MRI segmentation analysis in temporal lobe and idiopathic generalized epilepsy
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Temporal lobe epilepsy (TLE) and idiopathic generalized epilepsy (IGE) patients have each been associated with extensive brain atrophy findings, yet to date there are no reports of head to head comparison of both patient groups. Our aim was to assess and compare between tissue-specific and structural brain atrophy findings in TLE to IGE patients and to healthy controls (HC).
TLE patients were classified in TLE lesional (L-TLE) or non-lesional (NL-TLE) based on presence or absence of MRI temporal structural abnormalities. High resolution 3 T MRI with automated segmentation by SIENAX and FIRST tools were performed in a group of patients with temporal lobe epilepsy (11 L-TLE and 15 NL-TLE) and in15 IGE as well as in 26 HC. Normal brain volume (NBV), normal grey matter volume (NGMV), normal white matter volume (NWMV), and volumes of subcortical deep grey matter structures were quantified. Using regression analyses, differences between the groups in both volume and left/right asymmetry were evaluated. Additionally, laterality of results was also evaluated to separately quantify ipsilateral and contralateral effects in the TLE group.
All epilepsy groups had significantly lower NBV and NWMV compared to HC (p < 0.001). L-TLE had lower hippocampal volume than HC and IGE (p = 0.001), and all epilepsy groups had significantly lower amygdala volume than HC (p < = 0.004). In L-TLE, there was evidence of atrophy in both ipsilateral and contralateral structures.
Our study revealed that TLE and IGE patients demonstrated similar overall tissue-specific brain atrophy, although specific structures differences were appreciated. L-TLE also appeared to behave differently than NL-TLE, with atrophy not limited to the ipsilateral side.
KeywordsTemporal lobe epilepsy Idiopathic generalized epilepsy MRI segmentation Brain atrophy
Temporal lobe epilepsy
Idiopathic generalized epilepsy
Magnetic resonance imaging
Normal brain volume
Normal gray matter volume
Normal white matter volume
Mesial temporal sclerosis
Long term monitoring
Childhood absence epilepsy
Juvenile absence epilepsy
Juvenile myoclonic epilepsy
Epilepsy monitoring unit
Long term monitoring
Temporal lobe epilepsy (TLE) is the most common cause of partial epilepsy, and mesial temporal sclerosis (MTS) is the major pathological finding, occurring in roughly 50% of TLE patients. An estimated 30% of patients exhibit other identifiable magnetic resonance imaging (MRI) findings such as cortical dysplasia, low grade tumors or cavernous hemangiomas. The remaining 20% have no definite abnormalities observed visually on qualitative MRI assessment, and are often referred as non-lesional TLE  (NL TLE). Identifying the specific structures and neuronal pathways affected in TLE can help further understand the underlying mechanisms and disease chronicity. Different tissue-specific atrophy studies have been reported separately in epileptic syndromes including TLE, extra-temporal epilepsy, and idiopathic generalized epilepsy (IGE). In TLE, hippocampal involvement has been considerably investigated by various methods of MRI volumetric analyses, both manual and automatic [2, 3, 4, 5, 6, 7]. Most studies have found significant reductions in hippocampal volumes, predominantly ipsilateral to the seizure focus [4, 5, 6], although relation to disease duration and seizure severity remains controversial [8, 9, 10, 11, 12]. Additional studies in TLE have reported more extensive structural involvement outside the temporal structures [9, 10, 13], in particular bilateral atrophy of the thalami has been consistently reported [9, 11, 14, 15, 16].
IGE are a group of age-related epilepsies with complex genetic backgrounds, subdivided according to the predominant seizure types (absence, myoclonic, or generalized tonic-clonic) and age of onset. The IGE are typically divided in the following sub-syndromes: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with generalized tonic-clonic seizures . In IGE, various volumetric studies have reported findings of structural abnormalities [18, 19, 20, 21, 22, 23], though reports implicating the thalamus are still somewhat contradictory [15, 19, 20, 21, 22, 24]. While thalamic volumes in patients with IGE were not significantly different from those of normal control subjects in some reports , other studies reported evidence of regional atrophy in the thalamus, putamen and globus pallidus in IGE patients as compared to controls [20, 22]. Although specific structural atrophies were reported independently in both TLE and IGE, there are no reports of head to head comparison of both patient groups using the same atrophy analysis measures.
