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Keywords:

  • Hippocampal sclerosis;
  • Insula;
  • Mesial temporal lobe epilepsy;
  • Thalamus

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Purpose: To determine whether changes in gray matter volume (GMV) differ according to the affected side in mesial temporal lobe epilepsy/hippocampal sclerosis (MTLE/HS) syndrome, and moreover to test the hypothesis of more pronounced structural changes in right-sided MTLE/HS. This hypothesis (especially that the contralateral thalamus is more affected in right-sided MTLE/HS) arose from the results of our recent study, wherein more expressed structural and functional changes were observed in a small sample of patients with right-sided MTLE/HS (Brázdil et al., 2009).

Methods: Twenty patients with left-sided and 20 with right-sided MTLE/HS and 40 sex- and age-matched healthy controls were included in the study. Voxel-based morphometry (VBM) with a modulation step was applied to magnetic resonance imaging (MRI) brain images. Statistical parametric maps were used to compare structural changes between patients and controls separately for the left- and right-sided MTLE/HS subgroups. We also compared the local GMV of the brain structures (insula and thalamus) between the subgroups of patients.

Results: In the subgroup with right-sided MTLE/HS, a reduction of GMV was detected in the mesiotemporal structures and the ipsilateral thalamus (as in left-sided MTLE/HS), but also notably in the ipsilateral insula and contralateral thalamus. A statistical analysis revealed a significantly more extensive reduction of GMV in the ipsilateral/contralateral insula and the contralateral thalamus in the subgroup with right-sided compared to left-sided MTLE/HS.

Conclusion: We found asymmetrical morphologic changes in patients with left- and right-sided MTLE/HS syndrome (more pronounced in right-sided MTLE/HS). These differences could be theoretically explained by different neuronal networks and pathophysiologic changes in temporolimbic structures.

Mesial temporal lobe epilepsy (MTLE) is one of the most frequent forms of localization-related epilepsy and the most common human intractable epilepsy. The most common pathologic correlate of MTLE is hippocampal sclerosis (HS), which is histopathologically characterized by gliosis and neuronal loss.

Recent studies in patients with MTLE/HS repeatedly revealed structural and functional abnormalities in regions other than the hippocampus. Changes in volume and concentration (gray and white matter) as well as functional changes [electroencephalography (EEG), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), and single photon emission computed tomography (SPECT) studies] were repeatedly shown extending to other brain regions surrounding the hippocampus (the parahippocampal gyrus and the amygdala) and other distant structures (several neocortical regions, the thalamus, the striatal nuclei, the cerebellum, the internal capsule, and the brainstem). The abnormalities were found mainly ipsilateral to the side of the epileptic focus, as described in previous studies (Henry et al., 1993; Bernasconi et al., 1999; Kuzniecky et al., 2001; Keller et al., 2002; Bernasconi et al., 2004; Bonilha et al., 2004; Keller et al., 2004; Bonilha et al., 2005; Düzel et al., 2006; Guye et al., 2006; Mueller et al., 2006; Nelissen et al., 2006; Bonilha et al., 2007; Fojtíková et al., 2007;Keller et al., 2007; Keller & Roberts, 2008).

These functional and structural changes may be interpreted as a result of the repetitive spreading of seizure activity or as an alteration of an afferentation from the affected hippocampus or other structures of the mesial temporal/limbic network (Spencer, 2002; Wennberg et al., 2002; Mueller et al., 2006).

In this study, we investigated statistical parametric maps (SPMs) of gray matter volume (GMV) to identify focal atrophy (absolute amount of gray matter) within different brain structures. Previous studies disclosed a higher sensitivity of GMV, which may reveal subtle neuroanatomic changes within the brain not identified in standard analyses of gray mater concentration (GMC) (Keller et al., 2004; Brázdil et al., 2009). In addition to the investigation of SPMs of the whole brain, a statistical analysis of local GMV values of the thalamus and the insula (both ipsilateral and contralateral) was performed. We tested the hypothesis that damage to ipsilateral/contralateral regions (especially to the thalamus) is significantly different in right- and left-sided MTLE/HS. The hypothesis arose from our study (Brázdil et al., 2009) in which distinct structural and functional abnormalities of left- and right-sided MTLE/HS were detected. Interestingly, the changes (in the contralateral thalamus) were more pronounced in the subgroup of patients with right-sided MTLE/HS. Due to the small sample size of the previous study, we decided to perform a new voxel-based morphometry (VBM) study with more subjects included in the study. We also decided to test this hypothesis in the insula and the thalamus because of different SPM results of this study (Fig. 1).

