BLADDER COOLING REFLEX IN PATIENTS WITH MULTIPLE SCLEROSIS

0022-5347/00/1644-1280/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 164, 1280 –1284, October 2000 Printed in U.S.A.

Urological Neurology and Urodynamics BLADDER COOLING REFLEX IN PATIENTS WITH MULTIPLE SCLEROSIS ´ ATRICE BAYLE, PIERRE DENYS SAMER S. ISMAEL, THIERRY EPSTEIN, BE GERARD AMARENCO*

AND

From the Department of Neurologic Rehabilitation and Perineal Explorations, Rothschild Hospital, Paris, Cedex, France

ABSTRACT

Purpose: We describe the effect of intravesical ice water instillation in patients with multiple sclerosis and without an overactive bladder. Materials and Methods: Of 131 consecutive patients with multiple sclerosis who presented with a urinary disorder we selected for study 10 men and 29 women with a mean age plus or minus standard deviation of 50 ⫾ 9 years who had multiple sclerosis without an overactive bladder. Nonoveractive bladder was defined as no involuntary detrusor contraction up to 400 ml. of maximum fill on routine cystometry. We performed cystometry with saline at 25 to 30C at an infusion rate of 50 and 100 ml. per minute, and with ice water at 0 to 4C at a rate of 100 ml. per minute. Ice water cystometry was considered positive when an involuntary detrusor contraction occurred before 200, and between 200 and 400 ml. of filling. Ice water cystometry was considered negative when there was no involuntary detrusor contraction during ice water filling up to 400 ml. Results: Ice water cystometry enabled us to elicit involuntary detrusor contractions in 21 patients, which remained undetected by warm water cystometry at rates of 50 and 100 ml. per minute. The test was positive before 200, and between 200 and 400 ml. in 10 and 11 cases, respectively. Positive ice water cystometry was significantly associated with irritative signs or significant post-void residual urine volume. Conclusions: An involuntary detrusor contraction was not elicited by cystometry at 50 or 100 ml. per minute, implying that the afferent mechanoreceptor reflex limb via A⌬ fibers is not involved. In contrast, ice water cystometry at 100 ml. per minute elicited an involuntary detrusor contraction, suggesting involvement of an afferent reflex limb via capsaicin sensitive C fibers. These involuntary detrusor contractions revealed by ice water cystometry are probably relevant to an overactive bladder. In urinary disorders such a positive test indicates a spinal lesion. In multiple sclerosis it may have pathophysiological value, indicating a spinal rather than cerebral mechanism of overactive bladder, and diagnostic value, indicating multifocal demyelination. KEY WORDS: bladder, multiple sclerosis, urination disorders

The bladder cooling reflex is a true detrusor contraction in response to a cold intravesical stimulus. This contraction is a spinal reflex elicited by stimulation of specific cold receptors in the bladder and urethral walls, and mediated through unmyelinated C afferent capsaicin sensitive fibers.1– 4 Normally the archaic cooling reflex, which is present in children until age 4 years, is inhibited by supraspinal centers but in patients with upper motor neuron lesions it is not inhibited. According to the literature the ice water test involving the bladder cooling reflex is performed in patients with an overactive bladder to distinguish neurogenic from nonneurogenic detrusor overactivity. Geirsson et al reported the results of the ice water test in patients with multiple sclerosis and an overactive bladder.5 We describe the effects of ice water infusion on detrusor activity in 39 patients with multiple scle-

rosis who presented with a urinary disorder and without an overactive bladder on routine cystometry. MATERIALS AND METHODS

We evaluated 10 men and 29 women with a mean age plus or minus standard deviation of 50 ⫾ 9 years who had multiTABLE 1. Associations of urinary symptoms with nonoveractive bladder on routine cystometry in 39 patients with multiple sclerosis

Accepted for publication May 26, 2000. * Requests for reprints: Department of Neurologic Rehabilitation and Perineal Explorations, Rothschild Hospital, 33 bd de Picpus 75571, Paris, Cedex 12, France. 1280

No. Pts.

