RE: MRI in Medically Refractory Epilepsy: Not without Postprocessing
HorstUrbach, Neuroradiologist, University Medical Center Freiburg, Dept. of Neuroradiology
Other Contributors:
MarcelHeers, Epileptologist, University Medical Center Freiburg, Dept. of Epileptology
TheoDemerath, Neuroradiologist, University Medical Center Freiburg, Dept. of Neuroradiology
7 April 2025
We appreciate the work by Haughey and co-workers emphasizing the need to integrate clinical information into the interpretation of MRI findings in patients with drug-resistant focal epilepsies. Haughey and co-workers report on 148 initial interpretation errors in a cohort of 438 patients, in whom the epileptogenic lesion was identified after acquisition of an Epilepsy-dedicated 3 Tesla MRI protocol and discussion in an interdisciplinary epilepsy conference [1]. The rate of 31.5% is comparable to our 1993-1998 study, in which 37 interpretation errors occurred in 112 patients (33%) using a similar approach [2].
Some things however have changed over the years: In the 1993-1998 study, hippocampal sclerosis was the most common overlooked lesion (47/112 =42%).
In the Haughey study, only 13 of 233 (6%) mesial temporal sclerosis (≈ hippocampal sclerosis) were missed [1]. Hippocampal sclerosis can be clearly identified on coronal FLAIR and T2-weighted 3 Tesla images which are angulated perpendicular to the long axis of the hippocampus, and we did not encounter an overlooked, histopathologically proven hippocampal sclerosis on MRI during the past 10 years. An ongoing matter of discussion is the lesion “no hippocampal sclerosis/ gliosis only” which has no neuronal loss but is poorly defined, both on MRI and histopathology [3-6].
Most overlooked lesions are now FCD, which were missed in 19/56 (33.9%) patients and some are probably “hidden” in the 300 MRI negative cases [1]. FCD were rarely identified in the 1993-1998 study, which is due to the fact that only 2D FLAIR sequences with a poor signal to noise ratio could be acquired at this time. Despite the acquisition of 3D FLAIR and other sequences highlighting the subcortical abnormalities of (type II) FCD [7-8], subtle FCD are still overlooked even by experts (Fig. 1-2). It is therefore mandatory to make these lesions visible using post-processing tools. Several post-processing tools (surface- and voxel-based) are available and have clearly increased the number of FCD [9-13]. Even FCD that are too small to be categorized on histopathology but are clearly visible on MRI can be found this way [12]. We want to stress two other issues:
1) Enlargement of the ipsilateral amygdala is detected but the FCD nearby is overlooked (Fig. 2). In these cases, amygdala enlargement is not the epileptogenic lesion but likely a consequence of focal seizures. Normalization of amygdala enlargement following the resection of an epileptogenic lesion nearby also underlines this assumption.
2) Whether malrotated hippocampi are epileptogenic lesions is at least debated as malrotated hippocampi are also found in healthy patients (15).
In conclusion, a high number of overlooked FCD does not only require Epilepsy-dedicated 3 Tesla protocols, expert’s readings and interdisciplinary case conferences but also postprocessing to highlight the subtle features of these lesions [16].
1) Haughey AM, Gasner N, Krings T. MRI interpretation errors in adult patients with Medically Refractory Epilepsy. AJNR Am J Neuroradiol published online 5 February 2025
2) Von Oertzen J, Urbach H, Jungblut S, Kurthen M, Reuber M, Fernandez G, Elger CE. Standard MRI is inadequate for patients with refractory focal epilepsy. J Neurol Neurosurg Psychiatry 2002;73:643-647
3) Thom M, Zhou J, Martinian L, Sisodiya S (2005) Quantitative postmortem study of the hippocampus in chronic epilepsy: seizures do not inevitably cause neuronal loss. Brain 128:1344–1357
4) Blumcke I, Thom M, Aronica E, et al. The clinico-pathological spectrum of Focal Cortical Dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011; 52:158–174
5) Urbach H, Huppertz HJ, Schwarzwald R, Becker AJ, Wagner J, Bahri MD, Tschampa HJ. Is the type and extent of hippocampal sclerosis measurable on high-resolution MRI? Neuroradiology. 2014;56:731-5.
