Curr Urol Rep (2014) 15:426 DOI 10.1007/s11934-014-0426-1
PEDIATRIC UROLOGY (M CASTELLAN AND R GOSALBEZ, SECTION EDITORS)
Botulinum Toxin A’s Expanding Role in the Management of Pediatric Lower Urinary Tract Dysfunction Tarek Hassouna & Joseph M. Gleason & Armando J. Lorenzo
# Springer Science+Business Media New York 2014
Abstract Botulinum toxin A’s (Onabotulinum toxin A – OnabotA) utility in the pediatric population is evolving, and is currently being used in the treatment of lower urinary tract dysfunction, both in children with neuropathic compromise, and non-neuropathic overactive bladders. The results of having OnabotA injected directly into the bladder wall cystoscopically are: a more compliant bladder with reduced bladder pressure, avoiding renal compromise and upper urinary tract deterioration; increased bladder capacity; and the ability for children to reach an improved degree of urinary continence through a minimally invasive approach. A growing body of research in patients with either neuropathic bladders or overactive bladders (OAB), have shown excellent results when looking at urodynamic parameters, patient satisfaction and improvement in symptomatology. One of the main indications for the use of OnabotA in children with neuropathic bladders is to delay or avoid the need for augmentation cystoplasty. By achieving the aforementioned results, some children can delay or avoid this more invasive and permanent procedure. Prospective studies are needed to answer questions regarding optimal dosage and frequency, ideal patient selection criteria and assessment of long-term outcomes and complications. This article is part of the Topical Collection on Pediatric Urology T. Hassouna : J. M. Gleason : A. J. Lorenzo (*) Division of Paediatric Urology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada e-mail: [email protected] T. Hassouna e-mail: [email protected] J. M. Gleason e-mail: [email protected] A. J. Lorenzo Department of Surgery, University of Toronto, Toronto, ON, Canada
Keywords Onabotulinum toxin A . Pediatrics . Lower urinary tract dysfunction . Bladder function Abbreviations ACT OnabotA CIC OAB IC SP DLPP LD50 IDI UDS Ab RTX DESD
Anticholinergic therapy Onabotulinum toxin A Clean intermittent catheterization Overactive bladder Interstitial cystitis Substance P Detrusor leak point pressure Lethal dose in 50 % of subjects Intra-detrusor injection(s) Urodynamic study(ies) Antibody Resiniferatoxin Detrusor external sphincter dyssynergia
What is Botulinum Toxin OnabotA is a two-chain polypeptide neurotoxin protein produced by the bacteria Clostridium botulinum. With a median lethal intravenous dose of 1.3–2.1 ng/kg, systemic administration causes debilitating muscular paralysis including the muscles of respiration, thereby impeding gas exchange leading to coma and death [3]. Disruptions in the autonomic nervous system are also common where symptoms such as dry mouth, postural hypotension, and constipation can occur [34]. There are eight subtypes of botulinum neurotoxins: subtypes A, B, C (C1, C2), D, E, F, and G. Subtypes A and B are used clinically to treat spastic muscular disorders as well as for cosmetic purposes. Subtype A is marketed as Botox™, Dysport™, and Xeomin™ while subtype B is marketed as
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Myobloc™ (Table 1). While these forms are used for medical and cosmetic purposes, there are bioequivalency differences that prevent doses from being interchangeable. Both Botox™ and Dysport™ have protective proteins clustered around the toxin, which impact diffusion and migration, while Xeomin™ lacks some of these protective proteins, providing a different theoretical spread after local injection. Although clinical applications are similar, the biological and pharmacological differences between commercially available products should be kept in mind and considered when changing or introducing a new compound into clinical use. For the purposes of this review, we will focus on the most commonly employed product in pediatrics, subtype A.
