Stanford Medicine-led study identifies novel target for epilepsy treatment

Removing part of the brain’s temporal lobe is the only treatment available to the millions of people with a form of epilepsy that medications often don’t alleviate. But even that approach fails a third of the time.

A new study from Stanford Medicine researchers and their colleagues offers an explanation and suggests a more effective approach to treatment. They found that a previously overlooked region of the hippocampus, the fasciola cinereum, appears to be involved in instigating and propagating seizures. Removing or inhibiting the fasciola cinereum may help those patients who don’t find relief after surgery.

“The hippocampus is the best studied part of the brain by far, but there is shockingly little known about the fasciola cinereum,” said Ivan Soltesz, PhD, the James R. Doty Professor in Neurosurgery and Neurosciences and a senior author on the study. “This relatively small region was consistently involved in seizure activity in mice and in people undergoing pre-surgical electrical recordings. Our findings suggest that all patients with drug-resistant temporal lobe epilepsy should have depth electrodes placed in the fasciola cinereum as part of the surgery planning process.”

The work was published April 17 in Nature Medicine. Soltesz and Vivek Buch, MD, the Christina and Hamid Moghadam Faculty Scholar as well as the surgical director of the Stanford Comprehensive Epilepsy Center, are co-senior authors.

A tale of a tail

Worldwide, 65 million people live with epilepsy. Tens of millions have mesial temporal lobe epilepsy, with seizures originating, in part, from the amygdala, an almond-shaped structure involved in processing emotions, and the hippocampus, a region necessary for forming memories. When people with mesial temporal lobe epilepsy of just one hemisphere do not respond to anti-seizure drug therapies, the standard of care is surgery. In these procedures, the amygdala and most of the hippocampus in one hemisphere are either surgically removed or ablated, a technique that involves using a laser to heat up and destroy tissue. Because of the symmetry of the temporal lobe — both hemispheres of the brain have an amygdala and hippocampus — people who have these surgeries usually have minimal side effects, according to the researchers.

Before performing the surgery, physicians need to identify the brain tissue responsible for seizure activity. They do this by placing electrodes in areas of the brain suspected of starting or propagating seizures and taking recordings from the electrodes. This process, called stereoelectroencephalography, or sEEG, lets them map where in the brain seizure activity happens.

Though the amygdala and its next-door neighbor the hippocampus are common locations for sEEG recordings, the electrodes are typically placed in only the anterior and middle regions of the hippocampus. The human hippocampus, located deep in each hemisphere of the brain near the level of the ear, looks like a sea horse lying on its side, with its head pointing toward the front of the brain. sEEG electrodes are commonly placed in the anterior and medial regions, corresponding to the head, body and the beginnings of the tail of the sea horse.

The idea to record from the fasciola cinereum — the far tip of the sea horse’s tail — in patients with epilepsy undergoing sEEG for surgical planning first formed about three years ago, when Ryan Jamiolkowski, MD, PhD, co-lead author of the study and a resident in neurosurgery, joined the Soltesz lab.

At the time, Quynh-Anh Nguyen, PhD, co-lead author on the study and former postdoctoral scholar in the Soltesz lab who is now at Vanderbilt University, was screening for the hippocampal neurons that were active during seizures in mice. Unexpectedly, Nguyen discovered that neurons in a posterior region of the hippocampus, the fasciola cinereum, were involved in seizures.

Jamiolkowski and the research team used optogenetic techniques to test whether the fasciola cinereum could be a target for epilepsy interventions. The neurons in the fasciola cinereum were made to contain special proteins capable of shutting down neuronal activity when exposed to blue light. When electrical recordings from the hippocampus showed seizure activity, the researchers shined blue light onto the fasciola cinereum, shortening the duration of seizures in mice.

Recording from the human hippocampus tail

To understand the fasciola cinereum’s role in seizure activity in humans, Jamiolkowski and Buch recorded from the small region in six patients. All were undergoing sEEG to identify the source of their seizures in preparation for future surgeries to cure their epilepsy. The fasciola cinereum contributed recorded seizures in all six patients, including some episodes in which the head and body regions of the hippocampus were quiet.

One of the patients with mesial temporal lobe epilepsy of the left hemisphere had already undergone laser ablation of the amygdala and anterior and middle regions of the hippocampus. The patient continued having seizures, and follow-up sEEG showed that the only part of the hippocampus that remained, the fasciola cinereum, was involved in all recorded seizures. The patient underwent a second surgical ablation that removed almost all of the fasciola cinereum, and the frequency of the seizures decreased by 83%, from one to two each month to once every three months.

The researchers said that patients whose seizures involve the fasciola cinereum may need to undergo two surgeries because of the shape of the hippocampus.

“The hippocampus curves like a banana, and the optical fiber used for laser ablation is a straight line. Reaching anterior and posterior regions requires different trajectories that are not currently feasible to combine into one procedure. The results of our study do not challenge the importance of ablating the amygdala and anterior hippocampus but suggest considering a second ablation targeting the posterior hippocampal tail for the patients whose seizures recur,” Jamiolkowski said.

Three of the patients had bilateral involvement of the mesial temporal lobe, which means the amygdala and hippocampus in both the right and left hemisphere showed seizure activity. Because new memories cannot be formed without at least one intact hippocampus, these patients instead received responsive neurostimulation from a device that detects and interrupts seizure activity. However, most responsive neurostimulation units can be configured to target only the anterior regions of the hippocampus on both sides of the brain. The findings from this study suggest that a more personalized approach that also allows the device to monitor and interrupt seizure activity in the posterior hippocampal tail region might be more beneficial to patients.

“Because one-third of patients — a high percentage — do not get seizure freedom from surgery, we should be putting sEEG electrodes in the fasciola cinereum in all temporal lobe epilepsy patients; seizure activity in this region could be a reason why these surgeries sometimes fail,” Jamiolkowski added. “Knowing which patients have seizures involving the fasciola cinereum would let us target it with either ablation or neurostimulation and help us treat patients better than a one-size-fits all approach.”

A researcher from Cambridge University contributed to the study.

Funding for this study was provided by the Stanford Maternal and Child Health Research Institute, the Tashia and John Morgridge Endowed Fellowship, the Lennox-Gastaut Syndrome Foundation Cure 365, the Stanford Neuroscience Scholars Program, and the National Institutes of Health (grants R25NS065741, K99NS121399, K99NS126725, NS121106 and P30AG066515).