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Stanford Medicine-led study identifies novel target for epilepsy treatment

Researchers find that a little-understood part of the brain appears to be involved in starting seizures and keeping them going.

April 17, 2024 - By Kimberlee D'Ardenne

Stanford Medicine researchers and their colleagues found that removing or inhibiting the fasciola cinereum may help epilepsy patients who aren't helped by surgery. Tom - stock.adobe.com

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.

Ivan Soltesz

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.

Ryan Jamiolkowski

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).

• Kimberlee D'Ardenne Kimberlee D'Ardenne is a freelance writer.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

The majestic cell

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Brain-cell transplants are the newest experimental epilepsy treatment

Neurona Therapeutics’ epilepsy treatment could be a breakthrough for stem-cell technology.

• Antonio Regalado archive page

This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here .

Justin Graves was managing a scuba dive shop in Louisville, Kentucky, when he first had a seizure. He was talking to someone and suddenly the words coming out of his mouth weren’t his. Then he passed out. Half a year later he was diagnosed with temporal-lobe epilepsy.

Graves’s passion was swimming. He’d been on the high school team and had gotten certified in open-water diving. But he lost all that after his epilepsy diagnosis 17 years ago. “If you have ever had seizures, you are not even supposed to scuba-dive,” Graves says. “It definitely took away the dream job I had.”

You can’t drive a car, either. Graves moved to California and took odd jobs, at hotels and dog kennels. Anywhere on a bus line. For a while, he drank heavily. That made the seizures worse. 

Epilepsy, it’s often said, is a disease that takes people hostage.

So Graves, who is now 39 and two and half years sober, was ready when his doctors suggested he volunteer for an experimental treatment in which he got thousands of lab-made neurons injected into his brain. 

“I said yes, but I don’t think I understood the magnitude of it,” he says. 

The treatment, developed by Neurona Therapeutics, is shaping up as a breakthrough for stem-cell technology. That's the idea of using embryonic human cells, or cells converted to an embryonic-like state, to manufacture young, healthy tissue.

And stem cells could badly use a win. There are plenty of shady health clinics that say stem cells will cure anything, and many people who believe it. In reality, though, turning these cells into cures has been a slow-moving research project that, so far, hasn’t resulted in any approved medicines .

But that could change, given the remarkable early results of Neurona’s tests on the first five volunteers. Of those, four, including Graves, are reporting that their seizures have decreased by 80% and more. There are also improvements in cognitive tests. People with epilepsy have a hard time remembering things, but some of the volunteers can now recall an entire series of pictures.

“It’s early, but it could be restorative,” says Cory Nicholas, a former laboratory scientist who is the CEO of Neurona. “I call it activity balancing and repair.”

Starting with a supply of stem cells originally taken from a human embryo created via IVF, Neurona grows “inhibitory interneurons.” The job of these neurons is to quell brain activity—they tell other cells to reduce their electrical activity by secreting a chemical called GABA.

Graves got his transplant in July. He was wheeled into an MRI machine at the University of California, San Diego. There, surgeon Sharona Ben-Haim watched on a screen as she guided a ceramic needle into his hippocampus, dropping off the thousands of the inhibitory cells. The bet was that these would start forming connections and dampen the tsunami of misfires that cause epileptic seizures.

Ben-Haim says it’s a big change from the surgeries she performs most often. Usually, for bad cases of epilepsy, she is trying to find and destroy the “focus” of misbehaving cells causing seizures. She will cut out part of the temporal lobe or use a laser to destroy smaller spots. While this kind of surgery can stop seizures permanently, it comes with the risk of “major cognitive consequences.” People can lose memories, or even their vision. 

That’s why Ben-Haim thinks cell therapy could be a fundamental advance. “The concept that we can offer a definitive treatment for a patient without destroying underlying tissue would be potentially a huge paradigm shift in how we treat epilepsy,” she says. 

Nicholas, Neurona’s CEO, is blunter. “The current standard of care is medieval,” he says. “You are chopping out part of the brain.”

For Graves, the cell transplant seems to be working. He hasn’t had any of the scary “grand mal” attacks, that kind can knock you out, since he stopped drinking. But before the procedure in San Diego, he was still having one or two smaller seizures a day. These episodes, which feel like euphoria or déjà vu, or an absent blank stare, would last as long as half a minute. 

Now, in a diary he keeps as part of the study to count his seizures, most days Graves circles “none.”

Other patients in the study are also telling stories of dramatic changes. A woman in Oregon, Annette Adkins , was having seizures every week; but now hasn't had one for eight consecutive months, according to Neurona. Heather Longo, the mother of another subject, has also said her son has gone for periods without any seizures. She's hopeful his spirits are picking up and said that his memory, balance, and cognition, are improving.

Getting consistent results from a treatment made of living cells is not going to be easy, however. One volunteer in the study saw no benefit, at least initially, while Graves’s seizures tapered away so soon after the procedure that it’s unclear whether the new cells could have caused the change, since it can takes weeks for them to grow out synapses and connect to other cells.

“I don’t think we really understand all the biology,” says Ben-Haim.

Neurona plans a larger study to help sift through cause and effect. Nicholas says the next stage of the trial will enroll 30 volunteers, half of whom will undergo “sham” surgeries. That is, they’ll all don surgical gowns, and doctors will drill holes into their skulls. But only some will get the cells; for the rest it will be play-acting. That is to rule out a placebo effect or the possibility that, somehow, simply passing a needle into the brain has some benefit.

Graves tells MIT Technology Review he is sure the cells helped him. “What else could it be? I haven’t changed anything else,” he says.

Now he is ready to believe he can get parts of his life back. He hopes to swim again. And if he can drive, he plans to move home to Louisville to be near his parents. “Road trips were always something I liked,” he says. “One of the plans I had was to go across the country. To not have any rush to it and see what I want.”

Now read the rest of The Checkup 

Read more from mit technology review ’s archive.

This summer, I checked into what 25 years of research using embryonic stem cells had delivered. The answer: lots of hype and no cures …yet.

Earlier this month, Cassandra Willyard wrote about the many scientific uses of “organoids.” These blobs of tissue (often grown from stem cells) mimic human organs in miniature and are proving useful for testing drugs and studying viral infections. 

Our 2023 list of young innovators to watch included Julia Joung , who is discovering the protein factors that tell stem cells what to develop into.

There’s a different kind of stem cell in your bone marrow—the kind that makes blood. Gene-editing these cells can cure sickle-cell disease. The process is grueling, though. In December, one patient, Jimi Olaghere, told us his story.

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Latest Epilepsy Research News

Stay up to date with the latest developments across the epilepsy research community--from publications to news articles..

Research News

Virtual Stimulation of the Interictal EEG Network Localizes the Epileptic Zone

Researchers lead by recent CURE Epilepsy Taking Flight awardee Rachel June Smith built patient-specific network models from interictal intracranial electroencephalogram (iEEG) results to test whether a new, virtual approach using less-invasive stimulation methods could reveal information about the underlying brain network and identify highly excitable regions.

Seizures Detected at Low Levels of Central Thalamus Stimulation in Mice Study

Researchers at Massachusetts Institute of Technology and Massachusetts General Hospital are testing a method to electrically stimulate the central thalamus (CT), which is located deep in the brain. This method of stimulation, called CT-deep brain stimulation (DBS), can help arouse subjects from unconscious states induced by traumatic brain injury or anesthesia and can boost cognition and performance in awake animals. However, it can also result in seizures.

Study Identifies Genetic Cause of Severe Seizures in Children

Scientists at McGill University have identified a genetic cause of severe seizures in children, with the help of Kelly Cervantes's daughter Adelaide. The research team conducting the study analyzed samples from Adelaide and others with mutations in a gene called DENND5A. The scientists found that mutations in this gene stopped brain cells from dividing properly during development. The result is a developing brain with fewer stem cells, shortening the crucial time period that the brain forms as an embryo. The finding provides answers to families of people with this rare genetic condition.

Children’s Hospital of Philadelphia Researchers Use AI-Powered Method to Identify Genetic Epilepsies Much Earlier than Genetic Diagnosis

Researchers at the Epilepsy Genetics Initiative (ENGIN) at Children's Hospital of Philadelphia (CHOP) used machine learning and artificial intelligence to comb through medical records and use clinical notes to match symptoms with specific genetic epilepsies. Building upon previously developed techniques, the researchers aimed to identify early clinical features that could suggest a genetic diagnosis of epilepsy. 

University of Virginia Research Provides Better Understanding of Alzheimer’s, Epilepsy

Researchers from the University of Virginia School of Medicine have discovered functions of structures in the brain that could help understand and treat several neurological disorders.

Genetic ‘Episignatures’ Guide Researchers in Identifying Causes of Unsolved Epileptic Neurological Disorders

Scientists at St. Jude Children’s Research Hospital demonstrated the value of DNA methylation patterns for identifying the root cause of developmental and epileptic encephalopathies (DEEs). Their new study shows that specific gene methylation and genome-wide methylation “episignatures” can help identify the genes that cause DEE. DEEs affect 1 in 590 children and involve more than 825 genes. 

Propofol Shows Potential for Treating Epilepsy and Neurological Disorders

According to a new study led by researchers at Weill Cornell Medicine and Linköping University in Sweden, the general anesthetic propofol may hold the keys to developing new treatment strategies for epilepsy and other neurological disorders.

Brain Activity Patterns Can Foreshadow 24-Hour Seizure Risk

A team of epilepsy specialists at University of California San Francisco has developed a method to predict 24-hour seizure risk. The researchers, led by Vikram Rao, MD, PhD, a Distinguished Professor in Neurology, showed that the storm of brain activity characterizing a seizure is presaged by abnormal communication between specific areas of the brain.

The Power of Big Data in Epilepsy Research: ILAE Sharp Waves Podcast

The ILAE Sharp Waves Podcasts focuses on the Human Intracerebral EEG Platform, which is a cloud-based, collaborative environment that encourages the sharing of data and the conducting of research with state-of-the-art methodologies and software. This platform can be used to improve research methods and promote data sharing in order to best drive epilepsy research forward.

No Results Found

Pioneering Stem Cell Therapy Offers New Hope for Epilepsy Treatment

Summary: Researchers embarked on a groundbreaking clinical trial involving the injection of regenerative cells into the brain to treat epileptic seizures.

This experimental therapy, called NRTX-1001, has the potential to offer drug-resistant temporal lobe epilepsy patients a non-destructive cure for their seizures. The injected cells, derived from human stem cells, are aimed at restoring brain balance and calming seizures.

Early results show a more than 90% reduction in seizure frequency in initial patients post-treatment.

• UC San Diego Health is among the first health systems in the US to trial regenerative brain cell therapy, injecting inhibitory brain cells derived from human stem cells to treat epilepsy.
• This experimental therapy, NRTX-1001, aims to restore brain balance and calm seizures without destroying brain tissue, potentially revolutionizing the treatment for drug-resistant temporal lobe epilepsy.
• Preliminary data from the trial shows promising results, with a more than 90% reduction in seizure frequency observed in initial patients post-treatment.

Source: UCSD

In what could lead to a revolutionary advancement in the treatment of temporal lobe epilepsy, UC San Diego Health has become one of the first health systems in the country to inject regenerative cells into the brain to treat epileptic seizures. 

Part of a national clinical trial, UC San Diego Health’s multidisciplinary team performed the third ever experimental regenerative brain cell therapy procedure earlier this month. UC San Diego Health is the only nationally designated Level 4 Adult Epilepsy Center in the region.

During the surgery, Sharona Ben-Haim, MD, associate professor of neurological surgery at University of California San Diego School of Medicine and surgical director of epilepsy at UC San Diego Health, made multiple injections of inhibitory brain cells into mapped out precision points of the patient’s brain under the bright lights of the operating room. 

The cells, called interneurons, are derived from human stem cells. If successful, the first-ever regenerative human cell experimental therapy, NRTX-1001, could provide drug-resistant temporal lobe epilepsy patients with the first non-destructive option to potentially cure their seizures.

In between setting up multiple trajectory points on the patient’s brain prior to the cell insertion, Ben-Haim carefully studied the intra-operative magnetic resonance imaging scans that pinpoint her every move. 

While digitally rotating the brain three-dimensionally on screen to inspect her work, Ben-Haim explained, “This experimental therapy offers us the potential to essentially restore the balance in the brain to be able to calm and ideally stop the seizures, while retaining the normal function of that part of the brain. Currently, we do not have a therapy that allows us to do that, so this is really exciting.”

The clinical trial, sponsored by Neurona Therapeutics, is seeking to enroll 40 participants across the country to study the results of the implantation of the stem cells, which produce gamma-aminobutyric acid (GABA) — a neurotransmitter that blocks overactive impulses between nerve cells in the brain. 

“In drug-resistant temporal lobe epilepsy, some of the normal brain cells in the temporal lobe have been damaged or are dead,” said Jerry Shih, MD, professor of neurosciences at UC San Diego School of Medicine, neurologist and director of the Epilepsy Center at UC San Diego Health.

“This experimental cell therapy implants healthy human brain cells into the damaged temporal lobe with the hope that those new cells will begin establishing connections in the patient’s brain, to ultimately make a healthier temporal lobe.”

Epilepsy is the fourth most common neurological disorder in the U.S. after migraine, stroke and Alzheimer’s disease, according to the Centers for Disease Control and Prevention. An estimated 3.4 million Americans have epilepsy and approximately one-third of those individuals do not respond to anti-seizure medications.

Traditional seizure reduction therapies involve removing or laser-burning the parts of the brain where the seizures originate or implanting deep-brain electrodes to modulate seizure activities.

This new experimental regenerative therapy could potentially treat multiple parts of the brain without tissue removal, offering new hope to drug-resistant epilepsy patients.

“This first-in-human clinical trial represents a paradigm shift in the way we treat this disease process, shifting from procedures that destroy bad tissue to procedures that repair the bad tissue,” Shih said. “Our hope is that this procedure has such a high success rate and good tolerability that it becomes the standard of care for all drug-resistant focal epilepsies.”

Back in the operating room, Ben-Haim meticulously inspected her work on her patient’s brain. He is the third person in the nation to undergo the procedure, which was initiated at SUNY Upstate Medical University in Syracuse, New York in June 2022, followed by Oregon Health Sciences University in Portland, Oregon in November 2022.

“These patients are willing to try an experimental procedure in this clinical trial to get control of their seizures, and I think they are incredibly brave,” Ben-Haim said. “We are already seeing improvements in as early as one month. Our ultimate goal is to improve a patient’s long-term quality of life.”

Patients who participate in the trial will be monitored regularly for two years after the procedure to study the effects of the implanted stem cells. Preliminary data reported in June demonstrates a more than 90% reduction in seizure frequency in the first and second patients at one year and seven months, respectively, post-treatment. 

Shih, the principal investigator for UC San Diego Health’s involvement, said the study is the most complex clinical trial he’s served on in his career, spanning 25 years of conducting clinical trials at three leading academic institutions across the country.

“This study can only be conducted in an institution with a strong clinical and research infrastructure, which we are fortunate to have here at UC San Diego Health,” Shih said.

He added that it required tremendous coordination among UC San Diego teams, including faculty and staff from neurosciences, neurosurgery, cellular regenerative medicine, radiology, neuropsychology and neuro critical care; California Institute for Regenerative Medicine Alpha Clinic at the Sanford Stem Cell Clinical Center; Advanced Cell Therapy Lab; Center for Multimodal Imaging and Genetics and the Consortium for Regenerative Medicine.

“We would not have been able to participate in this study without the active collaboration of all these integral groups. It truly takes a village.”

About this stem cell and epilepsy research news

Author: Annie Pierce Source: UCSD Contact: Annie Pierce – UCSD Image: The image is credited to Neuroscience News

Good news above. Would it be possible to send me contact details of the person who’s conducted that epilepsy Research? I’m hugely affected by my lifelong unresponsive epilepsy as it keeps me constantly covered in new multiple injuries (including broken bones). I have a query about the people with epilepsy who were tested.

Comments are closed.

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New tech gives hope for a million people with epilepsy

Jon Hamilton

Aaron Scott

Gabriel Spitzer

The ROSA machine allows surgeons to more precisely target parts of the brain responsible for epileptic seizures. UC San Diego Health hide caption

The ROSA machine allows surgeons to more precisely target parts of the brain responsible for epileptic seizures.

Listen to Short Wave on Spotify , Apple Podcasts and Google Podcasts .

About three million people in the United States have epilepsy, including about a million who can't rely on medication to control their seizures.

For years, those patients had very limited options. Surgery can be effective, but also risky, and many patients were not considered to be candidates for surgery.

But now, in 2023, advancements in diagnosing and treating epilepsy are showing great promise for many patients, even those who had been told there was nothing that could be done.

One of those patients visited Dr. Jerry Shih at the Epilepsy Center at UC San Diego Neurological Institute, after getting a bleak prognosis a few years earlier.

"When I saw him, I said, 'You know what, we're in a unique situation now where we have some of the newer technologies that were not available in 2010." he says. "We knocked out that very active seizure focus. And he has subsequently been seizure free."

Using precise lasers, microelectronic arrays and robot surgeons, doctors and researchers have begun to think differently about epilepsy and its treatment.

"If you think about the brain like a musical instrument, the electrophysiology of the brain is the music." says Dr. Alexander Khalessi , a neurosurgeon at UCSD. "And so for so long, we were only looking at a picture of the violin, but now we're able to listen to the music a little bit better. And so that's going to help us understand the symphony that makes us us ."

Today on Short Wave, host Aaron Scott talks with NPR science correspondent Jon Hamilton about these advances in treating epilepsy. He explains why folks should ask their doctors about surgery — even if it wasn't an option for them a few years ago.

If you have a science question or idea for a show, we want to hear it. send us an email at [email protected] .

This episode was produced by Thomas Lu, edited by Gabriel Spitzer and fact checked by Anil Oza. The audio engineer for this episode was Hannah Gluvna.

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Sep. 27, 2024 Research Highlight Biology

Structural secrets of antiepileptic drugs uncovered

A cryo-electron microscopy study reveals how antiepileptic drugs are recognized by a key protein found in the synapses of neurons

Figure 1: Left: Synaptic vesicle glycoprotein 2A (SV2A; blue) targeted by the botulinum neurotoxin receptor-binding domain (gray). Right: The antiepileptic drug levetiracetam (red) is bound inside SV2A. © RIKEN

RIKEN researchers have discovered how the structure of drugs for treating epilepsy allows them to interact with a key protein found in synapses at the junctions of neurons 1 . This knowledge could help to design even better drugs for the condition.

Epilepsy is a brain disorder that causes recurrent seizures, which can strike without warning. It is thought to affect somewhere between 0.5% and 1% of people.

Fortunately, powerful drugs are available for treating the neurological disorder, including levetiracetam and brivaracetam. But no-one knows exactly how these drugs work.

Both drugs target a protein found in the small, membrane-bound sacs called synaptic vesicles that store and release neurotransmitters at the ends of neurons. This protein is known as synaptic vesicle glycoprotein 2A (SV2A).

“The exact function of SV2A is unknown, although it must play a key role in synaptic transmission,” says Atsushi Yamagata of the RIKEN Center for Biosystems Dynamics Research.

Interestingly, SV2A is also a receptor for the highly toxic botulinum neurotoxin. One of the most lethal substances known, botulinum neurotoxin can kill adults at levels of just a few hundred nanograms. But it is also used for a wide range of cosmetic and therapeutic purposes, including treating neuromuscular disorders, chronic pain and gastrointestinal disorders.

Now, by using cryo-electron microscopy, Yamagata and his co-workers have determined the structures of levetiracetam and brivaracetam when they are attached to SV2A, both when botulinum neurotoxin is present and absent (Fig. 1).

While the exact function of SV2A still remains unclear, the results suggest that SV2A may act as a membrane transporter and that levetiracetam and brivaracetam may inhibit this function.

The understanding of the structure “provides indirect evidence that SV2A functions as a membrane transporter,” notes Yamagata. “This function might be very important for understanding epilepsy caused by genetic mutations of SV2A.”

It is challenging to obtain a good-quality structure of SV2A using cryo-electron microscopy because the protein is quite small, but botulinum neurotoxin provided an unexpected benefit in this regard. “Luckily for us, when we attached a botulinum neurotoxin receptor-binding domain to SV2A, we could use it as a marker for cryo-electron microscopy image analysis,” explains Yamagata. “That allowed us to align SV2A particle images more precisely and determine the high-resolution cryo-electron microscopy structure.”

Yamagata and his team plan to extend this work. “We’re now trying to determine the structure of SV2A in complex with full-length botulinum toxin. This may help us to understand how the neurotoxin functions in synapses,” says Yamagata. “We also hope to elucidate the exact function of SV2A, although that’s very challenging.”

Related content

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• 1. Yamagata, A., Ito, K., Suzuki, T., Dohmae, N., Terada, T. & Shirouzu, M. Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A. Nature Communications 15, 3027 (2024). doi: 10.1038/s41467-024-47322-4

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A Comprehensive Review of Emerging Trends and Innovative Therapies in Epilepsy Management

Shampa ghosh.

