Search

Introduction and Aim of the Study: Most treatments of nocturnal enuresis (NE) are targeting the main pathophysiological mechanisms, i.e., excess nocturnal urine production, bladder reservoir dysfunction and inability to awaken to a full bladder. Although many children can be effectively treated with only one treatment modality, there is a significant number of treatment-refractory cases. We experience an increasing tendency to combine treatment modalities in those children. However, there is limited evidence regarding the efficacy and safety of such strategies., Materials and Methods: We reviewed files from all NE children seen in our outpatient incontinence clinic between January 1st and December 31st 2017 and identified children refractory to first line treatment receiving a combination of at least two treatment modalities concurrently. Age, gender, wet nights per week before treatment, follow-up time, previous treatment with desmopressin or alarm, phenotype of NE, number of simultaneous treatments tried and response as well as registered side effects during treatment was noted. We registered the outcomes and safety of the treatment modalities and evaluated prognostic factors., Results: We identified 59 children (13 girls) aged 6-15 yrs (mean 9.6 yrs) of whom 30 were monosymptomatic NE (MNE) and 29 were non-monosymptomatic NE (NMNE) patients. They all suffered at least three wet nights per week before treatment. In total, 38 children (61%) became dry on multimodal therapy. Eighteen children (30%) became dry on a combination of two treatment modalities, 16 (27%) on three modalities, and two (3%) on four modalities. Nine children (15%) achieved partial response whereas three (5%) showed no response despite multiple tries with combination therapies. A total of 18 children (30%) reported side effects to one or more of the modalities tried. Side effects that led to discontinuation of the treatment were uncommon (three patients)., Conclusions: Treatment refractory NE represents a challenge for the clinician. Although it seems possible to adequately treat refractory NE patients with multimodal treatment one should be aware of side effects as well as inform the families of the challenges in the treatment of refractory enuresis patients. Future RCT's should focus on providing further evidence for the role of multimodal therapy in NE treatment., Competing Interests: Conflict of interest Konstantinos Kamperis lecturer for Ferring Pharmaceuticals, consulting Kimberly–Clark and investigator for Astellas Pharma A/S., (Copyright © 2021 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Purpose: We provide updated, clinically useful recommendations for treating children with monosymptomatic nocturnal enuresis., Materials and Methods: Evidence was gathered from the literature and experience was gathered from the authors with priority given to evidence when present. The draft document was circulated among all members of the International Children's Continence Society as well as other relevant expert associations before completion., Results: Available evidence suggests that children with monosymptomatic nocturnal enuresis could primarily be treated by a primary care physician or an adequately educated nurse. The mainstays of primary evaluation are a proper history and a voiding chart. The mainstays of primary therapy are bladder advice, the enuresis alarm and/or desmopressin. Therapy resistant cases should be handled by a specialist doctor. Among the recommended second line therapies are anticholinergics and in select cases imipramine., Conclusions: Enuresis in a child older than 5 years is not a trivial condition, and needs proper evaluation and treatment. This requires time but usually does not demand costly or invasive procedures., (Copyright 2010 American Urological Association. Published by Elsevier Inc. All rights reserved.)

Purpose: We investigated bladder reservoir function in children with monosymptomatic nocturnal enuresis and in healthy controls., Materials and Methods: A total of 18 children with monosymptomatic nocturnal enuresis and 119 controls who were 7 to 13 years old were recruited. Children completed frequency volume charts and measurements of nocturnal urine production. Mean diuresis in the period preceding each voiding was calculated. Those with enuresis were grouped according to bladder capacity and hospitalized for 4 nights, including a baseline night and 3 with an oral water load. Enuresis volumes and post-void residual volume were estimated, allowing the calculation of bladder volume at the time of enuresis., Results: Nine children with monosymptomatic nocturnal enuresis were characterized as having normal bladder capacity and 9 had decreased bladder capacity. We found large intra-individual variability in daytime voided volume in all 3 groups of participants. Children with enuresis and small bladder capacity generally voided with volumes close to maximal voided volume. A total of 93 enuresis episodes were recorded. Large intra-individual variability was seen in bladder volume at enuresis and it was lower than maximal voided volume in more than 50% of episodes. Variability in bladder volume at enuresis was greatest in the patient group with decreased bladder capacity. We found a significant correlation between diuresis and bladder capacity in all groups during the day and night., Conclusions: There is a great intra-individual diurnal variability in voided volume in children with enuresis and in healthy children. Enuresis seems to occur at bladder volumes that are smaller and larger than the maximal voided volume obtained from voiding charts.

Purpose: We investigated the circadian rhythm of solute excretion and regulating hormones as well as blood pressure in patients with monosymptomatic nocturnal enuresis., Materials and Methods: We included 15 patients with a mean age +/- SE of 13.4 +/- 0.9 years who had monosymptomatic nocturnal enuresis with at least 3 wet nights weekly and a control group of 10 healthy children with a similar age and sex distribution. During inpatient circadian studies urine was collected during 6 periods and blood was drawn at 7 time points during 24 hours. Heart rate and blood pressure was recorded with an ambulatory blood pressure monitor every 30 to 60 minutes., Results: The total patient group excreted a significantly larger nocturnal urine volume than controls (p <0.01). Five patients had marked nocturnal polyuria (nocturnal urine volume greater than the mean in the control group +2 SD), whereas urine output in the remaining patients without polyuria were similar to controls. Nocturnal polyuria was caused mainly by increased nocturnal solute excretion, especially Na. Serum aldosterone and plasma angiotensin II showed a marked circadian rhythm in normal children with a nocturnal increase concomitant with a significant decrease in mean arterial blood pressure during sleep. In contrast, the group of patients with nocturnal polyuria showed a lack of circadian rhythm in all excretion variables as well as an attenuated rhythm in plasma angiotensin II and mean arterial blood pressure. Interestingly this group had normal circadian rhythms of the circadian rhythm markers plasma cortisol and heart rate., Conclusions: The study suggests that an abnormally large nocturnal excretion of Na caused by selectively attenuated circadian rhythms of Na regulating hormones might be an important pathogenic factor in monosymptomatic nocturnal enuresis.

