JORNAL DA INCONTINÊNCIA
URINÁRIA FEMININA


Up To Date
 
 

Treatment of vesical overactivity with botulin toxin

 

Vila, F. C. A.; Gomes, M. J. R.; Ramos, M. A. S. e Marcelo, F. G.
Serviço de Urologia do Centro Hospitalar do Porto
Unidade Hospital Geral de Santo António
Serviço de Urologia dos Hospitais Privados de Portugal - Porto
Rua Isolino Domingues da Silva, nº 220 2º E
4470-773 Vila Nova da Telha - Portugal

 

Abstract: Overactive bladder (OAB) is a challenge to the practicing urologist. Botulinum toxin may be useful in this setting.
Material and Methods: Retrospective study with review of clinical data and assessment of quality of life in the last 2.5 years.
Results: 17 patients were evaluated with a mean follow up length of 14.9 months. 70.5% were completely dry after treatment. No major complications were reported. All but one patient were satisfied with the therapy.
Conclusion: Botulinum toxin type A is effective and safe, representing an intermediate step between oral therapy and classic surgery in OAB.

Introduction: Overactive bladder (OAB) is a public health problem that affects 12.2% of the adult population in Europe1 with important repercussions on quality of life. In patients with detrusor overactivity (DO) due to a neurological disease, can occur deterioration of upper urinary tract. OAB refractory to first line therapy (change in lifestyle, biofeedback, oral anticholinergics) pose a challenge to the Urologist.
Botulin toxin is a potent neurotoxin produced by Clostridium botulinium, first isolated in 1897 by Van Emergan2. This substance binds to nerve terminals blocking the release of several neurotransmitters into the synaptic slit (acetylcholine, adenosine triphosphate, neuropeçptides such as substance P). It also plays an inhibitory role regulating the expression of vesical capsaicin and purinergics. Its vesical inhibitory effect can be mediated via motor and sensory pathways.  There are seven toxin serotypes, but type A is the most commonly used in urology due to its proven efficacy and clinical safety.
After treatment in some cases, nerve regeneration (sprouting) occurs and can require a new treatment. However, no evidence on tolerance a long term is available. A small percentage of patients become resistant to treatment by developing antitoxin antibodies4.
Initially utilized for the treatment of vesico- sphincterien dyssynergy in rachi-medullar5 trauma patients, botulin toxin was first used in the treatment of overactivity bladder in 2000 by Störer e Schurch6. Despite the large number of cases published over the past decade, urologic applications of this therapy have not been approved and remain  off-label.
The main objective of treatment of overactive bladder refractory to oral anti-cholinergics in neurogenic patients is to preserve renal function with low intravesical pressure, achieving acceptable social urinary continence, and reducing the number of urinary tract infections. In non-neurogenic patients, social continence and improved quality of life should be obtained.
The authors report their experience with this therapy in urologic practice.

Patients and methods: From July 2004 to March 2007, in retrospective study, were evaluated the clinical data, therapy and response to treatment in patients with overactive bladder followed up in two Urology Services All patients provided informed consent and  attended  the inclusion criteria: urodynamically diagnosed detrusor overactivity, no sphincteric insufficiency, resistance to first line treatments, desire and suitability for intermittent vesical catheterization. Patients without neurologic disease were injected with 200U of intradetrusor Botox® into 30 different sites sparing the trigone, while those showing  neurologic disease received either 300 U of Botox® or 1000 U of Dysport®.
All patients were assessed at 1, 3, 9 and 12 months after treatment. Quality of life after treatment was evaluated using the Qualiveen questionnaire.


Results: Of the 17 patients included in the study, 14 had neurogenic bladder suck as 11 rachi-medullar trauma (RMT), 1 multiple sclerosis (MS), 1 spina bifida (SB), 1 transverse myelitis (TM) and 3 idiopathic overactive bladder (IOB). Age ranged from 18 to 59 years (mean age = 40 years), and mean followup length was 14.9 ± 11.2 months. Before treatment, 65% of the patients showed no voluntary voiding, 7 were undergoing intermittent vesical catheterization, and 4 used a permanent vesical catheter. All patients showed involuntary urine loss: 47% used diapers daily; 23.5% had a underwelling catheter; 17.5% used pads (> 4); and  12%  used a urine collector.
A total of 22 botulin toxin applications were performed (5 reinjections): 6 injections of 1000 U of Dysport®, 13 of 300 U of  Botox®, and 3 of 200 U of Botox®.
The number of incontinence episodes reduced in all cases. After the first injection, 76% of the patients were completely dry (Table 1).
Complications observed after treatment with botulin toxin included 1 case of idiopathic hyperactive bladder that required prolonged intermittent vesical catheterization, and 1 case of urinary tract infection.  Mean time interval before retreatment was 11.2 months (range of 6 to 18 months).
Regarding quality of life and overall satisfaction,  76.5% of the patients were very satisfied, 17.6% were moderately satisfied, and failure occurred in 1 (5,9%) case.

