Epilepsy, antiepileptic drugs (AEDs), and adjuvant treatments may correlate with the development of subclinical atherosclerosis. We performed a systematic review and meta-analysis to evaluate the effects of epilepsy, AEDs, and adjuvant treatments on the structural and functional markers of subclinical atherosclerosis represented by carotid intima-media thickness (cIMT), epicardial adipose tissue thickness (EATT), and flow-mediated vasodilation (FMD). Weighted mean differences (WMD) and corresponding 95% confidence intervals (CIs) were analyzed. Thirty-one studies were included with 9 different outcomes. Compared with controls, the epileptic patients demonstrated significantly thicker cIMT (WMD [95% CI] = 0.063 [0.045-0.080], P < .001) and EATT (WMD [95% CI] = 1.985 [1.630-2.341], P < .001). There was no significant difference in FMD (P > .050). Moreover, cIMT was still thicker in the epileptic patients on old AEDs compared with those on new AEDs (WMD [95% CI] = 0.038 [0.000-0.076], P = .050), on multi-AEDs compared with on mono-AEDs (WMD [95% CI] = 0.025 [0.021-0.029], P < .001), and on enzyme-inducing AEDs compared with on non-enzyme-inducing AEDs (WMD [95% CI] = 0.027 [0.006-0.047], P = .011). No significant differences in cIMT were detected in any comparison of adjuvant treatments (ketogenic diet, Atkins diet, and folic acid supplements; all P > .050). Epilepsy and AEDs, especially old AEDs, multi-AEDs, and enzyme-inducing AEDs, could exacerbate the development of subclinical atherosclerosis. Early prevention as well as timely intervention for subclinical atherosclerosis should be considered for these patients.
BeghiE.The epidemiology of epilepsy. Neuroepidemiology. 2020;54(2):185-191.
2.
FiestKMSauroKMWiebeS, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology. 2017;88(3):296-303.
3.
FisherRSAcevedoCArzimanoglouA, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-482.
4.
BenskenWPFernandez-Baca VacaGJobstBC, et al. Burden of chronic and acute conditions and symptoms in people with epilepsy. Neurology. 2021;97(24):e2368-e2380.
5.
KhudaIENazishSZeeshanMA, et al. Non-HDL cholesterol, obesity, and metabolic syndrome in epileptic patients. Prim Care Companion CNS Disord. 2022;24(3):21m03057.
6.
GaertnerMLMintzerSDeGiorgioCM.Increased cardiovascular risk in epilepsy. Front Neurol. 2024;15:1339276.
7.
ElliottJOJacobsonMPHaneefZ.Cardiovascular risk factors and homocysteine in epilepsy. Epilepsy Res. 2007;76(2):113-123.
8.
Sarecka-HujarBSzołtysek-BołdysIKopytaI, et al. Concentrations of the selected biomarkers of endothelial dysfunction in response to antiepileptic drugs: a literature review. Clin Appl Thromb Hemost. 2019;25:1076029619859429.
9.
YuenAWCKeezerMRSanderJW. Epilepsy is a neurological and a systemic disorder. Epilepsy Behav. 2018;78:57-61.
10.
SitiHNKamisahYKamsiahJ.The role of oxidative stress, antioxidants and vascular inflammation in cardiovascular disease (a review). Vascul Pharmacol. 2015;71:40-56.
11.
WangJHuangPYuQ, et al. Epilepsy and long-term risk of arrhythmias. Eur Heart J. 2023;44(35):3374-3382.
12.
BardaiABlomMTvan NoordC, et al. Sudden cardiac death is associated both with epilepsy and with use of antiepileptic medications. Heart. 2015;101(1):17-22.
13.
OlesenJBAbildstrømSZErdalJ, et al. Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study. Pharmacoepidemiol Drug Saf. 2011;20(9):964-971.
14.
BrigoFLochnerPNardoneR, et al. Increased risk of stroke and myocardial infarction in patients with epilepsy: a systematic review of population-based cohort studies. Epilepsy Behav. 2020;104(Pt B):106307.
15.
CobbleMBaleB.Carotid intima-media thickness: knowledge and application to everyday practice. Postgrad Med. 2010;122(1):10-18.
16.
ConEYilmazASuygunH, et al. The relationship between epicardial adipose tissue thickness and coronary artery disease progress. Bratisl Lek Listy. 2023;124(7):545-548.
17.
MoensALGoovaertsIClaeysMJ, et al. Flow-mediated vasodilation: a diagnostic instrument, or an experimental tool?Chest. 2005;127(6):2254-2263.
