View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of Dental Sciences (2012) 7,85e88 Available online at www.sciencedirect.com journal homepage: www.e-jds.com CASE REPORT Phenytoin- and amlodipine-induced gingival overgrowth Ching-Wen Chang a,b, Chih-Jen Yang a, Yu-Lin Lai b,c* a Department of Dentistry, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan b School of Dentistry, National Yang-Ming University, Taipei, Taiwan c Department of Stomatology, Division of Endodontics and Periodontology, Taipei Veterans General Hospital, Taipei, Taiwan Final revision received 1 October 2011; accepted 31 December 2011 Available online 17 March 2012 KEYWORDS Abstract Drug-induced gingival overgrowth is an adverse event associated with three types amlodipine; of drugs, i.e., anticonvulsants, immunosuppressants, and calcium-channel blockers. It was drug-induced gingival shown that the combined use of an immunosuppressant (cyclosporine) and a calcium- overgrowth; channel blocker increases the prevalence and severity of gingival overgrowth. However, few gingivectomy; reports discussed the effects of the combinationofananticonvulsant(phenytoin)and phenytoin a calcium-channel blocker (amlodipine). In this case report, we present an epilepsy patient who was using both phenytoin and amlodipine, which caused extensive gingival overgrowth. After periodontal treatment and a gingivectomy, the gingival overgrowth was significantly reduced. A postoperative drug-substitution regimen and intensive professional care ensured a stable result 1 year after surgery. Copyright ª 2012, Association for Dental Sciences of the Republic of China. Published by Elsevier Taiwan LLC. All rights reserved. Introduction and neoplastic enlargement. Drug-induced gingival over- growth is a common consequence of the administration of some anticonvulsants, immunosuppressants, and calcium- Gingival overgrowth is associated with multiple factors 1 including inflammation, adverse events, systemic disease, channel blockers. Although the pathology of drug-induced gingival overgrowth is not definitively known, these disor- ders seem to be induced through disruption of homeostasis of collagen synthesis and degradation of gingival connective * Corresponding author. Department of Stomatology, Division of Endodontics and Periodontology, Taipei Veterans General Hospital, tissues. 201 Shih-Pai Road, Section 2, Beitou District, Taipei 112, Taiwan. It was shown that the combined use of cyclosporine and E-mail address: [email protected] (Y.-L. Lai). a calcium-channel blocker (CCB) increased the prevalence 1991-7902/$36 Copyright ª 2012, Association for Dental Sciences of the Republic of China. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.jds.2012.01.013 86 C.-W. Chang et al the posterior teeth revealed 20%w50% bone loss. There were subgingival caries around Tooth Numbers 27 and 36 (Fig. 2). The diagnosis of this case was drug-induced gingival overgrowth with plaque-induced chronic periodontitis. Following scaling and oral hygiene instructions given to the patient, surgical excision of the overgrowing gingiva under general anesthesia was scheduled because of the patient’s disability and uncooperative behavior. During the surgery, a gingivectomy and gingivoplasty were carried out using surgical knives as well as electrosurgery, which was used to delicately shape the gingival contour without causing active tissue bleeding. In addition, full-mouth scaling and root planing were performed after gingival contouring. After the surgery, the caries lesions of Tooth Numbers 27 and 36 were treated. The gingival contour was Figure 1 Preoperative view showing the severe generalized much improved. To prevent gingival regrowth, a plaque- gingival overgrowth. control program was begun for the patient. The patient’s physician substituted vaproic acid for phenytoin, and captopril [angiotensin-converting enzyme (ACE) inhibitor] and severity of gingival overgrowth compared with mono- for amlodipine. The 1-year postoperative follow-up therapy using cyclosporine or the CCB alone.2e5 However, revealed no recurrence of gingival overgrowth (Fig. 3). few reports mentioned the gingival status in those receiving The overall gingival inflammation had improved, and the a combination of phenytoin and a CCB. This article presents probing depths of the teeth were reduced to 3w4 mm. a case of probable synergism with the combined use of The excised tissues were sent for biopsy. Histologic phenytoin and a CCB that caused extensive gingival over- sections showed thickened epithelium and pseudoepithe- growth in a patient with epilepsy. liomatous hyperplasia (Fig. 4), a large amount of dense bundles of collagen fibers, and mononuclear inflammatory Case report