Oxcarbazepine administration and the serum levels of homocysteine, vitamin B12 and folate in epileptic patients: A systematic review and meta-analysis

Open ArchivePublished:November 24, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.016

      Highlights

      • OXC does not have any significant effect on tHcy level.
      • Hcy’s metabolism cofactors, vitamin B12 and folate levels, not influenced by OXC.
      • Vitamin B12 level lowered in children on OXC monotherapy than adults.

      Abstract

      The objectives were to determine the influence of oxcarbazepine (OXC) monotherapy on the serum levels of total homocysteine (tHcy), vitamin B12 and folate in patient with epilepsy pooling together case-control or interventional studies. A comprehensive literature search was done through four databases including MEDLINE/PubMed, Scopus, Embase and Web of Science from January 2000 to February 2016. A random effects model (the DerSimonian–Laird estimator) was utilized to pool the effect sizes of the individual studies. The between-study variance was assessed using the Q2 test (significance level p < 0.1) and quantified using the I2 test (>50% indicated evidence of heterogeneity). Overall, six studies found eligible for inclusion. The meta-analysis for tHcy revealed that the serum level of tHcy was no significant difference between patient on OXC monotherapy and healthy people [mean difference (MD) 0.31; 95% CI −1.05, 1.67, p = 0.653]. The meta-analysis for vitamin B12 [MD −46.51; 95% CI −113.63, 20.62, p = 0.174] and folate [MD −0.48; 95% CI −1.06, 0.11, p = 0.113] indicated that there was no significant difference between patients on OXC monotherapy and healthy people. In conclusion, the meta-analysis does not support the hypotheses that OXC monotherapy changes the serum levels of tHcy, vitamin B12 and folate.

      Keywords

      1. Introduction

      Epilepsy is one of the most prevalent neurological disorders in the world, affecting approximately 50 million people worldwide [

      WHO, Epilepsy February 2016. Available from: http://www.who.int/mediacentre/factsheets/fs999/en/.

      ]. Globally, an estimated of 2.4 million people are diagnosed with epilepsy each year. According to the World Health Organization (WHO) report, the incidence of epilepsy in high-income countries are between 30 and 50 per 100,000 people in the general population and in low- and middle-income countries, this statistic can be up to two times higher [

      WHO, Epilepsy February 2016. Available from: http://www.who.int/mediacentre/factsheets/fs999/en/.

      ].
      According to the contemporary proposal by the International League Against Epilepsy (ILAE), epilepsy is defined by any of the following conditions: (a) at least two unprovoked (or reflex) seizures occurring >24 h apart; (b) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the following 10 years; (c) diagnosis of an epilepsy syndrome [
      • Fisher R.S.
      • Acevedo C.
      • Arzimanoglou A.
      • Bogacz A.
      • Cross J.H.
      • Elger C.E.
      • et al.
      ILAE official report: a practical clinical definition of epilepsy.
      ].
      Epilepsy is a chronic condition that requires long term treatment with antiepileptic drugs (AEDs) [
      • McCorry D.
      • Chadwick D.
      • Marson A.
      Current drug treatment of epilepsy in adults.
      ]. Oxcarbazepine (OXC), is one of the newer antiepileptic drugs used as both monotherapy and adjunctive therapy for the treatment of partial seizures with or without secondary generalization [
      • Rabasseda X.
      Oxcarbapezine: anticonvulsant profile and safety.
      ]. Moreover, it is effective for treatment of the Trigeminal neuralgia as well [
      • Gronseth G.
      • Cruccu G.
      • Alksne J.
      • Argoff C.
      • Brainin M.
      • Burchiel K.
      • et al.
      Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies.
      ]. Earlier studies have depicted that cardiovascular diseases (CVD) among epileptic patients are higher than healthy people [
      • Hamed S.A.
      • Nabeshima T.
      The high atherosclerotic risk among epileptics: the atheroprotective role of multivitamins.
      ,
      • Elliott J.O.
      • Jacobson M.P.
      • Haneef Z.
      Cardiovascular risk factors and homocysteine in epilepsy.
      ]. One of the leading risk factors for CVD in these patients is using AEDs [
      • 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.
      ,
      • 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.
      ]. It is suggested that AEDs changes the levels of many biomarkers that are concomitant with developing atherosclerosis including altered lipid profile as increasing total cholesterol and low density lipoprotein [
      • Franzoni E.
      • Govoni M.
      • D’Addato S.
      • Gualandi S.
      • Sangiorgi Z.
      • Descovich G.C.
      • et al.
      Total cholesterol, high-density lipoprotein cholesterol, and triglycerides in children receiving antiepileptic drugs.
      ,
      • Eiris J.M.
      • Lojo S.
      • Del Rio M.C.
      • Novo I.
      • Bravo M.
      • Pavon P.
      • et al.
      Effects of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy.
      ,
      • Verrotti A.
      • Domizio S.
      • Angelozzi B.
      • Sabatino G.
      • Morgese G.
      • Chiarelli F.
      Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants.
      ], increasing serum levels of homocysteine [
      • Jakubus T.
      • Michalska-Jakubus M.
      • Łukawski K.
      • Janowska A.
      • Czuczwar S.J.
      Atherosclerotic risk among children taking antiepileptic drugs.
      ] and C-reactive protein (CRP) [
      • 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.
      ].
      Homocysteine (Hcy) is formed as an intermediate product during the metabolism of methionine to cysteine. For converting Hcy to methionine (re-methylation pathway) vitamin B12 and folic acid as cofactors are required [
      • Hoffer L.J.
      Homocysteine remethylation and trans-sulfuration.
      ,
      • Trabetti E.
      Homocysteine, MTHFR gene polymorphisms, and cardio-cerebrovascular risk.
      ]. The absence of these cofactors, as well as vitamin B6 (trans-sulfuration pathway) leads to hyperhomocysteinemia [
      • Welch G.N.
      • Loscalzo J.
      Homocysteine and atherothrombosis.
      ]. Several studies revealed that older AEDs increase tHcy and reduce the serum levels of folate, vitamin B6 and B12 [
      • Gorjipour F.
      • Asadi Y.
      • Osguei N.K.
      • Effatkhah M.
      • Samadikuchaksaraei A.
      Serum level of homocysteine, folate and vitamin-B12 in epileptic patients under carbamazepine and sodium valproate treatment: a systematic review and meta-analysis.
      ,
      • Ni G.
      • Qin J.
      • Fang Z.
      • Chen Y.
      • Chen Z.
      • Zhou J.
      • et al.
      Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis.
      ,
      • Karabiber H.
      • Sonmezgoz E.
      • Ozerol E.
      • Yakinci C.
      • Otlu B.
      • Yologlu S.
      Effects of valproate and carbamazepine on serum levels of homocysteine, vitamin B12, and folic acid.
      ,
      • Verrotti A.
      • Pascarella R.
      • Trotta D.
      • Giuva T.
      • Morgese G.
      • Chiarelli F.
      Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine.
      ]. However, for the newer AEDs including OXC, the association between using these drugs and the serum levels of tHcy and its cofactors on cardiovascular diseases is controversial [
      • Algin D.I.
      • Erdinc O.O.
      • Alatas O.
      • Toker A.
      • Colak O.
      • Oner S.
      Effects of oxcarbazepine on plasma homocysteine, vitamin B12, folic acid levels.
      ,
      • Vurucu S.
      • Gulgun M.
      • Yesilkaya E.
      • Unay B.
      • Akin R.
      The effects of oxcarbazepine treatment on vitamin B12 and folate levels, thyroid functions, sex hormones, and bone mineral density in epileptic patients.
      ]. Therefore, the aim of this systematic review and meta-analysis was to find the association between using OXC and tHcy, vitamin B9 and B12.

