Responsive Versus Continuous Deep Brain Stimulation for Speech in Essential Tremor: A Pilot Study.

BACKGROUND: Responsive deep brain stimulation (rDBS) uses physiological signals to deliver stimulation when needed. rDBS is hypothesized to reduce stimulation-induced speech effects associated with continuous DBS (cDBS) in patients with essential tremor (ET). OBJECTIVE: To determine if rDBS reduces cDBS speech-related side effects while maintaining tremor suppression. METHODS: Eight ET participants with thalamic DBS underwent unilateral rDBS. Both speech evaluations and tremor severity were assessed across three conditions (DBS OFF, cDBS ON, and rDBS ON). Speech was analyzed using intelligibility ratings. Tremor severity was scored using the Fahn-Tolosa-Marin Tremor Rating Scale (TRS). RESULTS: During unilateral cDBS, participants experienced reduced speech intelligibility (P = 0.025) compared to DBS OFF. rDBS was not associated with a deterioration of intelligibility. Both rDBS (P = 0.026) and cDBS (P = 0.038) improved the contralateral TRS score compared to DBS OFF. CONCLUSIONS: rDBS maintained speech intelligibility without loss of tremor suppression. A larger prospective chronic study of rDBS in ET is justified. © 2024 International Parkinson and Movement Disorder Society.

Impact of an integrated health, nutrition, and early child stimulation and responsive care intervention package delivered to preterm or term small for gestational age babies during infancy on growth and neurodevelopment: study protocol of an individually randomized controlled trial in India (Small Babies Trial).

BACKGROUND: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating. METHODS: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata of 1300 preterm and 1300 term SGA infants each to receive the intervention package or routine care. Infants will be followed until 12 months of age. Outcome data will be collected by an independent outcome ascertainment team at infant ages 1, 3, 6, 9, and 12 months and at 2, 6, and 12 months after delivery for mothers. DISCUSSION: The findings of this study will indicate whether providing an intervention that addresses factors known to limit growth and neurodevelopment can offer substantial benefits to preterm or term SGA infants. The results from this study will increase our understanding of growth and development and guide the design of public health programs in low- and middle-income settings for vulnerable infants. TRIAL REGISTRATION: The trial has been registered prospectively in Clinical Trial Registry - India # CTRI/2021/11/037881, Registered on 08 November 2021.

Neurostimulation as a Putative Method for the Treatment of Drug-resistant Epilepsy in Patient and Animal Models of Epilepsy.

A patient with epilepsy was shown to have neurobiological, psychological, cognitive, and social issues as a result of recurring seizures, which is regarded as a chronic brain disease. However, despite numerous drug treatments, approximately, 30%-40% of all patients are resistant to antiepileptic drugs. Therefore, newer therapeutic modalities are introduced into clinical practice which involve neurostimulation and direct stimulation of the brain. Hence, we review published literature on vagus nerve stimulation, trigeminal nerve stimulation, applying responsive stimulation systems, and deep brain stimulation (DBS) in animals and epileptic patient with an emphasis on drug-resistant epilepsy.

Implementing a group-based multi-component early child development intervention through the government health system in rural Bangladesh: A feasibility study.

Children in low- and middle-income countries face an increased risk of impaired cognitive development due to contaminated environments, poor nutrition, and inadequate responsive stimulation from caregivers. Implementing multi-component, community-level interventions may reduce these risks; however, there is little evidence supporting implementation of these interventions at scale. We assessed the feasibility of implementing a group-based intervention that included responsive stimulation, maternal and child nutrition, water and sanitation, and childhood lead exposure prevention through the government health system in Chatmohar, Bangladesh. After implementation, we conducted 17 in-depth interviews with frontline health service providers and 12 key informant interviews with their supervisors and managers to explore the facilitators and difficulties implementing such a complex programme within the health system. Factors facilitating implementation included: high quality training and skill level of providers, support from community members, family, and supervisors, positive relationships between providers and participants, and provision of children's toys and books free of cost. Difficulties included increased workload of the providers, complicated group-based yet stage-specific delivery where providers had to manage a large group of mother-child dyads representing many different child age-groups at once, and logistics difficulties in providing toys and books through a centralised health system process. Key informants made suggestions to ensure effective government-level scale-up including engaging relevant NGOs as partners, identifying feasible ways to make toys available, and offering providers meaningful even if non-monetary rewards. These findings can be used to shape the design and delivery of multi-component child development interventions to be delivered through the health system.