cell infiltration (Fig. 5). A woman 67 years of age presented at the Department Discussion of Dentistry in the Hsin-Chu Hospital in Taiwan, with a complaint of gum swelling around the entire dentition. Drug-induced gingival overgrowth is known to be an adverse The patient’s medical history disclosed epilepsy for more effect of three main types of drugs, i.e., phenytoin, an than 10 years due to left-brain trauma in a traffic accident. anticonvulsant; cyclosporine, an immunosuppressant; and She had taken phenytoin since that time. The patient had nifedipine, a CCB, which is widely used to manage cardio- a stroke attack 1 year before and subsequently took vascular disorders. The prevalence rate of drug-induced amlodipine in addition to phenytoin. gingival enlargement was reported to vary: 10%w15% for A clinical examination showed generalized gingival phenytoin, 8%w70% for cyclosporine, and 0.5%w83% for enlargement. The enlarged tissue covered from one-half to nifedipine.1 Gingival tissue reacts differently to various two-thirds of the crowns (Fig. 1). Excessive spacing of the types of medication. As an anticonvulsant, phenytoin has anterior teeth was also noted. Probing depths of gingival long been used to treat epilepsy, whereas valproic acid is pockets were at least 5 mm. The patient had compromised a new antiepileptic and appears to be as effective as oral hygiene. Generalized plaque accumulation and gingival phenytoin at controlling seizures. In addition, valproic acid inflammation were evident. A radiographic examination of also exhibited a lower occurrence of gingival enlargement.6 Figure 2 Initial periapical radiography. Drug-induced gingival overgrowth 87 Figure 3 One-year postoperative view revealing normal and Figure 5 Dense bundle of collagen fiber in subepithelium  stable gingival contour. (hematoxylin & eosin, 10). that the prevalence of gingival overgrowth was 58.3% for As an immunosuppressant, cyclosporine was the main cyclosporine use alone and was 84.3% for the combined use choice for organ transplantation in the last two decades. of cyclosporine and a CCB. Similarly, Greenberg and Tacrolimus is a new-generation immunosuppressant and is colleagues5 reported that the concomitant use of cyclo- an excellent alterative to cyclosporine due to its lower sporine and a CCB exhibited a higher occurrence of gingival incidence of gingival overgrowth and a comparable success overgrowth (76%) than in those treated with cyclosporine rate in organ-graft survival.7 As a CCB, nifedipine is alone (36%). The synergistic effect when using phenytoin extensively used to manage hypertension. Amlodipine is and cyclosporine caused severe gingival overgrowth in a third-generation dihydropyridine calcium antagonist that a kidney-transplant patient.9 However, few reports has similar pharmacodynamic effects as nifedipine. mentioned the gingival status related to the combined use However, amlodipine is characterized by nearly complete of phenytoin and a CCB, which was demonstrated in this absorption and slow hepatic biodegradation. Patients article. The pathogenesis of extensive gingival overgrowth undergoing monotherapy with amlodipine had less gingival following concomitant use of amlodipine and phenytoin in overgrowth than those taking nifedipine.8 A cohort study of this patient is not clear. Both phenytoin and the CCB inhibit 135 renal-transplantation patients demonstrated that the the intracellular uptake of calcium. This synergistic inhib- combined use of cyclosporine and nifedipine caused less itory action may have affected the secretory properties of gingival overgrowth (53%) than that in patients treated with gingival fibroblasts or the production of collagenase, cyclosporine and amlodipine (72%).8 subsequently exacerbating the development of gingival Many studies showed that the combined use of CCBs and enlargement10 (Table 1).2e5,7e9 immunosuppressants enhanced the risk and severity of e The most effective approach to ameliorate gingival gingival overgrowth.2 5 Spolidorio and colleagues4 found overgrowth is withdrawing or substituting medication. In this case, valproic acid and captopril (an ACE inhibitor) were substituted for phenytoin and amlodipine. Gingival hyperplasia associated with valproic acid seems to be extremely rare,6 and this drug was proposed as an alter- native medication in patients with phenytoin-induced gingival hyperplasia. ACE inhibitors are a group of phar- maceuticals that are primarily used to treat hypertension and congestive heart failure. It was suggested that long- term use of an ACE inhibitor may also limit the degree of fibrosis within grafts during chronic cyclosporine usage. To prevent the development of gingival overgrowth, ACE inhibitors