Closed-loop brain stimulation appears to reduce focal seizures via indirect changes to neural networks over time, rather than through direct, acute suppression of ictal activity, as previously thought.
Improved seizure control in patients with focal epilepsy did not immediately follow responsive neurostimulation (RNS) sessions. Instead, investigators observed a cumulative effect, suggesting the implanted RNS system remodels neural networks over time, making the brain less susceptible to seizures.
"Responsive neurostimulation was thought to work potentially through stopping an individual seizure in its tracks. We have shown that responsive neurostimulation actually disrupts the processes themselves that maintain seizure networks," principal investigator R. Mark Richardson, MD, PhD, of the Brain Modulation Laboratory in the Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pennsylvania, told Medscape Medical News.
Richardson explained the possible mechanism using a whack-a-mole game analogy.
"By popping the mole every time it sticks its head up, we are doing something to its underground system that prevents it from coming to the surface so often," he said.
The study was published online April 15 in JAMA Neurology.
The lack of a direct effect of RNS in seizure reduction runs contrary to previous reports. On the basis of these latest findings, the investigators believe repeated RNS increases neuroplasticity and leads to network-wide changes.
If this indirect modulation effect hypothesis holds true, this "constitutes a paradigm shift in thinking about neuromodulation for epilepsy," the investigators note.
The closed-loop RNS system (NeuroPace, Inc) was approved by the US Food and Drug Administration (FDA) in 2013 for focal-onset refractory epilepsy. Often described as a "pacemaker" for the brain, it automatically detects ictal activity and suppresses it via electrical stimulation.
Recent data from a long-term treatment trial of the system show that the RNS system led to a substantial reduction in seizures and yielded additional benefits, including improved quality of life and better cognition and memory. However, its "therapeutic mechanism of action and its overall efficacy remains suboptimal," the investigators note.
It was widely thought that the RNS electrical pulse acutely worked by directly interrupting the seizure. However, lead author Vasileios Kokkinos, PhD, said his observations told a different story.
"I realized this was not happening. I saw some examples of acute stopping of seizures, but that only accounted for 5% of all seizures. I couldn't explain the 60% to 70% of patients who responded to [RNS] treatment," he said in a release.
To learn more, the investigators visually analyzed 14,634 electrocorticographic readouts for electrographic seizure patterns (ESPs). From the data, they identified 5148 patterns in 11 patients who had been implanted with the RNS system between January 28, 2015, and June 6, 2017.
Study participants ranged in age from 19 to 65 years. The mean duration of epilepsy was 19 years (range, 5 to 37 years). The device automatically analyzes electrocortical potentials to detect seizures and rapidly delivers electrical stimulation to suppress seizure activity.
All participants completed extended Personal Impact of Epilepsy Scale questionnaires. The scale assesses the impact of seizures, adverse effects of medication, and overall quality of life for patients with epilepsy.
The investigators also assessed mean monthly seizure frequency before and after implantation. They estimated the mean severity of seizures on a scale of 1 to 5 and recorded mean duration of seizures in minutes.
Each outcome associated with indirect modulation was statistically significant. In contrast, none of the same metrics emerged as significant with direct neurostimulation.
Table 1. Indirect Modulation of Seizure Characteristics
|Odds Ratio||95% Confidence Interval||P Value|
|Frequency||Infinity||−Infinity to infinity||.005|
|Severity||Infinity||−Infinity to infinity||.007|
|Duration||28.0||1.35 to 580.60||.03|
The researchers observed frequency modulation in ESPs that did not receive triggered stimulation, "suggesting the presence of an underlying effect from chronic stimulation."
Overall, the indirect frequency modulation effects emerged a mean of 7 weeks after the investigators activated the RNS system.
Table 2. Direct Modulation of Seizure Characteristics
|Odds Ratio||95% Confidence Interval||P Value|
|Frequency||0.67||0.07 to 6.41||> .99|
|Severity||0.0||−Infinity to infinity||.10|
The findings demonstrate that RNS "can desynchronize seizure networks through a progressive change in neuroplasticity, and we can see this now for the first time in the electrophysiological data," Richardson said.
"Electrical stimulation over long periods of time may progressively disrupt the connectivity of the epileptogenic network and reduce the core synchronized population, rendering the clinical manifestation of seizures less severe or subclinical," the researchers write.
The small number of study participants prevented the investigators from detecting any synergistic or antagonistic interactions between the two types of modulation. In addition, they could not control for changes in use of antiepileptic drugs during the study.
Future work will aim to identify the most beneficial stimulation protocols.
"We are building a platform called BRAINStim [Biophysically Rational Analysis of Individual Neural Stimulation] that eventually will be able to automatically detect these response biomarkers and make recommendations for improving efficacy for individual patients in real time," Richardson said.
"An Important Study"
Commenting on the study for Medscape Medical News, Sheryl Haut, MD, professor of neurology, chief of the Neurology Service, and director of the Adult Epilepsy Program at Montefiore Medical Center and the Einstein College of Medicine in New York City, said the findings shed light on the treatment's underlying mechanisms.
"The findings of this study demonstrated that RNS produced indirect long-term effects on multiple neurophysiologic parameters that likely contributed to the antiseizure activity," said Haut.
"The neuromodulation demonstrated in the study holds great promise for further understanding the role of neurostimulation in epilepsy and other disorders," she added.
Haut was lead author of a study previously reported by Medscape Medical News that demonstrated that behavioral interventions can reduce seizures in patients with focal epilepsy.
Also commenting on the findings for Medscape Medical News, Robert C. Fisher, MD, PhD, the Maslah Saul, MD, professor of neurology and director of the Epilepsy Center at Stanford University, California, said this is the first study he's aware of that challenges the traditional hypothesis of how RNS works.
In terms of benefit, about two thirds of the seizures were reduced over time — an effect that did not seem to correlate with the acute stimulation, said Fisher.
He was the principal investigator of a study that led to FDA approval of a deep brain stimulation system for treatment of medication-resistant epilepsy, which was reported by Medscape Medical News at that time.
"This additional confirmation from an independent group shows the RNS can improve seizure number and severity and improve quality of life. That's all good," Fisher said.
He added that the findings do not rule out a direct effect on seizures and suggested there may be more than one mechanism.
The study was supported by grants from the Walter L. Copeland Fund of the Pittsburgh Foundation and the National Institute of Neurologic Disorders and Stroke. Richardson and Haut have reported no relevant financial relationships. Fisher is a consultant for Medtronic.
JAMA Neurol. Published online April 15, 2019. Abstract
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Cite this: Brain 'Pacemaker' Remodels Neural Networks to Stop Seizures Over Time - Medscape - Apr 19, 2019.