1.2.1

Urinary incontinence and urodynamic findings

From the patient’s perspective, incontinence is the most important symptom and all published studies have focused, as primary outcome measure, on the frequency of urinary incontinence episodes.

Schurch et al. published in 2005 the first phase II trial, which was a randomised, double-blind, placebo-controlled study using onabotulinumtoxinA to treat NDO and urinary incontinence . They recruited 59 patients (53 with SCI and 6 with MS) that were randomised to receive placebo or onabotulinumtoxinA 200 or 300 UI in the detrusor muscle, diluted in 30 ml saline and followed for 24 weeks. Injections were performed using a cystoscope, without anaesthesia, and the trigone was spared.

The authors showed a reduction in the incontinence episodes of approximately 50% in the active treatment groups. The difference, compared to placebo, was significant at 2 and 6 weeks after treatment and, in the 200 UI group, also at 24 weeks after injection.

Patients treated with onabotulinumtoxinA showed a significant increase in the maximum cystometric capacity (MCC), and a decrease in the maximum detrusor pressure during uninhibited bladder contraction (MDP) at all post-treatment time points. Also reflex detrusor volume (RDV) increased in the botulinum toxin groups compared to placebo; moreover, 23 patients did not show any uninhibited detrusor contraction for at least 1 follow-up visit, and among them, 23 were in the onabotulinumtoxinA group.

These results have been replicated in other open-label trials.

Reitz et al. published the first European experience of 200 patients treated with onabotulinumtoxinA for NDO . Among the 200 patients, 11 had MS. All patients received 300 UI of botulinum toxin into the detrusor muscle. Authors found a significant reduction of RDV, MCC and MDP at 12 and 36 weeks after treatment.

Schulte-Baukloh et al. in 2006 recruited 16 patients affected by MS and drug-refractory NDO with incontinence and injected 300 UI of onabotulinumtoxinA in both the detrusor and the striated sphincter (in 14 patients) and the detrusor only in the remaining two . Three hundred UI were diluted in 20 ml of saline. The sphincter received a dose between 50 and 100 UI. Patients were followed at 4 weeks, 3 and 6 months after treatment. Authors declared that this protocol was chosen to reduce the risk of urine retention and subsequent need for self-catheterisation. They found a significant reduction in frequency (night and daytime) and in the use of pads at 4 weeks and at 3 months, but not at 6 months. Also MCC and MDP changed significantly at 4 weeks and 3 months, while for MCC the positive result was not maintained at 6 months. In spite of external sphincter treatment, PVR was significantly increased, passing from 172.67 ± 26.34 ml before treatment to 298.80 ± 41.75 ml after treatment.

Kalsi et al. in 2007 recruited 43 patients with MS and NDO refractory to anticholinergic drugs . They were all treated with 300 UI of onabotulinumtoxinA in the detrusor muscle, diluted in 30 ml saline. All patients had a clinical and urodynamic evaluation before treatment and at 4 and 16 weeks after treatment. The primary endpoint was a reduction of 50% or greater in the number of urgency episodes. Afterwards, patients could ask for a second treatment if symptoms reappeared. Before being considered eligible for a new injection, urodynamic traces needed to be similar to baseline and bladder overactivity present according to a voiding diary.

Eight patients out of 10 achieved the primary endpoint, with a decrease of nearly 80% in the incontinence episodes and an amelioration of MCC of 303% at 4 weeks after treatment, along with a significant reduction of the MDP. These improvements were still present at the 16 weeks follow-up. Interestingly, the mean duration of the beneficial effect was 9.7 months and, of 11.7 months after repeated injections.

Game et al. in 2008 published the results of a prospective, non-randomised trial carried out in 30 patients with NDO (15 patients had MS) who managed the bladder by clean, intermittent self-catheterisation (CISC) and had recurrent urinary tract infections (UTI) . All patients received 300 UI of onabotulinumtoxinA into the detrusor muscle. The number of infections 6 months before and 6 months after treatment was recorded. Authors noted a significant reduction in the number of symptomatic UTI, along with an improvement in MCC, RDV and MDP. In the 3 patients who still had symptomatic UTI after treatment urodynamic parameters did not improve after injection. Authors suggested that the decrease in symptomatic UTI after onabotulinumtoxinA treatment was probably related to the effect of the drug on detrusor overactivity.

Deffontaines-Rufin et al. published their own experience in 71 patients with MS and refractory NDO, all treated with 300 UI of onabotulinumtoxinA in the detrusor muscle . Patients were divided in three groups according to clinical results:

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  “full success”: urge urinary incontinence totally disappeared and no evidence of involuntary bladder contractions during urodynamic assessment;

  
  
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  “improvement”: reduction of 50% of urge urinary incontinence episodes, with improvement of at least 50% in RDV, MCC and a decrease of MDP of at least 50%;

  
  
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  “total failure”: patients showed unchanged incontinence and/or urodynamic parameters.

