Nerve Stimulation Therapies for Bowel and Bladder Continence R. Keith Huffaker, MD, MBA, FACOG Quillen/ETSU Center for Pelvic Surgery and Urogynecology

Objectives Sacral nerve stimulation (SNS) InterStim Diagnoses Percutaneous tibial nerve stimulation (PTNS) Urgent PC

Where do InterStim and Urgent PC fit?

Interstim – Sacral Neuromodulation Indications Urinary Frequency Urinary Urgency Urge Urinary Incontinence Urinary Retention / Incomplete Bladder Emptying Fecal Incontinence Not for SUI

Micturition and Storage Reflexes Leng & Chancellor UNA 2005

It’s simply the muscles or the nerves Where Medications Work Efferent messages tell muscles to work. Medication may help muscle comply better Where InterStim works Sensory Messages (Afferent) tell the brain what is happening with the bladder and other voiding components InterStim modulates incorrect messages. Also has some effect on muscles/motor Conscious control occurs in the brain (pontine micturition center). As bladder stores urine, the detrusor relaxes and the pelvic floor tightens around the urinary sphincter. When bladder is full, and it is time to release the stored urine, the detrusor contracts and the sphincter/pelvic floor relaxes. InterStim: consider after two medications fail. Unlikely third or fourth will work.

InterStim Pre-test Requirements Patient has had condition for > 1 year Stress incontinence has been eliminated as major urinary complaint Patient failed conventional therapy: Behavior modifications Two medication failures Cannot comply with other treatment option (I.e. self-cath) Can complete urinary diary and use device Patient has improvement of 50% or > during test

Mechanism of Action Mechanism of action for SNS is not fully understood at this time - many theories exist. Generally agreed that stimulation of the sacral nerves modulates the neural reflexes that influence the bladder, sphincter and pelvic floor that control/influence voiding. (Afferent pathways) Basic science research is being conducted to better understand the mechanism of action of sacral nerve modulation. Reference: Chancellor MB, Chartier-Kastler EJ. Principles of sacral nerve stimulation (SNS) for the treatment of bladder and urethral sphincter dysfunctions. International Neuromodulation Society 2000; 3: 15-26.

But is it really doing anything? Dasgupta and Fowler. Changes in brain activity following sacral neuromodulation for urinary retention.J Urol. 2005 Dec;174(6):2268-72.

Therapy consists of 2 steps: Test stimulation procedure – allows trial of InterStim Therapy -simple (30-45) minutes -done in office (PNE) or outpatient room (PNE or Stage I) --test for a ½ to 1 week -percutaneous wire -external pulse generator -voiding diary 2. Implantation of device --full implant --Stage II --both steps target S3 foramen and nerves System includes a lead placed near the sacral nerve and programmable implantable neurostimulator – system provides stimulation to the sacral nerve. Two phases of therapy: Acute: test stimulation is done as an outpatient procedure usually in a clinic. Chronic: inpatient procedure where the patient is implanted with the InterStim system.

After Test Procedure Voiding diary Second step 50% improvement required for implantation Implantation is not required if you choose not to do so Second step PNE wires removed in office, or OR for staged approach Place neurostimulator Remove lead

Implant Procedure Patients with a successful test stimulation go on to implantation of the internal pulse generator. (50%) A pocket is typically created for the neurostimulator in the upper buttock.

Tined Lead

Patient Programmer Physician Programmer

Clinical Study Overview Multi-center randomized, prospective study* 23 centers: 9 European & 14 North American 581 patients (1993 – 1998) Measurements: Urge incontinence Number of leaking episodes /day Severity of leaking episodes Number of pads/diapers replaced/day Urgency-frequency Number of voids/day Volume voided/void Degree of urgency prior to void Retention Volume per catheterization Success was defined as a minimum of 50% improvement in at least one primary diary variable as compared to baseline. This same definition was used for qualifying after test stimulation but also to define clinical success after randomization. This 50% improvement has been chosen in other studies as well (behavior/ biofeedback training; NIH studies) and has been accepted by the NIH and AHCPR as a standardized measure. For this reason also in this study a 50% improvement in symptoms was chosen. Study initiated by Medtronic in December 1993 using the traditional implantation procedure (Staged Implant was not performed during this study; tined lead was not available for this study) Included voiding dysfunctions of: urge incontinence (184 patients), retention (177 patients), urgency/frequency (220 patients). Urge incontinence indication approved for market clearance on September 29, 1997 by U.S. Food & Drug Administration. Urgency/frequency and retention indications approved for market clearance on April 15, 1999 by U.S. Food & Drug Administration. * Staged Implant was not performed during this study

