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Editorial

Indian Pediatrics 2000;37: 135-140

Primary Nocturnal Enuresis_Where Do We Stand Today?

Enuresis is defined in many different ways, but the common thread to all involves a lack of bladder control beyond 5 years age, an age when most children would be expected to have control. Primary nocturnal enuresis (PNE) is the most common entity among the disorders in which enuresis is a symptom. As the name suggets, PNE is limited to night-time wetting in children who have never gained complete night-time control, without gross neurological or urological abnormalities. PNE is a source of discomfort to many pediatricians, as it is difficult to explain its cause to parents and the options for treatment have thus far been limited. Thus, most pediatricians make light of this condition, offering little beyond reassurance that it will get better with time. Many among us would even hesitate to label PNE as a disorder, given its strong tendency to be self-limiting. Thus, enuresis is viewed by some as simply an additional milestone to be achieved, a part of toilet training. Research interest was previously lacking because enuresis is neither fatal nor does it cause serious damage to health. Yet few conditions evoke such parental anxiety. The parent's expectations of pediatricians are to provide therapy that will allow all children to achieve night dryness at an expected and socially acceptable age.

Thankfully, recent advances in both the mechanisms as well as therapeutic options have improved our ability to provide relief to both parents and children with PNE. A considerable amount of research in the field of enuresis is now underway, and sufficient new data was available to warrant a recent international symposium on advances in this field (The 1st International Enuresis Symposium, Kyoto, 1997; Proceedings published as a supplement to European Urology, April 1998). Research is now underway in the Far East, Europe, Middle East and USA. Expectations are now high that we will continue to elucidate the mechanisms involved in achieving night-time bladder control and formulate strategies that result in long term cure.

Traditional theory regarding the cause of PNE focussed on family dynamics and psychosocial factors. Thus, PNE was perceived to be secondary to factors such as: (a) behavioral disorders in children; (b) negative parental responses to a failure of the child to achieve control; (c) social stresses at home and (d) defective or excessively strict toilet training(1-3). However, many of the studies describing psychosocial abnormalities had a selection bias towards children brought for treatment and tended to be retrospective. A comprehensive prospective population based study from New Zealand found that children with PNE had behavior patterns no different from controls(4). It is now believed that psychological disorders are an unlikely cause for PNE in children(5,6).

In the last few decades, the tide has shifted towards organic abnormalities in the pathogenesis of PNE. The current paradigm for regulation of night-time urinary continence involves an interplay between: (i) reduction in night-time urine production; (ii) a normal functional bladder capacity; and (iii) and effective sequence of arousal when the bladder is full, from deep sleep to light sleep to complete awakening. PNE therefore results when there is an imbalance between the above factors.

Some sort of maturational event occurs with older age that removes the imbalances and allows the above mechanisms to be active. The discovery that ADH secretion in PNE does not show its normal increase during sleep and thus urine production stays high(7) marked the beginning of serious research into actual somatic abnormalities.

Recently, Watanabe et al.(8) have proposed a new pathophysiologic classification system for PNE, based upon simultaneous overnight monitoring by EEG and cystometro-grams (CMG). This classification divides cases of PNE into 3 types: I, IIa and IIb. In type I, there is normal transmission of bladder sensa-tions and subsequent arousal of the activation center, but the progression from light sleep to complete awakening does not occur. In type IIa, bladder sensations are transmitted normally but the arousal center is not activated at all and the child remains in deep sleep. Finally, in type IIb, there is ineffective transmission of urinary sensory signals by a primary disturbance in bladder function. This pathophysiologic classi-fication may help direct treatment modes in the future.

Additionally, the strong familial predisposi-tion of PNE has prompted many studies for a putative gene defect underlying these somatic abnormalities. Using linkage analysis in families with a high prevalence of PNE, many different candidate genes have been described(9). Some of these genes have been specifically labeled as ENUR-1 (on chromosome 13q), ENUR-2 (12q), and ENUR-3 (22q)(9-11). Their exact roles in pathophysiology remain to be determined.

While there is a lack of clear evidence for psychological abnormalities as a causative factor in PNE, psychological disorders are frequently a result. Low self-esteem is a common problem in children with PNE and provides a strong reason to treat cases that present to physicians(12).

The evaluation of PNE is guided by a thorough history and physical examination and has been dealt with in many chapters and articles(5,6,13,14). It is worth noting that complicated urodynamic studies can be avoided by determining the "functional bladder capacity", i.e., that volume of urine the bladder can hold when awake or asleep. This contrasts with "anatomical bladder capacity" (the bladder volume under anesthesia, which always exceeds the functional capacity). Functional bladder capacity is determined as the largest volume voided after measuring each void for 3 consecutive days. The expected value is 10 ml/kg and normal is >70% of expected. It may have value in deciding the type of treatment, as given below.

