- Email: [email protected]
Urodynamic and imaging findings in infants with myelomeningocele may predict need for future augmentation cystoplasty
Journal Pre-proof Urodynamic and Imaging Findings in Myelomeningocele Infants May Predict Need for Future Augmentation Cystoplasty Lauren E. Corona, Ted Lee, Kathryn Marchetti, Courtney Streur, Vesna Ivancic, Kate H. Kraft, David A. Bloom, Julian Wan, John M. Park PII:
S1477-5131(19)30304-3
DOI:
https://doi.org/10.1016/j.jpurol.2019.09.015
Reference:
JPUROL 3276
To appear in:
Journal of Pediatric Urology
Received Date: 21 February 2019 Accepted Date: 15 September 2019
Please cite this article as: Corona LE, Lee T, Marchetti K, Streur C, Ivancic V, Kraft KH, Bloom DA, Wan J, Park JM, Urodynamic and Imaging Findings in Myelomeningocele Infants May Predict Need for Future Augmentation Cystoplasty, Journal of Pediatric Urology, https://doi.org/10.1016/j.jpurol.2019.09.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
Urodynamic and Imaging Findings in Myelomeningocele Infants May Predict Need for Future Augmentation Cystoplasty Lauren E. Corona, Ted Lee, Kathryn Marchetti, Courtney Streur, Vesna Ivancic, Kate H. Kraft, David A. Bloom, Julian Wan, John M. Park University of Michigan, Department of Urology 1500 E Medical Center Drive, SPC 5330 Ann Arbor, MI, USA Author emails: Corona: [email protected]; Lee: [email protected]; Marchetti: [email protected]; Streur: [email protected]; Ivancic: [email protected]; Kraft: [email protected]; Bloom: [email protected]; Wan: [email protected]; Park: [email protected]
Corresponding Author: Lauren E. Corona Email: [email protected]
Ethical Approval: The University of Michigan Institutional Review Board approved this study (HUM00114175).
Urodynamic and Imaging Findings in Myelomeningocele Infants May Predict Need for Future Augmentation Cystoplasty Summary: Introduction: Urologic issues are persistent and important causes of morbidity and mortality in myelomeningocele patients. Classically, patients with elevated bladder pressures despite adherence to clean intermittent catheterization and pharmacotherapy undergo augmentation cystoplasty (AC). Currently, there is little understanding of which infants are more likely to require later AC. Objective: In this context, we studied whether unfavorable urodynamic or imaging findings in myelomeningocele patients during infancy could predict future AC. We hypothesized that infants born with elevated bladder pressures, vesicoureteral reflux (VUR), and/or hydronephrosis would be more likely to undergo AC. Study design: We retrospectively identified myelomeningocele patients at our institution followed since infancy (<1 year of age) with a minimum of eight continuous years of follow-up. Standard
1
care protocol included cystometrogram, voiding cystourethrography (VCUG), and renal ultrasound during infancy. The primary outcome was AC for elevated bladder pressures despite attempts at more conservative management with medical therapy and CIC. Specifically, we evaluated for differences in augmentation rates based on gender, level of lesion, presence of detrusor leak point pressure or end fill pressure (DLPP/EFP) greater than 40 cm H2O, and presence of hydronephrosis, VUR, initiation of clean intermittent catheterization, and initiation of antimuscarinics in infancy. We excluded patients who underwent surgical intervention for urinary incontinence. Results: 97 patients met inclusion criteria. Median follow-up time was 13.8 years. AC was performed in 17 patients (17.5%) at a median age of 114 months (9.5 years). DLPP/EFP was greater than 40 cm H2O in 34.0% (33/97) of infant cystometrogram studies, while 30.9% (30/97) had VUR on infant VCUG and 20.6% (20/97) had hydronephrosis on infant renal ultrasound. Patients with DLPP/EFP greater than 40 cm H2O or VUR during infancy were more likely to undergo AC (p = 0.02, p = 0.03, respectively). Binomial logistic regression revealed that DLPP/EFP greater than 40 cm H2O (OR 4.28, 95% CI 1.34 – 13.62) and VUR (OR 3.73,
2
95% CI 1.18 – 11.77) were independent risk factors for future AC. Discussion: Myelomeningocele infants with elevated bladder pressures and VUR should be closely monitored with urodynamic testing and imaging studies. Parents can be counseled regarding the potentially greater risk for future AC in these patients. Nonetheless, the majority of high-risk infants will safely avoid AC with conservative management. Keywords: Augmentation cystoplasty, myelomeningocele, detrusor leak point pressure, vesicoureteral reflux Introduction Over the past several decades, improvements in the neurosurgical and urologic care of children with myelomeningocele have resulted in a significant increase in the survival rate such that the majority now survives well into adulthood [1]. As patients live longer, urologic manifestations become an important cause of morbidity and mortality [2]. Renal-related deaths, including infections or renal failure, are reported in up to one third of myelomeningocele patients followed longitudinally [3]. Thus, starting in infancy, lifelong
3
monitoring and management of the urinary tract is necessary. Despite maximal medical management with clean intermittent catheterization (CIC) and pharmacotherapy, some patients will have persistently elevated bladder pressures. These patients eventually undergo augmentation cystoplasty in order to protect the upper tracts [4]. Currently, there is little understanding as to which factors during infancy are associated with a higher likelihood of augmentation cystoplasty later in life. In this context, we identified myelomeningocele patients followed since infancy at our institution to determine whether unfavorable urologic imaging and functional testing during infancy is associated with an increased likelihood of undergoing augmentation cystoplasty. We hypothesized that the presence of elevated bladder pressures, vesicoureteral reflux (VUR), and hydronephrosis during infancy would be associated with future augmentation cystoplasty despite maximal medial management. Methods Dataset and Study Population Following Institutional Review Board approval, we retrospectively identified all patients with myelomeningocele at our institution followed between 1984 and 2017. Patients