1 GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, India

2 ICMR—National Institute of Nutrition, Tarnaka, Hyderabad 500007, India

Jitendra Kumar Sinha

Soumya ghosh, hitaishi sharma, rakesh bhaskar.

3 School of Chemical Engineering, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Republic of Korea

Kannan Badri Narayanan

4 Research Institute of Cell Culture, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Republic of Korea

Associated Data

Available on request.

Epilepsy is a complex neurological disorder affecting millions worldwide, with a substantial number of patients facing drug-resistant epilepsy. This comprehensive review explores innovative therapies for epilepsy management, focusing on their principles, clinical evidence, and potential applications. Traditional antiseizure medications (ASMs) form the cornerstone of epilepsy treatment, but their limitations necessitate alternative approaches. The review delves into cutting-edge therapies such as responsive neurostimulation (RNS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), highlighting their mechanisms of action and promising clinical outcomes. Additionally, the potential of gene therapies and optogenetics in epilepsy research is discussed, revealing groundbreaking findings that shed light on seizure mechanisms. Insights into cannabidiol (CBD) and the ketogenic diet as adjunctive therapies further broaden the spectrum of epilepsy management. Challenges in achieving seizure control with traditional therapies, including treatment resistance and individual variability, are addressed. The importance of staying updated with emerging trends in epilepsy management is emphasized, along with the hope for improved therapeutic options. Future research directions, such as combining therapies, AI applications, and non-invasive optogenetics, hold promise for personalized and effective epilepsy treatment. As the field advances, collaboration among researchers of natural and synthetic biochemistry, clinicians from different streams and various forms of medicine, and patients will drive progress toward better seizure control and a higher quality of life for individuals living with epilepsy.

1. Introduction

Epilepsy, a chronic neurological disorder characterized by recurrent seizures, affects millions of people worldwide [ 1 , 2 , 3 ]. Seizures result from abnormal electrical activity in the brain, leading to various physical and cognitive manifestations. While traditional antiseizure medications (ASMs) have been the cornerstone of epilepsy management for decades, a significant proportion of patients continue to experience seizures despite treatment [ 3 ]. This has spurred the exploration of innovative therapies and emerging trends in epilepsy management to address the unmet medical needs of individuals living with drug-resistant epilepsy [ 2 ]. The management of epilepsy has come a long way since its earliest descriptions in ancient texts, but challenges persist [ 4 ]. Traditional ASMs can be associated with adverse effects, including cognitive impairments, mood disturbances, and systemic toxicity [ 5 ]. Additionally, certain epilepsy syndromes may be particularly refractory to conventional treatments, necessitating alternative approaches to achieve better outcomes [ 6 ].

This review aims to comprehensively explore the latest advancements in epilepsy management, focusing on emerging trends and innovative therapies that offer new hope for individuals with drug-resistant epilepsy. By highlighting these groundbreaking approaches, we intend to shed light on potential transformative changes in the field and their implications for patient care. In the following sections, we delve into specific cutting-edge therapies and research directions that have shown promise in recent years. These include responsive neurostimulation (RNS), vagus nerve stimulation (VNS), deep brain stimulation (DBS), closed-loop stimulation, cannabidiol (CBD) as a novel adjunct therapy, the ketogenic diet, gene therapies, and the intriguing potential of optogenetics. Our primary objectives of this review are to provide a comprehensive overview of the current landscape of epilepsy management, highlighting the limitations of traditional ASMs and the need for alternative therapeutic approaches [ 7 ]. We have tried to present the latest findings and clinical evidence related to emerging therapies, including RNS, VNS, DBS, closed-loop stimulation, CBD, the ketogenic diet, gene therapies, and optogenetics. The discussions covering the assessment of the efficacy, safety, and tolerability of these innovative treatments in reducing seizure frequency and improving overall quality of life for epilepsy patients are also covered [ 3 ]. Additionally, we discuss the potential mechanisms of action underlying these therapies and their implications for understanding epilepsy pathophysiology. Finally, our objective is also to identify the potential challenges, limitations, and future research directions for each of the discussed therapies, fostering the development of more effective and patient-tailored treatments.

2. Traditional Approaches to Epilepsy Management

For decades, conventional ASMs have been the cornerstone of epilepsy management, providing significant relief to a large number of patients [ 8 , 9 ]. ASMs work by modulating the excitability of neurons, inhibiting the abnormal electrical activity that triggers seizures [ 10 ]. The advent of these medications has revolutionized epilepsy treatment and has been instrumental in achieving seizure control and improving the quality of life for many individuals with epilepsy [ 11 ]. Various classes of ASMs are available, each targeting specific mechanisms involved in seizure generation and propagation [ 12 ]. Common ASMs include phenytoin, carbamazepine, valproate, lamotrigine, and levetiracetam [ 13 , 14 ]. These drugs are typically prescribed based on the patient’s seizure type, epilepsy syndrome, age, and overall health. Despite their widespread use and effectiveness in a significant proportion of patients, ASMs have limitations that can hinder optimal epilepsy management. First, not all patients respond favorably to traditional ASMs, leading to drug-resistant epilepsy. Estimates suggest that approximately one-third of people with epilepsy continue to experience seizures despite adequate trials of two or more ASMs [ 15 ]. This phenomenon poses a significant clinical challenge and underscores the need for alternative therapeutic approaches to address drug-resistant epilepsy.

2.1. Challenges in Achieving Seizure Control with Traditional Therapies

Drug-resistant epilepsy represents a major clinical hurdle in epilepsy management [ 16 ]. Patients who are refractory to traditional ASMs face recurrent seizures that can severely impact their daily lives, disrupt social interactions, and limit educational and employment opportunities [ 17 , 18 , 19 ]. The unpredictable nature of seizures can lead to anxiety, depression, and a reduced overall quality of life. The reasons behind treatment resistance in epilepsy are complex and multifactorial. One significant challenge is the inherent variability in epilepsy. The condition is heterogeneous, and the underlying causes and mechanisms can differ greatly from one patient to another. As a result, ASMs that are effective for some individuals may not work as well for others due to differences in the brain’s structure and function [ 20 , 21 ]. The diversity in epilepsy subtypes, seizure types, and responses to treatment makes it challenging to achieve uniform seizure control with traditional therapies [ 22 ].

Pharmacokinetic variability is another factor contributing to treatment resistance [ 23 ]. The way ASMs are metabolized and distributed in the body can vary among individuals, affecting drug levels and therapeutic efficacy. Drug interactions and genetic factors can also influence AED metabolism, leading to differences in drug response and treatment outcomes [ 24 , 25 ]. This variability in drug levels can result in suboptimal seizure control and contribute to treatment resistance. Moreover, the mechanisms of action of ASMs may not address all aspects of seizure generation and propagation. While these medications primarily target ion channels and neurotransmitter receptors, certain epilepsy syndromes may involve complex networks of neurons, making them less responsive to the effects of traditional ASMs [ 26 ]. As a result, treatment with ASMs alone may not be sufficient to achieve complete seizure control in some cases [ 27 , 28 ]. Compliance issues also play a significant role in treatment resistance. Adherence to prescribed AED regimens is crucial for successful seizure management [ 29 , 30 ]. However, poor medication compliance can reduce the effectiveness of treatment and contribute to treatment resistance [ 29 , 30 ]. Factors such as forgetfulness, medication side effects, and the inconvenience of multiple daily doses can hinder patients’ consistent adherence to their treatment plans.

Tolerance and adaptation are additional challenges in epilepsy management [ 31 ]. Over time, some individuals may develop tolerance to the effects of ASMs, leading to decreased seizure control. The brain’s adaptability and compensatory mechanisms may reduce the long-term efficacy of certain medications, necessitating the need for alternative therapeutic approaches [ 32 ]. Furthermore, ASMs may be associated with side effects that impact treatment adherence and tolerability. Some patients may experience significant adverse effects such as dizziness, drowsiness, cognitive impairment, and mood disturbances [ 33 ]. For some individuals, these side effects may outweigh the benefits of seizure reduction, leading to treatment discontinuation or non-compliance.

Addressing the challenges of drug-resistant epilepsy requires a comprehensive and individualized approach. As we delve into the world of emerging therapies, it is important to recognize that traditional ASMs continue to be vital in managing epilepsy for many patients [ 34 ]. However, the limitations of these therapies underscore the need for innovative and personalized treatments. By understanding the complexities of treatment resistance and identifying novel targets, such as specific genes or neural circuits, researchers can develop more effective therapies to improve seizure control and enhance the quality of life for individuals living with epilepsy. As we move forward, collaboration between researchers, clinicians, and patients will play a pivotal role in advancing the field of epilepsy management, driving us closer to the day when drug-resistant epilepsy becomes a challenge of the past [ 35 ]. The pursuit of emerging trends and innovative therapies, along with a deeper understanding of the underlying mechanisms of epilepsy, offers hope for improved therapeutic options and a brighter future for people living with epilepsy. Through continued research, dedication, and unwavering commitment, we can transform the lives of those affected by epilepsy and pave the way for more effective and personalized treatments.

2.2. The Need for Novel Treatment Approaches to Address Drug-Resistant Epilepsy

The persistence of drug-resistant epilepsy highlights the critical necessity for novel and innovative treatment approaches [ 22 , 36 , 37 ]. Research and clinical efforts have intensified in recent years to develop therapies that target specific epilepsy subtypes, identify novel drug targets, and explore non-pharmacological interventions. The emergence of new technologies and a deeper understanding of the underlying mechanisms of epilepsy have paved the way for innovative therapeutic strategies [ 22 ]. Neurostimulation devices, such as RNS, VNS, and DBS, offer potential alternatives for patients who are unresponsive to traditional ASMs ( Figure 1 ) [ 37 ]. Additionally, advancements in precision medicine and personalized approaches hold promise for tailoring treatments to individual patients based on their unique genetic and molecular profiles [ 38 , 39 ] Gene therapies are also being explored as potential treatments for certain genetic epilepsy syndromes [ 40 ].

Recent technologies and therapies used in the management of epilepsy. The figure illustrates cutting-edge treatments and innovative therapies utilized in epilepsy management. Responsive neurostimulation (RNS)—An implantable neurostimulator device that detects and responds to abnormal brain activity, providing on-demand electrical stimulation to reduce seizure frequency. Vagus nerve stimulation (VNS)—A device that stimulates the vagus nerve through electrical impulses, helping to modulate brain activity and decrease seizure occurrences. Deep brain stimulation (DBS)—A neuromodulation technique that involves implanting electrodes in specific brain regions to deliver electrical stimulation and regulate neural activity for seizure control. Cannabidiol (CBD)—A natural compound derived from the cannabis plant, known for its potential anticonvulsant effects and often used as an adjunct therapy for certain epilepsy syndromes.

Non-pharmacological interventions such as the ketogenic diet and CBD have gained attention because of their anticonvulsant properties and have shown benefits in reducing seizure frequency in some patients [ 6 , 41 ]. The limitations of traditional therapies underscore the urgency to explore and implement innovative treatments to improve outcomes for individuals living with epilepsy [ 42 ].

3. Responsive Neurostimulation

Responsive neurostimulation (RNS) is a cutting-edge therapy designed to provide personalized and adaptive treatment for drug-resistant epilepsy [ 43 , 44 ]. The RNS system consists of a small neurostimulator device that is surgically implanted in the skull, along with one or two intracranial electrodes placed in or near the epileptogenic brain region responsible for seizure initiation [ 45 , 46 , 47 ]. The system operates on the fundamental principle of closed-loop neurostimulation, wherein it continuously monitors brain activity and delivers electrical stimulation in response to detected abnormal patterns [ 48 ]. The mechanism of action of RNS includes the following: (1) Monitoring brain activity: The implanted electrodes continuously record the electrical signals from the brain, detecting subtle changes that precede the onset of a seizure. Advanced algorithms within the RNS system analyze the recorded brain activity in real time. (2) Detecting seizure onset: The RNS system is programmed to recognize specific patterns of electrical activity associated with the onset of a seizure. This personalized detection algorithm is tailored to each individual based on their unique seizure characteristics. (3) Responsive stimulation: Once the system detects the pre-defined seizure activity, it delivers brief electrical pulses to the epileptic brain region. The stimulation is intended to disrupt the abnormal neural firing patterns and prevent the seizure from fully manifesting. (4) Adaptation and learning: The RNS system is designed to adapt and learn over time. As it continuously monitors brain activity and stimulation effectiveness, it can refine its algorithms to optimize seizure detection and stimulation parameters for each patient, enhancing treatment efficacy [ 46 , 48 ].

The efficacy of RNS in reducing seizure frequency and improving the quality of life for individuals with drug-resistant epilepsy has been supported by clinical studies and real-world evidence [ 49 , 50 ] In a pivotal clinical trial, the RNS system demonstrated significant benefits for patients with medically refractory focal epilepsy [ 51 , 52 ]. The trial included participants who experienced an average of eight or more disabling partial-onset seizures per month despite treatment with multiple ASMs. Results showed that RNS-treated patients experienced a substantial reduction in seizure frequency, with a median seizure reduction of 44% at one year and 53% at two years after implantation [ 51 ]. Furthermore, long-term follow-up studies and real-world experiences have reinforced the positive outcomes observed in the initial clinical trial [ 44 ]. Real-world evidence has shown that RNS provides sustained and durable seizure reduction, leading to improved seizure control and enhanced quality of life for patients over extended periods [ 52 , 53 ]. Additionally, RNS has demonstrated particular effectiveness in patients with seizures arising from focal brain regions that are not amenable to resective surgery, making it a valuable treatment option for those who are not suitable candidates for other surgical interventions [ 48 , 54 ].

Potential Side Effects and Safety Considerations in RNS

As with any medical intervention, RNS is associated with potential side effects and safety considerations [ 55 ]. However, it is crucial to recognize that adverse events associated with RNS are generally manageable and often outweighed by the benefits of seizure reduction [ 56 ]. The surgical risks included in the surgical procedure to implant the RNS system are the typical risks associated with brain surgery, such as infection, bleeding, and anesthesia-related complications [ 57 ]. However, advances in neurosurgical techniques have minimized the risk of these complications. There may be some stimulation-related side effects of RNS. For example, some patients may experience mild side effects related to the electrical stimulation, such as tingling sensations, muscle twitches, or changes in mood or cognition [ 58 ]. These effects are generally temporary and tend to diminish over time as the brain adapts to the stimulation. Nevertheless, there is also a possibility of hardware-related issues during the process of RNS [ 59 , 60 ]. The RNS system is a sophisticated medical device that requires regular monitoring and maintenance. Battery replacements and system adjustments may be necessary over time, and patients should remain under the care of a specialized epilepsy team [ 61 ].

Studies show that RNS might have some cognitive and memory effects [ 57 ]. While RNS is designed to minimize cognitive side effects, some individuals may experience mild cognitive changes, particularly during the early stages of treatment [ 62 ]. These effects are often localized to the brain region being stimulated and tend to be reversible upon adjustment of stimulation parameters. Nonetheless, RNS represents a promising and innovative therapeutic approach for drug-resistant epilepsy. By providing adaptive and personalized treatment based on real-time brain activity, RNS offers the potential to significantly reduce seizure frequency and improve the quality of life for patients who have not responded to traditional ASMs [ 57 , 63 , 64 ]. Although there are potential side effects and safety considerations associated with the treatment, the benefits of improved seizure control and enhanced quality of life make RNS a valuable addition to the armamentarium of epilepsy management options [ 57 , 65 , 66 , 67 ]. Nevertheless, it is essential to understand that RNS, along with deep brain and closed-loop stimulation, requires intracranial EEG monitoring and surgical device implantation, which inherently restricts its application to a specific subset of patients. This limitation arises from the meticulous assessment and individualized implantation procedures necessitated by the invasive nature of these interventions. While acknowledging this constraint, it is important to highlight that the potential benefits offered by RNS, particularly for patients who have exhausted alternative treatment avenues, underscore the ongoing need for research and technological advancements to make this approach more accessible and broaden its impact in the realm of epilepsy management.

4. Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is a neuromodulation therapy that involves the implantation of a device that stimulates the vagus nerve, a major nerve that extends from the brainstem to various organs in the body, including the heart and digestive system [ 68 , 69 , 70 ]. The VNS system consists of a small generator, typically implanted under the skin in the chest, connected to a lead wire that is wrapped around the left vagus nerve in the neck [ 70 ]. The exact mechanism by which VNS exerts its anticonvulsant effects is not fully understood, but it is believed to involve several interconnected processes. The vagus nerve plays a crucial role in the regulation of various bodily functions, and its stimulation is thought to modulate the balance of neuronal activity in the brain, promoting inhibitory pathways and dampening excessive excitatory activity that can lead to seizures [ 71 , 72 ].

VNS is designed to provide continuous, intermittent electrical stimulation to the vagus nerve at pre-defined parameters. This stimulation has been shown to reduce seizure frequency and severity in patients with drug-resistant epilepsy [ 73 , 74 ]. By altering the activity of brain regions involved in seizure generation, VNS helps to prevent the spread of abnormal electrical activity and disrupts the development of seizures [ 75 ]. VNS is primarily used as an adjunctive therapy for patients with partial-onset seizures that have not responded well to traditional ASMs [ 75 , 76 ]. Clinical studies have demonstrated that VNS can lead to a significant reduction in seizure frequency, with some patients experiencing a 50% or greater reduction in seizure occurrence [ 77 ]. Moreover, the benefits of VNS tend to increase over time, with long-term treatment associated with further improvements in seizure control [ 78 , 79 ].

4.1. Recent Advancements in VNS Technology

In recent years, advancements in VNS technology have focused on enhancing treatment efficacy and patient convenience. One notable improvement is the development of closed-loop or on-demand VNS systems, also known as responsive VNS [ 80 , 81 ]. These systems utilize real-time EEG monitoring to detect seizure activity and deliver VNS stimulation automatically when abnormal brain activity is detected [ 81 ]. By targeting stimulation specifically during seizure events, responsive VNS aims to optimize therapy effectiveness while minimizing side effects [ 81 , 82 ]. Furthermore, advancements in device design and programming options have allowed for more personalized and precise stimulation parameters. Clinicians can now tailor the VNS settings to individual patients, adjusting stimulation parameters such as pulse width, frequency, and intensity to optimize the therapeutic response [ 79 , 80 , 82 ]. This customization enables a more patient-centric approach, which may lead to improved seizure control and tolerability. Additionally, rechargeable VNS devices are being introduced, eliminating the need for regular battery replacement surgeries. These devices can be recharged externally, making the treatment more convenient for patients and reducing the burden of frequent surgical procedures [ 83 , 84 ].

4.2. Ongoing Research and Clinical Trials in VNS for Various Epilepsy Syndromes

VNS continues to be an area of active research, with ongoing clinical trials investigating its potential benefits for various epilepsy syndromes and patient populations. Studies are exploring the safety and efficacy of VNS in children with drug-resistant epilepsy. Early intervention with VNS may offer advantages in preventing cognitive and developmental delays associated with uncontrolled seizures in pediatric patient [ 85 , 86 ]. Lennox–Gastaut syndrome (LGS) is a severe and treatment-resistant childhood epilepsy syndrome [ 87 ]. Clinical trials are evaluating the effectiveness of VNS in reducing drop attacks and other seizure types characteristic of LGS [ 88 ]. Ongoing research and clinical trials are also exploring the applicability of VNS in other epilepsy syndromes, with the aim of expanding the range of patients who can benefit from this innovative therapy. Nevertheless, research is ongoing to identify subgroups of patients with drug-resistant focal epilepsy who may benefit the most from VNS. This includes investigating potential biomarkers and predictive factors for VNS responsiveness [ 89 ]. Novel VNS approaches, such as non-invasive vagus nerve stimulation (nVNS), are being studied to explore their effectiveness as a less invasive alternative to traditional VNS therapy [ 90 , 91 ]. Some studies are investigating the potential synergistic effects of combining VNS with other neuromodulation techniques or with specific ASMs to enhance seizure control [ 92 , 93 , 94 ]. As VNS research continues to evolve, ongoing clinical trials hold the promise of further elucidating the therapeutic potential of VNS in various epilepsy syndromes and refining patient selection criteria for optimal outcomes. Therefore, the understanding to date is that VNS has emerged as a valuable adjunctive therapy for drug-resistant epilepsy [ 95 ]. The stimulation of the vagus nerve through the implantation of a VNS device leads to neuromodulation, resulting in the modulation of neural activity to reduce seizure frequency and improve overall seizure control. Recent advancements in VNS technology, including responsive or closed-loop systems and customizable stimulation parameters, offer the potential for improved treatment efficacy and patient outcomes.