When comparing of the efficacy of therapeutic modalities, it is important to keep in mind the criteria for diagnosis and improve-ment used by the authors. These criteria vary widely and prevent an adequate comparison between treatment modalities(5). The frequency of wet nights for inclusion into therapeutic trials is frequently not mentioned or has varied from the DSM-IV definition of "2 wet nights per month"(15) to 7 of every 14 days(16). Similarly, the number of consecutive dry nights for "initial cure" varies between 14-42 days. At least ten different definitions of relapse exist in different studies(16). No one set of criteria has met with general approval so far.

Treatment modalities for PNE can be classified as: (i) Non pharmacological social and lifestyle modifications, e.g., fluid restriction after dinner, voiding prior to sleeping, rewards for dry nights, etc; (ii) Non pharmacological alarm use; and (iii) Pharmacological therapy, using tricyclic anti-depressants, anti-cholinergics, or desmopressin acetate (DDAVP). Full details of each are available in several recent reviews(5,6,13,14,17,18).

Enuresis alarms are moisture-sensing devices kept in the bed or the under clothes of the child. An audible or vibratory alarm is given off at the sensing of the first drop of urine. The child must then wake up and go void in the bathroom. Many different commercial alarms are available in Western countries, though less so in Third World countries. The initial success rates vary widely from 45-90%, with high relapse rates of approximately 30%(6,17,19). Nevertheless, long term success rates with prolonged use are superior to those obtained with drug therapy (50-70%). Their mechanism of action for long term cure is still debated. While the use of enuresis alarms represents a cost-effective form of treatment in Western countries(17), their use would still be beyond the reach of most in Third World countries. A recent study from Egypt describes the use of a simple alarm clock as a conditioning alarm(20). The child's parents initially had to determine the critical time after sleeping when the bladder would be full by monitoring the child during sleep for 2-3 days to see when bedwetting occurred. The alarm was then set to go off 15 minutes prior to this, enabling the child to wake up and void in the bathroom. The study assumed that this critical time was constant from night to night. The reported success rates were similar to those of currently used enuresis alarms.

Imipramine, a tricyclic anti-depressant, is one of the oldest and most inexpensive drug agents used in PNE(18,21). It was thought to affect sleep-arousal mechanisms, but it may also have a weak peripheral anti-cholinergic effect. Initial success rates with imipramine given for several weeks have varied widely from 10-75%(6). Long-term cure rates are much lower (25-40%), due to the high relapse rates(6,17). This drug has been used successfully in India as early as 1968(21). Its main drawbacks stem from its low safety profile. Side effects with imipramine are numerous and include insomnia, anxiety, personality changes, dry mouth and nausea. Acute accidental overdoses have been reported in both patients and siblings at home. Due to these adverse effects, imipramine has fallen out of favor in Western countries.

The most recent drug (and also the most expensive) in our armamentarium is desmo-pressin acetate (DDAVP). This drug is a synthetic analogue of arginine vasopressin with water retention effects on the distal nephron but no vasopressor effects. Intranasal DDAVP has been tried in several large studies(22,23). Initial success rates of 66-93% are reported. Long term success rates are lower (20-70%) because of high relapse rates, similar to other forms of therapy. While the success rates are similar to imipramine, DDAVP has fewer side effects and the onset of action is much more rapid. Thus this agent can also be used for quick short-term relief, as may be needed for an overnight trip. Long term use of intranasal DDAVP and the use of oral DDAVP have also been reported to be effective and safe(19,22). A response to DDAVP may be predictable based on functional bladder capacities, a small capacity being associated with high failure rates(24) and normal capacity with a greater chance of long term success(25). Patients with a small bladder capacity benefit most from the use of oxy-butynin or hyoscyamine, which are anti-cholinergic agents that relax the bladder musculature and stabilize uninhibited contractions.

A direct comparison of DDAVP and imipramine has been reported in only one study(26). Vertucci et al. used a crossover design in which the use of one drug for 3 weeks was followed by the use of the other for 3 weeks, and vice-versa. The use of DDAVP after imipramine was associated with a superior result, while the use of imipramine after DDAVP was associated with some deteriora-tion. On this basis the authors concluded that DDAVP was a better agent than imipramine. The use of DDAVP in combination with alarms holds promise of being more effective than either agent alone is(17,27). Other drugs have also been tried, such as indomethacin and alpha-adrenergic agonists, e.g., ephedrine(28,29). Data on their use has been limited and equivocal so far.

So what should we advocate for our patients with PNE? Is any one drug superior to others? Can we as physicians maintain our interest if non-pharmacological methods are the preferred modality? Is an integrated approach appropriate? The answers to these questions are by no means complete. Based on our current knowledge and understanding, a triple pronged approach, comprising social modifications, alarm use and judicious use of drug therapy would seem appropriate. A decision to treat, even for milder cases, is reasonable if parental anxiety is high and the child is motivated. The choice of drug is based on socio economic factors. If cost and availability are not an issue, DDAVP would be the preferred pharmacological agent today, probably in combination with alarms. However, it is extremely likely that most of our approach will change as we further our understanding of PNE pathophysiology.