4
were included if they initiated their care as an infant (defined as less than one year of age) and had a minimum of eight continuous years of follow-up. Patients were excluded if they had non-elevated bladder pressures but underwent augmentation cystoplasty to solely address urinary incontinence, if they initiated care at our institution after a year of age, if they did not follow continuously at our institution, or if they did not have sufficient length of follow-up (Figure 1). A standard care protocol for myelomeningocele infants included cystometrogram (CMG), voiding cystourethrography (VCUG), and renal ultrasound (RUS) during infancy. Both video and non-video CMGs were included. Newborns were started on CIC with or without antimuscarinics at birth if in retention, or at the time of first CMG demonstrating elevated bladder pressures or detrusor sphincter dyssynergia. RUS and CMG were repeated every one to two years until puberty to ensure stability. Patients who continued to have elevated bladder filling pressures (>40 cmH2O) on repeat studies despite maximum medical therapy with CIC and antimuscarinics underwent augmentation cystoplasty. Outcome The primary outcome was the likelihood of augmentation cystoplasty due to persistently elevated bladder filling
5
pressures despite maximal medical therapy (CIC and antimuscarinics). Persistently elevated bladder pressures were defined as pressures greater than 40 cmH2O demonstrated on more than one CMG. Statistical Analysis For our first analytic step, we evaluated for differences in augmentation cystoplasty rates based on gender, level of lesion, the presence of specific urodynamic and imaging findings during infancy including detrusor leak point pressure or end fill pressure (DLPP/EFP) greater than 40 cmH2O, hydronephrosis, VUR, initiation of CIC, and initiation of antimuscarinics during infancy. Association between these variables and augmentation was determined using Pearson’s chi-square test and Fisher’s exact test for categorical and continuous variables, respectively. Statistically significant variables of the univariate analysis were included for multivariate assessment by binomial logistic regression to evaluate whether these factors were associated with an increased odds of undergoing augmentation cystoplasty. The significance level was considered <0.05. Analysis was performed using statistical software (IBM SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, N.Y., USA).
Results
6
After excluding patients without urodynamic or imaging studies from infancy, we identified 111 myelomeningocele patients that were followed for a minimum of 8 continuous years at our institution. Fourteen additional patients were excluded, having undergone surgical intervention (continent catheterizable channel with or without augmentation) for an indication of urinary incontinence without elevated DLPP/EFP, leaving 97 patients that were included in our study. Over a median follow up time of 13.8 (range 8 to 30.8) years, augmentation cystoplasty was performed in 17 patients (17.5%) for persistently elevated DLPP/EFP >40 cmH2O. Median age at augmentation was 9.5 (range 4.4 to 17.4) years. There was no difference in mean age at augmentation between those with elevated DLPP/EFP >40 cmH2O during infancy compared to those without (126 vs 124 months, respectively, p=0.47). Augmentation was performed between 1999 and 2014 and the decision to augment was shared between surgeon, patient, and family. All augmented patients had attempts at more conservative management prior to proceeding. All patients were on CIC and 16/17 were on antimuscarinic therapy at time of augmentation. One patient had a prior vesicostomy, two male patients had a perineal urethrostomy (to facilitate urethral dilation), six had multiple attempts at urethral dilations, and one had two
7
onabotulinumtoxinA treatments. In 5/17 patients, declining renal function despite conservative management to reduce pressures prompted decision for augmentation. In the population as a whole, DLPP/EFP was greater than 40 cmH2O in 34% (33/97) of infant cystometrogram studies, 31% (30/97) had VUR on infant VCUG, and 20.6% (20/97) had hydronephrosis on infant renal ultrasound (Table 1). Eight of the infants had both elevated DLPP/EFP and VUR, while 25 patients had elevated DLPP/EFP without VUR and 22 patients had VUR without elevated DLPP/EFP. Patients with DLPP/EFP greater than 40 cmH2O or VUR during infancy were more likely to undergo augmentation cystoplasty (p = 0.02, p = 0.03, respectively). Gender, level of lesion, presence of hydronephrosis in infancy, initiation of CIC in infancy, or initiation of antimuscarinics in infancy were not associated with bladder augmentation later in life. Binomial logistic regression revealed that DLPP/EFP greater than 40 cmH2O in infancy (OR 4.28, 95% CI 1.34 – 13.62, p=0.014) and VUR in infancy (OR 3.73, 95% CI 1.18 – 11.77, p=0.025) were independent risk factors for future augmentation cystoplasty (Table 2). Discussion Our results suggest that myelomeningocele infants with elevated DLPP/EFP or VUR in infancy are at higher risk for
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augmentation cystoplasty later in life. Children with these risk factors should be monitored closely with urodynamic or imaging studies starting in infancy. Considering that prior studies have demonstrated the efficacy of CIC and pharmacotherapy in lowering rates of upper tract damage and augmentation cystoplasty, myelomeningocele infants with unfavorable urodynamic and VUR during infancy likely benefit most from early initiation of CIC and pharmacotherapy using antimuscarinics [5-7]. Additional interventions such as intradetrusor onabotulinumtoxinA injection, new generation antimuscarinics[8], beta agonists [9], and external urethral sphincter dilation [10] for those infants who do not respond adequately to maximal pharmacotherapy may help in further reducing the need for augmentation cystoplasty. Notably, the majority of patients with DLPP/EFP greater than 40 cmH2O and presence of VUR during infancy were successfully managed with medical therapy and avoided augmentation cystoplasty, especially those whose CIC frequency could be adjusted to keep the bladder volumes to be less than capacity where the DLPP/EFP pressures were high. Less than one third of infants with DLPP/EFP greater than 40 cmH2O (10/33) or VUR (9/30) underwent augmentation cystoplasty for elevated bladder pressures despite conservative measures such as medications,
