ULTRASOUND BLADDER MEASUREMENTS IN PATIENTS WITH PRIMARY NOCTURNAL ENURESIS: A URODYNAMIC AND TREATMENT OUTCOME CORRELATION

0022-5347/04/1716-2589/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 171, 2589 –2594, June 2004 Printed in U.S.A.

DOI: 10.1097/01.ju.0000112978.54300.03

ULTRASOUND BLADDER MEASUREMENTS IN PATIENTS WITH PRIMARY NOCTURNAL ENURESIS: A URODYNAMIC AND TREATMENT OUTCOME CORRELATION C. K. YEUNG,* B. SREEDHAR, V. T. LEUNG

AND

C. METREWELI

From the Division of Paediatric Surgery (CKY, BS), Department of Surgery, and Department of Diagnostic Radiology and Organ Imaging (VTL, CM), Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China

ABSTRACT

Purpose: Accurate assessment of bladder dysfunction associated with voiding dysfunctions often necessitates invasive urodynamic (UD) studies. We evaluate the use of a special ultrasound (US) protocol for the assessment of bladder dysfunction compared with urodynamic findings, and for prediction of treatment outcome in children with primary nocturnal enuresis (PNE). Materials and Methods: US measurements were performed on 514 children 5 to 18 years old (mean age 11.2) with PNE, and compared with those of 339 normal age matched children. A US protocol was specially designed for the evaluation of bladder parameters using bladder volume and wall thickness index (BVWI %), and expected percentage bladder volume index for kidney volume. Of the enuretic children 218 had severe enuretic symptoms with more than 3 wet nights a week. They underwent urodynamic studies for detailed assessment of any underlying bladder dysfunction. A standard 4-week course of desmopressin was given to these children after the US and UD studies. The US bladder parameters were then correlated with the UD findings and treatment response to desmopressin. Results: Comparing the BVWI in normal and enuretic children in correlation with functional bladder capacities we were able to delineate bladder wall thickness and capacity as BVWI less than 70 —small capacity bladder with thick wall, BVWI 70 to 130 —normal bladder capacity with normal wall thickness and BVWI greater than 130 —large bladder capacity with thin wall. There were statistically significant correlations between BVWI and treatment response. In addition, there was a high predictive value of normal bladder function with a normal BVWI. Patients with good response to treatment had normal BVWI, whereas poor response to treatment was significantly associated with pathological bladder conditions, that is small bladder capacity with thick bladder wall or large bladder capacity with thin bladder wall (p ⬍0.0001). Of note, abnormalities detected by UD correlated well with bladder abnormalities measured by US. Conclusions: PNE comprises a diverse spectrum of conditions resulting in a mismatch of nocturnal urine production in excess of nocturnal functional bladder capacity, and underlying bladder dysfunction has an important role in the pathophysiology especially in refractory cases. This US protocol can provide useful predictive clues, which may be helpful to differentiate treatment subtypes, guide clinical management and minimize the need for invasive urodynamic studies. KEY WORDS: ultrasonography, urodynamics, desmopressin, enuresis

Primary nocturnal enuresis (PNE) is a common disorder that affects around 15% to 20% of 5-year-old children, 10% 7 to 12-year-old children and up to 2% of adults.1 While the exact etiology of this condition is probably multifactorial and remains to be determined, the common pathophysiological factor appears to involve a mismatch of nocturnal urine output in excess of functional bladder capacity in conjunction with failure of conscious arousal to the sensation of bladder fullness. Recently, several studies have revealed an important role of reduced functional bladder capacity and bladder dysfunction in the pathogenesis of primary nocturnal enuresis, especially when refractory to treatment.2– 6 It has been shown that the response to treatment with desmopressin can be predicted based on functional bladder capacities. Reduced functional bladder capacity is significantly associated with a poorer response to desmopressin therapy, whereas normal

functional bladder capacity has a greater chance of long-term desmopressin success.7–9 Accurate assessment of bladder dysfunction associated with voiding dysfunction often necessitates invasive urodynamic (UD) studies. Recent reports have suggested that ultrasound (US) measurement of bladder wall thickness can be used as a predictor of lower urinary tract dysfunctions in children and adults.10 –13 However, US in children with PNE and in particular for the prediction of treatment response to desmopressin has not been evaluated to our knowledge. As a screening tool for possible underlying bladder dysfunction, US bladder measurement has the potential advantages of being highly reproducible, sensitive and noninvasive.14 –16 We evaluated the role of ultrasound bladder measurements to assess bladder dysfunction compared with urodynamic studies and to predict treatment outcome in enuretic children.

