latest epilepsy research

MIT Technology Review

• Newsletters

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.

From around the web

The share of abortions that are being carried out with pills in the US continues to rise, reaching 63%. The trend predates the 2022 Supreme Court decision allowing states to bar doctors from providing abortions. Since then, more women may have started getting the pills outside the formal health-care system. ( New York Times )

Excitement over pricey new weight-loss drugs is causing “pharmaco-amnesia,” Daniel Engber says. People are forgetting there were already some decent weight-loss pills that he says were “half as good … for one-30th the price.” ( The Atlantic )

Biotechnology and health

How scientists traced a mysterious covid case back to six toilets.

When wastewater surveillance turns into a hunt for a single infected individual, the ethics get tricky.

• Cassandra Willyard archive page

An AI-driven “factory of drugs” claims to have hit a big milestone

Insilico is part of a wave of companies betting on AI as the "next amazing revolution" in biology

The quest to legitimize longevity medicine

Longevity clinics offer a mix of services that largely cater to the wealthy. Now there’s a push to establish their work as a credible medical field.

• Jessica Hamzelou archive page

There is a new most expensive drug in the world. Price tag: $4.25 million

But will the latest gene therapy suffer the curse of the costliest drug?

Stay connected

Get the latest updates from mit technology review.

Discover special offers, top stories, upcoming events, and more.

Thank you for submitting your email!

It looks like something went wrong.

We’re having trouble saving your preferences. Try refreshing this page and updating them one more time. If you continue to get this message, reach out to us at [email protected] with a list of newsletters you’d like to receive.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Front Neurol

New Trends and Most Promising Therapeutic Strategies for Epilepsy Treatment

Antonella riva.

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

Alice Golda

Ganna balagura.

3 Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit, Amsterdam, Netherlands

Elisabetta Amadori

Maria stella vari, gianluca piccolo, michele iacomino.

4 Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy

Simona Lattanzi

5 Department of Experimental and Clinical Medicine, Neurological Clinic, Marche Polytechnic University, Ancona, Italy

Vincenzo Salpietro

Carlo minetti, pasquale striano.

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 2 ).

Advanced RCTs on new drugs for epilepsy treatment.

AEs, adverse events; ASMs, antiseizure medications; BDI, beck depression inventory; CaGI, caregiver global impression; CBD, cannabidiol; CSF, convulsive seizure frequency; d, day; drug-R, drug-resistant; DS, Dravet syndrome; LGS, Lennox-Gastaut syndrome; LINCL, late infantile neuronal ceroid lipofuscinoses; M, mean; n°, number; na, not assessed; OLE, open label extension; PAH, pulmonary arterial hypertension; PGIC, patient global impression of change; Pts, patients; RCT, randomized clinical trial; Ref, reference; SD, standard deviation; SF, seizure frequency; SUDEP, sudden unexpected death in epilepsy; STP, stiripentol; sz, seizures; VHD, valvular heart disease; w, weeks; y, years .

Advanced RCTs on new non-pharmacological treatments for epilepsy.

AEs, adverse events; ASMs, antiseizure medications; bpm, beats per minute; CBSDA, cardiac-based seizure detection algorithm; DRE, drug-resistant epilepsy; eTNS, external trigeminal nerve stimulation; FP, false positive; FU, follow-up; h, hours; iTC, ictal tachycardia; M, mean; n°, number; na, not assessed; Pts, patients; RCT, randomized clinical trial; Ref, reference; RNS, responsive neurostimulation; RR, retention rate; SF, seizure frequency; sGTC, secondarily generalized tonic-clonic; sz, seizures; VNS, vagal nerve stimulation; y, years .

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.

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.

• Open access
• Published: 17 September 2021

The pharmacological treatment of epilepsy: recent advances and future perspectives

• Emilio Perucca   ORCID: orcid.org/0000-0001-8703-223X 1 , 2  

Acta Epileptologica volume  3 , Article number:  22 ( 2021 ) Cite this article

32k Accesses

28 Citations

Metrics details

The pharmacological armamentarium against epilepsy has expanded considerably over the last three decades, and currently includes over 30 different antiseizure medications. Despite this large armamentarium, about one third of people with epilepsy fail to achieve sustained seizure freedom with currently available medications. This sobering fact, however, is mitigated by evidence that clinical outcomes for many people with epilepsy have improved over the years. In particular, physicians now have unprecedented opportunities to tailor treatment choices to the characteristics of the individual, in order to maximize efficacy and tolerability. The present article discusses advances in the drug treatment of epilepsy in the last 5 years, focusing in particular on comparative effectiveness trials of second-generation drugs, the introduction of new pharmaceutical formulations for emergency use, and the results achieved with the newest medications. The article also includes a discussion of potential future developments, including those derived from advances in information technology, the development of novel precision treatments, the introduction of disease modifying agents, and the discovery of biomarkers to facilitate conduction of clinical trials as well as routine clinical management.

The modern treatment of epilepsy started with the introduction of phenobarbital in 1912. The advent of phenytoin in the late thirties marked another milestone, because it was made possible by the introduction of animal models of antiseizure activity [ 1 ]. Similar models also played a key role in the subsequent development of many other antiseizure medications (ASMs). Today, the pharmacological armamentarium against epilepsy includes more than 30 drugs (Table  1 ). These drugs differ in their pharmacokinetics, efficacy, and adverse effect profile, thereby offering unprecedented opportunities to tailor treatment choices to individual needs [ 2 ]. Some of the ASMs introduced after 1985, usually referred to as second-generation drugs, have some safety advantages over older generation agents, but have not increased substantially the proportion of patients who achieve complete freedom from seizures [ 3 ]. For many of these patients, the feasibility of epilepsy surgery, or alternative therapies, should be given early consideration [ 4 , 5 ].

Despite the fact that pharmacoresistance has been little affected by the introduction of newer medications, the drug treatment of epilepsy has made major advances in the last 50 years. In particular, we learnt how to individualize drug selection based on specific patient characteristics such as age, gender, epilepsy syndrome, seizure type, comorbidities, comedications, and other factors affecting clinical response [ 6 ]. We also learnt how to optimize response by careful titration and adjustment of dosage, and use of serum drug levels whenever indicated [ 7 ]. We made major progress in understanding drug interactions, and recognizing the relative merits and indications of monotherapy and polytherapy [ 8 , 9 ]. Likewise, we improved our knowledge of the natural history of epilepsy syndromes, and characterized prognostic factors for seizure recurrence for patients in whom discontinuation of ASMs can be considered after an adequate period of freedom from seizures [ 10 ].

The purpose of the present article is to provide a concise overview of some advances in research on the drug treatment of epilepsy made in the last 5 years, and to discuss currently unmet needs as well as developments which are likely to occur in the foreseeable future.

Advances in characterizing the comparative effectiveness and safety of ASMs

A number of recent clinical trials and observational studies have provided valuable information which can assist physicians in making rational treatment selections. As a follow-up to the initial Standard and New Antiepileptic Drugs (SANAD) trials, which found lamotrigine to be superior to carbamazepine, oxcarbazepine, topiramate and gabapentin in time to treatment failure in patients with mostly focal epilepsy [ 11 ], and valproate to be superior to lamotrigine and topiramate in patients with mostly generalized and unclassified epilepsy [ 12 ], two more recent SANAD trials have been completed. In the first of these trials, 990 adults and children with newly diagnosed focal epilepsy were randomized to receive lamotrigine, levetiracetam or zonisamide, and followed-up for 2 years [ 13 ]. In the per-protocol analysis, lamotrigine was associated with a better 12-month remission from seizures compared with both levetiracetam and zonisamide. In the second SANAD-II trial, which used a similar protocol and enrolled 520 newly diagnosed adults and children, valproate was found to be more effective than levetiracetam in controlling seizures in a pooled cohort of patients with generalized or unclassified epilepsy [ 14 ]. These trials used a pragmatic design mimicking routine clinical practice, even though the possibility of assessment bias due to the open-label, unblinded design cannot be excluded. When considered together with other available lines of evidence, these findings confirm that lamotrigine should be regarded as one of the treatments of first choice for patients with focal seizures. Lamotrigine offers the advantage of being efficacious, generally devoid of adverse effects on mood and cognitive function, and with a low potential to cause adverse drug interactions, even though lamotrigine metabolisn can be affected by a variety of concurrently administered drugs [ 6 ]. One drawback of lamotrigine is the need for gradual titration in order to minimize the risk of serious skin rashes, and therefore it may not be the most appropriate drug for use in patients with frequent severe seizures requiring a prompt onset of antiseizure activity.

The findings from the SANAD studies that valproate is superior to lamotrigine, topiramate and levetiracetam in the treatment of patients with generalized epilepsy are consistent with other lines of evidence. In particular, a recent study from Denmark found that failure to achieve seizure freedom with valproate was the single most important predictor of pharmacoresistance in a cohort of 137 adults with idiopathic (genetic) generalized epilepsy [ 15 ]. The superior efficacy of valproate in controlling seizures associated with generalized epilepsy, however, creates a dilemma in the treatment of females of childbearing potential. In fact, valproate is regarded by the European Medicine Agency as contraindicated for use as first-line treatment in these women (unless the conditions of a rigorous pregnancy prevention programme are fulfilled), due to the higher risk of inducing teratogenic effects as well as impaired postnatal cognitive development in the offspring [ 16 , 17 ].

With respect to teratogenic potential of ASMs, prospective pregnancy registries have contributed greatly to characterize risks associated with individual medications. A particularly important advance was the 2018 publication of data from the international EURAP registry [ 18 ]. This study, based on analysis of 7355 prospective pregnancies exposed to 8 different ASM monotherapies provides risk estimates non only for specific ASMs, but also for different doses of the most commonly used drugs. Overall, the lowest prevalence of major congenital malformations (MCMs) in the offspring was associated with exposure to levetiracetam (2.8% prevalence), lamotrigine (2.9%) and oxcarbazepine (3.0%). Prevalence estimates were intermediate for topiramate (3.9%), carbamazepine (5.5%), phenytoin (6.4%) and phenobarbital (6.5%), and highest for valproate (10.3%). An increased risk with increasing dose was identified for lamotrigine and carbamazepine, and was most prominent for phenobarbital and valproate. In particular, the prevalence of MCMs (with 95% confidence intervals) associated with phenobarbital exposure was 2.7% (0.3–9.5%) at doses <  80 mg/day, 6.2% (3.0–11.1%) at doses > 80 to <  130 mg/day and 11.7% (4.8–22.6%) at doses > 130 mg/day. For valproate, the prevalence of MCMs was 6.3% (4.5–8.6%) at doses <  650 mg/day, 11.3% (9.0–13.9%) at doses > 650 to ≤ 1450 mg/day and 25.2% (17.6–34.2%) at doses > 1450 mg/day. These findings are important because they alert physicians about the need to consider teratogenic risks not only in relation to type of ASM prescribed, but also in relation to dose. A subsequent EURAP investigation documented a clear-cut decrease in the prevalence of MCMs over the period from 2000 to 2013 [ 19 ]. Specifically, there was a 27% decrease in prevalence of MCMs between pregnancies enrolled in the period 2010–2013 compared with those enrolled in the period 2000–2005 (Fig.  1 ). Further analysis of these data provided a strong indication that the improvement in pregnancy outcomes over time was related to changes in ASM prescription patterns, including a major decline in the proportion of pregnancies exposed to valproate. In fact, a reduction in teratogenic risk is one of the important advances associated with the introduction of second-generation ASMs [ 3 ].

Prevalence of major congenital malformations (MCMs) following prenatal exposure to monotherapy with antiseizure medications (ASMs) among cases enrolled in the EURAP international registry during three different periods. Number of exposures during each period (listed in brackets) refer to the eight most common monotherapies, which accounted for 96.7 to 98.1% of all monotherapy exposures. Based on data from Tomson et al [ 19 ].

Introduction of novel ASMs

During the last 5 years, five novel ASMs (brivaracetam, cannabidiol, cenobamate, everolimus and fenfluramine) have been introduced into the market. Key features of each of these medications are summarized in Table  2 . The history of these drugs is illustrative of different strategies being used in developing novel ASMs.

