- Department of Oral Medicine and Radiology, Government Dental College and Research Institute, Bangalore, Karnataka, India
- Department of Neurology, Bangalore Medical College and Research Institute, Bangalore, Karnataka, India
- Department of Clinical Biochemistry, Bangalore Medical College and Research Institute, Bangalore, Karnataka, India
Abhishek Singh Nayyar
Department of Clinical Biochemistry, Bangalore Medical College and Research Institute, Bangalore, Karnataka, India
DOI:10.4103/2152-7806.119232Copyright: © 2013 Nayyar AS This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Nayyar AS, Khan M, Vijayalakshmi KR, Subhas GT, Nataraju B, Anitha M. A study on gingival enlargement and folic acid levels in phenytoin-treated epileptic patients: Testing hypotheses. Surg Neurol Int 03-Oct-2013;4:133
How to cite this URL: Nayyar AS, Khan M, Vijayalakshmi KR, Subhas GT, Nataraju B, Anitha M. A study on gingival enlargement and folic acid levels in phenytoin-treated epileptic patients: Testing hypotheses. Surg Neurol Int 03-Oct-2013;4:133. Available from: http://sni.wpengine.com/surgicalint_articles/a-study-on-gingival-enlargement-and-folic-acid-levels-in-phenytoin-treated-epileptic-patients-testing-hypotheses/
Background:There have been studies that report clinical benefits of the use of folic acid as an adjuvant to the antiepileptic therapy in the prevention of antiepileptic drug-induced gingival enlargement. However, studies in the past have also reported precipitation of epileptic attacks in patients on folic acid adjuvant therapy due to fall in sera levels of phenytoin due to drug interactions. The study was planned to investigate the association of phenytoin-induced gingival enlargement and sera levels of folic acid in epileptic patients on phenytoin therapy. The statistical analysis was done using t-test and the baseline serum folate levels and the serum folate levels obtained after 6 months of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula.
Methods:A total of 25 patients aged between 18 and 50 years, clinically diagnosed with epilepsy prior to the start of phenytoin therapy were included based on selection criteria and written informed consents were obtained. Assessment of serum folic acid levels and gingival enlargement was done prior to the start of and after 6 months of phenytoin therapy.
Results:The results of the study confirmed a significant association between low serum folate levels with increasing severity as well as an early onset of phenytoin-induced gingival enlargement.
Conclusions:The results of the study suggest a higher incidence of gingival enlargement in phenytoin treated epileptic patients with a positive correlation with falling serum folic acid levels as the duration of the therapy increases.
Keywords: Epilepsy, gingival enlargement, folic acid, phenytoin
Despite the tremendous advances in the management of epilepsy, phenytoin still remains the drug of choice; however, the long-term administration of phenytoin has been seen to lead to a number of adverse effects. Gingival enlargement is a frequently reported adverse effect of phenytoin.[
The etio-pathogenesis of phenytoin-induced gingival enlargement is still not clearly understood, however, many studies indicate its multi-factorial etiology[
Folates administered at pharmacological doses, in contrast, though have been seen to lead to a substantial decrease in the incidence of gingival hyperplasia,[
Based on the conclusions drawn from the various studies correlating decreased plasma and tissue folate levels with phenytoin-induced gingival enlargement, folic acid has been tried, both topically and systemically, to prevent this inevitable adverse effect of long-term phenytoin therapy, though with varying results.[
Source of data
A total of 25 patients visiting the Department of Neurology, Victoria Hospital, Bangalore during the period of January-December 2009 clinically diagnosed with epilepsy were selected prior to the start of phenytoin therapy based on the defined inclusion and exclusion criteria.
Method of collection of data
Selected epileptic patients in the age group of 18-50 years, who were clinically diagnosed with epilepsy and being started with phenytoin therapy and who were with full complement of teeth without any carious or periodontal involvement or any other pathological process in the teeth and the jaws, were explained in detail about the planned study and written informed consents were obtained. The patients were exclusively being started on phenytoin therapy and were not supposed to take any other medication apart from phenytoin throughout the course of the study. The patients who required polytherapy with other drugs in combination with phenytoin were excluded from the study. These patients were subjected to a detailed history and a thorough clinical examination using a specially prepared proforma.
