Pediatric Urology Complete Primary Repair of Bladder Exstrophy Is Associated With Detrusor Underactivity Type of Neurogenic Bladder Hrair-George O. Mesrobian OBJECTIVE
METHODS RESULTS
CONCLUSION
To test the hypothesis that complete primary repair of bladder exstrophy (CPRE) is associated with detrussor underactivity. For this purpose, we review (1) our experience, (2) the results of the published literature as it pertains to bladder function, and (3) the known anatomic basis on which the mechanism of the observed outcome can be understood. The medical records of all patients who underwent CPRE by the author between 2004 and 2010 were reviewed. Attention was focused on the clinical, imaging, and urodynamic findings. Four men and 2 women underwent CPRE. Follow-up ranges from 2 to 8 years. Four underwent bilateral ureteral reimplantation combined with bladder neck repair in 3. Detrusor activity (or overactivity) was not recorded in the 5 patients who underwent urodynamic studies. Four patients achieved short periods of urinary continence. The percent predicted bladder capacity, adjusted for age, ranged from 25 to 70, with a median of 60. Of the 68 publications on CPRE since 1999, none reports the presence of detrusor activity. A description of the pelvic plexus anatomy by Walsh and Donker provides a basis for the mechanism of injury resulting in the previously mentioned results: (1) complete penile disassembly eliminates the distal fixation point of the bladder-urethral plate, (2) the subsequent dissection and mobilization result in shearing injury to the microscopic pelvic plexus branches to the bladder, external sphincter, and prostatic urethra. CPRE results in disruption of the branches of the pelvic plexus and a neurogenic bladder (detrussor underactivity). UROLOGY 83: 1139e1144, 2014. 2014 Elsevier Inc.
T
he surgical treatment of bladder exstrophy in the newborn continues to evolve. The complete primary repair of bladder exstrophy (CPRE) procedure first described in 1998 by Grady and Mitchell1,2 represented an alternative to the time tested staged repair described by Jeffs and Cendron and refined by Mathews and Gearhart3 over the last 3 decades. The stated rationale for abandoning the staged repair was to reduce the number of procedures required to attain the objectives of “urinary continence and allow voiding function”.1 Other notable approaches, which have been developed and described in the literature have not gained popularity in North America but deserve careful study.4-6 In this communication, we focus on describing the effects of CPRE on bladder function and providing an anatomic and pathophysiologic basis for the observed outcomes.
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Medical College and Children’s Hospital of Wisconsin Milwaukee, WI Reprint requests: Hrair-George O. Mesrobian, M.D., M.Sc., Department of Urology, Medical College and Children’s Hospital of Wisconsin Milwaukee, 999 N92nd Street, Suite C 330, Milwaukee, WI 53226. E-mail: [email protected] Submitted: September 4, 2013, accepted (with revisions): November 9, 2013
ª 2014 Elsevier Inc. All Rights Reserved
PATIENTS AND METHODS The medical records of all the patients who underwent CPRE by the author as primary surgeon were reviewed after obtaining institutional review board approval. During CPRE, attention was directed at the important steps of the procedure, which consist of extensive dissection of the perineum with deep incisions of the intersympheseal band and pelvic diaphragm fibers on either side of the prostatic urethral plate in men.7 This exposure becomes feasible because of penile disassembly, which provides direct access to the pelvic diaphragm (Fig. 1). The adequacy of this dissection is visually appreciated by the resultant cephalad and posterior movement of the bladder plate e urethral complex into the pelvis. The bladder and urethra are then tubularized followed by approximation of the corpora in the midline on top of the urethra, which assumes a hypospadiac position. In girls, the bifid clitoris is already “disassembled”, and therefore, dissection is directed at incising the pelvic diaphragm fibers on either side of the vagina e urethral plate complex.7 Because of the resulting cephalad movement of the bladder-urethral complex into the pelvis, the urethra becomes hypospadiac by default. An orthopedic surgeon with bladder exstrophy experience performed at the beginning of the procedure bilateral anterior osteotomies when manual approximation of the symphysis was judged to be insufficient after induction of anesthesia. For the urodynamic studies to be described, catheters were placed in the bladder and rectum under anesthesia at diagnostic 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.11.010
1139
Figure 1. Surgeon’s view of bladder exstrophy during complete primary repair of bladder exstrophy; the pelvic diaphragm separates the pelvic sphincter mechanism from the bulbospongiosus, superficial transverse perineal muscle, and associated neurovascular structures that pierce it. cystoscopy. The latter was indicated for evaluation of bladder and bladder neck anatomy, the presence of vesicoureteral refux (VUR; in conjunction with positional instillation cystography), or before a planned bladder neck injection with Deflux to provide outlet resistance. After initial cystoscopy, a 7F urodynamic air-charged catheter is inserted in the bladder and an abdominal pressure catheter in the rectum just past the external sphincter (T-DOC Company, Wilmington, DE; www.tdocllc. com). Surface patch electrodes are then applied just superior to the perineal body on either side of the midline. The anesthetic protocol was switched to one used for detection of evoked potentials during spinal surgery and consisted of total intravenous anesthesia.8 After calibration of the instrument, bladders were filled at a rate equal to 10% of expected capacity for age with methylene blue spiked, room temperature mixture of normal saline and contrast. A Medtronic Duet multiport (version 9.0; www.medtronic.com) was used to record peak bladder pressure at the first leak, bladder contractions with or without a leak or voiding, bladder wall compliance, and electromyography amplitude. The presence of VUR and the appearance of the bladder neck were observed under fluoroscopy. Capacity in the face of VUR was defined as the total volume infused before passive fluid leakage. The volume at which VUR was detected was recorded separately. A contraction was defined as a spike over baseline bladder pressure with or without voiding. The known anatomic literature of bladder exstrophy was reviewed with the intent of creating a 3-dimensional simplified medical illustration of the pertinent structures with specific attention to the pelvic neurovascular bundle (Fig. 2).9,10 1140
RESULTS Clinical A total of 6 patients (4 boys and 2 girls) underwent CPRE (3 each with and without osteotomy). Follow-up ranges from 2 to 8 years, with a median of 5. Four patients have achieved a degree of urinary continence (a minimum of 1 hour dry interval during the day). Three patients void by abdominal straining, and one has a catheterizable appendiceal channel. In 3 patients who could “void” on command, a uroflow followed by a bladder scan was obtained on at least 2 occasions: all had a flat uroflow profile (Fig. 3A) and a postvoid residual ranging from 30% to 50% of voided volume. The frequency of the febrile urinary tract infections (2-12/year/ patient) decreased as the children acquired the ability to better empty the bladder by abdominal straining (Table 1). Imaging All had initial bilateral VUR (hi grade in 5 units). Frequent febrile urinary tract infections prompted bilateral ureteral reimplantation in 4 combined with bladder neck repair (BNR) in 3. VUR resolved in all but 3 units (grade 1 in 2). Hydrouretronephrosis of grade 3, without VUR, persists in 1 of 12 units at risk. The bladders appear smooth on cystography (Fig. 3B). UROLOGY 83 (5), 2014
Figure 2. Sagittal illustration of left pelvic plexus and its terminal branches; note relationship to bladder plate, prostatic urethra, and corpora cavernosa. The pelvic diaphragm is not shown.
