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

Brain, awx341, https://doi.org/10.1093/brain/awx341

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 meta-analysing 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.

Participant demographics

The sample size-weighted mean age across all epilepsy samples was 34.4 (range: 26.2–40) years, and the weighted mean age of healthy controls was 33.3 (range: 25.2–42.3) years. The weighted mean age at onset of epilepsy and duration of epilepsy were 17.6 (range: 12.1–28.2) years and 17.4 (range: 8.3–28) years, respectively. Females comprised 57% of the total epilepsy sample (range: 34–75% by individual sample), and 53% of the controls (range: 31–71% by individual sample). Case-control differences in age were observed at 8 of 24 research centres, and case-control differences in sex were observed at 2 of 24 research centres (Supplementary Table 5); hence, age and sex were included as covariates in all group comparisons.

Volumetric findings

Compared to controls, the aggregate all-epilepsies group exhibited lower volumes in the left (d = −0.36; P = 1.31 × 10−6) and right thalamus (d = −0.37; P = 7.67 × 10−14), left (d = −0.35; P = 3.04 × 10−7) and right hippocampus (d = −0.34; P = 6.63 × 10−10), and the right pallidum (d = −0.32; P = 8.32 × 10−9). Conversely, the left (d = 0.29; P = 2.14 × 10−12) and right (d = 0.27; P = 3.73 × 10−15) lateral ventricles were enlarged across all epilepsies when compared to controls (Table 2 and Fig. 2A). A supplementary analysis of all-epilepsies, excluding individuals with hippocampal sclerosis or other lesions, revealed similar patterns of volume loss in the right thalamus and pallidum, and bilaterally enlarged ventricles; however, volume differences were not observed in the hippocampus (Supplementary Table 6).

Table 2

Effect size differences between epilepsy cases and healthy controls (Cohen’s d) for the mean volume of subcortical structures, controlling for age, sex and intracranial volume

Structure Phenotype Cohen’s d SE Z score 95% CI P-value I2 N80 Number of controls Number of cases
Amygdala (LH) All-other-epilepsies 0.327 0.065 5.024 0.199–0.455 5.05 x 10−7 45.470 148 1448 998
Amygdala (RH) All-other-epilepsies 0.218 0.057 3.799 0.106–0.33 1.46 x 10−4 31.256 335 1422 989
Hippocampus (LH) MTLE-L −1.728 0.191 −9.056 −2.102 to −1.354 1.35 x 10−19 85.532 7 1412 410
All epilepsies −0.353 0.069 −5.121 −0.488 to −0.217 3.04 x 10−7 71.845 127 1707 2125
Hippocampus (RH) MTLE-R −1.906 0.15 −12.694 −2.2 to −1.611 6.36 x 10−37 72.476 6 1286 336
All epilepsies −0.336 0.054 −6.175 −0.443 to −0.229 6.63 x 10−10 54.801 141 1719 2129
Lateral ventricle (LH) MTLE-L 0.465 0.089 5.203 0.289–0.640 1.96 x 10−7 43.124 74 1417 414
MTLE-R 0.39 0.081 4.808 0.231–0.549 1.52 x 10−6 26.750 105 1291 338
All epilepsies 0.288 0.041 7.025 0.207–0.368 2.14 x 10−12 23.338 191 1722 2135
All-other-epilepsies 0.198 0.045 4.373 0.109–0.287 1.23 x 10−5 0.218 402 1452 996
Lateral ventricle (RH) MTLE-R 0.444 0.065 6.867 0.317−0.57 6.57 x 10−12 0.003 81 1292 338
MTLE-L 0.363 0.093 3.917 0.1814−0.544 8.95 x 10−5 47.227 121 1418 414
All epilepsies 0.268 0.034 7.864 0.2−0.334 3.73 x 10−15 0 220 1722 2137
All-other-epilepsies 0.212 0.046 4.581 0.122−0.303 4.62 x 10−6 3.528 350 1453 996
Pallidum (RH) MTLE-L −0.452 0.09 −5.009 −0.628 to −0.275 5.48 x 10−7 43.985 78 1406 414
MTLE-R −0.451 0.089 −5.071 −0.624 to −0.276 3.96 x 10−7 36.432 79 1278 332
All epilepsies −0.316 0.055 −5.762 −0.424 to −0.208 8.32 x 10−9 55.575 159 1710 2112
All-other-epilepsies −0.235 0.060 −3.942 −0.352 to −0.118 8.07 x 10−5 36.141 286 1440 976
Putamen (LH) MTLE-L −0.385 0.079 −4.878 −0.539 to −0.23 1.07 x 10−6 28.474 107 1352 410
Thalamus (LH) MTLE-L −0.843 0.126 −6.693 −1.089 to −0.595 2.19 x 10−11 70.462 24 1384 408
All epilepsies −0.358 0.074 −4.839 −0.503 to −0.213 1.31 x 10−6 75.649 124 1687 2104
Thalamus (RH) MTLE-R −0.727 0.103 −7.066 −0.928 to −0.525 1.60 x 10−12 51.499 31 1285 335
MTLE-L −0.462 0.117 −3.941 −0.691 to −0.232 8.12 x 10−5 67.376 75 1412 414
IGE −0.403 0.087 −4.633 −0.574 to −0.233 3.60 x 10−6 39.715 98 1210 363
All epilepsies −0.368 0.049 −7.476 −0.464 to −0.271 7.67 x 10−14 44.822 117 1716 2137
All-other-epilepsies −0.305 0.047 −6.502 −0.397 to −0.213 7.92 x 10−11 4.985 170 1446 998

