Seizure Freedom in TLE Tied to Piriform Cortex Resection

Pauline Anderson

March 21, 2019

Removal of at least half of the piriform cortex is required to achieve freedom from seizures in the neurosurgical treatment of temporal lobe epilepsy (TLE), new research suggests.

A proof-of-concept study conducted by investigators at University College London, United Kingdom, showed that almost 60% of patients with TLE became seizure free if half of the piriform cortex was resected. By contrast, if less than half of this brain structure was removed, 9% of patients became seizure free.

Dr Matthias Koepp

"The study highlights the critical role of the piriform cortex in achieving seizure freedom in epilepsy patients," principal investigator Matthias J. Koepp, MD, PhD, professor of neurology, told Medscape Medical News.

The findings, added Koepp, should encourage epilepsy experts to "think outside the box."

The study was published online March 11 in JAMA Neurology.

Lack of Human Research

The piriform cortex, which resembles a ribbon, is located between the insula and the temporal lobe anteriorly and laterally of the amygdala. The function of the piriform cortex relates to olfaction.

The histologic properties of the piriform cortex are similar to those of the hippocampus, the authors note. This brain region is well connected to the limbic system, the orbitofrontal and insular cortex, and the thalamus and so serves as a corticosubcortical circuit hub.

Basic science has demonstrated the importance of the piriform cortex in triggering seizures in animals, but these findings have not been demonstrated in humans, said Koepp.

Surgeons have been working individually to determine how much, if any, of this brain region can be removed safely, he added.

"One has to be careful because it's close to important structures, with lots of tracts going into the frontal lobes that carry information," he said.

The researchers conducted a study to determine whether removal of the piriform cortex is associated with freedom from postoperative seizures in patients with medically refractory TLE. The study included 107 patients who underwent anterior temporal lobe resection at a single center from January 1, 2005, through December 31, 2013. Of these patients, 63.6% were women; the median age was 37 years.

Presurgical and postsurgical high-resolution structural MRI scans were performed using the same scanner. For all the study participants, the same neurosurgeon had performed the procedure. The postoperative follow-up period was of at least 2 years.

The researchers assessed seizure outcomes annually. Patients were considered to be seizure free (SF) if they had experienced no seizures or auras during the follow-up period, excluding acute postoperative seizures within the first week.

For statistical analyses, the study authors used the Mann-Whitney test and reported two-sided P values.

No Impact on Cognition, Anxiety, Psychosis

Of the total cohort, 43.0% remained completely seizure free during postoperative follow-up (median, 5 years; range, 2 – 11 years). There were no differences in clinical characteristics between the patients who were free of seizures and those who were not, except that among the non–seizure-free (NSF) patients, there was an increase in the risk for postoperative depression (26.1% vs 49.2%; P = .02).

Using voxel-based morphometry, the researchers determined there was greater loss of gray matter in the ipsilateral piriform cortex in postoperative vs preoperative scans in the SF group compared to the NSF group.

Preoperative reduction in volume of the ipsilateral piriform cortex was significantly associated with postoperative seizures (median in SF group, 0.5 mL; median in NSF group, 0.4 mL; P = .02). No association was found for the hippocampus, the amygdala, or the entorhinal cortex.

A significantly larger proportion of the piriform cortex was resected in the SF group compared to the NSF group (median, 83% vs 52%; P < .001).

This association remained significant after correction for presurgical piriform cortex volume and factors associated with postoperative outcome, including sex, presence of hippocampal sclerosis, history of generalized seizures, preoperative seizure frequency, and duration of epilepsy (adjusted odds ratio [OR] per 10% resected, 1.8; 95% confidence interval [CI], 1.4 – 2.4; P < .001).

After controlling for presurgical gray matter volume within several extratemporal areas, the proportion of the piriform cortex that was resected remained significantly associated with postsurgical outcomes (adjusted OR, 1.8; 95% CI, 1.3 – 2.5; P = .001).

The findings remained robust after adjusting for presurgical hippocampal volumes and the proportion of white matter tract disconnection.

The extent of piriform cortex removal did not influence postoperative cognitive outcome, anxiety, or psychosis. However, larger piriform cortex resections were associated with less postoperative depression.

To validate the results, the researchers used an external cohort of 31 participants with TLE from two other centers (12 SF and 19 NSF).