Practical considerations in epilepsy neurostimulation.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Wearable sensor-driven responsive deep brain stimulation for essential tremor.

BACKGROUND: Deep brain stimulation (DBS) is an effective surgical therapy for individuals with essential tremor (ET). However, DBS operates continuously, resulting in adverse effects such as postural instability or dysarthria. Continuous DBS (cDBS) also presents important practical issues including limited battery life of the implantable neurostimulator (INS). Collectively, these shortcomings impact optimal therapeutic benefit in ET. OBJECTIVE: The goal of the study was to establish a physiology-driven responsive DBS (rDBS) system to provide targeted and personalized therapy based on electromyography (EMG) signals. METHODS: Ten participants with ET underwent rDBS using Nexus-D, a Medtronic telemetry wand that acts as a direct conduit to the INS by modulating stimulation voltage. Two different rDBS paradigms were tested: one driven by one EMG (single-sensor) and another driven by two or more EMGs (multi-sensor). The feature(s) used in the rDBS algorithms was the pow2er in the participant's tremor frequency band derived from the sensors controlling stimulation. Both algorithms were trained on kinetic and postural data collected during DBS off and cDBS states. RESULTS: Using established clinical scales and objective measurements of tremor severity, we confirm that both rDBS paradigms deliver equivalent clinical benefit as cDBS. Moreover, both EMG-driven rDBS paradigms delivered less total electrical energy translating to an increase in the battery life of the INS. CONCLUSIONS: The results of this study verify that EMG-driven rDBS provides clinically equivalent tremor suppression compared to cDBS, while delivering less total electrical energy. Controlling stimulation using a dynamic rDBS paradigm can mitigate limitations of traditional cDBS systems.

Effects of a community health worker delivered intervention on maternal depressive symptoms in rural Tanzania.

Maternal depression affects one in four women in sub-Saharan Africa, yet evidence on effective and scalable interventions is limited. Our objective was to evaluate the effect of a community health worker (CHW) delivered home visit responsive stimulation, health and nutrition intervention, and conditional cash transfers (CCTs) for antenatal care and child growth monitoring attendance on maternal depressive symptoms. We conducted a cluster-randomized controlled trial in 12 villages in rural Ifakara, Tanzania (September 2017 to May 2019). Study villages were randomly assigned to one of three arms: (1) CHW, (2) CHW + CCT and (3) Control. Pregnant women and mothers with a child <12 months were enrolled. Maternal depressive symptoms were assessed using a Tanzanian-adapted version of the Hopkins Symptoms Checklist-25 (HSCL-25) after 18 months of follow-up. We used linear mixed-effects models to estimate intervention effects on HSCL-25 scores. Results showed that the CHW intervention significantly reduced HSCL-25 scores as compared with control [unadjusted mean difference (MD) -0.31, 95% confidence interval (CI) -0.47, -0.15]. The CHW + CCT intervention also appeared to lower HSCL-25 scores (MD -0.17, 95% CI -0.33, -0.01), but results were not statistically significant. Our findings showed that a low-intensity CHW-delivered home visit responsive stimulation, health and nutrition intervention, which did not explicitly aim to improve mental health, reduced maternal depressive symptoms, though the precise mechanisms of action remain unknown. CCTs for antenatal care and child growth monitoring appeared to provide limited to no additional benefit. Community-based integrated interventions that broadly consider maternal and child health, development and well-being have the potential to promote maternal mental health in rural Tanzania and similar settings.

Pregnancy outcomes of refractory epilepsy patients treated with Brain-responsive neurostimulation.

