- Email: [email protected]
Diabetic Cystopathy: Relationship to Autonomic Neuropathy Detected by Sympathetic Skin Response
0022-5347/97/1572-0580$03.00/0
Vol. 157. 580-584. February 1997 Printed in U.S.A.
THE JOURNAL OF UROLOGY Copynght 0 1997 by AMERICAN UROL~CICALASSOCIATION, h C
Urological Neurology and Urodynamics DLABETIC CYSTOPATHY: RELATIONSHIP TO AUTONOMIC NEUROPATHY DETECTED BY SYMPATHETIC SKIN RESPONSE TOMOHIRO UEDA, NAOKI YOSHIMURA AND OSAMU YOSHIDA From the Department of Urology, Kouga Public Hospital, Shiga, and Faculty
of
Medicine, Kyoto Uniuersity, Kyoto, Japan
ABSTRACT
Purpose: The possible relationship between bladder dysfunction and autonomic neuropathy was investigated in unselected diabetic patients. Materials and Methods: Bladder function was examined by cystometry in 53 unselected diabetic patients and 10 healthy controls. Sympathetic skin response was recorded in 23 of 53 patients and all control subjects to evaluate autonomic neuropathy associated with diabetes, and the results were compared to cystometric findings. Results: Cystometrograms exhibited significant increases in bladder volume at first desire to void and maximal bladder capacity, and a decrease in detrusor contractility in diabetic patients compared to those in controls. In addition, mean residual urine was significantly larger in diabetic patients than in controls. Among the 53 diabetic patients these bladder dysfunctions were also found in each subset of patients with no sign of retinopathy (33),no subjective urinary symptoms (32) or duration of diabetes less than 1 year (12). In 23 patients in whom sympathetic skin response was measured 12 without sympathetic skin responses had increased residual urine and decreased detrusor contraction pressure. The remaining 11 patients with a lower amplitude of sympathetic skin response and more prolonged latency than controls had a significant decrease in detrusor contraction pressure. Conclusions: Bladder dysfunction, characterized by loss of sensation, increased capacity and decreased contractility, was the main observation of diabetic cystopathy regardless of the duration or severity of the disease. The association of bladder dysfunction and autonomic neuropathy detected by the sympathetic skin response might indicate that diabetic cystopathy is a manifestation of peripheral neuropathy induced by diabetes. KEYWORDS: diabetes; bladder, neurogenic; sympathetic nervous system; skin Bladder dysfunction has been recognized as a frequent complication of diabetes mellitus, and has been characterized by impaired bladder sensation, increased bladder capacity and decreased bladder contractility, resulting in increased residual urine, urinary retention or overtlow inc0ntinence.l Experimental diabetic animals similarly exhibited bladder dysfunctions, such as increased threshold volume for reflex bladder contraction and altered detrusor contractility.2 The cystopathic findings in diabetic animals were reportedly associated with changes at various levels, including bladder innervating sensory and autonomic pathways and/or the detrusor muscle.3 Since clinical studies revealed that diabetic neuropathy, such as gastroparesis, abnormal sweating or orthostatic hypotension, was oRen found in patients with diabetic cystopathy, it has been generally admitted that peripheral neuropathy has an important role in diabetic cystopathy.4 However, the underlying mechanisms inducing bladder dysfunction in diabetes remain controversial. Several studies demonstrated that at an early stage of experimental diabetes bladder hypertrophy or altered receptor density of the detrusor muscle was observed in sucrose fed and diabetic rats, suggesting that diuresis caused by hyperglycemia might account for bladder dysfunction in diabetes.6 Others have shown that morphological changes in efferent and afferent pathways to the bladder were closely Accepted for publication June 21, 1996.
related to bladder dysfunction, and that these peripheral axonopathies were specifically induced in diabetic animals but not in diuretic animals.2.6 Thus, it might be of interest to investigate the correlation between bladder dysfunction and other autonomic dysfunctions in diabetic patients to determine whether bladder dysfunction is a manifestation of diabetic autonomic neuropathy. Therefore, we measured sympathetic skin response, which has recently been recognized as a reliable tool for assessing autonomic function in peripheral n e ~ r o p a t h y The . ~ sympathetic skin response that indicates sudomotor function of the extremity is a multisynaptic response involving various levels of the nervous system but mainly reflects the function of unmyelinated postganglionic sympathetic fibers due to the slow conduction of these fibers.? Reportedly, diabetic patients with autonomic neuropathy often have an absent sympathetic skin response or impaired nerve conduction, including low amplitude or prolonged latency of the sympathetic skin response.8.9 Therefore, we investigated bladder dysfunction and its possible relationship to autonomic dysfunction detected by sympathetic skin response recordings in unselected diabetic patients. MATERIALS AND METHODS
We investigated 53 unselected diabetic patients (28 women and 25 men 24 to 67 years old, mean age 61.7) who were
580
581
DIABETIC CYSTOPATHY AND AUTONOMIC NEUROPATHY
referred by the diabetic clinic for urodynamic examinations. Ten healthy volunteers (3 women and 7 men 22 to 80 years old, mean age 58.0) were also examined as normal controls. Diabetic patients were classified based on the duration of diabetes, type of treatment (diet only, oral hypoglycemic agents or insulin), Scott's classification of retinopathy ( 0 to 111) or subjective voiding symptoms. To examine bladder function 2 or 3 consecutive cystometrograms were obtained in all patients and healthy volunteers by infusion of physiological saline (30 ml. per minute) at room temperature through a 12F urethral catheter with the patient supine. Residual urine volume was also measured when the catheter was introduced. Three cystometric parameters, including volume at first desire to void, volume at maximal bladder capacity and maximal intravesical pressure on voiding, were measured for statistical comparison. Patients were requested to refrain from abdominal straining at voiding. Elevated intravesical pressure was considered to be due to bladder contractions when urine flow around the catheter was observed. In 10 patients intra-abdominal pressures were simultaneously recorded via a water-filled rectal catheter to confirm t h a t the increase in intra-abdominal pressure was negligible a t voiding. Sympathetic skin response was measured in 23 randomly selected cases among 53 patients and 10 healthy volunteers using a Mystro plus MS20 device.* The recording surface electromyographic electrodes were applied to the palm and dorsum of the hand. Stimulation was applied at 15 mA. for 0.2 msee. through a n electrical stimulator placed on the skin at the wrist. The stimuli were repeated 25 times at 1-minute intervals for each stimulation to avoid habituation of response. The response was recorded at a sweep velocity of 500 msec. per division with a band pass of 1.6 to 3,200 Hz. Skin temperature at the site was maintained a t 32C or greater a n d patients were requested to remain relaxed with the eyes open during the test. Response amplitude was measured from peak to peak, and the mean value was calculated from t h e 5 largest sympathetic skin responses. Latency was measured from stimulus artifact to the onset of first response and averaged by selecting the 5 shortest sympathetic skin responses with a clear onset. For statistical evaluation, "-tailed Student's t test for unpaired data was used. Data were regarded as significantly different at p (0.05. RESULTS
