Sodium valproate induced gingival enlargement with pre-existing chronic periodontitis.

Gingival enlargement is a common clinical feature of gingival and periodontal diseases. Currently, more than 20 prescription medications are associated with gingival enlargement. Although the mechanisms of action may be different, the clinical and microscopic appearance of drug-induced gingival enlargement is similar with any drug. Gingival enlargement produces esthetic changes, and clinical symptoms including pain, tenderness, bleeding, speech disturbances, abnormal tooth movement, dental occlusion problems, enhancement of caries development and periodontal disorders. Sodium valproate is considered to produce gingival enlargement, but very rarely. This case report features sodium valproate induced gingival enlargement in a patient with pre-existing chronic periodontitis, who came to the Dental Department, Chinmaya Mission Hospital, Bangalore. The case is special as the patient did not develop the enlargement in spite of taking phenytoin for 1 year and developed enlargement with sodium valproate within 6 months.

INTRODUCTION

Drug-induced gingival enlargement is the term now used to describe medication-related gingival hypertrophy or hyperplasia, a condition commonly induced by three main classes of drugs: anticonvulsants, antihypertensive calcium channel blockers, and immune suppressants. The pathogenesis of drug-induced gingival enlargement is uncertain and there appears to be no unifying hypothesis that links together the three commonly implicated drugs. Various risk factors and etiologic agents like age, drug doses, genetic factors, plaque-induced inflammation, etc. have been proposed.[1]

This condition brings major change in the quality of life for the patient as it interferes with esthetics and function.

Among the anticonvulsants, gingival enlargement is seen mostly with phenytoin (diphenylhydantoin). The other anticonvulsants that have the same effect are vigabatrin, sodium valproate, primidone, and phenobarbital [Figure 1].[2]

Figure 1

Sodium valproate induced gingival enlargement

This condition was first reported in 1939 by Kimball with chronic usage of the anti-epileptic drug, phenytoin. The histopathologic appearance of the various cases of drug-induced gingival enlargement is similar, regardless of the initiating drug. Several changes have been observed in both epithelium and connective tissue in drug-induced gingival overgrowth.

The mechanism of pathogenesis of gingival enlargement is an enigma that has intrigued researchers for decades. Some studies have found a positive correlation between plaque scores and the severity of gingival overgrowth.[3]

According to a report by American Academy of Periodontology, occurrence of gingival overgrowth due to sodium valproate is rare.[1]

Sodium valproate

Sodium valproate or valproate sodium is the sodium salt of valproic acid. Systematic name of sodium valproate is sodium 2-propylpentanoate (C8H15NaO2). Molecular mass is 166.20 g/mol. Pharmacokinetic data suggest protein binding capacity at 90–95%. The drug is metabolized by cytochrome P450 (CYP) enzymes. The half-life is 9–18 hours and 20% of the drug is excreted as glucuronide.

It is an anticonvulsant used in the treatment of epilepsy and bipolar disorder, as well as other psychiatric conditions requiring the administration of a mood stabilizer. It can be used to control acute episodes of mania. In pregnancy, valproate has the highest risk of birth defects of any of the commonly used anti-epileptic drugs. Some of the common adverse effects include tiredness, tremor, sedation, and gastrointestinal disturbances. In addition, about 10% of the users experience reversible hair loss and, rarely, gingival enlargement.

A report of a case which presented with sodium valproate induced gingival enlargement with pre-existing chronic periodontitis to Dental Department of Chinmaya Mission Hospital, Bangalore, is presented here.

CASE REPORT

A 60-year-old female patient presented to the dental outpatient department, Chinmaya Mission Hospital, with a complaint of severe gingival enlargement and halitosis. Clinical examination showed severe generalized fibrous gingival enlargement with areas of acutely inflamed red gingiva [Figure 1]. Oral hygiene was poor. Case history revealed that the enlargement had started 6 months before and had since been increasing [Figures 2 and 3]. Medical history showed that the patient had undergone neurosurgery for a tumor 18 months ago and since then had been put on phenytoin (Eptoin 100 mg tds) for a year. The drug was changed to sodium valproate (Valperin 200 mg tds) 6 months back. Since then, the enlargement had started.

Figure 2

Right side preoperative view

Figure 3

Left side preoperative view

Important clinical findings included grade II mobility in 16, and 27 was grade 3 mobile with deep pockets. 26 was extracted 3 years back and that edentulous area was also enlarged, which is quite rare as far as drug-induced enlargement is concerned.

The patient possibly had pre-existing periodontitis which got worsened due to drug-induced enlargement.

The radiologic examination showed generalized moderate to severe bone loss. 16 and 27 had a periodontal-endodontic lesion [Figure 4].

Figure 4

OPG showing moderate to severe bone loss

Severe oral malodor was present, which prevented the patient from socializing.

The neurological condition of the patient did not permit the substitution of sodium valproate immediately; so the patient was informed about the chances of recurrence, and surgical excision was planned.

The decision was made to save 16 as enlargement was observed in the edentulous spaces contrary to the evidence showing usually unaffected edentulous areas.[4]

After preoperative preparation including complete hemogram, 16 was endodontically treated. 27 was extracted. Full mouth flap surgery was carried out with the incisions, removing major part of the fibrous tissues and at the same time preserving considerable amount of outer gingiva [Figures 5 and 6].

Figure 5

Right side postoperative view

Figure 6

Left side postoperative view

Patient has since been on the follow-up for the last 6 months. The mobility reduced in 16 from grade II to grade I. Oral hygiene maintenance has improved a lot which has resulted in absence of malodor, thereby significantly increasing the patient's quality of life.

