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Prognosis for Resolution of Moderate, Primary Reflux in Girls
Vol. 115, March
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1976 by The Williams & Wilkins Co.
PROGNOSIS FOR RESOLUTION OF MODERATE, PRIMARY REFLUX IN GIRLS CHARLES B. MANLEY,* NEAL NEUMAN
AND
WILLIAM H. MCALISTER
From the Divisions of Pediatric Urology and Radiology, St. Louis Children's Hospital, Washington University Medical Center, St. Louis, Missouri
ABSTRACT
Detailed cystoscopic grading of ureteral orifices has proved unnecessary in our experience for determining the prognosis of reflux in girls. Medially placed orifices strongly predict spontaneous resolution medication, while radiographic pyelonephritic scarring grade III reflux failure to resolve. While placed ureteral orifices and low volume reflux a need for operation, they are prognostically less useful, vvhen those with III reflux are excluded. Cystitis and unrelated anomalies seem to be associated with the ultimate need for but are of uncertain significance. Primary reflux is the most common form of vesicoureteral reflux, occurring predominantly in white girls and showing a familial pattern. 1 • 2 Attenuation of the trigonal musculature allows lateral retraction of the ureteral orifice and shortening of the intramural ureter with consequent reflux of urine. 3 In the absence of recurring infections primary reflux may resolve spontaneously in roughly reverse proportion to its severity as judged by radiographic and cystoscopic means (fig. 1). Massive (grade reflux rarely, if ever, resolves while the converse is true for minimal (grade I) reflux. If resolution of moderate grades is to occur, it usually does so within 2 to 3 years of diagnosis in early childhood and has little to do with changes coincident with puberty. 4 A clearer definition of prognosis for operation in apparently similar degrees of moderate reflux would minimize the need for prolonged courses of preventive medication and repeated diagnostic procedures. MATERIALS AND METHODS
During the last 6 years 255 children were seen for a history of recurrent urinary tract infection. Of the 242 patients evaluated radiologically 139 (57 per cent) demonstrated vesicoureteral reflux, including 76 girls with primary reflux. Of the latter group 47 girls with moderate, primary reflux have been followed to successful resolution of the problem and constitute the basis for this study. There were 2 girls, 1 operated upon and 1 not, who have been lost to followup and, therefore, are excluded from the study. After initial urologic evaluation each patient was followed with outpatient, awake cystograms at 3 to 6-month intervals while on preventive medication. All cystoscopic grading of ureteral orifices and operative decisions were made by 1 urologist and all x-rays were performed and read by 1 radiologist. Decision for operation was based upon persistence or progression of reflux during the period of treatment. Reflux resolved without operation in 21 girls who had at least 1 negative cystogram or maximum grade I reflux and a minimum of 6 months followup without infection while on no medication. The mean duration of preventive medication necessary for resolution was 12 months, while the mean followup after the first negative cystogram was 30 months. After a mean observation of 11 months and 3 cystograms 26 girls required an operation. All girls in the study were assessed for factors of possible Accepted for publication June 20, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. * for reprints: St. Louis Children's HospitaL 500 S. St. Louis. Missoc.:ri 631100
307
prognostic value, including maximum reflux, minimum reflux pressure, pyelonephritic scarring, unilateral or bilateral reflux, urethral calibration, stage and grade of ureteral orifices, cystitis cystica, height and weight percentiles, and unrelated anomalies. Maximum reflux was graded according to the scale of Dwoskin and Perlmutter. 5 Girls with grade I or IV reflux were excluded. Cystoscopic classification of ureteral orifices was based upon the system of Lyon and associates. 6 Grade refers to the configuration of the ureteral orifice, while stage refers to the position of the orifice on the trigone. RESULTS
Figure 2 correlates the cystoscopic appearance of each ureteral orifice with its maximum grade of reflux. As expected, spontaneous resolution of reflux as indicated by the solid circles diminished progressively with either worsening cystoscopic grade or stage. However, stage was found to be more useful because of the more distinct correlation with maximum grade of reflux, that is all ureters with grade HI reflux had stage C orifices and 10 of 11 (91 per cent) required reimplantation. Conversely, ureters with stage A or B orifices had only IIA or IIB maximum reflux and with similar distributions. As a basis for operative prognosis figure 3 depicts the outcome of each girl according to the maximum grade of reflux and minimum pressure at which it occurred for the worst ureter as seen on cystogram. Only 1 girl with grade III reflux avoided an operation compared to either grade HA or IIB in which approximately half resolved. While the p value in this small sample is more than 5 per cent this finding confirms the previous observation of Dwoskin and Perlmutter that grade III reflux rarely resolves. 5 The majority of girls with low volume reflux required operation but not 'distinctively enough to be prognostically useful. Excluding those patients with grade III reflux low volume resolution increased to more than 30 per cent. Figure 4 shows the outcome of each girl according to the grade and stage of the worst ureteral orifice. Again, stage was found to be more useful because of the distinct difference in outcome between stage A or B orifices and stage C. Of the former 87 per cent resolved compared to only 26 per cent of the latter, with the difference being significant at the 0.1 per cent level. Thus, from our experience, the most useful information to be derived from cystoscopy is simply whether the ureteral orifices are laterally placed, with no distinction between the more medial positions. If the orifices are not laterally placed prognosis for spontaneous resolution is excellent of any other information. It is that the lateral or stage C inch-
308
MANLEY, NEUMAN AND MCALISTER
FIG. 1.
