Normal cerebral cortical thickness in first-degree relatives of temporal lobe epilepsy patients

Alhusaini, Saud; Kowalczyk, Magdalena A.; Yasuda, Clarissa Lin; Semmelroch, Mira; Katsurayama, Marilise; Zabin, Matheus; Zanão, Tamires; Nogueira, Mateus Henrique; Alvim, Marina K. M.; Ferraz, Victória R.; Tsai, Meng-Han; Fitzsimons, Mary; Lopes-Cendes, Íscia; Doherty, Colin P.; Cavalleri, Gianpiero L.; Cendes, Fernando; Jackson, Graeme D.; Delanty, Norman

doi:10.1212/wnl.0000000000006834

Cited by 8 publications

(12 citation statements)

References 28 publications

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“…Alhusaini and colleagues summarized the literature on familial traits in epilepsy before 2016 and found a probable familial component to hippocampal structural alterations, particularly in patients with TLE with a strong family history for seizures . Previous cohorts of sporadic TLE, including two recent studies, did not find significant hippocampal changes in unaffected relatives of patients with sporadic TLE, whereas one study observed a trend for bilaterally smaller hippocampi in unaffected siblings, similar to our results. One possible reason for the failure to detect hippocampal atrophy in the relatives of sporadic patients in previous studies is the use of an automated segmentation pipeline implemented in Freesurfer, which is known to be unreliable in small, sclerotic, or malrotated hippocampi .…”

Section: Discussionsupporting

confidence: 87%

“…In support of this, cortical thinning was previously associated with seizure frequency and duration of epilepsy and we also found a correlation with duration of epilepsy (Appendix ). On the other hand, two previous studies found altered cortical morphology driven by surface area contractions in siblings of patients with TLE, but there were no changes in cortical thickness . In our study, significant surface area abnormalities were found in patients with TLE but not in their siblings (Appendix ).…”

Section: Discussioncontrasting

confidence: 74%

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Shared hippocampal abnormalities in sporadic temporal lobe epilepsy patients and their siblings

et al. 2020

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Objective: To examine the shared familial contribution to hippocampal and extrahippocampal morphological abnormalities in patients with sporadic temporal lobe epilepsy (TLE) and their unaffected siblings. Methods: We collected clinical, electrophysiological, and T1-weighted magnetic resonance imaging (MRI) data of 18 sporadic patients with TLE without lesions other than hippocampal sclerosis (12 right, 6 left), their 18 unaffected full siblings, and 18 matched healthy volunteers. We compared between-group differences in cortical thickness and volumes of five subcortical areas (hippocampus, amygdala, thalamus, putamen, and pallidum). We determined the subregional extent of hippocampal abnormalities using surface shape analysis. All our imaging results were corrected for multiple comparisons using random field theory. Results: We detected smaller hippocampal volumes in patients (right TLE: median right hippocampus 1.92 mL, interquartile range [IQR] 1.39-2.62, P < .001; left TLE: left hippocampus 2.05 mL, IQR 1.99-2.33, P = .01) and their unaffected siblings (right hippocampus 2.65 mL, IQR 2.32-2.80, P < .001; left hippocampus 2.39 mL, IQR 2.18-2.53, P < .001) compared to healthy controls (right hippocampus 2.94 mL, IQR 2.77-3.24; left hippocampus 2.71 mL, IQR 2.37-2.89). Surface shape analysis showed that patients with TLE had bilateral subregional atrophy in both hippocampi (right > left). Similar but less-pronounced subregional atrophy was detected in the right hippocampus of unaffected siblings. Patients with TLE had reduced cortical thickness in bilateral premotor/prefrontal cortices and the right precentral gyrus.Siblings did not show abnormalities in cortical or subcortical areas other than the hippocampus. Significance: Our results demonstrate a shared vulnerability of the hippocampus in both patients with TLE and their unaffected siblings, pointing to a contribution of familial factors to hippocampal atrophy. This neuroimaging trait could represent an endophenotype of TLE, which might precede the onset of epilepsy in some individuals. |LONG et aL.

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Section: Discussionsupporting

confidence: 87%

Section: Discussioncontrasting

confidence: 74%

Shared hippocampal abnormalities in sporadic temporal lobe epilepsy patients and their siblings

et al. 2020

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“…Similarly, previous work in temporal lobe epilepsy failed to identify MRI-derived cortical thickness changes as a structural endophenotype, while other morphologic features, including localized contractions of cerebral surface area, showed correlated topologic alterations between patients and their firstdegree relatives. 14,46 In healthy people, cortical thickness is believed to be largely determined by prenatal and postnatal developmental processes. 47 Progressive cortical atrophy associated with longer disease duration and increased seizure frequency, a phenomenon often reported in epilepsy, likely represents a marker of disease severity.…”

Section: Discussionmentioning

confidence: 99%

“…12 In epilepsy, most effort has been dedicated to exploring MRI endophenotypes in focal syndromes, primarily temporal lobe epilepsy. 13,14 Conversely, structural MRI studies of JME have so far described group-level changes between patients and healthy controls, which have been interpreted as disease effect. 2 Our purpose was to assess the endophenotypic potential of structural MRI in JME.…”

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confidence: 99%

Developmental MRI markers cosegregate juvenile patients with myoclonic epilepsy and their healthy siblings