Urodynamic Five patients underwent urodynamic studies (3 after BNR). Urine leaked passively around the urodynamic catheter at pressures ranging from 28 to 47 cm of H2O (only 1 patient had a pressure exceeding 40 cm of H2O). We did not record a normal or abnormal detrusor contraction in any of these patients, including 2 in whom the study was done in day surgery a few hours after the patients had emerged from under general anesthesia (Fig. 3C). In the remaining 3, urodynamic recording was done after induction of general anesthesia but without maintenance of inhalational agents.11 The bladder capacity ranged from 45 ml at age 2 years to 200 ml in a 7-year-old patient. The percent predicted bladder capacity, adjusted for age, ranged from 25 to 70, with a median of 60%.12 A review of the literature reveals 68 publications concerning themselves with CPRE since 1999. Although the reported urinary continence rates range from 25% to 65%, the presence of detrusor activity or overactivity is not reported, documented, or commented on (even after a BNR).13,14
COMMENT Several techniques have been described for the surgical treatment of bladder exstrophy in the newborn. In 2007, a survey of 142 pediatric urologists revealed that 42% of those who adopted CPRE did so because of the hope that it would more closely mimic the normal anatomy and UROLOGY 83 (5), 2014
therefore physiology of the normal newborn bladder.15 CPRE relies on “moving the bladder and bladder neckproximal urethra unit posteriorly into the pelvis”.7 This radical mobilization maneuver is facilitated by complete penile disassembly of the corpora from each other and the urethral plate. Not only does this step allow for deep incisions of the intersympheseal band and the coalescence of the pelvic diaphragm, but also the unimpeded mobilization of the exstrophic bladder and prostatic urethral plate. It is believed that the resulting pelvic position of the bladder allows for bladder cycling of urine.7 Normal bladder cycling and development portend a storage function at or near age appropriate bladder capacity with normal compliance and voiding. Our results suggest that applying the CPRE procedure might not attain the latter objective. In fact, we present clinical, imaging, and urodynamic evidence that CPRE might lead to detrusor underactivity type of neurogenic bladder. We suggest a pathophysiologic basis by which CPRE might result in a flaccid bladder. In 1982, Walsh and Donker16 traced the autonomic innervations in the male fetus and newborn to determine the relationship between the pelvic plexus, the prostate, and urethra and pelvic diaphragm. This classic article formed the basis for nerve-sparing radical prostatectomy and preservation of potency. These results, which have been reproduced by numerous urologic surgeons all over the world, validate the anatomic basis.17 The most pertinent landmark is the position of the pelvic plexus by the rectum just posterior 1141
Figure 3. (A) Flat uroflow in a 3-year-old girl. (B) Typical cystogram obtained under anesthesia. (C) Urodynamic tracing in the same patient: leak point pressure (LPP) ¼ 28 cm of H2O: percent of predicted bladder capacity (PPBC) ¼ 70.
to the prostate and lateral to the urethra. In fetuses and newborns, it forms a fenestrated rectangular plate in the sagittal plane extending from the sacrum ventrally toward the pelvic diaphragm and measures 4 cm in length and 2.5-3 cm in height. The pelvic plexus provides visceral terminal branches that innervate the bladder, ureter, seminal vesicles, prostate, rectum, and urethra and corpora cavernosa. In addition, they innervate vessels in the area; supply the levator complex and striated urethral musculature. The cavernous branch follows closely the course of the urethra as it traverses the urogenital diaphragm. On the other side of the diaphragm, it pierces the corpora just behind and medial to the dorsal penile artery and nerve. Branches of the main plexus in addition form a network by joining branches emanating from the opposite side just posterior to the bladder and prostatic urethra. In girls, the pelvic plexus is triangular in shape with the distal ureter representing a fundamental anatomic surgical landmark.18 These branches spread on the anterior and lateral vaginal walls and the base of the bladder at the vesicourethral junction inferolaterally. Baader and Herrmann19 provide a detailed description of the topography of the pelvic autonomic nervous system in both genders. 1142
Kureel presents elegant anatomic descriptions of the branches of the pelvic plexus as they traverse the perineum in children with bladder exstrophy11; no differences were noted from normal. We propose that complete penile disassembly eliminates the distal fixation point of the bladder-urethral plate axis. Aggressive division of the intersympheseal ligament and pelvic diaphragm fibers (lateral to the prostatic urethra) allows for posterior and cephalad movement of the bladder-urethral plate complex at the expense of permanent shearing and or stretch injury to the microscopic pelvic plexus branches to the bladder, external sphincter, and prostatic urethra and to the branches of the perineal artery and nerve. It is not the deep divisions of the intersympheseal structures per se, which result in the injury. It is the unimpeded radical mobilization of the bladder-urethral plate complex in the direction of the pelvis. Although the intersympheseal structures are divided in the modern staged approach, the penis is not disassembled, and therefore the bladderurethral complex is not subjected to the radical mobilization described previously. Furthermore, the incisions are placed laterally and not medially in proximity UROLOGY 83 (5), 2014
BN, bladder neck; BNR, bladder neck repair; FRUTI/y, febrile recurrent urinary tract infections per year; LPP, leak point pressure; PPBC, percent predicted bladder capacity; PVR, post void residual; UNC, ureteral neocystostomy; VUR, vesicoureteral refux. * Transient urinary retention. y Recurrent urethral stricture. z Bladder neck closure. x Recent.