OBJECTIVE: To study the pregnancy outcomes, including obstetric complications and fetal outcomes, in pregnant women with epilepsy (WWE) treated with direct brain-responsive neurostimulation (RNS System). METHODS: Retrospective review of obstetric outcomes and fetal outcomes in WWE treated with the RNS System at nine comprehensive epilepsy centers in the United States from 2014-2020. In addition, changes in seizure frequency, anti-seizure medications, and RNS System setting adjustments during pregnancy were investigated. RESULTS: A total of 10 subjects and 14 pregnancies were identified. The mean age at conception was 30.6 ± 4.3 years old. The mean age at implantation was 29.8 ± 4.4 years old. The mean stimulation charge densities ranged from 1.0 to 3.0 µC/cm2 during pregnancy. Obstetric complications included recurrent miscarriage (1 patient), cesarean section (3 patients) due to preeclampsia, non-reassuring fetal heart rate tracing or prolonged labor, preterm birth (1 patient), and preeclampsia (1 patient). No still birth, gestational hypertension, gestational diabetes, eclampsia, or maternal mortality were observed. No RNS System-exposed pregnancies had major congenital malformations. One offspring had a minor congenital anomaly of cryptorchidism in a pregnancy complicated with risk factors of advanced maternal age and bicornuate uterus. SIGNIFICANCE: The present study is the first report of RNS System-exposed pregnancies in WWE to date. No major congenital malformations were identified. All of the obstetric complications were within the expected range of those in WWE based on previously published data. The sample size of our study is small, so accumulation of additional cases will further help depict the safety profile of treatment with the RNS System during pregnancy.

The Impact of Responsive Neurostimulation on the Treatment of Epilepsy.

There is a considerable number of patients with epilepsy that have drug resistant epilepsy (DRE). An additional option for these patients is resective surgery of ictal onset zones. However, a significant portion of DRE patients have unidentified or unresectable ictal zones. For these patients, RNS is a potential treatment option. The RNS system is a closed loop system that delivers stimulation in response to ECoG changes at seizure foci. It is programmed with an algorithm capable of detecting specific patterns of epileptogenic activity and triggers focal stimulation to interrupt seizures. The long term monitoring potential of the RNS system allows for a better understanding of the circadian rhythms behind epilepsy.

Practice trends and the outcome of neuromodulation therapies in epilepsy: A single-center study.

Neuromodulation therapies (VNS, RNS, and DBS) can improve seizure control in persons with epilepsy. However, there is a significant service gap in integrating these therapies in clinical care. Our epilepsy center has established an epilepsy neuromodulation clinic to improve access to patients, communication with referring physicians, track outcome and train future providers in programming neuromodulation devices. We report the (a) treatment outcome of the available neuromodulation therapies (ie, reduction in seizure frequency over 6-12 months follow-up); and (b) demonstrate the benefit of the specialized clinic (rapid titration, continuity of care, superior access for patient and vendors). In this single-center, retrospective study, forty-three adults (VNS = 27; RNS = 16) with drug-resistant epilepsy were followed in the clinic during the 19 months study period. About 44-69% of patients reported > 60% decrease in seizure. All patients were scheduled in the clinic within 2-4 weeks, and stimulations were optimized rapidly. About 40% of patients participated in research while 28% were referred for additional diagnostic studies. Nineteen students and fellows were trained in programming neurostimulator. Epilepsy neuromodulation clinic can serve as an optimal solution for patients as well as providers due to rapid access, better continuity of care, higher recruitment for research studies, and training health professionals.

Responsive Neurostimulation for the Treatment of Epilepsy.

There are a significant number of patients with epilepsy who are drug-resistant and for whom resective procedures are not an option. For these patients, neuromodulation may be an option, including closed-loop stimulation, such as responsive neurostimulation (RNS). The RNS System is a programmable and responsive device that consists of leads, a pulse generator, and an external programmer. An algorithm detects specific patterns of epileptogenic activity and triggers focal stimulation to interrupt a seizure. RNS is an effective and safe adjunctive therapy that in addition to seizure frequency reduction may have other applications, such as drug-response evaluation and long-term electrocorticography recording.

Using electrocorticogram baseline seizure frequency to assess the efficacy of responsive neurostimulation.