CI = confidence interval; LH = left hemisphere; RH = right hemisphere; SE = standard error; I= heterogeneity index; N80 = number of subjects required in each group to yield 80% power to detect significant group differences (P < 0.05, two-tailed). Uncorrected P-values are reported. Subcortical structures that failed to survive Bonferroni correction (P < 1.49 x 10−4) are not reported (see ‘Materials and methods’ section for statistical threshold determination). See Supplementary material for a full list of volume differences with adjustment for false discovery rate (FDR).

Figure 2

Subcortical volume findings. Cohen’s d effect size estimates for case-control differences in subcortical volume, across the (A) all-epilepsies, (B) mesial temporal lobe epilepsies with left hippocampal sclerosis (HS; MTLE-L), (C) mesial temporal lobe epilepsies with right hippocampal sclerosis (MTLE-R), (D) idiopathic generalized epilepsies (IGE), and (E) all-other-epilepsies groups. Cohen’s d effect sizes were extracted using multiple linear regressions, and pooled across research centres using random-effects meta-analysis. Subcortical structures with P-values < 1.49 × 10−4 are shown in heatmap colours; strength of heat map is determined by the size of the Cohen’s d (d < 0 = blue, d > 0 = yellow/red). Image generated using MATLAB, with annotations added using Adobe Photoshop. An interactive version of this figure is available online, via ‘ENIGMA-Viewer’: http://enigma-viewer.org/ENIGMA_epilepsy_subcortical.html. See Supplementary material for guidelines on how to use the interactive visualization.

The MTLE-L subgroup showed lower volumes in the left hippocampus (d = −1.73; P = 1.35 × 10−19), left (d = P = 2.19 × 10−11) and right thalamus (d = −0.46; P = 8.12 × 10−5), left putamen (d = −0.39; P = 1.07 × 10−6), and right pallidum (d = −0.45; P = 5.48 × 10−7). As in the overall group comparison, we observed larger left (d = 0.47; P = 1.96 × 10−7) and right lateral ventricles (d = 0.36; P = 8.95 × 10−5) in MTLE-L patients relative to controls (Table 2 and Fig. 2B).

The MTLE-R subgroup showed lower volumes across a number of regions in the right hemisphere only, including the hippocampus (d = −1.91; P = 6.36 × 10−37), thalamus (d = −0.73; P = 1.6 × 10−12), and pallidum (d = −0.45; P = 3.96 × 10−7), together with increased volumes of the left (d = 0.39; P = 1.52 × 10−6) and right lateral ventricles (d = 0.44; P = 6.57 × 10−12) compared to controls (Table 2 and Fig. 2C).

The IGE subgroup showed lower volumes in the right thalamus (d = −0.4; P = 3.6 × 10−6) compared to controls (Table 2 and Fig. 2D).

The all-other-epilepsies subgroup showed lower volumes in the right thalamus (d = −0.31; P = 7.9 × 10−11) and the right pallidum (d = −0.24; P = 8.1 × 10−5) compared to controls. The all-other-epilepsies subgroup also showed significant enlargements of the left (d = 0.33; P = 5.1 × 10−7) and right amygdala (d = 0.22; P = 1.46 × 10−4), and the left (d = 0.2; P = 1.2 × 10−5) and right lateral ventricles (d = 0.21; P = 4.62 × 10−6) compared to controls (Table 2 and Fig. 2E).

All volume differences can be visualized using the interactive ENIGMA-Viewer tool (Zhang et al., 2017), at http://enigma-viewer.org/ENIGMA_epilepsy_subcortical.html (Supplementary material). Volume differences significant after FDR adjustment can also be visualized at http://enigma-viewer.org/ENIGMA_epilepsy_subcortical_fdr.html (Supplementary Tables 26–30).

