Pediatric Annals

Primary Nocturnal Enuresis: Current Concepts About an Old Problem

Bradley A Warady, MD; Uri Alon, MD; Stanley Hellerstein, MD

Abstract

Primary nocturnal enuresis is a problem that has confronted pediatricians for years. In feet, descriptions of bed-wetting have been found in literature dating back to 1500 BC.1 Despite the long history of experience with this disorder, a definitive etiology and treatment plan remains elusive. However, recent studies have provided us with greater insight about these issues.2'"1 This article offers a practical approach to the child with primary nocturnal enuresis emphasizing the current concepts in the etiology and management of this disorder.

VOIDING PHYSIOLOGY

The normal development of urinary control follows a characteristic pattern in children, but at a somewhat individual rate. The attainment of the developmental "milestones" of urinary control appear to be the result of central nervous system maturation.5 The ages these "milestones" typically occur are:

* Birth to 6 months. Bladder emptying occurs frequently throughout the day and night as an uninhibited reflex action.

* 6 months to 1 2 months. Bladder emptying becomes less frequent due to central nervous system inhibition of reflex action.

* 1 to 2 years. The child consciously perceives Madder fullness, and central nervous system inhibition of bladder contractions and micturition increases.

* 3 to 5 years. Usually by the age of 5, the child's awareness of bladder fullness has increased, and the child has developed the ability to inhibit the need to void both voluntarily and unconsciously. This ability to consciously control voiding continues to develop until the child can control voiding at any degree of bladder fullness.

Control over urination is achieved earlier by girls than by boys. A useful operational definition for nocturnal enuresis is bed-wetting at least once weekly in a girl older than 5 or in a boy older than 6.6 Primary nocturnal enuresis is characterized by nocturnal enuresis without a period of dryness for 6 months or longer. Nocturnal enuresis is considered secondary when it occurs following an extended period without bed-wetting (ie, 6 months to 1 year). Approximately 80% of all nocturnal enuresis is primary. Daytime (diurnal) enuresis can occur with primary or secondary enuresis but is often indicative of some other form of voiding dysfunction or significant underlying pathology.

EPIDEMIOLOGY

It is generally accepted that nocturnal enuresis occurs in approximately 15% of 5 to 6 year olds, making it one of the most frequent problems brought to the pediatrician/family practitioner.' The spontaneous cure rate is 15% per year after the age of 5. It is estimated that only 1% of adults are enuretic.6 Nocturnal enuresis is more common in boys than in girls. In some studies, the prevalence correlates with social class, and it is commonly found in institutionalized children. There is good evidence for a genetic factor because enuresis is much more likely to occur in children whose parents were bed-wetters than in those without this history. As many as 77% of children are enuretic when both parents had a similar history in contrast to the 1 5% incidence when neither parent was enuretic.8

WHY THE CONCERN?

Nocturnal enuresis may be the only clinical problem in pediatrics in which there is usually spontaneous resolution without untoward side effects, but which regulatly affects the emotions and behavior of affected children and their parents. Without question, nocturnal enuresis is not a "socially acceptable behavior," and its significance is often magnified. Foxman et al9 found that two thirds of parents of children with nocturnal enuresis worried about their children, and more than one half of the children were found to be distressed by the problem. Haque et al10 found that parents of bed-wetters were frequently intolerant of the need to change their children's bed sheets and of…

Primary nocturnal enuresis is a problem that has confronted pediatricians for years. In feet, descriptions of bed-wetting have been found in literature dating back to 1500 BC.1 Despite the long history of experience with this disorder, a definitive etiology and treatment plan remains elusive. However, recent studies have provided us with greater insight about these issues.2'"1 This article offers a practical approach to the child with primary nocturnal enuresis emphasizing the current concepts in the etiology and management of this disorder.

VOIDING PHYSIOLOGY

The normal development of urinary control follows a characteristic pattern in children, but at a somewhat individual rate. The attainment of the developmental "milestones" of urinary control appear to be the result of central nervous system maturation.5 The ages these "milestones" typically occur are:

* Birth to 6 months. Bladder emptying occurs frequently throughout the day and night as an uninhibited reflex action.

* 6 months to 1 2 months. Bladder emptying becomes less frequent due to central nervous system inhibition of reflex action.

* 1 to 2 years. The child consciously perceives Madder fullness, and central nervous system inhibition of bladder contractions and micturition increases.

* 3 to 5 years. Usually by the age of 5, the child's awareness of bladder fullness has increased, and the child has developed the ability to inhibit the need to void both voluntarily and unconsciously. This ability to consciously control voiding continues to develop until the child can control voiding at any degree of bladder fullness.