Purpose: We investigated the role of urinary Ca excretion in monosymptomatic nocturnal enuresis, and defined normality and intra-individual variability in Ca excretion in healthy children., Materials and Methods: We included 46 Danish children with desmopressin resistant nocturnal enuresis and 96 healthy controls. We performed fractional urine collections at home during 2 days in controls or during hospitalization in children with enuresis. Urine volume, osmolality, and Ca and creatinine measurements were performed and Ca-to-creatinine ratios were calculated and compared between groups. Based on nocturnal urine output children with enuresis were characterized as having polyuria (nocturnal urine volume greater than 130% of expected bladder capacity) or not having polyuria., Results: We did not find any differences in controls compared with children with enuresis who did not and did have nocturnal polyuria in daytime Ca excretion (mean +/- SE 0.121 +/- 0.012, 0.078 +/- 0.014 and 0.095 +/- 0.020 mg/mg creatinine), nighttime Ca excretion (0.115 +/- 0.011, 0.092 +/- 0.019 and 0.139 +/- 0.029 mg/mg creatinine) or 24-hour Ca excretion (0.118 +/- 0.011, 0.083 +/- 0.014 and 0.106 +/- 0.020 mg/mg creatinine, respectively). Urinary Ca excretion was not influenced by patient age, sex or body weight and, furthermore, we did not find evidence of diurnal variation. However, we observed considerable intra-individual variability in diurnal, nocturnal and total 24-hour urinary Ca-to-creatinine ratios., Conclusions: These observations contradict several previous reports and speculations on a role of Ca in the pathogenesis of nocturnal enuresis.

Purpose: We evaluated combination treatment with desmopressin and oxybutynin in patients with enuresis who did not respond to desmopressin monotherapy. Furthermore, we compared 2 methods of estimating bladder capacity and evaluated the ability of these methods to predict the response to desmopressin and oxybutynin., Materials and Methods: A total of 60 children with a mean age +/- SD of 10.6 +/- 3.0 years who had monosymptomatic nocturnal enuresis completed the study. After a 2-week observation period maximal voided volume during free access to fluid intake was determined by a 2-day frequency-volume chart and maximal voided volume after water load was determined on a separate day. Patients then received 20 mug desmopressin intranasally at bedtime during 2 weeks. In nonresponders to desmopressin with less than a 50% decrease in wet nights 5 mg oxybutynin twice daily was added for another 2 weeks., Results: Of the patients 41 (68%) showed more than 50% decrease in wet nights during the 2-week desmopressin treatment period (4.6 +/- 1.6 to 0.7 +/- 0.8, p <0.001). In desmopressin nonresponders combined treatment with desmopressin and oxybutynin resulted in a further decrease in wet nights (4.0 +/- 1.2 to 1.7 +/- 1.4, p <0.001). Maximal voided volume during free access to fluid intake was significantly higher in desmopressin responders than in nonresponders (244 +/- 111 vs 160 +/- 65 ml, p <0.001). In contrast, maximal voided volume after water load was not significantly different between desmopressin responders and nonresponders., Conclusions: The study indicates a role for oxybutynin in combination with desmopressin in children who are not responding to desmopressin monotherapy. Maximal voided volume during free access to fluid intake is a clinically useful predictor of the response to desmopressin but not to oxybutynin.

Purpose: We investigate the nature of enuresis episodes in monosymptomatic nocturnal enuresis using a fluid provocation model., Materials and Methods: The study included 18 children 7 to 13 years old with monosymptomatic nocturnal enuresis. Based on basal home recordings patients were subgrouped into those with a normal nocturnal urine output and those with nocturnal polyuria (mean nocturnal urine production on wet nights exceeding 130% of functional bladder capacity, normal functional bladder capacity for age provided). Children were admitted to the hospital for 4 consecutive nights. After an adaptation night all children received orally 25 ml/kg water, 30 minutes before bedtime on the remaining 3 nights. A cordless alarm device enabled registration of enuretic episodes from another room and diapers allowed the measurement of enuresis volumes. Post-void residual volumes were measured by ultrasound. Pelvic floor electromyography was continuously recorded throughout the night, and its association to bladder emptying was investigated., Results: A total of 95 enuresis and 14 nocturia episodes were recorded. Significantly more enuresis episodes were registered on nights with oral fluid load, whereas no increase in number of nocturia episodes was seen. Of the enuresis episodes 46 were associated with incomplete bladder emptying (post-void residual volume greater than 10% of total bladder volume at time of enuresis). No difference between patient groups regarding post-void residual volume was seen. Abnormal bursts of electromyography activity were associated with incomplete micturitions., Conclusions: Enuresis nocturna episodes in polyuric and nonpolyuric patients are frequently incomplete micturitions. The present findings question the definition of nocturnal enuresis episode as normal complete voiding.

