1. Introduction

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Valproic acid (VPA) is the most widely prescribed antiepileptic drug worldwide and it is also prescribed in the management of bipolar and schizoaffective disorders, social phobias, and neuropathic pain. Valproate is effective against all seizure types and it can be used by patients who are refractory to other anticonvulsants. It is a gold standard antiepileptic drug for children [1-3]. Adverse reactions occur in about 20% of patients.

Common side effects of valproate include gastrointestinal disturbances, sialoadenitis, tremor, bodyweight gaining, encephalopathy symptoms, platelet disorders, pancreatitis, liver toxicity and teratogenicity [2-7]. There are only a few cases of reports about mucocutaneous side effects due to valproic acid in the literature [8-16]. We report a case of lip and gingival hyperpigmentation induced by VPA.

2. Case Report

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A 16 year-old male patient, with epilepsy presented to us with lip hyperpigmentation. He had personal and family history of penicillin allergy. Absence and myoclonic epilepsy were not controlled with phenobarbital and then the therapy was switched to valproate. Two weeks after VPA had been iniciated, hyper pigmentation on his lips and gingival mucous developed. He did not take concomitant medications. Physical examination showed slate-gray pigmentation without infiltration on his lips [Figure 1]. Laboratory testing included liver function test, complete blood cell count, serum urea and creatinine were normal. Lip and mucous hyperpigmentation due to valproic acid was suspected therefore management consisted of the replacement with phenytoin. One month after discontinuation of VPA clearing of lesions was noted.

Figure 1

3. Discussion

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Drug-induced hyperpigmentation frequently occurs as post-inflammatory changes of a resolving drug-induced rash, but also directly promote through stimulation of melanin production, deposition of iron following vessels damage and/or deposition of drug (or drug metabolite) within the skin. Drugs of several classes are associated with skin or mucous membrane pigmentation and include non-steroidal anti-inflamatory drugs, antimalarials, amiodarone, antineoplasic agents, tetracyclines, heavy metals, clofazimine, oral contraceptives, psycotropic drugs, anticonvulsants such as hydantoin, phenytoin and barbiturates [18-24]. Other drugs reported to induce skin hyperpigmentation are amiodarone and some antihypertensives such as diltiazem, telmisartan and amlodipine [25-29].

As an antiepileptic, valproic acid has been shown effective in adults and children with generalized seizures (absence, tonic-clonic seizures and myoclonic epilepsy), partial seizures (simple, complex, secondary generalised) and combination seizures. As for the mechanism of action of valproate, it involves a variety of mechanisms, including increased gamma-amino butyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission [3].

With regard to the published cutaneous secondary effects produced by valproate, there are several articles referred to valproate side effects [8-16].Cutaneous vasculitis is a reported side effect that was described in patients treated with valproate [12-13]. Change in hair colour and curly hair are rare side effect produced by valproate [9, 10]. Other reported side effects are a yellow nail pigmentation or onycholysis [15, 17].

Hyperpigmentation of the lips can be caused by many reasons, including physiologic changes, genodermatoses, inflammatory disease, endocrinologic disorders, drugs and chemicals, benign and malignant neoplasm and other non-melanotic conditions. Drugs may cause a post inflammatory hyperpigmentation that is a typical non-specific reaction of fixed drug reactions. Hyperpigmentation of the lips is a common presentation in clinical practice that require a systematic approach for the diagnostic that includes a complete medical history, family history, history of cosmetic and medication use, and evaluation of systemic symptoms (30). The list of medications that can cause lip or oral hyperpigmentation include sulphonamides, nonsteroidal anti-inflammatory drugs, carbamacepine, phenothiazines, minocycline, zidovudine, cyclophosphamide, doxorubicin, escitalopram, levodopa, nicotine, tacrolimus, cotrimazole, colchicines, ketoconazole, pyrimethamine and barbiturates [30, 31]. Blue-gray mucocutaneous discoloration associated with Ezogabine-a new anticonvulsant- has been reported [32]. To our knowledge this is the first reported case of lip and gingival hyper pigmentation due to valproic acid.

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