9
compliance with CIC, and urethral dilations. Thus, patients requiring augmentation cystoplasty remain the minority despite the presence of these risk factors. These findings suggest that pediatric urologists can safely counsel parents and guardians that the majority of myelomeningocele patients respond to and may be safely managed with CIC and pharmacotherapy until adulthood, regardless of infant testing results. Our finding of elevated DLPP/EFP and VUR being an independent prognostic factor is interesting in that in neurogenic bladder patients, VUR is thought to be secondary to elevated bladder pressure overcoming the ureterovesical junction competence. Because VUR may simply be a manifestation of a severe form of abnormal bladder pressures, we thought that they would not be independently predictive, but this was not the case in our analysis. We speculate that not all VUR in myelomeningocele patients is due to abnormal bladder pressures and some may be managed similar to primary VUR. Nevertheless, existing VUR, even if the DLPP/EFP is not over 40 cm H20, may be vulnerable to even moderately elevated pressures and may ultimately lead to upper tract changes and subsequent augmentation cystoplasty.
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Our study does have several limitations. Our strict inclusion criteria required exclusion of a large number of patients with myelomeningocele, resulting in limited sample size. However, long-term, longitudinal studies of this magnitude are sparse in the literature. Another limitation of our study is that the decision and timing for augmentation cystoplasty were not entirely objective nor standardized among the surgeons. Factors such as patient comorbidities and family support and motivation are difficult to gauge objectively, and it is known that bladder reconstruction rates vary across centers [11]. However, at our institution, we do recommend augmentation cystoplasty for patients with bladder pressures that remain elevated despite adherence to CIC and pharmacotherapy or for those with evidence of upper tract deterioration. It can also be argued that a pressure threshold of 40 cmH2O is conservative as new data have shown that 20 cmH2O is more sensitive in predicting upper tract damage [12]. It is unknown whether our results are applicable to current day practice considering availability of newer treatment options such as onabotulinumtoxinA and beta agonists. These options were not in routine use for the majority of subjects included in this study cohort. However, there is no definitive evidence that these newer treatment modalities help prevent upper tract deterioration and, thus, prevent augmentation in the myelomeningocele population. In addition, most of our patients underwent separate VCUG
11
and standard volume-pressure cystometrogram evaluations rather than a combined videourodynamics study, and therefore, it was not possible to assess the exact pressure and volume at which reflux occurred during bladder filling, precluding a more granular understanding on the effects of VUR on these measurements. Finally, although CIC was initiated for all patients with concerning urodynamic and imaging findings and attempts were made to document compliance to the prescribed medical regimen, detailed compliance rates are unknown over an extended period of time. However, the median follow-up time of nearly 14 years and minimal longitudinal follow-up of 8 years in a relatively large study population of an uncommon disease is a strength of our conclusion. Ultimately, these findings may improve risk stratification of myelomeningocele patients during infancy. If infant test results reveal elevated bladder pressures and VUR, it would be prudent to closely monitor these children with frequent urodynamic testing and imaging studies. In addition, parents can be counseled regarding the possibly higher risk for future augmentation cystoplasty. Nonetheless, these parents should be reassured that, with CIC and pharmacotherapy, the majority of high-risk infants will not require augmentation cystoplasty. Evaluating the value and significance of urodynamic testing and imaging studies during infancy may
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be more accurately and objectively studied with rigorously designed standardized clinical pathways that include longterm outcomes such as that currently accruing data by Routh et al and the Centers for Disease Control and Prevention [13]. This protocol might allow for the identification of additional management strategies to reduce the risk for augmentation cystoplasty. In addition, it could eventually provide long-term outcomes comparing high-risk patients that undergo augmentation cystoplasty to those that do not. Until these studies can be completed, our findings provide useful information for pediatric urologists providing care for the myelomeningocele patient population. In conclusion, our findings suggest that myelomeningocele infants with elevated DLPP/EFP or VUR in infancy may be at higher risk for augmentation cystoplasty later in life. However, given the low rate of augmentation overall even in the presence of these unfavorable parameters, they also suggest that parents can be counseled that the majority of high-risk infants will safely avoid augmentation cystoplasty with conservative management.
Conflict of Interest: The authors have no conflicts of interest to declare.
