Treatment of Voiding Dysfunction by Urethral Injection of Botulinum A toxin

1. 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 20-80 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 80-100 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 scoresand Quality of life index (IPSS) • Residual urine sensation or retention 0-5 • Intermittency 0-5 • Small caliber of urine or retention 0-5 • Straining to void 0-5 • Quality of life index 0-6 • Indwelling Foley catheter or on CISC

14. Botulinum A toxin

15. Botulinum A toxin therapy • 100 units (1vial) is diluted to 2ml • 50-100 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. Cystoscopic Urethral Injection in Men * * * *

19. Identification of External Sphincter in Man

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

21. 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

22. 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

23. Diseases and Enrolled Patients

24. 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

25. Therapeutic Results

26. Changes in Urodynamic Parameters in All Patients with Successful Results

27. Dysfunctional Voiding (Pseudodyssynergia) in CVA

28. Changes in Urodynamic Parameters in Patients with Dysfunctional Voiding

29. DESD in Multiple Sclerosis with Urinary Retention

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

31. Changes in Urodynamic Parameters in Patients with DESD

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

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

34. Changes in Urodynamic Parameters in Patients with Cauda Equina Lesion

35. Detrusor Areflexia due to Cauda Equina Lesion in MS

36. Recovery of detrusor contractility in detrusor underactivity

37. Changes in Urodynamic Parameters in Patients with Detrusor Failure

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

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

40. Changes in Urodynamic Parameters in Patients with Detrusor Areflexia

41. Reduction of MUCP in a women with peripheral neuropathy

42. Table 1.The Urodynamic Parameters at Baseline and after Botulinum Toxin in 53 Effective Patients MUCP=maximal urethral closure pressure, FPL=functional profile length, PVR= postvoid residual volume *Comparison between baseline and 2 weeks after treatment

43. 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

44. Relationship of Therapeutic Results and Botox Dose

45. Relationship of Therapeutic Results and Voiding Pressure Chi-square test, p= 0.063

46. Changes in Urodynamic Parameters in Patients with High Voiding Pressure

47. Changes in Urodynamic Parameters in Patients with Low Voiding Pressure

48. Relationship of Therapeutic Results and Sphincter Activity Chi-square test, p= 0.103

49. Changes in Urodynamic Parameters in Patients with Sphincter Hyperactivity

50. Changes in Urodynamic Parameters in Patients with Poor Relaxation of Urethral Sphincter