Diffusion imaging shows microstructural alterations in untreated, non-lesional patients already after a first unprovoked seizure

Abstract

Objective: Patients with newly diagnosed epilepsy exhibit brain white matter (WM) abnormalities, but the temporal dynamics of these are unknown. The literature suggests these alterations might be present before diagnosis. This study investigates WM microstructural integrity using diffusion imaging in non-lesional (NL), interictal epileptiform discharge (IED)-free, unmedicated patients who experienced a first unprovoked seizure compared to healthy controls. Furthermore, we evaluated whether the patients who developed epilepsy within a 1-year follow-up had a divergent pattern of WM alterations in contrast to those who did not. We also evaluated patients with established epilepsy.

Methods: We performed a diffusion imaging analysis in a cohort of 82 subjects. Twenty patients recently experienced a first unprovoked seizure (first-seizure group), 32 patients had chronic epilepsy (chronic-epilepsy group), and 30 healthy controls. The first-seizure patients were later classified into patients who developed epilepsy (early-epilepsy) and those who did not (single-seizure). Fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were calculated. Group differences were analyzed using tract-based spatial statistics and permutation analysis of linear models.

Results: Compared to controls, first-seizure patients showed decreased FA (p < .05, d = 1.3) in the corpus callosum and forceps minor, among other tracts. Similar changes were found in the single-seizure group (p < .05, d = 1.3), whereas the early-epilepsy patients showed decreases only in the corpus callosum (p < .05, d = 2.4). We confirmed that patients with chronic epilepsy have widespread FA decreases (p < .05, d = 1).

Significance: We provide evidence that, as early as after the first unprovoked seizure, patients considered NL by conventional methods harbor marked microstructural abnormalities detectable with diffusion magnetic resonance imaging (MRI). These findings suggest that WM alterations are present very early in the epileptogenic process even before the diagnosis can currently be made. These results have important implications for better understanding the epileptogenic process and preexisting structural difference in patients after a first seizure.

Keywords: TBSS; diffusion imaging; early epilepsy; imaging biomarkers; unprovoked seizures.

FIGURE 1

Altered fractional anisotropy in patients in comparison to controls. Results for FA decreases (red‐yellow) in (A) first seizure (n = 20), (B) single‐seizure (n = 14), (C) early‐epilepsy (n = 7), and (D) chronic epilepsy (n = 32) groups. All results were significant at p _(FWE) < .05 and corrected within contrasts. FSL “tbssfill” was used to aid visualization. FA, fractional anisotropy; L, left; R, right.

FIGURE 2

FA values in clusters of interest. FA values obtained from local maxima at coordinates specific for (A) corpus callosum and (B) internal capsule across controls (n = 30, blue), first‐seizure (n = 20, yellow), and chronic‐epilepsy (red, n = 32) patients. In the first‐seizure group, the individual FA values that correspond to the single‐seizure group (n = 14) are indicated with yellow circles, whereas the early‐epilepsy patients (n = 7) with red triangles. Decreased FA in the anterior limb of the internal capsule was observed in both groups. However, in the chronic group, this difference was significant at an uncorrected threshold (uncorrected = .003, d = .93; Table S4). The density, medians, and inter‐quartile ranges of the FA are shown (FWE corrected, *p < .01). Panels C and D show the anatomical location of the cluster in the corpus callosum (C) and the internal capsule (D), with the TBSS white matter skeleton (green) overlaid on the standard brain in sagittal and axial sections. Available anatomic locations were extracted using the “JHU White‐Matter Tractography Atlas,” “JHU ICBM‐DTI‐81 White‐Matter Labels,” and the “Harvard‐Oxford Cortical Structural Atlas. FA, fractional anisotropy; FEW, family‐wise error.