Purpose: We studied the characteristics of a group of monosymptomatic nocturnal enuretics successfully treated with the alarm system, with special reference to changes in functional bladder capacity., Materials and Methods: The diaries of 7 girls and 19 boys 7 to 13 years old with severe nocturnal enuresis, small daytime bladder capacity (70% or less of expected capacity for age) and poor or absent response to desmopressin were analyzed. Patients were treated with an alarm until complete dryness was achieved for 21 consecutive nights before ending therapy. Immediately after the treatment they recorded a 1-week followup diary of voiding and fluid intake., Results: Mean duration of the alarm treatment was 82 days, and there was no change in nocturnal or 24-hour diuresis from baseline to followup. Nocturia developed during the alarm treatment in 48% of the children. The nocturnal diuresis on nocturia nights was significantly higher than on nights without nocturia. Daytime functional bladder capacity increased significantly in children with and without nocturia., Conclusions: Treatment with an alarm system increases daytime functional bladder capacity significantly in children with and without nocturia. A higher nocturnal urine production on nocturia nights explains why some children have nocturia and others do not.

Purpose of Review: The purpose of this review is to highlight and comment upon important areas of enuresis research., Recent Findings: Current areas of pathophysiological focus are nocturnal urine production, in which alternative mechanisms other than deficient vasopressin secretion has been implicated in some patients. Bladder reservoir function has gained renewed interest, and has proved to be one of the best predictors of treatment response to desmopressin. Various aspects of central nervous system function, including arousability and pontine reflexes, are in focus, and molecular genetics has provided firm evidence of a link between enuresis and different chromosomal markers. The therapeutic focus is directed towards a differential approach based upon the underlying mechanism and towards combination therapies such as alarm devices and desmopressin as well as anticholinergic agents and desmopressin. Furthermore, new exciting treatment concepts such as laser acupuncture have shown promising results in initial studies., Summary: Despite recent advances in our understanding of nocturnal enuresis, we are still far from understanding in detail this socially discomfiting and scientifically intriguing condition, and many controversies remain. However, the substantiation that enuresis is a heterogeneous condition that requires a differential approach has provided the basis for further progress.

Objective: To collect data on voiding patterns at baseline (no treatment) and during short-term desmopressin treatment, with special reference to the functional and the mean bladder capacity., Patients and Methods: The study included 120 children (aged 6-16 years) with monosymptomatic nocturnal enuresis. While at home they recorded their fluid intake and diuresis in two separate periods, i.e. 2 weeks as a baseline registration and another 2 weeks during desmopressin titration. On four study days the children recorded the time and volume of all voids and of fluid intake. From the diaries their functional and mean bladder capacities, 24-h diuresis and day/night ratio of diuresis were determined., Results: The mean 24-h diuresis was significantly lower during short-term desmopressin treatment. In most of the enuretics the mean day/night ratio increased on desmopressin treatment. The mean functional and mean bladder capacities were unaffected by desmopressin. Those not responding had bladder capacities of approximately 100 mL less than full responders. Regardless of response, practically all the enuretics in the study had a smaller functional bladder capacity than expected for their age. Among responders the morning void was significantly larger than the following voids during the day, and among non-responders the fourth void was significantly larger than the previous voids in the day. Desmopressin treatment did not influence these volumes significantly., Conclusions: Short-term desmopressin treatment does not affect functional and mean bladder capacity; 24-h urine production was reduced significantly (P<0.01) during desmopressin treatment.

Purpose: We studied a large 4-generation family in which night and day voiding problems segregated in an autosomal dominant pattern with a high penetrance. We mapped the gene(s) causing these forms of incontinence using a total genome scan approach., Materials and Methods: The family comprises 74 subjects in 4 generations. The clinical phenotypes were evaluated by detailed questionnaires and frequency volume charts. Genetically, a genome scan approach with 500 polymorphic marker systems was used to localize a chromosome area for the trait(s) and to narrow down a candidate region. The 3 different genetic models studied were 1) a single gene causing either day, night or day and night incontinence; 2) a gene primarily causing night incontinence; and 3) 2 different genes each causing only day or night incontinence., Results: For model 2 we found 2 areas that gave a high lod score on 2-point analysis (D4S2960, 4p16.1, Z = 3.66 and D12S86, 12q24.2, Z = 3.22) on chromosome 4p and 12q. With an estimated penetrance of 75% only 4p linkage was significant. Models 1 and 3 were excluded as causes due to lack of the affected haplotype in affected subjects. Based on manual haplotype and 2-point analyses, all other areas were excluded for linkage., Conclusions: The most likely genetic model in this kindred seems to be a gene located on chromosome 4p16.1 causing primarily nocturnal enuresis. However, involvement of chromosome 12q24.3 cannot be excluded for linkage. The dopamine receptors DRD5 and D1B are mapped to chromosome 4p16. These genes are candidate genes for nocturnal enuresis and urge incontinence.

Purpose: We evaluated the intra-individual variability and reproducibility of nighttime urine production on wet nights and functional bladder capacity estimated by long-term home recordings of monosymptomatic nocturnal enuresis. In particular, the intention was to evaluate the validity of 1 versus 2 weeks of recording when estimating urine volume on wet nights and 1 versus 2 weekends of recording when estimating functional bladder capacity., Materials and Methods: We analyzed 120, 2-week home recordings of nighttime urine volume from patients with monosymptomatic nocturnal enuresis 6 to 16 years old (mean age 9.1) with at least 3 wet nights per week. Most patients were nonresponders or partial responders to desmopressin. Nighttime urine volume was estimated by weighing diapers before and after sleep, and measuring morning urine volume. Of the home recordings 62 included frequency volume charts for 2 weekends, which were evaluated for functional bladder capacity defined as the largest voided volume observed., Results: No significant overall week-to-week differences were observed in average urine volume on wet nights and functional bladder capacity. There was a large intra-individual variability in all measured variables, which was most pronounced for functional bladder capacity and least pronounced for urine volume on wet nights. With regard to repeatability, the limits of agreement of urine volume on wet nights were -32% and 36% (95% confidence interval) as opposed to -54% and 48% for functional bladder capacity., Conclusions: In this study intra-individual week-to-week estimates of average urine volume on wet nights demonstrated acceptable variability and repeatability in contrast to functional bladder capacity. A reliable estimate of urine volume on wet nights could be obtained by 7 nights of home recording, whereas 4 days of daytime recording were necessary when estimating functional bladder capacity. Similar studies of patients who respond to desmopressin are needed.

