Hellenic Urology

: 2020  |  Volume : 32  |  Issue : 3  |  Page : 103--108

Intravesical botulinum toxin Type A injection therapy in neurological patients: A single center experience

Ioannis Apostolidis, Efstathios Papaefstathiou, Eleni Ioannidou, Petros Georgopoulos, Konstantinos-Vaios Mytilekas, Marina Kalaitzi, Apostolos Apostolidis 
 2nd Department of Urology, “Papageorgiou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

Correspondence Address:
Apostolos Apostolidis
2nd Department of Urology, “Papageorgiou” General Hospital, Aristotle University of Thessaloniki, Ring Road, Nea Efkarpia, 56403 Thessaloniki


Objectives: The objective of this study is to present real-life data on the efficacy and safety of the intravesical injection of the approved dose of 200U BOTOX in patients with drug-resistant incontinence of neurogenic etiology. Available literature is relatively limited. Materials and Methods: We analyzed routinely collected prospective data from the treatment of patients with neurogenic drug-resistant incontinence who attended an academic neurourology outpatient clinic. All patients received at least one intravesical injection of 200U BOTOX, following urodynamic confirmation of neurogenic detrusor overactivity while recording the presence of urinary tract infection (UTI). Patients were followedup at 6 and 24 weeks with urodynamic retests. This protocol was followed with each repeat treatment, while recording the relapse time of incontinence. Results: Forty-nine patients (28 males, 21 females, mean age 47.04 ± 14.16 years) were treated; 18 (36.7%) suffered from spinal cord injury, 12 (24.54%) from multiple sclerosis, and the rest from other neurological conditions. Fifteen received a 2nd Botox treatment, 10 a 3rd, 6 a 4th, and one a 5th and 6th session. Forty-two (85.7%) patients had urodynamically proven incontinence and in 14 (28.6%) an UTI was identified before the first treatment. Subjective cure of incontinence was recorded in 73.7% of patients after the first treatment. There was no correlation of gender, neurological diagnosis, or presence of UTI before the BOTOX treatment with the persistence of incontinence. The median relapse time after the first two treatments was 6 (interquartile range = 5) and 10.5 months, respectively (P = 0.31). Significant improvements were recorded urodynamically in maximum cystometric capacity after each treatment (P < 0.001) and in maximum detrusor pressure after the first session compared to baseline (P < 0.05, Bonferonni correction). The presence of UTI did not affect the incontinence relapse time or urodynamic changes after initial treatment. Conclusions: In the present cohort, intravesical administration of 200U BOTOX achieved complete cure of neurogenic drug-resistant incontinence in a significant proportion of patients with sustained clinical and urodynamic changes after each repeat injection.

How to cite this article:
Apostolidis I, Papaefstathiou E, Ioannidou E, Georgopoulos P, Mytilekas KV, Kalaitzi M, Apostolidis A. Intravesical botulinum toxin Type A injection therapy in neurological patients: A single center experience.Hellenic Urology 2020;32:103-108

How to cite this URL:
Apostolidis I, Papaefstathiou E, Ioannidou E, Georgopoulos P, Mytilekas KV, Kalaitzi M, Apostolidis A. Intravesical botulinum toxin Type A injection therapy in neurological patients: A single center experience. Hellenic Urology [serial online] 2020 [cited 2021 Jun 15 ];32:103-108
Available from: http://www.hellenicurologyjournal.com/text.asp?2020/32/3/103/310044

Full Text


Patients with neurological disorders such as spinal cord injury (SCI) and multiple sclerosis (MS) often develop neurogenic overactivity of the detrusor muscle, characterized by the presence of involuntary contractions during the filling phase. Neurogenic lower urinary tract dysfunction may also lead to decreased bladder capacity, decreased bladder compliance, increased urinary frequency, urgency, urinary incontinence (UI), and deterioration of the quality of life. Sometimes, increased intravesical pressures may lead to severe incontinence, vesicoureteral reflux with renal damage, and end up to chronic renal disease.[1],[2],[3]