Mechanism of Action Acetylcholine (Ach) is a neurotransmitter of the parasympathetic and somatic nervous systems that binds to Ach receptors on skeletal and smooth muscle fibers. This biochemical interaction results in opening of ligand-gated sodium channels in the cell membrane, whereupon sodium ions enter the muscle cell and initiate a cascade of events to produce a muscle contraction. OnabotA contains a 50-kDa light chain protease enzyme that blocks a fusion protein (SNAP-25) at the neuromuscular junction, preventing neurotransmitter vesicles from anchoring to the pre-synaptic membrane, thus, effectively preventing release into the junction [7]. The toxin, thus, interferes with nerve impulses causing flaccid, but ultimately reversible, paralysis of the target muscle. In contrast, subtype B cleaves the synaptic Vesicle Associated Membrane Protein (VAMP), which is a component of the protein complex responsible for docking and fusion of the synaptic vesicle to the pre-synaptic membrane [7]. At the motor level, the mechanism of action of OnabotA has been clearly defined. However, blocking efferent Ach signal transduction does not fully explain the effect on the bladder at the sensory level. This refers to the urgency and pain symptoms in patients with OAB, chronic prostate pain and interstitial cystitis (IC). Molecular research has been done to determine which receptors and neurotransmitters are involved. Early studies have shown that in women with untreated IC, Substance P (SP) containing nerve fibers were present
in submucosa (not detrusor) and were frequently seen in juxtaposition to mast cells [20], suggesting that an increased number of SP-positive nerve fibers may be present in IC patients. Later studies demonstrated that in bladder biopsies of adult patients with bladder pain syndrome, prolonged exposure of the neurokinin 1 receptor (NKR1) to SP caused a decrease of NK1R mRNA levels, which leads to increased urothelial permeability and increased nerve sensitization [25]. Some have postulated that OnabotA intra-detrusor injections (IDI) affect bladder afferent pathways, inducing prominent decreases in expression of sensory receptors in suburothelial nerves [2]. Further evidence from Schulte-Baukloh demonstrated that in bladder dome resections of children with neuropathic detrusor overactivity, OnabotA IDI leads to significant reductions in muscular M2 and M3 receptors, and sensory P2X2 and P2X3 receptors [28]. There are P2X2 and P2X3 ATP-dependent receptors that are upregulated in patients with OAB. Additionally, a substantial upregulation of purinergic P2X1 and P2X2 receptors were found on detrusor smooth muscle in pediatric patients, who had untreated bladder pain syndromes. These findings provide increasing evidence that purinergic mechanisms may be involved in sensory signaling of pain syndromes of the bladder. Overall, cellular and molecular evidence suggests that both the receptor and neurotransmitter are involved in the overall mechanism of action of OnabotA.
Clinical Indications Before the introduction of OnabotA, many patients who failed anticholinergic therapy (ACT) for neuropathic bladders underwent elective bladder augmentation to increase bladder capacity and avoid dangerously high bladder pressures. Longterm complications arise including recurrent stone formation, frequent urinary tract infections, urinary incontinence, metabolic derangements, excessive mucous production (requiring frequent irrigations) and bladder rupture. During the last 15 years, different commercial preparations of botulinum toxins have been approved by the Food and Drug Administration (FDA) for adult use, and have gained popularity in pediatric urology, triggered by evidence from clinical studies. It has been used to treat both poor compliance and detrusor
Table 1 Various formulations and trademark names of botulinum toxins Trade name and Company
Subtype
FDA Approval
Specific Properties
Botox™ (Allergan) Dysport™ (Ipsen) Xeomin™ (Merz) Myobloc™ (Solstice)
A A A B
1989 2009 2010 2000 (for cervical dystonia)
Toxin with full complement of protective proteins that weigh approx. 900 kD Toxin with mixture of 500 kD and 300 kD protective proteins None None
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overactivity in neurogenic bladders and irritative symptoms in non-neurogenic bladders [9, 12, 24, 27]. Less commonly, it has also been used to mitigate detrusor external sphincteric dyssynergia (DESD), to reduce outlet resistance and improve bladder pressures [18, 22•, 23]. The main objectives in managing pediatric patients with neuropathic bladders are to avoid renal compromise and reach a social urinary continence through a minimally invasive approach. Common anticholinergic medications used currently include oxybutynin, which has non-specific anticholinergic effects, and tolterodine, which has relative detrusor selectivity over salivary glands, reducing bothersome adverse side effects including dry mouth, blurred vision, and constipation [37]. For those who fail ACT or cannot tolerate these adverse effects, OnabotA has been used as part of an escalated treatment regimen. For those on clean intermittent catheterization (CIC) protocols, higher doses can be safely used without concerns for acute urinary retention in order to improve efficacy. No serious adverse effects have been reported except for transient leg weakness [36], which is uncommon. Some patients with non-neuropathic detrusor overactivity may develop acute urinary retention with higher doses. Although this is also uncommon [31], it introduces a potential risk that many patients and families are not willing to accept due to the need to introduce catheterizations in a child who often has a sensate urethra. Otherwise, OnabotA has provided a safe alternative to invasive surgical therapies, and can be offered to patients and their families. Additionally, the transient nature of OnabotA has allowed the option of discontinuation if results are not satisfactory or an alternative treatment is more suitable.
