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Patients with suprasacral SCL or MS often have lower urinary tract dysfunction during the storage phase.[1, 2] Because of urinary UI and high detrusor pressure, NDO severely degrades QOL and upper urinary tract function. The major goal of any treatment of patients with NDO is the preservation of QOL and upper urinary tract function. First-line treatment for NDO secondary to SCL or MS is usually antimuscarinics with or without CIC. Antimuscarinics improve bladder compliance, reduce symptoms, prevent upper urinary tract damage and improve QOL. However, patients with NDO generally require a higher dose of antimuscarinics and have a high incidence of intolerable AE, such as dry mouth, constipation and blurred vision. Furthermore, in many cases, antimuscarinics are not efficacious.
BoNTA is a pharmacological neurotransmission blocking agent that cleaves the SNARE protein SNAP-25, preventing docking and fusion of vesicles with the nerve terminal. In the bladder, this causes relaxation of the detrusor muscle by inhibiting acetylcholine release from efferent nerves, and it might also inhibit sensory afferent pathways through the inhibition of other vesicle-dependent neurotransmitters and SNARE-dependent receptor expression.
BoNTA injection into the bladder was introduced in 2000 as a minimally-invasive treatment for NDO. Randomized, prospective studies have shown a significant improvement in continence status and QOL.[8, 9] To date, nearly 10 years after the first report of BoNTA injection into the bladder, the use of BoNTA continues to expand in the field of urology to treat idiopathic overactive bladder, interstitial cystitis/painful bladder syndrome, benign prostatic diseases and ureteral stent pain.[10-13] There are few studies of BoNTA injection for Japanese patients with non-neurogenic overactive bladder. However, to our knowledge, the clinical outcomes of BoNTA injection for Japanese patients with NDO have not been clarified.
Between January 2003 and March 2011, 40 injections of BoNTA were given to 11 patients with NDO who showed lack of antimuscarinic efficacy or intolerance as a result of AE. Therefore, the aim of the present study was to determine the clinical outcomes of BoNTA injection for Japanese patients with NDO.
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A total of six women and five men were treated. NDO was secondary to spinal cord injuries in seven patients, spinal bifida in two patients and MS in two patients. The mean patient age was 48.8 years (range 23–75 years), and the mean number of injections was 3.6 (range 1–9). The total number of injections was 40 (Table 1).
Table 1. Patients with NDO injected with BoNTA
|Patient no.||Urinary disease||Sex||Age (years)||No. injections|
|2||Spinal cord injury||Male||66||5|
|3||Spinal cord injury||Female||31||2|
|4||Spinal cord injury||Male||75||6|
|5||Spinal cord injury||Male||48||4|
|6||Spinal cord injury||Male||69||3|
|8||Spinal cord injury||Female||37||5|
|10||Spinal cord injury||Male||51||2|
The mean operative time was 13.7 ± 4.5 min (range 8–25 min). In 17 cases (42.5%), the injection was carried out under local anesthesia, and six cases (35.3%) complained of pain during the procedure. Gross hematuria occurred in four patients (10%), but disappeared the next day. Pyelonephritis occurred in one patient (2.5%; Table 2).
Table 2. Result of operation
|Operative time (min)||13.7 ± 4.5 min (range 8 to 25)|
|Local anesthesia (cases)||17 (42.5%)|
|General anesthesia (cases)||23 (57.5%)|
|Complications (cases)|| |
|Gross hematuria||4 (10%)|
A reduction in the KHQ score indicates better QOL. Analysis of the individual domain scores for the KHQ showed a significant improvement in eight of the nine scores at 8 weeks from baseline. This included incontinence impact, role limitations, physical and social limitations, personal relationships, emotions, sleep/energy, severity measures, and symptom severity (Table 3, Fig. 1).
Figure 1. Changes in the median KHQ domain scores from baseline and 8 weeks. KHQ domain scores showed a significant improvement without GH at 8 weeks from baseline. , Baseline; , 8 weeks.