image

Figure 1.   Abnormalities of gray matter volume (GMV). (A) Reduction in GMV in left-sided mesial temporal lobe epilepsy/hippocampal sclerosis (MTLE/HS) compared to healthy subjects. (B) Reduction in GMV in right-sided MTLE/HS compared to healthy subjects. Both maps are corrected at p < 0.05 FDR (false discovery rate).

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We used optimized VBM, an automatic whole-brain magnetic resonance imaging (MRI) analysis technique, with a modulation step to investigate gray matter abnormalities separately in patients with right- and left-sided MTLE/HS.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Subjects

We studied 20 patients with left-sided MTLE (14 female, 6 male) with a mean age of 39.5 years [standard deviation (SD) = 9.7; range 20–55 years] and 20 patients with right-sided MTLE (14 females, 6 males) with a mean age of 39.4 years (SD = 10.6; range 24–61 years). Patients were referred to the Brno Epilepsy Center, Department of Neurology. All the patients fulfilled the diagnostic criteria for MTLE/HS. The diagnosis was made according to the International League Against Epilepsy (ILAE) criteria (Commission on Classification and Terminology of ILAE, 1989). All of the patients had been routinely investigated, including long-term semi-invasive video-EEG monitoring (using sphenoidal electrodes), high resolution MRI, and neuropsychological testing. The diagnosis of unilateral MTLE in our patients was based on a consonance of history data, ictal and interictal EEG findings, ictal semiology, neuropsychology, and neuroimaging findings. Visual inspections of the MRI scans [MRI protocol included T1, T2, and fluid-attenuated inversion recovery (FLAIR) sequences (axial and coronal slices)] by two independent physicians (radiologist and epileptologist) revealed unequivocal unilateral HS in 20 patients on the left side and in 20 patients on the right side. All of our patients had MRI evidence of unilateral HS concordant with the EEG lateralization of the epileptogenic zone. None of our patients revealed other brain structural lesions on MRI scans, and none of the patients had undergone previous intracranial surgery. All patients had been seizure free for ≥24 h before the MRI investigation. The mean age of the patients with left-sided MTLE at the time of seizure onset was 8.7 years (SD = 9.3) and the mean disease duration was 31.2 years (SD = 12.2). The mean age of the patients with right-sided MTLE at the time of seizure onset was 10.3 years (SD = 10.8) and the mean disease duration was 29.1 years (SD = 13.3). The majority of patients had no history of precipitating events. Four patients with left-sided MTLE/HS had commotio cerebri, meningoencephalitis, or head trauma with subdural hematoma. Six patients with right-sided MTLE/HS had commotio cerebri, meningoencephalitis, head trauma, perinatal encephalopathy, or encephalitis. There was no significant variance between the subgroups in their positive history of febrile convulsions (seven in left-sided MTLE/HS and six in right-sided MTLE/HS); repetitions of febrile seizures occurred in one left-sided patient and in two cases in the subgroup with right-sided MTLE/HS. The majority of patients had a history of complex partial seizures. Ten patients in the left subgroup and eight patients in the right subgroup had secondary generalized seizures. One patient with left and one with right MTLE/HS had simple partial seizures. The subgroups did not significantly differ in the seizure frequency (range approximately 0–20 per month). With the exception of the number of prescribed antiepileptic drugs, there were no statistically significant divergences in the demographic and clinical data between the subgroups detected using a t-test (Table 1). There was a significant difference in the number of prescribed antiepileptic drugs (number of types): a mean of 2.3 medications for the left-sided MTLE/HS subgroup, and a mean of 1.8 medications for the right-sided MTLE/HS subgroup (Table1).

Table 1.   Demographic and clinical data
 Subgroup of left-sided MTLE/HS patientsSubgroup of right-sided MTLE/HS patientst-test
MeanSDMeanSD
  1. HS, hippocampal sclerosis; MTLE, mesial temporal lobe epilepsy; SD, standard deviation.