Patient Selection All candidates for OnabotA must undergo a detailed assessment of their underlying disease process, current and past treatments employed, degree of incontinence, history of urinary tract infections and recent hospitalizations. Anticholinergics, considered by many to be first line therapy, must have failed or present intolerable side effects. Currently, our practice is to consider alternative forms of administration for patients with side effects, particularly the transdermal delivery systems, which avoid or ameliorate many of the anticholinergic side effects by decreasing the impact of hepatic first-pass metabolism. Appropriate laboratory investigations, including urinalysis and urine culture should be completed, particularly to rule out infection as a cause of non-neuropathic symptoms. Additionally, patients should ideally have a baseline urodynamic evaluation, which includes the volume at which uninhibited detrusor contractions appear and their amplitude, maximum detrusor pressure during voiding, detrusor leak point pressures (DLPP), detrusor compliance, and maximum bladder capacity. Patients with neuropathic bladders ideally
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suited for a trial of treatment with OnabotA should be wet more than 50 % of the time between catheterizations, have reduced bladder capacity and compliance, high detrusor pressures, and/or DLPP exceeding 40 cm H2O despite maximal medical therapy. Obviously, lower levels of incontinence or less dramatic results in urodynamic parameters can be considered as acceptable for a trial. For patients with non-neuropathic bladders, Schurch et al., designed the international continence society (ICS) scoring system to objectively assess a patient's degree of incontinence [29]. The decision to use OnabotA in this population is purely to alleviate symptoms, and potential benefits must outweigh surgical and anesthetic risks, as upper urinary tract dysfunction is rarely seen. Urodynamic evaluation can be selectively used to supplement subjective data in this particular population. The important exception to this is the rare patient that presents with a “non-neurogenic neurogenic bladder”, as these children can have serious upper tract involvement and persistent incontinence.
Method of Administration in Children OnabotA is injected under flexible or rigid cystoscopic guidance (Fig. 1) in the detrusor muscle, typically distributed at ten to thirty sites. In adults, it has been shown that trigonal injection did not trigger an increase in the incidence of vesico-ureteric reflux (VUR), despite theoretical concerns to the contrary [14, 17]. However, there is paucity of data regarding the impact of botulinum toxin and the risk of developing de novo VUR following treatment in children. Botox™ is commercially available in 100 unit vials, and is commonly diluted to 10 units/mL with normal saline. In children, injection is typically performed under general anesthesia after administration of intravenous antibiotic prophylaxis, but can be done in the office with mild oral sedation in a select group of cooperative pediatric patients via flexible or rigid cystoscopy. The current standard is to perform injections as an outpatient or office procedure with immediate resumption of CIC in patients previously performing this. In those with nonneuropathic compromise and/or spontaneously voiding, it is crucial to assess for new symptoms (suggestive of inability to empty the bladder) and monitor post-void residuals soon after the first set of injections. It is clear that the need for anesthesia and cystoscopy is one of the main factors that impacts cost and acceptance by patients and families. Thus, alternative methods of delivery would be of great interest. Even though some preliminary evidence suggests that electromotive administration is feasible, [11], the large size of the molecule and needed depth of penetration challenge how effective this approach is. Nevertheless, with more supportive evidence, this may become an attractive alternative and increase botulinum toxin utilization in pediatric patients.