Yes Yes Yes/AVCz No/AVCx Yes No 28 30 25 47 Pending Pending 70 50 55 50 66 25 200 150 150 120 150 45 4 mls/s; 100 4 mls/s; 90 BN closed N/A 3 mls/s; 77 N/A Neg R/3 R/2 Bil/1 Neg Bil/3 Neg L/3 Neg Neg Neg Neg
BNR Hydro/Grade VUR/Grade Flow (mls/s)/PVR Capacity PPBC LPP cm H2O Continence
Yes Yes Yes No No No Bilateral Bilateral Bilateral No Bilateral No
UNC BN Deflux
Attempted Attempted Successful* Not attempted Not attempted Not attempted 2 2 4 5y 12 1
FRUTI/y VUR
Bil golf hole Bil golf hole B position B position Bil golf hole Bil golf hole No No No Yes Yes Yes 8/M 8/M 7/M 5/M 4/F 2/F
Patient Age/Gender Osteotomy
#1 #2 #3 #4 #5 #6
Table 1. Summary of patient characteristic variables after complete primary repair of bladder exstrophy
UROLOGY 83 (5), 2014
to the symphysis pubis away from the branches of perineal nerve and nervi erigentes. These and all terminal branches are especially vulnerable because their neurons are located many centimeters from their target tissue. The plexus itself is relatively fixed in the endopelvic fascial envelope. In addition, the microvessels associated with these branches are also subjected to shearing trauma adding further insult. During the period after injury, substantial changes might occur in the damaged neuron but also in preganglionic neurons and in the target organ.20 These changes consist of decrease in soma size, altered transmitter synthesis, changes in electrical properties, and effects on growth factor receptor expression. In some cases, the pelvic ganglion will die after axonal injury (axotomy) that then results in deprivation of target-derived neurotrophin factors with unknown effects on the regenerative process. These nerves do carry sympathetic, parasympathetic, and somatic projections. The same mechanism of injury applies to girls. Although peripheral axons can undergo physiologically a degree of stretch, the threshold for exceeding these levels has been variably reported to range from 4% to 21% per unit length.21 If we consider 4 cm to represent the distance between the pelvic plexus and the pelvic diaphragm, these percentages translate to absolute distances ranging from 0.16 to 0.84 cm above which significant stretch injury might be expected.10 On the basis of the final location of the urethral meatus after CPRE and our subjective estimation, we believe that the procedure exceeds the minimum threshold of “safe stretching” by several folds. Finally, the effect of division of the urogenital diaphragm, a structure unique to humans, is unknown at this point especially over future pregnancy.22 Our experience with these 6 patients might be modest; however, it might be sufficient to recommend consideration of alternative approaches to CPRE because of the compelling anatomic basis and the absence of a single publication documenting the presence of bladder contractions e 15 years since the original description. Concern is raised for future erectile function. The urodynamic evidence presented might be criticized for being obtained under anesthesia albeit while following a strict protocol.12 One should, in addition, be mindful of the fact that all these patients have a flat uroflow and clearly void by abdominal pressure and carry a significant residual. Furthermore, there is evidence to suggest that general anesthesia inhibits the ability to suppress bladder contractions and therefore allows for them to manifest.23 Although BNR in the exstrophy population has been shown to result in abnormal bladder contractions, none of our 3 patients who underwent a BNR manifested bladder contractions.24 We are aware of the report by Borer et al of normal bladder filling dynamics and absence of detrusor overactivity with “silent” electromyography of the external sphincter; however, evidence of uroflow tracing or detrusor contractions leading to bladder emptying is not presented.14 We would also like to suggest that variation in the outcome after CPRE from different 1143
centers might reflect variations in the extent to which deep incisions are made to the intersympheseal band and the coalescence of the pelvic diaphragm as emphasized by Mitchell.8 In fact, when these deep incisions are not made, the outcome of CPRE does not differ from that of modern staged repair as reported by Gargollo et al25 in direct contrast to the outcomes reported by Shnorhavorian et al26 when it comes to the need for bladder neck reconstruction. Clean intermittent catheterization after CPRE might obviate some of the complications known to occur in patients with neurogenic bladder dysfunction; however, the hypospadiac urethral meatus, especially in girls, might prohibit such an approach. Our results do not disprove the hypothesis that bladder cycling after newborn closure results in better capacity and volitional voiding rather that CPRE does not fulfill this promise. The observed periods of dryness might not reflect continence when the latter is not associated with “voiding”, be sustainable in the long term and not achievable by 71% of respondents to a survey regarding outcomes in pediatric urology.15,27,28 Other surgical approaches have reported volitional voiding in exstrophy, even when closure is performed later in infancy or childhood.29,30