Efficacy: Overactive Bladder

Efficacy: Urinary Retention

Implantation: Ranking of Adverse Events in First 12 Months Post-implant Pain at neurostimulator site 15.3% New pain 9.0% Suspected lead migration 8.4% Infection 6.1% Transient electric shock 5.5% Pain at lead site 5.4% Adverse change in bowel function 3.0% Note: Additional events occurred – each less than 2.0% Additional adverse events include technical problems (1.7%); suspected device problem (1.6%); change in menstrual cycle (1.0%); Adverse change in voiding function (0.6%); persistent skin irritation (0.5%); suspected nerve injury (0.5%); device rejection (0.5%). Overall surgical revision rate at 12 months = 29%. No reports of serious adverse device effects or permanent injury associated with the devices or the use of sacral nerve stimulation. At database closure, 9% of reported events were unresolved.

External anal sphincter defect, n=21 Chan and Tjandra. Sacral Nerve Stimulation for Fecal Incontinence: External Anal Sphincter Defect vs. Intact Anal Sphincter. Diseases of the Colon and Rectum:2008. Prospective study External anal sphincter defect, n=21 External anal sphincter intact, n=32 3,6,12mo f/u Anorectal physiology Wexner’s score Bowel diary QOL Q’s

All 53 benefited from SNS EAS defects: Weekly incont. episodes decreased from 13.8 to 5 at 12 mos. EAS intact 6.7 to 2 QOL scores improved for both groups +/- pudendal neuropathy irrelevant Size of EAS defect did not matter up to 120 degrees

Double-blind crossover design LeRoi, et al. Efficacy of Sacral Nerve Stimulation for Fecal Incontinence Results of a Multicenter Double-Blind Crossover Study. Annals of Surgery:2005. n=27 (most were women) SNS implanted Double-blind crossover design Randomized to on or off for one month periods Pt then chose the period of preference not knowing whether was actually on or off Placed in preferred mode for 3 months

Outcome measures FI Fecal urgency Delay in postponing defecation Manometry QOL Etc.

Significant improvement in all when on Clinical benefit not due to placebo

IE=incomplete bladder emptying; UUI=urge urinary incontinence; RKH SNS Results Diagnosis Procedure Success Implant Implant success IE SNS PNE No NA UUI Yes IE and UUI UUI and FI IE and MUI MUI IE and FI IE=incomplete bladder emptying; UUI=urge urinary incontinence; FI=fecal incontinence; MUI=mixed urinary incontinence

Interstim Bottom Line Interstim is FDA approved for refractory urgency and frequency urge incontinence incomplete bladder emptying fecal incontinence Not for pain (PBS/BPS/IC) Effective therapy with intermediate long-term follow-up. Support is critical

An Option Between Conservative and Surgical Treatments Urgent® PC An Option Between Conservative and Surgical Treatments Simple, Office-based Neuromodulation with Urgent® PC

What is PTNS? Defined in a variety of ways: Percutaneous Tibial Nerve Stimulation Posterior Tibial Nerve Stimulation Posterior Tibial Neurostimulation Example: New CPT® code 64566 “Posterior tibial neurostimulation - percutaneous electrode, single treatment, includes programming”

Potential Urgent PC Patients

Urgent® PC Easy to administer in twelve 30 minute sessions with maintenance therapy variable Effective – Approximately 2/3 of patients report a reduction in their symptoms May work even if other treatments have failed Low risk – Most common side-effects include transient mild pain or skin inflammation at or near the stimulation site

Treatment with Urgent® PC Stimulation delivered via a 34 ga. needle electrode Needle electrode inserted above medial malleolus The needle electrode is connected to a battery-powered stimulator Provides Percutaneous Tibial Nerve Stimulation (PTNS)

Treatment with Urgent® PC Impulse travels from the ankle along the tibial nerve to the sacral nerves

Urgent® PC Neuromodulation System

Office-based Treatment Patient is clothed and comfortable May be administered by qualified staff, under physician supervision Physician and staff can treat multiple patients at once

Treatment Frequency 12 weekly Urgent PC treatments Responders may need maintenance treatments to sustain improvements Slowly increase time between treatments If symptoms reappear or increase in severity, return to last frequency to sustain relief In OrBIT study, treatment interval increased to 24 days between treatments during months 6 – 12

