Iatrogenic nocturnal eneuresis – an overlooked side effect of anti histamines?

Nocturnal enuresis is a common disorder in childhood, but its pathophysiological mechanisms have not been fully elucidated. Iatrogenic nocturnal enuresis has been described following treatment with several psychotropic medications. Herein, we describe a 6-year-old child who experienced nocturnal enuresis during treatment with the antihistamine cetirizine. Drug rechallenge was positive. Several neurotransmitters are implicated in the pathogenesis of nocturnal enuresis, including noradrenaline, serotonin and dopamine. Antihistamine treatment may provoke functional imbalance of these pathways resulting in incontinence.

Introduction

Nocturnal enuresis (NE) is defined as nighttime bedwetting after developmental age when bladder control should have been established. Anatomical and functional integrity of noradrenaline, dopamine and serotonin systems is required for continence.[1] Iatrogenic NE is an adverse event commonly reported in patients taking several central nervous system agents, in particular antipsychotics, (risperidone and clozapine), SSRI and some antiepileptics (sodium valproate).[23] Despite enuresis being reported as a very rare adverse event in summary of product characteristics of some antihistamines, no single case report is available to date in literature. We herein report a case of a child presenting with NE after treatment with the antihistamine drug cetirizine.

Case Report

A 6-year-old female child presented with recurrent episodes of rhinitis, bronchitis and bronchospasm since the age of 2 years. Her family history was positive for allergic diatheses. The rest of her past medical history was unremarkable with normal developmental milestones having been reached. She never experienced episodes of NE after bladder control was achieved at the age of 3 years. During an episode of persistent dry coughing, which was unresponsive to oral betamethasone 1 mg/day, she was prescribed add-on oral cetirizine 5 mg/day in the evening for a week. On Day 2 cetirizine of she had NE. This continued through Day 7., and disappeared when cetirizine was stopped. No other medication was concurrently taken and urinary infections were excluded by appropriate analyses. Two months later, she was again treated with oral cetirizine at the same dosage for another episode of cough and bronchospasm. Once again she experienced night-time enuresis throughout drug treatment. No further episode of NE occurred after treatment withdrawn. A total score of 9 (probable) was obtained on the Naranjo causality scale.

Discussion

Mechanisms underlying enuresis are complex and not exhaustively explained. Recent investigations focused the main role of the catecholamine systems in continence maintaining.[4] In particular, a subtle regulation between noradrenaline, serotonin and dopamine pathways is required for appropriate bladder control.[4] Functional imbalance of these neurotransmitters within basal ganglion structures appears to be central in the pathophysiology of enuresis and urinary incontinence.[5] The substantial role of dopaminergic circuits is supported by the frequent neurogenic detrusor overactivity and voiding dysfunction in patients with Parkinson's disease or other extrapyramidal dysfunctions, due to nigrostriatal dopamine depletion. Noradrenergic and serotoninergic systems exert their effects on continence directly, but also by facilitating or inhibiting dopaminergic pathways, respectively. Overall, pharmacological agents depleting or blocking norepinephrine or dopamine cause incontinence or enuresis, while drugs increasing these pathways induce urinary retention [Table 1]. Experimental studies proved that the histaminergic system directly influences the serotonin transmission in the central nervous system, by the presynaptic inhibition of 5-hydroxytryptamine release.[5] Therefore, antihistamine treatment, acting on 5-hydroxytryptamine regulation, could involve a central serotonin disinhibition, leading to an imbalance of the serotonin/dopamine ratio.

Table 1

Drugs reported to be associated with enuresis

Antidepressants: Selective serotonin reuptake inhibitors

Antiepileptics: Valproic acid

Antihypertensives: Urapidil

Antineoplastic agents

Antipsychotics drugs: Clozapine, pimozide, risperidon

In particular, cetirizine in this patient could have enhanced serotonin pathways originating from raphe nucleus, which exert an inhibitory effect on dopamine release from the mesocortical tract. Thus, this disrupted serotonin modulation can lead to a relative dopaminergic depletion, which eventually causes enuresis.