Control over urination is achieved earlier by girls than by boys. A useful operational definition for nocturnal enuresis is bed-wetting at least once weekly in a girl older than 5 or in a boy older than 6.6 Primary nocturnal enuresis is characterized by nocturnal enuresis without a period of dryness for 6 months or longer. Nocturnal enuresis is considered secondary when it occurs following an extended period without bed-wetting (ie, 6 months to 1 year). Approximately 80% of all nocturnal enuresis is primary. Daytime (diurnal) enuresis can occur with primary or secondary enuresis but is often indicative of some other form of voiding dysfunction or significant underlying pathology.

EPIDEMIOLOGY

It is generally accepted that nocturnal enuresis occurs in approximately 15% of 5 to 6 year olds, making it one of the most frequent problems brought to the pediatrician/family practitioner.' The spontaneous cure rate is 15% per year after the age of 5. It is estimated that only 1% of adults are enuretic.6 Nocturnal enuresis is more common in boys than in girls. In some studies, the prevalence correlates with social class, and it is commonly found in institutionalized children. There is good evidence for a genetic factor because enuresis is much more likely to occur in children whose parents were bed-wetters than in those without this history. As many as 77% of children are enuretic when both parents had a similar history in contrast to the 1 5% incidence when neither parent was enuretic.8

WHY THE CONCERN?

Nocturnal enuresis may be the only clinical problem in pediatrics in which there is usually spontaneous resolution without untoward side effects, but which regulatly affects the emotions and behavior of affected children and their parents. Without question, nocturnal enuresis is not a "socially acceptable behavior," and its significance is often magnified. Foxman et al9 found that two thirds of parents of children with nocturnal enuresis worried about their children, and more than one half of the children were found to be distressed by the problem. Haque et al10 found that parents of bed-wetters were frequently intolerant of the need to change their children's bed sheets and of the smell of a wet bed. In almost 95% of cases, the problem was addressed by the family in some manner, reflecting its importance.

The child who seeks help with the problem of nocturnal enuresis is more commonly one who is under a great amount of stress- Many studies, some good and some less reliable, have addressed the effect of successful treatment on the self-concept of the child with nocturnal enuresis. The majority of studies suggest that children older than 8 manifest a significant improvement in self-concept following the resolution of enuresis.11 Accordingly, an active approach to this problem is warranted. Despite the belief of some that nocturnal enuresis is the result of an emotional disturbance, most children with bedwetting are normal and do not have psychiatric problems.

WHY DOES IT HAPPEN?

The exact cause of nocturnal enuresis is as yet unknown and is reflected by the numerous therapeutic approaches that exist. However, several factors are known that by themselves or jointly may result in bed-wetting.

Small Bladder Capacity

A less than normal functional bladder capacity may be present in some children with nocturnal enuresis.12'13 A relatively large volume of urine formed in the night can in turn predispose to bed-wetting. The normal bladder capacity is calculated in ounces as the age in years plus two.12 For example, the expected bladder capacity of a 7-year-old child is 9 ounces. Normal adult bladder capacity is 12 to 16 ounces (360 to 480 mL).

Nocturnal Polyuria/ Relative Vasopressin Deficiency

The concept of relative nocturnal polyuria leading to the development of enuresis was initially proposed approximately 40 years ago, but was largely ignored.1"1 However, recent studies by Norgaard et al have provided additional data that support this concept.2 These investigators found that the bladder capacity of older children with nocturnal enuresis was normal, but that nocturnal urine output was markedly greater than daytime urine production and exceeded the functional bladder capacity. The etiology of the polyuria in some patients may be insufficient nighttime plasma levels of vasopressin, the antidiuretic hormone. Of greater importance may be the presence of an abnormal diurnal rhythm of this hormone so the normal increase in the nighttime level of vasopressin and the associated decreased urine production is not present.2,3 The result is the production of an excessive amount of poorly concentrated urine at night.