It is imperative to recognize that VNS, while holding promising therapeutic potential, is not devoid of adverse effects, akin to many medical interventions. As said above, the mechanism of VNS involves the modulation of neural pathways via electrical impulses to the vagus nerve, with the intent of influencing neuronal activity and, consequently, ameliorating epileptic seizures. However, the intricacy of neural interactions can result in unintended repercussions. Stimulation of vagus nerve afferent fibers, responsible for conveying sensory information from peripheral tissues to the CNS, can induce various adverse outcomes. One notable consequence is vocal cord dysfunction, wherein the vagus nerve’s aberrant stimulation can disrupt the coordinated movements of the vocal cords during respiration, potentially leading to hoarseness, stridor, or even difficulty breathing [ 96 ]. Moreover, the stimulation may provoke laryngeal spasms, triggering involuntary contractions of the laryngeal muscles and further exacerbating respiratory difficulties. Concurrently, the activated vagus nerve fibers can provoke a cough reflex, causing persistent or severe coughing episodes that can be distressing and hinder daily functioning [ 97 , 98 ]. Additionally, the VNS-induced afferent signaling can elicit dyspnea, characterized by subjective feelings of breathlessness or discomfort during breathing [ 96 , 98 ]. This respiratory distress can be particularly concerning for individuals with compromised lung function. Moreover, the stimulation may evoke sensations of nausea and vomiting, which can detrimentally impact an individual’s overall well-being and compliance with the treatment regimen [ 97 ]. Furthermore, an intriguing but intricate association emerges between VNS and sleep apnea [ 99 , 100 ]. The electrical impulses targeting the vagus nerve’s afferent fibers can inadvertently influence respiratory centers in the brainstem, potentially altering breathing patterns during sleep [ 99 , 101 ]. This disruption is evidenced by an elevation in the apnea-hypopnea index, indicative of increased instances of sleep apnea events characterized by pauses in breathing or shallow breathing during slumber. The complex interplay between neural regulation, vagal stimulation, and respiratory control underscores the need for vigilant monitoring and individualized approaches when implementing VNS as an adjunctive therapy for epilepsy. By comprehensively addressing the intricate web of neural interactions and physiological consequences, we provide a more holistic perspective for clinicians, researchers, and individuals considering VNS as part of their therapeutic strategy.

5. Deep Brain Stimulation

Deep brain stimulation (DBS) is an advanced neuromodulation technique that has shown promise in the management of epilepsy, particularly in individuals with drug-resistant seizures [ 102 , 103 ]. Originally developed as a treatment for movement disorders such as Parkinson’s disease, DBS has evolved as a potential therapeutic option for patients whose epilepsy remains uncontrolled despite medical and surgical interventions [ 104 ]. Unlike traditional open-loop neurostimulation, DBS is designed to deliver electrical impulses to specific brain regions in a controlled and targeted manner, aiming to modulate aberrant neural activity associated with seizure generation [ 105 , 106 ]. DBS for epilepsy typically targets specific brain structures that are known to be involved in the initiation and propagation of seizures.

The most common target for DBS in epilepsy is the anterior nucleus of the thalamus (ANT), a region involved in relaying sensory and motor signals to the cerebral cortex [ 107 ]. The rationale behind targeting the ANT is based on its role in the limbic system, which plays a significant role in regulating emotions and behaviors, including seizure activity. The delivery of electrical stimulation to the ANT aims to alter the network dynamics of the limbic system, effectively dampening the excessive excitability that can lead to seizure development [ 108 , 109 ]. By disrupting the synchronization of neuronal firing patterns, DBS helps prevent the spread of abnormal electrical activity throughout the brain, reducing the likelihood of seizures [ 110 ]. Additionally, some studies have explored alternative targets, such as the hippocampus and subthalamic nucleus, with promising results in specific patient populations [ 111 , 112 , 113 ].

Clinical Evidence Illustrating the Efficacy and Safety of DBS

DBS holds promise as a promising neuromodulation technique for the treatment of drug-resistant epilepsy. By targeting specific brain regions involved in seizure generation, DBS aims to modulate neural activity and disrupt the propagation of abnormal electrical patterns. Numerous clinical studies and case reports have provided evidence for the efficacy and safety of DBS in reducing seizure frequency and improving overall seizure control in drug-resistant epilepsy [ 48 , 114 , 115 ]. A landmark multicenter randomized controlled trial (NCT00101933), known as the SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy) trial, demonstrated the effectiveness of DBS in reducing seizures [ 116 ]. The study involved individuals with drug-resistant epilepsy who received either active stimulation or sham stimulation. The results showed a significant reduction in seizure frequency in the active stimulation group, with >41% of patients at 1-year follow-up and >68% of patients at in 5-years follow-up experiencing a 50% or greater reduction in seizure frequency. Moreover, long-term follow-up studies of the SANTE trial participants have shown sustained benefits of DBS over time, with continued reductions in seizure frequency and improvements in quality of life observed years after the initial implantation [ 116 ]. By the end of the first year and continuing through the fifth year, both the Liverpool Seizure Severity Scale and the 31-item Quality of Life in Epilepsy measure demonstrated substantial improvements over their respective baselines. These improvements were statistically significant [ 116 ].

Case studies and real-world experiences have also contributed to the growing body of evidence supporting DBS efficacy [ 117 , 118 ]. Many of these reports involve patients with various types of epilepsy, including those with different etiologies and seizure semiologies [ 117 , 119 , 120 ]. These case studies have consistently demonstrated the positive impact of DBS on seizure control and have provided valuable insights into patient selection criteria, optimal stimulation parameters, and the potential risks and benefits of the procedures [ 120 ]. Regarding safety, DBS has generally been well-tolerated in the majority of patients. Adverse effects related to the stimulation itself are typically mild and transient, such as tingling sensations or muscle contractions [ 121 ]. Serious complications are infrequent but can include infection, lead migration, or hardware-related issues [ 122 ]. Overall, the risks associated with DBS need to be carefully balanced against the potential benefits, particularly in individuals with severe and drug-resistant epilepsy.

6. Closed-Loop Stimulation

Closed-loop stimulation, also known as on-demand or responsive stimulation, is an innovative neurostimulation approach that represents a significant advancement over traditional open-loop neurostimulation [ 123 , 124 , 125 , 126 ]. While open-loop neurostimulation involves delivering electrical impulses at pre-defined intervals or continuous patterns, closed-loop systems dynamically adjust stimulation based on real-time feedback from the patient’s brain activity [ 125 , 126 , 127 ]. This real-time feedback is typically obtained through the continuous monitoring of brain signals, such as via electroencephalography (EEG) or electrocorticography (ECoG), which provide valuable information about the brain’s electrical activity [ 128 ]. The primary advantage of closed-loop stimulation is its ability to adapt to the patient’s physiological state and dynamically intervene at the earliest signs of abnormal brain activity, such as pre-seizure or prodromal patterns [ 129 ]. By detecting these patterns in real time, closed-loop systems can promptly deliver targeted stimulation precisely when and where it is needed, effectively preventing the progression of seizures before they fully manifest [ 125 , 130 ]. This personalized approach not only improves the efficacy of the neurostimulation but also minimizes the risk of overstimulation and potential side effects that can occur with continuous, open-loop stimulation [ 131 , 132 ].

6.1. Recent Studies and Trials Evaluating Closed-Loop Systems

Recent studies and clinical trials investigating closed-loop systems have shown promising results in preventing seizures and improving seizure control in patients with drug-resistant epilepsy. One notable closed-loop stimulation device that has been evaluated in clinical trials is the NeuroPace RNS System [ 133 , 134 ]. The clinical trial for this system demonstrated significant seizure reduction in patients with medically refractory focal epilepsy [ 135 , 136 ]. Results showed that patients experienced a median reduction of 70% in seizure frequency at 12–15 months after implantation. Additionally, a subset of patients achieved a remarkably greater reduction in seizures, highlighting the potential for substantial seizure control with closed-loop stimulation [ 136 ]. Moreover, closed-loop systems have demonstrated the ability to detect and respond to specific brain patterns associated with seizures, allowing for the optimization of stimulation parameters and personalized treatment [ 131 , 134 ]. Some studies have shown that closed-loop stimulation can be tailored to individual patients, resulting in improved efficacy compared to standard open-loop approaches [ 137 , 138 , 139 , 140 ].

6.2. Potential for Personalized Closed-Loop Approaches

The potential for personalized closed-loop approaches in epilepsy management is a particularly exciting area of research. Each individual’s epilepsy is unique, with variations in seizure types, triggers, and brain activity patterns. Closed-loop systems have the inherent capability to capture and analyze this individual variability, allowing for the development of personalized treatment strategies [ 141 , 142 , 143 ]. Harnessing the power of patient-specific data, including EEG or ECoG recordings, genetic profiles, and clinical history, closed-loop systems have the potential to tailor the timing, intensity, and stimulation site to align precisely with each patient’s unique seizure patterns and needs. For example, a closed-loop system can be programmed to recognize the early signs of seizure activity in a particular patient and deliver stimulation precisely at those critical moments to halt seizure progression [ 144 ]. Furthermore, closed-loop systems have the potential to learn and adapt over time, continuously refining their algorithms and responsiveness based on patient feedback and long-term outcomes [ 105 ]. As technology and data analytics advance, closed-loop approaches are expected to become increasingly sophisticated, leading to further improvements in seizure prediction and prevention [ 120 ].

Despite the promising potential of closed-loop stimulation, challenges remain in optimizing closed-loop algorithms, validating their reliability, and determining the most effective stimulation parameters for different patient populations [ 120 , 131 ]. Additionally, the implementation of closed-loop systems requires robust data processing capabilities, advanced algorithms, and accurate seizure prediction models [ 124 , 143 ]. However, closed-loop stimulation represents a significant advancement in neurostimulation therapies for epilepsy management. By dynamically responding to real-time brain activity, closed-loop systems offer personalized and adaptive treatment approaches that can effectively prevent seizures before they fully develop.

7. Cannabidiol and Epilepsy

Cannabidiol (CBD) is one of the many compounds found in the Cannabis sativa plant, commonly known as hemp or marijuana. Unlike tetrahydrocannabinol (THC), another well-known cannabinoid, CBD does not produce psychoactive effects and is not associated with the feeling of being “high” [ 145 , 146 ]. CBD has gained significant attention in recent years for its potential therapeutic properties, including its anticonvulsant effects [ 146 ]. The exact mechanisms of action by which CBD exerts its anticonvulsant effects are not fully understood, but several potential pathways have been proposed. CBD is thought to interact with the endocannabinoid system, a complex signaling network that regulates various physiological processes in the body, including neural excitability [ 147 , 148 ]. By modulating the endocannabinoid system, CBD may reduce excessive neuronal excitability, which is a key factor in seizure generation [ 149 , 150 ]. CBD is also believed to influence other non-cannabinoid receptor systems, such as serotonin and transient receptor potential (TRP) channels, which play roles in pain perception, mood regulation, and neuroprotection [ 151 ]. These diverse interactions contribute to the multifaceted mechanisms of CBD in epilepsy management.

7.1. Clinical Trials and Evidence Supporting the Use of CBD

The anticonvulsant properties of CBD have been extensively studied ( Figure 2 ), leading to the approval of a CBD-based medication for certain epilepsy syndromes. Epidiolex® (cannabidiol) oral solution, a pharmaceutical-grade CBD formulation, has been approved by regulatory agencies for the treatment of specific epileptic conditions [ 152 ]. One of the most compelling lines of evidence supporting the use of CBD is its effectiveness in reducing seizures in patients with Dravet syndrome and Lennox–Gastaut syndrome (LGS), two severe childhood epilepsy syndromes that are notoriously challenging to manage with conventional therapies. Clinical trials of Epidiolex® in Dravet syndrome and LGS have shown a significant reduction in seizure frequency compared to placebo, leading to the approval of this medication for these specific indications [ 153 ]. Recent evidence has also provided valuable insights into the use of CBD for other epilepsy types and syndromes. Observational studies and patient registries have reported favorable responses to CBD in reducing seizure frequency and improving seizure control in various pediatric and adult epilepsy populations [ 5 ]. However, it is essential to note that individual responses to CBD can vary, and not all patients experience the same degree of benefit.

The mechanism of action of cannabidiol in the management of epilepsy. ( a ) Cannabinoid molecular mechanism of action in epilepsy. CBD performs an inhibitory role on FAAT resulting in activation of CB1, CB2, and TRPV1 receptors. Anandamide levels are also increased due to FAAH inhibition. ( b ) This image represents the type of cannabinoid receptors present in the human endocannabinoid system, i.e., CB1 and CB2, found in varying parts of body. It is a system having a lock and key mechanism with specific functions performed by both CB1 and CB2. CB1 has greater affinity for both THC and AEA as compared to CB2. Abbreviations: CBD: cannabinoid; AEA: anandamide; CB1: cannabinoid receptor1; D2: dopamine receptor 2; FAAH: fatty acid amide hydrolase. TRPV1: transient receptor potential vanilloid 1, THC: tetrahydrocannabinol.

7.2. Concerns and Considerations Regarding the Use of CBD

While CBD shows promise as an adjunctive therapy for epilepsy, there are several concerns and considerations that warrant attention. CBD can interact with certain medications metabolized by the liver’s cytochrome P450 enzyme system, potentially affecting their effectiveness or safety [ 154 , 155 ]. Therefore, it is essential for patients and healthcare providers to be aware of potential drug interactions when using CBD alongside other medications [ 5 , 156 ]. CBD is generally well-tolerated, but some individuals may experience side effects, such as fatigue, diarrhea, and changes in appetite or weight. Most side effects are mild and transient, but patients should be closely monitored during CBD treatment [ 156 ].

The regulatory landscape surrounding CBD products varies by country and region [ 157 , 158 ]. In some areas, CBD may be available as a prescription medication, while in others, it may be available as an over-the-counter supplement. It is crucial for patients to use high-quality CBD products from reputable sources to ensure safety and efficacy [ 159 ]. Not all patients respond to CBD in the same way, and some may not experience significant seizure reduction. It is essential to set realistic expectations and monitor the patient’s response to CBD therapy over time [ 159 , 160 ]. As with any new medication, the long-term safety of CBD requires further investigation, especially in populations that may require prolonged or continuous use. Finding the optimal dose of CBD for each patient can be challenging, and a gradual titration may be necessary to achieve the best therapeutic effect [ 161 ]. CBD has emerged as a potential adjunctive therapy for certain epilepsy syndromes, particularly Dravet syndrome and Lennox–Gastaut syndrome [ 162 , 163 ]. Its mechanisms of action are thought to involve interactions with the endocannabinoid system and other receptor systems in the brain [ 164 ]. Clinical trials and other evidence have demonstrated the efficacy of CBD in reducing seizure frequency and improving seizure control in specific epilepsy populations [ 165 ]. However, concerns and considerations, such as potential drug interactions with CBD, side effects, and individual response variations, highlight the need for careful patient selection, monitoring, and further research for its usage.

7.3. Emerging Therapeutic Avenues

In addition to cannabidiol, several other new antiepileptic drugs (ASMs) have emerged as potential therapeutic options for epilepsy management. One such notable candidate is cenobamate, which has shown promising results in the treatment of refractory focal epilepsy [ 166 , 167 ]. Cenobamate’s broad efficacy profile and the potential for achieving seizure freedom in challenging cases have garnered attention [ 167 ]. Clinical trials have demonstrated significant reductions in seizure frequency and notable improvements in seizure control [ 167 , 168 ]. With its novel mechanism of action targeting voltage-gated sodium channels, cenobamate presents a unique approach to addressing drug-resistant epilepsy [ 169 ]. While further studies are required to fully elucidate its long-term safety and efficacy, cenobamate holds promise as a valuable addition to the armamentarium of ASMs for epilepsy. The evolving landscape of epilepsy treatment highlights the ongoing efforts to provide patients with a diverse range of effective therapeutic options, each tailored to address specific needs and challenges. As new drugs such as cenobamate continue to demonstrate their potential, research and innovation remain pivotal in enhancing the quality of life for individuals living with epilepsy.

8. Ketogenic Diet and Epilepsy

The ketogenic diet is a high-fat, low-carbohydrate, and moderate-protein dietary approach designed to mimic the metabolic state of fasting [ 10 , 28 ]. When adhering to a ketogenic diet, the body shifts from primarily using carbohydrates for energy to utilizing fats as its primary fuel source [ 170 ]. This metabolic shift leads to the production of ketone bodies in the liver, which can provide an alternative energy source for the brain [ 171 ]. The therapeutic use of the ketogenic diet for epilepsy management dates back to the early 1920s when it was first introduced as a potential treatment for drug-resistant epilepsy [ 9 , 172 , 173 ]. The diet was initially implemented as a means to mimic the beneficial effects of fasting, which was known to reduce seizure frequency in some individuals. Over time, researchers and clinicians refined the diet’s composition and established specific ratios of fat, carbohydrates, and protein to optimize its effectiveness while maintaining nutritional balance [ 172 , 174 ].

Current research has continued to explore the efficacy of the ketogenic diet as a valuable and non-pharmacological treatment option for epilepsy [ 172 ]. Numerous clinical studies and trials have investigated the diet’s impact on seizure control in both pediatric and adult populations with various forms of drug-resistant epilepsy [ 175 , 176 ]. A meta-analysis of multiple studies revealed that approximately 50% of patients on the ketogenic diet experienced a significant reduction in seizure frequency, with around 10–15% achieving complete seizure freedom [ 177 ]. While the diet’s response may vary among individuals, evidence consistently indicates that the ketogenic diet can lead to clinically meaningful seizure reduction in a substantial proportion of patients [ 177 , 178 ]. Moreover, recent studies have expanded the applications of the ketogenic diet beyond refractory epilepsy, exploring its potential benefits in other neurological conditions, including some neurodevelopmental disorders and brain-tumor-related epilepsy [ 179 ].

Potential Mechanisms of Action and Variations of the Ketogenic Diet

The exact mechanisms by which the ketogenic diet exerts its anticonvulsant effects are not entirely understood, but several hypotheses have been proposed [ 180 , 181 ]. One of the key factors contributing to the diet’s efficacy is the elevation of ketone bodies in the bloodstream, which is believed to have anticonvulsant properties [ 182 , 183 ]. Ketone bodies provide an alternative fuel source for the brain, supporting neuronal function and stabilizing excitability, potentially reducing the likelihood of seizures [ 180 , 183 ]. Moreover, the ketogenic diet may influence the balance of neurotransmitters in the brain [ 183 , 184 ]. By promoting a reduction in excitatory neurotransmitters and an increase in inhibitory neurotransmitters, the diet can help dampen seizure activity and contribute to better seizure control [ 185 ].

Moreover, the diet’s impact on energy metabolism is thought to play a significant role in its anticonvulsant effects. By altering energy metabolism in the brain, the ketogenic diet may affect the availability of adenosine triphosphate (ATP), the primary energy currency of cells [ 178 , 186 ]. This alteration in energy availability can impact neuronal activity and contribute to seizure suppression [ 184 ]. The classic ketogenic diet typically consists of a 4:1 ratio of fats to combined carbohydrates and protein, with approximately 90% of the daily caloric intake coming from fats. Carbohydrates and protein are significantly restricted in this approach [ 187 ]. However, to accommodate different patient populations and preferences, variations of the ketogenic diet are available. These include the modified Atkins diet and the low glycemic index treatment (LGIT), which have lower fat-to-carbohydrate and protein ratios and are often easier to implement and sustain [ 188 ]. These variations can be particularly appealing for adolescents and adults seeking the benefits of the ketogenic diet without the strict adherence to the classic 4:1 ratio.

The ketogenic diet can be tailored to suit individual patient needs. Factors such as age, underlying medical conditions, dietary preferences, and lifestyle can all be considered in customizing the diet. This personalized approach may enhance adherence and increase the likelihood of successful seizure control [ 178 , 187 ]. Hence, the ketogenic diet remains a valuable and well-established therapeutic option for epilepsy management, particularly for drug-resistant epilepsy. Its historical role in epilepsy treatment has been reinforced by contemporary research, which continues to demonstrate its efficacy in reducing seizure frequency and improving seizure control. While the exact mechanisms of action are still under investigation, the diet’s ability to induce ketosis and alter brain metabolism likely plays a pivotal role in its anticonvulsant effects. The ketogenic diet stands as a testament to the significant impact that dietary interventions can have in the field of epilepsy [ 178 , 189 ]. For individuals seeking alternative or complementary treatments for their condition, the ketogenic diet may offer new possibilities and hope for improved seizure management and a better quality of life.

9. Gene Therapies for Epilepsy

Gene therapy is an innovative approach aimed at treating diseases by modifying or manipulating the genetic material of cells [ 190 , 191 ]. The fundamental principle of gene therapy is to correct or replace faulty genes that contribute to the development or progression of a particular condition. In the context of epilepsy, gene therapy holds the potential to address the underlying genetic abnormalities that give rise to seizure disorders [ 192 ]. By targeting specific genes associated with epilepsy, gene therapy aims to restore normal cellular function and inhibit seizure generation, providing a promising avenue for the development of novel and more targeted epilepsy treatments [ 40 , 186 , 193 ].

Recent advancements in gene editing technologies have revolutionized the field of gene therapy, enabling more precise and efficient targeting of specific genes. One of the most revolutionary gene editing tools is CRISPR-Cas9, which allows scientists to edit DNA sequences with remarkable accuracy [ 194 ]. With CRISPR-Cas9, researchers can modify or delete epilepsy-related genes and investigate their impact on seizure susceptibility [ 194 ]. For epilepsy, gene editing techniques are being utilized to explore the role of various genes implicated in the disorder. By targeting genes associated with ion channels, neurotransmitter receptors, or cellular signaling pathways, researchers can investigate how alterations in these genes contribute to epileptogenesis [ 195 , 196 ]. Additionally, gene editing tools are being used to correct disease-causing mutations in patient-derived cells or animal models, potentially paving the way for personalized gene therapies tailored to specific genetic defects [ 197 , 198 , 199 , 200 ].

