Can Sea Lions Expand Our Knowledge of Epilepsy?

In 2022, the Journal of Neurosurgery took the unusual step of publishing a case report of a nonhuman subject, in this case an 8-year-old male sea lion named Cronutt, who had severe epilepsy that in many ways mirrored the common form seen in humans.

A 2020 xenotransplantation of interneuron progenitor cells in the sea lion’s hippocampus may have cured him. “He’s doing fantastic,” said Scott Baraban, PhD, a professor of neurological surgery at the University of California San Francisco Weill Institute for Neurosciences. The procedure offered a confirmation of success stories in mice and could serve as a bridge to human studies, although the science remains murky. 

Cronutt’s story began the first time he was found stranded along the California coast in San Luis Obispo County, in November 2017, lethargic and disoriented. Nevertheless, he improved quickly under the care of the Marine Mammal Rescue Center in Sausalito, California, and they released him back into the wild 2 weeks later. Unfortunately, his troubles weren’t over. In the next 2 months, he came to the attention of the rehabilitation center two more times, and the resulting habituation to humans meant that he could not be re-released to the wild.

Things only got worse from there. He experienced a convulsive seizure and loss of consciousness in early 2018 and another seizure a year later. Despite anti-seizure medication, the episodes continued, and eventually, he stopped eating for long periods and lost a quarter of his body weight. It looked like euthanasia was the only alternative.

Neurosurgeons Take Notice

Baraban has devoted his career to animal models of epilepsy, focusing mainly on mice. He developed a method to transplant GABAergic interneurons from pigs, which can pick up the inhibitory role of endogenous neurons. In epileptic mice, mouse-derived progenitor cells mature into inhibitory synapses and dampen seizures, and even reverse behavioral problems. 

Baraban was intrigued by the potential of the procedure to help sea lions and potentially bridge the gap between murine and human studies, and he was eager to try the approach after he learned of Cronutt’s case through his colleague Paul Buckmaster atStanford University, Stanford, California, who had collaborated with the Marine Mammal Rescue Center to demonstrate that sea lions suffer hippocampal damage that is very similar to human temporal lobe epilepsy.

It turns out that surgery on a sea lion is more complicated than on a mouse. The surgeon needs to conduct an MRI scan to locate the lesion and guide the placement of transplanted cells, and the big animals need to be sedated and intubated. Their caretakers are not enthusiastic about invasive procedures, but Cronutt had already been imaged as part of an earlier study of the effects of exposure to domoic acid on the sea lion brain, giving neurosurgeons at UCSF the information they needed.

In 2020, they transplanted GABAergic interneurons into Cronutt’s hippocampus in a last-ditch effort to save his life. He improved rapidly, and his caregivers eventually tapered off his anti-seizure medications. Today, Cronutt is living seizure-free at the Six Flags Discovery Kingdom in Vallejo, California. He even began participating in shows at Six Flags. “He is able to learn things and do things cognitively that he couldn’t do before,” said Baraban.

The researchers have not followed up with more imaging. “We just haven’t had any reason to bother him. It’s very invasive to get him to an MRI center,” said Baraban.

There haven’t been any more procedures on sea lions, in part because sea lions at rescue centers must be returned to the wild within 6-8 months, and animals with pig-based progenitor cells can’t be released. Any sea lion that would undergo such a procedure would have to live permanently in captivity, potentially for 20-30 years. “It’s a huge undertaking and expense,” said Baraban. There are also logistical challenges with the need to have MRI and other facilities close at hand to where the sea lion is kept.

Human Connections

As a veterinarian interested in human epilepsy, Buckmaster sought to find additional animal models for human temporal lobe epilepsy. He later met a veterinarian who worked with the Marine Mammal Center, who told him about temporal lobe epilepsy in sea lions. 

Cronutt was just one of hundreds of California sea lions and other mammals rendered helpless by epileptic seizures induced by exposure to domoic acid, a chemical released by toxic algal blooms. Sea otters, whales, and even birds can likewise be affected. Humans, too, though it is rare: A domoic acid poisoning event in mussels from Prince Edward Island led to convulsions and an eventual diagnosis of temporal lobe epilepsy in an 84-year-old Canadian man, and three others died.

Most of Buckmaster’s work had been done in rats, but seizures are different than what are seen in humans. The damage isn’t unilateral, as in human epilepsy. The damage is unilateral in sea lions, and they suffer damage to similar neurons to those injured in humans. “In rats, you don’t see much loss of granule cells, which are the main neuron in the dentate gyrus, a region that’s really affected in temporal lobe epilepsy. In people, there’s a lot of variation, but [on average] you lose about half your granule cells, and that’s similar to sea lions. In rats, they just don’t lose them,” said Buckmaster.

That makes sea lions a useful model, but they hardly crack the case of human epilepsy. “To be humble about it, we don’t really know what’s causing the seizures. We have an idea of what region of the brain the seizures are coming from, but in terms of the cellular mechanisms, it’s still not clear,” said Buckmaster.

He also noted that, unlike sea lions, the vast majority of patients with human epilepsy have no exposure to domoic acid. That said, the case of sea lions and other marine animals makes researchers wonder. “This is speculative, but a lot of people with temporal epilepsy will have a history of some kind of precipitating event. Typically, it’s earlier in life, and a common one is prolonged febrile seizures. That could be a link to the domoic acid exposure in sea lions because the domoic acid exposure in sea lions frequently causes prolonged seizures. If the seizures are severe enough and long enough, they cause permanent brain damage, and that can cause temporal lobe epilepsy. That’s what we strongly believe is causing the temporal lobe epilepsy in sea lions. Prolonged, severe seizures can be caused by many things other than domoic acid, and that could be what causes it in many cases of human temporal lobe epilepsy,” said Buckmaster.

The approach taken with Cronutt makes sense to Buckmaster, who was not directly involved in the procedure. “The ideal treatment would be something that you would administer once, and it would cause cessation of seizures without any side effects. The transplantation of inhibitory cells is a treatment that would last and hopefully wouldn’t have any side effects and hopefully would provide complete control of seizures. It’s unlikely to reach all those goals, but it’s a step in the right direction, hopefully,” said Buckmaster.

He noted that Cronutt is only a single case and not proof that the procedure will work more generally. It’s possible the sea lion would have improved on his own without treatment, and the procedure itself could have influenced the brain. “That’s been the case with other neurological conditions that have attempted to be treated with cell transplantation,” said Buckmaster.

A phase 1/2 clinical trial, sponsored by Neurona Therapeutics, is currently recruiting patients to test transplant of human interneurons created from pluripotent stem cells into both temporal lobes of patients with drug-resistant bilateral mesial temporal lobe epilepsy.

Cronutt’s Course

Although he has improved dramatically, it’s possible that Cronutt continues to experience nonconvulsive seizures, which would not be easy to detect in an animal. “You don’t know if Cronutt’s seizures are controlled or not unless you can look at the electrical activity in Cronutt’s brain, and to my knowledge that has not been done,” said Buckmaster.

Previous studies in rats did repeatedly demonstrate the potential of the treatment approach. Despite the feel-good story of Cronutt, “That’s probably the most compelling evidence in support of that arm of treatment,” said Buckmaster.

Buckmaster and Barbaran had no relevant financial disclosures.

Jim Kling is a writer in Bellingham, Washington.