Lo-Res to Hi-Res, A Better way to Pinpoint Where Seizures Begin

When you replace an older cell phone or TV with a new high-resolution device, the visuals can be strikingly different – all of a sudden you have improved clarity and can see new details. Now, UC San Francisco epilepsy researchers have applied a similar principle to brain recordings in an effort that might make epilepsy surgeries more effective for patient outcomes.

For most people with epilepsy, seizures can be controlled with anti-seizure medications. But for about a third of epilepsy patients, medications fail to halt their seizures and surgery may be necessary to remove or disconnect damaged brain tissue responsible for causing seizures.

Dysfunctional tissue generates seizure activity, and the brain usually adapts to move normal functions out of the dysfunctional area. The challenge for epileptologists is pinpointing seizure onset zones (SOZ) so that the exact areas of the brain where seizures begin can be removed without impacting neurological functions that are critical to the daily life of the patient.

Traditional epilepsy surgery first involves implanting electrode arrays directly in brain tissue using depth electrode probes or on its surface with subdural grids and strips to pinpoint where the seizures start directly in the brain. The detail of these electrodes’ recordings is often lacking, however, because the electrodes sampling the underlying brain activity may be spaced too far apart.

To improve the clarity of how much tissue to remove during epilepsy surgery, UCSF researchers used intracranial electroencephalogram (EEG) recordings, which measure the electrical activity of the brain, and recreated electrode arrays of different densities to pinpoint SOZ. They then created seizure activity heatmap videos projected on reconstructed brain images to translate the data from the EEG recordings. They used the heat maps videos to study how differing electrode densities might influence judgment calls of epileptologists on SOZs.

The study published March 3, in eBioMedicine (open-access journal from The Lancet), found that using intracranial EEG recordings with high-density arrays resulted in better appraisals and better agreement about the location of SOZ among the epileptologists, compared to lower-density recordings.

“One of the worst feelings we get is when a patient who underwent surgery begins having seizures again. It suggests some of the bad, seizure-generating tissue is still present,” said senior study author Jon Kleen, MD, PhD, an epilepsy specialist and UCSF assistant professor of neurology in the Weill Institute for Neurosciences. “It can be hard to figure out where that bad spot is and precisely how far it extends, especially when brain imaging studies look normal. Our thought was similar to high-resolution TVs – more detail might be better. So we used additional electrodes between the electrodes we were already putting in. Our goal was to provide a direct and unbiased comparison of how higher electrode density might impact seizure localization relative to lower density.”

Fuller picture of where seizures begin

UCSF neurosurgeon Edward Chang, MD, placed high-density electrode grids in and on the brains of patients with drug-resistant epilepsy. Once electrodes were implanted, the patients spent several days in the hospital awaiting seizures so their onset locations could be pinpointed.

The researchers asked trained epileptologists to localize the SOZ for these patients using the full higher-density array recordings (4 to 5 mm inter-electrode spacing) versus lower-density (8 to 10 mm spacing) resampled versions of those same seizures.

The researchers projected seizure activity data as heatmaps videos on patient brain reconstructions and hid electrode locations. Using a single-blinded randomized crossover design, six epileptologists viewed these video visualizations under both higher-density and lower-density conditions, using a custom computer program to trace the outlines of the SOZ directly on the brain. Using higher-density depth and subdural intracranial EEG recordings increased agreement among epileptologists and resulted in them identifying larger extents of SOZ compared to lower-density recordings.

“The crossover study design made for a tightly controlled comparison,” said Kleen. “The seizure onset zone was consistently bigger with high-density compared to low-density across all the scores, and we did computer simulations verifying this. Using more electrodes always got you closer to the true extent of the SOZ because it shows activity for extra brain sites that way, some of which are also bad and might have been missed otherwise. The higher-density probes thus provided a fuller picture of the SOZ and where the seizures began.”

Kleen notes that high-density arrays might also allow for more precise mapping of brain region functions, a process done by physicians using electrical stimulation. While not evaluated in this study, it is possible extra detail from more electrodes could enhance the ability of surgeons to tailor surgical margins even more precisely for both normal and abnormal tissue.

The researchers suggest additional study is needed from more patients to assess whether higher densities lead to better surgical outcomes, but the results are clear: higher densities of electrodes on already-implanted hardware may provide better clarity about the location and full extent of the SOZ. “We’re hopeful this may enable better appraisals of pathophysiological tissue margins and move the needle in the effectiveness epilepsy surgery,” said Kleen.

Additional UCSF Authors: Ebenezer O. Chinedu-Eneh, Sharon Chiang, John P. Andrews, Joline M. Fan, Paul A. Garcia, Ernesto Gonzalez-Giraldo, Manu Hegde, Patrick Hullett, Vikram R. Rao, Robert C. Knowlton, Edward F. Chang.

Funding: This work was supported by the National Institutes of Health through NINDS grant K23NS110920 and through a UCSF Weill Institute for Neurosciences Pilot Award.

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