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Re: More than 15 Years of Experience with Intradetrusor OnabotulinumtoxinA Injections for Treating Refractory Neurogenic Detrusor Overactivity: Lessons to be Learned
VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY
regimen ended. The regimen consisted of 4 distinct phases: 1) therapy regarding anatomy and physiology of the pelvic floor muscles, followed by instructions about performing a corrected isolated pelvic floor contraction; 2) instructions about how to hold a contraction for about 5 to 10 seconds, followed by training to contract the muscle before and during coughing or other causes of increased intra-abdominal pressure (learning “the knack”); 3) learning how to contract the pelvic floor muscles during activities of daily living; and 4) an analysis of fluid intake, micturition and defecation habits with adjustment as necessary. Originally 64 patients with ISD and 69 with a “normotonic urethra,” all with SUI, were included in the study. Excluded were those with prior incontinence surgery, predominant overactive bladder symptomatology, symptomatic prolapse and acute urogenital infection. It does not seem as though there was a primary outcome indicator, but a number of variables were reported. The King’s Health Questionnaire was used, and whereas there was a change in “physical limitations” and “personal limitations” in the normotonic group, there was essentially none in the ISD group (52 to 51 for physical limitation and 45 to 42 for personal limitation [p <0.001]). So much for statistical vs clinical significance. Both were statistically positive in the normotonic group (51 to 30 for physical limitations and approximately 40 to 32 for personal limitations; judging from the bar graph the figures in the article table are incorrect). A change in King’s Health Questionnaire of 5 was accepted as clinical change. The maximal urethral closure pressure in the normotonic group went from 45 to 48 cm water, while the change in patients with ISD was from 14 to 18 cm water. The former showed a p value of less than 0.001 and the latter less than 0.05dagain, consider statistical vs clinical significance. Patients with a positive cough test in the ISD group went from 3 of 64 to 34 of 64 (p ¼ 0.02). In the normotomic group corresponding figures were 5 of 68 to 32 of 68 (p not significantdagain, consider clinical vs statistical significance). Urine leakage was not quantified. Incontinence impact changed in both groups, from 27 to 18 in the normotonic group and from 28 to 17 in the ISD group, which is interesting in view of the minimal and clinically insignificant (using the rule of 5) changes in physical and personal limitations. Except for the assessments at 1 week after the physiotherapy regimen, there was no further followup. The final conclusion is, “The option of physiotherapy should represent the first-line strategy even in SUI patients with ISD since physiotherapy has no deleterious side effects.” The results on selective parameters for each group are certainly recorded, without quantitation of urine loss. It is interesting that women with previous failed incontinence surgery (comprising a large group of the ISD population) were excluded. I would have expected more favorable changes in the normotonic group. Alan J. Wein, MD, PhD (hon)
Re: More than 15 Years of Experience with Intradetrusor OnabotulinumtoxinA Injections for Treating Refractory Neurogenic Detrusor Overactivity: Lessons to be Learned € hl-Roy, S. C. Knu € pfer, M. Walter, M. P. Schneider, J. Tornic, L. Leitner, S. Guggenbu U. Sammer, U. Mehnert and T. M. Kessler Neuro-Urology, Spinal Cord Injury Center and Research, University of Zu¨rich Balgrist University Hospital and Brain Research Institute, University of Zu¨rich, and Department of Health Sciences and Technology, Swiss Federal Institute of Technology Zu¨rich, Zu¨rich and Department of Urology, University Hospital Basel, Basel, Switzerland Eur Urol 2016; 70: 522e528. doi: 10.1016/j.eururo.2016.03.052
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27106070 Editorial Comment: This informative article looks at long-term outcome and patient adherence to intradetrusor onabotulinumtoxinA injections for refractory neurogenic detrusor overactivity. A total of 52 patients who underwent their first injections more than 10 years prior were retrospectively evaluated and followed. Mean SD duration since the first injection was 12 2 years. At the latest available followup 60% of the patients (31 of 52) were continuing treatment overall but only 14% of those (1 of 7) with multiple sclerosis. Four of the patients with multiple sclerosis discontinued treatment due to progressive disease. Inappropriate clinical and/or urodynamic effects and patient