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Fig. 1 Intra-detrusor injections in 10-30 sites throughout the bladder wall, each with 10 units of toxin (Botox™) in 1 mL normal saline
Dosage and Duration of Action Pediatric use of OnabotA was first reported in 2002 for children with neuropathic bladders [26••]. Since then, additional studies have reported improvements in urodynamic parameters, namely the number of uninhibited detrusor contractions, maximal detrusor pressure, bladder capacity, and compliance post-injection [1, 12, 15, 24, 27]. However, optimal dosage is still unclear, and it is important to stress the lack of bioequivalency, thus, equally effective doses vary depending on commercially available types and preparations, which are not interchangeable with one another. Studies with Botox™ have commonly experimented with single dosages of 10-12 units/kg up to a total of 300 – 360 units, depending on patient weight. Although the maximum dosing was originally described for adult patients, it appears to be safe in children as well, but the maximum safe dose remains unknown. For example, one study reported administering a total of 500 units Dysport™ in children with DESD [22•] and neuropathic bladder. The rationale for this was since more muscle tissue exists in striated muscle and neuropathic bladders, it is expected that a higher total dose would be needed to block the neuromuscular junctions. However, caution in dosing is recommended, as the human lethal dose in 50 % of patients (LD50) is estimated to be 3000 units for a 70 kg adult [30], and an exceedingly high dose in children could be potentially lethal. Overall, dosage studies are needed to optimize the effects and side effects of OnabotA. Duration of induced muscular paralysis and efficacy can vary widely between patients and between indications for treatment. Patient specific factors, such as associated bladder wall fibrosis, and additional treatment regimens implemented
simultaneously (biofeedback and bladder training) can affect the perceived duration of effect. Riccabona et al., demonstrated that IDI of OnabotA could last up to 10.5 months with clinical improvement [24]. Other groups with similar study parameters have shown a mean duration of action of up to six months with sustained clinical improvement [12, 27]. In a study of non-neuropathic detrusor overactivity refractory to less invasive urotherapy, it was reported that OnabotA lasted up to 12 months with patients experiencing resolution of urgency and dryness during the day [9]. Therefore, neurologic compromise appears to play a key role in the duration of action of OnabotA. It should also be noted that the presenting symptoms and goals of treatment with OnabotA differ between patients with and without neuropathic involvement (Table 2). In neuropathic bladders, patients often experience higher than normal detrusor pressure and decreased compliance compared to those without who tend to experience urgency, frequency and incontinence. As previously mentioned, Hinman syndrome (so called “non-neurogenic neurogenic bladder”) can often mimic findings and have a presentation consistent with a neuropathic insult. However, no studies to date of OnabotA on the Hinman syndrome have been published to prove this point. Therefore, the goals of treatment should aim to increase bladder capacity and decrease pressures in neuropathic bladders, but provide symptomatic relief those without neurological compromise. Studies addressing external sphincteric injection have demonstrated a 6-month mean duration of action with clinical improvement in post-void residuals and EMG sphincteric activity [18, 22•, 23]. Differences in duration of action could be attributed to faster re-innervation in striated muscle due to more axonal sprouting [10]. Nonetheless, while the effect of
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Table 2 The use of OnabotA injections in neurogenic and non-neurogenic bladders
Symptoms and results of investigations
Primary objective of OnabotA
Concern for urinary retention Dosage
Neurogenic
Non-Neurogenic
Increased bladder pressure Decreased compliance Decreased capacity Incontinence Paralyze bladder muscle increasing volume, decreasing pressure and preventing upper tract deterioration (DLPP70 %. We have not noted any complications to treatment thus far, and follow-up in this group is more than four years, on average. Although time will tell if augmentation cystoplasty is avoided (and not just delayed), with reinjection every six months or so, the majority of patients have avoided more invasive surgical options with known important side effects and morbidity.
Curr Urol Rep (2014) 15:426 Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Conclusion OnabotA is becoming an increasingly popular and wellstudied therapy in the treatment of lower urinary tract dysfunction in children. It can be helpful in the prevention of upper urinary tract deterioration and renal compromise, delaying or preventing the need for bladder augmentation and improvement of benign lower urinary tract symptoms and incontinence. Optimal dosing has yet to be definitively determined, as has the preferred frequency of treatment, and further research into these areas is needed. While other standard therapies are less invasive and carry a level of efficacy in the treatment of this patient population, IDI of OnabotA can be useful as an alternative to more invasive approaches, should first line therapies fail.
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Compliance with Ethics Guidelines
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Conflict of Interest Dr. Tarek Hassouna and Dr. Joseph M. Gleason each declare no potential conflicts of interest. Dr. Armando J. Lorenzo is a consultant for and has received travel/accommodations expenses covered or reimbursed by Allergan.