When the researchers combined the internal derivation data with data from the external validation cohorts (n = 138), only 8.5% of the total became seizure free if less than 50% of the piriform cortex was resected, compared with 59.3% if at least 50% was removed (P < .001).

Is More More?

Resection of at least half of the piriform cortex increased the odds of complete seizure freedom by a factor of 16 (95% CI, 5 – 47; P < .001).

"Our findings suggest that if the epileptic network in the piriform cortex is not sufficiently disrupted by removing at least half of this area, an individual has 16 times higher odds of having postoperative seizures," the authors note.

This is the first time that findings of an advanced imaging study were replicated in a totally different sample, noted Koepp.

The authors emphasized, however, that removal of at least 50% of the piriform cortex does not guarantee a favorable outcome. "Other factors play a role, and they might explain the remaining two-thirds of outcome variability," they write.

These factors include mislocalization or incomplete resection of the epileptogenic focus, and the generation of an occult, independent epileptogenic area outside of the anterior temporal lobe.

Koepp likened the piriform cortex to a "switch" in the brain's network. "What we think we're doing here by taking out the piriform cortex is possibly switching off the epilepsy rather than just cutting out part of a malfunctioning brain."

A deficit in smell might be a consequence of removal of the piriform cortex, as might visual acuity effects "if one goes too far into the neighboring white matter," said Koepp.

The new findings may have important implications for clinical practice, including possible development of new pharmacologic approaches. The findings may also provide a target for deep brain stimulation, said Koepp.

In addition, because the results suggest that the piriform cortex is a "central hub," the findings may apply to other types of epilepsy, he said.

Welcome Findings

Commenting on the study for Medscape Medical News, Daniel M. Goldenholz, MD, PhD, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, said he's "very excited" about the study.

"It provides evidence in humans that this structure should be targeted" during hippocampal sclerosis surgery in order to improve the seizure-free outcome long term.

"At present, improving that outcome has proven elusive, so this is a welcome finding," he said.

The investigators made several "very smart" decisions, said Goldenholz. One of these was choosing a relatively homogeneous population, over 80% of whom had a diagnosis of hippocampal sclerosis.

"By doing this, they increased their chances of finding something out about that subset of patients," he said.

Goldenholz also applauded the authors for defining seizure freedom as the absence of seizures for a period of at least 2 years.

"This is very strict criteria that is often ignored by studies like this," he said. By using this definition, the authors "are asking what factors impact lasting success, rather than short-lived successes."

Other important elements of the study include having a validation dataset from outside institutions, which lends weight to the results, and taking additional steps to test for confounding, said Goldenholz.

He expressed concern that the statistical choices for significance made by the authors "raise the possibility that the results may not be reproducible in other datasets or that the effect size is not very large."

However, Koepp said the sample size "is huge" for an imaging study and that the results "validate not only the statistical significance but the clinical relevance of our findings."

New Therapeutic Target?

Goldenholz noted that use of a subjective definition of the anatomic structure of the area in question "could create ambiguity when others attempt to reproduce these results."

But Koepp said he and his coauthors "applied some generally acceptable landmarks for defining this area" that others with proficiency and experience should be able to follow.

Goldenholz questioned the finding that a smaller piriform cortex presurgically led to a relatively bad outcome, whereas a larger resection of the same structure resulted in a good outcome.

"Although possibly true, understanding why this odd relationship exists was not straightforward," said Goldenholz.

Koepp said that it's the percentage of the piriform cortex that's removed, not the amount, that's important.

The study requires further validation from external laboratories, commented Goldenholz. If the results are reproduced, "I think we can expect most epilepsy surgical centers to pay close attention."

About 50% of patients with refractory focal epilepsy continue to have seizures after surgery. Even among those deemed highly likely to become seizure free after surgery, a large percentage don't, said Goldenholz.

"This study sheds light on a possible reason — an anatomical target that must be addressed in hippocampal sclerosis cases," he said.

This new research may inform epilepsy experts about which patients may not benefit from the surgery, added Goldenholz.

"It would be of great interest if the present study could lead us to a point where we could tell patients that they should avoid surgery because they are unlikely to be successful and be exposed to the risks of surgery without the benefit," he said.

The study was partially funded by the UK Department of Health. Koepp received grants from the UK Medical Research Council and the Wellcome Trust during the conduct of the study. Goldenholz has disclosed no relevant financial relationships.

JAMA Neurol. Published online March 11, 2019. Abstract

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