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Funding Source: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethical Approval: The University of Michigan Institutional Review Board approved this study (HUM00114175). References [1]
Shin M, Kucik JE, Siffel C, Lu C, Shaw GM, Canfield MA, et al. Improved survival among children with spina bifida in the United States. J Pediatr 2012;161:1132-37.
[2]
McDonnell GV, McCann JP. Issues of medical management in adults with spina bifida. Childs Nerv Syst 2000;16:222-27.
[3]
Oakeshott P, Hunt GM, Poulton A, Reid F. Expectation of life and unexpected death in open spina bifida: a 40-year complete, non-selective, longitudinal cohort study. Dev Med Child Neurourol 2010;52:749-53.
[4]
Snow-Lisy DC, Yerkes EB, Cheng EY. Update on urological management of spina bifida from prenatal diagnosis to adulthood. J Urol 2015;194:288-96.
[5]
Kaefer M, Pabby A, Kelly M, Darbey M, Bauer SB. Improved bladder function after prophylactic treatment of the high risk neurogenic bladder in newborns with myelomentingocele. J Urol 1999;162:1068-71.
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[6]
Wu HY, Baskin LS, Kogan BA. Neurogenic bladder dysfunction due to myelomeningocele: neonatal versus childhood treatment. J Urol 1997;157:2295-97.
[7]
Edelstein RA, Bauer SB, Kelly MD, Darbey MM, Peters CA, Atala A, et al. The long-term urological response of neonates with myelodysplasia treated proactively with intermittent catheterization and anticholinergic therapy. J Urol 1995;154:1500-04.
[8]
Aslan AR, Kogan BA. Conservative management in neurogenic bladdder dysfunction. Curr Opin Urol 2002;12: 473-7.
[9]
Park JS, Lee YS, Lee CN, Kim SH, Kim SW, Han SW. Efficacy and safety of mirabegron, a ß3-adrenoreceptor agonist, for treating neurogenic bladder in pediatric patients with spina bifida: a retrospective pilot study. World J Urol 2018; doi: 10.1007/s00345-018-2576-0. [Epub ahead of print]
[10]
Park JM, McGuire EJ, Koo HP, Schwartz AC, Garwood CK, Bloom DA. External urethral sphincter dilation for the management of high risk myelomeningocele: a 15-year experience. J Urol 2001;165: 2383-8.
[11]
Routh JC, Joseph DB, Liu T, Schechter MS, Thibadeau JK, Wallis MC, et al. Bladder reconstruction rates differ among centers participating in national spina bifida patient registry. J Urol 2018;199:268-73.
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[12]
Tarcan T, Sekerci CA, Akbal C, Tinay I, Tanidir Y, Sahan A, et al. Is 40 cm H2O detrusor leak point pressure cut-off reliable for upper urinary tract protection in children with myelodysplasia? Neurourol Urodyn 2017; 36: 759-63.
[13]
Routh JC, Cheng EY, Austin JC, Baum MA, Gargollo PC, Grady RW, et al. Design and methodological considerations of the Centers for Disease Control and prevention urologic and renal protocol for the newborn and young child with spina bifida. J Urol 2016;196:1728-34.
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Figure 1. Flow diagram summarizing inclusion and exclusion criteria
Table 1. Comparison of patient characteristics Conservative management (n = 80) (n, (%))
Augmentation cystoplasty (n = 17) (n, (%))
Female
38 (47.5)
8 (47.1)
Male
42 (52.5)
9 (52.9)
Thoracic
7 (8.8)
2 (11.8)
Lumbar
42 (52.5)
10 (58.8)
Lumbosacral
22 (27.5)
3 (17.6)
Sacral
9 (11.2)
2 (11.8)
23 (28.8)
10 (58.8)
0.02
17 (21.2)
3 (17.6)
0.74
Variable
p-value
Gender 0.98
Level of Lesion
DLPP/EFP > 40 cmH2O during infancy Hydronephrosis before 1 year∞ SFU grade 1 or 2
10 / 17 (58.8)
2 / 3 (66.7)
SFU grade 3 or 4
7 / 17 (41.2)
1 / 3 (33.3)
Presence of VUR before 1 year•
21 (26.3)
9 (52.9)
Grade 1 or 2
10 / 21 (47.6)
5 / 9 (55.6)
Grade 3 to 5
11 / 21 (52.4)
4 / 9 (44.4)
CIC* Noncompliance Antimuscarinics
68 (85) 12 / 68 (17.6) 66 (82.5)
17 (100) 3 / 17 (17.6) 16 (94.1)
0.87
0.99
0.03 0.69
0.04 1.00 0.11
DLPP: Detrusor Leak Point Pressure; EFP: End Fill Pressure; VUR: Vesicoureteral reflux. CIC: Clean Intermittent Catheterization ∞ Hydronephrosis SFU grades 1 or 2 versus grades 3 or 4 is not associated with augmentation cystoplasty • Low versus high grade of vesicoureteral reflux is not associated with augmentation cystoplasty *All patients with elevated DLPP/EFP greater than 40 cmH2O or vesicoureteral reflux during infancy started on CIC
Table 2. Infancy risk factors for augmentation cystoplasty (n=17) Variable
Odds Ratio
95% CI
p-value
DLPP/EFP > 40 cmH2O
3.89
1.26 – 11.99
0.02
VUR
3.51
1.14 – 10.85
0.03
Binomial logistic regression. DLPP: Detrusor Leak Point Pressure; EFP: End Fill Pressure; VUR: Vesicoureteral reflux; CI: Confidence Interval
CMG: Cystometrogram; US: Ultrasound; VCUG: Voiding Cystourethrogram; AC: Augmentation Cystoplasty
S1477-5131(19)30304-3
DOI:
https://doi.org/10.1016/j.jpurol.2019.09.015
Reference:
JPUROL 3276
To appear in:
Journal of Pediatric Urology
Received Date: 21 February 2019 Accepted Date: 15 September 2019
Please cite this article as: Corona LE, Lee T, Marchetti K, Streur C, Ivancic V, Kraft KH, Bloom DA, Wan J, Park JM, Urodynamic and Imaging Findings in Myelomeningocele Infants May Predict Need for Future Augmentation Cystoplasty, Journal of Pediatric Urology, https://doi.org/10.1016/j.jpurol.2019.09.015. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
Urodynamic and Imaging Findings in Myelomeningocele Infants May Predict Need for Future Augmentation Cystoplasty Lauren E. Corona, Ted Lee, Kathryn Marchetti, Courtney Streur, Vesna Ivancic, Kate H. Kraft, David A. Bloom, Julian Wan, John M. Park University of Michigan, Department of Urology 1500 E Medical Center Drive, SPC 5330 Ann Arbor, MI, USA Author emails: Corona: [email protected]; Lee: [email protected]; Marchetti: [email protected]; Streur: [email protected]; Ivancic: [email protected]; Kraft: [email protected]; Bloom: [email protected]; Wan: [email protected]; Park: [email protected]
