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Diabetic cystopathy
Diabetic Cyst0pathy
Steven A. Kaplan, MD Jerry G. Blaivas, MD Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York
ABSTRACT Diabetic cystopathy refers to the spectrum of voiding dysfunction in patients with diabetes mellitus. Diabetic cystopathy is marked by insidious onset and progression with minimal symptomology. The most common urodynamic findings are impairment of bladder sensation, increased post-void residual volume, decreased detrusor contractility that may progress to detrusor areflexia and diminished urinary flow. Treatment of diabetic cystopathy may be complicated by frequently occurring coexisting urologic conditions. The most common of these is bladder outlet obstruction. Therefore, treatment of diabetic cystopathy should be tailored to the symptom complex and clinical condition of the patient. Asymptomatic patients with manifestations of diabetic cystopathy may be treated with timed voiding. In contrast, the sine qua non for therapy in symptomatic patients is clean intermittent catheterization. While other modalities such as pharmacologic and surgical intervention have been described, none have been consistently effective. (The Journal of Diabetic Complications 2;3:133-139, 1988.)
INTRODUCTION
This paper was presented, in part, at the Diabetic Renal-Retinal Syndrome IV, New York, November 1987. Reprint requests: to be sent to Jerry G. Blaivas, MD, Columbia-Presbyterian Medical Center, 622 W. 168th Street, New York, NY 10032.
Many patients with neuropathic diseases complain of lower urinary tract symptoms and the etiology of these symptoms is usually attributed to the underlying disease. However, not infrequently these patients have co-existent urologic conditions, for example, urinary tract infection, bladder or prostate cancer, and/or benign prostatic hypertrophy which may be more important in the genesis of their symptoms. Therefore, before initiating treatment, it is vital to exclude these common urologic conditions and to determine the precise etiology of the complaints. The diagnosis and treatment of bladder symptoms of non-urologic origin requires a clear understanding of the neurophysiology of micturition and knowledge of how different neurologic lesions affect normal physiology. Moreover, one must have a lucid understanding of the purpose of urodynamic testing and apply those principles to diagnosis and treatment. Although beyond the scope of this article, certain aspects of the neurophysiology of micturition should be emphasized. The "micturition reflex" is a coordinated event characterized by contraction of the detrusor, opening of the bladder outlet and relaxation of the sphincter (Figure 1). 1 During the storage phase, the bladder fills with intravesical pressure t.hatremains constant. There is a gradual increase in electromyographic activity of the external urethral sphincter. During this period bladder pressure is-always lower than urethral pressure. The bladder neck remains closed at all times except during voiding and does not open even under periods of stress. Urine expulsion is initiated by the micturition reflex, which is characterized by relaxation of the 133
134
KAPLAN AND BLAIVAS
EXtoPS/~Ncter~ CONTRACTS FIG. 1 Physiologyof micturition.
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COMMAND TOVOID
ExternoI P
Urethral t Pressure Bladder J FIow
external urethral sphincter, a fall in urethral pressure, and the onset of a detrusor contraction. The proximal urethra is isobaric with the bladder during micturition. Contraction of the external urethral sphincter allows for the voluntary interruption of the urinary stream. During this tim e, intravesical pressure rises transiently with the detrusor contracting against a complete obstruction at the external urethral sphincter. Although organized in the rostral brain center, the micturition reflex requires the interplay of the somatic and parasympathetic components of the sacral spinal cord as well as the thoracolumbar sympathetics (Figure 2). 1'2 Voluntary control of the micturition reflex is established by several suprapontine pathways which are grouped as pathway 1. Interruption of this pathway results in the loss of control of the micturition reflex. The micturition reflex is intergrated in the rostral brain center (pathway 2). This pathway interconnects the "sacral micturition center" with the "pontine micturition center"; coordinated voiding depends on the integrity of this pathway. Interruption of this pathway usually results in detrusor external sphincter dyssynergia. Pathway 3 connects the pudendal nucleus that controls the external urethral sphincter with the motor cortex. Neurologic disorders that affect this pathway interfere with the ability to voluntarily contract the external urethral sphincter and interrupt the voided stream. The sympathetic system (pathway 4) has two functions. The alpha-adrenergic system prevents premature detrusor contractions by its effect on the parasympathetic synapse. Another alpha-adrenergic mechanism maintains tone at the vesical neck. The primary role of the sympathetic system is to modulate urine storage. Therefore, during voiding, both of these systems are "shut off." Finally, the "sacral micturition center" consists of both the afferent and efferent parasym-
pathetic "pelvic" pathways and the pudendal pathways. These are located between $2 and $4. Uncoordinated micturition results by initiating this micturition reflex. Neurologic lesions affecting this pathway result in bladder areflexia. Interruption of any portion of the micturition pathway results in voiding dysfunction. For example, interruption of the neural pathways connecting the brain stem with the "sacral micturition center" usually results in detrusor sphincter dyssynergia (DESD). This is characterized by involuntary contractions of both the detrusor and the striated sphincter. 1 Patients with untreated detrusor external sphincter dyssynergia are at considerable risk for developing such serious urologic complications as vesicoureteral reflux, hydronephrosis, urolithiasis, and sepsis. 3 Dyssynergia may be caused by disease processes such as multiple sclerosis, myelodysplasia, tumors, or arteriovenous malformations of the spinal cord above the level of the lumbar vertebrae. Neurologic lesions that interfere with the sacral reflex arc, for example, diabetic neuropathy and herniated discs, may cause a spectrum of symptoms from decreased bladder sensation and incomplete bladder emptying to detrusor areflexia. 4 Diabetic autonomic neuropathy may affect every organ system. The onset of symptoms is variable, often insidious, and has no typical pattern, s Some patients experience disabling symptoms; others have symptoms that are subclinical and difficult to detect. 6 Pathologically, the autonomic neuropathy is secondary to a metabolic derangement of the Schwann cell, resulting in the segmental demyelinization and impairment of nerve conduction. 7-9 Diabetes mellitus has been associated with a significant incidence of urinary tract dysfunction. In fact, Frimodt-Moller coined the phrase "diabetic
DIABETIC CYSTOPATHY
135 ciated with the diabetic bladder. ~~ When unselected diabetic patients have undergone routine urodynamic studies, the incidence of diabetic cystopathy ranges from 27 to 85%. ~4-16,18,19Of note, diabetic cystopathy correlates closely with the duration of symptoms (generally occurring about 10 years after onset of diabetes), but not with the severity of the diabetes as judged by theamount or type of pharmacologic therapy. 2~ Diabetic cystopathy almost always co-exists with signs of peripheral neu ropathy.14.16.17.19.21
URODYNAMIC FINDINGS
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FIG. 2
Neurophysiology of micturition.
