1. Buddhist Tzu Chi General Hospital
Treatment of Voiding Dysfunction by Urethral Injection of Botulinum A toxin
Hann-Chorng Kuo
Department of Urology
Buddhist Tzu Chi General Hospital

2. Voiding Dysfunction Neurogenic detrusor external sphincter dyssynergia
Dysfunctional voiding due to spastic urethral sphincter
Poor relaxation of sphincter & low detrusor contractility
Detrusor underactivity or Detrusor failure
Detrusor areflexia

3. Therapeutic modalities for voiding dysfunction
Medication: alpha-blocker, skeletal muscle relaxants, nitric oxide donors
Behavioral therapy: biofeedback, electrical stimulation, neuromodulation
Surgery: transurethral sphincterotomy, TUI-bladder neck, urethral stent
Clean intermittent catheterization
Indwelling Foley catheter or cystostomy

4. Background of Botulinum A toxin
Botulinum A toxin is an inhibitor of acetylcholine release at the presynaptic neuromuscular junction
Inhibition of acetylcholine release results in regional decreased muscle contractility at the injection site
This chemical devervation is a reversible process, axons resprout in about 3-6 months

5. Mechanism of Botulinum A Toxin in Neuromuscular Junction

6. Clinical usefulness of Botulinum A toxin
Focal dystonia, blepharospasm (Scott et al 1985)
Dysphonia (Whurr et al 1993)
Limb spasticity ( Hesse et al 1994)
Dysphagia (Schneider, et al 1994)
No severe adverse effects ever reported

7. Clinical application of botulinum A toxin in voiding dysfunction
Botulinum A toxin U successfully treated 11 SCI & DESD (Dykstra et al 1988)
In 21 of 24 SCI & DESD, BTX-A toxin 100 U reduced residual urine and MUCP (Schurch et al 1996)
Transperineal injection of BTX-A in 6 SCI improved voiding function (Schurch et al 1997)

8. Clinical application of botulinum A toxin in voiding dysfunction
Relief of voiding dysfunction due to prostatitis in 4 men (Maria et al 1998)
Improved bladder capacity and decreased maximal detrusor pressure after BTX-A in 5 SCI (Gallien et al 1998)
Effective in treating DESD (12), pelvic floor spasticity (8), and acontractile detrusor (1) by BTX-A IU (Michael et al 2001)

9. Improved Voiding Efficiency
Increased detrusor contractility in detrusor underactivity – nerve stimulation, increased nerve density
Reduced urethral resistance – urethral smooth muscles and striated muscles
Recovery of detrusor contractility in idiopathic detrusor acontractility

10. Patients suitable for Botulinum A toxin Treatment
Patients with voiding dysfunction who were refractory to medication or behavioral therapy
Chronic SCI & DESD with low empty efficiency
Cauda equina lesion and difficult urination
Peripheral neuropathy and difficult urination
Dysfunctional voiding
Idiopathic detrusor underactivity
Poor relaxation of urethral sphincter

11. Enrolled Patients Criteria
Patient is unable to void spontaneously, indwelling catheter, or on CISC
Difficult urination with low Qmax and large residual urine
Moderate to severe obstructive IPSS (>10 points)
High voiding pressure (>50 cm water) & low flow rate (Qmax <10ml/s) during urodynamic study
Poor relaxation or hyperactivity of sphincter EMG activity during pressure flow study

12. Pretreatment evaluation
Conventional treatment at least 3 months
Cystoscopy to exclude anatomical BOO
Postvoid residual urine volume
Videourodynamic study: voiding pressure, abdominal leak point pressure, Qmax, sphincteric EMG activity, urethral patency in VCUG
Obstructive score in IPSS

13. Obstructive symptom scores and Quality of life index (IPSS)
Residual urine sensation or retention 0-5
Intermittency
Small caliber of urine or retention
Straining to void
Quality of life index
Indwelling Foley catheter or on CISC

14. Botulinum A toxin

15. Botulinum A toxin therapy
100 units (1vial) is diluted to 2ml
units are used, 4 equivalent aliquot are injected via cystoscopy guide in men and around the urethra in women
Complete cardiorespiratory monitoring in OR
Foley catheter is indwelled for 1 day
Report adverse effect (AD, hematuria, UTI)

16. Evaluation of Treatment Outcome
Subjectively improved in voiding efficiency
Increase in voided volume
Reduction of residual urine volume
Decrease of voiding pressure (detrusor or abdominal pressure)
Decrease in frequency of catheterization
Removal of indwelled Foley catheter

