International

Urology and Nephrology 9 (3), pp. 217--224 (1977)

Vesico-Ureteral Reflux and Uninhibited Neurogenic Bladder T. KOYANAGI,T. ISHIKAWA,I. TsuJi Department of Urology, Hokkaido University School of Medicine, Sapporo, Japan (Received March 23, 1976)

Ureteral reflux in female patients who also have latent uninhibited neurogenic bladder occurs synchronously with uninhibited contraction, is blocked by buscopan and is aggravated by besacholine. Intrinsic neuromuscular antireflux mechanism of the vesicoureteral junction (VUJ) appears to be affected by unknown ways with uninhibited contraction. Urethrovesical reflux observed synchronously with uninhibited contraction seems to play an additional role in the genesis of urinary infection. A different look is required in the management of these refluxes, in that concomitant use of the anticholinergic drugs is recommended in addition to the conventional approach for the control of infection, reflux and voiding symptoms. The importance of uninhibited neurogenic bladder as a cause of recurrent urinary infection was already siressed [1]. The role o f vesico-ureteral reflux (VUR) in urinary infection has been repeatedly discussed. We found 5070 o f female patients with V U R to have uninhibited neurogenic bladder, denoting strong correlation between the two entities [2]. This study was undertaken to investigate further into their relationship and the effect of autonomic agents on VUR.

Materials and method Nine female patients (7 girls and 2 women) with history of refractory recurrent urinary infection, who were known to have both V U R and latent uninhibited neurogenic bladder, were chosen for the study. Cystometry was done as suggested by Lapides [3], with modification of radiopaque fluid as irrigant under fluoroscopic control on X-ray television. Following the control run, the effects of besacholine (bethanechol chloride) and buscopan (hyosin-N-butylbromid) upon ~VUR and uninhibited contraction were studied. A myelodysplastic patient and three patients with refluxing megaloureter were studied in a similar manner.

Case reports and results Case 1. K. M. A 6-year-old girl with two years' history of recurrent urinary infection and bilateral VUR. Abnormality in her voiding habit, characterized by marked diurnal urinary frequency, urgency, urge incontinence and nocturnal International Urology and Nephrology 9, 1977

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enuresis, was not given serious consideration until cystometry revealed an underlying uninhibited neurogenic bladder. Needless to say, no neurological deficit was present on physicalexamination. During the control run (Fig. la, left), when

the first uninhibited contraction arose at 30 ml bladder volume, the cystogram showed left VUR (Fig. lb). The stronger uninhibited contractions started to occur in successions toward the maximum bladder capacity of 90 ml, and this coincided with bilateral VUR (Fig. lc). Buscopan suppressed the uninhibited contraction, increased the vesical capacity (Fig. la, right), and abolished the VUR from both ureters (Fig. ld). NAME I~,~)~= PIJITIUMOTO HISTORYNUMBER ~ ~r F,

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a) Fig. la. Cystometry of Case 1, before (left) and after (right) i.v. buscopan

Fig. lb. Cystogram when the first uninhibited contraction was demonstrated in the cystometric curve Intcraational Urology and Nepbrology 9, 1 9 7 7

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Fig. lc. Bilateral V U R at maximum bladder capacity

Fig. ld. Cystogram after i.v. buscopan at maximum bladder capacity of 180 ml

Case 2. N. Y. This 10-year-old girl was also known to have chronic pyelonephritis and bilateral VUR (Fig. 2a). The latter was attributed to distal urethral stenosis, and frequent urethral dilatation was done without success in controlling recurrence of infection. Again the abnormality of voiding habit suggested a latent uninhibited neurogenic bladder which was confirmed in the recent study (Fig. 2b, left). The strong uninhibited contraction at 110 ml vesical capacity synchronized with left VUR (Fig. 2c). The incidental finding worthy of note is the urethrovesical reflux, during which urine is uninhibitedly passed, merely to be hold at the distal urethra by voluntary contraction of perineal striated muscle, and regurgitates International Urology and Nephrology 9, 1977

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back into the bladder. The significance of this phenomen shall be discussed later. Following the administration of buscopan, suppression of uninhibited contraction, VUR and urethrovesical reflux were observed.

