The study, published online September 9 in the Journal of Neurology Neurosurgery & Psychiatry 9 and conducted by a team led by Christopher M. DeGiorgio, MD, Department of Neurology, UCLA School of Medicine, Los Angeles, California, showed a significant reduction in seizure frequency with the low-dose but not the high-dose treatment vs placebo.

Dr. DeGiorgio told Medscape Medical News that the results of this study may reinvigorate interest in fish oil research for epilepsy.

“Previous studies of fish oil in epilepsy have been negative, which has been very disappointing after promising animal data. The disappointing clinical results have caused interest to wane, but this is the first study to look at a low dose,” he said.

He explained that the previous studies tested a dose of fish oil containing 1700 to 2000 mg of omega-3 fatty acids per day. This is similar to the higher dose in the current study, which also showed no effect.

But the lower dose in this study — 1000 mg of omega-3 fatty acids per day — showed a reduction in seizure frequency of about one third. “This is quite remarkable given that the patients included all had intractable epilepsy,” he commented.

Noting that the 1000-mg dose may also have some benefit in cardiovascular disease and has shown some promise in depression and cognition, Dr. DeGiorgio said, “We seem to have hit the sweet spot in terms of dose.”

But he cautioned that the current study was small and the results need to be confirmed in larger studies before any clinical recommendations can be made.

“It’s too early to make any definitive statements, but I am excited about what we found and what the future may hold,” he added.

Seizures Reduced by One Third

The randomized, double-blind study included 24 patients with intractable epilepsy who averaged 18 seizures per month while receiving placebo. In a 3-period crossover design, each patient underwent 3 treatment periods of 10 weeks’ duration with low-dose fish oil (1080 mg of omega-3 fatty acids daily as 3 fish oil capsules per day); high-dose fish oil (2160 mg daily as 3 fish oil capsules twice a day), or placebo.

In between each treatment period there was a 6-week washout. Patients continued to receive their current antiepileptic medication throughout the study.

Results showed that the low dose was associated with a 33.6% reduction in seizure frequency compared with placebo (P = .02). High-dose fish oil was no different than placebo in reducing seizures.

Table. Average Seizure Frequency

In the low-dose group, 2 patients (10%) actually achieved seizure-free status, which Dr. DeGiorgio said was “quite an achievement.”

He said he was surprised at first to see an effect with the low dose but not the high dose, but there is a potential explanation for these observations. “When we got the results back, I was shocked and a little perplexed at first, but having thought about it some more I am now very encouraged,” he told Medscape Medical News.

He noted that some animal studies have also suggested that lower doses of omega-3 fatty acids have a better effect on reducing seizures than do higher doses, and a great antidepressant effect has also been reported with a lower dose in a clinical study.

He adds: “It is not unusual to see a very narrow therapeutic index with epilepsy drugs. Two of the most popular drugs used — phenytoin and carbamazepine — can both exacerbate seizures if too much is given.”

Mechanism?

Dr. DeGiorgio explained that omega-3 fatty acids are believed to work by regulating the passage of sodium and calcium ions into brain cells. These ions increase excitability of the cells and can trigger seizures.

“Omega-3 fatty acids cause these ion channels to close earlier than normal, so blocking sodium and calcium entry to the cell. Too high a dose could cause sodium and calcium levels inside the cell to fall so low that other excitatory mechanisms are triggered,” he suggests.

He also pointed out that omega-3 fatty acids are believed to have an antiarrhythmic effect — again thought to be mediated by reducing the excitability of cardiac cells, and 1000 mg is the dose shown to beneficial in this indication. “This fits in perfectly with our data.”

“The 1000 mg/day dose has shown benefits in heart disease, and epilepsy patients have a higher risk of cardiovascular disease,” he says. However, the most recent trials of fish oil have failed to show a benefit in cardiovascular disease.

Dr. DeGiorgio noted that the 1000-mg dose may also reduce blood pressure and has shown some preliminary positive results in depression and cognition. “Indeed in our study, we also measured cognition, and while we haven’t processed the exact data yet, we are pretty sure we’ve seen an improvement in memory and thinking with the 1000-mg dose,” he noted.

He adds: “I obviously cannot recommend anyone take omega-3 fatty acids based just on this 1 study but I do believe it has many health benefits and very little risk. It is widely available and it could be a reasonable option to consider for patients with intractable epilepsy. If they are interested in this approach they should talk to their doctor about it.”

Before any definitive claims in epilepsy can be made, a larger study is needed, he added. Dr. DeGiorgio is hoping to conduct such a study and is optimistic that these results will help him acquire funding.

Most recent trials of fish oil in cardiovascular disease have failed to show any benefit.

The study was funded by grants from the National Institute of Health, National Center for Complementary and Alternative Medicine; Clinical Research Center Grant, and by the generous support of: James and Beverly Peters, The Kwock Family, Marc and Teri Jacoby, the Salter Family Trust, Pepper and Joseph Edmiston, Mrs Elsie Bierner-Johnson, Richard and Linda Lester, Robert and Linda Brill and their families. Dr. DeGeorgio is a part-time employee of NeuroSigma, a device company, which develops devices for epilepsy and other disorders.

J Neurol Neurosurg Psychiatry. Published online September 9, 2014. Abstract

It is indicated as initial monotherapy in patients 10 years of age or older with partial-onset seizures or primary tonic-clonic seizures, and also approved as adjunctive therapy in patients 2 years of age or older with partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome.

The new formulation is available in 25-, 50-, 100-, 150-, and 200-mg extended-release capsules, the statement notes. Capsules can be opened and the contents sprinkled on a spoonful of soft food to facilitate dosing. “This makes it the only approved extended-release topiramate product for patients who experience challenges swallowing whole capsules or tablets,” the release adds.

Another oral once-daily extended-release topiramate product (Trokendi XR, Supernus Pharmaceuticals Inc) was approved in August 2013. It is indicated for initial monotherapy in patients 10 years of age and older with partial-onset or primary generalized tonic-clonic seizures, adjunctive therapy in patients 6 years of age and older with partial-onset or primary generalized tonic-clonic seizures, and adjunctive therapy in patients 6 years of age and older with seizures associated with Lennox-Gastaut syndrome.

Approval for Qudexy XR is based on data from the phase 3 PREVAIL study, presented in December 2013 at the American Epilepsy Society 67th Annual Meeting, and reported by Medscape Medical News at that time.

PREVAIL included 249 patients with partial-onset seizures with 8 or more seizures and 21 or fewer seizure-free days during an 8-week baseline phase. Patients who were taking 1 to 3 other antiepileptic drugs (AEDs) were randomly assigned to also receive the active drug or placebo.

Results showed that at 11 weeks (3-week titration plus 8-week maintenance), the active treatment was associated with a significantly greater median percentage reduction in seizure frequency compared with placebo (39.5% vs 21.7%; P < .001.) The 50% responder rate was also significantly greater (37.9% vs 23.2%; P = .013).

Subgroup analysis revealed that the drug was effective in patients with all types of partial-onset seizures with a variety of concomitant AEDs and in the most refractory of patients.

“PREVAIL demonstrated that Qudexy XR was efficacious and generally well-tolerated, particularly with respect to the incidence of cognitive side effects,” said Steve Chung, MD, professor of neurology at the Barrow Neurological Institute in Phoenix and trial investigator, in the statement. “As a physician, I’m encouraged that Qudexy XR will be an available treatment option for many patients.”

Qudexy XR will be available to patients in the second quarter of 2014, the company notes. More information is available at www.qudexyxr.com.

Investigators at the University of California, Los Angeles (UCLA), reviewed the records of 10 patients who had undergone resective epilepsy surgery for medically refractory focal onset seizures at their institution between 1992 and 2012. Patients ages 60 and older (age range: 60 to 74) with a minimum follow-up of one year (range 1 to 7.5 years) were included in the study. Comorbidities at the time of surgery, including hypertension, hyperlipidemia, diabetes mellitus, hypothyroidism, osteoporosis, obstructive sleep apnea, depression, and falls, were noted. A modified Liverpool life satisfaction tool was administered postoperatively, with a maximum score of 40.

