Re: Is Long-Term Bladder Deterioration Inevitable Following Successful Isolated Bladder Outlet Procedures in Children With Neuropathic Bladder Dysfunction?

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bias in retrospective studies is acknowledged as one of the limitations of this review in the last paragraph of our discussion section. The strengths and limitations of any review are dependent on the quality of the original studies. Indeed, systematic reviews based on randomized controlled studies offer the highest quality of evidence. Since emphysematous pyelonephritis (EPN) is a rare disease, with fewer than 600 reported cases from 1966 to date, it may not be possible to recruit patients into a prospective randomized study. Indeed, most surgeons will only see isolated cases of EPN in their lifetime. Based on the current best available evidence, bearing in mind the potential limitations of the study for the reasons mentioned, we would consider management of EPN with a combination of fluid resuscitation, aggressive antibiotic therapy, correction of reversible precipitating factors and early percutaneous drainage, followed by elective nephrectomy where indicated, as the current standard of care.

Re: Is Long-Term Bladder Deterioration Inevitable Following Successful Isolated Bladder Outlet Procedures in Children With Neuropathic Bladder Dysfunction? S. Dave, J. L. Pippi Salle, A. J. Lorenzo, L. H. Braga, M. H. Peralta-Del Valle, D. Bagli and A. E. Khoury J Urol 2008; 179: 1991–1996.

To the Editor: The authors ask if bladder deterioration is inevitable following outlet procedures without augmentation for neurogenic incontinence. That answer is already known: No! In their small series bladder deterioration always required later augmentation. However, this finding contrasts with earlier reports, which the authors reference, showing secondary augmentation rates of only 28% to 37% in patients following artificial sphincter placement. In fact, their conclusion that significantly increased detrusor leak point pressure (DLPP) eventually results in bladder deterioration and the need for augmentation contradicts earlier findings from their own institution that hydronephrosis occurs in only 2% of patients after artificial sphincter placement, and bladder capacity and compliance increase with time.1 We published outcomes from bladder neck slings without augmentation for neurogenic incon-

tinence, finding that only 3% of patients needed later enterocystoplasty.2 The authors suggest differences in our results vs theirs can be explained by our shorter followup (mean 22 vs 40 months), and note that urodynamic studies at 6 months demonstrated decreased capacity and/or compliance in some of our patients. Followup in our series is now a mean of 37 months, the time at which the authors performed their secondary augmentations, yet we have performed no additional enterocystoplasties. They overlooked data in our table showing that volume/compliance had improved in most patients, and was stable in others, at more than 12 months postoperatively. The findings of Dave et al deserve closer scrutiny. Secondary augmentation was performed for upper tract changes (hydronephrosis or reflux) with or without incontinence. Urodynamics revealed decreases in capacity and compliance. However, it is unknown at what point these postoperative studies were performed. The authors state that these changes prompted increased anticholinergic medication and clean intermittent catheterization (CIC) but they do not provide dosages or CIC frequency. Most importantly, they do not report whether urodynamics were repeated to assess the adequacy of their medical therapy, or the interval from changes in therapy until augmentation. Other factors also put their conclusions into question. Of their 15 patients 4 had bladder trabeculation preoperatively, suggesting the need to decrease bladder pressures rather than enhance the outlet, an observation that the authors recently published.3 Two patients had persistent detrusor overactivity despite anticholinergics. Was outlet enhancement needed, or wise, in these cases without first controlling overactivity with increased anticholinergics or augmentation? Six patients subsequently underwent bladder neck closure or reoperative outlet procedures, implying persistent bladder neck incompetence. If so, how did they also have upper tract changes, especially if receiving adequate anticholinergics and CIC? Changes in 2 patients might be attributed to tethered spinal cord. Should these cases have been excluded from this analysis? Without more information regarding anticholinergic dosages, CIC intervals, patient compliance with followup, responses to changes in medical treatment when bladder changes were suspected and specific indications for enterocystoplasty the suggestion that augmentation is inevitable should be viewed with reservation. Had we operated at the first evidence of decreased capacity or compliance in our series, the augmentation rate would have increased unnecessarily to 53%.