Anticholinergic drugs with or without intermittent catheterizations constitute the current mainstay in the treatment of the symptoms of neurogenic bladder. However, the prolonged use of anticholinergics may be limited due to the development of drug-resistance or decreased tolerability to side effects such as dry mouth and constipation, which may already be present in the neurological patients.[4] Intradetrusor injection of botulinum toxin type A is an approved second-line therapy offered to patients with neurogenic incontinence due to MS or SCI who discontinue medication due to inadequate response or intolerable side effects from oral pharmacotherapy.

Botulinum neurotoxin (BoNT) is formed by the Gram-positive, anaerobic spore-forming bacteria Clostridium botulinum and is considered to be one of the most powerful neurotoxins in nature. Of the seven different types of BoNT (A, B, C, D, E, F, and G), only types A and B are used in medical practice (chronic migraines, chronic pain, head and neck dystonia, strabismus, hyperhidrosis, and other indications).[5] The use of BoNT type A (BoNT/A) in lower urinary tract disorders was first described by Dykstra et al. in 1988 as a treatment for detrusor-sphincter dysynergia. The use of intravesical injection of BoNT/A for the treatment of severe neurogenic detrusor overactivity (NDO) associated with UI was first described in 2000 by Schurch et al. in patients with SCI inadequately responding to anticholinergics.[6],[7],[8] Its action is now thought to involve the inhibition of acetylcholine release at the neuromuscular junction level, resulting in reduced spasticity of the overactive detrusor, while at the same time inhibiting the expression of sensory receptors in the mucosa and decreasing the pathological urgency to urinate and consequently, UI. Until recently, it was thought it had a low ability to migrate to surrounding and distal tissues, therefore selective injection allows specific paralysis of the overactive detrusor muscle.[9] It causes long-term but reversible chemical denervation of the bladder lasting about 9 months.[10] The side effects are generally rare, they are more commonly associated with higher doses or short intervals between injections. Quantities that reach systemic circulation are very small because the injections are localized, and the overall dose is much less than the lethal.[11]

The approval of intravesical botulinum toxin type A injection at the 200U dose of onabotulinumtoxinA (BOTOX®) as the second-line treatment for drug-resistant neurogenic UI[3],[10] was based on the results of two randomized Phase III multicenter studies of 52 weeks' duration by Cruz et al. in 2011 and Ginsberg et al. in 2012 in patients with NDO. Both studies showed that BoNT/A (BOTOX®) significantly reduced episodes of incontinence, improved urodynamic parameters, and quality of life compared to placebo.[12],[13] The long-term efficacy of BOTOX® therapy in this patient population was also confirmed in a 3-year, prospective multicenter study in which clinically significant improvements in storage symptoms and quality of life were observed.[2]

 Materials and Methods

Study design

This is an observational study of patients with drug-resistant incontinence of neurogenic etiology who attended the specialized neuro-urology outpatient clinic of the 2nd Urological Department of the Aristotle University of Thessaloniki in “Papageorgiou” General Hospital. Patients were informed about possible side effects such as decreased bladder contractility and urine retention, and the need to learn the use of self-catheterization for emptying their bladder posttreatment, if not already on clean intermittent catheterizations. After patient written consent was requested, all were subjected to urodynamic investigation and intravesical treatment with 200 units of botulinum toxin type A (BOTOX®, Allergan) while recording the presence of urinary tract infection (UTI). Patients were assessed for changes in the daily episodes of UI from baseline at 6 weeks posttreatment (primary outcome), while changes in maximum cystometric capacity (MCC), maximum detrusor pressure (Pdetmax) during the filling (PdetF), and emptying phases (PdetV) at the same time point were the secondary parameters under evaluation. Patients were screened at regular intervals (6 and 24 weeks) with urodynamic retests and some underwent repeat treatments, while the time of relapse of incontinence was recorded.