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Table 3. Median KHQ domain scores from baseline at 8 weeks
|KHQ domain||Baseline||8 weeks||P-value|
|General health perception||32.5 ± 5.3||20.0 ± 5.0||0.054|
|Incontinence impact||53.3 ± 7.4||24.9 ± 7.6||<0.05|
|Role limitations||46.7 ± 8.6||3.3 ± 3.3||<0.01|
|Physical and social limitations||40.0 ± 10.9||3.3 ± 3.3||<0.01|
|Personal relationships||39.9 ± 9.7||18.2 ± 8.4||<0.01|
|Emotions||22.2 ± 10.2||4.4 ± 2.9||<0.05|
|Sleep/energy||50.0 ± 9.3||17.7 ± 8.6||<0.01|
|Severity measures||48.9 ± 10.8||21.7 ± 11.1||<0.05|
|Symptom severity||49.4 ± 6.6||27.3 ± 6.4||<0.01|
On cystometric studies, the mean MCC increased significantly in all patients at 8 weeks (352.0 ± 18.6, P < 0.001) from baseline (180.8 ± 13.9). Bladder compliance at MCC was also significantly increased at 8 weeks (19.8 ± 1.9, P < 0.001) compared with baseline (4.7 ± 0.5; Table 4). The number of UI episodes per day at baseline was 2.58 ± 1.59, and significant improvement was seen after injection (0.14 ± 0.32 at 4 weeks, P < 0.001; 0.30 ± 0.78 at 8 weeks, P < 0.001; and 0.43 ± 0.88 at 12 weeks, P < 0.001). Overall, 31 patients (77.5%) become completely dry at 4 weeks, 29 patients (72.5%) at 8 weeks and 23 patients (57.5%) at 12 weeks (Table 5). The number of CIC per day at baseline was 6.35 ± 3.01. The number of CIC also improved after injection (5.05 ± 2.25 at 4 weeks, P = 0.023; 5.19 ± 1.99 at 8 weeks, P = 0.033; and 5.33 ± 2.02 at 12 weeks, P = 0.036; Table 5). Lack of efficacy appeared 7.15 ± 3.40 months (range 1–15 months) after treatment. The interval between BoNTA injections was 9.8 months (range 6–16 months; Table 6). Among the 40 injections, there were 14 cases (35%) of UTI over the 12 weeks; 12 cases were cystitis and two were pyelonephritis. They were treated by antibiotics and improved. No autonomic dysreflexia, respiratory distress, urosepsis or gastroenteric distress was noted after any of the injections (Table 7).
Table 4. Cystometric results of BoNTA injection
| ||Baseline||8 weeks||P-value|
|MCC (mL)||180.8 ± 13.9||352.0 ± 18.6||<0.01|
|Bladder compliance at MCC (mL/cmH2O)||4.7 ± 0.5||19.8 ± 1.9||<0.01|
Table 5. Clinical results of BoNTA injection
| ||Baseline||4 weeks||8 weeks||12 weeks|
|No. UI/day||2.58 ± 1.59||0.14 ± 0.32*||0.30 ± 0.78*||0.43 ± 0.88*|
|No. CIC/day||6.35 ± 3.01||5.05 ± 2.25**||5.19 ± 1.99**||5.33 ± 2.02**|
Table 6. Median lack of efficacy and interval between BoNTA injections
|Patient no.||Urinary disease||No. injections||Lack of efficacy (months)||Interval (months)|
|2||Spinal cord injury||5||11.0||15.5|
|3||Spinal cord injury||2||5.5||9.0|
|4||Spinal cord injury||6||5.4||15.5|
|5||Spinal cord injury||4||5.5||8.7|
|6||Spinal cord injury||3||5.7||8.5|
|8||Spinal cord injury||5||5.8||13.0|
|10||Spinal cord injury||2||6.0||10.0|
Table 7. Adverse events during 12 weeks
|UTI (cases)||14 (35%)|
|Autonomic dysreflexia (cases)||0 (0%)|
|Respiratory distress (cases)||0 (0%)|
|Urosepsis (cases)||0 (0%)|
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The primary goals of treatment for NDO are to protect the upper urinary tract by decreasing bladder pressure and improving QOL.
The first-line treatment for NDO is usually pharmacological therapy with antimuscarinics. A subset of patients might fail antimuscarinics secondary to poor drug efficacy or intolerability. As a result, these patients might require second-line treatment, such as BoNTA injections. Muscle contraction normally occurs after acetylcholine is released at the neuromuscular junction. BoNTA blocks neurotransmission by binding to acceptor sites on motor or sympathetic nerve terminals, entering the terminals and inhibiting the release of acetylcholine. Without acetylcholine release, the muscle is unable to contract. This inhibition occurs because the SNARE protein SNAP-25 necessary for the docking and release of acetylcholine from the vesicles within nerve endings is inactivated. As a result, BoNTA acts as a temporary biochemical neuromodulator. Schurch et al. reported the results of injections of BoNTA in a 6-month, single treatment, randomized, placebo-controlled study of patients with neurogenic UI, in which 59 patients with UI caused by NDO requiring CIC were randomized to receive a single dose of BoNTA (200 or 300 U) or placebo into the detrusor. They found significant post-treatment decreases in UI in both treatment groups, but not in the placebo group. They concluded that BoNTA injections could provide rapid, well-tolerated, clinically significant decreases in the signs and symptoms of UI caused by NDO during a 24-week study period.
