- Email: [email protected]
Vesicoureteral Reflux and Voiding Dysfunction: A Prospective Study
0022-534 7 /89 /l 422-0494$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 142, August
Printed in U.S.A.
VESICOURETERAL REFLUX AND VOIDING DYSFUNCTION: A PROSPECTIVE STUDY HENRIQUE SERUCA From the Division of Pediatric Urology, Section of Pediatric Surgery, Department of Pediatrics, Hospital de Santa Maria, Universidade Classica de Lisboa, Lisbon, Portugal
ABSTRACT
We prospectively studied 53 young children (45 less than 4 years old) between 1985 and 1988 with primary vesicoureteral reflux (grades I to V, 74 ureters). All patients had elevated bladder pressures during bladder filling and/or voiding on urodynamic evaluation, which sometimes were associated with abnormal perineal muscle activity. Baclofen, flavoxate, dicyclomine and diazepam were given individually or in combination for each type of dysfunction for 12 to 30 months. Reflux disappeared in 68 ureters (91.8 per cent) and it was downgraded in 6 (8.2 per cent). Urodynamic evaluation at the end of treatment revealed normal bladder pressures in 46 children (83.7 per cent of the ureters in which reflux resolved). Another group of 48 children with primary vesicoureteral reflux (grades I to IV, 67 ureters) seen between 1980 and 1985 was reviewed retrospectively. All patients had been treated with prophylactic antibiotics only. Reflux resolved in 53. 7 per cent of the ureters, and it was downgraded in 19.4 per cent, unchanged in 22.4 per cent and upgraded in 4.5 per cent. Urodynamic studies performed in 1985 showed that all persistent cases of reflux in the retrospective group had urodynamic findings similar to those found in the prospective group. These data suggest that vesicoperineal incoordination as well as bladder instability can be important factors in causing and perpetuating reflux, and that medical treatment of these factors individually or in combination may affect therapeutic perspectives of this pathological condition. (J. Ural., part 2, 142: 494-498, 1989) The association of urinary tract infection and vesicoureteral reflux with uninhibited bladder contractions is well established. 1-5 Enhancement of reflux resolution has been reported with the treatment of bladder dysfunction. 2 • 5 • 6 Bladder instability seems to be prevalent between the ages of 4 and 7 years in children undergoing a transitory phase between infantile and adult patterns of micturition. 7 - 9 Urinary tract obstruction due to contraction of the striated urinary sphincter during uninhibited bladder contractions or during voiding has been described, 1·2 • 4 and it can be associated with vesical and upper tract damage, 10 as well as increased complications of ureteral reimplantation. 3 ' 11 Hinman and Baumann have defined the problems caused by a "voluntary" dysfunctional sphincter, and they indicate a volitional contraction of the sphincter during voiding. 10• 12 It also has been suggested that a dysfunctional or unstable urethra could be the cause of bladder instability rather than the reverse.13 Nevertheless, only bladder instability has been treated when urodynamic anomalies have been associated with vesicoureteral reflux. 2•4 • 5 Vesico-sphincteric dyssynergia in neurologically normal children has been considered as functional1· 3·4 but the patients reported in such studies usually were older than 4 years. Although the voiding pattern in children in the O to 4year age group has been schematically described by Allen and Bright6 there are only a few studies describing urodynamic findings in this age group. The relationship between such findings and vesicoureteral reflux in this age group has not been reported. Contraction of the perineal floor during voiding, whether voluntary or otherwise, may contribute to dysfunctional voiding and upper tract damage. To avoid confusion we prefer to use the term vesicoperineal incoordination rather than vesico-sphincteric dyssynergia which should be reserved specifically for patients with identifiable neurological lesions. This study was performed in an attempt to establish an
etiological relationship among bladder instability, vesicoperineal incoordination and vesicoureteral reflux in neurologically normal young children, and to determine whether the treatment of each of those specific dynamic disorders could influence the evolution of reflux. MATERIAL AND METHODS
The study began in January 1985 and was terminated in January 1988. Two study groups were created: prospective and retrospective. It would have been preferable to create 2 prospective groups for comparison purposes but under the conditions of this study the number of patients in each group would have been reduced significantly. The prospective group consisted of 37 girls and 16 boys 6 months to 8 years old, including 45 children younger than 4 years (see figure). Vesicoureteral reflux was demonstrated radiologically at least 2 weeks after a urinary infection was eradicated. Of a total of 81 patients with vesicoureteral reflux we excluded 26 who presented with associated anomalies, such as urethral valves, ureteral duplication, ureterocele, megaureter, ectopic ureter, paraureteral saccules, obvious neuropathic bladder, history of urological or perineal surgery, or renal insufficiency. Of the remaining 55 patients with primary reflux 2 were excluded because of significant side effects with the medication used in the study. Initial evaluation of all patients included a history and physical examination. Of the 45 children younger than 4 years 10 were not bladder trained for continence and, therefore, the symptoms could not be evaluated reliably. All of the remaining 35 children had increased urinary frequency, 28 had urgency (and ocassionally daytime incontinence), 16 had hesitancy, 10 had to strain and 7 had discomfort on voiding. These symptoms occurred alone or in combination. Only 8 patients were older than 4 years, of whom 4 experienced urgency and increased urinary frequency. There were no obstructive type symptoms
494
VESICOTJRETERAL FtEFLL1:X A~JD VOIDI:r.;fC~ DYSF¥J~ICTI0N. AGE DISTRIJ3UTION AT THfE OF VUR ;JIAGNOSIS
------
No. of CASE::
<1
5
6
AGE (YEARS)
AGE DISTRIBUTION AT FIRST DIAGNOSED URINARY INFECTION No, of CASES
< 1
AGE (YEARS)
28.5 % soon after birth
55.3 % at bladder training time
Analysis of age distribution of 53 patients in prospective group at diagnosis of vesicoureteral reflux ( VUR) and first urinary infection.
in these older children, whereas hesitancy and straining were found in a significant number of younger patients. The other 4 older patients were free of voiding symptoms. None of the 53 patients had evidence of neurological disease on physical examination. Urinalysis and culture, voiding cystourethrogram, isotopic cystography with 99 mtechnetiurn (Tc)-pertechnetate, 14 excretory urogram (IVP), 99 mTc-dimercapto-succinic acid (DMSA) renal scan, 99 mTc-diethylenetriaminepentaacetic acid (DTPA) renogram and cystoscopy were performed in all patients. A complete urodynamic study was done, including initial uroflowmetry followed by simultaneous monitoring of total intravesical, intrarectal and intrinsic bladder pressures, surface pelvic floor electromyography during bladder filling and voiding, combined with a second uroflowmetry, as well as urethral pressure profilom.etry. The initial urodynamic study was executed with the patient free of any medication other than prophylactic antibiotics (cotrimoxazole or nitrofurantoin), awake and seated, using the Lectromed Urodynamic Investigation System 5000 with 5-channel recorders* and 5Ch feeding tube catheters for bladder filling and pressme recording. For perineal electromyography standard electrocardiogram electrodes, placed on either side of the anus with conductive gelt and secured with waterproof tape, were used. For each urodynamic study 2 consecutive cycles of filling and voiding graphics were recorded. Urodynamic testing in the infant and young child was performed as described previously. 15 It is much more time-consuming than in the older child but reliable results may be obtained once the patient becomes relaxed and participates in quiet games during the examination. One must remember that it takes time for the child to calm down and adjust to the introduction of the urethral catheter. It is only then that it is possible to proceed with the study. Followup evaluation consisted of clinical examination, urinalysis and culture at 1 and 3-month intervals. Isotopic cystography and DMSA renal scanning were performed at 6-month intervals until reflux disappeared on 2 consecutive cystographic
* Lectromed Ltd., St. Peter, Jersey Channel Islands, England.
t Aquasonic, Parker Laboratories, Inc., New Jersey.