The goal of this study was to assess the extent of tissue-specific and structural brain atrophy in patients with TLE compared with IGE and age-matched controls. We used an automated software tool for brain MRI segmentation into various regions of interest to enable quantitative analysis of the different brain structures [25, 26].
This was a retrospective study conducted at the Buffalo Neuroimaging Analysis Center (BNAC) and the Comprehensive Epilepsy Program at the Jacobs Neurological Institute, Department of Neurology, State University of New York at Buffalo, with approval of the study protocol by the institutional review board (IRB). The study consisted of comprehensive review of medical records. Brain MRI segmentation analysis was performed on the previously performed MRI. A waiver of informed consent was obtained from the IRB.
The study included three population groups: TLE patients, IGE patients and healthy controls. The first two patient population groups were retrieved through a patient epilepsy monitoring unit (EMU) database following IRB approval. All patient demographics were de-identified. The inclusion criteria for TLE patients consisted of: age >18 years at time of MRI, diagnosis of TLE supported by history, documented seizures on EMU long term monitoring (LTM) video electroencephalogram (EEG), and having underwent a 3 T MRI using a standard epilepsy protocol at a single site within 12 months of the LTM. The TLE patients’ were further subdivided into lesional (L-TLE) and non-lesional (NL-TLE) based on the presence or absence of temporal pathology on MRI as identified by the report of a certified neuro-radiologist. The inclusion criteria for IGE patients consisted of: age > 18 years, and supportive ictal findings on LTM. The IGE patients’ MRI were classified as normal or with a low number of non-specific white matter changes not related to the subcortical deep grey matter structures. The exclusion criteria included any MRI-detected structural abnormalities beyond abnormalities seen in TLE that would preclude the segmentation procedure. We enrolled only patients with TLE and IGE that were 18 years and older, as we only had age-matched MRI controls for this age group.
Clinical data of all TLE and IGE patients were obtained from medical history and LTM reports, and included location of epileptic focus (for TLE patients), International League Against Epilepsy seizure classification, frequency of seizures, age at epilepsy onset and duration of disease.
All subjects underwent MRI testing at a single 3 T GE Signa Excite HD 12.0 Twin Speed 8-channel scanner (General Electric, Milwaukee, WI). Volumetric analysis was based on an axial T1 Inversion Recovery Fast Spoiled Gradient Echo (IR-FSPGR) sequence with flip angle = 20°, repetition time = 9.46 ms, echo time = 3.87 ms, matrix size of 256×256 pixels, and voxels of 1 × 1 × 1.5 mm. The lesions were assessed on 2D scans (proton density [PD]/T2, Fluid attenuated inversion recovery [FLAIR] and spin echo [SE] T1), with 48 slices collected, with a thickness of 3 mm, and no gap between slices.
Image processing and volumetric analysis
To all images we applied an automatic inhomogeneity correction  to overcome distortions of intensity non-uniformity created by the scanner. The volumetric analyses were performed with the use of FMRIB tools (Oxford Centre for Functional MRI of the Brain, version 4.1) [25, 26]. The volumetric analysis was performed in a blinded manner in regard to the qualitative MRI results provided by the neuro-radiologist.
Statistical analysis was performed with R version 3.1.0 (http://www.R-project.org/). A GLM-based analysis of covariance (ANCOVA) model was used to evaluate group differences in volume measures between controls, IGE, NL-TLE, and L-TLE while controlling for variation in age and gender. Where group was a significant factor, post-hoc pair-wise comparisons were performed to identify specific differences. In the primary set of analyses, total tissue volumes and bilateral structure volumes were compared. In a secondary set of analyses, laterality was evaluated by comparing left/right asymmetry between groups. Asymmetry was calculated as the absolute difference between left and right structures divided by the total volume (left + right). Finally, ipsilateral and contralateral structures (as related to epileptic focus localization) in L-TLE were compared to HC to evaluate whether there was evidence of contralateral atrophy. For this final analyses, individual rather than left/right averaged structure volumes were used, so a mixed-effect model was employed using laterality, age, and gender as fixed effects and subject as a random effect. We used a conservative type 1 error threshold of p < 0.01 to correct for multiple testing.
