Journal of Pediatric Epilepsy 2015; 04(02): 061-066
DOI: 10.1055/s-0035-1555602
Original Article
Georg Thieme Verlag KG Stuttgart · New York

The Relationship between Nocturnal Enuresis and Sequential Changes of NAG/Morning Urine Gravity in Epileptic Children Treated with Valproate Sodium

Hideaki Kanemura
1   Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
Fumikazu Sano
1   Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
Tetsuo Ohyama
1   Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
Kanji Sugita
1   Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
Masao Aihara
2   Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan
› Author Affiliations
Further Information

Publication History

17 July 2014

18 January 2015

Publication Date:
31 July 2015 (online)


The aim of this study was to examine the presence of enuresis as an adverse effect of valproate sodium (VPA) and to prospectively evaluate renal tubular function in children receiving VPA as monotherapy and polytherapy. The study was conducted in 226 children. The patients were subdivided into the following four groups according to their therapy: VPA monotherapy as A; combination of VPA with other conventional antiepileptic drug (AED) therapy as B; and new AED administration after VPA therapy as C. To assess renal tubular function of all patient groups, urinary N-acetyl-β-glucosaminidase (NAG) levels and morning urine gravity were measured at baseline and after 2 weeks, 3 months, 6 months, and 1 year of treatment. Five (2.2%, A:B:C = 1:4:0) of 226 children presented with enuresis. Enuresis appeared at a median of 19 days after the beginning of therapy. All patients showed normal results on the urinary excretion of NAG through the study period; however, urinary NAG activity in the patients with enuresis was significantly higher than those without enuresis at 2 weeks (p = 0.0092), 3 months (p = 0.0097), and 6 months (p = 0.0021) of treatment with VPA. In contrast, morning urine gravity presenting with enuresis was significantly lower than that in the patients without enuresis after only 2 weeks of treatment (p = 0.035). The results of this study also revealed that VPA therapy does not always increase NAG excretion or decrease morning urine gravity. However, urinary NAG levels of reflected tubular function in the patients with enuresis were significantly higher than those in patients without enuresis. This change may have some effects on the development of enuresis.

  • References

  • 1 Murray CJL, Lopez AD , Eds. Global Comparative Assessment in the Health Sector; Disease Burden, Expenditures, and Intervention Packages. Geneva: World Health Organization; 1994
  • 2 Pellock JM, Nordli Jr. DR, Dulac O. Drug treatment in children. In: Engel Jr. J, Pedley TA, , eds. Epilepsy. A comprehensive Text Book. 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2008: 1249-1257
  • 3 Patsalos PN, Fröscher W, Pisani F, van Rijn CM. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43 (4) 365-385
  • 4 Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003; 2 (6) 347-356
  • 5 Kanemura H, Sano F, Tando T, Sugita K, Aihara M. Efficacy and safety of add-on levetiracetam in refractory childhood epilepsy. Brain Dev 2013; 35 (5) 386-391
  • 6 Cheng W, Lin X, Lu D. Sodium valproate-induced enuresis in a pediatric bipolar patient. Neuropsychiatr Dis Treat 2013; 9 (10) 1671-1672
  • 7 Zaïem A, Aouinti I, Lakhoua G , et al. Secondary nocturnal enuresis associated with valproic acid. Therapie 2013; 68 (1) 59-60
  • 8 Korinthenberg R, Wehrle L, Zimmerhackl LB. Renal tubular dysfunction following treatment with anti-epileptic drugs. Eur J Pediatr 1994; 153 (11) 855-858
  • 9 Otsuka T, Sunaga Y, Hikima A. Urinary N-acetyl-beta-glucosaminidase and guanidinoacetic acid levels in epileptic patients treated with anti-epileptic drugs. Brain Dev 1994; 16 (6) 437-440
  • 10 Yüksel A, Cengiz M, Seven M, Cengiz S, Cenani A. N-acetyl-beta-glucosaminidase and beta-galactosidase activity in children receiving antiepileptic drugs. Pediatr Neurol 1999; 20 (1) 24-26
  • 11 Watanabe K, Kojima T, Fukuda Y , et al. Reliability of urinary N-acetyl-beta-D-glucosaminidase as an indicator of renal tubular damage in neonates. Biol Neonate 1987; 52 (1) 16-21
  • 12 Novo MdeL, Izumi T, Yokota K, Fukuyama Y. Urinary excretion of N-acetyl-beta-glucosaminidase and beta-galactosidase by patients with epilepsy. Brain Dev 1993; 15 (2) 157-160
  • 13 Gür E, Turhan P, Can G , et al. Enuresis: prevalence, risk factors and urinary pathology among school children in Istanbul, Turkey. Pediatr Int 2004; 46 (1) 58-63
  • 14 Kajiwara M, Inoue K, Mutaguchi K, Usui T. The prevalence of overactive bladder and nocturnal enuresis in Japanese early adolescents: a questionnaire survey. Hinyokika Kiyo 2006; 52 (2) 107-111
  • 15 Egger J, Brett EM. Effects of sodium valproate in 100 children with special reference to weight. Br Med J (Clin Res Ed) 1981; 283 (6291) 577-581
  • 16 Herranz JL, Arteaga R, Armijo JA. Side effects of sodium valproate in monotherapy controlled by plasma levels: a study in 88 pediatric patients. Epilepsia 1982; 23 (2) 203-214
  • 17 Panayiotopoulos CP. Nocturnal enuresis associated with sodium valproate. Lancet 1985; 1 (8435) 980-981
  • 18 Choonara IA. Sodium valproate and enuresis. Lancet 1985; 1 (8440) 1276
  • 19 Gosavi DD, Suman A, Jain M. Sodium valproate induced increased frequency of micturition and enuresis. Indian J Pharmacol 2013; 45 (1) 87-88
  • 20 Kanemura H, Sano F, Maeda Y, Sugita K, Aihara M. Valproate sodium enhances body weight gain in patients with childhood epilepsy: a pathogenic mechanisms and open-label clinical trial of behavior therapy. Seizure 2012; 21 (7) 496-500
  • 21 Wellwood JM, Ellis BG, Price RG, Hammond K, Thompson AE, Jones NF. Urinary N-acetyl- beta-D-glucosaminidase activities in patients with renal disease. BMJ 1975; 3 (5980) 408-411
  • 22 Verrotti A, Greco R, Pascarella R, Matera V, Morgese G, Chiarelli F. Renal tubular function in patients receiving anticonvulsant therapy: a long-term study. Epilepsia 2000; 41 (11) 1432-1435
  • 23 Nevéus T. The role of sleep and arousal in nocturnal enuresis. Acta Paediatr 2003; 92 (10) 1118-1123
  • 24 Gozmen S, Keskin S, Akil I. Enuresis nocturna and sleep quality. Pediatr Nephrol 2008; 23 (8) 1293-1296
  • 25 Abou-Khadra MK, Amin OR, Ahmed D. Association between sleep and behavioural problems among children with enuresis. J Paediatr Child Health 2013; 49 (2) E160-E166
  • 26 Su MS, Li AM, So HK, Au CT, Ho C, Wing YK. Nocturnal enuresis in children: prevalence, correlates, and relationship with obstructive sleep apnea. J Pediatr 2011; 159 (2) 238-42.e1
  • 27 Yoshikawa H, Watanabe T, Abe T. Tubulo-interstitial nephritis caused by sodium valproate. Brain Dev 2002; 24 (2) 102-105