Corresponding Author: Lauren E. Corona Email: [email protected]
Ethical Approval: The University of Michigan Institutional Review Board approved this study (HUM00114175).
Urodynamic and Imaging Findings in Myelomeningocele Infants May Predict Need for Future Augmentation Cystoplasty Summary: Introduction: Urologic issues are persistent and important causes of morbidity and mortality in myelomeningocele patients. Classically, patients with elevated bladder pressures despite adherence to clean intermittent catheterization and pharmacotherapy undergo augmentation cystoplasty (AC). Currently, there is little understanding of which infants are more likely to require later AC. Objective: In this context, we studied whether unfavorable urodynamic or imaging findings in myelomeningocele patients during infancy could predict future AC. We hypothesized that infants born with elevated bladder pressures, vesicoureteral reflux (VUR), and/or hydronephrosis would be more likely to undergo AC. Study design: We retrospectively identified myelomeningocele patients at our institution followed since infancy (<1 year of age) with a minimum of eight continuous years of follow-up. Standard
1
care protocol included cystometrogram, voiding cystourethrography (VCUG), and renal ultrasound during infancy. The primary outcome was AC for elevated bladder pressures despite attempts at more conservative management with medical therapy and CIC. Specifically, we evaluated for differences in augmentation rates based on gender, level of lesion, presence of detrusor leak point pressure or end fill pressure (DLPP/EFP) greater than 40 cm H2O, and presence of hydronephrosis, VUR, initiation of clean intermittent catheterization, and initiation of antimuscarinics in infancy. We excluded patients who underwent surgical intervention for urinary incontinence. Results: 97 patients met inclusion criteria. Median follow-up time was 13.8 years. AC was performed in 17 patients (17.5%) at a median age of 114 months (9.5 years). DLPP/EFP was greater than 40 cm H2O in 34.0% (33/97) of infant cystometrogram studies, while 30.9% (30/97) had VUR on infant VCUG and 20.6% (20/97) had hydronephrosis on infant renal ultrasound. Patients with DLPP/EFP greater than 40 cm H2O or VUR during infancy were more likely to undergo AC (p = 0.02, p = 0.03, respectively). Binomial logistic regression revealed that DLPP/EFP greater than 40 cm H2O (OR 4.28, 95% CI 1.34 – 13.62) and VUR (OR 3.73,
2
95% CI 1.18 – 11.77) were independent risk factors for future AC. Discussion: Myelomeningocele infants with elevated bladder pressures and VUR should be closely monitored with urodynamic testing and imaging studies. Parents can be counseled regarding the potentially greater risk for future AC in these patients. Nonetheless, the majority of high-risk infants will safely avoid AC with conservative management. Keywords: Augmentation cystoplasty, myelomeningocele, detrusor leak point pressure, vesicoureteral reflux Introduction Over the past several decades, improvements in the neurosurgical and urologic care of children with myelomeningocele have resulted in a significant increase in the survival rate such that the majority now survives well into adulthood [1]. As patients live longer, urologic manifestations become an important cause of morbidity and mortality [2]. Renal-related deaths, including infections or renal failure, are reported in up to one third of myelomeningocele patients followed longitudinally [3]. Thus, starting in infancy, lifelong
3
monitoring and management of the urinary tract is necessary. Despite maximal medical management with clean intermittent catheterization (CIC) and pharmacotherapy, some patients will have persistently elevated bladder pressures. These patients eventually undergo augmentation cystoplasty in order to protect the upper tracts [4]. Currently, there is little understanding as to which factors during infancy are associated with a higher likelihood of augmentation cystoplasty later in life. In this context, we identified myelomeningocele patients followed since infancy at our institution to determine whether unfavorable urologic imaging and functional testing during infancy is associated with an increased likelihood of undergoing augmentation cystoplasty. We hypothesized that the presence of elevated bladder pressures, vesicoureteral reflux (VUR), and hydronephrosis during infancy would be associated with future augmentation cystoplasty despite maximal medial management. Methods Dataset and Study Population Following Institutional Review Board approval, we retrospectively identified all patients with myelomeningocele at our institution followed between 1984 and 2017. Patients
4
were included if they initiated their care as an infant (defined as less than one year of age) and had a minimum of eight continuous years of follow-up. Patients were excluded if they had non-elevated bladder pressures but underwent augmentation cystoplasty to solely address urinary incontinence, if they initiated care at our institution after a year of age, if they did not follow continuously at our institution, or if they did not have sufficient length of follow-up (Figure 1). A standard care protocol for myelomeningocele infants included cystometrogram (CMG), voiding cystourethrography (VCUG), and renal ultrasound (RUS) during infancy. Both video and non-video CMGs were included. Newborns were started on CIC with or without antimuscarinics at birth if in retention, or at the time of first CMG demonstrating elevated bladder pressures or detrusor sphincter dyssynergia. RUS and CMG were repeated every one to two years until puberty to ensure stability. Patients who continued to have elevated bladder filling pressures (>40 cmH2O) on repeat studies despite maximum medical therapy with CIC and antimuscarinics underwent augmentation cystoplasty. Outcome The primary outcome was the likelihood of augmentation cystoplasty due to persistently elevated bladder filling