CONCLUSION In summary, we present evidence that CPRE might be associated with detrusor underactivity resulting from shearing injury to the peripheral pelvic plexus branches in both girls and boys. Although the number of patients in whom we directly observed these changes is small, the sum total of the evidence based on the known anatomy of the pelvic neurovascular anatomy and the lack of any report describing the presence of detrusor contractions after CPRE is substantial. Future goals should include the design of nerve-sparing procedures for pelvic surgery in general and bladder exstrophy in particular, as many of these individuals are anticipated to transition into adulthood. References 1. Grady RW, Mitchell MD. Newborn exstrophy closure and Epispadias repair. World J Urol. 1998;16:200-204. 2. Grady RW, Mitchell ME. Complete primary repair of exstrophy. J Urol. 1999;162:1415-1420. 3. Mathews R, Gearhart JP. Exstrophy-Epispadias complex. In: Wein A, et al., eds. Campbell-Walsh Urology. 9th ed. Philadelphia: W.B. Saunders; 2007:3497-3553. 4. Purves JT. Modern approaches in primary exstrophy closure. Semin Ped Surg. 2011;20:79-84. 5. Kelly JH. Vesical exstrophy: repair using radical mobilization. Pediatr Surg Int. 1995;10:298-304. 6. Ebert AK, Schott G, Bals-Pratsch M, et al. Long-term follow up of male patients after reconstruction of the bladder-exstrophyepispadias complex: psychosocial status, continence, renal and genital function. J Pediatr Urol. 2010;6:6-10. 7. Mitchell ME. Bladder exstrophy repair: complete primary repair of exstrophy. Urology. 2005;65:5-8.
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8. Deiner SG, Kwatra SG, Lin H-M, et al. Patient characteristics and anesthetic technique are additive but not synergistic predictors of successful motor evoked potential monitoring. Anesthesia-Analgesia. 2010;11:421-425. 9. Kureel SN, Gupta A, Gupta RK. Surgical anatomy of urogenital diaphragm and course of its vessels in exstrophy-epispadias. Urology. 2011;78:159-163. 10. Wakim A, Barbet JP. Connections of the bladder plate and bladder neck with the bony pelvis in a fetus with classic bladder exstrophy. Urology. 2002;60:142-146. 11. Cannon TW, Damaser MS. Effect of anesthesia on cystometry and leak point pressure of the female rat. Life Sci. 2001;69:1193-1202. 12. Kaefer M, Zurakowski D, Bauer S, et al. Estimating normal bladder capacity in children. J Urol. 1997;158:2261-2264. 13. Husmann DA. Surgery insight: advantages and pitfalls of surgical techniques for the correction of bladder exstrophy. Nat Clin Pract. 2006;3:95-100. 14. Shoukry AI, Ziada AM, Morsi HA, et al. Outcome of complete primary bladder exstrophy repair: single center experience. J Pediatr Urol. 2009;5:496-499. 15. Mesrobian H-G: The results of a survey of the members of the section on urology regarding primary bladder closure provide insight into how surgical procedures for rare diseases evolve. Unpublished data. 16. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol. 1982;128:492-497. 17. Schlegel PN, Walsh PC. Neuroanatomical approach to radical cystoprostatectomy with preservation of sexual function. J Urol. 1987;138:1402-1406. 18. Mauroy B, Demondion X, Bizet B, et al. The female inferior hypogastric plexus: anatomical and radiological description of the plexus and its afferences- applications to pelvic surgery. Surg Radiol Anat. 2007;29:55-66. 19. Baader B, Herrmann M. Topography of the pelvic autonomic nervous system and its potential impact on surgical intervention in the pelvis. Clin anat. 2003;16:119-130. 20. Keast JR. Plasticity of pelvic autonomic ganglia and urogenital innervation. Int Rev Cytol. 2006;248:171-175. 21. Rikett T, Connell S, Gastijanic J, et al. Functional and mechanical evaluation of nerve stretch injury. J Med Syst. 2011;35:787-793. 22. Chung BI, Sommer G, Brooks JD. Anatomy of the lower urinary tract and male genitalia. In: Wein, ed. Campbell-Walsh Urology. 10th. ed. 2012; Chapter 2:40-41. 23. Weiss H, Baldani G. Effects of anesthesia on micturition and urodynamics. Int Anesthesiol Clin. 1993;31:1-24. 24. Diamond DA, Bauer SB, Dinlenc C, et al. Normal urodynamics in patients with bladder exstrophy: are they achievable? J Urol. 1999; 162:841-844. 25. Gargollo P, Hendren WH, Diamond DA, et al. Bladder neck reconstruction is often necessary after complete primary repair of exstrophy. J Urol 2011:2563-2571. 26. Shnorhavorian M, Grady RW, Andersen A, et al. Long term follow up of complete primary repair of exstrophy: the Seattle experience. J Urol 2008:1615-1619. 27. Chapple CR, Milsom I. Definition and classification of urinary incontinence. In: Wein A, et al., eds. Campbell-Walsh Urology. 9th ed., Chapter 63. Philadelphia: W.B. Saunders; 2012:1872-1873. 28. Prasad MM, Marks A, Vasquez E, et al. Published surgical success rates in pediatric urology- Fact or Fiction? J Urol. 2012;188:16431648. 29. Kureel SN, Gupta A, Kumar S, et al. A novel midline scrota-perineal approach facilitating innervations preserving sphincteroplasty and radical corporal detachment for reconstruction of Exstrophy-epispadias. Urology. 2011;78:668-674. 30. Caione P, Capozza N, Lais A, et al. Periurethral muscle complex reassembly for exstrophy-epispadias repair. J Urol. 2000;164:20622066.