      2. Methods

      The investigators performed the systematic review and meta-analysis according to the PRISMA protocol [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ]. This study was registered in PROSPERO with registration number: CRD42015029570.

      2.1 Literature searches

      A comprehensive literature search was done and four foremost databases namely MEDLINE/PubMed, Scopus, Web of Science (WOS) and Embase were searched for papers published from January 2000 to February 2016 by two autonomous investigators (SR and AA). The following key words were used; epilepsy; oxcarbazepine; trileptal; homocysteine; Hcy; “vitamin B12”; “vit B12”; cobalamin; folate; “folic acid”; “vitamin B9”; “vit B9”; “vitamin M”; “vit M”; “pteroylglutamic acid”. In PubMed and Embase for each keyword Medical Subject Heading (MeSH) and EMTREE databases were used; respectively. Based on each database search strategy was adjusted. Details of search strategy in all four databases; which mentioned above are available in the Supplementary part of this paper (Supp. Tables 1, 2, 3 & 4).
      To supplement the searches and ensure optimal and complete literature retrieval, Google scholar and the grey literature databases including Dissertations & Theses database of Proquest, clinicaltrials.gov and OpenGrey (system information on Grey literature in Europe) were also searched. Additionally, a manual check of the reference lists of all enrolled papers and pertinent systematic review and meta-analysis was accomplished.
      Literature search results were downloaded into EndNote (version X7), for Windows, Thomson Reuters, Philadelphia, PA, USA, (Release date: 30 September 2014) to merge retrieved citations, eliminate duplications and to facilitate the review process.

      2.2 Eligibility criteria

      Relevant studies were included if they fulfilled the following criteria: (1) case-control studies measured the levels of tHcy, vitamin B12 or folate, (2) interventional studies investigating to determine the influence of OXC monotherapy on the serum levels of tHcy, vitamin B12 or folate, (3) article was published in English, (4) the apparently healthy control group. Articles were excluded if they: (1) applied study design rather than case-control or interventional studies, (2) were animal or in vitro studies, (3) were studies rather than original article or article in press, (4) were studies without control group or absence of healthy control group, (5) did not report any of the serum levels of the tHcy, vitamin B12 or folate, (6) did not mention the influence of OXC as monotherapy.

      2.3 Study selection and data extraction

      Titles and abstracts of all articles retrieved in the initial search were evaluated independently by two reviewers (SR and AA). Then full texts of included papers were assessed and papers that did not meet the above criteria were discarded. Any disagreements were discussed and resolved by consensus.
      The following data were extracted from the included papers: Title, first author, year of publication, country, sample size, age, sex, study design, mean and standard deviation (SD) for serum homocysteine, vitamin B12 and folate.

      2.4 Data analysis

      To calculate the overall effect size, a mean difference (MD) for homocysteine, vitamin B12 and folate separately was calculated and then pooled by the generic inverse variance method by the user written “metan” command in Stata software (version 12). Effect size was pooled from all eligible studies using the DerSimonian–Laird random effects model (REM) for meta-analysis. This model was preferred to a fixed effect model, since it is based on the assumption that a distribution of effects exists, resulting in heterogeneity among study results. Results are presented in tables and forest plots where MD and 95% confidential intervals (95% CI) are figured out for every study inserted in the model and for the overall estimate. Heterogeneity was assessed using I2 statistic provided the relative amount of variance of the summary effect. In analyses if heterogeneity was observed, we explored possible sources of heterogeneity by sub-group analyses based on age of participants.
      To retrieve the extent of publication bias, Egger’s test and Begg’s test were computed with the user written “metabias” command in Stata (version 12) software. All statistical analyses were done by using Stata version 12 (StataCorp, College Station, Texas, USA).