5
pressures despite maximal medical therapy (CIC and antimuscarinics). Persistently elevated bladder pressures were defined as pressures greater than 40 cmH2O demonstrated on more than one CMG. Statistical Analysis For our first analytic step, we evaluated for differences in augmentation cystoplasty rates based on gender, level of lesion, the presence of specific urodynamic and imaging findings during infancy including detrusor leak point pressure or end fill pressure (DLPP/EFP) greater than 40 cmH2O, hydronephrosis, VUR, initiation of CIC, and initiation of antimuscarinics during infancy. Association between these variables and augmentation was determined using Pearson’s chi-square test and Fisher’s exact test for categorical and continuous variables, respectively. Statistically significant variables of the univariate analysis were included for multivariate assessment by binomial logistic regression to evaluate whether these factors were associated with an increased odds of undergoing augmentation cystoplasty. The significance level was considered <0.05. Analysis was performed using statistical software (IBM SPSS Statistics for Windows, version 24.0 (IBM Corp., Armonk, N.Y., USA).
Results
6
After excluding patients without urodynamic or imaging studies from infancy, we identified 111 myelomeningocele patients that were followed for a minimum of 8 continuous years at our institution. Fourteen additional patients were excluded, having undergone surgical intervention (continent catheterizable channel with or without augmentation) for an indication of urinary incontinence without elevated DLPP/EFP, leaving 97 patients that were included in our study. Over a median follow up time of 13.8 (range 8 to 30.8) years, augmentation cystoplasty was performed in 17 patients (17.5%) for persistently elevated DLPP/EFP >40 cmH2O. Median age at augmentation was 9.5 (range 4.4 to 17.4) years. There was no difference in mean age at augmentation between those with elevated DLPP/EFP >40 cmH2O during infancy compared to those without (126 vs 124 months, respectively, p=0.47). Augmentation was performed between 1999 and 2014 and the decision to augment was shared between surgeon, patient, and family. All augmented patients had attempts at more conservative management prior to proceeding. All patients were on CIC and 16/17 were on antimuscarinic therapy at time of augmentation. One patient had a prior vesicostomy, two male patients had a perineal urethrostomy (to facilitate urethral dilation), six had multiple attempts at urethral dilations, and one had two
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onabotulinumtoxinA treatments. In 5/17 patients, declining renal function despite conservative management to reduce pressures prompted decision for augmentation. In the population as a whole, DLPP/EFP was greater than 40 cmH2O in 34% (33/97) of infant cystometrogram studies, 31% (30/97) had VUR on infant VCUG, and 20.6% (20/97) had hydronephrosis on infant renal ultrasound (Table 1). Eight of the infants had both elevated DLPP/EFP and VUR, while 25 patients had elevated DLPP/EFP without VUR and 22 patients had VUR without elevated DLPP/EFP. Patients with DLPP/EFP greater than 40 cmH2O or VUR during infancy were more likely to undergo augmentation cystoplasty (p = 0.02, p = 0.03, respectively). Gender, level of lesion, presence of hydronephrosis in infancy, initiation of CIC in infancy, or initiation of antimuscarinics in infancy were not associated with bladder augmentation later in life. Binomial logistic regression revealed that DLPP/EFP greater than 40 cmH2O in infancy (OR 4.28, 95% CI 1.34 – 13.62, p=0.014) and VUR in infancy (OR 3.73, 95% CI 1.18 – 11.77, p=0.025) were independent risk factors for future augmentation cystoplasty (Table 2). Discussion Our results suggest that myelomeningocele infants with elevated DLPP/EFP or VUR in infancy are at higher risk for
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augmentation cystoplasty later in life. Children with these risk factors should be monitored closely with urodynamic or imaging studies starting in infancy. Considering that prior studies have demonstrated the efficacy of CIC and pharmacotherapy in lowering rates of upper tract damage and augmentation cystoplasty, myelomeningocele infants with unfavorable urodynamic and VUR during infancy likely benefit most from early initiation of CIC and pharmacotherapy using antimuscarinics [5-7]. Additional interventions such as intradetrusor onabotulinumtoxinA injection, new generation antimuscarinics[8], beta agonists [9], and external urethral sphincter dilation [10] for those infants who do not respond adequately to maximal pharmacotherapy may help in further reducing the need for augmentation cystoplasty. Notably, the majority of patients with DLPP/EFP greater than 40 cmH2O and presence of VUR during infancy were successfully managed with medical therapy and avoided augmentation cystoplasty, especially those whose CIC frequency could be adjusted to keep the bladder volumes to be less than capacity where the DLPP/EFP pressures were high. Less than one third of infants with DLPP/EFP greater than 40 cmH2O (10/33) or VUR (9/30) underwent augmentation cystoplasty for elevated bladder pressures despite conservative measures such as medications,