cystopathy" to describe the involvement of the lower urinary tract by autonomic neuropathyj0 The clinical features of diabetic cystopathy are marked by insidious onset and progression, with minimal symptoms. Impaired bladder sensation is the most common initial presentation. This is probably secondary to damage of visceral afferent fibers in the bladder wall. 11 This impairment of bladder sensation causes a gradual change in the pattern of a patient's voiding. Because of an increase in the time interval between voidings, patients may void only once or twice a day. In fact, the patient may be voiding "by the clock" without even experiencing the urge to void. As sensory impairment continues to progress, patients may experience difficulty in initiating and maintaining micturition. Therefore, patients may require abdominal straining.~ with a resulting weak, slow urinary stream and terminal dribbling. Diabetics do not generally complain about bladder symptoms, but if specifically questioned, 25 to 50% may, in fact, have experienced disturbances asso-
The principal urodynamic findings in patients with diabetic cystopathy include impaired bladder sensation, increased residual urine volume, decreased detrusor contractility (which may progress to detrusor areflexia), and impaired urinary flow. Abnormalities of bladder sensation are difficult to evaluate. This may be due to sensory impulses derived from structures contiguous to the bladder. 22 Sensation may be qualitatively evaluated cystometrically by measuring the bladder volume when the patient first becomes aware of bladder filling, when the patient has the first urge to void, when the patient feels that micturition is imminent and when bladder capacity is attained, e,1~176 Normal values of the first Sensation of bladder filling varied in these series with measures from 200 to 600 ml. However, these methods are difficult to assess quantitatively. If one were to use the criterion that the first sensation of bladder filling occurs at 50% of bladder capacity, 24 abnormalities in bladder sensation are seen in most unselected diabetic patients. However, when comparing the volumes of first sensation, both by urodynamic assessment and by cystometry, little correlation is noted. 26 Thus, in an attempt to assess bladder sensation in a more quantitative way, Frimodt-Moller developed a technique to measure the electrical perception threshold (EPT). Using a specifically designed catheter electrode, the bladder mucosa was electrically stimulated. The current at which the patient experiences a tingling sensation is defined as the EPT. Normal patients experienced the EPT at currents below 10 mA. Values above 15 mA were considered pathognomonic of sensory loss. However, the EPT is age dependent. 26 Besides, some nondiabetic patients with bladder outlet obstruction manifest pathologic EPTs. Therefore, in patients who may have diabetic cystopathy as well as bladder outlet obstruction it may be difficult to determine the etiology of impaired bladder sensation. In patients with diabetic cystopathy, the cystometric examination reveals increased bladder capacity. 10,14.1z.20 However, as is true for assessment of bladder sensation, quantitative measures of bladder capacity are difficult to extrapolate from one series to another. Although there is good correlation between bladder capacity noted on both urodynamic investigation and cystometry, there is .great variation between individual patients. The occurrence of neurogenic abnormalities noted in diabetics by cystometric examination varied between 461~ and 87%. ~s Furthermore, when comparing voided volume and bladder capacity between normal volunteers and unselected
136
KAPLAN AND BLAIVAS pared with age and sex matched controls. 2s In contrast, Norlen 2z reported that 6 of 12 diabetic patients awaiting renal transplantation for diabetic nephropathy had evidence of impaired detrusor contractility. Detrusor instability describes a bladder that contracts involuntarily or that can be made to contract involuntarily. This type of unstable bladder may affect as much as 10% of the normal population.28The two most common etiologies for this condition are neuropathy and outflow obstruction. Clinically, the cardinal symptom of detrusor instability is the sensation of impending voiding, Le., urgency. Other symptoms include frequency, nocturia, and occasionally pain. Of note, those patients who have no sensation of the involuntary contraction may suffer from urge incontinence. Of note, unpublished data from our urodynamics laboratory reveal that as many as 25% of symptomatic diabetics manifest detrusor instability. Similarly, of the five diabetic patients with large bladder capacities in the Weir study, 29 tWO exhibited detrusor instability. Norlen 27 also noted one patient of twelve who had detrusor instability.
FIG. 3 A typical multichannel video urodynamic study. Urinary flow rate is represented by Q and in this patient was only 6 ml/min. DIFFERENTIALDIAGNOSIS Although contrast agent is visible in the urethra, this flow rate is markedly abnormal. The detrusor pressure is represented by B :.Cleariy, the most important differential diagnosis and, and is equal to the urethral pressure. In this patient, the maximum ~ in fact, one frequently coexisting with diabetic cystopapressure that could be generated by the bladder was 20 cm H20. "thy, is bladder outlet obstruction. In a series of 124 Therefore, the combination of a low urinary flow rate and an patients with diabetes, 10 38% were noted to have diainadequate bladder contraction is consistent with a "diseased" betic cystopathy, whereas 26% were diagnosed as havbladder. In fact, this urodynamic study was of a long-term " ing bladder outlet obstruction (mostly benign prostatic diabetic who had increasing obstructive voiding symptoms.
