30371

||| Original Article ||| DOI: 10.3329/bsmmuj.v9i4.30371

 

Relation between serum vitamin B12 level and duration of treatment with carbamazepine in epilepsy patients

Mohammad Tariqul Islam, Khair M. Sobhan, Mahjabin Rahman Shawly, Shafiqur Saleheen, Mohammad Masum Emran and M. A. Hannan

Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh (MTI, MRS); Department of Neurology, Faculty of Medicine, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh (KMS, SS, MME, MAH)

Principal Contact

Abstract

Vitamin B12 levels in the serum of 58 epileptic patients receiving only carbamazepine for at least 6 months were measured. Same number of epilepsy patients with no history of taking antiepileptic medicine were taken as control. The mean level of vitamin B12 in carbamazepine-treated epileptic patients was 265.5 pg/mL whereas it was 478.3 pg/mL in control. Increased duration of treatment of carbamazepine in epilepsy caused significantly decreased level of serum vitamin B12 (Pearson correlation coefficient, r = -0.9, p<0.0001). In conclusion, serum vitamin B12 level significantly decreased in relation to duration of carbamazepine treatment in epileptic patients.


Introduction

Epilepsy is a chronic neurological disorder characterized by recurrent seizures of cerebral origin, with episodes of sensory, motor or autonomic manifestation with or without loss of consciousness.1 Antiepileptic drugs are the simplest and the safest means of controlling epilepsy. Several studies have suggested that treatment with distinct antiepileptic medicines like valproate, carbamazepine or phenytoin is associated with reduced mean serum levels of folate and vitamin B12. However, long-term administration of antiepileptic medicine has a number of adverse effects, one of which is the lower level of serum vitamin B12.1

While the reason for this reduced vitamin B12 level remain obscure, several mechanisms have been proposed. One hypothesis is the increased pH of the small intestine, inhibiting the intestinal conjugate activity and impairing the intestinal absorption of vitamin B12. Other hypotheses include direct competition between folate and antiepileptic drug for uptake sites, inhibition of vitamin B12 interconverting enzymes by antiepileptic medicine, increased catabolism of vitamin B12 by induction of vitamin B12 catabolic enzymes, inhibition of central appetite centers by antiepileptic medicine decreasing food intake, thereby leading to decreased tissue vitamin B12 concentrations.5

However, there are very few reported studies which estimate the serum vitamin B12 concentration in epileptic patients receiving carbamazepine for less than 6 months. Therefore, our study goal was to explore the level of serum vitamin B12 in epileptic patients receiving carbamazepine therapy for at least 6 months duration.


Materials and Methods

This study was conducted on 116 epileptic patients from July 2013 to December 2015. Half of the patients were receiving carbamazepine and the rest half were still not on any antiepileptic medicine. Epileptic patients were selected irrespective of sexes seeking treatment at the outpatient department. Patients were selected on the basis of inclusion and exclusion criteria. Patients aged between 14 to 60 years, diagnosed as epilepsy and receiving only carbamazepine for at least 6 months were included. Epileptic patients with other systemic diseases: Chronic liver disease, kidney disease, hypothyroidism, leukemia, inflammatory bowel disease and psoriasis or patients taking antitubercular medicines, other antiepileptic medicines, folic acid supplement, receiving vitamin B6 , vitamin B12 or on folate antagonists, smokers and pregnant lady were excluded from this study.

Detailed history and clinical examination were carried out for each patient using predesigned proforma. Baseline investigation of serum vitamin B12 level was collected.

Selected patients were send to the Department of Biochemistry of the same University for assessment of serum vitamin B12 level. The venous blood was collected after 6 hours of fasting.6 Assessment of serum vitamin B12 level was done by Chemiluminescent Microparticle Immunoassay (CMIA) technology with flexible assay protocols referred to as chemiflex.

After collection of sample, patients were grouped as follows: Group 1: Patients on carbamazepine; Group 2: Patients of control group.

Statistical analysis

Statistical analysis was performed Statistical Packages for Social Sciences (SPSS-21). Association between categorical variables were analyzed by chi-squared test and continuous variable by independent sample t-test used for normal distribution. Correlation was done by Pearson correlation coefficient test, as for normal distribution. Normality of distribution was seen by Shiparo-Wilk test. For all statistical tests, we considered p value <0.05 as statistically significant.


