MICA: Detecting ictogenicity and epileptogenesis

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

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

Technical Summary

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.

Planned Impact

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.
 
Description British Journal of Anaesthesia/Royal College of Anaesthetists Project Grant
Amount £52,856 (GBP)
Organisation National Institute of Academic Anaesthesia 
Sector Academic/University
Country United Kingdom
Start 11/2015 
End 11/2016
 
Description INFLAMED - INFLAmmatory pathways in Multimodal imaging of Epileptogenesis and Depression
Amount £87,476 (GBP)
Funding ID MR/T005335/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 02/2020 
End 02/2021
 
Description Alexander Hammers, King College London 
Organisation UK Clinical Research Collaboration
Department UKCRC Clinical Research Facility (Kings College)
Country United Kingdom 
Sector Academic/University 
PI Contribution Data sharing, development of quantitative analysis methods
Collaborator Contribution Re-analysis of pre-existing NMDA data set using different time windows and analysis methods
Impact Recent (failed) submission to Journal of Nuclear Medicine. Collaboration includes chemists, physicists and biologists
Start Year 2016
 
Description Collaboration Aarhuis (Prof Brooks) 
Organisation Aarhuis
Country Belgium 
Sector Private 
PI Contribution Exchange of data, creation of population input curves for quantitative analysis of 18F-GE179 PET data
Collaborator Contribution Exchange of data, creation of population input curves for quantitative analysis of 18F-GE179 PET data
Impact Multi-disciplinary collaboration with basic scientists and clinicians
Start Year 2012
 
Description Tri-patriate GE-Cambridge-UCL collaboration 
Organisation General Electric
Department Neurosciences; GE Healthcare
Country United Kingdom 
Sector Private 
PI Contribution Tracer validation
Collaborator Contribution Supply of precursor for tracer production in Cambridge and transport to UCL/UCLH
Impact multidisciplinary - currently PET data acquired / analysed
Start Year 2015
 
Description Departmental seminar (UCL, London, UK): NMDA-receptors in epilepsy, stroke and TBI. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact A talk was given at the departmental seminar of the UCL Institute for Nuclear Medicine. The talk presented the methodology and preliminary results and sparked interest in using these methods for further research projects.
Year(s) Of Engagement Activity 2017
 
Description International GE-179 user's analysis workshop (London, UK) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact On 17th March 2016, 28th July 2016, and 19th January 2017 international "GE-179 user's analysis workshops" were held in London, UK. The workshops were hosted by the UCL MICA project team. The meetings led to a consensus for the modelling approaches to be used for processing data acquired with this tracer, data sharing approaches and presentation of preliminary results.
Year(s) Of Engagement Activity 2016,2017
 
Description MPhil/PhD upgrade talk (UCL, London, UK): Biomarkers of epilepsy and epileptogenesis. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact 30 medical professionals and researchers attended this talk at UCL. The talk sparked interest in this new methodology.
Year(s) Of Engagement Activity 2017
 
Description Working group seminar (OHBA, Oxford, UK): PET-MR in Anti-NMDA receptor encephalitis. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact A presentation on GE-179 PET was given at the OHBA working group seminar in Oxford, UK. The talk focused on the use of PET-MR in Anti-NMDA receptor encephalitis. This laid the groundwork for future collaboration between UCL and Oxford University researchers on this topic using this methodology.
Year(s) Of Engagement Activity 2017