Safety and Efficacy of Gene Therapies

While gene therapy for epilepsy is still in the early stages of development, preclinical studies in animal models have shown promising results [ 184 , 201 , 202 ]. Animal models with specific epilepsy-related genetic mutations have been treated using gene therapy approaches, resulting in reduced seizure frequency and improved seizure control [ 202 , 203 , 204 , 205 ]. The preclinical studies have provided valuable insights into the potential therapeutic benefits of gene therapies and have identified potential target genes for further investigation [ 205 ]. In terms of clinical studies, several gene therapy trials for epilepsy are currently underway or in the planning stages. These trials aim to evaluate the safety and efficacy of gene therapies in human patients with specific genetic forms of epilepsy. One notable example is the development of adeno-associated virus (AAV) vectors as a delivery system for gene therapies [ 206 ]. AAV vectors have shown promise as a means to deliver therapeutic genes to specific brain regions in a controlled and targeted manner [ 206 , 207 ]. It is important to note that gene therapy approaches for epilepsy face unique challenges. The complexity of the brain and the diversity of genetic factors contributing to epilepsy necessitate rigorous evaluation of potential risks and benefits. Delivery methods, such as viral vectors, must be carefully engineered to ensure accurate and efficient gene transfer while minimizing immune responses and other adverse effects [ 207 , 208 ].

Long-term safety and potential off-target effects of gene editing in the brain remain areas of active investigation and consideration [ 209 ]. Ethical considerations, such as ensuring informed consent and addressing concerns about permanent genetic modifications, are crucial in developing responsible gene therapies for epilepsy [ 191 ]. Nevertheless, gene therapy represents a promising and innovative frontier in epilepsy treatment [ 210 ]. By targeting specific genes associated with epileptogenesis, gene therapies hold the potential to provide more precise and personalized treatments for individuals with genetic forms of epilepsy [ 211 ]. While challenges remain, gene therapies have the potential to revolutionize epilepsy treatment and improve the lives of individuals living with this challenging neurological disorder.

Emerging advancements in gene therapy hold significant promise for revolutionizing the landscape of epilepsy treatment. Gene therapy offers a groundbreaking approach to address the genetic anomalies contributing to seizure disorders by manipulating cellular genetic material. Through gene editing technologies such as CRISPR-Cas9, researchers can now target specific epilepsy-associated genes with remarkable accuracy, shedding light on the intricate molecular mechanisms underlying epileptogenesis. Recent preclinical studies in animal models demonstrate promising results, with gene therapy interventions effectively reducing seizure frequency and enhancing seizure control. Clinical trials focusing on human patients with specific genetic forms of epilepsy are underway, evaluating the safety and efficacy of gene therapies. While challenges in delivering genes to the brain and ensuring long-term safety remain, gene therapy’s potential to provide precise, personalized treatments for genetic forms of epilepsy is groundbreaking. Ethical considerations and rigorous evaluation are imperative, but the prospects of gene therapies offer hope for revolutionizing epilepsy treatment and improving the quality of life for those impacted by this complex neurological disorder.

10. Optogenetics in Epilepsy Research

Optogenetics is a cutting-edge technique that combines genetics and optics to control the activity of specific neurons in living tissue using light. This revolutionary method involves genetically engineering neurons to express light-sensitive proteins called opsins, which respond to specific wavelengths of light [ 212 , 213 ]. When these opsins are activated by light, they can either stimulate or inhibit the activity of the targeted neurons. Optogenetics allows precise and real-time manipulation of neural circuits, providing researchers with unprecedented control to study the function of specific brain regions and the mechanisms underlying various neurological disorders, including epilepsy [ 212 , 213 , 214 ].

In epilepsy research, optogenetics plays a vital role in unraveling the complex neural dynamics that lead to seizure generation and propagation [ 215 ]. By selectively activating or silencing specific populations of neurons in animal models of epilepsy, researchers can investigate the causal relationships between neural activity patterns and seizure development [ 205 , 216 ]. Optogenetics provides a powerful tool to explore how abnormal neuronal firing, circuit interactions, and network synchronization contribute to epileptic phenomena, thus advancing our understanding of epilepsy pathophysiology. Optogenetics has yielded groundbreaking findings in epilepsy research, shedding light on the intricate neural processes underlying seizure activity [ 217 , 218 ]. In animal models of epilepsy, researchers have utilized optogenetics to selectively activate or inhibit specific neuron populations in brain regions implicated in seizure generation [ 219 , 220 ]. One significant discovery is the identification of “seizure hotspots” in the brain, regions with a higher propensity to initiate and propagate seizures. By optogenetically stimulating these seizure hotspots, researchers have been able to trigger epileptic activity and observe the patterns of seizure propagation in real time. Conversely, inhibiting these regions using optogenetics can prevent seizure development, highlighting the critical role of these brain areas in epileptogenesis [ 219 ]. Additionally, optogenetics has elucidated the role of specific cell types, such as inhibitory interneurons, in controlling network excitability and seizure susceptibility [ 221 ]. By targeting these interneurons with optogenetic tools, researchers have shown that modulating their activity can either enhance or suppress seizure activity, providing insights into potential therapeutic strategies [ 222 , 223 ]. Optogenetics has been instrumental in investigating the dynamics of brain circuitry during seizures. By simultaneously recording and manipulating neuronal activity using optogenetics, researchers have gained a deeper understanding of how seizures spread through interconnected brain regions and how specific circuit abnormalities contribute to epileptic events.

Future Possibilities of Optogenetics in Clinical Applications

The potential clinical applications of optogenetics in epilepsy are both promising and challenging [ 215 , 216 ]. While optogenetics has primarily been used in preclinical research, its translation to clinical practice faces several significant hurdles. Directly applying optogenetics to human brains is currently not feasible due to the need for gene delivery and light-delivery systems that would require invasive procedures. However, the knowledge gained from optogenetics experiments in animal models can inform the development of more targeted and effective therapies. Optogenetics research can help identify specific neural targets or circuit components that can be manipulated through alternative means, such as targeted pharmacological interventions or neuromodulation techniques [ 224 ].

Optogenetics research can inspire the development of novel closed-loop neurostimulation systems [ 225 ]. By combining optogenetic techniques with responsive neurostimulation technologies, it may be possible to create closed-loop systems that detect aberrant neural activity and deliver precisely timed light stimulation to prevent or disrupt seizure activity [ 130 , 226 ]. This hybrid approach could potentially offer a personalized and adaptive therapy for individuals with drug-resistant epilepsy. Looking further ahead, advances in non-invasive techniques for optogenetic activation and the development of novel light-sensitive proteins may make it possible to non-invasively apply optogenetics to human brains [ 227 , 228 , 229 ]. Although this goal is still in the realm of basic research, it holds promise for the future of epilepsy therapy and other neurological disorders. Optogenetics is a powerful tool in epilepsy research, enabling precise control of neural activity to study the mechanisms underlying seizures. By combining optogenetics with other neurostimulation approaches, such as responsive neurostimulation, the future possibilities for personalized and adaptive epilepsy treatments are indeed promising [ 142 , 230 ].

11. Discussions

In this comprehensive review, we explored a range of innovative therapies for epilepsy management. We began with an overview of traditional approaches to epilepsy treatment, highlighting the limitations of conventional ASMs and the need for novel treatment strategies to address drug-resistant epilepsy. Importantly, poor medication compliance in ASMs can reduce the effectiveness of treatment in the long term and contribute to treatment resistance. It is widely recognized that consistent and timely adherence to prescribed medication regimens is crucial for achieving optimal outcomes in epilepsy management. When patients do not follow their medication schedule as prescribed, the therapeutic levels of antiseizure medications in their bloodstream may become insufficient, leading to breakthrough seizures and reduced seizure control. Over time, this can result in a reduced response to the medication, making the condition more resistant to treatment and necessitating adjustments to the treatment plan. We then delved into three emerging therapies: RNS, VNS, and DBS, discussing their mechanisms of action, clinical evidence, and potential benefits for different epilepsy syndromes. Next, we examined the role of CBD in epilepsy treatment, emphasizing the pharmacology of CBD, clinical trials supporting its use in specific epilepsy syndromes, and considerations for its adjunctive therapy. We further explored the potential of gene therapies and optogenetics in epilepsy research. Gene therapies offer a promising path to target specific genes associated with epilepsy, with recent advancements in gene editing techniques showing potential for precise and personalized treatments. Optogenetics, on the other hand, has enabled groundbreaking findings in understanding seizure mechanisms by allowing real-time manipulation of neural circuits in animal models. Although direct clinical applications of optogenetics in humans are currently challenging, the knowledge gained from this research may inform the development of future therapies.

The landscape of epilepsy management is rapidly evolving, with emerging trends and novel therapies continually reshaping the field. Staying updated with the latest research findings and advancements is critical for healthcare providers, researchers, and patients alike. Awareness of innovative therapies, such as responsive neurostimulation, gene therapies, and optogenetics, allows for informed decision making and the exploration of new treatment options for patients with drug-resistant epilepsy. Moreover, ongoing research and clinical trials may lead to the approval of new treatments and expanded indications for existing therapies. As epilepsy is a complex and heterogeneous disorder, understanding the full spectrum of available treatment options ensures that patients receive personalized and effective care tailored to their specific needs.

The review of emerging therapies for epilepsy management has provided insights into promising directions for future research. First and foremost, continued investigation into the mechanisms of action of RNS, VNS, DBS, and gene therapies is essential to optimize their therapeutic benefits and refine patient selection criteria. Long-term safety and efficacy data from clinical trials are crucial to ensure the responsible and evidence-based use of these therapies in routine practice. Furthermore, exploring the potential of combining various therapeutic approaches may yield synergistic benefits for epilepsy treatment. For instance, combining pharmacological treatments with neurostimulation techniques or using optogenetics to study how different therapies interact with specific neural circuits could lead to more comprehensive and tailored treatment regimens. The application of artificial intelligence (AI) and machine learning algorithms to epilepsy research and treatment is another promising avenue. AI-based algorithms can analyze large datasets, such as EEG recordings or genetic information, to identify patterns associated with seizure risk and treatment response [ 231 , 232 ]. Integrating AI with closed-loop neurostimulation systems may enable real-time seizure prediction and personalized neuromodulation, enhancing seizure control and quality of life for patients [ 233 , 234 , 235 , 236 ]. Additionally, ongoing research in the field of CBD and other cannabinoids may uncover new therapeutic applications and optimize dosing regimens for different epilepsy syndromes. Continued clinical trials will provide critical evidence for the long-term safety and efficacy of CBD and its potential role as a monotherapy or adjunctive treatment. Finally, collaborative efforts between researchers, clinicians, and industry partners are vital for advancing epilepsy management. Increased investment in research and development will drive the translation of preclinical findings into innovative therapies and ultimately benefit individuals living with epilepsy.

12. Conclusions

In the last few years, there has been significant progress made in epilepsy management through innovative therapies. From responsive neurostimulation and neuromodulation techniques, such as VNS and DBS, to the exploration of CBD as an anticonvulsant agent and the cutting-edge fields of gene therapies and optogenetics, researchers have expanded the horizons of epilepsy treatment. The importance of staying updated with emerging trends cannot be overstated, as new discoveries may offer hope for patients with drug-resistant epilepsy and open avenues for more targeted and effective therapies. Future research should focus on refining existing therapies, exploring combination approaches, and harnessing AI and machine learning to optimize epilepsy management. Collaborative efforts among researchers, clinicians, and industry partners will be key to realizing the full potential of these innovative therapies and advancing epilepsy care to new frontiers. Ultimately, the goal of ongoing research and progress in epilepsy management is to improve the lives of individuals living with epilepsy, providing them with greater seizure control, improved quality of life, and renewed hope for a brighter future.

Acknowledgments

Shampa Ghosh, Hitaishi Sharma, Soumya Ghosh and Jitendra Kumar Sinha acknowledge the research support from GloNeuro, India. Jitendra Kumar Sinha and Shampa Ghosh acknowledge support from International Brain Research Organization (IBRO) and Indian Council of Medical Research (ICMR), India. Kannan Badri Narayanan and Rakesh Bhaskar acknowledge the research support from Yeungnam University, Republic of Korea.

Funding Statement

Research support funding has been received from GloNeuro for the study.

Author Contributions

S.G. (Shampa Ghosh) and J.K.S. contributed to the conceptual framework as well as data collection, and curation. S.G. (Shampa Ghosh), J.K.S., S.G. (Soumya Ghosh), H.S., R.B. and K.B.N. contributed to final writing, editing and figure production in the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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Focus On Epilepsy Research

The epilepsies are a set of disorders characterized by recurring seizures, or disturbances in the electrical activity of the brain. Epilepsy affects people of all ages, from infants to the aged, and can result from many causes, including genetic variations, illness, head injury, or abnormal brain development. NIH / NINDS and its community-based research partners are dedicated to finding cures for the epilepsies and/or preventing epilepsy in individuals at risk for seizures.

Featured NINDS Epilepsy Research Initiatives

The NINDS established the Centers Without Walls program in 2010 to rapidly advance epilepsy research through promoting interdisciplinary, collaborative research. Four centers have been funded:

The Epilepsy 4000 (Epi4K) collaborative has examined genetic data from 4,000 individuals in order to understand the genes underlying epilepsy. See an NIH news release about the center .

The Center for SUDEP Research ( CSR ) brings together extensive expertise to understand Sudden Unexplained Death in Epilepsy. See an NIH news release about the center .

The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy ( EpiBiosS4Rx ) will use studies of animals and patients with traumatic brain injury (TBI) leading to post-traumatic epilepsy (PTE) in order to develop future clinical trials of epilepsy prevention therapies.

The Channelopathy-Associated Epilepsy Research Center ( CAERC ) will combine high-throughput technologies and high-content model systems to investigate the functional consequences of genetic variants in channelopathy-associated epilepsy.

The Epilepsy Multiplatform Variant Prediction ( EpiMVP ) Center Without Walls will develop a modular, highly integrated platform approach to accelerate determination of the functional, pharmacological, neuronal network and whole animal consequences of genetic variants among a range of clinical epilepsy types.

Estimates of Funding for Various Research, Condition, and Disease Categories

Additional funding information on epilepsy research projects funded by the ICARE members, including federal and nonprofit organizations can be accessed at the Interagency Collaborative to Advance Research in Epilepsy Research Portfolio.

Related Federal Programs

Other federal partners with epilepsy research programs include:

• The Department of Defense's  Epilepsy Research Program .
• The CDC's Epilepsy Program .

Proceedings & Outcomes

Status Epilepticus after Benzodiazepines: Seizures and Improving Long Term Outcomes This virtual workshop convened preclinical and clinical researchers, as well as relevant stakeholders to discuss and define the indications of potential therapeutics needed to improve outcomes following SE. Topics of discussion will include refractory SE, post SE neuropathology, current clinical trials, gaps in the research for follow-on treatments and barriers to transitioning therapies to the clinic. Outcomes of the workshop will include a clearer understanding of the unmet therapeutic needs and identification of key gaps in the research, increasing the potential for new therapeutics development.

• Workshop Summary

Post-Traumatic Epilepsy: Models, Common Data Elements and Optimization The conference will set the stage to optimize preclinical and clinical research to prevent epileptogenesis following TBI. The results will help improve biomedical research in posttraumatic epilepsy.

ICARE: Interagency Collaborative to Advance Research in Epilepsy, 2021 Epilepsy research needs reach across the missions of multiple NIH Institutes and Centers and across many organizations outside the NIH.  As the primary NIH Institute for epilepsy research, NINDS leads this working group, with broad representation from the NIH, other Federal agencies, and the research and patient advocacy communities. Annual meetings provide a forum for sharing information about ongoing and planned epilepsy research activities, highlighting advances and discussing needs and opportunities, and promoting increased collaboration toward common research goals.

• Meeting Summary

Curing the Epilepsies 2021 This conference, held January 4-6, 2021, was an opportunity for all epilepsy research stakeholders to provide input on the transformative research priorities for the field, and to come together to find ways to move forward "Curing the Epilepsies"

•   Conference Summary

Accelerating the Development of Therapies for Anti-Epileptogenesis and Disease Modification The “Accelerating the Development of Therapies for Anti-Epileptogenesis and Disease Modification” workshop, on August 6-7, 2018, brought together experts in the field of epilepsy to optimize and accelerate the development of therapies for anti-epileptogenesis and disease-modification in the epilepsies.

Benchmarks for Epilepsy Research

• 2021 Benchmarks for Epilepsy Research
• 2020 Editorial: The Benchmarks: Progress and Emerging Priorities in Epilepsy Research
• Epilepsy Benchmarks Area I: Understanding the Causes of the Epilepsies and Epilepsy-Related Neurologic, Psychiatric, and Somatic Conditions
• Epilepsy Benchmarks Area II: Prevent Epilepsy and Its Progression
• Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects
• Epilepsy Benchmarks Area IV: Limit or Prevent Adverse Consequence of Seizures and Their Treatment Across the Life Span
• 2014 Benchmarks for Epilepsy Research
• Epilepsy Research Benchmarks Progress Update 2007-2009
• 2007 Epilepsy Research Benchmarks

Resources and Tools

Adam Hartman, M.D. | Program Director, Office of Clinical Research [email protected]

George K. Essien Umanah, Ph.D. | Program Director, Channels, Synapses, and Circuits [email protected]

Miriam Leenders, Ph.D. | Program Director, Channels Synapses & Circuits [email protected]

Vicky Whittemore, Ph.D. | Program Director, Channels Synapses & Circuits [email protected]

Ben Churn, Ph.D. | Program Director, Channels Synapses & Circuits [email protected]

Brian Klein, Ph.D. | Program Director, Epilepsy Therapy Screening Program [email protected]

Funding Opportunities 

Epilepsy Funding Opportunities

This resource contains public and non-confidential chemical structures and biological data for compounds which have been screened for efficacy and toxicity in animal models of epilepsy and related seizure disorders as part of the Epilepsy Therapy Screening Program (ETSP) at the National Institute of Neurological Disorders and Stroke.

ICARE provides an interagency forum for sharing information about ongoing and planned epilepsy research activities.

The NINDS epilepsy common data elements provide data standards for clinical research in order to improve data quality and facilitate comparison and combination of data across studies.

The ERC provides information about grant and funding opportunities from non-profit and government organizations focused on epilepsy related research.

REVIEW article

New trends and most promising therapeutic strategies for epilepsy treatment.

• 1 Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
• 2 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
• 3 Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, Netherlands
• 4 Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
• 5 Department of Experimental and Clinical Medicine, Neurological Clinic, Marche Polytechnic University, Ancona, Italy

Background: Despite the wide availability of novel anti-seizure medications (ASMs), 30% of patients with epilepsy retain persistent seizures with a significant burden in comorbidity and an increased risk of premature death. This review aims to discuss the therapeutic strategies, both pharmacological and non-, which are currently in the pipeline.

Methods: PubMed, Scopus, and EMBASE databases were screened for experimental and clinical studies, meta-analysis, and structured reviews published between January 2018 and September 2021. The terms “epilepsy,” “treatment” or “therapy,” and “novel” were used to filter the results.

Conclusions: The common feature linking all the novel therapeutic approaches is the spasmodic rush toward precision medicine, aiming at holistically evaluating patients, and treating them accordingly as a whole. Toward this goal, different forms of intervention may be embraced, starting from the choice of the most suitable drug according to the type of epilepsy of an individual or expected adverse effects, to the outstanding field of gene therapy. Moreover, innovative insights come from in-vitro and in-vivo studies on the role of inflammation and stem cells in the brain. Further studies on both efficacy and safety are needed, with the challenge to mature evidence into reliable assets, ameliorating the symptoms of patients, and answering the challenges of this disease.

Introduction

Epilepsy is the enduring predisposition of the brain to generate seizures, a condition that carries neurobiological, cognitive, psychological, and social consequences ( 1 ). Over 50 million people worldwide are affected by epilepsy and its causes remain partially elusive, leaving physicians, and patients an unclear insight into the etiology of the disease and the best treatment approach ( 2 ). Over than 30% of individuals do not respond to common anti-seizure medications (ASMs) and are addressed to as “drug-resistant,” a term which the International League Against Epilepsy (ILAE) applies to those patients who do not respond to the combination of two appropriately chosen and administered ASMs ( 3 , 4 ). Hence, a great deal of responsibility laid upon the research and development of innovative pharmacological and non-pharmacological approaches given a targeted approach, aiming at improving the symptoms of patients and their quality of life (QoL), together with that of the caregivers.

As several investigations are currently in progress, this review aimed to discuss the novel therapeutic insights, with the hope they may establish as turning points in the treatment of patients in the next few years.

A search on PubMed, Scopus, and EMBASE databases using the terms “epilepsy,” “treatment” or “therapy,” and “novel” was conducted. The search covered the period between January 2018 and September 2021. Existing literature was reviewed, including both experimental and clinical studies, meta-analysis, and topic reviews summarizing the most up-to-date researches. Only studies published in English were reviewed.

