Therapy-resistant enuresis : In search of new therapies and prognostic markers

Abstract: A large minority of children with enuresis do not respond to treatment with either desmopressin or the enuresis alarm. Anticholinergics have not proven as successful as expected. The fourth evidence-based treatment of enuresis, the tricyclic antidepressant imipramine, is cardiotoxic when overdosed, which has led to diminished use. Since the long-term consequences of enuresis are potentially grave it is important that effective treatments of therapy-resistant enuresis are found.When investigating the enuretic child a full voiding-chart - in addition to the case history - is the method of choice. However, there is no robust evidence that daytime voiding chart data actually do predict nocturnal detrusor function.The aim of this thesis was to determine whether there is a role for the noradrenergic antidepressant reboxetine in the treatment of therapy-resistant enuresis, and whether anamnestic data and the voiding chart provides prognostic information regarding response to treatment with anticholinergics and antidepressants respectively in therapy-resistant patients.In a retrospective evaluation of 61 children who for humanitarian purposes had been treated with reboxetine 32(52%) responded to this treatment, 21 of them after desmopressin had been added. We then proceeded with a randomized placebo-controlled study with 18 patients, in which the reduction of wet nights was much better with either reboxetine in monotherapy or in combination with desmopressin than during the placebo period (p=0.002). However, no patient achieved complete dryness. No prognostic markers for therapy-response were found in either of these studies.In the randomized study we also sought to investigate whether reboxetine had any statistically significant effect on voiding-chart data. No such effect was found, but in respect to this secondary aim the sample size was too small. Nonetheless , this led to the speculation whether reboxetine exerts its antienuretic effect via modulation of arousal mechanisms.Prognostic markers were sought in a retrospective evaluation of 154 patients treated with anticholinergics or antidepressants, but few and inconsistent differences were found between the groups responding or not responding to the various treatment regimens, and this was true both for anamnestic and voiding chart data.In conclusion reboxetine seems to be an alternative in the treatment of enuretic children who have not responded to standard treatment, but further trials with higher doses and larger study populations are needed. The internationally recommended assessment of children with therapy-resistant enuresis does not seem to give the prognostic information intended.