Purpose: We determined the prevalence of positive family history of nocturnal enuresis in relation to response to desmopressin., Materials and Methods: A total of 328 children with nocturnal enuresis and 53 normal children were interviewed to determine the presence of family history of nocturnal enuresis. Response to desmopressin was confirmed in some cases by home recordings of enuresis episodes during 2 baseline weeks and 2 weeks of 20 to 40 microg. desmopressin intranasally., Results: Significantly more patients than normal children (75% versus 38%, p <0.001) reported a positive family history of enuresis (any relative). The high prevalence of a positive family history of nocturnal enuresis was present in severe/nonsevere or primary/secondary types of enuresis. Of the patients 141 completed 4 weeks of home recordings including 20 with a complete response (greater than 90% reduction in wet nights week), 25 with a partial response (50% to 90% reduction) and 96 with no response (less than 50% reduction). The prevalence of a positive family history (any relative) was no different among the response groups (80%, 84% and 78%, respectively). Similarly, family history, as defined by first order relatives only, showed no relation to treatment response., Conclusions: A positive family history of nocturnal enuresis is more prevalent in patients with enuresis than in normal children regardless of the nature of the nocturnal enuresis. In contrast to previous reports, a positive family history failed to predict a good response to desmopressin treatment. Hereditary factors are important to consider in desmopressin responding and desmopressin resistant cases.

Purpose: Formal studies of the genetics of enuresis have been performed since the 1930s and molecular genetics since 1995, both highlighting the importance of hereditary factors in the etiology of nocturnal enuresis. We summarize the current state of knowledge with respect to the genetics of nocturnal enuresis and its genotype-phenotype interactions., Materials and Methods: A comprehensive review of the published data available on the genetic basis of enuresis was performed., Results: Genetic factors are the most important in the etiology of nocturnal enuresis but somatic and psychosocial environmental factors have a major modulatory effect. Most commonly, nocturnal enuresis is inherited via an autosomal dominant mode of transmission with high penetrance (90%). However, a third of all cases are sporadic, and the difference between sporadic and familial forms is not known. Four gene loci associated with nocturnal enuresis have been identified but the existence of others is presumed (locus heterogeneity). All likely candidate genes have been excluded so far. There is no specific association among the different loci, type of wetting and other aspects of the phenotype. All subtypes of nocturnal enuresis (primary, secondary, combined day/night wetting) are susceptible to comparable genetic influences. Certain syndromes of day wetting follow their own genetic mechanisms but this association with the genetics of nocturnal enuresis is not known., Conclusions: Nocturnal enuresis is a common, genetic and heterogeneous disorder. The associations between genotype and phenotype are complex and are susceptible to environmental influences. Therefore, exact assessment of the clinical phenotype and identification of intermediary phenotypes or traits are needed. Future research will focus on the identification of genes, gene products and their interaction with environmental factors.

Objective: This study aimed to evaluate the effect of nicotine stimulation on pituitary release of plasma arginine vasopressin (P(AVP)) in patients with primary monosymptomatic nocturnal enuresis (PMNE) and healthy control subjects., Material and Methods: Postpubertal teenagers and adult enuretics as well as control subjects were enrolled into the study and admitted to hospital for measurements of P(AVP) in relation to intake of orally administered nicotine. Sixteen patients with PMNE (9 females, 7 males; aged 15-51 years, mean 23.5) and nine normal subjects (4 females, 5 males; aged 24-31 years, mean 27.3) were studied. The enuretics were characterized prior to investigation as either 1-desamino-8-D-arginine vasopressin (DDAVP) responders (n = 8; 16-51 years, mean 28.9) or DDAVP non-responders (n = 8; 15-24 years, mean 18.1) based on the reduction in the number of wet nights. P(AVP), mean arterial blood pressure (MAP) and heart rate (HR) were measured 0, 5, 10, 15 and 30 min, and plasma osmolality (P(osm)) 0 and 30 min after receiving 4 mg nicotine (Nicorette, Pharmacia & Upjohn) chewing gum., Results: In the compiled material a slight but statistically significant increase was observed in P(AVP) at 30 min compared with baseline levels, concurrent with significant rises in MAP and HR above baseline levels at 15 and 30 min. No difference was seen in P(osm) before and after nicotine administration. No other significant variation over time, assessed by an ANOVA, was detected. No difference was encountered in any measured parameter between controls and enuretics or between DDAVP responders and non-responders., Conclusion: Smokeless nicotine chewing gum induces non-osmotic vasopressin release in humans. The secretory AVP capacity to this stimulation is normal in PMNE.

Desmopressin responders tend to have a large volume of urine production at night, in contrast to desmopressin refractory patients who often produce normal volumes of urine. Controls and adolescent/adult primary monosymptomatic nocturnal enuretics were included in a study measuring urine volume and plasma vasopressin levels before and during a 24-hour water deprivation test. The results indicate a significantly higher urine production in desmopressin responders when compared with controls and non-responders. Before fluid deprivation, only the nocturnal polyuric patients showed a urine osmolality significantly lower than that of controls and desmopressin non-responders. A significant decrease in the clearance of osmols was evident in the desmopressin refractory group from day to night. All three groups showed a significant increase in plasma vasopressin during fluid deprivation, with polyuric, desmopressin-responding patients showing a lower increase that the non-responders and controls. Plasma vasopressin levels were normal in adolescent and adult enuretics regardless of their response to desmopressin. Moreover, response to fluid deprivation in both polyuric and enuretic patients resulted in a significant decrease in urine output from the first to the second night.

