Overactive bladder syndrome (OAB) is often provoked by external cues. One particularly provocative stimulus is external cold. We have introduced the term acute cold-induced urgency (ACIU) for this phenomenon. ACIU evoked by everyday cold stimuli is a frequent complaint of patients with OAB, wet or dry, but is also common in healthy individuals. Based on literature, around 50% of patients presenting with OAB experience urgency upon daily life cold exposure events (1,2). Despite epidemiological evidence linking aggravation of OAB to cold environmental temperatures, as well as extensive anecdotal evidence from urological practice (1), acute external cold-induced bladder responses have never been directly and systematically documented in humans. ACIU can be reliably evoked with brief, non-painful cold stimuli, even in anesthetized animals, and concomitantly measured using cystometry (3). This indicates that ACIU is a conserved reflex rather than subconscious conditioning. ACIU critically depends on the activity of the cold-activated ion channel Transient Receptor Potential M8 (TRPM8) (3). These preclinical results represent proof-of-concept that ACIU can be objectively measured to serve as a novel diagnostic tool, and that TRPM8 is a potential therapeutic target to treat ACIU symptoms, and form the starting point of the current project. 
The overall aim of the project is to translate these fundamental findings towards clinical applications, in order to improve the diagnosis, stratification and treatment of urinary urgency in patients. 

The primary goal of this pilot project is to establish that ACIU can be provoked during urodynamic investigations in humans, and to determine the cold stimulus that is most prone/or convenient to evoke ACIU.

In this pilot study we randomly selected 21 novel patients presenting in our outpatient clinic with complaints of urgency and/or urgency-incontinence. We only selected OAB patients because, based on literature, 50% of them experience urgency upon external cold (1,2).  

After obtaining written informed consent,  patients were asked to fill out an International Consultation on Incontinence Modular Questionnaire (ICIQ QoL and OAB), as well as a Cold Sensitivity Questionnaire (CSQ), a self-constructed questionnaire containing four questions about the influence of cold stimuli on lower urinary tract symptoms.   

All patients underwent a standard urodynamic test, which was immediately followed by a repeat test during which ACIU was provoked, using a protocol adapted from our ACIU protocol established in our preclinical studies (3). The subject’s bladder was filled to 80% of its capacity, at which point the infusion was halted. Subsequently, the subject was exposed to three distinct localized cold stimuli that are known to cause strong TRPM8-mediated cool sensations: immersion of one foot in 38°C-water during 30s immediately followed by immersions in 20°C-water for 30s, blowing a stream of cool air over the face for 30s, application of acetone on the skin of one forearm. These stimuli were applied in random order with 1-minute intervals, and the experiment was terminated when a voiding was evoked or all stimuli had been applied. Both subjective responses as well as urodynamic responses (detrusor contraction ≥ 15cmH2O; voiding) were recorded.

A total of 21 patients were enrolled in the study, 12 women and 9 men. When asked, 16 patients reported to experience an aggravation of their symptoms when exposed to cold stimuli, 5 patients did not experience ACIU. Thirteen patients (62%) showed a response on one or two of the cold stimuli, 8 patients did not show any subjective or urodynamic response. Of the 5 patients who did not experience ACIU in daily life, only one did not have a subjective or urodynamic response on the cold stimuli. Five patients (23.8%) had a subjective response on the acetone stimulus, of which one female patient had a detrusor contraction which evoked voiding. This patient did not receive the other two stimuli.  Four patients (19%) had a subjective response on the cold air stimulus and one patient had a detrusor contraction on urodynamic investigation. Eight patients (38%) had a subjective response on the cold water stimulus of which three patients had a detrusor contraction as well. Only three patients (14%) showed response on two stimuli. Two of them had a subjective response on the cold air and cold water stimulus. One patient had a subjective response on acetone and cold water.

In our study 8 patients (38%) did not have any response on the cold stimuli. But 7 of those patients told us to experience an aggravation of their OAB symptoms when exposed to cold stimuli in daily life. Sixty-two percent showed a reaction on a cold stimulus of which the cold water stimulus was the most provocative stimulus with the most response (8/13 – 62%). Three of those subjective responses were associated with a detrusor contraction  ≥ 15cmH2O. The cold water stimulus is known to be a very strong stimulus for activation of TRPM8 (3).

Based on the outcome of this experiment, we established that ACIU can be objectively measured in humans, using OAB patients as primary subjects. We determined that the cold water stimulus is the most provocative cold stimulus and this will be used to further standardize the ACIU protocol. We will use this ACIU test to evaluate ACIU occurrence and severity in various urological patient populations (patients with OAB, multiple sclerosis patients, patients with urinary stress incontinence and healthy controls).

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Kondo A, Saito M, Yamada Y, et al. Prevalence of hand-washing urinary incontinence in healthy subjects in relation to stress and urge incontinence. Neurourol Urodyn 1992;11:519-23.
Uvin P, Franken J, Pinto S, et al. Essential Role of Transient Receptor Potential M8 (TRPM8) in a model of Acute Cold-induced Urinary Urgency. European Urology 2015;68:655-661.