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AES Annual Meeting

Access daily, concise peer-reviewed reports from the AES Annual Meeting selected by the Neurology Today editors

Thursday, December 6, 2018

BY THOMAS R. COLLINS

NEW ORLEANS—Two-thirds of children who underwent laser ablation surgery for hypothalamic hamartoma (HH) emerged from one or more surgeries seizure-free, according to a presentation here at the American Epilepsy Society annual meeting.

The findings add to solid results that have been reported for an approach already regarded as a top choice for children with HH, a disorder characterized by non-neoplastic developmental malformations and associated with gelastic seizures, secondary epileptogenesis, and refractory epilepsy.

"This [option] should be considered; however, it will never be the only choice," said presenter Irfan Ali, MD, professor of neurophysiology at Baylor University.

Researchers did a retrospective review of the medical records of 44 patients with HH and refractory epilepsy who were referred to Texas Children's Hospital from 2012 to 2016. All of the patients underwent magnetic resonance imaging-guided stereotactic laser ablation.

All of the children — ages 10 months to 19 years old — had gelastic seizures, and some also had other seizure types: focal seizures (17) with impaired awareness; tonic seizures (five); myoclonic seizures (two); myoclonic-tonic seizures or spasms (two); and generalized tonic-clonic seizures (two).

Researchers found that seizures stopped in 61 percent of the patients and were significantly reduced in another 7 percent. Seizure frequency decreased in all of the patients. Post-surgery morbidity was minimal, with hospital stays averaging 1.6 days.

Researchers said there was no link between outcome and the number of surgeries performed. So additional laser surgeries were effective.

"Some of the children had better control of seizures but were not completely seizure-free," Dr. Ali said. "But once you re-do surgery with another ablation, they [can] become seizure-free."

He said the findings show that laser ablation should be the first option in many cases, since it avoids problems seen with other surgical approaches.

"We definitely have some co-morbidity associated with the open surgery," he said. "Children might lose a year or two before they see cognitive benefits with radiosurgery, for example, costing them important cognitive development time. With laser ablation, we have seen the cognitive effects immediately, and then they build on it."

Other surgery types will also sometimes have to be considered, he cautioned.

Dr. Ali explained that a large tumor may need debulking, and sometimes more than one session with laser ablation may be needed. But, he added, laser ablation can be repeated with less morbidity. "You can get the same results without the risks of open surgery," he said.

Sarah Bandt, MD, assistant professor of neurological surgery at Northwestern University, said laser ablation "has rapidly become the first line treatment option of choice for these lesions" and that these findings can give clinicians and surgeons even more confidence.

"Epilepsy specialists are hopeful that findings like this can bring more attention to surgical treatment options for the management of epilepsy," she said. "Approximately 30 percent of patients living with epilepsy don't achieve seizure freedom with medication alone. Surgery offers potential benefit to many of these patients."

Dr. Bandt offered this caveat, however. "While these preliminary findings are exciting and encouraging, we need to understand more about laser-targeting in patients with large lesions as well as ways to optimize seizure outcome for all patients undergoing this procedure."

Dr. Ali had no disclosures. Dr. Bandt received a stipend from the NFL for consulting work on neurotrauma and from Monteris for travel-related expenses.

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AES Abstract 3.331: Verma S, Ali I, Clarke DF, et al. Hypothalamic hamartoma and MRI-guided stereotactic laser ablation.

Thursday, December 6, 2018

BY THOMAS R. COLLINS

NEW ORLEANS—Medical providers including neurologists, pharmacists, and nurses are willing to prescribe cannabidiol (CBD) products but feel they lack adequate knowledge and training to do so, according to national survey findings presented here at the American Epilepsy Society annual meeting.

As CBD products become more widely available, the survey results point to training deficits that will need to be addressed for epilepsy patients to fully benefit from the products, according to researchers who conducted the survey for Greenwich Biosciences, a subsidiary of GW Pharmaceuticals, which manufactures the CBD product approved by the US Food and Drug Administration in June.

Magdalena Szaflarski, PhD, associate professor of sociology at the University of Alabama, who presented the findings, said that the results are not too surprising, given that CBD products have not been legal until recently and that laws on most products still vary by state.

"That's why we're seeing this gap between the willingness to prescribe it and their actually doing it," she said. "Providers do not have enough knowledge yet. Researchers don't even have enough knowledge about many of the cannabis-based therapies to be confident about prescribing it to patients. So there's a lot to be done."