The development of brivaracetam followed a paradigm which has been in place for a very long time, i.e. the structural modification of an already existing medication with the aim of improving its pharmacological profile. Examples of other ASMs developed with this strategy include methylphenobarbital and primidone (both structurally related to phenobarbital), the phenytoin derivative fosphenytoin, and oxcarbazepine and eslicarbazepine acetate, which represent successive modifications of the carbamazepine structure. In fact, levetiracetam itself was originally developed with the aim of improving the pharmacological profile of piracetam, and its antiseizure activity was discovered by chance. Brivaracetam was selected for development after extensive preclinical screening of a large numbers of levetiracetam derivatives. Compared with levetiracetam, brivaracetam has higher affinity for the synaptic vesicle 2A (SV2A), and a similar pharmacological profile [ 20 ]. Brivaracetam has been found to be superior to placebo in adjunctive-therapy trials in focal epilepsy, but its activity profile in other seizure types has not yet been defined in well designed controlled trials. One limitation of brivaracetam is its lack of efficacy when added-on to levetiracetam, presumably due to competition between the two drugs for the SV2A binding site. The still unanswered question about brivaracetam is whether, and to what extent, its efficacy and tolerability profile differs from that of levetiracetam. It has been suggested that brivaracetam is less likely to cause irritability and other behavioral disturbances compared with levetiracetam [ 20 ]. However, evidence on this remains inconclusive, because to date there have been no randomized head-to-head trials comparing these two drugs [ 21 ].

Another ASM recently approved for the treatment of focal seizures is cenobamate, a carbamate derivative which is also structurally related to previously developed drugs [ 22 ]. During clinical development, three confirmed cases of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), including one fatality, were reported when cenobamate was titrated rapidly (weekly or faster titration). Consequently, a revised dosing scheme involving initiation at a small dose and slow titration at 2-week intervals has been implemented. In a safety study, no cases of DRESS were reported when 1339 patients were titrated using the slow titration scheme, and the drug has since been approved in the U.S. and Europe [ 23 ]. In the pivotal adjunctive-therapy randomized trial in patients with refractory focal seizures that led to regulatory approval, the most remarkable finding was the relatively high proportion of patients who achieved seizure freedom (21% in the 400 mg/day cenobamate group versus 1% in the placebo group) [ 24 ]. This contrasts with seizure freedom rates ranging from 0 to 6.5% in comparable trials with other second-generation ASMs [ 25 ]. Comparisons of outcome data across trials, however, should be interpreted cautiously, because of differences in clinical settings and characteristics of the patients. Moreover, seizure freedom data in randomized clinical trials refer to limited assessment periods (typically, a 12-week maintenance period) and can be inflated by the last-observation-carried-forward (LOCF) analysis, whereby patients who did not experience seizures but exited the trial prematurely are still counted as seizure-free in the final analysis. In the pivotal cenobamate trial, the proportion of randomized patients who were seizure-free during the entire 12-week maintenance period and did not exit the trial prematurely was 14%, which is still a relatively high proportion [ 24 ].

All three remaining ASMs introduced in the last 5 years share a common feature, i.e. they were approved for orphan indications. Specifically, cannabidiol was approved for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex, fenfluramine was approved for the treatment of seizures associated with Dravet syndrome, and everolimus was approved for the add-on treatment of focal seizures in patients with tuberous sclerosis complex (Table 2 ). Introduction of ASMs for orphan indications is a novel development, made possible by increased awareness of the unmet needs associated with many rare epilepsies and by regulatory incentives to develop drugs for these indications, particularly for children. In fact, only 2 of the 25 ASMs developed prior to 2015 were developed for orphan indications, compared with 3 out of 5 ASMs developed in the last 5 years.

Cannabidiol is one of the many active principles contained in the Cannabis plant, which has been used as an herbal remedy in China as early as 2000 BC. Unlike tetrahydrocannabidol (THC), cannabidiol lacks unwarranted psychoactive effects. Its antiseizure efficacy in its approved indications has been demonstrated in several adjunctive-therapy randomized placebo-controlled trials [ 26 ]. In these trials, many patients received concomitant treatment with clobazam, and the improvement in seizure control observed after adding cannabidiol could be ascribed at least in part to a drug interaction. In fact, cannabidiol is a powerful inhibitor of cytochrome CYP2C19 and by this mechanism increases more than three-fold the serum concentration of norclobazam, the active metabolite of clobazam. There is, however, also evidence that cannabidiol retains independent antiseizure activity, unrelated to its interaction with clobazam [ 27 ].

Another ASM recently introduced for the treatment of seizures associated with Dravet syndrome is fenfluramine, which was first marketed in the sixties and widely used in Europe and the U.S. for over 30 years as an appetite suppressant, either as racemic fenfluramine or as its d-enantiomer dexfenfluramine. In 1997, fenfluramine and dexfenfluramine were withdrawn from the market following the discovery of their association with cardiac valvulopathy and pulmonary hypertension. Prior to its withdrawal from the market, however, fenfluramine had been found to improve seizure control in a small cohort of patients with Dravet syndrome, who were allowed to continue treatment with the drug [ 28 ]. These observations led to recent conduction of randomized placebo-controlled adjunctive therapy trials, which demonstrated a robust seizure-suppressing effect in patients with Dravet syndrome, and subsequent regulatory approval for this indication both in Europe and the United States [ 29 ]. Recent data suggest that fenfluramine may also be useful for the treatment of seizures associated with Lennox-Gastaut syndrome [ 30 ]. To date, no evidence of cardiovascular toxicity has been found in patients with epilepsy treated with fenfluramine, possibly because the doses used for seizure protection are generally lower than those used originally for appetite suppression. Yet, there are still many unanswered questions concerning fenfluramine, including the serum levels of parent drug and its active de-ethylated metabolite norfenfluramine required for seizure suppression in children in comparison with those known to be associated with cardiovascular toxicity in adults [ 29 ]. The potential efficacy and safety advantages of developing individual enantiomers of fenfluramine and norfenfluramine should also be considered [ 29 ].

The last medication discussion in this section, everolimus, is an inhibitor of mTOR (mammalian Target Of Rapamycin). Its use in the treatment of focal seizures associated with tuberous sclerosis complex (TSC) has been prompted by evidence linking the pathogenesis of TSC to mTOR overactivation [ 31 ]. Accordingly, everolimus is an example of a novel strategy in drug development, i.e. a precision treatment targeting the etiology of the disease. Everolimus has been found to be effective in reducing tumor growth as well as drug-resistant seizures in TSC patients. Up to 40% of TSC patients show a significant improvement in seizure control when given adjunctive treatment with everolimus. In the pivotal trial that led to its regulatory approval for use as ASM, seizure frequency decreased progressively over time during treatment, suggesting a possible disease modifying effect [ 32 ]. However, a clinically relevant antiepileptogenic or disease-modifying effect has not yet been clearly demonstrated. The age at which treatment is initiated may be important for the final outcome, but controlled trials in children below 2 years of age have not yet been completed [ 31 ].

Cannabidiol, fenfluramine and everolimus are also examples of drugs approved initially for other indications. In fact, cannabidiol was first marketed in a fixed combination product with THC as a nasal spray for the treatment of spasticity associated with multiple sclerosis, fenfluramine was used initially as an appetite suppressant, and everolimus was first approved for the treatment of advanced kidney cancer, subependymal giant cell astrocytoma (SEGA) associated with TSC, pancreatic neuroendocrine tumors, and other tumors. The repurposing for use in epilepsy of drugs initially approved for other indications is one of the options being pursued in the effort to develop precision treatments (see below).

Introduction of novel formulations

Advances in epilepsy treatment can be achieved not only by developing novel drugs, but also by improving the pharmaceutical formulation of already available medications. One area where particularly significant advances have been made in the last 5 years is the development of novel formulations of ASMs for the treatment of seizure clusters and acute repetitive seizures in the out-of-hospital setting [ 33 ]. Until 2018, the only FDA-approved rescue ASM for out-of-hospital use was diazepam rectal gel. In 2019, the FDA approved two additional products for this indication, namely intranasal midazolam [ 34 ] and intranasal diazepam [ 35 ]. Use of these medications is associated with a rapid onset of antiseizure effect, thereby stopping seizures before they progress to established status epilepticus. The intranasal route is generally well accepted by patients and caregivers, as it avoids the social embarrassment associated with use of the rectal route.

Alternative non-rectal rescue formulations of benzodiazepines for out-of-hospital use have been available in other countries for a number of years. In particular, a rapidly absorbed buccal formulation of midazolam has been available in Europe since 2011 [ 36 ]. Innovative formulations of ASMs under development as potential rescue therapy for emergency use include a diazepam buccal film, and an inhaled formulation of alprazolam [ 33 ]. Oral formulations can also be used at times as a rescue treatment, but they can be associated with drawbacks in this setting, such as slower or suboptimal absorption, need for patient cooperation (which is not always feasible) and risk of aspiration [ 36 ].

Future perspectives

Extensive research is ongoing in many areas, and important advances leading to improved epilepsy outcomes are likely to occur in a not too distant future. A few relevant examples will be discussed below.

Increased application of technological tools to epilepsy management

In recent years, information technology (IT)-based applications have been increasingly utilized in epilepsy management, as shown by the widespread use of smartphones to record seizures in the out-hospital setting, and the expanding opportunities offered by Internet-based services in areas such as distant education and telemedicine [ 37 ]. Smartphone applications (apps) are also being increasingly used to assist people with epilepsy to manage and cope with their disease. Most of these apps focus on issues such as treatment management, medication adherence, health care communication, and seizure tracking [ 38 ]. Other apps are aimed at assisting healthcare professionals (HCPs), on example being tools to improve epilepsy diagnosis in non-specialist settings [ 39 , 40 ]. We recently designed a smartphone app to help HCPs in selecting ASM selection for patients with seizure onset at age 10 years or above, particularly in settings where no specialized expertise is available [ 41 , 42 ]. This app is freely available on the Internet ( www.epipick.org ). In a recent validation study, selection of ASMs recommended by the app based on individual patient characteristics was found to be associated with improved seizure outcomes and fewer adverse effects compared with use of ASMs not recommended by the app [ 43 ]. In the future, individualized ASM selection is likely to empowered by more sophisticated technology, including artificial intelligence (machine learning)-based approaches. In a recent study, a machine learning approach combining clinical, genetic and clinical trial data derived from individual patients permitted to construct a computerized model that predicted response to a specific ASM [ 44 ].

In addition to facilitating treatment selection, technology will increasingly assist patients and physicians in monitoring response to treatment through a variety of tools, including seizure detection devices [ 45 ]. Efforts are also ongoing into development of sophisticated technology, including artificial intelligence, for the prediction of epileptic seizures [ 46 ]. This could pave the way to innovative treatment strategies, such as the intermittent use of ASMs prior to the time at which a seizure is predicted to occur.

Precision therapies

In recent years, our understanding of the molecular mechanisms involved in the pathogenesis of epilepsies has improved considerably. One area where advances have been greatest is the genetics of the epilepsies, and in particular the discovery of gene mutations responsible for a large proportion of patients with developmental and epileptic encephalopathies (DEEs) [ 47 ]. The elucidation of an epileptogenic mutation permits to establish the functional abnormality responsible for the epilepsy in the affected individual, and to identify (or develop) precision-therapy medications that may be able to correct such abnormality. One example of a precision therapy is the utilization of the ketogenic diet to control seizures associated with Glucose Transporter Type 1 (GLUT1) deficiency syndrome. In this condition, GLUT1 deficiency results in impaired brain uptake of glucose and consequent neuronal dysfunction, which can be overcome by supplying the brain with an alternative source of energy [ 48 ]. As discussed in recent reviews [ 49 , 50 , 51 ], precision treatments targeting the mechanisms responsible for epilepsy in individuals with specific gene mutations may involve use of drugs previously approved for other indications, a process known as drug repurposing. One example of repurposed drug is the mTOR inhibitor everolimus for the treatment of seizures associated with TSC, as discussed above in this article. Approaches to identify repurposed drugs for specific monogenic epilepsies have been described [ 52 ]. In some cases, improved outcomes can be achieved not by administering additional drugs, but by removing medications that can paradoxically aggravate seizures in these patients [ 49 ]. Importantly, precision therapies are applicable not only to genetic epilepsies, but also to epilepsies due to other etiologies, such metabolic, inflammatory or immune-mediated causes [ 53 ].

At present, application of precision therapies in the management of epilepsy is still in its early days, and will likely expand as further knowledge accrues and newer and more effective targeted treatments are introduced. For genetic epilepsies, targeted (precision) treatments have been reported to improve outcomes in a considerable proportion patients with identified gene mutations [ 54 ], although a more recent survey gave a more sober assessment of the current impact of these treatments [ 55 ].

