Figure. The location of afferent nerves and their receptor subtypes. Aδ-fibers have been observed in the muscle layer of the bladder, while C-fibers are located in the smooth muscle, urothelial and suburothelial layers. Aδ-fibers transmit normal filling sensations and are activated by low-intensity stimuli. When the bladder is stretched to maximal capacity or in certain disease states, C-fibers, which are activated by high-intensity stimuli, are more likely to be activated. Transient receptor potential cation channel subfamily V (TRPV) channels on the urothelium are implicated in sensing changes that are, for the most part, not stretch-related. Activation of α1d adrenoreceptors expressed on the urothelium and smooth muscle might have a role in the response of patients with overactive bladder symptoms to nonselective α-blockers. Reprinted with permission from Franco, Nat Rev Urol. 13(9):520-532.¹⁴ ATP indicates adenosine triphosphate; EP, prostaglandin E2 receptor; ICC, interstitial cell of Cajal; TRKA, high-affinity nerve growth factor receptor; TRPA, transient receptor potential cation channel subfamily A; TRPM, transient receptor potential cation channel subfamily; M, muscarinic; NK, neurokinin; P2X, P2X purinoceptor; VGCC, voltage-gated calcium channel.

Since our first review of botulinum toxin for use in children in 2009¹ we have had a significant change in the landscape of pediatric urology with the approval of onabotulinum toxin A for the treatment of neurogenic detrusor overactivity in children^2,3 and neurogenic and nonneurogenic detrusor overactivity^4,5 in adults. These strides have solidified our knowledge base utilizing randomized trials to show efficacy in onabotulinum toxin for detrusor overactivity. We will concentrate on discussing what we do know regarding who should be treated, when they should be treated, and how much should be injected in the patient with neurogenic detrusor overactivity.

Who Is a Candidate?

The patient who is 5 years of age or older who is not tolerating anticholinergic therapy or is refractory to anticholinergic or beta3 agonist therapy is considered a candidate for injection with onabotulinum toxin A based on recent Food and Drug Administration (FDA) approvals. Some centers are looking to lower these numbers in an attempt to be proactive. It is our practice to obliterate all detrusor overactivity in our patients regardless of end filling pressures since the persistent detrusor overactivity over the long term can lead to detrusor hypertrophy, which in turn can lead to further overactivity or fibrosis. Failure to do so in some patients can lead to irreversible fibrosis, which may account for failure of injections in untreated patients, or in patients who have had “wait and see” (nonproactively treated) therapy. In a study by Pascali et al⁶ they report a marked decrease in fibrosis between untreated bladders vs those treated with onabotulinum toxin A injections. Similar studies in adults by several groups^7-10 indicate that fibrosis was decreased in injected bladders and there was lack of inflammation or edema in the tissues as well. With these findings in mind, we see the rationale for earlier intervention with onabotulinum toxin A in children. The data from the most recent publication by Franco et al³ indicate that results are effective long-term. A patient who is refractory to botulinum toxin A could be indicative of ongoing tethering and not just failure of the botulinum toxin A due to tachyphylaxis or antibodies (both unlikely).

When Do You Treat?

At the present time, when to intervene in the patient with neurogenic detrusor overactivity with onabotulinum toxin A is not well defined. The guidelines put forth by the European Society of Pediatric Urology and International Children’s Continence Society call for proactive management of neurogenic patients. This calls for the early use of anticholinergics and, if need be, beta3 agonists if the patient is old enough to use these medications. If the patient can’t tolerate anticholinergics and a beta3 agonist is not an option, or if the patient is on both medications and contractions or pressures persist at high levels, then this patient becomes a candidate for onabotulinum toxin A injections. In this scenario it may be reasonable to consider the injection of a patient who is younger than the FDA-approved age if the only option is augmentation cystoplasty or vesicostomy. After the first injection it is advisable to obtain a urodynamic study within the 1-2 months to verify that there has been a positive result with the injection; this is especially important in nonverbal patients, in patients where dryness is not fully achievable, or where pressures were high without leakage. Once confirmation is obtained by urodynamics and the known safe bladder pressure is determined we can begin to use first morning cathed volume as a postinjection proxy for efficacy of the injection. This can be used as a benchmark to confirm when the injection is wearing off and to consider reinjection. Having patients track weekly first morning cathed volumes is a strategy that we employ to alert us of the need to reinject. After 2-3 injections many patients will be able to tell you when they need reinjection.

How Much to Inject?

The FDA-approved maximum dose for injection for neurogenic patients is 6 units/kg, which will translate to 200 units of onabotulinum toxin A in a ≥33-kg patient. In a systematic review by Hascoet et al¹¹ doses varied from 5 units to 10-12 units/kg with the maximum dose being 300 units. Some urologists are routinely utilizing 300 units, which was a treatment arm dose in the adult neurogenic study based on the fact that there were some data to support that the higher dose lasted longer. This has not been verified in any other studies but many veteran onabotulinum toxin A injectors continue to use this dose. There are some who are performing injections in the submucosa instead of in the detrusor. The rationale for this is that the space between the mucosa and lamina propia has an abundance of c fibers which have ach, trp, and purinergic receptors known to be affected by onabotulinum toxin A. There continue to be more data that support the theory that onabotulinum toxin A works by altering sensory pathways and not solely by a motor mechanism.^12,13

How Much Is Too Much?

When to decide that continued injections are not providing adequate efficacy or that some other procedure is in order to help the patient is something that in some cases comes down to a personal choice by the patient and in others is necessary because the well-being of the patient is in danger. The scenario of personal choice is exemplified by the patient who may have had adequate capacity when younger with onabotulinum toxin A but a subsequent growth spurt has now rendered the urinary output too high to feasibly remain dry at a diminished bladder volume making it socially and logistically impossible for the patient to cath as often as they need. An augmentation procedure would be an option to expand capacity, to make it easier for the patient to remain socially dry and improve their quality of life.

The scenario of endangered well-being is typified by the patient with high bladder pressures even when dry who is routinely getting bladder infections due to the high pressures because they do not cath at a reasonable volume and exceed their safe pressures at the higher volumes that have been achieved with onabotulinum toxin A. Onabotulinum toxin A injections become a double-edged sword in these patients because we can take them to volumes of 300-400 cc where if they cath they are in a safe zone, but once they exceed these volumes pressures rise precipitously and the patient puts themselves in danger of upper tract damage. This is something that one needs to be especially cognizant of in adolescents. The scenario where pressures rise or volumes drop precipitously with or without lower extremity changes should immediately trigger an investigation or referral for tethered cord.