Cortical excitability in refractory focal epilepsy treated with novel gene therapy and conventional resective surgery

Epilepsy is one of the most common neurological conditions, and affects around 50 million people worldwide. It is caused by increased excitability of the brain. Patients with epilepsy have recurrent seizures. Unfortunately about a third of patients have ongoing seizures despite taking the many anti-epileptic medications available. Seizures have risks that commonly include injuries but also rarely can result in fatality due to effects of the seizures on breathing and heart rate (known as Sudden Unexpected Death in Epilepsy). In some of these patients, an operation to remove the part of the brain that is causing the seizures, can help to cure seizures. However, there are risks of surgery, especially if the seizures start in or near parts of the brain that are vital for important functions, for example, movement, language or memory function. Another exciting possible new treatment is gene therapy, where a gene is introduced into the brain using a virus as a carrier. In our research institution at UCL, we have developed a gene therapy that works well to control seizures in rats with epilepsy. The next step is to test if this treatment also works in humans. There is a plan to start a clinical trial using a trial of gene therapy as a novel therapy for our patients who would normally be considered for epilepsy surgery.

Transcranial magnetic stimulation is useful and safe tool that uses a magnet held over the head to stimulate nerves in the brain and the response can be measured using recording electrodes on the muscles of the hand or by measuring brainwaves on the scalp. It is ideal for studying brain activity in patients with epilepsy, as it can directly probe the workings of brain circuits and give us measures of brain excitability.

In this study we plan to use transcranial magnetic stimulation to measure brain activity in patients with focal epilepsy, who are still having seizures, even though they are taking regular anti-epileptic medications. These patients will be treated with either the new gene therapy or the already established treatment of epilepsy surgery. We will take brain excitability measures before and after these treatments. This will help to improve our understanding of this type of epilepsy, and how brain excitability changes in these patients, compared to healthy people. In addition it will also help us understand how both these treatments affect brain excitability. In particular this will give us an insight into the effects of the new gene therapy treatment on the brain. The information we get from this study, will help us understand why some people may become seizure free with either of these treatments whereas others might not. In turn we envisage that, in future, this will help us to predict which patients will benefit most from either treatment. This will allow us to choose the best treatment for patients and improve their seizures and thereby their quality of life.

Epilepsy affects around 50 million people worldwide. The pathophysiology reflects altered excitability of cortical networks. Approximately 1/3 of patients have refractory seizures despite optimal medical management, with an annual risk of sudden unexpected death in epilepsy (SUDEP) of 0.5-1%. In some, surgical resection of the epileptogenic zone can result in seizure freedom; however, surgery has risks, in particular, damage to eloquent brain areas. Professor Walker (Co-Investigator) and colleagues have demonstrated successful treatment of an engineered potassium channel gene (KCNA1), packaged into a viral vector in a rodent model. The next step is the first in-human clinical trial in 10 patients from our presurgical cohort. At present, there are no surrogate markers for changes in brain excitability in this trial.
Transcranial magnetic stimulation (TMS) uses time-varying magnetic fields to explore cortical physiology non-invasively. In TMS-EMG, following motor cortex stimulation, neuronal excitability is measured indirectly by electromyography. More recently, TMS-EEG (TMS with high-density electroencephalography) has enabled more direct probing of cortical excitability. A few studies have demonstrated 'normalisation' of preoperative excitability using TMS-EMG, following successful epilepsy surgery, and differences in preoperative excitability in patients that became seizure free compared with those who did not. There have been no published studies to date of TMS-EEG.
We plan to apply TMS-EMG/ EEG to our patients with drug refractory epilepsy undergoing both novel gene therapy, and conventional resective surgery, in order to gain an insight into the effects on cortical excitability of the novel genetic therapy, using TMS as a biomarker, and to examine how these change post-operatively in both groups and identify predictive factors that may affect seizure freedom outcome. This may ultimately facilitate future patient selection for gene therapy versus surgery.