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.
| Original language | English |
|---|---|
| Article number | 787272 |
| Journal | Frontiers in Neuroscience |
| Volume | 15 |
| DOIs | |
| Publication status | Published - 24 Feb 2022 |
| Externally published | Yes |
Bibliographical note
Funding Information:JS has received personal fees from Eisai, UCB, GW Pharmaceuticals, Arvelle, and Zogenix, and research grants from UCB and GW Pharmaceuticals outside the submitted work. MK has received grants and honoraria from UCB Pharma, Desitin, Novartis, Eisai, GE, and Bial, outside the submitted work. MG has received honoraria from Bial Pharmaceutical and Nestlé Health Science outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding Information:
This work was supported by the Epilepsy Society, United Kingdom and was carried out at the National Institute for Health Research University College London Hospitals Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health’s Research Centres funding scheme. FX was supported by the Newton International Fellowship of Academy of Medical Sciences and Newton Fund (NIF\R5\264), and acknowledges support from National Natural Science Foundation of China (82001369), China Postdoctoral Science Foundation (2020M683321), and Post-Doctor Research Project, West China Hospital, Sichuan University (2020HXBH053). JS receives research support from the Dr. Marvin Weil Epilepsy Research Fund and Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie, Netherlands. JD receives NIHR senior investigator reward. LC received Ph.D. studentship from Brain Research UK. KT was supported by research fellowships from the European Academy of Neurology (EAN) and Austrian Society of Neurology (OEGN). Funders did not have any role in the study design. Wellcome Trust (079474) awarded to MK.
Funding Information:
This work was supported by the Epilepsy Society, United Kingdom and was carried out at the National Institute for Health Research University College London Hospitals Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health?s Research Centres funding scheme. FX was supported by the Newton International Fellowship of Academy of Medical Sciences and Newton Fund (NIF\R5\264), and acknowledges support from National Natural Science Foundation of China (82001369), China Postdoctoral Science Foundation (2020M683321), and Post-Doctor Research Project, West China Hospital, Sichuan University (2020HXBH053). JS receives research support from the Dr. Marvin Weil Epilepsy Research Fund and Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie, Netherlands. JD receives NIHR senior investigator reward. LC received Ph.D. studentship from Brain Research UK. KT was supported by research fellowships from the European Academy of Neurology (EAN) and Austrian Society of Neurology (OEGN). Funders did not have any role in the study design. Wellcome Trust (079474) awarded to MK.
Publisher Copyright:
Copyright © 2022 Xiao, Caciagli, Wandschneider, Joshi, Vos, Hill, Galovic, Long, Sone, Trimmel, Sander, Zhou, Thompson, Baxendale, Duncan and Koepp.
Keywords
- cognitive effect
- drug load
- epilepsy
- language functional MRI
- polytherapy