Nerve Stimulation For Drug-resistant Epilepsy Research Articles

Efficacy of vagus nerve stimulation for drug-resistant epilepsy after treatment for arteriovenous malformation: report of three cases

Efficacy of vagus nerve stimulation for drug-resistant epilepsy after treatment for arteriovenous malformation: report of three cases

Does response to vagus nerve stimulation for drug-resistant epilepsy differ in patients with and without Lennox-Gastaut syndrome?

Literature on outcomes of patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive vagus nerve stimulation (VNS) lacks information on seizure types and the time course of therapeutic effects. We have therefore performed what is to our knowledge the largest and most in-depth analysis of the effectiveness of VNS in LGS patients paying special attention to the impact of VNS Therapy on individual seizure types. The VNS Therapy Outcomes Registry includes over 7000 patients. A propensity score matching method was employed to match patients with LGS to non-LGS patients with drug-resistant epilepsy (DRE). Overall seizure frequencies were assessed prior to implantation and at 3-, 6-, 12-, 18-, and 24-month follow-ups to derive the main study outcomes: response rates and time to first response. A total of 564 LGS patients with sufficient data were identified in the registry and matched 2:1 to 1128 non-LGS patients. Responder rates at 24 months were 57.5% in the LGS group and 61.5% in the non-LGS group. Median seizure frequency reduction at 24 months was 64.3% versus 66.7% in the LGS versus non-LGS group, respectively. In both groups, VNS was most effective at reducing focal aware seizures, "other" seizures, generalized-onset non-motor seizures, and drop attacks with relative reduction rates for these seizure types at 24 months exceeding 90% in both groups. Time-to-first response did not differ between the groups; however, there was a significantly higher proportion of patients who regressed from bilateral tonic-clonic (BTC) seizure response in the LGS group versus the non-LGS group at 24 months: 22.4% versus 6.7%; p=.015. Although limited by its retrospective design, the study shows that the effectiveness of VNS is comparable in DRE patients with and without LGS; however, LGS patients may be more prone to fluctuating control of BTCs.

Efficacy of vagus nerve stimulation for drug-resistant epilepsy in a survivor of poor-grade subarachnoid hemorrhage: A case report

A man in his 60s had undergone clipping for a subarachnoid hemorrhage (SAH) due to a ruptured anterior communicating artery aneurysm in his 40s. He survived cerebral vasospasms following surgery for poor-grade SAH and required anti-seizure medications (ASMs) for post-stroke epilepsy. More than 20 years after the clipping, he developed focal impaired awareness seizure, which decreased his quality of life (QOL). Computed tomography (CT) showed an infarct in the left frontal lobe. 123I-iomazenil single-photon emission CT showed decreased benzodiazepine accumulation in the left frontal and medial temporal lobes. An interictal electroencephalogram showed epileptic discharges in the left temporal region. We diagnosed focal epilepsy and adjusted ASMs based on seizure control. However, the seizures were not controlled, and the adverse effects worsened with dosage increase. The condition was diagnosed as drug-resistant epilepsy, and the patient underwent vagus nerve stimulation. Postoperatively, we confirmed control of seizures and improvement of QOL.

Long-term outcome of vagus nerve stimulation for drug-resistant epilepsy using continuous assessment, with a note on mortality

