Late drug‐resistance in mild MTLE: Can it be influenced by preexisting white matter alterations?

Abstract

Objective: To identify early structural alterations preceding the development of drug-resistance in mild mesial temporal lobe epilepsy (mMTLE), a drug-responsive syndrome ideal for investigating epilepsy pathophysiology and potential prognostic markers of long-term clinical outcome, using magnetic resonance imaging (MRI) at baseline and after 12-year follow-up. Methods: Since 2002, a total of 55 participants with a baseline diagnosis of mMTLE underwent three-dimensional (3D) T1 1.5T MRI. Based on long-term outcome (follow-up 12 ± 3 years), we identified 39 patients with stable mMTLE (smMTLE) and 16 patients who had developed drug-resistance overtime (refractory MTLE [rMTLE]). At follow-up, 21 smMTLE and 13 rMTLE patients underwent 3T-MRI including diffusion-weighted scans. Structural images were processed using longitudinal voxel-based morphometry and standard Freesurfer analysis. Statistical analyses were carried out accounting for age, age at onset, gender, hippocampal volume, and hippocampal sclerosis (Hs). Results: Patients presented similar demographic, clinical, and Hs features. White matter volume of the arcuate fasciculi, corticospinal tracts, left retrosplenial cingulum, and left inferior longitudinal fasciculus was reduced only in rMTLE patients before the development of drug-resistance. At follow-up, rMTLE showed decreased fractional anisotropy in the corpus callosum, superior longitudinal fasciculi, and major bundles of the right hemisphere. Significance: White matter temporal and extratemporal abnormalities are preexisting in patients with mild MTLE who will develop drug-resistance, independently from the presence of Hs. Thus, these changes might be due to an inherited genetic alteration rather than a subordinate worsening after repeated seizures, multiple antiepileptic drugs, or initial precipitating factors. K E Y W O R D S drug-resistance, hippocampal sclerosis, long-term outcome of epilepsy, onset of drug resistance, structural MRI alterations | 925 LABATE ET AL.

Neurobehavioral and Clinical Comorbidities in Epilepsy: The Role of White Matter Network Disruption

“…In fact, temporal lobe FA was able to differentiate between refractory versus benign TLE with an AUC of 0.74. In a follow-up study, patients whose mild mesial TLE eventually evolved into refractory mesial TLE had distinct microstructural alterations in the corticospinal tracts, superior longitudinal fasciculus, left cingulum, and left inferior longitudinal fasciculus prior to the development of drug resistance (Labate and others 2020). These data suggest that greater WM pathology both within and beyond the temporal lobe may predispose patients to develop drug-resistant seizures.…”

Clinical and Instrumental Characterization of Patients With Late-Onset Epilepsy

“…Furthermore, imaging and post-processing imaging helps to identify early structural alterations preceding the development of drug-resistance in mild mesial temporal lobe epilepsy with LOE and to better understand pathophysiology in such syndrome (38)(39)(40)(41). However, it should be considered that the possibility of identifying some lesions (e.g., focal cortical dysplasia) in patients with LOE is lower compared to younger subjects (8,42,43).…”

Multi‐omic strategies applied to the study of pharmacoresistance in mesial temporal lobe epilepsy

“…At follow-up, these patients showed decreased fractional anisotropy in the corpus callosum, superior longitudinal fasciculi, and major bundles of the right hemisphere, independently of the presence of HS. 177 In addition, a research protocol for a longitudinal study has been published, aiming to evaluate preexisting brain connectivity, molecular information, and the outcome of pharmacologic treatment in patients with newly diagnosed focal epilepsy. 178 Finally, the contribution of integrating multi-omic data in the study of pharmacoresistant MTLE is still unexplored 179 (Table 7).…”

“…An interesting prospective study aimed to identify early brain abnormalities that could precede pharmacoresistance in patients with MTLE has recently been published by Labate et al 177 The authors reported that before patients became refractory to ASM, they presented abnormalities in the white matter volume of the arcuate fasciculi, corticospinal tracts, left retrosplenial cingulum, and left inferior longitudinal fasciculus reduced. At follow‐up, these patients showed decreased fractional anisotropy in the corpus callosum, superior longitudinal fasciculi, and major bundles of the right hemisphere, independently of the presence of HS 177 . In addition, a research protocol for a longitudinal study has been published, aiming to evaluate preexisting brain connectivity, molecular information, and the outcome of pharmacologic treatment in patients with newly diagnosed focal epilepsy 178 …”

“… 175 Indeed, endophenotypes could be a more direct result of genetic influences, and by studying these intermediary characteristics one could better disentangle complex phenotypes such as pharmacoresistance to ASMs. 176 An interesting prospective study aimed to identify early brain abnormalities that could precede pharmacoresistance in patients with MTLE has recently been published by Labate et al 177 The authors reported that before patients became refractory to ASM, they presented abnormalities in the white matter volume of the arcuate fasciculi, corticospinal tracts, left retrosplenial cingulum, and left inferior longitudinal fasciculus reduced. At follow‐up, these patients showed decreased fractional anisotropy in the corpus callosum, superior longitudinal fasciculi, and major bundles of the right hemisphere, independently of the presence of HS.…”