What’s new in neurogenic bladder dysfunction treatment? Storage and voiding phases; invasiveness vs effectiveness
the release of the reflexes of the detrusor contraction [6, 7]. Antimuscarinics increase bladder capacity, improve compliance and reduce the amplitude of detrusor contractions resulting in decreased intravesical pressure [1]. A higher dose or drug combination may be needed for better clinical outcomes, increasing, on the other hand, the complication rate and severity [8-14]. Although it is not established, a clear algorithm for drug selection and high-level evidence in neurogenic patients is missing [15 - 17], a lot of studies support the effectiveness of almost all antimuscarinic agents [18 - 21]. Beta 3 agonists, although they show promising signs of improving the symptoms of NLUTD, they did not have a proven urodynamic effect on capacity and detrusor pressure [22, 23]. Alpha-blockers are effective for bladder outlet resistance reduction, while parasympathomimetics are not recommended for improving detrusor contraction [1, 24]. Intermittent catheterisation using an aseptic technique, if it is possible, is the standard option for bladder emptying when spontaneous voiding is impossible or unsafe for the UUT [1, 24]. Indwelling catheters should be kept in case there is no other realistic option available. In this case the suprapubic route is preferable [24]. Intradetrusor botulinum toxin injection (using OnabotulinumtoxinA) is an effective minimally invasive treatment option for NDO [1, 2, 24]. Recently, AbobotulinumtoxinA has received a positive opinion in Europe for the management of urinary incontinence (UI) in adults with NDO due to spinal cord injury (SCI) (traumatic or non-traumatic) or multiple sclerosis (MS), who are regularly performing clean intermittent catheterisation (CIC) [25, 26]. The use of electrostimulation and neuromodulation has been applied in NLUTD. Sacral anterior root stimulation (SARS) accompanied by sacral deafferentation is not favourable nowadays despite the proven long-term good results due to the need for rhizotomies in the era of “regenerative medicine”. Additionally, the abandonment of the method did not allow the evolution of the relative equipment. On the other hand, Sacral Neuromodulation which is widespread for refractory Overactive bladder Syndrome (OAB) is not established as an officially approved treatment option for neurogenic patients. During the last years, SNS on neurogenic patients with incomplete lesions has been studied in several trials and results are very promising [27]. Tibial nerve stimulation has also been tested in NLUTD, but evidence for its effectiveness is still limited [1, 24]. In case minimally invasive treatment is not effective, a surgical approach is recommended [1, 24]. Bladder augmentation is an established procedure that guarantees a low-pressure reservoir with efficient capacity and normal compliance. In female patients where neurogenic Stress Urinary Incontinence (nSUI) is the case, placement of an autologous sling
the use of intermittent catheterisation, administration of alpha-blockers or sphincterotomy of the external sphincter. In some cases, the patient's comorbidities force less favourable solutions, such as continuous bladder drainage through indwelling catheters or incontinent stomas. Similar to a lot of things in medicine, the effectiveness of a treatment is increasing as the invasiveness is increasing as well (Figure 1). This means that the most effective treatment options are the most invasive ones. Intermittent catheterisations and antimuscarinics are the mainstream in the treatment of NLUTD. This management combination is less invasive and has relatively high effectiveness. References 1. Blok B, Castro-Diaz D, Del Popolo J, Groen J, Hamid R, Karsenty G, et al. EAU Guidelines on Neuro-Urology 2022. EAU Guidelines Office, Arnhem. The Netherlands. https://uroweb.org/guidelines/neuro-urology 2. Apostolidis A, Drake MJ, Emmanuel A, Gajewski J, Hamid R, Heesakkers J, et al.: Neurologic Urinary and Fecal Incontinence (Committee 10), In: Incontinence: 6th edition 2017, 6th International Consultation on Incontinence, Tokyo, September 2016. Editors Abrams P, Cardozo L, Wagg A, Wein A. 3. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol. 1981 Aug; 126 (2):205-9. doi: 10.1016/s0022-5347(17)54449-3. PMID: 7196460. 4. Tarcan T, Sekerci CA, Akbal C, Tinay I, Tanidir Y, Sahan A, Sahin B, Top T, Simsek F. Is 40cmH2O detrusor leak point pressure cut-off reliable for upper urinary tract protection in children with myelodysplasia? Neurourol Urodyn. 2017 Mar; 36(3):759-763. doi: 10.1002/ nau.23017. Epub 2016 Apr 15. PMID: 27080436. 5. Tarcan T, Demirkesen O, Plata M, Castro-Diaz D. ICS teaching module: Detrusor leak point pressures in patients with relevant neurological abnormalities. Neurourol Urodyn. 2017 Feb; 36(2):259-262. doi: 10.1002/nau.22947. Epub 2015 Dec 23. PMID: 26693834. 6. Andersson KE. Antimuscarinic mechanisms and the overactive detrusor: an update. Eur Urol. 2011 Mar; 59(3):377-86. doi: 10.1016/j.eururo.2010.11.040. Epub 2010 Dec 8. PMID: 21168951. 7. Yamaguchi O. Antimuscarinics and overactive bladder: other mechanism of action. Neurourol Urodyn. 2010; 29(1):112-5. doi: 10.1002/nau.20796. PMID: 19693952. 8. Horstmann M, Schaefer T, Aguilar Y, Stenzl A, Sievert KD. Neurogenic bladder treatment by doubling the recommended antimuscarinic dosage. Neurourol Urodyn. 2006; 25(5):441-5. doi: 10.1002/nau.20289. PMID: 16847942. 9. Appell RA. Overactive bladder in special patient populations. Rev Urol. 2003; 5 Suppl 8 (Suppl 8): S37-41. PMID: 16985989; PMCID: PMC1502390. 10. Cameron AP, Clemens JQ, Latini JM, McGuire EJ. Combination drug therapy improves compliance of the neurogenic bladder. J Urol. 2009 Sep; 182(3):1062-7. doi: 10.1016/j.juro.2009.05.038. Epub 2009 Jul 18. PMID: 19616807. 11. Amend B, Hennenlotter J, Schäfer T, Horstmann M, Stenzl A, Sievert KD. Effective treatment of neurogenic detrusor dysfunction by combined high-dosed antimuscarinics without increased side-effects. Eur Urol. 2008 May; 53(5):1021-8. doi: 10.1016/j. eururo.2008.01.007. Epub 2008 Jan 17. PMID: 18243516. 12. Nardulli R, Losavio E, Ranieri M, Fiore P, Megna G, Bellomo RG, Cristella G, Megna M. Combined antimuscarinics for treatment of neurogenic overactive bladder. Int J Immunopathol Pharmacol. 2012 Jan-Mar; 25(1 Suppl): 35S-41S. doi: 10.1177/03946320120250s106. PMID: 22652160. 13. Bennett N, O'Leary M, Patel AS, Xavier M, Erickson JR, Chancellor MB. Can higher doses of oxybutynin improve efficacy in neurogenic bladder? J Urol. 2004 Feb; 171(2 Pt 1):749-51. doi: 10.1097/01.ju.0000103274.38694.b1. PMID: 14713802. 14. Menarini M, Del Popolo G, Di Benedetto P, Haselmann J, Bödeker RH, Schwantes U, Madersbacher H; TcP128- Study Group. Trospium chloride in patients with neurogenic detrusor overactivity: is dose titration of benefit to the patients? Int J Clin Pharmacol Ther. 2006 Dec; 44(12):623-32. doi: 10.5414/cpp44623. PMID: 17190372. 15. Madersbacher H, Mürtz G, Stöhrer M. Neurogenic detrusor overactivity in adults: a review on efficacy, tolerability and safety of oral antimuscarinics. Spinal Cord. 2013 Jun; 51(6):432-41. doi: 10.1038/sc.2013.19. PMID: 23743498. 16. Madhuvrata P, Singh M, Hasafa Z, Abdel-Fattah M. Anticholinergic drugs for adult neurogenic detrusor