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PEDIATRIC UROLOGY (M CASTELLAN AND R GOSALBEZ, SECTION EDITORS)
Botulinum Toxin A’s Expanding Role in the Management of Pediatric Lower Urinary Tract Dysfunction Tarek Hassouna & Joseph M. Gleason & Armando J. Lorenzo
# Springer Science+Business Media New York 2014
Abstract Botulinum toxin A’s (Onabotulinum toxin A – OnabotA) utility in the pediatric population is evolving, and is currently being used in the treatment of lower urinary tract dysfunction, both in children with neuropathic compromise, and non-neuropathic overactive bladders. The results of having OnabotA injected directly into the bladder wall cystoscopically are: a more compliant bladder with reduced bladder pressure, avoiding renal compromise and upper urinary tract deterioration; increased bladder capacity; and the ability for children to reach an improved degree of urinary continence through a minimally invasive approach. A growing body of research in patients with either neuropathic bladders or overactive bladders (OAB), have shown excellent results when looking at urodynamic parameters, patient satisfaction and improvement in symptomatology. One of the main indications for the use of OnabotA in children with neuropathic bladders is to delay or avoid the need for augmentation cystoplasty. By achieving the aforementioned results, some children can delay or avoid this more invasive and permanent procedure. Prospective studies are needed to answer questions regarding optimal dosage and frequency, ideal patient selection criteria and assessment of long-term outcomes and complications. This article is part of the Topical Collection on Pediatric Urology T. Hassouna : J. M. Gleason : A. J. Lorenzo (*) Division of Paediatric Urology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada e-mail: [email protected] T. Hassouna e-mail: [email protected] J. M. Gleason e-mail: [email protected] A. J. Lorenzo Department of Surgery, University of Toronto, Toronto, ON, Canada
Keywords Onabotulinum toxin A . Pediatrics . Lower urinary tract dysfunction . Bladder function Abbreviations ACT OnabotA CIC OAB IC SP DLPP LD50 IDI UDS Ab RTX DESD
Anticholinergic therapy Onabotulinum toxin A Clean intermittent catheterization Overactive bladder Interstitial cystitis Substance P Detrusor leak point pressure Lethal dose in 50 % of subjects Intra-detrusor injection(s) Urodynamic study(ies) Antibody Resiniferatoxin Detrusor external sphincter dyssynergia
What is Botulinum Toxin OnabotA is a two-chain polypeptide neurotoxin protein produced by the bacteria Clostridium botulinum. With a median lethal intravenous dose of 1.3–2.1 ng/kg, systemic administration causes debilitating muscular paralysis including the muscles of respiration, thereby impeding gas exchange leading to coma and death [3]. Disruptions in the autonomic nervous system are also common where symptoms such as dry mouth, postural hypotension, and constipation can occur [34]. There are eight subtypes of botulinum neurotoxins: subtypes A, B, C (C1, C2), D, E, F, and G. Subtypes A and B are used clinically to treat spastic muscular disorders as well as for cosmetic purposes. Subtype A is marketed as Botox™, Dysport™, and Xeomin™ while subtype B is marketed as
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Myobloc™ (Table 1). While these forms are used for medical and cosmetic purposes, there are bioequivalency differences that prevent doses from being interchangeable. Both Botox™ and Dysport™ have protective proteins clustered around the toxin, which impact diffusion and migration, while Xeomin™ lacks some of these protective proteins, providing a different theoretical spread after local injection. Although clinical applications are similar, the biological and pharmacological differences between commercially available products should be kept in mind and considered when changing or introducing a new compound into clinical use. For the purposes of this review, we will focus on the most commonly employed product in pediatrics, subtype A.
