Sodium valproate induced gingival enlargement in 22 months old child.

Gingival enlargement is a common clinical feature seen in patients suffering from gingival and periodontal diseases and is a common side-effect of drugs such as anti-convulsants, calcium channel blockers and immunosuppresants. This is a case report of 22 months old child suffering from gingival enlargement following intake of sodium valproate. Among the anti-convulsants phenytoin is commonly associated with gingival enlargement; however, there are not many cases reported on sodium valproate induced gingival enlargement.

INTRODUCTION

Gingival enlargement, which may often be aesthetically disfiguring and compromising in function is a common side-effect seen with administration of drugs such as anticonvulsants, immunosuppresants and calcium channel blockers. Clinical features and histologic characteristics of gingival enlargement produced by all of these drugs appear indistinguishable from each other.[1] Gingival enlargements, which are influenced by drugs may often have a genetic predisposition explaining the inter-patient and intra-patient variation. Drug-induced gingival enlargement has a higher prevalence among children often within 3 months of drug intake, commonly involving the anterior gingiva resulting in changes in gingival contour modifying gingival size. When complicated by the presence of plaque there may be changes in the gingival color, increased gingival exudate and pronounced inflammatory response of gingiva which may decrease in severity following reduction in plaque.[2] Although drug influenced gingival enlargement can be found in periodontium with or without bone loss, it is not considered as etiology for attachment loss or pulp necrosis.[13]

This report presents a case of a 22-month-old child suffering gingival enlargement induced by sodium valproate. Valproate is a food and drug administration approved drug used to treat seizures and manic or mixed episodes associated with bipolar disorder and to prevent migraine headaches. Some of the common adverse effects include tiredness, tremor, sedation, gastrointestinal disturbances and reversible hair loss.

CASE REPORT

This is a case report of 22-month-old male child, presented to the department with the chief complaint of enlargement of gums since 1 month. Patient was being treated for epilepsy since age of 5 months and is on clobazam for the same since then. Sodium valproate syrup was combined with clobazam before 1 month and had never received phenytoin. His mother noticed slight enlargement of the gingiva on the 3rd day after starting sodium valproate which progressively increased within 15 days covering entire crowns of all the erupted deciduous teeth making patient clinically edentulous [Figures 1-3].

Figure 1

Gingival enlargement extending to occlusal surfaces within a month of commencement of sodium valproate intake

Figure 3

Enlargement rendering patient clinically edentulous

Gingival enlargement extending to occlusal surfaces of mandibular teeth

Intraoral examination revealed gingiva which was pale pink, smooth and shiny with enlargement involving entire surfaces of all erupted teeth. There was no spontaneous bleeding or bleeding on slightest provocation, which rules out leukemic involvement. The patient belonged to a middle socio-economic group without any evidence of nutritional deficiency. Age of the patient rules out chronic periodontitis and conditioned gingival enlargement. Enlargement was not solitary which excludes possibility of a benign tumor. No similar history of gingival enlargement in his sibling or any other family member rules out hereditary gingival hyperplasia.

Laboratory Investigations showed blood counts within the normal range and electroencephalogram showed abnormal sleep patterns. Based on the medical history, laboratory investigations and clinical examination, case was diagnosed as gingival enlargement induced by sodium valproate.

Patient was referred to the pediatric neurologist for alternate drug regimen and was prescribed levetiracetam as its alternative. Levetiracetam is an anticonvulsant medication used to treat epilepsy in adults and children. It is thought to bind to synaptic vesicle glycoproteins and inhibit presynaptic calcium channels eventually impeding impulse conduction across synapses.[4] Patient was recalled for follow-up and interventional therapy considered in case of persistence of enlargement.

At 1 month follow-up showed regression of the gingival enlargement following drug alteration [Figure 4]. Patient is kept on follow-up and interventional therapy will be considered only if complete regression does not occur.

Figure 4

Regression of gingival enlargement at 1 month following alternate drug regimen

DISCUSSION

The soft-tissue component of periodontium like gingiva may be enlarged in response to various interactions between the host and the environment. Although such enlargement usually represents an inflammatory response to bacterial plaque, increased susceptibility as a result of systemic factors or conditions should always be considered during the course of patient evaluation. Systemically related gingival enlargements may include scurvy, leukemia, puberty, pregnancy, multi-system syndromes, selected drugs and/or agents and idiopathic fibrotic gingival enlargement.[5]

Of the predisposing factors associated with disfiguring, disproportionate and functionally compromising overgrowth of gingival tissues, selected anti-convulsant drugs, calcium channel blockers and immunosuppressants have generated the most investigative attention in the scientific community.[6]