PurposeTo examine the outcome of vagus nerve stimulation (VNS) for drug-resistant epilepsy using data from a National Health Service VNS clinic. MethodsClinical records of patients implanted with VNS for epilepsy between1995 and 2010 were examined. Patients were selected for study who had at least one year of therapeutic stimulation (minimum 1 mA stimulator current) and follow-up by our service with analysable electronic records, providing continuous assessment of seizure control during available follow-up. Seizure status at each attendance was assessed and graded 1–4 (1=seizure free or <5 seizures/year; 2 =≥50%reduction in seizure frequency; 3=<50% reduction; 4=no improvement compared to baseline). Responders were those whose grades improved consistently (Grades 1,2 and 3). ResultsOf 464 patients, 171 fulfilled the inclusion criteria and were divided into three groups: a) Responders (n = 81); b) non-responders (n = 80) and c) others (n = 10), the latter showing a late step-wise change (six improved; four deteriorated). After initial ramping up of current, groups were very stable over subsequent periods varying from one to 12 years (median 3.8 years). Sixteen patients died, 10 of non-epilepsy causes with 6 epilepsy-related deaths. There was a significant relation between epilepsy-related deaths and response (p < 0.00001). Patients with longer time as non-responders had more likelihood of suffering an epilepsy death than responders, though numbers were small. ConclusionThis study shows that meaningful data can be obtained retrospectively from routine clinic records. In this cohort about half of patients treated with VNS responded and the response generally remaining stable over time.

Vagus nerve stimulation for drug-resistant epilepsy induced by tuberous sclerosis complex

ObjectiveThis study investigated the dynamic and long-term efficacy of vagus nerve stimulation (VNS) in patients with drug-resistant epilepsy (DRE) induced by tuberous sclerosis complex (TSC). In addition, the impact of VNS on cognition and emotion after a one-year follow-up was evaluated. MethodsA total of 17 patients diagnosed with DRE induced by TSC were retrospectively recruited between 2008 and 2019. Dynamic changes in seizure frequency were observed in the responders (≥50% reduction of seizure frequency at last follow-up) and non-responders. Clinical characteristics and seizure outcomes were comprehensively analyzed to determine factors associated with seizure outcomes. The Wechsler intelligence scale was applied in a subgroup of six pediatric patients, whereas the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were assessed in a subgroup of nine patients to determine the impact of VNS therapy on cognitive performance and emotional state. ResultsThe follow-up duration for the 17 patients who underwent VNS treatment ranged from 0.5 to 10 years (mean ± SD: 4.1 ± 3.2 years). Monthly seizures decreased significantly from three months to four years post-treatment (p < 0.05). At the last follow-up, 70.6% of the patients achieved at least a 50% reduction in seizure frequency, and three patients were completely seizure free. Comparatively, non-responder patients experienced deterioration of seizure frequency after the first year. Notably, after one-year follow-up the mean standard score of full-scale intelligence quotient increased from 67.33 to 69.5 (p = 0.078) while the mean, standard score of SDS decreased from 49.22 to 45.67 (p = 0.003) compared to preoperative neuropsychological evaluation results. ConclusionVNS is a safe and effective treatment for patients with DRE caused by TSC. Although early outcomes were encouraging, a follow-up of at least one-year was required to predict long-term outcomes in patients receiving VNS treatment. Moreover, VNS may improve depressive mood in patients with DRE caused by TSC. Further investigations are needed to validate the present results.

Underutilization of advanced presurgical studies and high rates of vagus nerve stimulation for drug-resistant epilepsy: a single-center experience and recommendations.

Epilepsy surgery continues to be profoundly underutilized despite its safety and effectiveness. We sought to investigate factors that may contribute to this phenomenon, with a particular focus on the antecedent underutilization of appropriate preoperative studies. We reviewed patient data from a pediatric epilepsy clinic over an 18-month period. Patients with drug-resistant epilepsy (DRE) were categorized according to brain magnetic resonance imaging (MRI) findings (lesional, MRI-negative, or multifocal abnormalities) and type of epilepsy diagnosis based on semiology and electroencephalography (EEG) (focal or generalized). We then analyzed the rates of diagnostic test utilization, surgical referral, and subsequent epilepsy surgery as well as vagus nerve stimulation (VNS). Of the 249 patients with a diagnosis of epilepsy, 138 (55.4%) were found to have DRE. Excluding the 10 patients with DRE who did not undergo MRI, 76 patients (59.4%) were found to be MRI-negative (non-lesional epilepsy), 37 patients (28.9%) were found to have multifocal abnormalities, and 15 patients (11.7%) were found to have a single epileptogenic lesion on MRI (lesional epilepsy). Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) were each completed in nine patients (7.0%) and magnetoencephalography (MEG) in four patients (3.1%). Despite the low utilization rate of adjunctive studies, over half (56.3%) ultimately underwent VNS alone, and 8.6% ultimately underwent definitive intracranial resection or disconnection surgery. The underutilization of appropriate non-invasive, presurgical testing in patients with focal DRE may in part explain the continued underutilization of definitive, resective/disconnective surgery. For patients without access to a high-volume, multidisciplinary surgical epilepsy center, adjunctive presurgical studies [e.g., PET, SPECT, MEG, electrical source imaging (ESI), EEG-functional magnetic resonance imaging (fMRI)], even when available, are rarely ordered, and this may contribute to excessive rates of VNS in lieu of definitive intracranial surgery.