Cystograms of girl with moderate, primary vesicoureteral reflux show progressive, spontaneous resolution during period of 15 months REFLUX
A eoo goo
000 0
m
GRADE WORST URETER 1------- ------1 I
ID
•••
IIB
••• ••o
!IA
REFLUX GRADE
,f\ I
=~
0000
eeooo eeoo
•••o tooo
•••• •• 000
•••o geeo eoo
eoo ooo
()
~
I
•
Void
I
0
50%
pa
II B
Ii) • •
0 ••
OO&fHII
High Vol
000000 00000
50%
•••• ..... ••••
0000 0000
•• Ill. 66%
J, I
l CYSTOSCOPIC
0000 0000
I I_______ ______ ..J
/~'-.
I
0
.
11%
PRESSURE
WORST URETER
2 GRADE
IIA
3
••••• •••• 56'Resolution
Low Vol
0000 000
Operation
• e •• 19%
00000 0000 0000 0000
Resolution
Operation
47 GIRLS
B •ooo
m
0000 000
•••
II B
...
••o
IIA
... REFLUX GRADE
FIG. 3. Outcome of each girl according to maximum reflux and minimum pressure for worst ureter on cystogram. Solid circles indicate spontaneous resolution and open circles indicate operative resolution.
••• •••
•••ooo •••ooo eooooo
00
•••• •• ••o
URETER AL WORST ORIFICE
000
•••oo •••oo
3
@0000 000
2
"'I
A
\__
\_ C
B
CYSTOSCOPIC
STAGE
F1G. 2. Correlation of A, ureteral orifice configuration and B, position on trigone with radiographic maximum grade ofreflux for each ureter. Solid circles indicate spontaneous resolution and open circles indicate operative resolution.
cate the need for operation particularly when those patients with grade III reflux were excluded, in which case nearly a third resolved spontaneously. As indicated in previous reports, the need for operation was evidenced by pyelonephritic scarring in a high percentage of the cases (91 per cent). In those patients with moderate reflux the changes were generally mild. It should be noted that in every instance the radiographic abnormalities were present
....•• 25%
•••• ••• 47%
0
STAGE
WORST ORIFICE
00000 00000 00000
C
0000 0000
B
I
I
GRADE
ORIFICES
••• ••• 86%
0
••• 75\
0
Resolution
Operation
A
• ••• •••• 26\
00000 00000 00000 00000 000
r-------
-------,
•••• ••• •••
0
87%
p, <.001
.... ------Resolution
0
_______ , Operation
47 GIRLS
FIG. 4. Outcome of each girl according to grade and stage of worst ureteral orifice on cystoscopy.
at the time of diagnosis, did not progress during the course of therapy and were not a factor in the decision for operation. Rather, the reflux to renal units with these changes simply did not subside. No clear association with severity of reflux was seen in 7 of 11 patients having grades less than III.