18.
SimonAMegnienJ-LChironiG.The value of carotid intima-media thickness for predicting cardiovascular risk. Arterioscler Thromb Vasc Biol. 2010;30(2):182-185.
19.
KonwerskiMGąseckaAOpolskiG, et al. Role of epicardial adipose tissue in cardiovascular diseases: a review. Biology. 2022;11(3):355.
20.
KimSHChungJHKwonBJ, et al. The associations of epicardial adipose tissue with coronary artery disease and coronary atherosclerosis. Int Heart J. 2014;55(3):197-203.
21.
XuYAroraRCHiebertBM, et al. Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis. Eur Heart J Cardiovasc Imaging. 2014;15(7):736-746.
22.
CalikMOzkanHYEthemogluO, et al. The measurement of both carotid intima-media thickness and epicardial adipose tissue thickness in children with epilepsy receiving antiepileptic drug therapy. Epilepsy Behav. 2018;85:110-114.
23.
KaratoprakETosunO.Effects of valproic acid and levetiracetam monotherapy on carotid intima-media and epicardial adipose tissue thickness in non-obese children with epilepsy. Brain Dev. 2020;42(2):165-170.
24.
YişUDoğanM.Effects of oxcarbazepine treatment on serum lipids and carotid intima media thickness in children. Brain Dev. 2012;34(3):185-188.
25.
KeenanNSadlierLGWiltshireE.Vascular function and risk factors in children with epilepsy: associations with sodium valproate and carbamazepine. Epilepsy Res. 2014;108(6):1087-1094.
26.
Safarpour LimaBMohamadzadehADadrasM, et al. Carotid intima-media and epicardial adipose tissue thickness in adult patients with epilepsy taking anti-seizure medication and its long-term significance. Epilepsy Behav. 2021;125:108432.
27.
MahrousDMMoustafaANHigaziMM, et al. Influence of different antiseizure medications on vascular risk factors in children with epilepsy. Children. 2022;9(10):1499.
28.
StroupDFBerlinJAMortonSC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008-2012.
29.
HigginsJPT. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-560.
30.
WuYSunDWangB, et al. The relationship of depressive symptoms and functional and structural markers of subclinical atherosclerosis: a systematic review and meta-analysis. Eur J Prev Cardiol. 2018;25(7):706-716.
31.
BanoSZuberiNAAlamSM.Correlation between hyperhomocysteinemia and common carotid artery intima media thickness in carbamazepine treated epileptic patients using ultrasonography. Pak J Med Sci. 2017;33(5):1205-1209.
32.
SankhyanNGulatiSHariS, et al. Noninvasive screening for preclinical atherosclerosis in children on phenytoin or carbamazepine monotherapy: a cross sectional study. Epilepsy Res. 2013;107(1-2):121-126.
33.
Serrano-CastroPJ.Eslicarbazepine acetate and carotid intima-media thickness in epileptic patients. Epilepsy Res. 2017;138:81-87.
34.
LaiQShenCZhengY, et al. Effects of antiepileptic drugs on the carotid artery intima-media thickness in epileptic patients. J Clin Neurol. 2017;13(4):371-379.
35.
ChuangYCChuangHYLinTK, et al. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia. 2012;53(1):120-128.
36.
CoppolaGNataleFTorinoA, et al. The impact of the ketogenic diet on arterial morphology and endothelial function in children and young adults with epilepsy: a case-control study. Seizure. 2014;23(4):260-265.
37.
De LucaMValvanoAStrianoP, et al. Effects of three-months folate supplementation on early vascular abnormalities in hyperhomocysteinemic patients with epilepsy. Seizure. 2022;103:120-125.
38.
DoksözÖGüzelOYılmazÜ, et al. The short-term effect of ketogenic diet on carotid intima-media thickness and elastic properties of the carotid artery and the aorta in epileptic children. J Child Neurol. 2015;30(12):1646-1650.
39.
El-FarahatyRMEl-MitwalliAAzzamH, et al. Atherosclerotic effects of long-term old and new antiepileptic drugs monotherapy: a cross-sectional comparative study. J Child Neurol. 2015;30(4):451-457.
40.
ErdemirAÇulluNYişU, et al. Evaluation of serum lipids and carotid artery intima media thickness in epileptic children treated with valproic acid. Brain Dev. 2009;31(10):713-716.
41.
HamedSAHamedEAHamdyR, et al. Vascular risk factors and oxidative stress as independent predictors of asymptomatic atherosclerosis in adult patients with epilepsy. Epilepsy Res. 2007;74(2-3):183-192.
