Pediatr Nephrol (1995) 9: 94-103 9 IPNA 1995

Pediatric Nephrology

Practical pediatric nephrology
Nocturnal enuresis
Uri S. Alon
Division of Pediatric Nephrology, The Children's Mercy Hospital, University of Missouri at Kansas City, 2401 Gillham Road, Kansas City, Missouri 64108, USA Received July 29, 1994; received in revised form August 23, 1994; accepted September 16, 1994

Abstract. Nocturnal enuresis is a very common pediatric problem which often has strong genetic roots. In the vast majority of children it resolves spontaneously, with time, therefore research and treatment of bedwetting cannot carry any risk to the child. The research on the etiology of bedwetting has been focused on sleep disturbances, nocturnal urine production and functional bladder capacity. So far it has not provided conclusive evidence of the pathophysiology of the phenomenon. It is possible that different factors may be predominant in different age groups. Although bedwetters are basically mentally healthy, several studies have shown that the problem may cause secondary emotional and social problems which can be alleviated with successful intervention. Of the treatment modalities currently available to the pediatrician, the most effective is the moisture alarm. Combined with its safety and low cost it should become the treatment of choice in most cases. Key words: Anti-diuretic hormone - Bedwetting - Imipramine - Nocturnal enuresis - Polyuria

Etiology

Genetics
Nocturnal enuresis is commonly a familial disorder with higher frequency in parents and siblings of bedwetters than in the general population [4]; The incidence in monozygotic twins is twice that in dizygotic twing [5, 6]. In 40% of enuretic children at least one of the parents was also enuretic and in 70% of children at least one other family member is or was enuretic [5-7]. The risk of enuresis in a child whose father was enuretic is 7.1 times greater than otherwise; the corresponding figure for a child of an enuretic mother is 5.2 [8]. In a study of 161 children raised in a kibbutz, in which children slept at hight separated from their parents and were toilet trained by someone other than their parents, 67% of enuretic children had enuretic siblings compared with 22% of the continent children [9]. This study illustrates the importance of genetics rather than family environment in the etiology of primary enuresis.

Bladder capacity
Introduction
Nocturnal enuresis is a common problem affecting 15% of 5-year-old children. Its natural history is of spontaneous resolution; its prevalence decreases to 7% in 10 year olds and to 1% in adults [1, 2]. The need for medical intervention is based on the emotional and social stigma associated with bedwetting as well as the inconvenience and possible family tensions it causes. The benign nature of the problem and its 15% spontaneous annual resolution rate [3] indicates that any kind of intervention must carry no risk and only minimal side effects and that it should have a cure rate significantly greater than the spontaneous cure rate before it is considered to be effective. This article will focus on nocturnal enuresis only and reviews the current data on etiology and the treatment modalities available to the pediatric nephrologist. Hallman [10] was the first to measure functional bladder capacities, studying 129 normal children and 63 enuretics following an oral water load. He observed that functional maximal capacity in enuretics was less than in the nonenuretics. Berger et al. [11] studied the bladder capacity in 132 children during cystoscopy or nuclear cystography. Bladder capacity correlated with age in a linear fashion between birth and 11 years. Based on their data they suggested the formula: bladder capacity (ml) = [age(years) +2] x32 ml ( _+64 ml SD) They next studied bladder capacities in 68 children with either primary enuresis, daytime frequency or infrequent voiding. Children of the latter group had bladder capacities larger than normal whereas those of the two other groups had smaller bladder capacities (Fig. 1).

whereas some overlap in bladder capacities between enuretics and non-enuretics was observed in older children.and sex-matched non- enuretic children. Close circles indicate children with enuresis and/or high daytime frequency (from ref [11] with permission) In the study by Vullimay [12] maximum bladder capacity was estimated from the single largest urine volume passed at one void. Readett and Morris [14] investigated the determinants of nocturnal enuresis in homozygous sickle cell (SS) disease by studying 16 enuretic and 16 age. Starfield [13] studied functional bladder capacity following oral water load in 221 enuretic children. 1. Non-enuretic bladder capacities were consistent with the formula later suggested by Berger et al. Maximum functional bladder capacity following oral fluid load in the non-enuretic children (395_+ 109 In]) significantly exceeded that of enuretic children (291 _+92. [11]. Solid line represents approximate expected bladder capacity and dashed lines indicate 95% confidence limits of predicted normal bladder capacity. Based on the results of their study.~ . In their patients Readett and Morris [14] found that in 10 of 14 in the enuretic group nocturnal urine volume exceeded maximum functional bladder capacity. 203 of their non-enuretic siblings and 92 unrelated nonenuretic children.005). Age compared with bladder capacity of children with voiding abnormalities.. they recommended the use of an enuresis alarm rather than anti-diuretic hormone (ADH) in patients with SS disease.J m I0 500 o o o / J / / O/ / O Q 200 0 0 . enuretic children had smaller bladder capacity compared with the two other groups.95 BOO25 O O 700 O o o O O O O 20 800 O / / o/ 500 0 O /o"j / o / /e / / E 400 mr" 0 o 0 0 0 W 0 ooo o / / / . Those of enuretic children were reduced. As a group.8 ml) (P < 0. Interestingly based on the mean age of the non-enuretic children of 10.01).4 / . . The difference in bladder capacity was clearer in children between ages 5 and 9 years. the estimated bladder capacity according to the formula of Berger et al.7 years 407 ml.4 /o J 5 o o /o I00 / / 0 I 2 J9 3 4 5 8 7 8 9 10 II 12 13 14 15 AGE ( Y E A R S ) Fig. [11] should have been 397 ml and that of the enuretic children with a mean age of 10.4 years. compared with only 1 of 14 in the non-enuretic group (P <0.