Mechanism of Action Acetylcholine (Ach) is a neurotransmitter of the parasympathetic and somatic nervous systems that binds to Ach receptors on skeletal and smooth muscle fibers. This biochemical interaction results in opening of ligand-gated sodium channels in the cell membrane, whereupon sodium ions enter the muscle cell and initiate a cascade of events to produce a muscle contraction. OnabotA contains a 50-kDa light chain protease enzyme that blocks a fusion protein (SNAP-25) at the neuromuscular junction, preventing neurotransmitter vesicles from anchoring to the pre-synaptic membrane, thus, effectively preventing release into the junction [7]. The toxin, thus, interferes with nerve impulses causing flaccid, but ultimately reversible, paralysis of the target muscle. In contrast, subtype B cleaves the synaptic Vesicle Associated Membrane Protein (VAMP), which is a component of the protein complex responsible for docking and fusion of the synaptic vesicle to the pre-synaptic membrane [7]. At the motor level, the mechanism of action of OnabotA has been clearly defined. However, blocking efferent Ach signal transduction does not fully explain the effect on the bladder at the sensory level. This refers to the urgency and pain symptoms in patients with OAB, chronic prostate pain and interstitial cystitis (IC). Molecular research has been done to determine which receptors and neurotransmitters are involved. Early studies have shown that in women with untreated IC, Substance P (SP) containing nerve fibers were present
in submucosa (not detrusor) and were frequently seen in juxtaposition to mast cells [20], suggesting that an increased number of SP-positive nerve fibers may be present in IC patients. Later studies demonstrated that in bladder biopsies of adult patients with bladder pain syndrome, prolonged exposure of the neurokinin 1 receptor (NKR1) to SP caused a decrease of NK1R mRNA levels, which leads to increased urothelial permeability and increased nerve sensitization [25]. Some have postulated that OnabotA intra-detrusor injections (IDI) affect bladder afferent pathways, inducing prominent decreases in expression of sensory receptors in suburothelial nerves [2]. Further evidence from Schulte-Baukloh demonstrated that in bladder dome resections of children with neuropathic detrusor overactivity, OnabotA IDI leads to significant reductions in muscular M2 and M3 receptors, and sensory P2X2 and P2X3 receptors [28]. There are P2X2 and P2X3 ATP-dependent receptors that are upregulated in patients with OAB. Additionally, a substantial upregulation of purinergic P2X1 and P2X2 receptors were found on detrusor smooth muscle in pediatric patients, who had untreated bladder pain syndromes. These findings provide increasing evidence that purinergic mechanisms may be involved in sensory signaling of pain syndromes of the bladder. Overall, cellular and molecular evidence suggests that both the receptor and neurotransmitter are involved in the overall mechanism of action of OnabotA.
Clinical Indications Before the introduction of OnabotA, many patients who failed anticholinergic therapy (ACT) for neuropathic bladders underwent elective bladder augmentation to increase bladder capacity and avoid dangerously high bladder pressures. Longterm complications arise including recurrent stone formation, frequent urinary tract infections, urinary incontinence, metabolic derangements, excessive mucous production (requiring frequent irrigations) and bladder rupture. During the last 15 years, different commercial preparations of botulinum toxins have been approved by the Food and Drug Administration (FDA) for adult use, and have gained popularity in pediatric urology, triggered by evidence from clinical studies. It has been used to treat both poor compliance and detrusor
Table 1 Various formulations and trademark names of botulinum toxins Trade name and Company
Subtype
FDA Approval
Specific Properties
Botox™ (Allergan) Dysport™ (Ipsen) Xeomin™ (Merz) Myobloc™ (Solstice)
A A A B
1989 2009 2010 2000 (for cervical dystonia)
Toxin with full complement of protective proteins that weigh approx. 900 kD Toxin with mixture of 500 kD and 300 kD protective proteins None None
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overactivity in neurogenic bladders and irritative symptoms in non-neurogenic bladders [9, 12, 24, 27]. Less commonly, it has also been used to mitigate detrusor external sphincteric dyssynergia (DESD), to reduce outlet resistance and improve bladder pressures [18, 22•, 23]. The main objectives in managing pediatric patients with neuropathic bladders are to avoid renal compromise and reach a social urinary continence through a minimally invasive approach. Common anticholinergic medications used currently include oxybutynin, which has non-specific anticholinergic effects, and tolterodine, which has relative detrusor selectivity over salivary glands, reducing bothersome adverse side effects including dry mouth, blurred vision, and constipation [37]. For those who fail ACT or cannot tolerate these adverse effects, OnabotA has been used as part of an escalated treatment regimen. For those on clean intermittent catheterization (CIC) protocols, higher doses can be safely used without concerns for acute urinary retention in order to improve efficacy. No serious adverse effects have been reported except for transient leg weakness [36], which is uncommon. Some patients with non-neuropathic detrusor overactivity may develop acute urinary retention with higher doses. Although this is also uncommon [31], it introduces a potential risk that many patients and families are not willing to accept due to the need to introduce catheterizations in a child who often has a sensate urethra. Otherwise, OnabotA has provided a safe alternative to invasive surgical therapies, and can be offered to patients and their families. Additionally, the transient nature of OnabotA has allowed the option of discontinuation if results are not satisfactory or an alternative treatment is more suitable.