UROLOGY 83 (5), 2014
METHODS RESULTS
CONCLUSION
To test the hypothesis that complete primary repair of bladder exstrophy (CPRE) is associated with detrussor underactivity. For this purpose, we review (1) our experience, (2) the results of the published literature as it pertains to bladder function, and (3) the known anatomic basis on which the mechanism of the observed outcome can be understood. The medical records of all patients who underwent CPRE by the author between 2004 and 2010 were reviewed. Attention was focused on the clinical, imaging, and urodynamic findings. Four men and 2 women underwent CPRE. Follow-up ranges from 2 to 8 years. Four underwent bilateral ureteral reimplantation combined with bladder neck repair in 3. Detrusor activity (or overactivity) was not recorded in the 5 patients who underwent urodynamic studies. Four patients achieved short periods of urinary continence. The percent predicted bladder capacity, adjusted for age, ranged from 25 to 70, with a median of 60. Of the 68 publications on CPRE since 1999, none reports the presence of detrusor activity. A description of the pelvic plexus anatomy by Walsh and Donker provides a basis for the mechanism of injury resulting in the previously mentioned results: (1) complete penile disassembly eliminates the distal fixation point of the bladder-urethral plate, (2) the subsequent dissection and mobilization result in shearing injury to the microscopic pelvic plexus branches to the bladder, external sphincter, and prostatic urethra. CPRE results in disruption of the branches of the pelvic plexus and a neurogenic bladder (detrussor underactivity). UROLOGY 83: 1139e1144, 2014. 2014 Elsevier Inc.
T
he surgical treatment of bladder exstrophy in the newborn continues to evolve. The complete primary repair of bladder exstrophy (CPRE) procedure first described in 1998 by Grady and Mitchell1,2 represented an alternative to the time tested staged repair described by Jeffs and Cendron and refined by Mathews and Gearhart3 over the last 3 decades. The stated rationale for abandoning the staged repair was to reduce the number of procedures required to attain the objectives of “urinary continence and allow voiding function”.1 Other notable approaches, which have been developed and described in the literature have not gained popularity in North America but deserve careful study.4-6 In this communication, we focus on describing the effects of CPRE on bladder function and providing an anatomic and pathophysiologic basis for the observed outcomes.
Financial Disclosure: The authors declare that they have no relevant financial interests. From the Department of Urology, Medical College and Children’s Hospital of Wisconsin Milwaukee, WI Reprint requests: Hrair-George O. Mesrobian, M.D., M.Sc., Department of Urology, Medical College and Children’s Hospital of Wisconsin Milwaukee, 999 N92nd Street, Suite C 330, Milwaukee, WI 53226. E-mail: [email protected] Submitted: September 4, 2013, accepted (with revisions): November 9, 2013
ª 2014 Elsevier Inc. All Rights Reserved
PATIENTS AND METHODS The medical records of all the patients who underwent CPRE by the author as primary surgeon were reviewed after obtaining institutional review board approval. During CPRE, attention was directed at the important steps of the procedure, which consist of extensive dissection of the perineum with deep incisions of the intersympheseal band and pelvic diaphragm fibers on either side of the prostatic urethral plate in men.7 This exposure becomes feasible because of penile disassembly, which provides direct access to the pelvic diaphragm (Fig. 1). The adequacy of this dissection is visually appreciated by the resultant cephalad and posterior movement of the bladder plate e urethral complex into the pelvis. The bladder and urethra are then tubularized followed by approximation of the corpora in the midline on top of the urethra, which assumes a hypospadiac position. In girls, the bifid clitoris is already “disassembled”, and therefore, dissection is directed at incising the pelvic diaphragm fibers on either side of the vagina e urethral plate complex.7 Because of the resulting cephalad movement of the bladder-urethral complex into the pelvis, the urethra becomes hypospadiac by default. An orthopedic surgeon with bladder exstrophy experience performed at the beginning of the procedure bilateral anterior osteotomies when manual approximation of the symphysis was judged to be insufficient after induction of anesthesia. For the urodynamic studies to be described, catheters were placed in the bladder and rectum under anesthesia at diagnostic 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.11.010
1139
Figure 1. Surgeon’s view of bladder exstrophy during complete primary repair of bladder exstrophy; the pelvic diaphragm separates the pelvic sphincter mechanism from the bulbospongiosus, superficial transverse perineal muscle, and associated neurovascular structures that pierce it. cystoscopy. The latter was indicated for evaluation of bladder and bladder neck anatomy, the presence of vesicoureteral refux (VUR; in conjunction with positional instillation cystography), or before a planned bladder neck injection with Deflux to provide outlet resistance. After initial cystoscopy, a 7F urodynamic air-charged catheter is inserted in the bladder and an abdominal pressure catheter in the rectum just past the external sphincter (T-DOC Company, Wilmington, DE; www.tdocllc. com). Surface patch electrodes are then applied just superior to the perineal body on either side of the midline. The anesthetic protocol was switched to one used for detection of evoked potentials during spinal surgery and consisted of total intravenous anesthesia.8 After calibration of the instrument, bladders were filled at a rate equal to 10% of expected capacity for age with methylene blue spiked, room temperature mixture of normal saline and contrast. A Medtronic Duet multiport (version 9.0; www.medtronic.com) was used to record peak bladder pressure at the first leak, bladder contractions with or without a leak or voiding, bladder wall compliance, and electromyography amplitude. The presence of VUR and the appearance of the bladder neck were observed under fluoroscopy. Capacity in the face of VUR was defined as the total volume infused before passive fluid leakage. The volume at which VUR was detected was recorded separately. A contraction was defined as a spike over baseline bladder pressure with or without voiding. The known anatomic literature of bladder exstrophy was reviewed with the intent of creating a 3-dimensional simplified medical illustration of the pertinent structures with specific attention to the pelvic neurovascular bundle (Fig. 2).9,10 1140
RESULTS Clinical A total of 6 patients (4 boys and 2 girls) underwent CPRE (3 each with and without osteotomy). Follow-up ranges from 2 to 8 years, with a median of 5. Four patients have achieved a degree of urinary continence (a minimum of 1 hour dry interval during the day). Three patients void by abdominal straining, and one has a catheterizable appendiceal channel. In 3 patients who could “void” on command, a uroflow followed by a bladder scan was obtained on at least 2 occasions: all had a flat uroflow profile (Fig. 3A) and a postvoid residual ranging from 30% to 50% of voided volume. The frequency of the febrile urinary tract infections (2-12/year/ patient) decreased as the children acquired the ability to better empty the bladder by abdominal straining (Table 1). Imaging All had initial bilateral VUR (hi grade in 5 units). Frequent febrile urinary tract infections prompted bilateral ureteral reimplantation in 4 combined with bladder neck repair (BNR) in 3. VUR resolved in all but 3 units (grade 1 in 2). Hydrouretronephrosis of grade 3, without VUR, persists in 1 of 12 units at risk. The bladders appear smooth on cystography (Fig. 3B). UROLOGY 83 (5), 2014
Figure 2. Sagittal illustration of left pelvic plexus and its terminal branches; note relationship to bladder plate, prostatic urethra, and corpora cavernosa. The pelvic diaphragm is not shown.