A total of 451 health professionals — evenly divided among neurologists, pharmacists, and nurses and nurse practitioners — responded to the survey across the US. Forty percent of the respondents worked in community settings and a quarter in academic settings, and their responses typically didn't differ according to setting, researchers said.

Answers to questions on beliefs and attitudes reflected an openness to CBD products. More than 80 percent said they somewhat agree, agree, or strongly agree with the statement, "I believe that CBD is effective in reducing seizure frequency." Nearly 90 percent of the neurologists said they somewhat agree, agree, or strongly agree with the statement, "If legalized, I would be comfortable prescribing the FDA approved and regulated version of CBD for treatment of epilepsy."

Only about 60 percent of respondents said they felt they had enough knowledge to prescribe CBD products, and approximately 80 percent said they needed more education about CBD treatment for epilepsy.

On questions gauging knowledge — among neurologists, pharmacists, and nurses (which included nurse practitioners) — 75 percent, 81 percent and 67 percent, respectively, correctly answered whether cannabis is legal (it's not). But only 38 percent, 59 percent, and 46 percent, respectively correctly answered whether hemp is legal (it is).

"We were particularly surprised that among neurologists there was this larger gap," Dr. Szaflarski said. "Neurologists seemed to know more than the other two provider groups, but still the gaps were pretty large, considering all the development on this issue in the last two years, within neurology and also specifically in epilepsy."

Dr. Szaflarski said there appears to be more willingness to prescribe CBD products than was seen in previous surveys. "What these new results show," she said, is "that more and more providers are coming on board and accepting these therapies, and many think that they're helpful and they would be willing to use them in their practice."

Joseph I. Sirven, MD, FAAN, professor of neurology at Mayo Clinic in Phoenix, AZ, said the findings demonstrate the confusion that surrounds CBD use.

"I believe there is such stigma surrounding the medication from its connection to marijuana — that we know so little and the laws seem so dynamic — that no one can keep up with the regulations," he said. "In the US, each state has its own laws and then there is a federal law with so many conflicting answers, it's hard to know what is correct. Even with the good news of this version of CBD being approved, there is still considerable confusion between this product and products available in dispensaries."

Greenwich Biosciences, Inc. funded the study. Dr. Szaflarski received consulting fees and research support from GW Pharmaceuticals, Inc. and Greenwich Biosciences, Inc. Dr. Sirven reported no disclosures.

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AES Abstract 3.469: Szaflarski M, McGoldrick P, Currens L, et al. Cannabinoid knowledge and attitudes among US healthcare providers.

Thursday, December 6, 2018

BY THOMAS R. COLLINS

NEW ORLEANS—The standardized mortality rate (SMR) for patients with psychogenic non-epileptic seizures (PNES) is 2.5 times that of the general population and similar to most patients with epilepsy, according to a retrospective cohort study covering 20 years at two tertiary hospital video electroencephalography (EEG) monitoring units in Melbourne, Australia.

The findings, presented here at the American Epilepsy Society annual meeting, shed light on the seriousness of a disorder that is considered understudied and subject to stigma.

When researchers excluded patients with a known brain tumor at the time of EEG and with a malignant neoplasm listed as their cause of death, there was no significant difference between the PNES patients and the epilepsy patients.

"We expected mortality in PNES to be much higher than the general population and this was the case, with PNES patients dying at a rate more than 2.5 times greater," said presenter Russell Nightscales, a medical student at the University of Melbourne. "But given that the mortality rate is so high in epilepsy centers with high rates of treatment-refractory epilepsy, we were surprised to discover that mortality in PNES was comparable to [the rate] in those with epilepsy."

Researchers calculated mortality rates for the 5,419 patients who underwent video EEG between 1995 and 2015, extracting clinical data from records, and linking to the Australian National Death Index for mortality and cause-of-death data. About 3,400 met inclusion criteria for the study.

The relative risk of mortality for those with PNES between ages 30 and 39 was more than seven times greater than that in the general population and remained significantly elevated above the general population until age 70, Nightscales said.

The proportion of patients with PNES who died from suicide was more than four times higher than in the general population, researchers found. Most of these deaths were in younger patients, with suicides and accidental poisonings accounting for almost half of all deaths in those younger than 50.

"The high incidence of preventable deaths in those with PNES was striking," Nightscales said. "These findings are clinically important as we may be looking at a subgroup of patients that require more follow-up or more wary management to avoid these deaths."