38 With Dysuria

26 With Urgency

23 With Pollakiuria

20 With Urge Incontinence

10 8 6 6 6 1 1 1

Yes Yes Yes Yes Yes Yes Yes No

Yes Yes No No Yes Yes No Yes

Yes No No Yes Yes No No Yes

Yes Yes No No No No Yes Yes

BLADDER COOLING REFLEX IN MULTIPLE SCLEROSIS

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FIG. 1. A, association of urinary symptoms (x axis) in 39 patients with multiple sclerosis and without overactive bladder. 1, dysuria, urgency, pollakiuria and urge incontinence. 2, dysuria, urgency and urge incontinence. 3, dysuria. 4, dysuria and pollakiuria. 5, dysuria, urgency and pollakiuria. 6, dysuria and urgency. 7, dysuria and urge incontinence. 8, urgency, pollakiuria and urge incontinence. B and C, ice water cystometry positive at filling volume up to 200 ml. EMG, electromyography.

ple sclerosis without an overactive bladder and who presented with urinary symptoms. Nonoveractive bladder was defined as no involuntary detrusor contraction up to 400 ml. of maximum filling on routine cystometry. The study group

was selected from 131 consecutive patients with multiple sclerosis who had urinary symptoms, including 92 (70%) in whom routine cystometry revealed an overactive bladder. Mean time plus or minus standard deviation from urody-

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BLADDER COOLING REFLEX IN MULTIPLE SCLEROSIS

FIG. 2. A and B, ice water cystometr positive at filling volume between 200 and 400 ml. EMG, electromyography

namic investigation to the onset of multiple sclerosis was 13 ⫾ 7 years. Urinary symptoms appeared a mean of 8 ⫾ 7 years after multiple sclerosis onset. Mean expanded disability status scale score6 was 4.8 ⫾ 1.9, while in 24 and 15 patients it was less than 6 and 6 to 15, respectively. Symptoms were dysuria in 38 cases, urgency in 26, pollakiuria in 23 and urge incontinence in 20 (table 1). One or more irritative signs were present in 33 patients, such as pollakiuria, urgency and/or urge incontinence. Physical examination demonstrated pyramidal signs in 34 of the 39 cases. Mid fill cystometry was performed 3 times in each case according to the urodynamic methodology recommended by the International Continence Society. With the patient supine filling was done through an 8Fr double lumen catheter and results were analyzed by computer. Tests 1 and 2 were performed using normal saline at 25 to 30C at a filling rate of 50 and 100 ml. per minute, respectively. A study inclusion criterion was toleration of the filling procedure until 400 ml. maximum cystometric volume was achieved without an involuntary detrusor contraction. Filling was routinely stopped at 400 ml. and the bladder was then considered nonoveractive. Subsequently cystometry was done at 100 ml. per minute with normal saline at 0 to 4C. Ice water filling was stopped when leakage occurred or a cystometric volume of 400 ml. was attained. Involuntary detrusor contractions at more than 15 cm. water were recorded as well as the volume at which the initial involuntary detrusor contraction occurred. If an involuntary detrusor contraction was noted during ice water cystometry, the test was considered positive when the contraction occurred at a volume of up to 200, and between 200 and 400 ml. (figs. 1 and 2). Otherwise the test was considered negative. Patients were asked to report any cold sensation during ice water filling. We determined the temperature of the water withdrawn 1 minute after the end of ice water infusion in 10 cases. Ice water cystometry was not routinely done in patients with an overactive bladder on routine cystometry. Only 24 of the 92 patients with an overactive bladder underwent this test. Post-void residual volume greater than 100 ml. was considered significant and documented. We also documented detrusor-sphincter dyssynergia, defined as involuntary external urethral sphincter contraction during an involuntary detrusor contraction or voiding.7 For statistical analysis of associations we performed the Student t test for patient age, mean expanded disability status scale score, time from multiple sclerosis and urinary disorder onset, and the chi-square test for the presence or absence of dysuria, pyramidal signs, post-void residual urine volume and irritative signs.

sor pressure and compliance were almost identical. Post-void residual urine was greater than 100 ml. in 74% of cases and detrusor-sphincter dyssynergia was noted in 89%. Ice water cystometry was associated with a cold sensation in the bladder, hypogastrium and/or urethra in 71% of patients. The test was negative and positive at a volume of up to 200, and between 200 and 400 ml. in 18, 10 and 11 cases, respectively. In the 10 patients in whom cold water temperature was measured mean temperature of the withdrawn ice water 1 minute after the end of instillation was 8C (range 2 to 10). We noted no significant association of positive ice water cystometry results with patient age (p ⫽ 0.51), mean expanded disability status scale score (p ⫽ 0.42), time from the onset of multiple sclerosis (p ⫽ 0.16) and urinary disorder (p ⫽ 0.86), sex (p ⫽ 0.23), dysuria (p ⫽ 0.35) or pyramidal signs (p ⫽ 0.77). However, positive ice water cystometry results were significantly associated with post-void residual urine volume and 1 or more irritative signs (p ⫽ 0.05). Ice water cystometry sensitivity was 44% and 61%, and specificity was 20% and 83% for retention and irritative symptoms, respectively. In the 24 patients with an overactive bladder who underwent

RESULTS

We noted no significant differences in the 50 and 100 ml. per minute filling rates (fig. 3 and table 2). Maximum detru-

FIG. 3. Distribution of 39 patients with multiple sclerosis according to response to ice water cystometry (IWT) and Kurtzke score of pyramidal function.