17. Botulinum A Toxin Urethral Injection in Woman*

18. Sphincter Injection Cystoscopy

19. Cystoscopic Urethral Injection in Men

20. Identification of External Sphincter in Man

21. Injection of 3,6, 9, and 12 o’clock Position of Urethral Sphincter

22. Clinical Results after Botulinum A toxin Urethral injection
50 –100 units of botulinum A toxin injected to urethral striated muscles
Effect appears 2-3 days after injection
Detrusor pressure or abdominal leak point pressure decreased and facilitate spontaneous voiding
Minimal adverse effect was noted

23. Materials & Methods
A total of 103 patients received urethral Botox injection
48 men and 55 women
Aged 16 to 94, mean 54 years old
45 patients had urinary retention
48 patients received 50U, 55 patients received 100U

24. Diseases and Enrolled Patients
Dysfunctional voiding 20
Detrusor hyperreflexia & external sphincter dyssynergia 29
Poor relaxation of urethral sphincter 19
Cauda equina lesion and detrusor areflexia 8
Detrusor underactivity or detrusor failure 13
Detrusor areflexia due to peripheral neuropathy 14

25. Outcome assessment
Excellent: (1) spontaneous voiding by reflex or abdominal straining in urinary retention patients; (2) improvement in voiding pressure (Pabd or Pdet), Qmax, and residual urine by >25%
Improved: improvement in voiding pressure, Qmax, and residual urine but <25%, patient is satisfactory to therapeutic effect
Failed: subjectively no improvement, persistent urinary retention, or persistent large residual urine

26. Therapeutic Results of Urethral Botox for Voiding Dysfunction
Excellent
Improved
Failure
DV (n=20)
6 (30%)
14 (70%)
DESD (n=29)
8 (27.6%)
15 (51.7%)
6 (20.7%)
PRES (n=19)
8 (42.1%)
7 (36.8%)
4 (21.1%)
CE (n=8)
5 (62.5%)
1 (12.5%)
2 (25%)
DF (n=13)
8 (61.5%)
4 (30.8%)
1 (7.7%)
DA (n=14)
5 (35.7%)
6 (42.9%)
3 (21.4%)
Total (n=103)
40 (38.8%)
47 (45.6%)
16 (15.5%)

27. Therapeutic Results of Urethral Botox for Voiding Dysfunction

28. Changes in Urodynamic Parameters in All Patients with Successful Results
Baseline
Post-Botox
P value
Capacity
321.5±144.5
317.5±147.5
0.818
Voiding pressure
62.8±40.4
42.8±31.3
0.000*
Qmax
7.1±6.4
10.6±6.4
PVR
226.4±164.8
88.8±111.5
N= 66

29. Urethral Botox in Treatment of Dysfunctional Voiding
20 patients with dysfunctional voiding
7 men and 13 women
High voiding pressure & a hyperactive urethral sphincter activity
6 had excellent result, 14 had improved result, no failed case
Success rate was 100%

30. Dysfunctional Voiding (Pseudodyssynergia) in CVA

31. Changes in Urodynamic Parameters in Patients with Dysfunctional Voiding
Baseline
Post-Botox
P value
Capacity
233.8±110.9
256.3±144.8
0.443
Qmax
10.7±7.1
10.3±4.8
0.803
Voiding pressure
46.8±25.1
31.1±12.0
0.008 *
PVR
141.7±135.9
57.3±63.4
0.026 *
N= 16

32. Urethral Botox in Treatment of Poor Relaxation of Sphincter
19 patients (12 men & 7 women) had a low voiding pressure and intermittent sphincter activity during voiding
8 had excellent result, 7 had improved result, 4 failed (all had psychological disorder)
In 5 patients with retention, 3 had excellent and 1 had improved result

33. Severe dysuria in Poor Relaxation of Urethral Sphincter

34. Changes in Urodynamic Parameters in Patients with Poor Relaxation of Urethral Sphincter
Baseline
Post-Botox
P value
Capacity
403.0±148.4
401.5±126.6
0.979
Qmax
10.9±7.9
16.6±8.3
0.176
Voiding pressure
39.6±26.3
27.9±13.9
0.091
PVR
161.6±149.4
24.3±25.1
0.034 *
N= 8

35. Urethral Botox in Treatment of DESD
29 patients with DESD, 24 men & 5 women
27 had spinal cord lesion, 2 had multiple sclerosis
8 had excellent result, 15 had improved result, 6 failed
4 patients with retention had excellent result
High pressure or low pressure DESD had similar success rate (84.6% v 75%)

