Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study

Abstract

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by metaanalysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = À0.24 to À0.73; P 5 1.49 Â 10 À4 ), and lower thickness in the precentral gyri bilaterally (d = À0.34 to À0.52; P 5 4.31 Â 10 À6 ). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = À1.73 to À1.91, P 5 1.4 Â 10 À19 ), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = À0.36 to À0.52; P 5 1.49 Â 10 À4 ). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = À0.29 to À0.54; P 5 1.49 Â 10 À4 ). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = À0.27 to À0.51; P 5 1.49 Â 10 À4 ). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b 5 À0.0018; P 5 1.49 Â 10 À4 ). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy

“…Reduced parahippocampal volume correlated with disease duration across all epilepsy subjects. Progressive atrophy of mesial temporal structures occurs in temporal lobe epilepsy, and reduced volume of subcortical structures, including the parahippocampal gyri, is associated with greater disease duration in the common epilepsies . Our data reinforce an association between reduced subcortical volume and disease duration.…”

“…The increased amygdala volume is relevant because of its marked influences on breathing; stimulation elicits apnea in human epilepsy and triggering of respiratory phase changes in animal models . Similar amygdala volume increases have been described in SUDEP and in the common epilepsies . Volume increases may result from multiple processes, including enhanced activation from experience and inflammatory processes .…”

Multimodal computational neocortical anatomy in pediatric hippocampal sclerosis

“…This was as expected given that the inclusion criteria for patients involved a radiological diagnosis of HS. The surface‐based approach, to calculate per‐vertex cortical thickness, normalized FLAIR signal intensity and gray–white matter intensity contrast, demonstrated that while pediatric TLE patients did not show the widespread cortical thinning present in adult cohorts,16, 17, 18, 19 they nevertheless had morphological and intensity changes in ipsi‐lesional temporopolar neocortex. Furthermore, temporopolar FLAIR hyperintensities were more marked in patients with a history of febrile convulsions and blurring of the gray–white matter boundary was correlated with earlier onset of epilepsy.…”

“…Beyond the hippocampus, there is a body of neuroimaging literature in adults, utilizing both volumetric and surface‐based methodologies, describing whole‐brain changes in gray matter volume,16 cortical thickness17, 18, 19 and T2/FLAIR intensity 20, 21. These changes are seen after several decades of illness duration, as seizures often start in childhood and adolescence.…”

Neuroimaging and connectomics of drug‐resistant epilepsy at multiple scales: From focal lesions to macroscale networks

“…International initiatives such as Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA)‐epilepsy have shown that it is possible to aggregate multimodal neuroimaging metrics and clinical information across different sites, and to coordinate analytical strategies. Such large‐scale, open, and concerted efforts will be instrumental for the robust validation of novel approaches and biomarkers.…”