PEDIATRIC UROLOGY Possible Impact of Comorbid Conditions on the Per- sistence of Nocturnal Enuresis: Results of a Long-Term Follow-up Study Pietro Ferrara,1 Maria Chiara De Angelis,2 Olga Caporale,2 Monica Malamisura,2 Valentina Del Volgo,2 Flaminia Vena,2 Antonio Gatto,1 Antonio Chiaretti1 1Institute of Pediatric, Catholic University of Sacred Heart, Rome, Italy. 2Campus Bio-Medico Uni- versity, Rome, Italy. Corresponding Author: Pietro Ferrara, MD Institute of Pediatric, Catholic University of Sacred Heart, Rome, Italy. Tel: +39 06 30154348 Fax: +39 06 3383211 E-mail: pferrara@rm.uni- catt.it Received January 2014 Accepted June 2014 Purpose: To describe the natural history of patients with nocturnal enuresis (NE) during a 10-year period and to evaluate possible impact of comorbid conditions on the persistence of NE. Materials and Methods: Ninety-five children (male to female ratio [M:F] 65:30), aged at first visit between 6 and 21 years were included in this study. Of study subjects 75 had primary monosymptomatic nocturnal enuresis (PMNE), 3 had secondary monosymptomatic nocturnal enuresis (SMNE) and 17 had non-mono- symptomatic nocturnal enuresis (NMNE). Demographic and NE-related details were assessed from electron- ic medical records and by telephone interview at the times 3, 6, 12 months and 3, 5, 10 years after the first examination. Sixty-seven of 95 patients were enrolled, of whom 57 had PMNE (M:F ratio 39:18, mean age 9.35 ± 2.81 years, mean age at improvement 11.5 ± 4.08 years), 8 had NMNE (M:F ratio 4:4, mean age 10.1 ± 2.64 years, mean age at improvement 12.6 ± 1.68 years) and 2 had SMNE (M:F ratio 1:1, mean age 12 years, mean age at improvement 13.5 ± 2.12 years). Results: The mean duration of follow up was 7.2 ± 2.5 years. All of the 67 children had 5 years follow up. Only 29 of 67 patients (19 with PMNE, 8 with NMNE and 2 with SMNE) had 10 years follow up and 4 of 19 with PMNE were still affected by NE. Out of 57 patients with PMNE 12 (2/12 with language disorders, 1/12 varicocele and 1/12 cryptorchidism) and out of 8 patients with NMNE 1 were still enuretic while all patients with SMNE were in remission. Conclusion: We observed that language disorders and testicular pathology in NE children could be comor- bidities associated with persistence of NE and treatment resistance. Keywords: nocturnal enuresis; risk factors; comorbidity; epidemiology; urination disorders. 1777 Pediatric Urology UROLOGY JOURNAL Vol. 11 No. 04 July - August 2014 1778 Comorbid Conditions and Persistence of Nocturnal Enuresis-Ferrara et al therapy with a chart for dries nights. Active treatment should be avoided in children < 6 years of age. The first line therapy for the subgroup of patients with PMNE associated with nocturnal polyuria and normal bladder function is desmopressin (dDAVP) and/or the NE alarm (both level 1 grade A recommendations).(1,14,15) dDAVP is an effective treatment for PMNE, it rapidly reduces the number of wet nights per week compared with placebo and with homotoxicological remedies.(16) Recent guidelines recommend an individualized treatment based on parameters obtained using a voiding diary.(17) Therefore, it is important to identify effective interventions because successful treatment of NE can result in improvement in health, self-esteem and quality of life.(11) The aim of this study is to evaluate the natural history of patients with NE investigating a 5 and 10-year follow up period to increase the knowledge on these conditions in particular the possible impact of comorbid conditions on the persistence of NE. MATERIALS AND METHODS Study Subjects Children with NE and/or LUTS who referred to the Pediatric Ne- phrology Clinic of “A. Gemelli” University Hospital of Rome be- tween January 2000 and December 2008 were eligible for inclusion in the study. Exclusion criteria were, urogenital malformations, re- nal failure and chronic disease such as diabetes. We analyzed retro- spectively data on medical records to identify signs and symptoms of voiding disorders and to evaluate behavioral characteristics of the child during the first examination and then by telephone interview which were performed at follow up periods of 3, 6 12 months and 3, 5 10 years. Demographic details (sex, age) at first observation, family history of NE, age at attaining diurnal continence, and characteristics related to