LONG-TERM SAFETY AND EFFICACY OF THE RNS™ SYSTEM IN ADULTS WITH MEDICALLY INTRACTABLE PARTIAL ONSET SEIZURES
Martha J. Morrell, Lawrence J. Hirsch, G. Bergey, G. Barkley, R. Wharen, Anthony Murro, B. Fisch, Marvin A. Rossi, D. Labar, R. Duckrow, Joseph I. Sirven, J. Drazkowski, Gregory A. Worrell and Ryder P. Gwinn
Rationale: The RNS™ System (NeuroPace,Inc.) is an investigational device being tested as an adjunctive therapy for adults with medically intractable partial onset seizures. The RNS™ System includes a cranially implanted programmable responsive neurostimulator connected to depth and/or subdural leads, a physician programmer, a patient data transmitter and a web based interactive data repository. A two-year multi-center feasibility trial collected safety and efficacy data after implantation of the neurostimulator and leads. Subjects were then able to transition into a 5-year long-term treatment trial to gather additional safety and efficacy data. Longer term efficacy and safety data as of April 20, 2008 are presented.
Methods: Subjects were 18-65 years of age with intractable partial-onset seizures localized to one or two epileptogenic onset region (s). Subjects with >12 simple partial (SP) sensory or motor seizures, complex partial seizures (CPS) and/or generalized tonic-clonic (GTC) seizures over an 84-day baseline period qualified for implantation of the neurostimulator and leads. Efficacy was assessed over the 84 days beginning one month after implantation of the neurostimulator and leads (primary), over the most recent 84 days of participation, and over the entire period of participation. Adverse events (AEs) were monitored throughout the
trial.
Results: During the primary evaluation period, the responder rate (RR = % of subjects with a 50% or greater reduction in seizures) in 50 subjects (excluding 1 subject with no disabling seizures at baseline and 14 subjects randomized to off) was 27% (12/44) for CPS, 65% (11/17) for GTC, and 24% (12/50) for total disabling seizures (TDS = SP motor, CPS and GTC). For the secondary evaluation over the most recent 84 days of
participation, the RR was 74% (14/19) for subjects with seizure onsets in the hippocampus, 37% (15/41) for seizure onsets in the neocortex and 48% for all 60 subjects combined (excluding 1 subject with no disabling
seizures at baseline and 4 subjects with incomplete or inconsistent seizure frequency data). The RR for TDS for all subjects increased from 25% at 3 months of treatment (n = 64), to 48% at 18 months (n = 61) and to 54%
for the 27 subjects for whom there was 36 months of data. In the 65 implanted subjects representing over 180 patient years of stimulation, there were no serious unanticipated device-related AEs, and responsive neurostimulation was well tolerated.
Conclusion: A feasibility and long-term treatment investigation of the RNS™ System demonstrated safety and a sustained reduction in disabling seizures. Preliminary results indicated that the RNS™ System
might provide a safe and effective adjunctive treatment for adults with intractable partial-onset epilepsy. A multi-center randomized double blinded pivotal trial is currently underway.
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CIRCADIAN PATTERNS OF EPILEPTIFORM ACTIVITY IN 65 PATIENTS WITH AN INTRACRANIAL RESPONSIVE NEUROSTIMULATOR FOR EPILEPSY (THE NEUROPACE RNS™ SYSTEM)
Christopher T. Anderson, F. Sun and T. Tcheng
Rationale: Epileptiform activity (EA) and seizure occurrence are known to fluctuate in a circadian pattern (i.e. 24 hour cycles). Prior studies of circadianicity of EA have been limited to small populations and short recording periods. This is the first study to evaluate long-term circadian patterns of EA in ambulatory patients. Our goals were: (1) to determine if EA exhibits a circadian rhythm in patients implanted with the NeuroPace RNS™ System, (2) to determine which times of the day are associated with peaks of EA, and (3) to determine if circadianicity is present for subgroups, segmented by location of seizure focus and by electrocorticographic (ECoG) epileptiform pattern.
Methods: We plotted chi-square (X2) periodograms of EA for each of 65 patients implanted with the NeuroPace RNS™ System to examine 6 to 42-hour cycles of EA, to measure circadianicity (24-hour periodicity),
and to quantify changes in the amount of circadianicity using the methods of Sokolove & Bushnell. Significance cut-offs at alpha < 0.001 and 0.05 were used.
To estimate the time of the day with the peak EA rate, we used a cosinor analysis to locate the temporal phase of the circadian peaks.We generated histograms by hour of day to visualize what clock times were associated with the highest rates of EA.We subjected the above data to subgroup analysis to determine if X2 was related to: (1) laterality of stimulation, (2) lobe of stimulation, (3) neocortical vs, hippocampal stimulation, and (4) detection type (segmented into the following classes of ECoG detection: beta, alpha, theta, delta, generic/burst, gamma, spike, voltage attenuation).
Results: The majority of patients had EA that clustered in a circadian rhythm for most the recording period (months to years), however the amount of circadianicity varied over time, and could have been influenced by seizures or medications. Circadianicity appeared to be a general characteristic of EA irrespective of electrode location or electrographic pattern. A significant circadian pattern was detected in both left and right hemispheres, all lobes (temporal, occipital, parietal, and frontal) and in the hippocampus. Significant circadian patterns were also observed for all types of electrographic activity (theta, delta, beta, bursts, gamma, spiking, and voltage attenuation). Phase analyses revealed peaks of EA across and within all subgroups between approximately 10 PM and 4 AM with another minor peak in the late afternoon.