PROGNOSIS FOR RESOLUTION OF MODERATE, PRIMARY REFLUX IN GIRLS
Prognostic observations for moderate, primary reflux in girls (s,90%)
p
Resolution Operation Operation Operation Operation
<.001 <.02 <.10 <.10 <.20
Most useful: Medial (stages A and B) orifices Pyelonephritic scarring Grade III reflux Unrelated anomalies(") Cystitis cystica (?)
p
Less useful: Lateral (stage C) orifices without grade III reflux Low volume reflux without grade Ill reflux
?
Operation
<.01
?
Operation
<.02
p
Not useful:
I!A or IIB reflux High volume or voiding pressure Unilateral or bilateral reflux Urethral calibration Height and weight percentiles
Cystitis was seen in 4 of those girls (15 per cent) requiring operation but in none with spontaneous resolution. Although this observation is of uncertain significance it is interesting that cystitis cystica is found in 2.4 per cent of children with urinary tract infections. 7 Apparently unrelated anomalies such as ventricular septa! defect, club foot or syndactylism provided another unexpected relationship with operation for reflux being necessary in 8 of 9 such patients. However, 4 of these girls had grade III reflux and others with central nervous system disease may have had occult neurovesical dysfunction, although none was detectable. Mean urethral calibration was virtually identical at 16.4 and 16.6F in the resolved and operated groups. Decreased height and weight percentiles, and bilateral rather than unilateral reflux occurred somewhat more often in the operated than non-operated groups but not enough to be of significance. DISCUSSION
The prognostic observations thought to be most useful from our experience are summarized in the table. Cystoscopic grade and stage of ureteral orifices as determined by 1 observer showed a positive linear correlation for outcome of reflux but were found to be unnecessarily complex for prognostic purposes. Estimation of orifice appearance seems prone to variation, particularly from one observer to another. Determination of grade is, at times, almost imperceptible and arbitrary, for example stadium versus horseshoe shape. No prognostic dif-
309
ference was found between medial and intermediate positions (stages A and B) on the trigone in sharp distinction to those with lateral (stage C) orifices. Thus, it seems necessary only to determine whether the orifices are laterally placed or not. This should be done after the bladder is fully distended since the orifices characteristically move laterally with filling. We prefer to use a foroblique lens. Resolution of reflux with medially placed orifices is consistent with the experience of King and associates who attributed the reflux to infection, which would stop after the inflammation had subsided.' However, most of our children showed no evidence of inflammation at the time of cystoscopy and many required a year or more for resolution despite absence of infection. In a few patients, initial worsening of reflux was observed to IIB) while uninfected and on preventive medication, only to subside at a later time. Failure of reflux resolution in those patients with pyelonephritic scarring and cystitis suggests a secondary rather than role of infection serving to fix the orifices in a fibrosis and, any more lateral nA•on,,rm possible lengthening of the intravesical ureter subsequent maturation of the trigonal musculature. The median interval between history of first urinary tract infection and initiation of effective preventive medication was somewhat longer in the group requiring operation but not enough to be of significance. However, the uncertain documentation of the first urinary tract infection leaves this possibility unresolved. Dr. Reimut Wette, Director of Biostatistics, Washington University Medical Center, St. Louis, Missouri assisted in the study. REFERENCES 1. Tanagho, E. A. and Hutch, J. A.: Primary reflux. J. Urol., 93: 158,
1965. 2. Burger, R.H. and Smith, C.: Hereditary and familial vesicoureteral
reflux. J. Urol., 106: 845, 1971. 3. Tanagho, E. A., Hutch, J. A., Meyers, F. H. and Rambo, 0. N., Jr.: Primary vesicoureteral reflux: experimental studies of its etiology. J. Urol., 93: 165, 1965. 4. King, L. R., Kazmi, S. 0. and Belman, A. E.: Natural history of vesicoureteral reflux. Outcome of a trial of nonoperative therapy. Urol. Clin. N. Amer., l: 441, 1974. 5. Dwoskin, J. Y. and Perlmutter, A. D.: Vesicoureteral reflux in children: a computerized review. J. Urol., !09: 888, 1973. 6. Lyon, R. P., Marshall, S. and Tanagho, E. A.: The ureteral orifice: its configuration and competency. J. Urol., 102: 504, 1969. 7. Kaplan, G. W. and King, L. R.: Cystitis cystica in childhood. J. Urol., 103: 657, 1970.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1976 by The Williams & Wilkins Co.