Nightscales said he hopes that the findings help bring more research attention to PNES and that the medical community more consistently regards it as a serious disorder.

"A diagnosis of PNES is often communicated to patients as being somewhat positive by way of exclusion of epilepsy," he said. "We can now conclude that this is not the case. We hope that our research is a major step in deconstructing these misconceptions. Showing the medical and general communities that this is an important diagnosis with serious implications is a key feature of our research."

Selim Benbadis, MD, FAAN, professor of neurology at the University of South Florida, said he at first thought the findings were surprising, but upon more reflection realized the high mortality rate in PNES makes sense.

"Not only do these patients have a mental disorder, but it's [often also] undiagnosed for years," Dr. Benbadis said. "They have other unexplained symptoms. Because they have multiple unexplained symptoms, once they are diagnosed with psychogenic seizures, they may not be taken seriously. People tend to dismiss everything as psychogenic, perhaps." This, he said, could delay care.

Patients with PNES need more care than they tend to get, including screening for depression, and that care can be hard to come by.

"Once diagnosed, they need to have serious treatment — that means psychiatric medication and psychological therapy. Getting mental health professionals interested in this is a challenge, as it has always been."

Nightscales and Dr. Benbadis reported no disclosures related to the study.

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AES Abstract 1.139: O'Brien TJ, Nightscales R, McCartney L, et al. Mortality in patients with psychogenic non-epileptic seizures.

Thursday, December 6, 2018

BY THOMAS R. COLLINS

NEW ORLEANS—Administering a Wnt antagonist after seizures are induced in a mouse model of temporal lobe epilepsy modulates neuronal network remodeling, offering new insight into a potential therapeutic target, researchers said here at the American Epilepsy Society annual meeting.

The Wnt pathway has many roles in the nervous system, making it an intriguing area of study in epilepsy, said presenter Kunal Gupta, MBBChir, PhD, chief resident in neurological surgery at Oregon Health & Science University.

"Within the nervous system, it is involved in axon pathfinding, dendrite outgrowth, neurogenesis, as well as behavioral tasks in mice, including memory and learning," he explained. "Epilepsy is characterized by a number of these neuronal changes, which have been proposed to be responsible for seizure production. It is therefore possible that Wnts are at least partly responsible for the production and maintenance of epileptic networks."

"We demonstrate that the Wnt pathway is critical to changes in neuronal behavior in the dentate gyrus and is dysregulated early in the post-ictal period," he and colleagues wrote in their abstract. "These changes are especially marked in the peri-ictal zones and may underlie the formation of epileptic foci away from the primary ictal zone. Therapies targeting Wnt activity and network remodeling may prevent the acquisition of delayed epilepsy in high-risk patients."

For the experiment, researchers injected kainic acid into the hippocampus, inducing generalized seizures, and afterward assessed the response in four quadrants — the ictal zone, or the ipsilateral dorsal region; the peri-ictal zones of the ipsilateral ventral region; contralateral dorsal region; and contralateral ventral region farthest from the injection site.

They found a 1.9-fold increase in neurogenesis (p<.05) and a 2.4-fold increase in dendrite arbor length (p<.05) in peri-ictal regions, and decreased neurogenesis in the ictal zone two weeks after the injection.

The research team administered a Wnt antagonist, XAV939, daily for two weeks after the injection. With that drug, they saw a 1.6-fold increase in dendritic arborization (p<.05), while neurogenesis remained unchanged.

In a transcriptional analysis, they found dysregulation of Wnt genes — Wnt 5A, Wnt 7A, Wnt 9A and DKK1 (p<.005 for the Wnt genes and p<.05 for DKK1).

"Intriguingly, certain Wnt genes demonstrated differential patterns of dysregulation between the ictal and peri-ictal zones," the study authors said. "These transcriptional changes might underpin the development of delayed epilepsy in this model."

Dr. Gupta said the goal would be to reduce seizure burden after inciting events by targeting the Wnt pathway but he acknowledged there is a lot that is not known.

"Initial studies would look for changes in post-ictal neuronal network remodeling to see if these changes normalize to baseline and if normal synaptic connections are maintained," he said. "Given the extensive scope of the Wnt pathway and its various roles in normal physiological processes, the key will be targeting the appropriate pathway and limiting off-target effects. Studies in a range of model platforms including in vitro and in vivo will help define these better and allow advancement to pre-clinical trials."

