Priority 6 from the Epilepsy (Canada) PSP

UNCERTAINTY: What are the brain changes, on a cellular level, that lead to seizure development?   (JLA PSP Priority 6)
Overall ranking 6
JLA question ID 0110/6
Explanatory note It is known that abnormal electrical activity in the brain leads to the onset of seizures. At the cellular level, it is clear that brain cells (neurons) becomes hyperexcitable and the normal balance of excitation and inhibition is disrupted. However, it is unclear what triggers this disruption, and why epilepsy can suddenly develop at any time in the absence of injury, trauma or family history. There are many potential mechanisms, including loss or degeneration of neurons, inflammation, structural changes, or changes in how neurons communciate with each other. It is not clear whether these reflect long-term or sudden changes. An important question is how to uncover the causes of epilespy in individuals where diagnostic testing (brain imaging, genetic testing) does not show any abnormalities.    
Evidence

Tatum, W. O., Rubboli, G., Kaplan, P. W., Mirsatari, S. M., Radhakrishnan, K., Gloss, D., . . . Beniczky, S. (2018). Clinical utility of EEG in diagnosing and monitoring epilepsy in adults. Clinical Neurophysiology, 129, 1056-1082. doi:10.1016/j.clinph.2018.01.019 
Health Research Classification System category Neurological 
Extra information provided by this PSP
Original uncertainty examples What causes epileptic seizures to happen every four to eight weeks? ~ Why is it that some people don't present symptoms until the age of 11 or 12? What changed in the brain to have resulted in show of symptoms? ~ Once an mri comes back with results showing normal is there ever a way to know what has caused someone to have epilepsy. ~ What changes occur that cause epilepsy to present itself later in life (20+ years old)?
Submitted by People with Seizures x 27, Caregivers x 5, Friend or Family Member x 18, Health Care provider x 2, Unknown x 1
PSP information
PSP unique ID 0110
PSP name Epilepsy (Canada)
Total number of uncertainties identified by this PSP. 96  (To see a full list of all uncertainties identified, please see the detailed spreadsheet held on the JLA website)
Date of priority setting workshop 6th & 7th April 2021