Results

The parameters of these two groups were more or less same (Table I). The mean age was found 25.3 years in patients and mean age was 25.8 years in control. The mean duration of illness was 62.3 months. The duration of diagnosis was 51.4 months while duration of treatment was 36.3 months.

Table I
Parameters of patients
CaseControl
Age (year), mean25.325.8
Sex   
Male4234
Female1624
Type of epilepsy   
Generalized-primary3524
Complex partial03
Secondary generalized2331
Duration of illness (month)62.34.6
Duration of diagnosis (month)51.4Newly diagnosed
Duration of treatment (month)35.3-

The level of serum vitamin B12 in patient of Group 1 was 265.5 pg/mL whereas it was 478.3 pg/mL in control. The differences were highly significant. In epileptic patients with carbamazepine therapy, normal level of serum vitamin B12 was found in 32 patients which accounted 55.2% and decreased level in 26 patients or 44.8%. On the other hand, in control group, 100% had normal value of serum vitamin B12 .

The distribution of patients according to low and high level of vitamin B12 (pg/mL). Median serum vitamin B12 was 333 pg/dL. This value was taken as cut off value. As per this cut off value, serum vitamin B12 was low in 45 patients and high in 13 patients in case. Serum vitamin B12 was low in 14 patients and high in 44 patients in control. There was statistical significant difference between this two groups.

Figure 1 shows correlation between serum vitamin B12 and duration of treatment of carbamazepine in epilepsy patients. As both serum vitamin B12 and duration of treatment were continuous variables and distribution normal, so Pearson correlation was done between them. Here, we found a negative and highly significant correlation coefficient (r = -0.959, p<0.0001). Therefore, we can conclude that increase duration of treatment of carbamazepine in epilepsy patients causes significantly decrease level of serum vitamin B12 .


Discussion

The main focus of this research work was to explore serum vitamin B12 level. Out of all epileptic patients using only carbamazepine as antiepileptic drugs found highly statistically decreased mean value of serum vitamin B12 than control group. Moreover, range of serum vitamin B12 level in carbamazepine treated patients was 134 to 392 pg/mL whereas that of 255 to 736 pg/mL in control group.

In a study it was found 6 months of carbamazepine therapy did not cause significant change in serum levels of vitamin B12; mean vitamin B12 at recruitment and at 6 months are in accordance with our findings.15 In another study it was found low vitamin B12 level in patients, which was comparable to this study.6,16 Another study concluded as in carbamazepine group serum vitamin B12 levels were lower than control group.6 Another study showed that mean serum level of vitamin B12 was significantly higher in all epileptic patients, whereas, its mean serum level was no significantly higher in antiepileptic drug users when compared to control.17 On the contrary, in a study showed that serum vitamin B12 concentration were elevated in all patients.11 Increased circulating vitamin B12 level, however, served as a sensitive biochemical index of hepatic damage due to anticonvulsants18. Prolonged drug treatment was possibly the cause of the slightly impaired ability of the liver to store vitamin B12.19

Considering normal level of vitamin B12 of 239-931 pg/mL20, decreased level was found in 44.8% in epileptic patients with only carbamazepine therapy and normal level in 55.2%. Whereas in control group, all had normal value of serum vitamin B12 which was highly statistically significant (p< 0.0001). In addition, on consideration of median value 333 pg/mL as cut off point, statistical significant difference was found between case and control group in frequency of patients. In a study it was found that 17.8% patients had low vitamin B12 levels.16 Nonetheless, on account of correlation between serum vitamin B12 and duration of treatment of carbamazepine in epilepsy patients, we found a negative and highly significant correlation coefficient (r = -0.959, p<0.0001). In epileptic patients using only carbamazepine as antiepileptic drugs, the mean (SD) value of serum vitamin B12 found 265.52 (74.28) pg/mL which significantly decreased value in context of control patients 478.34 (145.93) pg/mL (p<0.0001).


Conclusion

Increase duration of treatment of carbamazepine in epilepsy causes significantly decrease level of serum vitamin B12. As it is well known that reduced level of vitamin B12 related with hyperhomocystenamia whereas homocysteine is an atherogenic agent.

