DUBAI, UAE (UroToday.com) - Dr. Waleed Altaweel opened his lecture by listing those patients for whom Botulinum toxin A (BTX-A) is indicated - including patients who had low compliance with oral therapies and those who have failed oral agents and are not candidates or are unwilling to undergo more invasive treatments. We have a growing body of literature on the long term efficacy and safety of BTX-A conducted in multicenter studies. It is felt that at least 4% of the population who have OAB, have cases that are refractory to standard medications
In addition to non-neurogenic OAB, there are other urologic indications for BTX-A including refractory neurogenic OAB, detrusor-sphincter-dyssynergia (DSD), refractory idiopathic OAB, BPH and painful bladder syndrome. Beginning in 1987, with a publication of its use in DSD, Dr. Altaweel provided a very detailed history of the use of Botulinum Toxin A as outlined in various publications.
There are seven distinct serotypes of Botulinum Toxins (A, B, C1, D, E, F, G) but only types A and B are used clinically with Type A toxin (BTX-A) most commonly used as it is the most potent and longest lasting.
The pathophysiology of BTX-A is depicted in Figure 1. It cleaves to the cytosolic SNAP-25, thus preventing vesicle fusion with plasma membrane. It may also affect sensory nerve fibers and afferent signaling mechanisms that have an important role in the pathophysiology of idiopathic detrusor overactive bladder (IDO).
Pharmacologically, the beneficial effects occur with 3 to 4 months when injected in skeletal muscles and 6 to 9 months when injected into smooth muscles. Chemo-denervation occurs after 3–6 months when turnover of pre-synaptic molecules occurs and nerve sprouting from the nerve terminal forms a new functional synapse.
The lethal dose of BTX-A is 40 U/kg - with lower doses generally well tolerated with no serious or severe adverse events. Side effects include rash, transient flu-like symptoms, dysphagia, diplopia and blurred vision. Uncommon cases of generalized muscle weakness occurs in doses of BTX-A (140–300 u) and Dysport (1000u). Contraindications include anyone who has a sensitivity to neurotoxin and patients with neuromuscular disorders (e.g. Myasthenia gravis and Eaton‐Lambert syndrome). However, higher doses and shorter interval between injections contribute to resistance and some patients may develop a toxin immuno-resistance. To reduce antibodies formation, the clinician should wait 3 months between injections, avoid use of booster injections, and use the smallest dose that will achieve the desired clinical effects.
[refs: De Laet K, Wyndaele JJ. (2005) Adverse events after botulinum A toxin injection for neurogenic voiding disorders. Spinal Cord. 43(7):397-9.
Naumann M, Jankovic J. (2004) Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin. 20(7):981-90.]
Dr. Altaweel presented the technique for administrating BTX-A to include diluting 100-300u of BTYX-A in 10 to-30cc of normal saline and with a 25 gauge needle, inject 10 to 30 different sites with 1 cc of BYX-A at each site. BTX-A can be injected in the bladder using either a rigid or flexible cystoscope. Bladder sites include intra-detrusor in the trigone, lateral wall and posterior wall. Injections for DSD include via transurethral, perineal and transvaginal routes. Technique includes the use of a rigid cystoscope, 100U of BTX-A in 4 ml saline and a deep injection of 2 mls at 9 and 3 o’clock in the area of the sphincter which can be identified through a voluntary or reflex contraction.
As to the need of injection into the trigone, Karsenty (2007) injected 200U of BTX-A into the trigone in 12 patients with non-neurogenic overactive bladder (doing video UDS before and after the procedure) and found that it did not induce de novo vesico-ureteral reflux.
[ref: Karsenty G, Elzayat E, Delapparent T, St-Denis B, Lemieux MC, Corcos J. (2007). Botulinum toxin type a injections into the trigone to treat idiopathic overactive bladder do not induce vesicoureteral reflux. J Urol. 77(3):1011-4.]
According to Kalasi, (2008) improvement in urgency, frequency, incontinence can be seen in 2 days with urgency the most rapidly and consistently improved symptom.
[ref: Kalsi V, Apostolidis A, Gonzales G, Elneil S, Dasgupta P, Fowler CJ. (2008). Early effect on the overactive bladder symptoms following botulinum neurotoxin type A injections for detrusor overactivity. Eur Urol. 54(1):181-7.]
Dr. Altaweel went on to discuss the use in neurogenic detrusor overactivity (NDO). Patki, et al. reported on the first prospective assessment of intra-detrusor injections in patient with NDO using BTX-A (Dysport) developed in the UK. In 37 spinal cord injury (SCI) patients with drug-resistant NDO, 1000 U of the substance was cystoscopically injected in 30 different sites. There was a significant increase in the reflex volume and in the maximum cystometric bladder capacity .There was also a significant decrease in the maximum detrusor voiding pressure. The mean period of improvement was 9 months.
