Advertisement

Atherosclerosis in epilepsy: Its causes and implications

  • Sherifa A. Hamed
    Correspondence
    Department of Neurology and Psychiatry, Floor # 7, Room # 4, Hospital of Neurology and Psychiatry, Assiut University Hospital, P.O. Box 71516, Assiut, Egypt. Tel.: +2 88 2414840 6135 (work), +2 88 2374904 (private clinic), +2 1115324560 (mobile); fax: +2 88 2333327, +2 88 2332278.
    Affiliations
    Department of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt
    Search for articles by this author
Published:August 20, 2014DOI:https://doi.org/10.1016/j.yebeh.2014.07.003

      Abstract

      Evidence from epidemiological, longitudinal, prospective, double-blinded clinical trials as well as case reports documents age-accelerated atherosclerosis with increased carotid artery intima media thickness (CA–IMT) in patients with epilepsy. These findings raise concern regarding their implications for age-accelerated cognitive and behavioral changes in midlife and risk of later age-related cognitive disorders including neurodegenerative processes such as Alzheimer's disease (AD). Chronic epilepsy, cerebral atherosclerosis, and age-related cognitive disorders including AD share many clinical manifestations (e.g. characteristic cognitive deficits), risk factors, and structural and pathological brain abnormalities. These shared risk factors include increased CA–IMT, hyperhomocysteinemia (HHcy), lipid abnormalities, weight gain and obesity, insulin resistance (IR), and high levels of inflammatory and oxidative stresses. The resulting brain structural and pathological abnormalities include decreased volume of the hippocampus, increased cortical thinning of the frontal lobe, ventricular expansion and increased white matter ischemic disease, total brain atrophy, and β-amyloid protein deposition in the brain. The knowledge that age-accelerated atherosclerosis may contribute to age-accelerated cognitive and behavioral abnormalities and structural brain pathologies in patients with chronic epilepsy represents an important research path to pursue future clinical and management considerations.

      Abbreviations:

      AEDs (antiepileptic drugs), IMT (intima media thickness), Hcy (homocysteine), HHcy (hyperhomocysteinemia), TC (total cholesterol), TGs (triglycerides), LDL-c (low-density lipoprotein cholesterol), HDL-c (high-density lipoprotein cholesterol), IR (insulin resistance), CBZ (carbamazepine), PHT (phenytoin), VPA (valproate), PB (phenobarbital), ROS (reactive oxygen species), SCIs (subclinical infarcts), WALs (white matter lesions), AD (Alzheimer's disease)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Epilepsy & Behavior
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Reynolds E.H.
        The ILAE/IBE/WHO Global Campaign against Epilepsy: bringing epilepsy “out of the shadows”.
        Epilepsy Behav. 2000; 1: S3-S8
        • Osuntoku B.O.
        Epilepsy in the African continent.
        in: Peny J.K. The eighth international symposium. Raven Press, New York1977: 365-378
        • Hauser W.A.
        Incidence and prevalence.
        in: Engel J. Pedley T.A. Epilepsy: a comprehensive textbook. Lippincott-Raven, Philadelphia1997: 47-57
        • Aldenkamp A.P.
        • Bodde N.
        Behaviour, cognition and epilepsy.
        Acta Neurol Scand. 2005; 112: S19-S25
        • Piazzini A.
        • Canevini M.P.
        • Turner K.
        • Chifari R.
        • Canger R.
        Elderly people and epilepsy: cognitive function.
        Epilepsia. 2006; 47: 82-84
        • Hermann B.
        • Seidenberg M.
        • Jones J.
        The neurobehavioural comorbidities of epilepsy: can a natural history be developed?.
        Lancet Neurol. 2008; 7: 151-160
        • Hamed S.A.
        The aspects and mechanisms of cognitive alterations in epilepsy: the role of antiepileptic medications.
        CNS Neurosci Ther. 2009; 15: 134-156
        • Jones J.E.
        • Hermann B.P.
        • Barry J.J.
        • Gilliam F.G.
        • Kanner A.M.
        • Meador K.J.
        Rates and risk factors for suicide, suicidal ideation, and suicide attempts in chronic epilepsy.
        Epilepsy Behav. 2003; 4: S31-S38
        • Endermann M.
        • Zimmermann F.
        Factors associated with health-related quality of life, anxiety and depression among young adults with epilepsy and mild cognitive impairments in short-term residential care.
        Seizure. 2009; 18: 167-175
        • Hamed S.A.
        • Metwaly N.A.
        • Hassan M.M.
        • Mohamed K.A.
        • Ahmad M.A.
        • Soliman A.A.
        • et al.
        Depression in adults with epilepsy: relationship to psychobiological variables.
        World J Neurol. 2012; 2: 1-10
        • Hamed S.A.
        • Elserogy Y.E.