Urodynamic Five patients underwent urodynamic studies (3 after BNR). Urine leaked passively around the urodynamic catheter at pressures ranging from 28 to 47 cm of H2O (only 1 patient had a pressure exceeding 40 cm of H2O). We did not record a normal or abnormal detrusor contraction in any of these patients, including 2 in whom the study was done in day surgery a few hours after the patients had emerged from under general anesthesia (Fig. 3C). In the remaining 3, urodynamic recording was done after induction of general anesthesia but without maintenance of inhalational agents.11 The bladder capacity ranged from 45 ml at age 2 years to 200 ml in a 7-year-old patient. The percent predicted bladder capacity, adjusted for age, ranged from 25 to 70, with a median of 60%.12 A review of the literature reveals 68 publications concerning themselves with CPRE since 1999. Although the reported urinary continence rates range from 25% to 65%, the presence of detrusor activity or overactivity is not reported, documented, or commented on (even after a BNR).13,14
COMMENT Several techniques have been described for the surgical treatment of bladder exstrophy in the newborn. In 2007, a survey of 142 pediatric urologists revealed that 42% of those who adopted CPRE did so because of the hope that it would more closely mimic the normal anatomy and UROLOGY 83 (5), 2014
therefore physiology of the normal newborn bladder.15 CPRE relies on “moving the bladder and bladder neckproximal urethra unit posteriorly into the pelvis”.7 This radical mobilization maneuver is facilitated by complete penile disassembly of the corpora from each other and the urethral plate. Not only does this step allow for deep incisions of the intersympheseal band and the coalescence of the pelvic diaphragm, but also the unimpeded mobilization of the exstrophic bladder and prostatic urethral plate. It is believed that the resulting pelvic position of the bladder allows for bladder cycling of urine.7 Normal bladder cycling and development portend a storage function at or near age appropriate bladder capacity with normal compliance and voiding. Our results suggest that applying the CPRE procedure might not attain the latter objective. In fact, we present clinical, imaging, and urodynamic evidence that CPRE might lead to detrusor underactivity type of neurogenic bladder. We suggest a pathophysiologic basis by which CPRE might result in a flaccid bladder. In 1982, Walsh and Donker16 traced the autonomic innervations in the male fetus and newborn to determine the relationship between the pelvic plexus, the prostate, and urethra and pelvic diaphragm. This classic article formed the basis for nerve-sparing radical prostatectomy and preservation of potency. These results, which have been reproduced by numerous urologic surgeons all over the world, validate the anatomic basis.17 The most pertinent landmark is the position of the pelvic plexus by the rectum just posterior 1141
Figure 3. (A) Flat uroflow in a 3-year-old girl. (B) Typical cystogram obtained under anesthesia. (C) Urodynamic tracing in the same patient: leak point pressure (LPP) ¼ 28 cm of H2O: percent of predicted bladder capacity (PPBC) ¼ 70.
to the prostate and lateral to the urethra. In fetuses and newborns, it forms a fenestrated rectangular plate in the sagittal plane extending from the sacrum ventrally toward the pelvic diaphragm and measures 4 cm in length and 2.5-3 cm in height. The pelvic plexus provides visceral terminal branches that innervate the bladder, ureter, seminal vesicles, prostate, rectum, and urethra and corpora cavernosa. In addition, they innervate vessels in the area; supply the levator complex and striated urethral musculature. The cavernous branch follows closely the course of the urethra as it traverses the urogenital diaphragm. On the other side of the diaphragm, it pierces the corpora just behind and medial to the dorsal penile artery and nerve. Branches of the main plexus in addition form a network by joining branches emanating from the opposite side just posterior to the bladder and prostatic urethra. In girls, the pelvic plexus is triangular in shape with the distal ureter representing a fundamental anatomic surgical landmark.18 These branches spread on the anterior and lateral vaginal walls and the base of the bladder at the vesicourethral junction inferolaterally. Baader and Herrmann19 provide a detailed description of the topography of the pelvic autonomic nervous system in both genders. 1142
Kureel presents elegant anatomic descriptions of the branches of the pelvic plexus as they traverse the perineum in children with bladder exstrophy11; no differences were noted from normal. We propose that complete penile disassembly eliminates the distal fixation point of the bladder-urethral plate axis. Aggressive division of the intersympheseal ligament and pelvic diaphragm fibers (lateral to the prostatic urethra) allows for posterior and cephalad movement of the bladder-urethral plate complex at the expense of permanent shearing and or stretch injury to the microscopic pelvic plexus branches to the bladder, external sphincter, and prostatic urethra and to the branches of the perineal artery and nerve. It is not the deep divisions of the intersympheseal structures per se, which result in the injury. It is the unimpeded radical mobilization of the bladder-urethral plate complex in the direction of the pelvis. Although the intersympheseal structures are divided in the modern staged approach, the penis is not disassembled, and therefore the bladderurethral complex is not subjected to the radical mobilization described previously. Furthermore, the incisions are placed laterally and not medially in proximity UROLOGY 83 (5), 2014
BN, bladder neck; BNR, bladder neck repair; FRUTI/y, febrile recurrent urinary tract infections per year; LPP, leak point pressure; PPBC, percent predicted bladder capacity; PVR, post void residual; UNC, ureteral neocystostomy; VUR, vesicoureteral refux. * Transient urinary retention. y Recurrent urethral stricture. z Bladder neck closure. x Recent.