BACKGROUND: The effect of direct brain responsive neurostimulation on the frequency of electrographic seizures in patients with medically refractory focal epilepsy has not been evaluated by chronic ambulatory electrocorticographic monitoring. METHODS: This was a retrospective study of 9 patients who underwent implantation of the responsive neurostimulator (RNS) system from 2015 to 2017 at the University of California, Irvine. Leads were placed at the ictal onset zone as determined by intracranial electroencephalography (EEG). The neurostimulator was programmed to detect and deliver stimulation following identification of the individual's epileptiform patterns. Electrographic seizures were determined by review of all detections. The electrocorticography (ECoG) seizure frequency baseline was the average of the first 2 months postimplantation. The patient-reported seizure frequency baseline was the average of the 2 most recent months prior to RNS implantation. Seizure control was assessed at 3 months, 6 months, and 12 months. RESULTS: Nine patients were included in the study. All 9 patients have been treated with responsive stimulation for at least 3 months, 7/9 for 6 months, and 4/9 for 12 months. The mean change in seizure frequency was -10%, -19%, and -56% at 3, 6, and 12 months, respectively, using a self-reported seizure frequency baseline compared with -85%, -71%, and -56% at 3, 6, and 12 months, respectively, using the ECoG seizure frequency baseline. CONCLUSION: Chronic ECoG may provide a more accurate estimate of seizure frequency and provide additional insight into the true efficacy of the RNS system.

Clinical and electrocorticographic response to antiepileptic drugs in patients treated with responsive stimulation.

OBJECTIVE: The objective of this study was to explore whether chronic electrocorticographic (ECoG) data recorded by a responsive neurostimulation system could be used to assess clinical responses to antiepileptic drugs (AEDs). METHODS: Antiepileptic drugs initiated and maintained for ≥3 months by patients participating in clinical trials of the RNS® System were identified. Such "AED Starts" that produced an additional ≥50% reduction in patient-reported clinical seizure frequency were categorized as clinically beneficial, and the remaining as not beneficial. Electrocorticographic features recorded by the RNS® Neurostimulator were analyzed during three periods: 3 months before the AED Start, first month after the AED Start, and the first 3 months after the AED Start. RESULTS: The most commonly added medications were clobazam (n = 41), lacosamide (n = 96), levetiracetam (n = 31), and pregabalin (n = 25). Across all four medications, there were sufficient clinical data for 193 AED Starts to be included in the analyses, and 59 AED Starts were considered clinically beneficial. The proportion of AED Starts that qualified as clinically beneficial was higher for clobazam (53.7%) and levetiracetam (51.6%) than for lacosamide (18.8%) and pregabalin (12%). Across all AED Starts for which RNS ECoG detection settings were held constant, the clinically beneficial AED Starts were associated with a significantly greater reduction in the detection of epileptiform activity (p < 0.001) at 1 (n = 33) and 3 months (n = 30) compared with AED Starts that were not beneficial at 1 (n = 71) and 3 months (n = 60). Furthermore, there was a significant reduction in interictal spike rate and spectral power (1-125 Hz) associated with a clinically beneficial response to an AED Start at 1 (n = 32) and 3 months (n = 35) (p < 0.001). These reductions were not observed at either 1 (n = 59) or 3 months (n = 60) for AED Starts that were not clinically beneficial. CONCLUSIONS: Significant quantitative changes in ECoG data recorded by the RNS System were observed in patients who experienced an additional clinical response to a new AED. While there was variability across patients in the changes observed, the results suggest that quantitative ECoG data may provide useful information when assessing whether a patient may have a favorable clinical response to an AED.

Neurostimulation for Memory Enhancement in Epilepsy.

PURPOSE OF REVIEW: Memory is one of the top concerns of epilepsy patients, but there are no known treatments to directly alleviate the memory deficits associated with epilepsy. Neurostimulation may provide new therapeutic tools to enhance memory in epilepsy patients. Here, we critically review recent investigations of memory enhancement using transcranial electrical stimulation (tES), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), chronic intracranial stimulation, and acute intracranial stimulation. RECENT FINDINGS: Existing literature suggests that transcranial direct current stimulation (tDCS) produces a small enhancement in memory in neuropsychological patients, but transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) have not been found to have an effect on memory. Most studies of transcranial magnetic stimulation (TMS) have found that TMS has no positive effect on memory. Vagus nerve stimulation can acutely enhance memory, while chronic therapy does not appear to alter memory performance. We found that there is the most evidence for significant memory enhancement using intracranial stimulation techniques, especially chronic stimulation of the fornix and task-responsive stimulation of the lateral temporal lobe. Presently, there are no existing therapeutic options for directly treating epilepy-related memory deficits. While neurostimulation technologies for memory enhancement are largely still in the experimental phase, neurostimulation appears promising as a future technique for treating epilepsy-related memory deficits.

Changes in the electrocorticogram after implantation of intracranial electrodes in humans: The implant effect.