Efficacy of vagus nerve stimulation for drug-resistant epilepsy in children age six and younger

ObjectivesThe objective of the study were to examine the safety and efficacy of vagus nerve stimulation (VNS) for reducing seizure frequency and antiepileptic drugs (AEDs) in children younger than six years and to examine long-term VNS efficacy for children who receive the device at ages 1–3 and at ages 4–6. MethodsWe conducted a 10-year retrospective analysis of VNS implantations at UPMC Children's Hospital of Pittsburgh. Relevant data were collected within 12 months of VNS implantation and at six months, one, two, and four years after VNS implantation. ResultsThis analysis included 99 patients ages 0–3 (n = 40) and 4–6 (n = 59) at first VNS implantation. Eighty-six patients followed up for ≥4 years. There were no significant differences between age at VNS implant (0–3 vs. 4–6) and seizure etiology or most seizure semiologies. Patients took an average of 3.01 ± 1.29 AEDs prior to VNS and 3.84 ± 1.68 AEDs at their latest follow-up. The overall response to VNS therapy (≥50% seizure reduction) at one year, two years, and four years after VNS implantation was 55%, 60%, and 52%, respectively. At two years, 59% of 0- to 3-year-old patients responded to VNS and 52% of 4- to 6-year-old patients responded to VNS. The overall major complication rate was 5.6%, consistent with VNS use for older age groups. SignificanceThis study demonstrates the safety and efficacy of VNS for children with drug-resistant epilepsy (DRE) younger than six. One, two, and four years after VNS implantation, 55%, 60%, and 52% of these patients, respectively, achieved ≥50% reduction in seizure frequency. The safety of VNS is also comparable with older, better studied, age groups. Based on these data, VNS therapy should be considered for children younger than six.

Chronic vagus nerve stimulation for drug-resistant epilepsy may influence fasting blood glucose concentration

BackgroundCervical vagus nerve stimulation (VNS) has been widely accepted as adjunctive therapy for drug-resistant epilepsy and major depression. Its effects on glycemic control in humans were however poorly understood. The aim of our study was to investigate the potential effects of VNS on fasting blood glucose (FBG) in patients with drug-resistant epilepsy.MethodsPatients with drug-resistant epilepsy who had received VNS implants at the same hospital were retrospectively studied. Effects on FBG, weight, body mass index and blood pressure were evaluated at 4, 8 and 12 months of follow-up.Results32 subjects (11 females/21 males, 19 ± 9 years, body mass index 22.2 ± 4.0 kg/m2) completed 12-month follow-up. At the 4 months, there were no significant changes in FBG concentrations from baseline to follow-up in both Sham-VNS (4.89 ± 0.54 vs. 4.56 ± 0.54 mmol/L, N = 13, p = 0.101) and VNS (4.80 ± 0.54 vs. 4.50 ± 0.56 mmol/L, N = 19, p = 0.117) groups. However, after 8 (4.90 ± 0.42 mmol/L, N = 32, p = 0.001) and 12 (4.86 ± 0.40 mmol/L, N = 32, p = 0.002) months of VNS, FBG levels significantly increased compared to baseline values (4.52 ± 0.54 mmol/L, N = 32). Changes in FBG concentrations at both 8 (R2 = 0.502, N = 32, p < 0.001) and 12 (R2 = 0.572, N = 32, p < 0.001) months were negatively correlated with baseline FBG levels.ConclusionsOur study suggests that chronic cervical VNS elevates FBG levels with commonly used stimulation parameters in patients with epilepsy.Trial registration VNSRE, NCT02378792. Registered 4 March 2015—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02378792