Patients’ mean age at surgery was 65.4. The mean duration of epilepsy before surgery was 27.8 years. At the time of surgery, 70% of patients had at least one medical comorbidity in addition to refractory seizures. No patients experienced any postsurgical complications.

The patients were followed for a mean of 3.2 years. At the time of final follow-up, 90% of patients had a good postsurgical outcome. Half of the patients were completely seizure free. Quality of life data were available for nine patients, whose mean modified Liverpool life satisfaction score was 30.4 after surgery. Of the nine patients with additional life satisfaction data, six reported excellent satisfaction with their surgery, and three reported postoperative improvements in their health.

Resective surgery is seldom used in epilepsy patients ages 60 and older despite its potential to offer seizure freedom. Older age may discourage referrals to specialized epilepsy centers, given concerns about increased surgical risk because of age and the presence of other health problems common in the elderly.

“Our data demonstrate that referral to a comprehensive epilepsy center for resective epilepsy surgery evaluation should not be negatively influenced by advancing age,” said Sandra Dewar, RN, Patient Care Coordinator at UCLA Health and the lead study author. “Consideration of surgery in older adults is important, since seizure freedom may increase safety, independence, and happiness later in life.”

Surgical Site May Influence Epilepsy Surgery’s Effect on Mood and Behavior in Children
Epilepsy surgery may improve mood and behavior among children, researchers reported at the 67th Annual Meeting of the American Epilepsy Society. The hemisphere on which surgeons operate may influence the effect of surgery.

Children with epilepsy are at high risk for depression, anxiety, and behavioral functioning disorders. Epilepsy surgery in children is associated with changes or improvements in mood and behavior, but research into the extent of the change has produced inconsistent results.

To examine changes in mood, anxiety, and behavioral functioning following epilepsy surgery, a collaborative team of investigators from the Cleveland Clinic and the University of Pittsburgh studied 101 children (ages 5 to 16) who underwent epilepsy surgery. The investigators analyzed the role of surgical site (ie, frontal or temporal) and hemisphere (ie, left or right) in the outcomes.

Children in the study completed the Children’s Depression Inventory (CDI) and the Revised Children’s Manifest Anxiety Scale (RCMAS) as part of comprehensive neuropsychologic evaluations conducted approximately 10 months apart. The children’s primary caregivers completed the Achenbach Child Behavior Checklist (CBCL) at both evaluations.

Among children who underwent left-sided surgeries, patients with frontal lobe epilepsy or their caregivers endorsed more symptoms on the Social Anxiety subscale of the RCMAS and on the Withdrawal subscale of the CBCL before surgery than patients with temporal lobe epilepsy. Patients with frontal lobe epilepsy also demonstrated notable improvement in anxiety or mood following surgery. The investigators found no significant two-way interactions among children who underwent right-sided surgeries.

In addition, 21% of all patients (ie, 15% of patients with temporal lobe epilepsy and 33% of patients with frontal lobe epilepsy) reported improvements in overall depression symptoms after surgery. About 38% of the cohort (ie, 27% of patients with temporal lobe epilepsy and 45% of patients with frontal lobe epilepsy) reported postoperative improvements in overall anxiety symptoms.

“We were pleased to discover that children generally experience improvements in mood and behavior following epilepsy surgery,” said Elizabeth Andresen, PhD, postdoctoral fellow in neuropsychology at the Cleveland Clinic and lead author of the study. “While children with frontal lobe epilepsy had greater symptoms of depression and anxiety before surgery than children with temporal lobe epilepsy, these symptoms improved significantly following surgery to levels comparable to or below [those of] the temporal lobe group. Interestingly, these relationships were most apparent in children who underwent left-sided surgeries.”

Rapid AED Withdrawal During vEEG Monitoring May Be Safe and Effective
Discontinuation of antiepileptic drug (AED) therapy during concurrent video and EEG monitoring (vEEG) may be safe for patients with epilepsy, according to research presented at the 67th Annual Meeting of the American Epilepsy Society.

To determine the safety and long-term effects of AED withdrawal or discontinuation during this diagnostic procedure, investigators at the University of Saskatchewan in Saskatoon, Canada, conducted a prospective study of 150 patients with epilepsy admitted to their vEEG telemetry unit over a period of five years. Neurologists discontinued the patients’ medication therapy according to a standardized rapid AED withdrawal protocol. Rapid discontinuation was not performed for patients with a history of status epilepticus or phenobarbital exposure. The researchers then assessed the number of patients who had subsequent seizures, the safety of the withdrawal and telemetry procedures, and epilepsy surgery outcomes.

The group recorded seizures and nonepileptic events in 84.8% of the patients. This diagnostic yield was achieved over a mean monitoring duration of 4.53 days. The researchers found no benefit of longer monitoring. Habitual seizures were recorded in 107 patients to support a diagnosis of epilepsy. The investigators recorded nonepileptic events in 36 patients. The vEEG findings changed patient management for 93% of the cohort and likely improved quality of life by decreasing AED consumption and reducing seizure frequency.

Overall, 34% of the patients received epilepsy surgery. The probability of a good outcome (ie, Engel Class I or II) at 24 months was 78% among patients who underwent surgery and 40% among patients who did not. The overall complication rate of the surgery was 5.3%, and the most common complication was musculoskeletal pain secondary to clinical seizure activity. The investigators observed no mortality following surgery. In the first month following monitoring, 2.5% of patients were admitted to an emergency room for seizure clustering.

“VEEG telemetry monitoring with early cessation of AED therapy is safe and effective,” said Syed A. Rizvi, MD, a neurology resident at the University of Saskatchewan and lead author of the report. “Surgical outcomes are favorable and support the use of this technique under the supervision of a team comprising epileptologists, nurses, and EEG technologists.”

Prolonged Seizures During Childhood May Not Necessarily Damage the Brain
Childhood convulsive status epilepticus (CSE) may not damage the hippocampus unless it occurs years after the causative event, according to a study presented at the 67th Annual Meeting of the American Epilepsy Society. Prolonged febrile seizures also may not impair hippocampal growth in children.

Neurologists have long hypothesized that prolonged febrile seizures, the most common form of childhood CSE, cause mesial temporal sclerosis (MTS), which entails a loss of neurons and scarring of the hippocampus. Whether prolonged convulsions lead to long-term damage to the hippocampus or to MTS is uncertain.

A team of investigators from the United Kingdom and the United States used three-dimensional MRI imaging to measure hippocampal volume in 144 children. The cohort included 74 patients with seizures classified into four subgroups: prolonged febrile seizure, acute symptomatic (CSE at time of causative event such as meningitis or head injury), remote symptomatic (CSE months to years after causative event), and idiopathic or unclassified. The cohort also included 70 healthy controls.

Each hippocampal slice was measured independently by two investigators blind to clinical details. The hippocampal volume was measured on each side, and right–left asymmetry was calculated using asymmetry index. Volumetric images were taken at a mean follow up of 8.5 years (range 6.3 to 10 years) after the convulsive episode. The investigators also compared these measures across all patient groups.

The researchers found no significant corrected volumetric differences between the groups, except for the subgroup of children with remote symptomatic CSE, whose mean corrected hippocampal volume was 553 mm3 lower than that of controls. Asymmetry of the hippocampal structure also was significantly greater in the remote symptomatic subgroup, compared with the other groups. The investigators found no significant differences in asymmetry or corrected volume between the other CSE groups and healthy controls.

“On group analysis, hippocampal growth in children who had prolonged febrile seizures, acute symptomatic, and idiopathic or unclassified CSE was not impaired at a mean follow-up of 8.5 years post CSE,” said Suresh Pujar, MD, clinical research fellow in epilepsy at the Institute of Child Health, University College of London, and lead author of the study. “But children with remote symptomatic CSE have a significant reduction in hippocampal volume and increased asymmetry, compared with all the other groups in our study.”