Finally, as we have entered the age of the Internet, many websites are now available for parents who have access to the World Wide Web. As many urban Indians are now computer literate, it is essential for pediatricians to be aware of the resources on the Internet. The National Enuresis Society, based in the USA, maintains a website (http://www.peds.umn.edu/Centers/NES) which provides information for parents in simple and easy to understand language. Similarly, ongoing research in PNE is listed in simple language in the website for the International Enuresis Research Center (http://ierc.org), which is based in Europe.

Vikas R. Dharnidharka,
Assistant Professor,
Division of Pediatric Nephrology,
Shands Children's Hospital and University of Florida Health Science Center,
P.O. Box 100296, 1600 SW Archer Road.
Gainesville FL 32610-0296, USA 

E-mail: vikasmd@peds.ufl.edu

References

References

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2. Hussain SA. Childhood psychiatric disorders with physical manifestations. Indian J Pediatr 1984; 51: 205-216.

3. Thakur AK, Sharma KP. Stress factors and behavioral characteristics in enuretic children. Indian Pediatr 1995; 32: 997-998.

4. Feehan M, McGee R, Stanton W, Silva PA. A 6 year follow-up of childhood enuresis: Preva-lence in adolescence and consequences for mental health. J Pediatr Child Health 1990; 26: 75-79.

5. Jarvelin MR. Nocturnal enuresis. Acta Pediatr 1999; 88: 589-591.

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10. Eiberg H, Berendt I, Mohr J. Assignment of dominant inherited nocturnal enuresis (ENUR1) to chormosome 13q. Nat Genet 1995; 10: 354-356.

11. Arnell H, Hjalmas K, Jagervall M, Lackgren G, Stenberg A, Bengtsson B, et al. The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q. J Med Genet 1997; 34: 360-365.

12. Hagglof B, Andren O, Bergstrom E, Marklund L, Wendelius M. Self-esteem in children with nocturnal enuresis and urinary incontinence: Improvement of self-esteem after treatment. Eur Urol 1998; 33 (Suppl 3): 16-19.

13. Chandra M. Nocturnal enuresis in children. Curr Opin Pediatr 1998; 10: 167-173.

14. Singh H, Singh D. Jain BK. Enuresis updated. Indian Pediatr 1994; 31: 611-618.

15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Washington DC, American Psychiatric Association, Revised 3rd edition, 1994.

16. Butler RJ. Establishment of working definitions in nocturnal enuresis. Arch Dis Child 1991; 66: 267-271.

17. Lackgren G, Hjalmas K, van Gool J, von Gontard A, de Gennaro M, Lottmann H, et al. Nocturnal enuresis: A suggestion for a European treatment strategy. Acta Pediatr 1999; 88: 679-690.

18. Rushton HG. Older pharmacologic therapy for nocturnal enuresis. Clin Pediatr 1993; 32 (Spec No): 10-13.

19. Kahan E, Morel D, Amir J, Zelcer C. A controlled trial of desmopressin and behavioral therapy for nocturnal enuresis. Medicine 1998; 77: 384-388.

20. EI-Anany FG, Maghraby HA, Shaker SE, Abdel-Moneim AM. Primary nocturnal enuresis: A new approach to conditioning treatment. Urology 1999; 53: 405-408.

21. Kumar LR, Gopal B. Imipramine hydrochloride (Tofranil) in enuresis. Indian J Pediatr 1968; 35: 226-228.

22. Hjalmas K, Hanson E, Hellstromk AL, Kruse S, Sillen U. Long-term treatment with desmopressin in children with primary monosymptomatic nocturnal enuresis: An open multicenter study. Swedish Enuresis Trial (SWEET) Group. Br J Urol 1998; 82: 704-709.

23. Riccabona M, Oswald J, Glauninger P. Long-term use and tapered dose reduction of intranasal desmopressin in the treatment of enuretic children. Br J Urol 1998; 81 (Suppl 3): 24-25.

24. Rushton HG, Belman AB, Zaontz MR, Skoog SJ, Sihelnik S. The influence of small functional bladder capacity and other predictors on the response to desmopressin in the management of monosymptomatic nocturnal enuresis. J Urol 1996; 156 (2 Pt 2): 651-655.

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Key Messages

1. Recent advances in both the mechanisms as well as therapeutic options have improved our ability to provide relief to both parents and children with primary nocturnal enuresis.

2. Primary nocturnal enuresis results due to an imbalance between night-time urine production, functional bladder capacity and an effective sequence of arousal when the bladder is full.

3. It is now believed that psychological disorders are an unlikely cause for PNE in children.

4. If cost and availability are not at issue, DDAVP is the preferred pharmacological agent today, probably in combination with enuresis alarms.