External stimulation of the trigeminal nerve by wearing a gel electrode on the forehead for 12 hours a day was associated with a reduction in seizures and an improvement in depression in patients with drug resistant epilepsy in a new phase 2 study.
The study, the first randomized, active controlled trial of external trigeminal nerve stimulation in drug-resistant partial seizures, was published in the February 26 issue of Neurology.
The authors, led by Christopher M. DeGiorgio, MD, vice president of neurology at NeuroSigma, makers of the stimulator, and professor of neurology at the University of California, Los Angeles, conclude that the treatment was safe and well tolerated and resulted in within-group improvement in responder rate. Mood was also significantly improved.
They say the results justify a phase 3 multicenter trial of the technology for drug-resistant partial seizures.
"Very Exciting Area"
Commenting on the results for Medscape Medical News, Gregory Bergey, MD, from Johns Hopkins Epilepsy Center, Baltimore, Maryland, who was not involved in the study but has been involved in trials of an alternative implanted neurostimulator device, called this "very nice information."
"It definitely warrants going forward to phase 3," he said. "While some people may express disappointment that more of the endpoints were not significant, the 40% within-group responder rate shown at 18 weeks with the neurostimulation is very promising and within the same range as seen in trials of new drugs."
Dr. Bergey added that a longer blinded treatment period may be advisable for the larger study. "What seems to be becoming clear in all the neurostimulation studies is that the effect tends to increase over time. So we may need more than 18 weeks to see the full benefits."
He believes the whole idea of modulated brain activity by stimulating cutaneous nerves is a very exciting area.
"This is a different approach to drug therapy and therefore the effects may be additive. And many people may prefer a nondrug approach. The side effects are likely to be much less of an issue, and it would not likely be teratogenic, which is a problem with many of the epileptic drugs."
Vagal nerve stimulation with implanted electrodes has been available for some time, but several different neurostimulation approaches are now in development. This one, however, is the first to allow the electrode to be worn externally, which has the major advantage of preventing the need for an operation and general anesthetic, the authors note.
The device is already available in Europe, but a phase 3 trial is required for US approval.
In this study, patients had to wear the gel electrode for a minimum of 12 hours a day. Dr. Bergey said that this may not be that much of an inconvenience because it can be worn at night when patients are asleep and during the evening when they are at home.
"If it reduces seizures and people feel it is working then they will use it. Patients are attracted to alternatives to drug therapy. We don't know the optimum period of stimulation needed," he said. "They probably chose 12 hours as it was practical to wear at home for this amount of time. Yes, 8 hours would be more convenient, but we don't know if that would be sufficient. These things need more study."
For the current study, 50 patients with 2 or more partial-onset seizures per month (complex partial or tonic-clonic) underwent a 6-week baseline assessment period. They were then randomly assigned to neurostimulation at 120 Hz (30 seconds on after 30 seconds off) or an active control (2-Hz stimulation for 2 seconds followed by 90 seconds without stimulation, with a lower pulse duration). They were evaluated at 6, 12, and 18 weeks during the acute treatment period.
Randomization resulted in uneven groups, with the treatment group averaging 8.7 seizures per month at baseline compared with 4.8 seizures per month for the controls. An average of 3.35 antiepileptic drugs had failed in patients before enrollment, and the average duration of epilepsy was more than 20 years.
Two of 25 patients in the treatment group and 6 of 25 in the control group dropped out, leaving 42 patients who completed the study.
Results showed that the treatment was well tolerated, with adverse effects including anxiety (4%), headache (4%), and skin irritation (14%).
In terms of efficacy, trigeminal nerve stimulation was associated with a responder rate of 40.5% for the treatment group at 18 weeks. But the between-groups comparisons and other primary outcomes did not achieve significance.
Mood, which was a secondary outcome, showed a significant improvement on the Beck Depression Inventory. The authors write, "Since depression is a major comorbidity in persons with seizure disorders, and a major component of health-related quality of life in epilepsy, the ability of [trigeminal nerve stimulation] to positively impact mood in this population is an important discovery."
Table. Trigeminal Nerve Stimulation: Major Results
|Median change in number of seizures per month||-1.4||-0.5||P within group, .10; between groups, .51|
|50% responder rate at 18 weeks (%)||40.5||15.6||P within group, .0136; between groups, .078|
|50% responder rate, entire treatment period (%)||30.2||21.1||P between groups, .31; odds ratio, 1.73|
|Time to fourth seizure at baseline (d)||12.5||23|
|Time to fourth seizure with treatment (d)||15.0||18|
|Seizure frequency, response ratio||-13.9||-9.0||P within group, .04; between groups, .06|
|Change in Beck Depression Inventory score||-8.13||-3.95||P within and between groups, 0.02; odds ratio for remission, 5.5 (P = .002)|
Effect "Modest but Sufficient"
In an accompanying editorial, Edward Faught, MD, Emory University, Atlanta, Georgia, and William Tatum, MD, Mayo Clinic, Jacksonville, Florida, explain that it has been known for some time that stimulation of the ascending reticular activating system can have a desynchronizing effect on cortical rhythms.
This system receives collateral input from all sensory systems, leading to the idea of treating seizures by providing additional sensory input, and it has been reported that seizures can be stopped by patients pinching themselves, thinking certain thoughts; using auditory stimuli, or using "trigeminal stimulation" by applying supraorbital pressure.
They say the results of the current study provide Class II evidence that trigeminal nerve stimulation may be effective, but a robust effect was not apparent.
"Although we do not know the best electrical pathway to the brain for seizure control, the trigeminal nerve, as the largest cranial nerve, is a sort of superhighway," they conclude. "It has broad connections bilaterally, can be stimulated easily, and so is a contender. The beneficial effect demonstrated by DeGiorgio et al. was modest but is sufficient to encourage design of a more definitive study."
The study was supported by grants from the Epilepsy Therapy Project, the Epilepsy Foundation of America, the Michael Milken Family Foundation, and Boston Scientific. Dr. DeGiorgio is the inventor on patents related to trigeminal nerve stimulation and has an equity interest in NeuroSigma, which is the licensee on patents related to the technology. Coauthor Dr. Ian Cook is a consultant to Neuro-Sigma and inventor of patents licensed to NeuroSigma. Dr. Faught serves on data safety monitoring boards for Eisai, Lundbeck, and SK Life Sciences and on scientific advisory boards for Supernus, Sunovion, UCB Pharma, SK Life Sciences, and Zogenix; he receives research support from GlaxoSmithKline and Cyberonics. Dr Tatumhas disclosed reports no relevant financial relationships. Dr. Bergey has been involved in the trials of the NeuroPace's responsive neurostimulator but does not receive any compensation from the company.
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Cite this: Trigeminal Nerve Stimulation Reduces Seizures - Medscape - Mar 01, 2013.