bedwetting, e.g. frequency of wetting, daytime incontinence, urgen- cy, wetting during the early hours of sleep (before 12 pm) and early hours of morning (after 12 pm), deep sleep, snoring, left-handed- ness,(18) previous surgery, lumbosacral region trauma, allergies, con- stipation, encopresis, urinary tract infection (UTI), previous therapy, presence of stress and worrying events including socialization and school performance, polythelia and signs of spinal dysraphism,(19) were extracted from patients’ records. To diagnose constipation, we used the Rome III criteria. At least two of the following criteria must be met for ≥ 2 months before diagnosis (patients should not have a diagnosis of irritable bowel syndrome), ≤ 2 defecations in the toilet per week, ≥ 1 episode of fecal incontinence per week, history of retentive posturing or excessive volitional stool retention, history of painful or hard bowel movements, presence of a large fecal mass in the rectum and history of large diameter stools that may obstruct the toilet.Of the 95 eligible patients, 67 (male to female ratio [M:F] of 44:23, mean age at first visit 10 ± 2.78 years) participated in the telephone interview and were included in the study. Age of im- INTRODUCTION According to International Children’s Continence Society (ICCS), nocturnal enuresis (NE) is defined as intermit-tent incontinence while asleep in children older than 5 years age in which the sphincters control is acquired.(1) Night wetting is dichotomized into monosymptomatic NE (MNE) and non-monosymptomatic NE (NMNE).(2) MNE means bedwetting wit- hout any other lower urinary tract symptom (LUTS), and without a history of bladder dysfunction. NE in children with any other LUTS and with a history of bladder dysfunction is defined as non-monosy- mptomatic nocturnal enuresis (NMNE).(1,2) There are different types of MNE including primary monosymp- tomatic nocturnal enuresis (PMNE) diagnosed in child who has never achieve nocturnal urinary continence (UI) and has never been dry at night.(3) It is considered related to impaired sleep arousal, to nocturnal polyuria, to a small nocturnal bladder capacity, or to a combination of these factors. Secondary monosymptomatic noc- turnal enuresis (SMNE) describes children who acquired urinary continence for at least 6 months and it is usually secondary to psychological stress or organic causes.(4) Categorization into MNE and non-MNE, based on the absence or presence of bladder dysfunction, respectively, is important in clinical practice.(5) The estimated prevalence of NE are highly variable(6) be- cause there is a heterogeneity in diagnostic criteria with few studies using ICCS standardization.(1) The study of Nevéus and Sillén de- scribed the prevalence of NE and UI as approximately 10-15% at 5-year old, 5-10% at 7-year old, 3-8% at 10-year old children and 1-4% in adolescents with 0.5-2% in the untreated adults.(7) Bedwetting is more common in boys than girls until the teenage years.(8) Most studies show decreasing prevalence with increasing age, until about 1-2% in adulthood.(9) NE is a multifactorial disorder with a genetic underpinning. Butler described a conceptual model that NE occurs when there is poor arousal from sleep in response to a sensation of a full bladder associated with overactivity of bladder function or with an excessive overnight urine production, or both.(10) Other risk factors and correlates of NE include, delay in attaining bladder control, physiological factors such as constipation, fecal incontinence, daytime UI, caffeine consumption, sleep apnea, up- per airway obstructive symptoms, lower socioeconomic status and black race.(6,11,12) Family history of NE, is positive in 50% of cases. In particular PMNE may be polygenetic, candidate genes have been localized to chromosomes 13, 12 and 8.