The results of the study suggest that prolonged seizures, whether febrile or afebrile, may not have a lasting effect on hippocampal growth in children who were neurologically normal before CSE, according to the investigators.

Postsurgery Change in AEDs May Affect Seizure Recurrence, But Not Seizure Freedom
Late discontinuation of antiepileptic drugs (AEDs) following epilepsy surgery is associated with a lower rate of seizure recurrence, compared with early AED discontinuation, according to research presented at the 67th Annual Meeting of the American Epilepsy Society. The postsurgical timing of AED withdrawal may not influence the achievement of seizure freedom, however.

Although most patients with epilepsy become seizure-free after surgery, neurologists have no standard criteria for the timing of AED withdrawal following the procedure. In addition, the long-term effect of postoperative AED withdrawal is unclear.

Researchers at the Cleveland Clinic investigated the implications of AED withdrawal following surgery for drug-resistant temporal lobe epilepsy (TLE). The team reviewed data for all patients who underwent temporal lobectomy for drug-resistant TLE in their clinic from 1996 to 2011 and had at least six months of postoperative follow-up. Follow-up lasted as long as 16.7 years. The investigators noted patients’ clinical and imaging information; histopathological profiles; and dates of initiation, reduction, and termination of AEDs. Predictors of postoperative seizure outcome were defined using survival analyses and Cox-proportional hazard modeling.

More than 600 patients met the study criteria, including a patient cohort for whom medication was withdrawn and a second cohort for whom medication remained unchanged after surgery. The investigators used the latter group used as the control group. The researchers assessed the long-term recurrence of seizures following early and late withdrawal of AEDs postsurgery and compared those results with seizure recurrence when AEDs remained unchanged following surgery.

The number of AEDs per patient at the time of surgery ranged from 1 to 5, and the number of AEDs at last follow-up ranged from 0 to 5. At last follow-up, approximately 38% of patients had made no change in their baseline AEDs, about 21% of patients had stopped their AEDs, and approximately 42% had reduced their AEDs. The investigators found no relationship between AED management and the side of resection, MRI findings, baseline seizure-frequency, and presence or absence of convulsions. AEDs were more likely to be stopped in patients with tumors.

By the last follow-up, 55% of patients had seizure recurrence. Multivariate modeling indicated that higher baseline seizure frequency and history of generalization predicted seizure recurrence. For patients who stopped their AEDs, the mean timing of earliest AED change was shorter in patients with recurrent seizures (1.04 years), compared with patients who were seizure-free (1.44 years).

When the researchers analyzed patients who were seizure-free for at least six months postsurgery and compared seizure outcomes in the group with AED withdrawal to the cohort where AEDs were unchanged, they found no difference in long-term rates of seizure-freedom, regardless of etiology. The results of the large, retrospective, controlled cohort study need to be further evaluated in a well-designed, prospective, randomized trial, said the investigators.

Survey Indicates Positive Seizure and Psychosocial Outcomes of Epilepsy Surgery
Resective surgery may reduce seizures for the majority of patients with epilepsy, according to research presented at the 67th Annual Meeting of the American Epilepsy Society. The procedure may also improve patients’ daily functioning and social and emotional well-being.

To investigate the effect of epilepsy surgery on patients’ lives, researchers from the Comprehensive Epilepsy Program at the Henry Ford Hospital in Detroit conducted a long-term retrospective follow-up of surgical patients. The team correlated postsurgical psychosocial outcomes with seizure outcome and brain area that had been treated surgically.

The investigators conducted telephone interviews with more than half of all patients who had undergone epilepsy surgery at their center between 1993 and 2011. During the interviews, the researchers assessed current seizure frequency and psycho­social metrics such as driving, employment, and use of antidepressants. Of the respondents, 215 patients had undergone temporal lobe surgery and 38 had had surgery on other brain areas. The investigators recorded demographics, age at epilepsy onset and surgery, seizure frequency before surgery, and pathology.

Of the 253 patients surveyed, 32% were seizure-free and 75% had a favorable outcome (ie, Engel Class I or II). More than three-fourths of patients who had undergone temporal lobe surgery (78%) had a favorable outcome, and more than half of patients who had had extratemporal surgery (58%) had a similar outcome. In addition, almost all patients (92%) considered the surgery to have been worthwhile.

Half of the surgical patients (51%) were able to drive at the time of the survey, compared with 35% who were able to do so preoperatively. But after surgery, patients were less likely to be currently working full time, compared with before surgery (23% vs 42%). The difference in current full-time employment was significantly greater in patients with temporal resections, compared with patients with extratemporal resections (45% vs 26%).

More patients used antidepressants after surgery (30% vs 22%). Patients with a favorable surgical outcome were more likely than those with less favorable outcomes to be currently driving (65% vs 11%), more likely to be currently working (28% vs 8%), and less likely to be taking antidepressant medication (24% vs 47%).

“Resective epilepsy surgery not only yields favorable seizure outcomes, but [favorable] psychosocial outcomes as well,” said Vibhangini S. Wasade, MD, a neurologist at the Henry Ford Health System and lead author of the study. “Following surgery, more patients were able to drive, and those with favorable seizure outcomes were more likely to be employed full-time and less likely to be taking antidepressants. Overall, the great majority expressed satisfaction in having epilepsy surgery.”

Also on tap: studies of a new form of laser surgery for seizure ablation, a wearable seizure detector, and a device for home monitoring of anti-epileptic drug blood levels, said Kimford Meador, MD, of Stanford University in Stanford, Calif., the organization’s scientific program committee chairman.

Another study, led by Meador himself, examines whether children of mothers taking the epilepsy drug valproate while breastfeeding suffered adverse consequences at age 6 as a result. (Answer: it was definitely not harmful and may have been beneficial.)

Although a debate at the World Congress of Neurology in September questioned whether recent years had seen significant clinical progress in epilepsy, the AES agenda suggests the answer is a resounding Yes.

In an interview with MedPage Today ahead of the meeting, which begins Friday with symposia and special interest group meetings, Meador ticked off numerous studies to be presented that appear to move the field forward.

The first item on his list was the newly approved RNS responsive neurostimulator that, analogous to an implanted cardioverter-defibrillator, is silent until it detects abnormal electrical activity in the brain and then delivers pulses to previously identified seizure foci. The approval was for patients not responding to conventional drug therapy.

At the meeting, one of Meador’s Stanford colleagues is slated to report long-term follow-up data from clinical trial participants showing a sustained reduction of about 50% in seizure frequency. “That’s a pretty good response in refractory patients,” Meador said.

Another recently introduced treatment involves a minimally invasive, MRI-guided, water-cooled laser device for surgical ablation of seizure foci. Past studies have shown that it incurs “much less surgical morbidity” compared with standard open surgery, Meador said, with some patients able to go home the following day.

An abstract to be presented focuses on neuropsychiatric outcomes, suggesting that they are improved as well compared with conventional surgery, which can damage nontarget brain areas.

Addressing pediatric epilepsy, Meador highlighted a study that examines the problem of seizures in critically ill children — specifically finding that aggressive treatment of those seizures may improve overall outcomes.

Another abstract involving critically ill children indicates that status epilepticus often goes undetected, suggesting that continuous EEG monitoring may be worthwhile in pediatric ICUs. “There’s a lot more to be done in this area,” Meador commented.

One unmet need in epilepsy addressed at the meeting will be the problem of patients for whom no brain lesion can be detected with current imaging methods. A study slated for presentation shows that a novel type of MRI processing, called voxel-based morphometric analysis, was able to identify specific abnormalities in about half of such patients. The abstract has been selected for the AES’s annual Dreifuss award.

If validated in future studies, the method could lead to effective surgical treatments for many patients who currently can’t be helped, Meador said.

Another award-winning abstract (the Goldberg Kaufman Honor) looks at psychiatric outcomes in children undergoing epilepsy surgery, finding that surgeries targeting foci in certain brain regions improve mood and behavior. Meador noted that these issues are a major part of the clinical burden of pediatric epilepsy, insofar as they “interfere with how children function between seizures.”