After onabotulinumtoxinA treatment, 46% of patients was assigned to group 1 (full success), 31% to group 2 (improvement) and 23% to group 3 (total failure). Authors found that patients who had a disappointing result had longer duration of disease compared to the other two groups.

Most level 1 evidence about the treatment of NDO with onabotulinumtoxinA, however, has been published in the last three years.

In 2011 Herschorn et al. published the results of a randomised, double-blind, placebo-controlled trial conducted in Canada in a group of 57 patients with urinary incontinence due to NDO . The origin of NDO was SCI in 38 patients and MS in the remaining 19. The study was divided in two parts, the first, blinded, in which patients received either onabotulinumtoxinA 300 UI diluted in 30 ml of 0.9% saline or placebo in the detrusor using cystoscopy; patients were then followed up to 36 weeks. Then, patients of both groups were elected to receive onabotulinumtoxinA in the second, open-label part of the study, with a programmed follow-up of 6 months. The primary outcome measure was the number of urinary incontinence episodes per day at week 6 and secondary outcomes were urodynamic parameters at week 6 and at other time points. Authors found a reduction in urinary incontinence episodes of around 50% at weeks 6 and 24 and of 25% at week 36, which is comparable to what was observed by Schurch et al. . Also urodynamic parameters (RDV, MDP, MCC) improved significantly at weeks 6, and 24, with MDP that was still lower than baseline at week 36.

In 2011 and then in 2012 the results of a large randomised, double-blind, placebo-controlled trial (Double-Blind Investigation of Purified Neurotoxin Complex in Neurogenic Detrusor Overactivity [DIGNITY]) were published.

This study was carried out in 63 centres in Europe, North and Latin America, South Africa and Asia Pacific. The first results published by Cruz et al. included data of 275 patients with MS ( n = 154) and SCI ( n = 121) with urinary incontinence due to NDO, randomised to receive either placebo ( n = 92) or onabotulinumtoxinA 200 UI ( n = 92) or 300 UI ( n = 91) in the detrusor muscle . The objective was to evaluate the efficacy and safety of the treatment. The study was divided in 2 parts. The modalities of drug administration and study design for the first part was the same of Schurch et al. . For the second part, and at least 12 weeks after the first treatment, patients could request for reinjection. To qualify for reinjection criteria were to have a <30% reduction of weekly urinary incontinence episodes compared to baseline. Patients who received primarily onabotulinumtoxinA had the same treatment with the same doses, and patients who had placebo were randomised to receive either 200 or 300 UI.

Primary end point was the change from the baseline in the number of urinary incontinence episodes per week (the study was designed to detect a difference of 30% between the active and placebo groups). Then, secondary outcome measures were MCC, MDP, volume per void, detrusor compliance, volume at first involuntary detrusor contraction. The study was not powered for evaluation by aetiology (MS versus SCI).

Data showed a significant reduction in the number of urinary incontinence episodes in both 200 and 300 UI groups, as opposed to placebo, with no difference between the two doses, at 2, 6 and 12 weeks after treatment, confirming Schurch et al. findings . Nearly 40% of patients in the onabotulinumtoxinA groups were fully continent at week 6. There was also a significant improvement in all urodynamic parameters in both active treatment groups compared to placebo, with no meaningful difference between them. The median duration of effect (which was the time to patient-requested retreatment) was of 42.1 weeks for both onabotulinumtoxinA groups as opposed to 13.1 weeks for the placebo group.

After the second cycle of treatment, results were substantially repeated, with significant improvements in the number of urinary incontinence episodes and urodynamic parameters at 6 weeks.

The DIGNITY study program included also the second study, carried out in 85 centres and published in 2012 by Ginsberg et al. . This is the largest randomised, placebo-controlled, double-blind study of onabotulinumtoxinA for urinary incontinence in patients with NDO. The design, inclusion and exclusion criteria were the same of the study by Cruz et al. . Also primary and secondary end points were the same. In this study, authors included 416 patients (227 with MS and 189 with SCI), which were followed for 52 weeks. Of them, 329 (79%) completed the 52-week study.

This study showed again at week 6 a significant reduction in the number of urinary incontinence episodes in the treatment groups but not in the placebo group, which was slightly higher than previously reported (−30, −67 and −74% change from baseline for the placebo, for the 200 and 300 UI groups, respectively), with no difference between the active treatment groups. This study confirmed also the results of Schurch et al. and those of Cruz et al. about urodynamic improvements after onabotulinumtoxinA treatment. The median time to patient request for another treatment was significantly higher in the onabotulinumtoxinA groups compared to placebo (92, 256 and 254 days for the placebo, the 200 and the 300 UI respectively), as the median time for requalification for a new treatment (96, 295 and 337 days for the placebo, the 200 and the 300 UI respectively). Similar results were obtained in patients with MS and SCI.

