A Practical Approach To Urogynecology

Who Cares? Is this Really important? Incontinence affects 33 million Americans (17% of the population) Direct costs to USA in 2000: $19.5 Billion dollars Significant Adverse effects in multiple quality of life domains

Barriers to Treatment Women develop coping mechanisms like the avoidance of activities that provoke the leakage, wearing dark clothes, avoiding intercouse, and social interactions with others.

Barriers to Treatment Normal part of aging Nothing can be done Surgical treatment is invasive Catheters and daily management products are the best solutions

Incontinence Myths DON’T CALL A PLUMBER!!!!! They’re too expensive!

Barriers to Treatment Feeling of not being equipped to offer effective solutions “ I do not have the time” Feeling that incontinence is a “lost leader” Belief that urinary incontinece just isn’t a serious concern

What is Incontinence? Loss of voluntary control over your urinary functions May consist of the loss of a few drops of urine while coughing or laughing, or urine loss with a sudden urge to urinate

Classification of Incontinence Stress – loss of urine when the abdomen is under physical stress (e.g. coughing, laughing, sneezing, running) Urge – a sudden, strong urge to urinate combined with a sudden, uncontrollable leakage of urine (OVER ACTIVE BLADDER)

Classification of Incontinence Mixed (stress and urge) Overflow – frequent or constant dribble of urine

Transient Incontinence: DIAPPERS D Delirium or Acute Confusion I Infection A Atrophic Vaginitis P Phamacologic Agents P Psychotic Disorders E Excessive Urine output (CHF) R Restricted Mobility S Stool Impaction Consider with Frail and Elderly Women

Secondary Causes Interstitial Cystitis Multiple Sclerosis Parkinson’s Disease Diabetes Mellitus and Insipidus Bladder Cancer Urethral Diverticulum Fistula

Lifestyle Factors Caffeine Alcohol Opiods Sedentary Cigarette Smoking

Predisposing Factors Vaginal Delivery Age Genetics Obesity Prior Surgery Chronic Lung Disease/Smoking Medications

Evaluation of Pelvic Floor Disorders History Physical Examination Bedside Simple Cystometry Determination of Post Void Residual Supine and Standing Stress Test Urinalysis

Indications for Complex Urodynamic Evaluation Planning Surgery Mixed or confusing picture History inconsistent with Exam Elevated Post Void Residuals Failed Conservative Treatment History of Prior Pelvic floor Surgery History of Pelvic Radiation

Other Tests Voiding Diary Urine Cytology Cystoscopy Electrophysiologic Testing Radiologic Imaging of Pelvic Floor

Signs of Complicated Incontinence Recurrent Incontinence Continuous Leakage Treatment Failure Prolapse Beyond Hymen Elevated Post Void Residual Pain, Hematuria, Recurrent UTI History of Prior Pelvic floor Surgery History of Pelvic Radiation

How Does Stress Incontinence Occur?

How Does Stress Incontinence Occur? Weak Connective Tissue Supports Weak Musculature of pelvic floor Weakening of the bladder neck spinchter Abnormal nervous system

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Treatments for Stress Incontinence Alpha Agonists * Tricyclic Antidepressants* Urethral Bulking Agents Active use of Kegel with Provocative Event Catheters/Absorbent Products/Mechanical Devices EXMI Chair Surgery *non FDA Approved Indication

Surgery Highly effective minimally invasive sling surgery Burch Retropubic Colposuspension Needle Suspension Procedures Kelly Plication Traditional Pubovaginal Sling Highly effective minimally invasive sling surgery now available

Traditional Approach to Surgical Management Of Urinary Stress Incontinence No Hypermobility Normal Pressure Urethra Burch Hypermobility Sling ISD Periurethral Bulking Agents No Hypermobility

Principles of Action

TVT Kohli N, Miklos J, Lucente V. Tension-free vaginal tape: A minimally invasive technique for treating female SUI. Contemporary OB/GYN; Gynecare reprint: 1 – 10.

