Fenglai Xiao1,2,3, Lorenzo Caciagli2,3,4, Britta Wandschneider2,3,5, Bhavini Joshi2,3, Sjoerd B Vos2,3,6,7, Andrea Hill2,3, Marian Galovic2,3,8, Lili Long2,3,9, Daichi Sone2,3, Karin Trimmel2,3,10, Josemir W Sander1,2,3,11, Dong Zhou1, Pamela J Thompson2,3, Sallie Baxendale2,3, John S Duncan2,3, Matthias J Koepp2,3. 1. Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. 2. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom. 3. Chalfont Centre for Epilepsy, Chalfont St. Peter, United Kingdom. 4. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States. 5. Department of Neurology, The Royal London Hospital, London, United Kingdom. 6. UCL Centre for Medical Image Computing, London, United Kingdom. 7. Department of Neuroradiology, UCL Queen Square Institute of Neurology, London, United Kingdom. 8. Department of Neurology, Clinical Neuroscience Center, University Hospital Zürich, Zurich, Switzerland. 9. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China. 10. Department of Neurology, Medical University of Vienna, Vienna, Austria. 11. Stichting Epilepsie Instellingen Nederland, Heemstede, Netherlands.
Abstract
Background: In epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined. Methods: Here, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (n = 180). "Drug load" was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication. Results: In people taking "moderate" ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking "severe" ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with "moderate" ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex. Conclusion: Our study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect.
Background: In epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined. Methods: Here, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (n = 180). "Drug load" was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication. Results: In people taking "moderate" ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking "severe" ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with "moderate" ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex. Conclusion: Our study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect.
Authors: Marian Galovic; Irene Baudracco; Evan Wright-Goff; Galo Pillajo; Parashkev Nachev; Britta Wandschneider; Friedrich Woermann; Pamela Thompson; Sallie Baxendale; Andrew W McEvoy; Mark Nowell; Matteo Mancini; Sjoerd B Vos; Gavin P Winston; Rachel Sparks; Ferran Prados; Anna Miserocchi; Jane de Tisi; Louis André Van Graan; Roman Rodionov; Chengyuan Wu; Mahdi Alizadeh; Lauren Kozlowski; Ashwini D Sharan; Lohith G Kini; Kathryn A Davis; Brian Litt; Sebastien Ourselin; Solomon L Moshé; Josemir W A Sander; Wolfgang Löscher; John S Duncan; Matthias J Koepp Journal: JAMA Neurol Date: 2019-06-01 Impact factor: 18.302
Authors: Juri-Alexander Witt; Robert D Nass; Tobias Baumgartner; Randi von Wrede; Christian E Elger; Rainer Surges; Christoph Helmstaedter Journal: Epilepsia Date: 2020-10-15 Impact factor: 5.864
Authors: Karin Trimmel; Andre L van Graan; Lorenzo Caciagli; Anja Haag; Matthias J Koepp; Pamela J Thompson; John S Duncan Journal: Brain Date: 2018-08-01 Impact factor: 13.501
Authors: Lorenzo Caciagli; Britta Wandschneider; Fenglai Xiao; Christian Vollmar; Maria Centeno; Sjoerd B Vos; Karin Trimmel; Meneka K Sidhu; Pamela J Thompson; Gavin P Winston; John S Duncan; Matthias J Koepp Journal: Brain Date: 2019-09-01 Impact factor: 13.501
Authors: Clarissa Lin Yasuda; Maria Centeno; Christian Vollmar; Jason Stretton; Mark Symms; Fernando Cendes; Mitul A Mehta; Pamela Thompson; John S Duncan; Matthias J Koepp Journal: Epilepsy Res Date: 2013-01-17 Impact factor: 3.045