The efficacy of onabotulinumtoxinA on repeated injections was evaluated by Gaillet et al. that showed in a group of 31 patients (10 of them had MS) that the effect of the drug on the reduction of episodes of urinary incontinence and at urodynamic level was maintained up to 5 years. Previously, other authors have reported results of repeated intradetrusor onabotulinumtoxinA treatment for NDO . Only few patients with MS were included (4/66 patients in the paper by Grosse et al. and 2/20 patients in that of Reitz et al.). However, both studies showed that the efficacy of the treatment was maintained over time, with 17 patients that had at least 4 treatments in a study and 20 that had at least 5 treatments in the other .

1.2.2

Quality of Life (QoL)

Randomised, placebo-controlled studies have demonstrated that the treatment of NDO with onabotulinumtoxinA significantly improve QoL in patients with SCI and MS. This has been first shown by Schurch et al. ; in this study, QoL was evaluated with the Incontinence Quality of Life Questionnaire (I-QOL); patients in either 200 or 300 UI groups showed a meaningful improvement at all time points, maintained throughout the 24 study weeks. The complete results have been published thereafter , and data regarding the three subscales of I-QOL (avoidance and limiting behaviour, psychosocial impact and social embarrassment) presented. In the 300 UI group total and all subscale scores improved significantly compared to placebo at weeks 6, 12, 18 and 24, whereas patients in the 200 UI group had the same results except for Psychosocial Impact and Social Embarrassment Score at 24 weeks.

These results have been strongly confirmed by subsequent randomised, placebo-controlled trials , even if QoL was considered as a secondary outcome.

Other open-label studies have specifically evaluated QoL as a primary outcome measure.

Kalsi et al. in two studies evaluated QoL after onabotulinumtoxinA treatment for detrusor overactivity . In the first study , they assessed 48 patients, of whom 32 had NDO (and among them, 24 had MS), while 16 had IDO. Patients with NDO were treated with 300 UI of onabotulinumtoxinA and those with IDO with 200 UI. Even if, after treatment, 29 patients with NDO and 2 out of 16 with IDO had to perform CISC to empty bladder (respectively they were 14 in the NDO and 0 in the IDO group before treatment), QoL, evaluated by the Urinary Distress Inventory (UDI) and the Incontinence Impact Questionnaire (IIQ) was improved, at both 4 and 16 weeks after treatment.

In the second study performed on a group of 43 patients with MS, treated with onabotulinumtoxinA for NDO, Kalsi et al. again showed a significant improvement in QoL, measured by the same assessment tools.

The results of these two studies suggest that the need for de novo CISC had a less impact than the relief from the symptoms of urgency on a base of one or maximum two treatments.

Khan et al. addressed the question if the improvement in QoL would have persisted also in the longer term. They published the results of a prospective, open-label study done in 137 patients with MS and NDO over 8 years . Patients had been treated with 300 UI of onabotulinumtoxinA in the detrusor muscle, 6 times. The indication to repeat the treatment was the reoccurrence of symptoms with presence of detrusor overactivity during urodynamic evaluation. Of 137 patients, 99 returned for a second treatment, 47, 25, 14 and 5 returned for the treatments 3 to 6. Median interval between treatments was nearly 13 months. All patients had an evaluation of QoL using the UDI and the IIQ, at 4 and 16 weeks after each treatment. Results show that both scores had a significant improvement after each treatment. In this study, 76% of patients were completely continent 4 weeks after treatment, compared to 17% before treatment. Even if 95% of patients had to void bladder by CISC (65% before treatment), the improvement in QoL outweighed this adverse event.

1.2.3

OnabotulinumtoxinA and detrusor-sphincter dyssynergia

There is much less evidence about the effect of onabotulinumtoxinA in the striated sphincter in patients with MS. Gallien et al. published a randomised, placebo-controlled, double-blind study of the effects of onabotulinumtoxinA on DSD in patients with MS . Authors recruited 86 patients with MS and randomised the group to receive either 100 UI of onabotulinumtoxinA diluted in 4 ml of 0.9% saline or placebo into the striated sphincter, using a coaxial needle during electromyography. The primary outcome measure was the PVR at 1 month after treatment. Other urodynamic variables (among them MDP, maximal urethral pressure, cloture urethral pressure, MCC) were analysed. Also obstructive symptoms, pollakiuria, urgency, incontinence, voiding volume and International Prostatism Symptoms Score were recorded. Evaluations were done before and at 1, 2, and 3 months after treatment. No reduction in the PVR after treatment, and no amelioration of obstructive symptoms were observed after treatment as compared to placebo, even if patients treated with onabotulinumtoxinA showed at 1 and 2 months after treatment an increase in the voiding volume and a reduction in the MDP and in the maximal and cloture urethral pressure.