BLADDER COOLING REFLEX IN MULTIPLE SCLEROSIS TABLE 2. Ice water cystometry results versus post-void residual urine and irritative symptoms, including urgency, pollakiuria and/ or urge incontinence Retention: Yes No Irritative symptoms:* Yes No * Positive predictive value 95%.

Pos.

Neg.

13 8

16 2

20 1

13 5

ice water cystometry the test was positive, eliciting involuntary detrusor contractions. DISCUSSION

In adults ice water cystometry involves a sacral arc reflex that is not the normal voiding reflex. Activating specific cold receptors in the bladder wall causes a detrusor contraction mediated via capsaicin sensitive C afferent fibers and it is enhanced by exposure to menthol.1, 2 In contrast, the normal voiding reflex is activated by tension A⌬ receptors, involving a reflex loop via the pontine voiding center, and it is insensitive to cooling and menthol.4 The cooling reflex is thought to be a neonatal reflex that is suppressed by descending control at about the time that children achieve complete voluntary control of voiding. Hence, ice water cystometry is positive in neurologically normal children up to age 4 years but negative in those older than 6 years.8 This reflex in older children and adults indicates a lesion of the upper motor neuron and/or cerebrospinal pathway, resulting in release of the reflex from descending neuronal control. In this respect the ice water reflex may resemble the well-known Babinski reflex.4 In 1956 Bors et al initially suggested that the ice water test be done to elicit a mucosal spinal reflex in patients with a spinal cord lesion above the conus medullaris.9, 10 This reflex was always absent when the conus or cauda equina was destroyed. The indication for the ice water test was extended to assessing bladder function in patients with neurological impairment due to many causes5 and some nonneurological obstructive syndromes.11–13 Furthermore, others suggested that it should be done as an additional discriminatory parameter for subtyping overactive bladders.14 –16 Giersson et al described the results of ice water cystometry in patients with multiple sclerosis and an overactive bladder of various etiologies.5 In our study we only selected patients with a nonoveractive bladder. However, in our 24 patients with an overactive bladder who underwent ice water cystometry the test was positive with a significantly lower bladder volume at the initial involuntary detrusor contraction and higher maximum detrusor pressure, which was in accordance with the literature. The term nonoveractive bladder is not standard. The 400 ml. limit of filling was selected to enhance reproducibility and standardize the procedure. This volume seems to be a limit above which it is difficult to confirm the pathological character of uninhibited contractions and systematically consider them caused by an overactive bladder. We probably missed some involuntary detrusor contractions that occurred at a filling volume of greater than 400 ml. but we wished to standardize the procedure and avoid borderline conditions in which physiological and pathological phenomena are difficult to distinguish. Therefore, it is less surprising that we observed no differences in the 50 and 100 ml. per minute warm water filling procedures. An absent involuntary detrusor contraction was the inclusion criterion. We assessed only bladders stable up to 400 ml. of filling and maximal cystometric capacity was fixed since filling was routinely stopped at 400 ml. when leakage did not occur. However, the values of max-

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imal detrusor pressure and compliance were almost identical. Ice water cystometry provoked an involuntary detrusor contraction in more than 50% of cases. This result may be attributable to stimulating the cold receptor C fiber mediated reflex because the change in the filling rate only from 50 to 100 ml. per minute, supposedly to stimulate the A⌬ tension receptor response, did not result in any change in urodynamic parameters. Furthermore, mean temperature of the withdrawn ice water 1 minute after instillation was 8C (range 2 to 10), which was less than that recommended by Geirsson et al to achieve a sufficient cooling effect on the bladder wall.17 Ice water cystometry elicited overactivity and provided evidence of detrusor contractility. This overactivity, which was not detected by routine cystometry, may explain the presence of irritative signs. Because it demonstrates detrusor contractility, the test may contribute to distinguishing dysuria due to the lack of detrusor contractions from that due to detrusor-sphincter dyssynergia, which is common in various neurogenic disorders. The significant statistical associations that we identified are not surprising. The correlation of irritative signs with detrusor overactivity is well known. On the other hand, postvoid residual urine volume is an indirect indicator of detrusor-sphincter dyssynergia in 80% of overactive bladders in multiple sclerosis. As in the literature, sensitivity and specificity of the test are poor (61% and 44%, and 83% and 20%, respectively). For irritative signs the positive predictive value is 95%, indicating that patients with positive ice water cystometry results are likely to present with irritative signs. Thus, positive ice water cystometry probably indicates detrusor dysfunction. It is not necessary to demonstrate bladder overactivity before starting anticholinergic treatment when irritative symptoms are present. However, if therapeutic strategies are not modified by ice water cystometry results, followup strategies may be different in patients with positive test results. The finding of an overactive bladder on this provocative test may indicate a risk of future complications, such as bladder deformation, reflux and so forth, and indicate more attentive followup. Ice water cystometry may have pathophysiological and diagnostic value. It indicates the presence of a spinal lesion between the conus medullaris and pontine region. Detrusor overactivity in multiple sclerosis is cerebral (suprapontine) or medullary (infrapontine). However, positive ice water cystometry results are a strong argument for spinal cord involvement,5, 9 especially when associated with detrusorsphincter dyssynergia. In some cases a spinal rather than a cerebral lesion better explains the association of urinary disorder with multiple sclerosis. The presence of spinal lesions confirms the multifocal character of the disease, which is an essential diagnostic criterion in multiple sclerosis. CONCLUSIONS