Precision Medicine

Precision medicine (PM) is an outstanding approach tended to use the genetics, environment, and lifestyle of individuals to help determine the best “way” to prevent or treat disease ( 5 ). It embeds a holistic evaluation, assessing not only the effect of an own condition but also that of treatment ( 6 ). Precision medicine is endorsed in epilepsy management for many decades, as in the clinical practice ASMs are selected after a careful and pointful evaluation of seizure types of patients, their epilepsy syndrome, comorbidities, concomitant drugs, and expected vulnerability to specific adverse events (AEs) ( 7 ). Discoveries and progress in genetics have provided the strongest basis for PM: as more and more genes are being identified as disease-causing, hope has grown on possible targeted approaches ( 6 ). An “ideal” therapy would be able to both relieve symptoms and reverse the functional alterations caused by specific genetic mutations. This firstly implies identifying putative disease-causing genes and, secondly, the specific functional alterations caused by the pathogenic variants. Lastly, it should have been demonstrated that therapeutic intervention may modify the effect caused by the mutation.

The ketogenic diet (KD) used to treat glucose transporter 1 (GLUT1) deficiency syndrome is probably the best example of PM applied to epilepsy. In GLUT1 patients the uptake of glucose into the brain is impaired because of the SLC2A1 mutation, hence, the KD provides neurons with an alternative source of energy, compensating for the consequences of the metabolic defect ( 8 ). Another clear application of a PM-based approach is the avoidance of those drugs which may cause worsening of seizures by exasperating the underlying molecular defect, i.e., sodium channel blockers must be avoided in patients with Dravet syndrome (DS) carrying loss-of-function mutations in the sodium voltage-gated channel alpha subunit 1 ( SCN1A ). Another one is memantine for the treatment of GRIN-related disorders due to gain-of-function mutations in the NMDA receptor ( 8 – 11 ) or quinidine and retigabine for epilepsies caused by potassium channels genes mutations ( KCNT1 and KCNQ2 ) ( 6 , 12 ). In epileptic encephalopathies (EE), it would be also of interest to investigate the effect of a PM treatment on cognitive function, to that targeting a specific gene mutation and abolishing related epileptic activity may result in improved cognitive functions ( 10 ).

Precision medicine may prove complex, as the same mutation may cause quite different clinical phenotypes; moreover, additional genetic variants may contribute to modifying a phenotype. Again, wide-genome variations or even the epigenome may influence the resulting expression of pathogenic variants ( 5 ).

Nowadays, evidence indicates PM may be applied to individuals with both rare and common forms of epilepsy, and, consequently, drug development is increasingly being influenced by PM approaches. Although extensive research focuses on genome-guided therapies, important opportunities also derive from immunosuppressive therapies and neuroinflammation-targeting treatments ( 2 , 13 ). The identification of cellular and molecular biomarkers would possibly allow clinicians to have early prediction markers of a disease and its progression. Additionally, it could lead to the development of unique models to cost-effectively screen treatments and also decrease the costs of clinical trials through better patient selection ( 14 ).

Novel Mechanisms of Anti-Seizure Medications

Many medications are currently under study in clinical practice, ranging from those with a mechanism similar to that of well-known ASMs, like the GABA-A receptor agonists, to those with novel mechanisms such as the stimulation of melatonin receptors. Moreover, some drugs are yet known medications, previously used for other indications; while a large group remains orphan of a well-comprised mechanism of action ( 6 ). It is in this perspective, that the wider term ASMs should be addressed, aiming at referring to the large heterogeneity of action mechanisms nowadays available to counteract seizures.

Cannabidiol

In 2018, the Food and Drug Administration (FDA) approved the first-in-class drug derived from the cannabis plant. Although the precise mechanism by which the cannabidiol (CBD) exerts its anti-seizure effects is still poorly known, it seems not to act through interaction with known cannabinoid receptors ( 15 ), but holds an affinity for multiple targets, resulting in the reduction of neuronal excitability which is relevant for the pathophysiology of the disease ( 16 , 17 ).

Cannabidiol is approved for the treatment of seizures in children with DS or Lennox-Gastaut syndrome (LGS) aged 2 years or older, based on three pivotal phases 3 trials ( 12 ). In 2019 CBD gained approval in Europe in conjunction with clobazam (CLB), based on clinical trial data showing that the combination of both CBD and CLB resulted in greater efficacy outcomes ( 16 ).

The first clinical trial ( 17 ) included 120 patients with DS aged between 2 and 18 years. The median frequency of convulsive seizures decreased from 12.4 to 5.9 per month, as compared with a decrease from 14.9 to 14.1 per month with the placebo. Furthermore, 43% of patients in the active arm and 27% in the placebo group showed at least a 50% reduction in the convulsive-seizure frequency. Overall, 62% of patients under CBD did gain at least one category at the seven-category Caregiver Global Impression of Change scale, as compared to 34% in the placebo group. Five percent of patients under CBD became seizure-free, while none in the placebo group did.

Another randomized, double-blind, placebo-controlled, trial ( 18 ) included 171 LGS patients aged between 2 and 55 years and measured the reduction in drop-seizures. The median percentage reduction was 43.9% in the CBD group and 21.8% in the placebo group. In 2018, Devinsky et al. ( 19 ) compared a lower 10 mg/kg/day dose of CBD with the full 20 mg/kg/day in LGS patients. A median 41.9% reduction in drop-seizure frequency was observed in the 20-mg CBD group, while the median reduction was 37.2% in the 10-mg group and 17.2% in the placebo group. Although this study demonstrated patients may gain benefit in seizure reduction by increasing the dose to 20 mg/kg/day, it also displayed an increased risk in AEs. It is generally recommended to begin at 5 mg/kg divided into two intakes a day, then increase to 10 mg/kg/day. If the 10 mg/kg/day dose is well-tolerated and the anti-seizure effect continues, dosing can be increased to the maximum of 20 mg/kg/day ( 15 ).

Cannabidiol also proved to effectively reduce seizure frequency at long-term follow-up ( 20 ), retaining a consistent reduction (between 42.9 and 44.3%) in seizure frequency at 48 weeks of follow-up. Moreover, 5 out of 104 patients (4.8%) were convulsive seizure-free at 12 weeks of treatment, with more than 40% having a reduction of convulsive seizure frequency ≥50% at each programmed visit of follow-up ( 18 ). In terms of median percentage reduction in convulsive seizures, rates of responders, reduction in total seizures, and CGIC-assed improvements, CBD proved greater in the subset of patients concomitantly treated with CLB. Moreover, the combination CBD+CLB showed a benefit in the number of convulsive seizure-free days ( 16 ). However, a drug-to-drug interaction increasing levels of active metabolites of both compounds must be assessed and hence CLB dose reduction is recommended if patients experience somnolence or sedation ( 15 , 16 ).

In conclusion, RCTs settle CBD as a well-tolerated drug, with patients primarily experiencing somnolence, diarrhea, and decreased appetite. The elevation of liver transaminases may be observed mostly in patients on concomitant valproate, and the dose reduction of valproate or CBD is often decisive. The efficacy of CBD on both convulsive and drop seizures is established, with retained efficacy at long-term follow-up. New RCTs in other syndromic or isolated epilepsies populations may widen the field of use of CBD in the next few years.

Fenfluramine

Fenfluramine (FFA), formerly used at 10 times higher dosage (up to 120 mg/day) as a weight-loss drug, exerts its anti-seizure effect both through the release of serotonin which stimulates multiple 5-HT receptor subtypes, and by acting as a positive modulator of sigma-1 receptors ( 16 , 21 – 23 ). Fenfluramine has been approved by the FDA in June 2020 and is currently under evaluation by the European Medicines Agency (EMA). The drug proved significantly effective in reducing seizures in phase-3 trials on DS patients: the 0.8 mg/kg/day treated group did experience a mean 64% reduction in seizures as compared to 34% in the 0.2 mg/kg/day group. Notably, a >75% reduction in seizures occurred in 45% of patients under 0.8 mg/kg/day, in 20.5% of those on 0.2 mg/kg/day compared to 2.5% in the placebo group ( 23 ). Fenfluramine has then continued to provide a clinically meaningful reduction in convulsive seizure frequency over a median of 445 days of treatment. The median percent reduction in monthly convulsive seizures frequency was 83.3%. Overall, 62% of patients showed a 50% reduction in convulsive seizure frequency ( 16 ).

Together with the anti-seizure effect, FFA has also relatively few drug-drug interactions, primarily a moderate effect on stiripentol (STP), which requires the downward adjustment of FFA dosing to.5 mg/kg/day. No additional interaction with other drugs such as valproate, CLB, and CBD are known ( 15 ). The most common AEs reported under FFA treatment include decreases in appetite, weight loss, diarrhea, fatigue, lethargy, and pyrexia ( 16 ). The main AEs leading to FFA withdrawal as a weight-loss agent were the occurrence of valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), for which 6-month-echocardiographic monitoring is required together with an ECG. However, at the anti-seizure dosages, no VHD or PAH was observed after a median duration treatment of 256 days. No ECG alterations indicative of atrioventricular conduction or cardiac depolarization alterations were seen, and no mitral or aortic valve regurgitation greater than “trace” was observed in any of the 232 patients with DS who participated in the open-label extension (OLE) study ( 21 , 24 , 25 ).

Cenobamate ( Xcopri or YKP3089 ) is a new ASM that has recently gained approval by the FDA for the treatment of focal-onset seizures in adults. The EMA is currently reviewing the drug for approval as an adjunctive treatment in focal-onset epilepsies. Cenobamate is a tetrazole-derived carbamate compound with a dual mechanism of action; the drug can both enhance the inactivated state of voltage-gated sodium channels, and act as a positive allosteric modulator of the GABA-A receptors, binding at a non-benzodiazepine site ( 26 ).

A multicenter, randomized study of patients with uncontrolled focal seizures ( 27 ) showed that the adjunctive cenobamate, with dosage groups of 100, 200, and 400 mg/day led to a consistent reduction in focal-seizures frequency after 18-weeks of treatment, with the greatest reduction observed in the 200 and 400 mg/day doses groups. A similar dose-effect relationship was seen when evaluating the responder rates (≥50% in seizure reduction). Post-hoc analysis proved seizure frequencies decreased early during cenobamate titration; while, during the 12-week maintenance phase, significantly more patients under the active 200 or 400 mg/day harms achieved seizure freedom as compared to that receiving placebo. Cenobamate is overall well-tolerated, showing mild to moderate severity AEs on the CNS system, such as somnolence, dizziness, and disturbances in gait and coordination, with a linear incidence-dose correlation and disappearance at maintenance. Four cases of hypersensitivity adverse reactions occurred during two RCTs, including one serious AEs of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) ( 26 , 27 ). In this case, the rapid titration of 100 mg/week from 200 to 400 mg dose might have contributed to the higher rates of AEs in the 400 mg group; a lower starting dose and a slower titration rate have been shown to reduce the occurrence of hypersensitivity reactions, possibly through the development of immune tolerance ( 27 ). As cenobamate inhibits the P450 family cytochrome CYP2C19 * 18, dosing adjustment is needed when adding cenobamate to ASM regimens containing phenytoin or phenobarbital ( 28 ); moreover, a dose reduction of CLB should be considered, counteract the increase in plasma levels of desmethylclobazam, its active metabolite. Cenobamate has also been shown to decrease by 25% the plasma exposure to carbamazepine, through the induction of the CYP3A4. Cenobamate could shorten the QT-interval on the ECG in a dose-dependent manner. Hence, cenobamate is contraindicated in patients with familial short QT syndrome, and caution is required in co-administration with other drugs known to reduce the QT interval since a synergistic effect may occur ( 26 , 27 ). In a short time, data will help to assess cenobamate active time-window on seizures control and real-life data will help to acknowledge whether freedom rates will be borne out in clinical practice. The mechanisms of action and the potential additive or synergistic interactions of cenobamate with concomitant ASMs also warrant further investigation ( 26 ).

Novel Non-Pharmacological Treatments

Neurostimulation comprises different techniques, already implemented in the clinical practice, direct to deliver electrical or magnetic currents to the brain in a non-invasive or invasive way and hence modulating neuronal activity to achieve seizure suppression.

Vagal Nerve Stimulation

Vagal nerve stimulation (VNS) is approved both in Europe and in the United States as an adjunctive treatment in patients with refractory epilepsies, and it is routinely available in many epilepsy centers, with more than 100,000 patients treated worldwide ( 6 ). Vagal stimulation may then turn off seizures originating in regions susceptible to heightened excitability, such as the limbic system, thalamus, and thalamocortical projections. Moreover, an additional mechanism of action derives from the activation of the locus coeruleus and the raphe nuclei, and the regulation of the downstream release of norepinephrine and serotonin, both having antiepileptic effects ( 29 ).

Two large RCTs showed VNS efficacy in reducing seizures, achieving a 50% reduction in 31% of patients, and over 50% seizures reduction in 23.4% of the studied population. On the other hand, seizure freedom at long-term follow-up was observed in <10% of patients. Side effects are usually mild and include hoarseness, throat paraesthesia or pain, coughing, and dyspnea. This tends to improve over time or through the adjustment of setting parameters ( 6 ).

In conclusion, evidence suggests VNS is well-tolerated in both children and adults with drug-resistant partial epilepsies ( 30 – 32 ); moreover, the newest VNS models can detect ictal tachycardia and automatically deliver additional stimulation to abort seizures or reduce their severity ( 6 ).

Transcutaneous VNS

Developed as a non-invasive alternative to VNS, the transcutaneous VNS (tVNS) acts on the auricular branch of the vagus nerve (ABVN), targeting thick-myelinated afferent fibers in the cymba conchae, and hence activating the ipsilateral nucleus of the solitary tract (NTS) and locus coeruleus. This activation pathway overlaps with the classical central vagal projections, leading to a brain activation pattern similar to that produced by invasive VNS ( 33 ). The device consists of a programmable stimulation apparatus and an ear electrode ( 34 ). Stimulation setup is adjusted by applying decreasing and increasing intensity ramps and achieving a level just above the individual detection threshold, but clearly below that of pain. Patients usually apply tVNS for 1 h/three times per day ( 33 ) and adherence is usually high (up to 88%) ( 35 ). Trials converge in demonstrating up to 55% reduction in seizure frequency, with mild or moderate side effects mainly including local skin irritation, headache, fatigue, and nausea ( 6 , 35 ).

Deep Brain Stimulation

Deep brain stimulation (DBS) is a minimally invasive neurosurgical technique, which through implanted electrodes can deliver electrical stimuli to deep brain structures. Patients with refractory focal epilepsies and not eligible for surgery are usually good candidates ( 29 ). Both stimulation of the ictal onset zone and the anterior thalamus have gained approval by the FDA as effective stimulation sites , providing a significant and sustained reduction in seizures together with the improvement of the QoL. Nowadays, both DBS and responsive neurostimulation (RNS) are available, being the latter a system able to monitor electrical changes in cortical activity and give small pulses or bursts of stimulation to the brain to interrupt a seizure ( 36 ). The interim results of a prospective, open-label, and long-term study did show that the median 60% or greater reduction in seizure frequency is retained over years of follow-up. Moreover, the majority of patients took advantage of treatment with the RNS ® System, and 23% experienced at least one 6-month period of seizure freedom ( 37 ). The most relevant reported side effects were depressive mood and memory impairment, besides the local side effect of implantation. Nonetheless, it should be stated that RNS is a feasible option in most epilepsy centers in the US, but its use remains limited in other parts of the world. In these cases, DBS could be an option with targets and stimulation parameters selection are largely driven by the experience of the referred center ( 38 , 39 ).

Trigeminal Nerve Stimulation

Trigeminal nerve stimulation (TNS) is a novel neuromodulation therapy, designed to deliver high frequencies stimulation in a non-invasive way, hence modulating mood and relieving symptoms in drug-resistant epilepsies. The study of DeGeorgio et al. ( 40 ) found that the responder rate (at least 50% reduction in seizures) was 30.2% in the active group, while it was 21.1% in the control group. Moreover, the responder rate did further increase over the 18-week treatment period in the actively treated group. TNS was overall well-tolerated and, when occurring, treatment-related AEs were mild including anxiety (4%), headache (4%), and skin irritation (14%). However, long-term follow-up studies showed inconclusive results ( 6 ), meaning further studies and patient monitoring will be needed in the next years.

Transcranial Direct Current Stimulation

The transcranial direct current stimulation (tDCS) displays the use of two skull electrodes (anode and cathode) to induce widespread changes of cortical excitability through weak and constant electrical currents. Cortical excitability may increase following anodal stimulation, while it generally decreases after cathodal stimulation. Based on this principle, hyperpolarization using cathodal tDCS has been proposed to suppress epileptiform discharges. Major six clinical studies are promising with 4 (67%) showing an effective decrease in epileptic seizures and 5 (83%) exhibiting a reduction of epileptiform activity. However, some results may be misleading due both to the small and heterogeneous nature of the studied populations and to the different setting parameters applied. Hence, nowadays the major achievement is the demonstration that tDCS may be effective and safe in humans; however, further studies will be needed to define setting stimulation protocols and understand the long-term tDCS effectiveness ( 41 ).

Transcranial Magnetic Stimulation

The nerve cells of a brain to a maximum depth of 2 cm can be stimulated using transcranial magnetic stimulation (TMS). To this, low-frequency and repetitive magnetic stimulations have been shown to induce long-lasting reductions in cortical excitability and, hence, have been proposed as a treatment for drug-resistant epilepsies ( 4 ). Probably, it is the repeated nature of magnetic pulses which allows modulating the neuronal activity, wherein high frequencies (>5 Hz) would have an overall excitatory effect, while low-frequencies (0.5 Hz) would exert an inhibitory effect on neurons ( 29 ).

Despite the optimal stimulation parameters still needing to be clearly defined, they are likely of crucial importance because treatment intensity depends both on the number of pulses and the number of sessions applied over the treatment period. Superior results are achieved in patients with neocortical epilepsy, whit a calculated effect size of 0.71 and 58–80%. This makes sense taking into account the rapid decay of the strength of the magnetic field with distance hence no adequate secondary currents can be elicited in the deep cortex. However, evidence suggests the effects of repetitive TMS may not be restricted to the only site of stimulation but may spread from focal areas to wider areas of the brain.

In conclusion, results should be reproduced in larger cohorts with double-blinded randomized trials, but are promising if compared to the effects currently achieved with invasive neurostimulation techniques for the treatment of epilepsy ( 42 ).

Neuroinflammation and Immunomodulation

Nowadays, the neuroinflammatory pathways are known to contribute to both the development and progression of epilepsy and could be targeted for disease-modifying therapies in epilepsies of wide-range etiologies. Studies on patients with surgically resected epileptic foci have demonstrated inflammatory pathways may be involved, hence the neuroinflammation is not merely a consequence of seizures or brain neuropathology but may induce seizures and brain anatomical damage itself ( 2 ).

Finally, any inflammatory response within the brain will be associated with the blood-brain barrier (BBB) dysfunction. Evidence indicates that BBB opening and the subsequent exposure of brain tissue to serum proteins induces upregulation of proinflammatory cytokines and complement system components: this suggests positive feedback between increased brain permeability, local immune/inflammatory response, and neuronal hypersynchronicity ( 43 ).

It should also be considered that overall neuroinflammation is a negative disease modifier in epilepsy, however, some inflammatory processes may be involved in tissue repair and brain plasticity after injury hence interference with these beneficial mechanisms should be avoided: anti-inflammatory intervention in the wrong patient and at the wrong time could be ineffective or even harmful. Yet, it is for this reason that evidence remains set at the preclinical level with few reports of use in the clinical practice. The discovery of non-invasive biomarkers of pathological neuroinflammation would enable physicians to identify patients who could benefit from the treatments, also providing a potential marker of therapeutic response.

IL-1R1-TLR4 Signaling

The Interleukin IL-1R1-TLR4 signaling pathway originates the neuroinflammatory cascade in epilepsy through increased levels of either the endogenous agonists or their receptors, or even a combination of both ( 2 ). These findings prompted the clinical use of anakinra, the recombinant, and modified form of the human IL-1Ra protein. Case report studies of Anakinra in patients with intractable seizures did result in a significant reduction of seizure activity and improvement of cognitive skills ( 44 ). Moreover, IL-1R1 and TLR4 signaling have been targeted by specific, non-viral, small interfering RNAs (siRNAs) to knock down the inflammasomes or caspase 1 in rats with kindling-induced SE ( 45 ).

Prostanoids

Prostanoids are a family of lipid mediators generated from the cell membrane arachidonic acid by cyclooxygenase enzymes 1 and 2 (COX1 and COX2). Prostanoids bind to specific G protein-coupled receptors (GPCR), hence regulating both innate and adaptive immunity ( 46 ).