And another presentation that Meador said will be important examines the prevalence of folate supplementation in epileptic women of childbearing age — which can prevent adverse birth outcomes for those who become pregnant while taking anti-convulsant drugs.

Researchers found that only about half of such women who became pregnant had been taking supplements, raising questions about the adequacy of counseling they received or their compliance with it, he said.

More than half of epilepsy patients treated with the recently approved responsive neurostimulation device (RNS) had reductions of 50% from baseline in seizure frequency lasting for up to 80 months, researchers reported here.

Among 250 participants in the pivotal trial of the implanted RNS System neurostimulator, approved last month for treating drug-resistant focal epilepsy, long-term follow-up indicated that responder rates increased steadily over the first 2 to 3 years after implant, reaching about 55%, said Martha Morrell, MD, chief medical officer of NeuroPace, based in Mountain View, Calif., which manufactures the device.

The responder rate was maintained out to 80 months in patients continuing that long in the trial’s open-label extension, she said at a press briefing held before her formal presentation at the American Epilepsy Society’s annual meeting. A total of 177 patients had at least 4 years of follow-up.

At the end of the trial’s blinded, randomized phase 3 months after implant, the mean reduction from baseline in seizure frequency with the device switched on was 37.9%, compared with 17.3% in patients receiving the device but with it turned off (P=0.012), which was the primary basis for the approval.

Morrell said that during the extension serious adverse events remained rare.

Sudden unexplained death in epilepsy (SUDEP) occurred at a rate of 4.7 per 1,000 patient-years of stimulation, she said. That compares with rates “in the mid-sixes” per 1,000 patient-years in recent studies of SUDEP in medically treated patients, Morrell said, and a rate of 9.3 per 1,000 in an older study of patients with drug-resistant seizures.

Rates of other adverse events were, with one exception, all less than 10%.

These included implant site infections, early battery failure, increased seizure frequencies, status epilepticus, and skin lacerations due to seizures. The exception was use of EEG monitoring, which was used in 16% of patients, presumably to investigate adverse neurological events of different kinds.

Most adverse events occurred in the first year post-implant, Morrell reported.

The device is about the size of a large man’s thumb, and is implanted and incorporated into the skull bone, she explained. It has two leads, allowing one or two foci to receive the stimulation.

Another important feature of the device is that it does not provide continual stimulation; rather, it monitors electrical electrical activity silently at the lead placement sites and delivers stimulation only when abnormal activity is detected.

During the entire follow-up period, 20% of patients were seizure-free for periods of 6 months or more. The median reduction in seizure frequency from 6 to 9 months after implant was about 30%, increasing to 39% at 12 months and 51% at 24 months.

RNS for Epilepsy Has Long-Term Benefits

Median reductions and responder rates from years 3 to 6 were both in the range of 55% to 60%.

Other epilepsy specialists told MedPage Today that the device appeared to be very promising for patients not responding to drug therapies and for whom definitive surgery is not an option.

Dawn Eliashev, MD, of the University of California Los Angeles, said her clinic already had a list of patients to be considered for the device.

“One of the things that was very frustrating for us, with many patients, is that we made extreme efforts to localize where the seizures were coming from in these very difficult patients, and the patients were faced with the aggravation that we found out that those areas were very close to language areas, or areas that were important for motor function,” she said.

That made them poor candidates for conventional surgery because of the risk of collateral damage and severe functional impairments. “Now we have something for these patients that can directly [target] those areas,” said Eliashev, who was not involved in the device’s clinical studies.

She emphasized that the device should not be regarded as an alternative to surgery. The latter “is a cure for epilepsy,” whereas the neurostimulator provides seizure reduction but seldom complete seizure freedom. Eliashev noted, for example, that most patients receiving the device still would not be eligible to drive.

One of the trial’s many site investigators, Jason Schwalb, MD, of Henry Ford West Bloomfield Hospital near Detroit, said the participants “were the sickest of the sick, that weren’t really candidates for standard resection.”

He also stressed limitations to the device’s efficacy. “You’re not going to see really huge cure rates. But for patients where there really aren’t other options, patients do get some benefit that’s clinically meaningful.”

Schwalb added that patients definitely seem to think the less-than-complete reduction in seizures is still beneficial for them. He cited a case in which a trial participant’s battery failed, and the patient demanded an immediate replacement.

“When the battery goes dead, it’s almost a surgical emergency” from the patients’ perspective, he said.

The RNS device has not yet entered commercial distribution — typical for complex medical devices shortly after FDA approval — but Morrell said it would begin shipping within a few weeks to selected epilepsy specialty centers.

She noted that the current FDA approval is for adult patients only. However, she said, the device would be able to fit into the skulls of most children older than 7- to 9-year-old, and NeuroPace is considering pediatric trials.

The implantation of subdural electrodes for the treatment of intractable epilepsy is beneficial, but requires careful surveillance during the monitoring period, according to findings from a study of 91 consecutive patients.

This is especially true for those who undergo large subdural grid placement, as these patients have an increased risk for complications, Dr. Fernando L. Vale of the University of South Florida, Tampa, and his colleagues reported online in Clinical Neurology and Neurosurgery.

Of 508 patients who underwent surgical intervention for the evaluation and treatment of medically resistant epilepsy at a single center from 1999 to 2010, 91 (18%) required invasive subdural electrode placement and were included in this study.

Twenty-eight of those patients (31%) had a radiographic lesion on preoperative high-resolution magnetic resonance imaging (MRI), including 13 with evidence of neuronal migrational disorder, 9 with radiographic evidence of gliosis or encephalomalacia of unknown origin, 3 with benign neoplastic lesions, 2 with documented arachnoid cysts, and 1 with radiographic evidence of mesial temporal lobe sclerosis. Resective epilepsy surgery was performed in 70 (77%) of these patients, and 24 of those (34%) were seizure free at last follow-up, the investigators said (Clin. Neurol. Neurosurg. 2012 Nov. 5 [doi: 10.1016/j.clineuro.2012.10.007]).

A very strong trend was seen for improved outcomes in those with positive lesions on preoperative MRI, compared with those with a normal brain MRI, the investigators said.

No significant associations were found between outcomes and preoperative positron emission tomography (PET) results, ictal single photon emission computed tomography (SPECT) results, type of implant, or lateralization or localization of subdural implants, they noted.

Ten surgical complications occurred, including radiographically evident subdural or epidural hemorrhage in eight patients, a transient cerebrospinal fluid leak in one patient, and a subdural empyema following removal of the electrodes in one patient. The latter required prolonged intravenous antibiotics and removal of the bone flap.

Of the eight patients with hemorrhage, four were symptomatic and required evacuation of the hematoma, and two underwent removal of the electrodes during emergency craniotomy. All required observation with a prolonged intensive care unit stay.

“All but one of these patients had undergone placement of an electrode array that included a grid[,] and more significant[ly], all symptomatic subdural hemorrhage patients had undergone placement of a grid with or without additional subdural strip electrodes,” the investigators noted.

Indeed, placement of a subdural grid in any combination was significantly associated with complications, they said.

However, none of the patients died or experienced permanent morbidity.

The patients included in the study were 55 men and 36 women with an average age of 32.2 years who underwent subdural electrode placement between 1999 and 2010. The electrodes were placed when ictal recordings were inadequate due to extensive muscle artifact or poorly localized ictal onset, when preoperative scalp electrode encephalogram and neuroimaging findings were discordant, and/or when the epileptogenic zone was localized near eloquent cortex. More than half (57%) of the patients underwent strip placement only, 5 (5.5%) underwent grid placement only, and 34 (37%) underwent both. The mean duration of monitoring was 7 days, and patients were followed for at least 18 months (mean of 42 months).

The findings indicate that although the use of subdural electrode placement has diminished over the last two decades due to improvements in brain imaging, better definition of syndromes amenable to surgery, and better patient selection, such invasive monitoring can improve seizure control and the possibility of cure. Subdural electrode placement thus remains “a useful and necessary technique for the surgical treatment of intractable epilepsy,” despite the possibility of complications, they said.