Patients selected for the intravesical treatment with botulinum toxin type A presented urodynamic detrusor overactivity with urodynamically and/or clinically demonstrated UI, which was resistant to at least two trials of drug therapy (monotherapy or combination therapy) of at least 3-month duration each. Other criteria for the inclusion in the treatment were exceedingly high intravesical pressures during the filling phase and discontinuation of treatment due to unacceptable adverse effects. Any UTI present at baseline (upon urine culture performed a week before the injection) was treated with an antibiotic selected on the basis of the results of the urine culture and antibiogram.

The exclusion criteria were as follows:

  1. Nonacceptance of the risk of incomplete bladder emptying and the possible need for self-catheterizations posttreatment
  2. Inability of the patient and/or his/her caregivers to perform self-catheterization
  3. No prior treatment for neurogenic overactive bladder and associated incontinence
  4. Simultaneous therapy with botulinum toxin in a dose equal to or greater than 200U Botox for other pathological reasons (par example limb spasticity).

Injection technique

According to the dilution instructions of the formulation, two vials of 100 U BOTOX® were reconstituted each with 6 ml of sterile saline without preservatives. Four (4) ml of each vial were aspirated into each of two 10 ml syringes and 2 ml of each vial in a third 10 ml syringe. Reconstitution was completed by adding 6 ml of sterile saline to each of the three syringes. Finally, three 10 ml syringes were obtained with a total of 200U of reconstituted BOTOX solution and were used directly.[14]

Intravesical injections were performed using a rigid 17.5-French cystoscope and a 30° imaging optical fiber under regular local anesthesia at the cystoscopy outpatient clinic. A flexible cystoscope was used in two patients, while in another two patients BOTOX was administered under general anesthesia in the operating theater.

A flexible 27G needle was used with a length of 650 mm and a functional 5 mm needle length (UROMED UROject® Injection Cannula, distributor Vivamed GR) passing through the cystoscope.

Essential criteria for needle selection were as follows:

  • Avoiding the risk of piercing the bladder wall
  • Ensuring stable and targeted injections
  • Ease of use and low cost
  • Sharpness – easy and nontraumatic penetration to avoid bleeding
  • Lower risk of pain from the injections
  • Low chance of cystoscope damage
  • Flexibility of the shaft for better feel and use in the flexible cystoscope
  • Allowing connection with a syringe through luer lock.[14]

Thirty injections of 1 ml of reconstituted BOTOX solution (6.67U BOTOX per injection site) were delivered at different sites of the bladder, following the mapping of the bladder wall proposed in the product's datasheet, the distance between them was 1 and 1.5 cm with a half-full bladder to avoid over-distension and thinning of the wall [Figure 1]. The bladder triangle was avoided as in the original technique described by Schurch et al. and according to the product's (BOTOX®) data sheet, although some published studies have shown that trigonal BOTOX injections are safe and effective.[15],[16] The duration of the procedure ranged between 20 and 30 min. The first assessment of the patients was made 7 days posttreatment through telephone communication, when patients were questioned about symptomatic improvement and possible side effects.{Figure 1}

Statistical analysis

The data were analyzed using the IBM Statistical Package for the Social Sciences (SPSS), version 24 (IBM Corp., Armonk, N.Y., USA) for Windows. Initially, we calculated the frequencies of the variables as well as the position and dispersion measures for each of the parameters. We then checked the normality of the data and the appropriate parametric and nonparametric tests were selected. The data that were normally distributed are presented using the mean (MT) and standard deviation, while those not normally distributed are presented with the median (MD) and the interquartile range (IQR). The association of gender, initial neurological diagnosis, and presence of UTI with the persistence of incontinence (test x2) was then examined. MCC, PdetF, and PdetV were assessed at baseline and after each BOTOX injection (Friedman test), further analysis was performed on subgroups of patients after each session (paired t-test, Wilcoxon signed-ranks test – Bonferroni correction). In addition, the changes in MCC, PdetF, and PdetV were compared between the first 3 treatment sessions (repeated-measures analysis of variance [ANOVA] and Friedman test). In addition, the relapse time between the 1st and 2nd session was compared (Wilcoxon signed-ranks test). Finally, the effect of UTI on the time (measured in months) until the first relapse and on the changes in MCC, PdetF, and PdetV after the 1st treatment were examined (t-test, Mann–Whitney test). In all assays, the level of statistical significance was set at 0.05 and the confidence interval of 95% corrected by Bonferroni in the subgroup analyzes.


