White matter alterations in patients with MRI‐negative temporal lobe epilepsy and their asymptomatic siblings

Abstract

SUMMARYObjective: The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy. Methods: We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gendermatched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs). Results: Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset. Significance: These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusionbased endophenotype in the disorder. Further studies of narrow-sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results.

White matter abnormalities at a regional and voxel level in focal and generalized epilepsy: A systematic review and meta-analysis

“…The total number of people with epilepsy and controls was 1027 and 1122, respectively. Sixteen voxel-based studies were included, with 312 patients and 500 controls (Amarreh et al, 2014, Bonilha et al, 2015, Concha et al, 2012, Focke et al, 2014, Keller et al, 2013, Kim et al, 2012, Kim et al, 2014, Li et al, 2010, Liu et al, 2015, O'Muircheartaigh et al, 2011, Peng et al, 2014, Riley et al, 2010, Rugg-Gunn et al, 2001, Wang et al, 2011, Whelan et al, 2015, Yang et al, 2012). One of these studies was also included in the meta-analysis (Li et al, 2010).…”

White matter tractography for neurosurgical planning: A topography-based review of the current state of the art

“…By helping assess pre-surgical memory and language status, WMT provides valuable neuropsychological prognosis data that can help for counseling and then surgically treating patients (McDonald et al, 2008). White matter can display some alterations associated with epileptogenic cortical lesions as reported by Whelhan et al who described significant alterations of the fractional anisotropy and mean diffusivity of multiple tracts in mesial temporal epilepsy patients (Whelan et al, 2015). A better evaluation of these changes as well as any concomitant functional reorganization helps explain ictal spread patterns and provides a more comprehensive view when planning for surgery, particularly in when facing multiple epileptogenic lesions (Diehl et al, 2010).…”

Integrity of the corpus callosum in patients with benign temporal lobe epilepsy

“…Several morphometric and functional MRI studies have clearly demonstrated that extrahippocampal and extratemporal regions are involved in the epileptic network underlying MTLEand that alterations of brain tissue integrity in gray matter (GM) and white matter (WM) are present in patients with MTLE regardless of the presence of either HS or drug responsiveness . Indeed, several authors revealed significant extratemporal WM fractional anisotropy reductions in the corpus callosum (CC) together with other extratemporal regions, confirming the presence of microstructural WM alterations in patients with refractory MRI‐negative MTLE and providing preliminary support for a diffusion‐based endophenotype of the disorder . The CC is the largest commissural fiber bundle, connecting homotopic and heterotopic cortical regions of cerebral hemispheres, and it represents the most important pathway for the interhemispheric propagation of epileptic activity .…”

“…11,12 Indeed, several authors revealed significant extratemporal WM fractional anisotropy reductions in the corpus callosum (CC) together with other extratemporal regions, confirming the presence of microstructural WM alterations in patients with refractory MRI-negative MTLE and providing preliminary support for a diffusion-based endophenotype of the disorder. 13 The CC is the largest commissural fiber bundle, connecting homotopic and heterotopic cortical regions of cerebral hemispheres, and it represents the most important pathway for the interhemispheric propagation of epileptic activity. 14 Although these results are interesting, whether the observed structural alterations are related to the epileptic syndrome itself or to refractoriness and epilepsy duration remains in question.…”