Epileptic patients with other systemic diseases; with preexisting gingival enlargements due to any reasons as idiopathic, inflammatory, neoplastic, endocrinal, chronic vitamin C deficiency, mouth breathing or pregnancy; epileptic patients on any type of pharmacologic therapy including multi-vitamins or folate antagonists; and who had history of dental treatment and trauma to teeth were excluded from the study.
Based on the selection criteria, 25 patients clinically diagnosed with epilepsy were enrolled in the study with their written informed consents and then subjected to a thorough oral prophylaxis, routine hematological examination, and serum folic acid level assessment. Before the start of study, the ethical clearance was obtained by the ethical committee of the institution as well as from Bangalore Medical College and Research Institute and Associated Hospitals.
Assessment of serum folic acid
Assessment of serum folic acid level was done by chemiluminiscent method using Immulite kit prior to the start of phenytoin therapy. A minimum gap of 10 hours after the last meal followed by intake of drug was considered as the standard fasting period in the patients. For this, following an overnight fasting period, 5 ml of venous blood was taken from patients from the antecubital vein using a sterile disposable syringe in the sitting position between 8 A.M. and 10 A.M. Serum was immediately separated by ultracentrifugation. The supernatant was discarded and the rest of the sample was stored at −20°C. The Flurometer was set at 370 nm excitation with emission monitored at 470 nm. Flow rate was adjusted as 1.3 ml/min.
Controls were assessed only once based on their inclusion according to age and sex. They were free of any systemic disease process and were not on any drugs including supplementation with synthetic vitamin supplements or the drugs, which could have interfered with the absorption of such nutrients.
Assessment of gingival enlargement
The gingival status was assessed using the [GO INDEX].[
After a period of 2 months, the patients were reviewed and their gingival scores reassessed [
Method of statistical analysis
The statistical analysis was done using t-test and the baseline serum folate levels and the serum folate levels obtained after 6 months of phenytoin therapy were correlated with the respective grades of gingival enlargement using Pearson's coefficient formula.
The present study was designed in the Department of Oral Medicine and Radiology, Government Dental College and Research Institute, Bangalore during the period of January-December 2009 to assess the correlation between phenytoin-induced gingival enlargement and serum folate levels. Selected epileptic patients to be enrolled in the study based on defined inclusion and exclusion criteria were explained in detail about the planned study and written informed consents were obtained.
The study consisted of a total of 25 patients with 19 male (76%) and 6 female (24%) patients. The mean age of the study group was 30.08 years with an age range of 18-50 years. The mean age of the 19 male patients included in the study was 30.26 years with an age range of 18-50 years while for the 6 female patients with an age range of 20-36 years, the mean age was calculated to be 29.5 years.
The study revealed a higher incidence of gingival enlargement in phenytoin treated epileptic patients with the observation of gingival enlargement in all patients in the test group after 6 months of phenytoin administration, though to varying grades.
The study also observed serum folic acid levels in selected epileptic patients prior to the start of and after 6 months of phenytoin therapy in addition to the age and sex matched controls. Assessment of serum folic acid level was done by chemiluminiscent method using Immulite kit.
Average serum folate level in our study was 7.48 ± 3.91 ng/mL prior to the start of phenytoin therapy with an average serum folate level of 7.16 ± 2.19 ng/mL and a range of 3.87-10.9 ng/mL for the male and 8.49 ± 1.06 ng/mL with a range of 6.62-9.39 ng/mL for the female patients. The average serum folate level for the age and sex matched 10 control samples was found to be 14.46 ± 2.81 ng/mL.
The gingival status was assessed using the index originally described by Angelopoulos and Goaz and later modified by Miller and Damm Gingival Overgrowth Index (GO Index) prior to the start of and after 6 months of phenytoin therapy.
The average score of gingival enlargement prior to the start of phenytoin therapy in this study was found to be 1.7 ± 0.23. In this study, an average grade of 1.74 ± 0.21 was obtained for the gingival enlargement in the 19 male patients included in the study with a range of 1.33-2.17 and 1.58 ± 0.26 with a range of 1.33-2.08 for the 6 female patients. Among these, 22 patients were found to have an approximate grade 2 while 3 patients with grade 1 gingival enlargement.
