1 Neuromodulation for Genito-Urinary Disorders Steven W. Siegel, MD Centers for Continence Care and Female Urology and Female Urology Metropolitan Urologic Specialists Saint Paul, Minnesota

Disclosure –Medtronic, AMS, Uroplasty, Allergan Consultant, lecturer, proctor, grant/research support –Medical Advisor, Board Member or Equity Partner Uroplasty, Allergan, GT Medical, QIG –Off Label Usage: Interstim for pelvic pain, neurogenic disorders BoNT for OAB

Neuromodulation in Urology Sacral (InterStim) Tibial (Urgent PC) Spinal (VoCare) Chemodenervation (Botox)

Neuromodulation for GU Disorders Refractory OAB –Failed drugs and behavioral therapy Urinary Retention –Idiopathic non-obstructive Non-neurogenic etiology Fecal Incontinence

Current treatments for Overactive Bladder Behavioral therapies & Physical Therapy Drugs, anitcholinergic Intravesical Botox Neuromodulation –Sacral –PTNS Surgery –Augmentaton cystoplasty –Urinary diversion

How Likely Are Patients To Continue With Their Drug Therapy? Prescription persistency rates of OAB medications among patients new to market (n=21,362) 56% of patients chose not to refill their prescription a second time Only 15% of patient continued with their therapy through the first year

History of Sacral Neuromodulation 1981 Tanagho and Schmidt UCSF 1994 European CE Mark 1997 FDA approves for Urge Incontinence 1999 FDA approves for UF and NOUR 2002 FDA approves for OAB 2002 Wide use of fluoro, staged implant/tined lead 2006 Small stimulator 2011 FDA approval for bowel indication

InterStim Therapy Cumulative Use World-wide 100,000 patients have received InterStim Therapy Technique Change – 2002 Percutaneous Tined Lead Placement Number of Patients (in 1,000s)

Additional SNM Applications Pediatric patients/Dysfunctional elimination syndrome IC/Pelvic pain Bowel Dysfunction –Present indications* »Fecal incontinence »Fecal urgency-frequency (IBS) »Idiopathic chronic constipation –Many patients have both GU/GI symptoms –Often GI improvements most meaningful to patients Hoebeke P, JOU 2004 De Gennaro M, JOU 2004 Humphreys M, JOU 2006 Roth abstract 823, AUA 2007 Siegel S, JOU 2001 Comiter C, JOU 2003 Feler C, Anesth Clin NA 2003 Peters K, BJU 2004 Everaert K, Eur Urol 2004

Mechanism of Action Not a bladder specific therapy Central afferent modulation –Targets reflex centers in cord and pons Treats both OAB and retention –Blocks ascending sensory pathway inputs Turns on voiding reflexes by suppressing the guarding reflex pathways ‘Human Software’ Analogy Leng WW - Urol Clin North Am - 01-FEB-2005; 32(1): 11-8

Peripheral Neuroanatomy Parasympathetic –S2 – S4 afferent and efferent (Pelvic Nerve) –Excites bladder, inhibits urethra Sympathetic –T12 – L1 afferent and efferent (Hypogastric Nerve) –Excites urethra, inhibits bladder Somatic –S2 – S4 afferent and efferent (Pudendal Nerve) –Excites external urethral sphincter

Pelvic Floor Innervation Schematic

OAB Response (ITT and As Treated) Targets S3, S4 Pudendal N Dorsal Genital N

Anatomy: Sacral Canal

Relate Sacral Anatomy to Lead Location

Lateral Sacrum Posterior Sacrum

Trial Stimulation: PNE Insulated Needle with exposed tip placed at S3 –nerve location & function Sensory Response –Genital/anal sensation –Patient comfort Motor Response –Bellows & toe

Trial Period Criteria Success equals > 50% improvement number of leaks/day number of voids/day voided volume/void degree of urgency

Implantable Pulse Generator IPG Implantation Based on success of trial Outpatient procedure under local/sedation Patient unchanged if therapy denied/discontinued Can modulate stimulation parameters externally Permanent devices last up to 10 years (Interstim I)

Patient Selection Abnormal Voiding –May include other symptoms Pain Bowel dysfunction Younger (typical age 45-55) Non-neurogenic High tone pelvic floor muscle dysfunction

Poor Candidates for SNM Nerve damage –Peripheral neuropathy –Future need for MRI Pelvic malignancy Intrinsic abnormality of bladder –XRT –Fibrosis –Decompensation Pain without voiding complaints Very elderly

SNM: Clinical Efficacy Urge Incontinence 1 45% completely dry 34% experienced > 50% reduction in leaking episodes Urgency Frequency 2 31% returned to normal voids (4 to 7 voids/day) 33% experienced > 50% reduction in voids Retention 3 61% eliminated use of catheters 16% experienced > 50% amount of urine emptied from catheter usage N=33 N=38 SNS Study Group 1 JOU 1999;162, 2 JOU 2000;163, 3 JOU 2001;165

Brazelli, M. et al. Efficacy & Safety of Sacral Nerve Stimulation for the Treatment of Urinary Urge Incontinence: A Systematic Review. Journal of Urology. Vol , Mar Systematic Review: Urge Incontinence % of patients achieving continence or > 50% improvement in their symptoms Randomized Controlled Trials vs. Case Series Reports  Investigation of 1,827 implants from 34 clinical trials  SNM shown to be effective for the treatment of urinary urge incontinence 1

