Individual Patient Characteristics Should Guide Choice of Device for Epilepsy Seizure Control

VANCOUVER—For patients with refractory epilepsy who are not candidates for resective surgery, neuromodulatory devices can be helpful. But which device should be considered for which patient? “Individualize the treatment,” said Christianne Heck, MD, at the 68th Annual Meeting of the American Academy of Neurology. With open- and closed-loop treatments available, factors such as compliance and patient lifestyle are some of the considerations physicians should keep in mind.

Of the approximately 50 million people worldwide with epilepsy, more than one-third have drug-resistant epilepsy (DRE). “DRE is defined as the failure of two or more appropriate antiepileptic drugs to achieve complete seizure control,” said Dr. Heck, Medical Director of the University of Southern California Comprehensive Epilepsy Program at the Keck Medical Center in Los Angeles. “It is associated with major depression, an increased risk in injury and death, cognitive and attention deficits, lower quality of life, and increased healthcare costs.”

Even as new medications have become available, drug resistance rates have remained the same. In addition, adverse effects are quite common and interfere with daily living. “They’re the primary cause of treatment failure in 13% to 40% of patients, depending on the drug,” Dr. Heck noted. “Devices for epilepsy have demonstrated quality-of-life improvements and improvements in mood scores, as well as sustained effectiveness over time.”

Surgery is appropriate for about half of patients with DRE who undergo a presurgical workup in an epilepsy center. The other 50%, however, either have an epileptic zone that is not well defined or an epileptic zone that localizes to eloquent cortex that cannot be resected.

Vagus Nerve Stimulation

Open-loop devices provide automated continuous or nearly continuous stimulation to the area of focus. They control excess electrical activity in the brain by administering regular electrical impulses to reduce the frequency and severity of seizures. Among the open-loop systems is vagus nerve stimulation (VNS), which was approved by the FDA as adjunctive therapy in reducing the frequency of seizures in adults and in adolescents older than 12 with refractory partial onset seizures.

The VNS device is implanted under the skin in the left chest. A horizontal incision in the left neck allows for an electrode from the stimulator to be wrapped around the left vagus nerve. In the Vagus Nerve Stimulation Study Group E01-E05 trials, researchers observed a 43% responder rate—defined as a 50% or greater reduction in seizure frequency—among VNS users at three years.

While VNS is an open-loop system, patients who have auras and can tell when a seizure might occur can pass a special magnet near the implanted device to trigger stimulation outside of the programmed intervals on demand, Dr. Heck said. “However, some patients say they have no way to know when to use the magnet. I try to make it clear to them that magnet activation is a luxury, not a requirement.”

A closed-loop VNS device, AspireSR (Cyberonics), was approved by the FDA in 2015. Closed-loop devices provide stimulation only in response to a trigger. For AspireSR, elevated heart rate triggers stimulation. “The parameters for the change in heart rate can be adjusted based upon the individual’s cardiac changes,” said Dr. Heck. “But it also works in conjunction with its normal cycling, as well as magnet modes.”

One concern about using heart rate as a biomarker for epileptic seizures is that the definition of ictal tachycardia varies widely in the medical literature—from 100 bpm to 140 bpm to a 10-bpm increase. “It’s difficult at this point to determine whether heart rate is the ideal biomarker,” Dr. Heck noted.

The automated nature of VNS therapy lessens concerns about patient compliance, and the treatment has minimal side effects, Dr. Heck said. Patients may, however, experience hoarseness or other voice changes during stimulation—a consideration for those whose voice is an important part of their job, including singers. In addition, patients may become slightly out of breath during stimulation, which could be a concern for athletes. Furthermore, the device is costly and requires surgical implantation, yet there is no way to predict before surgery whether the patient’s seizures will be responsive to neurostimulation therapy.

Deep Brain Stimulation

Deep brain stimulation (DBS) for epilepsy targets the anterior nucleus of the thalamus. DBS for the treatment of epilepsy has not yet been approved in the US. During DBS surgery, two electrodes are placed deep inside the brain through small holes made in the skull. MRI or another imaging technique helps ensure the electrodes are placed correctly. The electrodes are connected to wires that run under the skin behind the ear and down the neck to a neurostimulator that is implanted under the skin in the upper chest, below the collarbone. As with VNS, a patient with auras can activate the device in addition to receiving automated treatment.