Age of patients (years)39.59.739.410.60.97
Age at the time of seizure onset (years)8.79.310.310.80.62
Mean disease duration (years)31.212.229.113.30.60
Seizure frequency per month1129.45.574.10.40
Number of antiepileptic drugs takenmean 2.3/day0.8mean 1.8/day0.60.03
 Total number of patients 
Precipitating events460.49
History of febrile convulsions760.74
Repetitions of febrile seizures120.56
Secondary generalized seizures1080.54

The control group consisted of 40 healthy subjects (30 female, 10 male) with a mean age of 37.6 years (SD = 9.8; ages ranged from 18–53 years). No significant differences in age (t = 0.97) between the two subgroups of patients and controls (t = 0.49 lefts vs. controls, t = 0.53 rights vs. controls) were detected. The majority of the healthy subjects in the control group were volunteers from the professional sector; no history of neurologic or psychiatric disease was presented in any controls.

Written informed consent was obtained from each participant after all of the procedures were fully explained. The study received the approval of the local ethics committee.

MR image acquisition

MRI examinations were performed on a 1.5 T scanner (Siemens Magnetom Symphony, Erlangen, Germany) using a multichannel head coil. The MRI protocol for VBM included three-dimensional (3D) T1-weighted magnetization prepared rapid gradient echo (MPRAGE) sequence with TR = 1.7 s, TE = 3.93 ms, TI = 1.1 s, FA = 15°, 512 × 512 matrix size, FOV 246 × 246 mm, and 160 sagittal slices with slice thickness = 1.17 mm.

Data processing

Anatomic MRI data were analyzed using SPM2 (Wellcome Department of Cognitive Neurology, http://www.fil.ion.ucl.ac.uk) running in MATLAB 6.5 (The MathWorks, Natick, MA, U.S.A.). Preprocessing of structural data was performed using a VBM2 toolbox (http://dbm.neuro.uni-jena.de/vbm/vbm2-for-spm2/). We used optimized VBM with modulation as described by Good et al. (2001b). Because a previous VBM study found significant left-right asymmetries in gray matter in healthy brains (Good et al.,2001a), we generated customized templates and customized priors for the first subgroup (patients with left-sided MTLE/HS and healthy controls) and the second subgroup (patients with right-sided MTLE/HS and healthy controls) separately. Some of the differences between left- and right-sided MTLE/HS might have been detected due to the different template/priors, so we also tested for the influence of the template/prior by comparing gray matter maps of controls. This test did not produce dissimilar results.

To create the customized template and customized priors, the original images of healthy controls (40 images) and MTLE/HS patients (20 images) were processed using the standard VBM toolbox. Priors were then applied to the original raw images of all participants to segment into gray matter partitions, which were then spatially normalized to the customized gray matter template. The deformation parameters (Jacobean determinants) obtained from the normalization step were then applied to the whole-brain structural image, and the brain extraction step was repeated to create optimally normalized gray matter brain images. The modulation step was performed for GMV inferences. Finally, smoothing with an 8-mm Gaussian kernel for modulated gray matter/white matter segment was performed.

The modulated gray matter images were analyzed using SPM2. The first analysis was performed as a comparison of GMV of the patients with left-sided MTLE/HS and healthy controls. The second analysis was performed as a comparison of GMV of the patients with right-sided MTLE/HS and healthy controls. Age, total intracranial volume, and sex were included as nuisance variables for analysis of variance (ANOVA) comparisons. We also included the duration of the epilepsy as a nuisance factor (Bonilha et al., 2006). No grand mean scaling, nonsphericity correction, and no implicit and explicit masks were set. Global calculation was omitted. The threshold for proportional masking was set to 0.1 and 100 contiguous voxels (the size of one voxel is 1 × 1 × 1 mm).

Contrasts were defined to detect whether each voxel of tissue had a lower probability of being gray matter between patients and controls. The resultant t statistic maps were thresholded at a p-value of <0.05 using false discovery rate (FDR). The resulting clusters are presented in Tables 2 and 3 with their family wise error (FWE)-corrected p-values.