LETTERS TO THE EDITOR/ERRATA

Given the well-known problems of augmentation, including death from rupture and malignancy, should we not reexamine indications for enterocystoplasty, especially when the goal is continence? Respectfully, Warren T. Snodgrass Pediatric Urology Section University of Texas Southwestern Medical Center at Dallas Dallas, Texas

Reply by Authors: We thank Snodgrass for his comments on our study. He compares our results to his published data on 30 patients who underwent isolated bladder neck sling for neurogenic incontinence.2 In that study the mean increase in DLPP was only 12 cm H2O, which represents a limited increase in outlet resistance. In the presence of neurogenic dysfunction the biological response of the detrusor muscle to an appropriate increase in resistance leads to muscle hypertrophy and deterioration of storage characteristics in a significant proportion of these patients despite maximal anticholinergic therapy. There are several key differences in these 2 series. First, the mean followup in our study was 135 months (not 40 months, as stated in the letter), compared to 22 months in the other series. This is a significant difference, since our mean time to augmentation cystoplasty was 39.6 ⫾ 28 months, and 5 of our patients underwent the augmentation after 37 months of followup. More importantly, the primary difference lies in the definition of dryness used in these 2 studies. The 25 cases defined as successfully improved in the series by Snodgrass et al included 17 with no or only occasional minimal leakage, 6 with dampness managed by 1 pad and 2 that required 2 pads daily.2 Our study included patients who achieved complete dryness, defined as a dry period of at least 4 hours on CIC. The other 4 patients underwent redo procedures until rendered dry using the same definition. Therefore, only 17 of the patients in the series by Snodgrass et al are comparable with our series of 15 patients. Another difference between our studies relates to the type of bladder outlet procedure performed, which included slings, artificial sphincters, Salle procedure and Young-Dees in our series. These outlet procedures vary in their efficacy in increasing the DLPP postoperatively and, therefore, yield varying results regarding the bladder outcome. We analyzed the urodynamic results in the 17 patients who were rendered dry in the study by Snodgrass et al (table 1 in article).2 Of the 14 patients who underwent urodynamics at 6 months of followup the capacity less than 40 cm H2O decreased in 7 (50%),

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increased in 5 (36%) and remained unchanged in 2. Simultaneously 8 patients (57%) exhibited a decrease in compliance (mean 10.8 cc/cm H2O) despite continuing anticholinergic therapy, which was also increased in some. Six patients (43%) showed an increase in compliance by a mean of 8.3 cc/cm H2O. On the second urodynamic study at a mean of 24 months, which was performed in 10 of these patients, the capacity was decreased compared to preoperative values in 4 (40%) and increased in 6 (60%). However, bladder compliance was less than preoperative values in 7 patients (70%) and greater in 3 (30%). Despite no further secondary augmentations, it is obvious that these results warrant continued surveillance and monitoring. We would like to clarify some aspects of our followup raised in the letter. All patients were followed at 6 to 12-month intervals with an ultrasound. Followup was also done to ensure continued compliance with anticholinergics and to keep the CIC frequency between 4 and 6 daily. Urodynamic studies were performed in all patients who presented with any change in continence or upper tract status. Magnetic resonance imaging was also performed when these changes occurred, to rule out a secondary tethered cord. In fact, 2 patients underwent cord untethering before augmentation. All patients received oxybutynin at a dose of at least 0.2 mg/kg 4 times daily, and some received higher doses until side effects were observed. Moreover, several patients were put on overnight catheter drainage besides CIC to alleviate filling pressures further in an attempt to avoid augmentation cystoplasty. Secondary augmentation was then performed if these conservative measures failed for continued wetting (not meeting our 4-hour dryness criteria) or persistent upper tract changes. The contention that 4 of these patients had minimal trabeculation preoperatively, which may have been treated by augmentation alone, is well taken. When reviewing these patients retrospectively the indication for performing an isolated outlet procedure was based on the fluoroscopic evidence of an open bladder neck. In our present preoperative evaluations we consider bladder trabeculation as a strong predictor of the need for augmentation cystoplasty alone without an outlet procedure. We compliment Snodgrass for the low augmentation rate in his patients, and would encourage publication of his long-term results in terms of the urodynamic data and, more importantly, continence status. We also agree entirely with the contention that avoiding augmentation cystoplasty is highly desirable. At the same time poor bladder compliance is also a well documented factor in causing upper tract damage that is equally harmful and irreversible. The 2 patients in our series in whom we persisted in performing bladder neck injections until