Dr. Heck cited a recent trial of DBS that included 110 patients with epilepsy who had experienced at least six seizures per month and failed at least three antiepileptic drugs. During long-term follow-up, the responder rate was 43% at one year and 68% at five years. Sixteen percent of the patients were seizure-free for at least six months, and scores on the Liverpool Seizure Severity Scale improved over baseline. There was an adverse event rate of 34%.

Noninvasive Stimulation

Another open-loop device is the external trigeminal nerve stimulator (eTNS), which is noninvasive and easy to use, Dr. Heck said. “It’s preset with a certain stimulation algorithm and therefore doesn’t require programming. The patient simply adjusts the current to [his or her] comfort level.”

The eTNS unit includes an electrode that is applied to the forehead. Patients can wear the device at night or under a cap during the day, Dr. Heck said. eTNS is approved for prescription use in the EU, Canada, and Australia as adjunctive therapy for epilepsy in patients ages 9 and older.

In a small, 18-week randomized active control trial of 50 patients with DRE who experienced two or more partial onset seizures per month, researchers observed a 40% improvement in the treatment group versus a 16% improvement in the control group. “Although we don’t have any data on this so far, eTNS may be a convenient way to test whether neuromodulation works for patients before they invest in an implantable device that is considerably more expensive,” Dr. Heck said.

Responsive Neurostimulation

Responsive neurostimulation (RNS) devices are placed under the scalp and within the skull. One or two electrodes connected to the neurostimulator are placed at the seizure focus site.

“At this point, I think that the RNS System [NeuroPace] is the gold standard for responsive closed-loop epilepsy therapy. It responds specifically to cortical activity that represents seizure,” Dr. Heck said. “The cranial implant is not visible, which is good for patients who care about scarring. The small stimulation pulses [are] delivered through the leads directly to the brain and those pulses add up to less than six minutes of electrical stimulation per day on average.” The RNS System received premarket approval by the FDA in late 2013 to treat medically refractory partial epilepsy.

Patients do not know when they are receiving stimulation. RNS “provides an alternative for localization-related DRE when surgery is not an option,” she added. RNS also may be appropriate for patients who have multiple seizure onset zones because more than one electrode can be used to cover various sites.

A disadvantage of using RNS is the shorter battery life, compared with VNS (three to four years vs four to 10 years, respectively). In addition, it is a complex device to use. “I began to work with this device in 2006 and I still would not claim to be an absolute expert yet. I think it’s an exciting kind of technology, but the actual parameters for therapy still need to be worked out,” Dr. Heck said. Because of the need for frequent follow-up visits to program the device, RNS may be a difficult treatment option for patients who must travel long distances.

The RNS System Pivotal trial evaluated responder rates at two years. Patients using RNS demonstrated gradual improvement, with median seizure reductions of approximately 53%, compared with baseline. There were no persistent clinically significant neurologic sequelae.

—Adriene Marshall

VANCOUVER—For patients with refractory epilepsy who are not candidates for resective surgery, neuromodulatory devices can be helpful. But which device should be considered for which patient? “Individualize the treatment,” said Christianne Heck, MD, at the 68th Annual Meeting of the American Academy of Neurology. With open- and closed-loop treatments available, factors such as compliance and patient lifestyle are some of the considerations physicians should keep in mind.

Of the approximately 50 million people worldwide with epilepsy, more than one-third have drug-resistant epilepsy (DRE). “DRE is defined as the failure of two or more appropriate antiepileptic drugs to achieve complete seizure control,” said Dr. Heck, Medical Director of the University of Southern California Comprehensive Epilepsy Program at the Keck Medical Center in Los Angeles. “It is associated with major depression, an increased risk in injury and death, cognitive and attention deficits, lower quality of life, and increased healthcare costs.”

Even as new medications have become available, drug resistance rates have remained the same. In addition, adverse effects are quite common and interfere with daily living. “They’re the primary cause of treatment failure in 13% to 40% of patients, depending on the drug,” Dr. Heck noted. “Devices for epilepsy have demonstrated quality-of-life improvements and improvements in mood scores, as well as sustained effectiveness over time.”

Surgery is appropriate for about half of patients with DRE who undergo a presurgical workup in an epilepsy center. The other 50%, however, either have an epileptic zone that is not well defined or an epileptic zone that localizes to eloquent cortex that cannot be resected.