Results of a prospective, randomized, multicenter study evaluating the safety and efficacy of InterStim Therapy at 6- month follow-up in subjects with symptoms of overactive bladder Frequency-UrgencyUrge Incontinence Siegel, et al AUGS 2012

Urgency-Frequency PF P < RP P = 0.01 BP P = 0.01 GH P = V P = 0.01 SF P = RE P = 0.17 MH P = 0.01 % of Patients Control (n=20)Implant (n=23)US Norm PF - Physical FunctioningBP - Bodily PainV - VitalityRE - Role Emotional RP - Role PhysicalGH - General HealthSF - Social FunctioningMH - Mental Health Improvement in Quality of Life, 6-Month SF-36 Scores Janknegt RA, Hassouna MM, Siegel SW, Schmidt RA, Gajewski JB, Rivas DA: Patient satisfaction and complications following sacral nerve stimulation for urinary retention, urge incontinence and perineal pain: A multicenter evaluation. Int Urogynaecol J, 11: 231, 2000

Five year results of SNM for voiding dysfunction: Outcomes of a prospective, worldwide clinical study 17 centers –163 patients, mean age 44.7, 87% females Success rate 5 years post implant –68% UI –56% UF –71% Retention If success at 1 year, rate of success at 5 years –89% UI –71% UF –78% Retention Van Kerrebroeck et al, JOU 2007

Complications Reoperation rate <20% –Loss of efficacy –Pain at lead or IPG site –Infection * Starkman, NUU 2007; van Voskuilen, BJU 2007; Kessler, Eur. Urol 2006

Behavioral PFM Rehab Drugs How Should We Treat OAB Patients? PTNS, SNM BoNT, Other surgery BoNT, Other surgery

Discussion

SNM PTNS Trail Phase 1-2 weeks 12 weeks Involves surgery/revisions Non invasive Implantable No implant possible Takes a lot of expertise Simple to perform Long term efficacy known Still a question See patients 1x/year Every 3 weeks Widely accepted by insurers A work in progress Expensive Comparatively cheap Reimburses well Not so much

Treatment Algorithm Urge Incontinence and Urgency-Frequency Initial Screening Voiding Diary Urodynamics Behavioral Techniques Interventional Techniques Medications Test Stimulation Continue as Appropriate Other Intervention Implant InterStim System

When to Use PTNS vs. SNM Patient choice Introduction to neuromodulation Very young or elderly Neurogenic –MRI compatibility Poor surgical candidates

Which is the target? Anticholinergics and BoNT are primarily end- organ therapies SNM is a systemic treatment

Percutaneous Tibial Nerve Stimulation Target Tibial N., near medial malleolus MOA: Sensory afferent modulation Trial: 12 weeks of therapy, q 7-10 days x 30 min Typically results reported at 12 weeks Tapering protocol if successful Marketed commercially as Urgent ® PC –FDA approved for OAB 2005

Randomized trial of PTNS versus extended release tolterodine 100 OAB patients (94 females) 1:1 12 weeks PTNS vs. Tolterodine 4mg/day Similar objective improvements Perception of improvement greater in PTNS arm Both safe - Drug had greater dry mouth/constipation - PTNS had more pain/bruising at needle site No placebo, not blinded J Urol 2009;182:

Long-term durability of PTNS for the treatment of OAB PTNS “responders” (35/49) entered extension trial –32/25 finished 6/12 months Treatment interval tapered to individual rates –Average interval q 22.6 days Measures include voiding diary, global/safety assessments Patient GRA improved 6/12 mo All outcome measures significant over baseline Sustained therapeutic effect of PTNS for OAB patients over 1 year showed efficacy and durability J Urol 2010; 183:

SNM vs. BoNT I use both in my own practice The therapies are not equivalent Certain clinical situations are better suited for one versus the other Failure to recognize the differences could lead to suboptimal patient care

Neuromodulation Neurotoxin Restores function  Takes it away Treats retention  Causes it Improves GI symptoms  No potential WYSIWYG  Commits to 6-9 mo Use BoNT if fails  9 months before SNM Long term benefit  Temporary Infrequent reoperation  Frequent retreatment

When to Use BoNT vs. SNM Neurogenic –Progressive –MRI compatibility Elderly Patient willing to perform ISC No coexisting bowel complaints Failed SNM Patient choice

OAB Response (ITT and As Treated) Bion Device

OAB Response (ITT and As Treated)

Pudendal Hype? Has been discussed for years and has not “ taken off ” Studies showing “ superiority ” misleading – No difference in objective symptoms – Difference in subjective related to EMG use? – Long term success appears poor A carefully placed sacral lead may be better

Overview Devices Targets Indications Attitudes

Indications SUI Pain Sexual Dysfunction – ED, arousal Pediatric Bowel – Constipation, fecal urgency, dyschezia

Sacral Neuromodulation InterStim Implantable, programmable neuromodulation system Two stage therapy –PNE: Test stimulation procedure – 3 to 7 days, temporary –Staged Lead Implant: Placement of potentially permanent lead for up to 4 weeks –Chronic Implant: Implantation neurostimulator (and lead when not done as a staged procedure)