LB15. Vagus nerve stimulation for drug-resistant epilepsy

LB15. Vagus nerve stimulation for drug-resistant epilepsy

Does emergent implantation of a vagal nerve stimulator stop refractory status epilepticus in children?

PurposeStatus Epilepticus can be a serious life threatening event in epileptic patients. The definition of refractory or super-refractory Status Epilepticus was based on the therapeutic response to anti-epileptic and anesthetic drugs. Vagal Nerve Stimulation showed efficacy in treating drug-resistant epilepsy but there are only few reports on emergentplacement of Vagal Nerve Stimulator for refractory or super-refractory Status Epilepticus. MethodsAmong 49 children implanted at our Institution with Vagal Nerve Stimulation for drug-resistant epilepsy, the authors retrospectively identified those implanted for refractory or super-refractory Status Epilepticus, according with the current definitions. Results4 patients were operated upon at ages ranging 7 to 17 months and reached the programmed output current of 1 mA over a time ranging from 24 to 36 h (fast ramping-up).In 3 out of 4 patient we observed the abrupt of Status Epilepticus; one patient was refractory both to drugs and Vagal Nerve Stimulation and later died, without recovering from SE. At follow up, ranging from 24 to 45 months, the remaining 3 patients showed a decrease of the seizures frequency >80% without relapse of Status Epilepticus; in all the patients, output current and/or Duty Cycle were increased later. ConclusionVNS can be effective in treating refractory or super-refractory Status Epilepticus.

Vagal nerve stimulation for drug-resistant epilepsy: Efficacy and adverse events in an epilepsy centre with long-term follow-up

Vagal nerve stimulation for drug-resistant epilepsy: Efficacy and adverse events in an epilepsy centre with long-term follow-up

Outcome of vagus nerve stimulation for drug-resistant epilepsy: the first three years of a prospective Japanese registry.

Vagus nerve stimulation (VNS) is an established option of adjunctive treatment for patients with drug-resistant epilepsy, however, evidence for long-term efficacy is still limited. Studies on clinical outcomes of VNS in Asia are also limited. We report the overall outcome of a national, prospective registry that included all patients implanted in Japan. The registry included patients of all ages with all seizure types who underwent VNS implantation for drug-resistant epilepsy in the first three years after approval of VNS in 2010. The registry excluded patients who were expected to benefit from resective surgery. Efficacy analysis was assessed based on the change in frequency of all seizure types and the rate of responders. Changes in cognitive, behavioural and social status, quality of life (QOL), antiepileptic drug (AED) use, and overall AED burden were analysed as other efficacy indices. A total of 385 patients were initially registered. Efficacy analyses included data from 362 patients. Age range at the time of VNS implantation was 12 months to 72 years; 21.5% of patients were under 12 years of age and 49.7% had prior epilepsy surgery. Follow-up rate was >90%, even at 36 months. Seizure control improved over time with median seizure reduction of 25.0%, 40.9%, 53.3%, 60.0%, and 66.2%, and responder rates of 38.9%, 46.8%, 55.8%, 57.7%, and 58.8% at three, six, 12, 24, and 36 months of VNS therapy, respectively. There were no substantial changes in other indices throughout the three years of the study, except for self/family-accessed QOL which improved over time. No new safety issues were identified. Although this was not a controlled comparative study, this prospective national registry of Japanese patients with drug-resistant epilepsy, with >90% follow-up rate, indicates long-term efficacy of VNS therapy which increased over time, over a period of up to three years. The limits of such trials, in terms of AED modifications and during follow-up and difficulties in seizure counting are also discussed.