Astrid Nehlig, PhD, research director at the National Institute of Health and Medical Research in Strasbourg, France, said that finding involvement of the Wnt pathway in neuronal remodeling after seizures in this model is "no big surprise."

"The strong seizures that occur in this model generate a devastating insult, which most likely involves a large number of pathways," she said. "At this point, nobody is able to tell what really happens during these changes and which ones are really critical that, if stopped, would prevent the disease."

She added that "the solution is likely going to come from studies using combined treatments."

"The study authors describe a pathway that appears to be involved in the process. But nobody can tell whether acting on this pathway would be sufficient to prevent or change the severity of epilepsy."

Drs. Gupta and Nelig reported no disclosures.

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AES Abstract 1.104: Gupta K, Schnell E. The small molecule WNT antagonist XAV939 modulates neuronal-network remodeling in a translational mouse model of temporal lobe epilepsy.

Wednesday, December 5, 2018

BY THOMAS R. COLLINS

NEW ORLEANS—A blood test that measures four key proteins combined with an algorithm for clinical risk factors helped differentiate psychogenic non-epileptic seizures (PNES) from epileptic seizures with a high degree of accuracy, according to findings presented here at the American Epilepsy Society annual meeting.

In preliminary findings, the test — developed and presented by officials from Cognizance Biomarkers, a subsidiary of Evogene, Inc. — distinguished PNES from epileptic seizures with 87 percent sensitivity and 100 percent specificity; the area under the curve (AUC) was 0.98 when administered within 24 hours of an event, researchers said.

"What we're doing that's different from the approach that other people have taken is that we're looking at a multi-protein signature response, as opposed to looking at one protein to say yes or no" to differentiate PNES, said John M. Gledhill, PhD, director of research and development at Cognizance Biomarkers.

If the test pans out, clinicians could use it as a tool to improve misdiagnoses, Dr. Gledhill said, noting that PNES patients account for the largest category of people misdiagnosed as having epilepsy. The test is now being assessed in a larger patient pool, he said. 

Researchers reviewed data from patients in an epilepsy monitoring unit, 31 of whom had epileptic seizures and 25 of whom had PNES. They had been admitted for surgical evaluation or to get a definitive diagnosis. They drew blood samples each morning and within 24 hours of a clinical event captured by video electroencephalography (EEG).

The research team assayed 51 proteins associated with neuroinflammation, and, through a machine-learning process, identified four proteins — TRAIL, ICAM-1, MCP-2, and TNF-R1 — that were best able to differentiate epileptic seizures from PNES. Dr. Gledhill said that the precise mechanisms that make these four proteins the most useful are not yet known. But with the four proteins, the test achieved a sensitivity of 81 percent and 94 percent specificity.

When the researchers factored in risk factors associated in the literature with PNES — such as major depressive disorder, physical or emotional trauma, and multiple allergies — the test improved to an AUC of 0.98.

"That's really what is going to be important for this test — using all available information," Dr. Gledhill said.

Dr. Gledhill projected the test could come to market in 2021.

Selim R. Benbadis, MD, FAAN, professor of neurology at the University of South Florida, said the data from the test are "intriguing."

He said the test would have reasonable feasibility but noted that the increasing accessibility of video EEG could call its usefulness into question.

In their poster, researchers introduced their findings by saying that video EEG "requires inpatient hospital stays," but Dr. Benbadis said that is no longer the case.

"You can do ambulatory home EEG video studies, and if I can have that, it would be a lot more powerful than any blood work," he said.

He also noted that, in their presentation, researchers described the biomarkers as helping to "triage suspected epileptic seizure patients for expert evaluation," suggesting it may ultimately be a kind of screen before video EEG.

"If it's going to be a screen, how does it compare in cost with prolactin and creatine kinase?" he asked, referring to two other tests that can sometimes be effective. "Is it really worth it? I'm not sure."

"This test might have an adjunctive role, but I'm a little bit skeptical about it. I don't think it's going to change our diagnostic pathway….but it's intriguing."

The research was conducted with grant support from the National Institutes of Health. Dr. Gledhill receives a salary from Evogene, Inc. Dr. Benbadis has received honoraria from LivaNova, Eisai, Greenwich, Lundbeck, Neuropace, and Sunovion Pharmaceuticals.

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AES Abstract 3.094: Gledhill JM, Brand E, St. Clair R, et al. Predictive blood test for psychogenic nonepileptic seizures: Post hoc assessment of plasma biomarkers and risk factors.