ARTICLE IN BRIEF
Investigators reported improvements in seizure reduction and mood in the first randomized, controlled trial of external trigeminal nerve stimulation in drug-resistant epilepsy.
For the 30 percent of epilepsy patients with drug-resistant epilepsy who are not candidates for epilepsy surgery, the treatment approaches are relatively limited. But a new study published in the Jan. 30 online issue of Neurology presents evidence for a nonsurgical method for seizure management — external trigeminal nerve stimulation (eTNS) — in intractable epilepsy patients.
Trigeminal nerve stimulation (TNS) involves “a small external pulse generator that the patient can wear on a belt or in their purse, and a wire that connects to an electric patch worn above the eyebrows, which stimulates branches of the trigeminal nerve,” lead study author Christopher M. DeGiorgio, MD, professor of neurology at the University of California, Los Angeles, and vice president of NeuroSigma, which is developing trigeminal nerve stimulation and other neuromodulation systems, told Neurology Today.
Located just beneath the skin covering the eyebrows, the trigeminal nerve is the largest cranial nerve and provides sensation to the face and head. TNS targets areas in the brain, which are known to play a role in seizures, mood, and attention, Dr. DeGiorgio explained.
DR. CHRISTOPHER M. D...Image Tools
This study, Dr. DeGiorgio said, “is the first randomized, controlled trial of external trigeminal nerve stimulation in drug-resistant epilepsy. It is also, to my knowledge, the only device study to demonstrate improvements in both seizures and mood within the same trial.”
This double-blind, randomized, active-control trial enrolled 50 people who had failed, on average, more than three antiepileptic drugs and experienced two or more partial onset seizures per month; 42 completed the study. Participants were randomized to the stimulation treatment at high intensity or active control stimulation at low intensity parameters. Eight percent of the 25 randomized to treatment dropped out; 24 percent of the 25 in the active control group dropped out. Subjects were evaluated at 6, 12, and 18 weeks.
Out of the three pre-defined endpoints: change in seizure frequency, responder rate, and time to fourth seizure; only responder rate — the percentage exhibiting 50 percent or greater reduction in seizures from baseline — was significant. Responder rate for the treatment group increased to 40.5 percent at 18 weeks (p = 0.0136).
The side effects were mild and the therapy was well-tolerated. The most common side effects were anxiety (4 percent), headache (4 percent) and skin irritation (14 percent). There were no serious device-related adverse events and no deaths occurred at any time during the 18-week acute trial period.
Mood was an important secondary outcome of the study. The investigators used the Beck Depression Inventory (BDI) — a 21-item questionnaire that captures a self-reported sense of sadness, pessimism, fatigue, among other symptoms — as the primary measure to assess mood. BDI was measured at baseline, and at each treatment visit. At study entry, the average BDI score for the treatment group was in the moderately depressed range (16.7); however, by the end of the treatment period, the mood score had improved more than 50 percent — significantly better than the control group.
Joseph I. Sirven, MD, professor of neurology at the Mayo Clinic in Scottsdale, AZ, said that this study was important because “it represents another evolution in the neuromodulation or stimulation approach to epilepsy.” Although the size of the study is small, he said, “what is fascinating and important is that a noninvasive external device targeting the trigeminal nerve was able to reduce seizure frequency in a group of patients with epilepsy.”
This is important, he continued, “because all other stimulation paradigms involve devices that must be surgically implanted. This device is external which, in essence, changes the rules of the game; the apparent lack of risk from not being invasive makes this option much more appealing and a potential alternative to medications over the long term.” Moreover, he said, the patients showed improved mood and other benefits.
In an accompanying editorial also published in Neurology, William Tatum, MD, and Edward Faught, MD, wrote that “better descriptions of patient experiences are needed. Some patients may find adherence to use of the device for 12 hours per day onerous. Application only during sleep would be a pragmatic and desirable goal of TNS.”
Gregory Krauss, MD, professor of neurology at Johns Hopkins University, said that the results, though preliminary, were interesting and promising. He added that it is difficult to find an adequate control group with stimulation treatment and particularly to a sensory nerve.
There have been other studies, he said, where sensory stimuli can sometimes reduce seizures. The mechanism for this type of treatment is not entirely understood, he said. “There's probably some type of operant conditioning going on, and TNS may be a method for providing conditioning to reduce seizures that's less invasive than VNS [vagus nerve stimulation].”
He continued: “One question with these types of stimulation treatments, though, is whether they are going to be palliative, modulatory treatments that reduce seizure severity and frequency slightly? Or will there be some patients who have marked improvement?”
The other question, Dr. Krauss said, if the stimulation of the trigeminal nerve is done overnight, and much of the day the patient is not wearing the stimulation device, how long will the treatment effect carry over?
Stimulation effects are often delayed, as shown in many of the studies of VNS, thalamic stimulation, he added; so, the possibility of delayed effect should be incorporated into the next study design. Dr. DeGiorgio also noted that the progressive improvement from visit to visit over the 18-week study is common with device trials for epilepsy, and said that there is often an “induction effect” with neuromodulation, which has been seen in virtually every device study for epilepsy published to date.
“They need a larger trial with as cautious a control as possible,” Dr. Krauss said. “They may have to do some kind of ranging of stimuli to validate the effect, and it would be important to incorporate the possibility that there will be delayed effects of stimulation into the larger phase 3 study.”
The results of this study, Dr. DeGiorgio said, will serve as a basis to inform and power a larger multicenter, phase 3 study. He said that they are looking at external TNS for potential use in post-traumatic stress disorder and attention deficit disorder. They are also working on an implantable version of TNS. “We envision TNS as two complementary therapies — an external form and an implantable form — we think many patients will like the external version of this because it's non-invasive, but some patients may elect to have a permanent implantable version that would just go under the eyebrows.”
Currently, the FDA has only approved one device-related therapy for epilepsy: VNS in 1997; however, VNS requires a surgical procedure. The key advantages to TNS are that it can be “delivered non-invasively, bilaterally and at high frequencies, with positive effects on mood,” Dr. DeGiorgio said.
In the European Union, eTNS has recently been approved as an adjunctive therapy for epilepsy in adults and children ages 9 and above, he said.
TUNE IN, LISTEN UP: Christopher M. DeGiorgio, MD, professor of neurology at the University of California-Los Angeles, and vice president of NeuroSigma, discusses the benefits of external trigeminal nerve stimulation, and how it could affect epilepsy treatment for patients with drug-resistant epilepsy: http://bit.ly/rCBryX.
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