in the adolescent and young adult the expected normal response to a full bladder is waking up. Other studies did not find a correlation between sleep patterns and enuresis [24].5) 5 NS (62. This organ is also associated with the waking mechanisms [30].8. Indeed Boyd [28] compared arousability of 100 schoolage enuretic children with an age. This opinion is shared by Salmon et al. Therefore it seems that the factor of "deep sleep" and arousability are of limited importance in the young enurefic.6) P <0.3) l (6. Of the 100 enuretic children. 47 had a family history of enuresis.01 2 17 (53. Sleep level and the central nervous system Inoue et al. 32]. Recovery from nocturnal enuresis was almost always associated with normalization of maximum bladder capacity. Diurnal rhythm in urine flow was later demonstrated by Mills [22]. We recently investigated factors involved in nocturnal enuresis by interviewing 37 newly diagnosed children with insulin-dependent diabetes mellitus and their families [27]. Table 1.8) Urine volume It has long been known that nocturnal urine flow is diminished in normal subjects [22].8.and sex-matched control group.1 2 years (mean 8. 69 had a day/night ratio of less than 1. Ditman and Blinn [23] found in adults that nocturnal enuresis is not due to sound sleeping and that bedwetting can occur at any stage of somnolence. perhaps by different mechanisms.1 2 years (mean 7. although the latter tended to be higher in the enuretics. They found a delay in the age-related normal decrease in rhythmic slow electroencephalogram waves which they interpreted as possibly caused by immaturity of the sleep mechanism in enuretic children.05 (37. [25] studied 15 children with primary enuresis and 10 controls.05 11 30 (78. young children do not respond as well as do older children. at a time their diabetes was under good control. She speculated that low functional bladder capacity in bedwetters may be the result of nocturnal enuresis rather than its cause. Poulton [4] investigated 100 children aged 4 ." which is often familial with a high rate of spontaneous resolution.1 4 years. Berg et al. demonstrating equal bladder volumes at 40 cm water pressure. [20] did not find a correlation between the success of treatment with the alarm devise and maximum functional bladder capacity. It thus seems very possible that maturafional delay or abnormalities in the central nervous system may account for nocturnal enuresis in both the young child and the adult. rather than a unique phenomenon for children with nocturnal enuresis. However. It thus seems that the response to a full bladder by waking up is age dependent.4) 14 NS (93.96 Zaleski et al. As shown in Table 1. They found that enuretics had smaller maximum bladder capacities than non-enuretics. Similarly. [29] found that stimulation of the hypothalamic region causes contraction of the bladder. Fielding [21] did not find an increase in bladder capacity in those children successfully responding to treatment with a moisture alarm. significantly more of the younger children developed nocturnal enuresis. including altogether 67 enuretic relatives of whom 52 had recovered at the time of the study. This means that in the 1st decade of life not responding to a full bladder by waking up is the norm. This was demonstrated by studying the bladder capacities under general anesthesia.90 in the non-enuretics and there was no difference between the two groups with regard to nocturnal urine volume.5) (81. Bladder control and response to thirst in newly diagnosed children with diabetes mellitus Age (years) 4-8 Number Bedwetting (%) Up to drink (%) Daytime accidents (%) 8 7 P <0.8 years). The role of the central nervous system in bladder control is reflected by the higher rate of bedwetters among developmentally delayed children and those with low birth weight [8. The ratio was independent of age and the lowest day/night ratio was 1. The enuretic children's bladders were only functionally but not structurally smaller than the non-enuretic bladders. Increase in the small bladder capacity of enuretic children with successful treatment was reported by Troup and Hodgson [17]. maturation of neuronal pathways and the level of sleep. [26].3 years) with 24 nonenurefic children aged 4 . Readett and Morris [14] did not find a significant difference between enuretic and non-enurefic children with SS disease with regard to nocturnal urine osmolality or volume following water deprivation. .5) (14.3 times that excreted by night.93 in the enurefics and 1. Of these 69 children.1) 0 (0) 4 (10. Average day/night urine volume was 1. Martin [31] suggested that the fundamental defect in enuretic children concerns subcorfical centers controlling micturition. Hagglund and Parkulainen [16] demonstrated by cystometry a 34% increase in bladder capacity in children successfully treated with imipramine.5 s. All children returned to continence within 6 weeks. [15] studied 229 normal children and 75 enuretics aged 4 . Starfield and Mellits [18] and Esperanca and Gerrard [19]. All children were previously continent and 17 started to wet the bed concomitantly with the development of polyuria.005 (87. In the latter group he found that the volume of urine excreted by day was generally 2 . Poulton concluded that many of the enuretic children had "relative nocturnal polyuria.3) (45.1 6 years with enuresis and 18 continent children who served as controls.5) 3 P < 0.5) 8-12 12-18 Total 15 14 37 8 P <0. Ranson et al. The average time for non-enuretics was 20. Vullimay [12] compared urine volumes in 22 enuretic children aged 5 . It took the enuretic children on average 16 s to wake up in response to calling their name or gently shaking their shoulder.