PROGNOSIS FOR RESOLUTION OF MODERATE, PRIMARY REFLUX IN GIRLS CHARLES B. MANLEY,* NEAL NEUMAN
AND
WILLIAM H. MCALISTER
From the Divisions of Pediatric Urology and Radiology, St. Louis Children's Hospital, Washington University Medical Center, St. Louis, Missouri
ABSTRACT
Detailed cystoscopic grading of ureteral orifices has proved unnecessary in our experience for determining the prognosis of reflux in girls. Medially placed orifices strongly predict spontaneous resolution medication, while radiographic pyelonephritic scarring grade III reflux failure to resolve. While placed ureteral orifices and low volume reflux a need for operation, they are prognostically less useful, vvhen those with III reflux are excluded. Cystitis and unrelated anomalies seem to be associated with the ultimate need for but are of uncertain significance. Primary reflux is the most common form of vesicoureteral reflux, occurring predominantly in white girls and showing a familial pattern. 1 • 2 Attenuation of the trigonal musculature allows lateral retraction of the ureteral orifice and shortening of the intramural ureter with consequent reflux of urine. 3 In the absence of recurring infections primary reflux may resolve spontaneously in roughly reverse proportion to its severity as judged by radiographic and cystoscopic means (fig. 1). Massive (grade reflux rarely, if ever, resolves while the converse is true for minimal (grade I) reflux. If resolution of moderate grades is to occur, it usually does so within 2 to 3 years of diagnosis in early childhood and has little to do with changes coincident with puberty. 4 A clearer definition of prognosis for operation in apparently similar degrees of moderate reflux would minimize the need for prolonged courses of preventive medication and repeated diagnostic procedures. MATERIALS AND METHODS
During the last 6 years 255 children were seen for a history of recurrent urinary tract infection. Of the 242 patients evaluated radiologically 139 (57 per cent) demonstrated vesicoureteral reflux, including 76 girls with primary reflux. Of the latter group 47 girls with moderate, primary reflux have been followed to successful resolution of the problem and constitute the basis for this study. There were 2 girls, 1 operated upon and 1 not, who have been lost to followup and, therefore, are excluded from the study. After initial urologic evaluation each patient was followed with outpatient, awake cystograms at 3 to 6-month intervals while on preventive medication. All cystoscopic grading of ureteral orifices and operative decisions were made by 1 urologist and all x-rays were performed and read by 1 radiologist. Decision for operation was based upon persistence or progression of reflux during the period of treatment. Reflux resolved without operation in 21 girls who had at least 1 negative cystogram or maximum grade I reflux and a minimum of 6 months followup without infection while on no medication. The mean duration of preventive medication necessary for resolution was 12 months, while the mean followup after the first negative cystogram was 30 months. After a mean observation of 11 months and 3 cystograms 26 girls required an operation. All girls in the study were assessed for factors of possible Accepted for publication June 20, 1975. Read at annual meeting of American Urological Association, Miami Beach, Florida, May 11-15, 1975. * for reprints: St. Louis Children's HospitaL 500 S. St. Louis. Missoc.:ri 631100
307
prognostic value, including maximum reflux, minimum reflux pressure, pyelonephritic scarring, unilateral or bilateral reflux, urethral calibration, stage and grade of ureteral orifices, cystitis cystica, height and weight percentiles, and unrelated anomalies. Maximum reflux was graded according to the scale of Dwoskin and Perlmutter. 5 Girls with grade I or IV reflux were excluded. Cystoscopic classification of ureteral orifices was based upon the system of Lyon and associates. 6 Grade refers to the configuration of the ureteral orifice, while stage refers to the position of the orifice on the trigone. RESULTS
Figure 2 correlates the cystoscopic appearance of each ureteral orifice with its maximum grade of reflux. As expected, spontaneous resolution of reflux as indicated by the solid circles diminished progressively with either worsening cystoscopic grade or stage. However, stage was found to be more useful because of the more distinct correlation with maximum grade of reflux, that is all ureters with grade HI reflux had stage C orifices and 10 of 11 (91 per cent) required reimplantation. Conversely, ureters with stage A or B orifices had only IIA or IIB maximum reflux and with similar distributions. As a basis for operative prognosis figure 3 depicts the outcome of each girl according to the maximum grade of reflux and minimum pressure at which it occurred for the worst ureter as seen on cystogram. Only 1 girl with grade III reflux avoided an operation compared to either grade HA or IIB in which approximately half resolved. While the p value in this small sample is more than 5 per cent this finding confirms the previous observation of Dwoskin and Perlmutter that grade III reflux rarely resolves. 5 The majority of girls with low volume reflux required operation but not 'distinctively enough to be prognostically useful. Excluding those patients with grade III reflux low volume resolution increased to more than 30 per cent. Figure 4 shows the outcome of each girl according to the grade and stage of the worst ureteral orifice. Again, stage was found to be more useful because of the distinct difference in outcome between stage A or B orifices and stage C. Of the former 87 per cent resolved compared to only 26 per cent of the latter, with the difference being significant at the 0.1 per cent level. Thus, from our experience, the most useful information to be derived from cystoscopy is simply whether the ureteral orifices are laterally placed, with no distinction between the more medial positions. If the orifices are not laterally placed prognosis for spontaneous resolution is excellent of any other information. It is that the lateral or stage C inch-
308
MANLEY, NEUMAN AND MCALISTER
FIG. 1.