DISCUSSION

Gingival enlargement produces esthetic changes and clinical symptoms including pain, tenderness, bleeding, speech disturbances, abnormal tooth movement, dental occlusion problems, enhancement of caries development, and periodontal disorders. Valproic acid has been linked to gingival overgrowth, apart from phenytoin. However, prevalence rates have been not studied.[5]

According to one study, epileptic children on valproate are at risk of periodontal problems.[6]

The results from one study suggested that sodium valproate may be considered a safe alternative, regarding the periodontal aspects, to phenytoin for the treatment of adult-onset epilepsy, which is contrary to this case where patient had developed enlargement after discontinuation of phenytoin and starting of sodium valproate.[7]

Most of the studies to evaluate pathogenesis of drug-induced gingival enlargement involving anticonvulsants have been done with phenytoin, as sodium valproate is rarely associated with gingival enlargement.

Although the mechanisms of action may be different, the clinical and microscopic appearance of drug-induced gingival enlargement is similar with any drug. It begins as a firm, nodular enlargement of the interdental papilla, within 3 months of taking enlargement inducing medicines, which is limited to keratinized portions of the gingiva. The target cell is the gingival fibroblast, as all lesions are characterized by an increase in the connective tissue component. This case also presented similar clinical features. Hyperplasia of the mucosa in edentulous mouth has been reported, but is rare. In the present case, hyperplasia of edentulous space 26 was present.

Inflammation is a prerequisite for development of the enlargement. The importance of plaque as a cofactor in the etiology of drug-induced gingival enlargement has been recognized in the most recent classification system of periodontal disease.[8] In this case, severe gingival inflammation was also present.

It has been hypothesized that in non-inflamed gingival, fibroblasts are less active or quiescent and do not respond to circulating drug, whereas fibroblasts within the inflamed tissue are in an active state as a result of inflammatory mediators and endogenous growth factors present.[9]

Seymour et al., in their review on the pathogenesis of drug-induced gingival overgrowth, consider it as a multifactorial model involving an interaction of several factors like drug metabolite interacting with the gingival fibroblasts, along with age, genetic predisposition, pharmacokinetic variables, drug-induced alterations in gingival connective tissue homeostasis, histopathologic and ultrastructural factors, inflammatory changes, and drug-induced action on growth factors.[3]

The pharmacokinetics of inducing drugs and the gingival binding affinities of these drugs are determinants in the pathogenesis of drug-induced gingival overgrowth. It would seem that certain threshold concentrations of the drug or its metabolite are necessary to activate gingival fibroblasts or to alter connective tissue homeostasis, but this concentration may vary markedly between patients. Some studies suggest that whole blood and salivary concentrations of the drug are important determinants in the expression of gingival overgrowth; others have failed to substantiate these findings.[7]

One property that is common to these three classes of drugs is that they all directly affect cellular calcium metabolism. Since cellular production of collagenase is modulated by calcium influx, fibroblasts from patients treated with these drugs may produce an inactive form of collagenase, being responsible for an increase in extracellular matrix.[5]

Some studies have suggested that tumor necrosis factor (TNF) -a and phenytoin (PHT) together cause impaired collagen metabolism by suppression of enzymatic degradation with matrix metalloproteinases MMPs/ tissue inhibitors of metalloproteinases TIMP-1 and integrin-mediated endocytosis. These synergistic effects may also be involved in TNF-a– and PHT-induced collagen accumulation, leading to gingival overgrowth.[10]

A genetic predisposition to gingival enlargement has been suggested in relation to the susceptibility of different phenotypes of gingival fibroblasts. Whether such phenotypes relate to human leukocyte antigen (HLA) phenotypes remain to be determined. Genetic factors either in the expression of HLA frequency or in the determination of the fibroblast phenotype may be important in the development of gingival overgrowth. Phenotypical differences within gingival fibroblasts are involved in the pathogenesis of drug-induced gingival overgrowth.[9]

Recent studies suggest that these disorders seem to be induced by the disruption of homeostasis in collagen synthesis and degradation of gingival connective tissue, predominantly through the inhibition of collagen phagocytosis of gingival fibroblasts. The integrins are a large family of heterodimeric transmembrane receptors for extracellular matrix molecules. α2β1 integrin serves as a specific receptor for type I collagen on fibroblasts, and α2 integrin has been shown to play a crucial role in collagen phagocytosis. Actin filaments, which are assembled from monomers and oligomers, are involved in collagen internalization after binding to integrins.[11]

Definitive treatment of gingival enlargement involves surgical elimination of the excess gingival tissue through implementation of either gingivectomy procedure or periodontal flap approach. The clinician's decision to choose between these two surgical techniques should be made on an individual basis, encompassing careful consideration of the following aspects: the extent of area requiring surgery, the presence of periodontitis and osseous defects, the amount of keratinized gingiva, and the position of the base of the pockets in relation to the existing mucogingival junction. This case was treated with flap surgery as there was pre-existing periodontitis.[1]

CONCLUSION

Sodium valproate induced gingival enlargement is a rare phenomenon. There are very few studies regarding the etiopathogenesis of sodium valproate induced gingival enlargement. When all the evidences are considered, there appears to be three significant factors which are important in the expression of these gingival changes, namely, drug variables, plaque-induced inflammatory changes in the gingival tissues, and genetic factors which determine the heterogeneity of the fibroblast.