Urology and Andrology

Open journal

ISSN 2572-4665

Botulinum Toxin Type A in Neurogenic Overactive Bladder Dysfunction in Patients with Multiple Sclerosis

Villalba Bachur Roberto F*, Kohan Diego F, Fernandez C. Gaston, Angeloni Guido, Koren Claudio A, Longo Emilio M

Villalba Bachur Roberto F, MD

Urologist, Urology Department, Complejo Médico Churruca Visca, Buenos Aires, Argentina; Tel. +5493878645281; ORCID ID: 0000-0002-4488-3568; E-mail: robybachur@gmail.com

INTRODUCTION

Multiple sclerosis (MS) is the most common progressive neurological disorder of young people. The average age of start is 30-years-old and a prevalence of 108 cases per 100.000 people in Europe.1 It has a progressive course and there are four types of MS. The relapsing-remitting is the most reported, in about 85%. There are a lot of different symptoms consequence of the central nervous system demyelination and the subsequent altered nerve conduction.2,3

The presence of urinary symptoms is really frequent with a prevalence of 37-99% for OAB syndrome, characterized by storage symptoms. For voiding symptoms the prevalence is 34-79% and for chronic urinary retention is 25%.4 Women are affected twice as commonly as men; however, men usually have a worse clinical presentation. The most frequent voiding disorder is spastic bladder and neurogenic detrusor overactivity.5

The International Continence Society (ICS) define the OAB Syndrome as urinary urgency, usually with an increase of frequency and nocturia, with or without urinary incontinence.6,7

Urological involvement can condition the long-term prognosis of the disease due to the development of infections and renal complications. Thus, the correct diagnosis and treatment in these patients can provide greater control of the disease as well as, provide a better quality of life (QoL).8

The standard treatment of patients with overactive detrusor are the antimuscarinics drugs (also known as anticholinergics), which act blocking parasympathetic nerve impulses to the detrusor muscle, making it relax and thereby improving bladder capacity. Beta-3 adrenergic drugs are also prescribed for these patients. Their mechanism of action is the stimulation of sympathetic receptors with the same purpose. Lack of response is not infrequent and the adverse effects of anticholinergics such as xerostomia, constipation, blurry vision, among others, often lead patients to abandon the treatment.

Despite this, anti-cholinergics or beta-3 adrenergics are the first line of pharmacological treatment for neurogenic OAB syndrome.9

There are some alternative treatments such as bladder injection of botulinum toxin type A, tibial nerve stimulation, pelvic floor kinesiology, sacral nerve modulation and surgery.

Botulinum toxin type A blocks the release of acetylcholine at the neuromuscular junction and leads to temporary chemodenervation of the bladder. Motor effects on the bladder have been studied extensively, leading to approval by the US Food and Drug Administration (FDA) in August 2011 for the treatment of refractory neurogenic OAB in patients with MS and spinal cord injury.

In those patients’ intolerant or refractory to oral drugs, we investigated the effectiveness of endovesical therapy with injection of botulinum toxin type A into the detrusor.

To evaluate the effectiveness and impact of the botulinum toxin type A on the quality of life of MS patients with neurogenic overactive detrusor, who are intolerant of or refractory to oral therapy.

MATERIALS AND METHODS

Data from the medical records of all patients diagnosed with neurogenic OAB with MS defined by neurologists, refractory and/ or intolerant to oral medical therapy with anticholinergics or B3 agonists dopaminerics, who received endovesical therapy with botulinum toxin in the Urology department of the Churruca-Visca Medical Complex from January 1, 2016 to January 1, 2019 were retrospectively analyzed.

The inclusion criteria were patients with diagnosis of MS with OAB were considered, with postvoid residual less than 1/3 of their bladder capacity and without a history of recurrent urinary infections, negative urine culture at the time of the procedure and none were self catheterising.