Monoacyl Glycerol Lipase

The monoacyl glycerol lipase (MAGL) is a lipase constitutively expressed by neurons and a key enabler of 2-arachidonoylglycerol (2-AG) hydrolysis. 2-Arachidonoylglycerol is an endocannabinoid, which likewise prostaglandins are involved in seizures genesis. Hence, the upstream inhibition of the MAGL has the potential to be an effective target in epilepsy therapy ( 2 ). In 2018 Terrone et al. ( 47 ) did demonstrate CPD-4645 (a selective and irreversible MAGL inhibitor) was effective in terminating diazepam-resistant status epilepticus (SE) in mice. Moreover, clinically relevant outcomes such as reduced cognitive deterioration were ensured by CPD-4645 action: reducing post-SE brain inflammation to prevent neural cell damage. Lastly, the authors noted that SE was more promptly stopped in those mice concomitantly receiving the KD, hence suggesting brain inflammation is the common, final, target. Striking inflammation through different inflammatory pathways may enhance neuroprotection and seizure control.

COX2 Inhibitors and Prostaglandin Receptor Antagonists

Targeting the inducible enzyme COX2 to that of blocking the prostanoid cascade has been tested to interfere with acute seizures or SE. The importance of timing was demonstrated by early anti-inflammatory interventions showing worsening seizures as compared to late-onset interventions ( 2 , 48 ). Prostaglandin F 2α (PGF), which is anti-ictogenic, is indeed predominant in the first hour after SE onset, then the ratio between PGF and the pathogenic prostaglandin E 2 (PGE) normalizes in association with an increase in COX2 synthesis ( 2 ). Hence, punctual COX2-related treatments have been considered to prevent epileptogenesis and reduce the frequency of seizures in epileptic patients. COX2 inhibition could either be selective ( coxibs = selective COX2 inhibitors) or non-selective ( aspirin ). In two in-animal studies testing celecoxib and parecoxib over evoked SE, treatment with celecoxib or parecoxib did show to consistently reduce the number and severity of seizures, together with the improvement of spatial memory deficits ( 2 ).

Non-selective blockade of COX2 has been also tested in experimental models of epilepsy, and ASA administration over the chronic, latent, epileptic phase could consistently suppress recurrent spontaneous seizures and inhibit the seizure-induced neuronal loss, preventing aberrant neurogenesis in the hippocampus. Thus, ASA is being actively investigated and has the potential to prevent the epileptogenic processes, including SE occurrence, and may avoid pathological alterations in CNS areas ( 2 , 49 ). Potential cardiotoxicity is the main limit, bordering COX2 inhibition in clinical practice.

Shifting attention downstream to prostaglandin receptors, highly potent PGE receptor (EP2R) antagonists administered from a 4 h-starting point after the onset of pilocarpine-induced SE, proved to mitigate deleterious consequences such as delayed mortality, functional deficits, alterations of the BBB permeability, and hippocampal neurodegeneration ( 50 ). The delayed timepoint of administration further brings evidence that EP2R blockade may allow obtaining neuroprotection later in SE stages, mainly reducing long-term sequelae ( 2 ).

Inflammatory Response Lipid Mediators

Specialized pro-resolving lipid mediators that activate GPCRs have a major role in controlling inflammatory responses in peripheral organs. G protein-coupled receptors activation leads both to reduced expression of pro-inflammatory molecules and increased synthesis of anti-inflammatory mediators which can modulate immune cell trafficking and restore the integrity of the BBB. Neuroinflammation was reduced after the intracerebroventricular injection of the omega-3 (n-3) docosapentaenoic acid-derived protectin D1 (PD1 n−3DPA ) in mouse models of epilepsy. Interestingly, recognition of memory deficits after SE also gained improvements ( 2 , 51 ). Since PD1 n−3DPA derives from n-3 polyunsaturated fatty acids (PUFAs), in humans, it may be possible to non-invasively increase PD1 n−3DPA levels through the dietary intake of n-3 PUFAs, which are found in flaxseed, walnuts, marine fish, and mammals ( 52 ). Another way may then be the developing stable analogs of pro-resolving lipids ( 51 ).

Oxidative Stress

Activation of the Toll-like receptors (TLRs) can lead to reactive oxygen species (ROS) production, hence promoting and sustaining inflammatory pathways. The detrimental effects of ROS are usually counteracted through the activation of the nuclear factor E2-related factor 2 (Nrf2). Activated Nrf2 translocates to the nucleus where it heterodimerizes with the small Maf proteins (sMaf) and binds to the antioxidant response element (ARE 5′-TGACXXXGC-3′) battery activating transcription of genes that are involved in antioxidant and cytoprotective tasks ( 53 ).

Transient administration of N -acetyl-cysteine (NAC), a glutathione precursor, did prove to activate Nrf2 in mouse models of SE, thus inhibiting high mobility group box 1 (HMGB1) cytoplasmic translocation in the hippocampal neural and glial cells and preventing the linkage between oxidative stress and neuroinflammation for which the redox-sensitive protein HMGB1 is central ( 2 ). Also, high doses (4–6 g/day) of NAC were used in Unverricht-Lundborg disease (ULD), progressive myoclonus epilepsy (PME), showing overall improvement of myoclonus, ataxia, and generalized tonic–clonic and absence seizures. Neuroprotection and improvements in spatial learning abilities were also observed with retained beneficial effects during treatment ( 54 , 55 ).

Adeno-associated viral (AAV) vectors gene delivery may provide long-term, persistent, induction of Nrf2 expression in a variety of cell types in the brain, with minimal toxicity. The injection of AAV coding for human Nrf2 in the hippocampus of mice with spontaneously recurrent seizures resulted in a reduction in the number and duration of generalized seizures, which interestingly was performed in the already established epileptic phase, highlighting the direct potential of such interventions in the treatment of epilepsy ( 56 ).

Inhibition of P-Glycoproteins

One of the major neurobiological mechanisms proposed to cause drug resistance in epilepsies lays in the removal of ASMs from the epileptogenic tissue through the expression of multidrug efflux pumps such as the P-glycoproteins (P-gps). P-glycoproteins are the final encoded product of the human multi-drug resistance-1 ( MDR-1 ) gene, and play a role in treatment response possibly inducing MDR ( 57 , 58 ). The increased activity of P-gps reduces clinically effective concentrations of ASMs despite adequate serum concentrations, reversing the anti-seizure effects on epileptogenic areas in the parenchyma of the brain ( 3 ).

Following the general rule that the higher the lipophilicity of a drug, the faster the entrance into the brain ( 59 ), available ASMs are very lipophilic, but more than one-third of the patients do not respond to treatment. The possible reason may be ASMs serve as P-gps substrates; secondly, the P-gps levels are higher ( 3 ). Different clinical studies had shown poor prognoses associated with MDR1 gene products, which gave rise to extensive experimental research on the P-gps ( 3 ). The adjunctive use of a P-gps inhibitor might counteract drug resistance and efficiently decrease seizure frequency. In addition to verapamil, other first-generation P-gps inhibitors include nifedipine, quinidine, amiodarone, nicardipine, quinine, tamoxifen, and cyclosporin A. It is primarily due to the lack of selectivity and the pharmacokinetic interactions that trials using such agents failed to rule out P-gps inhibition efficacy in other fields such that of oncology ( 60 , 61 ). First-generation MDR inhibitors required high concentrations to reverse MDR and thus were associated with unacceptable toxicity. In recent years, second and third-generation compounds have been developed which are more selective, highly potent, and non-toxic. Notwithstanding second-generation agents have better tolerability, they still have unpredictable pharmacokinetic interactions (i.e., valspodar is a substrate for cytochrome P450, altering plasma availability of co-administered drugs) and may inhibit other transport proteins. Third-generation inhibitors have more advantages such as high specificity for P-gp, lack of non-specific cytotoxicity, relatively long duration of action with reversibility, and good oral bioavailability. However, despite their selectivity and potency, also this last generation of MDR modulators is far from being perfect and further studies will be needed to outline their effectiveness and safely overcome drug resistance ( 3 , 60 ). As pertains to clinical research, Iannetti et al. ( 62 ) first demonstrated the action of verapamil in a case of prolonged refractory SE and then, subsequently on small series of other types of drug-resistant epilepsies ( 63 , 64 ).

A novel, yet preclinical, approach for reversing multidrug resistance in epilepsy may derive from the modulation of P-gp by herbal constituents. Nowadays, several herbal formulations and drugs which act by modulating P-gps are available and can be explored as alternative treatment strategies. For example, curcumin (the natural dietary constituent of turmeric) orally administered to pentylenetetrazole-kindled epileptic mice models is known to prevent seizures and related memory impairments ( 65 ). The mechanism of action may lie on that curcumin and can reverse multidrug resistance. Hence, curcumin synthetic analogs, which hold more favorable pharmacodynamic properties, have been developed (i.e., GO-Y035); or curcumin has been encapsulated in nanoparticles (NPs) enhancing its solubility and sustaining release inside the brain ( 66 ).

Again, piperine (an alkaloid present in black pepper) and capsaicin (the active component of chili peppers) are known to increase curcumin and other P-gps substrates bioavailability and can be therefore used as basic molecules for the development of non-toxic P-gps inhibitors ( 67 , 68 ).

In conclusion, the identification of an optimal P-gps inhibitor that is potent, effective, and well-tolerated, is desirable to reverse MDR in epileptic patients and will be the challenge of the upcoming years.

Gene Therapies

Currently lying at the preclinical evidence, gene-based therapy modulates gene expression by introducing exogenous nucleic acids into target cells. The delivery of these large and negatively charged macromolecules is typically mediated by carriers (called vectors) ( 69 ). In treating epilepsy, the main hitch is the BBB, which prevents genetic vectors from entering the brain from the bloodstream. Consequently, an invasive approach may be needed ( 29 ). Moreover, several considerations need to be taken into account when translating gene therapy into clinical practice, namely the choice of the viral vector, promoter, and transgene ( 6 ).

Viral Vectors

Viral gene therapy may employ three classes of viral vectors, namely, adenovirus (AD), adeno-associated virus (AAV), and lentivirus. All these three viral vectors have successfully demonstrated to attain high levels of transgene delivery in in-vivo disease models and clinical trials. However, the risks of immunogenic responses and transgene mis-insertions, together with problems in large-scale production are still a deal to face ( 70 ).

Adeno-associated viruses belong to the Parvoviridae family and proved to retain favorable biology, leading their recombinant forms (rAAVs) to become the main platform for current in-vivo gene therapies ( 29 ). A limited clinical trial on patients with late-infantile neuronal ceroid lipofuscinosis (LINCL) did prove neurosurgical gene therapy to be practical and safe, supporting the potentialities of this kind of approach ( 71 ). However, in the view of removing invasiveness, interest was moved to engineered capsid which can confer the ability to cross the BBB and transduce astrocytes and neurons, allowing direct intravenous injection. This was achieved through a process of directed selection in a mouse strain, and further work would be needed to develop a similar variant for use in humans ( 6 , 72 ).

Retroviruses such as lentivirus share with AAVs the ability to infect neurons and lead to a stable expression of transgenes. Lentiviral vectors (lentivectors) are RNA viruses and the transgenes can integrate into the host genome through the reverse transcriptase gene. However, possible insertional mutagenesis may be reduced by using integration-deficient lentivectors, which simultaneously ensure stable transduction ( 73 ). Lastly, lentivectors can package larger genes or regulatory elements as compared to AAVs ( 6 ).

Different viral vectors intrinsically tend to infect different neuronal and glial subtypes, but the high specificity of the target is far from their properties. Hence, several efforts have been made that to identify specific neuron-type targeting promoters: the calcium/calmodulin-dependent protein kinase II (CamKII) promoter is suitable to manipulate excitatory neurons in the forebrain; on the other hand, targeting inhibitory interneurons may be difficult as promoters for specific GABAergic neurons are poorly defined ( 6 ). Finally, the optimal promoter should provide the expression of a level of transgene which is sufficient to moderately alter cell properties but avoids cytotoxicity ( 6 , 74 ).

As for the transgene, gene therapies have been commonly built on the basis that the excitation–inhibition balance is altered in epilepsy. Hence, on a general principle, gene therapy may work through modulating the expression of neuropeptides, and regulation of the neuropeptide Y (NPY) did already show promise, acting both on pro-excitatory Y1 and pro-inhibiting Y2 receptors in the hippocampus ( 6 , 75 ). Another way may be that of regulating potassium channels; overexpression of the potassium channel Kv1.1 proved effective in preventing epileptogenesis in a mouse model of focal epilepsy, the physiological basis may lie on the modulation of both neuronal excitability and neurotransmitter release ( 76 , 77 ). Lastly, chemogenetics refers to the possibility to use gene transfer to express receptors that are insensitive to endogenous neurotransmitters but highly sensitive to exogenous drugs, in a receptor-to-drug therapeutic approach. This promising approach will also allow adjusting the activating drugs to find the optimum dosage with low interference with normal brain function but efficiently suppressing seizures ( 6 ). Further refinements of chemogenetics have jet got underway, which may use receptors detecting out-of-range extracellular elevations of the concentration of glutamate and, therefore, inhibiting neurons, preventing drug administration. Although attractive, this strategy will need further work to assess the risk of immunogenicity ( 6 ).

Non-viral Strategies

Some of the issues of viral vector-based gene therapy may be overcome by non-viral gene strategies, which provide advantages with regards to the safety profile, localized gene expression, and cost-effective manufacturing. Non-viral gene delivery systems are engineered complexes or NPs composed of the required nucleic acid (pDNA or RNAs) and other materials, such as cationic lipids, peptides, polysaccharides, and so on ( 70 ). These vectors have low production costs, can be topically administered, can carry large therapeutic genes, use expression vectors (such as plasmids) that are non-integrating, and do not elicit detectable immune response also after repeated administrations ( 29 , 70 ). Cationic lipid-based vectors are currently the most widely used non-viral gene carriers. Limitations may include low efficacy due to the poor stability and rapid clearance, or the possible generation of inflammatory or anti-inflammatory responses. Hence, cationic polymers, such as poly(L-lysine) (PLL) or modified variants (PEGylated PLL), constitute alternative non-viral DNA vectors that are attractive for their immense chemical diversity and their potential for functionalization ( 69 ).

Antisense Oligonucleotides Therapies

Oligonucleotides are unmodified or chemically modified single-stranded DNA sequences (of up to 25 nucleotides) that hybridize to specific complementary mRNAs. Once bound to targeted mRNAs, oligonucleotides can either promote RNA degradation or prevent the translational machinery through an occupancy-only mechanism, referred to as steric blockage . Anyhow, the process leading to protein formation is inhibited. Synthesizing antisense oligonucleotides (ASOs) must deal with making a structure that must be suitable for a stable and selective oligonucleotide/mRNA complex. Moreover, oligonucleotides are rapidly degraded by endo- and exonucleases and the mononucleotides products may be cytotoxic ( 29 , 78 ). Hence, the use of ASOs in clinical practice requires overcoming problems related to the design, bioavailability, and targeted delivery ( 78 ). To date, few in-human studies have been conducted that primarily addressed invariably progressive and fatal diseases such as PMEs ( 79 , 80 ). The authors proved the feasibility of the ASOs-based approach by specifically customizing oligonucleotides over the genetic defect of patients. This opens the way to N-of-1 trials, which will hopefully be the road of the next few years not only in oncology but also in epileptic patients ( 81 ).

Stem Cell Therapy

Recurrent seizures are associated with the loss of inhibitory GABAergic interneurons. Herby, the replacement of lost interneurons through grafting of GABAergic precursors might improve the inhibitory synaptic and reduce the occurrence of spontaneous seizures ( 6 ).

Currently, in a pioneering way, progenitors from the medial ganglionic eminence (MGE) derived either from fetal brains or, to avoid the need for immune suppression, from human induced pluripotent stem cells (hiPSCs) proved the most suitable for treating epilepsy, particularly with temporal lobe onset features. Medial ganglionic eminence cells show pervasive migration, differentiate into distinct subclasses of GABAergic interneurons, and efficiently get incorporated into the hippocampal circuitry improving inhibitory synaptic neurotransmission ( 82 , 83 ). An important point is that MGE progenitors from fetal brains hoist ethical issues, and it is also a challenge to obtain the adequate amount of cells required for clinical application ( 82 ). Consequently, the MGE progenitors derived from hiPSCs appear the most suitable donor cell type, as they do not raise ethical problems and are also compatible with patient-specific cell therapy in non-genetic epileptic conditions. However, it will be important to understand whether the suppression of spontaneous recurrent seizures is transient or enduring after the GABAergic progenitor cells grafting ( 82 ); moreover, it will be important to assess the safety profile of these hiPSCs, hence they may either exhibit genomic instability or cause undesired differentiation raising concerns for in human application ( 6 ). In conclusion, the results are exciting, but some points need to be addressed in the next years, before starting a true in human application.

Conclusions

A variety of drugs are being investigated for the treatment of epilepsy, many of whom target previously neglected pathophysiological pathways but demonstrate a favorable efficacy profile, together with low to mild grade AEs ( 15 ). Traditional ASMs, given alone or in a fair combination, are invariably the initial therapeutic approach; afterward, if drug resistance occurs, more than one underlying pathophysiological mechanism may likely contribute ( 14 ). Currently, uncontrolled epilepsy is often disabling, with patients experiencing increased comorbidity, psychological, and social dysfunction, combined with an increased risk of premature death. In younger patients, cognitive and neurodevelopmental impairments are severe consequences of recurrent spontaneous seizures, impacting the QoL and future independence ( 44 ). Accordingly, gaining a reduction of either the severity or frequency of seizures might have benefits ( 44 ) and hitherward new therapeutical strategies are in the pipeline.

Cannabidiol, FFA, and cenobamate have been shown to efficiently control seizures and are generally well-tolerated; particularly, an increase in the number of seizure-free days was observed with positive outcomes on the QoL of patients ( 16 ). Comparison of treatments such as VNS, DBS, and TNS are needed to decide which modality is the most effective; moreover, data collection on promising non-invasive neurostimulation modalities will allow getting a precise estimate of their therapeutic efficacy and long-term safety ( 30 ) ( Tables 1 , 2 ).

Table 1 . Advanced RCTs on new drugs for epilepsy treatment.

Table 2 . Advanced RCTs on new non-pharmacological treatments for epilepsy.

Evidence on the role of neuroinflammation in epilepsy suggests that drugs that modulate specific inflammatory pathways could also be used to control seizures and improve neurological comorbidities, such as cognitive deficits and depression. Notably, many anti-inflammatory drugs are already available and could be repurposed in patients with epilepsy. Another mechanism likely involved in drug-resistant epilepsies is the undue expression of multidrug efflux transporters such as P-gps ( 52 ); however, the use of P-gps inhibitors in the clinical practice did prove disadvantageous for inseparable systemic toxicity ( 3 ). This arises the need to directly modulate not the transport but the expression of the P-gps ( 3 ). Finally, epilepsy represents a field suitable for the development of personalized approaches, requiring integration of clinical measures with both genomics and other -omics modalities ( 14 ).

Today epilepsy carries restrictions in the everyday life of the affected people, together with social burdens, and eventually high-level burdens for caregivers in EE. Hitherward, the continuous pursuit of the best treatment approach that nowadays, with the widening understanding of the pathophysiological basis of the epilepsies, is inevitably moving toward a “ precision ” approach. Gene hunting and new genes discovery proved essential in this way, but further support derives from functional in-vitro and in-vivo studies, i.e., in epileptic channelopathies it is crucial to understand whether the phenotype is caused by the loss- or gain-of-function mutations in the encoded protein through patch-clamp studies ( Figure 1 ). Likewise, if a novel gene is identified it is fundamental to understand through which mechanism it may cause the disease, consequently identifying the best treatment to reverse the functional defect. However, given a PM-based approach, this may not yet be enough, and a holistic evaluation of the patient involves the clinician to deeply know an own expected vulnerability to drugs through pharmacogenomics ; thus, avoiding potential AEs.

Figure 1 . Example for precision medicine in epileptic channelopathies. Toward N-of-1 trials. Created with BioRender.com . ASOs, antisense oligonucleotides; GoF, gain of function; LoF, loss of function.

Targeting the biological mechanism responsible for epilepsy could lead either to repurpose as ASMs and adjust dosages of drugs yet used in other fields of medicine (i.e., FFA, COX2 inhibitors, or inhibitors of P-gps) or even to develop outstanding treatments such as gene therapy. Great advances have been achieved in gene-based therapies, ranging from the development of new delivery material to the improved potency and stability of delivered nucleic acids. However, this field is still actually limited by the little understanding of exogenous-endogenous DNAs interaction and the invasive nature of some neurosurgical approaches. Moreover, targeted approaches (i.e., gene therapy, but also innovative drugs) currently carry high economic costs, which are covered by pharmaceutical industries during clinical trials but are hardly affordable for patients. In the new few years, the standardization of drug development, together with a larger use, and faster approval by regulatory agencies will probably make these treatments cheaper for patients.

The inflammatory pathways are common over epilepsies of different etiology and may therefore be reliable targets for treatment. However, targeting such complex and cross-interacting pathways of the human system may prove difficult, potentially altering basic life signals and causing a plethora of AEs further impacting the QoL of patients. Hence, also from this site, the next few years will be important to expand our knowledge and act consciously or even early, having fully comprised the red flags (biomarkers) of altered pathways through -omics studies.