        • Abdou M.A.
        • Abdellah M.M.
        The risks of suicidality in adult patients with epilepsy.
        World J Psychiatry. 2012; 2: 33-42
        • Hamed S.A.
        • Elserogy Y.E.
        • Abd-ElHafeez H.A.
        Psychopathological and peripheral level of neurobiological correlates of obsessive compulsive symptoms with epilepsy: a hospital-based study.
        Epilepsy Behav. 2013; 27: 409-415
        • Gaitatzis A.
        • Sisodiya S.M.
        • Sander J.W.
        The somatic comorbidity of epilepsy: a weighty but often unrecognized burden.
        Epilepsia. 2012; 53: 1282-1293
        • Apeland T.
        • Mansoor M.A.
        • Strandjord R.E.
        Antiepileptic drugs as independent predictors of plasma total homocysteine levels.
        Epilepsy Res. 2001; 47: 27-35
        • Sener U.
        • Zorlu Y.
        • Karaguzel O.
        • Ozdamar O.
        • Coker I.
        • Topbas M.
        Effect of common anti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12, folic acid and vitamin B6.
        Seizure. 2006; 15: 79-85
        • Hamed S.A.
        • Nabeshima T.
        The high atherosclerotic risk among epileptics: the atheroprotective role of multivitamins.
        J Pharmacol Sci. 2005; 98: 340-353
        • Hamed S.A.
        • Hamed E.A.
        • Hamdy R.
        • Nabeshima T.
        Vascular risk factors and oxidative stress as independent predictors of asymptomatic atherosclerosis in adult patients with epilepsy.
        Epilepsy Res. 2007; 74: 183-192
        • Calandre E.P.
        • Rodriquez-Lopez C.
        • Blazquez A.
        • Cano D.
        Serum lipids, lipoproteins and apolipoproteins A and B in epileptic patients treated with valproic acid, carbamazepine or phenobarbital.
        Acta Neurol Scand. 1991; 83: 250-253
        • Eris J.
        • Novo-Rodriguez M.I.
        • Del Rio M.
        • Meseguer P.
        • Del Rio M.C.
        • Castro-Gago M.
        The effects on lipid and apolipoprotein on serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy.
        Epilepsy Res. 2000; 41: 1-7
        • Schwaninger M.
        • Ringleb P.
        • Annecke A.
        • Winter R.
        • Kohl B.
        • Werle E.
        • et al.
        Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients.
        J Neurol. 2000; 247: 687-690
        • Voudris K.A.
        • Attilakos A.
        • Katsarou E.
        • Drakatos A.
        • Dimou S.
        • Mastroyianni S.
        • et al.
        Early and persistent increase in serum lipoprotein (a) concentrations in epileptic children treated with carbamazepine and sodium valproate monotherapy.
        Epilepsy Res. 2006; 70: 211-217
        • Kim D.W.
        • Lee S.Y.
        • Shon Y.M.
        • Kim J.H.
        Effects of new antiepileptic drugs on circulatory markers for vascular risk in patients with newly diagnosed epilepsy.
        Epilepsia. 2013; 54: e146-e149
        • Isojarvi J.I.
        • Laatikainen T.J.
        • Knip M.
        • Pakarinen A.J.
        • Juntunen K.T.
        • Myllyla V.V.
        Obesity and endocrine disorders in women taking valproate for epilepsy.
        Ann Neurol. 1996; 39: 579-584
        • Pylvanen V.
        • Pakarinen A.
        • Knip M.
        • Isojarvi J.
        Characterization of insulin secretion in valproate-treated patients with epilepsy.
        Epilepsia. 2006; 47: 1460-1464
        • Hamed S.A.
        Leptin and insulin homeostasis in epilepsy: relation to weight adverse conditions.
        Epilepsy Res. 2007; 75: 1-9
        • Hamed S.A.
        • Fida N.M.
        • Hamed E.A.
        States of serum leptin and insulin in children with epilepsy: risk predictors of weight gain.
        Eur J Pediatr Neurol. 2009; 13: 261-268
        • Isojärvi J.I.
        • Turkka J.
        • Pakarinen A.J.
        • Kotila M.
        • Rättyä J.
        • Myllylä V.V.
        Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy.
        Epilepsia. 2001; 42: 930-934
        • Verrotti A.
        • Basciani F.
        • Morresi S.
        • Morgese G.
        • Chiarelli F.
        Thyroid hormones in epileptic children receiving carbamazepine and valproic acid.
        Pediatr Neurol. 2001; 25: 43-46
        • Hamed S.A.
        • Hamed E.A.
        • Kandil M.R.
        • El-Shereef H.K.
        • Abdellah M.M.
        • Omar H.
        Serum thyroid hormone balance and lipid profile in patients with epilepsy.
        Epilepsy Res. 2005; 66: 173-183
        • Hamed S.A.