1.2.4

Adverse events

After onabotulinumtoxinA treatment in the detrusor muscle, the main adverse events that have been reported in literature are urinary tract infections and urinary retention.

Urinary tract infections (UTI) have been reported in a significant proportion of patients after both onabotulinumtoxinA and placebo treatment. The proportion of UTI vary between studies: Schurch et al. found a prevalence between 14.3% (placebo group) and 31.6% (200 UI group), Herschorn et al. reported that 55% of patients in the placebo group and 57% of those in the onabotulinumtoxinA 200 UI group had UTI. Cruz et al. showed a frequency of UTI of 22.2–38.2% of patients. In the largest trial, performed by Ginsberg et al., the frequency of UIT was between 18 and 28% during the first 12 weeks, and of 34–50% during the entire first, blinded, part of the study.

Frequency of UTI did not significantly differ among placebo and onabotulinumtoxinA groups, except in the largest study ; authors found a similar incidence of UTI in all groups in the SCI population but a higher incidence in the patients with MS that received onabotulinumtoxinA. However, it should be noted that in all these studies the adverse event term of UTI did not distinguish between symptomatic and asymptomatic UTI, because it was primarily based on a positive urine culture. Clinicians and patients should be aware that symptomatic UTI is a very common condition among patients with NDO, affecting 29 to 36% of patients, as evident from a large study on 46,000 patients .

At present time, no evidence exists about antibiotic prophylaxis of UTI before and after onabotulinumtoxinA intradetrusor injections, even if it seems to be a common practice among clinicians . Mouttalib et al. in a case series reported an incidence of UTI in 7.1% (3 out of 42 patients) in the first week after onabotulinumtoxinA treatment in patients with NDO of different origin. Based on this data and their experience, they recommended an antibiotic prophylaxis after the procedure. Many injectors also accept this point of view.

Urinary retention can be partially considered as a logical consequence of the inhibitory effect of onabotulinumtoxinA on the detrusor muscle contraction. Urinary retention is reflected by the increase in the PVR. At present time, a consensus does not exist about at which volume CISC should be initiated. However, an upper limit of the PVR of 100 ml is considered in the UK guidelines as an indication to start CISC in patients with MS . It should be remembered that patients with MS are frequently reluctant to start catheterisation and/or can have sensory, cerebellar and visual disturbances that may prevent or make difficult CISC.

The proportion of patients that required CISC to void the bladder varies in the different studies. Kalsi et al. reported that 88% of patients with NDO required CISC after onabotulinumtoxinA treatment. In a subsequent study done on patients with MS, by which 65% were performing CISC before treatment, all but 1 patient (out of 43) needed catheterisation after injection.

Similarly, Khan et al. reported that the proportion of subjects that relied on CISC to void the bladder passed from 65% before treatment to 95% after treatment.

Similarly, Ginsberg et al. showed that, out of 60% of patients who did not catheterise before treatment, 42% of those treated with 300 UI of onabotulinumtoxinA, 35% of those that received 200 UI and 10% of those who had placebo initiated catheterisation. It should be pointed out that, as the protocol had no defined PVR at which to initiate CISC, initiating catheterisation due to urinary retention was based on investigator assessment. This result can be read in different ways: the most obvious is that patients with NDO who are treated with onabotulinumtoxinA frequently need to start CISC, but also that a relevant proportion of patients with NDO have the indication to start CISC.

Finally, to reduce the risk of urinary retention, Mehnert et al. performed a study including 12 patients with MS and NDO who were treated with only 100 UI of onabotulinumtoxinA into the detrusor muscle, diluted in 10 ml of saline 0.9%. The objective was to assess if this dose was sufficient to control symptoms and to avoid urinary retention. Their results showed that 100 UI of onabotulinumtoxinA was able to ameliorate urodynamic parameters (MCC, FDV and MDP) and urgency at 12 weeks, while the control of urinary incontinence was only significant at 6 weeks after treatment and not at 12 weeks. Moreover, even if CISC was necessary only in 2 patients (and one needed a suprapubic catheter), PVR significantly increased. In this study, the need for CISC was based on symptoms instead of a certain volume of PVR. Authors concluded that 100 UI onabotulinumtoxinA are effective in reducing urgency and frequency and in ameliorating urodynamic parameters in MS patients, but cannot completely avoid the risk of utilising CISC.