The study material included 49 patients, 28 men (57%) and 21 women (43%). The mean age of the patients was 47.04 ± 14.16 years; 4 patients with meningomyelocele underwent the first BOTOX treatment in childhood, following approval by the Greek Food and Drug Administration. Eighteen (36.7%) patients suffered from SCI, 12 (24.54%) had MS, and the remaining 19 (38.7%) other (neurological) conditions: 5 patients with meningomyelocele, 1 with Parkinson's disease, 1 with spinal cord ependymoma, 1 with Addison's disease/thalassemia/secondary hypogonadism, 1 with postradiotherapy myelopathy, 1 with Adamantiadis-Behçet syndrome, 1 with hereditary spastic paraparesis, 1 with arteriovenous malformation at the 8th thoracic vertebra, 1 with anterior spinal cord syndrome, 1 with cervical myelitis, 1 with cerebellar tumor, 1 with spinal cord hemorrhage, 1 with cervical myelopathy, and 2 with undefined neurological problems. Nearly 85.7% of the patients (42 individuals) suffered from incontinence and in 28.6% (14 individuals) symptomatic UTI was diagnosed before the first treatment. All patients received at least one bladder BOTOX session, 15 were treated with a 2nd BOTOX injection, 10 with a 3rd, 6 with a 4th, and one with a 5th and a 6th injection, respectively. After the first treatment, incontinence was cured in 73.7% of patients, 73.3% after the 2nd session, 60% after the 3rd, 66.6% after the 4th, 100% after the 5th, and 100% after the 6th injection. There was no statistically significant correlation of gender, initial disease condition or presence of UTI before the BOTOX treatment, and the persistence of incontinence (treatment failure) [Table 1].{Table 1}

The median relapse time after the first treatment was 6 months (IQR = 5) and after the 2nd treatment 10.5 months (IQR = 9) (Wilcoxon signed-ranks test, P = 0.31). As for the urodynamic findings at baseline and after each treatment (results from the first 3 sessions), there was a statistically significant difference in MCC and PdetV values [Table 2].{Table 2}

Further, subgroup-analysis between the groups revealed an increase in MCC after each treatment compared with the initial value. On the other hand, Pdetmax (both filling and voiding) showed a statistically significant reduction only after the first session [Table 3].{Table 3}

Regarding the efficacy of BOTOX after successive sessions, the increase in MCC and the reductions in PdetF and PdetV were compared between the first three sessions. There was no statistically significant difference in MCC increase (P = 0.867 Friedman test), PdetF (P = 0.813 repeated measures ANOVA), and PdetV reductions (P = 0.565, Friedman test) between the three sessions.

In addition, the effect of treated pre-BOTOX UTIs on the time (months) until the 1st relapse was investigated (MD = 6, IQR = 4 for those who did not suffer from UTI compared to MD = 11 months IQR = 6 in UTI patients, P = 0.313 Man–Whitney test).

The impact of UTIs on urodynamic values was also examined. There was no difference in MCC increase after BOTOX injection in patients with a pretreatment UTI compared to those without infection (MD = 206.5 ml IQR = 428.5 ml in those who did not have UTI versus MT shift = 408 ml ± 332 ml in those with UTI P = 0.361, Mann–Whitney test). Similarly, there was no significant difference in Pdet filling (P = 0.227, t-test,) and Pdet voiding (P = 0.836, t-test) reduction when controlled for UTI.