        • Abdellah M.M.
        • El-Melegy N.T.
        Blood levels of trace elements, electrolytes and oxidative stress/antioxidant systems in epileptic patients.
        J Pharmacol Sci. 2004; 96: 465-473
        • Mintzer S.
        • Skidmore C.T.
        • Abidin C.J.
        • Morales M.C.
        • Chervoneva I.
        • Capuzzi D.M.
        • et al.
        Effects of antiepileptic drugs on lipids, homocysteine, and C reactive protein.
        Ann Neurol. 2009; 65: 448-456
        • Chuang Y.C.
        • Chuang H.Y.
        • Lin T.K.
        • Chang C.C.
        • Lu C.H.
        • Chang W.N.
        • et al.
        Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis.
        Epilepsia. 2012; 53: 120-128
        • Verrotti A.
        • Scardapane A.
        • Franzoni E.
        • Manco R.
        • Chiarelli F.
        Increased oxidative stress in epileptic children treated with valproic acid.
        Epilepsy Res. 2008; 78: 171-177
        • de Chadarevian J.P.
        • Legido A.
        • Miles D.K.
        • Katsetos C.D.
        Epilepsy, atherosclerosis, myocardial infarction, and carbamazepine.
        J Child Neurol. 2003; 18: 150-151
        • Erdemir A.
        • Cullu N.
        • Yiş U.
        • Demircioğlu F.
        • Kir M.
        • Cakmakçi H.
        • et al.
        Evaluation of serum lipids and carotid artery intima media thickness in epileptic children treated with valproic acid.
        Brain Dev. 2009; 31: 713-716
        • Tan T.Y.
        • Lu C.H.
        • Chuang H.Y.
        • Lin T.K.
        • Liou C.W.
        • Chang W.N.
        • et al.
        Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis.
        Epilepsia. 2009; 50: 1579-1586
        • Yildiz M.
        • Simsek G.
        • Uzun H.
        • Uysal S.
        • Sahin S.
        • Balci H.
        Assessment of low-density lipoprotein oxidation, paraoxonase activity, and arterial distensibility in epileptic children who were treated with anti-epileptic drugs.
        Cardiol Young. 2010; 20: 547-554
        • Tokgoz H.
        • Aydin K.
        • Oran B.
        • Kiyici A.
        Plasma leptin, neuropeptide Y, ghrelin, and adiponectin levels and carotid artery intima media thickness in epileptic children treated with valproate.
        Childs Nerv Syst. 2012; 28: 1049-1053
        • Sankhyan N.
        • Gulati S.
        • Hari S.
        • Kabra M.
        • Ramakrishnan L.
        • Kalra V.
        Noninvasive screening for preclinical atherosclerosis in children on phenytoin or carbamazepine monotherapy: a cross sectional study.
        Epilepsy Res. 2013; 107: 121-126
        • Annegers J.F.
        • Hauser W.A.
        • Shirts S.B.
        Heart disease mortality and morbidity in patients with epilepsy.
        Epilepsia. 1984; 25: 699-704
        • Muuronen A.
        • Kaste M.
        • Nikkila E.A.
        • Tolppanen E.M.
        Mortality from ischemic heart disease among the patients using anticonvulsive drugs: a case–control study.
        BMJ. 1985; 291: 1481-1483
        • Lhatoo S.D.
        • Johnson A.L.
        • Goodridge D.M.
        • MacDonald B.K.
        • Sander J.W.
        • Shorvon S.D.
        Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, population-based cohort.
        Ann Neurol. 2001; 49: 336-344
        • Hsieh C.Y.
        • Lai E.C.
        • Yang Y.H.
        • Lin S.J.
        Comparative stroke risk of antiepileptic drugs in patients with epilepsy.
        Epilepsia. 2013; 54: 172-180
        • Cleary P.
        • Shorvon S.
        • Tallis R.
        Late-onset seizures as a predictor of subsequent stroke.
        Lancet. 2004; 363: 1184-1186
        • Chang C.S.
        • Liao C.H.
        • Lin C.C.
        • Lane H.Y.
        • Sung F.C.
        • Kao C.H.
        Patients with epilepsy are at an increased risk of subsequent stroke: a population-based cohort study.
        Seizure. 2014; https://doi.org/10.1016/j.seizure.2014.02.007
        • Lin J.J.
        • Mula M.
        • Hermann B.P.
        Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan.
        Lancet. 2012; 380: 1180-1192
        • Martin R.
        • Vogtle L.
        • Gilliam F.
        • Faught E.
        What are the concerns of older adults living with epilepsy?.
        Epilepsy Behav. 2005; 7: 297-300
        • Knopman D.
        • Boland L.L.
        • Mosley T.
        • Howard G.
        • Liao D.
        • Szklo M.
        • et al.