      3. Results

      3.1 Study selection

      The literature search identified 175 potential papers for inclusion in the study, 19 records from PubMed, 70 records from Scopus, 17 records from WOS and 69 records from Embase. Among them, 92 were duplicate and discarded. Following abstract screening, 79 papers excluded since they were review, consensus, guideline and case report. Thirteen papers remained for detailed full-text evaluation based on inclusion criteria. In the next step, full text of the remaining papers screened precisely and among them nine papers discarded [
      • Vurucu S.
      • Gulgun M.
      • Yesilkaya E.
      • Unay B.
      • Akin R.
      The effects of oxcarbazepine treatment on vitamin B12 and folate levels, thyroid functions, sex hormones, and bone mineral density in epileptic patients.
      ,
      • Badiou S.
      • Breton H.
      • Peyriere H.
      • Charasson V.
      • Crespel A.
      • Gelisse P.
      • et al.
      Comparison of carbamazepine and oxcarbazepine effects on aminothiol levels.
      ,
      • Herrmann W.
      • Obeid R.
      Special issue on advances and controversies in B vitamins and choline.
      ,
      • 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.
      ,
      • Kampman M.T.
      Folate status in women of childbearing age with epilepsy.
      ,
      • Elliott J.O.
      • Jacobson M.P.
      • Haneef Z.
      Homocysteine and bone loss in epilepsy.
      ,
      • Kim D.W.
      • Shon Y.-M.
      • Lee S.-Y.
      • Kim J.H.
      Effects of newer generation antiepileptic drugs on vascular risk factors in newly diagnosed epilepsy patients.
      ,
      • Linnebank M.
      Antiepileptic drugs and B-vitamins: epidemiological and electrophysiological data.
      ,
      • Aslan K.
      • Bozdemir H.
      • Unsal C.
      • Güvenc B.
      The effect of antiepileptic drugs on vitamin B12 metabolism.
      ]. For those articles which have no basic data for the analysis, we requested the corresponding author via email; however, none of them responded. Therefore, four papers enrolled to this study through searching in these databases. Moreover, searching Google scholar manually resulted in two new conference papers [
      • Gümüş H.
      • Kumandaş S.
      • Per H.
      ETP028 Effects of common anti-epileptic drugs and oxcarbazepine monotherapy on serum levels of homocysteine, vitamin B12, folic acid.
      ,
      • Bozlu G.
      • Okuyaz C.
      • Eskandari G.
      • Mert E.
      ETP027 Effects of oxcarbazepine on serum lipid, lipoprotein (a), homocysteine, folate and vitamin B12 levels in children with partial epilepsy.
      ]. Subsequently, six records included for the meta-analysis [
      • Algin D.I.
      • Erdinc O.O.
      • Alatas O.
      • Toker A.
      • Colak O.
      • Oner S.
      Effects of oxcarbazepine on plasma homocysteine, vitamin B12, folic acid levels.
      ,
      • Gümüş H.
      • Kumandaş S.
      • Per H.
      ETP028 Effects of common anti-epileptic drugs and oxcarbazepine monotherapy on serum levels of homocysteine, vitamin B12, folic acid.
      ,
      • Bozlu G.
      • Okuyaz C.
      • Eskandari G.
      • Mert E.
      ETP027 Effects of oxcarbazepine on serum lipid, lipoprotein (a), homocysteine, folate and vitamin B12 levels in children with partial epilepsy.
      ,
      • Linnebank M.
      • Moskau S.
      • Semmler A.
      • Widman G.
      • Stoffel-Wagner B.
      • Weller M.
      • et al.
      Antiepileptic drugs interact with folate and vitamin B12 serum levels.
      ,
      • Emeksiz H.C.
      • Serdaroglu A.
      • Biberoglu G.
      • Gulbahar O.
      • Arhan E.
      • Cansu A.
      • et al.
      Assessment of atherosclerosis risk due to the homocysteine-asymmetric dimethylarginine-nitric oxide cascade in children taking antiepileptic drugs.
      ,
      • Kurul S.
      • Unalp A.
      • Yis U.
      Homocysteine levels in epileptic children receiving antiepileptic drugs.
      ] (Fig. 1). The articles that were included in our analysis are shown in Table 1.
      Table 1Summary of studies included in the meta-analysis.
      CaseControl
      StudyYearCountrySample sizeStudy typeGenderAge, y
      This study presented the age as the Mean±SD as well as serum levels of homocysteine, vitamin B12 and folate.
      Hcy
      This study presented the age as the Mean±SD as well as serum levels of homocysteine, vitamin B12 and folate.


      (μmol/L)
      Vit B12

      (pg/ml)
      Folate

      (ng/ml)
      Sample sizeGenderAge, yHcy

      (μmol/L)
      Vit B12

      (pg/ml)
      Folate

      (ng/ml)
      Emeksiz et al.2013Turkey27CCM(11)/F(16)10.8 ± 3.210.1 ± 3.9499.8 ± 194.48.5 ± 3.124M(13)/F(11)12.1 ± 3.39.1 ± 3.4515.5 ± 217.28.9 ± 2.5
      Linnebank et al.2011Germany96CCM(48)/F(48)35.7 ± 15.7379 ± 1876.1 ± 3.3200366 ± 1606.3 ± 3.7
      Algin et al.2009Turkey12CCM(7)/F(5)46.3 ± 1.28.7 ± 10.6313.2 ± 76.76.9 ± 1.130M(14)/F(16)45 ± 2.410.6 ± 4.7413.1 ± 2247.6 ± 2.3
      Kurul et al.2007Turkey6CC11.4 ± 3.37.06 ± 1.6364.1 ± 146.99.1 ± 4.110M(4)/F(6)12 ± 3.97.6 ± 2.3406.8 ± 172.19.7 ± 3.5
      Gumus et al.
      In both studies the study populations were children; however, the mean±SD for age did not mentioned.
      2007Turkey30CC<1810.2 ± 81.5665.5 ± 369.65.7 ± 3.230<187.3 ± 16.7600 ± 557.710.04 ± 11.2
      Bozlu et al.
      In both studies the study populations were children; however, the mean±SD for age did not mentioned.
      2007Turkey19CC<18307.8 ± 156.916<18490.4 ± 234.07
      Abbreviation: M, male; F, female; Hcy, homocysteine; Vit B12, vitamin B12; CC, case control.
      a This study presented the age as the Mean ± SD as well as serum levels of homocysteine, vitamin B12 and folate.
      b In both studies the study populations were children; however, the mean ± SD for age did not mentioned.

