On advanced brain-imaging scans, epileptic seizures look like thunderstorms viewed from space: split-second bursts of electrical energy that light up the entire globe. Some experts even call them “brain storms.”
Soon—perhaps within two years—we'll see the first generation of early-warning devices that can monitor brain activity for signs of a coming storm and send electrical pulses to reduce or even stop it in its tracks.
Seizures occur when electrical impulses from neurons in the brain become synchronized in an abnormal way. The result is a disruption of electrical communication between these neurons that leads to the release of excessive energy.
Anticonvulsant medications can reduce the frequency of seizures for many of the 50 million people worldwide who have epilepsy, but they are ineffective for as many as one in three. For these patients, the promise of the new devices is long awaited. A surgeon implants the device while the patient is under general anesthesia, and once the apparatus is in place, patients barely notice the stimulation as anything more than a slight tingle.
At the forefront of this research are two systems currently being tested in clinical trials around the country: the Intercept Epilepsy Control System by Medtronic, Inc.; and the Responsive Neurostimulator System (RNS) by NeuroPace, Inc.
These implantable devices are called closed-loop systems because they contain all of the components needed to detect a seizure and send electrical counter-signals in response. Both systems contain microchips that recognize the first signs of a seizure by analyzing the brain's electrical activity in real time. Then, a stimulator component delivers an electrical burst to restore normal brain activity, explains Brian Litt, M.D., assistant professor of neurology and bioengineering at the University of Pennsylvania's Neuroengineering Research Lab.
“Closed-loop seizure devices were inspired by cardiac defibrillators, or pacemakers, which are very successful in heart patients,” says Dr. Litt, who helped develop the RNS system. “Similar technology is used to control seizures.”
The RNS and Intercept both use a tiny electroencephalogram (EEG) to monitor and record electrical activity in the brain. When abnormal activity is detected, a stimulator sends electrical signals through two thin electrodes to the anterior nucleus of the thalamus—a part of the brain just behind the hairline that is believed to regulate epileptic seizures. Seizures are essentially waves of electrical energy, and stimulators deliver counter-waves that work much like the way sound-cancellation headphones make the cockpit of a 747 as quiet as a library.
THE INTERCEPT SYsTEM
The Intercept system stimulates both sides of the anterior nucleus of the thalamus using two electrodes implanted into the brain, a battery pack implanted into the chest, and a lead wire running up the patient's neck and beneath the scalp. The electrodes and leads are permanent, and the power pack—about the size of an iPod mini—requires a battery with a life-span of about five years, after which it can be replaced. After a brief period of discomfort as their wounds heal, patients quickly adjust to implants. Most say they are rarely aware of the device or the stimulation it delivers.
The Intercept was proven safe in a 2005 trial; its effectiveness at stopping seizures is now being tested, though as of press time, patients are no longer being recruited. All patients receive implants and are monitored for 13 months, with long-term follow-up until the device is approved or the study is stopped. Epilepsy medications will be continued during the trial. Candidates are adults with partial-onset epilepsy who have an average of six or more seizures per month and for whom at least three antiepileptic drugs have proven ineffective. Partial-onset seizures affect only one half of the brain and usually do not cause the person to lose consciousness.
THE RNS SYSTEM
The RNS device, which has been in clinical trials since February 2007, is a matchbox-sized titanium-coated microprocessor that is surgically implanted into the cranium. Because seizures don't progress the same way in all people, the RNS is preprogrammed to detect patient-specific seizures patterns and the electrodes may be implanted in a number of different places. When the RNS spots an oncoming seizure, it automatically delivers a 0.5- to 10-volt burst of electricity.
This battery-operated system can also be reprogrammed by a physician in response to changes in the patient's condition over time. The doctor passes a wand over the data component, wirelessly downloading the information into a laptop loaded with programming software.
Although animal studies have suggested that brain stimulation can cause functional changes in the brain—even seizures in rare cases—these devices have passed rigorous safety testing in human volunteers. In an earlier NeuroPace-sponsored study of 65 patients with medically uncontrolled seizures, patients experienced no serious side effects related to the RNS device, and most had less frequent and severe seizures.
The FDA approved a trial of the device in 2005, allowing the company to enroll 220 people with medically uncontrolled partial-onset seizures at 28 sites across the United States. The company has completed enrollment and will soon be planning its next trial.
Martha Morrell, M.D., chief medical officer at NeuroPace and a professor of neurology at Stanford University School of Medicine, in Stanford, Calif., told Neurology Now that patients can volunteer to participate in the study up until the company submits its final data to the FDA for approval in approximately two years.
She also said the researchers hope to learn more than whether the device works or not: The RNS records EEG data that can then be uploaded through a hand-held wand to a computer for further study, and Dr. Morrell hopes the data will provide electrical “signatures” of seizures far earlier than are currently detectible.
“Many of us believe that if you wait until the seizure has taken hold, it has already spread to a larger portion of the neuronal network and could be more difficult to stop,” Dr. Litt says. “But no trials have clearly demonstrated that yet.”
Dr. Morrell expects the RNS will detect seizures so mild that the patient doesn't even notice them. The device may even be able to detect an unusual EEG pattern before a seizure starts. And here, in the calm before the storm, may be the best place to forecast and forestall a seizure.
▾ INTERCEPT: Medtronic, Inc. is testing the Intercept Epilepsy Control System in adults with partial-onset epilepsy whose treatments have included at least three antiepileptic drugs that have been ineffective. It's called the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial (clinicaltrials.gov/ct/show/NCT00101933? order = 10.) Volunteers receive an implanted device and are monitored for 13 months. As of press time, patients are no longer being recruited.
▾ RNS: In the Study of a Responsive Neurostimulator System to Treat Epilepsy Trial, sponsored by NeuroPace, Inc., physicians will document each participant's seizure type, frequency, and severity and assess epilepsy-related physical and emotional health before and after RNS implantation. Patients range from 18 to 65 years of age. Although this trial is no longer open for enrollment, information about NeuroPace's next trial will be posted at neuropace.com/trials/overview.