All patients had a 6-month follow-up and completed a urological evaluation consisting in anamnesis, physical examination, 24-hour voiding diary, urine culture, renal function, renal and bladder ultrasound, and urodynamic study.

The urodynamic study was carried out according to the “Good Urodynamic Practices” recommended by the International Society of Continence with the Urodynamic ECUD® team from Medware Argentina.

An overactive bladder evaluation questionnaire (PotenzianiQol/VH-26) was performed. The Potenziani scale is a quality of life self-questionnaire related to urinary problems, initially developed for patients with spinal trauma and its validation has been extended to patients affected by MS.

It has 26 items which measure the affectation of the urinary disorders in four specific domains and their impact on quality of life: Frequency, Urgency, Incontinence and Nocturia. Each item has a response scale from 0 to 2 points, 0 indicates the absence of impact on quality of life and 2 means a severe affectation. The total score is represented by the sum of each item, being a low impact from 0 to 10, moderate from 11 to 26 and severe from 27 to 52 severe.10

Patients were informed about the endovesical botulinum toxin administration technique and its adverse effects, highlighting the possible need for subsequent intermittent catheterization. Informed consent was signed.

Endoscopic injection was performed according to the technique proposed by Schurch et al. Under antibiotic coverage according to antibiogram, in lithotomy position, under neuroleptoanalgesia and using a Prostaject® needle with a 19 Fr Storz cystoscope. 200 IU of onabotulinumtoxin A diluted in 20 ml of physiological solution were injected, distributed in 20 puncture sites of 1 mL each distributed on all sides of the bladder but respecting the trigone.

After the application, we again carried out the quality of life and overactive bladder questionnaire (PotenzianiQol/VH-26) at 3 and 6-months respectively, as well as a urodynamic study at 3-months.

The information was saved in the excel database and later analyzed using the statistical package Stata 13.0. The sample was described with measurements of central tendency and dispersion for the numerical variables and percentagefor categorical ones. The comparison between the baseline data, at three and six months for the different variables were analyzed using the Wilcoxon test. For the comparison of the related variables, McNemar test was used. Statistical significance was considered with p<0.05.

The protocol was evaluated and approved by the Churruca Visca Medical Complex bioetichs committee.

OUTCOMES

Between January 1, 2016 and January 1, 2019, 16 patients diagnosed with OAB with MS intolerant or refractory to medical therapy were treated with botulinum toxin (200 IU). 75% of patients were women. The average age was 45-years, with an age range of 19 to 62-years. All had previously received individual or combined medical therapy. The mean oral therapy time was 10.93-months (Table 1). Seven (7) patients had adverse effects: 5 presented with a dry mouth, and 2 with constipation. Only one patient discontinued medication due to cognitive impairment. Only one patient discontinued medication due to cognitive impairment.

 

Table 1. Sample Description

Variable

Total (n=16)

Female n (%)

12 (75)

Age Average (range)

43,81 (19–62)

Time of tacking Anticholinergics Average (range)

10, 93 (6–18)

 

Solifenacin was indicated in 37.5% of the cases, darifenacin in 25%, combined treatment with anticholinergic therapy+b3 agonist in 31.25% and tolterodine in 6.25%, prior to Botulinum toxin therapy.

The quantification of symptoms using the QoL/VH26 questionnaire showed a progresive decrease when comparing baseline values and those at 3-6-months after botulinum toxin injection with a result of 34.43, 24.06 and 17.5 respectively (p 0.0013).

The average daily pre-botulinum toxin urination was 10.62. Improvement was evidenced in the daily voiding survey at 3 and 6-months with an average of 7.81 and 6.87 (p 0.0002). The mean number of incontinence episodes was 3.37. After the injection, there was a decrease to 1.31 episodes at 3-months and from 0.75 at 6-months (p<0.0026) (Table 2).