After 6 months of phenytoin therapy, the average serum folate level in the study group was found to be 3.9 ± 5.31 ng/mL with an average 3.63 ± 2.01 ng/mL for male patients while 4.77 ± 1.58 ng/mL for the female patients with a range of 2.02-8.71 ng/mL and 2.46-7.43 ng/mL, respectively.
After 6 months of phenytoin treatment, average grade for gingival enlargement was found to be 2.04 ± 0.38 with a range of 1.17-2.67 in the male patients while 2.14 ± 0.23 with a range of 1.83-2.42 for the female patients. Among these, 20 patients were found to have nearing grade 2, 2 patients, grade 1, and 3 patients, grade 3 gingival enlargement.
The statistical analysis was done using t-test and the baseline serum folate levels and the serum folate levels obtained after 6 months of phenytoin therapy were then correlated with the respective grades of gingival enlargement using Pearson's coefficient formula.
The results arrived found the reduction in mean serum folate levels before and after 6 months of phenytoin treatment to be statistically significant [
Despite tremendous advances in the management of epilepsy in the recent decade, the antiepileptic drug phenytoin still remains the prime drug of choice in the management of epileptic patients in India.[
Chronic administration of phenytoin has been associated with a number of adverse effects.[
Numerous reports suggest that phenytoin-induced gingival enlargement is more commonly seen in younger age groups. This is in concordance with the observations of the several epidemiological studies. In addition, both genders have been reported to be equally susceptible to phenytoin-induced gingival enlargement in the literature.[
The study revealed a high incidence of gingival enlargement in epileptic patients on phenytoin therapy with the observation of varying grades of gingival enlargement in all patients in test group after 6 months of phenytoin administration.
The incidence of phenytoin-induced gingival enlargement as reported by a study by Kimball was found to be 57% while other studies in relation to incidence of phenytoin-induced gingival enlargement have revealed wide incidence range of 20-40%[
Drug-induced gingival enlargement normally begins at the interdental papillae and is more frequently found in the anterior segments of the jaws though it often involves all the surfaces of teeth and is generalized in its distribution.[
All the clinical features of phenytoin-induced gingival enlargement were confirmed in this study wherein we observed a predominantly firm and fibrotic nature of the gingival enlargement in most of the patients with local factors’ induced secondary inflammatory changes having a minor role, if any, to play in the clinical picture of the phenytoin-induced lesions of gingival enlargement as the oral hygiene was meticulously maintained. The observations of our study also revealed that the interdental papillae were the most common sites of involvement for the phenytoin-induced gingival enlargements. The tissues affected were though not subjected to a detailed histo-pathological analysis as the patients were not subjected to surgical therapeutic options for the treatment that carries a high probability for recurrence.[
In addition, significant was the observation that the gingival enlargement induced by phenytoin was usually generalized with involvement of all surfaces of the teeth in all the quadrants but was more severe in the anterior segments of the jaws as per the observations of the prior studies possibly because of a relative lack of oral hygiene maintenance in these areas of the jaws.
A review of the gingival enlargement indices proposed in the literature clearly demonstrates their diversity, from the most simple gingival enlargement index proposed to the most elaborate one. Different authors have used different criteria for grading the gingival enlargement in their studies, however, there is no universal criteria that can be adopted for the same as every criteria has a more or less subjective methodological approach for the assessment of gingival enlargement and depends on the author's discretion for following the same. The majority of the indices used to quantify gingival enlargement are difficult to reproduce because they lack an objective criteria to differentiate between the degree of horizontal and vertical overgrowth.
In this study, the gingival status was assessed using the index originally described by Angelopoulous and Goaz[
The results obtained could not be compared with the observations of other studies as the indices followed were either different; modified Harris and Ewalt index in a study by Prasad et al. on the role of folic acid in the prevention of phenytoin-induced gingival enlargement on 60 epileptic children in the age range of 8-13 years;[
In our study, assessment of serum folic acid was done by chemiluminiscent method using Immulite kit prior to the start and after 6 months of phenytoin therapy. Other methods used to assess serum folates that have been described in the literature include the one of immunoassay method and the less reliable and a relatively less sensitive assay of serum folate levels using Lactobacillus casei as the test organism. Average range of serum folate levels in normal controls as standardized by few studies has been found to be 3-17 ng/mL.