(4,13) Although different treatments (pharmacological, psychological/be- havioral and alternative interventions) have been tried for NE, the relative effectiveness of each one remains uncertain. Simple behav- ioral interventions are often the first line treatment tried by parents or caregivers at home with minimal professional involvement, in- cluding the reduction fluid intake after 6 or 7 pm and motivational (68.4%); constipation 3/57 (5.2%); left-handedness 12/57 (21%); deep sleep 53/57 (92.9%); UTIs 3/57 (5.2%) and polythelia 6/57 (10.5%). Thirty of 57 (52.6%) children were treated with dDAVP; 10/30 (33.3%) with nasal spray, 13/30 (43.3%) oral tablets 0.2 mg and 7/30 (23.3%) oral dDAVP lyophilisate 120 µg (MELT). The characteristics of these patients group were M:F ratio of 23:7; mean age at first examina- tion 9.6 ± 2.6 years and mean age at remission 11.8 ± 3.73 years. At the different follow-up times the percentages of remission in children with drug therapy were 16/30 (53.3%) at 3 months; 18/30 (60.0%) at 6 months; 18/30 (60.0%) at 1 year; 19/30 (63.3%) at 3 years and 23/30 (76.7%) at 5 years. At 10 years we had data only for 12/30 chil- dren; 9/12 (75.0%) were in remission and 3/12 (25.0%) had PMNE (Table 1). Of these patients, 2/12 (16.7%) were affected by language disturbances, 1/12 (8.3%) had dyslexia, 1/12 (8.3%) had delayed lan- guage development, 1/12 (8.3%) child had varicocele and another 1/12 (8.3%) had cryptorchidism. Among 3 patients still bedwetting, 1 was affected by dyslexia, 1 had delayed language development and crypt- orchidism and 1 was affected by varicocele. Twenty-seven of 57 (47.4%) children were never treated with phar- macologic therapy, M:F ratio of 16:11, mean age at first examination 9.0 ± 2.9 years and mean age at remission 11.6 ± 4.47 years. At the different follow up time the percentage of remission in untreated chil- dren were 3/27 (11.1%) at 3 months; 4/27 (14.8%) at 6 months; 8/27 (29.6%) at 1 year; 19/27 (70.4%) at 3 years and 22/27 (81.5%) at 5 years. At 10 years we had data only for 7/27 children; 6/7 (85.7%) were in remission and 1/7 (14.3%) had PMNE. The rate of remission in 39/57 (68.4%) children with PMNE and pos- itive family history was 12/39 (30.8%) at 3 months, 15/39 (38.5%) at 6 months; 21/39 (53.9%) at 1 year; 27/39 (69.2%) at 3 years and 32/39 (82.1%) at 5 years. At 10 years we had data only for 12 patients and rate of remission not considered. The rate of remission in children without family history of NE 18/57 (31.6%) was 4/18 (22.2%) at 3 months; 5/18 (27.8%) at 6 months; 7/18 (38.9%) at 1 year; 11/18 (61.1%) at 3 years and 13/18 (72.2%) at 5 provement, compliance to treatment and length of treatment were assessed by telephone interview at the follow up times of 3, 6 12 months and 3, 5 10 years after the first visit. Using ICCS definitions of PMNE (child who has never achieve noc- turnal urinary continence and has never been dry at night), SMNE (child who has acquired control for at least 6 months and it is usually secondary to psychological stress or organic causes) and NMNE pa- tients were included in 3 groups. Of the 67 eligible patients there were 57 children with PMNE, 39 (68.4%) male and 18 (31.6%) female with mean age at first exam- ination 9.35 ± 2.81 years; 2 with SMNE, 1 (50%) male and 1 (50%) female, they were both 12 years old at first observation and 8 children with NMNE, 4 (50%) male and 4 (50%) female with mean age at first observation 10.12 ± 2.64 years. Data referring to the treatment response were classified as follows: “partial response” as a reduction of wet nights of 50-90%, and “full response” as a reduction of at least 90%. Statistical Analysis Data are presented as frequency, percentage and standard deviation. Comparison of remission in patients who received and didn’t receive special treatments is analyzed using chi-square test and P < 0.05 was considered statistically significant. The same statistical method is used to analyze data on positive family history. RESULTS Ninety-five children were eligible for the study, 75/95 (78.9%) with PMNE, 17/95 (17.9%) with NMNE and 3/95 (3.2%) with SMNE. Of the 75 eligible children with PMNE, 57 (76.0%) had completed in- terviews and agreed to give information, while 13 (17.3%) did not participate due to disconnected telephone number and 5 (6.7%) didn’t participate due to parental refusal, parents affirmed that their children had never suffered from NE. Eight of 17 (47.0%) patients with NMNE and 2/3 (66.7%) with SMNE participated in the telephone interview. The characteristic of the 57 patients with PMNE were: mean age at remission 11.5 ± 4,08 years; positive family history for NE 39/57 Table 1. Characteristics of treated and untreated children with primary monosymptomatic nocturnal enuresis. Variables Therapy No therapy P Value Patients (no.) 30 27 ----- Male 23 16 ----- Female 7 11 ----- Mean age at first visit (years) 9.6 9.0 ----- Mean age at remission (years) 11.8 11.6 ----- Remission at (%) ----- 3 months 53.3 11.1 .0007 6 months 60.0 14.8 .0005 1 year 60.0 29.6 .02 3 years 63.3 70.4 .57 5 years 76.7 81.5 .65 10 years 75.0 85.7 .58 1779 Pediatric Urology UROLOGY JOURNAL Vol. 11 No. 04 July - August 2014 1780 with PMNE, in particular, children with familial aggregation PNE are more likely to be severe symptoms and bladder dysfunction.