Careful surveillance during the monitoring period, along with a good working hypothesis, assessment of the risk-benefit ratio, patient selection, and meticulous surgical technique, is a must for minimizing complications and achieving better outcomes, they concluded.

Given the limitations of a single-center, retrospective study, however, the authors recommend additional study to corroborate the clinical findings.

Dr. Vale said there are no disclosures for any of the authors of this article.

The device has been evaluated in clinical trials conducted at the University of California, Los Angeles (UCLA) and the University of Southern California. It consists of an external pulse generator and disposable electric patches placed on the forehead that are replaced daily and are worn primarily during sleep.

“In clinical studies, eTNS was well tolerated and has been shown to substantially reduce seizures in patients with epilepsy and improve mood in patients with depression,” note the manufacturers in a written release. The company says that they are planning to make the device available in the fourth quarter of 2012 in the EU and will seek approvals in other parts of the world.

In the United States, the company will be submitting a request to the US Food and Drug Administration for an Investigational Device Exemption to commence a multicenter eTNS pivotal trial in epilepsy.

According to the release, trigeminal nerve stimulation was developed at UCLA and is exclusively licensed to NeuroSigma. Research efforts were led by Dr. Christopher DeGiorgio, MD, vice-president of neurology at NeuroSigma and professor of neurology at UCLA School of Medicine.

“As a non-invasive neuromodulation therapy, trigeminal nerve stimulation may represent a paradigm shift in the way we treat major depression and offers the potential to significantly improve the lives of millions of people without the side-effects common to medication treatment,” said Ian A. Cook, MD, who led clinical and human mechanism of action studies of the device in depression.

Dr. Cook is a senior medical advisor to NeuroSigma and a professor-in-residence at UCLA School of Medicine’s Department of Psychiatry, where he serves as director of the UCLA Depression Research and Clinic Program.

The company is currently developing an implantable TNS system, the release notes.

ERSET was a multicenter randomized, controlled, parallel group trial led by Engel and colleagues at UCLA, comparing early TLR to best medical management in patients with pharmacoresistant MTLE. Strict criteria for entry into the study were designed to obtain as pure a population of “early” MTLE patients as possible. Patients were eligible for enrollment if they were >12 years old, diagnosed with MTLE, and had disabling seizures that persisted for no more than 2 years following adequate trials of 2 AEDs. Patients had to undergo a lengthy protocol-driven enrollment process including neuropsychological assessment, magnetic resonance imaging/positron emission tomography imaging and inpatient video-EEG telemetry, all of which had to be consistent with a diagnosis of MTLE. Unfortunately this, along with other factors such as patients who had decided on surgery not wanting to be randomized, led to slow patient accrual. The study was terminated early, after enrolling only 38 patients out of a target goal of 200. Nevertheless, the ERSET trial contains important data that can be used by neurosurgeons and inform us for future trials.

Of the 38 patients, 23 were randomized to the medical group, and 15 to the surgical group. Although the medical group was, on average, younger and more likely to be male, the groups were remarkably comparable with similar durations of epilepsy, number of AEDs used, IQ scores, and pre-op quality of life (QOL) scores. The primary outcome measure was seizure freedom in the second year of follow-up.

Strikingly, 0/23 patients in the medical group and 11/15 patients in the surgery group were seizure-free in the second year. QOL scores were significantly higher in the surgery group at 6, 12, and 18 months post-randomization (Figure). There were no significant differences in cognitive outcomes with respect to the primary memory and non-memory measures used. Surgery patients tended to perform worse on memory measures, however, and specifically performed statistically worse on delayed recall and naming tasks. The small sample size precludes any definitive conclusions to be made about the cognitive effects of surgery.

The ERSET trial reflects both the possibility of TLR to positively impact MTLE patients’ lives and the difficulties involved in recruiting them. While clinicians should be cautious about interpreting trials that have been stopped early because of a possible positive bias effect, it should be noted that this study was stopped early solely because of slow patient accrual. Combined with similar previous results,2 the clinical benefit of surgery for seizure freedom in this study was so large as to make its benefit seem unquestionable. If early surgery for MTLE has such positive benefits for patients in terms of seizure freedom, why is it still so difficult for these patients to reach a neurosurgeon’s office? There is little data on barriers to referral,4 but patient attitudes towards surgery as a “last resort” and clinicians’ concerns about surgical risks and cognitive deficits likely both contribute. Regardless, this study supports the use of TLR for MTLE patients soon after pharmacoresistance has been established.

There is additional importance in ERSET’s inability to recruit surgical candidates. Accurate estimates for recruitment for surgical randomized trials is critical to avoid trials being shut down for lack of enrollment. MTLE is now again being studied with randomization to either TLR or gamma knife radiosurgery (ROSE trial). While surgeons may believe in clinical equipoise between these 2 treatment arms, patients often view them very differently in terms of their potential risks and benefits. Hopefully the ERSET trial’s limited but very positive results will provide momentum to the population of untreated MTLE patients to seek surgical treatment. It remains to be seen whether ERSET will help the ROSE trial to adequately randomize its treatment arms, rather than serve as a harbinger of the difficulty of trying to enroll a randomized MTLE surgical trial.

Abstract and Introduction

Epilepsy is a devastating disease, often refractory to medication and not amenable to resective surgery. For patients whose seizures continue despite the best medical and surgical therapy, 3 stimulation-based therapies have demonstrated positive results in prospective randomized trials: vagus nerve stimulation, deep brain stimulation of the thalamic anterior nucleus, and responsive neurostimulation. All 3 neuromodulatory therapies offer significant reductions in seizure frequency for patients with partial epilepsy. A direct comparison of trial results, however, reveals important differences among outcomes and surgical risk between devices. The authors review published results from these pivotal trials and highlight important differences between the trials and devices and their application in clinical use.

Introduction

Epilepsy affects nearly 1 in 100 people, leading to substantial morbidity, mortality, and economic burden.^[2,17,18] Up to one-third of these patients are not helped by antiepileptic medications.^[17,18] For patients with medically refractory epilepsy, a potentially curative option is resection of the epileptic foci when they can be clearly delineated and safely resected.^[27] However, many patients are not suitable candidates for resection, and morbidity exists for surgery.^[3,16] Because of this, there is a substantial need for additional treatment modalities.

Electrical stimulation of the nervous system is a rapidly evolving treatment for refractory epilepsy, offering a reversible, adjunctive therapeutic option for patients who are otherwise not surgical candidates. Therapeutic stimulation can occur directly via DBS or indirectly via stimulation of peripheral nerves. Three modalities of stimulation now have Class I evidence supporting their use: VNS, DBS of the ANT, and RNS. This review will examine the evidence for each treatment modality and delineate which sets of patients might benefit most from each.

Vagus Nerve Stimulation

The VNS modality is the only US FDA– and CE Mark–approved stimulation therapy for epilepsy. The device consists of pliable, spiral-shaped electrodes that wrap around the vagus nerve and an IPG that is implanted below the clavicle and connected to the electrodes with subcutaneously tunneled wires (Fig. 1).^[10] The left vagus nerve is typically used due to concerns about inducing bradycardia or other arrhythmias when stimulating the right vagus, although recently reports of successful right-sided VNS have been published.^[22]

The vagus nerve is largely afferent (approximately 80%) and is composed predominantly of unmyelinated C fibers.^[10] These fibers project to the nucleus tractus solitarius in the brainstem, which in turn projects widely to other areas within the brainstem and to the cortex. It is presumably by these broad neuromodulatory influences that VNS exerts its antiseizure effect. Nevertheless, the exact mechanism by which VNS reduces seizure frequency is unknown, although studies have implicated a variety of neurotransmitters, such as noradrenaline^[15] and γ-aminobutyric acid.^[1]

There have been 2 randomized, double-blind clinical trials investigating the efficacy of VNS, titled EO3^[26] and EO5,^[11] and both were funded by the manufacturer of the VNS device, Cyberonics, Inc. In both trials, patients were randomized to receive either typical VNS (denoted “high”) or an active, low-frequency control VNS (denoted “low”) (Fig. 2). The patients remained on AEDs throughout the trial. High VNS consisted of a 20- to 50-Hz stimulation frequency, “on” times of 30–90 seconds, “off” times of 5–10 minutes, and the ability to activate the VNS system manually with an external magnet. The low VNS (control) group had stimulation frequencies of 1–2 Hz, “on” times of 30 seconds, “off” times of 1–3 hours, and no ability to activate the device manually

After approximately 3 months of treatment (12–16 weeks), both trials showed significant reductions in seizure frequency compared with patient baselines (24.5% and 27.9%, respectively; Table 1). This is compared with the low-stimulation groups, which had reductions of 6.1% and 15.2%, respectively. The proportion of patients experiencing a reduction of ≥ 50% in their seizures at this same 3-month time point was between 23.4% and 31% (Table 1), again compared with 13% and 15.7% in the low-stimulation groups, respectively.

