MICA: Detecting ictogenicity and epileptogenesis

The lifetime risk for a single seizure is 1:20, but 1:200 for epilepsy. Epilepsy develops in 20% of individuals after a severe head injury, but this can occur >20 years after the injury. We don't know the exact mechanisms pertinent to the development of epilepsy, or progression after the condition is established (=epileptogenesis). In only about 75% of patients with chronic epilepsy, we are able to localise an epileptogenic lesion, but even then we cannot quantify the capacity of this lesion to generate seizures (=ictogenicity). There are >20 so-called "anti-epileptic drugs" with different mode of actions to suppress seizures, but none prevents or cures epilepsy, and ~30% of patients are drug-refractory.
Our objective is to improve understanding of the molecular and cellular mechanisms involved in epileptogenesis and ictogenicity.
Better understanding of the underlying mechanisms of epileptogenesis could permit selection of patients with the highest risk for developing epilepsy, and allow staging of the epileptogenic process. A quantitative measure of epileptogenicity would allow monitoring the brain's response to treatment and documenting prevention and cure. Specifically, this will help to:
1. pursue aggressive surgical approaches in those with established epilepsy and localised presence of active epileptogenesis that would indicate good prognosis, if the are of hyperexcitability is surgically amenable
2. diagnose and treat patients at high-risk of developing epilepsy following TBI or CVA and a 1st seizure to prevent further seizures

Rationale:
To validate the positron emission tomography (PET) tracer [18F]GE-179, which binds to the open NMDA receptor (NMDA-R), as a diagnostic tool to detect epileptogenic foci to guide invasive EEGs and refine surgery, and to identify those who will develop epilepsy after 1st late unprovoked seizure following either traumatic brain injury (TBI) or cerebro-vascular accident (CVA).
Methods:
(i) To detect brain tissue capable of generating seizures (ictogenicity), 30 patients with refractory focal epilepsy will be scanned prior to surgical resections. Of those, about 60-70% (~18-21) patients are expected to be seizure-free 1 year after surgery.
(ii) To detect on-going ictogenicity, patients with focal epilepsies will be re-scanned either 1 year following surgery, if seizure-free, or at time of seizure-relapse. .
(iii) To detect the development of epilepsy (epileptogenesis), we will study a further 50 subjects at-risk of developing epilepsy after 1st late (>7 days) unprovoked seizure following either TBI or CVA. Of those, about 30-40% (~15-20) patients are expected to have a 2nd seizure within 2 years.
Twenty healthy controls will be studied for comparison, of those ten will be scanned twice for determining test-retest variability.
We expect a 10% failure rate in chemistry production and 10% scan failure for subject-related reasons. Based on previous studies and pilot data, our group sizes are sufficient to detect a large effect size (0.8) with approximately 80% power.
Hypotheses:
[18F]GE-179 will show increased uptake in individual patients (i) with refractory epilepsy at the epileptogenic focus in those who benefit from surgery, (ii) localised increases outside the area to be surgically resected in those who relapse following surgery on stable or reduced medications, and (iii) who will develop epilepsy after their 1st unprovoked seizure following TBI or CVA.

Impact on Clinical practice: Our research will lead to the development of clinically-useful, validated imaging biomarkers, which will improve chances for seizure-freedom in patients undergoing surgery. Research in neuroimaging of epilepsies so far has mainly focused on the prediction of response to surgical treatment for the relatively small number of patients undergoing respective surgery for medically refractory epilepsy. The stage is now set to combine and extend these methodologies to the prediction or response to drug therapies in those who had become seizure-free following surgery, but remained on medication. This will have a much wider impact as it will potentially be of benefit to all patients whose seizures are satisfactorily controlled by anti-epileptic drugs (AEDs), but were at-risk of relapse if AEDs were tapered or withdrawn (~30% of all patients).

Impact on drug development: Our programme extends the knowledge base relevant to improving human health. Our project is truly translational, as the knowledge from pre-clinical studies on epileptogenic mechanisms of the brain will lead to the development of drug-companion tests, which will be of potential benefit to the pharmaceutical industry during drug development and characterization of novel compounds aimed at preventing or modifying epileptogenesis.

Impact on society and costs: The cost of epilepsy is huge, ~1 billion £ per year in the UK, and the majority of these costs are indirect, in relation to the socio-economic consequences of uncontrolled seizures and side-effects. Healthcare costs are likely to fall, and the UK will benefit from avoidance of unnecessary AED treatments in those cured from the condition who no longer require medication. Economic development and scientific competitiveness will benefit from the potential for commercialisation of validated biomarkers of epileptogenesis, as this is the condition-sin-qua-non for the development of disease-modifying strategies.