495
studies. Every patient undenvent a final DTP A reno gram to assess any changes in glomemlar filtration rate. All drugs were then discontinued, and 1 month later a final urodynamic evaluation was performed. Cystography demonstrated grade I reflux in 8 ureters, grade II in 33, grade III in 27, grade IV in 4 and grade V in 2, according to the International Reflux Study Committee classification. 16 Cystoscopy failed to show any evidence of obstruction. Ureteral orifices ranged from Bl to C3 according to Lyons' classification. C2 and C3 lateral displacement of ureteral orifices was noted in cases of higher grade reflux. There were mild degrees of trabeculation in all bladders. Three different urodynamic patterns were found: 17 patients (32.1 per cent) only exhibited bladder instability and high pressures during bladder filling, 13 (24.1 per cent) only showed perineal incoordination on voiding, as demonstrated by high intrinsic bladder pressures during or immediately after voiding, increased electromyographic activity, residual urine (10 to 80 ml.) and high values on the ureteral pressure profile, and 23 (43.4 per cent) demonstrated high ureteral pressure profile values with residual urine, increased perinea! electromyographic activity and high pressures during bladder filling and voiding. Thus, all patients had high total and intrinsic bladder pressures during filling and/or voiding phases. Of the children 40 (75.5 per cent) had bladder instability alone or associated with perineal incoordination and 36 (67.9 per cent) had vesicoperineal incoordination alone or associated with bladder instability. Low dose antibiotic prophylaxis was prescribed for all children for the first 6 months and then it was stopped. The drugs included cotrimoxazole or nitrofurantoin at a quarter to half of the weight-adjusted recommended daily therapeutic dose. Only 2 patients had constipation, which was treated. Every patient who was toilet-trained for bladder continence was encouraged to void every 3 hours or as soon as urgency was experienced in the awake state. Those patients with bladder instability alone were started on anticholinergic drugs. Oral administration was preferred. For infants we used the liquid medication and for older children we used tablets. None of the drugs was available in liquid and tablets and, therefore, we had to use alternative drugs in the same category. For those patients less than 3 years old we used 8 mg,/kg. dicyclomine 1 7 ' 18 divided in 3 daily doses, while in patients older than 3 years we used 15 mg./kg. flavoxate 19 • 20 divided in 3 daily doses. Those patients with perinea! incoordination, either alone or associated with bladder instability, and younger than 3 years received a combination of the same doses of dicyclomine with liquid diazepam 21 • 22 (0.5 mg,/kg. divided in 3 daily doses), while those older than 3 years received doses. Special precau1 mg./kg. baclofen 23 ' 24 divided in 3 tions were taken with baclofen, since the manufacturers did not provide guidelines for its use in children less than 12 years old. V•/ e began with a sixteenth to a twentieth of the total daily dose, increasing dosage gradually every 3 days until the maintenance dose was reached. Before treatment was stopped we gradually reduced doses until the starting dose was reached. A complete medical examination was performed and hematological, hepatic and renal functions were evaluated before and 1 month after the beginning of treatment and every 3 months thereafter; values remained normal during the entire treatment period. The only side effect with diazepam was moderate excitement in 2 children. The side effects with baclofen consisted of dizziness (2 patients), transient headaches (2), moderate excitement (6), and abnormal psychological reactions of excitement and aggressive behavior (2). The latter 2 children stopped treatment and they were excluded from the study. All drugs were maintained for 6 months after vesicoureteral reflux resolution and for a maximum of 30 months. The retrospective group consisted of 36 girls and 12 boys 4 to 12 years old. Vesicoureteral reflux was demonstrated radio-
.496
SERUCA
graphically and they were under medical treatment exclusively from 1980 to 1985. Whether reflux was cured was not a factor. This group was selected in 1985, according to the same criteria as the prospective group, from a larger group of 76 patients with reflux to obtain a group with primary reflux. Initially urodynamic evaluation had not been performed. Treatment consisted of low dose antibiotic prophylaxis with cotrimoxazole or nitrofurantoin at a quarter to half of the weight-adjusted recommended daily therapeutic dose. The initial radiological (IVP and voiding cystourethrogram) and the cystoscopic findings were reviewed. The initial voiding cystourethrogram showed vesicoureteral reflux grade I in 12 ureters, grade II in 35, grade III in 18 and grade IV in 2. Complete physical examination, urinalysis and culture, voiding cystourethrogram, isotopic cystography, 99mTc-DMSA renal scintigraphy, 99mTcDTP A renogram and a complete urodynamic study as described previously were performed in 1985. RESULTS
All findings were statistically analyzed by computer with the Statistical Package for IBM PC, the SPSS/PC, and with the Mann-Whitney U-Wilcoxon rank sum W test. The prospective group was analyzed according to age distribution at the time of vesicoureteral reflux diagnosis and the first urinary infection (see figure). We noted 2 peaks in the incidence of initial urinary tract infection: during the first months of life and at the age of onset of bladder training, which indicates a functional disturbance as an etiological factor. Moreover, during and after treatment only 1 patient had an acute episode of clinical pyelonephritis, which was immediately controlled. A month after beginning treatment the voiding symptoms in the prospective group had improved significantly or had disappeared. The 53 patients in the prospective group received a complete course of treatment with the aforementioned drugs for a minimum of 12 months and a maximum of 30 months. These patients had 74 refluxing ureters at the beginning of the study. The rate of reflux resolution in the entire group, according to grade of reflux is presented in table 1. Reflux improved to grade II in 6 ureters (8.2 per cent) and it resolved in 68 (91.8 per cent). Patients with persistent reflux had received less than 30 months of treatment, had higher grades of reflux at entry into the study and still had urodynamic anomalies at the end of the study. The final urodynamic evaluation after the second cystography study showed resolution of reflux 1 month after stopping all medication in 50 of the 53 patients in the prospective group. In the remaining 3 patients with unresolved reflux the second urodynamic evaluation was performed at the end of this study in January 1988 while they were still receiving medication. In 46 patients with resolved reflux (62 ureters, 83.7 per cent) the urodynamic studies and bladder pressures were normal. In the remaining 4 patients with resolved reflux (6 ureters, 8.1 per cent) and in the 3 patients with persistent reflux (6 ureters, 8.1 per cent) urodynamic anomalies and high bladder pressures were still present. Thus, a total of 46 patients (86.8 per cent) TABLE