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rendered dry, who then exhibited a deterioration in upper tract status, made us realize that perhaps a less strict definition of dryness (as accepted by Snodgrass) is safer for these children. This safety pop-off valve prevents long-term upper tract damage in children with a neuropathic bladder. However, one must not lose sight of the indication for surgery in these individuals, which is to render them dry. Almost dry does not constitute true success. Therefore, we think that the question asked in the title remains unanswered, and we expectantly await the results from the series of Snodgrass et al2 and other such studies. 1. Churchill BM, Gilmour RF, Khoury AE and McLorie GA: Biological response of bladders rendered continent by insertion of artificial sphincter. J Urol 1987; 138: 1116. 2. Snodgrass WT, Elmore J and Adams R: Bladder neck sling and appendicovesicostomy without augmentation for neurogenic incontinence in children. J Urol 2007; 177: 1510. 3. Khoury AE, Dave S, Peralta-Del Valle MH, Braga LH, Lorenzo AJ and Bagli D: Severe bladder trabeculation obviates the need for bladder outlet procedures during augmentation cystoplasty in incontinent patients with neurogenic bladder. BJU Int 2008; 101: 223.

Botulinum Toxin A— When is a Unit Not a Unit? To the Editor: As a consultant pediatric surgeon, I have treated several children and young adults suffering from neuropathic bladder with intravesical injections of botulinum toxin A (BTX-A). Numerous studies have been published on the use of this product in various clinical settings in the adult and pediatric populations, many in The Journal of Urology®, which is a leading publication in the field.1–5 However, I wish to draw attention to a shortcoming in the way the use of this product is reported. There are 2 commercially available BTX-A preparations. However, these preparations are not bioequivalent and the unit designations are not interchangeable. Indeed, to this day there are no international units to measure the potency of botulinum toxin-A. The methods used for performing the potency assay are specific to each product. The most commonly available product, Botox®, is packaged as vials containing 100 Allergan units of toxin, with 1 unit corresponding to the calculated median intraperitoneal lethal dose in mice. The other form, Dysport®, is available in vials of 500 Speywood units, with 1 unit corresponding to the median intraperitoneal lethal dose in mice, although these must be different mice, since the accepted conversion rate is 3 Dysport units for 1 Botox unit. Although Dysport is not currently available in the United States, it is used by many European teams.

Reporting can lead to confusion since, even if most authors refer to the actual product used in the materials and methods section of the full text version of the article, this information does not appear in the abstract.1–5 Some authors remark in their conclusions on a specific efficacious dose of BTX-A without specifying the product to which they are referring.3 Others refer to international units, which to this day do not exist.4,5 The lack of equivalence between both measuring systems is not sufficiently specified or known, thus risking errors in prescription, especially with regard to the pediatric population. Until there is a homogenization of the unit of measure of BTX-A it is our duty to ensure that there is as much clarity as possible when referring to this potentially dangerous product. Respectfully, Luke Harper Division of Pediatric Surgery CHU Pellegrin Bordeaux, France 1. Giannantoni A, Porena M, Costantini E, Zucchi A, Mearini L and Mearini E: Botulinum A toxin intravesical injection in patients with painful bladder syndrome: 1-year followup. J Urol 2008; 179: 1031. 2. Neel KF, Soliman S, Salem M, Seida M, Al-Hazmi H and Khatab A: Botulinum-A toxin: solo treatment for neuropathic noncompliant bladder. J Urol 2007; 178: 2593. 3. Kuo HC: Comparison of effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin A for idiopathic detrusor overactivity. J Urol 2007; 178: 1359. 4. Radojicic ZI, Perovic SV and Milic NM: Is it reasonable to treat refractory voiding dysfunction in children with botulinum-A toxin? J Urol 2006; 176: 332. 5. Kajbafzadeh AM, Moosavi S, Tajik P, Arshadi H, Payabvash S, Salmasi AH et al: Intravesical injection of botulinum toxin type A: management of neuropathic bladder and bowel dysfunction in children with myelomeningocele. Urology 2006; 68: 1091.

Reply: I agree with Harper in the context of the responsible tone and intent of the letter. I believe this letter clearly indicates that botulinum toxin preparations between different providers are not bioequivalent or interchangeable. This point is clearly emphasized in the summary of product characteristics for all botulinum toxin products. This lack of interchangeability refers not only to dosing recommendations, but also to efficacy and safety data using any particular brand. Therefore, I believe caution needs to be applied when considering any form of dose conversion factor because it is more than just the dose—it is also the other aspects relating to penetration of the toxin at its target. Any form of dose conversion assumes similar levels of safety and efficacy across brands, which is clearly not proved at present. We are beholden as clinicians, considering the lack of randomized controlled data in this area, to consider the data for