      3.2 Study characteristics

      Among included papers, four papers [
      • Algin D.I.
      • Erdinc O.O.
      • Alatas O.
      • Toker A.
      • Colak O.
      • Oner S.
      Effects of oxcarbazepine on plasma homocysteine, vitamin B12, folic acid levels.
      ,
      • Gümüş H.
      • Kumandaş S.
      • Per H.
      ETP028 Effects of common anti-epileptic drugs and oxcarbazepine monotherapy on serum levels of homocysteine, vitamin B12, folic acid.
      ,
      • Emeksiz H.C.
      • Serdaroglu A.
      • Biberoglu G.
      • Gulbahar O.
      • Arhan E.
      • Cansu A.
      • et al.
      Assessment of atherosclerosis risk due to the homocysteine-asymmetric dimethylarginine-nitric oxide cascade in children taking antiepileptic drugs.
      ,
      • Kurul S.
      • Unalp A.
      • Yis U.
      Homocysteine levels in epileptic children receiving antiepileptic drugs.
      ] had the serum levels of all three parameters of this study namely; tHcy, vitamin B12 and folate and one of them had levels of vitamin B12 and folate [
      • Linnebank M.
      • Moskau S.
      • Semmler A.
      • Widman G.
      • Stoffel-Wagner B.
      • Weller M.
      • et al.
      Antiepileptic drugs interact with folate and vitamin B12 serum levels.
      ] and the last one had solely level of vitamin B12 [
      • Bozlu G.
      • Okuyaz C.
      • Eskandari G.
      • Mert E.
      ETP027 Effects of oxcarbazepine on serum lipid, lipoprotein (a), homocysteine, folate and vitamin B12 levels in children with partial epilepsy.
      ]. All the included studies were case-control and measured the serum levels of tHcy, vitamin B12 and folate in healthy people and patients on OXC monotherapy more than 6 months, except one study that did not mention the precise time for patients on OXC therapy [
      • Linnebank M.
      • Moskau S.
      • Semmler A.
      • Widman G.
      • Stoffel-Wagner B.
      • Weller M.
      • et al.
      Antiepileptic drugs interact with folate and vitamin B12 serum levels.
      ]. Among the included papers, three of them indicated that study participants were free from any comorbidities including history of cardiac or peripheral vascular disease, and renal, hepatic, or thyroid disease and were not on any medications or supplements [
      • Algin D.I.
      • Erdinc O.O.
      • Alatas O.
      • Toker A.
      • Colak O.
      • Oner S.
      Effects of oxcarbazepine on plasma homocysteine, vitamin B12, folic acid levels.
      ,
      • Emeksiz H.C.
      • Serdaroglu A.
      • Biberoglu G.
      • Gulbahar O.
      • Arhan E.
      • Cansu A.
      • et al.
      Assessment of atherosclerosis risk due to the homocysteine-asymmetric dimethylarginine-nitric oxide cascade in children taking antiepileptic drugs.
      ,
      • Kurul S.
      • Unalp A.
      • Yis U.
      Homocysteine levels in epileptic children receiving antiepileptic drugs.
      ].

      3.3 Meta-analysis

      3.3.1 Homocysteine

      Four studies included for meta-analysis. The overall pooled MD of 0.31 (95% CI: −1.05, 1.67) and P value of 0.653, indicate that the serum levels of tHcy did not differ significantly between 74 cases and 94 healthy control subjects (Fig. 2). There was no heterogeneity found between studies (I-squared = 0.0%, p = 0.631). Egger’s test showed no publication bias (Egger test, P = 0.6).
      Fig. 2
      Fig. 2Pooled estimate of mean difference of the serum total homocysteine level in patients with epilepsy who received oxcarbazepine monotherapy.

      3.3.2 Vitamin B12

      Six studies included for meta-analysis. The overall pooled MD of −46.51 (95% CI: −113.63, 20.62) and P value of 0.174 indicate that the serum levels of vitamin B12 did not differ significantly between 189 cases and 310 healthy control subjects. Statistically significant heterogeneity was found among these studies (I-squared = 55.7% and p = 0.046) (Fig. 3). Egger’s test showed no publication bias (Egger test, p = 0.326).
      Fig. 3
      Fig. 3Pooled estimate of mean difference of the serum vitamin B12 level in patients with epilepsy who received oxcarbazepine monotherapy.

      3.3.3 Folate

      Five studies included for meta-analysis. The overall pooled MD of −0.48 (95% CI: −1.06, 0.11) and P value of 0.113 indicate that the serum levels of vitamin B12 did not differ significantly between 170 cases and 294 healthy control subjects. There was no heterogeneity found among studies (I-squared = 0.0%, p = 0.444) (Fig. 4). Egger's test showed no publication bias (Egger test, p = 0.191).
      Fig. 4
      Fig. 4Pooled estimate of mean difference of the serum folate level in patients with epilepsy who received oxcarbazepine monotherapy.

