LETTRE À LA RÉDACTION Thérapie 2013 Janvier-Février; 68 (1): 59–60 DOI: 10.2515/therapie/2013004 © 2013 Société Française de Pharmacologie et de Thérapeutique Secondary Nocturnal Enuresis Associated with Valproic Acid Énurésie nocturne secondaire associée à l’acide valproïque Ahmed Zaïem 1,2 , Imen Aouinti 1 , Ghozlane Lakhoua 1,2 , Sarrah Kastalli 1,2 , Riadh Daghfous 1,2 , Mohamed Lakhal 1,2 and Sihem El Aïdli 1,2 1 National Pharmacovigilance Centre, Tunis, Tunisia 2 University of Medicine, Pharmacology Department, Tunis, Tunisia Text received February 14 th , 2012; accepted December 10 th , 2012 Case reported to the National Tunisian Pharmacovigilance Centre, January 27 th , 2011 Keywords: valproic acid; nocturnal enuresis; adverse effect. Mots clés : acide valproïque ; énurésie nocturne ; effet indésirale 1. Introduction Valproic acid is one of the most frequently prescribed antiepi- leptic drugs worldwide for generalized and focal epilepsies. Its main adverse effects are gastrointestinal disturbances, weight gain, hair loss and tremor. Enuresis is a rare adverse effect. [1,2] We report a case of nocturnal secondary enuresis in a child associated with val- proic acid. 2. Case report A boy had been treated with valproic acid for febrile seizure from the age of one year until the age of six. According to the parents, the psychomotor development was normal. The age of sphincter control was not precised, but was reached before school age. In november 2010, at the age of 11 years, valproic acid was reintro- duced at the dose of 500 mg twice a day, for recurrence of febrile seizure. Two days later, the child has presented nocturnal secondary enuresis. Etiological investigations had eliminated organic causes and psychological troubles. Early morning plasma level of valproic acid was 124 μg/mL 12 hours after the night dose, above the upper therapeutic limit. Valproic acid was stopped. Enuresis improved gradually until total cessation within ten days. The case was reported to the Tunisian National Pharmacovigi- lance Centre in January 27 th 2011, and analyzed according to the French method of imputation. [3] The causality of valproïc acid was retained with an imputation score of I2 (possible). 3. Discussion The role of valproic acid was retained in the genesis of the noc- turnal enuresis because of chronological data (compatible delay and suggestive evolution marked with the remission of enuresis after val- proic acid withdrawal) and compatible semiology (negative inves- tigations). [3] Nocturnal enuresis is a common problem that can be troubling for children and their families. The causes are mostly functional impairments such as bladder dysfunction. The causes are rarely underlying anatomical or neurological diseases such as tubulopa- thies, chronic renal failure or diabetes insipidus. [4] Only a few drugs have been associated with enuresis such as clozapine, risperidone, aprazolam or cisapride. [1] Enuresis is an exceptional adverse effect of valproic acid repor- ted only in ancient articles. [5,6] A study reported the cases of two girls treated with valproic acid for absence seizure with clonic move- ments and automatism, in the first case, and tonic-clonic seizures in the second one. [5] Valproic acid was delivered at the dose of 200 mg three times a day in the first case, and 100 mg three times a day in the second one. These 2 girls had a normal development outside these disorders and a sphincter control at normal age. After the intro- duction of valproic acid, both patients presented a nocturnal secon- dary enuresis respectively two and three days after starting treatment. In the first case, remission of nocturnal enuresis was achieved by reducing the valproate dose to 200 mg twice daily and giving the last daily dose after an early dinner. In the second case, valproic acid was discontinued because of the enuresis. This treat- ment was reintroduced later, face to an unbalanced epilepsy at a dose of 150 mg three times a day. Recurrence of nocturnal enuresis occur- red from the third day of treatment. [5] Choonara reported in his com- ments to this study that enuresis is an adverse effect of valproic acid in 1 to 7% of the cases. [6] Actually, this author reported the results of a retrospective analysis of 100 children with epilepsy treated with sodium valproate published in 1981, investigating excessive weight gain under treatement. [7] Among the frequent, but mild adverse reactions reported in these children, nocturnal enuresis occurred in seven patients and stopped without treatment after a few months. The pathophysiological explanation of the association between enuresis and valproic acid seems to be a central effect on the thirst centre resulting in polydipsia or an increased depth of sleep asso- ciated with valproic acid. [6] Article publié par EDP Sciences