The duration of diabetes in the 53 patients ranged from 3 months to 50 years (mean plus or minus standard deviation 9.9 ? 1.6 years), and in 12 (23%)it was 12 months since onset of the disease. Diabetic retinopathy (Scott's classification I to 111) was found in 20 of 53 patients (38%). Diabetes was treated by diet only in 25 patients (4770),oral hypoglycemic agents in 13 (25%)and insulin in 15 (28%).All patients were initially asymptomatic but, upon careful questioning, 21 of 53 (40%) complained of voiding symptoms, including urinary
* Medelec, Italy
frequency, incontinence, hesitancy, weak stream or sensation of residual urine. Transrectal ultrasonography and digital examination revealed no apparent signs of benign prostatic hypertrophy (BPH) in any man. Urinary tract infection in 2 patients was treated with antibiotics before cystometric evaluation. Since cystometric parameters were fairly consistent in consecutive cystometrographic recordings in each patient or normal volunteer, the data obtained from initial cystometrography were used for statistical analysis instead of a n average value. In 12 patients no strong sensations of filling were perceived in excess of 600 ml. infusion, although a slight sensation of filling was usually perceived during cystometrography. In these patients the volume of 600 ml. was regarded as the maximum bladder capacity for statistical comparison. First desire to void occurred at 133 t 11 ml. (mean plus or minus standard error) in normal controls, whereas the volume a t first desire to void was significantly (p ~ 0 . 0 1 increased ) to 184 t 20 ml. in diabetic patients. Maximum bladder capacity was also greater in diabetic patients (364 t 20 ml., p <0.001) than in controls (284 rt 10 ml.). Detrusor instability, defined as uninhibited bladder contractions greater than 15 cm. water on the filling phase of cystometrography, was detected in 7 women and 6 men (25%) with a history of cerebrovascular disease. Detrusor areflexia was not found in any patient except 1who was unable to void when the bladder was infused with 600 ml. saline, while voiding around the catheter was observed in the remaining 52 patients as well as healthy volunteers. Mean maximal bladder contraction pressure (39 t 3 cm. water, range 0 to 100) in diabetic patients was significantly (p CO.001) lower than in controls (80 +- 4 cm. water), among whom bladder contraction pressure in male volunteers (81.4 t 5.1 cm. water, range 70 to 100)was not significantly different from that in female volunteers (76.7 t 3.3 cm. water, range 70 to 80). In addition, diabetic patients had greater residual urine (99 r ~ _ 16 ml., p <0.01)than normal controls ( 5 t 2 ml., table 1). Bladder dysfunction was also found in the subgroups of diabetic patients with no signs of retinopathy or subjective symptoms of voiding dysfunction, or with diabetes for less than 12 months. Patients without diabetic retinopathy (33) had elevated volumes at first desire to void (197 t 25 ml., p <0.05) and maximum bladder capacity (384 t 23 ml., p <0.01), increased residual urine (92 2 20 ml., p C0.05) and decreased bladder contraction pressure (38 t 4 cm. water). The volumes at first desire to void (185 -t 24 ml., p <0.05) and maximum bladder capacity (364 24 ml., p <0.001) were larger in the 32 patients who did not have urological symptoms than in the normal controls. These patients also had decreased bladder contraction pressure (40 t 4 cm. water, p <0.001) but no significant changes in residual urine. The 12 patients with diabetes for less than 12 months also had changes in cystometrographic parameters, such as increased maximum bladder capacity (403 t 28 ml., p <0.01) and decreased bladder contraction pressure (27 t 4 cm. water, p <0.001). In 25 patients in whom diabetes was treated by diet only the volumes at first desire to void and maximum
*
T ~ L 1. E Cystometrographic parameters in controls and diabetics Diabetics Control
No. pts. Total No. ots. Mean c SE: Vol. at first desire to void (ml.) Max.bladder capacity (ml.) Bladder pressure (cm. water) Residual urine (ml.) * p c0.05compared to controls. t p <0.01 compared to controls.
10 139 -t 11 284 C 10 80 c 4 5c2
No Retinopathy
No Urinary Symptom
Duration Less Than 1 Yr.
Treatment Diet
53
33
32
12
25
184 2 20' 364 f 20t 39 2 3t 99 16*
197 f 25* 23: 384 I 38 -c 4t 92 2 2*
185 2 24* 364 2 24t 40 2 4t 58 i- 14
216 2 39 403 ? 28t 27 c 4t 32 I 16
189 2 27. 369 2 30t 42 ? 5t
f_
82 2 19
DIABETIC CYSTOPATHY AND AUTONOMIC NEUROPATHY
582
bladder capacity were larger (189 2 27 ml., p c 0 . 0 5 and 369 t 30 ml., p <0.001, respectively) and mean bladder contraction pressure was less (42 5 5 ml., p <0.001)t h a n those in normal subjects (table 1). A sympathetic skin response was present in 100% of 10 normal subjects (part A of figure) and in 11 of 23 diabetics ( 4 8 4 ) in whom sympathetic skin response was measured, while it was absent in t h e remaining 12 (5296, part B of figure). However, in t h e 11 patients with a sympathetic skin response onset latency was significantly longer (1.55 2 0.07 versus 0.83 2 0.01 seconds, p <0.0001) and mean amplitude was significantly less than those in normal controls (0.66 2 0.17 versus 1.49 -t 0.06 mV., p <0.0001, table 2 and p a r t C of figure). Cystometric evaluations revealed a significant decrease in bladder contraction pressure (48 8 cm. water, p <0.05) and an increase i n residual urine (194 +_ 58 ml., p <0.01) in patients with a n absent sympathetic skin response compared to those in the controls. In addition, patients with a sympathetic skin response had a lower bladder contraction pressure (41 2 8 em. water, p cO.01) than controls. There were no significant differences i n cystometric parameters between patients with and without a sympathetic skin response (table 3).
TABLE2 Sympathetic skin response latency and amplitude
in
10
controls and 12 diabetics with a sympathetrc skin response Controls Mean latency f SE (secs Mean amplitude 2 SE ( m V I * p
Diabetics'
083 t 001 1 49 t 0 06
1 55 :0 07 066?017 -~
TABLE3 Cystonefrographicparameters i n diabetics with or without a sympathetic skin response Controls
Total No. pts. Mean f SE: Val. at first desire to void (ml.) Max. bladder capacity (ml.) Bladder pressure (cm. water) Residual urine (rn1.1 * p 10.05 compared to controls. t p <0.01compared to controls.