        Atherosclerosis Risk in Communities (ARIC) Study Investigators. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Cardiovascular risk factors and cognitive decline in middle-aged adults.
        Neurology. 2001; 56: 42-48
        • Wendell C.R.
        • Zonderman A.B.
        • Metter E.J.
        • Najjar S.S.
        • Waldstein S.R.
        Carotid intimal medial thickness predicts cognitive decline among adults without clinical vascular disease.
        Stroke. 2009; 40: 3180-3185
        • Haley A.P.
        • Tarumi T.
        • Gonzales M.M.
        • Sugawara J.
        • Tanaka H.
        Subclinical atherosclerosis is related to lower neuronal viability in middle-aged adults: a 1H MRS study.
        Brain Res. 2010; 1344: 54-61
        • Romero J.R.
        • Beiser A.
        • Seshadri S.
        • Benjamin E.J.
        • Polak J.F.
        • Vasan R.S.
        • et al.
        Carotid artery atherosclerosis, MRI indices of brain ischemia, aging, and cognitive impairment: the Framingham study.
        Stroke. 2009; 40: 1590-1596
        • Sander K.
        • Bickel H.
        • Förstl H.
        • Etgen T.
        • Briesenick C.
        • Poppert H.
        • et al.
        Carotid- intima media thickness is independently associated with cognitive decline. The INVADE study.
        Int J Geriatr Psychiatry. 2010; 25: 389-394
        • Mathiesen E.B.
        • Waterloo K.
        • Joakimsen O.
        • Bakke S.J.
        • Jacobsen E.A.
        • Bonaa K.H.
        Reduced neuropsychological test performance in asymptomatic carotid stenosis: the Tromso study.
        Neurology. 2004; 62: 695-701
        • Smith P.J.
        • Blumenthal J.A.
        • Babyak M.A.
        • Hoffman B.M.
        • Doraiswamy P.M.
        • Waugh R.
        • et al.
        Cerebrovascular risk factors, vascular disease, and neuropsychological outcomes in adults with major depression.
        Psychosom Med. 2007; 69: 578-586
        • van Oijen M.
        • de Jong F.J.
        • Witteman J.C.
        • Hofman A.
        • Koudstaal P.J.
        • Breteler M.M.
        Atherosclerosis and risk for dementia.
        Ann Neurol. 2007; 61: 403-410
        • Manolio T.A.
        • Burke G.L.
        • O'Leary D.H.
        • Evans G.
        • Beauchamp N.
        • Knepper L.
        • et al.
        Relationships of cerebral MRI findings to ultrasonographic carotid atherosclerosis in older adults: the cardiovascular health study. CHS collaborative research group.
        Arterioscler Thromb Vasc Biol. 1999; 19: 356-365
        • Dubois M.F.
        • Hebert R.
        The incidence of vascular dementia in Canada: a comparison with Europe and East Asia.
        Neuroepidemiology. 2001; 20: 179-187
        • Dufouil C.
        • Alperovitch A.
        • Ducros V.
        • Tzourio C.
        Homocysteine, white matter hyperintensities, and cognition in healthy elderly people.
        Ann Neurol. 2003; 53: 214-221
        • Seshadri S.
        • Beiser A.
        • Selhub J.
        • Jacques P.F.
        • Rosenberg I.H.
        • D'Agostino R.B.
        • et al.
        Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.
        N Engl J Med. 2002; 346: 476-483
        • Panza F.
        • D'Introno A.
        • Colacicco A.M.
        • Capurso C.
        • Pichichero G.
        • Capurso S.A.
        • et al.
        Lipid metabolism in cognitive decline and dementia.
        Brain Res Brain Res Rev. 2006; 51: 275-292
        • Greenwood C.E.
        • Winocur G.
        High-fat diets, insulin resistance and declining cognitive function.
        Neurobiol Aging. 2005; 26: 42-45
        • Young S.E.
        • Mainous III, A.G.
        • Carnemolla M.
        Hyperinsulinemia and cognitive decline in a middle-aged cohort.
        Diabetes Care. 2006; 29: 2688-2693
        • Zhu D.F.
        • Wang Z.X.
        • Zhang D.R.
        • Pan Z.L.
        • He S.
        • Hu X.P.
        • et al.
        fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism.
        Brain. 2006; 129: 2923-2930
        • Resta F.
        • Triggiani V.
        • Barile G.
        • Benigno M.
        • Suppressa P.
        • Giagulli V.A.
        • et al.
        Subclinical hypothyroidism and cognitive dysfunction in the elderly.
        Endocr Metab Immune Disord Drug Targets. 2012; 12: 260-267
        • Aghili R.
        • Khamseh M.E.
        • Malek M.
        • Hadian A.
        • Baradaran H.R.
        • Najafi L.
        • et al.
        Changes of subtests of Wechsler Memory Scale and cognitive function in subjects with subclinical hypothyroidism following treatment with levothyroxine.