(20,21) Our study instead showed that at 5 years of follow up 82% of children with family history for NE were in remission vs. 72.2% of whom without family history of NE and the same trend was also observed in all pre- vious follow up. These data could be analyze considering the associa- tion between genotype and phenotype to evaluate eventually genotype associated with the persistence of enuresis. In our study we observed that the highest percentage of remission (33.3%) occurred in the age group of 9-11 years and that, also among children who had never received pharmacologic thera- py, 48.2% achieve spontaneous remission between 9-11 ages. However, details on reasons of this age distribution of remis- sions remain unknown. We observed that only 5.2% of children with PMNE presented constipation, despite of previous studies which showed that prevalence of constipation in children affected by NE was significantly higher (12.6%).(22-24) Furthermore, in our study, none of the children who were still affected by NE at 5 and 10 years had con- stipation. Our study also showed an interesting relationship between oral language disorders and NE; 2/12 children who, after 10 years from the first visit, were still affected by NE, presented oral language disorders, dyslexia in one case and delayed language development in the other case. According to several studies the frequency of language disorders in the general population varied from 10-15% at 2 years old to 3% at 5 years old. This association at 10 years follow up was very strong so also considering the limit of small size of our study popu- lation this data is very significant. These data indicate that enuretic children present a higher percentage of oral language disorders when compared to non-enuretic children.(25) Previous researches have instead suggested the association between NE and attention deficit hyperactivity disorder (ADHD), probably related to delays in central nervous system maturation.(26) Comorbid- ity between NE and ADHD could either be due to common etiologic pathways underlying these two conditions or due to “causal” relations in which the non-resolution or treatment of one disorder increases the risk for the other disorder.(27) There aren’t data that showed a correlation between NE and testicular pathology, while we had observed that 2 children with long-term NE presented this kind of problems: cryptorchidism in a case and varico- cele in another one. years. At 10 years we had data only for 7 patients and rate of remission was not considered (Table 2). Of the 17 children affected by NMNE, 8 had completed telephone interview: 4/8 (50%) had positive family history, 6/8 (75%) had deep sleep and none had UTI or left-handedness. Mean age at recovery was 12.6 ± 1.68 years. Pharmacological treatment was administered for 4/8 children (50%). The characteristics of this group were: M:F ratio of 3:1; mean age at first examination 9.7 ± 2.21 years and mean age at remission 12.7 ± 0.95 years. At the different follow up points the per- centage of remission were 1/4 (25%) at 3, 6 and 12 months; 3/4 (75%) at 3 and 5 years and 4/4 (100%) at 10 years. At 10 years follow up, all the patients were in remission. One had a complete remission after 1 month of therapy, 2 had a partial response until the complete remis- sion after 3 years, 1 child didn’t respond to therapy but he had a com- plete remission after 6 years spontaneously. Four of 8 children, M:F ratio of 1:3, with NMNE were never treated with drug therapy, mean age at first visit was 10.25 ± 3.31 years; mean age at recovery was 12.5 ± 2.38 years. At the follow-up after 3, 6 and 12 months and after 3, 5 and 10 years from the first visit, the percentage of remission were at 3 months 1/4 (25%); at 6 months 1/4 (25%); at 1 year 2/4 (50%); at 3 years ¾ (75%); at 5 years 4/4 (100%) at 10 years 4/4 (100%). Of the 3 children with SMNE, 2 completed telephone interview, 1 was male, who was never treated