* Correspondence: Division of Paediatric Surgery, Department of PATIENTS AND METHODS Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, US bladder measurements were performed on 514 children Shatin, Hong Kong, China (telephone: (852) 26322953; FAX: (852) 5 to 18 years old (mean age 11.2) with monosymptomatic 26377974; e-mail: [email protected]). 2589

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PNE referred to our enuresis clinic from 1998 to 2002 and 339 normal age matched children without urinary symptoms who were referred for other minor surgical problems. Scans were performed with the patient supine using ATL 500 (Advanced Technology Laboratories, Bothell, Washington) and ESAOTE Technos (Genoa, Italy) ultrasound unit with a 5 MHz frequency probe. Children were encouraged to drink as much water as possible before US assessment. After 20 minutes children were scanned in a standard supine position. Both renal volumes were measured and calculated using a standard formula for an ovoid, length ⫻ maximum transverse short axis diameter ⫻ maximum transverse long axis diameter ⫻ 0.523. The transverse diameter was taken in a plane transverse to the long axis of the child and at the maximum cross-sectional area, which was usually at or near the renal hilum to give the total renal volume, from which the expected maximum bladder volume index (BVI) and expected bladder wall thickness (BT) were read (table 1). The bladder volume index was measured by assessing the bladder from the longitudinal and transverse planes when the children said they were full and wished to empty the bladder (first urge). Measurements were taken using the onboard calipers of US unit at a maximum magnification. From the longitudinal plane (LS) the maximum length of the bladder was measured from the fundus of the bladder to the internal opening of the urethra. After this the probe was turned 90 degrees to the transverse plane (TS), the maximum transverse diameter and maximum anteroposterior diameter (AP) were measured. The bladder volume index was calculated based on the equation, (BVI ⫽ LS ⫻ TS ⫻ AP). No attempt was made to convert this volume into a “true” volume. If the measured bladder volume index was less than 70% of expected, the child would be asked to wait longer until he/she either achieved a volume greater than 70%, were obviously distressed or were actually incontinent. This technique worked very well in the age group concerned and ensured that there was little chance of over diagnosing small bladders.

TABLE 1. Expected maximum bladder volume index and expected mean BVI/BT Age

Mean Total Renal Vol

Expected Max BVI

Expected Mean BVI/BT

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5

50 57 63 69 75 81 88 94 100 106 113 119 125 131 138 144 150 156 163 169 175 181 188 194 200 206 213 219 225 231 238 244

100 130 160 190 220 250 280 310 340 370 400 430 460 490 520 550 580 610 640 670 700 730 760 790 820 850 880 910 940 970 1000 1030

— 440 530 592 635 740 880 970 1036 1126 1230 1320 1425 1485 1590 1680 1785 1875 1980 2070 2175 2265 2355 2460 2550 2640 2745 2835 2940 3030 3135 3225