Table 1. Randomized controlled trials of VNS compared with other stimulation-based therapies*

Study	No. Patients (no. in active group)	% w/Seizure Reduction, Blinded (95% CI)	% w/Seizure Reduction, 1 Yr	% Responder Rate, Blinded	% Responder Rate, 1 Yr	Regulatory Approval
						FDA	CE Mark
VNS						yes	yes
EO3	114 (54)	24.5 (14.1–34.9)	43	31
EO5	196 (94)	27.9 (21.0–34.8)	45	23.4	35
thalamic DBS—SANTE	109 (54)	40.4 (NR)	41	NR	43	†	yes
cortical stimulation—RNS	191 (97)	37.9 (27.7–46.7)	NR	29	43	†	†

* Seizure reduction is defined as change in actively treated patients compared with their baseline seizure frequency. Responder rates are defined as a ≥ 50% reduction in seizure frequency experienced in actively treated patients. The ≥ 50% responder rate is not reported in the SANTE trial, although it was not significantly different from the untreated group. NR = not reported.
† Pending review.

Table 1. Randomized controlled trials of VNS compared with other stimulation-based therapies*

Study	No. Patients (no. in active group)	% w/Seizure Reduction, Blinded (95% CI)	% w/Seizure Reduction, 1 Yr	% Responder Rate, Blinded	% Responder Rate, 1 Yr	Regulatory Approval
						FDA	CE Mark
VNS						yes	yes
EO3	114 (54)	24.5 (14.1–34.9)	43	31
EO5	196 (94)	27.9 (21.0–34.8)	45	23.4	35
thalamic DBS—SANTE	109 (54)	40.4 (NR)	41	NR	43	†	yes
cortical stimulation—RNS	191 (97)	37.9 (27.7–46.7)	NR	29	43	†	†

* Seizure reduction is defined as change in actively treated patients compared with their baseline seizure frequency. Responder rates are defined as a ≥ 50% reduction in seizure frequency experienced in actively treated patients. The ≥ 50% responder rate is not reported in the SANTE trial, although it was not significantly different from the untreated group. NR = not reported.
† Pending review.

The inclusion criteria were similar between the 2 trials. Both required patients to have ≥ 6 seizures per month, be ≥ 12 years old, use at most 3 AEDs, and have medically refractory seizures. The EO3 trial, however, required seizures to be “predominantly partial,” whereas EO5 required that the 6 minimum seizures all be partial, but permitted other seizure types in excess of the minimum. The EO5 trial also added an upper age limit of 65 years, limited time between seizures to a maximum of 21 days, and required that AEDs be at steady state before the patient’s induction into the trial.

Adverse events were common in both high- and low-stimulation groups, although only voice alteration and dyspnea were significantly increased in the high versus low groups. Overall, 66.3% of actively treated patients experienced voice alteration; 45.3% had cough; 34.7% had pharyngitis; 28.4% had pain; 25.3% had dyspnea; 24.2% had headache; 17.9% had dyspepsia, vomiting, and paresthesias; 14.7% had nausea; 12.6% had accidental injury; and 11.6% had fever and infection (Table 2).

Both Class I trials were short term, lasting only 12–16 weeks. After the trials were unblinded, the patients were continually followed, and the results seemed to improve over time. After 1 year, for example, patients in the EO5 study experienced a 45% reduction in seizure frequency, and 35% had a reduction of ≥ 50% in seizures.^[7] In the EO3 trial, those patients who were randomized initially to high stimulation had a reduction of 43.0%, whereas those switched from low to high stimulation experienced a 27.5% reduction.^[9] Nevertheless, these unblinded extensions do not constitute Class I evidence.

Anterior Nucleus Stimulation

The ANT projects to both the frontal and temporal lobes and is part of the classic circuit of Papez.^[24] Because of this integral role in the limbic system, an area intimately associated with epilepsy, many groups have attempted stimulating the anterior nucleus in humans in an effort to suppress seizures, with varying degrees of success.^{[5,6,12,14,19,21]}

The SANTE trial (ClinicalTrials.gov NCT00101933) was a double-blind, randomized, prospective clinical trial of DBS of the ANT.^[8] It began in 2005, and results were published in 2010. It was sponsored by Medtronic, Inc. After accruing patients and determining their baselines for 3 months, all patients were implanted with a Model 7428 Kinetra Neurostimulator and Model 3387 DBS leads (both from Medtronic) (Figs. 3 and 4). One month after implantation, patients were randomized to active treatment, with stimulation parameters of 5-V pulses at 145 Hz, with 1 minute “on” and 5 minutes “off,” versus 0-V pulses with identical frequency and duty cycle in the control group (Fig. 2).

Inclusion criteria for the SANTE trial were similar to the VNS trials that preceded it: age range 18–65 years, partial seizures, ≥ 6 seizures per month, and medically refractory epilepsy (defined as at least 3 failed AEDs). Important differences are the minimum age of 18 years, rather than 12 years used in the VNS trials, and a maximum of 4 AEDs used concurrently at baseline (compared with 3 in the VNS trials). The SANTE trial also excluded patients with > 10 seizures per day and patients with brain tumors, neurodegenerative diseases, psychogenic seizures, or IQ < 70. If the prospective SANTE patients had VNS devices, these were removed at the time of DBS implantation.

After a follow-up of 3 months, treated patients had a median decrease in seizures of 40.4%, compared with 14.5% in the control group. As with the VNS patients, the SANTE patients were then unblinded and followed for an additional time period. After 2 years, the treated SANTE patients (in this unblinded cohort) had a 56% median reduction in seizure frequency, and 54% of patients had a reduction in seizures of ≥ 50% (Table 1).

Table 1. Randomized controlled trials of VNS compared with other stimulation-based therapies*

Study	No. Patients (no. in active group)	% w/Seizure Reduction, Blinded (95% CI)	% w/Seizure Reduction, 1 Yr	% Responder Rate, Blinded	% Responder Rate, 1 Yr	Regulatory Approval
						FDA	CE Mark
VNS						yes	yes
EO3	114 (54)	24.5 (14.1–34.9)	43	31
EO5	196 (94)	27.9 (21.0–34.8)	45	23.4	35
thalamic DBS—SANTE	109 (54)	40.4 (NR)	41	NR	43	†	yes
cortical stimulation—RNS	191 (97)	37.9 (27.7–46.7)	NR	29	43	†	†

* Seizure reduction is defined as change in actively treated patients compared with their baseline seizure frequency. Responder rates are defined as a ≥ 50% reduction in seizure frequency experienced in actively treated patients. The ≥ 50% responder rate is not reported in the SANTE trial, although it was not significantly different from the untreated group. NR = not reported.
† Pending review.

Over the course of the 1st year, adverse events directly related to the device in the SANTE trial included paresthesias in 18.2%, implant site pain in 10.9%, implant site infections in 9.1%, and lead replacement in 8.2% of patients. Note that these frequencies include the unblinded portion of the trial—the adverse events in the blinded portion are displayed in Table 2. Adverse events that were significantly different between groups in the blinded phase were depression (14.8% of treated patients) and memory impairment (13.0%).

