An update on research on epilepsies

Prof. Rima Nabbout, pediatric neurologist at Necker-Enfants malades hospital AP-HP, head of the rare epilepsies Reference Center for Rare Diseases and coordinator of the research project around this pathology at Imagine Institute, reviews the latest advances.

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Known about for a long time, epilepsy affects more than 500,000 people in France; half of these cases start in childhood. For those who are unfamiliar with it, this disease is characterized by episodic seizures. “However, this is only the tip of the iceberg, clarifies Prof. Rima Nabbout. Rare epilepsies in children are often accompanied by behavioral problems, psychiatric disorders, and cognitive and social disorders.” To date, there is no cure. The treatment mainly consists of controlling the seizures and associated problems, but the group of rare epilepsies presents high levels of resistance to any type of treatment. When the region of the brain involved is sufficiently located, epilepsy surgery can then be performed.

Not one epilepsy, but epilepsies

In reality, epilepsy covers a range of different pathologies. “In a third of patients, the seizure quickly affects the whole brain; known as generalized epilepsy. For others, the seizure is located in a region of the brain. This is focal epilepsy. Clarifies Prof. Rima Nabbout.  

Epilepsies are classified according to the type of seizure, the type of epilepsy syndrome and in parallel, according to their etiology.  Advances in brain imaging and genetic knowledge have been very valuable in this field.”

Making the correct diagnosis

The diagnosis is a crucial time for the treatment of epilepsies: it has to involve clinical exams, imaging, an electroencephalogram, a targeted metabolic profile and now a genetic analysis. “We now have a panel of 150 known genes associated with different forms of epilepsy, explains the pediatric neurologist. If an anomaly is identified, it supplements the data obtained with other diagnostic tools, which helps us to accurately define the nature of the pathology and therefore offer the most suitable treatment.”

At the same time, Prof. Nathalie Boddaert, radiologist at Necker-Enfants malades hospital AP-HP and head of an associated team at Imagine Institute, develops new imaging technologies (functional MRI and high-resolution electroencephalogram) to better define regions of the brain that are involved and therefore facilitate knowledge of patients who are candidates for surgery.

Better understanding epilepsy

Knowing the genetic origin also paves the way for exploring the mechanisms involved. Indeed, epilepsy seems to be a brain developmental disorder in the same way as some mental deficiencies, forms of autism, learning disabilities. Some genetic alterations even seem to be found in several pathologies. Prof. Jean Paul Bonnefond’s team has developed a gene panel dedicated to epilepsies. Patients who are negative after this panel come into the scope of research at Imagine within the genetic teams, with exome and genome studies in Prof. Nabbout’s group in Dr Kabashi’s unit.

Equipe Edor Kabashi et Rima Nabout
Equipe Edor Kabashi et Rima Nabout © Laurent Attias

“Since the year 2000, we have seen a huge increase in the number of genes discovered, notes Prof. Rima Nabbout. In addition to defining a new classification of the disease, it is an essential stage in the discovery of targeted treatments that can treat young children.”

Indeed, for a long time, the treatments offered were anti-epileptic drugs, often with a simple adjustment of the dose and an extrapolation of studies done in adults.  This approach is now accepted and validated for focal epilepsies, which have common mechanisms in different age groups, but we have been seeing the start of specific treatments for epileptic syndromes from childhood with the development of orphan drugs. Prof. Nabbout quotes a few recent examples on this development, like in Bourneville tuberous sclerosis and Dravet syndrome.

With Edor Kabashi’s team, Rima Nabbout deploys integrated approaches to make the connection between physiopathology and genetics. Indeed, epilepsy is characterized by a dysfunctional neuronal activity and transmission problems between neurons. By turning to very specialized tools, and with the cohort of patients that is available to them, they hope to better characterize the different forms of epilepsies and determine the specific pathogenic mechanisms by developing complete translational cell and animal models. From this knowledge, treatments that are able to check defective mechanisms will emerge and therefore finally treat young patients.