Radiosurgery of epilepsy using synchrotron x-ray microbeams – Epirad

Despite the development of new molecules, about a third of epileptic patients cannot be controlled by anti-epileptic drugs. Among these patients, only a limited number may benefit from resective surgery after invasive monitoring. Radiosurgery has proven to be an efficient alternative, especially for the treatment of small/circumcised epileptic foci. However, when seizures arise in eloquent cortex (ex: motor, language areas), resective surgeries, as well as radiosurgical procedures are inapplicable, because of the unacceptable resulting functional deficit. To date, there is only one surgical procedure, termed “multiple subpial transections” that allow seizure relief arising from such eloquent structures. The method consists in performing 5mm-spaced parallel cuts in the cortical gray matter, oriented perpendicularly to the neuronal layers of the targeted cortex, in order to preserve the integrity of the so-called cortical “columns”, and therefore the physiological signals travelling vertically towards the subcortical structures. However, the procedure is very invasive and is associated with significant morbidity.
After several years of development, EPIRAD proposes a novel method of radiosurgery using synchrotron-generated x-ray microbeams (MBs), with which it is possible to perform radio-transections by depositing several hundreds Gy into thin regions separated by virtually non-irradiated tissue. The sharpness of the lateral dose fall-off is such that it is possible to perform with an excellent precision parallel tissue transections in small animal models of epilepsy. This geometry, which is non-achievable by current clinical devices, should stop seizure initiation and/or propagation by preventing widespread synchronization of neurons within and in the vicinity of the seizure onset zone.
The deposition of high homogeneous doses of x-rays by interlaced MBs has proven its efficacy in the treatment of brain tumors, and a recent collaboration between the Grenoble Institute of Neuroscience and the European Synchrotron Radiation Facility has revealed some of the cellular mechanisms implicated in the antiepileptic effects of x-ray radiation in an animal model of absence epilepsy. Based on this experimental background, EPIRAD will further explore the effects and applications of x-ray MB transections by addressing the following questions:
1. How x-ray MB transections can be optimized to effectively cut axon bundles or dendrites, while minimizing damage in resulting tissue slices?
2. Are x-ray MB cortical transections effective in the prevention of seizure initiation and/or spread, in two rodent models of epilepsy?
3. What are the behavioral side-effects of the transection of the sensory/motor cortex, and how can they be minimized?
The answers to these questions will open the way to the pre-clinical investigation of x-ray transection efficacy in the non-human primate. To this aim, EPIRAD will require an important transfer of technology to adapt x-ray MB transections to monkeys. The biomedical beamline of the ESRF will develop the instrumentation. EPIRAD should lead to the implementation of a radiosurgery platform compatible with human patients for future clinical trials. Because of the simultaneous development of new compact clinical sources (such as the Thom-X project), the method developed by EPIRAD should be applicable in hospitals in the near future.