        Arch Med Sci. 2012; 8: 1096-1101
        • Tay S.Y.
        • Ampil E.R.
        • Chen C.P.L.H.
        • Auchus A.P.
        The relationship between homocysteine, cognition and stroke subtypes in acute stroke.
        J Neurol Sci. 2006; 250: 58-61
        • Blasko I.
        • Hinterberger M.
        • Kemmler G.
        • Jungwirth S.
        • Krampla W.
        • Leitha T.
        • et al.
        Conversion from mild cognitive impairment to dementia: influence of folic acid and vitamin B12 use in the VITA cohort.
        J Nutr Health Aging. 2012; 16: 687-694
        • Hassing L.B.
        • Dahl A.K.
        • Thorvaldsson V.
        • Berg S.
        • Gatz M.
        • Pedersen N.L.
        • et al.
        Overweight in midlife and risk of dementia: a 40-year follow up study.
        Int J Obes (Lond). 2009; 33: 893-898
        • Mueller K.
        • Sacher J.
        • Arelin K.
        • Holiga S.
        • Kratzsch J.
        • Villringer A.
        • et al.
        Overweight and obesity are associated with neuronal injury in the human cerebellum and hippocampus in young adults: a combined MRI, serum marker and gene expression study.
        Transl Psychiatry. 2012; 2: e200
        • Marqués-Iturria I.
        • Pueyo R.
        • Garolera M.
        • Segura B.
        • Junqué C.
        • García-García I.
        • et al.
        Frontal cortical thinning and subcortical volume reductions in early adulthood obesity.
        Psychiatry Res. 2013; 214: 109-115
        • Shinton R.A.
        • Gill J.S.
        • Zezulka A.V.
        • Beevers D.G.
        The frequency of epilepsy preceding stroke. Case–control study in 230 patients.
        Lancet. 1987; 1: 11-13
        • Ubbink J.B.
        • Becker P.J.
        • Vermaak W.J.H.
        • Del Ponte R.
        Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine.
        Clin Chem. 1995; 41: 1033-1037
        • Kishi T.
        • Fujita N.
        • Eguchi T.
        • Ueda K.
        Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy.
        J Neurol Sci. 1997; 145: 109-112
        • Vilaseca M.A.
        • Monros E.
        • Artuch R.
        • Colome C.
        • Farre C.
        • Valls C.
        • et al.
        Anti-epileptic drug treatment in children: hyperhomocysteinaemia, B-vitamins and the 677C–>T mutation of the methylenetetrahydrofolate reductase gene.
        Eur J Paediatr Neurol. 2000; 4: 269-277
        • Verrotti A.
        • Pascarella R.
        • Trotta D.
        • Giuva T.
        • Morgese G.
        • Chiarelli F.
        Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine.
        Epilepsy Res. 2000; 41: 253-257
        • Wegner C.
        • Nau H.
        Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis.
        Neurology. 1992; 42: 17-24
        • Hogervorst E.
        • Ribiero H.M.
        • Molyneux A.
        • Budge M.
        • Smith D.
        Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease.
        Arch Neurol. 2002; 59: 787-793
        • Tanne D.
        • Haim M.
        • Goldbourt U.
        • Boyko V.
        • Doolman R.
        • Adler Y.
        • et al.
        Prospective study of serum homocysteine and risk of ischemic stroke among patients with preexisting coronary heart disease.
        Stroke. 2003; 34: 632-636
        • Kloppenborg R.P.
        • Nederkoorn P.J.
        • van der Graaf Y.
        • Geerlings M.I.
        Homocysteine and cerebral small vessel disease in patients with symptomatic atherosclerotic disease. The SMART-MR study.
        Atherosclerosis. 2011; 216: 461-466
        • Stein J.H.
        • McBride P.E.
        Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening and treatment.
        Arch Intern Med. 1998; 158: 1301-1306
        • Thambyrajah J.
        • Townend J.N.
        Homocysteine and atherothrombosis — mechanisms for injury.
        Eur Heart J. 2000; 21: 967-974
        • Schroecksnadel K.
        • Frick B.
        • Wirleitner B.
        • Winkler C.
        • Schennach H.
        • Fuchs D.
        Moderate hyperhomocysteinemia and immune activation.
        Curr Pharm Biotechnol. 2004; 5: 107-118
        • Yamamoto M.
        • Hara H.
        • Adachi T.
        Effects of homocysteine on the binding of extracellular–superoxide dismutase to the endothelial cell surface.
        FEBS Lett. 2000; 486: 159-162
        • Riba R.
        • Nicolaou A.
        • Troxler M.
        • Homer-Vaniasinkam S.
        • Naseem K.M.
        Altered platelet reactivity in peripheral vascular disease complicated with elevated plasma homocysteine levels.
