Keywords

Why Endourological Techniques for Management of Pathologic Conditions of the Lower Urinary Tract in Children?

Urology has traditionally been an endoscopic specialty, being at the forefront of minimally invasive and diagnostic interventions based on this technology. With scientific advances and miniaturization of equipment, access devices initially designed for adults have been easier to transfer to the pediatric population. Indeed, it is this process that has allowed for easier (nontraumatic) entry through the meatus and urethra, avoiding subsequent problems, most notably iatrogenic trauma and stricture formation. The ultimate testament to this miniaturization process has been the commonplace use of transurethral resection of posterior urethral valves or incision of obstructing ureteroceles in neonates, considered by many the standard of care for the initial management of these conditions with the use of infant resectoscopes.

In many ways, endoscopic techniques represent one of the most common forms of “natural opening” surgery, gaining access to the lower urinary tract via the urethral meatus. Far from being solely employed as a diagnostic intervention (as often seen in older patients), access allows delivery of different substances directly into the bladder neck, trigone, or detrusor muscle, aided by a needle with standardized depth mark(s). As such, endourological access is a means of delivery, rather than a surgical technique per se; the challenge centers on performing the actual administration and the rationale for selecting such intervention over other options. These procedures are commonly shorter in duration and associated with quicker recovery, with the obvious advantage of not generating visible scars. Nevertheless, although appealing in its simplicity and lack of invasiveness, contrast with traditional (open) techniques often demonstrates lower efficacy and – due to their novelty – shorter follow-up.

The STING Revolution

With little doubt, pediatric urology grew as a subspecialty with the acceptance of vesicoureteral reflux as an important clinical entity, amenable to surgical correction in order to limit short- and long-term morbidity [1]. This popularization generated a “need” for surgical treatment, questioned by many due to the morbidity of the procedure, particularly for low grades of reflux in otherwise healthy children, thus fueling the role of nonsurgical and less-invasive surgical options. The widespread use of endoscopic injection has its origins on the landmark work by Puri and O’Donnell who pioneered the use of Teflon® as a bulking agent to manage this condition in a minimally invasive fashion [2]. The technique (so-called classic STING) involved a single submucosal injection at the 6 o’clock position of the ureteral meatus. Although initially met with skepticism and some resistance, a few decades later this delivery modality (with some modifications) has surpassed in popularity other surgical options in many parts of the world. Even though the employed bulking substance has changed, currently heavily favoring dextranomer/hyaluronic acid, the administration principles remain fundamentally unchanged. In addition, the attractiveness of lower surgical morbidity by taking advantage of natural entry points fueled enthusiasm for expanding the application to other conditions. It is probably fair to say that the contemporary success and enthusiasm for endoscopic injection largely rest on this pioneer work.

Basic Principles of Surgical Technique

The “art” of endoscopic treatment heavily weighs on the injection technique rather than access. Cystoscopy is a basic urological skill, and getting to the injection site adds little in terms of additional challenge, except for minor adjustments that are required when employing a straight working channel (angled or offset ocular) scope, as well as negotiating the urethra, of limited caliber and potentially more delicate than in adults. On occasion, entry options may be limited or favored to a catheterizable channel (i.e., Mitrofanoff or Monti-Yang), which needs to be negotiated as gently as possible, and drug delivery adjusted based on the limitations imposed by the different “view” obtained.

The injection technique itself has to be adapted to the indication for surgery and the substance to be delivered. For vesicoureteral reflux, most commonly treated by injection of dextranomer/hyaluronic acid, the compound is precisely placed in a submucosal plane – through one or two injection sites – at the level of the ureteral orifice and intramural ureter. Similarly, in selected cases, this substance can be delivered at the bladder neck/proximal urethra level to create resistance (or “controlled obstruction”), in an attempt to address stress urinary incontinence. In contrast, botulinum toxin is injected at multiple sites in order to cover the muscle mass targeted for temporary paralysis. The latter case is seemingly less impacted by a steep learning curve, yet requires skill avoiding limited visualization as the case progresses due to early injury of large submucosal vessels, as well as good spatial planning in order to evenly distribute the fixed predetermined dose of diluted botulinum toxin throughout the treatment area.

In the following paragraphs, we will address specific issues based on injection sites and pathology, attempting to create a clear distinction between the detrusor muscle, ureterovesical junction, and bladder neck/sphincter. In addition, the authors’ preference for endoscopic management is summarized in Tables 24.1, 24.2, and 24.3.