Trans-Obturator Approach Easy to implant Operative time is reduced Minimally invasive Local, regional or general anesthesia can be utilized

The Micturition Cycle Storage phase Emptying phase Bladder pressure Normal desire to void Bladder filling The normal micturition cycle consists of a storage phase and an emptying phase. The storage phase encompasses bladder filling, the first sensation to void, and the desire to void. The emptying phase is characterized by a volitional contraction of the detrusor muscle leading to a rise in bladder pressure and emptying of the bladder. As the bladder begins to refill, the cycle is repeated. First sensation to void Bladder filling

Innervation of the LUT Sympathetic Parasympathetic T10-L2 Somatic Inferior mesenteric ganglion Sympathetic Trigone Urethra Hypogastric nerves Parasympathetic Pelvic nerves T10-L2 Bladder emptying is a complex process involving communication among several parts of the central nervous system, or CNS. These include the cerebral cortex, limbic system, hypothalamus, thalamus, basal ganglia, cerebellum, brain stem, and spinal cord, linked to each other and to the peripheral nervous system. The nerves responsible for micturition pass through the S2 through S4 segments of the spinal cord. External urethral sphincter Somatic S2-S4 Pudendal nerves Muscles of the pelvic floor Adapted from Abrams P, Wein AJ. The Overactive Bladder: A Widespread and Treatable Condition. Erik Sparre Medical AB; 1998.

Distribution of Cholinergic and Adrenergic Receptors in the LUT Μ = Muscarinic Ν = Nicotinic α = α1-adrenergic β = β2-adrenergic Detrusor muscle (M,β) Trigone (α) The distributions of cholinergic and adrenergic receptors have been characterized in the lower urinary tract. The muscarinic M3 receptor is located in the detrusor smooth muscle and is the primary mediator of bladder contraction. The M2 receptor is also believed to mediate detrusor contraction, by inhibiting sympathetically mediated detrusor relaxation in rats. The 2-adrenergic receptors are also located in detrusor muscle and appear to be involved in bladder relaxation. The 1-adrenergic receptors predominate in the trigone, bladder neck, and urethra, and may be involved in contraction. Nicotinic receptors are located in the pelvic floor and play a role in contraction. Pelvic floor (N) Bladder neck (α) Urethra (α) Adapted from Abrams P, Wein AJ. The Overactive Bladder: A Widespread and Treatable Condition. Erik Sparre Medical AB; 1998.

Characteristic Symptoms of OAB Frequency and Urgency Urge incontinence Bladder pressure greater than urethral pressure The characteristic symptoms of OAB are urinary frequency and urgency, with or without urge incontinence. Urinary incontinence occurs when, involuntarily, the bladder pressure is greater than the urethral pressure.

Treatment: Lifestyle Changes Avoid Bladder Irritants Caffeine Alcohol Chocolate Cigarettes Acidic/Spicy foods

Treatment: Lifestyle Changes Fluid Management:Avoid Excess intake Drink 6-8 cups of fluids/day Drink throughout day instead of “binge” Drink most of fluid in day and afternoon Avoid excessive restriction: concentrated urine

Treatment: Lifestyle Changes Evaluate contributing Factors: Medications Avoid Constipation: Add Fiber to Diet Obesity

Treatment: Lifestyle Changes Medications affect Bladder Function by: Decreasing Bladder Contractility Increasing Bladder Contractility Increasing Urethral Sphincter Tone Decreasing Urethral Sphincter Tone

Treatment: Lifestyle Changes Medications that Decrease Bladder Contractility Anticholinergics Beta-adrenergic Agonists Calcium Channel Blockers Alcohol (Also act as ADH inhibitor) Antihistamines, sedatives, narcotics Antidepressants Antipsychotics

Treatment: Lifestyle Changes Medications that increase detrussor irritability/diuresis Diuretics Caffeine Alcohol

Treatment: Lifestyle Changes Medications increase Urethral Sphincter Tone: Alpha-Adrenergic Agonists Amphetamines Tricyclic Antidepressants