Biomarker-guided therapies

The search for biomarkers continues to be a hot topic in epilepsy research. Biomarkers can be based on a variety of measures such as genetic, molecular, cellular, imaging, and electrophysiological measures, other clinical or laboratory data, or a combination of these [ 56 , 57 ]. Biomarkers could potentially be used for different purposes, for example to improve diagnostic accuracy, to identify ongoing epileptogenesis and its mechanisms, to predict seizure response (or lack of response) to specific treatments, to assess the probability of seizure recurrence after treatment withdrawal, or to evaluate susceptibility to adverse drug effects. Some biomarkers, such as the HLA-B*15:02 antigen to identify individuals at high risk of carbamazepine-induced serious cutaneous adverse reactions among Han Chinese and other South Asian ethnic groups, are already in routine clinical use [ 58 ].

With respect to potential therapeutic advances, identification and validation of biomarkers could improve treatment outcomes in many ways [ 56 , 57 , 59 ]. First, biomarkers could be used to identify individuals at high risk of developing epilepsy after an epileptogenic insult, thereby permitting selection of these individuals for clinical trials of potential antiepileptogenic therapies. Second, identification of biomarkers predictive of seizure recurrence could facilitate decision on whether to start or withhold ASM therapy in patients who experienced a single seizure. Third, biomarkers predictive of a favorable response to a specific medication would be valuable to select patients to be enrolled in clinical trials of that medication, thereby increasing responder rate and sparing non-responders the burden of receiving placebo or an ineffective treatment. Fourth, biomarkers could theoretically be used to monitor response to treatment, by informing physicians at an early stage on whether the prescribed medication has the required efficacy and safety in a specific individual. Lastly, and most importantly, biomarkers could in the future inform physicians on which ASM is most likely to control seizures effectively and with fewest adverse effects. This may change radically treatment paradigms: for example, the value of a drug which is effective in achieving complete seizure control in 5% of patients with pharmacoresistant epilepsy would be greatly enhanced if we had a biomarker that can identify beforehand those patients who are responsive to that drug. In that scenario, we would use that drug only in responsive patients, thereby increasing the success rate to 100%.

In practice, in most situations it is unlikely that a single biomarker will provide optimal information for any intended purpose. More realistically, breakthroughs are likely to come from algorithms that utilize a combination of biomarkers and other clinical information. The development of artificial intelligence-based tools can facilitate greatly these approaches [ 44 ].

Novel drugs and the search for disease-modifying therapies

The modest impact of second-generation ASMs on seizure outcome in patients resistant to older agents justifies continuing efforts to develop newer and potentially more effective treatments (Table  3 ). Drug development is currently benefiting from many advances, including deeper knowledge of the mechanisms of epileptogenesis and seizure generation in relation to specific etiologies, improved understanding of mechanisms of pharmacoresistance, and availability of disease-specific models as well as models of pharmacoresistance [ 53 , 60 ]. These advances are changing the paradigms used to discover and develop new drugs.

An important paradigm change is a switch from a focus on medications aimed at suppressing seizures to a focus on treatments targeting the underlying disease, i.e. specific etiologies and the molecular mechanisms associated with such etiologies [ 51 , 61 ]. Future precision treatments emerging from this approach will include repurposed drugs [ 50 , 62 ], novel small molecules, and other treatments based on innovative technologies such as antisense oligonucleotides [ 63 , 64 ] and gene therapy [ 65 ]. Some of these therapies require invasive routes of administration, which are also being explored for innovative uses of already established medications [ 66 ].

A closely related paradigm change consists in targeting specifically epileptogenesis and other manifestations of the disease [ 60 , 62 , 67 ]. Such treatment could potentially be used to prevent epilepsy, to inhibit its progression (in those syndromes showing a progressive course), or to alter the appearance or progression of comorbidities such as intellectual disability and other disorders. A wide variety of compounds have been found to possess antiepileptogenic and/or neuroprotective activity in preclinical models through antiinflammatory, antioxidant and other mechanisms [ 68 , 69 , 70 , 71 ]. In addition to novel molecules, these compounds includes naturally occurring substances such as phytocannabinnoids, melatonin, erythropoietin, vitamins and other dietary constituents [ 68 , 70 , 72 , 73 , 74 ], as well as medications already approved for other indications, such as metformin [ 75 ], montelukast [ 76 ], atorvastatin, ceftriaxone, and losartan [ 62 ]. Whether these properties documented in animal models translate into benefit in the clinical setting remains to be demonstrated. Of note, a number of precision treatments directed at specific etiologies of epilepsy could exhibit disease-modifying effects, although it is possible that any medication acting on a single molecular pathway may not address all the complex comorbidities associated with aberrant neural networks [ 61 ].

As discussed above, clinical trials of investigational new drugs could be facilitated by development of biomarkers to detect the occurrence of epileptogenesis at an early stage, to identify drug responsive patients and to monitor response to treatment. Despite claims to the contrary [ 77 ], demonstrating that a chronically administered treatment started before seizure onset prevents the occurrence of seizures in patients still receiving that treatment does not prove epilepsy prevention, because any ASM having a purely symptomatic effect could also produce such an outcome. Likewise, some comorbidities, such as progression of cognitive disability, may be prevented solely as a result of seizure suppression. Truly innovative trial designs will be required to generate unequivocal evidence that a drug is effective in preventing epilepsy, or has a direct disease modifying effect [ 78 ].

Conclusions

Despite the fact that second-generation ASMs have not reduced substantially the burden of pharmacoresistance, advances in the drug treatment of epilepsy continue to be made. These advances result mostly from improved understanding of the comparative efficacy and safety of existing ASMs and from the introduction of newer medicines and innovative formulations. Further advances can be ascribed to technological tools for distant education, telemedicine, and patient empowerment made possible by self-management smartphone-based apps.

It likely that further important therapeutic advances will occur in the coming years. Thanks to ongoing multidisciplinary efforts, clinical outcome for people with epilepsy is likely to improve due to advances in IT technology, development of novel precision therapies, identification of biomarkers to guide drug development as well as routine clinical management, and, ultimately, introduction of truly innovative disease modifying therapies.

Availability of data and materials

Not applicable.

Abbreviations

Antiseizure medication

Developmental and epileptic encephalopathy

Cerebrospinal fluid

Drug Reaction with Eosinophilia and Systemic Symptoms

Dravet syndrome

Cytochrome P450

Electroencephalography

International Registry of Antiepileptic Drugs and Pregnancy

Food and Drug Administration (United States)

Healthcare professional

Gamma-aminobutyric acid

G protein-coupled receptor 55

Information technology

Lennox-Gastaut syndrome

Major congenital malformation

Last-observation-carried-forward

Mammalian Target Of Rapamycin

P-glycoprotein

Standard and New Antiepileptic Drugs

Subependymal giant cell astrocytoma

Synaptic vesicle 2A

Transient receptor potential vanilloid type 1

Tuberous sclerosis complex

Uridine 5′-diphospho-glucuronosyltransferase

Perucca E. Antiepileptic drugs: evolution of our knowledge and changes in drug trials. Epileptic Disord. 2019;21(4):319–29. https://doi.org/10.1684/epd.2019.1083 .

Article   PubMed   Google Scholar  

Moshé SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: new advances. Lancet. 2015;385(9971):884–98. https://doi.org/10.1016/S0140-6736(14)60456-6 .

Perucca E, Brodie MJ, Kwan P, Tomson T. 30 years of second-generation antiseizure medications: impact and future perspectives. Lancet Neurol. 2020;19(6):544–56. https://doi.org/10.1016/S1474-4422(20)30035-1 .

Article   CAS   PubMed   Google Scholar  

Dalic L, Cook MJ. Managing drug-resistant epilepsy: challenges and solutions. Neuropsychiatr Dis Treat. 2016;12:2605–16. https://doi.org/10.2147/NDT.S84852 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Perucca P, Scheffer IE, Kiley M. The management of epilepsy in children and adults. Med J Aust. 2018;208(5):226–33. https://doi.org/10.5694/mja17.00951 .

Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011;10(5):446–56. https://doi.org/10.1016/S1474-4422(11)70047-3 .

Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI, et al. Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239–76. https://doi.org/10.1111/j.1528-1167.2008.01561.x .

Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord. 2014;16(4):409–31. https://doi.org/10.1684/epd.2014.0714 .

Schmidt D. Drug treatment strategies for epilepsy revisited: starting early or late? One drug or several drugs? Epileptic Disord. 2016;18(4):356–66. https://doi.org/10.1684/epd.2016.0882 .

Lamberink HJ, Otte WM, Geerts AT, Pavlovic M, Ramos-Lizana J, Marson AG, et al. Individualised prediction model of seizure recurrence and long-term outcomes after withdrawal of antiepileptic drugs in seizure-free patients: a systematic review and individual participant data meta-analysis. Lancet Neurol. 2017;16(7):523–31. https://doi.org/10.1016/S1474-4422(17)30114-X .

Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369(9566):1000–15. https://doi.org/10.1016/S0140-6736(07)60460-7 .

Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet. 2007b;369(9566):1016–26. https://doi.org/10.1016/S0140-6736(07)60461-9 .

Marson A, Burnside G, Appleton R, Smith D, Leach JP, Sills G, et al. The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet. 2021;397(10282):1363–74. https://doi.org/10.1016/S0140-6736(21)00247-6 .

Marson A, Burnside G, Appleton R, Smith D, Leach JP, Sills G, et al. The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial. Lancet. 2021;397(10282):1375–86. https://doi.org/10.1016/S0140-6736(21)00246-4 .

Gesche J, Khanevski M, Solberg C, Beier CP. Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies. Epilepsia. 2017;58(4):e64–9. https://doi.org/10.1111/epi.13702 .

Meador K. Teratogenicity and antiseizure medications. Epilepsy Curr. 2020;20(6_suppl):15S–7S.

Article   Google Scholar  

Tomson T, Battino D, Perucca E. Teratogenicity of antiepileptic drugs. Curr Opin Neurol. 2019;32(2):246–52. https://doi.org/10.1097/WCO.0000000000000659 .

Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, et al. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17(6):530–8. https://doi.org/10.1016/S1474-4422(18)30107-8 .

Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, et al. Declining malformation rates with changed antiepileptic drug prescribing: an observational study. Neurology. 2019;93(9):e831–40. https://doi.org/10.1212/WNL.0000000000008001 .

Steinhoff BJ, Staack AM. Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience. Ther Adv Neurol Disord. 2019;12:1756286419873518.

Subramonian A, Farrah K. Brivaracetam versus levetiracetam for epilepsy: a review of comparative clinical safety: Canadian Agency for Drugs and Technologies in Health, Ottawa, Ontario, Canada; 2020. Available at: https://cadth.ca/sites/default/files/pdf/htis/2020/RC1322%20Comparing%202%20Antiepileptic%20Drugs%20Final.pdf (accessed June 8, 2021)

Löscher W, Sills GJ, White HS. The ups and downs of alkyl-carbamates in epilepsy therapy: how does cenobamate differ? Epilepsia. 2021;62(3):596–614. https://doi.org/10.1111/epi.16832 .

Roberti R, De Caro C, Iannone LF, Zaccara G, Lattanzi S, Russo E. Pharmacology of cenobamate: Mechanism of action, pharmacokinetics, drug-drug interactions and tolerability. CNS Drugs. 2021. https://doi.org/10.1007/s40263-021-00819-8 (online ahead of print).

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(1):38–48. https://doi.org/10.1016/S1474-4422(19)30399-0 .

Vossler DG. Remarkably high efficacy of cenobamate in adults with focal-onset seizures: a double-blind, randomized, placebo-controlled trial. Epilepsy Curr. 2020;20(2):85–7. https://doi.org/10.1177/1535759720903032 .

Article   PubMed   PubMed Central   Google Scholar  

Franco V, Bialer M, Perucca E. Cannabidiol in the treatment of epilepsy: current evidence and perspectives for further research. Neuropharmacology. 2021;185:108442. https://doi.org/10.1016/j.neuropharm.2020.108442 .

Bialer M, Perucca E. Does cannabidiol have antiseizure activity independent of its interactions with clobazam? An appraisal of the evidence from randomized controlled trials. Epilepsia. 2020;61(6):1082–9. https://doi.org/10.1111/epi.16542 .

Ceulemans B, Schoonjans AS, Marchau F, Paelinck BP, Lagae L. Five-year extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine. Epilepsia. 2016;57(7):e129–34. https://doi.org/10.1111/epi.13407 .

Odi R, Invernizzi RW, Gallily T, Bialer M, Perucca E. Fenfluramine repurposing from weight loss to epilepsy: what we do and do not know. Pharmacol Ther. 2021;226:107866. https://doi.org/10.1016/j.pharmthera.2021.107866 .

Bialer M, Johannessen SI, Koepp MJ, Levy RH, Perucca E, Perucca P, et al. Progress report on new antiepileptic drugs: a summary of the fifteenth Eilat conference on new antiepileptic drugs and devices (EILAT XV). II. Drugs in more advanced clinical development. Epilepsia. 2020;61(11):2365–85. https://doi.org/10.1111/epi.16726 .

