In the 1990s, the examination of structural abnormalities in people with mTLE was extended beyond the epileptogenic hippocampus. Using quantitative MRI tools that focused on manually delineated volumes to assess brain size, investigators first probed hippocampal related structures and found atrophy in neocortical temporal lobes 59
, entorhinal cortex 88, 89
, fornix 90
, parahippocampal gyrus 89
, and amygdala 89, 91
. Quantitative volumetric studies were also applied to other subcortical structures and yielded abnormalities in the basal ganglia 92, 93
, thalamus 92, 94, 95
, and cerebellum 96, 97
. Thus, these studies demonstrated that anatomical abnormalities in mTLE were certainly not limited to the epileptogenic hippocampus. However, these early volumetric techniques only permitted examinations of one, or a limited number of predetermined structures, rather than simultaneously characterizing a broad range of deficits throughout the entire brain.
The first glimpse of the distributed nature of structural abnormalities in mTLE came from Sisodiya and colleagues 98
. Instead of manually tracing structures with defined borders, they divided each hemisphere into blocks and quantified the amount of cortical gray matter and white matter throughout the entire brain. Each anatomical block of a patient with mTLE was compared to normal controls in order to assess for disproportional distribution of gray and white matter. Indeed, a majority of patients with hippocampal sclerosis had diffuse abnormalities throughout the cerebral cortex, but the exact location could not be elucidated from this technique.
With the emergence of automated analysis tools such as voxel based morphometry (VBM), the whole brain now can be scrutinized voxel by voxel in the same patient group to more precisely localize brain regions that are affected in mTLE. This unbiased examination of the entire brain facilitated appreciation of the distribution and relative degree of structural burden carried by many patients. In that regard, a very helpful summary of the presence and distribution of structural abnormalities associated with TLE is provided by Keller and Roberts 99
. They summarized 18 VBM studies and found 26 brain regions that showed reduced volumes in TLE, compared to healthy controls. The distribution of abnormalities was widespread, involving mesial, extramesial temporal lobe, subcortical and extratemporal lobe cortical regions.
Although VBM studies provide an anatomical profile of the extent of abnormalities, the pathological nature of these changes was uncertain 99
. Gray matter measurements in VBM are sensitive to both losses in gray matter as well as increases in CSF volume, as well as differences in cortical surface curvature, which cannot be distinguished from each other. These limitations provided the impetus to examine changes in other brain features such as indices of gyrification, cortical thickness, and surface area. Lin and colleagues examined cortical thickness in a group of mTLE patients with pathologically confirmed hippocampal sclerosis and found that these patients to have up to a 30% decrease in cortical thickness, with significant thinning of frontal poles, frontal operculum, orbitofrontal, lateral temporal, and occipital regions (). Interestingly, reductions in cortical thickness were evident in bilateral cerebral hemispheres, despite unilateral seizure onset 100
. Other investigators have also reported bilateral cortical mantel thinning in select regions throughout the entire cerebral cortex, but most consistently in the frontal, central and temporal regions101–103
. Widespread abnormalities in gyrification patterns were found in multiple cortical regions, both ipsilateral and contralateral
Figure 4 Reduced gray matter thickness and white matter integrity in left MTLE. a | Mean percent reduction in cortical thickness as a percentage of control average. Red areas in the bilateral in the frontal poles, frontal operculum, orbitalfrontal, lateral temporal (more ...)
In addition to gray matter abnormalities, aberrant white matter tracts and connections are present in chronic TLE. The advent of diffusion tensor imaging (DTI) techniques has allowed investigators to measure white matter tract integrity by assessing magnetic resonance signal of water diffusion and its directionality in three-dimensional space. Parallel to early quantitative gray matter volumetric studies, initial DTI studies also focused on the limbic system and found diffusion abnormalities in the bilateral of fornix and cingulum 104
. Postulating on a more diffuse epileptogenic network in TLE, other investigations extended this initial finding to frontal-temporal (uncinate fasciculus and arcuate fasciculus) 105–107
, temporal-occipital (inferior longitudinal fasciculus)108
, frontal-occipital (inferior frontal occipital fasciculus)108
and interhemispheric connections (corpus callosum) 109–111
. More recently, whole brain voxelwise analysis techniques have mapped white matter profiles and delineated systemic differences between TLE patients and healthy individuals, without a priori bias for specific tracts or brain regions. Focke and colleagues (2008) used such a voxelwise technique to evaluate diffusion abnormalities in patients with mTLE and found that reduced white matter integrity was present in mesial and lateral temporal lobe, limbic system (thalamus, fornix and cingulum), and extratemporal regions (arcuate fasciculus, external capsule and corpus collosum), The white matter changes were more pronounced ipsilateral to side of seizure onset ()112
. Other studies have also showed demonstrated extensive bilateral white matter diffusion abnormalities, particularly in the temporal and frontal lobes ipsilateral to the side of seizure onset 113–115
In summary, there is converging evidence that while the primary epileptic zone may be contained within the confines of the hippocampus, considerable anatomic abnormality exists outside this region, affecting a myriad of cortical, subcortical, and cerebellar regions and their direct and indirect connectivity.