Table 24.1 Subureteric endoscopic injection with bulking agent for treatment of vesicoureteral reflux
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Table 24.2 Bladder neck injection with bulking agent for urinary incontinence
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Table 24.3 Bladder wall botulinum toxin injection for neuropathic dysfunction
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Specific Conditions Addressed by Endourological Injection in Children

Vesicoureteral Reflux

Contemporary knowledge on vesicoureteral reflux management is limited and filled with controversies, fuelled by limited data of modest quality [3]. Nevertheless, as previously mentioned, reflux management opened the way for endoscopic drug and substance delivery in pediatric urology. Although there has been a progressive transition based on concerns raised by different compounds (i.e., Teflon®, particle distal migration; collagen, poor long-term durability; and polydimethylsiloxane, difficulty injecting the substance), dextranomer/hyaluronic acid has gained wide acceptance and is currently one of the most commonly employed products in many parts of the world. Although at a slight cure rate disadvantage against the gold standard – ureteral reimplantation – success rates have been consistently favorable and high enough to sustain interest and demand for the procedure due to its less-invasive nature [4]. As experience has grown, so have the scope of indications and the severity of reflux approached with endoscopic injection. Indeed, it has been postulated that the rather benign risk profile and favorable effectiveness challenges the time-honored view of employing antibiotic prophylaxis as the mainstay initial strategy, thus creating a paradigm shift whereby minimally invasive endoscopic intervention is offered soon after diagnosis. Although debatable, the situation highlights the impact of disruptive technology in the management of a disease process [5].

Aside from grade of reflux and the presence of associated abnormalities (such as duplication anomalies, ureteroceles, previous reimplantation, and lower urinary tract dysfunction causing secondary reflux), experience and surgical technique appear to play an important role in successful reflux correction. Undoubtedly, there is an important learning curve. Accurate location and depth of the injection is paramount in bulking the ureter at the level of the orifice and intramural ureter, maximizing the probability of creating an anti-reflux mechanism (Fig. 24.1; see accompanying Video 24.1, Case 1). In addition, the introduction of the so-called double hydrodistention-implantation technique (HIT) – which entails two separate injection sites at the intramural ureter and at the interior aspect of the orifice – has translated into excellent results in some series, seemingly better than single injection STING technique [6]. Cure rates in excess of 90 % reported with this modification have even led many to question the need for routine voiding cystourethrogram in treated children, formerly a requisite in many centers due to the novelty of the intervention and the perceived inferior cure rate.

Fig. 24.1
figure 1

Double HIT technique for endoscopic correction of vesicoureteral reflux. Panel (a) shows the “first HIT,” deposited in the intramural aspect of the ureter, followed by injection at the 6 o’clock position of the ureteral orifice (b, classic STING technique), creating a “volcano” appearance, effectively raising the ureteral orifice (arrow)

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There are three possible causes of failure with endoscopic injections: bolus displacement, loss of volume over time, and extrusion. Following implantation, volume can decrease up to 20 % during the initial tissue response and loss of the injected vehicle molecule. Precise delivery and injection of larger volumes (generally at or above 1 cc, which is the arbitrary amount of dextranomer/hyaluronic acid present in the commercial formulation, Deflux®) helps minimize the occurrence of these scenarios, with an associated small – albeit not insignificant – risk of creating obstruction [7, 8]. As this rare outcome is difficult to predict and not always associated with symptoms, regular monitoring with ultrasound after implantation remains reasonable (Fig. 24.2). Importantly, patients with secondary reflux and underlying anatomical abnormalities may be at higher risk, thus should be considered a relative contraindication for endoscopic injection and trigger diligent postoperative monitoring if done.

Fig. 24.2
figure 2

Rare occurrence of obstruction following dextranomer/hyaluronic acid injection in a patient with vesicoureteral reflux. Panel (a) demonstrates severe hydronephrosis, with ureteral dilation down to the level of the implant (b). This problem was addressed by cystoscopically identifying the bulking agent mound (c) and advancing a ureteral stent under fluoroscopic guidance (d). The patient experiences resolution of the hydronephrosis following stent removal 6 weeks later

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Even with a negative cystogram, some children present with subsequent recurrent pyelonephritis, and a subset will experience recurrence of vesicoureteral reflux [9]. Although this can also be seen with more invasive procedures, the situation calls into question long-term cure in a growing child who has a bolus of fixed volume. Ultimately, the lack of long-term data should be taken into account when offering endoscopic injection for reflux, and due consideration should be paid to reevaluating with a cystogram in patients that develop pyelonephritis despite previous reflux resolution. Children found to have recurrent or persistent reflux after endoscopic injection may benefit from a second attempt at correction with this approach, being mindful that additional attempts appear to become increasingly futile, thus shifting the risk/benefit discussion towards alternative surgical interventions.