Yes Yes Yes/AVCz No/AVCx Yes No 28 30 25 47 Pending Pending 70 50 55 50 66 25 200 150 150 120 150 45 4 mls/s; 100 4 mls/s; 90 BN closed N/A 3 mls/s; 77 N/A Neg R/3 R/2 Bil/1 Neg Bil/3 Neg L/3 Neg Neg Neg Neg
BNR Hydro/Grade VUR/Grade Flow (mls/s)/PVR Capacity PPBC LPP cm H2O Continence
Yes Yes Yes No No No Bilateral Bilateral Bilateral No Bilateral No
UNC BN Deflux
Attempted Attempted Successful* Not attempted Not attempted Not attempted 2 2 4 5y 12 1
FRUTI/y VUR
Bil golf hole Bil golf hole B position B position Bil golf hole Bil golf hole No No No Yes Yes Yes 8/M 8/M 7/M 5/M 4/F 2/F
Patient Age/Gender Osteotomy
#1 #2 #3 #4 #5 #6
Table 1. Summary of patient characteristic variables after complete primary repair of bladder exstrophy
UROLOGY 83 (5), 2014
to the symphysis pubis away from the branches of perineal nerve and nervi erigentes. These and all terminal branches are especially vulnerable because their neurons are located many centimeters from their target tissue. The plexus itself is relatively fixed in the endopelvic fascial envelope. In addition, the microvessels associated with these branches are also subjected to shearing trauma adding further insult. During the period after injury, substantial changes might occur in the damaged neuron but also in preganglionic neurons and in the target organ.20 These changes consist of decrease in soma size, altered transmitter synthesis, changes in electrical properties, and effects on growth factor receptor expression. In some cases, the pelvic ganglion will die after axonal injury (axotomy) that then results in deprivation of target-derived neurotrophin factors with unknown effects on the regenerative process. These nerves do carry sympathetic, parasympathetic, and somatic projections. The same mechanism of injury applies to girls. Although peripheral axons can undergo physiologically a degree of stretch, the threshold for exceeding these levels has been variably reported to range from 4% to 21% per unit length.21 If we consider 4 cm to represent the distance between the pelvic plexus and the pelvic diaphragm, these percentages translate to absolute distances ranging from 0.16 to 0.84 cm above which significant stretch injury might be expected.10 On the basis of the final location of the urethral meatus after CPRE and our subjective estimation, we believe that the procedure exceeds the minimum threshold of “safe stretching” by several folds. Finally, the effect of division of the urogenital diaphragm, a structure unique to humans, is unknown at this point especially over future pregnancy.22 Our experience with these 6 patients might be modest; however, it might be sufficient to recommend consideration of alternative approaches to CPRE because of the compelling anatomic basis and the absence of a single publication documenting the presence of bladder contractions e 15 years since the original description. Concern is raised for future erectile function. The urodynamic evidence presented might be criticized for being obtained under anesthesia albeit while following a strict protocol.12 One should, in addition, be mindful of the fact that all these patients have a flat uroflow and clearly void by abdominal pressure and carry a significant residual. Furthermore, there is evidence to suggest that general anesthesia inhibits the ability to suppress bladder contractions and therefore allows for them to manifest.23 Although BNR in the exstrophy population has been shown to result in abnormal bladder contractions, none of our 3 patients who underwent a BNR manifested bladder contractions.24 We are aware of the report by Borer et al of normal bladder filling dynamics and absence of detrusor overactivity with “silent” electromyography of the external sphincter; however, evidence of uroflow tracing or detrusor contractions leading to bladder emptying is not presented.14 We would also like to suggest that variation in the outcome after CPRE from different 1143
centers might reflect variations in the extent to which deep incisions are made to the intersympheseal band and the coalescence of the pelvic diaphragm as emphasized by Mitchell.8 In fact, when these deep incisions are not made, the outcome of CPRE does not differ from that of modern staged repair as reported by Gargollo et al25 in direct contrast to the outcomes reported by Shnorhavorian et al26 when it comes to the need for bladder neck reconstruction. Clean intermittent catheterization after CPRE might obviate some of the complications known to occur in patients with neurogenic bladder dysfunction; however, the hypospadiac urethral meatus, especially in girls, might prohibit such an approach. Our results do not disprove the hypothesis that bladder cycling after newborn closure results in better capacity and volitional voiding rather that CPRE does not fulfill this promise. The observed periods of dryness might not reflect continence when the latter is not associated with “voiding”, be sustainable in the long term and not achievable by 71% of respondents to a survey regarding outcomes in pediatric urology.15,27,28 Other surgical approaches have reported volitional voiding in exstrophy, even when closure is performed later in infancy or childhood.29,30
CONCLUSION In summary, we present evidence that CPRE might be associated with detrusor underactivity resulting from shearing injury to the peripheral pelvic plexus branches in both girls and boys. Although the number of patients in whom we directly observed these changes is small, the sum total of the evidence based on the known anatomy of the pelvic neurovascular anatomy and the lack of any report describing the presence of detrusor contractions after CPRE is substantial. Future goals should include the design of nerve-sparing procedures for pelvic surgery in general and bladder exstrophy in particular, as many of these individuals are anticipated to transition into adulthood. References 1. Grady RW, Mitchell MD. Newborn exstrophy closure and Epispadias repair. World J Urol. 1998;16:200-204. 2. Grady RW, Mitchell ME. Complete primary repair of exstrophy. J Urol. 1999;162:1415-1420. 3. Mathews R, Gearhart JP. Exstrophy-Epispadias complex. In: Wein A, et al., eds. Campbell-Walsh Urology. 9th ed. Philadelphia: W.B. Saunders; 2007:3497-3553. 4. Purves JT. Modern approaches in primary exstrophy closure. Semin Ped Surg. 2011;20:79-84. 5. Kelly JH. Vesical exstrophy: repair using radical mobilization. Pediatr Surg Int. 1995;10:298-304. 6. Ebert AK, Schott G, Bals-Pratsch M, et al. Long-term follow up of male patients after reconstruction of the bladder-exstrophyepispadias complex: psychosocial status, continence, renal and genital function. J Pediatr Urol. 2010;6:6-10. 7. Mitchell ME. Bladder exstrophy repair: complete primary repair of exstrophy. Urology. 2005;65:5-8.