 

Table 2. QoL Intervention

Variable

Pre-Botox 3-months 6-months

p

QoL Average (range)

34.43 (17-50)

24.06 (11-38) 17.5 (8-27)

0.0013

Daily voidings (Number) Average (range)

10.62 (8-14)

7.81 (5-11) 6.87 (4-10)

0.0002

Urinary incontinence (Number of episodes) Average (range)

3.37 (2-6)

1.31 (0-3) 0.75 (0-3)

0.0026

Firedman’s Anovatrans formation test

In urodynamics studies, after an average of 12 weeks of application of botulinum toxin type A, we observed an increase in maximum cystometric capacity and an increase in bladder compliance.

Mean bladder capacity improved from 191 ml to 338 ml (p<0.0004). In urodynamics, 12 patients (75%) did not evidence detrusor overactivity (p<0.0005) (Table 3).

 

Table 3. Analysis of the Intervention

Variables

Pre- Botox 3-months

p

Overactive Bladder1 n=(%)

16 (100)

4 (25)

0.0005

Bladder Capacity2 (ml) Average (range)

191.25 (150-280)

338.75 (290-420)

0.0004

1. McNemar Test; 2. Wilcoxon Test

 

Thirteen (13) patients (81.25%) achieved spontaneous voids with residues ≤100 ml, while 3 patients received catheterization for post-void residue greater than 100 ml.

Maximum efficacy was evidenced three-months after treatment. No systemic or local complications were observed. 68.75% of the patients, who were treated with botulinum toxin type A, were reapplied at least once more.

Three presented episodes of urinary tract infection in the 6-month follow-up period.

DISCUSSION

The general and long-term goals of treatment in patients with overactive bladder syndrome secondary to MS are to protect the upper urinary tract, achieve continence, and improve quality of life. Antimuscarinics remains the first line of treatment for overactive bladder after lifestyle changes.11,12 However, these medications have side effects that generate low adherence rates.

In a 2009 Cochrane review, the authors did not find enough evidence for the significant benefit of antimuscarinics in people with MS. In turn, high incidences of adverse effects were described in more than 1 in 5 participants.13 The findings of the review did not show significant differences between the different drugs.

The consumption of the medication reduces the sensation of voiding urgency, improves continence, and increases bladder capacity, mainly in the first months of use.14 Antimuscarinics have collateral effects such as dry mouth, constipation, among others. Oral mucosa dryness was reported in 1/3 of the patients with anticholinergic therapy,15 in our series we found similar results regarding mucosal dryness, being almost 32%, of which none abandoned therapy.

Currently, the evidence about the efficacy and safety of botulinum toxin is through randomized, placebo-controlled studies in which the authors evaluated patients with urinary incontinence and neurogenic overactive bladders of different etiologies, mainly spinal cord injuries and multiple sclerosis. There are few studies that include only patients with diagnosis of multiple sclerosis and OAB.

Botulinum toxin type A is the only type of botulinum toxin evaluated for the management of lower urinary tract dysfunctions through multicenter, randomized, controlled and randomized trials.16,17 Injections of botulinum toxin type A in the detrusor are highly effective in reducing the incidence of incontinence, in improving urodynamic parameters and, consequently, in the quality of life of patients.18,19

Two double blind, randomized, placebo- controlled trials in patients with diagnosis of MS or spinal cord injury evaluated the difference between the doses of botulinum toxin (200-300 IU) without significant evidence on therapeutic efficacy of one over the other.18,20

An important consideration when faced with a patient with neurogenic overactive bladder undergoing botulinum toxin therapy is the eventual need for clean intermittent catheterization after therapy, as it can affect bladder voiding.

In trials, 31.4% of patients with MS spontaneously voiding at baseline initiated clean intermittent catheterization after treatment with botulinum toxin,21,22 however this procedure does not affect the quality of life.22,23 In our work, 18.75% of patients (n=3) had to perform intermittent catheterization for the first time due to high postvoid residual volume, data similar to those provided by Mehnert et al.24

Post-treatment urinary tractinfections, are one of the most frequent complications with a reported incidence of 51.8 to 56%.25 In our work, 18.75% of urinary infections were recorded. These patients may be those with higher residual volumes who started self-catheterization plan.