Urgent PC Contraindications Patients who are pregnant or planning to become pregnant while using this product Patients with pacemakers or implantable defibrillators Patients prone to excessive bleeding Patients with nerve damage that could impact either percutaneous tibial nerve or pelvic floor function Not intended for intra-cardiac or trans-thoracic use Concurrent use of medical monitoring equipment during stimulation is not recommended Not suitable for use in the presence of a flammable anesthetic mixture with air or with oxygen or nitrous oxide

PTNS Clinical Effectiveness 30+ peer reviewed publications demonstrate safety and efficacy Reduce urgency, urge incontinence & frequency Significant objective and subjective improvements No serious adverse events or side-effects Improved quality of life Objective urodynamic data 2/3 of patients respond well Change reference to MacDiarmid, Staskin, Current Bladder Dysfunction 0520108C01/10

Meta-Analysis of 7 PTNS Studies Martinson, M. (2008). Meta-Analysis of PTNS for Urinary Disorders. Sponsored by Uroplasty, Inc.

60 – 80% Response Kari: Use the newest patient response chart from PTNS brochure. MacDiarmid, S., & Staskin, D. (2009). PTNS: A literature based assessment . Curr Bladder Dys , 4, 29-33. 0520108C01/10

PTNS compared to Drug Patient perception of cure/improvement: 80% in PTNS group; 55% in tolterodine LA group Physician perception of cure/improvement: 80% in PTNS group; 61% of tolterodine LA group Comparable reductions in voiding episodes and urge incontinence Side-effects: No serious adverse events were associated with either treatment. Constipation and dry mouth reported more often in tolterodine LA group Peters, K.M., Leong, F.C., Shobeiri, S.A., MacDiarmid, S.A., Rovner, E.S., Wooldridge, L.S., et al. (2008). Randomized multicenter study comparing percutaneous tibial nerve stimulation with pharmaceutical therapy for the treatment of overactive bladder. Abstract, American Urologic Association, Annual Meeting, Orlando, FL.

PTNS Long-Term Follow-up Retrospective analysis of 256 patients (178 were treated for OAB symptoms) Sixty percent (107/178) of patients with OAB symptoms were responders Results stable at three-year mean follow-up when initial series was followed by maintenance therapy Only 10% of patients showed significant reduction of the obtained results Cappellano F., Finazzi Agro E., Giollo A., Petta F., Catanzaro M., Miano R., Germani S., Catanzaro F. (2006). Percutaneous tibial nerve stimulation (PTNS): results at long term follow-up. Abstract presented at the SIUD Congresso Nationale 2006, 27-30 September, Rome, Italy.

OrBIT – UPC vs. Detrol® LA Multicenter, RCT 12 week phase 12 month responder follow-up 1:1 randomization (n=100) Physician and patient GRA Voiding diaries, QoL measures

OrBIT Results at 12 Weeks

OrBIT Results at 12 Weeks *p-value: 0.053  

OrBIT – Side Effects Constipation reported less often in PTNS arm compared to drug arm (p=0.04) Dry mouth reported less often in PTNS arm compared to drug arm (p=0.0004) PTNS group reported pain, discomfort or redness at ankle (assessed for PTNS group only)

OrBIT Results – Long-term Statistically significant improvement sustained from 12 weeks thru 12 months Frequency -2.8 voids/day (p<0.001) Nighttime voids -0.8 voids/night (p<0.05) Urgency -3.7/day (p<0.01) Voided volume +39 cc (p<0.05) Incontinence episodes -1.6/day (p<0.001) QOL measure (p<0.01) No serious adverse events or device malfunctions

OrBIT Results – Long-term Responders continued treatment 90% for 6 months 73% for 12 months Sustained improvements at 12 months

OrBIT – Treatment Interval

Risks of Treatment The risks of Urgent PC are low Side-effects include: Transient moderate pain at or near the stimulation site Transient mild pain or skin inflammation at or near the stimulation site Transient mild bleeding at needle insertion site

RKH PTNS Results n=2; both successful Diagnosis Procedure Success UUI Yes n=2; both successful

What’s Next for PTNS Shorter therapy protocols Determination of prolonged treatment protocols Fecal urgency and incontinence Constipation Incomplete bladder emptying Chronic pelvic pain Chronic non-bacterial prostatitis pain Pediatric use for LUTS