Serum folate levels were earlier quantified by means of a radioimmunoassay method using a SimulTRAC Radioassay kit in a study by Majola et al.[
The mean serum folate level as assayed with the help of Lactobacillus casei method was found to be 4.76 ng/mL in the normal controls and 3.96 ng/mL in the epileptic patients in the study by Reynolds et al.[
Serum folate levels were, in contrast, found to be 8.8 ± 3.6 ng/mL with a range of 2.9-16.1 ng/mL in controls while 4.1 ± 1.6 ng/mL with a range of 1.2-6.7 ng/mL in 16 among a total of 75 epileptic patients on phenytoin therapy in the study by Sener et al.[
The wide variations found in the mean and average range of serum folate levels in different age groups and genders from the previous studies likely reflected the differences among the study samples in terms of age and health status as well as differences in the assessment procedures.
In addition, numerous studies in the past suggest the possible role of folic acid in the prevention of phenytoin-induced gingival enlargement as well as its recurrence following a surgical removal.[
This is, however, a preliminary study; the results of the study suggest a higher incidence and severity of gingival enlargement in phenytoin treated epileptic patients with a positive correlation between serum folic acid levels and gingival enlargement before and after 6 months of phenytoin administration. No available published reports with similar methodology have been found in the literature.
This is a preliminary study, which aims at the assessment of serum folate levels in epileptic patients who are on long-term phenytoin therapy and their association with phenytoin-induced gingival enlargement.
The statistical analysis of the results suggests:
A high incidence and increased severity of gingival enlargement in epileptic patients on phenytoin therapy A positive correlation between gingival enlargement and average serum folate levels before and after phenytoin administration; and A significant drop in serum folate levels after 6 months of phenytoin treatment.
A high incidence and increased severity of gingival enlargement in epileptic patients on phenytoin therapy
A positive correlation between gingival enlargement and average serum folate levels before and after phenytoin administration; and
A significant drop in serum folate levels after 6 months of phenytoin treatment.
Thus, the use of folic acid as an adjuvant to phenytoin therapy in the prevention of phenytoin-induced gingival enlargement calls for further studies in future keeping in mind the precipitation of epileptic attacks seen in a significant number of patients on folic acid adjuvant therapy secondary to fall in the sera levels of phenytoin due to the propensity of drug interactions between the two. Since this is only a baseline study, the results of the study encourage for further studies with larger sample size and estimation of tissue level folates to conclude the results.
The authors thank all the people who directly and indirectly contributed for the study as the study required intense efforts from the people outside their Department including Department of Neurology and Department of Clinical Biochemistry, Bangalore Medical College and Research Institute and Associated Hospitals.
1. Angelpoulous AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia. Oral Surg Oral Med Oral Pathol. 1972. 34: 898-906
2. Angelopoulos AP. Diphenhydantoin gingival hyperplasia: A clinico-pathological review of Incidence, clinical features and histopathology. J Can Dent Assoc. 1975. 41: 103-6
3. Arya R, Gulati S, Kabra M, Sahu JK, Kalra V. Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children. Neurology. 2011. 76: 1338-43
4. Benton D, Haller J, Fordy J. The vitamin status of young British adults. Int J Vit Nutr Res. 1997. 67: 34-40
5. Berg MJ, Rivey MP, Vern BA, Fischer LJ, Schottelius DD. Phenytoin and folic acid: Individualized drug-drug interaction. Ther Drug Monit. 1983. 5: 395-9