Cortical thickness findings

The all-epilepsies group showed reduced thickness of cortical grey matter across seven regions bilaterally, including the left (d = −0.38; P = 1.82 × 10−18) and right precentral gyri (d = −0.4; P = 8.85 × 10−20), left (d = −0.32; P = 2.11 × 10−15) and right caudal middle frontal gyri (d = −0.31; P = 2.09 × 10−9), left (d = −0.31; P = 2.05 × 10−6) and right paracentral gyri (d = −0.32; P = 2.19 × 10−9), left (d = −0.19; P = 1.29 × 10−4) and right pars triangularis (d = −0.2; P = 4.25 × 10−8), left (d = −0.28; P = 1.51 × 10−7) and right superior frontal gyri (d = −0.27; P = 4.49 × 10−6), left (d = −0.19; P = 1.05 × 10−5) and right transverse temporal gyri (d = −0.18; P = 2.81 × 10−5), and left (d = −0.23; P = 9.87 × 10−5) and right supramarginal gyri (d = −0.22; P = 5.24 × 10−5). The all-epilepsies group also showed unilaterally thinner right cuneus (d = −0.2; P = 9.68 × 10−8), right pars opercularis (d = −0.18; P = 6.48 × 10−7), right precuneus (d = −0.28; P = 2.7 × 10−5), and left entorhinal gyrus (d= −0.26; P = 2.04 × 10−5), compared to healthy controls (Table 3 and Fig. 3A). Supplementary analysis in a non-lesional epilepsy subgroup revealed a similar pattern of cortical thickness differences compared to controls, suggesting that the changes observed in our main analysis were not driven by the inclusion of patients with hippocampal sclerosis or other common lesions (Supplementary Table 7).

Table 3

Effect size differences between epilepsy cases and healthy controls (Cohen’s d) for the mean thickness of cortical structures, controlling for age, sex and intracranial volume