Shaffer et al. Baker [44] found no difference between enuretic children and a control group in the results of a battery of psychological tests. the relapse rate and the long-term success rate. thus close monitoring during this period is recommended. Complete success has been suggested to describe those children who do not relapse within 2 years of their initial success.2% had a 75% or more reduction in wet nights.4% still wet the bed but only about half could be regarded as having primary enuresis. Poussaint and Ditman [49] canied out a double-blind. Couchells et al. In addition. individual and interpersonal distress. Relapses can be defined as more than 2 wet nights in 2 weeks. Imipramine In 1960 MacLean [48] was the first to suggest that imipramine might be of value in the treatment of enuresis. less anxious and more grown-up. Butler et al. confirming previous studies [34. A low longterm cure rate was also observed by Shaffer et al. on follow-up testing cured enuretics demonstrated improvement in their selfimage. Nearly all relapses occur within the first 6 months of treatment. Moffat et al. Marked improvement was observed with doses up to 75 mg after 10 years of age and 50 mg below that age. children who were slow to develop in their early life were slower to obtain nocturnal bladder control. such as increased happiness and outgoing behavior. Parents with a grade school level of education punished their bedwetting children at twice the rate of more educated parents. In general these children were reported to be happier. Treated children exhibited significant improvment in selfconcept. he defined initial successful response to therapy as 14 consecutive dry nights within 16 weeks of treatment. at the end of the follow-up period only 4. successful treatment also will result in many cases in improved family relationships. Poor outcome was associated with family difficulties which adversely influenced the rate of initial response. Treatment with imipramine was superior to placebo and dependent on dosage. Enurefic children displayed more problem and immatua'e behavior than their non-enuretic counterparts. only 24% of the children were completely dry off medication and another 19% were dry on continuous treatment. Successful treatment of bedwetting has positive psychological aspects. placebo-controlled study of imipramine in 47 enuretic children. and found that the majority of enuretic children were psychologically normal. [52] and Kunin et al. Maternal anger was associated with a greater drop-out rate. Since then numerous studies have been conducted to evaluate the medication. They did not find any correlation between bedwetting and psychosocial factors.7% were cured and another 30. .6 0 % [31. improved self-esteem and diminished worry. However. [38] found that there were no differences between enuretic and non-enuretic children in the number of stressful events in early life or the age at which toilet training commenced. [36] concluded that the etiology of primary enuresis is mainly biological and that psychosocial factors play little part. Higher doses do not seem to be more effective [50]. At 8 years of age 7. This opinion was shared by Forsythe and Merrett [51]. Fergusson et al. Naturally. [36] conducted an 8-year longitudinal study on 1. The relapse rate after discontinuing the medication was found to be 4 0 % . cure may have had beneficial effects on the parent-child relationship. In their extensive review of the effect of pharmacotherapy on nocturnal enuresis Blackwell and Currah [54] concluded that complete cure occurred in only a minority of patients. [40] also studied factors which may affect the outcome of treatment with an enuresis alarm.1990. 52].97 Behavioral and psychological aspects Werry and Cohrssen [33] evaluated 34 enuretic children with a mean age of 10 years and 34 control siblings of the same age. 37]. The change was greatest for those who had the largest decreases in wetting frequency. enuresis can result in psychological. However.265 children in New Zealand and found that at 5 years of age 15. [45] randomized 121 enuretic children to receive conditioning therapy or a 3-month waiting period. In addition. [42] found in an epidemiological study that parents reported that more than half of the enuretic children were distressed by this problem. The patient's motivation was found to be an important predicting factor to the success of intervention by Wagner et al. This group of researchers concluded that there may be mental health benefits in children successfully treated for bedwetting. Haque et al. It is recommended that future studies of treatment modalities for bedwetting rely on these criteria in order to enable comparison of their results with current data. Fireman [46] reviewed the psychological and behavioral aspects of nocturnal enuresis and concluded that most children who wet the bed are well-adjusted children from loving families. [35]. [43] found that parents of bedwetters were frequently intolerant of the need to change their children's bed sheets and of the smell of the wet bed. Of 106 children treated by Forsythe and Merrett [51]. Fergusson et at. There was no dif- ference in the anxiety scale or in parental rating of the child's behavior between the treated and untreated groups. Lack of evidence for an excess of behavioral disturbances in bedwetters was also noted by Hallgren [34] and Wagner et al. [39] studied predictive factors for treatment with moisture alarms. Based on articles published in the period 1969 . but both showed a trend for improvement with time. Treatment Recently Butler [47] tried to develop working definitions for nocturnal enuresis. A better response was predicted by the child's report of being teased by siblings. which may be a stressor in this age group. [53]. Martin [31] reported that a slow withdrawal decreases the relapse rate. Dische et al. Nonetheless. Foxman et al. Delvin and O'Cathain [41] found that family stress and degree of concern shown by the child were the most important prognostic factors.7% wet the bed. [35]. Children with a family history of enuresis attained bladder control significantly later than others. assuming responsibility and venturing into new activities.

