CHICAGO — Ongoing clinical trials for two implanted devices designed to interrupt or predict seizures herald an area of clinical research that has quickly gained ground during the last 5 years, Dr. Brian Litt said at the annual meeting of the American Neurological Association.
Research into seizure prediction, most of which has occurred in the past 15 years, has been “very controversial,” mostly because of people getting too excited about findings very early on, said Dr. Litt, of the departments of neurology and bioengineering at the University of Pennsylvania, Philadelphia.
Early studies were plagued by overreliance on abstract functions rather than on clinical physiological parameters, and they lacked statistical rigor.
As a result, the databases were biased toward seizures because much of the data were taken from inpatients who had many seizures during hospital stays.
“Those data are not what it's like to live with epilepsy; you might have one seizure a month, you might have four a month. But clearly the preponderance of the data is interictal,” he said.
A data set heavily enriched with seizures makes it much more likely that attempts to predict seizures at broad intervals will, in fact, detect a seizure. This made it impossible to reproduce the claims of seizure prediction that were announced in early studies.
“We also found that listening to patients was really important,” Dr. Litt said, because many patients tell their physicians that sometimes hours or days before a seizure onset, they have a feeling—or prodrome—that tells them they are likely to have a seizure. And the patients may or may not have a seizure.
“The model [for predicting seizures] has to account for this,” he said.
These lessons taught Dr. Litt and his colleagues that they were very unlikely to predict an exact seizure, but that it was likely they could identify periods of time in which the probability of a seizure's occurring is greatly increased.
No efficacy data are yet available for the two devices that are being tested in phase III trials, but no adverse events have occurred.
In Medtronic Inc.'s Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) trial, about 150 adult patients with medically refractory partial-onset epilepsy will receive the Intercept Epilepsy Control System. The implanted device, which bilaterally stimulates the anterior nucleus of the thalamus but does not sense or respond to EEG activity, will be turned on in some patients but not in others during the trial's double-blind phase. Medtronic decided to continue the SANTE trial after it recently passed its midterm analysis, according to Dr. Litt.
The Responsive Neurostimulator (RNS) system from NeuroPace Inc. will be tested in about 240 adult patients to determine if it can reduce the frequency of medically uncontrolled and disabling partial-onset seizures. All patients will be implanted with the device, which scans EEG recordings for particular patterns associated with seizure onset or impending seizures, and then stimulates epileptogenic foci through intracranial electrodes.
In a safety study of about 50 patients with more than four seizures per month who were implanted with the RNS device, 43% of those with complex partial seizures and 35% of those with disabling motor seizures had a 50% or greater reduction in seizures, Dr. Litt said.
“Is this a home run? No. Does it mean that it's effective? No. Does it mean that there's proof of principle enough to perhaps go forward? I think it does,” Dr. Litt said.
“Remember, this is a first-generation device. Judge this as a work in progress, like the first pacemaker,” he added.
Dr. Litt has contributed patents through the University of Pennsylvania for NeuroPace's RNS device.
He is a consultant to BioNeuronics Corp., and he helped to found BioQuantix Corp. through the University of Pennsylvania.
Major questions still remain in understanding and mapping epileptic networks in the brain, such as where to place electrodes, where to sense seizure onset, and where to stimulate the brain. Researchers also want to know how seizures are generated over time.
To answer these questions, Dr. Litt and his associates have examined seizures in patients with RNS devices, which save about a minute of data prior to stimulation and also for a short period afterward.
Analyses of the 2-second period before a seizure began in thousands of events distinguished between effective and ineffective types of stimulation. For particular stereotyped seizure onsets, the researchers used specific characteristics of synchrony, frequency of activity, and the relationship between the stimulus and the seizure waveform to determine if stimulation would be effective or not.