diabetics, Frimodt-Moller 25 noted significant differences. Bladder capacity was noted to be 625 ml for normal patients and 913 ml for diabetic patients. Additionally, voided volume was 513 ml for normal controls and 655 ml for patients with diabetes. However, a large bladder capacity is not pathognomonic for nor diagnostic of a diabetic bladder. In a series of 3,500 patients who were evaluated urodynamically, 26 109 were noted to have a bladder capacity greater than 2 SD from the mean value (500 ml) of the entire group:These 109 patients had a bladder capacity ranging from 800 to 1500 ml. Of the 109 patients, only five (4.8%) had diabetes mellitus, (one was otherwise urodynamically normal, one had impaired detrusor contractility, one had an acontractile bladder, and two had detrusor instability). The dynamics of micturition are characterized by various interactions between the propulsive forces of the detrusor and the "resistance" offered by the urethra. Clinically, abnormalities of micturition may manifest in a variety of ways. At one extreme, patients may complain of urinary frequency and urgency; at the other, a weak urinary stream or urinary retention. Determination of the urinary flow rate is an excellent screening procedure for identifying bladder outlet obstruction. However, it is not widely appreciated that a poor urinary flow rate and incomplete bladder emptying may also be due to poor detrusor contractility (Figure 3). In fact, another frequent manifestation of diabetic cystopathy is impaired detrusor contractility. In the Frimodt-Moller series, patients with diabetes did not manifest reduced voiding pressure corn-
hypertrophy). Fagerberg is reported a similar incidence of bladder outlet obstruction, but sophisticated urodynamic evaluation was not obtained to confirm this clinical impression. An important caveat is that screening uroflowmetry is of little use in making the distinction between bladder outlet obstruction and diabetic cystopathy because either condition may result in a diminished uroflow. This can be accomplished only by the simultaneous measurement of detrusor pressure and urinary flow rate. As one would expect in diabetic cystopathy; detrusor pressure during voiding is low. However, the diagnosis becomes more complicated when a patient has evidence of both diabetic cystopathy and bladder outlet obstruction. In these patients, the only method that can ascertain to what degree bladder outlet obstruction contributes to the symptom complex is performance of the micturitional static urethral pressure profile, as described by Anderson 22 and Yalla. 30 This entails measuring intraurethral pressure along the entire length of the urethra, which helps in localizing the urethral resistance.
TREATMENT To treat the symptoms associated with diabetic cystopathy adequately, one must have a clear comprehension of the underlying pathophysiology. This is most important when making the distinction between diabetic cystopathy and bladder outlet obstruction. Such proced-d'res as prostatectomy, which are designed to reduce bladder outlet obstruction, only alleviate symptoms of prostatism. However, they are of no value in patients who have impaired detrusor contractility only and they
DIABETICCYSTOPATHY
131
may actually prove harmful. Recommendations regardsively large bladder capacities or residual urine volumes ing therapy should be tailored to individual patients and should undergo urodynamic investigation. Because of take into account some of the associated manifestations the danger of upper tract damage, this is particularly imof diabetes in the genitourinary tract. portant in those diabetics who may have coexistent bladThe symptom complex exhibited by diabetic patients der outlet obstruction, detrusor hypertonicity, or poor should be differentiated from that of patients with either bladder compliance. 32 It is also prudent to treat asympbladder outlet obstruction (usually BPH) or detrusor intomatic bacteriuria with culture-specific antibiotics. stability primarily because of the different therapeutic regimens required for each disease category. Therefore, Symptomatic patients with diabetic cystopathy: The sine qua patients with low uroflow or retention should undergo non for therapy in patients with bladder disturbances simultaneous detrusor pressure/uroflow measurements. from diabetes is clean self-intermittent catheterization Those patients who generate an adequate detrusor con(CISC). 3~ If infection exists it should be treated with traction, Le., 75 cm H20 in the presence of a low flow culture-specific antibiotics in conjunction with CISC. AI'-, rate, have bladder outlet obstruction. The most common though several therapeutic regimens, listed below, have etiology of bladder outlet obstruction is BPH however, been recommended in this group of patients, none, in the and cystoscopic examination will rule out other potential authors' opinions, are effective. Bethanecol chloride, a causes such as strictures, tumors, or stones. parasympathomimetic, has been recommended to stimIn contrast, patients who manifest irrative voiding ulate detrusor contractility and bladder emptying. 34.35 symptoms, for example those with detrusor instabilHowever, most recent clinical studies show that bethaneity, require urodynamic assessment to distinguish these chol chloride does not significantly improve voiding. 36-38 symptoms from other causes of "urge", 29 which include For bethanechol chloride to be effective, the integrity of bladder hy.persensitivity from infection, stress incontithe lower motor neuron must be intact, allowing for the nence, and prostatitis. Therapy for these patients ranges "reflex bladder function" that is necessary for the drug from antibiotics for infections to anticholinergic agents to be of use. Therefore, patients with either detrusor for detrusor relaxation and surgical procedures such as i areflexia or complete lower motor neuron lesions are not augmentatiOn cystoplasty. candidates for parasympathetic agonists. Those series Chronic pyelonephritis occurs at a four to five times that have demonstrated some efficacy of this therapy higher rate!in diabetics than in the nondiabetic popuhave used much higher 'dosages, usually administered lation (based on autopsy studies). 31 Additionally, many - subcutaneously, than the dosages recommended by the series report a markedly increased incidence of bacFDA. Sonda 34 recommended subcutaneous doses of 2.5 teriuria and urinary tract infection in patients with to 10 mg bethanechol every 4 hours to initiate treatdiabetes. 