Structure Phenotype Cohen’s d SE Z score 95% CI P-value I2 N80 Number of controls Number of cases
Caudal middle frontal gyrus (LH) MTLE-L −0.403 0.07 −5.789 −0.538 to −0.2663 7.07 x 10−9 13.807 98 1344 412
All epilepsies −0.319 0.04 −7.935 −0.397 to −0.24 2.11 x 10−15 17.112 156 1650 2061
All other epilepsies −0.291 0.045 −6.425 −0.38 to −0.202 1.32 x 10−10 0 197 1447 1000
Caudal middle frontal gyrus (RH) MTLE-L −0.441 0.087 −5.089 −0.611 to −0.271 3.61 x 10−7 39.444 82 1348 412
All epilepsies −0.307 0.051 −5.991 −0.407 to −0.206 2.09 x 10−9 46.443 168 1653 2059
All other epilepsies −0.212 0.045 −4.699 −0.301 to −0.124 2.62 x 10−6 0 350 1451 998
Cuneus (RH) All other epilepsies −0.234 0.045 −5.186 −0.323 to −0.146 2.15 x 10−7 0 288 1449 996
All epilepsies −0.204 0.038 −5.333 −0.279 to −0.129 9.68 x10−8 11.423 379 1651 2057
Entorhinal gyrus (LH) MTLE-L −0.445 0.072 −6.158 −0.5865 to −0.303 7.35 x 10−10 0 81 1102 303
All epilepsies −0.264 0.062 −4.261 −0.385 to −0.142 2.04 x 10−5 56.648 227 1402 1724
Fusiform gyrus (LH) MTLE-L −0.359 0.069 −5.183 −0.494 to −0.223 2.19 x 10−7 13.465 123 1339 412
Lateral occipital gyrus (RH) All other epilepsies −0.211 0.045 −4.659 −0.299 to −0.122 3.18 x 10−6 2.50 x 10−3 354 1450 997
Lingual gyrus (RH) All other epilepsies −0.180 0.045 −3.972 −0.268 to −0.091 7.12 x 10−5 1.25 x 10−2 491 1450 996
Paracentral gyrus (LH) MTLE-R −0.505 0.102 −4.944 −0.705 to −0.305 7.67 x 10−7 52.283 63 1292 338
MTLE-L −0.426 0.099 −4.313 −0.62 to −0.232 1.61 x 10−5 53.165 88 1344 412
All epilepsies −0.311 0.065 −4.748 −0.439 to −0.182 2.05 x 10−6 67.476 164 1650 2061
All other epilepsies −0.257 0.045 −5.680 −0.346 to −0.168 1.34 x 10−8 0 239 1447 1000
Paracentral gyrus (RH) MTLE-R −0.421 0.064 −6.538 −0.548 to −0.295 6.24 x 10−11 0.407 90 1296 338
MTLE-L −0.378 0.075 −5.021 −0.526 to −0.231 5.14 x 10−7 23.536 111 1348 412
All other epilepsies −0.351 0.045 −7.733 −0.44 to −0.262 1.05 x 10−14 3.43 x 10−3 129 1451 998
All epilepsies −0.315 0.053 −5.983 −0.418 to −0.212 2.19 x 10−9 49.261 160 1654 2059
Parahippocampal gyrus (LH) MTLE-L −0.3 0.073 −4.11 −0.444 to −0.1572 3.95 x 10−5 19.366 176 1335 410
Pars opercularis (RH) MTLE-R −0.271 0.071 −3.8 −0.411 to −0.131 1.45 x 10−4 12.105 215 1295 338
All epilepsies −0.177 0.036 −4.976 −0.247 to −0.107 6.48 x 10−7 2.624 503 1652 2059
Pars triangularis (LH) All epilepsies −0.192 0.05 −3.828 −0.2897 to −0.094 1.29 x 10−4 44.414 427 1650 2060
Pars triangularis (RH) MTLE-L −0.285 0.06 −4.738 −0.403 to −0.167 2.16 x 10−6 0 195 1346 412
All epilepsies −0.199 0.036 −5.48 −0.27 to −0.128 4.25 x 10−8 4.66 398 1652 2058
All other epilepsies −0.210 0.045 −4.650 −0.299 to −0.122 3.32 x 10−6 2.58 x 10−3 357 1449 998
Precentral gyrus (LH) MTLE-L −0.466 0.081 −5.755 −0.625 to −0.307 8.64 x 10−9 31.602 74 1339 412
MTLE-R −0.415 0.09 −4.596 −0.592 to −0.238 4.31 x 10−6 40.044 93 1287 338
All epilepsies −0.384 0.044 −8.768 −0.469 to −0.298 1.82 x 10−18 27.649 108 1645 2058
All other epilepsies −0.375 0.046 −8.237 −0.464 to −0.286 1.76 x 10−16 5.59 x 10−3 113 1442 997
IGE −0.342 0.071 −4.78 −0.482 to −0.201 1.75 x 10−6 0.003 136 1043 297
Precentral gyrus (RH) MTLE-R −0.52 0.086 −6.073 −0.687 to −0.352 1.25 x 10−9 33.288 60 1293 337
MTLE-L −0.492 0.078 −6.335 −0.6436 to −0.339 2.37 x 10−10 26.33 66 1345 412
All epilepsies −0.399 0.044 −9.102 −0.485 to −0.313 8.85 x 10−20 27.929 100 1649 2054
IGE −0.39 0.072 −5.442 −0.531 to −0.25 5.27 x 10−8 0.005 105 1044 295
All other epilepsies −0.348 0.045 −7.672 −0.437 to −0.259 1.70 x 10−14 0 131 1448 996
Precuneus (LH) MTLE-L −0.536 0.135 −3.965 −0.801 to −0.271 7.35 x 10−5 75.18 56 1343 412
All other epilepsies −0.178 0.047 −3.819 −0.27 to −0.087 1.34 x 10−4 4.474 497 1446 998
Precuneus (RH) MTLE-L −0.473 0.104 −4.558 −0.676 to −0.27 5.16 x 10−6 57.498 72 1348 412
All epilepsies −0.275 0.066 −4.197 −0.404 to −0.147 2.70 x 10−5 67.608 209 1654 2055
All other epilepsies −0.238 0.053 −4.471 −0.343 to −0.134 7.78 x 10−6 22.378 279 1451 994
Superior frontal gyrus (LH) MTLE-L −0.411 0.06 −6.804 −0.529 to −0.292 1.02 x 10−11 0 94 1343 412
All epilepsies −0.283 0.054 −5.251 −0.389 to −0.177 1.51 x 10−7 51.773 197 1649 2059
All other epilepsies −0.243 0.059 −4.138 −0.358 to −0.128 3.51 x 10−5 34.545 267 1446 999
Superior frontal gyrus (RH) MTLE-L −0.365 0.06 −6.051 −0.483 to −0.246 1.44 x 10−9 0 119 1345 412
All epilepsies −0.269 0.059 −4.588 −0.385 to −0.154 4.49 x 10−6 59.483 218 1650 2058
All other epilepsies −0.235 0.052 −4.489 −0.337 to −0.132 7.15 x 10−6 20.049 286 1448 997
Superior parietal gyrus (LH) All other epilepsies −0.224 0.045 −4.954 −0.313 to −0.136 7.27 x 10−7 0.001 314 1444 996
Superior parietal gyrus (RH) All other epilepsies −0.220 0.045 −4.864 −0.309 to −0.131 1.15 x 10−6 0.002 326 1450 997
Supramarginal gyrus (LH) All epilepsies −0.232 0.06 −3.894 −0.348 to −0.115 9.87 x 10−5 59.391 293 1606 1965
Supramarginal gyrus (RH) All epilepsies −0.223 0.055 −4.045 −0.331 to −0.115 5.24 x 10−5 52.895 317 1597 1971
All other epilepsies −0.206 0.047 −4.418 −0.297 to −0.115 9.95 x 10−6 0 371 1395 961
Temporal pole (LH) MTLE-L −0.315 0.068 −4.649 −0.447 to −0.182 3.33 x 10−6 10.901 160 1341 410
Transverse temporal gyrus (LH) MTLE-R −0.312 0.073 −4.249 −0.456 to −0.168 2.15 x 10−5 15.614 163 1289 338
All epilepsies −0.192 0.044 −4.406 −0.278 to −0.107 1.05 x 10−5 28.178 427 1647 2061
Transverse temporal gyrus (RH) All epilepsies −0.182 0.044 −4.188 −0.267 to −0.097 2.81 x 10−5 27.918 475 1654 2059
All other epilepsies −0.18 0.045 −3.982 −0.269 to −0.091 6.84 x 10−5 0.012 486 1451 998