Efficacy of Vagal Nerve Stimulation for Drug-Resistant Epilepsy: Is it the Stimulation or Medication?

Vagus nerve stimulation (VNS) therapy has been widely recognized as an alternative for the treatment of drug-resistant epilepsy, although modification of antiepileptic drugs (AEDs) during VNS treatment could explain the improvement in patients. We retrospectively assessed the efficacy of VNS in 30 adult patients with epilepsy treated with >6 months of follow-up. The criteria for implantation were the following: (1) not a candidate for resective epilepsy surgery, (2) drug-resistant epilepsy, (3) impairment of quality of life, (4) no other option of treatment, and (5) patients with idiopathic generalized epilepsy who fail to be controlled with appropriate AEDs. We assessed sociodemographics, seizure etiology, seizure classification, and AEDs used during treatment with VNS. We assessed adverse effects and efficacy. Responder rate was defined as >50% seizure improvement from baseline. Thirty patients (females, 18; males, 12; age, 35.1±13.3 years) were included. After 6, 12, 24, and 36 months of follow-up, the response rates were: 13/30 (43%), 13/27 (48%), 9/22 (41%), and 8/16 (50%), respectively; none was seizure free. Fifty-seven percent, 33%, 59%, and 81% of patients had changes of medication type or dose at 6, 12, 24, and 36 months respectively. In the majority of patients, the change of medication consisted of an increase in the dose of AEDs. Our study shows that VNS is an effective therapy, although significant changes in medications were done along with the therapy; therefore, the real effect of VNS could be controversial.

Vagal Nerve Stimulation for Drug-Resistant Epilepsy: Adverse Events and Outcome in a Series of Patients with Long-Term Follow-Up.

Vagal nerve stimulation (VNS) is a palliative treatment option for drug-resistant epilepsy. The aim of this study was to describe the clinical and demographic features of selected patients scheduled for VNS and to evaluate the long-term efficacy of VNS in seizure control. Between 2006 and 2013, 32 consecutive epileptic patients (14 male and 18 female) were enrolled at our Institute for VNS implantation. In all cases resective surgery had previously been excluded by the use of a noninvasive presurgical study protocol. Mean age was 32 years (range 18-50), and mean epilepsy duration 23 years (range 11-39). All subjects were followed-up for at least 2 years (mean 6 years, range 2-9) after VNS implantation. Patients were considered responders when a reduction of seizures of more than 50 % was reported. All patients had complex partial seizures, in 81 % of the patients with secondary generalization and in 56 % with drop attacks. Neurological examination revealed focal deficits in 19 % of the patients. Brain magnetic resonance imaging (MRI) was positive in 47 % of the patients. No surgical complications were observed in this series. Three patients were lost to follow-up. Twelve patients were classified as responders. Among the others, 1 patient experienced side effects (snoring and groaning during sleep) and the device was removed. Our data confirm that VNS is a safe procedure and a valid palliative treatment option for drug-resistant epileptic patients not suitable for resective surgery.

Adverse Effects and Surgical Complications in Pediatric Patients Undergoing Vagal Nerve Stimulation for Drug-Resistant Epilepsy.

Vagal nerve stimulation (VNS) is an effective treatment for drug-resistant epilepsy that is not suitable for resective surgery, both in adults and in children. Few reports describe the adverse effects and complications of VNS. The aim of our study was to present a series of 33 pediatric patients who underwent VNS for drug-resistant epilepsy and to discuss the adverse effects and complications through a review of the literature.The adverse effects of VNS are usually transient and are dependent on stimulation of the vagus and its efferent fibers; surgical complications of the procedure may be challenging and patients sometimes require further surgery; generally these complications affect VNS efficacy; in addition, hardware complications also have to be taken into account.In our experience and according to the literature, adverse effects and surgical and hardware complications are uncommon and can usually be managed definitely. Careful selection of patients, particularly from a respiratory and cardiac point of view, has to be done before surgery to limit the incidence of some adverse effects.