Overall, research has changed our approach to epileptic patients, but PM is not always straightforward, and the pathophysiology of diseases may be more complex than what we can model , as different concomitant genetic variants, epigenetics, or the environment may modulate phenotypes in unintelligible and irreproducible ways. Moreover, nowadays patients are still often belatedly diagnosed raising the need to better define the way clinicians address phenotyping , which if incomplete could lead primarily toward the application of NGS epilepsy panels and then to whole-exome or genome sequencing, but invariably delaying diagnosis. Hence, also newer and standardized means of phenotyping will be needed, and wide opportunities in this are opened by the human phenotype ontology (HPO), a standardized vocabulary to describe phenotypic abnormalities. The hope will remain that of early diagnosis, early and non-invasive treatment to heal symptoms, improving the QoL of patients, and, in encephalopathies, improving the learning curve of patients.

Author Contributions

AR: conceptualization, writing-original draft, writing-review, and editing lead. AG: writing-original draft. GB: writing-review and editing support. EA, MV, GP, MI, SL, VS, and CM: writing-review and editing support. PS: conceptualization, funding acquisition, supervision, writing-review, and editing. All authors contributed to the article and approved the submitted version.

This work was developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016).

Conflict of Interest

AR has received honoraria from Kolfarma s.r.l and Proveca Pharma Ltd. PS has served on a scientific advisory board for the Italian Agency of the Drug (AIFA); has received honoraria from GW Pharma, Kolfarma s.r.l., Proveca Pharma Ltd., and Eisai Inc., and has received research support from the Italian Ministry of Health and Fondazione San Paolo.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

The authors thank the Italian Ministry of Health Ricerca Corrente 2021.

1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. (2014) 55:475–82. doi: 10.1111/epi.12550

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol. (2019) 15:459–72. doi: 10.1038/s41582-019-0217-x

3. Garg N, Joshi R, Medhi B. A novel approach of targeting refractory epilepsy: need of an hour. Brain Res Bull. (2020) 163:14–20. doi: 10.1016/j.brainresbull.2020.07.012

4. Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia. (2018) 59:2179–93. doi: 10.1111/epi.14596

5. Sisodiya SM. Precision medicine and therapies of the future. Epilepsia. (2020) 62(Suppl 2):S90–105. doi: 10.1111/epi.16539

6. Mesraoua B, Deleu D, Kullmann DM, Shetty AK, Boon P, Perucca E, et al. Novel therapies for epilepsy in the pipeline. Epilepsy Behav. (2019) 97:282–90. doi: 10.1016/j.yebeh.2019.04.042

7. Koch H, Weber YG. The glucose transporter type 1 (Glut1) syndromes. Epilepsy Behav. (2019) 91:90–3. doi: 10.1016/j.yebeh.2018.06.010

8. Isom LL, Knupp KG. Dravet syndrome: novel approaches for the most common genetic epilepsy. Neurotherapeutics. (2021) doi: 10.1007/s13311-021-01095-6. [Epub ahead of print].

9. Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. (2014) 1:190–8. doi: 10.1002/acn3.39

10. Striano P, Minassian BA. From genetic testing to precision medicine in epilepsy. Neurotherapeutics. (2020) 17:609–15. doi: 10.1007/s13311-020-00835-4

11. Papa FT, Mancardi MM, Frullanti E. Personalized therapy in a GRIN1 mutated girl with intellectual disability and epilepsy. Clin Dysmorphol. (2018) 27:18–20. doi: 10.1097/MCD.0000000000000205

12. Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett. (2018) 667:27–39. doi: 10.1016/j.neulet.2017.01.014

13. Olson MV. Precision medicine at the crossroads. Hum Genomics. (2017) 11:23. doi: 10.1186/s40246-017-0119-1

14. Walker LE, Mirza N, Yip VLM. Personalized medicine approaches in epilepsy. J Intern Med. (2015) 277:218–34. doi: 10.1111/joim.12322

15. Perry MS. New and emerging medications for treatment of pediatric epilepsy. Pediatr Neurol. (2020) 107:24–7. doi: 10.1016/j.pediatrneurol.2019.11.008

16. Strzelczyk A, Schubert-Bast S. Therapeutic advances in Dravet syndrome: a targeted literature review. Expert Rev Neurother. (2020) 20:1065–79. doi: 10.1080/14737175.2020.1801423

17. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. (2017) 376:2011–20. doi: 10.1056/NEJMoa1611618

18. Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. (2018) 391:1085–96. doi: 10.1016/S0140-6736(18)30136-3

19. Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. (2018) 378:1888–97. doi: 10.1056/NEJMoa1714631

20. Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia. (2019) 60:294–302. doi: 10.1111/epi.14628

21. Balagura G, Cacciatore M, Grasso EA, Striano P, Verrotti A. Fenfluramine for the treatment of Dravet syndrome and Lennox-Gastaut syndrome. CNS Drugs. (2020) 34:1001–7. doi: 10.1007/s40263-020-00755-z

22. Sullivan J, Simmons R. Fenfluramine for treatment-resistant epilepsy in Dravet syndrome and other genetically mediated epilepsies. Drugs Today (Barc). (2021) 57:449–54. doi: 10.1358/dot.2021.57.7.3284619

23. Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. (2019) 394:2243–54. doi: 10.1016/S0140-6736(19)32500-0

24. Sullivan J, Scheffer IE, Lagae L, Nabbout R, Pringsheim M, Talwar D, et al. Fenfluramine HCl (Fintepla ® ) provides long-term clinically meaningful reduction in seizure frequency: analysis of an ongoing open-label extension study. Epilepsia. (2020) 61:2396–404. doi: 10.1111/epi.16722

25. Lai WW, Galer BS, Wong PC, Farfel G, Pringsheim M, Keane MG, et al. Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing long-term open-label extension study. Epilepsia. (2020) 61:2386–95. doi: 10.1111/epi.16638

26. Lattanzi S, Trinka E, Zaccara G, Striano P, Del Giovane C, Silvestrini M, et al. Adjunctive cenobamate for focal-onset seizures in adults: a systematic review and meta-analysis. CNS Drugs. (2020) 34:1105–20. doi: 10.1007/s40263-020-00759-9

27. Krauss GL, Klein P, Brandt C, Lee SK, Milanov I, Milovanovic M, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo controlled, dose-response trial. Lancet Neurol. (2020) 19:38–48. doi: 10.1016/S1474-4422(19)30399-0

28. Sperling MR, Klein P, Aboumatar S, Gelfand M, Halford JJ, Krauss GL. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study. Epilepsia. (2020) 61:1099–108. doi: 10.1111/epi.16525

29. Riva A, Guglielmo A, Balagura G, Marchese F, Amadori E, Iacomino M, et al. Emerging treatments for progressive myoclonus epilepsies. Expert Rev Neurother. (2020) 20:341–50. doi: 10.1080/14737175.2020.1741350

30. Boon P, De Cock E, Mertens A, Trinka E. Neurostimulation for drug-resistant epilepsy: a systematic review of clinical evidence for efficacy, safety, contraindications and predictors for response. Curr Opin Neurol. (2018) 31:198–210. doi: 10.1097/WCO.0000000000000534

31. Orosz I, McCormick D, Zamponi N, Varadkar S, Feucht M, Parain D, et al. Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. Epilepsia. (2014) 55:1576–84. doi: 10.1111/epi.12762

32. Boon P, Vonck K, van Rijckevorsel K, El Tahry R, Elger CE, Mullatti N, et al. A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation. Seizure. (2015) 32:52–61. doi: 10.1016/j.seizure.2015.08.011

33. Barbella G, Cocco I, Freri E, Marotta G, Visani E, Franceschetti S, et al. Transcutaneous vagal nerve stimulation (t-VNS): an adjunctive treatment option for refractory epilepsy. Seizure. (2018) 60:115–9. doi: 10.1016/j.seizure.2018.06.016

34. Hamer HM, Bauer S. Lessons learned from transcutaneous vagus nerve stimulation (tVNS). Epilepsy Res. (2019) 153:83–4. doi: 10.1016/j.eplepsyres.2019.02.015

35. Bauer S, Baier H, Baumgartner C, Bohlmann K, Fauser S, Graf W, et al. Transcutaneous vagus nerve stimulation (tVNS) for treatment of drug-resistant epilepsy: a randomized, double-blind clinical trial (cMPsE02). Brain Stimul. (2016) 9:356–63. doi: 10.1016/j.brs.2015.11.003

36. Matias CM, Sharan A, Wu C. Responsive neurostimulation for the treatment of epilepsy. Neurosurg Clin N Am. (2019) 30:231–42. doi: 10.1016/j.nec.2018.12.006

37. Bergey GK, Morrell MJ, Mizrahi EM, Goldman A, King-Stephens D, Nair D, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology. (2015) 84:810–7. doi: 10.1212/WNL.0000000000001280

38. Yan H, Toyota E, Anderson M, Abel TJ, Donner E, Kalia SK, et al. A systematic review of deep brain stimulation for the treatment of drug-resistant epilepsy in childhood. J Neurosurg Pediatr. (2018) 23:274–84. doi: 10.3171/2018.9.PEDS18417

39. Balak N. Deep brain stimulation for refractory epilepsy. Neurochirurgie. (2021) 67:639. doi: 10.1016/j.neuchi.2021.01.004

40. DeGiorgio CM, Soss J, Cook IA, Markovic D, Gornbein J, Murray D, et al. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology. (2013) 80:786–91. doi: 10.1212/WNL.0b013e318285c11a

41. San-Juan D, Morales-Quezada L, Orozco Garduño AJ, Alonso-Vanegas M, González-Aragón MF, González-Aragón MF, et al. Transcranial direct current stimulation in epilepsy. Brain Stimul. (2015) 8:455–64. doi: 10.1016/j.brs.2015.01.001

42. Carrette S, Boon P, Dekeyser C, Klooster DC, Carrette E, Meurs A, et al. Repetitive transcranial magnetic stimulation for the treatment of refractory epilepsy. Expert Rev Neurother. (2016) 16:1093–110. doi: 10.1080/14737175.2016.1197119

43. Vezzani A, Friedman A. Brain inflammation as a biomarker in epilepsy. Biomark Med. (2011) 5:607–14. doi: 10.2217/bmm.11.61

44. Jyonouchi H, Geng L. Intractable epilepsy (IE) and responses to anakinra, a human recombinant IL-1 receptor agonist (IL-1ra): case reports. J Clin Cell Immunol. (2016) 7:1–5. doi: 10.4172/2155-9899.1000456

CrossRef Full Text | Google Scholar

45. Meng XF, Tan L, Tan MS, Jiang T, Tan CC Li MM, et al. Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus. J Neuroinflammation. (2014) 11:212. doi: 10.1186/s12974-014-0212-5

46. Hirata T, Narumiya S. Prostanoids as regulators of innate and adaptive immunity. Adv Immunol. (2012) 116:143–74. doi: 10.1016/B978-0-12-394300-2.00005-3

47. Terrone G, Pauletti A, Salamone A, Rizzi M, Villa BR, Porcu L, et al. Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet. Epilepsia. (2018) 59:79–91. doi: 10.1111/epi.13950

48. Holtman L, van Vliet EA, Edelbroek PM, Aronica E, Gorter JA. Cox-2 inhibition can lead to adverse effects in a rat model for temporal lobe epilepsy. Epilepsy Res. (2010) 91:49–56. doi: 10.1016/j.eplepsyres.2010.06.011

49. Ma L, Cui XL, Wang Y, Li XW, Yang F, Wei D, et al. Aspirin attenuates spontaneous recurrent seizures and inhibits hippocampal neuronal loss, mossy fiber sprouting and aberrant neurogenesis following pilocarpine-induced status epilepticus in rats. Brain Res. (2012) 1469:103–13. doi: 10.1016/j.brainres.2012.05.058

50. Jiang J, Quan Y, Ganesh T, Pouliot WA, Dudek FE, Dingledine R. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation. Proc Natl Acad Sci USA. (2013) 110:3591–6. doi: 10.1073/pnas.1218498110

51. Frigerio F, Pasqualini G, Craparotta I, Marchini S, van Vliet EA, Foerch P, et al. n-3 Docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis. Brain. (2018) 141:3130–43. doi: 10.1093/brain/awy247

52. Taha AY, Burnham WM, Auvin S. Polyunsaturated fatty acids and epilepsy. Epilepsia. (2010) 51:1348–58. doi: 10.1111/j.1528-1167.2010.02654.x

53. Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2. Antioxid Redox Signal. (2018) 29:1727–45. doi: 10.1089/ars.2017.7342

54. Hurd RW, Wilder BJ, Helveston WR, Uthman BM. Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine. Neurology. (1996) 47:1264–8. doi: 10.1212/WNL.47.5.1264

55. Ben-Menachem E, Kyllerman M, Marklund S. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res. (2000) 40:33–9. doi: 10.1016/S0920-1211(00)00096-6

56. Mazzuferi M, Kumar G, van Eyll J, Danis B, Foerch P, Kaminski RM. Nrf2 defense pathway: experimental evidence for its protective role in epilepsy. Ann Neurol. (2013) 74:560–8. doi: 10.1002/ana.23940

57. Asadi-Pooya AA, Sperling MR. Potentiation of anti-epileptic drugs effectiveness by pyronaridine in refractory epilepsy. Med Hypotheses. (2007) 69:560–3. doi: 10.1016/j.mehy.2006.12.054

58. Hartz AMS, Pekcec A, Soldner ELB, Zhong Y, Schlichtiger J, Bauer B. P-gp protein expression and transport activity in rodent seizure models and human epilepsy. Mol Pharm. (2017) 14:999–1011. doi: 10.1021/acs.molpharmaceut.6b00770

59. Wilkens S. Structure and mechanism of ABC transporters. F1000Prime Rep. (2015). 7:14. doi: 10.12703/P7-14

60. Palmeira A, Sousa E, Vasconcelos MH, Pinto MM. Three decades of P-gp inhibitors: skimming through several generations and scaffolds. Curr Med Chem. (2012) 19:1946–2025. doi: 10.2174/092986712800167392

61. Borlot F, Wither RG, Ali A, Wu N, Verocai F, Andrade DM, et al. Pilot double-blind trial using verapamil as adjunctive therapy for refractory seizures. Epilepsy Res. (2014) 108:1642–51. doi: 10.1016/j.eplepsyres.2014.08.009

62. Iannetti P, Spalice A, Parisi P. Calcium-channel blocker verapamil administration in prolonged and refractory status epilepticus. Epilepsia. (2005) 46:967–9. doi: 10.1111/j.1528-1167.2005.59204.x

63. Iannetti P, Parisi P, Spalice A, Ruggieri M, Zara F. Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. Epilepsy Res. (2009) 85:89–95. doi: 10.1016/j.eplepsyres.2009.02.014

64. Nicita F, Spalice A, Papetti L, Nikanorova M, Iannetti P, Parisi P. Efficacy of verapamil as an adjunctive treatment in children with drug-resistant epilepsy: a pilot study. Seizure. (2014) 23:36–40. doi: 10.1016/j.seizure.2013.09.009

65. Mehla J, Reeta KH, Gupta P, Gupta YK. Protective effect of curcumin against seizures and cognitive impairment in a pentylenetetrazole-kindled epileptic rat model. Life Sci. (2010) 87:596–603. doi: 10.1016/j.lfs.2010.09.006

66. Murakami M, Ohnuma S, Fukuda M, Chufan EE, Kudoh K, Kanehara K, et al. Synthetic analogs of curcumin modulate the function of multidrug resistance-linked ATP-binding cassette transporter ABCG2. Drug Metab Dispos. (2017) 45:1166–77. doi: 10.1124/dmd.117.076000

67. Singh DV, Godbole MM, Misra K. A plausible explanation for enhanced bioavailability of P-gp substrates in presence of piperine: simulation for next generation of P-gp inhibitors. J Mol Model. (2013) 19:227–38. doi: 10.1007/s00894-012-1535-8

68. Bedada SK, Appani R, Boga PK. Capsaicin pretreatment enhanced the bioavailability of fexofenadine in rats by P-gp modulation: in vitro, in situ and in vivo evaluation. Drug Dev Ind Pharm. (2017) 43:932–8. doi: 10.1080/03639045.2017.1285310

69. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet. (2014) 15:541–55. doi: 10.1038/nrg3763

70. Foldvari M, Chen DW, Nafissi N, Calderon D, Narsineni L, Rafiee A. Non-viral gene therapy: gains and challenges of non-invasive administration methods. J Control Release. (2016) 240:165–90. doi: 10.1016/j.jconrel.2015.12.012

71. Souweidane MM, Fraser JF, Arkin LM, Sondhi D, Hackett NR, Kaminsky SM, et al. Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations. J Neurosurg Pediatr. (2010) 6:115–22. doi: 10.3171/2010.4.PEDS09507

72. Deverman BE, Pravdo PL, Simpson BP, Kumar SR, Chan KY, Banerjee A, et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol. (2016) 34:204–9. doi: 10.1038/nbt.3440

73. Yáñez-Muñoz RJ, Balaggan KS, MacNeil A, Howe SJ, Schmidt M, Smith AJ, et al. Effective gene therapy with nonintegrating lentiviral vectors. Nat Med. (2006) 12:348–53. doi: 10.1038/nm1365

74. Dimidschstein J, Chen Q, Tremblay R, Rogers SL, Saldi GA, Guo L, et al. A viral strategy for targeting and manipulating interneurons across vertebrate species. Nat Neurosci. (2016) 19:1743–9. doi: 10.1038/nn.4430

75. Woldbye DPD, Angehagen M, Gøtzsche CR, Elbrønd-Bek H, Sørensen AT, Christiansen SH, et al. Adeno-associated viral vector-induced overexpression of neuropeptide Y Y2 receptors in the hippocampus suppresses seizures. Brain. (2010) 133:2778–88. doi: 10.1093/brain/awq219

76. Wykes RC, Heeroma JH, Mantoan L, Zheng K, MacDonald DC, Deisseroth K, et al. Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci Transl Med. (2012). 4:161ra152. doi: 10.1126/scitranslmed.3004190

77. Heeroma JH, Henneberger C, Rajakulendran S, Hanna MG, Schorge S, Kullmann DM. Episodic ataxia type 1 mutations differentially affect neuronal excitability and transmitter release. Dis Model Mech. (2009) 2:612–9. doi: 10.1242/dmm.003582

78. Dias N, Stein CA. Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther. (2002) 1:347–55.

PubMed Abstract | Google Scholar

79. Matos L, Duarte AJ, Ribeiro D, Chaves J, Amaral O, Alves S. Correction of a splicing mutation affecting an Unverricht-Lundborg disease patient by antisense therapy. Genes (Basel). (2018) 9:455. doi: 10.3390/genes9090455

80. Kim J, Hu C, El Achkar CM, Black LE, Douville J, Larson A, et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N Engl J Med. (2019) 381:1644–52. doi: 10.1056/NEJMoa1813279

81. Openshaw-Lawrence N. Precision medicine in monogenic epilepsies (from the Dianuland Conference). In: ERN epiCARE. European Reference Network for Rare or Low Prevalence Complex Diseases (Flower Mound, TX: ILAE).

82. Shetty AK, Upadhya D. GABA-ergic cell therapy for epilepsy: advances, limitations and challenges. Neurosci Biobehav Rev. (2016) 62:35–47. doi: 10.1016/j.neubiorev.2015.12.014

83. Upadhya D, Hattiangady B, Castro OW, Shuai B, Kodali M, Attaluri S, et al. Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration. Proc Natl Acad Sci USA. (2019) 116:287–96. doi: 10.1073/pnas.1814185115

Keywords: anti-seizure medications, epilepsy, genetics, inflammation, precision medicine

Citation: Riva A, Golda A, Balagura G, Amadori E, Vari MS, Piccolo G, Iacomino M, Lattanzi S, Salpietro V, Minetti C and Striano P (2021) New Trends and Most Promising Therapeutic Strategies for Epilepsy Treatment. Front. Neurol. 12:753753. doi: 10.3389/fneur.2021.753753

Received: 05 August 2021; Accepted: 28 October 2021; Published: 07 December 2021.

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Copyright © 2021 Riva, Golda, Balagura, Amadori, Vari, Piccolo, Iacomino, Lattanzi, Salpietro, Minetti and Striano. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Pasquale Striano, pasqualestriano@gaslini.org

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Epilepsy articles within Nature Reviews Neurology

Review Article | 17 June 2024

From spreading depolarization to blood–brain barrier dysfunction: navigating traumatic brain injury for novel diagnosis and therapy

Overall survival rates for traumatic brain injury have improved, but affected individuals often experience persistent and debilitating long-term complications. In this Review, the authors discuss recent evidence for the role of spreading depolarization in the initiation of long-term pathology in traumatic brain injury, including effects on blood–brain barrier dysfunction and neuroinflammation.

• Gerben van Hameren
• , Refat Aboghazleh
•  &  Alon Friedman

Review Article | 17 May 2024

IDH inhibition in gliomas: from preclinical models to clinical trials

Gliomas are the most common malignant primary brain tumours in adults, and they frequently contain mutations in the isocitrate dehydrogenase 1 ( IDH1 ) or IDH2 gene. Small-molecule inhibitors of mutant IDH are emerging as a new therapeutic strategy for IDH -mutant cancers, and this Review charts their pathway of development for IDH -mutant gliomas.