36. DESD in Multiple Sclerosis with Urinary Retention

37. Reduction of voiding pressure in a SCI patient with DESD

38. Changes in Urodynamic Parameters in Patients with DESD
Baseline
Post-Botox
P value
Capacity
243.3±106.3
236.3±109.3
0.860
Qmax
6.8±5.7
9.2±7.7
0.077
Voiding pressure
45.7±22.7
30.7±15.5
0.016 *
PVR
160.2±124.0
104.6±134.6
0.227
N= 18

39. Urethral Botox in Treatment of Cauda Equina Lesion
8 patients with cauda equina lesion
4 men and 4 women
5 had excellent, 1 had improved result
In 6 patients with urinary retention, 4 had excellent result, 1 improved
Repeat urethral Botox injection was necessary in 1 with hypertonic sphincter

40. Cauda Equina Lesion with Detrusor Areflexia & Isolated Sphincter Obstruction

41. Reduction of abdominal pressure in patient with cauda equina lesion

42. Detrusor Areflexia due to Cauda Equina Lesion in MS

43. Changes in Urodynamic Parameters in Patients with Cauda Equina Lesion
Baseline
Post-Botox
P value
Capacity
454.7±86.4
493.9±146.4
0.445
Qmax
1.3±0.5
7.7±7.9
0.065
Voiding pressure
75.1±43.2
52.7±48.0
0.207
PVR
445.7±99.8
200.0±214.1
0.042 *
N=7

44. Urethral Botox in Treatment of Detrusor Failure
13 patients with detrusor failure or underactivity, 1 man & 12 women
8 had excellent, 4 had improved result
All 7 patients with retention could void after urethral Botox treatment
Detrusor contractions reappeared in patients with detrusor failure

45. Recovery of Detrusor Contractility in Detrusor Failure after Botox

46. Changes in Urodynamic Parameters in Patients with Detrusor Failure
Baseline
Post-Botox
P value
Capacity
360.5±153.1
354.3±142.4
0.864
Qmax
7.5±6.5
9.8±4.8
0.291
Voiding pressure
54.9±30.9
38.5±19.3
0.025 *
PVR
242.1±180.4
95.4±75.9
0.034 *
N= 12

47. Urethral Botox in Treatment of Detrusor Areflexia
14 women had detrusor areflexia after previous radical hysterectomy
Patients voided by abdominal straining
5 had excellent, 6 had improved result
2 failed cases had bladder neck obstruction
Improved voiding noted after TUI-BN
1 patient received 2nd injection successfully

48. Detrusor Areflexia after Radical Hysterectomy,s/p Botox injection

49. Reduction of Abdominal Voiding Pressure in Detrusor Areflexia after Radical Hysterectomy

50. Changes in Urodynamic Parameters in Patients with Detrusor Areflexia
Baseline
Post-Botox
P value
Capacity
405.4±139.4
404.8±181.0
0.992
Qmax
4.5±4.6
8.3±4.6
0.112
Voiding pressure
118.1±65.6
92.3±51.1
0.033 *
PVR
329.3±130.4
195.0±186.9
0.025 *
N= 14

51. Reduction of MUCP in a women with peripheral neuropathy

52. The Urethral Pressure Profile Parameters at Baseline and after Botulinum Toxin Injection
Post-Botox
Statistics*
MUCP (cm water)
97.1±31.7
51±23.2
0.027 *
FPL (cm)
3.35±0.59
3.30±0.33
0.773
MUCP=maximal urethral closure pressure, FPL=functional profile length,

53. Factors for an Effective Urethral Botox Injection
Adequate dose of Botulinum A Toxin
Exact injection into urethral sphincter
Hyperactive urethral sphincter is less favorable than non-relaxing sphincter
Psychological inhibition of sphincter relaxation is less favorable than organic non-relaxing sphincter

54. Relationship of Therapeutic Results and Botox Dose
Excellent
Improved
Failure
50 Unit (n=48) 19 22 7
100 Unit (n=55) 21 25 9
Total (n=103) 40 47 16

55. Relationship of Therapeutic Results and Botox Dose

56. Relationship of Therapeutic Results and Voiding Pressure
Excellent
Improved
Failure
High pressure voiding (n=33)
10 (30.3%)
21 (63.6%)
2 (6%)
Low pressure voiding (n=70)
30 (42.9%)
26 (37.1%)
14 (20%)
Chi-square test, p= 0.063