Vagus Nerve Stimulation

Open-loop devices provide automated continuous or nearly continuous stimulation to the area of focus. They control excess electrical activity in the brain by administering regular electrical impulses to reduce the frequency and severity of seizures. Among the open-loop systems is vagus nerve stimulation (VNS), which was approved by the FDA as adjunctive therapy in reducing the frequency of seizures in adults and in adolescents older than 12 with refractory partial onset seizures.

The VNS device is implanted under the skin in the left chest. A horizontal incision in the left neck allows for an electrode from the stimulator to be wrapped around the left vagus nerve. In the Vagus Nerve Stimulation Study Group E01-E05 trials, researchers observed a 43% responder rate—defined as a 50% or greater reduction in seizure frequency—among VNS users at three years.

While VNS is an open-loop system, patients who have auras and can tell when a seizure might occur can pass a special magnet near the implanted device to trigger stimulation outside of the programmed intervals on demand, Dr. Heck said. “However, some patients say they have no way to know when to use the magnet. I try to make it clear to them that magnet activation is a luxury, not a requirement.”

A closed-loop VNS device, AspireSR (Cyberonics), was approved by the FDA in 2015. Closed-loop devices provide stimulation only in response to a trigger. For AspireSR, elevated heart rate triggers stimulation. “The parameters for the change in heart rate can be adjusted based upon the individual’s cardiac changes,” said Dr. Heck. “But it also works in conjunction with its normal cycling, as well as magnet modes.”

One concern about using heart rate as a biomarker for epileptic seizures is that the definition of ictal tachycardia varies widely in the medical literature—from 100 bpm to 140 bpm to a 10-bpm increase. “It’s difficult at this point to determine whether heart rate is the ideal biomarker,” Dr. Heck noted.

The automated nature of VNS therapy lessens concerns about patient compliance, and the treatment has minimal side effects, Dr. Heck said. Patients may, however, experience hoarseness or other voice changes during stimulation—a consideration for those whose voice is an important part of their job, including singers. In addition, patients may become slightly out of breath during stimulation, which could be a concern for athletes. Furthermore, the device is costly and requires surgical implantation, yet there is no way to predict before surgery whether the patient’s seizures will be responsive to neurostimulation therapy.

Deep Brain Stimulation

Deep brain stimulation (DBS) for epilepsy targets the anterior nucleus of the thalamus. DBS for the treatment of epilepsy has not yet been approved in the US. During DBS surgery, two electrodes are placed deep inside the brain through small holes made in the skull. MRI or another imaging technique helps ensure the electrodes are placed correctly. The electrodes are connected to wires that run under the skin behind the ear and down the neck to a neurostimulator that is implanted under the skin in the upper chest, below the collarbone. As with VNS, a patient with auras can activate the device in addition to receiving automated treatment.

Dr. Heck cited a recent trial of DBS that included 110 patients with epilepsy who had experienced at least six seizures per month and failed at least three antiepileptic drugs. During long-term follow-up, the responder rate was 43% at one year and 68% at five years. Sixteen percent of the patients were seizure-free for at least six months, and scores on the Liverpool Seizure Severity Scale improved over baseline. There was an adverse event rate of 34%.

Noninvasive Stimulation

Another open-loop device is the external trigeminal nerve stimulator (eTNS), which is noninvasive and easy to use, Dr. Heck said. “It’s preset with a certain stimulation algorithm and therefore doesn’t require programming. The patient simply adjusts the current to [his or her] comfort level.”

The eTNS unit includes an electrode that is applied to the forehead. Patients can wear the device at night or under a cap during the day, Dr. Heck said. eTNS is approved for prescription use in the EU, Canada, and Australia as adjunctive therapy for epilepsy in patients ages 9 and older.

In a small, 18-week randomized active control trial of 50 patients with DRE who experienced two or more partial onset seizures per month, researchers observed a 40% improvement in the treatment group versus a 16% improvement in the control group. “Although we don’t have any data on this so far, eTNS may be a convenient way to test whether neuromodulation works for patients before they invest in an implantable device that is considerably more expensive,” Dr. Heck said.

Responsive Neurostimulation

Responsive neurostimulation (RNS) devices are placed under the scalp and within the skull. One or two electrodes connected to the neurostimulator are placed at the seizure focus site.