There are few studies on long-term follow-up of patients on therapy with botulinum toxin for neurogenic OAB. Baron et al26 conducted a 10-year retrospective study looking for the reason for discontinuation of therapy. They showed that more than half of the patients with neurogenic overactive bladder abandoned therapy within 10-years, the main causes were therapeutic failures, patient decision, neurological condition progression and adverse events.

CONCLUSION

To conclude, botulinum toxin has a significant impact on the quality of life of patients diagnosed with multiple sclerosis with a neurogenic overactive bladder, being a safe and highly effective procedure, demonstrated in several trials in recent years. In our work, a significant improvement in the quality of life of patients could be evidenced, however, we consider the need for new trials with a larger sample size and prospective designs, with a longer follow-up time to obtain better levels of evidence.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

We obtained the ethics approval.

AVAILABILITY OF DATA AND MATERIAL

The information was obtained from patient medical records.

FUNDING

There are no funding sources.

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

1. Multiple Sclerosis International Federation. Atlas of MS 2013: mapping multiple sclerosis around the world. 2013. Web site. http://www.msif.org/wp-content/uploads/2014/09/Atlas-ofMS.pdf. Accessed April 15, 2020.

2. Nortvedt MW, Riise T, Frugård J, Mohn J, Bakke A, Skår AB, et al. Prevalence of bladder, bowel and sexual problems among multiple sclerosis patients two to five years after diagnosis. Mult Scler. 2007; 13(1): 106-112. doi: 10.1177/1352458506071210

3. Stoffel JT. Contemporary management of the neurogenic bladder for multiple sclerosis patients. Urol Clin North Am. 2010; 37(4): 547-557. doi: 10.1016/j.ucl.2010.06.003

4. de Sèze M, Ruffion A, Denys P, Joseph PA, Perrouin-Verbe B, GENULF. The neurogenic bladder in multiple sclerosis: Review of the literature and proposal of management guidelines. Mult Scler. 2007; 13(7): 915-928. doi: 10.1177/1352458506075651

5. Akkoç Y, Ersöz M, Yüceyar N, Tunç H, Köklü K, Yoldaş TK, et al. Overactive bladder symptoms in patients with multiple sclerosis: Frequency, severity, diagnosis and treatment. J Spinal Cord Med. 2016; 39(2): 229-233. doi: 10.1179/2045772315Y.0000000021

6. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function: Report from the standardisation sub-committee of the International Continence Society. Urology. 2003; 61: 37-49. doi: 10.1016/s0090-4295(02)02243-4

7. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J. 2010; 21(1): 5-26. doi: 10.1007/s00192-009-0976-9

8. Kalsi V, Fowler C. Therapy insight: Bladder dysfunction associated with multiple sclerosis. Nat Clin Pract Urol. 2005; 2(10): 492-501. doi: 10.1038/ncpuro0323

9. Buser N, Ivic S, Kessler TM, Kessels AGH, Bachmann LM. Efficacy and adverse events of antimuscarinics for reating overactive bladder: Network meta-analyses. Eur Urol. 2012; 62(6): 1040-60. doi: 10.1016/j.eururo.2012.08.060

10. Potenziani BJC. Vejiga hiperactiva. Actualización 2005, CD Educación Médica Continua. Lithomedia Mayo. 2005.

11. Chancellor MB, Anderson RU, Boone TB. Pharmacotherapy for neurogenic detrusor overactivity. Am J Phys Med Rehabil. 2006; 85: 536-545. doi: 10.1097/01.phm.0000219229.92056.c2

12. De Ridder D, Ost D, Van der Aa F, Stagnaro M, Beneton C, Gross-Paju K, et al. Conservative bladder management in advanced multiple sclerosis. Mult Scler. 2005; 11: 694-699. doi: 10.1191/1352458505ms1237oa

13. Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev. 2009; (1): CD004193. doi: 10.1002/14651858.CD004193.pub2

14. Madhuvrata P, Singh M, Hasafa Z, Abdel-Fattah M. Anticholinergic drugs for adult neurogenic detrusor overactivity: A systematic review and metaanalysis. Eur Urol. 2012; 62: 816-830. doi: 10.1016/j.eururo.2012.02.036

15. Zonić-Imamović M, Imamović S, Čičkušić A, Delalić A, Hodžić R, Imamović M, et al. Effects of treating an overactive urinary bladder in patients with multiple sclerosis. Acta Med Acad. 2019; 48(3): 271-277. doi: 10.5644/ama2006-124.267

16. Schurch B, de Sèze M, Denys P, Chartier-Kastler E, Haab F, Everaert K, Plante 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. 2005; 174: 196-200. doi: 10.1097/01.ju.0000162035.73977.1c

17. Ehren I, Volz D, Farrelly E, Berglund L, Brundin L, Hultling C, et al. Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity. Scand J Urol Nephrol. 2007; 41: 335-340. doi: 10.1080/00365590601068835

18. Ginsberg D, Gousse A, Keppenne V, Sievert K-D, Thompson C, Wayne Lam, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol. 2012; 187: 2131-2139. doi: 10.1016/j.juro.2012.01.125

19. Mangera A, Andersson K-E, Apostolidis A, Chapple C, Dasgupta P, Giannantoni A, et al. Contemporary management of lower urinary tract disease with botulinum toxin A: A systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA). Eur Urol. 2011; 60: 784-795. doi: 10.1016/j.eururo.2011.07.001

20. Cruz F, Herschorn S, Aliotta P, Brin M, Thompson C, Lam W, et al. Efficacy and safety of onabotulinumtoxin A in patients with urinary incontinence due to neurogenic detrusor overactivity: A randomised, double-blind, placebo-controlled trial. Eur Urol. 2011; 60: 742-750. doi: 10.1016/j.eururo.2011.07.002

21. Ginsberg D, Cruz F, Herschorn S, Gousse A, Keppenne V, Aliotta P, et al. OnabotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivityregardless of concomitant anticholinergic use or neurologic etiology. Adv Ther. 2013; 30: 819-833. doi: 10.1007/s12325-013-0054-z

22. Tullman M, Chartier-Kastler E, Kohan A, Keppenne V, Brucker BM, Egerdie B, et al. OnabotulinumtoxinA improves urinary symptoms in noncatheterizing patients with MS. Neurology. 2018; 91(7): e657-e665. doi: 10.1212/WNL.0000000000005991

23. Amundsen CL, Richter HE, Menefee SA, Komesu YM, Arya LA, Gregory WT, et al. OnabotulinumtoxinA vs sacral neuromodulation on refractory urgency urinary incontinence in women: A randomized clinical trial. JAMA. 2016; 316(13): 1366-1374. doi: 10.1001/jama.2016.14617

24. Mehnert U, Birzele J, Reuter, K, Schurch B. The effect of botulinum toxin type a on overactive bladder symptoms in patients with multiple sclerosis: A pilot study. J Urol. 2010; 184: 1011-1016. doi: 10.1016/j.juro.2010.05.035

25.  Rovner E, Dmochowski R, Chapple C, Thompson C, Lam W, Haag-Molkenteller C. OnabotulinumtoxinA improves urodynamic outcomes in patients with neurogenic detrusor overactivity. Neurourol Urodyn. 2013; 32(8): 1109-1115. doi: 10.1002/nau.22376

26. Baron M, Peyronnet B, Aublé A, Hascoet J, Castel-Lacanal E, Miget G, et al. Long-term discontinuation of botulinum toxin A intradetrusor injections for neurogenic detrusor overactivity: A multicenter study. J Urol. 2019; 201(4): 769-776. doi: 10.1016/j.juro.2018.10.012

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