Treatment: Lifestyle Changes Medications that Decrease Urethral Sphincter Tone: Alpha-Adrenergic Blockers

Behavioral Modification Timed voiding Education Behavioral Modification Pelvic floor exercises Delayed voiding Various forms of behavioral modification can be helpful in the management of OAB. Useful strategies for behavioral modification include patient education, timed or delayed voiding, and positive reinforcement of any changes made. Pelvic floor exercises have been found useful for women, primarily those with stress urinary incontinence. Reinforcement

Pelvic Floor Excercises Self management program utilizing the Kegel technique or pelvic muscle exercises May not see an improvement in bladder control for up to 3 to 6 weeks May be improved with Biofeedback or Electical Stimulation

Bladder Retraining Best with management of urinary frequency and urgency Goal is to trick the bladder into thinking that it is always empty in an effort to regain voluntary control over bladder emptying.

When the Urge Strikes! Stop and stay still Squeeze pelvic floor muscles Relax rest of body Concentrate on suppressing urge Wait until the urge subsides Walk to bathroom at normal pace

Limitations of Behavior and Lifestyle Changes Require motivation in both patient and Provider Success depends on intensity of program High cost in terms of Provider time

Treatments for Over Active Bladder Behavioral Therapy Pelvic Floor Rehabilitation (Kegels) Biofeedback Electrical Stimulation Neuromodulation (Interstim, Tibial Nerve Stimulation) Botox Bladder injections Medications

Medications for Over Active Bladder Tolterodine Oxybutynin (oral and Patch) Darifenacin Troposium Solifenacin

Neurotransmitter Receptors Cholinergic Receptors Adrenergic Receptors Nicotinic Muscarinic α-Adrenergic β-Adrenergic Both cholinergic and adrenergic receptors are involved in the regulation of micturition in humans. Acetylcholine liberated from cholinergic nerves acts through muscarinic receptors to serve as a major mediator of the voiding response. Five distinct subtypes of muscarinic receptors, M1 through M5, have been identified in humans. Although -adrenergic receptors do not appear to be involved in bladder control in normal individuals, their function may be altered in pathologic states and may facilitate contraction in patients with overactive bladder. The -adrenergic receptors may be involved in relaxation of the human detrusor muscle. Subtypes M1, M2, M3, M4, M5 Adapted from Wein AJ. Exp Opin Invest Drugs. 2001;10:65-83.

Muscarinic Receptor Distribution M1 : Neural Tissue M2: Detrussor, Cardiac M3: Detrussor, Salivary Glands and Bowel M4: Cerbral Cortex, Lungs

Why Treat OAB with Antimuscarinics Detrusor contraction in the normal bladder is primarily mediated via muscarinic receptors release acetylcholine from cholinergic nerves stimulation of muscarinic receptors on the detrusor smooth muscle

Clinical Effects of Antimuscarinic Therapy Stabilizing effect on bladder (detrusor) muscle Diminishes frequency of involuntary bladder contractions Increases functional bladder capacity Delays initial urge to void

Considerations in Choosing Anticholinergic Medications Provides efficacy by inhibiting involuntary bladder contractions Does not prevent normal micturitions Is selective for the bladder over other organs, resulting in reduced side effects and improved tolerability Provides clinical effectiveness—the optimal balance of efficacy, tolerability, and compliance/persistency

Distribution of Muscarinic Receptors in Target Organs of the Parasympathetic Nervous System Iris/Ciliary Body = Blurred Vision CNS Lacrimal Gland = Dry Eyes Dizziness Somnolence Impaired Memory & Cognition Salivary Glands = Dry Mouth Heart = Tachycardia Gall Bladder Stomach = Dyspepsia Muscarinic receptors are widely distributed throughout the body. In addition to the bladder, these receptors are located in a variety of organs of the parasympathetic nervous system, as well as in the CNS. The distribution of muscarinic receptors helps to explain the side effects associated with antimuscarinic drugs. Common CNS side effects are dizziness, somnolence, and impaired memory and cognition. Effects at the iris or ciliary body can lead to blurred vision, whereas effects at the lacrimal gland may cause dry eyes. Inhibition of salivary secretion leads to dry mouth. Cardiac effects may take the form of tachycardia. Inhibition of muscarinic receptors may also be associated with effects in the stomach, or dyspepsia, and colon, or constipation. Colon = Constipation Muscarinic receptors are also located in the CNS. Bladder (detrusor muscle) Adapted from Abrams P, Wein AJ. The Overactive Bladder: A Widespread and Treatable Condition. Erik Sparre Medical AB; 1998.