Table 2.   Hippocampal and extrahippocampal GMV reduction in patients with left-sided MTLE/HS
Cluster (subclusters)ClusteraClusterwiseVoxelwiseCoordinates (MNI )
p-value corrected (FWE )TZ-scorexy
  1. amin. size 100 voxels.

  2. GMV, gray matter volume; HS, hippocampal sclerosis; MTLE, mesial temporal lobe epilepsy; FWE, family wise error; MNI, Montreal Neurological Institute.

Ipsi hippocampus11355<0.0018.626.81−27−18−17
 Ipsi parahippocampal gyrus5012      
 Ipsi hippocampus 1012      
 Ipsi thalamus1708      
 Ipsi amygdala778      
 Contra thalamus333      
 Ipsi brainstem141      
Table 3.   Hippocampal and extrahippocampal GMV reduction in patients with right-sided MTLE/HS
Cluster (subclusters)ClusteraClusterwiseVoxelwiseCoordinates (MNI )
p-value corrected (FWE)TZ-scorexyz
  1. amin. size 100 voxels.

  2. GMV, gray matter volume; HS, hippocampal sclerosis; MTLE, mesial temporal lobe epilepsy; FWE, family wise error; MNI, Montreal Neurological Institute.

Ipsi parahippocampal gyrus17917<0.0018.976.9934−15−20
 Ipsi parahippocampal gyrus5566      
 Ipsi hippocampus942      
 Ipsi amygdala570      
 Ipsi thalamus2242      
 Contra thalamus990      
 Ipsi insula1428      
 Ipsi superior temporal gyrus404      
 Ipsi middle temporal gyrus481      
 Ipsi claustrum180      
 Ipsi brainstem180      
 Ipsi caudate102      

The third statistical analysis was used to compare the adjusted local GMV values of the thalamus (ipsilateral and contralateral) and the insula (ipsilateral and contralateral). The local GMV values were calculated as an average intensity value within the region of gray matter–modulated segments, specified by mask of the thalamus and the insula. The masks were created using the WFU Pickatlas (ver. 2.3) (Maldjian et al., 2003, 2004) and AAL Atlas (Tzourio-Mazoyer et al., 2002). The data of the local GMV (of controls and patients) were adjusted to the unitary volume. The local GMV of each subject was divided by the total intracranial volume of each subject [computed as total gray matter (gm) volume + total white matter (wm) volume] and multiplied by a maximum of the total intracranial volumes of the respective subgroup (left- or right-sided/patients or control). The purpose was to reduce variances of brain size. These results were then assessed. We used a t-test to evaluate the hypothesis that differences of adjusted local GMV of the ipsilateral and contralateral thalamus and the ipsilateral and contralateral insula between controls and subgroups of patients are more extensive in right-sided MTLE/HS.

t-Tests were performed to determine differences of ages, onsets, disease duration, and other clinical data among subgroups (Table 1).

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Regions with significantly reduced GMV in patients with MTLE/HS syndrome are given in Tables 2 and 3. Significant decreases in GMV in the left-sided MTLE/HS subgroup were observed predominantly in the ipsilateral hippocampus, parahippocampal gyrus, amygdala, and thalamus; there were also subtle changes in the contralateral thalamus (Fig. 1A). All of these structures were parts of a greater cluster with its maximum in the hippocampus (Table 2). A more obviously extensive GMV reduction was revealed in the patients with right-sided MTLE/HS (Fig. 1B). In patients of this subgroup, the reduction of volume was clearly detected, mainly in the ipsilateral hippocampus, parahippocampal gyrus, and thalamus, but also notably in the ipsilateral insula and contralateral thalamus. As in the subgroup with left-sided MTLE/HS, all structures were parts of one big cluster for the patients with right-sided MTLE/HS (Table 3).

Interestingly, in the subgroup with right-sided MTLE/HS, a statistical analysis (t-test) of adjusted local gray matter values revealed a significantly greater reduction of volume in the ipsilateral insula (p < 0.01) (Fig. 2), and unexpectedly in the contralateral insula (p < 0.01) (Fig. 2). A more pronounced gray matter reduction was found in the contralateral thalamus (p < 0.001) (Fig. 3) in the subgroup with right-sided MTLE/HS compared to the subgroup with left-sided MTLE/HS. The results in the ipsilateral thalamus were not significant (p = 0.13) (Fig. 3).

image

Figure 2.   Reduction in the volume of the ipsilateral (A)/contralateral insula (B) [differences between the values of the adjusted analyzed variables in both patients and healthy controls, presented separately for the subgroups of patients with left- and right-sided mesial temporal lobe epilepsy/hippocampal sclerosis (MTLE/HS)].