10,20,31 It remains unclear whether diabetic ment in patients with severely decompensated bladders. cystopathy is the most significant factor in the increased To closely monitor the possible side effects of these incidence of urinary tract infection. However, it is vital parasympathetic agents, it is recommended that the drug that any patient who exhibits the risk factors of increased be administered to the patient in conjunction with CISC postresidual volume, bacteriuria, and urinary tract infecin the hospital. If the patient cannot void efficiently aftion be treated aggressively. ter 3 days, bethanechol is discontinued and the patient continued on intermittent catheterization. Oral maintenance doses averaged 50 mg four times daily, but higher TREATMENT GUIDELINES dosages are often necessary. Asymptomatic patients with diabetic cystopathy: Very little is AIpha-adrenolytic agents have been used to decrease known about the natural history of untreated asympbladder outlet resistance. When used in conjunction with tomatic patients with diabetic cystopathy. In addition, parasympathomimetics, these agents promote bladder there appears to be few short-term complications associemptying. 39 However, most studies of alpha-adrenolytic ated with this condition. It therefore seems justifiable eiagents have been performed on patients with bladder ther to treat aggressively with close monitoring of urine outlet obstruction caused by prostatic hypertrophy or cultures or to treat conservatively with reversible and detrusor sphincter dyssynergia. 40-43 In one study of panoninvasive therapy. A simple and effective method for tients with "autonomous bladders," Norlen 39 found that coping with the sensory abnormalitywhich leads to inalpha-adrenolytic therapy in the form of phenoxybenzafrequent emptying of the bladder is scheduled voiding. mine increased bladder capacity and at the same time Large residual urine volumes may be obviated by doureduced residual urine. Phenoxybenzamine is no longer ble or triple timed voiding. Some patients may benefit by recommended for prolonged usage because it is mutastraining to void. This is best monitored by determining genic in mice. Prazosin, a postsynaptic alpha-adrenergic if the flow of urine increases when straining. However, blocking agent, has fewer side effects than phenoxybenthose patients who manifest a decrease in the uroflow zamine. Norlen 39 reported that 2 mg of prazosin is equivduring straining should be specifically cautioned not to alent to 10 mg of phenoxybenzamine. strain during micturition. Many investigators support performing transurethral One question arises. At what time, if any, should uro- ---prostatic or bladder neck resection in diabetics to redynamic evaluation occur in asymptomatic diabetic paduce residual urine volume, lz,43.44 However, it is difficult tients? It is of utmost importance to ascertain if certain to evaluate these series quantitatively because the only risk factors are present in those patients and if further criterion for success of the procedure was a decrease in investigation is required. Therefore, patients with excesresidual urine volume. Because urodynamic criteria were
138
not used either before or after surgery, it is impossible to know whether or not these patients had concommitant bladder outlet obstruction. Our experience is that patients who have impaired detrusor contractility and subsequent poor urinary flow do not benefit by transurethral reduction of the bladder outlet. T o treat large capacity, low pressure bladders with high residual urine, several investigators have employed reduction cystoplasty and vesicoplication. 45 However, the major sequela of this procedure is that the large bladder capacity and residual urine recur within a year. Moreove[, there were no data in any of these studies to suggest that the patients being treated did, in fact, have diabetic cystopathy. Finally, another method for increasing bladder emptying is the Cred~ maneuver. 17 However, for the Crede maneuver to be clinically efficacious, even on theoretical grounds, certain baseline criteria must be met. That is, the increase in intravesical pressure w h i c h is transmitted by the Cred6 maneuver must be entirely transmitted to the flow controlling zone in the urethra while the bladder neck is open and the external sphincter relaxed. These simul'taneous phenomena rarely occur. In fact, in a series by Barbalias et al., 46 only 1% of patients would benefit by the Cred~ maneuver, and in those patients who have high outlet resistance or have vesicoureteral reflux, the Cred6 maneuver may be harmful.
REFERENCES 1. Blaivas JG: The neurophysiology of micturition: A clinical study of 550 patients. J Urol 127:958, 1982. 2. deGroat WC, Booth AM, Krier J, Milner RJ, Morgan C, Nadelhaft h Neural control of the urinary bladder and large intestine, in Chandler BM, Koizumi K, Sato A (eds), Intergrative Functions of the Autonomous Nervous System. Amsterdam, Elssevier Biomedical Press, 1979, Ch. 4. 3. Blaivas JG, Barbalias GA: Detrusor external sphincter dyssynergia in men with multiple sclerosis: An ominous urologic condition. J Urol 131:94, 1984. 4. McGuire EJ, Wagner FC, Jr: The effects of sacral denervation on bladder and urethral function. Surg Gynecol Obstet 144:343, 1977. 5. Clarke BF, Ewing DJ, Campbell IW: Clinical features of diabetic autonomic neuropathy. Horm Metab Res (Suppl) 9:50, 1980. 6. Ewing DJ, Campbell IW, Clarke BF: Mortality in diabetic autonomic neuropathy. Lancet 1:601, 1976. 7. Thomas PK, Lasceiles RG: The pathology of diabetic neuropathy. Q J Med 35:489, 1978. 8. Faerman I, Glacer C, Celener D, Jadzinsky M, Fox D, Maler M, Alverex E: Autonomic nervous system and diabetes. Histological and histochemical study of the autonomic nerve fibers of the urinary bladder in diabetic patients. Diabetes 22:255, 1973. 9. Ellenberg M: Neurologic changes in early diabetes.Advances in Metabolic Disorders 2:459, 1973. 10. Frimodt-Moller C: Diabetic cystopathy. 1: A clinical study on the frequency of bladder dysfunction in diabetics. Dan Med Bull 23:267, 1976. 11. Buck AC, Reed PI, Siddiq YK, Chisolm GD, Fraser TR: Bladder dysfunction and neuropathy in diabetes. Diabetetologia 12:251, 1976. 12. Spring M, Hymes J: Neurogenic bladder dysfunction as a complication of diabetes. Diabetes 2:199, 1966. 13. Martin MM: Diabetic neuropathy. Brain 76:594, 1953. 14. Ellenberg M, Weber H: The incipient asymptomatic diabetic bladder. Diabetes 16:331, 1967.
KAPLAN AND BLAIVAS 15. Faerman I, Maler M, Jadzinski M, Fox D, AIvarez E, Ziibervarg J, Cibeira JB, Colinas R: Asymptomatic neurogenic bladder in juvenile diabetes. Diabetologia 7:169, 1971. 16. Fagerberg SE, Kock NG, Peterson I, Stener h Urinary bladder disturbances in diabetics. Scand J Urol 1:19, 1967. 17. Kahan M, Goldberg PD, Mandel EE: Neurogenic vesical dysfunction in diabetes mellitus. NY State J Med 2:2448, 1970. 18. Reed PI, Buck AC, McRae CU, Siddig YK, Chisolm GD, Fraser TR: Vesico-urethral dysfunction and neuropathy in diabetes. Proc VIII Congress of the Internat Diab Fed Brussels 1973.