Contraindications for Anticholinergics Renal Failure Hepatic Failure Narrow Angle Gluacoma Gastric Retention History of an Allergic Reaction

Medication Failures Tolerability of side effects Lack of efficacy High rate of noncompliance

Drug Therapy Persistence is Poor Among OAB Patients Prescription persistency rates of OAB medications among patients new to market (n=21,362) 20% 40% 60% 80% 100% 56% of patients chose not to refill their prescription a second time Only 15% of patients continued with their therapy through the first year Source: The 2002 Gallup Study of the Market for Prescription Incontinence Medication. Princeton, NJ: Multi-Sponsor Surveys, Inc 2002

InterStim Therapy Sacral Nerve Stimulation for Urinary Control Sacral nerve stimulation provides an effective alternative for voiding dysfunction patients who have not been helped- or could not tolerate- more conventional treatments, including pharmacotherapy.

InterStim® Therapy Utilizes mild electrical pulses to the nerves associated with voiding function. Through neurostimulation, significantly improved or normal voiding is restored. Medtronic-Confidential

History of Sacral Nerve Stimulation 1981 – Department of Urology, University of California at San Francisco initiated clinical program. 1985-1992 – Multi-center trial conducted by Urosystems, Inc. 1994 – Medtronic CE mark (approval to market in Europe) for InterStim Therapy in Europe for treatment of urge incontinence, retention and urgency-frequency. September 1997 – FDA grants Medtronic approval of the InterStim System for treatment of urge incontinence in the US. April 1999 - FDA approval of the InterStim System for treatment of symptoms of urgency-frequency and urinary retention. September 2002 – FDA approval of tined lead August 2005 – Over 21,000 patients implanted worldwide

Who Can Benefit from InterStim Therapy? Patients whose symptoms did not improve with more conventional treatments, such as medications Patients with non-obstructive urinary retention Patients with symptoms of overactive bladder, including urinary urge incontinence and urgency-frequency Patients who cannot tolerate the side effects from medications

Benefits of InterStim Therapy Effective Treatment in properly screened patients Safe Reversible Does not preclude use of alternative treatments

Test Stimulation Procedure A test is done prior to implant to determine how a patient will respond to the implanted device Performed in the office or surgery center A lead is surgically implanted near the S3 nerve Lead is connected to an external device worn on the patient’s belt for a period of 3-7 days Patient will record his/her voiding behavior in a diary

Test Stimulation Procedure Locate & identify sacral nerves Verify neural integrity Allow the patient to feel the stimulation Assess viability of sacral nerve stimulation on voiding behavior (goal is efficacy > 50% improvement in symptoms) Help physician & patient make an informed choice about the long-term therapeutic value The test stimulation phase is conducted to assess a patient’s functional response to SNS. Note: Other than test stimulation, there are no pretreatment tests — including urodynamics — that can help to predict the outcome of surgery.

Test Stimulation Procedure Video Test Stimulation (click to start and pause video) [Test Stimulation, Slides 24-32] After finding the bony landmarks, the foramen needle is inserted. Then, using the foramen needle and a test stimulator, a test is done to assess sensory and/or motor responses of the sacral nerves.

Implant Procedure After successful test stimulation, the physician may implant the InterStim System A pocket is typically created for the neurostimulator in the upper buttock

Tined Lead Model #3889 shown, Model #3093 not shown

Using the Tined Lead with the Lead Introducer (CLICK ON THE PICTURE TO BEGIN THE VIDEO, CLICK CONTINUE & RESUME IF PROMPTED) If the animation takes too long to download, you can find the same graphic On the tined lead CD.

