Notes on Practice: The Use of Botulinum Toxin in the Treatment of Refractory Overactive Bladder

  Overactive bladder (OAB) is a symptom complex that comprises urinary urgency, with or without urge urinary incontinence (UUI), and often involves increased urinary frequency and nocturia.¹ Behavioral interventions and recent pharmacological advancements have offered symptom relief in many patients. Botulinum toxin (BTX) has provided an additional alternative in the treatment of refractory OAB.

Patient History and Diagnosis

  Ms. M is a 62-year-old woman with severe complaints of urinary frequency, urgency, and rare urgency urinary incontinence. Her initial evaluation (history, physical examination [pelvic and neurologic], urinalysis, and post-void residual) was within normal limits. She also completed a voiding diary. She was started on behavioral and oral antimuscarinic therapy. She experienced no significant improvement in symptoms and subsequently underwent a complete lower urinary tract evaluation, including a cystoscopy and a pressure flow urodynamic study (PFUDS). She was found to have detrusor overactivity with urgency and urgency incontinence; the rest of the evaluation was unremarkable. Neurologic consultation ruled out a neurogenic cause for her symptoms.

  Ms. M’s working diagnosis was idiopathic detrusor overactivity with urgency and urgency incontinence.

Treatment

  Ms. M tried five different antimuscarinic medications and continued bladder training, biofeedback-assisted pelvic floor muscle training, and behavioral modifications including dietary changes with no significant improvement in her symptoms. Further discussion then was directed toward surgical intervention. She underwent a trial of sacral nerve stimulation with no improvement. When this failed, Ms. M was given the options of intradetrusor injections of botulinum-A toxin (BTX-A) or bladder augmentation. After a lengthy discussion, she decided to undergo BTX injection.

  Ms. M tolerated the procedure well. She underwent the procedure as an outpatient with monitored anesthesia care in the operating room. After cystoscopy revealed a normal-appearing bladder mucosa, 300 units of BTX-A was injected into 30 different sites throughout the detrusor muscle of the bladder. She had excellent results. Her urinary frequency dramatically decreased and she had a complete resolution of her urinary urgency and urinary incontinence. Her last visit was 4 months post procedure and she continues to have a durable response. She plans to contact her physician when the efficacy of the treatment is significantly decreased and she wishes to repeat another injection course.

Discussion

  This case study highlights the use of BTX, the most potent naturally occurring toxin known to man, in the treatment of refractory OAB. The potential lethal effects of BTX, most of which consist of some neuromuscular dysfunction, have been harnessed. The effects of BTX have been used for a number of medicinal purposes, including reducing wrinkles, migraine headaches, and excessive sweating. The use of BTX in urology and, more specifically, the lower urinary tract, is increasing. It is a treatment option under active study for use in neurogenic and non-neurogenic OAB, detrusor sphincter dyssynergia, interstitial cystitis, urinary retention, and prostate disorders.

  BTX serotypes. The seven distinct serotypes of BTX are designated A, B, C1, E, F, and G; BTX-A (Botox [Allergan, Inc., Irvine, Calif] and Dysport [Ipsen, Inc., Europe]) and BTX-B (Myobloc (Solstice Neurosciences, Inc., Malvern, PA) are available commercially. Each serotype of botulinum toxin works by inhibiting the release of neurotransmitters, most notably acetylcholine, from the presynaptic neuromuscular junction.² The result is inhibition of muscular contractions and paralysis.

  Currently, the use of BTX in the lower urinary tract is not approved by the FDA. However, due to the limitations of drug and surgical therapies for the treatment of OAB, alternative therapies such as the use of BTX are being investigated. Studies in both the adult and pediatric population using BTX in neurogenic and non-neurogenic OAB, detrusor sphincter dyssynergia, and urinary retention have been performed. Many small case series and a few placebo-controlled studies have been performed recently with BTX. Some of these published studies follow.

  Schmid et al³ used BTX in 100 patients with idiopathic OAB syndrome refractory to anticholinergics in a prospective, non-randomized clinical trial where 88% of patients showed a significant improvement in bladder function in regard to symptoms, quality of life, and PFUDS at 4 and 12 weeks after injection of 100 units of BTX-A into the detrusor muscle. Urgency and incontinence disappeared in more than 80% of patients after 1 to 2 weeks, with significant reductions in frequency and nocturia. Urodynamic studies post-BTX injection revealed overall increases in bladder capacity and compliance, as well as resolution of detrusor instability in 72% of patients. Side effects were minimal and the duration of effect was 6 (±2) months.

  Rapp et al⁴ evaluated the use of BTX-A in 35 patients with non-neurogenic OAB with symptoms of frequency, urgency, and/or urge incontinence. All patients had failed medical therapy. A total of 300 units of BTX-A was injected in 30 different sites within the bladder detrusor muscle. Patients had a significant improvement in quality of life and incontinence questionnaire scores – symptoms were completely resolved in 34% of patients; improvement was sustained up to 6 months.