Cystograms of girl with moderate, primary vesicoureteral reflux show progressive, spontaneous resolution during period of 15 months REFLUX
A eoo goo
000 0
m
GRADE WORST URETER 1------- ------1 I
ID
•••
IIB
••• ••o
!IA
REFLUX GRADE
,f\ I
=~
0000
eeooo eeoo
•••o tooo
•••• •• 000
•••o geeo eoo
eoo ooo
()
~
I
•
Void
I
0
50%
pa
II B
Ii) • •
0 ••
OO&fHII
High Vol
000000 00000
50%
•••• ..... ••••
0000 0000
•• Ill. 66%
J, I
l CYSTOSCOPIC
0000 0000
I I_______ ______ ..J
/~'-.
I
0
.
11%
PRESSURE
WORST URETER
2 GRADE
IIA
3
••••• •••• 56'Resolution
Low Vol
0000 000
Operation
• e •• 19%
00000 0000 0000 0000
Resolution
Operation
47 GIRLS
B •ooo
m
0000 000
•••
II B
...
••o
IIA
... REFLUX GRADE
FIG. 3. Outcome of each girl according to maximum reflux and minimum pressure for worst ureter on cystogram. Solid circles indicate spontaneous resolution and open circles indicate operative resolution.
••• •••
•••ooo •••ooo eooooo
00
•••• •• ••o
URETER AL WORST ORIFICE
000
•••oo •••oo
3
@0000 000
2
"'I
A
\__
\_ C
B
CYSTOSCOPIC
STAGE
F1G. 2. Correlation of A, ureteral orifice configuration and B, position on trigone with radiographic maximum grade ofreflux for each ureter. Solid circles indicate spontaneous resolution and open circles indicate operative resolution.
cate the need for operation particularly when those patients with grade III reflux were excluded, in which case nearly a third resolved spontaneously. As indicated in previous reports, the need for operation was evidenced by pyelonephritic scarring in a high percentage of the cases (91 per cent). In those patients with moderate reflux the changes were generally mild. It should be noted that in every instance the radiographic abnormalities were present
....•• 25%
•••• ••• 47%
0
STAGE
WORST ORIFICE
00000 00000 00000
C
0000 0000
B
I
I
GRADE
ORIFICES
••• ••• 86%
0
••• 75\
0
Resolution
Operation
A
• ••• •••• 26\
00000 00000 00000 00000 000
r-------
-------,
•••• ••• •••
0
87%
p, <.001
.... ------Resolution
0
_______ , Operation
47 GIRLS
FIG. 4. Outcome of each girl according to grade and stage of worst ureteral orifice on cystoscopy.
at the time of diagnosis, did not progress during the course of therapy and were not a factor in the decision for operation. Rather, the reflux to renal units with these changes simply did not subside. No clear association with severity of reflux was seen in 7 of 11 patients having grades less than III.