Overwater IE, Rietman AB, van Eeghen AM, de Wit MCY. Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives. Ther Clin Risk Manag. 2019;15:951–5. https://doi.org/10.2147/TCRM.S145630 .

French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056):2153–63. https://doi.org/10.1016/S0140-6736(16)31419-2 .

Fedak Romanowski EM, McNamara NA, Neil EE, Gottlieb-Smith R, Dang LT. Seizure rescue medications for out-of-hospital use in children. J Pediatr. 2021;229:19–25. https://doi.org/10.1016/j.jpeds.2020.10.041 .

Bouw MR, Chung SS, Gidal B, King A, Tomasovic J, Wheless JW, et al. Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray. Epilepsy Res. 2021;171:106567. https://doi.org/10.1016/j.eplepsyres.2021.106567 .

Boddu SHS, Kumari S. A short review on the intranasal delivery of diazepam for treating acute repetitive seizures. Pharmaceutics. 2020;12(12):1167. https://doi.org/10.3390/pharmaceutics12121167 .

Article   CAS   Google Scholar  

Gidal B, Klein P, Hirsch LJ. Seizure clusters, rescue treatments, seizure action plans: unmet needs and emerging formulations. Epilepsy Behav. 2020;112:107391. https://doi.org/10.1016/j.yebeh.2020.107391 .

Fesler JR, Stanton S, Merner K, Ross L, McGinley MP, Bena J, et al. Bridging the gap in epilepsy care: a single-center experience of 3700 outpatient tele-epilepsy visits. Epilepsia. 2020;61(8):e95–e100. https://doi.org/10.1111/epi.16619 .

Alzamanan MZ, Lim KS, Akmar Ismail M, Abdul GN. Self-management apps for people with epilepsy: systematic analysis. JMIR Mhealth Uhealth. 2021;9(5):e22489. https://doi.org/10.2196/22489 .

Patterson V. The development of a smartphone application to help manage epilepsy in resource-limited settings. Seizure. 2020;79:69–74. https://doi.org/10.1016/j.seizure.2020.03.020 .

Giuliano L, Cicero CE, Trimarchi G, Todaro V, Colli C, Crespo Gómez EB, et al. Usefulness of a smartphone application for the diagnosis of epilepsy: validation study in high-income and rural low-income countries. Epilepsy Behav. 2021;115:107680. https://doi.org/10.1016/j.yebeh.2020.107680 .

Asadi-Pooya AA, Beniczky S, Rubboli G, Sperling MR, Rampp S, Perucca E. A pragmatic algorithm to select appropriate antiseizure medications in patients with epilepsy. Epilepsia. 2020;61(8):1668–77. https://doi.org/10.1111/epi.16610 .

Beniczky S, Rampp S, Asadi-Pooya AA, Rubboli G, Perucca E, Sperling MR. Optimal choice of antiseizure medication: agreement among experts and validation of a web-based decision support application. Epilepsia. 2021;62(1):220–7. https://doi.org/10.1111/epi.16763 .

Hadady L, Klivényi P, Asadi-Pooya AA, Rampp S, Fabó D, Bereczki C, et al. Web-based decision support system for patient-tailored selection of antiseizure treatment medication in adolescents and adults: An external validation study. 2021 (submitted).

Google Scholar  

de Jong J, Cutcutache I, Page M, Elmoufti S, Dilley C, Fröhlich H, et al. Towards realizing the vision of precision medicine: AI based prediction of clinical drug response. Brain. 2021:awab108. https://doi.org/10.1093/brain/awab108 Online ahead of print.

Beniczky S, Wiebe S, Jeppesen J, Tatum WO, Brazdil M, Wang Y, et al. Automated seizure detection using wearable devices: a clinical practice guideline of the international league against epilepsy and the International Federation of Clinical Neurophysiology. Epilepsia. 2021;62(3):632–46. https://doi.org/10.1111/epi.16818 .

Rasheed K, Qayyum A, Qadir J, Sivathamboo S, Kwan P, Kuhlmann L, et al. Machine learning for predicting epileptic seizures using EEG signals: a review. IEEE Rev Biomed Eng. 2021;14:139–55. https://doi.org/10.1109/RBME.2020.3008792 .

Perucca P, Bahlo M, Berkovic SF. The genetics of epilepsy. Annu Rev Genomics Hum Genet. 2020;21(1):205–30. https://doi.org/10.1146/annurev-genom-120219-074937 .

Daci A, Bozalija A, Jashari F, Krasniqi S. Individualizing treatment approaches for epileptic patients with glucose transporter Type1 (GLUT-1) deficiency. Int J Mol Sci. 2018;19(1):122. https://doi.org/10.3390/ijms19010122 .

Article   CAS   PubMed Central   Google Scholar  

Perucca P, Perucca E. Identifying mutations in epilepsy genes: impact on treatment selection. Epilepsy Res. 2019;152:18–30. https://doi.org/10.1016/j.eplepsyres.2019.03.001 .

Specchio N, Pietrafusa N, Perucca E, Cross JH. New paradigms for the treatment of pediatric monogenic epilepsies: progressing toward precision medicine. Epilepsy Behav. 2021:107961. https://doi.org/10.1016/j.yebeh.2021.107961 Online ahead of print.

Byrne S, Enright N, Delanty N. Precision therapy in the genetic epilepsies of childhood. Dev Med Child Neurol. 2021. https://doi.org/10.1111/dmcn.14929 Online ahead of print.

Atkin TA, Maher CM, Gerlach AC, Gay BC, Antonio BM, Santos SC, et al. A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy. Epilepsia. 2018;59(4):802–13. https://doi.org/10.1111/epi.14037 .

Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72(3):606–38. https://doi.org/10.1124/pr.120.019539 .

Peng J, Pang N, Wang Y, Wang X-L, Chen J, Xiong J. Next-generation sequencing improves treatment efficacy and reduces hospitalization in children with drug-resistant epilepsy. CNS Neurosci Ther. 2019;25(1):14–20. https://doi.org/10.1111/cns.12869 .

Balestrini S, Chiarello D, Gogou M, Silvennoinen K, Puvirajasinghe C, Jones WD, et al. Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies. J Neurol Neurosurg Psychiatry. 2021:jnnp-2020-325932. https://doi.org/10.1136/jnnp-2020-325932 Online ahead of print.

Kobylarek D, Iwanowski P, Lewandowska Z, Limphaibool N, Szafranek S, Labrzycka A, et al. Advances in the potential biomarkers of epilepsy. Front Neurol. 2019;10:685. https://doi.org/10.3389/fneur.2019.00685 .

Engel J Jr, Pitkänen A. Biomarkers for epileptogenesis and its treatment. Neuropharmacology. 2020;167:107735. https://doi.org/10.1016/j.neuropharm.2019.107735 .

Chang CJ, Chen CB, Hung SI, Ji C, Chung WH. Pharmacogenetic testing for prevention of severe cutaneous adverse drug reactions. Front Pharmacol. 2020;11:969. https://doi.org/10.3389/fphar.2020.00969 .

Simonato M, Agoston DV, Brooks-Kayal A, Dulla C, Fureman B, Henshall DC, et al. Identification of clinically relevant biomarkers of epileptogenesis - a strategic roadmap. Nat Rev Neurol. 2021;17(4):231–42. https://doi.org/10.1038/s41582-021-00461-4 .

Galanopoulou AS, Löscher W, Lubbers L, O'Brien TJ, Staley K, Vezzani A, et al. Antiepileptogenesis and disease modification: Progress, challenges, and the path forward-report of the preclinical working group of the 2018 NINDS-sponsored antiepileptogenesis and disease modification workshop. Epilepsia Open. 2021;6(2):276–96. https://doi.org/10.1002/epi4.12490 .

Kearney H, Byrne S, Cavalleri GL, Delanty N. Tackling epilepsy with high-definition precision medicine: a review. JAMA Neurol. 2019;76(9):1109–16. https://doi.org/10.1001/jamaneurol.2019.2384 .

Klein P, Friedman A, Hameed MQ, Kaminski RM, Bar-Klein G, Klitgaard H, et al. Repurposed molecules for antiepileptogenesis: missing an opportunity to prevent epilepsy? Epilepsia. 2020;61(3):359–86. https://doi.org/10.1111/epi.16450 .

Han Z, Chen C, Christiansen A, Ji S, Lin Q, Anumonwo C, et al. Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Sci Transl Med. 2020;12(558):eaaz6100.

Ahonen S, Nitschke S, Grossman TR, Kordasiewicz H, Wang P, Zhao X, et al. Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease. Brain. 2021:awab194. https://doi.org/10.1093/brain/awab194 Online ahead of print.

Higurashi N, Broccoli V, Hirose S. Genetics and gene therapy in Dravet syndrome. Epilepsy Behav. 2021:108043. https://doi.org/10.1016/j.yebeh.2021.108043 Online ahead of print.

Cook M, Murphy M, Bulluss K, D'Souza W, Plummer C, Priest E, et al. Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: a first-in-man study. EClinicalMedicine. 2020;22:100326. https://doi.org/10.1016/j.eclinm.2020.100326 .

Löscher W. The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments. Neuropharmacology. 2020;167:107605. https://doi.org/10.1016/j.neuropharm.2019.04.011 .

Rahman MH, Akter R, Kamal MA. Prospective function of different antioxidant containing natural products in the treatment of neurodegenerative disease. CNS Neurol Disord drug targets 2020 Jul 22. Doi: https://doi.org/10.2174/1871527319666200722153611 . Online ahead of print.

Leavy A, Jimenez Mateos EM. Perinatal brain injury and inflammation: lessons from experimental murine models. Cells. 2020;9(12):2640. https://doi.org/10.3390/cells9122640 .

Yang N, Guan QW, Chen FH, Xia QX, Yin XX, Zhou HH, et al. Antioxidants targeting mitochondrial oxidative stress: promising neuroprotectants for epilepsy. Oxidative Med Cell Longev. 2020:6687185. https://doi.org/10.1155/2020/6687185 .

Zavala-Tecuapetla C, Cuellar-Herrera M, Luna-Munguia H. Insights into potential targets for therapeutic intervention in epilepsy. Int J Mol Sci. 2020;21(22):8573. https://doi.org/10.3390/ijms21228573 .

Frajewicki A, Laštůvka Z, Borbélyová V, Khan S, Jandová K, Janišová K, et al. Perinatal hypoxic-ischemic damage: review of the current treatment possibilities. Physiol Res. 2020;69(Suppl 3):S379–401. https://doi.org/10.33549/physiolres.934595 .

Murugan M, Boison D. Ketogenic diet, neuroprotection, and antiepileptogenesis. Epilepsy Res. 2020;167:106444. https://doi.org/10.1016/j.eplepsyres.2020.106444 .

Stone NL, Murphy AJ, England TJ, O'Sullivan SE. A systematic review of minor phytocannabinoids with promising neuroprotective potential. Br J Pharmacol. 2020;177(19):4330–52. https://doi.org/10.1111/bph.15185 .

Sanz P, Serratosa JM, Sánchez MP. Beneficial effects of metformin on the central nervous system, with a focus on epilepsy and Lafora disease. Int J Mol Sci. 2021;22(10):5351. https://doi.org/10.3390/ijms22105351 .

Tesfaye BA, Hailu HG, Zewdie KA, Ayza MA, Berhe DF. Montelukast: the new therapeutic option for the treatment of epilepsy. J Exp Pharmacol. 2021;13:23–31. https://doi.org/10.2147/JEP.S277720 .

Kotulska K, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, Jansen F, et al. Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP trial. Ann Neurol. 2021;89(2):304–14. https://doi.org/10.1002/ana.25956 .

Franco V, French JA, Perucca E. Challenges in the clinical development of new antiepileptic drugs. Pharmacol Res. 2016;103:95–104. https://doi.org/10.1016/j.phrs.2015.11.007 .

Download references

Acknowledgments

This article was not supported by any funding source.

Author information

Authors and affiliations.

Department of Internal Medicine and Therapeutics, Division of Clinical and Experimental Pharmacology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy

Emilio Perucca

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, 3004, Australia

You can also search for this author in PubMed   Google Scholar

Contributions

The author was solely responsible for the conception and preparation of this article. The author read and approved the final manuscript.

Corresponding author

Correspondence to Emilio Perucca .

Ethics declarations

Ethics approval and consent to participate, consent for publication.

The author gave consent for publication of this article.

