Pain during ice water test distinguishes clinical bladder hypersensitivity from overactivity disorders

The bladder cooling reflex (BCR) is a segmental reflex believed to be triggered by menthol sensitive cold receptors in the bladder wall, mediated by a spinal reflex pathway [1‐3]. It is thought to be a neonatal reflex that becomes suppressed by descending signals from higher centres at approximately the time when the child gains full voluntary control of voiding. Thus, it is typically absent in older children (> 4 years) and adults with stable bladders [2]. The BCR re-emerges in adults with central nervous system disorders, and was originally introduced by Bors and Blinn as a provocation test to differentiate upper from lower motor neuron lesions [3] – the presence of BCR supports the diagnosis of an upper motor neuron lesion [1‐4].

The BCR evoked by cooling the bladder wall by intravesical instillation of cold saline (Ice Water test), is activated at bladder volumes or pressures below threshold for the ordinary voiding reflex, suggesting that it originates from specific cold receptors rather than mechanoreceptors [1]. This hypothesis is in accord with the identification of a cool and menthol receptor TRPM8 in the urinary bladder [5]. In a recent study, we demonstrated an increased expression of TRPM8 in suburothelial nerve fibres of patients with painful bladder syndrome (PBS) and idiopathic detrusor overactivity (IDO) [6].

Previous studies have demonstrated the BCR to be most consistently present in neurogenic detrusor overactivity (NDO) [7]. It has been proposed that as a consequence of loss of central descending inhibition in conditions such as spinal cord injury or multiple sclerosis, the BCR emerges as a segmental sacral spinal reflex mediated by C fibre afferents, which may themselves be increased by sprouting secondary to bladder hypertrophy. Fall and colleagues [4] observed that a number of patients with idiopathic bladder overactivity (IDO) and a positive ice water test (IWT) later showed overt signs of neurological diseases during long-term follow-up. Thus, a positive IWT in IDO may be an early warning sign of future neurological disease.

The urinary bladder C fibres are considered to be normally inactive, and termed "silent" C-fibres [8]. Their sensitisation, sprouting or phenotypic changes, induced by pathological conditions including inflammation and hypertrophy, may be associated with functional changes such as increased urination frequency and urgency, as well as suprapubic pain [9, 10]. It has been hypothesized that chronic bladder pathological states result in recruitment of C fibres, which may contribute to painful and overactive symptoms [8].

The significance of the increase of nerve fibres expressing the cool and menthol receptor TRPM8 in both overactive bladders and PBS is uncertain, with respect to the BCR and sensory dysfunction – in the absence of a superimposed bladder infection NDO is usually a painless condition, while pain predominates in PBS. We were not aware of any previous studies of the BCR in PBS. We therefore studied the BCR in patients with overactive and painful bladder syndromes, and compared the results with controls. We also recorded the symptoms associated with intravesical ice water instillation in these patients.

This is the first study to evaluate the outcome of ice water test in patients with painful bladder syndrome, in comparison with overactive bladder disorders and controls. None of our controls or PBS patients had a positive IWT, indicating the inhibitory signals from higher centres being preserved, result in a negative IWT (Fig 3a, 4b). All our NDO patients demonstrated a positive IWT, which is in agreement with studies that demonstrate a positive test in up to 90% of patients with upper motor neuron lesions [13, 14]. The BCR thus reflects the loss of central inhibition in DO, analogous to the positive Babinsky sign in CNS pyramidal lesions (Fig 3b). One-fourth (27.3%) of our IDO patients showed a positive IWT. In a previous study, Petersen and colleagues [15] noted a positive bladder cooling test in 15% of patients with unstable detrusor and no known neurological disease. A positive IWT has also been observed in 27–47% detrusor overactivity secondary to bladder outlet obstruction (BOO) [16, 17]. Steers and De Groat [18] have suggested that obstruction produces neural plasticity, presumably from hypertrophy and increased production of nerve growth factor, resulting in a spinal reflex which may contribute to detrusor dysfunction. Similar increase in NGF levels have also been found in bladder of patients with IDO [19, 20]. Furthermore, it has been observed that patients with IDO and positive IWT later developed overt signs of neurological diseases during long-term follow-up [4]. In this study, patients with evidence of BOO on urodynamics were excluded. Thus, the positive IWT seen in our IDO patients may be a result of neural plasticity, with associated decreased central inhibition as a result of occult neurological disease (Fig 4a).