Sympathetic Skin Response Absent
10
11
1 3 9 k 11 284 k 10 80 z 4 5 5 2
85 t 25 275 2 43 48 I 8' 194 2 58:
Svmaathetic . Skin Response Present 12 106 313 41 71
f 21
t 45 t 8t t 31
vaned among studies.'0-13 For example, bladder dysfunction was found in 36% of 53 patients investigated when it waa defined as a n increase i n bladder capacity t o more than 400 Our study demonstrated that diabetic patients exhibited ml. with a flat trace on cystometrography according to the significant bladder dysfunction, including impaired bladder criteria proposed by Kahan e t a1.10 Using t h e criterion that sensation a n d increased bladder capacity. It is difficult t o bladder capacity exceeding 500 ml. was regarded a s abnorjudge whether each diabetic patient had bladder dysfunction, mal,13.14 32% of our patients had diabetic cystopathy. These since the normal value for bladder sensation or capacity calculated incidences were not different from the 30 to 80% rates i n other clinical studies.15 Frimodt-M~llerfirst reported detailed characteristics of bladder dysfunction, such as loss of bladder sensation and increased bladder capacity, in unselected diabetic patients.', 11 In t h a t series diabetic cystopathy was characterized as loss of sensation detected by elevated electrical bladder perception threshold, and it was found i n 38% of 100 unselected diabetic patients. Urodynamic investigations between healthy volunteers and unselected patients have also exhibited increments in bladder capacity a t first sensation and maximal cystometric capacity concomitant with significant residual urine a s found in our study." Our study also revealed a decreased bladder contraction pressure i n diabetic patients compared to con500 mS trols. In our cystometric evaluation a n elevation in intravesical pressure was likely t o be due to detrusor contraction because voiding around the catheter was observed along with a sustained increase i n intravesical pressure and, in some cases, a n increase in intra-abdominal pressure was confirmed to be negligible during urination. It h a s been recognized that some diabetic patients concomitantly exhibited bladder outlet obstruction mainly due to BPH.",'5 Since bladder contraction pressure was not different between male and female volunteers, it is unlikely t h a t healthy controls exhibited high bladder contraction pressure due to bladder outlet obstruction. In addition, bladder contraction pressure in male diabetics was not greater than t h a t in male controls. However, the possibility might exist t h a t our study included a patient with impaired bladder contractility and bladder outlet obstruction, since a detailed urodynamic evaluation, such a s pressure-flow study, was not performed. Nevertheless, since the bladder contraction pressure was measured under t h e same conditions in all controls and diabetics, it would be justified to compare t h e values hetwrern the 2 groups. Therefore, the decrease in hladder contraction pressure in diahetic patients seems to indicate impairment of hladder contractility. Overall. it is rcasonahle to conclude I that hypoactive deti-usor function is the main diaracteristic Sympathetic skin response. A, nonnal control subject. B and C. ' diabetic patients without and with sympathetic skin response, re- of diabetic cvstooathv. It should be noted t h a t 2.5'4 of our diahetic patients had spectively. Note that sympathetic skin response in part c' showed more prolonged latency and lower amplitude than that in part A . detrusor hyperreflexia. It has heen docuructntcd t h a t detrusor DISCUSSION
Il
-2
DIABETIC CYSTOPATHY AND AUTONOMIC NEUROPATHY
583
overactivity is a manifestation of diabetic patients.lI.15 HowExperimental studies using hereditary or chemically inever, it is uncertain whether diabetes induces detrusor over- duced diabetic animals have shown cystometric changes simactivity since other concomitant conditions, including supra- ilar to those observed in humans. Diabetic animals exhibited sacral neurological lesion or BPH, possibly cause the same increased threshold volume for micturition reflex and decondition. In fact, all of the patients with detrusor hyperre- creased amplitude of bladder contractions, resulting in inflexia had a history of cerebrovascular disease, which is a competent micturition associated with increased residual main cause of detrusor overactivity.16 In addition, detrusor urine and/or overflow incontinence.2.22 Steers et a1 showed overactivity was found almost equally in our patients of both changes in afferent and efferent pathways innervating the sexes, suggesting that BPH might not be a dominant cause of bladder in streptozotocin induced diabetic rats.23 Autonomic detrusor hyperreflexia in diabetic patients. neuropathy, confirmed by significant decreases of acetylchoWe also demonstrated that a short history or early stage of hesterase staining and activity in detrusor muscle, has been diabetes did not exclude the existence of diabetic cystopathy, found in spontaneously diabetic Chinese hamsters.3 In addisince bladder dysfunction was observed in patients with di- tion, the morphological changes in pelvic and hypogastric abetes for less than 12 months, no retinopathy or treatment nerves found in spontaneously diabetic BB rats were simiby diet only. It has been reported that retinopathy was ob- larly detected in other sensory and parasympathetic served in 40 to 60% of patients with diabetic cystopathy’ and nerves.6.24’ Therefore, these experimental data indicate that 25% of those treated with oral hypoglycemic agents that diabetic cystopathy is attributable to axonopathy in andior diet had bladder dysfunction.” Overall, one should be sensory and autonomic pathways innervating the bladder. aware of bladder dysfunction regardless of the severity or However, some of the alterations in the bladder were found duration of diabetes. In addition, our study demonstrated not only in diabetic animals but also in nondiabetic animals bladder dysfunction in patients without voiding symp- fed with sucrose, suggesting that bladder dysfunction in ditoms. Kaplan et a1 recently reported that the etiology of abetes is not solely due to peripheral neuropathy, particuvoiding dysfunction in diabetic patients with persistent void- larly in the early phase of diabetes. Tammela et a1 reported ing symptoms was attributable not only to classic diabetic that sucrose fed and streptozotocin-induced diabetic rats cystopathy but also to other pathophysiological conditions, similarly exhibited the increases in bladder mass and volume including bladder outlet obstruction or detrusor hyper- threshold for micturition reflex.26 In addition, Fukumoto et reflexia.I5 Although 25% of our patients had detrusor al showed the up regulation of detrusor muscarinic receptors hyperreflexia, more than half of them did not complain of any in sucrose fed and diabetic rats, leading to an increase in irritable urinary symptoms, probably due to loss of sensation. bladder strip contractility responding to field stimulation or Thus, early changes in bladder function in diaTherefore, it is suggested that patients with voiding symp- carba~hol.~? toms are not representative of the total population of diabetic betes might be due to functional adaptation to hyperglycemia patients with voiding dysfunction, which is in line with pre- induced diuresis. However, the comparisons between diuretic vious findings that 25 to 50% of diabetic patients did not and diabetic rats have exhibited specific changes in the bladder innervating peripheral pathway with diabetes.2.28 Furcomplain of voiding symptoms unless carefully questioned. The most interesting finding in our study was that auto- thermore, Par0 et al demonstrated that ganglioside, which nomic neuropathy detected by the sympathetic skin response has been shown to improve axonal regeneration capacity,29 coexisted with bladder dysfunction in a significant percent- restored cystometric changes in association with prevention age of diabetic patients. It has been demonstrated that the of axonopathy in pelvic nerves using diabetic BB rats, indisympathetic skin response is a simple and valuable test to cating that peripheral axonopathy is the main cause of diaassess diabetic peripheral neuropathy and early subclinical betic cystopathy.22 Overall, axonopathy in bladder innervatautonomic disturbance^.^. 17 Our cases without a sympathetic ing peripheral nerves is likely to be of primary importance in skin response which were considered to be definitely abnor- inducing diabetic bladder dysfunction, such as loss of sensama17 showed a significant increase in residual urine and a tion andlor decreased detrusor contractility as noted in our decrease in detrusor contractility. The remaining patients clinical study, although some of the changes in detrusor whose sympathetic skin response had a decreased amplitude muscle are attributable to hypoglycemia induced diuresis. and prolonged latency compared to controls also had impaired bladder contraction. Changes in amplitude or latency CONCLUSIONS of the sympathetic skin response have also been regarded as In unselected diabetic patients bladder dysfunction, chara significant sign of autonomic axonopathy.ls$19Therefore, it is reasonably assumed that bladder innervating nerve fibers acterized by loss of sensation, increased bladder capacity and undergo similar changes as observed in sympathetic postgan- decreased detrusor contractility, was observed regardless of the duration or seventy of diabetes. Since bladder dysfuncglionic axons to induce bladder dysfunction, although no tion was closely associated with autonomic neuropathy dedirect evidence of autonomic axonopathy innervating the tected by the sympathetic skin response, diabetic cystopathy bladder was shown in our study. This conclusion is further is likely to be a manifestation of peripheral neuropathy insupported by the findings of MacLeod et a1 who showed that, duced by diabetes. using expired-to-inspired beat-to-beat ratio measurements, the changes in sympathetic skin responses of diabetic paREFERENCES tients were more significantly correlated with those in the cholinergic parasympathetic nerve, which is the major inner1. Frimodt-Mdler, C.: Diabetic cystopathy. A review of the urodyvating pathway to the bladder, than in the adrenergic symnamic and clinical features of neurogenic bladder dysfunction in diabetes mellitus. Dan. Med. Bull., 25: 49,1978. pathetic nerve as evaluated with dark adapted pupil diame2. Paro, M., Italiano, G., Travagli, R. A , Petrelli, L., ZanoN, R., ter measurement.20 In contrast to our study, Maselli et a1 Prosdocimi, M. and Fiori, M. G.: Cystometric changes in alfailed to show a significant correlation between absent symloxan diabetic rats: evidence for functional and structural corpathetic skin response and bladder dysfunction in diabetic relates of diabetic autonomic neuropathy. J. Auton. Nerv. patients with symptoms of peripheral neuropathy.21 This Syst., 3 0 1, 1990. discrepancy might be due to a possible underestimation of 3. Itoh, H., Morikawa, A. and Makino, I.: Urinary bladder dysfuncthe incidence of bladder dysfunction, which was diagnosed by tion in spontaneously diabetic Chinese hamsters. Diabetes subjective symptoms alone. As shown in our study, bladder Res. Clin. Pract., 2 2 163,1994. 4. Ewing, D.J., Campbell, I. W. and Clarke, B. F.: The natural dysfunction was observed in diabetic patients with and withhistory of diabetic autonomic neuropathy. Quart.J. Med., 185: out subjective voiding symptoms when examined urodynamically. 95,1980.