Competing interests

The author received speaker’s or consultancy fees from Angelini-Arvelle, Biogen, Eisai, GW Pharma, Sanofi, Sun Pharma, UCB Pharma, Xenon Pharma and Zogenix.

Additional information

This article is dedicated to the memory of Professor Alan Richens (1938–2021), my mentor and dear friend, in recognition of his outstanding contribution to advancing the pharmacological treatment of epilepsy.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Perucca, E. The pharmacological treatment of epilepsy: recent advances and future perspectives. Acta Epileptologica 3 , 22 (2021). https://doi.org/10.1186/s42494-021-00055-z

Download citation

Received : 28 June 2021

Accepted : 30 July 2021

Published : 17 September 2021

DOI : https://doi.org/10.1186/s42494-021-00055-z

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Drug therapy
• Antiepileptic drugs
• Antiseizure medications

Acta Epileptologica

ISSN: 2524-4434

• Submission enquiries: Access here and click Contact Us

• Skip to main content
• Keyboard shortcuts for audio player

• LISTEN & FOLLOW
• Apple Podcasts
• Google Podcasts
• Amazon Music
• Amazon Alexa

Your support helps make our show possible and unlocks access to our sponsor-free feed.

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.

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts

Epilepsy articles within Nature Reviews Neurology

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

EAN VIRTUAL 2020 — THE LARGEST NEUROLOGY CONFERENCE IN HISTORY

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.

News & Views | 04 December 2018

How safe is switching antiepileptic drug manufacturers?

A nationwide German study of prescription data has demonstrated that switching to an antiepileptic drug from a different manufacturer increases the risk of seizure relapse. This finding sparks a debate about the reason for seizure worsening after switching and whether or not it is a pharmacological issue.

• Martin Holtkamp

Review Article | 19 November 2018

POLG -related disorders and their neurological manifestations

Pathogenic variants in POLG , which encodes the catalytic subunit of DNA polymerase γ, cause a spectrum of overlapping disease phenotypes. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG -related disorders, focusing particularly on the neurological manifestations.

• Shamima Rahman
•  &  William C. Copeland

Review Article | 17 November 2018

From molecules to medicines: the dawn of targeted therapies for genetic epilepsies

New technological advances in genomics have enabled the rapid discovery of hundreds of gene mutations linked to epilepsy. This Review considers the prospects for precision medicine in genetic epilepsies, the use of conventional and novel experimental models to unpick the complex pathogenic mechanisms of these diseases and the opportunities and challenges that face basic and clinical researchers.

• Scott T. Demarest
•  &  Amy Brooks-Kayal

Browse broader subjects

• Neurological disorders
• Diseases of the nervous system

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

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: Image 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 . Image 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 . Image 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. Image 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. Image 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

Related Topics  PANAChE Database 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. Epilepsy Therapy Screening Program (ETSP) 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: Interagency Collaborative to Advance Research in Epilepsy ICARE provides an interagency forum for sharing information about ongoing and planned epilepsy research activities. Epilepsy Common Data Elements 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 Epilepsy Research Connection (ERC) The ERC provides information about grant and funding opportunities from non-profit and government organizations focused on epilepsy related research.

• Our Mission
• Become a Partner
• Our Partners
• Impact Reports
• Grants Awarded
• Epilepsy Genetics
• Infantile Spasms
• Post-Traumatic Epilepsy
• EEM / Jeavons Syndrome

Epilepsy News

• CURE Epilepsy in the News
• Seizing Life Podcast
• Epilepsy Explained
• CURE EPILEPSY CARES
• Personal Stories
• UNITE to CURE Epilepsy 2023
• CURE Epilepsy’s 25th Anniversary Gala
• Attend an Event
• Host An Event
• How to donate
• Monthly giving
• Tribute gifts
• Major gifts
• Online giving
• Corporate giving
• Planned giving
• Stock donations
• Matching Gifts
• Workplace giving
• Say the Word #SayEpilepsy
• What is Epilepsy?
• What causes epilepsy?
• What is a Seizure?
• Seizure Classification
• Phases of Seizures
• Risks Associated with Epilepsy
• Diagnosis and Therapies
• Medication Access
• How is epilepsy diagnosed?
• Diagnostic Tests
• Other Diagnostic Tests
• Epilepsy Syndromes
• Adults and Pediatric Patients
• Epilepsy Medications
• Epilepsy Surgery
• Dietary Therapies
• Alternative Therapies
• Neurostimulation Devices
• Seizure Action Plan
• Clinical Trials
• Patient Opportunities
• COVID-19 and Epilepsy
• Epilepsy Centers
• Grants Program
• Research Resources
• CURE Epilepsy-Sponsored Conferences
• Researcher Updates

March 11, 2024

Cure epilepsy discovery: fcd genes in epilepsy, one piece of the mosaic.

2017 CURE Epilepsy grantee Dr. Jack Parent and his team designed a novel system using human neurons grown in a dish to discover the genes behind focal cortical dysplasia (FCD), a common cause of intractable epilepsy.

December 22, 2023

Cure epilepsy update december 2023.

An Update full of events and the latest updates for the epilepsy community!

• CURE Epilepsy Discovery
• Press Release
• Publication

Filter By Topic

• Clinical Trial
• Drug Resistant/Refractory Epilepsy
• Focal Epilepsy
• Human Interest
• Ketogenic Diet
• Pediatric Epilepsy
• Rare Epilepsies
• Temporal Lobe Epilepsy

April 15, 2024

Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy (pte).

Featuring work of CURE Grantees Drs. Michelle Olsen and Michelle Theus. This work supports the ideas that astrocytes play a vital role in the progression of epileptogenesis following TBI.

Praxis Precision Medicines Reports Positive Results of PRAX-628 Study Evaluating Photo Paroxysmal Response (PPR) Achieving 100% Response in Treated Patients

“With such a clear response, we have advanced our planning of the focal epilepsy efficacy study for PRAX-628, expected to begin in the second half of 2024. We extend our thanks to the patients who participated in this PPR study,”

Study Reveals Key Mechanisms of a Rare Form of Epilepsy

This study reveals that the presence of KCNQ2 G256W variants affects both molecular and cellular aspects of KCNQ channel activity, including their ion-carrying capacity, expression, and placement within cells.

New Method Developed for Triggering and Imaging Seizures in Epilepsy Patients

Featuring work from CURE Epilepsy Grantee Dr. Maxime O. Baud. Researchers have developed a new method for triggering and imaging seizures in epilepsy patients, offering physicians the ability to collect real-time data to tailor epilepsy surgery.

March 19, 2024

Genotype–phenotype associations in individuals with scn1a-related epilepsies.

Understanding genotype–phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management.

Study Data on Lacosamide and Pregnancy

Most pregnancies with LCM exposure resulted in healthy live births, and no new medication concerns were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.

Patterns Across Epilepsy Syndromes Study

These findings highlight the cerebellum as a potential target for therapeutic intervention in epilepsy and underscore the importance of incorporating the cerebellum into neurobiological models of epilepsy. 

Study Looks at the Burden of Illness of Lennox–Gastaut Syndrome on Patients, Caregivers, and Society

A high burden of LGS on individuals, caregivers, and healthcare systems was identified. The burden may be alleviated by reducing the clinical symptoms.

Epilepsy and the Risk of COVID-19-Related Hospitalization and Death

Study results may have implications for prioritizing future COVID-19 treatments and vaccinations for people with epilepsy. The study shows the importance of characterizing this risk to inform patients and for future health and care planning.

Post-Traumatic Epilepsy Associated with Long-Term Dementia Risk

Dementia risk was significantly higher with PTE than with epilepsy/seizure or head injury alone. These results highlight the significance of prevention of head injuries and PTE following these injuries.

February 14, 2024

Death rate higher than expected for patients with functional, nonepileptic seizures.

The death rate for patients with functional, nonepileptic seizures is higher than expected, with a rate comparable to epilepsy and severe mental illness, a Michigan Medicine-led study finds.

Specialists in the Department of Neurology evaluate and treat more than 7,000 people with epilepsy annually, including medical and surgical care for both common and complex problems in children with epilepsy. Multidisciplinary teams work together to find root etiology of epilepsy — whether genetic, structural, autoimmune or neurometabolic — and manage complex cases with pharmacological and nonpharmacological options including surgery, ketogenic diet, and neuromodulation or brain stimulation therapies.

A number of ongoing research endeavors and clinical trials are underway at Mayo Clinic to improve treatment for patients with epilepsy. Efforts include improved imaging techniques, stereotactic minimally invasive laser surgery, intraoperative functional brain mapping, and neuromodulation and brain stimulation for drug-resistant epilepsy. These efforts, among others, are leading to the next generation of epilepsy management.

As a part of the Epilepsy Subspecialty Group, Mayo Clinic neurologists are also researchers and educators. New diagnostic and treatment options include inpatient monitoring and state-of-the art imaging protocols to improve identification of seizure type and localization of seizure focus. Ongoing research includes studying causes, potential diagnostic tests and potential treatments for epilepsy, including medications and electrical brain stimulation, and conducting clinical trials.

Collaborative research

In collaboration with the Center for Multiple Sclerosis and Autoimmune Neurology , the Department of Neurology has made groundbreaking progress on epilepsy and it continues rigorous efforts toward more scientific discoveries.

Faculty members collaborating on basic and clinical research related to epilepsy include:

• Benjamin (Ben) H. Brinkmann, Ph.D.
• Jeffrey W. Britton, M.D.
• David B. Burkholder, M.D.
• Gregory D. Cascino, M.D.
• Amy Z. Crepeau, M.D.
• Joseph F. Drazkowski, M.D.
• Cornelia N. Drees, M.D.
• Anteneh M. Feyissa, M.D.
• Nicholas (Nick) M. Gregg, M.D.
• Dora Hermes Miller, Ph.D.
• Matthew T. Hoerth, M.D.
• Charles L. Howe, Ph.D. — Translational Neuroimmunology Laboratory
• Terrence D. Lagerlund, M.D., Ph.D.
• Alfonso (Sebastian) S. Lopez Chiriboga, M.D.
• Brian N. Lundstrom, M.D., Ph.D.
• Katherine C. Nickels, M.D.
• Katherine H. Noe, M.D., Ph.D.
• Erik K. St Louis, M.D.
• Steven M. Sine, Ph.D. — Receptor Biology Laboratory
• Joseph I. Sirven, M.D.
• Elson So, M.D.
• William Tatum, D.O.
• Elaine C. Wirrell, M.D.
• Lily C. Wong-Kisiel, M.D.
• Gregory A. Worrell, M.D., Ph.D. — Bioelectronics Neurophysiology and Engineering Lab
• LongJun (Long-Jun) Wu, Ph.D. — Neuroimmune Interaction in Health and Disease Laboratory
• Paul E. Youssef, D.O.

Contact the Department of Neurology at Mayo Clinic for information about collaboration or educational opportunities in epilepsy and seizures research.

• Contact Contact
• Appointments at Mayo Clinic - Contact Appointments at Mayo Clinic
• Clinical Trials

Learn about current clinical trials in epilepsy.

The Bioelectronics Neurophysiology and Engineering Lab uses electrophysiological analysis to improve diagnosis and treatments of epilepsy and seizure disorders.

Collaborators

Researchers in the Department of Neurology work collaboratively with investigators in other Mayo Clinic departments.

• Tanya M. Brown, Ph.D., L.P.
• Fredric B. Meyer, M.D.
• Kai J. Miller, M.D., Ph.D.
• Jamie J. Van Gompel, M.D.

More about research at Mayo Clinic

• Research Faculty
• Laboratories
• Core Facilities
• Centers & Programs
• Departments & Divisions
• Institutional Review Board
• Postdoctoral Fellowships
• Training Grant Programs
• Publications

Mayo Clinic Footer

• Request Appointment
• About Mayo Clinic
• About This Site

Legal Conditions and Terms

• Terms and Conditions
• Privacy Policy
• Notice of Privacy Practices
• Notice of Nondiscrimination
• Manage Cookies

Advertising

Mayo Clinic is a nonprofit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any of the third party products and services advertised.

• Advertising and sponsorship policy
• Advertising and sponsorship opportunities

Reprint Permissions

A single copy of these materials may be reprinted for noncommercial personal use only. "Mayo," "Mayo Clinic," "MayoClinic.org," "Mayo Clinic Healthy Living," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education and Research.

