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Rapid Seizure Spread Associated with Surgical Failure in Temporal Lobe Epilepsy

Article In Brief

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“The study advances the notion of tailoring epilepsy surgery to achieve seizure freedom by quantifying rapid spread on intracranial electroencephalogram to guide removal of relevant brain tissue without disrupting neurological functions. The [findings from the] study certainly [have] broad implications for thinking about how we treat patients with epilepsy from a surgical perspective.”—DR. JENNIFER L. HOPP

Rapid seizure spread beyond the anteromedial temporal resection margins plays a major role in seizure recurrence, investigators found in a large study. Investigating areas of early spread as possibilities for resection or neuromodulation may achieve better seizure control after epilepsy surgery, they concluded.

Although surgery for drug-resistant focal epilepsy — notably temporal lobe epilepsy (TLE) — has been proven superior to medical management, 30 percent of patients experience seizure recurrence within three years after surgical resection. The cause of surgical failure is unclear, but emerging evidence implicates a network of epileptogenic areas that are separate from the seizure onset zone and not aimed for resection, according to the authors of a new study by investigators at Yale University.

The report, published in the December 3, 2018, online edition of JAMA Neurology, found that rapid seizure spread beyond the anteromedial temporal resection margins plays a major role in recurrence. Investigating areas of early spread as possibilities for resection or neuromodulation may achieve better seizure control after epilepsy surgery, the study authors concluded.

“Evolving therapeutic and diagnostic techniques in epilepsy, such as stereo electroencephalography (sEEG), stereotactic ablation, and responsive neurostimulation, have yet to improve seizure control over open resection,” they wrote. “Identifying the epileptogenic foci or network that are responsible for continued or recurrent seizures postoperatively remains at the forefront of epilepsy research to improve seizure outcomes.”

The study authors performed a retrospective review of medical records from patients with medial TLE who had a standard anteromedial temporal resection by a single (identical) surgeon. Some individuals underwent intracranial monitoring with depth electrodes and extensive neocortical coverage confirming medial temporal lobe seizure onset. An analysis of a cohort with long-term seizure outcome data led to identification of patients at highest risk for recurrent seizures after surgery.

“We know that if the seizures spread more rapidly to another area of the brain, the second site is likely to be the new seizure initiator when they recur following resection,” said the study's corresponding author Dennis D. Spencer, MD, professor and chair emeritus of the department of neurosurgery at Yale University School of Medicine.

If the seizure spread occurs in the nondominant lateral temporal lobe, it would be safe to remove additional tissue from that area without causing cognitive or neurological deficits, Dr. Spencer said. If the spread migrates to a site that is not amenable to resection, however, implanting a neurostimulator would offer the patient a higher probability of seizure freedom.

“In our practice, it changes the way that we approach the patients who may require temporal lobe study with intracranial electrodes,” said Dr. Spencer, who directs the epilepsy and pituitary tumor programs at Yale. “We hope that in the future it will increase the positive outcome and control the seizures in many more of our patients.”

Methodology and Results

To delineate the characteristics of surgically refractory TLE, investigators examined the medical records of 131 patients from Yale's comprehensive epilepsy center. All patients had undergone a standard anteromedial temporal resection by Dr. Spencer from January 1, 2000, to December 31, 2015.

The researchers excluded 13 patients with less than one year of follow-up, while identifying other patients at the highest risk for seizure recurrence. Intracranial electroencephalogram (iEEG) analyses generated three-dimensional seizure spread representations and measured rapid seizure spread. In June 2017 the investigators conducted the final analyses of seizure outcome and follow-up data.

For all patients, they evaluated the Engel class seizure outcome postoperatively, denoting seizure recurrence as Engel class II or greater. Intracranial recordings of neocortical grids/strips and depth electrodes provided visual analysis for seizure spread. Fast beta power was projected onto reconstructions of patients' brain magnetic resonance imaging scans and then quantified to compare power within versus outside resection margins.

Of the 118 patients with at least one year of follow-up, the cumulative probability of continuous Engel class I seizure freedom since surgery at postoperative year 10 and afterward was 65.6 percent, with 92 percent of recurrences documented in years one to three.

The selection for iEEG study was the most reliable indicator of seizure recurrence, with a mixed-effects model projecting that the Engel score in the iEEG cohort was higher by a mean of 1.1 (p=.001), according to multivariable statistical analyses. In patients with iEEG results, rapid seizure spread of less than 10 seconds correlated with recurrence (p<.01).

In the first 10 seconds of seizures, fast beta power activity outside the resection margins in the lateral temporal cortex was notably more elevated in patients with seizure recurrence compared with those who were seizure-free (p<.05).