The BVI was repeated and bladder emptying efficiency was calculated from ([BVI max ⫺ BVI empty)/BVI max]) as a percentage. If it was greater than 90% the child was judged to have emptied normally and if less than 90%, the child was asked to void a second time. Bladder wall thickness measurements would only be considered reliable if bladder emptying was more than 90% of a maximally full bladder. To measure the bladder wall thickness, the transducer was applied transversely in the sagittal plane of the abdomen with zoom and resolution optimized for viewing the bladder wall. Measurements were made perpendicular to the luminal surface of the anterolateral, lateral and posterolateral wall of the bladder. The mean bladder wall thickness was then calculated as an average of the 3 measurements (BT ⫽ [anterior ⫹ lateral ⫹ posterior]/3). The bladder volume and wall thickness index were calculated as, bladder volume and wall thickness index (BVWI %) ⫽ (measured BVI max/measured BT). This volume was then expressed as a percentage of the expected from the table (table 1). A total of 159 boys and 59 girls with severe enuretic symptoms (greater than 3 wet nights a week) were selected for further urodynamic studies as described previously.4 Briefly, each patient was evaluated with natural fill and conventional fill cystometry study during the day, followed by overnight simultaneous monitoring of encephalography and cystometric changes. Natural fill cystometric studies were performed using an ambulatory urodynamic recorder with continuous on-line pressure display during bladder filling and emptying. Conventional fill cystometry was performed using a computerized urodynamic system. Overnight encephalography monitoring was performed using a modified polygraphic signal analyzer for 2 consecutive nights. Data on natural fill and conventional fill cystometry studies performed during the day were compared with the data obtained by the cystometric recordings at night. The patients were then categorized into those with normal daytime urodynamics and bladder capacity, but abnormal bladder function during sleep (group 1), and those with abnormal daytime urodynamics associated with reduced functional bladder capacity day and night (group 2) as described previously.6 The pediatric radiologist and sonographer who performed the ultrasound bladder measurements and the pediatric urologist who made the urodynamic evaluations were completely blinded to the results and interpretations of the other study. A standard 4-week course of 400 ␮g desmopressin treatment before bedtime was given to the enuretic children after the US and UD assessments. The number of wet nights was compared before and after treatment. Enuretic children were then classified into complete response— complete dryness, good response— greater than 90% reduction in wet nights compared with the baseline, partial response greater than 50% but less than 90% reduction in wet nights compared with the baseline and no response—no effect or less than 50% reduction in wet nights compared with the baseline. The US bladder measurements were then correlated with UD findings and the treatment response to desmopressin using chisquare test. Differences between the groups were analyzed using Mann Whitney U test with p ⬍0.05 considered statistically significant. RESULTS

When comparing the bladder wall thickness alone with response to desmopressin there was a clear relationship between increasing thickness and lack of response (fig. 1). Nevertheless there was marked overlap of measurements between different treatment response groups and the means were still within the normal range of bladder wall thickness (table 2). Therefore, it was not possible to select a clear cutoff value with clinically adequate sensitivity and specificity although bladder wall thickness remained relatively stable

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FIG. 1. Treatment responses in enuretic children vs bladder wall thickness

TABLE 2. Bladder volume and wall thickness index in different treatment response groups Treatment Outcome Completely dry Good response Partial response No response Overall

No. Pts

Mean BT ⫾ SD

Mean BVI ⫾ SD

39 56 60 63 218

0.3633 ⫾ 0.098 0.3763 ⫾ 0.10 0.4153 ⫾ 0.14 0.4143 ⫾ 0.15 0.3953 ⫾ 0.13

636 ⫾ 232.6 564 ⫾ 264 527.96 ⫾ 273.5 454 ⫾ 275.57 535 ⫾ 261.27

throughout the age range of enuretic patients involved. We also observed an inverse relationship between bladder volume index and patient response to desmopressin (fig. 2). However, it was also difficult to use this parameter alone because allowance had to be made for age or weight of the child, and US is not an accurate method of determining true bladder volume. In addition, there was also a wide overlap of measurements between different groups and the means were also within the normal range as well (table 2). The bladder volume and wall thickness index (BVWI) was correlated with patient response to desmopressin. BVWI was 70 to 130 in children with a very good response to treatment (fig. 3). Those with partial and no response mostly had significantly lower BVWI (implying smaller bladders

with a thicker wall). Of the complete response group 80% had normal BVWI compared to 55% with good, 10% partial and 11% no responses, while 77% of the partial and 69% of the no response groups had BVWI less than 70 (p ⬍0.001, table 3, fig. 3). Moreover, we also identified a group of children with BVWI greater than 130 (partial response 13%, no response 21%), which implies that these children had relatively larger bladder capacity with relatively thinner walls. In addition, normal daytime urodynamics were significantly associated with normal BVWI, whereas abnormal bladder function detected by UD correlated well with abnormal US bladder parameters. Of the 218 enuretic children 66 had normal daytime urodynamics (group 1) and 152 had abnormal daytime urodynamics (group 2). Of group 1 children 73% had normal BVWI (70 to 130), whereas 70% of those in group 2 had BVWI less than 70 (p ⬍0.001, table 4, fig. 4). DISCUSSION

Several reports have shown that children with PNE have smaller functional bladder capacities compared to age matched nonenuretic controls.2– 6 It has been suggested that a normal functional bladder capacity is associated with a higher chance of long-term success for desmopressin treat-

FIG. 2. Treatment responses in enuretic children vs bladder volume index

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FIG. 3. Relationship between bladder volume and wall thickness index and treatment outcome of patients with PNE

TABLE 3. Treatment response of enuretic children corresponding to the bladder volume and wall thickness index Treatment Outcome

No. BVWI 70–130 (%)

No. BVWI Less Than 70 (%)

No. BVWI Greater Than 130 (%)

Total No.