• Alzheimer's disease & dementia
• Arthritis & Rheumatism
• Attention deficit disorders
• Autism spectrum disorders
• Biomedical technology
• Diseases, Conditions, Syndromes
• Endocrinology & Metabolism
• Gastroenterology
• Gerontology & Geriatrics
• Health informatics
• Inflammatory disorders
• Medical economics
• Medical research
• Medications
• Neuroscience
• Obstetrics & gynaecology
• Oncology & Cancer
• Ophthalmology
• Overweight & Obesity
• Parkinson's & Movement disorders
• Psychology & Psychiatry
• Radiology & Imaging
• Sleep disorders
• Sports medicine & Kinesiology
• Vaccination
• Breast cancer
• Cardiovascular disease
• Chronic obstructive pulmonary disease
• Colon cancer
• Coronary artery disease
• Heart attack
• Heart disease
• High blood pressure
• Kidney disease
• Lung cancer
• Multiple sclerosis
• Myocardial infarction
• Ovarian cancer
• Post traumatic stress disorder
• Rheumatoid arthritis
• Schizophrenia
• Skin cancer
• Type 2 diabetes
• Full List »

share this!

April 26, 2024

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

Gene linked to epilepsy and autism decoded in new study

by Kristin Samuelson, Northwestern University

A genetic change or variant in a gene called SCN2A is a known cause of infantile seizures, autism spectrum disorder, and intellectual disability, as well as a wide range of other moderate-to-profound impairments in mobility, communication, eating, and vision.

The severity of these disorders can vary widely from person to person, but little is known about what is happening at the level of the SCN2A protein to cause these differences.

A new Northwestern Medicine study helps explain how changes in the SCN2A gene affect whether or not a child will develop autism or epilepsy, the age at which seizures start for those with epilepsy, and the severity of the child's other impairments.

The study is published in Brain .

These findings will help better identify patients who are most appropriate for clinical trials of new precision therapies, including those targeting the SCN2A gene itself.

Analyzing sodium channels

The study represents a collaboration between an academic laboratory at Northwestern and the FamilieSCN2A Foundation, a parent-led rare disease advocacy group. The SCN2A Clinical Trials Readiness Study (SCN2A-CTRS) recruited 81 families from around the world and collected detailed clinical data and information to identify their SCN2A variants. The median age was 5.4 years. The youngest age participant was 1 month old and the oldest was 29 years old.

The Northwestern team extensively analyzed the functional effects of each SCN2A variant on the sodium channels —tiny gates in the membranes of nerve cells that control the flow of sodium ions into the cell and help neurons in the brain fire properly. Variants in the SCN2A gene alter how the sodium channel functions.

Depending on the individual variant , the channel may be hyperactive (sodium ions flowing more freely) or completely inactive (the channel not working at all). There are variants that make the channel work in ways that are more complex.

The study found a spectrum of effects of the SCN2A variants on sodium channel function, from hyperactive channels to completely inactive channels. Importantly, the clinical condition of the child varied with the functional impact on the channel.

Hyperactive channels were generally associated with seizure onset in the first week of life. More impaired channel function was more common when the age of seizure onset was older. In fact, almost all of those without seizures had completely inactive sodium channels.

The severity of other disease-related features also followed this gradient with those most severely impaired (unable to walk, communicate, eat, use their hands), having the youngest age at seizure onset, and hyperactive channels. As age at seizures-onset increased and channels became less active, severe neurological impairments in the child tended to be less severe.

"We previously knew that genetic changes in the SCN2A gene were associated with seizures beginning as early as the newborn period and up through the first few years of life," said co-corresponding author Dr. Alfred George, chair of pharmacology at Northwestern University Feinberg School of Medicine. "We had an overly simplistic understanding of these associations.

"Our new study clarifies the relationship between the functional consequences of SCN2A mutations, the primary phenotype (autism versus epilepsy and age at seizure onset in those with epilepsy), and the overall severity of the child's impairments (mobility, etc.)."

Findings challenge prevalent understanding

There is a prevalent understanding among scientists that early-onset seizures are associated only with hyperactive sodium channels, and underactive or inactive channels are associated with autism, George said. However, it's more complicated, and children with early onset—in the first three months but after the immediate newborn period—don't have hyperactive channels.

"This is important because new precision medicines that are best suited for hyperactive SCN2A variants could be harmful to those with underactive or inactive variants," George said. "Relying only on the age of seizure onset as a criterion for clinical trial enrollment risks inclusion of inappropriate patients."

Dr. Anne Berg, adjunct professor of neurology at Feinberg, lead investigator of the SCN2A-CTRS and the co-corresponding study author, emphasized that "in the era of precision medicine for rare genetic diseases, this collaboration between a family foundation and a large NIH-funded project is an exemplar of the new partnerships that are needed and increasingly being developed to provide rapid answers to critical questions and lay foundation for successful drug development for severe neurodevelopmental disorders such as those associated with SCN2A."

Explore further

Feedback to editors

Research shows 'profound' link between dietary choices and brain health

Apr 27, 2024

Component of keto diet plus immunotherapy may reduce prostate cancer

Study finds big jump in addiction treatment at community health clinics

Positive childhood experiences can boost mental health and reduce depression and anxiety in teens

Blood test finds knee osteoarthritis up to eight years before it appears on X-rays

Apr 26, 2024

Researchers find pregnancy cytokine levels impact fetal brain development and offspring behavior

Study finds biomarkers for psychiatric symptoms in patients with rare genetic condition 22q

Clinical trial evaluates azithromycin for preventing chronic lung disease in premature babies

Scientists report that new gene therapy slows down amyotrophic lateral sclerosis disease progression

Using stem cell-derived heart muscle cells to advance heart regenerative therapy

Related stories.

A simple eye reflex test may be able to assess autism in children

Feb 28, 2024

Researchers provide complete clinical landscape for gene linked to epilepsy and autism

Mar 17, 2021

Researchers reveal a possible new pathway for treating epileptic seizures in patients with autism

Sep 14, 2021

Unique brain channel combats epileptic seizures

Dec 3, 2021

'Missing mutation' found in severe infant epilepsy

Mar 20, 2018

New genetic variants linked to brain malformation

Aug 17, 2023

Recommended for you

People with rare longevity mutation may also be protected from cardiovascular disease

Analysis identifies 50 new genomic regions associated with kidney cancer risk

Study finds RNA modification is responsible for disruption of mitochondrial protein synthesis in Alzheimer's disease

Apr 25, 2024

Blocking gene may halt growth of breast cancer cells

Let us know if there is a problem with our content.

Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form . For general feedback, use the public comments section below (please adhere to guidelines ).

Please select the most appropriate category to facilitate processing of your request

Thank you for taking time to provide your feedback to the editors.

Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages.

E-mail the story

Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Medical Xpress in any form.

Newsletter sign up

Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties.

More information Privacy policy

Donate and enjoy an ad-free experience

We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account.

E-mail newsletter

Robotic nerve 'cuffs' could help treat a range of neurological conditions

Researchers have developed tiny, flexible devices that can wrap around individual nerve fibres without damaging them.

The researchers, from the University of Cambridge, combined flexible electronics and soft robotics techniques to develop the devices, which could be used for the diagnosis and treatment of a range of disorders, including epilepsy and chronic pain, or the control of prosthetic limbs.

Current tools for interfacing with the peripheral nerves -- the 43 pairs of motor and sensory nerves that connect the brain and the spinal cord -- are outdated, bulky and carry a high risk of nerve injury. However, the robotic nerve 'cuffs' developed by the Cambridge team are sensitive enough to grasp or wrap around delicate nerve fibres without causing any damage.

Tests of the nerve cuffs in rats showed that the devices only require tiny voltages to change shape in a controlled way, forming a self-closing loop around nerves without the need for surgical sutures or glues.

The researchers say the combination of soft electrical actuators with neurotechnology could be an answer to minimally invasive monitoring and treatment for a range of neurological conditions. The results are reported in the journal Nature Materials .

Electric nerve implants can be used to either stimulate or block signals in target nerves. For example, they might help relieve pain by blocking pain signals, or they could be used to restore movement in paralysed limbs by sending electrical signals to the nerves. Nerve monitoring is also standard surgical procedure when operating in areas of the body containing a high concentration of nerve fibres, such as anywhere near the spinal cord.

These implants allow direct access to nerve fibres, but they come with certain risks. "Nerve implants come with a high risk of nerve injury," said Professor George Malliaras from Cambridge's Department of Engineering, who led the research. "Nerves are small and highly delicate, so anytime you put something large, like an electrode, in contact with them, it represents a danger to the nerves."

"Nerve cuffs that wrap around nerves are the least invasive implants currently available, but despite this they are still too bulky, stiff and difficult to implant, requiring significant handling and potential trauma to the nerve," said co-author Dr Damiano Barone from Cambridge's Department of Clinical Neurosciences.

The researchers designed a new type of nerve cuff made from conducting polymers, normally used in soft robotics. The ultra-thin cuffs are engineered in two separate layers. Applying tiny amounts of electricity -- just a few hundred millivolts -- causes the devices to swell or shrink.

The cuffs are small enough that they could be rolled up into a needle and injected near the target nerve. When activated electrically, the cuffs will change their shape to wrap around the nerve, allowing nerve activity to be monitored or altered.

"To ensure the safe use of these devices inside the body, we have managed to reduce the voltage required for actuation to very low values," said Dr Chaoqun Dong, the paper's first author. "What's even more significant is that these cuffs can change shape in both directions and be reprogrammed. This means surgeons can adjust how tightly the device fits around a nerve until they get the best results for recording and stimulating the nerve."

Tests in rats showed that the cuffs could be successfully placed without surgery, and they formed a self-closing loop around the target nerve. The researchers are planning further testing of the devices in animal models, and are hoping to begin testing in humans within the next few years.

"Using this approach, we can reach nerves that are difficult to reach through open surgery, such as the nerves that control, pain, vision or hearing, but without the need to implant anything inside the brain," said Barone. "The ability to place these cuffs so they wrap around the nerves makes this a much easier procedure for surgeons, and it's less risky for patients."

"The ability to make an implant that can change shape through electrical activation opens up a range of future possibilities for highly targeted treatments," said Malliaras. "In future, we might be able to have implants that can move through the body, or even into the brain -- it makes you dream how we could use technology to benefit patients in future."

The research was supported in part by the Swiss National Science Foundation, the Cambridge Trust, and the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI).

• Brain Injury
• Neuroscience
• Brain-Computer Interfaces
• Medical Technology
• Engineering
• Energy Technology
• Neural Interfaces
• Artificial Intelligence
• Ethanol fuel
• Electrical engineering
• Sleep disorder
• Controversy about ADHD
• Passive infrared sensors
• Psychopathology

Story Source:

Materials provided by University of Cambridge . The original text of this story is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License . Note: Content may be edited for style and length.

Journal Reference :

• Chaoqun Dong, Alejandro Carnicer-Lombarte, Filippo Bonafè, Botian Huang, Sagnik Middya, Amy Jin, Xudong Tao, Sanggil Han, Manohar Bance, Damiano G. Barone, Beatrice Fraboni, George G. Malliaras. Electrochemically actuated microelectrodes for minimally invasive peripheral nerve interfaces . Nature Materials , 2024; DOI: 10.1038/s41563-024-01886-0

Cite This Page :

Explore More

• Mice Given Mouse-Rat Brains Can Smell Again
• New Circuit Boards Can Be Repeatedly Recycled
• Collisions of Neutron Stars and Black Holes
• Advance in Heart Regenerative Therapy
• Bioluminescence in Animals 540 Million Years Ago
• Profound Link Between Diet and Brain Health
• Loneliness Runs Deep Among Parents
• Food in Sight? The Liver Is Ready!
• Acid Reflux Drugs and Risk of Migraine
• Do Cells Have a Hidden Communication System?

Trending Topics

Strange & offbeat.

Multi-scale modelling of the epileptic brain: advantages of computational therapy exploration

Affiliations.

• 1 School of Computer Science, Centre for Human Brain Health, University of Birmingham, Birmingham, United Kingdom.
• 2 UCB Biopharma SRL, Brussels, Belgium.
• 3 Research Centre for Frontier Fundamental Studies, Zhejiang Lab, Hangzhou, People's Republic of China.
• PMID: 38621378
• DOI: 10.1088/1741-2552/ad3eb4

Objective : Epilepsy is a complex disease spanning across multiple scales, from ion channels in neurons to neuronal circuits across the entire brain. Over the past decades, computational models have been used to describe the pathophysiological activity of the epileptic brain from different aspects. Traditionally, each computational model can aid in optimizing therapeutic interventions, therefore, providing a particular view to design strategies for treating epilepsy. As a result, most studies are concerned with generating specific models of the epileptic brain that can help us understand the certain machinery of the pathological state. Those specific models vary in complexity and biological accuracy, with system-level models often lacking biological details. Approach : Here, we review various types of computational model of epilepsy and discuss their potential for different therapeutic approaches and scenarios, including drug discovery, surgical strategies, brain stimulation, and seizure prediction. We propose that we need to consider an integrated approach with a unified modelling framework across multiple scales to understand the epileptic brain. Our proposal is based on the recent increase in computational power, which has opened up the possibility of unifying those specific epileptic models into simulations with an unprecedented level of detail. Main results : A multi-scale epilepsy model can bridge the gap between biologically detailed models, used to address molecular and cellular questions, and brain-wide models based on abstract models which can account for complex neurological and behavioural observations. Significance : With these efforts, we move toward the next generation of epileptic brain models capable of connecting cellular features, such as ion channel properties, with standard clinical measures such as seizure severity.