We suggest that ice water cystometry be done for routine cystometric evaluation of urinary disorders in multiple sclerosis. It is valuable for identifying bladders with an element of overactivity that is undetectable by routine cystometry. This test may indicate the spinal neurogenic origin of urinary disorders and reveal the multifocal character of the disease. Furthermore, ice water cystometry may have predictive value for bladders evolving toward overactivity. Longitudinal followup in patients with positive ice water cystometry results is necessary to confirm this hypothesis. REFERENCES

1. Mazie`res, L., Jiang, C. and Lindstro¨m, S.: The C fibre reflex of the cat urinary bladder. J Physiol (Lond), 513: 531, 1998

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2. Lindstrom, S. and Mazie`res, L.: Effect of menthol on the bladder cooling reflex in the cat. Acta Physiol Scand, 141: 1, 1991 3. Geirsson, G.: Evidence of cold receptors in the human bladder: effect of menthol on the bladder cooling reflex. J Urol, 150: 427, 1993 4. deGroat, W. C., Vizzard, M. A., Araki, I. et al: Spinal interneurons and preganglionic neurons in sacral autonomic reflex pathways. Progr Brain Res, 107: 97, 1996 5. Geirsson, G., Fall, M. and Lindstrom, S.: The ice-water test—a simple and valuable supplement to routine cystometry. Br J Urol, 71: 681, 1993 6. Kurtzke, J. F.: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology, 33: 1444, 1983 7. Blaivas, J. G., Sinha, H. P., Zayed, A. A. H. et al: Detrusorexternal sphincter dyssynergia: a detailed electromyographic study. J Urol, 125: 545, 1981 8. Gladh, G., Lindstrom, S. and Mattsson, S.: Proceedings of 3rd International Children Continence Symposium, Sydney, Australia, p. 1, 1995 9. Bors, E., Ma, K. T. and Parker, R. B.: Observations on some modalities of bladder sensation. J Urol, 76: 566, 1956 10. Bors, E.: Neurogenic bladder. Urol Surv, 7: 177, 1957

11. Tammela T. L. J., Hellstrom, P. A. and Kontturi, M. J.: Cold sensation and bladder instability in patients with outflow obstruction due to benign prostatic hyperplasia. Br J Urol, 70: 404, 1992 12. Ishigooka, M., Hashimoto, T., Hayami, S. et al: Ice-water test in patients with overactive bladder due to cerebrovascular accidents and bladder outlet obstruction. Urol Int, 58: 84, 1997 13. Chai, T. C. and Gray, M. L., Steers, W. D.: The incidence of a positive ice water test in bladder outlet obstructed patients: evidence for bladder neural plasticity. J Urol, 160: 34, 1998 14. Fall, M., Ohlsson, B. L. and Carlsson, C. A.: The neurogenic overactive bladder. Classification based on urodynamics. Br J Urol, 64: 368, 1989 15. Fall, M., Geirsson, G. and Lindstro¨m, S.: A debate of the ICS nomenclature of bladder overactivity. Neurourol Urodyn, 9: 413, 1990 16. Fall, M., Geirsson, G. and Lindstro¨m, S.: Toward a new classification of overactive bladders. Neurourol Urodyn, 14: 635, 1995 17. Geirsson, G., Lindstro¨m, S. and Fall, M.: Pressure, volume and infusion speed criteria for the ice-water test. Br J Urol, 73: 498, 1994