Monosymptomatic nocturnal enuresis (MNE) in children is partly the result of inadequate reduction in the rate of urine output at night. This nocturnal polyuria is due to the lack of a rise in the anti-diuretic hormone, arginine vasopressin (AVP), and can be reduced or eliminated by treatment with desmopressin at bedtime. Since there is a 1% incidence of MNE among adults, this study investigated the circadian pattern of solute and water balance in nine young adult enuretics before and during desmopressin therapy and compared the results with nine-age- and sex-matched, healthy controls. Before treatment, enuretics and controls had similar total fluid intake, urine output, urine osmolality, plasma osmolality, plasma total protein, mean arterial pressure and plasma AVP. The circadian pattern of fluid intake was also normal in enuretics. This abnormality could not be attributed to a deficiency of plasma AVP or an increase in solute excretion, since both variables were similar to controls. Rather, their nocturnal polyuria appeared to be due to a marked nocturnal reduction in renal sensitivity to the antidiuretic effect of vasopressin. In seven enuretics, restudied during treatment with desmopressin (10-30 micrograms o.d.), circadian urine output was normal and enuresis was absent. These results indicate that: (i) The circadian pattern of urine output in healthy adults is largely due to a nocturnal decrease in solute excretion rather than a rise in plasma AVP; (ii) The subset of adults with persistent MNE also have nocturnal polyuria as a result of insensitivity to the antidiuretic action of AVP; (iii) These defects can be corrected by treatment with desmopressin.

The aim of this study was to investigate linkage of nocturnal enuresis to a locus on chromosome 22 in 35 German families and to analyse associations with the clinical phenotype. One hundred and sixty-seven enuretic children aged 5-11 years were examined using a somatic, psychiatric and psychological diagnostic protocol; a detailed pedigree over three generations was also compiled. Forty-two children (mean age: 8.11 years) were selected for further molecular genetic examination. EDTA blood samples were taken from the patients and 130 relatives, and polymorphisms of the microsatellite markers D22S446, D22S156 and D22S257 on chromosome 22 were analysed. Positive linkage was found in 11 families of 14 children, indicating that 39.3% of families were compatible with linkage to the markers on chromosome 22. The phenotype included primary nocturnal enuresis and combined day and night wetting. The results for chromosome 22, as with previous loci for nocturnal enuresis on chromosomes 8, 12 and 13, support the hypothesis for genetic and clinical heterogeneity.

Objective: Desmopressin may be a useful treatment in some, but not all, patients with nocturnal enuresis. We have evaluated a relation between nocturnal urine output in patients with primary monosymptomatic nocturnal enuresis and the treatment response to synthetic vasopressin., Design: Adolescent or adult enuretics and normal subjects were enrolled in the study and admitted to hospital for a 24 hour investigation of the diurnal variation in urine output, plasma vasopressin (AVP) and plasma atrial natriuretic peptide (ANP). The enuretics were characterized prior to investigation as either 1-desamino-8-D-arginine vasopressin (DDAVP) responders or non-responders. During admission the fluid intake was restricted to 25 ml/kg per day., Patients: Twenty-four patients (15-37 years) with primary monosymptomatic nocturnal enuresis and 9 normal subjects (24-31 years)., Measurements: Circulating levels of AVP, ANP, plasma electrolytes and plasma osmolality were measured (1400, 2000, 2300, 0200, 0500 and 0800 hours) together with urine volume, urine osmolality and urine electrolytes during daytime and nighttime. Tubular reabsorptive capacity for water, osmoles and creatinine were assessed as well as urinary and fractional excretion rates of sodium and potassium., Results: Controls and DDAVP non-responders had a significant decrease in urine output at night concomitant with a significant plasma AVP amplitude in peak/nadir values although both groups lacked a significant nocturnal increase in AVP. In contrast, in DDAVP responders there was no circadian variation in urine output and thus a nocturnal polyuria together with no oscillation in plasma AVP. The DDAVP responding group had a nocturnal urine production significantly larger than the two other groups. However, the mean 24 hour AVP levels were similar in all groups. The excessive urine production at night in DDAVP responders was accompanied by nocturnal natriuresis due to an increased fractional excretion of sodium. In contrast, nocturnal antidiuresis in controls and DDAVP non-responding enuretics coincided with diminished sodium excretion. Average ANP levels were elevated in both enuretic groups compared to normals, whereas a circadian variation was detected only in the latter., Conclusion: It is concluded that DDAVP responsiveness is linked to the nocturnal urine production and that no pathophysiological role can be ascribed to AVP or ANP in DDAVP refractory adolescent and adult enuretics. Moreover, it is suggested that an abnormal tubular handling of sodium may contribute to the nocturnal polyuria seen in DDAVP responders.

Forty-two children with nocturnal enuresis (27 with primary, 4 with secondary nocturnal enuresis and 11 with combined primary nocturnal enuresis and daytime wetting) were selected retrospectively from a study of 167 consecutive children with enuresis. The aim of the study was to collect formal genetic data, perform molecular genetic linkage-analyses with five microsatellite markers on chromosomes 13q, 12q or 8q and specify the associations between genetic findings and clinical, as well as psychiatric diagnoses. Positive linkage of nocturnal enuresis to one of the microsatellite markers was possible in 27 children from 23 families and was not possible in 15 children. Somatic findings in both the groups with and without possible assignment of nocturnal enuresis to a marker were heterogeneous. Psychiatrically, a low rate of behavioural problems was apparent. These findings support the hypothesis of genetic and phenotypical heterogeneity of nocturnal enuresis, without linkage of specific psychiatric and somatic phenotypes to certain chromosome markers.