Contraindications to Interstim Therapy Failure to respond by more than 50% to test stimulation Outlet Obstruction Patient without mental capacity to manage device Bladder Cancer

Patient Programmer Patient is given a programmer to control the settings on their own without visiting his/her physician or nurse Allows patient to turn the device on and off, and adjust the levels of stimulation within physician-set limits

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. Data (MDT-103): 1993 - 1998 * Staged Implant was not performed during this study

Efficacy: Overactive Bladder Data (MDT-103): 1993 - 1998

Efficacy: Urinary Retention Data (MDT-103): 1993 - 1998

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. Data (MDT-103): 1993 - 1998

InterStim® Therapy: Healthcare Utilization 1 year Before & After Implant Kaiser Permanente® Healthcare System1 After one year 73% of patients indicated an improvement of 50% or greater Outpatient visits and costs were reduced by 73% Annual drug expenditures were reduced by 30% N=65 patients Pre-Implant Mean Post Implant Mean Mean Change P Value Voiding Related Diagnostic & Therapeutic Procedures 1.03 0.06 -1.0 procedures <0.0001 Urinary Tract Infections 0.43 0.24 -0.19 UTIs 0.0959 Outpatient Visits 3.02 0.82 -2.3 visits Outpatient Costs $994 $265 -$729 Procedure Costs $655 $59 -$596 Drug Expenditures $693 $483 -$210 0.021 Aboseif, S. et al. Sacral Neuromodulation: Cost Considerations and Clinical Benefits. Manuscript Pending Acceptance. 2006 Medtronic-Confidential

Quality of Life Medtronic-Confidential Patients implanted with InterStim System reported significantly improved ratings (p < 0.00625) in health-related quality of life (HRQOL) measures.1 The largest gain was noted in the subject’s perceived ability to increase their level of work performance or other daily activity. 1 An improvement of 10% to 40% in Beck Depression Inventory scores has been shown in urge incontinent patients.2 Improved results in both (HRQOL & depression) have been seen at three months and sustained for a 12-month period of follow-up.1 1 Das, A.K. et al. Improvement in Depression and Health-Related Quality of Life After Sacral Nerve Stimulation Therapy for Treatment of Voiding Dysfunction. Urology 64: 62-68, 2004. 2. Shaker, H.S. and Hassouna, M. Sacral Nerve Root Modulation: An Effective Treatment for Refractory Urge Incontinence. J Urol, 159: 1516, 1998 Medtronic-Confidential

InterStim Therapy Patients with no daily leakage episodes2 Patient Selection: Who Benefits Most? Patients who are most likely to discontinue drug therapy may have the best chance for remaining completely dry Adjusted Odds Ratio of age as a predictor of treatment drug discontinuation1 InterStim Therapy Patients with no daily leakage episodes2 . (referent) Campbell, U.B, Stang, P, Barron, R, Galt Associates, Inc., Allergan, Inc. Survey Assessment of Compliance and Satisfaction with Treatment for Urinary Incontinence. Poster Presentation, ICS Conference, 2005 Amundsen, C.L. et al. Sacral Neuromodulation for Intractable Urge Incontinence: Are There Factors Associated With Cure? Urology 66: 746-750 2005. Medtronic-Confidential

Summary Patients are more often prescribed medical therapy and polypharmacy before further treatment options, such as InterStim Therapy, are discussed Because of the challenging compliance issues associated with medical management, patients may be placed in a cycle of being a “perpetual new patient” often discontinuing the healthcare system or accepting their condition before InterStim Therapy is presented to them Randomized controlled trials may confirm long term results vs. more conservative treatments InterStim Therapy is an effective treatment option in the treatment of voiding dysfunction, offering not only sustained results, but may also provide significant economic & quality of life considerations to payors and patients Medtronic-Confidential