Keywords: computational neuroscience; epilepsy; multiscale modelling; seizure.

© 2024 IOP Publishing Ltd.

Publication types

• Research Support, Non-U.S. Gov't
• Brain* / physiopathology
• Computer Simulation*
• Epilepsy* / physiopathology
• Epilepsy* / therapy
• Models, Neurological*
• Nerve Net / physiopathology

• Tools & Resources
• Find Your Local Chapter
• Use my current location

Research & Funding

We want to create a world without epilepsy. To make this vision a reality, the Epilepsy Foundation supports research that leads to better treatments and care. Learn more about our epilepsy research programs.

Our Research Mission

Since 2003, we’ve funded nearly half of the therapies in the epilepsy clinical pipeline. We are developing an epilepsy research ecosystem that covers all parts of therapy, from idea to market. Our research initiatives include:

• Innovation programs that test new ideas and follow new research leads
• Engagement programs that improve communication between people with epilepsy, their families, advocates, researchers, and investors
• Digital tools that support research infrastructure
• Funding that supports young researchers to bring their ideas to life

Through these efforts, we're supporting research towards better treatment by developing the next generation of scientists. We strive for excellence, innovation, and radical thinking to find cures.

About Our Research & Funding

As part of our mission, we make sure the brightest new researchers become involved in epilepsy research. With the help of our partners, our investments in new therapies are bringing better treatments to people living with epilepsy.

Research Roundtable for Epilepsy (RRE)

We started this initiative to fix roadblocks in the research and development of epilepsy treatment. Each roundtable focuses on a single critical issue and allows an in-depth discussion in a pre-competitive space.

Epilepsy Pipeline Conference

This conference showcases the latest developments in epilepsy innovations. People with epilepsy, healthcare professionals and other members of the epilepsy community come together to learn about the latest treatments.

We invite entries representing the most innovative new ideas in epilepsy treatment and care. The winner(s) of the Shark Tank Competition receive international recognition and monetary prize awards to support the development and commercialization of an important new product, technology, or therapeutic concept to help people with epilepsy.

Startup Accelerator Course

Each week for six weeks beginning in the spring of 2024, we bring featured experts in epilepsy and successful entrepreneurs to startup founders to provide participants selected for the program with multiple perspectives and considerations to commercialize a venture.

Fellowship Programs

There is a shortage of epilepsy specialists in the U.S. We need to invest in our workforce to ensure the best and brightest are tackling the challenges our epilepsy community faces. We’re supporting the next generation of scientists with funding, training, and apprenticeship.

The Epilepsy Learning Healthcare System (ELHS)

Imagine a healthcare system that brings together families, communities, clinicians, researchers, and health system leaders. By learning from each other, we can empower all people with epilepsy to live their highest quality of life. ELHS is a system for how we work together to improve quality of life, seizure control, and seizure freedom.

Rare Epilepsy Network (REN)

Each year, more people get diagnosed with a rare form of epilepsy. Because each syndrome population is small, research to unlock answers in treatment is not moving fast enough. We’ve joined forces with over 32 organizations to create the first ever registry for rare epilepsy.

Related Resources

With over 3.4 million U.S. citizens living with epilepsy, the impact of our work matters.

Find a Clinical Trial

Find ongoing epilepsy clinical trials that you can consider.

Epilepsy Pipeline

A community-supported tool that provides updates on new drugs, devices, and more.

Epilepsy Device Wiki

Explore our searchable catalog of devices and apps developed for epilepsy.

Research News & Stories

Explore news and stories about the latest epilepsy research and innovations.

Emily’s Clinical Trial: An Opportunity that Made a Difference

Emily started having seizures at nearly 5 months old. When she was 7, she began a clinical trial that ultimately improved her quality of life. Emily’s parents Brian and Stacy give the full story of finding and participating in the clinical trial.

Help Fund Our Research Efforts

Since 2003, we have provided funding to half of the therapies in the epilepsy clinical pipeline. Generous donors are the ones that make our research efforts possible. Help us create a world without epilepsy that lives free from seizures and side effects.

Wait! Try this Special Offer

Subscribe now and save 15%.

• Facebook . opens in new tab
• Twitter . opens in new tab
• LinkedIn . opens in new tab
• Open Athens/Shibboleth
• Activate Print Subscription
• Create Account
• Renew subscription

Stay Informed, with Concise, Evidence-Based Information

Renew today to continue your uninterrupted access to NEJM Journal Watch.

Stay Informed

Subscribe Or Renew

Sign into your account

Forgot Password? Login via Athens or your Institution

Already a print subscriber? Activate your online access.

• SUMMARY AND COMMENT | 

April 23, 2024

Predictors of Poor Seizure Control in Women with Generalized Epilepsy Who Replace Valproate

Tanya J.W. McDonald, MD, PhD , reviewing Cerulli Irelli E et al. Neurology 2024 May

A multicenter, retrospective cohort study identifies four risk factors for poor seizure control in women with generalized epilepsy after switching from valproate to an alternate medication.

Valproate (VPA) is an effective antiseizure medication for people with idiopathic generalized epilepsy (IGE). However, its use during pregnancy elevates the risk for major congenital malformations and adverse effects on fetal neurodevelopment. In a multicenter, retrospective study, investigators sought to identify (1) predictors of poor seizure control in women with IGE who replaced valproate with an alternative medication and (2) an effective therapeutic alternative in such circumstances. They collected follow-up 1- and 2-year data on seizure control, including recurrence of seizures in people previously seizure free or a more than 50% increase in seizure frequency, from 426 women seen at 16 centers who replaced valproate due to teratogenicity concern (58.6%), side effects (29.4%), or lack of effectiveness (5.6%). Alternate medications selected included levetiracetam (LEV; 46.2%), lamotrigine (LTG; 32.9%), phenobarbital (5.2%), topiramate (4.5%), and others (11.2%).

More than half the cohort had juvenile myoclonic epilepsy (JME), and most patients (84.5%) had convulsive seizures before VPA switch. Most patients had no convulsive seizures 1 year (77.7%) and 2 years (64.8%) after VPA switch. In multivariable analysis, higher number of seizure types, higher VPA dosage, longer convulsive seizure freedom period, and catamenial pattern of seizures before VPA switch independently predicted convulsive seizure recurrence or worsening at 1-year follow-up in the full cohort and in the subgroup of patients switching VPA due to teratogenicity concerns. Comparing seizure control after switching to LEV or LTG, convulsive seizure worsening/recurrence occurred in 25.4% of those who switched to LEV and 40% of those who switched to LTG.

Although subject to retrospective design limitations, this study provides useful information to guide clinicians replacing valproate in women with IGE. Importantly, most patients did not have convulsive seizures after switching. The lower risk for seizure recurrence with switch to levetiracetam over lamotrigine should be confirmed in non-JME forms of IGE.

Dr. McDonald is Assistant Professor of Neurology, Department of Neurology, Division of Epilepsy, Johns Hopkins University School of Medicine, Baltimore.

Cerulli Irelli E et al. Predictors of seizure recurrence in women with idiopathic generalized epilepsy who switch from valproate to another medication. Neurology 2024 May; 102:e209222. ( https://doi.org/10.1212/WNL.0000000000209222 )

Facebook  |  Twitter  |  LinkedIn  |  Email  |  Copy URL

Latest In General Medicine

• Apr 18, 2024

Long-Acting Octreotide Reduces Bleeding in Patients with Gastrointestinal Angiodysplasia

Rahul B. Ganatra, MD, MPH

Correction: A Next-Generation Version of the Multitarget Stool DNA Test (Cologuard)

Physician empathy is associated inversely with chronic pain outcomes.

Thomas L. Schwenk, MD

• Apr 16, 2024

Characteristics of Drug-Induced Liver Injury from Anabolic Steroids and Selective Androgen-Receptor Modulators

• Apr 11, 2024

Diagnosing Heparin-Induced Thrombocytopenia: How Accurate Is the Recommended Algorithm?

Daniel D. Dressler, MD, MSc, MHM, FACP

Aprocitentan, a Newly Approved Drug for Resistant Hypertension

Allan S. Brett, MD

Plus 2 free gifts

• For Journalists
• News Releases
• Latest Releases
• News Release

Gene linked to epilepsy, autism decoded in new study

Changes in SCN2A gene affect age of seizure onset, severity of other neurological impairments in affected children

Media Information

• Release Date: April 26, 2024

Media Contacts

Kristin Samuelson

• (847) 491-4888
• Email Kristin

Journal: Brain

• SCN2A related-disorders, although rare in the general population, are one of the more common single-gene neurodevelopmental conditions characterized by infantile seizures, autism spectrum disorder and intellectual disabilities
• Severity of these disorders varies widely from person to person
• Findings should help better identify patients who are most appropriate for clinical trials of new precision medicines and gene therapies

CHICAGO --- A genetic change or variant in a gene called SCN2A is a known cause of infantile seizures, autism spectrum disorder and intellectual disability, as well as a wide range of other moderate-to-profound impairments in mobility, communication, eating and vision.

The severity of these disorders can vary widely from person to person, but little is known about what is happening at the level of the SCN2A protein to cause these differences.

A new Northwestern Medicine study helps explain how changes in the SCN2A gene affect whether or not a child will develop autism or epilepsy, the age at which seizures start for those with epilepsy and the severity of the child's other impairments.

The study was published April 24 in Brain, a top neurology journal.

These findings will help better identify patients who are most appropriate for clinical trials of new precisions therapies, including those targeting the SCN2A gene itself.

Analyzing sodium channels

The study represents a collaboration between an academic laboratory at Northwestern and the FamilieSCN2A Foundation , a parent-led rare disease advocacy group. The SCN2A Clinical Trials Readiness Study (SCN2A-CTRS) recruited 81 families from around the world and collected detailed clinical data and information to identify their SCN2A variants. The median age was 5.4 years. The youngest age participant was 1 month old and the oldest was 29 years old.

The Northwestern team extensively analyzed the functional effects of each SCN2A variant on the sodium channels — tiny gates in the membranes of nerve cells that control the flow of sodium ions into the cell and help neurons in the brain fire properly. Variants in the SCN2A gene alter how the sodium channel functions. Depending on the individual variant, the channel may be hyperactive (sodium ions flowing more freely) or completely inactive (the channel not working at all). There are variants that make the channel work in ways that are more complex.

The study found a spectrum of effects of the SCN2A variants on sodium channel function from hyperactive channels to completely inactive channels. Importantly, the clinical condition of the child varied with the functional impact on the channel. Hyperactive channels were generally associated with seizure onset in the first week of life. More impaired channel function was more common when the age of seizure onset was older. In fact, almost all of those without seizures had completely inactive sodium channels.  

The severity of other disease-related features also followed this gradient with those most severely impaired (unable to walk, communicate, eat, use their hands), having the youngest age at seizure onset and hyperactive channels. As age at seizures-onset increased and channels became less active, severe neurological impairments in the child tended to be less severe.

“We previously knew that genetic changes in the SCN2A gene were associated with seizures beginning as early as the newborn period and up through the first few years of life,” said co-corresponding author Dr. Alfred George , chair of pharmacology at Northwestern University Feinberg School of Medicine. “We had an overly simplistic understanding of these associations.

“Our new study clarifies the relationship between the functional consequences of SCN2A mutations, the primary phenotype (autism versus epilepsy and age at seizure onset in those with epilepsy) and the overall severity of the child’s impairments (mobility, etc.).”

Findings challenge prevalent understanding

There is a prevalent understanding among scientists that early-onset seizures are associated only with hyperactive sodium channels and underactive or inactive channels are associated with autism, George said. However, it’s more complicated, and children with early onset — in the first three months but after the immediate newborn period — don’t have hyperactive channels.  

“This is important because new precision medicines that are best suited for hyperactive SCN2A variants could be harmful to those with underactive or inactive variants,” George said. “Relying only on the age of seizure onset as a criterion for clinical trial enrollment risks inclusion of inappropriate patients.”