had reached normal adult urodynamic levels, normal bladder pressures and reflux resolution. In 31 kidneys from patients in the prospective group renal scars were detected by a 99mTc-DMSA renal scan at the beginning of the study, corresponding to 41.8 per cent of the ureters with reflux. At the end of the study the final DMSA renal scan and DTPA renogram showed no increase in existing renal scars, no new renal scars and no change in total renal function in any patient. Patients in the retrospective study group were older than those in the prospective group. The rate of reflux resolution according to reflux grade is shown in table 2. Reflux did not change in 15 ureters (22.4 per cent), increased from grade II to III in 3 (4.5 per cent), improved to grade II in 13 (19.4 per cent) and resolved in 36 (53.7 per cent). Urodynamic studies performed in 1985 revealed that 18 patients with resolved reflux had normal adult urodynamic levels. Eight other patients with resolved reflux and all 22 patients with persistent reflux had urodynamic anomalies. The abnormalities found in this group included bladder instability with high pressures during bladder filling in 9 patients (30 per cent), perineal incoordination with high pressures during voiding in 8 (26.6 per cent) and a combination of both in 13 (43.3 per cent). These urodynamic anomalies were similar in type and frequency to those in the prospective group before treatment. We found significantly better results (p = 0.001) in the prospective group, in which voiding dysfunctions were treated with anticholinergics and striated muscle relaxants compared to the retrospective group, in which the patients received only antibiotics when reflux modifications were analyzed after treatment (table 3). We evaluated the renal scars in patients of the retrospective group with DMSA renal scintigraphy, related them to the initial grade of reflux and to the number of ureters with reflux, and compared the results to those obtained for the prospective group at the end of the study (table 4). Until 1985 all ureters with grade V and most with grade IV reflux were treated by reimplantation surgery and they were excluded from this study. Thus, we could only compare cases of grades I, II and III reflux. The prospective group had a smaller percentage of renal scars TABLE
2. Rate of reflux resolution in the retrospective group of patients according to grade of reflux
Grade I II III IV V Total No.(%)
No. No. No. No. No. Increased to Improved to Ureters Unchanged Resolved Grade III Grade II 12 35 18 2 O* 68
I II III IV V Total No.(%)
8 33 27 4 2
74
No. Unchanged 0 0 0 0 0
0
No. Improved to Grade II 0 0 1 3 2
6 (8.2)
No. Resolved 8 33 26 1 0 68 (91.8)
0 0 13 0 0
-3 (4.5)
-
3 2 0
15 (22.4)
---
13 (19.4)
12 22 2 0 0
-
36 (53.7)
TABLE 3. Results of treatment on reflux in prospective and retrospective groups comparing treatment of voiding dysfunction in prospective group
according to grade of reflux No. Ureters
0 10
* All patients with grade V reflux and most of those with grade IV reflux underwent antireflux surgery before the study was undertaken.
1. Rate of reflux resolution in the prospective group of patients
Grade
0 3 0 0 0
Reflux upgraded Reflux unchanged Reflux downgraded Reflux disappearance
1985-1988: Prospective Group*
1980-1985: Retrospective Groupt
No. Ureters (%)
No. Ureters(%) 3 15 13 36
0 0 6 (8.2)
68 (91.8) p
(4.5) (22.4) (19.4) (53.7)
= 0.001
* Anticholinergic and striated muscle relaxants and antibiotics. t Antibiotics only.
VESICOURE'TERAL REFLUX AJ\ID ·voID!NG DYELITU~:c~fION T'ABLE
40 Ren,,al scars after treat;nent related to the initial grade of
reflux in both groups of patients No. Renal Scars/Refluxing Ureters After Medical Treatment(%) Grade
I II III IV V
Totals
Prospective Group
Retrospective Group
(12.5) (33.3) (±1.8) (75) (100)
3/12 (25) 14/35 (40) 10/18 (55.5) 2/2 (100) No cases
31/74 (41.8)
29/68 (43.8)
1/8 11/33 14/24 3/4 2/2
compared to the retrospective group but this was not statistically significant. DISCUSSION
This study indicates a cause and effect relationship between bladder-perineal dynamic abnormalities and the presence of vesicoureteral reflux. Of course, other associated factors, such as maturation of adrenergic fibers in the bladder 25 and sufficient length of the intravesical ureter, 26 have an important role in the presence or absence of reflux. Indeed, in some patients with urodynamic abnormalities and high intrinsic bladder pressures reflux resolves spontaneously as they get older, which may be of particular importance in younger children who are in the learning phases of coordinating vesical and perineal activity. Due to the structural anatomy of the bladder and urethra, the intravesical portion of the ureter increases its functional length during normal voiding, 27 In the presence of simultaneous strong detrusor contraction and vesicoperineal incoordination with voluntary constriction of the external sphincter the intravesical ureter cannot increase its functional length normally, which may contribute to the development or persistence of reflux in younger patients with otherwise anatomically shorter intravesical ureters. An important aspect of this study is that reflux resolved in all patients in whom the bladder-perineal anomalies and intrinsic bladder pressure normalized, Also, nearly 70 per cent of the patients with primary vesicoureteral reflux presented with a perinea! dynamic problem leading to functional obstruction. It has been stated that voluntary constriction of the external sphincter in an attempt to keep from wetting during uninhibited bladder contractions can cause bladder-sphincteric dyssynergia and urinary obstruction. 1 • 2 • 4 • 6 • 7 Current attitudes toward vesico-sphincteric dyssynergia favor keeping this diagnosis limited to patients with demonstrable neurological lesions. It is known that the treatment of bladder instability with anticholinergic increases the threshold for uninhibited contractions, enlarges the functional of the bladder thus, reduces intravesical pressure 2 •5 and improves reflux resolution with medical therapy, These reports show reflux resolution in 80 per cent of the cases with a reduction in the duration of treatment to half that required with long-term antibacterial prophylaxis alone. 2 • 5 However, 20 per cent of these patients had persistent vesicoureteral reflux and required surgery, representing the same results of conservative treatment with longterm antibiotic prophylaxis, 28 The results of our study suggest that sphincteric functional obstruction caused by bladder-perinea! incoordination is a major causative factor in vesicoureteral reflux in young children and that its treatment can improve reflux resolution on a medical basis compared to exclusive longterm antibiotic prophylaxis 28 and to exclusive treatment of bladder instability, 2• 5 • 6 thus reducing significantly the need for surgery. It is possible that the competitive life-style in modern society and the compulsive attitude of parents toward early bladder training may have a role in the development ofbladder-perineal