6) Hattingen E, Enkirch SJ, Jurcoane A, Kruse M, Delev D, Grote A, Becker A. Hippocampal “gliosis only” on MR imaging represents a distinct entity in epilepsy patients. Neuroradiology (2018) 60:161–168
7) Chen X, Qian T, Kober T, et al. Gray-matter-specific MR imaging improves the detection of epileptogenic zones in focal cortical dysplasia: A new sequence called fluid and white matter suppression (FLAWS). NeuroImage Clin 2018;20:388–97.
8) Middlebrooks EH, Kin C, Westerhold E. Improved Detection of Focal Cortical Dysplasia Using a Novel 3D Imaging Sequence: Edge-Enhancing Gradient Echo (3D-EDGE) MRI. NeuroImage: Clinical 28 (2020) 102449
9) David B, Kröll-Seger J, Schuch F, Wagner J, Wellmer J, Woermann F, Oehl B, Van Paesschen W, Breyer T, Becker A, Vatter H, Hattingen E, Urbach H, Weber B, Surges R, Elger CE, Huppertz HJ, Rüber T (2021) External validation of automated focal cortical dysplasia detection using morphometric analysis. Epilepsia 62:1005-1021.
10) Gill RS, Lee HM, Chaldairou B, Hong SJ, Barba C, Deleo F, D’Incerti L, Coelho VCM, Lenge M, Semmelroch M, Schrader D, Bartolomei F, Guye M, Schulze-Bonhage A, Urbach H, Cho KH, Cendes F, Guerrini R, Jackson G, Hogan RE, Bernasconi N, Bernasconi A. Automated Detection of Focal Cortical Dysplasia using deep learning: A multicenter validation study, Neurology. 2021;97:e1571-e1582
11) Spitzer H, Ripart M, Whitaker K, D'Arco F, Mankad K, Chen AA, Napolitano A, De Palma L, De Benedictis A, Foldes S, Humphreys Z, Zhang K, Hu W, Mo J, Likeman M, Davies S, Güttler C, Lenge M, Cohen NT, Tang Y, Wang S, Chari A, Tisdall M, Bargallo N, Conde-Blanco E, Pariente JC, Pascual-Diaz S, Delgado-Martínez I, Pérez-Enríquez C, Lagorio I, Abela E, Mullatti N, O'Muircheartaigh J, Vecchiato K, Liu Y, Caligiuri ME, Sinclair B, Vivash L, Willard A, Kandasamy J, McLellan A, Sokol D, Semmelroch M, Kloster AG, Opheim G, Ribeiro L, Yasuda C, Rossi-Espagnet C, Hamandi K, Tietze A, Barba C, Guerrini R, Gaillard WD, You X, Wang I, González-Ortiz S, Severino M, Striano P, Tortora D, Kälviäinen R, Gambardella A, Labate A, Desmond P, Lui E, O'Brien T, Shetty J, Jackson G, Duncan JS, Winston GP, Pinborg LH, Cendes F, Theis FJ, Shinohara RT, Cross JH, Baldeweg T, Adler S, Wagstyl K. Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study Brain. 2022;145:3859-3871
12) Urbach H, Scheiwe C, Shah MJ, Nakagawa JM, Heers M, San Antonio-Arce MV, Altenmueller D, Schulze-Bonhage A, Huppertz HJ, Demerath T, Doostkam S. Diagnostic accuracy of epilepsy-dedicated MRI with post-processing. Clin Neuroradiol. 2023;33:709-719
13) Urbach H, Heers M, Altenmueller DM, Schulze-Bonhage A, Staack AM, Bast T, Reisert M, Schwarzwald R, Kaller CP, Huppertz HJ, Demerath T. “Within a minute” detection of focal cortical dysplasia (FCD). Neuroradiology. 2022;64:715-726
14) Shakhatreh L, Sinclair B, McLean C, et al. Amygdala enlargement in temporal lobe epilepsy: Histopathology and surgical outcomes. Epilepsia 2024;
15) Fu TY, Ho CR, Lin CH, Lu YT, Lin WC, Tsai MH. Hippocampal Malrotation: A Genetic Developmental Anomaly Related to Epilepsy? Brain Sci. 2021;11:463
16) Bernasconi A, Cendes F, Theodore WH, Gill RS, Koepp MJ, Hogan RE, et al. (2019). Recommendations for the Use of Structural Magnetic Resonance Imaging in the Care of Patients with Epilepsy: A Consensus Report from the International League against Epilepsy Neuroimaging Task Force. Epilepsia 60, 1054–1068
We appreciate the work by Haughey and co-workers emphasizing the need to integrate clinical information into the interpretation of MRI findings in patients with drug-resistant focal epilepsies. Haughey and co-workers report on 148 initial interpretation errors in a cohort of 438 patients, in whom the epileptogenic lesion was identified after acquisition of an Epilepsy-dedicated 3 Tesla MRI protocol and discussion in an interdisciplinary epilepsy conference [1]. The rate of 31.5% is comparable to our 1993-1998 study, in which 37 interpretation errors occurred in 112 patients (33%) using a similar approach [2].
