BACKGROUND: There is consensus that the basic underlying mechanisms behind enuresis, i.e. nocturnal polyuria, detrusor overactivity and high arousal thresholds, can be addressed by the established first-, second- and third-line therapies, i.e. the enuresis alarm, desmopressin, anticholinergics and tricyclic antidepressants. Still there remains a group of subjects for which neither of these therapies in isolation will help. Even double therapy with desmopressin and other alternatives will not always lead to dry nights. We have, out of compassion and necessity, treated these extremely therapy-resistant subjects with combinations of three or four drugs, often including the sympathomimetic mirabegron. METHODS: Retrospective evaluation of all subjects with enuresis given triple- or quadruple antienuretic therapy at our tertiary center. All had without benefit tried the following: the enuresis alarm, desmopressin, anticholinergics + desmopressin, and amitriptylin + desmopressin. None had untreated constipation. They were given various combinations of 3-4 of the following: desmopressin, anticholinergics (mostly fesoterodine 4-8 mg), mirabegron (25-50 mg) and amitriptylin (25-50 mg), all drugs given in the evening. The choice was made on an individual basis taking side effects and family preferences into account. All subjects have been followed for at least 6 months. RESULTS: Presently 23 subjects have been treated. All but one of them are male. Their ages range from 8 to 40 years (median 12); two of them are adults. Of these 23, 16 became completely dry, three reduced enuresis frequency by at least 50%, three were nonresponders and one family failed to report the benefit of therapy. One discontinued antidepressant therapy due to mood swings and one developed constipation and enuresis relapse during mirabegron and anticholinergic therapy. After 0.5-4 years of follow-up five are dry without medication, four are dry on desmopressin monotherapy, three (including one adult) are dry on two drugs, seven (including the other adult) are dry but need 3-4 drugs to maintain dryness and four are still suffering from enuresis. CONCLUSIONS:Most subjects with enuresis resistant to first-, second- and third-line antienuretic therapies will become dry when several of the presumed pathogenetic factors are addressed simultaneosly with 3-4 drugs, and most of these can then stay dry on one or two drugs.