19. Larcan A, Huriet C, Vaillandet M, Fauchier JP: Les manifestations vesicales au cours du diabete. Interet de lay cystomanometrie. La Presse Medicale (Paris) 73:273, 1965. 20. Frimodt-Moller C: Diabetic cystopathy. Ih Relationship to some late diabetic manifestations. Dan Med Bull 23:279, 1976. 21. Bartley O, Brolin I, Fage[berg SE, Wilhemsen L: Neurogenic disorders of the bladder in diabetes mellitus. Acta Med Scand 108:187, 1966. 22. Anderson JT, Bradley WE: Neurourological investigation in urinary bladder dysfunction. Intern Urol Nephrol 9(2):133, 1977. 23. Motzkin D: The significance of deficient bladder sensation. J Urol 100:445, 1968. 24. Faerman I, Maler M, Jadzinsky M, et ah Asymptomatic neurogenic bladder in juvenile diabetes. Diabetologia 7:169, 1971. 25. Frimodt-Moller C: Diabetic cystopathy. Dan Med Bull 25:49, 1978. 26. Frimodt-Moller C, Hald T: A new method for quantitative evaluation of bladder sensibility. Scand J Urol Nephrol 6:135, 1972. 27. Norlen L, Blaivas JG, Gabel H: Cystopathy in patients with severe diabetic nephropathy. Diab Neph 2:17, 1983. 28. Munday AR: The unstable bladder. Urol Clin North Am 12(2):317, 1985. 29. Weir J, Jaques PF: Large capacity bladder. A urodynamic survey. Urology 4:544, 1974. 30. Yalla SV, Sharma GVRK, Barsamian EM: Micturitional urethral pressure profile during voiding and the implications. J Urol 124:649, 1980. 31. Edmonson HA, Martin HE, Evans N: Necrosis of renal papillae and acute pyelonephritis in diabetes mellitus. Arch Intern Med 79:148, 1947. 32. McGuire EJ, Woodside JR, Borden TA, weiss RM: Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 121:774, 1979. 33. Lapidas J, Dionko AC, Gould FR, Lowe BS: Further observations of self catheterization. J Urol 116:169, 1976. 34. Sonda LP, Gershon C, Dionko AC, Lapides J: Further observations on the cystometric and uroflowmetric effects of bethanacol chloride on the human bladder. J Urol 122:775, 1979. 35. Downie JW, Moochhala SM, Bialik JG: The role of reflexes in modifying the response to bethanacol chloride: a basis for selectivity of action on the bladder. Neurology and Urodynamics 2:301, 1983. 36. Barrett DM: The effect of oral bethanacol chloride on voiding in female patients with excessive residual urine: A randomized double blind study. J Urol 126:640, 1981. 37. Light KJ, Scott FB: Bethanacol chloride and the traumatic cord bladder. J Urol 128:85, 1982. 38. Wein A J, Hanno PM, Dixon DO, Raezer DM, Benson GS: The effect of oral bethanacol chloride on the cystometr0gram of the normal male adult. J Urol 120:300, 1978. 39. Norlen L, Sundin T: AIpha-adrenolytic treatment in patients with autonomous bladders. Acta Pharmacol Toxicol (Copenh) 43:31, 1978. 40.-'Caine M, Pfau A, Perlberg S: The use of alpha adrenergic blockers in benign prostatic obstruction. Br J Urol 48:255, 1976. 41. Caine M, Periberg S, Meretyk S: A placebo-controlled double-blind study of the effect of phenoxybenzamine in
DIABETIC CYSTOPATHY
benign prostatic obstruction. Br J Urol 50:551, 1978. 42. Caine M, Perlberg S, Shapiro A: Phenoxybenzamine for benign prostatic obstruction. Urology 17:542, 1981. 43. Emmett JL, Daut RV, Sprague RG: Transurethral resection for neurogenic vesical dysfunction in cases of diabetic neuropathy. J Urol 61:244, 1949. 44. Weinberg SR: Transurethral resection of the vesical neck
13g for relief of diabetic neurogenic dysfunction of the bladder. NY State J Med 56:882, 1956. 45. Stewart HH: The surgical treatment of severechronic retention without large diverticula. Br J Urol 38:685, 1966. 46. Barbalias GA, Klauber GT, Blaivas JG: Critical evaluation of the Crede maneuver: Urodynamic study of 207 patients. J Urol 130:720, 1983.
Steven A. Kaplan, MD Jerry G. Blaivas, MD Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York
ABSTRACT Diabetic cystopathy refers to the spectrum of voiding dysfunction in patients with diabetes mellitus. Diabetic cystopathy is marked by insidious onset and progression with minimal symptomology. The most common urodynamic findings are impairment of bladder sensation, increased post-void residual volume, decreased detrusor contractility that may progress to detrusor areflexia and diminished urinary flow. Treatment of diabetic cystopathy may be complicated by frequently occurring coexisting urologic conditions. The most common of these is bladder outlet obstruction. Therefore, treatment of diabetic cystopathy should be tailored to the symptom complex and clinical condition of the patient. Asymptomatic patients with manifestations of diabetic cystopathy may be treated with timed voiding. In contrast, the sine qua non for therapy in symptomatic patients is clean intermittent catheterization. While other modalities such as pharmacologic and surgical intervention have been described, none have been consistently effective. (The Journal of Diabetic Complications 2;3:133-139, 1988.)
INTRODUCTION
This paper was presented, in part, at the Diabetic Renal-Retinal Syndrome IV, New York, November 1987. Reprint requests: to be sent to Jerry G. Blaivas, MD, Columbia-Presbyterian Medical Center, 622 W. 168th Street, New York, NY 10032.
Many patients with neuropathic diseases complain of lower urinary tract symptoms and the etiology of these symptoms is usually attributed to the underlying disease. However, not infrequently these patients have co-existent urologic conditions, for example, urinary tract infection, bladder or prostate cancer, and/or benign prostatic hypertrophy which may be more important in the genesis of their symptoms. Therefore, before initiating treatment, it is vital to exclude these common urologic conditions and to determine the precise etiology of the complaints. The diagnosis and treatment of bladder symptoms of non-urologic origin requires a clear understanding of the neurophysiology of micturition and knowledge of how different neurologic lesions affect normal physiology. Moreover, one must have a lucid understanding of the purpose of urodynamic testing and apply those principles to diagnosis and treatment. Although beyond the scope of this article, certain aspects of the neurophysiology of micturition should be emphasized. The "micturition reflex" is a coordinated event characterized by contraction of the detrusor, opening of the bladder outlet and relaxation of the sphincter (Figure 1). 1 During the storage phase, the bladder fills with intravesical pressure t.hatremains constant. There is a gradual increase in electromyographic activity of the external urethral sphincter. During this period bladder pressure is-always lower than urethral pressure. The bladder neck remains closed at all times except during voiding and does not open even under periods of stress. Urine expulsion is initiated by the micturition reflex, which is characterized by relaxation of the 133
134
KAPLAN AND BLAIVAS
EXtoPS/~Ncter~ CONTRACTS FIG. 1 Physiologyof micturition.