CI = confidence interval; LH = left hemisphere; RH = right hemisphere; SE = standard error; I= heterogeneity index; N80 = number of subjects required in each group to yield 80% power to detect significant group differences (P < 0.05, two-tailed). Uncorrected P-values are reported. Cortical regions that failed to survive Bonferroni correction (P < 1.49 x 10−4) are not reported (see ‘Materials and methods’ section for statistical threshold determination). See Supplementary material for a full list of cortical differences with adjustment for false discovery rate (FDR).

Figure 3

Cortical thickness findings. Cohen’s d effect size estimates for case-control differences in cortical thickness, across the (A) all-epilepsies, (B) mesial temporal lobe epilepsies with left hippocampal sclerosis (MTLE-L), (C) mesial temporal lobe epilepsies with right hippocampal sclerosis (MTLE-R), (D) idiopathic generalized epilepsies (IGE), and (E) all-other-epilepsies groups. Cohen’s d effect sizes were extracted using multiple linear regressions, and pooled across research centres using random-effects meta-analysis. Cortical structures with P-values < 1.49 × 10−4 are shown in heatmap colours; strength of heat map is determined by the size of the Cohen’s d (d < 0 = blue, d > 0 = yellow/red). Image generated using MATLAB with annotations added using Adobe Photoshop. An interactive version of this figure is available online, via ‘ENIGMA-Viewer’: http://enigma-viewer.org/ENIGMA_epilepsy_cortical.html. See Supplementary material for guidelines on how to use the interactive visualization. HS = hippocampal sclerosis.

The MTLE-L and MTLE-R subgroups showed distinct patterns of cortical thickness reductions when compared to healthy controls (Table 3Fig. 3B and C). In MTLE-R, lower cortical thickness was reported across four motor regions, including the left (d = −0.51; P = 7.67 × 10−7) and right paracentral gyri (d = −0.42; P = 6.24 × 10−11), and the left (d = −0.42; P = 4.31 × 10−6) and right precentral gyri (d = −0.52; P = 1.25 × 10−9). The MTLE-R subgroup also showed thickness changes in the left transverse temporal gyrus (d = −0.31; P = 2.15 × 10−5), and right pars opercularis (d = −0.27; P = 1.45 × 10−4) (Table 3 and Fig. 3C). By contrast, in MTLE-L, lower thickness was observed across six regions of the motor cortex, including the left (d = −0.43; P = 1.61 × 10−5) and right paracentral gyri (d = −0.38; P = 5.14 × 10−7), left (d = −0.47; P = 8.64 × 10−9) and right precentral gyri (d = −0.49; P = 2.37 × 10−10), and left (d = −0.54; P = 7.35 × 10−5) and right precuneus (d = −0.47; P = 5.16 × 10−6). The MTLE-L group also showed thickness changes across five regions of the frontal cortex, including the left (d= −0.41; P = 1.02 × 10−11) and right superior frontal gyri (d = −0.37; P = 1.44 × 10−9), left (d = −0.4; P = 7.07 × 10−9) and right caudal middle frontal gyri (d = −0.44; P = 3.61 × 10−7), and the right pars triangularis (d= −0.29; P = 2.16 × 10−6). In MTLE-L, thickness alterations were also observed in four regions of the temporal cortex, including the left temporopolar cortex (d = −0.32; P = 3.33 × 10−6), left parahippocampal gyrus (d = −0.3; P = 3.95 × 10−5), left entorhinal gyrus (d = −0.45; P = 7.35 × 10−10), and left fusiform gyrus (d = −0.36; P = 2.19 × 10−7) (Table 3and Fig. 3B).

The IGE subgroup showed reduced thickness in the left (d = −0.34; P = 1.75 × 10−6) and right precentral gyri (d = −0.39; P = 5.27 × 10−8), when compared to healthy controls (Table 3 and Fig. 3D).