This is the first clinical investigation of the outcome of BoNTA injection for NDO in Japanese patients. In our experience, the median daily number of UI episodes decreased from baseline. The effect appeared by 4 weeks at least, and continued for more than 12 weeks. The median percent decrease from baseline was 94.5% at 4 weeks, 88% at 8 weeks and 83% at 12 weeks. The number of CIC also decreased. Lack of efficacy appeared 7.15 ± 3.40 months (range 1–15 months) after treatment; this period was almost the same as in other reports. Because of the small number of patients in the present study, the factors of poor response in this study are not clear. Schlte-Baukloh et al. showed that BoNTA antibodies can develop after injection of BoNTA, and the antibodies can lead to therapy failure. In addition, Compérat et al. reported that responders to the BoNTA injections had less fibrosis and edema of the bladder wall than non-responders. On cystometric study, MCC increased significantly in all patients at 8 weeks from baseline. Bladder compliance at MCC also increased significantly at 8 weeks from baseline. These results are very similar to those of other reports. With respect to QOL, general health perception on the KHQ was not significantly improved, but other parts were significantly improved. Kalsi et al., in a population of patients with IDO overactivity and NDO, reported significant improvements in QOL as assessed by the UDI-6 and IIQ-7 after treatment. They reported a significant correlation between improvement in QOL, and improvements in urgency and urge UI in patients with IDO and NDO. In our experience, KHQ improvements were seen along with the improvements on urodynamic studies, and the numbers of UI episodes and CIC. As the number of UI episodes is a significant contributor to poor QOL, it is not surprising that there was exceptionally high acceptance of this treatment.
With respect to injection technique, in earlier studies, injections of BoNTA were carried out with a rigid cystoscope under spinal or general anesthesia. Currently, less-invasive techniques with a flexible cystoscope under local anesthesia are more common. Typically, BoNTA is injected into 30 sites, 10 U/mL each (300 U total), in the detrusor, sparing the trigone. In the present study, injections were given using a rigid cystoscope under local or general anesthesia. Six patients who underwent local anesthesia complained of pain. When the procedure is carried out under local anesthesia, use of a flexible cystoscope should be considered.
Significant side-effects of BoNTA injections are exceedingly uncommon, and the injections are well tolerated. Although there is no uniform documentation system, the most commonly reported AE include injection site pain, mild hematuria (2–21%), UTI (2–32%) and an increase in postvoid residual urine, which at times results in urinary retention (0–33%) or CIC (6–88%). However, recently, severe systematic AE of BoNTA injections, such as botulism-like symptoms and general muscular weakness, have been reported when BoNTA was used for muscular spasticity. Even respiratory disorders and death have been linked to BoNTA treatment. In the present series, 14 cases (35%) of UTI occurred over 12 weeks. Symptomatic UTI (pyelonephritis) occurred in one case, and 13 cases of UTI were asymptomatic. There were no botulism-like symptoms or general muscular weakness.
The accepted dose of BoNTA for patients with NDO who are self catheterizing is 300 units. In contrast, in some reports, 200 units and 300 units have been injected, and there were no significant differences between the two doses. Bordic et al. reported a basic experimental histological assessment of dose-related diffusion and muscle fiber responses after injections of BoNTA. The study showed that BoNTA produces a gradient of denervation in a given muscle, and that both the magnitude of denervation and the extent of the gradient are dose-dependent. Schurch et al. did not show a clear difference in clinical effects between the 200- and 300-unit doses. Cruz et al. also reported that both doses significantly reduced UI, and improved urodynamics and QOL in MS and SCL patients with NDO. Both doses were well tolerated, with no clinically relevant differences in efficacy or duration of effect between the two doses. Recently, Ginsberg et al. showed phase 3 data for BoNTA in NDO. A total of 416 patients with MS or spinal cord injury and UI were randomized to double-blind treatment with BoNTA injection (200 units: n = 135 or 300 units: n = 132) or placebo (n = 149). There was no observed benefit with the 300 units dose over the 200 units dose and in addition, the incidence of CIC appeared to increase with the dose.[24, 25] In 2011, injections of 200 units BoNTA were approved by the Federal Drug Administration of USA for NDO, such as MS or SCL. In the present series, the dose was 300 units and it resulted in no severe AE, but we have to consider changing this dose to 200 units.
With respect to repeated injections of BoNTA, histopathological studies have not shown any enhanced pathological innervation, muscle cell damage or excessive connective tissue deposition in the bladder as a result of BoNTA injections. In another study, injection of BoNTA did not produce significant inflammatory changes, fibrosis or dysplastic changes in the human bladder urothelium or suburothelium after a single injection and a limited number of repeat treatment biopsies.
Increasing evidence supports the efficacy of intradetrusor injections of BoNTA for NDO, although few randomized, placebo-controlled trials are reported in the literature.[8, 29] Injections of BoNTA are well tolerated and provide clinically beneficial improvements in patients with NDO. These improvements are seen for up to 7 months after injection.