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image

Figure 3.   Reduction in the volume of the ipsilateral (A)/contralateral thalamus (B) [differences between the values of the adjusted analyzed variables in both patients and healthy controls, presented separately for the subgroups of patients with left- and right-sided mesial temporal lobe epilepsy/hippocampal sclerosis (MTLE/HS)].

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Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Our study confirmed the diminished volume of the ipsilateral mesial temporal lobe (MTL) in the hippocampus, amygdala, and entorhinal cortex (part of the parahippocampal gyrus) on the side of the focus in both subgroups. This is in agreement with the understanding of mesial temporal circuitry (Bernasconi et al., 1999). Moreover, we detected morphometric differences in the ipsilateral and contralateral thalamus (in both subgroups) and the ipsilateral insula (in the subgroup with right-sided MTLE). These results are in congruence with those of other studies, although the studies themselves varied in the representation of the diminished volume of these extrahippocampal structures (Keller & Roberts, 2008).

The role of the ipsilateral thalamus in the medial temporal/limbic epileptic network was repeatedly confirmed by MRI study (Düzel et al., 2006), PET study (Henry et al., 1993), and MRS study (Fojtíková et al., 2007), and changes in the contralateral thalamus were observed in a MRS study by Hetherington et al. (2007). The thalamus has reciprocal connection to the parietal, frontal, and temporal cortices through corticopulvinocortical circuitry. It may play a role in the regulation or coordinating of corticocortical communication and cortical signal processing (Shipp, 2003). Morphometric studies (DeCarli et al., 1998; Labate et al., 2008) and EEG studies described a temporolimbic pathway, including the thalamus and playing a major role in the pathogenesis of TLE seizures (Guye et al., 2006). Moreover, the medial pulvinar may serve as a relay for spreading epileptic activity (Guye et al., 2006).

In addition, an affecting of the insula in patients with TLE was described, for example, in the work of Guenot & Isnard, 2008. Seizures arising from the temporal lobe always invade the insular region, but in approximately 10% of cases, the seizures originate in the insular cortex itself (Guenot & Isnard, 2008).

Interestingly, the results from our study revealed the alterations in the volume of the ipsilateral/contralateral insula and contralateral thalamus in MTLE to be significantly more extensive in patients with right-sided MTLE/HS. These differences could not be attributed to a different present disease severity, type of seizure, type of precipitating events, epilepsy duration, or seizure frequency, since those factors did not differ significantly between the left and right-sided MTLE/HS subgroups (Table 1). Unfortunately we are not able to compare the whole case history and disease progression of these subgroups due to fragmentary data from patients and other epileptic clinics where the patients were treated. The number of seizures and their seriousness throughout the disease duration probably makes a difference in the influence of the brain structures (Labate et al., 2008). The influence of the different templates/priors was tested using comparison gray matter maps from the control groups generated by the two templates/priors. No significant differences were detected between the control’s gray matter maps.

Interestingly, there was a significant difference in the number of antiepileptic drugs (number of types) taken (the left-sided MTLE/HS subgroup had a mean of 2.3, compared to right-sided MTLE/HS subgroup with a mean of 1.8), which is in contrast with volumetric abnormalities (Table 1). This aspect reinforces the assumption that the seriousness of affection is not necessarily related to seizure severity (Labate et al., 2008).

In contrast to our results, some studies did not confirm rightward asymmetry and revealed a more widespread neuronal loss in patients with left-sided MTLE (Bonilha et al., 2004, 2007; Bernhardt et al., 2008; Riederer et al., 2008) or an identical pattern of gray matter decrease in the two subgroups of patients (Bernasconi et al., 2004). These discrepancies among the studies (variations in GMV decreases) probably reflect variations in methodology, for example, the absence of customized templates (Bernasconi et al., 2004), the comparison of contrasts of correlations between patients and controls (Bonilha et al., 2007), the cortical thickness measurements (Bernhardt et al., 2008), or the t-test of adjusted local GMV in our study. Some results were observed in a small sample size (Riederer et al., 2008). It is significant that all of our patients had been seizure-free for 24 h, because seizures very close to scanning might consequentially influence the VBM analysis.