The authors acknowledged several limitations of their study. Among these they highlighted that the findings from this retrospective cohort “should be interpreted with appropriate caution until they are validated in a prospective manner.” They also noted that despite the long-term follow-up involving many patients, system modifications in medical centers and evolving methods for data collection led to incomplete sets of information for some individuals.

The study provides further justification for the general neurologist to refer patients with drug-resistant epilepsy to a tertiary care center for surgical evaluation, rather than persist in adding or changing medications to try to bring seizures under control, Dr. Spencer said. The scientific literature indicates that a patient whose seizures continue after two different pharmacological interventions is highly unlikely to respond to other medications, he said.

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“Given that about half of patients continue to experience seizures after temporal lobe surgery, new insight into lessening the burden in this group is highly welcome. The patient population in this study is in a way the poster child for people who have epilepsy surgery, yet the procedure only works half the time, and it is important that we know why.”—DR. LARA JEHI

With proper patient selection, “the risk of surgery is very small,” Dr. Spencer added, citing a mortality rate of less than one-tenth of 1 percent. “The ideal time to have a patient come to a possible surgical solution is when they're young, because you can stop their seizures during or before high school.” Early intervention during the formative years enhances education and socialization, making it possible to work and drive, he said.

“The average age of patients in the US coming to surgery is 30” for temporal lobe epilepsy, Dr. Spencer said. “That's about 15 years too late. It just reflects that they're given more medication for too long of a period of time.”

Expert Commentary

The investigators examined the medical records of a fairly homogenous group of patients, who underwent an identical procedure with the same surgeon, noted Lara Jehi, MD, a neurologist and director of research at the Cleveland Clinic Epilepsy Center. But the study “addresses a very important clinical question,” Dr. Jehi said, “which is understanding the mechanism of seizure recurrence after epilepsy surgery.”

In 2017 Dr. Jehi was awarded a $3.4 million grant from the National Institutes of Health (NIH) to lead a multicenter team whose objective is to design a more comprehensive model for predicting epilepsy surgery outcomes.

“Given that about half of patients continue to experience seizures after temporal lobe surgery, new insight into lessening the burden in this group is highly welcome,” said Dr. Jehi, who is also chair of the Surgical Therapies Commission at the International League Against Epilepsy. “The patient population in this study is in a way the poster child for people who have epilepsy surgery, yet the procedure only works half the time, and it is important that we know why,” she said.

Utilizing an innovative approach, the investigators visualized EEG activity of patients' brains in three dimensions, said Dario J. Englot, MD, PhD, surgical director of epilepsy, and assistant professor of neurological surgery, radiology and radiological sciences, and biomedical engineering at Vanderbilt University Medical Center.

The team successfully demonstrated an association between persistent seizures after surgery and rapid seizure spread outside the resection margins. Their research also showed that patients without this phenomenon were more likely to be cured of their seizures, Dr. Englot said.

“This is an important and novel finding that may lead to improved techniques for delineating the amount of brain that must be removed to stop seizures and will allow improved patient counseling about the chances of seizure freedom with epilepsy surgery,” he said.

For decades specialists have known that in mesial temporal lobe epilepsy, both ipsilateral and contralateral propagation of ictal discharge is slow or nonexistent, accounting for patients' auras in isolation, said Jerome Engel Jr., MD, PhD, FAAN, professor of neurology, neurobiology, psychiatry, and biobehavioral sciences, and director of the Seizure Disorder Center at the David Geffen School of Medicine at UCLA.

“This study is a nice confirmation [of this observation,” Dr. Engel said. But, he added, “The question is: Where are the seizures actually coming from and what else needs to be resected?” Dr. Engel said. “The study doesn't confirm that performing a larger resection would render a patient seizure-free,” he noted. “The challenge is to decide how much to resect.”

Jennifer L. Hopp, MD, FAAN, associate professor in the department of neurology and director of the University of Maryland Epilepsy Center, said: “The study advances the notion of tailoring epilepsy surgery to achieve seizure freedom by quantifying rapid spread on intracranial electroencephalogram to guide removal of relevant brain tissue without disrupting neurological functions. The [findings from the] study certainly [have] broad implications for thinking about how we treat patients with epilepsy from a surgical perspective.”

Disclosures

Drs. Spencer and Jehi had no disclosures. Dr. Hopp is the site principal investigator of the Maryland Consortium Hub and is involved in several epilepsy related trials, including the Established Status Epilepticus Treatment Trial, Neurological Emergencies Treatment Trials, and a randomized double-blind, placebo-controlled trial to evaluate the efficacy and safety of SAGE-547 injection in the treatment of subjects with super-refractory status epilepticus.

Link Up for More Information

• Andrews JP, Gummadavelli A, Farooque P, et al. Association of seizure spread with surgical failure in epilepsy https://jamanetwork.com/journals/jamaneurology/fullarticle/2717818. JAMA Neurol 2018; Epub 2018 Dec 3.