Dr. Anne Berg , adjunct professor of neurology at Feinberg, lead investigator of the SCN2A-CTRS and the co-corresponding study author emphasized that, “in the era of precision medicine for rare genetic diseases, this collaboration between a family foundation and a large NIH-funded project is an exemplar of the new partnerships that are needed and increasingly being developed to provide rapid answers to critical questions and lay foundation for successful drug development for severe neurodevelopmental disorders such as those associated with SCN2A.”  

The CTRS was driven by the patient community stakeholders and represents precisely the kind of efforts encouraged by the recent U.S. Food and Drug Administration Patient-Focused Drug Development Guidance program, which itself was in response to a mandate from the 21st Century Cures Act, Berg said.

Christopher Thompson , research assistant professor of pharmacology at Feinberg, is a co-first author of the study.

This research was funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health(grant U54-NS108874), the FamilieSCN2A Foundation and the Simons Foundation Autism Research Initiative.

• See us on facebook
• See us on twitter
• See us on youtube
• See us on linkedin
• See us on instagram

Brain organoids and assembloids are new models for elucidating, treating neurodevelopmental disorders

Stanford Medicine research on Timothy syndrome — which predisposes newborns to autism and epilepsy — may extend well beyond the rare genetic disorder to schizophrenia and other conditions.

April 24, 2024 - By Bruce Goldman, Erin Digitale

In this 2019 photo, Timothy syndrome patient Holden Hulet, left, rides in a side-by-side ATV driven by his dad, Kelby Hulet, at sand dunes near their home in southern Utah.  Courtesy of the Hulet family

For a long time, no one understood that Holden Hulet was having seizures.

“He would just say ‘I feel tingly, and my vision kind of goes blurry,’” said Holden’s mom, JJ Hulet. “But he couldn’t communicate exactly what was going on.”

JJ and Kelby Hulet could see their son was having short spells of incoherent speech, rapid back-and-forth eye movements and odd physical changes. “He’d kind of go — I don’t want to say ‘limp’ because he would stand just fine — but his body would just be in zombie mode,” JJ said. The episodes lasted less than a minute.

The parents were puzzled and worried, as they had been many times since Holden was born in 2008 and they learned that their newborn had an extremely rare genetic disease. “I was thinking it was his heart,” Kelby Hulet, Holden’s dad, said.

Holden’s condition, Timothy syndrome, causes long, irregular gaps in heart rhythm. He spent his first six months hospitalized in a neonatal intensive care unit in his family’s home state of Utah while he grew big enough to receive an implantable cardioverter defibrillator. The device sends an electrical signal to restart his heart when it pauses for too long.

As a small child, Holden would sometimes pass out before the defibrillator shocked his heart back into action. When Holden started telling his parents about the blurry-vision episodes at age 6, Kelby initially believed it was a new version of the same problem, and he kept a time stamp on his phone for each episode. But the records from Holden’s defibrillator showed that these times did not line up with any heart-rhythm problems.

The family’s pediatrician was confused, too. Perhaps Holden was having periods of low blood sugar, another possible Timothy syndrome complication, he suggested. Initial testing at the local medical center did not turn up clear answers.

But Kelby, who was training to become an operating room nurse, realized Holden’s episodes reminded him of what he was learning about warning signs for stroke. JJ called Holden’s cardiologist in Utah and asked for a detailed neurologic evaluation, which enabled the mysterious episodes to be diagnosed as seizures. Holden began taking anti-seizure medication, which helped, to his parents’ great relief.

Researching a rare disease

A few months after Holden was born, Sergiu Pasca , MD, arrived at Stanford Medicine to pursue a postdoctoral fellowship in the lab of Ricardo Dolmetsch, PhD, then an assistant professor of neurobiology, who was redirecting his research to autism spectrum disorder. At the time, Pasca did not know the Hulet family. But his work soon became focused on the disorder that has shaped Holden’s life.

Caused by a defective gene on the 12th chromosome, Timothy syndrome is vanishingly rare, with no more than 70 diagnosed cases. Children with this disorder rarely survive to late adolescence. It is caused by a mutation in the gene coding for a type of calcium channel — a protein containing a pore that selectively opens or closes, respectively permitting or blocking the flow of calcium across cells’ membranes. While a prominent feature — severe heart malfunction — can be tackled with a pacemaker, most children with Timothy syndrome will end up with lifelong brain disorders including autism, epilepsy and schizophrenia.

By mid-2009, Pasca had succeeded in generating nerve cells from induced pluripotent stem cells (which can be induced to form virtually any of the body’s numerous cell types). These included cells derived from the skin of two patients with Timothy syndrome. Later that year he observed defects in how the patient-derived neurons were handling calcium. This advance — the creation of one of the initial in-a-dish models of brain disease, built from neurons with defects that precisely mirrored those of a patient’s brain — was published in Nature Medicine in 2011.

Pasca and colleagues continued to monitor these Timothy-syndrome neurons in standard two-dimensional culture — growing as single layers in petri dishes — over the next few years. While this two-dimensional culture method was limited in its ability to sustain viable neurons, it was soon superseded by a genuine scientific breakthrough.

Pioneering the first assembloids

The constraints of two-dimensional culture, including the inability to keep these neurons for long periods of time so that they could reach key stages of neural development, prompted Pasca in 2011 to start developing an unprecedented three-dimensional method. The novel technology produced what came to be known as brain organoids. These constructs recapitulated some of the architecture and physiology of the human cerebral cortex. The organoids can survive for several years in culture, enabling neuroscientists to view, non-invasively, the developing human brain up close and in real time. The scientists wrote a seminal Nature Methods paper , published in 2015, that described their discovery.

Pasca’s group subsequently showed that culturing brain organoids in different ways could generate organoids representing different brain regions (in this case, the cerebral cortex and a fetal structure called the subpallium). In a breakthrough set of experiments, Pasca’s team found ways to bring these organoids into contact so that they fuse and forge complex neuronal connections mimicking those that arise during natural fetal and neonatal development. Pasca named such constructs assembloids.

In their paper on the research, which was published in Nature in 2017, Pasca’s team showed that after fusion, a class of inhibitory neurons originating in the subpallium migrates to the cortex, proceeding in discrete, stuttering jumps. (See animation .) These migrating neurons, called interneurons, upon reaching their destinations — excitatory neurons of the cortex — form complex circuits with those cortical neurons.

But in assembloids derived from Timothy syndrome patients, the motion of interneurons as they migrate from the subpallium is impaired — they jump forward more often, but each jump is considerably shorter, so they fail to integrate into the appropriate circuitry in the cortex. This wreaks havoc with signaling in cortical circuits. Pasca’s team tied this aberrant neuronal behavior on the part of Timothy syndrome neurons to the key molecular consequence of the genetic defect responsible for the condition: namely, malfunction of the critical channels through which calcium must pass to cross neurons’ outer membranes.

A family’s struggles

While Pasca was developing assembloids, the Hulet family was progressing through their own journey of discovery with Holden. They faced painful uncertainty at every stage, starting when Holden was discharged from the NICU in the summer of 2009, after several months of hospitalization and multiple heart surgeries.

“Even when we brought him home, [his doctors] said ‘Don’t get your hopes up. We don’t usually see them make it past age 2,” JJ recalled. Many children with Timothy syndrome die from cardiac failure in early life.

“It’s really hard to be positive in that kind of situation, and for a long time I did let it get to me,” JJ said. “I finally got to a point where I said, ‘I have to live my life and we just keep fighting.’”

JJ runs a child care center and has years of experience working with special-needs kids, which motivated her to push for an autism evaluation when she saw signs of autism in Holden. He’s much more verbal than many children with autism, which paradoxically made it more difficult to get an official diagnosis.

“That was frustrating,” JJ said. Although the family’s pediatric cardiologist in Salt Lake City was familiar with the vagaries of Timothy syndrome, their local caregivers in the small town where they live in southern Utah were not. “They kept saying ‘Oh, no, it’s just developmental delays because he was so premature,’” she said. She wonders whether it would have been easier to have Holden’s autism diagnosed had more been known about Timothy syndrome at the time.

“I think research is important so that parents and children have the support they need,” she said, noting how lonely and painful it can be to advocate for a child when his condition is poorly understood — and when, as a parent, you may be doubted by medical professionals. “It’s a really hard thing to deal with.”

Her voice breaks briefly. She continues, “I think research brings validity to that.”

Sergiu Pasca

Implanting organoids

In 2022, Pasca published a  study in  Nature describing the transplantation of human cortical organoids into neonatal rats’ brains, which resulted in the integration of human neurons along with supporting brain cells into the brain tissue of rats to form hybridized working circuits. The implanted human organoids survived, thrived and grew. Individual neurons from the human organoids integrated into young rats’ brains were at least six times as big as those — generated the same way, at the same time — that remained in a dish. The transplanted neurons also exhibited much more sophisticated branching patterns. Pasca and his colleagues observed marked differences in the electrical activity of, on one hand, human neurons generated from a Timothy syndrome patient, cultured as organoids and transplanted into one side of a rat’s brain, and, on the other hand, those generated from a healthy individual and transplanted, as an organoid, into the corresponding spot on the other side of the same rat’s brain. The Timothy syndrome neurons were also much smaller and were deficient in sprouting branching, brush-like extensions called dendrites, which act as antennae for input from nearby neurons.

“We’ve learned a lot about Timothy syndrome by studying organoids and assembloids kept in a dish,” Pasca said. “But only with transplantation were we able to convincingly see these neuronal-activity-related differences.”

That same year, the FDA Modernization Act 2.0 was signed into law, exempting certain categories of new drug-development protocols from previously mandated animal testing. The act was predicated on the understanding that recent advancements in science offer increasingly viable alternatives to animal testing, so the findings based on the organoid- and assembloid-culture technologies may be adequate to justify clinical trials in some neurodevelopmental conditions.

Most recently, in a Nature paper published April 24, Pasca and his colleagues demonstrated, in principle, the ability of antisense oligonucleotides (ASOs) to correct the fundamental defects that lead to Timothy syndrome by nudging calcium-channel production toward another form of the gene that does not carry the disease-causing mutation. Using ASOs to guide production of the functional rather than defective form of this channel reversed the defect’s detrimental downstream effects: Interneuronal migration proceeded similarly to that procedure in healthy brains, and the altered electrical properties of the calcium channel reverted to normalcy. This therapeutic correction was demonstrated in a lab dish — and, critically, in rat-transplantation experiments, suggesting that this therapeutic approach can work in a living organism.

Pasca is now actively searching the globe for carriers of the genetic defect, in preparation for the pursuit of a clinical trial at Stanford Medicine to test the safety and therapeutic potential of ASOs in mitigating the pathological features of Timothy syndrome.

“We are also actively engaged in conversations with other scientists, clinicians in the field and ethicists about the best way to move forward and safely bring this therapeutic approach into the clinic,” he said.

Pasca added that the calcium channel that is mutated in Timothy syndrome is, in fact, “the hub” of several neuropsychiatric diseases including schizophrenia and bipolar disorder. So it may be that the lessons learned — and the therapies derived — from his 15-year focus on a rare disease may have broad application in a number of widespread and troubling psychiatric conditions.

‘Amazing’ teenager

Today, in defiance of his doctors’ warning that he might not live past age 2, Holden Hulet is 15 years old and doing well.

“I think a lot of times, autism is perceived as ‘They’re not neurotypical and they’re not capable of certain things.’ But he is brilliant,” JJ said. “He’s amazing with techie stuff or Legos. He’s funny and super honest and very self-aware.”

Kelby often takes Holden to visit the farm where he grew up. Holden loves to ride the farm equipment and enjoys hanging out with the animals, especially the farm dogs and calves. Like a lot of kids, he keeps an eye out for good rocks, Kelby said with a chuckle.

“He’s always either throwing them or collecting them,” JJ said. “That’s something I really like about him: He’s always got a pocket full of something.”

Although navigating a rare disease is one of the most challenging things they have faced, the Hulets see light in their situation, and would offer encouragement to any family facing a new Timothy syndrome diagnosis.

“There is hope,” JJ said. “There are people out there who care, people out there who fight for you who don’t even know you. I think that’s what is so important about research — that you’re fighting a battle for people you don’t even know.”

The study published April 24 was supported by the National Institute of Mental Health (grants R01 MH115012 and K99 MH119319P), the Wu Tsai Neuroscience Institute, the Autism Speaks Postdoctoral Fellowship, the Kwan Funds, the Senkut Funds, the Coates Foundation, the Ludwig Family Foundation, the Alfred E. Mann Foundation, and the Stanford Maternal and Child Health Research Institute Postdoctoral Fellowship.

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 .

Artificial intelligence

Exploring ways AI is applied to health care