497
incoordination and the of patterns. Vesicoperineal incoordination that occurs normal patients is a different entity from dyssynergia that occurs in µa.cHau,,, with neurological lesions, The interpretation of measurements of external sphincter acis a subject of controversy, m 11eu1unJ,_;1o.;auy normal children, Surface electromyography as advocated Firlit and associates is widely used. 7 This method may lack precision in reflecting specific of the external sphincter but it does indicate the state of contraction of the perineal floor, of which the external sphincter is an integral component. Objections may be raised as to the occurrence of perineal incoordination during the urodynamic examination, such as stress of the examination as well as urethral and bladder irritation, Nevertheless, its repetitive occurrence in some patients and its total absence in others have led us to believe that some patients may indeed be voiding with an incompletely relaxed perineum of which the external sphincter is an integral component, Although this may be difficult to prove without round-the-dock monitoring of the sphincteric/perineal activity, we believe that we have gathered enough data to demonstrate that abnormalities of the vesico-sphincteric complex may not be limited to patients with obvious neurological anomalies. Rather, one is more likely to find milder forms of functional dyssynergia or incoordination that may contribute to the etiology and persistence of reflux. Objective evidence of the existence of anomalies of the vesicoperineal-sphincteric complex and its contributory role in the perpetuation of reflux may be in the prospective group and 30 in found in our 66 ""'"'~'-'""' the retrospective group) vvho exhibited incomplete siduals 10 to 80 ml.). This issue can only be definitively resolved by Holter-type monitoring. Recognition of the fact that vesicoperineal incoordination may contribute to reflux should be considered in the study and management of patients with reflux, REFERENCES 1. Koff, S. A., Lapides, J. and Piazza, D. H.: Association of urinary tract infection and reflux with uninhibited bladder contractions and voluntary sphincteric obstruction. J. Urol., 122: 373, 1979. 2. Koff, S. A. and Murtagh, D.S.: The uninhibited bladder in children: effect of treatment on recurrence of urinary infection and on vesicometeral reflux resolution. J, Urol., 130: 1138, 1983. 3. Allen, T. D,: Vesicournteral reflux as a manifestation of dysfunctional voiding. In: Reflux Nephropathy. Edited by J. Hodson and P, Kincaid-Smith, New York: Masson Publishing USA, sect. 5, 18, p, 171, 1979. 4. Koff, A., Lapid.es, J. and Piazza, D. H.: The uninhibited bladder in children: a cause for urinary obstruction, infection, and reflux. In: Reflux Edited by J- Hodson and P. Kincaid.Smith, New Publishing, USA, sect, 5, chapt, 17, p. 161, 1979. 5. Homsy, Y. L., Nsou!i, L, Hamburger, R, Laberge, I. and Schick, E.: Effects of oxybutynin on vesicoureteml reflux in children. J, Urol., 134: 1168, 1985. 6, Allen, T. D, and Bright, T. C", HI: Urodynamic patterns in children with dysfunctional voiding problems. J. UroL, 119: 247, 1978, 7. Firlit, C. F., Smey, P. and King, L. R.: Mictmition urodynamic flow studies in children. J. UroL, 119: 250, 1978. 8. Hanna, M. K., Di Scipio, W., Suh, K. K., Kogan, S. J., Levitt, S, B. and Donner, K.: Urodynamics in children. Part II. The pseudoneurogenic bladder, J. Urol., 125: 534, 1981. 9. Lapid.es, J. and Diokno, A. C.: Persistence of the infant bladder as a cause for urinary infection in girls. J. Urol., 103: 243, 1970. 10. Hinman, F. and Baumann, F, W.: Vesical and ureteral dam~;: from voiding dysfunction in boys without neurologic or obstructive disease. J. Urol., 109: 727, 1973. 11. Noe, H. N.: The role of dysfunctional voiding in failure or complication of ureteral reimplantation for primary reflux. J. Urol., 134: 1172, 1985. 12. Hinman, F,, Jr.: Nonneurogenic neurogenic bladder (the Hinman
498
SERUCA
syndrome)-15 years later. J. Urol., 136: 769, 1986. 13. Hindmarsh, J. R., Gosling, P. T. and Deane, A. M.: Bladder instability. Is the primary defect in the urethra? Brit. J. Urol., 55: 648, 1983. 14. Schoutens, A. and Schulman, C. C.: Functional studies with radionuclides. Dial. Ped. Urol., 7: 2, Feb. 1984. 15. Bauer, S. B., Hallett, M., Khoshbin, S., Lebowitz, R. L., Winston, K. R., Gibson, S., Colodny, A. H. and Retik, A. B.: Predictive value of urodynamic evaluation in newborns with myelodysplasia. J.A.M.A., 252: 650, 1984. 16. International Reflux Study Committee: Medical versus surgical treatment of primary vesicoureteral reflux: a prospective international reflux study in children. J. Urol., 125: 277, 1981. 17. Awad, S. A., Bryniak, S., Downie, J. W. and Bruce, A. W.: The treatment of the uninhibited bladder with dicyclomine. J. Urol., 117: 161, 1977. 18. Fischer, C. P., Diokno, A. and Lapides, J.: The anticholinergic effects of dicyclomine hydrochloride in uninhibited neurogenic bladder dysfunction. J. Urol., 120: 328, 1978. 19. Bradley, D. V. and Cazort, R. J.: Relief of bladder spasm by flavoxate. A comparative study. J. Clin. Pharm., 10: 65, 1970. 20. Jonas, U., Petri, E. and Kissel, J.: Effect offlavoxate on hyperactive detrusor muscle. Eur. Urol., 5: 106, 1979. 21. Chadduck, W. M., Loar, C.R. and Denton. I. R.: Vesical hypoton-
icity with diazepam. J. Urol., 109: 1005, 1973. 22. Bogash, M., Wolgin, W., Kugler, F. and Sadoughi, N.: Functional evaluation of voiding in patients with neurogenic bladder. J. Urol., 112: 338, 1974. 23. Taylor, M. C. and Bates, C. P.: A double-blind crossover trial of baclofen-a new treatment for the unstable bladder syndrome. Brit. J. Urol., 51: 504, 1979. 24. Leyson, J. F. J., Martin, B. F. and Sporer, A.: Baclofen in the treatment of detrusor-sphincter dyssynergia in spinal cord injury patients. J. Urol., 124: 82, 1980. 25. Kiruluta, H. G., Fraser, K. and Owen, L.: The significance of the adrenergic nerves in the etiology of vesicoureteral reflux. J. U rol., 136: 232, 1986. 26. King, L. R.: Vesicoureteral reflux: history, etiology, and conservative management. In: Clinical Pediatric Urology. Edited by P. P. Kelalis and L. R. King. Philadelphia: W. B. Saunders Co., vol. 1, chapt. 11,pp. 342-366, 1976. 27. Buzelin, J.-M.: Bases anatomiques de la physiologie vesico-sphincterienne. In: Urodynamique - Bas Appareil Urinaire. Paris: Masson, chapt. 1,pp. 3-18, 1984. 28. Edwards, D., Norman, I. C. S., Prescod, N. and Smellie, J. M.: Disappearance ofvesicoureteral reflux during long-term prophylaxis of urinary tract infection in children. Brit. Med. J ., 2: 285, 1977.