Wandschneider¹,

Hong²,

Bernhardt³

et al. 2019

Neurology

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Objective MRI studies of genetic generalized epilepsies have mainly described group-level changes between patients and healthy controls. To determine the endophenotypic potential of structural MRI in juvenile myoclonic epilepsy (JME), we examined MRI-based cortical morphologic markers in patients and their healthy siblings. MethodsIn this prospective, cross-sectional study, we obtained 3T MRI in patients with JME, siblings, and controls. We mapped sulco-gyral complexity and surface area, morphologic markers of brain development, and cortical thickness. Furthermore, we calculated mean geodesic distance, a surrogate marker of cortico-cortical connectivity. ResultsCompared to controls, patients and siblings showed increased folding complexity and surface area in prefrontal and cingulate cortices. In these regions, they also displayed abnormally increased geodesic distance, suggesting network isolation and decreased efficiency, with strongest effects for limbic, fronto-parietal, and dorsal-attention networks. In areas of findings overlap, we observed strong patient-sibling correlations. Conversely, neocortical thinning was present in patients only and related to disease duration. Patients showed subtle impairment in mental flexibility, a frontal lobe function test, as well as deficits in naming and design learning. Siblings' performance fell between patients and controls. ConclusionMRI markers of brain development and connectivity are likely heritable and may thus serve as endophenotypes. The topography of morphologic anomalies and their abnormal structural network integration likely explains cognitive impairments in patients with JME and their siblings. By contrast, cortical atrophy likely represents a marker of disease.Glossary ANOVA = analysis of variance; JME = juvenile myoclonic epilepsy.

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“…Interestingly, both Alhusaini et al and Yaakub et al found reduced cortical surface areas in anteromedial temporal regions of asymptomatic siblings of sporadic MTLE‐HS patients, but no significant changes in cortical thickness. This lack of cortical thickness changes has been confirmed in 127 asymptomatic first‐degree relatives of MTLE‐HS patients from three independent cohorts, each with a healthy control group . These findings altogether indicate that the previously characterized progressive cortical thinning in patients with MTLE‐HS is not heritable and is likely driven by disease‐related factors, whereas changes in the cortical surface area may represent an inherited trait that preceded seizure onset.…”

mentioning

confidence: 54%

Evidence for a genetic effect in altered cortical surface area but not in cortical thinning in siblings of patients with mesial temporal lobe epilepsy

Cendes

2018

Epilepsia

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Although studies have shown cortical and subcortical changes in first-degree relatives of patients with familial forms of temporal lobe epilepsy, few studies have addressed extrahippocampal morphology changes in unaffected siblings of patients with sporadic mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Alhusaini et al 1 described subtle reduced cortical volumes in the anteromedial temporal cortex of asymptomatic siblings of sporadic MTLE-HS patients, suggesting that such localized traits are possibly heritable. In this issue of Epilepsia, Yaakub et al 2 replicated these findings in firstdegree asymptomatic relatives of patients with MTLE-HS. 2 A positive history of simple febrile convulsions before the age of 4 years was present in two relatives in this study. 2 Both these relatives had values above the median of the relative group for the reduced surface area in the anteromedial temporal cortex, further strengthening the possibility that these subtle morphological changes are inherited. 2 Limitations of this study include the small number of subjects studied and that they side-flipped the images to increase power to detect differences, thus treating both hemispheres as if they were equal, which is not the case, as shown recently by Kong et al. 3 The study by Alhusaini et al 1 showed that the alterations of cortical morphology found in anteromedial regions of unaffected siblings of subjects with left MTLE-HS (more in the left entorhinal cortex and parahippocampal gyrus) differed from those found in unaffected siblings of subjects with right MTLE-HS (more in the right entorhinal cortex and temporal pole).It is of relevance that both studies 1,2 used FreeSurfer (http://surfer.nmr.mgh.harvard.edu), which measures cortical volume as a product of two distinct aspects of the cortical architecture: cortical thickness and surface area. 4 Cortical thickness and surface area measurements appear to represent different early neurodevelopmental events with distinct genetic influences, as shown by Panizzon et al 5 in a magnetic resonance imaging study of twins. They found that, although cortical thickness and surface area are both highly heritable (>0.80), they are mostly unrelated genetically (genetic correlation = 0.08). 5 These results suggest some independence of these two surface-based measures, and potentially, their asymmetry patterns. A recent study that mapped cortical brain asymmetry in 17 141 healthy individuals showed regions with different asymmetrical patterns in cortical thickness and surface area and a significant heritability of these asymmetry characteristics. 3 Effect sizes of cortical thickness and surface area were independent, and the asymmetry was generally more prominent for surface area compared with that of cortical thickness. 3 Most regions showed significant asymmetry in surface area, although with no clear directional pattern affecting neighboring regions, or along the anterior-posterior axis, as they observed for cortical thickness. 3 Widespread cerebral cortical thinning ha...

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Normal cerebral cortical thickness in first-degree relatives of temporal lobe epilepsy patients

Cited by 8 publications

References 28 publications

Shared hippocampal abnormalities in sporadic temporal lobe epilepsy patients and their siblings

Shared hippocampal abnormalities in sporadic temporal lobe epilepsy patients and their siblings

Developmental MRI markers cosegregate juvenile patients with myoclonic epilepsy and their healthy siblings

Evidence for a genetic effect in altered cortical surface area but not in cortical thinning in siblings of patients with mesial temporal lobe epilepsy

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