overactivity: a systematic review and meta-analysis. Eur Urol. 2012 Nov; 62(5):816-30. doi: 10.1016/j. eururo.2012.02.036. Epub 2012 Feb 25. PMID: 22397851. 17. Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev. 2009 Jan 21; (1):CD004193. doi: 10.1002/14651858.CD004193.pub2. Update in: Cochrane Database Syst Rev. 2015; 6: CD004193. PMID: 19160231 18. van Rey F, Heesakkers J. Solifenacin in multiple sclerosis patients with overactive bladder: a prospective study. Adv Urol. 2011;2011:834753. doi: 10.1155/2011/834753. Epub 2011 May 5. PMID: 21687581; PMCID: PMC3114086. 19. Amarenco G, Sutory M, Zachoval R, Agarwal M, Del Popolo G, Tretter R, Compion G, De Ridder D. Solifenacin is effective and well tolerated in patients with neurogenic detrusor overactivity: Results from the double-blind, randomized, active- and placebo-controlled SONIC urodynamic study. Neurourol Urodyn. 2017 Feb;36(2):414-421. doi: 10.1002/nau.22945. Epub 2015 Dec 29. PMID: 26714009. 20. Kaga K, Yamanishi T, Kaga M, Fuse M, Kamasako T, Ishizuka M. Urodynamic efficacy of fesoterodine for the treatment of neurogenic detrusor overactivity and/or low compliance bladder. Int J Urol. 2020 Oct;27(10):899- 904. doi: 10.1111/iju.14319. Epub 2020 Aug 7. PMID: 32767525; PMCID: PMC7589380. 21. Konstantinidis C, Samarinas M, Tzitzika M, Kratiras Z, Panagiotakopoulos G, Giannitsas K, Athanasopoulos A. Efficacy of fesoterodine fumarate (8mg) in neurogenic
Dr. Charalampos Konstantinidis Dept. of Urology, Neuro-Urology Unit National Rehabilitation Center, Athens (GR)
The treatment strategy for Neurogenic Lower Urinary Tract Dysfunction (NLUTD) is based on the individual pathophysiology of the dysfunction as it is documented by urodynamics. Additional aggravating factors such as lithiasis or reflux have to be considered., as well as some specific conditions related to the nature of the neurogenic disease impairing cognitive function or resulting in severe disability. Understanding each patient's needs and dexterities is essential for offering realistic management options [1]. In cases where the restoration of the Lower Urinary Tract (LUT) function is impossible, the management of NLUTD contains two main goals. The first one is the protection of the upper urinary tract. This is a matter of life for these patients. We can achieve this goal by establishing sufficient bladder capacity and compliance accompanied by storage under low pressure and complete voiding under acceptable pressure [2]. The second goal, with equal importance, is the achievement of urinary continence or at least contained continence. This is a matter of Quality of Life. Although there are no clear data regarding the exact secure pressure for the Upper Urinary Tract (UUT) we accept 40cm/H2O as a safe cut pressure in the storage phase [3] and during the voiding phase up to 80cm/H2O. Special consideration has to be taken for impaired compliance. The storage phase takes place during 99.8% of the daytime, so in the case of a low compliance bladder, the upper urinary tract is exposed to higher pressures over a prolonged period, increasing the potential danger for reflux and renal dilatation [4, 5]. Assisted bladder emptying by bladder expression or triggered voiding is not recommended as the LUT is exposed to a high-pressure condition putting the UUT in danger. In exceptional conditions, where relatively low pressures have been documented by urodynamics, assisted bladder emptying can be allowed, under close patient follow-up. Antimuscarinics are the first-line treatment for Neurogenic Detrusor Overactivity (NDO). Their action, in the filling phase, is not only limited to the inhibition of the detrusor contraction but also mediated to the inhibition of afferent stimuli (the sensory part), resulting in the inhibition or delay of
detrusor overactivity due to spinal cord lesion or multiple sclerosis: A prospective study. Neurourol Urodyn. 2021 Nov;40(8):2026-2033. doi: 10.1002/ nau.24790. Epub 2021 Sep 9. PMID: 34498773.