Epilepsy or seizure activity affects 3-6% of the population therefore making it the second most prevalent nervous system disorder after stroke.[7] Chronic convulsive disorders results in brief episodes of seizures associated with disturbance or loss of consciousness, these episodes are usually accompanied by characteristic body movements and sometimes by autonomic hyperactivity and are always correlated with abnormal encephalographic discharges. The first description of a drug causing an enlargement of gingiva was associated with the use of phenytoin. Phenytoin which is used on a chronic regimen for control of epileptic seizures induces enlargements in approximately 50% of patients using this agent.[8] Gingival hyperplasia is uncommon side effect of sodium valproate therapy; its first case has been reported in a 15-month-old child by Syrjänen and Syrjänen in 1979,[9] followed by a case in a 14-year-old girl by Behari in 1991 and in 9-years-old girl by Anderson et al. in 1997. A study on gingival enlargement in children treated with anti-epileptics conducted by Tan et al. in 2004 showed that duration of drug had a significant effect on gingival enlargement but not on gingival index, plaque index and probing pocket depth. A case of fetal valproate syndrome with congenital gingival hyperplasia in a neonate was reported by Rodriguez-Vazquez et al. in the year 2007 and a case of valproate induced gingival enlargement in pre-existing chronic periodontitis in a 60-year-old female was reported by Joshipura in 2012.

Patil et al. in 2014 reported a case of sodium valproate induced gingival enlargement in a 5 year old child in association with Gobal developmental delay.[10]

Pathogenesis of gingival lesions is found in events at the cellular, subcellular and molecular levels, regardless of whether such individuals are treated by phenytoin or any other epileptic drug, institutionalized or not and retarded or not. Histological appearance of gingival overgrowth such as an increase in extracellular ground substance and number of fibroblasts are common characteristics. One of the prominent theories of etiology of gingival enlargement in anti-epileptics suggests that the accumulation of genetically distinct populations of gingival fibroblasts causes connective tissue accumulation resulting from reduced catabolism of collagen molecule. There is increase in rapidly proliferating gingival fibroblasts and increase in production of matrix macromolecules such as collagen, glycosaminoglycans and proteoglycans. Despite pharmacological diversity, drugs causing gingival overgrowth appear similar at cellular level. These drugs may directly influence gingival connective tissues by stimulating an increase in number of gingival fibroblasts and production of connective tissue matrix. This increase in cell number may be coupled with a reduction in breakdown of gingival connective tissue.[11]

The inflammatory changes within the gingival tissues appear to influence the interaction between the inducing drug and the fibroblastic activity. Although the connective tissue changes may be predominant, the epithelium exhibits parakeratosis, proliferation and elongation of the rete ridges, which extend some distance into the lamina propria. A ten-fold increase in epithelial width, inflammatory changes accompanied by edema and infiltrates of lymphocytes and plasma cells was reported.[11]

Sodium valproate and other anti-epileptics such as phenytoin and carbamazepine along with having a broad therapeutic spectrum unfortunately are complicated by their unique pharmacokinetic properties. They exhibit marked intra- and inter-individual as well as ethnic variability in the relationship between the serum concentrations and dose resulting in narrow therapeutic window. The accepted therapeutic range of sodium valproate is 40-100 μg/ml. Monitoring of serum and salivary samples may help to identify non-compliance and aid in maximizing seizure control without serious adverse effects. Salivary samples besides being simple and easy to collect, it is non-invasive and inexpensive. It is possible to monitor salivary concentrations as an alternative to serum concentrations of anti-epileptics as salivary levels may reflect their free levels in tissues and therefore have greater clinical relevance. However according to available studies there is an controversial relationship between the severity of the gingival enlargement and drug dose, duration of therapy and drug concentrations in serum, saliva and gingival crevicular fluid.[12]

The clinical manifestation of gingival over-growth is similar with all the three agents. The enlargement is confined to the papillary and marginal gingiva, usually painless, firm and resilient, beginning in the papillary tissues and extending outward, involving both facial and lingual gingival margins, pale pink in color without tendency to bleed. The color and texture is influenced by the presence of plaque-induced inflammation and the underlying periodontal condition. Red or bluish red discoloration with edema and increased bleeding tendency may be seen sometimes when complicated with inflammation.[713]

The enlargement may hamper routine oral hygiene maintenance resulting in poor plaque control. It may result in difficulty in speech, mastication, eruption and aesthetic problems. Surgical reduction of the overgrown tissues is frequently necessary and may consist of gingivectomy in addition to scaling and root planning. Patients must be informed of the tendency for the recurrence of gingival enlargement as long as the associated medication is continued. In instances where alternate medications can be used, regression of enlargement resulted following cessation of the associated agent.[14]

CONCLUSION

Although gingival enlargement influenced by drugs is rather a common entity, there are not many cases reported with sodium valproate induced gingival enlargement. This case report would add to the literature assuming a stronger role of sodium valproate in causing gingival enlargement in epileptic children.