l
II '[
~
COMMAND TOVOID
ExternoI P
Urethral t Pressure Bladder J FIow
external urethral sphincter, a fall in urethral pressure, and the onset of a detrusor contraction. The proximal urethra is isobaric with the bladder during micturition. Contraction of the external urethral sphincter allows for the voluntary interruption of the urinary stream. During this tim e, intravesical pressure rises transiently with the detrusor contracting against a complete obstruction at the external urethral sphincter. Although organized in the rostral brain center, the micturition reflex requires the interplay of the somatic and parasympathetic components of the sacral spinal cord as well as the thoracolumbar sympathetics (Figure 2). 1'2 Voluntary control of the micturition reflex is established by several suprapontine pathways which are grouped as pathway 1. Interruption of this pathway results in the loss of control of the micturition reflex. The micturition reflex is intergrated in the rostral brain center (pathway 2). This pathway interconnects the "sacral micturition center" with the "pontine micturition center"; coordinated voiding depends on the integrity of this pathway. Interruption of this pathway usually results in detrusor external sphincter dyssynergia. Pathway 3 connects the pudendal nucleus that controls the external urethral sphincter with the motor cortex. Neurologic disorders that affect this pathway interfere with the ability to voluntarily contract the external urethral sphincter and interrupt the voided stream. The sympathetic system (pathway 4) has two functions. The alpha-adrenergic system prevents premature detrusor contractions by its effect on the parasympathetic synapse. Another alpha-adrenergic mechanism maintains tone at the vesical neck. The primary role of the sympathetic system is to modulate urine storage. Therefore, during voiding, both of these systems are "shut off." Finally, the "sacral micturition center" consists of both the afferent and efferent parasym-
pathetic "pelvic" pathways and the pudendal pathways. These are located between $2 and $4. Uncoordinated micturition results by initiating this micturition reflex. Neurologic lesions affecting this pathway result in bladder areflexia. Interruption of any portion of the micturition pathway results in voiding dysfunction. For example, interruption of the neural pathways connecting the brain stem with the "sacral micturition center" usually results in detrusor sphincter dyssynergia (DESD). This is characterized by involuntary contractions of both the detrusor and the striated sphincter. 1 Patients with untreated detrusor external sphincter dyssynergia are at considerable risk for developing such serious urologic complications as vesicoureteral reflux, hydronephrosis, urolithiasis, and sepsis. 3 Dyssynergia may be caused by disease processes such as multiple sclerosis, myelodysplasia, tumors, or arteriovenous malformations of the spinal cord above the level of the lumbar vertebrae. Neurologic lesions that interfere with the sacral reflex arc, for example, diabetic neuropathy and herniated discs, may cause a spectrum of symptoms from decreased bladder sensation and incomplete bladder emptying to detrusor areflexia. 4 Diabetic autonomic neuropathy may affect every organ system. The onset of symptoms is variable, often insidious, and has no typical pattern, s Some patients experience disabling symptoms; others have symptoms that are subclinical and difficult to detect. 6 Pathologically, the autonomic neuropathy is secondary to a metabolic derangement of the Schwann cell, resulting in the segmental demyelinization and impairment of nerve conduction. 7-9 Diabetes mellitus has been associated with a significant incidence of urinary tract dysfunction. In fact, Frimodt-Moller coined the phrase "diabetic
DIABETIC CYSTOPATHY
135 ciated with the diabetic bladder. ~~ When unselected diabetic patients have undergone routine urodynamic studies, the incidence of diabetic cystopathy ranges from 27 to 85%. ~4-16,18,19Of note, diabetic cystopathy correlates closely with the duration of symptoms (generally occurring about 10 years after onset of diabetes), but not with the severity of the diabetes as judged by theamount or type of pharmacologic therapy. 2~ Diabetic cystopathy almost always co-exists with signs of peripheral neu ropathy.14.16.17.19.21
URODYNAMIC FINDINGS
=. (
::
-.
FIG. 2
Neurophysiology of micturition.
cystopathy" to describe the involvement of the lower urinary tract by autonomic neuropathyj0 The clinical features of diabetic cystopathy are marked by insidious onset and progression, with minimal symptoms. Impaired bladder sensation is the most common initial presentation. This is probably secondary to damage of visceral afferent fibers in the bladder wall. 11 This impairment of bladder sensation causes a gradual change in the pattern of a patient's voiding. Because of an increase in the time interval between voidings, patients may void only once or twice a day. In fact, the patient may be voiding "by the clock" without even experiencing the urge to void. As sensory impairment continues to progress, patients may experience difficulty in initiating and maintaining micturition. Therefore, patients may require abdominal straining.~ with a resulting weak, slow urinary stream and terminal dribbling. Diabetics do not generally complain about bladder symptoms, but if specifically questioned, 25 to 50% may, in fact, have experienced disturbances asso-
The principal urodynamic findings in patients with diabetic cystopathy include impaired bladder sensation, increased residual urine volume, decreased detrusor contractility (which may progress to detrusor areflexia), and impaired urinary flow. Abnormalities of bladder sensation are difficult to evaluate. This may be due to sensory impulses derived from structures contiguous to the bladder. 22 Sensation may be qualitatively evaluated cystometrically by measuring the bladder volume when the patient first becomes aware of bladder filling, when the patient has the first urge to void, when the patient feels that micturition is imminent and when bladder capacity is attained, e,1~176 Normal values of the first Sensation of bladder filling varied in these series with measures from 200 to 600 ml. However, these methods are difficult to assess quantitatively. If one were to use the criterion that the first sensation of bladder filling occurs at 50% of bladder capacity, 24 abnormalities in bladder sensation are seen in most unselected diabetic patients. However, when comparing the volumes of first sensation, both by urodynamic assessment and by cystometry, little correlation is noted. 26 Thus, in an attempt to assess bladder sensation in a more quantitative way, Frimodt-Moller developed a technique to measure the electrical perception threshold (EPT). Using a specifically designed catheter electrode, the bladder mucosa was electrically stimulated. The current at which the patient experiences a tingling sensation is defined as the EPT. Normal patients experienced the EPT at currents below 10 mA. Values above 15 mA were considered pathognomonic of sensory loss. However, the EPT is age dependent. 26 Besides, some nondiabetic patients with bladder outlet obstruction manifest pathologic EPTs. Therefore, in patients who may have diabetic cystopathy as well as bladder outlet obstruction it may be difficult to determine the etiology of impaired bladder sensation. In patients with diabetic cystopathy, the cystometric examination reveals increased bladder capacity. 10,14.1z.20 However, as is true for assessment of bladder sensation, quantitative measures of bladder capacity are difficult to extrapolate from one series to another. Although there is good correlation between bladder capacity noted on both urodynamic investigation and cystometry, there is .great variation between individual patients. The occurrence of neurogenic abnormalities noted in diabetics by cystometric examination varied between 461~ and 87%. ~s Furthermore, when comparing voided volume and bladder capacity between normal volunteers and unselected
136
KAPLAN AND BLAIVAS pared with age and sex matched controls. 2s In contrast, Norlen 2z reported that 6 of 12 diabetic patients awaiting renal transplantation for diabetic nephropathy had evidence of impaired detrusor contractility. Detrusor instability describes a bladder that contracts involuntarily or that can be made to contract involuntarily. This type of unstable bladder may affect as much as 10% of the normal population.28The two most common etiologies for this condition are neuropathy and outflow obstruction. Clinically, the cardinal symptom of detrusor instability is the sensation of impending voiding, Le., urgency. Other symptoms include frequency, nocturia, and occasionally pain. Of note, those patients who have no sensation of the involuntary contraction may suffer from urge incontinence. Of note, unpublished data from our urodynamics laboratory reveal that as many as 25% of symptomatic diabetics manifest detrusor instability. Similarly, of the five diabetic patients with large bladder capacities in the Weir study, 29 tWO exhibited detrusor instability. Norlen 27 also noted one patient of twelve who had detrusor instability.
