"I think cooling is the most promising approach," says Miller, who collaborates on cooling research led by a University of Washington colleague. "If a particular cooling temperature can be found that prevents seizures, but does not injure the brain or interfere with normal brain function, it would be possible to maintain the region of brain around the seizure focus at that temperature all the time, so that it would not be necessary to detect the seizures to apply the therapy."
Targeted drug delivery
The third possible mode of operation for closed-loop devices would use convection-enhanced drug delivery (CED). CED involves feeding seizure-halting medications directly to specific areas of brain tissue through an implanted catheter; the concept of CED is designed to avoid the systemic side effects of giving medications orally and having them suffuse through the bloodstream in order to reach the brain.
Yet CED may ultimately prove more useful on a set infusion schedule, rather than linked to a responsive, automated seizure-detection system. "Our current conception of how CED would be used in epilepsy is that patients would receive periodic infusions of a long-lasting antiseizure agent into the epileptic brain region," says Michael Rogawski, chair of neurology at the University of California, Davis, whose lab is working with British Columbia–based biopharmaceutical company MedGenesis Therapeutix to develop an implantable CED device for epilepsy. "Seizure control might be maintained for months," he says. "This approach greatly simplifies the technical challenges in comparison with a device that must sense and deliver a drug on a moment-to-moment basis."
With electrical stimulation, too, some patients will find that an open-loop device that fires consistently works better—like the VNS, or Medtronic's Deep Brain Stimulation (DBS) implant for epilepsy, which the FDA is now reviewing. Similar to the company's widely-used DBS technology for Parkinson’s disease, the DBS for epilepsy is placed within the brain and consistently stimulates a region called the anterior nucleus of the thalamus, which helps control the electrical excitability of the cortex.
Unlike closed-loop devices, which typically require a distinct seizure focus, the DBS can be used to treat patients whose seizures appear to engulf the entire brain, or large portions of it, at once. "If you look at the population of patients who have these very unlocalizable, diffuse seizure disorders, folks who are having many, many seizures a day and are just devastated—if you can control some of those seizures even in some of those patients, you've done a great good for the families and the patients," says Dennis Spencer, chair of neurosurgery and director of the Epilepsy Surgery Program at Yale University School of Medicine. "We think that the DBS will open up a path for therapy."
Closing the loop
Closed-loop technologies for epilepsy face several hurdles. Skeptics note that brain surgery poses significant risks, and that the benefits of implanted devices will not always outweigh those dangers. There are also concerns about the possibility of false positives—detection of electrical activity that turns out not to be a seizure. "If the intervention did cause a transient interruption in brain function, it would be undesirable for the patient," Miller says. "For example, if the area that was being affected mediated language, the person might have a brief interruption in the ability to speak."
Researchers also acknowledge that in a condition as variable as epilepsy, there will never be a single solution, such as cooling, stimulation or drug delivery alone. "We may need to use more than one modality to fully control epilepsy," Osorio says. "But all of that hinges on the ability to detect in real time—and to quantify—seizures."
Although the design of first-generation closed-loop devices is just beginning, theoretical development of the second generation is already underway. Because people with epilepsy never know when and where a seizure will occur, the goal of second-generation closed-loop devices will be finding a way to predict seizures before they begin and intervene to prevent them. "You can detect seizures, but you're still detecting them too late to really have a major therapeutic possibility," Spencer says. "Prediction is where we're really looking to put our eggs—in that basket."