This survey describes the evolution of our concept of monosymptomatic bedwetting over the last decades. It takes you briefly through psychology and enuresis. The minor role of bladder pathology is described ending up with focusing on the mismatch between bladder capacity at night-time and urine production. Monosymptomatic bedwetting should currently be regarded as an umbrella diagnosis allocated to children where daytime urinary problems have been excluded. Within the diagnosis of monosymptomatic bedwetting we can nowadays identify at least two groups. One is related to children who have a large night-time urine production and a normal bladder capacity, and the other is related to children who have a large night-time production, but a bladder capacity too small for the normal urine production. The genetic aspects are currently investigated. The results and this kind of research will probably end up in a further subgrouping.

Purpose: We investigated the effect of imipramine on nocturnal urine output in patients with nocturnal enuresis., Materials and Methods: There were 15 monosymptomatic enuretic patients 15 to 37 years and 8 control subjects 25 to 32 years old. We measured nocturnal urine output, urine osmolality, creatinine clearance, osmolal clearance, free water clearance, excretion of solutes, fractional excretion of sodium, fractional excretion of potassium and plasma vasopressin with and without a single oral dose of imipramine (1 mg./kg. of body weight) taken at 8 p.m., Results: Baseline studies showed significantly larger and less concentrated nocturnal urine among enuretics compared with controls. We observed a marked antidiuretic effect of imipramine in 6 enuretics with severe nocturnal polyuria. The imipramine induced decrease in urine output was accompanied by reduced osmolal clearance. Approximately a third of the observed decrease in solute excretion was attributed to lower excretion of sodium and potassium. The remaining two-thirds were most likely caused by an increased tubular reabsorption of urea, which may be secondary to a sympathomimetic effect of imipramine tubules, possibly because of altered adrenal medullary function with an increase in proximal tubular sodium and water reabsorption. The resultant lower tubular flow rate facilitates tubular reabsorption of urea in the distal part of the nephron., Conclusions: Imipramine has a vasopressin independent antidiuretic effect if nocturnal polyuria is present. The antidiuretic effect of imipramine can be attributed primarily to increased alpha-adrenergic stimulation in the proximal tubules with a secondary increased urea and water reabsorption more distally in the nephron.

Fifty-five normal children, aged between 7 and 12 years, were hospitalised for four consecutive nights. On three of these nights, the subjects received 25 ml/kg body weight of fluid prior to bedtime. Such fluid-loading provoked 28 enuresis-like episodes in 17 children, most of which occurred during the first few hours of sleep. The incidence of these enuretic events decreased with increasing age, more boys than girls were affected, there was a statistically significant correlation between total enuresis volume and nocturia volume, and the micturition was frequently incomplete, leaving large volumes of residual urine in the bladder. It was concluded that if nocturnal urine production exceeds bladder capacity, enuresis may be provoked, even in children who do not normally wet the bed. Furthermore, the definition of nocturnal enuresis as a complete emptying of the bladder during sleep may need revision.

A 2-week, home-based study was conducted on 75 children with nocturnal enuresis to monitor the frequency of enuretic episodes and the volume of nocturnal urine production. The objectives of the study were to correlate nocturnal urine production to the occurrence of nocturnal enuresis and response to desmopressin (Minirin, DDAVP) treatment. Furthermore, patient compliance was evaluated. Enuresis episodes and nocturnal urine production was recorded every night during two base-line weeks without treatment and during 2 weeks with 20-40 micrograms desmopressin at bedtime. During both periods fluid intake and micturition volumes were recorded for 2 days. Desmopressin response was defined as > 50% reduction in wet nights during treatment. It was found that patient compliance was acceptable in most patients. Regarding urine output it was found that base-line nocturnal urine production was significantly higher during nights when enuresis occurred than during "dry" nights and significantly higher in desmopressin responders compared with desmopressin non-responders. During treatment with desmopressin, nocturnal urine production in desmopressin responders decreased to levels similar to those of non-responders. The results confirm inpatient circadian studies of urine output and emphasise the importance of nocturnal polyuria in patients with monosymptomatic enuresis. The response to desmopressin was found to correlate with the occurrence of nocturnal polyuria. Home studies were considered to be a useful tool in the characterisation of patients with nocturnal enuresis.

The objective of the current study was to identify the associations between phenotype and genotype in children with nocturnal enuresis. Of the total of 167 wetting children, aged 5-10 years, without neurological or structural forms of incontinence, 110 were nocturnal enuretics. The examinations included a full psychiatric and psychological assessment, a paediatric and neurological examination, a family history with pedigree, ultrasonography, uroflowmetery, urinanalysis and bacteriology. Children with secondary nocturnal enuresis (n = 28) had a significantly higher rate of behavioural disorders, life events and continuous psychosocial stress than those with primary nocturnal enuresis (n = 82). Of the latter group, children with primary monosymptomatic nocturnal enuresis (n = 50) had an especially low rate of behavioural problems, when in comparison to primary non-monosymptomatic nocturnal enuretics (n = 32). Formal genetics point to a high genetic predisposition to nocturnal enuresis in all subgroups. Linkage studies to markers on chromosomes 8, 12 and 13 demonstrate both clinical, as well as genetic heterogeneity in nocturnal enuresis.

