A conceptual framework for the use of neuroimaging to study and predict pharmacoresistance in epilepsy

Abstract

SUMMARYTwenty percent to 49% of newly treated patients with epilepsy will develop pharmacoresistance (PR). The mechanisms leading to PR are unclear. There is currently no unifying theory to explain the variety of presentations of PR and the diversity of potential contributing factors. Etiology of seizures seems to play a critical role in at least a subset of PR. Many magnetic resonance imaging (MRI) studies in the advanced stages of epilepsy suggest a strong association between lesions such as hippocampal sclerosis and focal cortical dysplasia and PR. Unfortunately, almost all of these studies are cross-sectional and retrospective. There is a need for a new perspective on the role of preexisting lesions in the evolution of epilepsy and PR.We propose in this article to study a unique population of drug-naive patients with either first seizure or new-onset epilepsy longitudinally with advanced MRI imaging techniques, including magnetic resonance spectroscopy and diffusion tensor imaging. We hope to be able to monitor imaging findings and the development of PR early in the course of the disease in a subset of these patients with temporal lobe epilepsy (TLE). Our goal is to understand the pathogenesis of PR, to dissect changes associated with the development of PR from changes associated with chronic seizures and medication, and ultimately to predict PR at the onset of disease.

Progression of gray matter atrophy in seizure‐free patients with temporal lobe epilepsy

“…The GM volume reduction in patients with pharmacoresistant TLE and MRI signs of HS found in previous studies occurs beyond the mesiotemporal structures in areas such as the temporal neocortex and thalamus, as well as areas in the frontal and occipital lobes and cerebellum . However, it is not clear if such abnormalities represent the consequence of repeated seizures or reflect other aspects of the epileptogenic process . Certainly, one possible mechanism to explain the widespread GM decrease in patients with TLE is seizure activity propagation.…”

“…3,[17][18][19][20][21][22][23][24] However, it is not clear if such abnormalities represent the consequence of repeated seizures or reflect other aspects of the epileptogenic process. 6,17,24 Certainly, one possible mechanism to explain the widespread GM decrease in patients with TLE is seizure activity propagation. For example, ongoing seizure activity via the interhemispheric pathway could explain the contralateral thalamic atrophy.…”

“…In addition, in patients with pharmacoresistant TLE, there is an apparent progression of atrophy over time, which was found to be associated with recurrent seizures in some studies . However, it is not clear whether these areas of diffuse atrophy in TLE are involved in the perpetuation of the seizures or they are actually a consequence of them …”

“…4 However, it is not clear whether these areas of diffuse atrophy in TLE are involved in the perpetuation of the seizures or they are actually a consequence of them. 5,6 Although TLE is classically associated with pharmacoresistant seizures, especially in patients with hippocampal sclerosis (HS), 7 a "mild" form of TLE, with seizures easily controlled with medication, is recognized. 8 In these patients, the presence of HS does not determine the outcome, 9,10 and other factors, like genetic and environmental, play an important role in determining seizure severity.…”

Resting‐state functional brain networks in adults with a new diagnosis of focal epilepsy

“…Comparatively, newly diagnosed epilepsy is rarely studied despite this being a key point in time to understand the underlying biology of epilepsy and to identify potential interventions and biomarkers for seizure and cognitive outcomes. The translation of what we understand in long-standing epilepsy to people with a new diagnosis of epilepsy is confounded by several factors, including the chronic effects of seizures and anti-epileptic drugs (Pohlmann-Eden, Crocker, & Schmidt, 2013). This lack of investigation is most notably due to access to patients; many specialist and academic centres do not see epilepsy until it is well established.…”