Some things however have changed over the years: In the 1993-1998 study, hippocampal sclerosis was the most common overlooked lesion (47/112 =42%).
In the Haughey study, only 13 of 233 (6%) mesial temporal sclerosis (≈ hippocampal sclerosis) were missed [1]. Hippocampal sclerosis can be clearly identified on coronal FLAIR and T2-weighted 3 Tesla images which are angulated perpendicular to the long axis of the hippocampus, and we did not encounter an overlooked, histopathologically proven hippocampal sclerosis on MRI during the past 10 years. An ongoing matter of discussion is the lesion “no hippocampal sclerosis/ gliosis only” which has no neuronal loss but is poorly defined, both on MRI and histopathology [3-6].
Most overlooked lesions are now FCD, which were missed in 19/56 (33.9%) patients and some are probably “hidden” in the 300 MRI negative cases [1]. FCD were rarely identified in the 1993-1998 study, which is due to the fact that only 2D FLAIR sequences with a poor signal to noise ratio could be acquired at this time. Despite the acquisition of 3D FLAIR and other sequences highlighting the subcortical abnormalities of (type II) FCD [7-8], subtle FCD are still overlooked even by experts (Fig. 1-2). It is therefore mandatory to make these lesions visible using post-processing tools. Several post-processing tools (surface- and voxel-based) are available and have clearly increased the number of FCD [9-13]. Even FCD that are too small to be categorized on histopathology but are clearly visible on MRI can be found this way [12]. We want to stress two other issues:
1) Enlargement of the ipsilateral amygdala is detected but the FCD nearby is overlooked (Fig. 2). In these cases, amygdala enlargement is not the epileptogenic lesion but likely a consequence of focal seizures. Normalization of amygdala enlargement following the resection of an epileptogenic lesion nearby also underlines this assumption.
2) Whether malrotated hippocampi are epileptogenic lesions is at least debated as malrotated hippocampi are also found in healthy patients (15).
In conclusion, a high number of overlooked FCD does not only require Epilepsy-dedicated 3 Tesla protocols, expert’s readings and interdisciplinary case conferences but also postprocessing to highlight the subtle features of these lesions [16].
1) Haughey AM, Gasner N, Krings T. MRI interpretation errors in adult patients with Medically Refractory Epilepsy. AJNR Am J Neuroradiol published online 5 February 2025
2) Von Oertzen J, Urbach H, Jungblut S, Kurthen M, Reuber M, Fernandez G, Elger CE. Standard MRI is inadequate for patients with refractory focal epilepsy. J Neurol Neurosurg Psychiatry 2002;73:643-647
3) Thom M, Zhou J, Martinian L, Sisodiya S (2005) Quantitative postmortem study of the hippocampus in chronic epilepsy: seizures do not inevitably cause neuronal loss. Brain 128:1344–1357
4) Blumcke I, Thom M, Aronica E, et al. The clinico-pathological spectrum of Focal Cortical Dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011; 52:158–174
5) Urbach H, Huppertz HJ, Schwarzwald R, Becker AJ, Wagner J, Bahri MD, Tschampa HJ. Is the type and extent of hippocampal sclerosis measurable on high-resolution MRI? Neuroradiology. 2014;56:731-5.
6) Hattingen E, Enkirch SJ, Jurcoane A, Kruse M, Delev D, Grote A, Becker A. Hippocampal “gliosis only” on MR imaging represents a distinct entity in epilepsy patients. Neuroradiology (2018) 60:161–168
7) Chen X, Qian T, Kober T, et al. Gray-matter-specific MR imaging improves the detection of epileptogenic zones in focal cortical dysplasia: A new sequence called fluid and white matter suppression (FLAWS). NeuroImage Clin 2018;20:388–97.