The all-other-epilepsies subgroup showed lower thickness across six cortical regions bilaterally, including the left (d = −0.38; P = 1.76 × 10−16) and right precentral gyri (d = −0.35; P = 1.7 × 10−14), left (d = −0.26; P = 1.34 × 10−8) and right paracentral gyri (d = −0.35; P = 1.1 × 10−14), left (d = −0.29; P = 1.32 × 10−10) and right caudal middle frontal gyri (d = −0.21; P = 2.62 × 10−6), left (d = −0.22; P = 7.27 × 10−7) and right superior parietal gyri (d = −0.22; P = 1.15 × 10−6), left (d = −0.24; P = 3.51 × 10−5) and right superior frontal gyri (d = −0.23; P = 7.15 × 10−6), and the left (d = −0.18; P = 1.34 × 10−4) and right precuneus (d = −0.24; P = 7.78 × 10−6) compared to controls. The all-other-epilepsies group also showed unilaterally reduced thickness in six right hemispheric regions, including the cuneus (d = −0.23; P = 2.15 × 10−7), lateral occipital gyrus (d = −0.21; P = 3.18 × 10−6), pars triangularis (d = −0.21; P = 3.32 × 10−6), supramarginal gyrus (d = −0.21; P = 9.95 × 10−6), transverse temporal gyrus (d = −0.18; P = 6.84 × 10−5), and lingual gyrus (d = −0.18; P = 7.12 × 10−5), compared to controls (Table 3 and Fig. 3E).

An interactive 3D visualization of these results is available via the ENIGMA-Viewer tool (Zhang et al., 2017), at http://enigma-viewer.org/ENIGMA_epilepsy_cortical.html (Supplementary material). Cortical thickness differences significant after FDR adjustment can also be visualized at http://enigma-viewer.org/ENIGMA_epilepsy_cortical_fdr.html (Supplementary Tables 31–35).

Duration of illness, age at onset, and age-by-diagnosis effects on brain abnormalities

A secondary analysis identified significant associations between duration of epilepsy and several affected brain regions in the all-epilepsies, MTLE-R, and all-other-epilepsies groups. In the all-epilepsies group, duration of epilepsy negatively associated with volume measures in the left hippocampus (b = −8.32; P = 8.16 × 10−13), left (b = −13.58; P = 3.52 × 10−15), and right thalamus (b = −12.25; P = 1.58 × 10−13), and right pallidum (b = −2.67; P = 1.78 × 10−7), in addition to bilateral thickness measures in the left (b = −0.003; P = 2.99 × 10−11) and right pars triangularis (b = −0.002; P = 4.24 × 10−9), left (b = −0.003; P = 1.61 × 10−15) and right caudal middle frontal gyri (b = −0.003; P = 1.65 × 10−17), left (b = −0.003; P = 1.77 × 10−13) and right supramarginal gyri (b = −0.003; P = 2.58 × 10−19), left (b = −0.003; P = 5.84 × 10− 12) and right precentral gyri (b = −0.003; P = 2.54 × 10−24), left (b = −0.004; P = 1.94 × 10−12) and right superior frontal gyri (b = −0.003; P = 4.65 × 10−11), left (b = −0.004; P = 1.05 × 10−10) and right transverse temporal gyri (b = −0.003; P = 8.24 × 10−10), and left (b = −0.002; P = 5.22 × 10−6) and right paracentral gyri (b = −0.002; P = 5.63 × 10−6). Duration of epilepsy also negatively associated with unilateral thickness measures in the right precuneus (b = −0.003; P = 6.03 × 10−21), right pars opercularis (b = −0.003; P = 5.59 × 10−13), and right cuneus (b = −0.002; P = 1.1 × 10−9Supplementary Table 8). In the MTLE-R subgroup, duration of epilepsy negatively associated with volume measures in the right hippocampus (b = −22.42; P = 1.1 × 10−7), and the right thalamus (b = −18.11; P = 1.84 × 10−5), and thickness measures in the left transverse temporal gyrus (b = −0.007; P = 8.39 × 10−5Supplementary Table 8). In the all-other-epilepsies subgroup, duration of epilepsy negatively associated with bilateral thickness measures in the left (b = −0.003; P = 3.39 × 10−7) and right caudal middle frontal gyri (b = −0.003; P = 6.91 × 10−8), left (b = −0.003; P = 1.36 × 10−9) and right superior frontal gyri (b = −0.003; P = 3.16 × 10−7), and the left (b = −0.003; P = 3.17 × 10−5) and right precuneus (b = −0.003; P = 5.01 × 10−9), in addition to unilateral thickness measures in the right precentral gyrus (b = −0.004; P = 1.16 × 10−12), right cuneus (b= −0.003; P = 8.57 × 10−8), right pars triangularis (b = −0.003; P = 5.16 × 10−7), and right supramarginal gyrus (b = −0.003; P = 2.24 × 10−7). Duration of epilepsy also showed a positive association with the size of the left lateral ventricle in the all-other-epilepsies group (b = 13.6; P = 1.17 × 10−5).