  Dykstra et al⁵ studied patients with refractory OAB using botulinum-B toxin. They found that 14 of 15 patients reported decreased frequency and overall subjective improvements. Ghei et al⁶ used BTX-B injections in non-neurologic and neurologic refractory detrusor overactivity and found patients experienced decreased urgency, frequency, and incontinence lasting about 6 weeks. Although BTX-B seems to have a shorter duration of efficacy, these studies suggest it may be beneficial in patients who have experienced tachyphylaxis to BTX-A.

  Schurch et al⁷ evaluated the use of BTX in patients with spinal cord injury and refractory detrusor hyperreflexia (neurogenic detrusor overactivity) and incontinence who required clean intermittent self-catheterization. A total of 21 patients were studied; they received injections of 200 to 300 units of BTX-A. Excellent initial results were seen at 6 weeks – 17 of 19 patients were completely continent. These patients also were able to either decrease or completely discontinue use of oral anticholinergic medications. At 16 and 36 weeks, 11 patients who originally responded and were able to be assessed in follow-up remained improved.

  In 2004, Reitz et al⁸ performed a multicenter, double-blind, placebo-controlled randomized study comparing two doses of BTX-A (200 and 300 units) to placebo. They studied 59 patients with neurogenic detrusor overactivity (53 with spinal cord injuries and six with multiple sclerosis). After a single injection, fewer episodes of incontinence occurred and urodynamic parameters and quality of life were improved. No significant difference was observed in the different doses administered.

  Administration. The optimal dosing and treatment options have yet to be determined. In most studies, 100 to 300 units of BTX were diluted to different concentration with injectable saline. The BTX is provided as an outpatient procedure with or without the use of sedatives. Intradetrusor injections are administered via a cystoscopic needle, usually distributed throughout the bladder muscle via 10 to 30 injection sites with or without injections into the bladder trigone.

  Safety. Studies of BTX in the lower urinary tract have shown it to be safe. It is thought that BTX typically affects only the local tissue into which it is injected. A few reports of adverse effects usually consisted of self-limited hypoasthenia and generalized muscle weakness.^9,10 When these symptoms occur, they may be due to systemic diffusion of the BTX.

  Patients who are treated long-term with BTX may develop antibodies which appear to cause no other side effect other than rendering subsequent BTX treatments less effective or ineffective.¹¹ If this occurs with BTX treatments of the bladder, some evidence suggests that switching to a different formulation of BTX may be effective.

  Contraindications. Contraindications include pregnancy, breast feeding, mysasthenia gravis, Eaton-Lambert Syndrome, amyotrophic lateral sclerosis, and the concomitant use of aminoglycosides. It also should be noted that all available forms currently use stabilizers such as albumin derived from human blood, which may be a cultural or religious issue with some patients.

Conclusion

  The use of BTX appears to be a safe and effective treatment for refractory OAB. It can be administered in a minimally invasive manner and provides hope for many who fail medical therapy due to ineffectiveness or side effects. Active research in the field will help determine the optimal dose and technique for administration and expand BTX’s urologic applications.

This article was not subject to the Ostomy Wound Management peer-review process.

1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation subcommittee of the International Continence Society. Urology. 2003;61:37-49.

2. Brin MF. Botulinum toxin: chemistry, pharmacology, toxicity, and immunology. Muscle Nerve Suppl. 1997;6:S146-S168.

3. Schmid DM, Sauermann P, Werner M, et al. Experience with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. J Urol. 2006;176(1):177-185.

4. Rapp DE, Lucioni A, Katz EE, et al. Use of botulinum-A toxin for the treatment of refractory overactive bladder symptoms: an initial experience. Urology. 2004;63(6):1071-1075.

5. Dykstra D, Enriquez A, Valley M. Treatment of overactive bladder with botulinum toxin type B: a pilot study. Int Urogynecol J. 2003;14(6):424-426.

6. Ghei M, Maraj BH, Miller R, et al. Effects of botulinum toxin B on refractory detrusor overactivity: a randomized, double-blind, placebo controlled, crossover trial. J Urol. 2005;174(5):1873-1877.

7. Schurch B, Stohrer M, Kramer G, et al. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol. 2000;164(3 Pt 1):692-697.

8. Reitz A, Stohrer M, Kramer G, et al. 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. 2004;45(4):510-515.

9. Wyndaele JJ. Van Dromme SA. Muscular weakness as side effect of botulinum toxin injection for neurogenic detrusor overactivity. Spinal Cord. 2002;40(11):599-600.

10. Dykstra DD. Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehabil. 1990;71(1):24-26.

11. Botox: (Botulinum toxin type A, purified neurotoxin complex) product information. Available at: 2000.http//botox.com/prescribing_info.html. Accessed November 15, 2006.