will be presented for the blinded efficacy evaluation period.
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SUBTRACTED ACTIVATED SPECT (SAS) VALIDATES PROPAGATION OF DIRECT NEUROSTIMULATION THERAPY IN DOUBLE BAND HETEROTOPIA WHITE MATTER
Marvin A. Rossi, O. Graf, T. J. Hoeppner, G. Stebbins, R. W. Byrne, T. Stoub,M. A. Stein, D. Bergen, A. Balabanov, A. M. Kanner and M. C. Smith
Rationale: A novel approach is presented for implanting investigational responsive neurostimulation (RNS) therapy depth electrodes for maximally influencing the epileptic network of a double band heterotopia.
White matter pathways are targeted for RNS therapy near ictal-related transient regions of hyperperfusion. The biophysical properties of axons are used to propagate electrical current beyond the source of stimulation.
Methods: Scalp video-EEG monitoring and subtracted ictal SPECT co-registered to MRI (SISCOM) localized two active right posterior-inferior parietal epileptic sources for a subject with a previously identified
double band heterotopia. Stereotactic guidance for two 4-contact 3.5mm center-center depth electrodes employed the subject's diffusion tensor imaging data set. Diffusion tensor tractography was generated (MRDiffusion) using seed regions of interest (ROI) taken from 3D electric fields (radius 3.75mm) predicted to activate the surrounding white matter (COMSOL Multiphysics). The two depth electrodes were implanted in an orthogonal orientation in the right posterior-inferior parietal region overlapping the seed ROI. Both electrode tips extended to the wall of the right lateral ventricle. SAS acquisition and analysis (AnalyzeR) were performed 5 months following implantation of the RNS system. Bipolar stimulation of the posterior two of four depth lead contacts was performed during peripheral intravenous administration of Tc99- HMPAO. The injection of radiotracer occurred during delivery of 12 high frequency stimuli (200Hz) at 0.5Hz (stimulation intensity=5mA, pulse width=160µsec, burst duration=100msec). A post-stimulation baseline SPECT was acquired 24 hours following the stimulation session. The data were normalized, subtracted and co-registered to the subject's 3D Fourier transform SPGR magnetic resonance neuroimaging dataset.
Results: Transient hyper- and hypo-perfusion related changes associated with repetitive bipolar stimulation of white matter were seen in the visual cortices medially and bilaterally. In addition, a region of transient hyper-perfusion was seen in the ipsilateral basal frontal cortex. Behaviorally, repetitive bipolar stimulation of the subject's posterior-inferior parietal depth contacts was associated with bright elementary flashes of light in the left upper visual quadrant. No afterdischarges were recorded by electrocorticography during stimulation.
Conclusion: SAS demonstrates propagation of RNS therapy beyond the electrode's generated electric field to distant epileptic tissue of a double band heterotopia. These data ostensibly represent the extent of cortical modulation for a given set of focal stimulation parameters delivered though a specific electrode contact shape, orientation and location in white matter. Presurgical planning can predict axonal pathways that
direct the spread of RNS current to distant neural tissue. As a result, a greater extent of the epileptic circuit can be potentially modulated with a minimum number of electrodes.
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RESPONSIVE NEUROSTIMULATION MODULATES CORTICAL RHYTHMS IN PATIENTS WITH EPILEPSY
Vikaas S. Sohal and F. T. Sun
Rationale: Responsive neurostimulation may be a useful treatment for epilepsy, and may act in part by modulating ongoing brain rhythms. Here we measured how responsive neurostimulation modulates activity within different frequency bands in patients with epilepsy.
Methods: Electrocorticographic (ECOG) signals were recorded from 65 patients participating in a clinical investigation to assess the safety of an implantable responsive neurostimulation system (RNSTM System, NeuroPace, Inc.). In each patient, 4-channel bipolar recordings of one or two epileptogenic regions were made using chronically implanted intracranial electrodes. The cranially implanted neurostimulator processes the
signals in real-time, delivers responsive stimulation, and stores ECOG records. Whenever recording sites changed, data from that patient was treated as a new dataset, resulting in 146 datasets. To study rhythmic
activity at a frequency, f, we band-pass filtered each recording between f + 2.5 Hz, then convolved the filtered signal with a wavelet with frequency f to obtain an amplitude and phase. The amplitude measured the
strength of activity at frequency f. For each pair of recordings from each dataset, we computed phase differences, converted these to unit vectors in the complex plane, and used the amplitude of the average of these unit vectors to measure the synchrony at frequency f. We compared the strength and synchrony of oscillations 0.2 sec before and 0.8 sec after stimulation, and omitted data containing stimulation artifacts. We measured
the statistical significance of phase-locking by bootstrapping.