      3.4 Subgroup analysis

      In subgroup analysis by age [1–18 and >18 years], there was no significant difference between two groups in all three parameters (P > 0.05). However, the heterogeneity remain significant after subgroup analysis in vitamin B12 (1–18 years, I-squared = 38.3%, p = 0.182; >18 years, I-squared = 78.8%, p = 0.030) (Table 2).
      Table 2Sub-group analysis.
      Sub-group analyses based on age of participants (1–18 years or >18 years)
      CategoryPooled WMD (95%CI), pI2, pIncluded papers
      (A) OXC and total homocysteine
      1–18 years0.19 (−1.21, 1.59), 0.7890.0%, 0.527
      • Gümüş H.
      • Kumandaş S.
      • Per H.
      ETP028 Effects of common anti-epileptic drugs and oxcarbazepine monotherapy on serum levels of homocysteine, vitamin B12, folic acid.
      ,
      • Emeksiz H.C.
      • Serdaroglu A.
      • Biberoglu G.
      • Gulbahar O.
      • Arhan E.
      • Cansu A.
      • et al.
      Assessment of atherosclerosis risk due to the homocysteine-asymmetric dimethylarginine-nitric oxide cascade in children taking antiepileptic drugs.
      ,
      • Kurul S.
      • Unalp A.
      • Yis U.
      Homocysteine levels in epileptic children receiving antiepileptic drugs.
      >18 years2.10 (−3.31, 7.51), 0.447
      • Algin D.I.
      • Erdinc O.O.
      • Alatas O.
      • Toker A.
      • Colak O.
      • Oner S.
      Effects of oxcarbazepine on plasma homocysteine, vitamin B12, folic acid levels.
      (B) OXC and vitamin B12
      1–18 years−62.39 (−135.01, 10.24), 0.09238.3%, 0.182
      • Gümüş H.
      • Kumandaş S.
      • Per H.
      ETP028 Effects of common anti-epileptic drugs and oxcarbazepine monotherapy on serum levels of homocysteine, vitamin B12, folic acid.
      ,
      • Bozlu G.
      • Okuyaz C.
      • Eskandari G.
      • Mert E.
      ETP027 Effects of oxcarbazepine on serum lipid, lipoprotein (a), homocysteine, folate and vitamin B12 levels in children with partial epilepsy.
      ,
      • Emeksiz H.C.
      • Serdaroglu A.
      • Biberoglu G.
      • Gulbahar O.
      • Arhan E.
      • Cansu A.
      • et al.
      Assessment of atherosclerosis risk due to the homocysteine-asymmetric dimethylarginine-nitric oxide cascade in children taking antiepileptic drugs.
      ,
      • Kurul S.
      • Unalp A.
      • Yis U.
      Homocysteine levels in epileptic children receiving antiepileptic drugs.
      >18 years−7.59 (−46.91, 31.73), 0.70578.8%, 0.030
      • Algin D.I.
      • Erdinc O.O.
      • Alatas O.
      • Toker A.
      • Colak O.
      • Oner S.
      Effects of oxcarbazepine on plasma homocysteine, vitamin B12, folic acid levels.
      ,
      • Linnebank M.
      • Moskau S.
      • Semmler A.
      • Widman G.
      • Stoffel-Wagner B.
      • Weller M.
      • et al.
      Antiepileptic drugs interact with folate and vitamin B12 serum levels.
      (C) OXC and folate
      1–18 years−0.83 (−2.19, 0.53), 0.23330.5%, 0.237
      • Gümüş H.
      • Kumandaş S.
      • Per H.
      ETP028 Effects of common anti-epileptic drugs and oxcarbazepine monotherapy on serum levels of homocysteine, vitamin B12, folic acid.
      ,
      • Emeksiz H.C.
      • Serdaroglu A.
      • Biberoglu G.
      • Gulbahar O.
      • Arhan E.
      • Cansu A.
      • et al.
      Assessment of atherosclerosis risk due to the homocysteine-asymmetric dimethylarginine-nitric oxide cascade in children taking antiepileptic drugs.
      ,
      • Kurul S.
      • Unalp A.
      • Yis U.
      Homocysteine levels in epileptic children receiving antiepileptic drugs.
      >18 years−0.39 (−1.05, 0.26), 0.2370.0%, 0.465
      • Algin D.I.
      • Erdinc O.O.
      • Alatas O.
      • Toker A.
      • Colak O.
      • Oner S.
      Effects of oxcarbazepine on plasma homocysteine, vitamin B12, folic acid levels.
      ,
      • Linnebank M.
      • Moskau S.
      • Semmler A.
      • Widman G.
      • Stoffel-Wagner B.
      • Weller M.
      • et al.
      Antiepileptic drugs interact with folate and vitamin B12 serum levels.
      Abbreviation: OXC, oxcarbazepine.