Discussion: Botulin toxin type A has more an alternative therapeutic of proven efficacy in several nosological urologic entities. This was further demonstrated by the clinical heterogeneity verified in our series.
This therapy is recent, the adequate dose and surgical technique for injection remain discussible3. Since the beginning of our experience, we have used either 300 U of Botox® or 1000 U of Dysport® in neurogenic patients, and 200 U of Botox® in idiopathic overactive bladder. According to some authors7, 200 U of Botox® shows the same clinical efficacy in neurogenic overactive bladder. However, higher doses8 ( 400 U of  Botox®) have been associated with a higher rate of complications, as well as higher costs. The number of applications per treatment has also been under debate. Some advocate the use of 10 spots than the 30 application sites used by the majority of the authors, based on  the assumption that the suburothelial diffusion of the toxin is the major determinant of clinical efficacy added to the fact the it makes the procedure less painful reducing the need for associated anesthetics9.
In this study, the vesical trigone was spared during injections. However, some authors regard its inclusion as necessary to achieve greater clinical efficacy without risk of vesicourethral reflux3. There seems to be consensus on avoiding the anterior vesical wall due to the risk of intestinal injuries.
Invonlutary urine loss is known to be symptom that, from the urologic standpoint, most negatively influences global quality of life scores. Botulin toxin therapy reduced overall urine loss allowing 12 of the patients treated to no longer need diapers, 4 to undergo IVC and thus benefit from the clinical advantages inherent to not having to use a permanent vesical catheter, and 2 to quit using a urine collector, which had very important positive effects on quality of life.
Despite the small size of our sample, the degree of success was lower among the patients without an underlying neurologic disease(3). This found might be related with the lower dose of botulin toxin used (200 U). Among these patients, pretreatment maximum detrusor pressure is predictive of therapy success with values over 110 cm for H2O reducing success rate10. The presence of wall fibrosis and low vesical compliance are also associated with less favorable outcomes.
The mean time interval before retreatment was necessary, complications and overall satisfaction rate observed in this study are in line with those currently reported in the literature.

Conclusion: Botulin toxin type A therapy is safe and effective, with long-lasting results in patients with refractory overactive bladder. It has, thereby, been gaining acceptance as an intermediate step between oral therapy and surgical procedures for the treatment of refractory overactive bladder.

 
 
 
 
 
 


Table 1: Outcomes of different treatments.

Pre-treatment condition

Treatment

Outcome

Permanent vesical catheter
4  Rachi-Medullar Trauma (RMT)

1000 U Dysport® /
300 U Botox®

All patients with intermittent catheterization without diapers

With diapers
5 RMT, 1 MS, 1 SB, 1 TM

1000 U Dysport® /
300 U Botox®

Without diaper (8)

daily pads
3 IOB

200 U Botox®

From 4 pads to 0 (1)
From 4 pads to 1 (1)
Same number of  pads (1)

External collector
2 RMT

300 U Botox®

Without urine collector (1)
Number of incontinence episodes reduced by half (1)

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
References
 
  1. LAZZERI, M.; SPINELI, M. The challenge of Overactive Bladder Therapy: Alternative to Antimuscarinic Agents. Int Braz J Urol, v.32,  p. 620-30, 2006.
  2. KARSENTY G.; DENYS, P.; AMARENCO, G. et al. Botulinum Toxin A (Botox®) Intradetrusor Injections in Adults with Neurogenic Detrusor Overactivity/ Neurogenic Overactive Bladder: A Systematic Literature Review. Eur Urol, v.53, p. 275-287, 2008.
  3. RAPP D.E.; LUCIONI A.; BALES, G.T. Botulinum Toxin Injection: A Review of Injection Principles and Protocols. Int Braz J Urol, v.33, p. 132-41, 2007.
  4. DOELGASST, G.J.; BROWN, J.E.; KOUFMAN, J.A. et al. Sensitive assay for measurement of antibodies to Clostridium botulinum neurotoxins A, B and E: use  of hapten-labeled-antibody elution to isolate specific complexes. J Clin Microbiol, v. 35, p. 578-83, 1998.
  5. DYKSTRA, D.D.; SIDI, A.A. Treatment of detrusor-sphincter dyssinergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehabil, v.71, p. 24-6, 1990.
  6. SCHURCH, B. ; STÖRER, 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, v.164,  p. 692-7, 2000.
  7. SCHURCH, B. ; SÈZE, M., DENYS, P. et al. 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, v.174,  p. 196-200, 2005.
  8. HAJEBRAHIMI, S.; ALTAWEEL, W.; CADORET, J. et al. Efficacy of botulinum-A toxin in adults with neurogenic overactive bladder: initial results. Can J Urol, v.12, p. 2543-6, 2005.
  9. KARSENTY, G.; CARSENAC, A.; BOY, S. et al. Botulinum toxin-A (BTA) in the treatment of neurogenic detrusor overactivity incontinence (NDOI) – a prospective randomized study to compare 30 vs. 10 injection sites. Eur Urol, Suppl 6, p.245 (abstract no. 890), 2007.
  10.  SAHAI, A.; KHAN, M.S.; GALL, N. et al. Urodynamic Assessment of Poor Responders After Botulinum Toxin-A Treatment for Overactive Bladder. J Urol, v. 71, p 455-59, 2008.