        Atherosclerosis. 2004; 175: 69-75
        • Harpel P.C.
        • Chang V.T.
        • Borth W.
        Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential link between thrombosis, atherogenesis, and sulfhydryl compound metabolism.
        Proc Natl Acad Sci U S A. 1992; 89: 10193-10197
        • Sauls D.L.
        • Wolberg A.S.
        • Hoffman M.
        Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia.
        J Thromb Haemost. 2003; 1: 300-306
        • Aggarwal A.
        • Singh V.
        • Batra S.
        • Faridi M.M.
        • Sharma S.
        Effect of carbamazepine therapy on serum lipids in children with partial epilepsy.
        Pediatr Neurol. 2009; 40: 94-97
        • Isojärvi J.I.
        • Pakarinen A.J.
        • Rautio A.
        • Pelkonen O.
        • Myllylä V.V.
        Liver enzyme induction and serum lipid levels after replacement of carbamazepine with oxacarbazepine.
        Epilepsia. 1994; 35: 1217-1220
        • Eirís J.
        • Novo-Rodríguez M.I.
        • Del Río M.
        • Meseguer P.
        • Del Río M.C.
        • Castro-Gago M.
        The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy.
        Epilepsy Res. 2000; 41: 1-7
        • Nikolaos T.
        • Stylianos G.
        • Chryssoula N.
        • Irini P.
        • Christos M.
        • Dimitrios T.
        • et al.
        The effect of long-term antiepileptic treatment on serum cholesterol (TC, HDL, LDL) and triglyceride levels in adult epileptic patients on monotherapy.
        Med Sci Monit. 2004; 10: 50-52
        • Nebert D.W.
        • Russell D.W.
        Clinical importance of the cytochromes P450.
        Lancet. 2002; 360: 1155-1162
        • Luoma P.V.
        • Myllyla V.V.
        • Sotaniemi E.A.
        • Lehtinen I.A.
        • Hokkanen E.J.
        Plasma high-density lipoprotein cholesterol in epileptics treated with various anticonvulsants.
        Eur Neurol. 1980; 19: 67-72
        • Domingo N.
        • Mastellone I.
        • Gres S.
        • Marin V.
        • Lorec A.M.
        • Tosini F.
        • et al.
        The endothelial cholesterol efflux is promoted by the high density lipoprotein anionic peptide factor.
        Metabolism. 2005; 58: 1087-1094
        • Fielding P.E.
        • Fielding C.J.
        • Havel R.J.
        • Kane J.P.
        • Tun P.
        Cholesterol net transport, esterification, and transfer in human hyperlipidemic plasma.
        J Clin Invest. 1983; 71: 449-460
        • Kondo A.
        • Li J.
        • Manabe M.
        • Saito K.
        • Kanno T.
        • Maekawa M.
        Relationship between high-density lipoprotein–cholesterol and malondialdehyde modified low-density lipoprotein concentrations.
        J Atheroscler Thromb. 2003; 10: 72-78
        • Easter D.
        • O'Brvan-Tear C.G.
        • Verity C.
        Weight gain with valproate or carbamazepine — a reappraisal.
        Seizure. 1997; 6: 121-125
        • Maggioni F.
        • Ruffatti S.
        • Dainese F.
        • Mainardi F.
        • Zanchin G.
        Weight variations in the prophylactic therapy of primary headaches: 6-month follow-up.
        J Headache Pain. 2005; 6: 322-324
        • Drieling T.
        • Biedermann N.C.
        • Scharer L.O.
        • Strobi N.
        • Langosch J.M.
        Psychotropic drug-induced changes of weight: a review.
        Fortschr Neurol Psychiatr. 2007; 75: 65-80
        • Arroy S.
        • Anhut T.
        • Kugler A.R.
        • Lee C.M.
        • Knapp L.E.
        • Garofalo E.A.
        • et al.
        Pregabalin 1008-011 International Study Group. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose response study in adults with partial seizures.
        Epilepsia. 2004; 45: 20-27
        • Novak G.P.
        • Maytal J.
        • Alshansky A.
        • Eviatar L.
        • Sy-Kho R.
        • Siddique Q.
        Risk of excessive weight gain in epileptic children treated with valproate.
        J Child Neurol. 1999; 14: 490-495
        • Pylvanen V.
        • Knip M.
        • Pakarinen A.
        • Kotila M.
        • Turkka J.
        • Isojarvi J.I.
        Serum insulin and leptin levels in valproate-associated obesity.
        Epilepsia. 2002; 43: 514-517
        • Richens A.
        • Davidson D.L.
        • Cartlidge N.E.
        • Easter D.J.
        A multicentre comparative trial of sodium valproate and carbamazepine in adult onset epilepsy. Adult EPITEG collaborative group.
        J Neurol Neurosurg Psychiatry. 1994; 57: 765-771
        • Janousek J.