FIG. 3 A typical multichannel video urodynamic study. Urinary flow rate is represented by Q and in this patient was only 6 ml/min. DIFFERENTIALDIAGNOSIS Although contrast agent is visible in the urethra, this flow rate is markedly abnormal. The detrusor pressure is represented by B :.Cleariy, the most important differential diagnosis and, and is equal to the urethral pressure. In this patient, the maximum ~ in fact, one frequently coexisting with diabetic cystopapressure that could be generated by the bladder was 20 cm H20. "thy, is bladder outlet obstruction. In a series of 124 Therefore, the combination of a low urinary flow rate and an patients with diabetes, 10 38% were noted to have diainadequate bladder contraction is consistent with a "diseased" betic cystopathy, whereas 26% were diagnosed as havbladder. In fact, this urodynamic study was of a long-term " ing bladder outlet obstruction (mostly benign prostatic diabetic who had increasing obstructive voiding symptoms.
diabetics, Frimodt-Moller 25 noted significant differences. Bladder capacity was noted to be 625 ml for normal patients and 913 ml for diabetic patients. Additionally, voided volume was 513 ml for normal controls and 655 ml for patients with diabetes. However, a large bladder capacity is not pathognomonic for nor diagnostic of a diabetic bladder. In a series of 3,500 patients who were evaluated urodynamically, 26 109 were noted to have a bladder capacity greater than 2 SD from the mean value (500 ml) of the entire group:These 109 patients had a bladder capacity ranging from 800 to 1500 ml. Of the 109 patients, only five (4.8%) had diabetes mellitus, (one was otherwise urodynamically normal, one had impaired detrusor contractility, one had an acontractile bladder, and two had detrusor instability). The dynamics of micturition are characterized by various interactions between the propulsive forces of the detrusor and the "resistance" offered by the urethra. Clinically, abnormalities of micturition may manifest in a variety of ways. At one extreme, patients may complain of urinary frequency and urgency; at the other, a weak urinary stream or urinary retention. Determination of the urinary flow rate is an excellent screening procedure for identifying bladder outlet obstruction. However, it is not widely appreciated that a poor urinary flow rate and incomplete bladder emptying may also be due to poor detrusor contractility (Figure 3). In fact, another frequent manifestation of diabetic cystopathy is impaired detrusor contractility. In the Frimodt-Moller series, patients with diabetes did not manifest reduced voiding pressure corn-
hypertrophy). Fagerberg is reported a similar incidence of bladder outlet obstruction, but sophisticated urodynamic evaluation was not obtained to confirm this clinical impression. An important caveat is that screening uroflowmetry is of little use in making the distinction between bladder outlet obstruction and diabetic cystopathy because either condition may result in a diminished uroflow. This can be accomplished only by the simultaneous measurement of detrusor pressure and urinary flow rate. As one would expect in diabetic cystopathy; detrusor pressure during voiding is low. However, the diagnosis becomes more complicated when a patient has evidence of both diabetic cystopathy and bladder outlet obstruction. In these patients, the only method that can ascertain to what degree bladder outlet obstruction contributes to the symptom complex is performance of the micturitional static urethral pressure profile, as described by Anderson 22 and Yalla. 30 This entails measuring intraurethral pressure along the entire length of the urethra, which helps in localizing the urethral resistance.