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178
VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY
request to switch to another treatment (antimuscarinics in 5 patients and neuromodulation in 4) despite appropriate efficacy were the main reasons for discontinuation. Of the 6 patients voiding spontaneously before injection treatment 4 had to perform de novo intermittent self-catheterization, and in time all of these patients switched to neuromodulation. A dose change from 300 to 200 U did not have a significant effect on outcome measures. The clinical and urodynamic parameters before the first injection were similar among those who continued and discontinued injection therapy. There was no significant difference in mean number of injections yearly. Gender and locomotion did not have a significant impact on treatment discontinuation. Of the 11 patients who were considered nonresponders after a mean number of 6.5 repeat injections 3 showed neurophysiologically proved onabotulinumtoxinA resistance, all of whom had spinal cord injury. Of the patients who discontinued injection therapy 6 underwent bladder augmentation, 2 underwent cystectomy, 5 switched to antimuscarinic drugs, 4 changed to neuromodulation and 4 switched to indwelling catheterization. The authors suggest that because the meeting of patient expectations is related to increased satisfaction, all prospective neurological patients should be given information such as reflected in this article regarding discontinuation in time among those with refractory neurogenic detrusor overactivity as a part of the informed consent procedure. More reports such as this would certainly be welcome. Alan J. Wein, MD, PhD (hon)
Re: Different Number of Intravesical OnabotulinumtoxinA Injections for Patients with Refractory Detrusor Overactivity do Not Affect Treatment Outcome: A Prospective Randomized Comparative Study C. H. Liao, S. F. Chen and H. C. Kuo Division of Urology, Department of Surgery, Cardinal Tien Hospital, Fu-Jen Catholic University School of Medicine, Taipei and Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan Neurourol Urodyn 2016; 35: 717e723. doi: 10.1002/nau.22780
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25914349 Editorial Comment: The conclusion of this article was that decreasing the number of intravesical injections while maintaining the same dose of onabotulinumtoxinA and total injection volume does not change the therapeutic effect. This was a single-blind, randomized, parallel, actively controlled trial using 10, 20 or 40 intravesical injections of 100 U drug in 10 ml into the bladder body. All patients had refractory overactive bladder with at least 1 episode of urgency or urge urinary incontinence per day as recorded in a 3-day voiding diary. In fact, the number of incontinence episodes for a 3-day period in the 3 groups were 9.86, 5.29 and 8.95 (10, 20 and 40 sites), respectively. Corresponding urgency episodes totaled 29, 27 and 32. There are a few caveats. Injection was into the suburothelium, not the muscle, at the posterior and lateral walls of the bladder. The procedures were done under light general anesthesia and a catheter was left indwelling for a day. Injection volumes were 1.0 ml, 0.5 ml and 0.25 ml for the 10, 20 and 40 injection sites, respectively. The primary outcome indicator was a global response assessment using apparently nonvalidated categorization of markedly worse, moderately worse, mildly worse, no change, mildly improved, moderately improved and markedly improved bladder symptoms. Success was noted as a result of mildly improved or greater. The respective number of patients in each group who actually finished the analysis at 3 months were 21, 21 and 18, and at 6 months 8, 19 and 14. There were no statistically significant differences in the global response assessment result. There were no significant differences in urgency incontinence episodes for the 3 days or urgency episodes for the 3 days, but numerically the greatest results in those latter 2 parameters were achieved in the 10 and 40-site groups, with no parallel variation in the 20-site group, a puzzling result. The overactive bladder symptom scores and patient perception of bladder condition scores did not seem to be different in any particular group compared to another. Unfortunately the discomfort associated with the procedure, for those who do these injections under local anesthesia, could not be assessed as the patients were under light general anesthesia. The global response assessment at 3 months improved at least 1 grade in 86% of the 10-site group, 76% of the