Purpose: We evaluated whether a water load before bedtime provoked enuresis episodes in healthy children with no previous enuresis. We also studied pelvic floor activity during an enuresis episode and the completeness of bladder emptying, attempted to identify a possible trigger mechanism for nocturnal enuresis, and investigated any age and sex differences regarding the frequency of provoked enuresis episodes., Materials and Methods: We evaluated 55 healthy volunteers (22 girls and 33 boys) 7 to 12 years old who were dry from age 5 years and had no urological or other complaints. Subjects were admitted to the hospital for 4 consecutive nights. Night 1 was for adaptation without a water load. On nights 2 to 4, 25 ml./kg. body weight of water were given orally half an hour before bedtime. During the night pelvic floor activity was monitored, and the time and volume of enuresis and nocturia episodes were noted., Results: In 17 subjects 28 enuresis-like episodes were provoked, generally comprising incomplete voidings with large residual volumes mostly in younger children and in boys. Enuresis and nocturia episodes were provoked at a volume specific for each individual without a relation to the bladder filling rate., Conclusions: Our results support the hypotheses that nocturnal polyuria is an important pathogenetic factor in enuresis and that arousal failure can be provoked in nonenuretic subjects.

The pharmacokinetics of desmopressin (1-desamino-8-D-arginine vasopressin) were investigated in 8 patients with nocturnal enuresis, of whom 4 were known to respond completely to desmopressin and 4 were nonresponders. A decrease in urine production was confirmed in responders after the administration of desmopressin while the drug did not cause antidiuresis in nonresponders. Absorption and excretion of desmopressin were identical in each group. Results indicate at least 2 pathophysiological mechanisms in nocturnal enuresis, including insufficient nocturnal production of arginine vasopressin and impaired renal sensitivity to arginine vasopressin and desmopressin. Each type results in high nocturnal urine production.

The efficacy and safety of 6 weeks of treatment with desmopressin tablets at doses of 200 to 400 micrograms.at bedtime were investigated in 33 children with monosymptomatic nocturnal enuresis. During an initial 1 to 2-week dose titration period 22 patients (67%) became either completely dry or showed improvement, 7 (21%) showed no response and 4 (12%) dropped out of therapy. During tablet treatment 17 patients on 400 micrograms.and 5 on 200 micrograms.at bedtime increased the number of weekly dry nights from 2.0 +/- 1.6 (standard deviation) during a 2-week observation period to 5.2 +/- 1.9 (p < 0.001). During a subsequent 2-week period 40 micrograms.intranasal desmopressin showed a similar overall efficacy, with a mean of 5.4 +/- 1.6 dry nights per week. In addition, intranasal treatment was able to increase the number of dry nights in 2 of the 7 nonresponders to tablet treatment.

An update of the pathogenesis and treatment of monosymptomatic bedwetting is presented. This frequently occurring entity seems to have a multifactorial pathogenesis incorporating arousal disturbances and disturbances to the circadian rhythm of diuresis modulating hormones. It has recently been substantiated that the bladder reservoir function in monosymptomatic bedwetting is normal. This is further underlined by the fact that treatment of instability of the bladder has proven futile. In a substantial part of the monosymptomatic bedwetters the changes in circadian rhythm of antidiuretic hormone can be counteracted by desmopressin diacetate (DDAVP), which abolishes the symptom in more than 2/3 of the patients. Monitoring circadian rhythms of arginine vasopressin (AVP) and treatment with DDAVP have led to increased understanding of the pathogenesis of monosymptomatic bedwetting and opened new fields of investigation.

The circadian variation of plasma atrial natriuretic peptide (ANP) in relation to urinary excretion of sodium (UNa) and potassium (UK) as well as clearance of creatinine (Ccrea) was assessed in 15 juvenile patients with enuresis nocturna and compared with 11 age-, sex-, and weight-matched normal subjects. Normal juveniles showed a highly significant diurnal variation (p less than 0.001) of plasma ANP with diurnal peak levels at midnight (0000 hours) and minimum levels at 0400 hours. Enuretic patients showed a similar diurnal rhythmicity with normal levels during day and night. In normals both UNa and UK showed significant diurnal rhythmicity with a marked reduction from daytime to night-time. Although the total diurnal excretions of UNa and UK were similar to normals, patients with enuresis showed abnormal diurnal variation in both UNa (p less than 0.05) and UK (p less than 0.01). The abnormal circadian rhythm of UNa and UK in enuretics seemed to be caused by abnormal tubular handling as similar abnormalities were found in the fractional excretions and as the circadian variation of Ccrea was normal. Especially during the first hours of sleep (2200 hours to 0000 hours), the patients showed polyuria (230 +/- 138 ml vs 116 +/- 58 ml, p less than 0.01), natriuresis (20.9 +/- 16.3 mmol l-1 vs 10.7 +/- 6.8 mmol l-1, p less than 0.01), and kaliuresis (7.3 +/- 6.3 mmol l-1 vs 3.7 +/- 2.3 mmol l-1, p less than 0.05), despite normal levels of plasma ANP. In conclusion, the study describes the diurnal variation of plasma ANP in relation to urinary excretion of sodium and potassium in a juvenile normal population. Patients with nocturnal enuresis show abnormal diurnal rhythmicity in the urinary excretion of sodium and potassium that is not correlated to the plasma levels of ANP.

Eight patients with monosymptomatic nocturnal enuresis (age 11-24 years) were investigated prior to and after 24 weeks of desmopressin treatment in order to evaluate the impact on the endogenous vasopressin secretion and urinary output. No effect on plasma vasopressin, diurnal urinary volume, and urinary osmolality were found after this long-term treatment. Overall no changes in either body weight, blood pressure, or hematological variables were demonstrated. This supports previous findings that the treatment appears to be well tolerated and free of side effects in longer term.