whereas imipramine blocks these effects. its purpose was to improve nursing care in children's wards [58]. Less common but more serious side effects include acrocyanosis [55] and sudden death [56]. In 9 patients nocturnal urine production exceeded bladder capacity. while the other half regularly slept through. [64] measured AVP concentrations during the diurnal cycle in eight recumbent healthy young male adults. Young [58] tabulated the results of 18 studies conducted between 1938 and 1964 on a total of 1. Success rates ranged between 63% and 100% (average 83%) and relapse rates between 9% and 52% (average 23%). 59] the subjects were those who failed to respond to previous interventions. They suggested that the dietary restrictions eliminate factors in the diet which can cause an increase in bladder tone and diminution in bladder capacity. convulsions and lethal cardiotoxicity.000 ml and another of 5. this study was recently criticized by Fefferman [66] for the possibility that the enuretics may have had a higher fluid intake in the evening. . Moisture alarm The original moisture alarm apparatus was made in 1904 by Pfaundler. One patient had a 24-h urine output of 4. a brief period of supplemental therapy with imipramine was recommended.m. Individual data on AVP values were not provided. Within 3 months. Meadow [62] reported his experience with the moisture alarm in 100 enuretic children: 85% became dry within 4 months of therapy.1 2 p. For the whole group there was a trend for AVP to decrease in the period 8 . Once they became dry the great majority of children slept throughout the night. with only a relatively few children still getting up at night to void. Baker [44] compared the effect of the conditioning device with a waiting list period and a wake-up treatment. [65] assessed diurnal ADH levels in 11 enuretics (aged 14-39 years. A very similar relapse rate and response to extended treatment was observed by Forsythe and Redmond [61].635 patients. namely that it made no difference whether the drug was withdrawn suddenly or gradually. The response of urination is inhibited by waking and this inhibition of micturation by a conditioning process ultimately occurs spontaneously without the necessity for awakening. [63] concluded that bladder capacity is a major factor in enuresis and that urine volumes which exceed bladder capacity at night may be caused by lack of the anticipated normal increase in nocturnal AVR The conditions under which the study were conducted are not specified. Delvin and O'Cathain [41] found a 84% initial success rate of the moisture alarm in 96 enuretic children. Norgaard et al. A fluid deprivation test performed in 4 subjects showed a normal decrease in urine output and increase in both urine osmolality and AVR Six patients had reduced bladder capacity as measured by cystometrics. Treatment consists of associating the same stimulus with a wakening stimulus caused by activation of the alarm when urination starts. Eleven children (12%) relapsed and required further treatment.1 3 years and found that when combined with a restricted diet the cure rate with imipramine was 60%. the majority during the first 2 months. 67% were cured and by the end of 12 months of therapy 92% were cured. 1 patient 7 years) in relation to urine production and functional bladder capacity. but most relapsers responded to a second course of treatment with the moisture alarm. Treatment with imipramine may be associated with side effects. which include restlessness. however a significant increase in serum osmolality preceded the peak of AVP in every individual. This increase in secretion was not associated with changes in blood sugar or sodium concentration. constipation and loss of weight [31. headache. in particular whether fluid or alcohol consumption was permitted during the evening hours. [63]. In the first 4 months of dryness about half the children got up at night to go to the lavatory. The conditioning treatment was found to be superior to the two other approaches. most of them minimal. Esperanca and Gerrard [19] studied 50 children aged 4 . The relapse rate was 10% with most relapses responding quickly to reinstitution of treatment with the alarm. George et al. 4 patients had a decrease in urine production during the night. abdominal pain. In many of these series [58. sleep disturbances. hnipramine overdose is known to cause coma. of whom 9 achieved full dryness again. 49]. difficulty with concentration. Dische [60] treated 84 enuretic children with the moisture alarm device. already showed marked improvement (decrease in number of wet nights) long before their treatment ended. especially in young children [57].98 [52] demonstrated the opposite. Young himself [58] compared the effect of the alarm apparatus with that of a variety of medications in 68 consecutive new patients 4 . In six subjects a significant increase of 140% in nocturnal AVP was observed.125 ml. then the "corrected" success rate of that series would have been 92%. In a few cases in which the alarms failed to waken the child. Moreover they found that children who became continent at night were those who demonstrated an increase in bladder capacity which was even greater when accompanied by the hypoallergenic diet. Its regular use over a period of time had a beneficial effect on enuresis. 6 had an increase and in 1 patient the ratio was close to one. Many of those who were cured with long-term treatment Desmopressin Following the development of a reliable radioimmunoassay for plasma arginine vasopressin (AVP) by Robertson et al.1 5 years of age. The theory of the conditioning process of the enuretic child by this treatment has been well described [58]: the enuretic child responds to the stimulus of a full bladder by urination. Parental and child cooperation were found to be essential for the success of treatment. Indeed. The relapse rate in the series of Dische [60] was 30%. Norgaard et al. If only the 6 patients who did not awake to the sound of the alarm were regarded as failures (1 of the children was partially deaf). The main reason for failure of the moisture alarm was lack of parental cooperation. The success rate was significantly higher with the alarm device: 65% versus 26%.