“At this point, I think that the RNS System [NeuroPace] is the gold standard for responsive closed-loop epilepsy therapy. It responds specifically to cortical activity that represents seizure,” Dr. Heck said. “The cranial implant is not visible, which is good for patients who care about scarring. The small stimulation pulses [are] delivered through the leads directly to the brain and those pulses add up to less than six minutes of electrical stimulation per day on average.” The RNS System received premarket approval by the FDA in late 2013 to treat medically refractory partial epilepsy.

Patients do not know when they are receiving stimulation. RNS “provides an alternative for localization-related DRE when surgery is not an option,” she added. RNS also may be appropriate for patients who have multiple seizure onset zones because more than one electrode can be used to cover various sites.

A disadvantage of using RNS is the shorter battery life, compared with VNS (three to four years vs four to 10 years, respectively). In addition, it is a complex device to use. “I began to work with this device in 2006 and I still would not claim to be an absolute expert yet. I think it’s an exciting kind of technology, but the actual parameters for therapy still need to be worked out,” Dr. Heck said. Because of the need for frequent follow-up visits to program the device, RNS may be a difficult treatment option for patients who must travel long distances.

The RNS System Pivotal trial evaluated responder rates at two years. Patients using RNS demonstrated gradual improvement, with median seizure reductions of approximately 53%, compared with baseline. There were no persistent clinically significant neurologic sequelae.

—Adriene Marshall

VANCOUVER—For patients with refractory epilepsy who are not candidates for resective surgery, neuromodulatory devices can be helpful. But which device should be considered for which patient? “Individualize the treatment,” said Christianne Heck, MD, at the 68th Annual Meeting of the American Academy of Neurology. With open- and closed-loop treatments available, factors such as compliance and patient lifestyle are some of the considerations physicians should keep in mind.

Of the approximately 50 million people worldwide with epilepsy, more than one-third have drug-resistant epilepsy (DRE). “DRE is defined as the failure of two or more appropriate antiepileptic drugs to achieve complete seizure control,” said Dr. Heck, Medical Director of the University of Southern California Comprehensive Epilepsy Program at the Keck Medical Center in Los Angeles. “It is associated with major depression, an increased risk in injury and death, cognitive and attention deficits, lower quality of life, and increased healthcare costs.”

Even as new medications have become available, drug resistance rates have remained the same. In addition, adverse effects are quite common and interfere with daily living. “They’re the primary cause of treatment failure in 13% to 40% of patients, depending on the drug,” Dr. Heck noted. “Devices for epilepsy have demonstrated quality-of-life improvements and improvements in mood scores, as well as sustained effectiveness over time.”

Surgery is appropriate for about half of patients with DRE who undergo a presurgical workup in an epilepsy center. The other 50%, however, either have an epileptic zone that is not well defined or an epileptic zone that localizes to eloquent cortex that cannot be resected.

Vagus Nerve Stimulation

Open-loop devices provide automated continuous or nearly continuous stimulation to the area of focus. They control excess electrical activity in the brain by administering regular electrical impulses to reduce the frequency and severity of seizures. Among the open-loop systems is vagus nerve stimulation (VNS), which was approved by the FDA as adjunctive therapy in reducing the frequency of seizures in adults and in adolescents older than 12 with refractory partial onset seizures.

The VNS device is implanted under the skin in the left chest. A horizontal incision in the left neck allows for an electrode from the stimulator to be wrapped around the left vagus nerve. In the Vagus Nerve Stimulation Study Group E01-E05 trials, researchers observed a 43% responder rate—defined as a 50% or greater reduction in seizure frequency—among VNS users at three years.

While VNS is an open-loop system, patients who have auras and can tell when a seizure might occur can pass a special magnet near the implanted device to trigger stimulation outside of the programmed intervals on demand, Dr. Heck said. “However, some patients say they have no way to know when to use the magnet. I try to make it clear to them that magnet activation is a luxury, not a requirement.”

A closed-loop VNS device, AspireSR (Cyberonics), was approved by the FDA in 2015. Closed-loop devices provide stimulation only in response to a trigger. For AspireSR, elevated heart rate triggers stimulation. “The parameters for the change in heart rate can be adjusted based upon the individual’s cardiac changes,” said Dr. Heck. “But it also works in conjunction with its normal cycling, as well as magnet modes.”