        • Barber A.
        • Goldman L.
        • Klein P.
        Obesity in adults with epilepsy.
        Epilepsy Behav. 2013; 28: 391-394
        • Irace C.
        • Scavelli F.
        • Carallo C.
        • Serra R.
        • Cortese C.
        • Gnasso A.
        Body mass index, metabolic syndrome and carotid atherosclerosis.
        Coron Artery Dis. 2009; 20: 94-99
        • Duntas L.H.
        • Wartofsky L.
        Cardiovascular risk and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence?.
        Thyroid. 2007; 17: 1057-1084
        • Huesca-Gómez C.
        • Franco M.
        • Luc G.
        • Montaño L.F.
        • Massó F.
        • Posadas-Romero C.
        • et al.
        Chronic hypothyroidism induces abnormal structure of high-density lipoproteins and impaired kinetics of apolipoprotein A–I in the rat.
        Metabolism. 2002; 51: 443-550
        • Spacilova J.
        • Limanova Z.
        • Aschermann M.
        Subclinical hypothyroidism with emphasis on the cardiovascular system.
        Cas Lek Cesk. 2003; 142: 643-647
        • Maesaka J.K.
        • Fishban S.
        Regulation of renal urate excretion: a critical review.
        Am J Kidney Dis. 1998; 32: 917-933
        • Kanellis J.
        • Kang D.H.
        Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease.
        Semin Nephrol. 2005; 25: 39-42
        • Patterson R.A.
        • Horsley E.T.
        • Leake D.S.
        Prooxidant and antioxidant properties of human serum ultrafiltrates toward LDL: important role of uric acid.
        J Lipid Res. 2003; 44: 512-521
        • Culleton B.F.
        • Larson M.G.
        • Kannel W.B.
        • Levy D.
        Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study.
        Ann Intern Med. 1999; 131: 7-13
        • de la Torre J.C.
        Critically attained threshold of cerebral hypoperfusion: can it cause Alzheimer's disease?.
        Ann N Y Acad Sci. 2000; 903: 424-436
        • Dede D.S.
        • Yavuz B.
        • Yavuz B.B.
        • Cankurtaran M.
        • Halil M.
        • Ulger Z.
        • et al.
        Assessment of endothelial function in Alzheimer's disease: is Alzheimer's disease a vascular disease?.
        J Am Geriatr Soc. 2007; 55: 1613-1617
        • Sparks D.L.
        • Scheff S.W.
        • Hunsaker III, J.C.
        • Liu H.
        • Landers T.
        • Gross D.R.
        Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol.
        Exp Neurol. 1994; 126: 88-94
        • Miklossy J.
        Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's disease.
        Neurol Res. 2003; 25: 605-610
        • Bell R.D.
        • Zlokovic B.V.
        Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer's disease.
        Acta Neuropathol. 2009; 118: 103-113
        • Zhang C.E.
        • Tian Q.
        • Wei W.
        • Peng J.H.
        • Liu G.P.
        • Zhou X.W.
        • et al.
        Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus.
        Neurobiol Aging. 2008; 29: 1654-1665
        • Umeda T.
        • Tomiyama T.
        • Kitajima E.
        • Idomoto T.
        • Nomura S.
        • Lambert M.P.
        • et al.
        Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice.
        Life Sci. 2012; 91: 1169-1176
        • Kuusisto J.
        • Koivisto K.
        • Mykkänen L.
        • Helkala E.L.
        • Vanhanen M.
        • Hänninen T.
        • et al.
        Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype.
        BMJ. 1997; 315: 1045-1049
        • Talbot K.
        • Wang H.Y.
        • Kazi H.
        • Han L.Y.
        • Bakshi K.P.
        • Stucky A.
        • et al.
        Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.
        J Clin Invest. 2012; 122: 1316-1338
        • Fishel M.A.
        • Watson G.S.
        • Montine T.J.
        • Wang Q.
        • Green P.S.
        • Kulstad J.J.
        • et al.
        Hyperinsulinemia provokes synchronous increases in central inflammation and amyloid in normal adults.
        Arch Neurol. 2005; 62: 1539-1544
        • Hamed S.A.
        • Abd Elaal R.F.
        • Mohamad K.A.
        • Youssef A.H.
        • Abdou M.A.
        Neuropsychological, neurophysiological and laboratory markers of direct brain injury in type 2 diabetes mellitus.
        J Neurol Neurosci. 2012; 3: 2https://doi.org/10.3823/326
        • Kruman I.I.
        • Culmsee C.
        • Chan S.L.
        • Kruman Y.
        • Guo Z.
        • Penix L.
        • et al.
        Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.
        J Neurosci. 2000; 20: 6920-6936
        • Langmeier M.
        • Folbergrova J.
        • Haugvicova R.
        • Pokorny J.
        • Mares P.