A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy

BackgroundExternal trigeminal nerve stimulation (eTNS) is an emerging noninvasive therapy for drug-resistant epilepsy (DRE). We report the long-term safety and efficacy of eTNS after completion of a phase II randomized controlled clinical trial for drug-resistant epilepsy. MethodsThis was a prospective open-label long-term study. Subjects who completed the phase II randomized controlled trial of eTNS for DRE were offered long-term follow-up for 1year. Subjects who were originally randomized to control settings were crossed over to effective device parameters (30s on, 30s off, pulse duration of 250s, frequency of 120Hz). Efficacy was assessed using last observation carried forward or parametric imputation methods for missing data points. Outcomes included change in median seizure frequency, RRATIO, and 50% responder rate. ResultsThirty-five of 50 subjects from the acute double-blind randomized controlled study continued in the long-term study. External trigeminal nerve stimulation was well tolerated. No serious device-related adverse events occurred through 12months of long-term treatment. At six and twelve months, the median seizure frequency for the original treatment group decreased by -2.39 seizures per month at 6 months (-27.4%) and -3.03 seizures per month at 12 months (-34.8%), respectively, from the initial baseline (p<0.05, signed-rank test). The 50% responder rates at three, six, and twelve months were 36.8% for the treatment group and 30.6% for all subjects. ConclusionThe results provide long-term evidence that external trigeminal nerve stimulation is a safe and promising long-term treatment for drug-resistant epilepsy.

Complications of vagal nerve stimulation for drug-resistant epilepsy: A single center longitudinal study of 143 patients

PurposeTo longitudinally study surgical and hardware complications to vagal nerve stimulation (VNS) treatment in patients with drug-resistant epilepsy. MethodsIn a longitudinal retrospective study, we analyzed surgical and hardware complications in 143 patients (81 men and 62 women) who between 1994 and 2010 underwent implantation of a VNS-device for drug-resistant epilepsy. The mean follow-up time was 62±46 months and the total number of patient years 738. Results251 procedures were performed on 143 patients. 16.8% of the patients were afflicted by complications related to surgery and 16.8% suffered from hardware malfunctions. Surgical complications were: superficial infection in 3.5%, deep infection needing explantation in 3.5%, vocal cord palsy in 5.6%, which persisted in at least 0.7% for over one year, and other complications in 5.6%. Hardware-related complications were: lead fracture in 11.9% of patients, disconnection in 2.8%, spontaneous turn-off in 1.4% and stimulator malfunction in 1.4%. We noted a tendency to different survival times between the two most commonly used lead models as well as a tendency to increased infection rate with increasing number of stimulator replacements. ConclusionIn this series we report on surgical and hardware complications from our 16 years of experience with VNS treatment. Infection following insertion of the VNS device and vocal cord palsy due to damage to the vagus nerve are the most serious complications related to the surgery. Avoiding unnecessary reoperations in order to reduce the appearances of these complications are of great importance. It is therefore essential to minimize technical malfunctions that will lead to additional surgery. Further studies are needed to evaluate the possible superiority of the modified leads.

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

In the article “Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy” ( Neurology ® 2013;80:786–791) by DeGiorgio et al., two corrections are needed. The first is in the …

Trigeminal nerve stimulator

In their article “Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy” (Neurology 2013;80:786–791), Dr. DeGiorgio and colleagues studied the safety and effectiveness of a new kind of treatment for seizures. They used a new device called a trigeminal nerve stimulator (TNS). The device is electronic, and sends small electrical impulses through the skin, using small “stick-on” electrodes. These impulses go to a nerve in the face called the trigeminal nerve. The impulses are then transmitted back to deep parts of the brain where they help to decrease seizures.

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59-0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.