8) Middlebrooks EH, Kin C, Westerhold E. Improved Detection of Focal Cortical Dysplasia Using a Novel 3D Imaging Sequence: Edge-Enhancing Gradient Echo (3D-EDGE) MRI. NeuroImage: Clinical 28 (2020) 102449
9) David B, Kröll-Seger J, Schuch F, Wagner J, Wellmer J, Woermann F, Oehl B, Van Paesschen W, Breyer T, Becker A, Vatter H, Hattingen E, Urbach H, Weber B, Surges R, Elger CE, Huppertz HJ, Rüber T (2021) External validation of automated focal cortical dysplasia detection using morphometric analysis. Epilepsia 62:1005-1021.
10) Gill RS, Lee HM, Chaldairou B, Hong SJ, Barba C, Deleo F, D’Incerti L, Coelho VCM, Lenge M, Semmelroch M, Schrader D, Bartolomei F, Guye M, Schulze-Bonhage A, Urbach H, Cho KH, Cendes F, Guerrini R, Jackson G, Hogan RE, Bernasconi N, Bernasconi A. Automated Detection of Focal Cortical Dysplasia using deep learning: A multicenter validation study, Neurology. 2021;97:e1571-e1582
11) Spitzer H, Ripart M, Whitaker K, D'Arco F, Mankad K, Chen AA, Napolitano A, De Palma L, De Benedictis A, Foldes S, Humphreys Z, Zhang K, Hu W, Mo J, Likeman M, Davies S, Güttler C, Lenge M, Cohen NT, Tang Y, Wang S, Chari A, Tisdall M, Bargallo N, Conde-Blanco E, Pariente JC, Pascual-Diaz S, Delgado-Martínez I, Pérez-Enríquez C, Lagorio I, Abela E, Mullatti N, O'Muircheartaigh J, Vecchiato K, Liu Y, Caligiuri ME, Sinclair B, Vivash L, Willard A, Kandasamy J, McLellan A, Sokol D, Semmelroch M, Kloster AG, Opheim G, Ribeiro L, Yasuda C, Rossi-Espagnet C, Hamandi K, Tietze A, Barba C, Guerrini R, Gaillard WD, You X, Wang I, González-Ortiz S, Severino M, Striano P, Tortora D, Kälviäinen R, Gambardella A, Labate A, Desmond P, Lui E, O'Brien T, Shetty J, Jackson G, Duncan JS, Winston GP, Pinborg LH, Cendes F, Theis FJ, Shinohara RT, Cross JH, Baldeweg T, Adler S, Wagstyl K. Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study Brain. 2022;145:3859-3871
12) Urbach H, Scheiwe C, Shah MJ, Nakagawa JM, Heers M, San Antonio-Arce MV, Altenmueller D, Schulze-Bonhage A, Huppertz HJ, Demerath T, Doostkam S. Diagnostic accuracy of epilepsy-dedicated MRI with post-processing. Clin Neuroradiol. 2023;33:709-719
13) Urbach H, Heers M, Altenmueller DM, Schulze-Bonhage A, Staack AM, Bast T, Reisert M, Schwarzwald R, Kaller CP, Huppertz HJ, Demerath T. “Within a minute” detection of focal cortical dysplasia (FCD). Neuroradiology. 2022;64:715-726
14) Shakhatreh L, Sinclair B, McLean C, et al. Amygdala enlargement in temporal lobe epilepsy: Histopathology and surgical outcomes. Epilepsia 2024;
15) Fu TY, Ho CR, Lin CH, Lu YT, Lin WC, Tsai MH. Hippocampal Malrotation: A Genetic Developmental Anomaly Related to Epilepsy? Brain Sci. 2021;11:463
16) Bernasconi A, Cendes F, Theodore WH, Gill RS, Koepp MJ, Hogan RE, et al. (2019). Recommendations for the Use of Structural Magnetic Resonance Imaging in the Care of Patients with Epilepsy: A Consensus Report from the International League against Epilepsy Neuroimaging Task Force. Epilepsia 60, 1054–1068