In the all-epilepsies group, age at onset of epilepsy negatively associated with thickness measures in the left (b = −0.003; P = 2.66 × 10−15) and right superior frontal gyri (b = −0.003; P = 9.77 × 10−10), left (b = −0.003; P = 2.78 × 10−9) and right pars triangularis (b = −0.003; P = 6.51 × 10−7), right pars opercularis (b = −0.003; P = 5.4 × 10−14), left transverse temporal gyrus (b = −0.003; P = 1.03 × 10−8), and right cuneus (b = −0.001; P = 4.9 × 10−6). In the all-other-epilepsies subgroup, age at onset negatively correlated with thickness measures in the left (b = −0.003; P = 3.21 × 10−8) and right superior frontal gyri (b= −0.002; P = 1.18 × 10−4), left (b = −0.002; P = 8.42 × 10−6) and right precuneus (b = −0.002; P = 7.23 × 10−5), right pars triangularis (b = −0.003; P = 2.53 × 10−5), and right supramarginal gyrus (b = −0.002; P= 2.38 × 10−6). Age at onset also positively associated with the size of the right lateral ventricle in the all-other-epilepsies subgroup (b = 57.73; P = 1.62 × 10−7).

Age at onset negatively associated with other regional volumetric and thickness measures in the all-epilepsies, IGE, MTLE-L, MTLE-R, and all-other-epilepsies groups, but these associated areas showed no significant structural differences in the primary case-control analysis (Table 1 and Supplementary Table 8).

There were no interaction effects between age and syndromic diagnosis in the all-epilepsies, MTLE-L, MTLE-R, IGE, or all-other-epilepsies groups.

Power analyses for detection of case-control differences

In our sample of 2149 individuals with epilepsy and 1727 healthy controls, we had 80% power to detect Cohen’s d effect sizes as small as d = 0.091 at the standard alpha level of P < 0.05 (two-tailed), and 80% power to detect Cohen’s d effect sizes as small as d = 0.149 at the study’s stringent Bonferroni-corrected threshold of P < 1.49 × 10−4.

N80, the number of cases and controls required to achieve 80% power to detect group differences using a two-tailed t-test at P < 0.05, ranged from N80 = 6, to detect group effects in the right hippocampus in our MTLE-R group, to N80 = 503, to detect group effects in the right pars opercularis in our ‘all epilepsies’ group (Tables 2 and 3).

Discussion

In the largest coordinated neuroimaging study of epilepsy to date, we identified a series of quantitative imaging signatures—some shared across common epilepsy syndromes, and others characteristic of selected, specific epilepsy syndromes. Our sample of 2149 individuals with epilepsy and 1727 controls provided 80% power to detect differences as small as d = 0.091 (P < 0.05, two-tailed), allowing us to identify subtle, consistent brain abnormalities that are typically undetectable on visual inspection, or overlooked using smaller case-control designs. This international collaboration addresses prior inconsistencies in the field of epilepsy neuroimaging, providing a robust, in vivo map of structural aberrations, upon which future studies of disease mechanisms may expand.

In the first of five cross-sectional MRI analyses, we investigated a diverse aggregation of epilepsy syndromes, putative causes, and durations of disease. This all-epilepsies group exhibited shared, diffuse brain structural differences across several regions including the thalamus, pallidum, precentral, paracentral, and superior frontal cortices. With the exception of hippocampal volume and entorhinal thickness differences (Supplementary material), these structural alterations were not driven by any specific syndrome or dataset (Supplementary Figs 3 and 7). Our findings suggest a common neuroanatomical signature of epilepsy across a wide spectrum of disease types, complementing recent evidence for shared genetic susceptibility to a wide spectrum of epilepsies (International League Against Epilepsy Consortium on Complex Epilepsies, 2014). Some structural and genetic pathways may be shared across syndromes, despite the heterogeneity of epilepsy and seizure types. This shared MRI signature underpins the contemporary shift towards the study of epilepsies as network phenomena (Caciagli et al., 2014).

In MTLE, as expected, we observed hippocampal volume abnormalities ipsilateral to the patient’s side of seizure onset. Neither MTLE-L nor MTLE-R showed significant contralateral hippocampal volume reductions, confirming that sporadic, unilateral MTLE is not routinely underpinned by bilateral hippocampal damage (Blümcke et al., 2013). Both MTLE groups showed extrahippocampal abnormalities in the ipsilateral thalamus and pallidum, with widespread reductions in cortical thickness, supporting a growing body of literature indicating that MTLE, as an example of a specific disease constellation in the epilepsies, is also a network disease, extending beyond the mesial temporal regions (Keller et al., 2014de Campos et al., 2016). Disruption of this network, notably in the thalamus (Keller et al., 2015He et al., 2017) and thalamo-temporal white matter tracts (Keller et al., 20152017), may be associated with postoperative seizure outcome in MTLE.