Vol. 142, August
Printed in U.S.A.
VESICOURETERAL REFLUX AND VOIDING DYSFUNCTION: A PROSPECTIVE STUDY HENRIQUE SERUCA From the Division of Pediatric Urology, Section of Pediatric Surgery, Department of Pediatrics, Hospital de Santa Maria, Universidade Classica de Lisboa, Lisbon, Portugal
ABSTRACT
We prospectively studied 53 young children (45 less than 4 years old) between 1985 and 1988 with primary vesicoureteral reflux (grades I to V, 74 ureters). All patients had elevated bladder pressures during bladder filling and/or voiding on urodynamic evaluation, which sometimes were associated with abnormal perineal muscle activity. Baclofen, flavoxate, dicyclomine and diazepam were given individually or in combination for each type of dysfunction for 12 to 30 months. Reflux disappeared in 68 ureters (91.8 per cent) and it was downgraded in 6 (8.2 per cent). Urodynamic evaluation at the end of treatment revealed normal bladder pressures in 46 children (83.7 per cent of the ureters in which reflux resolved). Another group of 48 children with primary vesicoureteral reflux (grades I to IV, 67 ureters) seen between 1980 and 1985 was reviewed retrospectively. All patients had been treated with prophylactic antibiotics only. Reflux resolved in 53. 7 per cent of the ureters, and it was downgraded in 19.4 per cent, unchanged in 22.4 per cent and upgraded in 4.5 per cent. Urodynamic studies performed in 1985 showed that all persistent cases of reflux in the retrospective group had urodynamic findings similar to those found in the prospective group. These data suggest that vesicoperineal incoordination as well as bladder instability can be important factors in causing and perpetuating reflux, and that medical treatment of these factors individually or in combination may affect therapeutic perspectives of this pathological condition. (J. Ural., part 2, 142: 494-498, 1989) The association of urinary tract infection and vesicoureteral reflux with uninhibited bladder contractions is well established. 1-5 Enhancement of reflux resolution has been reported with the treatment of bladder dysfunction. 2 • 5 • 6 Bladder instability seems to be prevalent between the ages of 4 and 7 years in children undergoing a transitory phase between infantile and adult patterns of micturition. 7 - 9 Urinary tract obstruction due to contraction of the striated urinary sphincter during uninhibited bladder contractions or during voiding has been described, 1·2 • 4 and it can be associated with vesical and upper tract damage, 10 as well as increased complications of ureteral reimplantation. 3 ' 11 Hinman and Baumann have defined the problems caused by a "voluntary" dysfunctional sphincter, and they indicate a volitional contraction of the sphincter during voiding. 10• 12 It also has been suggested that a dysfunctional or unstable urethra could be the cause of bladder instability rather than the reverse.13 Nevertheless, only bladder instability has been treated when urodynamic anomalies have been associated with vesicoureteral reflux. 2•4 • 5 Vesico-sphincteric dyssynergia in neurologically normal children has been considered as functional1· 3·4 but the patients reported in such studies usually were older than 4 years. Although the voiding pattern in children in the O to 4year age group has been schematically described by Allen and Bright6 there are only a few studies describing urodynamic findings in this age group. The relationship between such findings and vesicoureteral reflux in this age group has not been reported. Contraction of the perineal floor during voiding, whether voluntary or otherwise, may contribute to dysfunctional voiding and upper tract damage. To avoid confusion we prefer to use the term vesicoperineal incoordination rather than vesico-sphincteric dyssynergia which should be reserved specifically for patients with identifiable neurological lesions. This study was performed in an attempt to establish an
etiological relationship among bladder instability, vesicoperineal incoordination and vesicoureteral reflux in neurologically normal young children, and to determine whether the treatment of each of those specific dynamic disorders could influence the evolution of reflux. MATERIAL AND METHODS
The study began in January 1985 and was terminated in January 1988. Two study groups were created: prospective and retrospective. It would have been preferable to create 2 prospective groups for comparison purposes but under the conditions of this study the number of patients in each group would have been reduced significantly. The prospective group consisted of 37 girls and 16 boys 6 months to 8 years old, including 45 children younger than 4 years (see figure). Vesicoureteral reflux was demonstrated radiologically at least 2 weeks after a urinary infection was eradicated. Of a total of 81 patients with vesicoureteral reflux we excluded 26 who presented with associated anomalies, such as urethral valves, ureteral duplication, ureterocele, megaureter, ectopic ureter, paraureteral saccules, obvious neuropathic bladder, history of urological or perineal surgery, or renal insufficiency. Of the remaining 55 patients with primary reflux 2 were excluded because of significant side effects with the medication used in the study. Initial evaluation of all patients included a history and physical examination. Of the 45 children younger than 4 years 10 were not bladder trained for continence and, therefore, the symptoms could not be evaluated reliably. All of the remaining 35 children had increased urinary frequency, 28 had urgency (and ocassionally daytime incontinence), 16 had hesitancy, 10 had to strain and 7 had discomfort on voiding. These symptoms occurred alone or in combination. Only 8 patients were older than 4 years, of whom 4 experienced urgency and increased urinary frequency. There were no obstructive type symptoms
494
VESICOTJRETERAL FtEFLL1:X A~JD VOIDI:r.;fC~ DYSF¥J~ICTI0N. AGE DISTRIJ3UTION AT THfE OF VUR ;JIAGNOSIS
------
No. of CASE::
<1
5
6
AGE (YEARS)
AGE DISTRIBUTION AT FIRST DIAGNOSED URINARY INFECTION No, of CASES
< 1
AGE (YEARS)
28.5 % soon after birth
55.3 % at bladder training time
Analysis of age distribution of 53 patients in prospective group at diagnosis of vesicoureteral reflux ( VUR) and first urinary infection.
in these older children, whereas hesitancy and straining were found in a significant number of younger patients. The other 4 older patients were free of voiding symptoms. None of the 53 patients had evidence of neurological disease on physical examination. Urinalysis and culture, voiding cystourethrogram, isotopic cystography with 99 mtechnetiurn (Tc)-pertechnetate, 14 excretory urogram (IVP), 99 mTc-dimercapto-succinic acid (DMSA) renal scan, 99 mTc-diethylenetriaminepentaacetic acid (DTPA) renogram and cystoscopy were performed in all patients. A complete urodynamic study was done, including initial uroflowmetry followed by simultaneous monitoring of total intravesical, intrarectal and intrinsic bladder pressures, surface pelvic floor electromyography during bladder filling and voiding, combined with a second uroflowmetry, as well as urethral pressure profilom.etry. The initial urodynamic study was executed with the patient free of any medication other than prophylactic antibiotics (cotrimoxazole or nitrofurantoin), awake and seated, using the Lectromed Urodynamic Investigation System 5000 with 5-channel recorders* and 5Ch feeding tube catheters for bladder filling and pressme recording. For perineal electromyography standard electrocardiogram electrodes, placed on either side of the anus with conductive gelt and secured with waterproof tape, were used. For each urodynamic study 2 consecutive cycles of filling and voiding graphics were recorded. Urodynamic testing in the infant and young child was performed as described previously. 15 It is much more time-consuming than in the older child but reliable results may be obtained once the patient becomes relaxed and participates in quiet games during the examination. One must remember that it takes time for the child to calm down and adjust to the introduction of the urethral catheter. It is only then that it is possible to proceed with the study. Followup evaluation consisted of clinical examination, urinalysis and culture at 1 and 3-month intervals. Isotopic cystography and DMSA renal scanning were performed at 6-month intervals until reflux disappeared on 2 consecutive cystographic
* Lectromed Ltd., St. Peter, Jersey Channel Islands, England.
t Aquasonic, Parker Laboratories, Inc., New Jersey.