PROGNOSIS FOR RESOLUTION OF MODERATE, PRIMARY REFLUX IN GIRLS
Prognostic observations for moderate, primary reflux in girls (s,90%)
p
Resolution Operation Operation Operation Operation
<.001 <.02 <.10 <.10 <.20
Most useful: Medial (stages A and B) orifices Pyelonephritic scarring Grade III reflux Unrelated anomalies(") Cystitis cystica (?)
p
Less useful: Lateral (stage C) orifices without grade III reflux Low volume reflux without grade Ill reflux
?
Operation
<.01
?
Operation
<.02
p
Not useful:
I!A or IIB reflux High volume or voiding pressure Unilateral or bilateral reflux Urethral calibration Height and weight percentiles
Cystitis was seen in 4 of those girls (15 per cent) requiring operation but in none with spontaneous resolution. Although this observation is of uncertain significance it is interesting that cystitis cystica is found in 2.4 per cent of children with urinary tract infections. 7 Apparently unrelated anomalies such as ventricular septa! defect, club foot or syndactylism provided another unexpected relationship with operation for reflux being necessary in 8 of 9 such patients. However, 4 of these girls had grade III reflux and others with central nervous system disease may have had occult neurovesical dysfunction, although none was detectable. Mean urethral calibration was virtually identical at 16.4 and 16.6F in the resolved and operated groups. Decreased height and weight percentiles, and bilateral rather than unilateral reflux occurred somewhat more often in the operated than non-operated groups but not enough to be of significance. DISCUSSION
The prognostic observations thought to be most useful from our experience are summarized in the table. Cystoscopic grade and stage of ureteral orifices as determined by 1 observer showed a positive linear correlation for outcome of reflux but were found to be unnecessarily complex for prognostic purposes. Estimation of orifice appearance seems prone to variation, particularly from one observer to another. Determination of grade is, at times, almost imperceptible and arbitrary, for example stadium versus horseshoe shape. No prognostic dif-
309
ference was found between medial and intermediate positions (stages A and B) on the trigone in sharp distinction to those with lateral (stage C) orifices. Thus, it seems necessary only to determine whether the orifices are laterally placed or not. This should be done after the bladder is fully distended since the orifices characteristically move laterally with filling. We prefer to use a foroblique lens. Resolution of reflux with medially placed orifices is consistent with the experience of King and associates who attributed the reflux to infection, which would stop after the inflammation had subsided.' However, most of our children showed no evidence of inflammation at the time of cystoscopy and many required a year or more for resolution despite absence of infection. In a few patients, initial worsening of reflux was observed to IIB) while uninfected and on preventive medication, only to subside at a later time. Failure of reflux resolution in those patients with pyelonephritic scarring and cystitis suggests a secondary rather than role of infection serving to fix the orifices in a fibrosis and, any more lateral nA•on,,rm possible lengthening of the intravesical ureter subsequent maturation of the trigonal musculature. The median interval between history of first urinary tract infection and initiation of effective preventive medication was somewhat longer in the group requiring operation but not enough to be of significance. However, the uncertain documentation of the first urinary tract infection leaves this possibility unresolved. Dr. Reimut Wette, Director of Biostatistics, Washington University Medical Center, St. Louis, Missouri assisted in the study. REFERENCES 1. Tanagho, E. A. and Hutch, J. A.: Primary reflux. J. Urol., 93: 158,
1965. 2. Burger, R.H. and Smith, C.: Hereditary and familial vesicoureteral
reflux. J. Urol., 106: 845, 1971. 3. Tanagho, E. A., Hutch, J. A., Meyers, F. H. and Rambo, 0. N., Jr.: Primary vesicoureteral reflux: experimental studies of its etiology. J. Urol., 93: 165, 1965. 4. King, L. R., Kazmi, S. 0. and Belman, A. E.: Natural history of vesicoureteral reflux. Outcome of a trial of nonoperative therapy. Urol. Clin. N. Amer., l: 441, 1974. 5. Dwoskin, J. Y. and Perlmutter, A. D.: Vesicoureteral reflux in children: a computerized review. J. Urol., !09: 888, 1973. 6. Lyon, R. P., Marshall, S. and Tanagho, E. A.: The ureteral orifice: its configuration and competency. J. Urol., 102: 504, 1969. 7. Kaplan, G. W. and King, L. R.: Cystitis cystica in childhood. J. Urol., 103: 657, 1970.