Pilot study of trigeminal nerve stimulation (tns) for epilepsy: a proof-of-concept trial

Epilepsia, 47(7):1213–1215, 2006
Blackwell Publishing, Inc.
C 2006 International League Against Epilepsy Pilot Study of Trigeminal Nerve Stimulation (TNS) for Epilepsy: ∗Christopher M. DeGiorgio, ∗†Alan Shewmon, ‡Diane Murray, and §Todd Whitehurst ∗UCLA Departments of Neurology and †Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles; ‡Olive View/UCLA Medical Center, Sylmar; and §Advanced Bionics, Valencia, California, U.S.A. Summary: The safety and preliminary efficacy of trigeminal
experienced a ≥50% reduction in seizure frequency. The results nerve stimulation (TNS) for epilepsy was evaluated in a pilot fea- of this pilot study support further investigation into the safety and sibility study of transcutaneous stimulation of the infraorbital and efficacy of TNS for epilepsy. Key Words: Trigeminal nerve
supraorbital branches of the trigeminal nerve. TNS was well tol- stimulation—Epilepsy—Neurostimulation.
erated. Four (57%) of seven subjects who completed ≥3 months Thirty to forty percent of adults with epilepsy are refrac- tory to antiepileptic drug (AED) treatment (1). For those Research committee approval was obtained for a pi- for whom AEDs fail, epilepsy surgery is extremely effec- lot study of TNS. Inclusion and exclusion criteria were tive. Unfortunately, many patients are not ideal surgical ages 18–65 years; three or more complex partial or gen- candidates or have limited access to specialized epilepsy eralized tonic–clonic seizures per month; no significant centers. For such patients, neurostimulation is a promising cardiac or medical conditions; the ability to maintain ac- adjunct to AEDs (2). Trigeminal nerve stimulation (TNS), curate seizure calendars; no history of trigeminal neuralgia via cutaneous branches in the face, offers the opportunity or facial pain; no implantation of a vagus nerve stimulator; of a minimally invasive method of neurostimulation. Re- and exposure to at least two AEDs, in appropriate doses, sponse can be assessed before surgical implantation with including at least one trial of levetiracetam, topiramate, or self-adhesive cutaneous electrodes (3,4).
In their seminal report, Fanselow et al. (3) found Stimulation was supplied using an Food and Drug that TNS significantly reduced pentylenetetrazol-induced seizures in rats. Seizure severity and duration were re- 120 Hz, 250 μs, ≤30 s on and 30 s off (EMS 400 duced in a frequency-dependent fashion at frequencies> Wisdomking.com, Oceanside, CA, U.S.A.). The stimula- 100 Hz (3). Bilateral stimulation was more effective than tor delivers an asymmetrical biphasic square wave pulse unilateral stimulation, and stimulation was well tolerated adjustable from 0 to 100 mAs. The 1.25-inch disposable, hypoallergenic, silver-gel, self-adhesive, stimulating elec- Recently, we reported the first two humans to be treated trodes were used (Superior Silver-Permagel Electrodes, with TNS for epilepsy (4). We now present the results of Tyco Healthcare/Uni-Patch, Wabasha, MN, U.S.A.).
a pilot feasibility study of TNS in seven subjects with in- Power was supplied by 9-volt lithium medical-grade tractable epilepsy who completed at least the first-month batteries (Eveready Energizer L522, Energizer, St. Louis, treatment visit, including the two subjects reported previ- MO, U.S.A.). Subjects replaced the battery every other Initially, infraorbital stimulation was used, (subjects 1– 3), with right-sided stimulation alternating every other daywith left-sided stimulation. The 1.25-inch hypoallergenic silver gel discs were applied over the face, with the positive Address correspondence and reprint requests to Dr. C.M. DeGior- electrode placed over the infraorbital foramen, and the gio at 710 Westwood Plaza, Los Angeles, CA 90095, U.S.A. E-mail:[email protected] negative electrode placed 1 to 1 inch posterolateral, in line with the nasolabial fold. Supraorbital stimulation allowed On the first day of stimulation, the tolerability of acute TNS was assessed. Output current was gradually increasedto identify the threshold for perception and pain. In the firstthree subjects, unilateral infraorbital stimulation was initi-ated. All subsequent subjects underwent bilateral supraor-bital stimulation (supraorbital was preferred because elec-trodes could be concealed, and stimulation could be de-livered bilaterally by using two electrodes).