6. Brown RS, Di Stanislao PT, Beaver WT, Bottomley WK. The administration of folic acid to Institutionalized epileptic adults with phenytoin-induced gingival hyperplasia: A double-blind, randomized, placebo-controlled, parallel study. Oral Surg Oral Med Oral Pathol. 1991. 71: 565-8
7. Brown RS, Sein P, Corio R, Bottomley WK. Nitrendipine- induced gingival hyperplasia: First case report. Oral Surg Oral Med Oral Pathol. 1990. 10: 533-6
8. Brunet L, Miranda J, Farré M, Berini L, Mendieta C. Gingival enlargement induced by drugs. Drug Saf. 1996. 15: 219-31
9. Cals MJ, Bories PN, Devanlay M, Desveaux N, Luciani L, Succari M. Extensive laboratory assessment of nutritional status in fit, health-conscious, elderly people living in the Paris area. J Am Coll Nutr. 1994. 6: 646-57
10. Ch’ien LT, Krumdieck CL, Scott CW, Butterworth CE. Harmful effect of megadoses of vitamins: Electroencephalogram abnormalities and seizures induced by intravenous folate in drug-treated epileptics. Am J Clin Nutr. 1975. 28: 51-8
11. Ciancio SG, Yaffe SJ, Catz CC. Gingival hyperplasia and diphenylhydantoin. J Periodontol. 1972. 43: 411-4
12. Drew HJ, Vogel RI, Molofsky W, Baker H, Frank O. Effect of folate on phenytoin hyperplasia. J Clin Periodontol. 1987. 14: 350-6
13. Ferro-Luzzi A, Mobarhan S, Maiani G, Scaccini C, Sette S, Nicastro A. Habitual alcohol consumption and nutritional status of the elderly. Eur J Clin Nutr. 1988. 42: 5-13
14. Hallmon WW, Rossmann JA. The role of drugs in the pathogenesis of gingival overgrowth: A collective review of current concepts. Periodontol. 1999. 21: 176-96
15. Hassell TM.editors. Epilepsy and the Oral Manifestations of Phenytoin Therapy. Basel, Switzerland: Karger; 1981. p.
16. Hassell TM, Burtner AP, McNeal D, Smith RG. Hypertrophic Oral problems and genetic aspects of individuals with epilepsy. Periodontol 2000. 1994. 6: 68-78
17. Hassessian A, Marcucci G, Guimarães J. Freqüência da hyperplasia gengival medicamentosa em 48 pacientes tratados com nifedipina. Revista Abo Nacional, Rio de Janeiro. 2003. 11: 28-32
18. Kapur RN, Girgis S, Little TM, Masotti RE. Diphenylhydantoin-induced gingival hypertrophy and its relationship to dose and serum level. Dev Med Child Neurol. 1973. 15: 483-7
19. Lennox WG. The drug therapy of epilepsy. JAMA. 1940. 114: 1347-54
20. Majola MP, McFadyen ML, Connolly C, Nair YP, Govender M, Laher MH. Factors influencing phenytoin-induced gingival enlargement. J Clin Periodontol. 2000. 27: 506-12
21. Marshall RI, Bartold PM. A clinical review of drug induced gingival overgrowth. Aust Dent J. 1999. 44: 219-32
22. Poppell TD, Keeling SD, Collins JF, Hassell TM. Effect of folic acid on recurrence of phenytoin-induced gingival overgrowth following gingivectomy. J Clin Periodontol. 1991. 18: 134-9
23. Prasad VN, Chawla HS, Goyal A, Gauba K, Singhi P. Folic acid and phenytoin induced gingival overgrowth-Is there a preventive effect. J Indian Soc Pedod Prev Dent. 2004. 22: 82-91
24. Reynolds EH. Effects of folic acid on the mental state and fit-frequency of drug-treated epileptic patients. Lancet. 1967. 1: 1086-8
25. Reynolds EH, Preece J, Johnson AL. Folate metabolism in epileptic and psychiatric patients. J Neurol Neurosurg Psychiatry. 1971. 34: 726-32
26. Rosenberg IH, Bowman BB, Cooper BA, Halsted CH, Lindenbaum J. Folate nutrition in the elderly. Am J Clin Nutr. 1982. 36: 1060-6
27. Scheinfeld N. Phenytoin in cutaneous medicine: Its uses, mechanisms and side effects. Dermatol Online J. 2003. 93: 6-
28. 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. Seizure. 2006. 15: 79-85
29. Vogel RI. Gingival hyperplasia and folic acid deficiency from anticonvulsive drug therapy: A theoretical relationship. J Theor Biol. 1977. 67: 269-78
30. Weggemans RM, de Groot LCPGM, Haller J. Factors related to plasma folate and vitamin B12. The Senega study. Int J Food Sci Nutr. 1997. 48: 141-50
31. Whitehead N, Reyner F, Lindernbaum J. Megaloblastic changes in the cervical epithelium. Association with oral contraceptive therapy and reversal with folic acid. JAMA. 1973. 226: 1421-4
32. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001. 345: 311-8