As in earlier published studies, in our patient cohort, there was a significant improvement in incontinence episodes with ¾ of them being cured, which appeared to be sustained in at least two repeat sessions. Of the factors examined (gender, initial disease diagnosis, and UTI), none seemed to affect the improvement of incontinence negatively. Furthermore, the time intervals between repeat administrations of BOTOX (determined by the time of relapse of incontinence) were no different. Similarly, the urodynamic findings demonstrated that the 1st BOTOX session significantly improved both MCC and Pdetmax without any difference in efficacy between repeat sessions (with evaluable data up to three injections). Finally, the presence of a treated UTI before the 1st BOTOX injection did not affect the interval up to the 1st relapse or the change in MCC and the maximum detrusor pressure during the filling phase before and after the initial treatment.

This real-life study demonstrates significant improvements with the 200U dose of BOTOX in the primary treatment outcome which was reduction in incontinence episodes. Complete cure of incontinence was achieved in a significant percentage of patients (73.7%) from the first intravesical injection. Similarly, we noted significant increases in MCC and reductions in maximum detrusor pressure in the filling phase, with changes in MCC sustained with each repeat injection. In addition, in our study, the presence of UTI, which was treated, did not appear to affect the results of the 1st treatment with botulinum toxin Type A.

The results are consistent with previously well-designed studies.[1],[2],[17] More specifically, in a Phase III study of 52 weeks investigating the efficacy of BOTOX 200U in 195 patients suffering from neurogenic overactive bladder, Denys et al. demonstrated a reduction in UI episodes from the first intravesical injection in the majority of patients (83.1% [162/195]). Patients were stratified into the following response groups: <50% UI reduction (Group 1; n = 33); 50%–74% UI reduction (Group 2; n = 23); and 75%–100% UI reduction (Group 3; n = 139). The mean percent reduction in daily UI episodes at treatment 1 was 4.9%, 64.4%, and 96.0% in response Groups 1, 2, and 3, respectively.

In a prospective long-term study by Kennelly et al. on the efficacy and safety of botulinum toxin type A treatment in 396 patients, 240 of which were followed for 4 years, a decrease of >50% in incontinence episodes per day was observed in 83%, while the percentage of patients with complete incontinence cure ranged from 43% to 56%.[2]

In an earlier analysis of two randomized, multicenter, double-blind, placebo-controlled studies, which evaluated the efficacy of 200U and 300U BOTOX treatment, Rovner et al. found that 2/3 of the patients did not show involuntary contraction of the detrusor after the first treatment, while in the remaining 1/3, the maximum detrusor pressure was significantly reduced in the involuntary contraction phase. Furthermore, the urine volume upon the first involuntary detrusor contraction increased significantly. Increase was also noted in MCC (P < 0.001) after the first intravesical injection without significant difference between the two groups (200/300U). The average reduction of UI episodes was 69% and 68% for the 200U and 300U group, respectively, while complete cure of incontinence was achieved in 37% and 40.9% of patients, respectively (200/300U).[17]

There are conflicting reports about whether intradetrusor botulinum toxin type A injection can reduce UTI s in patients with neurogenic bladder. Gamé et al. reported that intravesical injection of botulinum toxin type A significantly reduced the incidence of symptomatic UTI in patients with neurogenic bladder.[18] However, Herschorn et al. in a double-blind study reported that the incidence of UTIs remained unchanged in patients with neurogenic overactive bladder.[19] Finally, Cruz F. et al. showed that the incidence of UTIs remained unchanged in patients with spinal cord injuries and increased in patients with MS following an intravesical injection of botulinum toxin type A into the overactive detrusor.[13]

The small number of patients with neurogenic overactive bladder is a limitation of our study and may not allow for robust conclusions.


In this real-life study of a small cohort of patients with NDO, intravesical injection of BOTOX 200U achieved complete cure of drug resistant incontinence in a significant proportion of patients, with sustained changes in urodynamic parameters and symptomatic improvement with each repeat injection.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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