Patient Selection All candidates for OnabotA must undergo a detailed assessment of their underlying disease process, current and past treatments employed, degree of incontinence, history of urinary tract infections and recent hospitalizations. Anticholinergics, considered by many to be first line therapy, must have failed or present intolerable side effects. Currently, our practice is to consider alternative forms of administration for patients with side effects, particularly the transdermal delivery systems, which avoid or ameliorate many of the anticholinergic side effects by decreasing the impact of hepatic first-pass metabolism. Appropriate laboratory investigations, including urinalysis and urine culture should be completed, particularly to rule out infection as a cause of non-neuropathic symptoms. Additionally, patients should ideally have a baseline urodynamic evaluation, which includes the volume at which uninhibited detrusor contractions appear and their amplitude, maximum detrusor pressure during voiding, detrusor leak point pressures (DLPP), detrusor compliance, and maximum bladder capacity. Patients with neuropathic bladders ideally
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suited for a trial of treatment with OnabotA should be wet more than 50 % of the time between catheterizations, have reduced bladder capacity and compliance, high detrusor pressures, and/or DLPP exceeding 40 cm H2O despite maximal medical therapy. Obviously, lower levels of incontinence or less dramatic results in urodynamic parameters can be considered as acceptable for a trial. For patients with non-neuropathic bladders, Schurch et al., designed the international continence society (ICS) scoring system to objectively assess a patient's degree of incontinence [29]. The decision to use OnabotA in this population is purely to alleviate symptoms, and potential benefits must outweigh surgical and anesthetic risks, as upper urinary tract dysfunction is rarely seen. Urodynamic evaluation can be selectively used to supplement subjective data in this particular population. The important exception to this is the rare patient that presents with a “non-neurogenic neurogenic bladder”, as these children can have serious upper tract involvement and persistent incontinence.
Method of Administration in Children OnabotA is injected under flexible or rigid cystoscopic guidance (Fig. 1) in the detrusor muscle, typically distributed at ten to thirty sites. In adults, it has been shown that trigonal injection did not trigger an increase in the incidence of vesico-ureteric reflux (VUR), despite theoretical concerns to the contrary [14, 17]. However, there is paucity of data regarding the impact of botulinum toxin and the risk of developing de novo VUR following treatment in children. Botox™ is commercially available in 100 unit vials, and is commonly diluted to 10 units/mL with normal saline. In children, injection is typically performed under general anesthesia after administration of intravenous antibiotic prophylaxis, but can be done in the office with mild oral sedation in a select group of cooperative pediatric patients via flexible or rigid cystoscopy. The current standard is to perform injections as an outpatient or office procedure with immediate resumption of CIC in patients previously performing this. In those with nonneuropathic compromise and/or spontaneously voiding, it is crucial to assess for new symptoms (suggestive of inability to empty the bladder) and monitor post-void residuals soon after the first set of injections. It is clear that the need for anesthesia and cystoscopy is one of the main factors that impacts cost and acceptance by patients and families. Thus, alternative methods of delivery would be of great interest. Even though some preliminary evidence suggests that electromotive administration is feasible, [11], the large size of the molecule and needed depth of penetration challenge how effective this approach is. Nevertheless, with more supportive evidence, this may become an attractive alternative and increase botulinum toxin utilization in pediatric patients.