weight. Total range is shown. together with hatched areas with median value and first quantile on each side. 2).5 times interquantile length are plotted as individual points (from ref [65] with permission) In another study by the same Danish group.5 SD) and 10 enuretics aged 6 . 2. 4o 0 L~. 0 _ 2.. L i . no decrease in nocturnal urine volume nor increase in osmolality were observed in urine collections obtained by transurethral catheters from the enuretics.4• mU/h).1 0 years (mean 6 .5+2.and sex-matched non-enuretic adolescents. Enuretic children demonstrated reversal of the circadian rhythm with a daytime ADH excretion rate of 2.05).1 4 years (9. This increase was less pronounced in the enuretics and reached significantly lower levels compared with controls. i i ii 7A_J: 0 | | $ I I ~m i .8 • 5 mU/h) was significantly lower than their nighttime rate (3. ' i T? 8am 12am 4pro 8pro 12pro 4 lm aam Sampling Time Fig. There were no differences between the groups with respect to total 24-h urine volume and functional bladder capacity. [67] speculated that the lack of diurnal rhythm in their enuretic population may be attributed to a defect or delayed maturation of the circadian rhythm. . The normal children's daytime urinary ADH excretion rate (1. In the normal subjects a significant increase in nocturnal AVP was noted.m 1 | i | i L 0 J i I ! w q~ . Diurnal concentrations of plasma vasopressin (PAvP) studied twice in 11 non-enuretic normal subjects (D) and 15 patients with enuresis ( ~ ) . P <0. Puff [68] studied urinary ADH excretion rates in 5 normal children ages 4 . Ritting et al.99 i s i . Extreme values exceeding 1. although some overlapping between the two groups was observed (Fig. Rittig et al. Contrary to controls.8 years..8) years with 11 age-. [67] compared 15 enuretics aged 11-17 (mean 13. .8-t-5 mU/h and a nighttime rate of .

Aladjem et al. but about half relapsed after the medicine was stopped. Side effects were infrequent. [80] reviewed all 18 randomized controlled trials of DDAVP published in the English literature. disorientation. such as in the child who fails to respond to other therapies or the child who needs an intervention that works quickly and for a short period of time. generalized seizures and coma [82-85]. Dimson [70] suggested that DDAVP acts largely by anti-diuresis and speculated that failures could be attributed to increased fluid intake in the evening hours and/or either non-compliance with the DDAVP or impaired absorption of the medicine. Comparitive studies Wagner et al. Treatment with DDAVP resulted in increased urine osmolality in 12 children.500. but the children were able to normally concentrate their urine in response to dehydration. He recommended a strict fluid restriction in enuretics instead of DDAVR There have been a few reports of hyponatremia in children treated with DDAVP [82-84]. Less serious side effects of DDAVP treatment included transient headaches.4 mU/h. rhinitis.032-t-147 mosmol/kg H20 before treatment and 1. 10 non-responders and 8 controls. Miller et al. According to Miller et al. In 6 children in this group 12-h day and nighttime urine collections showed lack of diurnal variations. Their conclusion was supported by Rappaport [81] who recommended using DDAVP for special situations. 74].U. conjunctivitis. However. A negative family history was associated with poor response. However. Children over 10 years fared better than younger children. but only about half remained dry after stopping therapy.2 0 gg DDAVP/day. The best results were achieved if urine osmolality increased beyond 1. osmolaiity and vasopressin concentration between 8 responders. [77] a complete successful course of therapy with DDAVP costs approximately U. only 4 remained dry after discontinuing therapy. [78] found that with long-term low-dose DDAVP treatment 54% of children were dry. Key et al. Serum electrolytes measured in some of the patients were normal. Of 20 enuretic children treated with 10 gg DDAVP in a nasal spray each evening. In a later double-blind cross-over study of 20 gg DDAVP versus placebo in 17 children aged 6 . [72] studied 22 enuretic children: following discontinuation of DDAVP therapy 7 children remained dry. Based on their analysis. chills. dizziness. The long-term treatment was well tolerated in both studies.006• mosmol/kg H20 during DDAVP treatment. Birkasova et al. Tuvemo [71] conducted a double-blind study on 18 children aged 6 .S. there was a partial response in another 8. Children with a positive family history responded better than those without a family history of enuresis.000 mosmol/kg H20. Moffatt et al. [73] speculated that the effect of DDAVP may not be mediated through a decrease in nocturnal urine output but through other possible effects of DDAVP on the central nervous system [73.S. Of the 21 dry responders. one should note that in this study children treated with the moisture alarm were seen in the . Response to treatment was significantly better in children older then 10 years. These trials included a total of 580 subjects treated with DDAVR Despite a significant decrease in wet nights. 2 children became completely dry and another 5 showed marked improvement on DDAVP compared with none on the placebo [70]. Results were significantly poorer if urine osmolality failed to reach 1. 