31 (79.5) 31 (55.4) 6 (10) 7 (11.1)

6 (15.4) 21 (37.5) 46 (76.7) 43 (68.3)

2 (5.1) 4 (7.1) 8 (13.3) 13 (20.6)

39 56 60 63

Complete response Good response Partial response No response Totals

75

116

TABLE 4. Bladder volume and wall thickness index in different urodynamic groups Urodynamic Category Normal Abnormal Totals

Bladder Volume and Wall Thickness Index

Total No.

No. BVWI 70–130 (%)

No. BVWI Less Than 70 (%)

No. BVWI Greater Than 130 (%)

48 (72.7) 27 (17.8)

11 (16.7) 105 (69.1)

7 (10.6) 20 (13.2)

66 152

75

116

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ment, whereas patients with a small bladder capacity would benefit more from combined use of enuretic alarm and antimuscarinic agents that help to dampen down uninhibited detrusor contractions. Ultrasound measurement of bladder wall thickness has been proposed as a highly reproducible and sensitive method for screening pathological bladder conditions. Studies by Robinson et al reported that women with detrusor instability have a thicker bladder wall compared to those with genuine stress incontinence.15 Other studies reported that ultrasound measured bladder wall thickness could be used as a sensitive tool for differentiating the presence and absence of anatomical intravesical obstruction.10, 13 Gilsanz et al identified increased bladder wall thickness on ultrasound in patients with bladder outlet obstruction.17 However, the potential use of US measured bladder wall thickness in the clinical assessment of children with primary nocturnal enuresis has not been fully evaluated. Based on the measurements of normal bladder wall in 410 children Jequier and Rousseau concluded that US bladder wall thickness determination needs to be standardized according to the state of bladder filling because bladder wall thickness changes continuously with bladder filling.18 The chart that we used to obtain the bladder volume index/bladder wall thickness is given in table 1. Our results confirm that there is a correlation between increased bladder wall

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thickness and lack of response, and that bladder volume correlates inversely with desmopressin response. Unfortunately the significant overlap measurements between groups and with the normal range make these 2 parameters poorly discriminatory clinical tools. As the most accurate measure of bladder volume is when volume is maximal and the most accurate measure of bladder wall thickness is when the bladder is empty, combining the figures in such a ratio allows the differences to be magnified. Expressing the resulting value as a percentage of expected for that particular child, using total renal volume rather than age reduces the effects of normal variation with age and results in a clinically useful discriminator. Some technical limitations must be observed during US measurements of the bladder wall. Kaefer et al observed thicker wall measurements when they obtained US images during voiding than those obtained before or after voiding.13 To prevent a false impression of increased wall thickening, we repeated the bladder wall thickness measurement if the first void did not achieve 90% emptying efficiency and in some cases after the second void. In addition, since the bladder capacity in children varies with age and size, a standard value of ultrasound estimated maximal bladder volume and wall thickness must be determined to allow judgment of degree of deviation from the normal standard in an individual. With this in mind, we applied a method involving ultrasound estimated maximal bladder volume and bladder wall thickness between patients and normal children adjusted for total renal volume. The reasons for this unusual design of protocol are the subject of another report. In this study ultrasound measured bladder volume and wall thickness index correlated well with the presence or absence of underlying bladder dysfunction, as indicated by the urodynamic studies. As described in a previous report patients with PNE and desmopressin resistant enuresis had 2 main bladder functional patterns that caused a reduction in