OBJECTIVE: Subacute and long-term electrocorticographic (ECoG) changes in ambulatory patients with depth and cortical strip electrodes were evaluated in order to determine the length of the implant effect. METHODS: ECoG records were assessed in patients with medically intractable epilepsy who had depth and/or strip leads implanted in order to be treated with brain-responsive stimulation. Changes in total spectral power, band-limited spectral power, and spike rate were assessed. RESULTS: 121 patients participating in trials of the RNS® System had a total of 93994 ECoG records analyzed. Significant changes in total spectral power occurred from the first to second months after implantation, involving 55% of all ECoG channels (68% of strip and 47% of depth lead channels). Significant, but less pronounced, changes continued over the 2nd to 5th post-implant months, after which total power became more stable. Similar patterns of changes were observed within frequency bands and spike rate. CONCLUSIONS: ECoG spectral power and spike rates are not stable in the first 5 months after implantation, presumably due to neurophysiological and electrode-tissue interface changes. SIGNIFICANCE: ECoG data collected in the first 5 months after implantation of intracranial electrodes may not be fully representative of chronic cortical electrophysiology.

Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography.

OBJECTIVE: Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video-electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. METHODS: Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. RESULTS: Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0-376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. SIGNIFICANCE: About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.

Quality of life and mood in patients with medically intractable epilepsy treated with targeted responsive neurostimulation.

PURPOSE: The primary efficacy and safety measures from a trial of responsive neurostimulation for focal epilepsy were previously published. In this report, the findings from the same study are presented for quality of life, which was a supportive analysis, and for mood, which was assessed as a secondary safety endpoint. METHODS: The study was a multicenter randomized controlled double-blinded trial of responsive neurostimulation in 191 patients with medically resistant focal epilepsy. During a 4-month postimplant blinded period, patients were randomized to receive responsive stimulation or sham stimulation, after which all patients received responsive neurostimulation in open label to complete 2years. Quality of life (QOL) and mood surveys were administered during the baseline period, at the end of the blinded period, and at year 1 and year 2 of the open label period. RESULTS: The treatment and sham groups did not differ at baseline. Compared with baseline, QOL improved in both groups at the end of the blinded period and also at 1year and 2years, when all patients were treated. At 2years, 44% of patients reported meaningful improvements in QOL, and 16% reported declines. There were no overall adverse changes in mood or in suicidality across the study. Findings were not related to changes in seizures and antiepileptic drugs, and patients with mesial temporal seizure onsets and those with neocortical seizure onsets both experienced improvements in QOL. CONCLUSIONS: Treatment with targeted responsive neurostimulation does not adversely affect QOL or mood and may be associated with improvements in QOL in patients, including those with seizures of either mesial temporal origin or neocortical origin.

Cardiac-based vagus nerve stimulation reduced seizure duration in a patient with refractory epilepsy.

PURPOSE: A novel vagus nerve stimulation (VNS) device was recently approved in Europe which rapidly detects increases in heart rates (HR) and applies an additional stimulus if HR-increases exceed a given threshold. The effects of HR-triggered VNS-pulses on seizures were not reported yet under controlled conditions. Here, we quantified the effects of HR-triggered VNS-pulses on the seizure duration in one patient. METHODS: The novel VNS device was implanted in a 29-year old man with refractory epilepsy. After implantation, the patient underwent video-EEG telemetry for 68h with no changes in anticonvulsant drugs. On the first day the patient only received sham-stimulation. During the following 46h HR-related VNS-stimulation was set to 2mA. Seizure duration was determined based on clinical signs. RESULTS: Twelve stereotypical seizures were recorded (six during sham- and six during the active stimulation). The VNS device recognised a total of 139 events as a seizure and correctly identified 11 seizures. The HR-triggered VNS-stimulation significantly reduced the total seizure duration from 33.2±4.8s to 26.5±5s and the remaining seizure duration after the onset of the extra-stimulation from 27.8±4.3s to 16.2±3.2s. With the given configuration in this patient, sensitivity and specificity of HR-based seizure-detection amounted to 92% and 13.5%, respectively. CONCLUSIONS: This case illustrates that VNS-stimulation in response to seizure-related HR-increases is able to significantly reduce seizure duration. Despite the limitations of our case, its promising results should prompt larger studies to confirm the clinical benefit of this novel device.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

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.