Conclusion: EA as detected by the NeuroPace RNS™ System occurs in a circadian rhythm with the most robust peaks of EA between approximately 10 PM and 4 AM. This appears true regardless of site or type
of ECoG detection. Circadianicity of EA should be taken into account in the research, design, development, use, and study of intracranial stimulation for epilepsy. To maximize the clinical benefit of any device, device
parameters may need to be titrated to match endogenous patterns of EA; this is an area of active and ongoing research.
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EVALUATING SEIZURE ONSET LATERALIZATION USING PROLONGED OUTPATIENT INTRACRANIAL HIPPOCAMPAL EEG RECORDING
Yong Park, R. Esteller, Anthony Murro, Suzanne M. Strickland and P. Ray
Rationale: Epilepsy surgery candidates with unsatisfactory scalp EEG localization often require invasive intracranial EEG monitoring to accurately determine seizure focus localization. Among those patients with bilateral hippocampal seizure activity, we commonly assume that the relative frequency of right and left hippocampal seizure onsets obtained from inpatient EEG recording closely represents the pattern of seizure onset that would occur in an outpatient setting. The purpose of this study was to evaluate this hypothesis by comparing the patterns of seizure lateralization obtained in an epilepsy monitoring unit with the patterns of seizure onset obtained by prolonged outpatient intracranial EEG recording.
Methods: This study analyzed information from four patients with intractable temporal lobe epilepsy. Ictal scalp EEG recordings suggested bilateral temporal activity in all cases. Intracranial EEG recordings supported bilateral temporal lobe seizure activity in 3 of 4 patients. Incongruent data indicated bilateral temporal lobe seizure activity in the fourth case. All subjects received prolonged outpatient intracranial hippocampal EEG recording as participants in a FDA approved multi-center study of a responsive neurostimulator system (RNS™). The neurostimulator system includes two intracranial recording subdural or depth hippocampal
electrodes. This implantable device is capable of detecting and storing epileptic seizures. The recording duration ranged from 3 to 39 months. We analyzed 1,503 3-minute ictal outpatient intracranial EEG recordings.
We compared inpatient and outpatient EEG recordings.
Results: The pattern of seizure onsets obtained in the inpatient monitoring unit corresponded closely to the prolonged outpatient intracranial EEG recordings for two subjects. The third subject showed a significant discrepancy between the inpatient and outpatient recordings. In this subject, the intracranial inpatient EEG recording of 13 right onset seizures and 5 left onset seizure indicated a 0.72 probability of right sided seizure onset (0.49-0.87, 95% confidence interval). The outpatient recordings recorded a total of 1158 seizures over 37 months. The outpatient recordings showed a significantly lower 0.31 probability for right sided onset (p < 0.05). The fourth subjects had inadequate number of outpatient ictal recordings for evaluation.
Conclusion: Physicians commonly assume that inpatient intra-cranial EEG recording of many seizures will correctly represent the frequency of right or left seizure onsest in the outpatient setting. Our results indicate that there are individual cases where this assumption may fail. A more detailed statistical evaluation of the pattern of seizure onsets may provide additional understanding of this process in patients with bilateral hippocampal epilepsy.
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SUBTRACTED ACTIVATED SPECT VALIDATES DEPTH LEAD PLACEMENT IN WHITE MATTER FOR RESPONSIVE NEUROSTIMULATION THERAPY IN REFRACTORY PARTIAL-ONSET EPILEPSY
Marvin A. Rossi, T. J. Hoeppner, R. W. Byrne, D. Greene, A. M. Kanner, T. Stoub, M. Stein, A. Balabanov, D. Bergen and Michael C. Smith
Rationale: A novel approach for implanting investigational responsive neurostimulation (RNS) therapy electrodes is presented for potentially interfacing with epileptic circuits that extend beyond the electrode's generated electric field. Juxtacortical white matter pathways are targeted such that the biophysical properties of axons are used to propagate electrical current distant from the source of stimulation. This hypothesis was tested following RNS depth lead implantation in three subjects enrolled in the RNS multi-center clinical trials.
Methods: Three subjects (CH, RK and TS) with at least one mesial temporal epileptic source were implanted with a depth electrode in mesial temporal white matter. Stereotactic guidance was used for each subject to place the cylindrical depth lead immediately lateral and adjacent to hippocampal grey matter. The depth electrode followed the longitudinal axis of the hippocampal formation. Delivery of stimulation occurred while
employing subtracted activated SPECT (SAS) to capture transient focal blood flow changes. SAS acquisition and analysis (AnalyzeR) for each subject were performed at 12, 18 and 4 months, respectively 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 6-12 high frequency stimuli (100-200 Hz) at 0.5 Hz (stimulation intensity = 4.5-5 mA, pulse width = 160 μsec, pulse duration = 100 msec). No afterdischarges were recorded by electrocorticography
during stimulation. A post-stimulation baseline SPECT was acquired for each subject 36 to 48 hours following the stimulation session. The data were normalized, subtracted and co-registered to each respective subject's
3D Fourier tansform SPGR magnetic resonance neuroimaging dataset.
Results: Upon repetitive bipolar stimulation of RK's posterior temporal depth contacts, propagation to an ipsilateral epileptic source in primary visual cortex was observed by semiology and blood flow measures. The sensory response overlapped his typical visual aura in distribution, color, form and movement. For CH and TS, transient hypo- and hyperperfusionrelated changes were demonstrated both ipsi- and contralaterally, concordant with preoperatively determined epileptic tissue.
Conclusion: Direct cortical stimulation of mesial temporal white matter validates influencing distant epileptic sources as determined presurgically. These data ostensibly represent the extent of cortical modulation for a given set of focal stimulation parameters delivered through 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 modulated with a minimum number of electrodes. Such data will underscore the need to regard the partial-onset epilepsies as potentially extensive pathological neural networks.
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