      4. Discussion

      In response to the question of this review that “How does oxcarbazepine influence on the serum levels of total homocysteine, vitamin B12 and folate?”, the results of this systematic review and meta-analysis depicted OXC does not have any significant influence on the tHcy level and its metabolism cofactors, vitamin B12 and folate as well.
      Hcy is a thiol-containing amino acid that is formed following breakdown of amino acid methionine [
      • Verhoef P.
      • Hennekens C.H.
      • Malinow M.R.
      • Kok F.J.
      • Willett W.C.
      • Stampfer M.J.
      A prospective study of plasma homocyst (e) ine and risk of ischemic stroke.
      ]. High level of tHcy leads to several disadvantageous effects on the body [
      • Varga E.A.
      • Sturm A.C.
      • Misita C.P.
      • Moll S.
      Homocysteine and MTHFR mutations: relation to thrombosis and coronary artery disease.
      ]. For intercepting cytotoxic accumulation of Hcy, cells convert it to its non-cytotoxic metabolites. Two pathways are available for homocysteine metabolism, re-methylation and trans-sulfuration. Vitamin B12 and folate are cofactors for re-methylation pathway and vitamin B6 for trans-sulfuration pathway. As a result, sufficient amount of these vitamins is essential for maintaining homocysteine homeostasis. Lacks of these cofactors disrupt this homeostasis and leads to hyperhomocysteinemia [
      • Jacobsen D.W.
      Biochemistry and metabolism.
      ].
      Hyperhomocysteinemia is an dominant probable risk factor for several disorders including coronary artery disease [
      • Clarke R.
      • Daly L.
      • Robinson K.
      • Naughten E.
      • Cahalane S.
      • Fowler B.
      • et al.
      Hyperhomocysteinemia: an independent risk factor for vascular disease.
      ,
      • Cavalca V.
      • Cighetti G.
      • Bamonti F.
      • Loaldi A.
      • Bortone L.
      • Novembrino C.
      • et al.
      Oxidative stress and homocysteine in coronary artery disease.
      ,
      • Soinio M.
      • Marniemi J.
      • Laakso M.
      • Lehto S.
      • Ronnemaa T.
      Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus.
      ,
      • Nygard O.
      • Nordrehaug J.E.
      • Refsum H.
      • Ueland P.M.
      • Farstad M.
      • Vollset S.E.
      Plasma homocysteine levels and mortality in patients with coronary artery disease.
      ], stroke [
      • Kelly P.J.
      • Rosand J.
      • Kistler J.P.
      • Shih V.E.
      • Silveira S.
      • Plomaritoglou A.
      • et al.
      Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic stroke: results of a meta-analysis.
      ,
      • McIlroy S.P.
      • Dynan K.B.
      • Lawson J.T.
      • Patterson C.C.
      • Passmore A.P.
      Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland.
      ,
      • 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.
      ,
      • Li Z.
      • Sun L.
      • Zhang H.
      • Liao Y.
      • Wang D.
      • Zhao B.
      • et al.
      Elevated plasma homocysteine was associated with hemorrhagic and ischemic stroke, but methylenetetrahydrofolate reductase gene C677T polymorphism was a risk factor for thrombotic stroke: a multicenter case-control study in China.
      ,
      • Iso H.
      • Moriyama Y.
      • Sato S.
      • Kitamura A.
      • Tanigawa T.
      • Yamagishi K.
      • et al.
      Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese.
      ], carotid artery stenosis [
      • Selhub J.
      • Jacques P.F.
      • Bostom A.G.
      • D’Agostino R.B.
      • Wilson P.W.
      • Belanger A.J.
      • et al.
      Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis.
      ,
      • Malinow M.R.
      • Nieto F.J.
      • Szklo M.
      • Chambless L.E.
      • Bond G.
      Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The atherosclerosis risk in communities study.
      ,
      • McQuillan B.M.
      • Beilby J.P.
      • Nidorf M.
      • Thompson P.L.
      • Hung J.
      Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS).
      ], heart failure [
      • Vasan R.S.
      • Beiser A.
      • D’Agostino R.B.
      • Levy D.
      • Selhub J.
      • Jacques P.F.
      • et al.
      Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction.
      ], venous thromboembolic disease [
      • den Heijer M.
      • Koster T.
      • Blom H.J.
      • Bos G.M.
      • Briet E.
      • Reitsma P.H.
      • et al.
      Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.
      ,
      • Ray J.G.
      Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease.
      ,
      • den Heijer M.
      • Rosendaal F.R.
      • Blom H.J.
      • Gerrits W.B.
      • Bos G.M.
      Hyperhomocysteinemia and venous thrombosis: a meta-analysis.
      ,
      • Pancharuniti N.
      • Lewis C.A.
      • Sauberlich H.E.
      • Perkins L.L.
      • Go R.C.
      • Alvarez J.O.
      • et al.
      Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease.
      ], osteoporosis [
      • van Meurs J.B.
      • Dhonukshe-Rutten R.A.
      • Pluijm S.M.
      • van der Klift M.
      • de Jonge R.
      • Lindemans J.
      • et al.
      Homocysteine levels and the risk of osteoporotic fracture.
      ,
      • McLean R.R.
      • Jacques P.F.
      • Selhub J.
      • Tucker K.L.
      • Samelson E.J.
      • Broe K.E.
      • et al.
      Homocysteine as a predictive factor for hip fracture in older persons.
      ,
      • Dhonukshe-Rutten R.A.
      • Pluijm S.M.
      • de Groot L.C.
      • Lips P.
      • Smit J.H.
      • van Staveren W.A.
      Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people.
      ], Alzheimer disease [
      • 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.
      ,
      • Morris M.S.
      Homocysteine and Alzheimer’s disease.
      ], dementia [
      • 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.
      ] and neural-tube defects [
      • Mills J.L.
      • McPartlin J.M.
      • Kirke P.N.
      • Lee Y.J.
      • Conley M.R.
      • Weir D.G.
      • et al.
      Homocysteine metabolism in pregnancies complicated by neural-tube defects.
      ]. Several mechanisms were suggested for developing atherosclerosis due to hyperhomocysteinemia, (a) Free radicals generation during the oxidation of homocysteine may directly injure endothelial cells especially hydrogen peroxide [
      • Thambyrajah J.
      • Townend J.N.