DIABETIC CYSTOPATHY AND AUTONOMIC NEUROPATHY
584
5. Malmgren, A., Andersson, P. 0. and Uvelius, B.: Bladder func-
23. Steers, W. D., Mackway-Gerardi, A. M., Ciambotti, J. and
tion in rats with short- and long-term diabetes: effects of age and muscarinic blockade. J. Urol., 1 4 2 1608, 1989. Paro, M., Prosdocimi. M.. Zhang, W. X., Sutherland, G. and Sima, A. A.: Autonomic neuropathy in BB rats and alterations in bladder function. Diabetes, 38: 1023, 1989. Shahani. B. T.. Halperin, J. J., Boulu, P. and Cohen, J.: Sympathetic skin response-a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J. Neural. Neurosurg. Psychiat., 47: 536, 1984. Watahiki, Y., Baba, M., Matsunaga, M., Takebe, K. and Onuma, T.: Sympathetic skin response in diabetic neuropathy. Electromyogr. Clin. Neurophysiol., 2 9 155, 1989. Zgur, T., Vodusek, D. B., Krzan, M., Vrtovec, M., Denislic, M. and Sibanc, B.: Autonomic system dysfunction in moderate diabetic polyneuropathy assessed by sympathetic skin response and Valsalva index. Electromyogr. Clin. Neurophysiol.,
de Groat, W. C.: Alterations in neural pathways to the urinary bladder of the r a t in response to streptozotocin-induced diabetes. J. Auton. Nerv. Sys.. 47: 83, 1994. 24. Sima, A. A., Bouchier, M. and Christensen, H.: Axonal atrophy in sensory nerves of the diabetic BB-Wistar rat: a possible early correlate of human diabetic neuropathy. Ann. Neurol.. 13:264,
6.
7.
8. 9.
33: 433, 1993. 10. Kahan, M., Goldberg, P. D. and Mandel, E. E.: Neurogenic vesical dysfunction and diabetes mellitus. N.Y. J. Med., 70: 2448, 1970. 11. Frimodt-Msller, C.: Diabetic cystopathy. I: A clinical study on
the frequency of bladder dysfunction in diabetics. Dan. Med. Bull., 23: 267, 1976. 12. Kaplan, S. A. and Blaivas, J. G.: Diabetic cystopathy. J. Diab. Complicat., 2: 133, 1988. 13. Ellenberg, M. and Weber, M.: The incipient asymptomatic diabetic bladder. Diabetes, 16 331, 1967. 14. Faerman, I., Maler, M., Jadzinsky, M., Alvarez, E., Fox, D., Zilbervarg, J.. Cibeira, J. B. and Colinas, R.: Asymptomatic neurogenic bladder in juvenile diabetics. Diabetologia, 7: 168, 1971. 15. Kaplan, S. A., Te, A. E. and Blaivas, J. G.: Urodynamic findings in patients with diabetic cystopathy. J. Urol., 153: 342, 1995. 16. Starer, P. and Libow, L.: Cystometric evaluation of bladder dys-
function in elderly diabetic patients. Arch. Intern. Med., 150 810,1990. 17. Shahani, B. T., Day, T. J., Cros, D., Khalil, N. and Kneebone,
C. S.: RR interval variation and the sympathetic skin response in the assessment of autonomic function in peripheral neuropathy. Arch. Neurol., 47: 659, 1990. 18. Levy, D. M., Reid, G., Rowley, D. A. and Abraham, R. R.: Quantitative measures of sympathetic skin response in diabetes: relation to sudomotor and neurological function. J. Neurol. Neurosurg. Psychiat., 55: 902, 1992. 19. Tzeng, S. S., Wu, Z. A. and Chu, F. L.: The latencies of sympathetic skin responses. Eur. Neurol., 33: 65, 1993. 20. MacLeod, A. F., Smith, S . A., Cowell, T., Richardson, P. R. and Sonksen, P. H.: Non-cardiac autonomic tests in diabetes: use of galvanic skin response. Diabetic Med., 8: 67, 1991. 21. Maselli, R. A., Jaspan. J. B., Soliven, R. C., Green. A. J., Spire, J. P. and Arnason, B. G.: Comparison of sympathetic skin response with quantitative sudomotor axon reflex test in diabetic neuropathy. Muscle Nerve, 12:420, 1989. 22. Paro, M.. Prashar, A., Prosdocimi. M., Cherian, P. V., Fiori. M. G. and Sima. A. A. F.: Urinary bladder dysfunction in the BB/W diabetic rat: effect of ganglioside treatment on functional and structual alterations. J. Urol.. 151: 781. 1994.
1983. 25. Yagihashi, S. and Sima, A. A,: Diabetic autonomic neuropathy in
BB rat: ultrastructural and morphometric changes in parasympathetic nerves. Diabetes, 35: 733, 1986. 26. Tammela, T. L. J., Leggett, R. E., Levin, R. M. and Longhurst, P. A,: Temporal changes in micturition and bladder contractility after sucrose diuresis and streptozotocin-induced diabetes mellitus in rats. J. Urol., 153: 2014, 1995. 27. Fukumoto, Y., Yoshida, M., Weiss, R. M. and Latifpour, J.: Reversibility of diabetes- and diuresis-induced alterations in rat bladder dome muscarinic receptors. Diabetes, 43: 819, 1994. 28. Kudlacz, E. M., Chun, A. L., Skau, K. A., Gerald, M. C. and
Wallace, L. J.: Diabetes and diuretic-induced alterations in function of rat urinary bladder. Diabetes, 37: 949, 1988. 29. Triban, C., Guidolin, D., Fabris, M., Marini, P., Schiavinato, A,, Dona, M., Bortolami, M. C., Di Giamberardino, L. and Fiori, M. G.: Ganglioside treatment and improved axonal regeneration capacity in experimental diabetic neuropathy. Diabetes,
38: 1012, 1989. EDITORIAL COMMENT This article on diabetic cystopathy is important because it details the spectrum of urological dysfunction in a group of nonselect diabetic patients. Kaplan e t a1 (reference 15 in article) recently showed that detrusor hyperreflexia was the predominant finding in a select group of diabetic patients with voiding symptoms who were referred for urodynamic testing. This finding is important and helpful for urologists taking care of diabetic patients. However, t h e general medical community may misinterpret that detrusor hyperreflexia is the most common urological manifestation in all diabetic patients. The authors were able to study a group of nonselect diabetic patients, many without urological symptoms and with variable duration of diabetes. They clearly demonstrated that autonomic neuropathy with diminished bladder sensation and contractility is the predominant urological dysfunction in diabetic cystopathy. With diminished sensation and increased bladder capacity, patients with diabetic cystopathy may delay seeking urological evaluation. The take-home message of this article is that all physicians taking care of diabetic patients should be aware that bladder dysfunction can occur silently and early in the course of diabetes. Careful surveillance for voiding symptoms and screening for elevated residual urine by health care providers may be helpful to prevent long-term complications secondary to diabetic cystopathy. Michael B. Chcmccllor D e p w t r n t w f of' Urology Jefferson Mediccil C'ollcgge Ph ilndelphrn, Pen nsyluania
Vol. 157. 580-584. February 1997 Printed in U.S.A.