Impaired Arousal

Whether a child has a less than normal functional bladder capacity or produces excessive urine because of relative vasopressin deficiency, it is the child's inability to sense a full bladder and awaken that results in nocturnal enuresis. This may be the result of a maturational delay in the central nervous system that resolves with time. However, although a maturational delay may be postulated as a cause for bedwetting in the 6 or 7 year old, it seems an unlikely explanation for nocturnal enuresis in older children. While previous studies suggested that patients with nocturnal enuresis were "deep sleepers," more recent data have demonstrated that nocturnal enuresis is independent of sleep stage and can take place during both light and deep sleep.15

EVALUATION

Most children with nocturnal enutesis have neither an organic nor a psychiatric illness. Accordingly, excessive investigation should be discouraged. The typical child with uncomplicated nocturnal enuresis has a history of bed-wetting from infancy on, but with a normal daytime voiding pattern. There is often a positive family history of nocturnal enuresis and the absence of a history of urinary tract infections. However, just as "all children who wheeze don't have asthma," all children who wet the bed don't have uncomplicated nocturnal enuresis. The "investigation," which consists primarily of a complete history and physical examination, should detect the majority of children with "complicated" enuresis. The Table outlines the points that should be addressed with the history and physical examination and their clinical relevance. A urinalysis should be performed in all enuretic children in order to rule out the presence of a urinary tract infection, diabetes mellitus, or an active urinary sediment that may suggest the presence of underlying kidney disease. Only when abnormal findings are noted from the history and physical examination or a urinalysis should imaging studies (eg, intravenous pyelogram, renal ultrasound, and voiding cystourethrogram) and a urodynamic evaluation be considered.

Table

TABLEEvaluating Children With Nocturnal Enuresis

TABLE

Evaluating Children With Nocturnal Enuresis

TREATMENT

The treatment of the child with nocturnal enuresis should, in all cases, emphasize education about the problem and the correction of misconceptions. The need for education was emphasized in one study that revealed between 30% and 70% of parents punish their enuretic child for a disorder which is completely beyond the child's control.10 In the authors' experience, punishment has ranged from having the child sleep in a chicken coop or a bathtub to outright physical abuse. Thus, it is imperative for the care provider to understand the perceptions of the family and to correct these perceptions when necessary. The child requires and deserves reassurance about the problem and factual information as to its cause and likely course. The parent and child should be informed that there is no underlying kidney abnormality and the problem will most likely resolve with time. The older child should assume responsibility for the bed-wetting and its consequences while treatment regimens are being introduced since the problem is the child's and not the parents' problem. Specifically, any assistance the child can give his or her parents with laundering of bed linens will improve the overall family atmosphere. As mentioned previously, parents can be intolerant of the regular need for laundering and the smell of a wet bed. The child's participation in this endeavor can improve the family's perception of the situation and lead to the provision of family support that the child requires. Dedicated interest and support exhibited by the pediatrician is also extremely valuable. This "motivational counseling" approach has resulted in significantly fewer episodes of nocturnal enuresis in more than 70% of patients studied and should be used in conjunction with any of the other treatment regimens mentioned below.16

The two treatment options that are currently recommended most frequently for patients with nocturnal enuresis are conditioning therapy (eg, signal alarm system) and pharmacologie therapy.

Conditioning Therapy

Conditioning therapy centers on the use of a signal alarm device. This device consists of a moisture sensor and a buzzer that is attached to the child's pajamas. As opposed to the previously used bell and pad alarms, these devices no longer are associated with ulcerations of the skin and perineum. As a conditioning device, the alarm is designed to wake the child as soon as he or she begins to void in bed. In this manner, the alarm "teaches" the child to become aware of the sensation of a full bladder and to awaken to void. When used by children for 3 to 4 months and with the help of ongoing support from the family and the health care provider, success rates as high as 70% can be achieved. Current systems include the Nytone Alarm (Nytone Medicals Products, Salt Lake City, Utah) and the Wet Stop Alarm (Palco Laboratories, Scotts Valley, California).

Although the signal alarm device was previously recommended by as few as 3% of physicians in the United States, the development of safer equipment and the high long-term success rate have resulted in much more frequent use of this technique in recent years. The disadvantage of the signal alarm device is the noncompliance rate of 10% to 20%, most often related to the prolonged usage necessary before dryness can be achieved and the need for the child to get up at night to go to the bathroom. In addition, because success with the device depends on the motivation of the child, these devices should probably not be recommended for children younger than 8 years old.

Pharmacologie Therapy

The lure of drug therapy is the rapid response rate that is noted in many children. In turn, despite the feet that as early as 1972 it was recommended that drugs should not be first-line therapy for nocturnal ennresis because of potential side effects, 32% to 50% of physicians prescribe drug therapy.9 The two medications that are most often prescribed and that have been found most successful in the treatment of nocturnal enuresis are imipramine hydrochloride (Tofranil) and desmopressin (DDAVP).

Imipramine effectively treats nocturnal enuresis with continued usage in as many as 60% of patients.6 Its mechanism of action is not definitely known, but is probably related to an anticholinergic effect that increases bladder capacity. While previous theories suggested that imipramine worked by altering sleep and arousal mechanisms in the enuretic patient, the fact that enuresis can occur in all stages of sleep and that with treatment children do not awaken to void but maintain bladder control throughout the night appears to contradict this belief.