TREATMENT To treat the symptoms associated with diabetic cystopathy adequately, one must have a clear comprehension of the underlying pathophysiology. This is most important when making the distinction between diabetic cystopathy and bladder outlet obstruction. Such proced-d'res as prostatectomy, which are designed to reduce bladder outlet obstruction, only alleviate symptoms of prostatism. However, they are of no value in patients who have impaired detrusor contractility only and they
DIABETICCYSTOPATHY
131
may actually prove harmful. Recommendations regardsively large bladder capacities or residual urine volumes ing therapy should be tailored to individual patients and should undergo urodynamic investigation. Because of take into account some of the associated manifestations the danger of upper tract damage, this is particularly imof diabetes in the genitourinary tract. portant in those diabetics who may have coexistent bladThe symptom complex exhibited by diabetic patients der outlet obstruction, detrusor hypertonicity, or poor should be differentiated from that of patients with either bladder compliance. 32 It is also prudent to treat asympbladder outlet obstruction (usually BPH) or detrusor intomatic bacteriuria with culture-specific antibiotics. stability primarily because of the different therapeutic regimens required for each disease category. Therefore, Symptomatic patients with diabetic cystopathy: The sine qua patients with low uroflow or retention should undergo non for therapy in patients with bladder disturbances simultaneous detrusor pressure/uroflow measurements. from diabetes is clean self-intermittent catheterization Those patients who generate an adequate detrusor con(CISC). 3~ If infection exists it should be treated with traction, Le., 75 cm H20 in the presence of a low flow culture-specific antibiotics in conjunction with CISC. AI'-, rate, have bladder outlet obstruction. The most common though several therapeutic regimens, listed below, have etiology of bladder outlet obstruction is BPH however, been recommended in this group of patients, none, in the and cystoscopic examination will rule out other potential authors' opinions, are effective. Bethanecol chloride, a causes such as strictures, tumors, or stones. parasympathomimetic, has been recommended to stimIn contrast, patients who manifest irrative voiding ulate detrusor contractility and bladder emptying. 34.35 symptoms, for example those with detrusor instabilHowever, most recent clinical studies show that bethaneity, require urodynamic assessment to distinguish these chol chloride does not significantly improve voiding. 36-38 symptoms from other causes of "urge", 29 which include For bethanechol chloride to be effective, the integrity of bladder hy.persensitivity from infection, stress incontithe lower motor neuron must be intact, allowing for the nence, and prostatitis. Therapy for these patients ranges "reflex bladder function" that is necessary for the drug from antibiotics for infections to anticholinergic agents to be of use. Therefore, patients with either detrusor for detrusor relaxation and surgical procedures such as i areflexia or complete lower motor neuron lesions are not augmentatiOn cystoplasty. candidates for parasympathetic agonists. Those series Chronic pyelonephritis occurs at a four to five times that have demonstrated some efficacy of this therapy higher rate!in diabetics than in the nondiabetic popuhave used much higher 'dosages, usually administered lation (based on autopsy studies). 31 Additionally, many - subcutaneously, than the dosages recommended by the series report a markedly increased incidence of bacFDA. Sonda 34 recommended subcutaneous doses of 2.5 teriuria and urinary tract infection in patients with to 10 mg bethanechol every 4 hours to initiate treatdiabetes. 10,20,31 It remains unclear whether diabetic ment in patients with severely decompensated bladders. cystopathy is the most significant factor in the increased To closely monitor the possible side effects of these incidence of urinary tract infection. However, it is vital parasympathetic agents, it is recommended that the drug that any patient who exhibits the risk factors of increased be administered to the patient in conjunction with CISC postresidual volume, bacteriuria, and urinary tract infecin the hospital. If the patient cannot void efficiently aftion be treated aggressively. ter 3 days, bethanechol is discontinued and the patient continued on intermittent catheterization. Oral maintenance doses averaged 50 mg four times daily, but higher TREATMENT GUIDELINES dosages are often necessary. Asymptomatic patients with diabetic cystopathy: Very little is AIpha-adrenolytic agents have been used to decrease known about the natural history of untreated asympbladder outlet resistance. When used in conjunction with tomatic patients with diabetic cystopathy. In addition, parasympathomimetics, these agents promote bladder there appears to be few short-term complications associemptying. 39 However, most studies of alpha-adrenolytic ated with this condition. It therefore seems justifiable eiagents have been performed on patients with bladder ther to treat aggressively with close monitoring of urine outlet obstruction caused by prostatic hypertrophy or cultures or to treat conservatively with reversible and detrusor sphincter dyssynergia. 40-43 In one study of panoninvasive therapy. A simple and effective method for tients with "autonomous bladders," Norlen 39 found that coping with the sensory abnormalitywhich leads to inalpha-adrenolytic therapy in the form of phenoxybenzafrequent emptying of the bladder is scheduled voiding. mine increased bladder capacity and at the same time Large residual urine volumes may be obviated by doureduced residual urine. Phenoxybenzamine is no longer ble or triple timed voiding. Some patients may benefit by recommended for prolonged usage because it is mutastraining to void. This is best monitored by determining genic in mice. Prazosin, a postsynaptic alpha-adrenergic if the flow of urine increases when straining. However, blocking agent, has fewer side effects than phenoxybenthose patients who manifest a decrease in the uroflow zamine. Norlen 39 reported that 2 mg of prazosin is equivduring straining should be specifically cautioned not to alent to 10 mg of phenoxybenzamine. strain during micturition. Many investigators support performing transurethral One question arises. At what time, if any, should uro- ---prostatic or bladder neck resection in diabetics to redynamic evaluation occur in asymptomatic diabetic paduce residual urine volume, lz,43.44 However, it is difficult tients? It is of utmost importance to ascertain if certain to evaluate these series quantitatively because the only risk factors are present in those patients and if further criterion for success of the procedure was a decrease in investigation is required. Therefore, patients with excesresidual urine volume. Because urodynamic criteria were
138
not used either before or after surgery, it is impossible to know whether or not these patients had concommitant bladder outlet obstruction. Our experience is that patients who have impaired detrusor contractility and subsequent poor urinary flow do not benefit by transurethral reduction of the bladder outlet. T o treat large capacity, low pressure bladders with high residual urine, several investigators have employed reduction cystoplasty and vesicoplication. 45 However, the major sequela of this procedure is that the large bladder capacity and residual urine recur within a year. Moreove[, there were no data in any of these studies to suggest that the patients being treated did, in fact, have diabetic cystopathy. Finally, another method for increasing bladder emptying is the Cred~ maneuver. 17 However, for the Crede maneuver to be clinically efficacious, even on theoretical grounds, certain baseline criteria must be met. That is, the increase in intravesical pressure w h i c h is transmitted by the Cred6 maneuver must be entirely transmitted to the flow controlling zone in the urethra while the bladder neck is open and the external sphincter relaxed. These simul'taneous phenomena rarely occur. In fact, in a series by Barbalias et al., 46 only 1% of patients would benefit by the Cred~ maneuver, and in those patients who have high outlet resistance or have vesicoureteral reflux, the Cred6 maneuver may be harmful.
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benign prostatic obstruction. Br J Urol 50:551, 1978. 42. Caine M, Perlberg S, Shapiro A: Phenoxybenzamine for benign prostatic obstruction. Urology 17:542, 1981. 43. Emmett JL, Daut RV, Sprague RG: Transurethral resection for neurogenic vesical dysfunction in cases of diabetic neuropathy. J Urol 61:244, 1949. 44. Weinberg SR: Transurethral resection of the vesical neck
13g for relief of diabetic neurogenic dysfunction of the bladder. NY State J Med 56:882, 1956. 45. Stewart HH: The surgical treatment of severechronic retention without large diverticula. Br J Urol 38:685, 1966. 46. Barbalias GA, Klauber GT, Blaivas JG: Critical evaluation of the Crede maneuver: Urodynamic study of 207 patients. J Urol 130:720, 1983.