Opinion varies with respect to thermal perception from the bladder mucosa. Some investigators [21] have concluded that the bladder mucosa can distinguish between hot and cold fluids, while others have report that thermal sensation is perceived exclusively by urethral receptors and not by receptors in the bladder mucosa [22, 23]. In our study, all patients undergoing the IWT described a cold sensation in the urethra, indicating the presence of thermal receptors. Cold sensation in the suprapubic region was reported during the IWT by 6 patients, presumably referred from the bladder or urethra. We noted no significant association of this finding with a positive IWT or pain.

The most interesting finding of this study was the report of pain during intravesical instillation of ice water by PBS patients but not by other groups. The BCR is thought to be triggered by TRPM8 receptors in the bladder, with afferent signals relayed by unmyelinated fibres [1]. In a previous study [6], we demonstrated increased expression of TRPM8-immunoreactive nerve fibres in PBS bladder biopsies, with a significant correlation of these fibres with pain. An increase in TRPM8 transcripts has also been shown in the bladder of rats with spinal cord injury [24]. The report of pain in PBS, but not in DO patients, may indicate peripheral and/or central sensitisation in PBS; hence sensory symptoms are evoked (Fig 4b). The bladder cooling reflex thus indicates hyper-reflexia, not pain (hence this reflex is presents in normal babies, and reappears after CNS lesions in patients who do not report bladder pain). It would be of interest to perform the IWT test in patients with DO and inter-current bladder infection.

Significantly higher pain scores were seen in the PBS patients during the ice water test and at capacity during urodynamics, compared to baseline scores prior to urodynamics. One of the limitations of the study was that the order of urodynamic investigation (normal saline at room temperature vs cold saline) was not randomized. However, the hyperalgesia to bladder filling in PBS has been demonstrated in previous studies [25]. Altered visceral sensations from the urinary bladder (i.e., pain at bladder filling) that accompany PBS may be the consequence of many factors, including changes in the properties of peripheral bladder afferents, which respond in an exaggerated manner to normally innocuous stimuli (allodynia) [26]. The key novel finding of the study was the significantly higher pain scores in PBS patients during ice water instillation compared to the baseline, or equivalent amount of bladder filling (100 mls) with saline at room temperature. Cold sensitive nociceptors are normally activated by temperatures below 20°C [1]. Thus, the observation of pain during ice water instillation may suggest that the cold sensitive nociceptors may be sensitised in PBS, hence the pain. TRPM8 is activated at about 25°C and down to 10°C, and may be modulated or sensitised in bladder afferents to mediate these effects; alternative molecular mechanisms, that do not involve TRPM8, are also possible.

Clinical trials in PBS/IC have thus far used visual analogue scales for pain rating, and have lacked well defined tools for evaluation of pathophysiologic mechanisms that produce pain. The ice water-induced bladder pain may prove to be a useful marker for recruitment and assessment of efficacy in PBS clinical trials, particularly for antagonists of TRPM8. This may also apply to other targets expressed by polymodal small nerve fibres, even TRPV1. The test is simple, rapid and minimally-invasive.

The pain elicited by ice water instillation in patients with Painful Bladder Syndrome suggests peripheral and/or central sensitisation, evoking pain symptoms without reflex detrusor contractions. The ice water test may be a useful marker for clinical trials in PBS, and to differentiate this condition from overactive bladder disorders.