The initial dose of imipramine is usually 25 mg for patients 6 to 8 years old taken 1 hour before bedtime. Older children should receive either 50 mg (8 to 12 years old) or 75 mg (more than 12 years old) per night. Doses greater than 75 mg do not improve efficacy and may lead to toxicity. In most cases, the drug should be given for 2 to 3 months and then gradually tapered over 3 to 4 months.

The two major drawbacks to the use of imipramine are the high relapse rate (greater than 90%) after discontinuing the drug and the potential for drug toxicity. While the relapse rate can be decreased by slowly tapering the drug as opposed to discontinuing it abruptly, the risk of toxicity is inherent in the drug's narrow therapeutic index. Common (10% to 15%) and mild side effects include headaches, nervousness, abdominal pain, decrease in appetite, insomnia, and anxiety. More severe but rare manifestations include coma, convulsions, and cardiac arrythmias. Unfortunately, younger siblings of enuretic patients often present in the emergency room with acute imipramine toxicity after ingesting a large amount of the medication that has been carelessly monitored. Accordingly, when prescribing imipramine to families, it is imperative that they be informed about all of the possible side effects.

Desmopressin (DDAVP), an analogue of the anti' diuretic hormone vasopressin, recently has shown promising results in the treatment of nocturnal enuresis, Dimson17 described the use of desmopressin for the treatment of nocturnal enuresis 15 years ago. Its use was predicated on the theory that a large urine volume was the basis for enuresis. More recently, studies by Norgaard et al and Rittig et al have revealed nocturnal enuresis in some children is associated with a relatively large urine volume in the absence of a rise in nighttime values of plasma vasopressin and suggest that there may be a scientific basis for the use of desmopressin.2,3

While it is possible that the success of desmopressin in treating enuresis is based on its antidiuretic properties, some patients with normal nocturnal vasopressin levels and enuresis also have responded to the medication. Numerous short-term studies have been conducted, the majority of which have demonstrated success rates comparable to imipramine but with a relapse of symptoms almost invariably following discontinuation of the drug.18 However, more recent work with long-term treatment by Rittig et al4 and Miller et al19 have demonstrated persistent resolution of bed-wetting in as many as 70% of patients continuously maintained on the drug with minimal side effects and the absence of drug tolerance.

As with imipramine, patients who are likely to respond to DDAVP usually will do so within the first 2 weeks of therapy. Most physicians experienced with the drug recommend initiating therapy with a nightly dose of 20 u,g (a single 10 u,g puff into each nostril from the metered spray). If unsuccessful, the dose can be increased to 40 u,g nightly. In most cases, increasing the dose further will not improve efficacy and may precipitate complications. Miller and colleagues recommend that once the patient is dry for 2 consecutive weeks, the dose of desmopressin should be decreased by 10 µg.19 Further tapering at 2-week intervals should take place as long as the patient is completely dry at night. Relapse following drug lowering should be followed by an increase to the previous dosage. Obviously, this approach is intended to maintain control of the enuresis until the patient no longer experiences bed-wetting, most likely as a result of the expected "spontaneous cure" that will occur in most patients over time. Further experience with such long-term therapy will be necessary before this approach can be recommended.

Adverse effects associated with desmopressin usage are rare but have included epistaxis, nostril pain, nasal congestion, and headache. Nasal congestion may require the prior usage of a decongestant to insure adequate absorption of the drug from the nasal mucosa. The most serious side effects are water intoxication and seizures, which have occurred in one child who took an excessive dose of the drug and a second child with cystic fibrosis (a salt-losing disorder) and nasal polyps. We would not recommend giving desmopressin to any child who is in any way predisposed to the development of hyponatremia. In addition, children using desmopressin should be instructed to restrict fluid intake in the evening to prevent this complication. It is also probably wise to evaluate serum electrolytes in any child receiving desmoptessin 1 week after initiating therapy.

The cost of desmopressin can be substantial, more than $100 per month as compared to the much lower cost of imipramine or the signal alarm device. However, in many cases where desmopressin dosage can be tapered over time or the medication can be used on an intermittent basis only (eg, sleepovers or overnight camp), expense can be significantly lowered.

A third drug that has been used occasionally for the treatment of nocturnal enuresis is oxybutynin chloride (Ditropan). However, this drug, which is an antispasmodic agent ideal for patients with uninhibited bladder contractions, has been shown not to be useful for patients with uncomplicated nocturnal enuresis and should not be recommended.