57. Relationship of Therapeutic Results and Voiding Pressure

58. Changes in Urodynamic Parameters in Patients with High Voiding Pressure
Baseline
Post-Botox
P value
Capacity
221.3±107.7
257.8±140.2
0.222
Qmax
9.7±6.7
10.1±6.1
0.745
Voiding pressure
52.1±23.3
33.3±14.1
0.000*
PVR
141.9±133.2
92.5±128.1
0.203
N= 24

59. Changes in Urodynamic Parameters in Patients with Low Voiding Pressure
Baseline
Post-Botox
P value
Capacity
377.2±136.8
364.2±160.2
0.531
Qmax
5.8±6.1
10.0±6.9
0.000 *
Voiding pressure
69.2±53.8
50.5±41.7
0.000*
PVR
271.5±166.9
116.8±141.7
N= 50

60. Relationship of Therapeutic Results and Sphincter Activity
Excellent
Improved
Failure
Sphincter Hyperactivity (n=68)
22 (32.4%)
36 (52.9%)
10 (14.7%)
Sphincter Hypoactivity (n=35)
18 (51.4%)
11 (31.4%)
6 (17.1%)
Chi-square test, p= 0.103

61. Relationship of Therapeutic Results and Sphincter Activity

62. Changes in Urodynamic Parameters in Patients with Sphincter Hyperactivity
Baseline
Post-Botox
P value
Capacity
268.7±130.0
271.7±139.3
0.889
Qmax
9.0±6.7
11.1±7.3
0.070
Voiding pressure
44.4±23.9
29.9±13.7
0.000*
PVR
154.6±128.4
71.8±101.0
0.002*
N= 43

63. Changes in Urodynamic Parameters in Patients with Sphincter Hypoactivity
Baseline
Post-Botox
P value
Capacity
406.9±132.2
410.1±156.5
0.908
Qmax
4.5±5.3
8.7±5.4
0.004*
Voiding pressure
88.8±56.4
64.4±45.7
0.000*
PVR
329.9±162.2
158.2±162.7
N=31

64. Relationship of Therapeutic Results with Age and Sex
Excellent
Improved
Failure
Male (n=48) 14 24 10
Female (n=55) 26 22 7
P=0.153
Age < 50 years (n=39) 18 11
Age > 50 years (n=64) 30 28 6
P=0.018 *

65. Relationship of Therapeutic Results with Age and Sex

66. Presumptive Causes for Patients Failed Urethral Botox Treatment
NOCE
Sex
Age
Disease
Dose
Reason 1 M 62
PRES
100
Psychogenic 2 F 31 3 30 4 59 50 5
DESD
Low detrusor contractility 6 43 7 39
Sphincter Hyperactivity 8 33
Bladder outlet obstruction* 9 26 10 53 11 14 CE 12 36 13 80 DF 64 DA
Bladder neck obstruction* 15 48
Bladder neck obstruction 16
Sphincter Hypertonicity
* Voiding is smooth after transurethral incision of bladder neck

67. Bladder Neck Dysfunction Resulting in Failure Botox Treatment in Detrusor Areflexia

68. Reduction of MUCP after Urethral Botox in Detrusor Areflexia due to Hysterectomy

69. DESD and Bladder neck dysfunction after TUI-BN

70. Return of Detrusor Contractility after Botulinum A toxin injection
In 7 patients, return of detrusor contractility was noted at 1- 2 months after botulinum A toxin injection
Frequency, urgency or urge incontinence developed in 6 patients with detrusor underactivity
Rhythmic detrusor contractions developed in one SCI patients with DESD and dysuria

71. Recovery of detrusor contractility in detrusor underactivity

72. Rhythmic detrusor contractions in SCI with DESD after Botox

73. Adverse Effects of Botulinum A Toxin
No urinary tract infection developed
One 15 y/o girl had high fever lasting for 2 weeks after injection (failed case with reduced MUCP & leak pressure)
Six women had mild incontinence during sleep (2 DV, 4 DA)

74. Conclusions
Botulinum A toxin in units is effective in reducing urethral resistance and facilitate voiding efficiency in 84.5% of patients with voiding dysfunction and 82.9% of detrusor underactivity
Patients with chronic retention may have a chance to urinate by abdominal straining after botulinum A toxin injection
Good quality of life without catheter was achieved after botulinum A toxin therapy

75. Thank you for your attention