Welcome Diversion

For some, a neurostimulator implant may stop seizures before they start

By Gary Goettling

Research

Kay Hinton

TAKING THE WHEEL Thanks to a tiny neurostimulator implanted in her skull, Janie Norman is now seizure-free and able to drive for the first time.

When it comes to his epilepsy treatment research, “good is the enemy of best,” says Robert Gross, transposing Voltaire’s aphorism. “Once you’ve developed a good therapy, sometimes there’s a tendency toward complacency.”

The Emory neurosurgeon, MBNA Bowman chair, and professor is not one to rest on his past accomplishments. With a $5 million, five-year grant from the National Institutes of Health (NIH)— part of the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative—Gross, who also serves as director of the Emory Neuromodulation Technology Innovation Center, is studying ways to improve the performance of a new neurostimulator to prevent epilepsy seizures.

An epileptic seizure typically presents as a loss of control or function, suggesting disorganized cellular signaling in a particular part of the brain. In fact, the neurons are too organized and are firing all at the same time, in effect overloading the nerve pathways, explains Gross.

“Think about it this way,” he continues. “If you go into a theater and somepeople are whispering in a low voice, there’s no problem. If everyone whispers the same thing at the same time, the sound would be deafening.”

Gross specializes in the treatment of “medically intractable” epilepsy, meaning the condition does not respond to medication. For these individuals, who comprise about a third of the estimated four million epilepsy patients in the US, there are two options. One is to surgically remove the section of brain determined to be the source of the seizures—most commonly situated in the mesial temporal lobe within a structure called the hippocampus, which is responsible for memory. This approach carries a high risk that the patient will also lose some degree of brain function, depending on what part of the brain is ablated.

“Few areas of the brain are dispensable,” Gross says. “When we’re dealing with a part of the brain that has a function people don’t want to lose, we have to pursue nondestructive means to try and stop the seizures.”

The other option is a “responsive” neurostimulator in which two electrodes are implanted in the area of the brain where the seizures originate. Wires connect the electrodes to a battery-powered electric stimulator implanted into the skull.

“When the algorithm running on the computer in the device detects epileptic activity, then and only then, it stimulates the brain electrically and can block progression of the seizures,” Gross says.

The device was introduced three years ago after a successful clinical trial that involved the participation of Gross and the Emory team. One of the Emory patients even testified before the Food and Drug Administration about the device.

Aside from the surgical aspect, the procedure poses little risk and few adverse effects, and for that reason this year Emory has performed more of the neurostimulator implants than any other hospital in the country, Gross notes. But the implant does have one major drawback: It prevents only 50 to 65 percent of a patient’s seizures, and rarely stops seizures altogether.

Here is where the NIH BRAIN award—and Voltaire—come into play.

“It’s a good device, but not a great device,” says Gross. “How do we move to 100 percent seizure reduction with no adverse effects? We have to figure out how to advance from here.”

Gross is pioneering a new approach to neurostimulation for epilepsy. The basic concept was discovered a number of years ago by his collaborator, Steve Potter of the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Potter was growing brain cells in culture over an array of sixty-four electrodes and recording their activity. He saw that the cells had begun rhythmically and simultaneously firing and not firing bursts of electrical signals.The phenomenon is familiar to science: Under certain conditions, similar-type oscillators may spontaneously begin to act in unison.

“Steve recognized that this pattern of activity was reminiscent of epileptic neurons—so-called epileptiform activity,” Gross says.

Further experimentation revealed that stimulating the neuron culture via the electrodes all at once intensified the epileptiform activity, but firing the electrodes in an asynchronous manner, where each one didn’t fire at the same time as any of its neighbors, completely suppressed the excessive synchronous signal bursting because it had disrupted its rhythm. This technique of asynchronous bursting is a critical aspect of the neurostimulator’s function.

It took several years to take these results out of the cell culture, but last year Gross’s lab demonstrated in rodents that the asynchronous neurostimulation technique was significantly more effective in suppressing seizures than the standard approach used by the responsive neurostimulator.

The way forward includes ongoing research into the causes and mechanisms of epilepsy with the hope of figuring out ways to use its mechanisms against it, according to Gross. In translating the new approach into patient clinical trials, however, studies involving nonhuman primate models will be key.

“We’ll pioneer the new technology in nonhuman primates and, if things work out, we’ll do an early feasibility study in patients with a new type of device where, instead of having to measure the seizures themselves, we measure the signals in the brain—biomarkers—that go hand in hand with seizures so that we can tune our device very quickly.”

Seizure-Free Means New Freedom

When everything else has failed, and a promising but unproved treatment comes along, “you go for it,” says Janie Norman.

Diagnosed with epilepsy thirty-four years ago when she was eleven, Norman experienced seizures every single day—sometimes several times a day. She was able to attend college, get married, and have children, but her quality of life was severely curtailed in other ways:She couldn’t participate in sports, go to the movies, or go shopping by herself. She had no way of getting around on her own because the threat of seizures made driving too risky.

After years of trying, no drug or combination of drugs worked.

When Norman moved from south Georgia to metro Atlanta a few years ago, her neurologist referred her to Emory, where Gross performed several weeks of intracranial monitoring and determined that surgery wasn’t an option. He then tried something new: In 2008, as part of a clinical study, he implanted the NeuroPace RNS (responsive neurostimulator) system. After months of fine-tuning the system, it was fully activated in January 2009. She has been free of seizures ever since.

“I don’t really think about it,” she says. “Everything happens internally, so I don’t feel anything different when the device is activated.”

Norman’s experience, while promising for others with epilepsy, is uncommon. Subsequent implants on additional patients have yielded success rates more typically of 50 percent to 65 percent. Gross’s ongoing research aims to improve these numbers.

In early 2013 Norman testified before the Food and Drug Administration’s (FDA) Neurological Devices Panel as it was considering approval of the NeuroPace RNS. She summarized the device’s most profound benefit for her: “The most obvious aspect of my life affected by my seizures was the fact that I could not drive. I could not be independent and go places on my own. Not just for myself, but for my kids also,” she told the group. The RNS device, added Norman, “enabled me to have the freedom that I had wanted for a very long time.”

The RNS received FDA approval later that year.

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