Abstract
Objective: Hippocampal atrophy (HA), the main lesion associated with drug-resistant temporal lobe epilepsy, can be reliably evaluated using conventional magnetic resonance imaging (MRI) with satisfactory lateralization of the epileptogenic focus. Post-processing quantitative techniques permit better evaluation of extratemporal volume abnormalities, including cortical and subcortical gray matter (GM) structures, with more consistent findings in the hemisphere ipsilateral to the epileptogenic focus, including the thalamus and adjacent gyri. We aimed to analyze the relationship between subcortical GM volume and temporal lobe epilepsy associated with hippocampal atrophy (TLE-HA), including hippocampal subfield analysis.
Design: A transversal observational study conducted with patients from Clinics Hospital of the Federal University of Paraná, and a group control of healthy participants from Diagnostico Avançado por Imagem – DAPI.
Setting: This study was conducted at Diagnostico Avançado por Imagem (Clinical Imaging Institution in Curitiba, Brazil) and Clinics Hospital of the Federal University of Paraná, Brazil.
Participants: Patients with TLE-HA referred for surgical planning between September 2013 and August 2018 and individuals without pathologies on MRI scans other than HA were included.
Methods: Subcortical GM volumes of the hippocampus, amygdala, and basal ganglia were obtained using automated techniques from the MRI scans of 38 patients with TLE-HA (17 with left TLE-HA) and compared with those of 59 healthy controls.
Results: Patients with right TLE-HA demonstrated no significantly lower volumes in the subcortical structures; however, contralateral amygdala enlargement was observed (t = 3.802, P < 0.001). No significant volume loss was observed in the left TLE-HA group, the contralateral hippocampus, or hippocampal subfield comparisons; however, enlargement of the contralateral hippocampal amygdala transitional area was observed (t = 2.57, P = 0.012 for R-TLE-HA; t = 2.20, P = 0.031 for L-TLE-HA).
Conclusion: Our findings suggest different patterns of subcortical volume abnormalities in patients with left and right TLE-HA, which may indicate different neural network abnormalities on the ictal side. No significant volume abnormalities existed in the contralateral hippocampus in the TLE-HA group or specific hippocampal subfields in automated analysis. Subtle contralateral amygdala enlargement was present in both groups and may play a specific role in the epileptogenic mechanisms.
Epilepsy is a significant neurological disease with several clinical and social impairments, and almost one-third of patients do not achieve appropriate control of seizures with pharmacologic therapy.1–4 Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults, with a characteristic history, seizure semiology, and epileptogenic foci localized on electroencephalography (EEG) during the episode. It is also the most common type of epilepsy referred for surgical treatment.5,6 The primary structural lesion associated with TLE is hippocampal sclerosis, which is present in magnetic resonance imaging (MRI) of hippocampal atrophy (HA) and T2 hyperintensity.6,7 Although TLE associated with HA (TLE-HA) is usually related to alterations restricted to the mesial portion of the temporal lobe on conventional MRI, several studies have demonstrated extrahippocampal white and gray matter abnormalities in the contralateral side to the epileptogenic focus.8-10 The gray matter volume loss in TLE-HA is correlated with poor surgical outcomes.
Because these findings are often not accessible in conventional MRI studies, quantitative techniques can improve the detection of HA.6 Moreover, it can indicate extrahippocampal findings in the deep gray matter and extratemporal findings. Automated segmentation of the cortex and gray matter subcortical structures permits comparison between two or more groups of participants and has been frequently used in studies on gray matter volume abnormalities associated with epilepsy and other neurological disorders.9,11,12 Moreover, new segmentation techniques permit a better evaluation of hippocampal subfields. However, data from several studies are conflicting, particularly regarding the structures contralateral to the epileptic focus.8,13
This study aimed to identify possible subcortical gray matter abnormalities in patients with TLE-HA in a tertiary healthcare center using FreeSurfer volumetry and segmentation techniques, including hippocampal subfield analysis, and compare control groups and patients with left and right TLE.
Methods
Study Participants
This study was approved by the Ethics in Research Committee of the Clinics Hospital of the Federal University of Paraná, and the patients provided written informed consent. We included 38 patients (21 with right TLE-HA, including 8 males, and 17 with left TLE-HA, including 6 males) referred for surgical planning between September 2013 and August 2018 and without pathologies on MRI scans other than HA. All patients had drug-resistant epilepsy, as defined by the ILAE.14 The patients were evaluated clinically using EEG recordings during the crisis, with findings consistent with TLE. We compared these patients with 59 healthy controls with no history of neurological conditions. Clinical data on age, sex, disease duration, education, and laterality were obtained from the medical records and video-EEG (VEEG) reports.
