🧠 Epilepsy: new hope for treatment-resistant forms

Researchers from Inserm and Grenoble Alpes University (UGA) have discovered a new therapeutic avenue for combating drug-resistant epilepsies. Fractionated administration of microbeam X-rays induces a significant reduction in seizure occurrence for 2 months in treated animals: a first proof in favor of a clinical application.

Non-invasive, this technique could bring new hope to patients who often have run out of options. These promising results are published in the journal Epilepsia.


In France, over 650,000 people suffer from epilepsy, nearly half of whom are under 20 years old. Known for its sudden seizures, epilepsy is actually a brain disease encompassing various symptoms such as cognitive, sleep, or language disorders - the most spectacular of which are indeed these famous seizures.

There are about fifty epileptic diseases (or epileptic syndromes) which all have one thing in common: a synchronized and abnormal excitation of a more or less extensive group of neurons in the brain.

Today, the vast majority of epilepsies are treated with drug-based solutions. However, these are only effective in 60 to 70% of cases. One third of people with epilepsy continue to suffer from uncontrolled seizures. In cases of drug resistance (pharmacoresistance), surgery targeting and resecting the affected brain area may be considered under certain conditions.

In practice, it is only feasible for a minority of patients. For others, more or less invasive palliative approaches have been developed over the past thirty years. Stereotactic radiosurgery (Gamma Knife), which uses a broad gamma ray to lesion and deactivate the epileptic focus in the brain, is currently the most used non-invasive therapy for focal epilepsies. However, the beam is not very precise, and the therapy is only effective in 50% of cases with significant side effects.


To overcome these limitations, a research team from the Grenoble Institute of Neuroscience (Inserm/UGA) has been exploring a new, more meticulous radiosurgery approach for about ten years, called Microbeam Radiation Therapy (MRT), to combat resistant epilepsies. Specifically, researchers use a synchrotron, a large electromagnetic instrument, to divide an X-ray beam into extremely thin microbeams (50 µm, or about the width of a human hair (0.002 inches)).

These microbeams are capable of delivering very high doses of X-rays locally and meticulously, allowing lesioning of only the targeted areas while sparing neighboring tissues. MRT has been developed at the European Synchrotron Radiation Facility in Grenoble since the 2000s, notably with promising results against brain tumors.

"X-ray microbeams initially proved effective in eliminating tumors, as was Gamma Knife, the reference radiosurgery for epilepsy. The latter proved effective against cancers before finding an application for targeting epileptic foci in the brain. This translation seemed relevant to us, and our results prove it," explains Loan Samalens, PhD student and first author of the study.

The research team tested MRT in a well-established model of mesial temporal lobe epilepsy in mice, a form of focal epilepsy that is resistant to pharmacological treatments and for which surgical resection is generally offered to patients. They show that irradiating the affected area in the brains of these epileptic mice with these X-ray microbeams induces an antiepileptic effect for 2 months. The treated animals experienced a significant and lasting reduction in seizure occurrence.

"We started by irradiating the relevant brain areas with a single trajectory at increasing doses. The higher the dose, the more effective the treatment but the higher the mortality. However, by dividing the same dose into several trajectories, allowing the delivered X-ray dose to be distributed, we get better results. The treatment is more effective with fewer toxic effects. The results obtained are even more robust and relevant than the current reference treatment, Gamma Knife. A therapeutic effect is achieved without inducing the major side effects usually observed with conventional radiotherapies", continues Loan Samalens.

Histological analyses confirm that the irradiated tissues remain well preserved and suggest a role of vascular and/or neuronal remodeling in the antiepileptic mechanism. These first preclinical results constitute a promising proof of concept. The team is currently working to optimize the irradiation parameters, specify their long-term therapeutic effects, and better understand the mechanisms by which these microlesions modulate the neuronal networks responsible for epilepsies.

"MRT could represent an effective non-invasive therapeutic alternative for treatment-resistant forms of epilepsy, but this technique still needs to be brought closer to clinical use. The synchrotron in Grenoble remains quite unique. We are therefore seeking to test mini-beams (375 µm / ~0.015 inches) like those that less powerful but already hospital-based X-ray irradiators can produce. The goal is to verify that the principle of spatial fractionation can be applied without a synchrotron, with machines realistic for medical practice and grounded in reality for patients", explains Antoine Depaulis, Inserm emeritus research director.

With ongoing technology transfer efforts, the team hopes this strategy could lead to a medium-term clinical application.