with pharmacologic therapy and had a complete remission after 3 years spontaneously; the other 1 was fe- male, she was treated with MELT with a full response and complete remission after 1 month of therapy. At the follow up after 5 and 10 years, both of them were in remission. DISCUSSION According to other studies, our results confirm the recurrence of pos- itive family history for NE. Approximately 32% of cases are sporadic and 68% seems to follow a genetic predisposition. Many authors had identified some associated genetic loci on different chromosomes, mainly a gene on chromosome 13 responsible for the dominant inher- itance of NE and a gene on chromosome 12, on 22 and probably on 8.(4,13) Thus, molecular genetics have shown that NE is a genetically complex disorder with locus heterogeneity and presumed gene-envi- ronment interactions. Von Gontard and colleagues and Wang and colleagues demonstrated that a positive family history had significant effects on the children Table 2. Rate of remission in children with and without family history of nocturnal enuresis.* Follow up Periods Children with Positive Family History Children without Family History P Value 3 months 30.8 22.2 .50 6 months 38.5 27.8 .43 1 year 53.9 38.9 .29 3 years 69.2 61.1 .54 5 years 82.1 72.2 .39 10 years 75 85.7 .58 * Data are presented as percentage. Comorbid Conditions and Persistence of Nocturnal Enuresi-Ferrara et al Case Report 1471 13. Wei CC, Wan L, Lin WY, Tsai FJ. Rs 6313 polymorphism in 5‐hydroxy- tryptamine receptor 2A gene association with polysymptomatic primary nocturnal enuresis. J Clin Lab Anal. 2010;24:371-5. 14. O’Flynn N. Nocturnal enuresis in children and young people: NICE clin- ical guideline. Br J Gen Pract. 2011;61:360-2. 15. Ferrara P, Romano V, Cortina I, Ianniello F, Fabrizio GC, Chiaretti A. Oral desmopressin lyophilisate (MELT) for monosymptomatic enuresis: Structured versus abrupt withdrawal. J Pediatr Urol. 2014;10:52-5. 16. Ferrara P, Marrone G, Emmanuele V, et al. Homotoxicological reme- dies versus desmopressin versus placebo in the treatment of enuresis: a randomised, double-blind, controlled trial. Pediatr Nephrol. 2008;23:269- 74. 17. Walle JV, Rittig S, Bauer S, Eggert P, Marschall-Kehrel D, Tekgul S. Practical consensus guidelines for the management of enuresis. Eur J Ped. 2012;171:971-83. 18. Ferrara P, Ruggiero A, Diociaiuti L, Paoletti FP, Chiozza M, Caione P. Primary nocturnal enuresis and left-handedness. Scand J Urol Nephrol. 2001;35:184-5. 19. Ferrara P, Costa S, Rigante D, et al. Intramedullary epidermoid cyst pre senting with abnormal urological manifestations. Spinal Cord. 2003;41:645-8. 20. von Gontard A, Heron J, Joinson C. Family history of nocturnal enuresis and urinary incontinence: results from a large epidemiological study. J Urol. 2011;185:2303-6. 21. Wang QW, Wen JG, Song DK, Su J, Zhu QH, Liu K. Bed-wetting in Chinese children: epidemiology and predictive factors. Neurourol Uro- dyn. 2007;26:512-7. 22. Loening-Baucke V. Prevalence rates for constipation and faecal and uri- nary incontinence. Arch Dis Child. 2007;92:486-9. 23. Shadpour P, Shiehmorteza M. Enuresis persisting into adulthood. Urol J. 2006;3:117-29. 24. Barghi M. The relation of enuresis and irritable bowel syndrome with premature ejaculation: a preliminary report. Urol J. 2005;2:201-5. 25. Birenbaum TK, Cunha MC. Oral language disorders and enuresis in chil- dren. Pro Fono. 2010;22:459-64. 26. Park S, Kim B-N, Kim JW, et al. Nocturnal Enuresis Is Associated with Attention Deficit Hyperactivity Disorder and Conduct Problems. Psychi- atry Investig. 2013;10:253-8. 27. Merikangas KR, Angst J, Isler H. Migraine and psychopathology: re- sults of the Zurich cohort study of young adults. Arch Gen Psychiatry. 1990 ; 47:849 -53. CONCLUSION Considering the possible correlation between language disorders, tes- ticular pathology and long term NE, it could be suggested that pedia- tricians, when dealing with this kind of diseases in enuretic children, pay more attention to the NE treatment, in a bio-psychical approach. Future investigations on larger sample are useful to clarify this hypoth- esis. If this association will be confirmed the treatment in this children could be more strong both in drug and motivational therapy. CONFLICT OF INTEREST None declared. REFERENCES 1. 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