regimen ended. The regimen consisted of 4 distinct phases: 1) therapy regarding anatomy and physiology of the pelvic floor muscles, followed by instructions about performing a corrected isolated pelvic floor contraction; 2) instructions about how to hold a contraction for about 5 to 10 seconds, followed by training to contract the muscle before and during coughing or other causes of increased intra-abdominal pressure (learning “the knack”); 3) learning how to contract the pelvic floor muscles during activities of daily living; and 4) an analysis of fluid intake, micturition and defecation habits with adjustment as necessary. Originally 64 patients with ISD and 69 with a “normotonic urethra,” all with SUI, were included in the study. Excluded were those with prior incontinence surgery, predominant overactive bladder symptomatology, symptomatic prolapse and acute urogenital infection. It does not seem as though there was a primary outcome indicator, but a number of variables were reported. The King’s Health Questionnaire was used, and whereas there was a change in “physical limitations” and “personal limitations” in the normotonic group, there was essentially none in the ISD group (52 to 51 for physical limitation and 45 to 42 for personal limitation [p <0.001]). So much for statistical vs clinical significance. Both were statistically positive in the normotonic group (51 to 30 for physical limitations and approximately 40 to 32 for personal limitations; judging from the bar graph the figures in the article table are incorrect). A change in King’s Health Questionnaire of 5 was accepted as clinical change. The maximal urethral closure pressure in the normotonic group went from 45 to 48 cm water, while the change in patients with ISD was from 14 to 18 cm water. The former showed a p value of less than 0.001 and the latter less than 0.05dagain, consider statistical vs clinical significance. Patients with a positive cough test in the ISD group went from 3 of 64 to 34 of 64 (p ¼ 0.02). In the normotomic group corresponding figures were 5 of 68 to 32 of 68 (p not significantdagain, consider clinical vs statistical significance). Urine leakage was not quantified. Incontinence impact changed in both groups, from 27 to 18 in the normotonic group and from 28 to 17 in the ISD group, which is interesting in view of the minimal and clinically insignificant (using the rule of 5) changes in physical and personal limitations. Except for the assessments at 1 week after the physiotherapy regimen, there was no further followup. The final conclusion is, “The option of physiotherapy should represent the first-line strategy even in SUI patients with ISD since physiotherapy has no deleterious side effects.” The results on selective parameters for each group are certainly recorded, without quantitation of urine loss. It is interesting that women with previous failed incontinence surgery (comprising a large group of the ISD population) were excluded. I would have expected more favorable changes in the normotonic group. Alan J. Wein, MD, PhD (hon)
Re: More than 15 Years of Experience with Intradetrusor OnabotulinumtoxinA Injections for Treating Refractory Neurogenic Detrusor Overactivity: Lessons to be Learned € hl-Roy, S. C. Knu € pfer, M. Walter, M. P. Schneider, J. Tornic, L. Leitner, S. Guggenbu U. Sammer, U. Mehnert and T. M. Kessler Neuro-Urology, Spinal Cord Injury Center and Research, University of Zu¨rich Balgrist University Hospital and Brain Research Institute, University of Zu¨rich, and Department of Health Sciences and Technology, Swiss Federal Institute of Technology Zu¨rich, Zu¨rich and Department of Urology, University Hospital Basel, Basel, Switzerland Eur Urol 2016; 70: 522e528. doi: 10.1016/j.eururo.2016.03.052
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27106070 Editorial Comment: This informative article looks at long-term outcome and patient adherence to intradetrusor onabotulinumtoxinA injections for refractory neurogenic detrusor overactivity. A total of 52 patients who underwent their first injections more than 10 years prior were retrospectively evaluated and followed. Mean SD duration since the first injection was 12 2 years. At the latest available followup 60% of the patients (31 of 52) were continuing treatment overall but only 14% of those (1 of 7) with multiple sclerosis. Four of the patients with multiple sclerosis discontinued treatment due to progressive disease. Inappropriate clinical and/or urodynamic effects and patient