Each subject’s response to initial stimulation was as- sessed after a 1-month prospective baseline period. Onthe first day of stimulation, the output current was gradu-ally increased, and the subject’s perception was assessedon a 0–10 intensity scale. At first perception of sensa-tion, patients reported a mild tingling in the canine teeth(infraorbital stimulation) or the scalp (supraorbital stim-ulation). As current was increased, patients consistentlyreported progressively increased tingling. At device set-tings >4 (output currents generally >20 mA), stimulationbecame progressively uncomfortable, and the current wasreduced. Subjects indicated that stimulation between out-put settings of 2 and 4 (<20 mA) were comfortable. Thesesettings were chosen for stimulation. Tolerance to stimula-tion generally tended to improve with time. Patients wereable to carry out their normal activities of living with- FIG. 1. A: Schematic of electrode placement for infraorbital and
out discomfort and minimal awareness of stimulation. No supraorbital electrodes. The positive electrodes are situated di- subject discontinued treatment because of discomfort.
rectly over the palpable supraorbital and infraorbital foramen. B:
Drawing showing a subject with the electrodes placed over the
On the first day of stimulation, heart rate and systolic supraorbital foramen for stimulation of the first division of the and diastolic blood pressure were monitored every 5 min trigeminal nerve (supraorbital nerve). Subjects preferred supraor- for 1 h. No blood pressure, pulse, or ECG changes were bital nerve stimulation, because the stimulating electrodes couldbe covered by a cap or hat. Bilateral stimulation was achieved by detected during stimulation. After 24 h of stimulation, placement of one electrode over each foramen.
blood pressure and heart rate were again monitored every5 min for 60 min during stimulation, and again, no acuteeffects on vital signs were identified.
bilateral simultaneous stimulation with the use of only two Throughout the study, TNS was well tolerated, and sub- jects reported that the hypoallergenic adhesive electrodes After informed consent, subjects meeting all inclu- were easy to apply and maintain. Tingling or pressure in sion criteria were enrolled. During a 4-week prospective the forehead or canine teeth was reported, but these were pretreatment baseline, subjects kept a diary of all seizures minimized by a reduction in current. Overall, patients pre- and quantified the date and character of each seizure.
ferred supraorbital stimulation to infraorbital stimulation, Diaries were verified, and all complex-partial or general- as they could wear a cap or hat to cover the electrodes.
ized tonic–clonic seizures were counted and validated by Six subjects used the stimulator 24 h/day; subject 7, the study physician. An average daily seizure frequency because her seizures only occurred at night or in the early for the sum of all complex partial or generalized tonic– morning, elected to undergo stimulation at night for a total clonic seizures was calculated at each study visit. At no time during baseline or the 3-month or 6-month treatment Table 1 summarizes average daily seizure frequencies period were AED changes allowed: changes in AEDs re- during baseline and the treatment period for the seven sub- jects who completed at least the 1-month treatment follow-up visit. Overall, the average change in seizure frequency was –43.7% at the last treatment visit. Four (57%) of seven Ten subjects have been enrolled in this ongoing pilot responded with a ≥50% reduction in seizure frequency at study; data are complete on seven subjects. One exited 3 months, and four of five who completed 6 months had after 2 weeks because of poor compliance and the need to a >50% reduction in seizure frequency. Because of the adjust his AEDs. Two subjects have not yet completed the small sample size, these differences were not significant TABLE 1. Summary of results in the seven subjects who completed at least the 1-month follow-up visit
Percentage reduction in seizure frequency is at the last completed visit (3 or 6 months).
DISCUSSION
unifying hypothesis is true, then studies can be designedso that subjects first receive transcutaneous stimulation The data from this pilot study indicate that transcuta- and then, if they respond, an implantable device. The cost neous stimulation of the supraorbital and infraorbital di- of transcutaneous TNS is also favorable: stimulators cost visions of the trigeminal nerve was safe and well tolerated ∼$180.00 each, and the monthly retail cost of batteries for the duration of the 3- and 6-month treatment periods.
and electrodes is ∼$150–$170.00/month.
After adjustment in output current on day 1 of stimula- We believe that the results of this pilot study justify tion, all subjects tolerated high-frequency TNS without further investigation into the safety and efficacy of TNS significant pain or discomfort. Most subjects expressed for epilepsy. We are now planning further studies of both a preference for supraorbital stimulation, because of the transcutaneous and implantable TNS for epilepsy.
ability to conceal the electrodes with a cap or hat.
Although the sample size is small in this pilot study, Acknowledgment: This study was funded by a grant from
preliminary efficacy data indicate that four (57%) of seven Advanced Bionics, Valencia, California, U.S.A.
experienced a ≥50% reduction in seizures. Interpretationof the efficacy data must be approached with caution, as REFERENCES
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