Sleep Architecture in Valproate-Induced Nocturnal Enuresis in Primary School and Preschool Children

Abstract

Nocturnal enuresis is one of the side effects of valproic acid treatment, and generally underdiagnosed by clinicians. Studies reported that a variable incidence of valproic acid–induced nocturnal enuresis is 2.2% to 24% with unclear explanations of the reasons behind valproic acid–induced nocturnal enuresis. A retrospective study was carried out on 260 children (aged 5-12 years) diagnosed with idiopathic epilepsy, treated with valproic acid to evaluate the nocturnal enuresis secondary to valproic acid, and to discuss the characteristics of their sleep architecture. Nocturnal enuresis was reported in 28 (10.7%) patients after a mean exposure time to valproate of 18.78±8.4 days. Nocturnal enuresis was significantly associated with younger age and serum level of valproate ( P = .05). The polysomnographic study suggested that the underlying mechanism may be related to impaired sleep efficiency, frequent arousals, prolonged sleep latency, snoring, or increased sleep depth which may impair a child’s ability to awaken to the sense of bladder fullness or contractions. Clinical trial registration: ClinicalTrials.gov identifiers: NCT04191863

Sodium valproate-induced nocturnal enuresis in epilepsy: Three case reports and a review of the literature

“…In our study, we stated that the average VPA concentration of all the 58 presented cases at the onset of enuresis was 80.76 μg/mL, which was within the recommended effective therapeutic range. Similarly, Esmael reported that, compared to the non-enuresis group, VPA concentration in the enuresis group was higher, ranging from 75.44 to 94.2 μg/mL ( 15 ). Ozan et al also reported that the VPA concentration was 76.5 ± 3.4 μg/mL when enuresis occurred, which was within the therapeutic range, while in the non-enuresis group, it was 70.8 ± 16.9 μg/mL ( 9 ).…”

“…As an adverse effect, secondary enuresis was previously reported only in pediatric patients, and there has been no literature examining adult patients, which may be attributed to two factors. First, younger age was reported to be the only significant factor in predicting the development of enuresis ( 1 , 15 ). To our knowledge, in this study, we reported the first case of VPA-induced enuresis in an adult patient with epilepsy.…”

“…Esmael et al carried out polysomnography for 28 children with secondary VPA-induced enuresis and 28 age- and sex-matched control children ( 15 ). They found that latency, the number of awakenings, sleep arousal, and the snoring index were significantly increased, and the total sleep time, sleep efficiency, rapid eye movement sleep percentage, and lowest oxygen saturation were significantly reduced ( 15 , 25 ). VPA has been reported to affect sleep by mediating melatonin ( 26 , 27 ).…”

“…Three new cases of nocturnal enuresis associated with VPA therapy from the clinics of the Second Xiangya Hospital were reported. The English-language literature in the PubMed database was searched from its inception to 30 July 2022, and the Chineselanguage literature was searched in Wanfang and CNKI databases (9,(12)(13)(14)(15)(16)(17). The following keywords and associated medical subject headings were searched: sodium valproate, enuresis, drug-induced enuresis, and epilepsy.…”

Psychobehavioural and Cognitive Adverse Events of Anti-Seizure Medications for the Treatment of Developmental and Epileptic Encephalopathies

“…Reports on the effects of VPA on sleep have been conflicting, with positive, neutral and negative effects on various aspects of sleep observed across seven small studies in patients with various epilepsy conditions [38]. Further to this, VPA-associated cases of nocturnal enuresis have been reported, with studies suggesting a link to sleep architecture problems [39,40]. Overall, the effects of VPA on sleep need to be addressed in larger dedicated studies in DEEs, although the prevalent use of this ASM suggests that problems are likely to be minimal.…”