495
studies. Every patient undenvent a final DTP A reno gram to assess any changes in glomemlar filtration rate. All drugs were then discontinued, and 1 month later a final urodynamic evaluation was performed. Cystography demonstrated grade I reflux in 8 ureters, grade II in 33, grade III in 27, grade IV in 4 and grade V in 2, according to the International Reflux Study Committee classification. 16 Cystoscopy failed to show any evidence of obstruction. Ureteral orifices ranged from Bl to C3 according to Lyons' classification. C2 and C3 lateral displacement of ureteral orifices was noted in cases of higher grade reflux. There were mild degrees of trabeculation in all bladders. Three different urodynamic patterns were found: 17 patients (32.1 per cent) only exhibited bladder instability and high pressures during bladder filling, 13 (24.1 per cent) only showed perineal incoordination on voiding, as demonstrated by high intrinsic bladder pressures during or immediately after voiding, increased electromyographic activity, residual urine (10 to 80 ml.) and high values on the ureteral pressure profile, and 23 (43.4 per cent) demonstrated high ureteral pressure profile values with residual urine, increased perinea! electromyographic activity and high pressures during bladder filling and voiding. Thus, all patients had high total and intrinsic bladder pressures during filling and/or voiding phases. Of the children 40 (75.5 per cent) had bladder instability alone or associated with perineal incoordination and 36 (67.9 per cent) had vesicoperineal incoordination alone or associated with bladder instability. Low dose antibiotic prophylaxis was prescribed for all children for the first 6 months and then it was stopped. The drugs included cotrimoxazole or nitrofurantoin at a quarter to half of the weight-adjusted recommended daily therapeutic dose. Only 2 patients had constipation, which was treated. Every patient who was toilet-trained for bladder continence was encouraged to void every 3 hours or as soon as urgency was experienced in the awake state. Those patients with bladder instability alone were started on anticholinergic drugs. Oral administration was preferred. For infants we used the liquid medication and for older children we used tablets. None of the drugs was available in liquid and tablets and, therefore, we had to use alternative drugs in the same category. For those patients less than 3 years old we used 8 mg,/kg. dicyclomine 1 7 ' 18 divided in 3 daily doses, while in patients older than 3 years we used 15 mg./kg. flavoxate 19 • 20 divided in 3 daily doses. Those patients with perinea! incoordination, either alone or associated with bladder instability, and younger than 3 years received a combination of the same doses of dicyclomine with liquid diazepam 21 • 22 (0.5 mg,/kg. divided in 3 daily doses), while those older than 3 years received doses. Special precau1 mg./kg. baclofen 23 ' 24 divided in 3 tions were taken with baclofen, since the manufacturers did not provide guidelines for its use in children less than 12 years old. V•/ e began with a sixteenth to a twentieth of the total daily dose, increasing dosage gradually every 3 days until the maintenance dose was reached. Before treatment was stopped we gradually reduced doses until the starting dose was reached. A complete medical examination was performed and hematological, hepatic and renal functions were evaluated before and 1 month after the beginning of treatment and every 3 months thereafter; values remained normal during the entire treatment period. The only side effect with diazepam was moderate excitement in 2 children. The side effects with baclofen consisted of dizziness (2 patients), transient headaches (2), moderate excitement (6), and abnormal psychological reactions of excitement and aggressive behavior (2). The latter 2 children stopped treatment and they were excluded from the study. All drugs were maintained for 6 months after vesicoureteral reflux resolution and for a maximum of 30 months. The retrospective group consisted of 36 girls and 12 boys 4 to 12 years old. Vesicoureteral reflux was demonstrated radio-
.496
SERUCA
graphically and they were under medical treatment exclusively from 1980 to 1985. Whether reflux was cured was not a factor. This group was selected in 1985, according to the same criteria as the prospective group, from a larger group of 76 patients with reflux to obtain a group with primary reflux. Initially urodynamic evaluation had not been performed. Treatment consisted of low dose antibiotic prophylaxis with cotrimoxazole or nitrofurantoin at a quarter to half of the weight-adjusted recommended daily therapeutic dose. The initial radiological (IVP and voiding cystourethrogram) and the cystoscopic findings were reviewed. The initial voiding cystourethrogram showed vesicoureteral reflux grade I in 12 ureters, grade II in 35, grade III in 18 and grade IV in 2. Complete physical examination, urinalysis and culture, voiding cystourethrogram, isotopic cystography, 99mTc-DMSA renal scintigraphy, 99mTcDTP A renogram and a complete urodynamic study as described previously were performed in 1985. RESULTS
All findings were statistically analyzed by computer with the Statistical Package for IBM PC, the SPSS/PC, and with the Mann-Whitney U-Wilcoxon rank sum W test. The prospective group was analyzed according to age distribution at the time of vesicoureteral reflux diagnosis and the first urinary infection (see figure). We noted 2 peaks in the incidence of initial urinary tract infection: during the first months of life and at the age of onset of bladder training, which indicates a functional disturbance as an etiological factor. Moreover, during and after treatment only 1 patient had an acute episode of clinical pyelonephritis, which was immediately controlled. A month after beginning treatment the voiding symptoms in the prospective group had improved significantly or had disappeared. The 53 patients in the prospective group received a complete course of treatment with the aforementioned drugs for a minimum of 12 months and a maximum of 30 months. These patients had 74 refluxing ureters at the beginning of the study. The rate of reflux resolution in the entire group, according to grade of reflux is presented in table 1. Reflux improved to grade II in 6 ureters (8.2 per cent) and it resolved in 68 (91.8 per cent). Patients with persistent reflux had received less than 30 months of treatment, had higher grades of reflux at entry into the study and still had urodynamic anomalies at the end of the study. The final urodynamic evaluation after the second cystography study showed resolution of reflux 1 month after stopping all medication in 50 of the 53 patients in the prospective group. In the remaining 3 patients with unresolved reflux the second urodynamic evaluation was performed at the end of this study in January 1988 while they were still receiving medication. In 46 patients with resolved reflux (62 ureters, 83.7 per cent) the urodynamic studies and bladder pressures were normal. In the remaining 4 patients with resolved reflux (6 ureters, 8.1 per cent) and in the 3 patients with persistent reflux (6 ureters, 8.1 per cent) urodynamic anomalies and high bladder pressures were still present. Thus, a total of 46 patients (86.8 per cent) TABLE