Responsive Neurostimulation

The RNS device is designed to detect seizures as they start and then stimulate the seizure focus to abort the propagation. This idea has empirical evidence supporting its feasibility.^[20] Responsive neurostimulation is a closed-loop system, in which subdural and depth electrodes record electrographic activity and trigger bursts of stimulation when a seizure is detected, in the hope of terminating the seizure before it is clinically apparent (Fig. 3).

In the RNS System Pivotal Trial (ClinicalTrials.gov NCT00264810), 191 patients were implanted with the NeuroPace RNS system (NeuroPace, Inc.) following a 3-month baseline period.^[23] Two months after surgery (and after optimizing seizure detection parameters), patients were randomized to responsive stimulation or pure detection of seizures without stimulation. Both groups were followed for 12 weeks in this blinded period (Fig. 2).

Inclusion criteria were age 18–70 years, partial seizures, medically refractory epilepsy (failure of ≥ 2 AEDs), 3 or more seizures per month (on average), and an EEG workup showing 1 to 2 epileptogenic regions. Over the 3-month follow-up period, stimulated patients reported a decrease in seizure frequency of 37.9%, versus 17.3% in the sham-treated group. In addition, 29% of patients reported a decrease in seizures of ≥ 50%, although 27% of sham-treated patients had this responder rate as well (Table 1).

Table 1. Randomized controlled trials of VNS compared with other stimulation-based therapies*

Study	No. Patients (no. in active group)	% w/Seizure Reduction, Blinded (95% CI)	% w/Seizure Reduction, 1 Yr	% Responder Rate, Blinded	% Responder Rate, 1 Yr	Regulatory Approval
						FDA	CE Mark
VNS						yes	yes
EO3	114 (54)	24.5 (14.1–34.9)	43	31
EO5	196 (94)	27.9 (21.0–34.8)	45	23.4	35
thalamic DBS—SANTE	109 (54)	40.4 (NR)	41	NR	43	†	yes
cortical stimulation—RNS	191 (97)	37.9 (27.7–46.7)	NR	29	43	†	†

* Seizure reduction is defined as change in actively treated patients compared with their baseline seizure frequency. Responder rates are defined as a ≥ 50% reduction in seizure frequency experienced in actively treated patients. The ≥ 50% responder rate is not reported in the SANTE trial, although it was not significantly different from the untreated group. NR = not reported.
† Pending review.

As in the VNS trials and the SANTE trial, patients were followed continually after the end of the blinded phase. The RNS-treated patients continued to benefit from the device at 1 and 2 years postimplant, with 43% and 46%, respectively, achieving a ≥ 50% reduction in seizures (Table 1).

Table 1. Randomized controlled trials of VNS compared with other stimulation-based therapies*

Study	No. Patients (no. in active group)	% w/Seizure Reduction, Blinded (95% CI)	% w/Seizure Reduction, 1 Yr	% Responder Rate, Blinded	% Responder Rate, 1 Yr	Regulatory Approval
						FDA	CE Mark
VNS						yes	yes
EO3	114 (54)	24.5 (14.1–34.9)	43	31
EO5	196 (94)	27.9 (21.0–34.8)	45	23.4	35
thalamic DBS—SANTE	109 (54)	40.4 (NR)	41	NR	43	†	yes
cortical stimulation—RNS	191 (97)	37.9 (27.7–46.7)	NR	29	43	†	†

* Seizure reduction is defined as change in actively treated patients compared with their baseline seizure frequency. Responder rates are defined as a ≥ 50% reduction in seizure frequency experienced in actively treated patients. The ≥ 50% responder rate is not reported in the SANTE trial, although it was not significantly different from the untreated group. NR = not reported.
† Pending review.

During the blinded evaluation period, there was no difference between the treatment and sham-treated groups in terms of reported adverse events. Nevertheless, when compiled over the study’s entire 1st year, adverse events included incision site infections in 5.2% of patients, headache in 10.5%, dysesthesia in 6.3%, increased complex partial seizures in 5.8%, increased tonic-clonic seizures in 4.7%, memory impairment in 4.2%, depression in 3.1%, and dizziness and paresthesias in 2.6%. Adverse events that occurred strictly within the blinded phase are displayed in Table 2.

Choice of Therapy

Only VNS is approved by the FDA and therefore currently remains the primary choice of most US providers as an adjunctive treatment for refractory epilepsy (Table 1). Nevertheless, both NeuroPace and Medtronic have applied for FDA approval of the RNS System and DBS of the ANT, respectively. NeuroPace applied in July 2010 and is awaiting a panel meeting and recommendation before the FDA takes action. The FDA panel has convened and voted to approve Medtronic’s ANT DBS device. However, the FDA at large rejected the panel’s recommendation, due to continued questions about the clinical data from the SANTE trial, and Medtronic continues to work with the FDA to move toward approval.

Table 1. Randomized controlled trials of VNS compared with other stimulation-based therapies*

Study	No. Patients (no. in active group)	% w/Seizure Reduction, Blinded (95% CI)	% w/Seizure Reduction, 1 Yr	% Responder Rate, Blinded	% Responder Rate, 1 Yr	Regulatory Approval
						FDA	CE Mark
VNS						yes	yes
EO3	114 (54)	24.5 (14.1–34.9)	43	31
EO5	196 (94)	27.9 (21.0–34.8)	45	23.4	35
thalamic DBS—SANTE	109 (54)	40.4 (NR)	41	NR	43	†	yes
cortical stimulation—RNS	191 (97)	37.9 (27.7–46.7)	NR	29	43	†	†

* Seizure reduction is defined as change in actively treated patients compared with their baseline seizure frequency. Responder rates are defined as a ≥ 50% reduction in seizure frequency experienced in actively treated patients. The ≥ 50% responder rate is not reported in the SANTE trial, although it was not significantly different from the untreated group. NR = not reported.
† Pending review.

On the other hand, CE Mark approval has been granted to both VNS and Medtronic’s DBS of the ANT. Therefore, patients in Europe can take advantage of either modality, depending on patient and physician preference (Table 1).

Table 1. Randomized controlled trials of VNS compared with other stimulation-based therapies*

Study	No. Patients (no. in active group)	% w/Seizure Reduction, Blinded (95% CI)	% w/Seizure Reduction, 1 Yr	% Responder Rate, Blinded	% Responder Rate, 1 Yr	Regulatory Approval
						FDA	CE Mark
VNS						yes	yes
EO3	114 (54)	24.5 (14.1–34.9)	43	31
EO5	196 (94)	27.9 (21.0–34.8)	45	23.4	35
thalamic DBS—SANTE	109 (54)	40.4 (NR)	41	NR	43	†	yes
cortical stimulation—RNS	191 (97)	37.9 (27.7–46.7)	NR	29	43	†	†

* Seizure reduction is defined as change in actively treated patients compared with their baseline seizure frequency. Responder rates are defined as a ≥ 50% reduction in seizure frequency experienced in actively treated patients. The ≥ 50% responder rate is not reported in the SANTE trial, although it was not significantly different from the untreated group. NR = not reported.
† Pending review.

Concerning efficacy, it is difficult to compare the trials directly, given limited access to raw data and different inclusion criteria. Both DBS of the ANT and RNS show a trend toward greater seizure reduction than VNS in blinded clinical trials (40.4% and 37.9% vs 24.5% and 27.9%, respectively; Table 1). This effect disappears in the unblinded follow-ups, however, with SANTE reporting 41%, compared with 43% and 45%, respectively, in the EO3 and EO5 trials of VNS at 1 year. Responder rates (≥ 50% reduction in seizures) show conflicting results. The VNS trials reported rates of 31% and 23.4%, both significantly different than their matched, low-stimulation groups. However, the RNS trial reported a responder rate of 29%, which was comparable to VNS but not significantly different than the RNS trial’s sham-treated group. That is, whereas patients had a significant decrease in seizure frequency compared with the control group, the number of patients experiencing a ≥ 50% reduction was not significantly different than the control group. The SANTE trial also had a response rate that was not significantly different than the control response.