42.
KapetanakisMLiubaPOdermarskyM, et al. Effects of ketogenic diet on vascular function. Eur J Paediatr Neurol. 2014;18(4):489-494.
43.
KolekarVSindgikarSUppoorR, et al. Effects of long-term antiepileptic therapy on carotid artery intima-media thickness. J Pediatr Neurosci. 2021;16(2):131-136.
44.
MahmoudAAAboelgharHMAbdelmageedSM, et al. Assessment of asymmetric dimethylarginine and homocysteine in epileptic children receiving antiepileptic drugs. Pediatr Res. 2022;92(6):1606-1612.
45.
HamedSAHermannBPMoussaEMM, et al. Evaluation of penile vascular status in men with epilepsy with erectile dysfunction. Seizure. 2015;25:40-48.
46.
McDonaldTJWRatchfordEVHenry-BarronBJ, et al. Impact of the modified Atkins diet on cardiovascular health in adults with epilepsy. Epilepsy Behav. 2018;79:82-86.
47.
MehrpourMShojaieMZamaniB, et al. Atherogenic consequence of antiepileptic drugs: a study of intima-media thickness. Neurol Sci. 2014;35(2):253-257.
48.
NasefKAElmalaMKSayed AhmedAM, et al. The study of carotid artery intima-media thickness in children with epilepsy on anti-epileptic drugs. Glob Pediatr Health. 2023;10:2333794X231200205.
49.
ÖzdemirRGüzelOKüçükM, et al. The effect of the ketogenic diet on the vascular structure and functions in children with intractable epilepsy. Pediatr Neurol. 2016;56:30-34.
50.
SchwaningerMRinglebPAnneckeA, et al. Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients. J Neurol. 2000;247(9):687-690.
51.
TalaatFMKamelTRabahAM, et al. Epilepsy and antiepileptic drugs: risk factors for atherosclerosis. Int J Neurosci. 2015;125(7):507-511.
52.
TalariHBahramiMArdestaniA, et al. Effects of folate supplementation on carotid intima-media thickness, biomarkers of inflammation, and oxidative stress in carbamazepine-treated epileptic children. Int J Prev Med. 2019;10:4.
53.
Viloria-AlebesqueABellosta-DiagoENavarro-PérezMP, et al. Circadian rhythm of blood pressure in patients with drug-resistant mesial temporal lobe epilepsy. Seizure. 2023;108:43-48.
54.
TanTYLuCHChuangHY, et al. Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia. 2009;50(6):1579-1586.
55.
ZhaoJLuoXZhangM, et al. Effects of valproate on the carotid artery intima-media thickness in epileptics. Indian J Pharmacol. 2015;47(1):45-48.
56.
GorjipourFAsadiY, K Osguei N, et al. Serum level of homocysteine, folate and vitamin-B12 in epileptic patients under carbamazepine and sodium valproate treatment: a systematic review and meta-analysis. Iran Red Crescent Med J. 2013;15(3):249-253.
57.
RowleySPatelM.Mitochondrial involvement and oxidative stress in temporal lobe epilepsy. Free Radic Biol Med. 2013;62:121-131.
58.
WinterbournCC.Reconciling the chemistry and biology of reactive oxygen species. Nat Chem Biol. 2008;4(5):278-286.
59.
D’AutréauxBToledanoMB.ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007;8(10):813-824.
60.
HultheJFagerbergB.Circulating oxidized LDL is associated with subclinical atherosclerosis development and inflammatory cytokines (AIR study). Arterioscler Thromb Vasc Biol. 2002;22(7):1162-1167.
61.
Di PietroNFormosoGPandolfiA. Physiology and pathophysiology of oxLDL uptake by vascular wall cells in atherosclerosis. Vascul Pharmacol. 2016;84:1-7.
62.
IsogawaAYamakadoMYanoM, et al. Serum superoxide dismutase activity correlates with the components of metabolic syndrome or carotid artery intima-media thickness. Diabetes Res Clin Pract. 2009;86(3):213-218.
63.
PaffenEdeMaatMPM. C-reactive protein in atherosclerosis: a causal factor?Cardiovasc Res. 2006;71(1):30-39.
64.
LenartNBroughDDenesA.Inflammasomes link vascular disease with neuroinflammation and brain disorders. J Cereb Blood Flow Metab. 2016;36(10):1668-1685.
65.
HollisALukensJR. Role of inflammasomes and neuroinflammation in epilepsy. Immunol Rev. 2025;329(1):e13421.