Fig. 2a. C y s t o g r a m o f C a s e 2 at age of 8 y e a r s

Since the concomitant administration of anticholinergic drugs with the ordinary regimen of follow up two patients are totally free of recurrence. Voiding symptoms such as abnormal diurnal voiding pattern and enuresis are well under control. Case 3. E. I. This 46-year-old woman was recently discovered to have latent uninhibited neurogenic bladder as a contributing factor of bilateral chronic pyelonephritis and left VUR. The control run cystometric curve showed several uninhibited contractions only toward the end, while the cystogram demonstrated V U R limited to the left ureter. Twenty minutes after subcutaneous besacholine, more prominent uninhibited contractions were induced and VUR were noted in both ureters. Incidentally cystoscopy showed the ureteral orifice to be normal in the right and stadium shaped in the left according to Lyon's criteria [4]. International Urology and Nephrology 9, 1977

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Summing up the above findings and those from the other six cases, the following conclusions were drawn. 1. VUR and uninhibited contraction occur almost synchronously. 2. Buscopan (an anticholinergic drug) prevents not only uninhibited contraction but also VUR and urethrovesical reflux. 3. Besacholine (a cholinergic drug) aggravates the established VUR and uninhibited contraction, and induces VUR in the borderline vesicoureteral junction (VUJ). The last point was reaffirmed in the study of a myelodysplastic girl, who showed no reflux during the control run o f cystometry. With positive response to besacholine left VUR was induced, which promptly vanished after buscopan.

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Fig. 2b. Cystometry of Case 2 at age of 10 years, before (left) and after (right) i.v. buscopan

Fig. 2c. Cystogram of Case 2 at age of 10 years. Note left V U R and efflux of contrast into the urethra synchronizing with uninhibited contraction International Urology and Nephrology 9, 1977

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On the other hand, all three cases of refluxing megaloureter showed no uninhibited contractions or evidence of chronic denervation of the bladder, but only the large capacity of bladder. VUR was entirely of low pressure type, unrelated to abnormal contraction of the bladder.

Discussion

Although our pilot study was small in number, it suggested that uninhibited contraction made the VUJ incompetent ghrough an unknown pathway. The majority of investigators on the antireflux mechanism of VUJ consider the muscular role more important than the neural one [5, 6]. Earlier studies on the neurogenic role in VUR were limited to the experimental investigations by section of the pelvic nerve [7] or hypogastric nerve [5 ], or in overt neurogenic bladder of myelodysptastic or paraplegic patients. Our patients with uninhibited neurogenic bladder are those who do not show any neurological deficit on careful physical examinations and are not infrequently encountered in the daily practice with abnormal voiding symptoms or recurrent urinary infection. The role of this latent neurogenic bladder in VUR has not yet been studied. Recently studies on ureteral innervation made remarkable advancements, Abundance of both adrenergic and cholinergic nerve components appears to be a well-established fact. Elbadawi and Schenk stated that the activities of the two autonomic components of VUJ could be synchronized as a unitary response to a massive neural discharge, regulated in relation to each other and would form the basis for a neurally mediated antireflux mechanism of the distal ureteral sheath [8, 9]. The presence of both stimulating (c0 and inhibitory (fi) receptors in the ureteral and detrusor muscle was demonstrated [10]. Malin and Boyarsky casted the intriguing question that possible activation of inhibitory receptors during bladder contraction might be contributing to VUR in dogs after unilateral section of pelvic nerve [11 ]. Considering the existence of modulating post-ganglionic synapses in peripheral urethro-vesico-ureteral autonomic pathways as suggested by Elbadawi and Schenk [12] and the possibility of mechanical action of muscle being influenced by the sensory input from the epithelium or muscle to the intrinsic nervous mechanism as proposed by Duarte-Escalante [13], uninhibited contraction p e r se or neuralimpulse responsible for uninhibited contraction does seem to impose some influence upon the neuromuscular antireflux mechanism of VUJ. Hinman and Miller stated that transmission of increasing tension during bladder filling and micturition from the vesical neck to the intravesical and intramural ureter was essential for the normal voiding and prevention of VUR [14]. When this elevation of mural tension is sudden and excessive as seen in unihibited contraction, fi-effect could conceivably be put into play as a part of inherent reflex of the smooth muscle. Interesting is the response of VUR synchronous with uninhibited contraction to the fi-blocking agent. Of course, as not all uninhibited neurogenic bladders demonstrate VUR, the succinct statemenet that uninhibited International Urology and Nephrology 9, 1977