MRI Acquisition
MRI was performed in the interictal period using a 3T Siemens MAGNETOM Skyra scanner (Erlangen, Germany). The morphometry protocol consists of a 3D T1 MP-RAGE (three-dimensional magnetization prepared rapid acquisition gradient-echo) sequence acquired in the sagittal plane (176 slices, FoV 256 mm, slice thickness 1 mm, voxel volume 1 mm³, TE 3.36 ms, TR 2530 ms, TI 1100 ms, pixel bandwidth 200 Hz/px, flip angle 7°). We acquired additional sequences of coronal T2-weighted fast spin-echo perpendicular to the hippocampus, 3D T2 fluid-attenuated inversion recovery, susceptibility-weighted imaging, and diffusion tensor imaging. The scans were read by two neuroradiologists (GRS and SEO), and the unilateral HA diagnosis and the affected side were established by consensus, considering visual and qualitative parameters: hippocampal height, morphology, and altered signal. All patients had concordant HA and ictal changes on VEEG.
MRI Volumetry
T1-weighted MRI scans were processed using the FreeSurfer software package (http://surfer.nmr.mgh.harvard.edu/), stable version 6.0 (January 2017), run in CentOS 6 Linux Stable, as previously documented in other studies.15–32 The 3D T1 morphometric sequence was chosen for the segmentation analysis because it provided better cortical and white matter definitions in our protocol than other sequences. We ran the recon-all script by adding the hippocampalsubfields-T1 flag and extracted the subcortical gray matter and hippocampal subfield volumes (in cubic millimeters), as in our previous studies.30,31 Whole hippocampal volume was obtained and 12 subfields were determined by automated segmentation: the hippocampal tail, subiculum, CA1, hippocampal fissure, presubiculum, parasubiculum, molecular layer, granule cell layer of the dentate gyrus (GC-DG), CA3, CA4, fimbria, and hippocampal amygdala transitional area. The results were satisfactory, and minor errors in volumes detected in the visual inspection were not considered for editing, as bias due to over- or under-correction during the process could occur. We used the database of the control group to obtain the reference volumes. Hippocampal volumes, subfields, and subcortical gray matter structures were corrected for estimated total intracranial volume (eTIV).
Statistical Analysis
We used Jamovi Software version 2.3 for Windows (Jamovi Project, 2023, Sidney, Australia) for the statistical analysis. The chi-square test was used to evaluate demographic data (sex), seizure subtype, and the presence of a contralateral focus in EEG records. ANOVA was used to analyze patients’ age between the groups, and Mann–Whitney tests were used to analyze disease duration and age of disease onset, as these variables did not present a normal distribution in the Shapiro–Wilk test (P<0.05). The percentage of eTIV (%eTIV) obtained from subcortical structures and hippocampal subfields was compared with means and SD, applying the standard Student’s t-test for group samples (P value < 0.05 was considered significant).
Results
Table 1 describes the demographic data and clinical features. There were no significant differences in age (P = 0.62), sex (P = 0.98), age at epilepsy onset (P = 0.96), or disease duration between the groups (P = 0.85), nor in seizure subtypes (P = 0.43) or main electroencephalographic abnormalities (P = 0.92). Post-processed subcortical %eTIV comparisons of patients with TLE-HA and controls are shown in Table 2. In the R-TLE-HA group, contralateral amygdala enlargement was detected (0.131 ± 0.020 / 0.113 ± 0.018, P<0.001), but not in the L-TLE-HA group (0.122 ± 0.033 vs. 0.120 ± 0.018, P = 0.664). No statistically significant differences were observed in the ipsilateral amygdala in either group, nor in the thalami or basal ganglia.
Comparisons of demographic and clinical data of the patient and control groups
Ratio volumes of subcortical structures (%eTIV) in controls and patients with left and right TLE-HAb
The post-processed hippocampal subfield comparisons are shown in Tables 3 and 4. As expected, a significant %eTIV reduction was observed in almost all ipsilateral atrophic hippocampal segments, including the whole hippocampus (0.1828 ± 0.0259 vs. 0.02385 ± 0.0355, P < 0.001 for L-TLE-HA; 0.01836 ± 0.0241 vs. 0.02436 ± 0.0013, P < 0.001 for R-TLE-HA), as well as in the CA1 (0.0334 ± 0.0052 vs. 0.00429 ± 0.0067, P < 0.001 for L-TLE-HA; 0.00343 ± 0.0044 vs. 0.00453 ± 0.0072, P < 0.001 for R-TLE-HA) and CA4 (0.0119 ± 0.0019 vs. 0.0173 ± 0.0026, P < 0.001 for L-TLE-HA; 0.0120 ± 0.0019 vs. 0.0178 ± 0.0026, P < 0.001 for R-TLE-HA.
Hippocampal subfields volumetry data of patients with left TLE-HA patients compared to that of the control group
Hippocampal subfields volumetry data of patients with right TLE-HA patients compared to that of the control group.