THE JOURNAL OF UROLOGY Copynght 0 1997 by AMERICAN UROL~CICALASSOCIATION, h C
Urological Neurology and Urodynamics DLABETIC CYSTOPATHY: RELATIONSHIP TO AUTONOMIC NEUROPATHY DETECTED BY SYMPATHETIC SKIN RESPONSE TOMOHIRO UEDA, NAOKI YOSHIMURA AND OSAMU YOSHIDA From the Department of Urology, Kouga Public Hospital, Shiga, and Faculty
of
Medicine, Kyoto Uniuersity, Kyoto, Japan
ABSTRACT
Purpose: The possible relationship between bladder dysfunction and autonomic neuropathy was investigated in unselected diabetic patients. Materials and Methods: Bladder function was examined by cystometry in 53 unselected diabetic patients and 10 healthy controls. Sympathetic skin response was recorded in 23 of 53 patients and all control subjects to evaluate autonomic neuropathy associated with diabetes, and the results were compared to cystometric findings. Results: Cystometrograms exhibited significant increases in bladder volume at first desire to void and maximal bladder capacity, and a decrease in detrusor contractility in diabetic patients compared to those in controls. In addition, mean residual urine was significantly larger in diabetic patients than in controls. Among the 53 diabetic patients these bladder dysfunctions were also found in each subset of patients with no sign of retinopathy (33),no subjective urinary symptoms (32) or duration of diabetes less than 1 year (12). In 23 patients in whom sympathetic skin response was measured 12 without sympathetic skin responses had increased residual urine and decreased detrusor contraction pressure. The remaining 11 patients with a lower amplitude of sympathetic skin response and more prolonged latency than controls had a significant decrease in detrusor contraction pressure. Conclusions: Bladder dysfunction, characterized by loss of sensation, increased capacity and decreased contractility, was the main observation of diabetic cystopathy regardless of the duration or severity of the disease. The association of bladder dysfunction and autonomic neuropathy detected by the sympathetic skin response might indicate that diabetic cystopathy is a manifestation of peripheral neuropathy induced by diabetes. KEYWORDS: diabetes; bladder, neurogenic; sympathetic nervous system; skin Bladder dysfunction has been recognized as a frequent complication of diabetes mellitus, and has been characterized by impaired bladder sensation, increased bladder capacity and decreased bladder contractility, resulting in increased residual urine, urinary retention or overtlow inc0ntinence.l Experimental diabetic animals similarly exhibited bladder dysfunctions, such as increased threshold volume for reflex bladder contraction and altered detrusor contractility.2 The cystopathic findings in diabetic animals were reportedly associated with changes at various levels, including bladder innervating sensory and autonomic pathways and/or the detrusor muscle.3 Since clinical studies revealed that diabetic neuropathy, such as gastroparesis, abnormal sweating or orthostatic hypotension, was oRen found in patients with diabetic cystopathy, it has been generally admitted that peripheral neuropathy has an important role in diabetic cystopathy.4 However, the underlying mechanisms inducing bladder dysfunction in diabetes remain controversial. Several studies demonstrated that at an early stage of experimental diabetes bladder hypertrophy or altered receptor density of the detrusor muscle was observed in sucrose fed and diabetic rats, suggesting that diuresis caused by hyperglycemia might account for bladder dysfunction in diabetes.6 Others have shown that morphological changes in efferent and afferent pathways to the bladder were closely Accepted for publication June 21, 1996.
related to bladder dysfunction, and that these peripheral axonopathies were specifically induced in diabetic animals but not in diuretic animals.2.6 Thus, it might be of interest to investigate the correlation between bladder dysfunction and other autonomic dysfunctions in diabetic patients to determine whether bladder dysfunction is a manifestation of diabetic autonomic neuropathy. Therefore, we measured sympathetic skin response, which has recently been recognized as a reliable tool for assessing autonomic function in peripheral n e ~ r o p a t h y The . ~ sympathetic skin response that indicates sudomotor function of the extremity is a multisynaptic response involving various levels of the nervous system but mainly reflects the function of unmyelinated postganglionic sympathetic fibers due to the slow conduction of these fibers.? Reportedly, diabetic patients with autonomic neuropathy often have an absent sympathetic skin response or impaired nerve conduction, including low amplitude or prolonged latency of the sympathetic skin response.8.9 Therefore, we investigated bladder dysfunction and its possible relationship to autonomic dysfunction detected by sympathetic skin response recordings in unselected diabetic patients. MATERIALS AND METHODS
We investigated 53 unselected diabetic patients (28 women and 25 men 24 to 67 years old, mean age 61.7) who were
580
581
DIABETIC CYSTOPATHY AND AUTONOMIC NEUROPATHY
referred by the diabetic clinic for urodynamic examinations. Ten healthy volunteers (3 women and 7 men 22 to 80 years old, mean age 58.0) were also examined as normal controls. Diabetic patients were classified based on the duration of diabetes, type of treatment (diet only, oral hypoglycemic agents or insulin), Scott's classification of retinopathy ( 0 to 111) or subjective voiding symptoms. To examine bladder function 2 or 3 consecutive cystometrograms were obtained in all patients and healthy volunteers by infusion of physiological saline (30 ml. per minute) at room temperature through a 12F urethral catheter with the patient supine. Residual urine volume was also measured when the catheter was introduced. Three cystometric parameters, including volume at first desire to void, volume at maximal bladder capacity and maximal intravesical pressure on voiding, were measured for statistical comparison. Patients were requested to refrain from abdominal straining at voiding. Elevated intravesical pressure was considered to be due to bladder contractions when urine flow around the catheter was observed. In 10 patients intra-abdominal pressures were simultaneously recorded via a water-filled rectal catheter to confirm t h a t the increase in intra-abdominal pressure was negligible a t voiding. Sympathetic skin response was measured in 23 randomly selected cases among 53 patients and 10 healthy volunteers using a Mystro plus MS20 device.* The recording surface electromyographic electrodes were applied to the palm and dorsum of the hand. Stimulation was applied at 15 mA. for 0.2 msee. through a n electrical stimulator placed on the skin at the wrist. The stimuli were repeated 25 times at 1-minute intervals for each stimulation to avoid habituation of response. The response was recorded at a sweep velocity of 500 msec. per division with a band pass of 1.6 to 3,200 Hz. Skin temperature at the site was maintained a t 32C or greater a n d patients were requested to remain relaxed with the eyes open during the test. Response amplitude was measured from peak to peak, and the mean value was calculated from t h e 5 largest sympathetic skin responses. Latency was measured from stimulus artifact to the onset of first response and averaged by selecting the 5 shortest sympathetic skin responses with a clear onset. For statistical evaluation, "-tailed Student's t test for unpaired data was used. Data were regarded as significantly different at p (0.05. RESULTS