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Fig. 1 Intra-detrusor injections in 10-30 sites throughout the bladder wall, each with 10 units of toxin (Botox™) in 1 mL normal saline
Dosage and Duration of Action Pediatric use of OnabotA was first reported in 2002 for children with neuropathic bladders [26••]. Since then, additional studies have reported improvements in urodynamic parameters, namely the number of uninhibited detrusor contractions, maximal detrusor pressure, bladder capacity, and compliance post-injection [1, 12, 15, 24, 27]. However, optimal dosage is still unclear, and it is important to stress the lack of bioequivalency, thus, equally effective doses vary depending on commercially available types and preparations, which are not interchangeable with one another. Studies with Botox™ have commonly experimented with single dosages of 10-12 units/kg up to a total of 300 – 360 units, depending on patient weight. Although the maximum dosing was originally described for adult patients, it appears to be safe in children as well, but the maximum safe dose remains unknown. For example, one study reported administering a total of 500 units Dysport™ in children with DESD [22•] and neuropathic bladder. The rationale for this was since more muscle tissue exists in striated muscle and neuropathic bladders, it is expected that a higher total dose would be needed to block the neuromuscular junctions. However, caution in dosing is recommended, as the human lethal dose in 50 % of patients (LD50) is estimated to be 3000 units for a 70 kg adult [30], and an exceedingly high dose in children could be potentially lethal. Overall, dosage studies are needed to optimize the effects and side effects of OnabotA. Duration of induced muscular paralysis and efficacy can vary widely between patients and between indications for treatment. Patient specific factors, such as associated bladder wall fibrosis, and additional treatment regimens implemented
simultaneously (biofeedback and bladder training) can affect the perceived duration of effect. Riccabona et al., demonstrated that IDI of OnabotA could last up to 10.5 months with clinical improvement [24]. Other groups with similar study parameters have shown a mean duration of action of up to six months with sustained clinical improvement [12, 27]. In a study of non-neuropathic detrusor overactivity refractory to less invasive urotherapy, it was reported that OnabotA lasted up to 12 months with patients experiencing resolution of urgency and dryness during the day [9]. Therefore, neurologic compromise appears to play a key role in the duration of action of OnabotA. It should also be noted that the presenting symptoms and goals of treatment with OnabotA differ between patients with and without neuropathic involvement (Table 2). In neuropathic bladders, patients often experience higher than normal detrusor pressure and decreased compliance compared to those without who tend to experience urgency, frequency and incontinence. As previously mentioned, Hinman syndrome (so called “non-neurogenic neurogenic bladder”) can often mimic findings and have a presentation consistent with a neuropathic insult. However, no studies to date of OnabotA on the Hinman syndrome have been published to prove this point. Therefore, the goals of treatment should aim to increase bladder capacity and decrease pressures in neuropathic bladders, but provide symptomatic relief those without neurological compromise. Studies addressing external sphincteric injection have demonstrated a 6-month mean duration of action with clinical improvement in post-void residuals and EMG sphincteric activity [18, 22•, 23]. Differences in duration of action could be attributed to faster re-innervation in striated muscle due to more axonal sprouting [10]. Nonetheless, while the effect of
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Table 2 The use of OnabotA injections in neurogenic and non-neurogenic bladders
Symptoms and results of investigations
Primary objective of OnabotA
Concern for urinary retention Dosage
Neurogenic
Non-Neurogenic
Increased bladder pressure Decreased compliance Decreased capacity Incontinence Paralyze bladder muscle increasing volume, decreasing pressure and preventing upper tract deterioration (DLPP70 %. We have not noted any complications to treatment thus far, and follow-up in this group is more than four years, on average. Although time will tell if augmentation cystoplasty is avoided (and not just delayed), with reinjection every six months or so, the majority of patients have avoided more invasive surgical options with known important side effects and morbidity.
Curr Urol Rep (2014) 15:426 Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
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Conclusion OnabotA is becoming an increasingly popular and wellstudied therapy in the treatment of lower urinary tract dysfunction in children. It can be helpful in the prevention of upper urinary tract deterioration and renal compromise, delaying or preventing the need for bladder augmentation and improvement of benign lower urinary tract symptoms and incontinence. Optimal dosing has yet to be definitively determined, as has the preferred frequency of treatment, and further research into these areas is needed. While other standard therapies are less invasive and carry a level of efficacy in the treatment of this patient population, IDI of OnabotA can be useful as an alternative to more invasive approaches, should first line therapies fail.
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Compliance with Ethics Guidelines
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Conflict of Interest Dr. Tarek Hassouna and Dr. Joseph M. Gleason each declare no potential conflicts of interest. Dr. Armando J. Lorenzo is a consultant for and has received travel/accommodations expenses covered or reimbursed by Allergan.
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