Thursday, April 19, 2018

External trigeminal nerve stimulation for drug-resistant epilepsy

Slaght SJ, Nashef L. An audit of external trigeminal nerve stimulation (eTNS) in epilepsy. Seizure. 2017 Nov;52:60-62.

External trigeminal nerve stimulation (eTNS) is a non-invasive neurostimulation treatment for drug refractory epilepsy. There is limited published data on the efficacy of eTNS and none relating to quality of life, mood or effect on sleep quality.

We audited its use in 42 patients with drug refractory epilepsy at a tertiary centre, between 02/04/2013 and 14/08/2015. Data was collected on seizure frequency, quality of life, mood and sleep quality before and after initiating treatment.

45% of patients continued to use eTNS at the end of the audit period. We observed a significant improvement in both quality of life and mood in those without intellectual disabilities. A decrease in seizures (-11.0%, min -60, max +65) was observed though this did not reach statistical significance with the relatively small numbers available for analysis.

Further controlled studies are required to confirm the efficacy of eTNS. However, as it is non-invasive, flexible and safe eTNS can be considered as an option in patients with drug refractory epilepsy.

Soss J, Heck C, Murray D, Markovic D, Oviedo S, Corrale-Leyva G, Gordon S, Kealey C, DeGiorgio C. A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy. Epilepsy Behav. 2015 Jan;42:44-7.

External 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.

This 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.

Thirty-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.

The results provide long-term evidence that external trigeminal nerve stimulation is a safe and promising long-term treatment for drug-resistant epilepsy.

DeGiorgio CM, Soss J, Cook IA, Markovic D, Gornbein J, Murray D, Oviedo S, Gordon S, Corralle-Leyva G, Kealey CP, Heck CN. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology. 2013 Feb 26;80(9):786-91.

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.

Boon P, De Cock E, Mertens A, Trinka E. Neurostimulation for drug-resistant epilepsy: a systematic review of clinical evidence for efficacy, safety, contraindications and predictors for response. Curr Opin Neurol. 2018 Apr;31(2):198-210.

Neurostimulation is becoming an increasingly accepted treatment alternative for patients with drug-resistant epilepsy (DRE) who are unsuitable surgery candidates. Standardized guidelines on when or how to use the various neurostimulation modalities are lacking. We conducted a systematic review on the currently available neurostimulation modalities primarily with regard to effectiveness and safety.

For vagus nerve stimulation (VNS), there is moderate-quality evidence for its effectiveness in adults with drug-resistant partial epilepsies. Moderate-to-low-quality evidence supports the efficacy and safety of deep brain stimulation (DBS) and responsive neurostimulation (RNS) in patients with DRE. There is moderate-to-very low-quality evidence that transcranial direct current stimulation (tDCS) is effective or well tolerated. For transcutaneous vagus nerve stimulation (tVNS), transcranial magnetic stimulation (TMS) and trigeminal nerve stimulation (TNS), there are insufficient data to support the efficacy of any of these modalities for DRE. These treatment modalities, nevertheless, appear well tolerated, with no severe adverse events reported.

Head-to-head comparison of treatment modalities such as VNS, DBS and RNS across different epileptic syndromes are required to decide which treatment modality is the most effective for a given patient scenario. Such studies are challenging and it is unlikely that data will be available in the near future. Additional data collection on potentially promising noninvasive neurostimulation modalities like tVNS, TMS, TNS and tDCS is warranted to get a more precise estimate of their therapeutic benefit and long-term safety.

Chan AY, Rolston JD, Rao VR, Chang EF. Effect of neurostimulation on cognition and mood in refractory epilepsy. Epilepsia Open. 2018 Feb 13;3(1):18-29.

Epilepsy is a common, debilitating neurological disorder characterized by recurrent seizures. Mood disorders and cognitive deficits are common comorbidities in epilepsy that, like seizures, profoundly influence quality of life and can be difficult to treat. For patients with refractory epilepsy who are not candidates for resection, neurostimulation, the electrical modulation of epileptogenic brain tissue, is an emerging treatment alternative. Several forms of neurostimulation are currently available, and therapy selection hinges on relative efficacy for seizure control and amelioration of neuropsychiatric comorbidities. Here, we review the current evidence for how invasive and noninvasive neurostimulation therapies affect mood and cognition in persons with epilepsy. Invasive therapies include vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). Noninvasive therapies include trigeminal nerve stimulation (TNS), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Overall, current evidence supports stable cognition and mood with all neurostimulation therapies, although there is some evidence that cognition and mood may improve with invasive forms of neurostimulation. More research is required to optimize the effects of neurostimulation for improvements in cognition and mood.

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