Patients with left and right MTLE showed distinct patterns of structural abnormalities when compared to controls, resolving conflicting findings from smaller studies, some reporting an equal distribution of structural differences (Liu et al., 2016), and others indicating more diffuse abnormalities, either in left MTLE (Keller et al., 20022012Bonilha et al., 2007Kemmotsu et al., 2011de Campos et al., 2016) or in right MTLE (Pail et al., 2009). The structural differences observed in the present study may reflect a younger age at onset of epilepsy in left MTLE, which occurred, on average, 1.2 years earlier than those with right MTLE (Supplementary Table 20). Independent, large-scale studies of MTLE patients have confirmed a significantly earlier age at onset in left, compared to right, MTLE (Blümcke et al., 2017). Duration-related effects were also observed in right, but not left, MTLE, pointing to possible biological distinctions between the two.

In IGE, a clinically and biologically distinct group of epilepsies typically associated with ‘normal’ MRI on clinical inspection (Woermann et al., 1998), we identified reduced volume of the right thalamus, and thinner precentral gyri in both hemispheres, supporting prior reports of structural (Bernhardt et al., 2009a), electroencephalographic, and functional (Gotman et al., 2005) abnormalities in IGE. These IGE cases were considered typical by reviewing neurologists, suggesting that this common type of epilepsy is also associated with quantifiable structural brain abnormalities.

The precentral gyri, site of the primary motor cortex, showed bilateral structural deficits across all epilepsy groups (all-epilepsies, IGE, MTLE-L, MTLE-R, and all-other-epilepsies), without detectable inter-cohort or between-disease heterogeneity (Supplementary Figs 3–12). Atrophy of the motor cortex has been linked to seizure frequency and duration of epilepsy in MTLE (Coan et al., 2014); here, we observed a negative correlation between precentral (and postcentral) grey matter thickness and duration of epilepsy in the aggregate all-epilepsies group.

The right thalamus also showed evidence of structural compromise across all epilepsy cohorts, re-emphasizing the importance of the thalamus as a major hub in the epilepsy network (He et al., 2017Jobst and Cascino, 2017). Loss of feed-forward inhibition between the thalamus and its neocortical connections may be epileptogenic (Paz and Huguenard, 2015), and thalamocortical abnormalities have previously been reported in IGE (Gotman et al., 2005Bernhardt et al., 2009aO’Muircheartaigh et al., 2012) and MTLE (Mueller et al., 2010Bernhardt et al., 2012). These findings support prior ‘system epilepsies’ hypotheses of pathophysiology (Avanzini et al., 2012), suggesting that a broad range of common epilepsies share vulnerability within a thalamocortical structural pathway involved in, and likely affected by, seizures (Liu et al., 2003Bernhardt et al., 2013). Given this study’s cross-sectional design, we cannot determine if these are causative changes, consequences of recurrent seizures, prolonged drug treatment, or a combination of factors. The epilepsies, as a broad group, may involve progressive structural change (Caciagli et al., 2017), indicating the need for large-scale longitudinal studies.

A heterogeneous subgroup of individuals without confirmed diagnoses of IGE or MTLE with hippocampal sclerosis showed similar patterns of structural alterations to those observed in the aggregate all-epilepsies cohort. The findings included enlarged ventricles, smaller right pallidum and right thalamus, and reduced thickness across the motor and frontal cortices.

Hippocampal abnormalities were not observed in this subgroup, suggesting that the patterns of reduced hippocampal grey matter observed in the aggregate group were driven by the inclusion of MTLEs with hippocampal sclerosis. Unlike the IGE, MTLE, and aggregate epilepsy cohorts, this subgroup also showed bilateral enlargement of the amygdala—a phenomenon previously reported in non-lesional localization-related epilepsies (Reyes et al., 2017) and non-lesional MTLEs (Takaya et al., 2012Coan et al., 2013). Non-lesional MTLEs formed a large proportion of this ‘all-other-epilepsies’ cohort (43.3%; 445 individuals), but the subgroup included many other focal and unclassified syndromes, potentially obscuring specific biological interpretations. Future, sufficiently powered studies will stratify this cohort into finer-grained subtypes to delineate syndrome-specific effects.

Despite its international scale, our study has limitations. All results were derived from cross-sectional data: we cannot distinguish between historical acute damage and progressive abnormalities. We cannot disentangle the relative contributions of environmental and treatment-related factors, including antiepileptic medications, seizure types and frequencies, disease severity, language dominance, and other initial precipitating factors. On average, duration of epilepsy was at least 10 years; longitudinal investigations of new-onset and paediatric epilepsies will provide a more comprehensive understanding. Despite using standardized image processing protocols, quality control, and statistical techniques, some brain measures showed a wide distribution of effect sizes across research centres, which may reflect sample heterogeneity and differences in scanning protocols (Supplementary material).

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awx341/4818311

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