The diurnal variation of plasma vasopressin (AVP), urinary excretion rate, urinary osmolality, and serum osmolality was studied twice in 15 patients with enuresis and in 11 age, weight, and sex matched nonenuretic normal subjects. A diurnal rhythm of AVP with constant levels during the day (8 AM-10 PM) and a highly significant increase during the night (10 PM-8 AM) was found in normal subjects. In contrast, enuretics showed a significantly less pronounced nocturnal increase in AVP with significantly lower nocturnal levels than normal subjects. Normal subjects showed a diurnal rhythm in urinary excretion rate reciprocal to urinary osmolality with a low and highly concentrated nocturnal urinary output. In enuretics, however, this normal diurnal rhythm was absent. In conclusion, an abnormal diurnal rhythm of AVP seems to be an important pathophysiological factor in enuresis, explaining the abnormally high nocturnal urinary volume and the low nocturnal urinary osmolality found in these patients.

In 8 adult patients with monosymptomatic nocturnal enuresis (age 18-44 years) we twice investigated the circadian rhythm of plasma vasopressin, plasma atrial natriuretic peptide, serum osmolality, serum electrolytes as well as urinary excretion in relation to urodynamic variables. Seven of the patients showed a lack of diurnal rhythmicity in plasma vasopressin at both diurnal studies with no night-time increase. The nocturnal urinary volumes exceeded the bladder capacities with an average of 155%. This was mainly caused by a large excretion of poorly concentrated urine during the first hours of sleep. Although a slight nocturnal peak in plasma atrial natriuretic peptide was found no clear pathophysiological role could be determined for this peptide. It is concluded that the previously established vasopressin production abnormality in juvenile enuresis seems to persist in adult enuretics.

In patients with monosymptomatic enuresis we investigated bladder activity together with electroencephalography during sleep on two consecutive nights. Thirty-one patients were investigated. Enuretic episodes were found to be normal micturitions not related to any specific sleep stage. Except for a very few bladder contractions outside the enuresis episode we did not observe any bladder activity. In the few instances where bladder activity was seen it was not associated with changes in EEG activity. The bladder contractions were all eliminated by pelvic floor activity, and this could be seen without any disturbances of the sleep indicating that voiding can be inhibited without the child waking up.

A combined analysis was done of sleep and bladder filling during sleep. Cystometry did not specifically affect sleep, since most of the cystometry studies in cases of enuresis did not lead to sleep stage changes on electroencephalography. Bladder instability was not accompanied by lighter sleep. Increasing patient age did not appear to have any influence on sleep or bladder behavior. We conclude that it is possible to provoke enuresis at any sleep stage and that sleep is unaffected by bladder filling in enuretic patients.

During the last decades, the development of the modern disposable diaper (DD) has changed the way we diaper our children, as they are safe, easy to use, comfortable and easy to dispose, compared to cloth diapers used earlier. Concurrently, the age of initiating toilet training (TT) is rising. We aimed to investigate the connection between DD usage and the tendencies seen in TT and childhood urinary incontinence, with specific interest on studies evaluating the effect of diapering on enuresis. A literature search was conducted in PubMed and Embase. A systematic literature search was conducted, revealing 309 studies in Embase and 269 studies in Pubmed. After removing duplicates, 400 studies were eligible for screening. All abstracts were screened, and 12 relevant abstracts where identified, but only eight studies were eligible. No prospective intervention studies specifically evaluating the effect of diaper on enuresis were identified. Literature on TT and diapers in general was identified using the respective search terms on both databases. The eight studies identified showed a tendency towards diaper use being related to a delay on obtaining continence in children, but no secure conclusions can be made, as the literature is inadequate. Based on the available literature no secure conclusions can be drawn although an association is suggested. In order to evaluate the effect of diapers on incontinence, prospective randomized studies are needed. [Display omitted] [ABSTRACT FROM AUTHOR]

Desmopressin is a long-established treatment for nocturnal enuresis with clear guidelines regarding its usage. A sex difference in renal sensitivity has recently been reported in adults. The objective of this study was to investigate real-life desmopressin prescription in the Danish pediatric population, and prescription patterns which may reflect a sex difference in pediatric usage. Formulation, dose, treatment duration, and safety (hyponatremia) were investigated. 40,596 children received 214,220 desmopressin prescriptions between 2004 and 2011 in the Danish National Prescription Registry. Data were linked to hyponatremia diagnoses from the National Patient Registry. Although the lowest recommended dose of desmopressin oral lyophilisate is 120 μg, around a fifth of children were prescribed 60 μg for long-term use. A greater proportion of girls (22.6%) than boys (19.8%) received this low dose. Treatment duration was longer for boys than girls on oral lyophilisate (mean 489-524 vs. 414-462 days) and tablet (0.1 mg: 204 vs. 161 days). Prescribed daily dose was consistent with time between prescriptions, indicating no significant drug holidays. There were no admissions for hyponatremia during the observation period.Conclusion: Danish national prescription data on pediatric desmopressin dosage are consistent with a greater sensitivity to desmopressin in girls than boys. Further studies are required. What is Known: • Desmopressin has been used for pediatric nocturnal enuresis for decades • Recent evidence suggests a sex difference in desmopressin sensitivity in adults What is New: • For the first time, desmopressin prescription practices in nocturnal enuresis are documented for an entire country • A higher proportion of girls than boys received a low dose of desmopressin, consistent with the sex difference in sensitivity reported in adults. [ABSTRACT FROM AUTHOR]