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compliance with CIC, and urethral dilations. Thus, patients requiring augmentation cystoplasty remain the minority despite the presence of these risk factors. These findings suggest that pediatric urologists can safely counsel parents and guardians that the majority of myelomeningocele patients respond to and may be safely managed with CIC and pharmacotherapy until adulthood, regardless of infant testing results. Our finding of elevated DLPP/EFP and VUR being an independent prognostic factor is interesting in that in neurogenic bladder patients, VUR is thought to be secondary to elevated bladder pressure overcoming the ureterovesical junction competence. Because VUR may simply be a manifestation of a severe form of abnormal bladder pressures, we thought that they would not be independently predictive, but this was not the case in our analysis. We speculate that not all VUR in myelomeningocele patients is due to abnormal bladder pressures and some may be managed similar to primary VUR. Nevertheless, existing VUR, even if the DLPP/EFP is not over 40 cm H20, may be vulnerable to even moderately elevated pressures and may ultimately lead to upper tract changes and subsequent augmentation cystoplasty.
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Our study does have several limitations. Our strict inclusion criteria required exclusion of a large number of patients with myelomeningocele, resulting in limited sample size. However, long-term, longitudinal studies of this magnitude are sparse in the literature. Another limitation of our study is that the decision and timing for augmentation cystoplasty were not entirely objective nor standardized among the surgeons. Factors such as patient comorbidities and family support and motivation are difficult to gauge objectively, and it is known that bladder reconstruction rates vary across centers [11]. However, at our institution, we do recommend augmentation cystoplasty for patients with bladder pressures that remain elevated despite adherence to CIC and pharmacotherapy or for those with evidence of upper tract deterioration. It can also be argued that a pressure threshold of 40 cmH2O is conservative as new data have shown that 20 cmH2O is more sensitive in predicting upper tract damage [12]. It is unknown whether our results are applicable to current day practice considering availability of newer treatment options such as onabotulinumtoxinA and beta agonists. These options were not in routine use for the majority of subjects included in this study cohort. However, there is no definitive evidence that these newer treatment modalities help prevent upper tract deterioration and, thus, prevent augmentation in the myelomeningocele population. In addition, most of our patients underwent separate VCUG
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and standard volume-pressure cystometrogram evaluations rather than a combined videourodynamics study, and therefore, it was not possible to assess the exact pressure and volume at which reflux occurred during bladder filling, precluding a more granular understanding on the effects of VUR on these measurements. Finally, although CIC was initiated for all patients with concerning urodynamic and imaging findings and attempts were made to document compliance to the prescribed medical regimen, detailed compliance rates are unknown over an extended period of time. However, the median follow-up time of nearly 14 years and minimal longitudinal follow-up of 8 years in a relatively large study population of an uncommon disease is a strength of our conclusion. Ultimately, these findings may improve risk stratification of myelomeningocele patients during infancy. If infant test results reveal elevated bladder pressures and VUR, it would be prudent to closely monitor these children with frequent urodynamic testing and imaging studies. In addition, parents can be counseled regarding the possibly higher risk for future augmentation cystoplasty. Nonetheless, these parents should be reassured that, with CIC and pharmacotherapy, the majority of high-risk infants will not require augmentation cystoplasty. Evaluating the value and significance of urodynamic testing and imaging studies during infancy may
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be more accurately and objectively studied with rigorously designed standardized clinical pathways that include longterm outcomes such as that currently accruing data by Routh et al and the Centers for Disease Control and Prevention [13]. This protocol might allow for the identification of additional management strategies to reduce the risk for augmentation cystoplasty. In addition, it could eventually provide long-term outcomes comparing high-risk patients that undergo augmentation cystoplasty to those that do not. Until these studies can be completed, our findings provide useful information for pediatric urologists providing care for the myelomeningocele patient population. In conclusion, our findings suggest that myelomeningocele infants with elevated DLPP/EFP or VUR in infancy may be at higher risk for augmentation cystoplasty later in life. However, given the low rate of augmentation overall even in the presence of these unfavorable parameters, they also suggest that parents can be counseled that the majority of high-risk infants will safely avoid augmentation cystoplasty with conservative management.
Conflict of Interest: The authors have no conflicts of interest to declare.
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Funding Source: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethical Approval: The University of Michigan Institutional Review Board approved this study (HUM00114175). References [1]
Shin M, Kucik JE, Siffel C, Lu C, Shaw GM, Canfield MA, et al. Improved survival among children with spina bifida in the United States. J Pediatr 2012;161:1132-37.