One concern about using heart rate as a biomarker for epileptic seizures is that the definition of ictal tachycardia varies widely in the medical literature—from 100 bpm to 140 bpm to a 10-bpm increase. “It’s difficult at this point to determine whether heart rate is the ideal biomarker,” Dr. Heck noted.

The automated nature of VNS therapy lessens concerns about patient compliance, and the treatment has minimal side effects, Dr. Heck said. Patients may, however, experience hoarseness or other voice changes during stimulation—a consideration for those whose voice is an important part of their job, including singers. In addition, patients may become slightly out of breath during stimulation, which could be a concern for athletes. Furthermore, the device is costly and requires surgical implantation, yet there is no way to predict before surgery whether the patient’s seizures will be responsive to neurostimulation therapy.

Deep Brain Stimulation

Deep brain stimulation (DBS) for epilepsy targets the anterior nucleus of the thalamus. DBS for the treatment of epilepsy has not yet been approved in the US. During DBS surgery, two electrodes are placed deep inside the brain through small holes made in the skull. MRI or another imaging technique helps ensure the electrodes are placed correctly. The electrodes are connected to wires that run under the skin behind the ear and down the neck to a neurostimulator that is implanted under the skin in the upper chest, below the collarbone. As with VNS, a patient with auras can activate the device in addition to receiving automated treatment.

Dr. Heck cited a recent trial of DBS that included 110 patients with epilepsy who had experienced at least six seizures per month and failed at least three antiepileptic drugs. During long-term follow-up, the responder rate was 43% at one year and 68% at five years. Sixteen percent of the patients were seizure-free for at least six months, and scores on the Liverpool Seizure Severity Scale improved over baseline. There was an adverse event rate of 34%.

Noninvasive Stimulation

Another open-loop device is the external trigeminal nerve stimulator (eTNS), which is noninvasive and easy to use, Dr. Heck said. “It’s preset with a certain stimulation algorithm and therefore doesn’t require programming. The patient simply adjusts the current to [his or her] comfort level.”

The eTNS unit includes an electrode that is applied to the forehead. Patients can wear the device at night or under a cap during the day, Dr. Heck said. eTNS is approved for prescription use in the EU, Canada, and Australia as adjunctive therapy for epilepsy in patients ages 9 and older.

In a small, 18-week randomized active control trial of 50 patients with DRE who experienced two or more partial onset seizures per month, researchers observed a 40% improvement in the treatment group versus a 16% improvement in the control group. “Although we don’t have any data on this so far, eTNS may be a convenient way to test whether neuromodulation works for patients before they invest in an implantable device that is considerably more expensive,” Dr. Heck said.

Responsive Neurostimulation

Responsive neurostimulation (RNS) devices are placed under the scalp and within the skull. One or two electrodes connected to the neurostimulator are placed at the seizure focus site.

“At this point, I think that the RNS System [NeuroPace] is the gold standard for responsive closed-loop epilepsy therapy. It responds specifically to cortical activity that represents seizure,” Dr. Heck said. “The cranial implant is not visible, which is good for patients who care about scarring. The small stimulation pulses [are] delivered through the leads directly to the brain and those pulses add up to less than six minutes of electrical stimulation per day on average.” The RNS System received premarket approval by the FDA in late 2013 to treat medically refractory partial epilepsy.

Patients do not know when they are receiving stimulation. RNS “provides an alternative for localization-related DRE when surgery is not an option,” she added. RNS also may be appropriate for patients who have multiple seizure onset zones because more than one electrode can be used to cover various sites.

A disadvantage of using RNS is the shorter battery life, compared with VNS (three to four years vs four to 10 years, respectively). In addition, it is a complex device to use. “I began to work with this device in 2006 and I still would not claim to be an absolute expert yet. I think it’s an exciting kind of technology, but the actual parameters for therapy still need to be worked out,” Dr. Heck said. Because of the need for frequent follow-up visits to program the device, RNS may be a difficult treatment option for patients who must travel long distances.

The RNS System Pivotal trial evaluated responder rates at two years. Patients using RNS demonstrated gradual improvement, with median seizure reductions of approximately 53%, compared with baseline. There were no persistent clinically significant neurologic sequelae.

—Adriene Marshall