66.
HeYHaraHNúñezG.Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012-1021.
67.
SinghSSinghTG.Emerging perspectives on mitochondrial dysfunctioning and inflammation in epileptogenesis. Inflamm Res. 2021;70(10):1027-1042.
68.
HoseiniZSepahvandFRashidiB, et al. NLRP3 inflammasome: its regulation and involvement in atherosclerosis. J Cell Physiol. 2018;233(3):2116-2132.
69.
HuangQZhangZFanR, et al. Association of blood count-derived immunoinflammatory makers and risk of epilepsy: a prospective cohort of 497,291 participants. Seizure. 2024;123:9-16.
70.
LiaoMLiuLBaiL, et al. Correlation between novel inflammatory markers and carotid atherosclerosis: a retrospective case-control study. PLoS One. 2024;19(5):e0303869.
71.
RhoJMBoisonD.The metabolic basis of epilepsy. Nat Rev Neurol. 2022;18(6):333-347.
72.
MintzerSSkidmoreCTAbidinCJ, et al. Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann Neurol. 2009;65(4):448-456.
73.
SusiAAudryDWAndiKB, et al. Lipid profile between epileptic patients with Cyp-450 enzyme inducer versus Cyp-450 enzyme inhibitor as a monotherapy anti epileptic drug: a comparative study. Eur J Mol Clin Med. 2020;7(7):1123-1130.
74.
MohammedABAl-JawadFHKadhimHM.Effects of cytochrome p-450 inducer and inhibitor antiepileptic drugs on lipid profile in normal and diabetic rabbits. Iraqi J Med Sci. 2016;14(2):137-145.
75.
BramswigSSudhopTLuersC, et al. Lipoprotein(a) concentration increases during treatment with carbamazepine. Epilepsia. 2003;44(3):457-460.
76.
FrancaVGomesEILde CamposEVS, et al. Relationship between lipoprotein (a) and subclinical carotid atherosclerosis in asymptomatic individuals. Clinics. 2022;77:100107.
77.
HuangHLZhouHWangN, et al. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients. Biomed Rep. 2016;5(4):413-416.
78.
BochynskaALipczynska-LojkowskaWGugala-IwaniukM, et al. The effect of vitamin B supplementation on homocysteine metabolism and clinical state of patients with chronic epilepsy treated with carbamazepine and valproic acid. Seizure. 2012;21(4):276-281.
79.
El-GendiSSBakeetMYEl-HamedEA, et al. The value of lipoprotein (a), homocysteine, and Doppler of carotid and femoral arteries in assessment of atherosclerosis in asymptomatic cardiovascular risk patients. J Cardiol. 2008;52(3):202-211.
80.
GuthikondaSHaynesWG.Homocysteine: role and implications in atherosclerosis. Curr Atheroscler Rep. 2006;8(2):100-106.
81.
BrodieMJMintzerSPackAM, et al. Enzyme induction with antiepileptic drugs: cause for concern?Epilepsia. 2013;54(1):11-27.
82.
Tolou-GhamariZ.Antiepileptic drugs (AEDs) polypharmacy could lead to buried pharmacokinetic interactions due to CYP450. Drug Metab Lett. 2012;6(3):207-212.
83.
WangYXiaLLiR, et al. Comparison of long-term outcomes of monotherapy and polytherapy in seizure-free patients with epilepsy following antiseizure medication withdrawal. Front Neurol. 2021;12:669703.
84.
AmirshahrokhiKImaniM.Therapeutic effect of levetiracetam against thioacetamide-induced hepatic encephalopathy through inhibition of oxidative stress and downregulation of NF-κB, NLRP3, iNOS/NO, pro-inflammatory cytokines and apoptosis. Inflammation. 2024;47(5):1762-1775.
85.
WangZXuGZhanX, et al. Carbamazepine promotes specific stimuli-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury in mice. Arch Toxicol. 2019;93(12):3585-3599.
86.
NazishS.Obesity and metabolic syndrome in patients with epilepsy, their relation with epilepsy control. Ann Afr Med. 2023;22(2):136-144.
87.
RabkinSW.The relationship between epicardial fat and indices of obesity and the metabolic syndrome: a systematic review and meta-analysis. Metab Syndr Relat Disord. 2014;12(1):31-42.
88.
ElshorbagyHHFoudaERKamalNM, et al. Evaluation of epicardial fat and carotid intima-media thickness in obese children. Iran J Pediatr. 2016;26(1):e2968.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