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McDonnell GV, McCann JP. Issues of medical management in adults with spina bifida. Childs Nerv Syst 2000;16:222-27.
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Oakeshott P, Hunt GM, Poulton A, Reid F. Expectation of life and unexpected death in open spina bifida: a 40-year complete, non-selective, longitudinal cohort study. Dev Med Child Neurourol 2010;52:749-53.
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Snow-Lisy DC, Yerkes EB, Cheng EY. Update on urological management of spina bifida from prenatal diagnosis to adulthood. J Urol 2015;194:288-96.
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Kaefer M, Pabby A, Kelly M, Darbey M, Bauer SB. Improved bladder function after prophylactic treatment of the high risk neurogenic bladder in newborns with myelomentingocele. J Urol 1999;162:1068-71.
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[6]
Wu HY, Baskin LS, Kogan BA. Neurogenic bladder dysfunction due to myelomeningocele: neonatal versus childhood treatment. J Urol 1997;157:2295-97.
[7]
Edelstein RA, Bauer SB, Kelly MD, Darbey MM, Peters CA, Atala A, et al. The long-term urological response of neonates with myelodysplasia treated proactively with intermittent catheterization and anticholinergic therapy. J Urol 1995;154:1500-04.
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Aslan AR, Kogan BA. Conservative management in neurogenic bladdder dysfunction. Curr Opin Urol 2002;12: 473-7.
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Park JS, Lee YS, Lee CN, Kim SH, Kim SW, Han SW. Efficacy and safety of mirabegron, a ß3-adrenoreceptor agonist, for treating neurogenic bladder in pediatric patients with spina bifida: a retrospective pilot study. World J Urol 2018; doi: 10.1007/s00345-018-2576-0. [Epub ahead of print]
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Park JM, McGuire EJ, Koo HP, Schwartz AC, Garwood CK, Bloom DA. External urethral sphincter dilation for the management of high risk myelomeningocele: a 15-year experience. J Urol 2001;165: 2383-8.
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Routh JC, Joseph DB, Liu T, Schechter MS, Thibadeau JK, Wallis MC, et al. Bladder reconstruction rates differ among centers participating in national spina bifida patient registry. J Urol 2018;199:268-73.
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[12]
Tarcan T, Sekerci CA, Akbal C, Tinay I, Tanidir Y, Sahan A, et al. Is 40 cm H2O detrusor leak point pressure cut-off reliable for upper urinary tract protection in children with myelodysplasia? Neurourol Urodyn 2017; 36: 759-63.
[13]
Routh JC, Cheng EY, Austin JC, Baum MA, Gargollo PC, Grady RW, et al. Design and methodological considerations of the Centers for Disease Control and prevention urologic and renal protocol for the newborn and young child with spina bifida. J Urol 2016;196:1728-34.
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Figure 1. Flow diagram summarizing inclusion and exclusion criteria
Table 1. Comparison of patient characteristics Conservative management (n = 80) (n, (%))
Augmentation cystoplasty (n = 17) (n, (%))
Female
38 (47.5)
8 (47.1)
Male
42 (52.5)
9 (52.9)
Thoracic
7 (8.8)
2 (11.8)
Lumbar
42 (52.5)
10 (58.8)
Lumbosacral
22 (27.5)
3 (17.6)
Sacral
9 (11.2)
2 (11.8)
23 (28.8)
10 (58.8)
0.02
17 (21.2)
3 (17.6)
0.74
Variable
p-value
Gender 0.98
Level of Lesion
DLPP/EFP > 40 cmH2O during infancy Hydronephrosis before 1 year∞ SFU grade 1 or 2
10 / 17 (58.8)
2 / 3 (66.7)
SFU grade 3 or 4
7 / 17 (41.2)
1 / 3 (33.3)
Presence of VUR before 1 year•
21 (26.3)
9 (52.9)
Grade 1 or 2
10 / 21 (47.6)
5 / 9 (55.6)
Grade 3 to 5
11 / 21 (52.4)
4 / 9 (44.4)
CIC* Noncompliance Antimuscarinics
68 (85) 12 / 68 (17.6) 66 (82.5)
17 (100) 3 / 17 (17.6) 16 (94.1)
0.87
0.99
0.03 0.69
0.04 1.00 0.11
DLPP: Detrusor Leak Point Pressure; EFP: End Fill Pressure; VUR: Vesicoureteral reflux. CIC: Clean Intermittent Catheterization ∞ Hydronephrosis SFU grades 1 or 2 versus grades 3 or 4 is not associated with augmentation cystoplasty • Low versus high grade of vesicoureteral reflux is not associated with augmentation cystoplasty *All patients with elevated DLPP/EFP greater than 40 cmH2O or vesicoureteral reflux during infancy started on CIC
Table 2. Infancy risk factors for augmentation cystoplasty (n=17) Variable
Odds Ratio
95% CI
p-value
DLPP/EFP > 40 cmH2O
3.89
1.26 – 11.99
0.02
VUR
3.51
1.14 – 10.85
0.03
Binomial logistic regression. DLPP: Detrusor Leak Point Pressure; EFP: End Fill Pressure; VUR: Vesicoureteral reflux; CI: Confidence Interval
CMG: Cystometrogram; US: Ultrasound; VCUG: Voiding Cystourethrogram; AC: Augmentation Cystoplasty