• Roberta Rudà
• , Craig Horbinski
•  &  Riccardo Soffietti

Review Article | 08 May 2024

Artificial intelligence in epilepsy — applications and pathways to the clinic

Integration of artificial intelligence into epilepsy management could revolutionize diagnosis and treatment. In this Review, the authors provide an overview of artificial intelligence applications that have been developed in epilepsy and discuss challenges that must be addressed to successfully integrate artificial intelligence into clinical practice.

• Alfredo Lucas
• , Andrew Revell
•  &  Kathryn A. Davis

Review Article | 03 April 2024

Insights into epileptogenesis from post-traumatic epilepsy

Post-traumatic epilepsy is a major driver of disability associated with traumatic brain injury. This article reviews the epidemiology and clinical features of post-traumatic epilepsy and discusses how an understanding of the underlying epileptogenic mechanisms might inform the development of anti-epileptogenic medications.

• Matthew Pease
• , Kunal Gupta
•  &  James F. Castellano

In Brief | 05 March 2024

Metabolic changes in status epilepticus

Status epilepticus is associated with changes in metabolic pathways, a new study has shown.

In Brief | 07 February 2024

Neurosteroids alleviate seizures in rats

Review Article | 24 November 2023

Rare genetic brain disorders with overlapping neurological and psychiatric phenotypes

Clinical boundaries between neurology and psychiatry hamper understanding of disorders with phenotypes that span these disciplines. In this Review, Peall et al. discuss rare genetic brain disorders with neurological and psychiatric phenotypes, and consider common underlying mechanisms that could be therapeutic targets.

• Kathryn J. Peall
• , Michael J. Owen
•  &  Jeremy Hall

In Brief | 09 October 2023

Seizure-associated changes in the Golgi apparatus

• Heather Wood

News & Views | 30 May 2023

Cardiovascular risk factors for epilepsy and dementia

A new study using the UK Biobank database has shown that people with epilepsy are at an increased risk of developing dementia. The results demonstrate that this risk is multiplied in individuals who also have high cardiovascular risk, highlighting the importance of addressing modifiable cardiovascular risk factors.

• Michele Romoli
•  &  Cinzia Costa

In Brief | 05 May 2023

New blood biomarker of refractory epilepsy

• Sarah Lemprière

Research Highlight | 10 March 2023

Blood–brain barrier disruption following seizures

New research reports changes in serum blood–brain barrier (BBB) markers after bilateral tonic–clonic seizures, corroborating earlier observations in animal models.

In Brief | 03 March 2023

MRI-based deep learning for TLE diagnosis

News & Views | 15 December 2022

From precision diagnosis to precision treatment in epilepsy

Technological advances over the past decade have made precision genetic diagnosis available to many patients. The findings of a new study demonstrate that genetic diagnosis in epilepsy can lead to changes in clinical management that manifest as positive outcomes for the patient. The results herald a new era in which precision diagnosis will lead to precision medicine.

• Katrine M. Johannesen

News & Views | 12 December 2022

‘On-demand’ gene therapy for epilepsy

Gene therapies show promise for treating epilepsy, but most strategies target cells across an entire brain region rather than selecting pathologically hyperexcited neurons. Researchers have now developed a conditional gene therapy strategy that downregulates firing activity only in neurons that are pathologically overactive and switches off when brain circuit activity has returned to baseline.

• Pasquale Striano
•  &  Fabio Benfenati

Research Highlight | 22 November 2022

Targeting connexin hemichannels to treat temporal lobe epilepsy

Review Article | 14 November 2022

Adaptive and maladaptive myelination in health and disease

In this Review, the authors provide an overview of evidence that activity-regulated myelination is required for brain adaptation and learning, and discuss how dysregulation of activity-dependent myelination contributes to neurological disease and could be a new therapeutic target.

• Juliet K. Knowles
• , Ankita Batra
•  &  Michelle Monje

Review Article | 24 October 2022

Astrocytes in the initiation and progression of epilepsy

In this Review, Vezzani et al. discuss how dysregulation of key astrocyte functions — gliotransmission, cell metabolism and immune function — contribute to the development and progression of hyperexcitability in epilepsy and consider strategies to mitigate astrocyte dysfunction.

• Annamaria Vezzani
• , Teresa Ravizza
•  &  Detlev Boison

In Brief | 07 September 2022

Seizures induce NLRP3 inflammasome signalling

Review Article | 20 July 2022

Epigenetic genes and epilepsy — emerging mechanisms and clinical applications

This Review considers how variants in genes encoding proteins that regulate epigenetic mechanisms might contribute to epilepsy. The discussion is structured around five categories of epigenetic mechanisms: DNA methylation, histone modifications, histone–DNA crosstalk, non-coding RNAs and chromatin remodelling.

• Karen M. J. Van Loo
• , Gemma L. Carvill
•  &  David C. Henshall

Comment | 23 June 2022

The importance of getting evidence into practice

Neurological diseases cause a massive burden, which will increase as populations age. Rapid advances in our understanding of disease mechanisms must be translated into human benefits. We cannot stop once technologies have been developed, but must ensure that evidence and pipelines are in place for their implementation to reduce burden and inequalities.

• Anthony G. Marson

Perspective | 10 May 2022

Why won’t it stop? The dynamics of benzodiazepine resistance in status epilepticus

Many episodes of status epilepticus do not respond to first-line treatment with benzodiazepines. In this Perspective, Richard Burman and colleagues discuss seizure-induced alterations to the sensitivity of the GABA receptor to benzodiazepines, presenting these changes as a possible mechanism of treatment resistance.

• Richard J. Burman
• , Richard E. Rosch
•  &  Joseph V. Raimondo

Review Article | 31 March 2022

The metabolic basis of epilepsy

In this Review, the authors highlight the growing recognition that disruptions in cellular metabolism can be both a cause and a consequence of epileptic seizures and discuss how this emerging science might be exploited to develop innovative therapeutic strategies.

• Jong M. Rho

In Brief | 20 December 2021

High rate of epilepsy in young individuals who died with COVID-19

• Sarah Lempriere

Research Highlight | 09 December 2021

Safety and efficacy of COVID-19 vaccines in people with neurological disorders

Review Article | 26 November 2021

Genetic generalized epilepsies in adults — challenging assumptions and dogmas

In this Review, the authors consider how current understanding of four genetic generalized epilepsy syndromes that commonly occur in adults challenges traditional concepts about these conditions and suggests that they are not distinct but sit on a neurobiological continuum.

• Bernd J. Vorderwülbecke
• , Britta Wandschneider
•  &  Martin Holtkamp

Review Article | 29 October 2021

Autonomic manifestations of epilepsy: emerging pathways to sudden death?

The close connection between epileptic networks and the autonomic nervous system is illustrated by a range of autonomic manifestations during a seizure. This article reviews the spectrum and diagnostic value of these manifestations, focusing on presentations that could contribute to sudden unexpected death in epilepsy.

• Roland D. Thijs
• , Philippe Ryvlin
•  &  Rainer Surges

Review Article | 22 September 2021

Neurobehavioural comorbidities of epilepsy: towards a network-based precision taxonomy

This Review offers a novel theoretical perspective on the neurobehavioural comorbidities of adult and childhood epilepsy, involving new analytical approaches, derivation of new taxonomies and consideration of the diverse forces that influence cognition and behaviour in individuals with epilepsy.

• Bruce P. Hermann
• , Aaron F. Struck
•  &  Carrie R. McDonald

Research Highlight | 02 September 2021

Cortical thinning in epilepsy is linked to microglial activation

Comment | 19 August 2021

Treating epilepsy in forcibly displaced persons: timely, necessary, affordable

The burden of epilepsy among forcibly displaced persons is thought to be high, and access to treatment is limited. In June 2021, the WHO Secretariat published a draft intersectoral action plan aimed at redressing the global epilepsy treatment gap, providing a valuable opportunity to improve epilepsy treatment for forcibly displaced persons.

• Farrah J. Mateen

Review Article | 26 July 2021

Headache in people with epilepsy

Headaches and epilepsy frequently co-exist in the same individual, but the pathophysiological mechanisms underlying this relationship are not yet clear. Here, the authors discuss the epidemiological and pathophysiological links between epilepsy and headache, and apply this knowledge to the clinical management of the two disorders.

• Prisca R. Bauer
• , Else A. Tolner
•  &  Josemir W. Sander

Review Article | 11 June 2021

Amyloid-β: a potential link between epilepsy and cognitive decline

People with epilepsy have an elevated risk of dementia, and seizures have been detected in the early stages of Alzheimer disease. Here, the authors review evidence that amyloid-β forms part of a shared pathway between epilepsy and cognitive decline.

• , Arjune Sen

Review Article | 15 March 2021

Cycles in epilepsy

In this Review, the authors provide an overview of the evidence for daily, multi-day and yearly cycles in epileptic brain activity. They also discuss advances in our understanding of the mechanisms underlying these cycles and the potential clinical applications of this knowledge.

• Philippa J. Karoly
• , Vikram R. Rao
•  &  Maxime O. Baud

In Brief | 09 March 2021

Blood purine levels as a biomarker in epilepsy

Review Article | 16 February 2021

Identification of clinically relevant biomarkers of epileptogenesis — a strategic roadmap

Biomarkers of epileptogenesis would enable identification of individuals who are risk of developing epilepsy after an insult or as a result of a genetic defect. In this article, Simonato et al. review progress towards such biomarkers and set out a five-phase roadmap to facilitate their development.

• Michele Simonato
• , Denes V. Agoston
•  &  Karen S. Wilcox

Review Article | 19 October 2020

Impact of predictive, preventive and precision medicine strategies in epilepsy

The anti-seizure medications used to treat patients with epilepsy can improve symptoms but do not address the underlying cause of the condition. In this Review, the authors discuss the ongoing shift towards personalized treatments for specific epilepsy aetiologies.

• Rima Nabbout
•  &  Mathieu Kuchenbuch

Research Highlight | 08 October 2020

Ultra-high-field MRI improves detection of epileptic lesions

Comment | 06 October 2020

Drug-resistant epilepsy — time to target mechanisms

Despite the development of many new anti-seizure drugs over the past two decades, around one-third of individuals with epilepsy are without effective treatment. This pharmacoresistance is poorly understood, but new treatments targeting epileptogenesis instead of seizures have shown potential in animal models and are now being translated into the clinic.

• Holger Lerche

Research Highlight | 02 July 2020

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News & Views | 02 July 2020

Gene tests in adults with epilepsy and intellectual disability

A recent study describes the yield and clinical utility of epilepsy gene panel testing in a cohort of adults with epilepsy and intellectual disability. These findings are similar to those in children with developmental epileptic encephalopathies and support the utility of testing in this subgroup of adults with epilepsy.

• Ruth Ottman
•  &  Annapurna Poduri

Review Article | 16 June 2020

MicroRNAs as regulators of brain function and targets for treatment of epilepsy

In this Review, Brennan and Henshall discuss how microRNAs determine and control neuronal and glial functions, how this process is altered in states associated with hyperexcitability, and the prospects for microRNA targeting for the treatment of epilepsy.

• Gary P. Brennan

Review Article | 19 May 2020

Zoonotic and vector-borne parasites and epilepsy in low-income and middle-income countries

Zoonotic and vector-borne parasites are important preventable risk factors for epilepsy. The authors explore the pathophysiological basis of the link between parasitic infections and epilepsy and consider preventive and therapeutic approaches to reduce the epilepsy burden associated with parasitic disorders.

• Gagandeep Singh
• , Samuel A. Angwafor

In Brief | 02 March 2020

High risk of epilepsy in children with Zika-related microcephaly

In Brief | 30 January 2020

Antisense oligonucleotide hope for childhood epilepsies

News & Views | 08 January 2020

Cenobamate for focal seizures — a game changer?

In the first published efficacy study of cenobamate for treatment-resistant focal seizures, high doses produced high seizure-free rates, suggesting cenobamate can outperform existing options. A risk of serious rash and low tolerability at higher doses means further safety studies and clinical experience are needed to determine its clinical value.

• Jacqueline A. French

Research Highlight | 18 December 2019

Blood–brain barrier pathology linked to epilepsy in Alzheimer disease

Review Article | 12 December 2019

Cannabinoids and the expanded endocannabinoid system in neurological disorders

In this Review, Cristino, Bisogno and Di Marzo outline the biology of cannabinoids, the endocannabinoid system and the expanded endocannabinoid system and discuss the involvement of these systems and the therapeutic potential of cannabinoids across the spectrum of neurological disease.

• Luigia Cristino
• , Tiziana Bisogno
•  &  Vincenzo Di Marzo

Review Article | 24 July 2019

Changing concepts in presurgical assessment for epilepsy surgery

In patients with drug-resistant focal epilepsy, the success of surgery depends on predicting which resection or disconnection strategy will yield full seizure control. This Review highlights recent advances in presurgical assessment and discusses how concepts of focal epilepsy are changing.

• Maeike Zijlmans
• , Willemiek Zweiphenning
•  &  Nicole van Klink

Comment | 01 July 2019

Neuroinflammation — a common thread in neurological disorders

Inflammatory processes contribute to neurological disorders, and many therapeutic breakthroughs in neurological disease have been immune-targeted. The choice of neuroinflammation as the theme for the 5th European Academy of Neurology Congress in 2019 and of this Focus issue highlights its importance to neurologists across the discipline.

• Nils Erik Gilhus
•  &  Günther Deuschl

Review Article | 01 July 2019

Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy

In this Review, Vezzani and colleagues discuss inflammatory pathways that are activated in pharmacoresistant epilepsy and can be modulated to therapeutic effect in animal models. They consider how targeting these pathways could overcome limitations of existing anti-epileptic treatments.

• , Silvia Balosso
•  &  Teresa Ravizza

Year in Review | 07 January 2019

Teamwork aids management and raises new issues in epilepsy

Publications on epilepsy in 2018 have shed light on the aetiology and management of the condition and raised new questions. Translation from mechanisms to clinical practice, driven by cooperation among multiple fields, will be crucial to further advances.

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Epilepsy Research

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Epilepsy Research provides for publication of high quality articles in both basic and clinical epilepsy research, with a special emphasis on translational research that ultimately relates to epilepsy as a human condition. The journal is intended to provide a forum for reporting the best and most rigorous epilepsy research from all disciplines ranging from biophysics and molecular biology to epidemiological and psychosocial research. As such the journal will publish original papers relevant to epilepsy from any scientific discipline and also studies of a multidisciplinary nature. Clinical and experimental research papers adopting fresh conceptual approaches to the study of epilepsy and its treatment are encouraged. The overriding criteria for publication are novelty, significant clinical or experimental relevance, and interest to a multidisciplinary audience in the broad arena of epilepsy. Review articles focused on any topic of epilepsy research will also be considered, but only if they present an exceptionally clear synthesis of current knowledge and future directions of a research area, based on a critical assessment of the available data or on hypotheses that are likely to stimulate more critical thinking and further advances in an area of epilepsy research.

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A New Hope for Patients With Epilepsy

March 24, 2021

Epilepsy, also known as a seizure disorder, is a condition that can seriously disrupt a patient’s everyday life. About 3.4 million people of all ages in the United States have this neurological disorder. But unlike with other brain-related conditions, about two dozen medications can successfully treat many cases of epilepsy . Although there is no cure, these anti-seizure drugs turn the disease into a chronic, but well-managed condition for many to the point where it barely interferes with life.

But about one-third of patients aren’t so lucky. They experience no relief from anti-seizure drugs and are looking for additional treatment options.

Now they may have found one in a new generation of neurostimulation devices used for epilepsy. In 2018, the Food and Drug Administration (FDA) approved a deep brain stimulation (DBS) device, manufactured by Medtronic, that sends electrical pulses through the brain to reduce the frequency of seizures. (It works by stimulating an important relay station deep in the brain called the thalamus.) And in June 2020, the FDA approved the Percept PC, also from Medtronic. Facilitating more customized therapy, this modified version allows doctors to treat epilepsy and record electrical activity from deep in the brain. (The Percept PC is also approved for other conditions, such as Parkinson’s disease and essential tremor.)

Last year, the Yale Comprehensive Epilepsy Center became the first epilepsy center in the U.S. to implant the device in a patient with epilepsy. As of March 2021, eight epilepsy patients have been implanted with the Percept PC device at Yale.

What is epilepsy?

At the most basic level, everything we think, feel, and do is controlled by brain cells communicating with one another. They send messages through neurotransmitters like dopamine or via electrical pulses that travel through axons—long nerve fibers that connect the cells, or neurons, to each other.  

Normally, these electrical signals move between cells in a steady, consistent pattern. When a person has a seizure, however, the pattern is disrupted so that large groups of neurons send messages at the same time. This produces a flood of electrical activity that temporarily prevents areas of the brain responsible for language, memory, emotion, and consciousness from functioning.  

“Epilepsy is a sort of electrical activity that builds up over time before it is released and causes abnormality throughout the brain,” says Yale Medicine neurologist Imran Quraishi, MD, PhD .  

There are many different types of seizures, with a variety of causes. Focal (partial) epilepsy refers to seizures that start in one part of the brain. In some seizures, the electrical activity stays in that part of the brain and can cause a variety of symptoms including an inability to speak, “spacing out,” and memory lapses. In other seizures, the activity either spreads to or starts on both sides of the brain and can cause a person to pass out, faint, or even stop breathing.  

There are many treatment options for patients with focal epilepsy, including medications, surgical resection, laser ablation, dietary therapy, and neurostimulators. In some cases, however, neurostimulation is the only option that is effective, says Dr. Quraishi.

How deep brain stimulation can help with epilepsy

The 2018-approved DBS device uses electrical pulses to regulate the brain’s electrical activity. It’s similar to a pacemaker, which sends electrical signals to keep the heart beating normally.  

The device has two components: a neurostimulator, which is surgically implanted in a patient’s chest, and electrodes that are inserted into the brain. The neurostimulator releases electrical pulses through thin wires connected to electrodes that transfer the electricity to an area of the brain called the thalamus.  

“The thalamus connects a lot of areas of the brain,” says Lawrence Hirsch, MD , co-director of the Yale Comprehensive Epilepsy Center. “It’s a central networking place for electric signals in the brain. You can think of it like a big airport where flights pass through to connect to other places.” With DBS, electricity inside neurons in the path of an electrical pulse gets turned off. “This helps to make the brain less excitable or less likely to cause seizures,” he adds.

The Percept PC approved last June is Medtronic’s same DBS device, but with one significant difference—it records a patient’s brain signals.        

Our goal is to have an app connected to the device that tells patients they have, for example, a 90% chance of having a seizure that day. Yale Medicine neurologist Imran Quraishi, MD, PhD

Using information collected by the Percept PC, Dr. Hirsch explains, neurologists can more precisely adjust the device’s programming. “We may start the pulses at 30 seconds on and five minutes off during a 24-hour cycle and make changes from there,” he says.  

So far, the device is only approved for adults with focal epilepsy.

Research shows how the deep brain stimulation device improves symptoms

The FDA approved Medtronic’s 2018 DBS device for epilepsy based on data gathered from the SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy) clinical trial. This randomized double-blind study enrolled 110 adults who were experiencing an average of six seizures per month. In the first several months of the trial, half the patients had their device turned on and half did not; neither the patients nor the assessing physicians knew whether the device was on or off. Those with the device turned on had fewer seizures than those with the device off. The benefit continued to increase over time, says Dr. Hirsch.  

The study followed patients for seven years. In the first year after the device was implanted, 43% of participants with it had experienced half as many seizures as they’d been having when the study began. After seven years, researchers found that 74% of patients experienced the same reduction in seizure frequency—seizures were cut in half or better, says Dr. Hirsch—according to Medtronic. And in that same seven-year period, patients experienced a median of 75% fewer seizures from their baseline.

More data for more accurate predictions

Neurologists have been collecting patient data from the new Percept PC for several months, but it’s too soon to know if the new device will help patients more than the previous model.   

“We’re hoping that by relying on the patient’s seizure patterns from the Percept, we’ll be able to make adjustments more quickly and won’t have to wait years to get the maximum benefit from the device,” Dr. Hirsch says.   

You can think of it [the thalamus] like a big airport where flights pass through to connect to other places. Lawrence Hirsch, MD, co-director of the Yale Comprehensive Epilepsy Center

For his part, Dr. Quraishi hopes that when reams of data have been collected from enough people, neurologists may have better insight into how to more accurately predict a patient’s risk of a seizure. This could lead to a significant improvement in quality of life for people with treatment-resistant epilepsy, since being able to forecast one’s daily risk of a seizure would make everyday activities feel less risky.  

To give a sense of how this would work, Dr. Quraishi compares the device to common apps we all use to plan our activities. “Right now, before you go outside you check a weather app,” Dr. Quraishi says. “Our goal is to have an app connected to the device that tells patients they have, for example, a 90% chance of having a seizure that day.” If that’s the case, patients would know they might want to stay home and get extra rest, he adds.  

Or even better, says Dr. Hirsch, they may be able to take extra medications based on the prediction algorithm to prevent that seizure from even happening.

[ Read about what happens when the diagnosis isn't epilepsy, but "psychogenic non-epileptic seizure” or PNES. ]

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