We suppose the underlying difference among the previous studies and our study is the use of statistical analysis of adjusted local volume differences between the two subgroups (left and right). ROI (region of interest) analysis makes it possible to perform statistical analysis of volume differences between these two subgroups (left and right). We presume we would be able to see more extensive damage in a statistical parametric mapping of one subgroup, but without this statistical analysis we are not able to say if it is significant.

Neuronal damage in the brains of patients with MTLE follows an anatomic route for the spread of ictal activity (Spencer, 2002). Because neuronal damage to different regions observed in the brains of patients with MTLE correlates with the neuron’s connection to other regions (Bonilha et al., 2005), according to our results of GMV alterations it seems that there is asymmetry between the right and left mesiotemporal connectivity (more pronounced damage of volume in the right-sided MTLE subgroup), especially to the contralateral thalamus. Similar results of asymmetry between hemispheres were presented in a previous study, which demonstrated that in healthy controls the magnitude and extent of right hippocampal connectivity to other brain regions is greater than that of the left hippocampus (Wang et al., 2006). One SPECT study demonstrated a clear-cut asymmetry between left- and right-sided MTLE concretely in the contralateral hippocampus. With right-sided MTLE, interictal hypoperfusion of the contralateral hippocampus was more frequent (Tae et al., 2005). Asymmetry in connection to the right and left hemispheres could be also substantiated by work of Chassoux et al., 2004. Mesiotemporal seizure onset without evidence of early ictal spread patterns beyond the temporal lobe is more common when the focus of epilepsy is in the left hemisphere, whereas mesiolateral seizure onset is more widespread in the subgroup of patients with a right-hemisphere epileptic focus. However, these results might be confusing, because Chassoux discusses a selection bias of patients for the right predominance in the mesiolateral seizures. Anterior mesiolateral seizure spread is equally represented in both subgroups (Chassoux et al., 2004).

Interestingly we observed that our left-sided patients took a greater number of antiepileptic drugs than the right-sided, and in one study the slight but still significant predominance of left-sided temporal lobe epilepsy with HS was presented by Janszky et al. (2003). More intense cognitive impairment in patients with left-sided MTLE/HS was described by Bonilha et al., 2007. These results raise the question of the causation of more disease seriousness of left-sided MTLE/HS. There are several concepts of the pathophysiology of human epilepsy. One recent concept suggests the idea of a large human neural network as a dynamic structure containing a multiplicity of potential ictal generators (Spencer, 2002) and regulators of the stability of the network (Netoff et al., 2004). The medial temporal/limbic epileptogenic network is discussed in the example of TLE (Spencer, 2002), and the network stability increases with the rise of connection per the brain structure (Netoff et al., 2004). We speculate that it is possible that the magnitude and extent of right mesiotemporal connectivity to other brain regions is greater than that of the left-sided (especially to the contralateral thalamus). It might stabilize the neural network and might play more important roles in the modulation of the medial temporal/limbic epileptic network in the right hemisphere than in the left hemisphere. Due to this, the seriousness of the illness (of left-sided MTLE/HS) might have been more intense. The other explanation is discussed by Bonilha et al., 2007. Patients with left MTLE exhibit more intense cognitive impairment because cognitive assessment relies heavily on language-based tasks. The pathophysiologic foundation of our findings in the contralateral insula (more pronounced volumetric changes in the right-sided subgroup) is unknown and uncertain.

To sum our results: We found asymmetrical morphologic changes in patients with left- and right-sided MTLE/HS. More expressed structural abnormalities were detected in the right-sided MTLE/HS subgroup, especially in the ipsilateral insula and the contralateral thalamus. These differences could be theoretically explained by different neuronal networks, connections among brain areas, and pathophysiologic changes in the temporolimbic structures. It seems that the degree and location of neuronal cell loss are dependent on the side of MTLE/HS.

Acknowledgments

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The study was supported by MŠMT ČR Research Program no. MSM0021622404. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Disclosure: None of the authors has any conflict of interest to disclose.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References