The duration of diabetes in the 53 patients ranged from 3 months to 50 years (mean plus or minus standard deviation 9.9 ? 1.6 years), and in 12 (23%)it was 12 months since onset of the disease. Diabetic retinopathy (Scott's classification I to 111) was found in 20 of 53 patients (38%). Diabetes was treated by diet only in 25 patients (4770),oral hypoglycemic agents in 13 (25%)and insulin in 15 (28%).All patients were initially asymptomatic but, upon careful questioning, 21 of 53 (40%) complained of voiding symptoms, including urinary
* Medelec, Italy
frequency, incontinence, hesitancy, weak stream or sensation of residual urine. Transrectal ultrasonography and digital examination revealed no apparent signs of benign prostatic hypertrophy (BPH) in any man. Urinary tract infection in 2 patients was treated with antibiotics before cystometric evaluation. Since cystometric parameters were fairly consistent in consecutive cystometrographic recordings in each patient or normal volunteer, the data obtained from initial cystometrography were used for statistical analysis instead of a n average value. In 12 patients no strong sensations of filling were perceived in excess of 600 ml. infusion, although a slight sensation of filling was usually perceived during cystometrography. In these patients the volume of 600 ml. was regarded as the maximum bladder capacity for statistical comparison. First desire to void occurred at 133 t 11 ml. (mean plus or minus standard error) in normal controls, whereas the volume a t first desire to void was significantly (p ~ 0 . 0 1 increased ) to 184 t 20 ml. in diabetic patients. Maximum bladder capacity was also greater in diabetic patients (364 t 20 ml., p <0.001) than in controls (284 rt 10 ml.). Detrusor instability, defined as uninhibited bladder contractions greater than 15 cm. water on the filling phase of cystometrography, was detected in 7 women and 6 men (25%) with a history of cerebrovascular disease. Detrusor areflexia was not found in any patient except 1who was unable to void when the bladder was infused with 600 ml. saline, while voiding around the catheter was observed in the remaining 52 patients as well as healthy volunteers. Mean maximal bladder contraction pressure (39 t 3 cm. water, range 0 to 100) in diabetic patients was significantly (p CO.001) lower than in controls (80 +- 4 cm. water), among whom bladder contraction pressure in male volunteers (81.4 t 5.1 cm. water, range 70 to 100)was not significantly different from that in female volunteers (76.7 t 3.3 cm. water, range 70 to 80). In addition, diabetic patients had greater residual urine (99 r ~ _ 16 ml., p <0.01)than normal controls ( 5 t 2 ml., table 1). Bladder dysfunction was also found in the subgroups of diabetic patients with no signs of retinopathy or subjective symptoms of voiding dysfunction, or with diabetes for less than 12 months. Patients without diabetic retinopathy (33) had elevated volumes at first desire to void (197 t 25 ml., p <0.05) and maximum bladder capacity (384 t 23 ml., p <0.01), increased residual urine (92 2 20 ml., p C0.05) and decreased bladder contraction pressure (38 t 4 cm. water). The volumes at first desire to void (185 -t 24 ml., p <0.05) and maximum bladder capacity (364 24 ml., p <0.001) were larger in the 32 patients who did not have urological symptoms than in the normal controls. These patients also had decreased bladder contraction pressure (40 t 4 cm. water, p <0.001) but no significant changes in residual urine. The 12 patients with diabetes for less than 12 months also had changes in cystometrographic parameters, such as increased maximum bladder capacity (403 t 28 ml., p <0.01) and decreased bladder contraction pressure (27 t 4 cm. water, p <0.001). In 25 patients in whom diabetes was treated by diet only the volumes at first desire to void and maximum
*
T ~ L 1. E Cystometrographic parameters in controls and diabetics Diabetics Control
No. pts. Total No. ots. Mean c SE: Vol. at first desire to void (ml.) Max.bladder capacity (ml.) Bladder pressure (cm. water) Residual urine (ml.) * p c0.05compared to controls. t p <0.01 compared to controls.
10 139 -t 11 284 C 10 80 c 4 5c2
No Retinopathy
No Urinary Symptom
Duration Less Than 1 Yr.
Treatment Diet
53
33
32
12
25
184 2 20' 364 f 20t 39 2 3t 99 16*
197 f 25* 23: 384 I 38 -c 4t 92 2 2*
185 2 24* 364 2 24t 40 2 4t 58 i- 14
216 2 39 403 ? 28t 27 c 4t 32 I 16
189 2 27. 369 2 30t 42 ? 5t
f_
82 2 19
DIABETIC CYSTOPATHY AND AUTONOMIC NEUROPATHY
582
bladder capacity were larger (189 2 27 ml., p c 0 . 0 5 and 369 t 30 ml., p <0.001, respectively) and mean bladder contraction pressure was less (42 5 5 ml., p <0.001)t h a n those in normal subjects (table 1). A sympathetic skin response was present in 100% of 10 normal subjects (part A of figure) and in 11 of 23 diabetics ( 4 8 4 ) in whom sympathetic skin response was measured, while it was absent in t h e remaining 12 (5296, part B of figure). However, in t h e 11 patients with a sympathetic skin response onset latency was significantly longer (1.55 2 0.07 versus 0.83 2 0.01 seconds, p <0.0001) and mean amplitude was significantly less than those in normal controls (0.66 2 0.17 versus 1.49 -t 0.06 mV., p <0.0001, table 2 and p a r t C of figure). Cystometric evaluations revealed a significant decrease in bladder contraction pressure (48 8 cm. water, p <0.05) and an increase i n residual urine (194 +_ 58 ml., p <0.01) in patients with a n absent sympathetic skin response compared to those in the controls. In addition, patients with a sympathetic skin response had a lower bladder contraction pressure (41 2 8 em. water, p cO.01) than controls. There were no significant differences i n cystometric parameters between patients with and without a sympathetic skin response (table 3).
TABLE2 Sympathetic skin response latency and amplitude
in
10
controls and 12 diabetics with a sympathetrc skin response Controls Mean latency f SE (secs Mean amplitude 2 SE ( m V I * p
Diabetics'
083 t 001 1 49 t 0 06
1 55 :0 07 066?017 -~
TABLE3 Cystonefrographicparameters i n diabetics with or without a sympathetic skin response Controls
Total No. pts. Mean f SE: Val. at first desire to void (ml.) Max. bladder capacity (ml.) Bladder pressure (cm. water) Residual urine (rn1.1 * p 10.05 compared to controls. t p <0.01compared to controls.
