Marian Galovic1,2,3, Irene Baudracco1, Evan Wright-Goff1, Galo Pillajo1,4,5, Parashkev Nachev1, Britta Wandschneider1,2, Friedrich Woermann6, Pamela Thompson1, Sallie Baxendale1,7, Andrew W McEvoy1, Mark Nowell1, Matteo Mancini8,9, Sjoerd B Vos2,8,9, Gavin P Winston1,2, Rachel Sparks8,9,10, Ferran Prados8,11, Anna Miserocchi1, Jane de Tisi1, Louis André Van Graan1, Roman Rodionov1,2, Chengyuan Wu12,13, Mahdi Alizadeh12,13, Lauren Kozlowski14, Ashwini D Sharan12, Lohith G Kini15, Kathryn A Davis15,16, Brian Litt15,16,17, Sebastien Ourselin8,9,10,18, Solomon L Moshé19,20,21, Josemir W A Sander1,2, Wolfgang Löscher22,23, John S Duncan1,2, Matthias J Koepp1,2. 1. UK National Institute for Health Research, University College London (UCL) Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom. 2. Epilepsy Society MRI Unit, Epilepsy Society, Chalfont St Peter, United Kingdom. 3. Department of Neurology, Kantonsspital St Gallen, St Gallen, Switzerland. 4. Department of Imaging, Hospital de Especialidades Eugenio Espejo, Quito, Ecuador. 5. Division of Neuroanatomy, Facultad de Medicina, Universidad Internacional del Ecuador, Quito. 6. Magnetic Resonance Imaging Unit, Klinik Mara, Bethel Epilepsy Centre, Bielefeld, Germany. 7. Institute of Cognitive Neuroscience, UCL, London, United Kingdom. 8. Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Bioengineering, UCL, London, United Kingdom. 9. Wellcome EPSRC Centre for Interventional and Surgical Sciences, UCL, London, United Kingdom. 10. School of Biomedical Engineering and Image Sciences, Kings College London, London, United Kingdom. 11. Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Institute of Neurology, London, United Kingdom. 12. Department of Neurosurgery, Vickie and Jack Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania. 13. Jefferson Integrated Magnetic Resonance Imaging Center, Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania. 14. medical student at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania. 15. Center for Neuroengineering and Therapeutics, Department of Bioengineering, University of Pennsylvania, Philadelphia. 16. Department of Neurology, Hospital of the University of Pennsylvania, Philadelphia. 17. Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia. 18. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom. 19. Laboratory of Developmental Epilepsy, Saul R. Korey Department of Neurology, Montefiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York. 20. Dominick P. Purpura Department of Neuroscience, Montefiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York. 21. Department of Pediatrics, Montefiore/Einstein Epilepsy Management Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York. 22. Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany. 23. Center for Systems Neuroscience, University of Veterinary Medicine, Hannover, Germany.