Table 1. Randomized controlled trials of VNS compared with other stimulation-based therapies*

Study	No. Patients (no. in active group)	% w/Seizure Reduction, Blinded (95% CI)	% w/Seizure Reduction, 1 Yr	% Responder Rate, Blinded	% Responder Rate, 1 Yr	Regulatory Approval
						FDA	CE Mark
VNS						yes	yes
EO3	114 (54)	24.5 (14.1–34.9)	43	31
EO5	196 (94)	27.9 (21.0–34.8)	45	23.4	35
thalamic DBS—SANTE	109 (54)	40.4 (NR)	41	NR	43	†	yes
cortical stimulation—RNS	191 (97)	37.9 (27.7–46.7)	NR	29	43	†	†

* Seizure reduction is defined as change in actively treated patients compared with their baseline seizure frequency. Responder rates are defined as a ≥ 50% reduction in seizure frequency experienced in actively treated patients. The ≥ 50% responder rate is not reported in the SANTE trial, although it was not significantly different from the untreated group. NR = not reported.
† Pending review.

Trial design is also a potential source of concern when attempting to compare the studies directly. The primary criticism for the EO3 and EO5 trials is that the “control” group was actually stimulated, just at a lower stimulation frequency. Therefore, strictly interpreted, the trials really only show significant benefit of one stimulation paradigm versus the other, as opposed to best medical management alone.

The SANTE and RNS trials avoid this pitfall by using sham stimulation with no current delivery. However, again, the significant comparison being made in these trials is DBS “on” in patients versus DBS “off” in patients. No data directly compare DBS versus best medical management. In all cases, this is because of the inherent difficulty in creating truly blinded surgical trials. The fact that the VNS trials required a device to be on, but firing at a low rate, is a testament to the high frequency of easily noted side effects by the patients, such as voice alteration and paresthesias. Patients in the SANTE and RNS trials, on the other hand, could be successfully evaluated in blinded fashion, even with the devices delivering no active stimuli.

A potential criticism of the SANTE trial is that, with intention-to-treat analysis, there was a sharp increase in the frequency of seizures in treated patients during the 1st month of blinded evaluation, with the model estimating a 19% difference between groups (that is, more seizures in the treated than control group).^[8] However, as explained in the trial’s report, this difference appears to be due to a single patient, who had 210 partial seizures in response to the on/off cycling of his DBS device during the first 3 days of stimulation. If this patient is excluded, the benefit of the DBS is more significant, but there will always be concern generated by excluding patients from final analyses. This is probably why much of the data in the SANTE trial are reported using the median, rather than the mean, because the median is less sensitive to outliers when present.

All trials restricted their analysis to patients with partial seizures and medically refractory epilepsy. Although all trials were restricted to partial seizures in patients with medically refractory disease, there are differences in inclusion criteria that might make one particular therapy more appropriate than others for particular subgroups. For example, only the VNS trials examined patients < 18 years old, so it is unclear how DBS or RNS will work in adolescent patients. However, the adolescent age group was not analyzed separately in the VNS trials, so we have no Class I evidence examining this subgroup in particular. Nevertheless, open label studies are promising, with responder rates for pediatric patients of 50%^[13] to 68%.^[25]

An important difference between RNS and the other therapies is that all included patients in the RNS trial were required to have 1–2 identified epileptogenic foci. We do not know how the RNS system would fare in patients with nonlocalized epilepsy or in those with a larger number of foci. This particular question was addressed more directly in the SANTE trial, in which 9.3% of the stimulated patients had diffuse or multifocal epilepsy. These patients fared well, with a 35.0% reduction in seizures compared with the control group’s 14.1%, although this difference was not significant, probably due to the low number of patients within this subgroup. Neither the EO3 nor EO5 trial analyzed patients in terms of the number of epileptogenic foci, so there remains no Class I evidence for the use of VNS in this subgroup. However, unblinded trials suggest that VNS is effective in multifocal epilepsy: for example, there was a 75% seizure reduction after 3 years in one trial of adults and pediatric patients.^[4] Unblinded studies also support the use of VNS in epilepsy from causes such as Lennox-Gastaut syndrome, tuberous sclerosis, postinfections, and others.^[25] The data from the RNS system and DBS of the ANT are still developing, and as of yet the results have not addressed these alternative etiologies directly.

Adverse events appear to be most frequent with the use of VNS; for example, two-thirds of patients experience voice alteration, nearly half experience new cough, and one-quarter have headaches (Table 2). This compares with headaches in 3.7% of the SANTE patients and 2.6% of the RNS patients. Although depression and memory impairment were reported in both the SANTE and the RNS trials, they were more likely to occur with DBS of the ANT (14.8% and 13.0%, respectively) than with RNS (3.1% and 4.2%, respectively, over the entire 1st year). Moreover, these complaints were significantly more likely to occur in actively stimulated patients in the SANTE trial than in controls, whereas there was no difference in adverse events in controls versus patients in the RNS trial. Importantly, there were no catastrophic adverse events, such as periprocedural death, stroke, or paralysis, in any of the 4 randomized controlled trials.

Some practical considerations for these devices include battery life and implications for imaging. Because DBS of the ANT requires high stimulation currents and frequent stimulation, patients require battery replacement for their device more frequently than do those being treated with VNS (yearly in some patients with DBS of the ANT vs every several years for typical VNS-treated patients). Although all devices are compatible with low-strength (1.5-T) MRI, high-field MRI is not approved while the devices are in place. Moreover, whereas VNS generators can be safely explanted, the associated stimulation cuffs cannot be, due to adherence to the nerve. There is currently no published safety information on MRI in these patients with retained stimulation cuffs. Therefore, MRIs should be performed with extreme caution in patients with explanted VNS devices, pending further study. Because DBS leads can be fully removed, this consideration is not present for DBS of the ANT or the RNS system.

Conclusions

There are now 3 stimulation-based neuromodulation therapies for epilepsy with positive Class I evidence: VNS, DBS of the ANT, and RNS. There are no head-to-head comparisons of these therapies, but all appear to have some limited effectiveness, and all might have application for particular subgroups of patients (Table 3). Depending on which metric is used, any one of the modalities might be viewed as more efficacious than another. The device-related morbidity appears to be specific to the surgical procedure and target of stimulation. The DBS of the ANT and RNS methods have, strictly speaking, fewer adverse events than VNS, although the makeup of events is incongruous (for example, voice changes with VNS vs depression with DBS). Moreover, the intracranial implantation of DBS leads and subdural electrodes is arguably a more invasive procedure than peripheral VNS implantation.

Importantly, however, the rate of serious adverse events such as death or paralysis was < 1%–2% across all devices. Although the RNS system has fewer reported adverse events than DBS of the ANT or VNS, the RNS system is untested on multifocal or diffuse epilepsy, whereas DBS seems to have benefit, although it is not statistically significant. Similarly, unblinded trials suggest that VNS is efficacious for multifocal epilepsy; however, again, Class I evidence is lacking. Adolescent patients were included in the VNS trials, whereas RNS and DBS used only patients ≥ 18 years of age, and unblinded studies support the use of VNS in pediatric patients. We will have to await further studies to determine the effectiveness of DBS of the ANT and RNS for pediatric use. Last, only VNS is FDA approved in the US, making it the only option for most patients. In Europe, both VNS and DBS of the ANT are approved, allowing more choice for patients and physicians. However, the RNS system is under review, and DBS of the ANT is also awaiting further decision on its FDA status. In the future, as more treatments become available, comparing efficacy between stimulation modalities across the broad range of causes of epilepsy will become increasingly important. However, in any case, the advent of increasingly more sophisticated methods of treating epilepsy represents great progress in the field, and the outlook for further advancements is promising.

Acknowledgments
The authors thank Dr. Robert Fisher of the SANTE trial, Dr. Rosana Esteller of NeuroPace, and Dr. Robert E. Gross for helpful discussions.