Sympathetic Skin Response Absent
10
11
1 3 9 k 11 284 k 10 80 z 4 5 5 2
85 t 25 275 2 43 48 I 8' 194 2 58:
Svmaathetic . Skin Response Present 12 106 313 41 71
f 21
t 45 t 8t t 31
vaned among studies.'0-13 For example, bladder dysfunction was found in 36% of 53 patients investigated when it waa defined as a n increase i n bladder capacity t o more than 400 Our study demonstrated that diabetic patients exhibited ml. with a flat trace on cystometrography according to the significant bladder dysfunction, including impaired bladder criteria proposed by Kahan e t a1.10 Using t h e criterion that sensation a n d increased bladder capacity. It is difficult t o bladder capacity exceeding 500 ml. was regarded a s abnorjudge whether each diabetic patient had bladder dysfunction, mal,13.14 32% of our patients had diabetic cystopathy. These since the normal value for bladder sensation or capacity calculated incidences were not different from the 30 to 80% rates i n other clinical studies.15 Frimodt-M~llerfirst reported detailed characteristics of bladder dysfunction, such as loss of bladder sensation and increased bladder capacity, in unselected diabetic patients.', 11 In t h a t series diabetic cystopathy was characterized as loss of sensation detected by elevated electrical bladder perception threshold, and it was found i n 38% of 100 unselected diabetic patients. Urodynamic investigations between healthy volunteers and unselected patients have also exhibited increments in bladder capacity a t first sensation and maximal cystometric capacity concomitant with significant residual urine a s found in our study." Our study also revealed a decreased bladder contraction pressure i n diabetic patients compared to con500 mS trols. In our cystometric evaluation a n elevation in intravesical pressure was likely t o be due to detrusor contraction because voiding around the catheter was observed along with a sustained increase i n intravesical pressure and, in some cases, a n increase in intra-abdominal pressure was confirmed to be negligible during urination. It h a s been recognized that some diabetic patients concomitantly exhibited bladder outlet obstruction mainly due to BPH.",'5 Since bladder contraction pressure was not different between male and female volunteers, it is unlikely t h a t healthy controls exhibited high bladder contraction pressure due to bladder outlet obstruction. In addition, bladder contraction pressure in male diabetics was not greater than t h a t in male controls. However, the possibility might exist t h a t our study included a patient with impaired bladder contractility and bladder outlet obstruction, since a detailed urodynamic evaluation, such a s pressure-flow study, was not performed. Nevertheless, since the bladder contraction pressure was measured under t h e same conditions in all controls and diabetics, it would be justified to compare t h e values hetwrern the 2 groups. Therefore, the decrease in hladder contraction pressure in diahetic patients seems to indicate impairment of hladder contractility. Overall. it is rcasonahle to conclude I that hypoactive deti-usor function is the main diaracteristic Sympathetic skin response. A, nonnal control subject. B and C. ' diabetic patients without and with sympathetic skin response, re- of diabetic cvstooathv. It should be noted t h a t 2.5'4 of our diahetic patients had spectively. Note that sympathetic skin response in part c' showed more prolonged latency and lower amplitude than that in part A . detrusor hyperreflexia. It has heen docuructntcd t h a t detrusor DISCUSSION
Il
-2
DIABETIC CYSTOPATHY AND AUTONOMIC NEUROPATHY
583
overactivity is a manifestation of diabetic patients.lI.15 HowExperimental studies using hereditary or chemically inever, it is uncertain whether diabetes induces detrusor over- duced diabetic animals have shown cystometric changes simactivity since other concomitant conditions, including supra- ilar to those observed in humans. Diabetic animals exhibited sacral neurological lesion or BPH, possibly cause the same increased threshold volume for micturition reflex and decondition. In fact, all of the patients with detrusor hyperre- creased amplitude of bladder contractions, resulting in inflexia had a history of cerebrovascular disease, which is a competent micturition associated with increased residual main cause of detrusor overactivity.16 In addition, detrusor urine and/or overflow incontinence.2.22 Steers et a1 showed overactivity was found almost equally in our patients of both changes in afferent and efferent pathways innervating the sexes, suggesting that BPH might not be a dominant cause of bladder in streptozotocin induced diabetic rats.23 Autonomic detrusor hyperreflexia in diabetic patients. neuropathy, confirmed by significant decreases of acetylchoWe also demonstrated that a short history or early stage of hesterase staining and activity in detrusor muscle, has been diabetes did not exclude the existence of diabetic cystopathy, found in spontaneously diabetic Chinese hamsters.3 In addisince bladder dysfunction was observed in patients with di- tion, the morphological changes in pelvic and hypogastric abetes for less than 12 months, no retinopathy or treatment nerves found in spontaneously diabetic BB rats were simiby diet only. It has been reported that retinopathy was ob- larly detected in other sensory and parasympathetic served in 40 to 60% of patients with diabetic cystopathy’ and nerves.6.24’ Therefore, these experimental data indicate that 25% of those treated with oral hypoglycemic agents that diabetic cystopathy is attributable to axonopathy in andior diet had bladder dysfunction.” Overall, one should be sensory and autonomic pathways innervating the bladder. aware of bladder dysfunction regardless of the severity or However, some of the alterations in the bladder were found duration of diabetes. In addition, our study demonstrated not only in diabetic animals but also in nondiabetic animals bladder dysfunction in patients without voiding symp- fed with sucrose, suggesting that bladder dysfunction in ditoms. Kaplan et a1 recently reported that the etiology of abetes is not solely due to peripheral neuropathy, particuvoiding dysfunction in diabetic patients with persistent void- larly in the early phase of diabetes. Tammela et a1 reported ing symptoms was attributable not only to classic diabetic that sucrose fed and streptozotocin-induced diabetic rats cystopathy but also to other pathophysiological conditions, similarly exhibited the increases in bladder mass and volume including bladder outlet obstruction or detrusor hyper- threshold for micturition reflex.26 In addition, Fukumoto et reflexia.I5 Although 25% of our patients had detrusor al showed the up regulation of detrusor muscarinic receptors hyperreflexia, more than half of them did not complain of any in sucrose fed and diabetic rats, leading to an increase in irritable urinary symptoms, probably due to loss of sensation. bladder strip contractility responding to field stimulation or Thus, early changes in bladder function in diaTherefore, it is suggested that patients with voiding symp- carba~hol.~? toms are not representative of the total population of diabetic betes might be due to functional adaptation to hyperglycemia patients with voiding dysfunction, which is in line with pre- induced diuresis. However, the comparisons between diuretic vious findings that 25 to 50% of diabetic patients did not and diabetic rats have exhibited specific changes in the bladder innervating peripheral pathway with diabetes.2.28 Furcomplain of voiding symptoms unless carefully questioned. The most interesting finding in our study was that auto- thermore, Par0 et al demonstrated that ganglioside, which nomic neuropathy detected by the sympathetic skin response has been shown to improve axonal regeneration capacity,29 coexisted with bladder dysfunction in a significant percent- restored cystometric changes in association with prevention age of diabetic patients. It has been demonstrated that the of axonopathy in pelvic nerves using diabetic BB rats, indisympathetic skin response is a simple and valuable test to cating that peripheral axonopathy is the main cause of diaassess diabetic peripheral neuropathy and early subclinical betic cystopathy.22 Overall, axonopathy in bladder innervatautonomic disturbance^.^. 17 Our cases without a sympathetic ing peripheral nerves is likely to be of primary importance in skin response which were considered to be definitely abnor- inducing diabetic bladder dysfunction, such as loss of sensama17 showed a significant increase in residual urine and a tion andlor decreased detrusor contractility as noted in our decrease in detrusor contractility. The remaining patients clinical study, although some of the changes in detrusor whose sympathetic skin response had a decreased amplitude muscle are attributable to hypoglycemia induced diuresis. and prolonged latency compared to controls also had impaired bladder contraction. Changes in amplitude or latency CONCLUSIONS of the sympathetic skin response have also been regarded as In unselected diabetic patients bladder dysfunction, chara significant sign of autonomic axonopathy.ls$19Therefore, it is reasonably assumed that bladder innervating nerve fibers acterized by loss of sensation, increased bladder capacity and undergo similar changes as observed in sympathetic postgan- decreased detrusor contractility, was observed regardless of the duration or seventy of diabetes. Since bladder dysfuncglionic axons to induce bladder dysfunction, although no tion was closely associated with autonomic neuropathy dedirect evidence of autonomic axonopathy innervating the tected by the sympathetic skin response, diabetic cystopathy bladder was shown in our study. This conclusion is further is likely to be a manifestation of peripheral neuropathy insupported by the findings of MacLeod et a1 who showed that, duced by diabetes. using expired-to-inspired beat-to-beat ratio measurements, the changes in sympathetic skin responses of diabetic paREFERENCES tients were more significantly correlated with those in the cholinergic parasympathetic nerve, which is the major inner1. Frimodt-Mdler, C.: Diabetic cystopathy. A review of the urodyvating pathway to the bladder, than in the adrenergic symnamic and clinical features of neurogenic bladder dysfunction in diabetes mellitus. Dan. Med. Bull., 25: 49,1978. pathetic nerve as evaluated with dark adapted pupil diame2. Paro, M., Italiano, G., Travagli, R. A , Petrelli, L., ZanoN, R., ter measurement.20 In contrast to our study, Maselli et a1 Prosdocimi, M. and Fiori, M. G.: Cystometric changes in alfailed to show a significant correlation between absent symloxan diabetic rats: evidence for functional and structural corpathetic skin response and bladder dysfunction in diabetic relates of diabetic autonomic neuropathy. J. Auton. Nerv. patients with symptoms of peripheral neuropathy.21 This Syst., 3 0 1, 1990. discrepancy might be due to a possible underestimation of 3. Itoh, H., Morikawa, A. and Makino, I.: Urinary bladder dysfuncthe incidence of bladder dysfunction, which was diagnosed by tion in spontaneously diabetic Chinese hamsters. Diabetes subjective symptoms alone. As shown in our study, bladder Res. Clin. Pract., 2 2 163,1994. 4. Ewing, D.J., Campbell, I. W. and Clarke, B. F.: The natural dysfunction was observed in diabetic patients with and withhistory of diabetic autonomic neuropathy. Quart.J. Med., 185: out subjective voiding symptoms when examined urodynamically. 95,1980.