22. Krhut J, Borovička V, Bílková K, Sýkora R, Míka D, Mokriš J, Zachoval R. Efficacy and safety of mirabegron for the treatment of neurogenic detrusor overactivity- Prospective, randomized, double-blind, placebo- controlled study. Neurourol Urodyn. 2018 Sep; 37(7):2226-2233. doi: 10.1002/nau.23566. Epub 2018 Mar 31. PMID: 29603781. 23. Welk B, Hickling D, McKibbon M, Radomski S, Ethans K. A pilot randomized-controlled trial of the urodynamic efficacy of mirabegron for patients with neurogenic lower urinary tract dysfunction. Neurourol Urodyn. 2018 Nov; 37(8):2810-2817. doi: 10.1002/nau.23774. Epub 2018 Aug 31. PMID: 30168626. 24. Ginsberg DA, Boone TB, Cameron AP, Gousse A, Kaufman MR, Keays E, Kennelly MJ, Lemack GE, Rovner ES, Souter LH, Yang CC, Kraus SR. The AUA/SUFU Guideline on Adult Neurogenic Lower Urinary Tract Dysfunction: Treatment and Follow-up. J Urol. 2021 Nov;206(5):1106-1113. doi: 10.1097/ JU.0000000000002239. Epub 2021 Sep 8. PMID: 34495688. 25. Kennelly M, Cruz F, Herschorn S, Abrams P, Onem K, Solomonov VK, Del Rosario Figueroa Coz E, Manu-Marin A, Giannantoni A, Thompson C, Vilain C, Volteau M, Denys P; Dysport CONTENT Program Group. Efficacy and Safety of AbobotulinumtoxinA in Patients with Neurogenic Detrusor Overactivity Incontinence Performing Regular Clean Intermittent Catheterization: Pooled Results from Two Phase 3 Randomized Studies (CONTENT1 and CONTENT2). Eur
is recommended. In males with nSUI, an artificial sphincter placement is a valuable option when there is an increased complication rate, compared to non- neurogenic individuals. A summary of all treatment options for the establishment of low pressure in the LUT is demonstrated in Table I. During the Storage Phase, the administration of antimuscarinics, beta3 agonists and/or botulinum toxin is usually an effective treatment option. If conservative or minimally invasive treatment fails, surgical intervention, mainly by bladder augmentation, is an available and very efficient management option. During the Voiding Phase, low pressure is obtained by
Urol. 2022 Aug;82(2):223-232. doi: 10.1016/j. eururo.2022.03.010. Epub 2022 Apr 7. PMID: 35400537.
26. Denys P, Castaño Botero JC, Vita Nunes RL, Wachs B, Mendes Gomes C, Krivoborodov G, Tu LM, Del-Popolo G, Thompson C, Vilain C, Volteau M, Kennelly M; Dysport CONTENT program group. AbobotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity regardless of spinal cord injury or multiple sclerosis etiology: Pooled analysis of two phase III randomized studies (CONTENT1 and CONTENT2). Neurourol Urodyn. 2023 Jan;42(1):153-167. doi: 10.1002/nau.25062. Epub 2022 Nov 2. PMID: 36321799. 27. van Ophoven A, Engelberg S, Lilley H, Sievert KD. Systematic Literature Review and Meta-Analysis of Sacral Neuromodulation (SNM) in Patients with Neurogenic Lower Urinary Tract Dysfunction (nLUTD): Over 20 Years' Experience and Future Directions. Adv
Figure 1. Treatment options for NLUTD. Invasiveness and effectiveness correlation
Ther. 2021 Apr;38(4):1987-2006. doi: 10.1007/ s12325-021-01650-9. Epub 2021 Mar 13. PMID: 33713279; PMCID: PMC8004509.
Saturday 11 March 13:10 - 13:20 ESFFU Meeting: The complex world of treatment of non-neurogenic and neurogenic bladder dysfunctions Blue Area, Room 1
Table I. Treatment options for NLUTD
European Urology Today
February/March 2023
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