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8. Deiner SG, Kwatra SG, Lin H-M, et al. Patient characteristics and anesthetic technique are additive but not synergistic predictors of successful motor evoked potential monitoring. Anesthesia-Analgesia. 2010;11:421-425. 9. Kureel SN, Gupta A, Gupta RK. Surgical anatomy of urogenital diaphragm and course of its vessels in exstrophy-epispadias. Urology. 2011;78:159-163. 10. Wakim A, Barbet JP. Connections of the bladder plate and bladder neck with the bony pelvis in a fetus with classic bladder exstrophy. Urology. 2002;60:142-146. 11. Cannon TW, Damaser MS. Effect of anesthesia on cystometry and leak point pressure of the female rat. Life Sci. 2001;69:1193-1202. 12. Kaefer M, Zurakowski D, Bauer S, et al. Estimating normal bladder capacity in children. J Urol. 1997;158:2261-2264. 13. Husmann DA. Surgery insight: advantages and pitfalls of surgical techniques for the correction of bladder exstrophy. Nat Clin Pract. 2006;3:95-100. 14. Shoukry AI, Ziada AM, Morsi HA, et al. Outcome of complete primary bladder exstrophy repair: single center experience. J Pediatr Urol. 2009;5:496-499. 15. Mesrobian H-G: The results of a survey of the members of the section on urology regarding primary bladder closure provide insight into how surgical procedures for rare diseases evolve. Unpublished data. 16. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol. 1982;128:492-497. 17. Schlegel PN, Walsh PC. Neuroanatomical approach to radical cystoprostatectomy with preservation of sexual function. J Urol. 1987;138:1402-1406. 18. Mauroy B, Demondion X, Bizet B, et al. The female inferior hypogastric plexus: anatomical and radiological description of the plexus and its afferences- applications to pelvic surgery. Surg Radiol Anat. 2007;29:55-66. 19. Baader B, Herrmann M. Topography of the pelvic autonomic nervous system and its potential impact on surgical intervention in the pelvis. Clin anat. 2003;16:119-130. 20. Keast JR. Plasticity of pelvic autonomic ganglia and urogenital innervation. Int Rev Cytol. 2006;248:171-175. 21. Rikett T, Connell S, Gastijanic J, et al. Functional and mechanical evaluation of nerve stretch injury. J Med Syst. 2011;35:787-793. 22. Chung BI, Sommer G, Brooks JD. Anatomy of the lower urinary tract and male genitalia. In: Wein, ed. Campbell-Walsh Urology. 10th. ed. 2012; Chapter 2:40-41. 23. Weiss H, Baldani G. Effects of anesthesia on micturition and urodynamics. Int Anesthesiol Clin. 1993;31:1-24. 24. Diamond DA, Bauer SB, Dinlenc C, et al. Normal urodynamics in patients with bladder exstrophy: are they achievable? J Urol. 1999; 162:841-844. 25. Gargollo P, Hendren WH, Diamond DA, et al. Bladder neck reconstruction is often necessary after complete primary repair of exstrophy. J Urol 2011:2563-2571. 26. Shnorhavorian M, Grady RW, Andersen A, et al. Long term follow up of complete primary repair of exstrophy: the Seattle experience. J Urol 2008:1615-1619. 27. Chapple CR, Milsom I. Definition and classification of urinary incontinence. In: Wein A, et al., eds. Campbell-Walsh Urology. 9th ed., Chapter 63. Philadelphia: W.B. Saunders; 2012:1872-1873. 28. Prasad MM, Marks A, Vasquez E, et al. Published surgical success rates in pediatric urology- Fact or Fiction? J Urol. 2012;188:16431648. 29. Kureel SN, Gupta A, Kumar S, et al. A novel midline scrota-perineal approach facilitating innervations preserving sphincteroplasty and radical corporal detachment for reconstruction of Exstrophy-epispadias. Urology. 2011;78:668-674. 30. Caione P, Capozza N, Lais A, et al. Periurethral muscle complex reassembly for exstrophy-epispadias repair. J Urol. 2000;164:20622066.
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