      Homocysteine and atherothrombosis—mechanisms for injury.
      ,
      • Mansoor M.A.
      • Bergmark C.
      • Svardal A.M.
      • Lonning P.E.
      • Ueland P.M.
      Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Homocysteine and peripheral vascular disease.
      ,
      • Starkebaum G.
      • Harlan J.M.
      Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine.
      ]. (b) Decline nitric oxide (NO) bioavailability, consequently progress deleterious effects that are concomitant with diminishing of NO including vasoconstriction, smooth muscle proliferation, increase platelet activation and leucocyte recruitment [
      • Thambyrajah J.
      • Townend J.N.
      Homocysteine and atherothrombosis—mechanisms for injury.
      ,
      • Hossain M.
      • Qadri S.M.
      • Liu L.
      Inhibition of nitric oxide synthesis enhances leukocyte rolling and adhesion in human microvasculature.
      ]. (c) Inhibit glutathione peroxidase activity [
      • Welch G.N.
      • Loscalzo J.
      Homocysteine and atherothrombosis.
      ]. (d) Enhance the production of several pro-inflammatory cytokines [
      • Lawrence de Koning A.B.
      • Werstuck G.H.
      • Zhou J.
      • Austin R.C.
      Hyperhomocysteinemia and its role in the development of atherosclerosis.
      ]. (e) Develop lipid peroxidation [
      • Santilli F.
      • Davì G.
      • Patrono C.
      Homocysteine methylenetetrahydrofolate reductase, folate status and atherothrombosis: a mechanistic and clinical perspective.
      ]. (f) Promotes oxidative modification of low-density lipoproteins [
      • Thambyrajah J.
      • Townend J.N.
      Homocysteine and atherothrombosis—mechanisms for injury.
      ]. Moreover, previous studies in animal model indicated that hyperhomocysteinemia could enhance seizure activity and as well leads to antiepileptic drug resistance [
      • Baldelli E.
      • Leo G.
      • Andreoli N.
      • Fuxe K.
      • Biagini G.
      • Agnati L.F.
      Homocysteine potentiates seizures and cell loss induced by pilocarpine treatment.
      ,
      • Sener U.
      • Zorlu Y.
      • Karaguzel O.
      • Ozdamar O.
      • Coker I.
      • Topbas M.
      Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, Vitamin B12, folic acid and Vitamin B6.
      ,
      • Kubová H.
      • Folbergrová J.
      • Mareš P.
      Seizures induced by homocysteine in rats during ontogenesis.
      ].
      OXC is one of the newer and common AEDs that prescribed for the treatment of partial seizures. OXC is the 10-keto-analogue of carbamazepine with fewer adverse effects []. Effect of OXC on serum level of tHcy was controversial and some papers depicted OXC increase level of serum tHcy [
      • 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.
      ,
      • Linnebank M.
      • Moskau S.
      • Semmler A.
      • Widman G.
      • Stoffel-Wagner B.
      • Weller M.
      • et al.
      Antiepileptic drugs interact with folate and vitamin B12 serum levels.
      ,
      • Belcastro V.
      • Striano P.
      • Gorgone G.
      • Costa C.
      • Ciampa C.
      • Caccamo D.
      • et al.
      Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs.
      ] and some papers did not show this effect [
      • Algin D.I.
      • Erdinc O.O.
      • Alatas O.
      • Toker A.
      • Colak O.
      • Oner S.
      Effects of oxcarbazepine on plasma homocysteine, vitamin B12, folic acid levels.
      ,
      • Emeksiz H.C.
      • Serdaroglu A.
      • Biberoglu G.
      • Gulbahar O.
      • Arhan E.
      • Cansu A.
      • et al.
      Assessment of atherosclerosis risk due to the homocysteine-asymmetric dimethylarginine-nitric oxide cascade in children taking antiepileptic drugs.
      ].
      Earlier studies revealed older AEDs as carbamazepine and valproate increase tHcy and attenuate serum levels of vitamin B12 and folate [
      • Gorjipour F.
      • Asadi Y.
      • Osguei N.K.
      • Effatkhah M.
      • Samadikuchaksaraei A.
      Serum level of homocysteine, folate and vitamin-B12 in epileptic patients under carbamazepine and sodium valproate treatment: a systematic review and meta-analysis.
      ,
      • Ni G.
      • Qin J.
      • Fang Z.
      • Chen Y.
      • Chen Z.
      • Zhou J.
      • et al.
      Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis.
      ]. In a study by Ni et al., to determine how valproate could effect on the serum level of tHcy, patients with epilepsy on valproate have higher levels of tHcy in comparison to healthy subjects [
      • Ni G.
      • Qin J.
      • Fang Z.
      • Chen Y.
      • Chen Z.
      • Zhou J.
      • et al.
      Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis.
      ]. On the other hand, a study by Gorjipour et al., showed that the serum level of tHcy in patient on CBZ were significantly higher than healthy control subjects. The serum level of folate was significantly lower in cases on CBZ than healthy control group nonetheless CBZ did not have any significant effect on vitamin B12 level. Results of analysis for patients on valproate exhibited that valproate similar to CBZ increase tHcy level significantly; however, valproate does not have any effect on folate. Results of this study for vitamin B12 in patients on valproate is debatable since the results of the vitamin B12 in the context of the paper is in contrast as in the table of this study, they indicated in the context that valproate decrease vitamin B12 significantly; though, in the table of this paper data displayed valproate increase the serum level of vitamin B12 significantly [
      • Gorjipour F.
      • Asadi Y.
      • Osguei N.K.
      • Effatkhah M.
      • Samadikuchaksaraei A.
      Serum level of homocysteine, folate and vitamin-B12 in epileptic patients under carbamazepine and sodium valproate treatment: a systematic review and meta-analysis.
      ].
      Results of the current study revealed that the pooled MD serum level of tHcy is higher in cases treated with OXC monotherapy than control group even though p-value of 0.346, displayed OXC does not have any significant effect on tHcy. The pooled MD of serum vitamin B12 and folate are higher in control group than cases treated with OXY group nevertheless this effect is not significant for vitamin B12 (p = 0.562) and folate (p = 0.113) as well. The main reason for this difference between carbamazepine and its derivative oxcarbazepine which both are categorized in P450-inducing AEDs is the enzyme-inducing effect of OXC is lower than the carbamazepine [