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FIG. 4. Relationship between bladder volume and wall thickness index and urodynamic category of patients with PNE

nocturnal bladder capacities.6 Patients had normal functional bladder capacity during the day but significant reduction in nocturnal functional bladder capacity associated with appearance of detrusor overactivity after sleep at night (group 1) or they had reduced bladder functional capacity day and night associated with occult voiding dysfunction or bladder outflow obstruction (group 2). Other reports have indicated that detrusor instability after sleep at night in patients with normal daytime urodynamics may be associated with a dysfunction of the brainstem during sleep.19, 20 Notwithstanding this, patients in group 1 would benefit from a combination treatment of desmopressin with oxybutynin, whereas patients in group 2 would need a formal evaluation and treatment of the underlying bladder dysfunction and/or outflow obstruction. Results from this study indicate that the 2 groups of patients can be distinguished using the US protocol as the majority of patients in group 1 had a normal BVWI (70 to 130) whereas a significant number of children in group 2 had an abnormal BVWI. This latter finding could either be a small capacity bladder with thick bladder wall (BVWI less than 70) or a large capacity bladder with a thin wall (BVWI greater than 130). The most important finding in our study is the high predictive value of BVWI for treatment response to desmopressin. Of the complete response group 80% had normal BVWI (70 to 130). In contrast, greater than 70% of patients with a partial or poor response had abnormal BVWI, indicating either a small thick walled bladder or a large thin walled bladder. This result confirms findings from previous studies indicating that a small functional bladder capacity is predictive of a poor response to desmopressin therapy.7–9 Surprisingly this technique also revealed a group with large volume, thinner walled bladders, which may represent bladder decompensation and would require further studies. To our knowledge, there are no published studies on US measured bladder volume and wall thickness for identifying pathological bladder conditions and prediction of treatment response in patients with PNE. Our results demonstrate a high predictive value using US bladder measurements to distinguish between enuretic children with normal urodynamics from those with various bladder dysfunctions. Complete response to treatment with desmopressin can be reliably predicted with a normal bladder volume and wall thickness, whereas nonresponsiveness is significantly associated with abnormal bladder parameters. According to our results a value of normal BVWI (70 to 130) is highly predictive of normal bladder function and good treatment response to desmopressin.

CONCLUSIONS

Our results demonstrate that US measured bladder parameters can provide useful predictive clues for the underlying bladder dysfunction as well as treatment outcome. These data are useful for differentiation of enuretic patients into different treatment subtypes, and can also be used as a reliable guide for the appropriate choice of further invasive urodynamic studies and individually tailored treatment strategy.

REFERENCES

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12. Muller, T., Bergstorm, M., Hellstrom, E., Svensson, E. and Jacobson, B.: Standardized ultrasound method for assessing detrusor muscle thickness in children. J Urol, 164: 134, 2000 13. Kaefer, M., Barnewolt, C., Retik, A. B. and Peters, C. A.: The sonographic diagnosis of intravesical obstruction in children: evaluation of bladder wall thickness indexed to bladder filling. J Urol, 157: 989, 1997 14. Ukimura, O., Kojima, M. E., Ochiai, A., Naya, Y., Kawauchi, A. and Wantanabe, H.: Noninvasive evaluation of bladder compliance in children using ultrasound estimated bladder weight. J Urol, 160: 1459, 1998 15. Robinson, D., Anders, K., Cardozo, L., Bidmead, J., Toozs-Hobson, P. and Khullar, V.: Can ultrasound replaces ambulatory urodynamics when investigating women with irritative urinary symptoms? BJOG, 109: 145, 2000

16. Svitac, J., Ciliak, M., Tomaskin, R. and Kliment, J.: Ultrasonographic bladder wall thickness in newborns: normal and pathological findings. Br J Urol, suppl., 89: 62, 2002 17. Gilsanz, V., Miller, J. H. and Reid, B. S.: Ultrasonic characteristics of posterior ureteral valves. Radiology, 145: 143, 1982 18. Jequier, S. and Rousseau, O.: Sonographic measurements of the normal bladder wall in children. AJR Am J Roentgenol, 149: 563, 1987 19. Neveus, T., Lackgren, G. and Stenberg, A.: Sleep and nighttime behavior of enuretics and non-enuretics. Br J Urol, suppl., 81: 72, 1998 20. Wantanabe, H. and Azuma, Y.: A proposal for classification system of enuresis based on overnight simultaneous monitoring of electroencephalography and cystometry. Sleep, 12: 257, 1989