had reached normal adult urodynamic levels, normal bladder pressures and reflux resolution. In 31 kidneys from patients in the prospective group renal scars were detected by a 99mTc-DMSA renal scan at the beginning of the study, corresponding to 41.8 per cent of the ureters with reflux. At the end of the study the final DMSA renal scan and DTPA renogram showed no increase in existing renal scars, no new renal scars and no change in total renal function in any patient. Patients in the retrospective study group were older than those in the prospective group. The rate of reflux resolution according to reflux grade is shown in table 2. Reflux did not change in 15 ureters (22.4 per cent), increased from grade II to III in 3 (4.5 per cent), improved to grade II in 13 (19.4 per cent) and resolved in 36 (53.7 per cent). Urodynamic studies performed in 1985 revealed that 18 patients with resolved reflux had normal adult urodynamic levels. Eight other patients with resolved reflux and all 22 patients with persistent reflux had urodynamic anomalies. The abnormalities found in this group included bladder instability with high pressures during bladder filling in 9 patients (30 per cent), perineal incoordination with high pressures during voiding in 8 (26.6 per cent) and a combination of both in 13 (43.3 per cent). These urodynamic anomalies were similar in type and frequency to those in the prospective group before treatment. We found significantly better results (p = 0.001) in the prospective group, in which voiding dysfunctions were treated with anticholinergics and striated muscle relaxants compared to the retrospective group, in which the patients received only antibiotics when reflux modifications were analyzed after treatment (table 3). We evaluated the renal scars in patients of the retrospective group with DMSA renal scintigraphy, related them to the initial grade of reflux and to the number of ureters with reflux, and compared the results to those obtained for the prospective group at the end of the study (table 4). Until 1985 all ureters with grade V and most with grade IV reflux were treated by reimplantation surgery and they were excluded from this study. Thus, we could only compare cases of grades I, II and III reflux. The prospective group had a smaller percentage of renal scars TABLE
2. Rate of reflux resolution in the retrospective group of patients according to grade of reflux
Grade I II III IV V Total No.(%)
No. No. No. No. No. Increased to Improved to Ureters Unchanged Resolved Grade III Grade II 12 35 18 2 O* 68
I II III IV V Total No.(%)
8 33 27 4 2
74
No. Unchanged 0 0 0 0 0
0
No. Improved to Grade II 0 0 1 3 2
6 (8.2)
No. Resolved 8 33 26 1 0 68 (91.8)
0 0 13 0 0
-3 (4.5)
-
3 2 0
15 (22.4)
---
13 (19.4)
12 22 2 0 0
-
36 (53.7)
TABLE 3. Results of treatment on reflux in prospective and retrospective groups comparing treatment of voiding dysfunction in prospective group
according to grade of reflux No. Ureters
0 10
* All patients with grade V reflux and most of those with grade IV reflux underwent antireflux surgery before the study was undertaken.
1. Rate of reflux resolution in the prospective group of patients
Grade
0 3 0 0 0
Reflux upgraded Reflux unchanged Reflux downgraded Reflux disappearance
1985-1988: Prospective Group*
1980-1985: Retrospective Groupt
No. Ureters (%)
No. Ureters(%) 3 15 13 36
0 0 6 (8.2)
68 (91.8) p
(4.5) (22.4) (19.4) (53.7)
= 0.001
* Anticholinergic and striated muscle relaxants and antibiotics. t Antibiotics only.
VESICOURE'TERAL REFLUX AJ\ID ·voID!NG DYELITU~:c~fION T'ABLE
40 Ren,,al scars after treat;nent related to the initial grade of
reflux in both groups of patients No. Renal Scars/Refluxing Ureters After Medical Treatment(%) Grade
I II III IV V
Totals
Prospective Group
Retrospective Group
(12.5) (33.3) (±1.8) (75) (100)
3/12 (25) 14/35 (40) 10/18 (55.5) 2/2 (100) No cases
31/74 (41.8)
29/68 (43.8)
1/8 11/33 14/24 3/4 2/2
compared to the retrospective group but this was not statistically significant. DISCUSSION
This study indicates a cause and effect relationship between bladder-perineal dynamic abnormalities and the presence of vesicoureteral reflux. Of course, other associated factors, such as maturation of adrenergic fibers in the bladder 25 and sufficient length of the intravesical ureter, 26 have an important role in the presence or absence of reflux. Indeed, in some patients with urodynamic abnormalities and high intrinsic bladder pressures reflux resolves spontaneously as they get older, which may be of particular importance in younger children who are in the learning phases of coordinating vesical and perineal activity. Due to the structural anatomy of the bladder and urethra, the intravesical portion of the ureter increases its functional length during normal voiding, 27 In the presence of simultaneous strong detrusor contraction and vesicoperineal incoordination with voluntary constriction of the external sphincter the intravesical ureter cannot increase its functional length normally, which may contribute to the development or persistence of reflux in younger patients with otherwise anatomically shorter intravesical ureters. An important aspect of this study is that reflux resolved in all patients in whom the bladder-perineal anomalies and intrinsic bladder pressure normalized, Also, nearly 70 per cent of the patients with primary vesicoureteral reflux presented with a perinea! dynamic problem leading to functional obstruction. It has been stated that voluntary constriction of the external sphincter in an attempt to keep from wetting during uninhibited bladder contractions can cause bladder-sphincteric dyssynergia and urinary obstruction. 1 • 2 • 4 • 6 • 7 Current attitudes toward vesico-sphincteric dyssynergia favor keeping this diagnosis limited to patients with demonstrable neurological lesions. It is known that the treatment of bladder instability with anticholinergic increases the threshold for uninhibited contractions, enlarges the functional of the bladder thus, reduces intravesical pressure 2 •5 and improves reflux resolution with medical therapy, These reports show reflux resolution in 80 per cent of the cases with a reduction in the duration of treatment to half that required with long-term antibacterial prophylaxis alone. 2 • 5 However, 20 per cent of these patients had persistent vesicoureteral reflux and required surgery, representing the same results of conservative treatment with longterm antibiotic prophylaxis, 28 The results of our study suggest that sphincteric functional obstruction caused by bladder-perinea! incoordination is a major causative factor in vesicoureteral reflux in young children and that its treatment can improve reflux resolution on a medical basis compared to exclusive longterm antibiotic prophylaxis 28 and to exclusive treatment of bladder instability, 2• 5 • 6 thus reducing significantly the need for surgery. It is possible that the competitive life-style in modern society and the compulsive attitude of parents toward early bladder training may have a role in the development ofbladder-perineal