      • Isojärvi J.I.T.
      • Myllylä V.V.
      • Pakarinen A.J.
      • Rautio A.
      • Pelkonen O.
      Serum sex hormone levels after replacing carbamazepine with oxcarbazepine.
      ,
      • Schmidt D.
      Drug treatment of epilepsy: options and limitations.
      ,
      • Rogawski M.A.
      • Loscher W.
      The neurobiology of antiepileptic drugs.
      ].
      Earlier studies revealed that oxcarbazepine is an inducer of cytochrome P450 system [
      • Schmidt D.
      • Elger C.E.
      What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs?.
      ]. It was shown that effect of OXC was dose-dependent and it had been found to induce hepatic enzymes when given at high doses to adult patients [
      • Patsalos P.N.
      • Zakrzewska J.M.
      • Elyas A.A.
      Dose dependent enzyme induction by oxcarbazepine?.
      ,
      • Rattya J.
      • Vainionpaa L.
      • Knip M.
      • Lanning P.
      • Isojarvi J.I.
      The effects of valproate, carbamazepine, and oxcarbazepine on growth and sexual maturation in girls with epilepsy.
      ].
      Albeit, folate and vitamin B12 considered as main probable mechanism for increasing tHcy; however, because of the vital role of these vitamins in body, reduction of them are associated with miscellaneous types of diseases which both or any of them are involved including anemia [
      • Duthie S.J.
      Folic acid deficiency and cancer: mechanisms of DNA instability.
      ,
      • Reynolds E.H.
      The neurology of folic acid deficiency.
      ], cognitive decline and impairment [
      • Reynolds E.
      Vitamin B12, folic acid, and the nervous system.
      ], osteoporosis [
      • Dhonukshe-Rutten R.A.
      • Lips M.
      • de Jong N.
      • Chin A.P.M.J.
      • Hiddink G.J.
      • van Dusseldorp M.
      • et al.
      Vitamin B-12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men.
      ,
      • Tucker K.L.
      • Hannan M.T.
      • Qiao N.
      • Jacques P.F.
      • Selhub J.
      • Cupples L.A.
      • et al.
      Low plasma vitamin B12 is associated with lower BMD: the Framingham osteoporosis study.
      ], cancer [
      • Zhou X.
      • Meng Y.
      Association between serum folate level and cervical cancer: a meta-analysis.
      ,
      • Abolhassani H.
      • Mohammadzadeh Honarvar N.
      • Mosby T.T.
      • Mahmoudi M.
      Nutrition, immunity, and cancers.
      ], psychiatric disease [
      • Reynolds E.
      Vitamin B12, folic acid, and the nervous system.
      ] and congenital malformations [
      • Black M.M.
      Effects of vitamin B12 and folate deficiency on brain development in children.
      ]. various mechanisms for attenuation of the level of folate and vitamin B12 in patients on AEDs have been proposed: (a) impairment of folate and vitamin B12 absorption, (b) as folate is cofactor for several cytochrome P450 enzymes reactions, induction of liver microsomal enzymes by prolong use of AEDs increase folate metabolism and consequently increase folate demands that eventually leads to folate depletion [
      • Canter P.H.
      Herb, nutrient and drug interactions: clinical implications and therapeutic strategies.
      ,
      • Kishi T.
      • Fujita N.
      • Eguchi T.
      • Ueda K.
      Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy.
      ,
      • Labadarios D.
      • Dickerson J.W.
      • Parke D.V.
      • Lucas E.G.
      • Obuwa G.H.
      The effects of chronic drug administration on hepatic enzyme induction and folate metabolism.
      ,
      • Maxwell J.D.
      • Hunter J.
      • Stewart D.A.
      • Ardeman S.
      • Williams R.
      Folate deficiency after anticonvulsant drugs: an effect of hepatic enzyme induction?.
      ].
      Subgroup analysis of age for vitamin B12 revealed that vitamin B12 level was lower in children [MD −62.39; 95% CI −135.01, 10.24] than adult [MD −7.59; 95% CI −46.91, 31.73]. Previous studies depicted that activity of cytochrome P450 system was higher in children than adults. This is due to the fact that OXC is an inducer of CYP450 system, hence, it could accelerate attenuation of the serum levels of vitamin B12 in children more than adults [
      • Anderson G.D.
      Children versus adults: pharmacokinetic and adverse-effect differences.
      ]. Moreover, differences in the dose of OXC in the included papers could be another reason for this difference. However, the dose of the OXC did not mention in the included papers.
      There are some limitations in this study that should need to be recognized. First, the number of the included studies in our meta-analysis was relatively limited. Second, OXC dose did not mention due to lack of reports in several included studies. Third, some other confounding factors were unable to be taken into consideration due to the absence of the data in the included papers, such as other atherogenic parameters including lipid profiles. The strength of the study was a comprehensive search that was done which all the vital databases namely, MEDLINE/PubMed, Scopus, Web of Science and Embase were searched and as well Google scholar and some grey literature databases were search manually for possible studies from other literature sources. The other property was, merely studies were included that assessed OXC as monotherapy and did not have any comorbidity disorders.

      5. Conclusion

      In conclusion, this meta-analysis does not support the hypothesis that OXC monotherapy changes the serum levels of tHcy, vitamin B12 and folate. It seems that OXC can be prescribed with less concern than older AEDs as carbamazepine and valproate in developing atherosclerosis or other disorders that are concomitant with elevated tHcy and declined vitamin B12 and folate.

      Funding

      No external funding or sponsorship was received for this work.

      Conflict of interests

      The authors declare that there is no conflict of interest.

      Author contributions

      SR and AA designed the study. SR and AA contributed to the literature searches, data extraction, and independent reviewing. SR, AA and SS-b performed the statistical analyses and wrote a first draft of the manuscript. SS-b and KD prepared final draft. All authors read the manuscript and approved it.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

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