84]. Recently Moffatt et al. reporting a 21% cure rate. epistaxis. Success rate with the former was 83% compared with 33% for the latter and 8% for a control waiting list. with discontinuation of the treatment the children relapsed. Dimson [69] was the first to try desmopressin (DDAVP) for nocturnal enuresis in children. less than enuretics.100 1. there was a tendency for the responders to have higher baseline urine volumes and lower osmolalities and urinary vasopressin concentrations. However. Fefferman [66] recently pointed out that children with central diabetes insipidus require only 5 . The role of family history in predicting response to DDAVP was studied by Hogg and Husmann [76]. Children were given 20 gg DDAVP or placebo for 28 days.5___0. Only 4% remained dry after stopping treatment.000 . nausea and abdominal pain [80. The serum sodium concentration remained normal. Urine osmolalities measured on second-morning urine specimens were 1. In general there seemed to be a dose-response effect. $1. Discontinuation of the medication resulted in relapse. Some of these children developed neurological symptoms. Children older than 9 years fared better than younger children. [80] concluded that treatment with DDAVP is inferior to a conditioning alarm. Long-term outcome of the patients was not reported. with a significant correlation between high urine osmolality and success of treatment. Only one study addressed directly long-term outcome after stopping DDAVP. These authors found no statistical difference in nocturnal urine volume. There was no difference between the groups with respect to daytime urinary ADH. When DDAVP was stopped most children reverted to bedwetting. only 25% achieved short-term dryness. including headaches. 11 became completely dry and another 4 mostly dry. Recently Evans and Meadow [79] reported that only 18% of 55 children treated with DDAVP became completely dry after 1 month of therapy and 11% after 3 months of therapy. nostril pain. The effect of age on the short-term response to DDAVP was also reported by Post et al. [75] who found that children over 9 years responded much better to treatment than did younger patients. Results were excellent in 8 children. [35] compared the moisture alarm with imipramine treatment.7% long-term cure rate. nasal congestion. Aladjem et al. [77] treated and followed 55 children over a long period of time and found that 28 (51%) became completely dry.000 mosmol/kg H20 or if it was already this high before treatment. [73] studied the effect of DDAVP in 15 children of whom 6 stopped bedwetting entirely and another 6 partially. but enuretic children had a significantly lower nocturnal urinary ADH excretion rate.1 2 years with primary nocturnal enuresis. $1. Three other studies which indirectly reported on this matter observed a 5.1 3 years who previously failed to respond to drugs or an enuresis alarm.

Interestingly. The etiology of bedwetting is still unknown. hypothalamic activity resulting in reduced secretion of AVP [90]. Treatment with DDAVP is Miscellaneous causes and treatments o f nocturnal enuresis There have been several reports implicating uncommon. The decrease in urine osmolality during treatment with the moisture alarm was explained by relaxing the restrictions on the evening fluid intake in the successfully treated subjects. The major question in this age group is why these patients do not wake up in response to the full bladder as is expected. compared with 87% for the alarm. Thus intervention is justified. [87] randomized 28 children with primary nocturnal enuresis to a combination of moisture alarm plus 20 gg DDAVP or alarm and placebo for 2 weeks. While the medication is very successful in children with uninhibited bladder contractions. The question here is whether the small functional capacity is the cause or the result of bedwetting. [73] could be due to the fact that they measured urine osmolality late in the morning whereas Wille measured it at 5 a. Conclusions and recommendations Bedwetting is essentially a benign condition but it may cause a considerable amount of distress for the child and the parents. Is it a functional part of the phenomenon or is it an acquired behavior after many years of bedwetting? In the younger child most studies have shown reduced bladder capacity which normalized with successful treatment. whereas morning urine osmolality increased with DDAVP it decreased during treatment with the moisture alarm. The reported long-term success rate of treatment with DDAVP (25%) is close to the spontaneous cure rate and may be similar to that of intervention limited to behavioral modification and moral support. Weider et al. there is not enough experience with its use in primary enuresis. This may indicate that the moisture alarm device does not operate on decreasing nocturnal urine output and that this factor in general is of lesser importance in the pathophysiology of nocturnal enuresis. [91] reported on a mixed group of 22 children with nocturnal or diurnal enuresis who were found to be constipated too. It is apparent that genetics plays a role in the majority of children with bedwetting and that the etiology and the key to successful treatment reside in the central nervous system.4 dry nights per week compared with 4. This anti-spasmodic agent exerts a direct