[Ref:Patki P, Hamid R, et al. (2006). Botulinum toxin-type A in the treatment of drug-resistant neurogenic detrusor overactivity secondary to traumatic spinal cord injury. BJU Int. 98(1):77-82].
There have been randomized placebo controlled trials addressing the use of BTX-A in patients with idiopathic OAB with outcomes of 3.88 fewer UI episodes per day and improved quality of life scores using Urogenital Distress Inventory data. However, there was a 9-fold increased odds of increased post-void residual volume.
[refs: Anger JT, Weinberg A, Suttorp MJ, Litwin MS, Shekelle PG. (2010) Outcomes of intravesical botulinum toxin for idiopathic overactive bladder symptoms: a systematic review of the literature. J Urol. 183(6):2258-64.
Brubaker L, Richter HE, Visco A, Mahajan S, Nygaard I, Braun TM, Barber MD, Menefee S, Schaffer J, Weber AM, Wei J; Pelvic Floor Disorders Network. (2008) Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol. 180(1):217-22.
Flynn MK, Amundsen CL, Perevich M, Liu F, Webster GD. (2009) Outcome of a randomized, double-blind, placebo controlled trial of botulinum A toxin for refractory overactive bladder. J Urol. 181(6):2608-15.
Sahai A, Khan MS, Dasgupta P. (2007). Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol. 177(6):2231-6.]
The use of BTX-A in children with myelomeningocele (MMC) has been reported. Schulte-Baukloh used 12 U/kg (maximum 300U) and reported a 100% success rate. Altaweel (2006) evaluated 20 children with MMC and injected 5u/kg(max 300u) in 30 different sites with a 65% success rate and mean duration of effects 8 months. Neel (2010) reported on 10 females and 3 males with vesicoureteral reflux who were injected with BTX-A. This was performed to protect the upper tracts, maintain the bladder at safe pressure and provide an improved quality of life. None reported adverse effects related to toxin.
[refs: Altaweel W, Jednack R, Bilodeau C, Corcos J. (2006) Repeated intradetrusor botulinum toxin type A in children with neurogenic bladder due to myelomeningocele. J Urol. 175(3 Pt 1):1102-5.
Schulte-Baukloh H, Michael T, Schobert J, Stolze T, Knispel HH. (2002) Efficacy of botulinum-a toxin in children with detrusor hyperreflexia due to myelomeningocele: preliminary results. Urology. 59(3):325-7.
Neel KF. (2010) Total endoscopic and anal irrigation management approach to noncompliant neuropathic bladder in children: a good alternative. J Urol. 184(1):315-8.]
There have been reports on the effect of BTX-A in patients with DSD. Dykstra et al. first reported on the transperineal approach that aims at minimizing the risk of autonomic dysreflexia. But these authors abandoned the technique very soon because of poor results of the treatment. Schurch et al. (1990) reported good results of both techniques (transurethral versus transperineal), when using the same amount of toxin. Similarly, Gallien et al. (1998) reported on good results using the transperineal approaches. de Seze et al. (2002) compared the efficacy and tolerance of Botulinum toxin (100 units of Botox in 4 ml saline) versus lidocaine (4 ml at 0.5%) applied into the external urethral sphincter with a single transperineal injection. They found a significant improvement in the post-void residual volume in the botulinum group but not in the lidocaine group
[refs: de Seze, et al. (2002) Botulinum A toxin and detrusor-sphincter dyssynergia: a double blind lidocaine-controlled study in 13 patients with spinal cord disease. Eur Urol.;42(1):56–62.
Dykstra DD, Sidi AA. (1990) Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehabil. 71(1):24-6.
Gallien, et al. (1998) Treatment of detrusor-sphincter dyssynergia by transperineal injection of botulinum toxin. Arch Phys Med Rehabil.;79(6):715–7.
Schurch, et al. (1990) Effets de la toxine botulinique A sur le sphincter strie´ periure´tral desvessies neuroge`nes. J Urol. 96(4):375–80].
In a multicenter evaluation of BTX-A by Schurch, et.al. (2005) in treating neurogenic UI secondary to SCI or multiple sclerosis (MS), there was a significant improvement in UI and bladder capacity, improvement in all UDS parameters, marked increase in QOL and no side effects. In a study of 200 patients with SCI, MMC, MS, 132 regained continence, antimuscarinic OAB medications were discontinued in 45 patients with dosage reduced in 118 patients. Wefer (2010) studied 214 patients with SCI, MMC, and MS and found a decrease in infections, incontinence and pad use.
[Refs: Reitz A, Stöhrer M, Kramer G, Del Popolo G, Chartier-Kastler E, Pannek J, Burgdörfer H, Göcking K, Madersbacher H, Schumacher S, Richter R, von Tobel J, Schurch B. (2004) European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol. 45(4):510-5.
Schurch B, de Sèze M, Denys P, Chartier-Kastler E, Haab F, Everaert K, Plante P, Perrouin-Verbe B, Kumar C, Fraczek S, Brin MF; Botox Detrusor Hyperreflexia Study Team. (2005).
Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol. 174(1):196-200
Wefer B, Ehlken B, Bremer J, Burgdörfer H, Domurath B, Hampel C, Kutzenberger J, Seif C, Sievert KD, Berger K, Pannek J. (2010). Treatment outcomes and resource use of patients with neurogenic detrusor overactivity receiving botulinum toxin A (BOTOX) therapy in Germany. World J Urol. 28(3):385-90.]
Schulte-Baukloh, et al. (2006) studied the efficacy of BTX-A in 16 patients with MS and showed significant improvement in UDS with significant patient satisfaction. But the authors mentioned the need to inform patients about the possibility of increased residual urine.
[Ref: Schulte-Baukloh H, Schobert J, Stolze T, Stürzebecher B, Weiss C, Knispel HH. (2006) Efficacy of botulinum-A toxin bladder injections for the treatment of neurogenic detrusor overactivity in multiple sclerosis patients: an objective and subjective analysis. Neurourol Urodyn. 25(2):110-5.]
A question asked by many patients is “how long does it last?” Well, there are several studies that looked at when the effect decreased and reinjection was needed. The consensus seems to be that BTX-A reinjection is needed usually within 7 months but there is significant improvement after repeat injections.
[refs: Karsenty G, Reitz A, Lindemann G, Boy S, Schurch B. (2006) Persistence of therapeutic effect after repeated injections of botulinum toxin type A to treat incontinence due to neurogenic detrusor overactivity. Urology. 68(6):1193-7
Reitz A, Denys P, Fermanian C, Schurch B, Comperat E, Chartier-Kastler E. (2007) Do repeat intradetrusor botulinum toxin type a injections yield valuable results? Clinical and urodynamic results after five injections in patients with neurogenic detrusor overactivity. Eur Urol. 52(6):1729-35.]
One of the most important outcomes is quality of life. Significant improvements in the QOL of patients with either NDO or IDO have been seen at least up to 16 weeks after treatment in patients with neurogenic UI (Kalsi, 2006). Schurch (2007) showed improved QOL in patients with neurogenic UI. Gamé (2010) showed improved HRQL in both NDO and IDO patients but HRQL was greater and the duration of efficacy shorter in NDO patients after the first injection with no significant difference after subsequent injections.
[refs: Gamé X, Khan S, Panicker JN, Kalsi V, Dalton C, Elneil S, Hamid R, Dasgupta P, Fowler CJ. (2010)Comparison of the impact on health-related quality of life of repeated detrusor injections of botulinum toxin in patients with idiopathic or neurogenic detrusor overactivity. BJU Int. Oct 29.
Kalsi V, Apostolidis A, Popat R, Gonzales G, Fowler CJ, Dasgupta P. (2006) Quality of life changes in patients with neurogenic versus idiopathic detrusor overactivity after intradetrusor injections of botulinum neurotoxin type A and correlations with lower urinary tract symptoms and urodynamic changes. Eur Urol. 49(3):528-35.
Schurch B, Denys P, Kozma CM, Reese PR, Slaton T, Barron RL. (2007) Botulinum toxin A improves the quality of life of patients with neurogenic urinary incontinence. Eur Urol.52(3):850-8.]
Cost-effectiveness when comparing the use of BTX-A and antimuscarinic drugs using a Markov decision analysis model developed for this comparison and it showed that BTX-A was cost-effective compared to anticholinergic but it become less cost-effective if patients were highly compliant with medications. Pasmanabhan (2010) reported on the 5 years cost-effectiveness of BTX-A when compared to bladder augmentation.
[refs: Padmanabhan P, Scarpero HM, Milam DF, Dmochowski RR, Penson DF. (2011). FIve-year cost analysis of intra-detrusor injection of botulinum toxin type A and augmentation cystoplasty for refractory neurogenic detrusor overactivity. World J Urol. 29(1):51-7.
Wu JM, Siddiqui NY, Amundsen CL, Myers ER, Havrilesky LJ, Visco AG. (2009).Cost-effectiveness of botulinum toxin a versus anticholinergic medications for idiopathic urge incontinence. J Urol. 181(5):2181-6.]
Dr. Altaweel ended his lecture noting that there are significant adverse events seen with antimuscarinic drugs. There is now long term efficacy and safety of BTX-A and significant improvement after repeat injections. BTX-A is cost effective in comparison to patients who are non-complaint with drug therapy and it should become a standard treatment for refractory OAB.
Presented by Waleed Altaweel, MD, FRCSC at the 7th Pan Arab Continence Society (PACS) Annual Meeting - February 3 - 5, 2011 - Dubai, United Arab Emirates
Reported for UroToday by Diane K. Newman, RNC, MSN, CRNP, FAAN and Continence Nurse Practitioner Specialist - University of Pennsylvania Medical Center.
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