        Neuronal cell death in hippocampus induced by homocysteic acid in immature rats.
        Epilepsia. 2003; 44: 299-304
        • Cramer C.
        • Haan M.N.
        • Galea S.
        • Langa K.M.
        • Kalbfleisch J.D.
        Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study.
        Neurology. 2008; 71: 344-350
        • Ullrich C.
        • Pirchl M.
        • Humpel C.
        Hypercholesterolemia in rats impairs the cholinergic system and leads to memory deficits.
        Mol Cell Neurosci. 2010; 45: 408-417
        • Debette S.
        • Beiser A.
        • Hoffmann U.
        • Decarli C.
        • O'Donnell C.J.
        • Massaro J.M.
        • et al.
        Visceral fat is associated with lower brain volume in healthy middle-aged adults.
        Ann Neurol. 2010; 68: 136-144
        • Harvey J.
        • Shanley L.J.
        • O'Malley D.
        • Irving A.J.
        Leptin: a potential cognitive enhancer?.
        Biochem Soc Trans. 2005; 33: 1029-1032
        • Facchini F.S.
        • Hua N.
        • Abbasi F.
        • Reaven G.M.
        Insulin resistance as a predictor of age-related diseases.
        J Clin Endocrinol Metab. 2001; 86: 3574-3578
        • Chiu S.
        • Chen C.
        • Cline H.
        Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo.
        Neuron. 2008; 58: 708-719
        • Hamed S.A.
        • Youssef A.H.
        • Elserogy Y.E.
        • Herdan O.
        • Abd-Elaal R.F.
        • Metwaly N.A.
        • et al.
        Cognitive function in patients with type 2 diabetes mellitus: relationship to stress hormone (cortisol).
        J Neurol Neurosci. 2013; 4: 3https://doi.org/10.3823/335
        • Adeghate E.
        • Donath T.
        • Adem A.
        Alzheimer disease and diabetes mellitus: do they have anything in common?.
        Curr Alzheimer Res. 2013; 10: 609-617
        • Bernard C.
        • Helmer C.
        • Dilharreguy B.
        • Amieva H.
        • Auriacombe S.
        • Dartigues J.F.
        • et al.
        Time course of brain volume changes in the preclinical phase of Alzheimer's disease.
        Alzheimers Dement. 2014; 10: 143-151
        • Hermann B.
        • Seidenberg M.
        • Bell B.
        • Rutecki P.
        • Sheth R.D.
        • Wendt G.
        • et al.
        Extratemporal quantitative MR volumetrics and neuropsychological status in temporal lobe epilepsy.
        J Int Neuropsychol Soc. 2003; 9: 353-362
        • Natsume J.
        • Bernasconi N.
        • Andermann F.
        • Bernasconi A.
        MRI volumetry of the thalamus in temporal, extratemporal, and idiopathic generalized epilepsy.
        Neurology. 2003; 60: 1296-1300
        • Briellmann R.S.
        • Wellard R.M.
        • Jackson G.D.
        Seizure-associated abnormalities in epilepsy: evidence from MR imaging.
        Epilepsia. 2005; 46: 760-766
        • Kövari E.
        • Herrmann F.R.
        • Hof P.R.
        • Bouras C.
        The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease.
        Neuropathol Appl Neurobiol. 2013; 39: 498-509
        • Radhakrishnan A.
        • Radhakrishnan K.
        • Radhakrishnan V.V.
        • Mary P.R.
        • Kesavadas C.
        • Alexander A.
        • et al.
        Corpora amylacea in mesial temporal lobe epilepsy: clinico-pathological correlations.
        Epilepsy Res. 2007; 74: 81-90
        • Ben-Menachem E.
        • Axelsen M.
        • Johanson E.H.
        • Stagge A.
        • Smith U.
        Predictors of weight loss in adults with topiramate-treated epilepsy.
        Obes Res. 2003; 11: 556-562
        • Kim D.W.
        • Yoo M.W.
        • Park K.S.
        Low serum leptin level is associated with zonisamide-induced weight loss in overweight female epilepsy patients.
        Epilepsy Behav. 2012; 23: 497-499
        • Pugh M.J.
        • Knoefel J.E.
        • Mortensen E.M.
        • Amuan M.E.
        • Berlowitz D.R.
        • Van Cott A.C.
        New-onset epilepsy risk factors in older veterans.
        J Am Geriatr Soc. 2009; 57: 237-242
        • Etminan M.
        • Samii A.
        • Brophy J.M.
        Statin use and risk of epilepsy: a nested case–control study.
        Neurology. 2010; 75: 1496-1500
        • Hankey G.J.
        • Ford A.H.
        • Yi Q.
        • Eikelboom J.W.
        • Lees K.R.
        • Chen C.
        • et al.
        Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis.
        Stroke. 2013; 44: 2232-2239