Abstract
Importance: A functional area associated with the piriform cortex, termed area tempestas, has been implicated in animal studies as having a crucial role in modulating seizures, but similar evidence is limited in humans. Objective: To assess whether removal of the piriform cortex is associated with postoperative seizure freedom in patients with temporal lobe epilepsy (TLE) as a proof-of-concept for the relevance of this area in human TLE. Design, Setting, and Participants: This cohort study used voxel-based morphometry and volumetry to assess differences in structural magnetic resonance imaging (MRI) scans in consecutive patients with TLE who underwent epilepsy surgery in a single center from January 1, 2005, through December 31, 2013. Participants underwent presurgical and postsurgical structural MRI and had at least 2 years of postoperative follow-up (median, 5 years; range, 2-11 years). Patients with MRI of insufficient quality were excluded. Findings were validated in 2 independent cohorts from tertiary epilepsy surgery centers. Study follow-up was completed on September 23, 2016, and data were analyzed from September 24, 2016, through April 24, 2018. Exposures: Standard anterior temporal lobe resection. Main Outcomes and Measures: Long-term postoperative seizure freedom. Results: In total, 107 patients with unilateral TLE (left-sided in 68; 63.6% women; median age, 37 years [interquartile range {IQR}, 30-45 years]) were included in the derivation cohort. Reduced postsurgical gray matter volumes were found in the ipsilateral piriform cortex in the postoperative seizure-free group (n = 46) compared with the non-seizure-free group (n = 61). A larger proportion of the piriform cortex was resected in the seizure-free compared with the non-seizure-free groups (median, 83% [IQR, 64%-91%] vs 52% [IQR, 32%-70%]; P < .001). The results were seen in left- and right-sided TLE and after adjusting for clinical variables, presurgical gray matter alterations, presurgical hippocampal volumes, and the proportion of white matter tract disconnection. Findings were externally validated in 2 independent cohorts (31 patients; left-sided TLE in 14; 54.8% women; median age, 41 years [IQR, 31-46 years]). The resected proportion of the piriform cortex was individually associated with seizure outcome after surgery (derivation cohort area under the curve, 0.80 [P < .001]; external validation cohorts area under the curve, 0.89 [P < .001]). Removal of at least half of the piriform cortex increased the odds of becoming seizure free by a factor of 16 (95% CI, 5-47; P < .001). Other mesiotemporal structures (ie, hippocampus, amygdala, and entorhinal cortex) and the overall resection volume were not associated with outcomes. Conclusions and Relevance: These results support the importance of resecting the piriform cortex in neurosurgical treatment of TLE and suggest that this area has a key role in seizure generation.
Importance: A functional area associated with the piriform cortex, termed area tempestas, has been implicated in animal studies as having a crucial role in modulating seizures, but similar evidence is limited in humans. Objective: To assess whether removal of the piriform cortex is associated with postoperative seizure freedom in patients with temporal lobe epilepsy (TLE) as a proof-of-concept for the relevance of this area in humanTLE. Design, Setting, and Participants: This cohort study used voxel-based morphometry and volumetry to assess differences in structural magnetic resonance imaging (MRI) scans in consecutive patients with TLE who underwent epilepsy surgery in a single center from January 1, 2005, through December 31, 2013. Participants underwent presurgical and postsurgical structural MRI and had at least 2 years of postoperative follow-up (median, 5 years; range, 2-11 years). Patients with MRI of insufficient quality were excluded. Findings were validated in 2 independent cohorts from tertiary epilepsy surgery centers. Study follow-up was completed on September 23, 2016, and data were analyzed from September 24, 2016, through April 24, 2018. Exposures: Standard anterior temporal lobe resection. Main Outcomes and Measures: Long-term postoperative seizure freedom. Results: In total, 107 patients with unilateral TLE (left-sided in 68; 63.6% women; median age, 37 years [interquartile range {IQR}, 30-45 years]) were included in the derivation cohort. Reduced postsurgical gray matter volumes were found in the ipsilateral piriform cortex in the postoperative seizure-free group (n = 46) compared with the non-seizure-free group (n = 61). A larger proportion of the piriform cortex was resected in the seizure-free compared with the non-seizure-free groups (median, 83% [IQR, 64%-91%] vs 52% [IQR, 32%-70%]; P < .001). The results were seen in left- and right-sided TLE and after adjusting for clinical variables, presurgical gray matter alterations, presurgical hippocampal volumes, and the proportion of white matter tract disconnection. Findings were externally validated in 2 independent cohorts (31 patients; left-sided TLE in 14; 54.8% women; median age, 41 years [IQR, 31-46 years]). The resected proportion of the piriform cortex was individually associated with seizure outcome after surgery (derivation cohort area under the curve, 0.80 [P < .001]; external validation cohorts area under the curve, 0.89 [P < .001]). Removal of at least half of the piriform cortex increased the odds of becoming seizure free by a factor of 16 (95% CI, 5-47; P < .001). Other mesiotemporal structures (ie, hippocampus, amygdala, and entorhinal cortex) and the overall resection volume were not associated with outcomes. Conclusions and Relevance: These results support the importance of resecting the piriform cortex in neurosurgical treatment of TLE and suggest that this area has a key role in seizure generation.
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