effect on the smooth muscle. depriving the bladder of the stimulus to increase its capacity. The improvement rate was 70% in the group given DDAVP and 86% in the group treated with the alarm. relax and allow storage of a larger urine volume until the morning. resulting in its relaxation and consequently increased bladder capacity. Nine of the children were subjected to a placebo-controlled doubleblind reintroduction of provoking foods. Based on the information currently available. it also explains the low cure rate of treatment with DDAVR With this latter treatment nocturnal urine volume decreases. with cross-over.4 dry nights per week with the alarm and placebo (P <0.1 __0. If indeed this is the mechanism by which the child is taught how to be able to hold a larger urine volume. This has also been our experience. leaving the long-term success rate with DDAVP at 42%. based on the psychosocial benefits to the child and his family. Aggressive treatment of the constipation with enemas resulted in marked improvment in bladder control. They mention that although it has been shown by Esperanca and Gerrard [19] that treatment with a restrictive diet can result in expansion of a small bladder.101 clinic for follow-up much more frequently than children in the two other groups. O'Regan et al. Oxybutynin chloride is often used in children with voiding dysfunction due to increased intravesical pressure resulting from uninhibited contractions of the detrusor muscle.1 +_0. treatable causes for bedwetting. significantly more patients on DDAVP relapsed compared with those treated with the moisture alarm. In 12 of these children who developed the enuresis at the same time as the symptoms of upper airway obstruction the cure rate of bedwetting following surgery was 100%. In the older child and the young adult it seems that nocturnal polyuria. Wille [86] argues that the lack of increase in urine osmolality during DDAVP treatment observed by Aladgem et al. possibly due to insufficient secretion of ADH. results in bedwetting. The combined therapy resulted in 5. However. Researchers using the moisture alarm report that once the child is cured usually he or she does not get up at night to void but rather stays asleep all night long. 6 relapsed during testing with the incriminated foods and none with placebo.05). Sukhai et al. It therefore can be speculated that the conditioning treatment is based on enhancement of the maturation of the elements in the central nervous system which command the bladder wall to inhibit its contractions. Evidently future studies addressing the effect of the different treatment modalities on urine osmolality will have to take into consideration the timing of the urine specimen. During treatment with DDAVP morning urine osmolality (987 +_46 mosmol/kg H2 O) was significantly higher than in the placebo group (841 _+49 mosmol/kg H20). there are also reports indicating high volumes of dilute urine during migraine attacks which may be due to altered . this end result has not been attributed to a decrease in nocturnal urine volume but rather to an increase in functional bladder capacity. The authors were not sure whether the findings from their selected population can be projected to the child with primary enuresis. [89] noticed cure or improvement in bedwetting when children were treated with a restrictive diet for migraine and/or hyperkinetic behavior. [88] reported that in 115 children with symptoms of upper airway obstruction and nocturnal enuresis surgical relief of the upper airway obstruction resulted in significant improvement in bedwetting. Wille [86] randomized 46 children with primary nocturnal enuresis to receive DDAVP or moisture alarm.m. Egger et al. It is possible that nocturnal enuresis is the final common pathway of several abnormal neurological pathways.

Starfield B (1967) Functional bladder capacity in enuretic and nonenuretic children. Hallgren B (1960) Nocturnal enuresis in twins. Woodward V. Low long-term success rate has also been reported by most researchers studying the role of imipramine. Arch Neurol Psychiatry 33:467-477 30. Moreover. $ 50. Dev Med Child Neurol 24:479 38. The child should be asked to keep a record of the dry and wet nights and should be praised by his parents and caregivers for his success and may be rewarded [93]. Reassuring the child and his parents.S.0% of enuretic children were treated with this method [33]. In: Kolvin I. Acta Psycho1 Neurol Scand 35:73-77 7. pp 95-109 16. Tsukahara N. J Pediatr 101:302-307 36. The current price in the United States for a moisture alarm device is U. Hallgren B (1958) Nocturnal enuresis: aetiologic aspects. Philadelphia. Hodgson NB (1971) Nocturnal functional bladder capacity in enuretic children. Philadelphia. J Pediatr 72:483-487 19. Johnson SB. Meadows SR (eds) Bladder control and enuresis. Lippincott. Gerrard JW. Tajika Y. MacKeith RC. Berg I. Ditman SK. and the child and his family need to receive ongoing professional advice and encouragement. Parkulainen KV (1964) Enuretic children treated with imipramine (Tofranil): a cystomeuic study. advising both how to handle the problem. Rider RV (1968) Social. pp 39-46 4. Mellits E (1968) Increase in functional bladder capacity and improvement in enuresis. Forsythe I. Kaffman M. Philadelphia. Brewin CR. preoptic region