Results: For each frequency and pair of recordings, statistically significant phase-locking occurred in 13% of cases, using a criterion of p<0.01. After stimulation, significant phase-locking decreased by an average of 19%. Phase-locking decreased for frequencies between 10-80 Hz (p<0.001), but not between 80-100 Hz. Note that when recordings contained events that in other cases would have led to stimulation, but the stimulator was turned off, we observed marginal and inconsistent changes in phase-locking. When we analyzed all data, we found that following stimulation, rhythmic amplitudes increased between 30-100 Hz (p<0.01). By contrast, when we only analyzed cases in which statistically significant phase-locking was present, rhythmic amplitudes from 10-80 Hz decreased after stimulation (p<0.001). Again, these results were not present
when recordings contained events that otherwise would have led to stimulation, but stimulation was not delivered.
Conclusion: These results suggest that responsive neurostimulation suppresses 10-80 Hz oscillations that are phase-locked across recording sites, but enhances 30-100 Hz oscillations that are not phase-locked
across recording sites. Thus, a potential therapeutic effect of neurostimulation may be to suppress large-scale, lower-frequency oscillations while enhancing high-frequency, local oscillations, and selecting stimulation
parameters which maximize these effects may help to optimize the therapeutic efficacy of neurostimulation for epilepsy and other disorders.
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EFFECT OF SEIZURE CLUSTERING ON ONSET REGION IN PATIENTS WITH MULTIFOCAL TEMPORAL LOBE SEIZURES
A. Sreenivasan, Christophe C. Jouny, P. J. Franaszczuk and G. K. Bergey
Rationale: It is commonly believed that in patients with potential multifocal epilepsy, seizures occuring in a cluster tend to occur from the same focus and therefore seizures in clusters may be less helpful in presurgical evaluations of seizure localization. Recent investigations of responsive neurostimulation have provided opportunities to study long-term recordings from intracranial electrodes in humans. This allows assessment of seizure onset over time in relation to seizure clusters.
Methods: Two patients with known bilateral independent mesial temporal lobe onset seizures had implantation of bilateral depth electrodes arrays in conjunction with the pivotal trials of responsive neurostimulation with the NeuroPace device. Data were collected and downloaded to a remote server over a 10-month period; antiepileptic medications were not changed during this period. The side of seizure onset and date and time of occurrence of each seizure were noted. A cluster of seizures was defined by the occurrence of more than one seizure during a fixed window of time. Seizures were assigned to either Non-Cluster Seizures (NCS) or Cluster Seizures (CS) groups. The side of seizure onset was also compared to the previous seizure. Therefore each seizure was assigned a value of 0 if its onset was ipsilateral to the previous seizure and 1 if the onset was contralateral to the previous seizure. The number of seizures for each group and each value were collected in a contingency table for both patients. The group factor distinguishes seizures occuring within a cluster or not (NCS vs CS). Chi-square statistic was not corrected for continuity as the number of seizures was sufficient in all cases.
Results: Using a window of 24-hour for the definition of a cluster, NCS shows a baseline L/R ratio of 22/21 for patient 1 and 6/39 for patient 2 and CS shows a L/R ratio of 17/15 and 17/38 respectively. Patient 1 shows no difference in L/R ratio when seizures occur in clusters (p=0.41) but patient 2 shows a greater occurrence of left-sided seizures (p=0.037) during cluster. Contingency tables for the change of side of onset of seizures show that neither patient has a change in the distribution of change of onset side when seizures occur in cluster (Patient 1: p=0.41 and Patient 2: p=0.88).
Conclusion: Conclusions: In these two patients with known independent bilateral mesial temporal onset seizures, long-term recordings with stable antiepileptic drug regimens do not support the hypothesis that seizures occuring in clusters are more likely to originate from the same seizure focus.
Support by NeuroPace, Inc. (GKB)
| |
Onset Side |
|
Change of Side |
| |
Left |
Right |
No |
Yes |
| Patient 1 |
NCS |
22 |
21 |
NCS |
18 |
11 |
| CS |
17 |
15 |
CS |
9 |
9 |
| Patient 2 |
NCS |
6 |
39 |
NCS |
23 |
9 |
| CS |
17 |
38 |
CS |
30 |
11 |
|
Table 1 for 1.016. Contingency table of number of seizures for both patients. NCS: Non-cluster seizures. CS:Cluster seizures. Change of side is compared to onset side of previous seizure if within the same cluster or non-cluster period.
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