177
178
VOIDING FUNCTION, BLADDER PHYSIOLOGY AND PHARMACOLOGY, AND FEMALE UROLOGY
request to switch to another treatment (antimuscarinics in 5 patients and neuromodulation in 4) despite appropriate efficacy were the main reasons for discontinuation. Of the 6 patients voiding spontaneously before injection treatment 4 had to perform de novo intermittent self-catheterization, and in time all of these patients switched to neuromodulation. A dose change from 300 to 200 U did not have a significant effect on outcome measures. The clinical and urodynamic parameters before the first injection were similar among those who continued and discontinued injection therapy. There was no significant difference in mean number of injections yearly. Gender and locomotion did not have a significant impact on treatment discontinuation. Of the 11 patients who were considered nonresponders after a mean number of 6.5 repeat injections 3 showed neurophysiologically proved onabotulinumtoxinA resistance, all of whom had spinal cord injury. Of the patients who discontinued injection therapy 6 underwent bladder augmentation, 2 underwent cystectomy, 5 switched to antimuscarinic drugs, 4 changed to neuromodulation and 4 switched to indwelling catheterization. The authors suggest that because the meeting of patient expectations is related to increased satisfaction, all prospective neurological patients should be given information such as reflected in this article regarding discontinuation in time among those with refractory neurogenic detrusor overactivity as a part of the informed consent procedure. More reports such as this would certainly be welcome. Alan J. Wein, MD, PhD (hon)
Re: Different Number of Intravesical OnabotulinumtoxinA Injections for Patients with Refractory Detrusor Overactivity do Not Affect Treatment Outcome: A Prospective Randomized Comparative Study C. H. Liao, S. F. Chen and H. C. Kuo Division of Urology, Department of Surgery, Cardinal Tien Hospital, Fu-Jen Catholic University School of Medicine, Taipei and Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan Neurourol Urodyn 2016; 35: 717e723. doi: 10.1002/nau.22780
Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25914349 Editorial Comment: The conclusion of this article was that decreasing the number of intravesical injections while maintaining the same dose of onabotulinumtoxinA and total injection volume does not change the therapeutic effect. This was a single-blind, randomized, parallel, actively controlled trial using 10, 20 or 40 intravesical injections of 100 U drug in 10 ml into the bladder body. All patients had refractory overactive bladder with at least 1 episode of urgency or urge urinary incontinence per day as recorded in a 3-day voiding diary. In fact, the number of incontinence episodes for a 3-day period in the 3 groups were 9.86, 5.29 and 8.95 (10, 20 and 40 sites), respectively. Corresponding urgency episodes totaled 29, 27 and 32. There are a few caveats. Injection was into the suburothelium, not the muscle, at the posterior and lateral walls of the bladder. The procedures were done under light general anesthesia and a catheter was left indwelling for a day. Injection volumes were 1.0 ml, 0.5 ml and 0.25 ml for the 10, 20 and 40 injection sites, respectively. The primary outcome indicator was a global response assessment using apparently nonvalidated categorization of markedly worse, moderately worse, mildly worse, no change, mildly improved, moderately improved and markedly improved bladder symptoms. Success was noted as a result of mildly improved or greater. The respective number of patients in each group who actually finished the analysis at 3 months were 21, 21 and 18, and at 6 months 8, 19 and 14. There were no statistically significant differences in the global response assessment result. There were no significant differences in urgency incontinence episodes for the 3 days or urgency episodes for the 3 days, but numerically the greatest results in those latter 2 parameters were achieved in the 10 and 40-site groups, with no parallel variation in the 20-site group, a puzzling result. The overactive bladder symptom scores and patient perception of bladder condition scores did not seem to be different in any particular group compared to another. Unfortunately the discomfort associated with the procedure, for those who do these injections under local anesthesia, could not be assessed as the patients were under light general anesthesia. The global response assessment at 3 months improved at least 1 grade in 86% of the 10-site group, 76% of the