and septum. Salmon MA. Ann Pediatr Fenn 11:53-59 17. Pediatrics 42:627-641 33. safe and inexpensive. In the child treated with a moisture alarm he or she needs to be actively involved and assume full responsibility for the treatment. Arch Dis Child 57:394-396 21. Behav Res Ther 18:305-317 22. Firlit FC (1983) Bladder capacity (ounces) equals age (years) plus 2 predicts normal bladder capacity and aids in diagnosis of abnormal voiding patterns. After initial evaluation by a physician. Starfield B. The parents are advised not to punish the child for wetting but to express their hope for improvement. Couchells SM.153 9. Hagglund TB. Acta Paediatr Scand 77:148 . Treatment with the moisture alarm is effective. Esperanca M. Johnson SB. DDAVP may be indicated for acute short-term purposes. Howard CP (1992) Urine volume. J Child Psychol Psychiatr 29:501-509 References 1. The child should be responsible for changing the bed clothes. Acta Paediatr 39:87-93 11. Taylor DC. Cohrssen J (1965) Enuresis . pp 78-83 25. Karbat H. Harper PA. De Jonge GA (1973) Epidemiology of enuresis: a survey of the literature. Shokeir MHK (1973) Nocturnal enuresis: the importance of small bladder capacity. Philadelphia. Alon U. Weir K (1982) Night and day wetting amongst a population of three-years-old. Lee D (1973) On the EGG in enuresis. Poulton ME (1952) Relative nocturnal polyuria as a factor in enuresis. MacKeith RC. J Psychosom Res 4:274-281 29. Lancet II: 133-135 31. In: Kolvin I. J Pediatr 67:423-431 34. Meadows SR (eds) Bladder control and enuresis. treatment with imipramine carries a higher risk of complications for the child and his younger siblings. Lippincott. Lippincott. Vikevalnen-Tervonen L. Walker D. J Pediatr 99:812-816 39. Arch Dis Child 65:615-618 15. Meadows SR (eds) Bladder control and enuresis. Fergusson DM. Chiba H. Conway JJ.102 very expensive relative to other modalities. MacKeith RC. Graham P (1973) Depth of sleep and enuresis: a critical review. Pediatr Clin North Am 34:719-732 2. Meadow SR (eds) Bladder control and enuresis. Forsythe WI (1988) A comparison of two approaches to the treatment of nocturnal enuresis and the prediction of effectiveness using pre-treatment variables. Blinn AK (1955) Sleep levels in enuresis. Am J Psychiatry 111:913-920 24. psychological and neurological factors associated with nocturnal enuresis. Zaleski A. J Pediatr 70:777-781 14. Moilanen I. Vullimay D (1956) The day and night output of urine in enuresis. MacKeith RC. Bakwin H (1973) The genetics of enuresis. Oppel WC. Huttunen NP (1988) Enuresis in seven-year-old children. pp 78-83 27. In: Kolvin I. pp 73-77 6. Meadow SR (eds) Bladder control and enuresis. Werry JS. Walker D (1981) Behavioral and environmental characteristics of treated and untreated enuretic children and matched nonenuretic controls. Boyd MM (1960) The depth of sleep in enuretic school children and in non-enuretic controls. J Physiol 113: 528 -536 23. Ranson SW. Philadelphia. treatment of the uncomplicated primary enuretic child can be carried on by other health professionals trained and motivated to take care of children with the problem [92]. Carter R.an etiologic and therapeutic study. Acta Paediatr [Suppl] 118:66-44 8. It should be at the forefront of therapy. Hallman N (1950) On the ability of enuretic children to hold urine. Fitzwater D. Strom-Olsen R (1950) Enuresis in adults and abnormality of sleep. Clin Pediatr (Phila) 308-310 3. Moran CG. Monogr Soc Res Child Dev 42: 2-12 10. Inoue M. Wittner J (1982) A controlled comparison of two treatments for nocturnal enuresis. Elizur E (1977) Infants who become enuretics: a longitudinal study of 161 Kibbutz children. Novello JR (1987) Enuresis. Child Hosp Q 4: 157-160 28. Lippincott. Taka K (1987) Rhythmic slow wave observed on nocturnal sleep encephalogram in children wkh idiopathic nocturnal enuresis. focusing the child's attention on the problem and checking regularly on the child's progress is an important part of any kind of intervention for bedwetting. Lancet II: 906-907 5. $ 4 0 . Novello AC. In: Kolvin I. 13. Horwood LJ. Hons BA. Jarvelin MR. Acta Psychiatr Neurol Scand 32 [Suppl 114]: 1-159 35. Sleep 10:570-579 26. Success ultimately depends on the child's motivation. S . Pediatrics 78:884-890 37. Mills JN (1951) Diurnal rhythm in urine flow. Arch Dis Child 31:439-443 . J Urol 105: 129-132 18. Magoun HW (1935) Autonomic responses to electrical stimulation of hypothalamus. Carter R. Martin IG (1971) Imipramine pamoate in the treatment of childhood enuresisl Am J Dis Child 122:42-47 32. Gerrard JW (1969) Nocturnal enuresis. A recent survey reported that only 3. J Urol 129:347-349 12. Shimojima H. Macknin ML (1992) Risk/benefit ratio in enuresis therapy. In: Kolvin I. Maizels M.U . Morris J (1990) Determinants of nocturnal enuresis in homozygous sickle cell disease. Fielding D (1980) The response of day and night wetting children and children who wet only at night to retention control training and the enuresis alarm. Butler RJ. Shannon FT (1986) Factors related to the age of attainment of nocturnal bladder control: an 8-year longitudinal study. Readett J. Tronp CW. Berger MR. Can Med Assoc J 101:721-724 20. Hallgren B (1957) Enuresis: a clinical and genetic study. Wagner W. MacKeith RC. 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