Incontinence Due to Bladder Neck/Sphincter Incompetence

In line with the enthusiasm for use of bulking agents in pediatric patients, and partly based on data from addressing the bladder neck employing similar agents in adults with incontinence, endoscopic interventions have been introduced for management of urinary leakage, particularly for children with neuropathic compromise or previous surgical reconstruction. The main patient populations targeted include children with spinal dysraphism and patients with bladder exstrophy. In addition, the scope has been broadened beyond loss of urine per urethra, also encompassing incontinence experienced through surgically created access channels. These include appendicovesicostomies (Mitrofanoff channel), reconfigured bowel channels (Monti-Yang), and antegrade continence enema accesses (MACE procedure).

The potential for benefit cannot be underestimated, as these children have often undergone major prior procedures or have important comorbidities that make minimally invasive options appealing. Unfortunately, modest to low success rates have been the norm, particularly following long-term follow-up [10]. Despite these less-than-favorable outcomes, many have proposed that there is little to lose by trying, being a reasonable “first step” before embarking on more invasive interventions. Clearly, this is dependent on many factors, including the underlying bladder dynamics, family and patient expectations, degree of incontinence, and where the leakage is coming from (urethra vs. surgically created channel or both). It is noteworthy that recurrence or worsening incontinence after an attempt at addressing the lower urinary tract outlet or failure to address the problem despite what appeared to be a straightforward uncomplicated intervention should prompt the surgeon to consider hostile bladder pressures and compliance as a potential culprit. In addition, the success of the injection can be adversely impacted by previous surgery to the surgical area (as scar tissue prevents the bulking agent from elevating the submucosal plane), degree of bladder neck incompetence, and the employed approach (transurethral vs. suprapubic access). In that regard, bladder neck reconstructions that generate scar tissue at the very same location where the injection is targeted are bound to make the attempt at bulking the area rather unrewarding. An exception to this rule is prior reconstruction that created a flap-valve mechanism (most notably the Pippi Salle bladder neck procedure), whereby – in the absence of a fistula – injection can be directed at the supple tissue present in the flap itself and provide a reasonable implant. In all cases, a widely patent and patulous bladder neck with effacement that extends into the proximal urethra (including the verumontanum in boys) provides little reassurance that enough resistance can be generated to provide continence. Therefore, assessment of this area on a cystogram and during diagnostic cystoscopy is of great value in planning ahead. Lastly, for reasonable candidates, due consideration should be given to deliver the bulking agent through a suprapubic access which avoids instrumentation at the same site of the injection and provides a better view of the bladder neck before and after deposition of the implant [11].

One of the main drawbacks from injection of a bulking agent in the course or entry point of a catheterizable channel [10, 12], or at the level of the bladder neck, is the tissue reaction that can be triggered. Remembering the reported success rates, which are commonly far from ideal and often close to 50 %, it is not unreasonable to consider what to do in case of failure and if this preliminary step is going to create problems in those children that fail. Anecdotally, bladder neck reconstructive interventions after injection have been considered to be more difficult, yet recent data challenges that notion and provides reassurance particularly with the most commonly employed agent, dextranomer/hyaluronic acid [13].

Neuropathic Detrusor Overactivity and Incontinence

It has been known for quite some time now that, in a subset of children, management with anticholinergics and clean intermittent catheterization is not going to render them dry and/or will be associated with progressive upper tract damage. Until recently, these children were considered to be good candidates for major reconstruction, often centered on increasing bladder capacity and improving compliance by anastomosis of a detubularized segment of bowel (i.e., augmentation cystoplasty). Although an effective way to deal with the problem at hand, the long-term complications and health concerns are neither minor nor inconsequential [14, 15].

Following experience with adults with neuropathic bladder, endoscopic injection of botulinum toxin has been carefully introduced in the pediatric arena. Currently, this novel strategy has been offered to children who are unable to tolerate anticholinergics (or experience important side effects with dose escalation) as well as those who continue to experience adverse outcomes related to neurogenic detrusor overactivity despite maximal medical therapy. Reported symptomatic and urodynamic improvement rates have been extremely favorable, and side effects are very rare [16]. Aside from patients who have a previously documented adverse reaction to botulinum toxin injection or with an unacceptable anesthetic risk, it is often a good strategy to consider before embarking on more aggressive surgical reconstruction (Fig. 24.3). In addition, injection can often help determine the role of bladder neck incompetence in the urinary incontinence picture. This “therapeutic challenge” can be quite informative, considering that children who continue to leak despite improvement in bladder urodynamic parameters following injection should be considered for concomitant bladder neck procedures, such as a bladder neck sling [17]. An important point when offering botulinum toxin injection is to ensure compliance with catheterization, as an effective detrusor neuromuscular blockade without effective regular emptying can have serious upper tract deleterious effects (Fig. 24.4).