For both sides, contralateral enlargement of the hippocampus amygdala transition area (HATA) was detected (0.0048 ± 0.0008 vs. 0.0043 ± 0.0007, P = 0.028 for L-TLE-HA; 0.0046 ± 0.0007 vs. 0.0042 ± 0.0006, P = 0.01 for R-TLE-HA). A discrete reduction in ipsilateral HATA was also detected in the L-TLE-HA group (0.0038 ± 0.0005 vs. 0.0042 ± 0.0006, P = 0.043), but not in the R-TLE-HA group (0.0041 ± 0.0007 vs. 0.0043 ± 0.0007, P = 0.314).
Discussion
We quantitatively analyzed subcortical gray matter in patients with TLE and HA. In addition to determining the epileptogenic focus in TLE, MRI post-processing techniques are useful for determining extra-hippocampal findings utilizing automated quantitative analysis and specific hippocampal analysis with subfield analysis.8,9,33
We found a statistically significant left amygdala enlargement in the R-TLE-HA group and a volume increase in the HATA in both subfield analysis groups. The amygdala consists of a group of nuclei connected to several cortical and subcortical structures and is related to emotional and behavioral aspects.
In TLE, it may be implied in seizure semiology and symptoms, such as sensation of fear, olfactory hallucinations, and autonomic disorders.34,35 There is considerable evidence of amygdala enlargement in TLE, principally in “non-lesional” negative MRI studies,8,36,37 although there is no consensus regarding it being considered an isolated syndrome.38,39 However, there are correlations with later age of onset of epilepsy, more impaired consciousness crisis, and a better response to pharmacologic treatment.40 Moreover, the histological analysis after surgical resection demonstrated different results, including gliosis, cortical dysplasia, and tumors.41 Amygdala enlargement associated with hippocampal sclerosis has been reported by Coan et al.,42 with more than 90% of patients having contralateral volume abnormality in the ictal zone. An earlier age of onset of seizures was described in the amygdala enlarged group, which could also represent a marker of early TLE. However, those patients were previously selected based on amygdala enlargement defined by a volume higher than two standard deviations from the median of the control group, which differs from our patients with more subtle volume abnormalities. Therefore, there is an evident difference between the median amygdala volume in our sample and the referred study, although our patients had a similar median age of onset of epilepsy (right TLE-HA: 10 years [1–34 years]; left TLE-HA: 10 years [1–18 years]) to the AE group previously reported (11 years [1–38 years]).42
Our analysis revealed no significant volume loss in the contralateral hippocampus. The connections between the hippocampus and its role in epileptogenic spread are well-defined;42-44 however, previous data regarding contralateral hippocampal volume are conflicting.11,13,44 We found no statistically significant differences in the contralateral hippocampal subfield analysis. Our subfield analysis revealed a significant reduction in nearly all ipsilateral hippocampal segments, including CA1 and CA4. Recent results with automated FreeSurfer analysis showed no correlation between ipsilateral hippocampal segmentation and clinical data such as patient age, age at epilepsy onset, disease duration, and seizure frequency.10,45,46 However, there appears to be better surgical outcomes in patients with CA1 and CA4 atrophy in the ipsilateral hippocampus,44 as well as a good overlap between subfield analysis with high-resolution MRI and hippocampal sclerosis types in histology.45
Our study has some limitations. Our sample size was small, but the groups evaluated were homogeneous, with the same parameters in the clinical evaluation of MRI scans, although we did not apply correlation tests with clinical data. In addition, some imprecisions are unavoidable in automated analysis, although these methods have been validated in several previous studies. Correlating these findings with histological data is impossible, because surgical resection is not indicated for contralateral findings.
Conclusion
Automated post-processing techniques are valuable for quantitatively analyzing subcortical gray matter and hippocampal subfields in TLE. Quantitative analysis of the subcortical gray matter showed statistically significant volume abnormalities in the amygdala in the R-TLE-HA group and the transitional area in the subfield analysis in both groups. The role of the amygdala in TLE appears to be complex, and further studies are necessary to evaluate its involvement in different types of epilepsy.
Acknowledgments
We would like to thank Editage (www.editage.com.br) for English language editing.
Footnotes
Disclosures: The authors declare there are no personal, professional or financial conflicts of interest related to this study. This study did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. Participants were provided by the Epilepsy and EEG Service from the Hospital de Clinicas, Curitiba, Brazil, and MRI scans and exams post-processing were provided by Diagnostico Avançado por Imagem – DAPI, at no cost for participants and authors. Informed consent was obtained from all participants included in the study. All procedures involving human participants were performed in accordance with the ethical standards of the Institutional (Hospital de Clínicas of the Federal University of Paraná) Research Committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was registered in Plataforma Brazil (CAAE: 05201412.4.0000.0096) and was approved by the Ethics in Research Committee.
- Received December 7, 2023.
- Revision received September 15, 2024.
- Accepted November 11, 2024.
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