497
incoordination and the of patterns. Vesicoperineal incoordination that occurs normal patients is a different entity from dyssynergia that occurs in µa.cHau,,, with neurological lesions, The interpretation of measurements of external sphincter acis a subject of controversy, m 11eu1unJ,_;1o.;auy normal children, Surface electromyography as advocated Firlit and associates is widely used. 7 This method may lack precision in reflecting specific of the external sphincter but it does indicate the state of contraction of the perineal floor, of which the external sphincter is an integral component. Objections may be raised as to the occurrence of perineal incoordination during the urodynamic examination, such as stress of the examination as well as urethral and bladder irritation, Nevertheless, its repetitive occurrence in some patients and its total absence in others have led us to believe that some patients may indeed be voiding with an incompletely relaxed perineum of which the external sphincter is an integral component, Although this may be difficult to prove without round-the-dock monitoring of the sphincteric/perineal activity, we believe that we have gathered enough data to demonstrate that abnormalities of the vesico-sphincteric complex may not be limited to patients with obvious neurological anomalies. Rather, one is more likely to find milder forms of functional dyssynergia or incoordination that may contribute to the etiology and persistence of reflux. Objective evidence of the existence of anomalies of the vesicoperineal-sphincteric complex and its contributory role in the perpetuation of reflux may be in the prospective group and 30 in found in our 66 ""'"'~'-'""' the retrospective group) vvho exhibited incomplete siduals 10 to 80 ml.). This issue can only be definitively resolved by Holter-type monitoring. Recognition of the fact that vesicoperineal incoordination may contribute to reflux should be considered in the study and management of patients with reflux, REFERENCES 1. Koff, S. A., Lapides, J. and Piazza, D. H.: Association of urinary tract infection and reflux with uninhibited bladder contractions and voluntary sphincteric obstruction. J. Urol., 122: 373, 1979. 2. Koff, S. A. and Murtagh, D.S.: The uninhibited bladder in children: effect of treatment on recurrence of urinary infection and on vesicometeral reflux resolution. J, Urol., 130: 1138, 1983. 3. Allen, T. D,: Vesicournteral reflux as a manifestation of dysfunctional voiding. In: Reflux Nephropathy. Edited by J. Hodson and P, Kincaid-Smith, New York: Masson Publishing USA, sect. 5, 18, p, 171, 1979. 4. Koff, A., Lapid.es, J. and Piazza, D. H.: The uninhibited bladder in children: a cause for urinary obstruction, infection, and reflux. In: Reflux Edited by J- Hodson and P. Kincaid.Smith, New Publishing, USA, sect, 5, chapt, 17, p. 161, 1979. 5. Homsy, Y. L., Nsou!i, L, Hamburger, R, Laberge, I. and Schick, E.: Effects of oxybutynin on vesicoureteml reflux in children. J, Urol., 134: 1168, 1985. 6, Allen, T. D, and Bright, T. C", HI: Urodynamic patterns in children with dysfunctional voiding problems. J. UroL, 119: 247, 1978, 7. Firlit, C. F., Smey, P. and King, L. R.: Mictmition urodynamic flow studies in children. J. UroL, 119: 250, 1978. 8. Hanna, M. K., Di Scipio, W., Suh, K. K., Kogan, S. J., Levitt, S, B. and Donner, K.: Urodynamics in children. Part II. The pseudoneurogenic bladder, J. Urol., 125: 534, 1981. 9. Lapid.es, J. and Diokno, A. C.: Persistence of the infant bladder as a cause for urinary infection in girls. J. Urol., 103: 243, 1970. 10. Hinman, F. and Baumann, F, W.: Vesical and ureteral dam~;: from voiding dysfunction in boys without neurologic or obstructive disease. J. Urol., 109: 727, 1973. 11. Noe, H. N.: The role of dysfunctional voiding in failure or complication of ureteral reimplantation for primary reflux. J. Urol., 134: 1172, 1985. 12. Hinman, F,, Jr.: Nonneurogenic neurogenic bladder (the Hinman
498
SERUCA
syndrome)-15 years later. J. Urol., 136: 769, 1986. 13. Hindmarsh, J. R., Gosling, P. T. and Deane, A. M.: Bladder instability. Is the primary defect in the urethra? Brit. J. Urol., 55: 648, 1983. 14. Schoutens, A. and Schulman, C. C.: Functional studies with radionuclides. Dial. Ped. Urol., 7: 2, Feb. 1984. 15. Bauer, S. B., Hallett, M., Khoshbin, S., Lebowitz, R. L., Winston, K. R., Gibson, S., Colodny, A. H. and Retik, A. B.: Predictive value of urodynamic evaluation in newborns with myelodysplasia. J.A.M.A., 252: 650, 1984. 16. International Reflux Study Committee: Medical versus surgical treatment of primary vesicoureteral reflux: a prospective international reflux study in children. J. Urol., 125: 277, 1981. 17. Awad, S. A., Bryniak, S., Downie, J. W. and Bruce, A. W.: The treatment of the uninhibited bladder with dicyclomine. J. Urol., 117: 161, 1977. 18. Fischer, C. P., Diokno, A. and Lapides, J.: The anticholinergic effects of dicyclomine hydrochloride in uninhibited neurogenic bladder dysfunction. J. Urol., 120: 328, 1978. 19. Bradley, D. V. and Cazort, R. J.: Relief of bladder spasm by flavoxate. A comparative study. J. Clin. Pharm., 10: 65, 1970. 20. Jonas, U., Petri, E. and Kissel, J.: Effect offlavoxate on hyperactive detrusor muscle. Eur. Urol., 5: 106, 1979. 21. Chadduck, W. M., Loar, C.R. and Denton. I. R.: Vesical hypoton-
icity with diazepam. J. Urol., 109: 1005, 1973. 22. Bogash, M., Wolgin, W., Kugler, F. and Sadoughi, N.: Functional evaluation of voiding in patients with neurogenic bladder. J. Urol., 112: 338, 1974. 23. Taylor, M. C. and Bates, C. P.: A double-blind crossover trial of baclofen-a new treatment for the unstable bladder syndrome. Brit. J. Urol., 51: 504, 1979. 24. Leyson, J. F. J., Martin, B. F. and Sporer, A.: Baclofen in the treatment of detrusor-sphincter dyssynergia in spinal cord injury patients. J. Urol., 124: 82, 1980. 25. Kiruluta, H. G., Fraser, K. and Owen, L.: The significance of the adrenergic nerves in the etiology of vesicoureteral reflux. J. U rol., 136: 232, 1986. 26. King, L. R.: Vesicoureteral reflux: history, etiology, and conservative management. In: Clinical Pediatric Urology. Edited by P. P. Kelalis and L. R. King. Philadelphia: W. B. Saunders Co., vol. 1, chapt. 11,pp. 342-366, 1976. 27. Buzelin, J.-M.: Bases anatomiques de la physiologie vesico-sphincterienne. In: Urodynamique - Bas Appareil Urinaire. Paris: Masson, chapt. 1,pp. 3-18, 1984. 28. Edwards, D., Norman, I. C. S., Prescod, N. and Smellie, J. M.: Disappearance ofvesicoureteral reflux during long-term prophylaxis of urinary tract infection in children. Brit. Med. J ., 2: 285, 1977.