Demographic and clinical characteristics of the study groups
Demographic and clinical characteristics
N (Males: Females)
42.1 ± 17.2 (18–72)
31.7 ± 11.7 (18–59)
38.6 ± 14.3 (19–61)
Age of onset, years
24.1 ± 20.3
12.5 ± 6.5
Epilepsy duration in years
17.9 ± 18.6
19.2 ± 15.6
Seizure frequency per month*
15 non-lesional, 11 lesional
In the TLE group, 16 had the seizure focus on the left hemisphere and 10 in the right hemisphere (for L-TLE alone, 4 right, 7 left). Fifteen patients in the TLE group had complex partial seizures with secondary generalization where 11 had complex partial seizures without secondary generalization. In the IGE group, 14/15 subjects had generalized tonic-clonic seizures, 11/15 had absence seizure and myoclonic seizures. MRI abnormalities included hippocampal atrophy in 5 patients and other findings in the 6 patients (cortical dysplasia 1, venous anomaly 1, atrophy 2, and non-specifc juxtacortical lesions 2).
Tissue- and structure-specific atrophy comparisons
In this study we compared L-TLE, NL-TLE, IGE, and healthy controls using the same methodology and same 3 T-scanner. Our study revealed that patients with TLE and IGE demonstrated similar tissue-specific atrophies in the whole brain and white matter. After correcting for age and gender, normal brain volume, normal grey matter volume and normal white matter volume were lower in the epilepsy group (TLE plus IGE) compared to controls, but predominantly as a result of white matter volume loss.
Our results in L-TLE patients were similar to varying TLE study reports in relation to atrophy at various subcortical structures such as the hippocampus and basal ganglia [6, 9, 11, 13, 15, 37]. The extent of atrophy noted in TLE patients suggests that the impact of temporal seizures is more widespread than the immediate temporal vicinity of the epileptogenic region. Furthermore, the bilateral distribution of tissue-specific atrophy suggests that the neuronal atrophy extends to both hemispheres, regardless of the side of focal epileptic origin [38, 39, 40].
Our results suggest that patients with chronic epilepsy, whether TLE or IGE, have chronic atrophy, mostly of white matter and of various subcortical deep grey matter structures: particularly hippocampi and amygdale bilaterally. Altered white matter integrity has been reported in TLE, with association to cognitive and clinical profiles as measured on diffusion tensor imaging (DTI) studies in the temporal, cerebellar and fronto-parietal structures [41, 42, 43]. Extensive white matter tracts abnormalities on DTI were identified also in JME .
Findings of ipsilateral thalamic hypometabolism on positron emission tomography (PET) studies have been described in patients with TLE, often attributed to a diaschisis effect. It has been postulated that hippocampal cell loss may result in decreased efferent synaptic activity to the thalamus and basal ganglia, causing decreased neuronal activity in these structures with consequent hypometabolism. It remains unknown whether the process of subcortical deep grey matter atrophy seen in volumetric studies is due to a similar mechanism to the ipsilateral hypometabolism seen in PET studies in TLE patients [45, 46].
Several limitations in our study which may have impacted our results and statistical power should be acknowledged. Our study was retrospective, and included a relatively small patient sample. Consesquently this might have altered our ability to detect subtle volume changes. In particular, we saw many intriguing statistical trends that should be investigated in a larger study. In addition, we performed a cross-sectional evaluation, making it difficult to ascertain progressive developments. We also did not have sufficient power to analyze the impact of medication, which may have modified atrophy rates. Another limitation may be that the IGE group was younger and although we corrected for age in our analysis the earlier onset age of epilepsy in this group may be an interfering factor.
In conclusion, our study supports that TLE and IGE are both associated with significant atrophy compared to healthy controls These changes appear to occur beyond the local temporal epileptogenic region for TLE patients. It remains unknown whether these changes are associated with neurological and cognitive morbidities often seen in patients with chronic epilepsy.
Prior to the initiation of the study, approval was obtained from the Institutional Review Board of the State University of New York at Buffalo.
There was no industry sponsorship or funding for this project.
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