Ethical Issue

The aim of the study along with its procedure, risk and benefits was explained to the respondents in easily understandable local language and informed written consent was taken from each patient. It was assured that all information and record would be kept confidential and the result of the study would be helpful both for the physicians and patients in making rational approach of the management of epilepsy. Approval from the Institutional Review Board of Bangabandhu Sheikh Mujib Medical University was obtained prior to the commencement of this study.


References

1. Sridharan R. Epidemiology of epilepsy. Curr Sci. 2002; 82: 664-70.

2. World Health Organization. Epilepsy: Epidemiology, aetiology and prognosis. WHO Factsheet 2001, Number 165. Available at: http://www.who.int/mediacentre/factsheets/fs999/en/. Viewed on 25/03/2016.

3. Mannan MA. Epilepsy in Bangladesh. Neurol Asia. 2004; 9(Suppl 1): 18.

4. Shorvon SD. Handbook of epilepsy treatment. 3rd ed. Oxford, Wiley-Blackwell, 2010, p 1-418.

5. Kishi T, Fujita N, Eguchi T, Uedak K. Mechansm for reduction of serum folate by antiepileptic drugs during prolonged therapy. J Neurol Sci. 1997; 145: 109-12.

6. Karabiber H, Sonmezgoz E, Ozerol E, Yakinci C, Otlu B, Yologlus S. Effects of valproate and carbamazepine on serum levels of homocysteine, vitamin B12 and folic acid. Brain Dev. 2003; 25: 113-15

7. Tan TY, Lu CH, Chuang HY, Lin TK, Liou CW, Chang WN, et al. Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia 2009; 50: 1579-86.

8. Jakubus T, Michalska-Jakubus M, Lukawski K, Janowska A, Czuczwar SJ. Atherosclerotic risk among children taking antiepileptic drugs. Pharmacol Rep. 2009; 61: 411-23.

9. Hamed SA, Hamed EA, 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: 183-92.

10. Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG. Cause-specific mortality in epilepsy: A cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia 1997; 38: 1062-68.

11. Tamura T, Aiso K, Johnston KE, Black L, Faught E. Homocysteine, folate, vitamin B12 and vitamin B6 in patients receiving antiepileptic drug monotherapy. Epilepsy Res. 2000; 40: 7-15.

12. Anneger JF, Hauser WA, Shirts SB. Heart disease mortality and morbidity in patients with epilepsy. Epilepsia 1984; 25: 699-704.

13. Chambers JC, Seddon MD, Shah S, Kooner JS. Homocysteine: A novel risk factor for vascular disease. J R Soc Med. 2001; 94: 10–13.

14. Mintzer S, Skidmore CT, Abidin CJ, Morales MC, Chervoneva I, Capuzzi DM, et al. Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann Neurol. 2009; 65: 448-56.

15. Kumar V, Aggarwal A, Sharma S, Chillar N, Mittal H, Faridi MM, et al. Effect of carbamazepine therapy on homocysteine, vitamin B12 and folic acid levels in children with epilepsy. Indian Pediatr. 2013; 50: 469-72.

16. Aslan K, Bozdemir H, Unsal C, Guvenc B. The effect of antiepileptic drugs on vitamin B12 metabolism. Int J Lab Hematol. 2008; 30: 26-35.

17. El Dayem SMA, Saleh ON, Emara NA, Kandil ME, Shatla RH, Elgammal S. Evaluation of homo-cysteine, folic acid and vitamin B12 levels among egyptian children with idiopathic epilepsy. Maced J Med Sci. 2014; 7: 109-13.

18. Dastur DK, Dave UP. Effect of prolonged anticonvulsant medication in epileptic patients: Serum lipids, vitamins B6, B12, and folic acid, proteins, and fine structure of liver. Epilepsia 1987; 28: 147-59.

19. Frank O, Baker H, Leavy CM. Vitamin binding capacity of experimentally injured liver. Nature 1964; 203: 302-03.

20. Clinical laboratory and standards institute. How to define and determine reference intervals in the clinical laboratory: Approved Guideline. 2nd ed. CLSI document C28-A2. Wayne, PA, 2000, p 24.



Copyright (c) 2016 Bangabandhu Sheikh Mujib Medical University Journal