DIABETIC CYSTOPATHY AND AUTONOMIC NEUROPATHY
584
5. Malmgren, A., Andersson, P. 0. and Uvelius, B.: Bladder func-
23. Steers, W. D., Mackway-Gerardi, A. M., Ciambotti, J. and
tion in rats with short- and long-term diabetes: effects of age and muscarinic blockade. J. Urol., 1 4 2 1608, 1989. Paro, M., Prosdocimi. M.. Zhang, W. X., Sutherland, G. and Sima, A. A.: Autonomic neuropathy in BB rats and alterations in bladder function. Diabetes, 38: 1023, 1989. Shahani. B. T.. Halperin, J. J., Boulu, P. and Cohen, J.: Sympathetic skin response-a method of assessing unmyelinated axon dysfunction in peripheral neuropathies. J. Neural. Neurosurg. Psychiat., 47: 536, 1984. Watahiki, Y., Baba, M., Matsunaga, M., Takebe, K. and Onuma, T.: Sympathetic skin response in diabetic neuropathy. Electromyogr. Clin. Neurophysiol., 2 9 155, 1989. Zgur, T., Vodusek, D. B., Krzan, M., Vrtovec, M., Denislic, M. and Sibanc, B.: Autonomic system dysfunction in moderate diabetic polyneuropathy assessed by sympathetic skin response and Valsalva index. Electromyogr. Clin. Neurophysiol.,
de Groat, W. C.: Alterations in neural pathways to the urinary bladder of the r a t in response to streptozotocin-induced diabetes. J. Auton. Nerv. Sys.. 47: 83, 1994. 24. Sima, A. A., Bouchier, M. and Christensen, H.: Axonal atrophy in sensory nerves of the diabetic BB-Wistar rat: a possible early correlate of human diabetic neuropathy. Ann. Neurol.. 13:264,
6.
7.
8. 9.
33: 433, 1993. 10. Kahan, M., Goldberg, P. D. and Mandel, E. E.: Neurogenic vesical dysfunction and diabetes mellitus. N.Y. J. Med., 70: 2448, 1970. 11. Frimodt-Msller, C.: Diabetic cystopathy. I: A clinical study on
the frequency of bladder dysfunction in diabetics. Dan. Med. Bull., 23: 267, 1976. 12. Kaplan, S. A. and Blaivas, J. G.: Diabetic cystopathy. J. Diab. Complicat., 2: 133, 1988. 13. Ellenberg, M. and Weber, M.: The incipient asymptomatic diabetic bladder. Diabetes, 16 331, 1967. 14. Faerman, I., Maler, M., Jadzinsky, M., Alvarez, E., Fox, D., Zilbervarg, J.. Cibeira, J. B. and Colinas, R.: Asymptomatic neurogenic bladder in juvenile diabetics. Diabetologia, 7: 168, 1971. 15. Kaplan, S. A., Te, A. E. and Blaivas, J. G.: Urodynamic findings in patients with diabetic cystopathy. J. Urol., 153: 342, 1995. 16. Starer, P. and Libow, L.: Cystometric evaluation of bladder dys-
function in elderly diabetic patients. Arch. Intern. Med., 150 810,1990. 17. Shahani, B. T., Day, T. J., Cros, D., Khalil, N. and Kneebone,
C. S.: RR interval variation and the sympathetic skin response in the assessment of autonomic function in peripheral neuropathy. Arch. Neurol., 47: 659, 1990. 18. Levy, D. M., Reid, G., Rowley, D. A. and Abraham, R. R.: Quantitative measures of sympathetic skin response in diabetes: relation to sudomotor and neurological function. J. Neurol. Neurosurg. Psychiat., 55: 902, 1992. 19. Tzeng, S. S., Wu, Z. A. and Chu, F. L.: The latencies of sympathetic skin responses. Eur. Neurol., 33: 65, 1993. 20. MacLeod, A. F., Smith, S . A., Cowell, T., Richardson, P. R. and Sonksen, P. H.: Non-cardiac autonomic tests in diabetes: use of galvanic skin response. Diabetic Med., 8: 67, 1991. 21. Maselli, R. A., Jaspan. J. B., Soliven, R. C., Green. A. J., Spire, J. P. and Arnason, B. G.: Comparison of sympathetic skin response with quantitative sudomotor axon reflex test in diabetic neuropathy. Muscle Nerve, 12:420, 1989. 22. Paro, M.. Prashar, A., Prosdocimi. M., Cherian, P. V., Fiori. M. G. and Sima. A. A. F.: Urinary bladder dysfunction in the BB/W diabetic rat: effect of ganglioside treatment on functional and structual alterations. J. Urol.. 151: 781. 1994.
1983. 25. Yagihashi, S. and Sima, A. A,: Diabetic autonomic neuropathy in
BB rat: ultrastructural and morphometric changes in parasympathetic nerves. Diabetes, 35: 733, 1986. 26. Tammela, T. L. J., Leggett, R. E., Levin, R. M. and Longhurst, P. A,: Temporal changes in micturition and bladder contractility after sucrose diuresis and streptozotocin-induced diabetes mellitus in rats. J. Urol., 153: 2014, 1995. 27. Fukumoto, Y., Yoshida, M., Weiss, R. M. and Latifpour, J.: Reversibility of diabetes- and diuresis-induced alterations in rat bladder dome muscarinic receptors. Diabetes, 43: 819, 1994. 28. Kudlacz, E. M., Chun, A. L., Skau, K. A., Gerald, M. C. and
Wallace, L. J.: Diabetes and diuretic-induced alterations in function of rat urinary bladder. Diabetes, 37: 949, 1988. 29. Triban, C., Guidolin, D., Fabris, M., Marini, P., Schiavinato, A,, Dona, M., Bortolami, M. C., Di Giamberardino, L. and Fiori, M. G.: Ganglioside treatment and improved axonal regeneration capacity in experimental diabetic neuropathy. Diabetes,
38: 1012, 1989. EDITORIAL COMMENT This article on diabetic cystopathy is important because it details the spectrum of urological dysfunction in a group of nonselect diabetic patients. Kaplan e t a1 (reference 15 in article) recently showed that detrusor hyperreflexia was the predominant finding in a select group of diabetic patients with voiding symptoms who were referred for urodynamic testing. This finding is important and helpful for urologists taking care of diabetic patients. However, t h e general medical community may misinterpret that detrusor hyperreflexia is the most common urological manifestation in all diabetic patients. The authors were able to study a group of nonselect diabetic patients, many without urological symptoms and with variable duration of diabetes. They clearly demonstrated that autonomic neuropathy with diminished bladder sensation and contractility is the predominant urological dysfunction in diabetic cystopathy. With diminished sensation and increased bladder capacity, patients with diabetic cystopathy may delay seeking urological evaluation. The take-home message of this article is that all physicians taking care of diabetic patients should be aware that bladder dysfunction can occur silently and early in the course of diabetes. Careful surveillance for voiding symptoms and screening for elevated residual urine by health care providers may be helpful to prevent long-term complications secondary to diabetic cystopathy. Michael B. Chcmccllor D e p w t r n t w f of' Urology Jefferson Mediccil C'ollcgge Ph ilndelphrn, Pen nsyluania