Other therapies that are occasionally recommended and have demonstrated some success in patients with small functional bladder capacities include restricting fluids at night to minimize urine volume and bladder stretching exercises. The "exercises" are conducted by urging the child to withhold voiding when the initial urge to void arises. Elimination diets have been used and may be beneficial in the child with an allergic history. Although not widely practiced, hypnotherapy also has been reported to be remarkably successful and deserves further investigation.20

When addressing the treatment of enuresis, it is important to emphasize that no therapeutic option is exclusive of another. Combination therapy may be beneficial in some children. As we noted previously, motivational counseling should be practiced no matter what other therapeutic option is chosen. Other studies also have demonstrated greater success with combination therapies of the pharmacological and conditioning modalities when compared to either therapy alone.

SUMMARY

In summary, all children and families who present with nocturnal enuresis should be offered education, reassurance, and ongoing support as a premier component of any treatment regimen. At the same time, the family should be informed about all the treatment options that exist with a goal of tailoring the specific treatment to the individual patient. In most cases, this approach will lead to child, family, and physician satisfaction.

REFERENCES

1. Norgard, J, Rittig S,Djurhuus J. Nocturnal enuresis; an approach to treatment base on pathogenesis. J Pediarr. 1989;Il4;705-710,

2. Norgaard J, Pedersen E, Djuthuus J. Diurnal ann-diuretic-bonnone lewis in J Vrul. 1985U34:1029-1031

3. Ritrig 5, Knudsen J, Nnrgasrd E, Pedersen K, Djurhuus J. Abnonisal diurnal rhythm of plasma vasopressin and urinary ourpur in patients with enuresia. Am i Physissl. l989;25 6:664.67 I.

4. Rirtig S. Knnduen U, Sorensen S. Djurhuus J, Norgased J. Ltng.tems douhle'blind crass-over study ci desmopressin inrusnasal spray in the management ci nocturnal enuresis, Presented at the Royal College ci Physicians International Symposium; 990; London.

5 Crawford I Trisarnissnt ci nocturnal pnltreuic introductory comments J Pediatr 1989; 11 4:687 -690.

6. Novello A, Novello J. Enuresis. Pediatr Clin North Am. 1987;)4:7L9-733.

7. Rushron H. Nuctumal enuresis: epidemiology, evaluation, and currently available treatment oprtons. J Pediatr. 1989;! 14:691-696.

8. Bakwin H. The genetics of enuresis. In: Kelvin 1. MacKeith R. Meadtws W. edv Biadder CanatA ana Enureiu. London: Htinenumn Medical, 1973:73-7-737.

9. R>xman B, VaIJe; B, Brink R. Childhood enuresis: prevalence, perceived impact, and preitnbed rreatments. PcJiûmis. 1986:77:402-467.

10. Haque M. Ellersrein N, Gundy i, et al. Parental perceptions ot enuttsia. Am! Dis Ch(U. 1981;135:809-811.

11. Moflan M. Nocturnal enuresis; psychologie implicai u BIS ni treatment and nontreatmern. J Peaair. 19T9;! 14:697-704.

12. SchmitI B. Nocturnal enuresis: finding ihe treatment that tits ihe child. Cuniempifrar? Pediatrics. 1990:70-97

13. Starfield B. Functional Bladder capacity in enuretic and nonenuretic children. ) Peduur. 1967:70:777-781.

14. Poulton E. Relaave nocturnal polyuria as a ractor in enuresis. Lancet. ]952;2:906907

15. Notgaard J, Hansen J, Nielsen ], et al. Simultaneous registration of sleep stages and h ladder activity in enuresis. Uroiojp. I985;26:il6-Î19.

16. Marshall S, Marshall H1 Lyons R. Enuresis: an analysis of various therapeutic approaches. Pediatrics. ?97?;5?:T13-817.

17. Dimion S. Desmopressin as a treatment for enuresis. Lancet. 1977;?;1260.

18. Klauher G. Clinical efficacy and safety of desmopressin in the treatment ot nocttim.il enuresis. J Peaan. 1989;114:719-722.

19. Miller K, Goldherjj S, Atkin B. Nocturnal enuresis: experience wilh limg-term usi- of intranasally administeted desmopressin J Pediotr. 1U89;1 14t72î-726.

20. Olness K. The use of self-hypnosis in the treatment of childhood nocturnal enuresis. Clin Pediott. 1975;14:273-279.

TABLE

Evaluating Children With Nocturnal Enuresis

10.3928/0090-4481-19910501-08

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