Clinical Study On Relationship Between Serum Homocysteine And Epilepsy

Backgroud: Epilepsy is a serious brain disorder which is characterized by an enduring predisposition to generate epileptic seizures and the neurobiological, cognitive,psychological, and social results. Many diseases can trigger seizures, such as genetic mutation, infection, brain injury, cerebrovascular disease, brain tumors and so on. With the rapid development of long-range video electroencephalogram, cranial magnetic resonance imaging(MRI), PET/CT and the other means of applications, it has been greatly improved for the clinical diagnosis of epilepsy and the etiology exploring. However, for many patients, the etiologies still have not been discovered yet. And the current main antiepileptic treatment is symptomatic therapy.Epidemiological studies have showed that 10% to 40% of epileptics with hyperhomocysteinemia(HHcy). A few experiments revealed that Hcy can trigger or aggravate seizures in animals and administrated it with Vitamin B12 or folate might reduced the Hcy level as well as convulsion. Thus, it rises that higher level of serum Hcy may play a role in seizures and epilepsy.Homocysteine(Hcy) is a sulphur-containing amino acid that is not a dietary constituent and does not form proteins. Plasma Hcy is metabolized via two pathways:(a.)remethylation to methionine, which requires 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase, and folic acid and vitamin B12 as co-factors;(b.)trans-sulfuration to cysteine, which requires cystathionine-beta-synthase and pyridoxal-5-phosphate, the vitamin B6 coenzyme. Hcy contains a thiol group which is highly active. Auto-oxidation of Hcy leads to formation of homocystine, Hcy-mixed disulfides, thiolactone or hydroxyl radicals, and lipid peroxidation initiators, which promote the creation of a prothrombotic environment and the excitotoxic damage.Previously, it has been reported that the elevation of serum Hcy levels can be a risk factor for atherosclerotic vascular disease. Then some studies have demonstrated that HHcy were neurotoxic and it might involved in the pathophysiology of many neuropsychiatric disorders, including epilepsy, brain atrophy, and cognitive disorder. It has been considered that Hcy induces or exacerbate convulsive seizure by stimulating N-methyl D aspartate receptor(NMDAR) and group I metabotropic glutamate receptors(m Glu Rs) and which would lead to excitotoxic damage. But since the lack of large sample of clinical research,and the relationship between AEDs and serum Hcy is controversial, it is till not clear about the relationshiop between Hcy and epilepsy.Objective: The aim of this study is to investigate the relationship between Hcy and epilepsy. And to abtain the goal, we would compared the level of serum Hcy of epileptics and controls(healthy people and cerebral infarction patients). Besides, the association of the commonly used AEDs with Hcy serum levels and the in?uence of vitamin B12 supplementation on the serum total Hcy and seizure frequences still would be involved.We are looking forward to all that it can do a favor for the etiology diagnosis and the treatment of epilepsy.Methods: From September 2013 to December 2014, we recruited 613 serial inpatients and outpatients with epilepsy at the Department of Neurology, Xijing Hosital, Fourth Military Medical University, China. Among them 346 epileptic patients who were over 19,they were classified into the case group and they were matched with 342 healthy controls.In addition, 351 patients who had cerebral infarction were enrolled as disease controls. All subjects were meet the criterion. Basic demographic characteristics and detailed case data of all the people was recorded. At recruitment, venous blood sample was collected for the measurement of biological indicators which included the serum level of Hcy, Vitmin B12,folate and the genetic polymorphisms of MTHFR( C677 T, A1298C). Then compared the indicators between different groups. For the epileptic patients with HHcy, they would be supplemented of 0.5 mg Vitmin B12 per day and the level of Hcy and sezure frequences before and after supplementation had to be compared.Results: A total of 613 epileptic patients were recruited and 346 of them were over 19 years old. Of these 613 patients, 364 were males and 249 were femals. The media age was20.0 and the media disease duration was 6.0 years. At the first visit, 77 patients were not treated with AEDs, 115 patients were treated with Valproic acid(VPA), 67 were treated with lamotrigine(LTG), 98 were treated with oxcarbazepine(OXC), 27 were treated with levetiracetam(LEV), 27 were treated with carbamazepine(CBZ), 165 were treated with 2AEDs, 19 were treated with more than 2 AEDs and 18 patients were for the other treatment. A total of 346 epileptic patients were recruited for cases group, 342 for healthy controls and 351 for case controls.⑴ Hcy levels were significantly higher in case group than the healthy controls(P<0.05).There was no statistically signi?cant difference in Hcy levels between case and case control groups(P>0.05). In case group serum folate were highter than healthy and case control groups(P<0.05). Compared with healthy and case group, the distribution of Hcy(<15μmol/L, 16-30 μmol/L, 31-50 μmol/L, >50 μmol/L) was significantly different(P<0.05), and epileptic patients were larger in the level of Hcy >30 μmol/L and Hcy >50μmol/L. The comparition between case and case control group was similar.⑵ There was no difference in Hcy levels between epileptic patients treated with AEDs monotherapies(or different AED monotherapies), AEDs polytherapies and no therapy(P> 0.05). And no significant difference was detected in the contribution of Hcy( ≤15μmol/L, 16-30 μmol/L, 31-50 μmol/L, >50 μmol/L) among epileptic patients with different AEDs therapy(P>0.05).⑶ A significant negative correlation was detected between the mean serum levels of vitamin B12 and Hcy in all epileptic patients(r=-0.347,P<0.001), and as well as the mean serum levels of folate and Hcy(r=-0.382, P<0.001).⑷ The distribution of MTHFR(C677T, A1298C) genotypes were significantly different in epileptic patients(P < 0.05). And the patients who had higher serum Hcy level(>15μmol/L) were more like to have homozygous mutation for C677 T.⑸ For the epileptic patients who had been supplemented with vitamin B12 at our department, 119 returned 4 weeks later, 59 returned 12 weeks later. Compared to baseline,the serum level of Hcy were significantly decreased at 4 weeks and 12 weeks later(P<0.05).⑹ Within 21 epileptic patients, after 12 weeks of vitamin B12 supplementation, except for one patient, the rest of the patients had more or less decreased in seizure frequency(P <0.05).Conclusions: In our study we found that serum Hcy level of epileptic patients was similar to patients with cerebral infarction, while it was higher than the health people.AED therapy(VPA、LTG、OXC、LEV、CBZ) was not signi?cantly associated with HHcy. With the decreased level of serum Hcy, supplementation with Vit B12 can still do a favor for the seizure control. So all of the evidences may suggest that the increase level of serum Hcy may be a risk factor for epilepsy. And for the epileptics who has HHcy, they may benefit greatly from Hcy-lowering strategies, such as vitamin B12 supplementation.