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contraction is the sole factor o f V U R cannot be made. After all, the VUJ of the bladder which shows both V U R and uninhibited contraction appears to have both intrinsic muscular abnormality and disorders of the intrinsic neural antireflux mechanism. We believe that for the proper management of these patients with both V U R and uninhibited neurogenic bladder, thorough understanding of the latter entity is required as suggested by Lapides [1 ]. Although he stressed the role of hydrostatic pressure which causes tissue ischemia as a primary factor in initiating bacterial infection in the bladder, our finding of urethrovesical reflux seen under fluoroscopy and synchronizing with uninhibited contraction appears to give another explanation for the entry of urethral flora into the bladder Corrierre et al. found this phenomenon in normal mongrel dogs [15]. In girls with uninhibited contraction, this is observed in a more exaggerated form. R e a d y access of bacteria from the urethra to the kidney is an easily understandable sequence when V U R is also present. Although Politano and Leadbetter stated that parasympathomimetic drugs were effective in preventing V U R [16], our study o f the patients with both V U R and uninhibited contraction showed beneficial effect of buscopan and deleterious effect of besacholine upon V U R and uninhibited contraction. We propose to manage conservatively these patients with anticholinergic drugs along with the conventional chemotherapy and triple voiding, because their V U J appears to have potency to develop into one with adequate neuromuscular antireflux mechanism just as these "infant" bladders (Lapides) gain cortico-regulatory control with age [1 ]. V U J of congenital refluxing megaloureter, on the other hand, would not be expected to obtain adequate antireflux mechanism during the conservative management, and antireflux surgery should be indicated.

References 1. Lapides, J., Diokno, A. C. : Persistence of the infant bladder as a cause for urinary infection in girls. 3". tiroL, 100, 445 (1968). 2. Koyanagi, T., Ishikawa I.: The study on recurrent urinary tract infection among female subjects. Etiological explanation from the functional study of the lower urinary tract. .Tap. J. Urol., 64, 67 (1973). 3. Lapides, J.: Cystometry. JAMA, 201, 618 (1967). 4. Lyon, R. P., Marshall, S., Tanagho, E. : The ureteral orifice: Its configuration and competency. J. Urol., 102, 504 (1969). 5. Tanagho, E. A., Hutch, J. A., Meyers, F. H., Rambo, O. N., Jr. : Primary vesicoureteral reflux: Experimental studies of its etiology. J. Urol., 93, 165 (1965). 6. Stephens, F. D., Lenaghan, O.: The anatomical basis and dynamics of vesicoureteral reflux. J. Urol., 87, 669 (1962). 7. Torbey, K. Leadbetter, W. F.: Innervation of the bladder and lower ureter: Studies of pelvic nerve section and stimulation in the dog. J. Urol., 90, 395 (1963). 8. Elbadawi, A., Schenk, E. : A new theory of the innervation of bladder musculature. Part 2. The innervation apparatus of the ureterovesical junction. J. Urol., 105, 368 (1971). International Urology and Nephrology 9, 1977

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9. Elbadawi, A.: Anatomy and function of the ureteral sheath. J. UroL, 102, 224 (1972). 10. Kaplan, N., Elkin, M., Sharkey, J. : Ureteral peristalsis and the autonomic nervous system. lnvest. Urol., 5, 468 (1968). 11. Malin, J. M., Jr., Boyarsky, S. : The effect of cholinergic and adrenergic drug stimulation of detrusor muscle. Invest. Urol., 8, 286 (1970). 12. Elbadawi, A, Sehenk, E. A. : A new theory of the innervation of bladder musculature. Part 3. Postganglionic synapses in uretero-vesico-urethral autonomic pathways. J. Urol., 105, 372 (1971). 13. Duarte-Escalante, L., Labay, P., Boyarsky, S.: The neurohistochemistry of mammalian ureter: A new combination of histochemical procedures to demonstrate adrenergic, cholinergic and chromaff-m structures in ureter. J. Urol., 101, 803 (1969). 14. Hinman, F., Jr., Miller, E. R.: Mural tension in vesical disorders and ureteral reflux. J. Urol., 91, 33 (1964). 15. Corrierre, J. N., Jr., McClare, M. M. J. III., Lipschultz, L. I.: Contamination of bladder urine by urethral particles during voiding: Urethro-vesical reflux. J. Urol., 107, 399 (1972). 16. Politano, V A., Leadbetter, W . F . : An operative technique for correction of vesicoureteral reflux. J. UroL, 79, 932 (1958).

International Urology and Nephrology 9, 1977

Vesico-ureteral reflux and uninhibited neurogenic bladder.

International Urology and Nephrology 9 (3), pp. 217--224 (1977) Vesico-Ureteral Reflux and Uninhibited Neurogenic Bladder T. KOYANAGI,T. ISHIKAWA,I...
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