Fig. 24.3
figure 3

Improvement in upper tract dilation in a child with neuropathic bladder and no evidence of secondary vesicoureteral reflux. Following injection, monitoring ultrasound showed a decrease in bilateral hydroureteronephrosis, which correlated with improved bladder dynamics (enhanced compliance, increase in bladder capacity, and absent detrusor overactivity during filling phase)

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Fig. 24.4
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Degree of hydronephrosis before (a) and after (b) botulinum toxin injection in a teenager that refused regular catheterization following the intervention. Notice dramatic increase in dilation (b), associated with doubling of serum creatinine, which rapidly improved after placement of an indwelling catheter (c)

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The procedure itself is rather simple (see accompanying Video 24.2, case 2). The most commonly employed substance, onabotulinum toxin A (Botox®, Allergan, Irvine, CA), is diluted in sterile normal saline at a concentration of 10 units/cc. Based on an empirical dosing scheme of 10 units/kg up to a maximum of 300 units, doses are injected throughout the bladder wall in an intra-detrusor/submucosal location. It is paramount to remember that botulinum toxin formulations are not comparable in terms of clinical effect and risk of side effects at equal doses, thus use must be based on data relevant to the particular toxin selected for use [18]. The effect of the medication is not permanent, and reinjections are the rule, often at intervals of ~6 months (twice a year). Concerns regarding problems with depth of injection or triggering vesicoureteral reflux if the trigone is injected have been unfounded [19], and thus far, no evidence for tachyphylaxis [20], development of neutralizing antibodies [21], or progressive fibrosis [22] from repeated injections has been consistently reported. The main drawbacks from this intervention are related to costs, demand on resources (operating room), and need for regular anesthetics in children and young adolescents. Indeed, as these patients get older (and particularly in those with a higher sensory level), injection through a flexible cystoscope in the clinic setting may help alleviate some of these concerns and improve efficiency.

Dysfunctional Elimination Syndrome and Detrusor Sphincter Dyssynergia

As a natural next step following the above mentioned experience with botulinum toxin, endoscopic injection has been expanded to the management of non-neuropathic conditions, most notable dysfunctional voiding and difficult to treat non-neurogenic detrusor overactivity. Often down the list in terms of treatment options [23], due to the need for anesthesia and the risk of worsening incontinence or need for catheterization, experience is limited and often anecdotal. The surgical technique is adapted to the source of the problem: bladder neck/sphincter area in children with evidence of true dysfunctional voiding (i.e., triggering pelvic floor/sphincter activity during micturition) and bladder wall in those with urodynamic evidence of significant detrusor overactivity despite optimal pharmacological therapy. Bladder wall administration mimics the technique described above, while the sphincter and bladder neck area are endoscopically injected at three or four quadrants, each injection delivering 25–33 % of the total amount desired to be given. The doses are often lower than for the neuropathic group (~2–4 units/kg), up to a maximum of 100 units for onabotulinum toxin A, and reinjections reserved for those that present with recurrent symptoms, often at longer intervals, or not required at all [24]. In addition, injections in children with predominant complaint of urgency may be theoretically better when delivered at the submucosal level, attempting to address the non-cholinergic aspect of botulinum toxin neurotransmitter blockade (See accompanying Video 24.2, case 2).

Concluding Remarks

There are some evident differences in goal and treatment philosophy with the abovementioned indications. Although all are “minimally invasive,” some aim at permanent deposit of substance to hopefully remain unchanged and undisplaced after tissue response and remodeling, while the other one is a means of local drug delivery for molecules too large to reach the target organ by mere instillation. Despite this, growing acceptance of endoscopic injection as a viable alternative to managing many lower urinary tract conditions clearly indicates that the future will include expanding strategies based on this technology. Some challenges remain, particularly in terms of more definitive or permanent improvement, higher success rates, and avoidance of need for a general anesthetic. This latter point is particularly worrisome, considering the need for further procedures in many children, due to emerging data raising neurotoxicity concerns in children exposed to anesthetic agents [25]. Ultimately, as with grapple with issues related to success rate and surgical morbidity, long-term monitoring coupled with research for better treatment options not dependent on surgical access to the lower urinary tract [26], as well as dose optimization based on age and underlying pathology, is certainly warranted.