Restoring Function by Targeting Bladder-Brain Communication in Idiopathic OAB Patients Leading Theories in Mechanism of Action Sacral Neuromodulation

Overview of Overactive Bladder (OAB) 2

Sacral Neuromodulation Mechanism of Action Current scientific evidence supports the following concepts on the effect of SNM in OAB patients: Production of action potentials that modulate central nervous system (CNS) processing of bladder afferent input Modulation of abnormal afferent (sensory) activity Normalization of brain activity Restoration of bladder function 3

The International Continence Society Definition of OAB OAB is diagnosed and defined based on symptoms 1 Urgency with or without urge incontinence, usually with frequency and nocturia, in absence of pathologic or metabolic factors to explain symptoms Urgency is defined as the complaint of a sudden compelling desire to pass urine, which is difficult to defer Reference: 1. Abrams P, Cardozo L, Fall M, et al. Urology. 2003;61:

OAB is a Widespread Problem That is Expected to Increase Approximately 37.4 million adults in the United States have symptoms of OAB 1,2 Epidemiologic surveys suggest that the incidence of OAB rises as the population ages 1 References: 1. Stewart WF, Van Rooyen JB, Cundiff GW, et al. World J Urol. 2003;20: United Nations, Department of Economic and Social Affairs, Population Division (2011). World Population Prospects: The 2010 Revision, CD-ROM Edition. 3. Centers for Disease Control and Prevention (CDC). Air Pollution and Respiratory Health Branch, National Center for Environmental Health [asthma prevalence [asthma]. Atlanta, Georgia: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; National Diabetes Information Clearinghouse. National Diabetes Statistics, Atlanta, GA: U.S. Department of Health and Human Services. 5. Whitehead WE, Borrud L, Goode PS, et al. Gastroenterology. 2009;137: National Osteoporosis Foundation. What is osteoporosis. Accessed October 25, Alzheimer’s Association. Alzheimer’s facts and figures. Accessed August 23,

The Fundamental Cause of OAB May Be Multifactorial The pathophysiology of OAB may depend on gender and age 1 Myogenic and neurogenic centric hypotheses have been proposed as causes of OAB 1 Functional MRI studies have shown diminished brain activity in certain regions, suggesting the central nervous system (CNS) plays a role in OAB 1,2 These hypotheses may not be mutually exclusive, and may vary across patient and disease types 1 References: 1. Fowler CJ, Griffiths D, de Groat WC. Nat Rev Neurosci. 2008;9(6): Griffiths D, Derbyshire S, Stenger A, Resnick N. J Urol. 2005;174:

OAB Patients Have Altered Brain Responses Abnormal response in areas processing urge and social propriety 1,2 Diminished response in areas responsible for voluntary voiding 1,2 References: 1. Griffiths D, Tadic SD. Neurourol Urodyn. 2008;27: Griffiths D, Derbyshire S, Stenger A, Resnick N. J Urol. 2005;174:

Neurophysiology of the Bladder 8

The Lower Urinary Tract (LUT) Urine storage and micturition depend on the coordination of the bladder, bladder neck, urethra, and urethral sphincter 1 Coordination between the muscles of the LUT is mediated by neural pathways in the brain, spinal cord, and peripheral nerves 1 Reference: 1. Fowler CJ, Griffiths D, de Groat WC. Nat Rev Neurosci. 2008;9(6):

A Healthy LUT Requires Neural Coordination with the Spinal Cord and Brain Afferent pathways convey sensory information on bladder fullness 1,2 Efferent motor pathways respond, resulting in voluntary urine control 3,4 Dysfunction of the afferent neural pathways alters the balance of inhibitory and excitatory stimuli critical to voluntary bladder control 5 References: 1. Andersson KE. Nat Clin Pract Urol. 2004;1(2): Chancellor MB, Chartier- Kastler EJ. Neuromodulation. 2000;3(1): Fowler CJ, Griffiths D, de Groat WC. Nat Rev Neurosci. 2008;9(6): de Groat WC. Br J Pharmacol. 2006;147:S25-S Leng WW, Morrisroe SN. Urol Clin N Am. 2006;33:

Urine Storage Reflex 11 Low-level afferent signals are organized in the spinal cord and promote urine storage via efferent signals from the CNS 1,2 References: 1. Fowler CJ, Griffiths D, de Groat WC. Nat Rev Neurosci. 2008;9(6): de Groat WC. Br J Pharmacol. 2006;147:S25-S40.

Urine Voiding Reflex – A Positive Feedback Loop 12 References: 1. Andersson KE. Nat Clin Pract Urol. 2004;1(2): Fowler CJ, Griffiths D, de Groat WC. Nat Rev Neurosci. 2008;9(6): Leng WW, Morrisroe SN. Urol Clin N Am. 2006;33: High afferent signals are stimulated by intravesical pressure, resulting in increased activity to the brain 1 Descending efferent pathways then cause voluntary bladder contraction and the flow of urine 2 Normal voiding is, therefore, a function of a positive feedback mechanism 3

Dysfunction of Afferent Signaling in OAB OAB may be a result of increased, abnormal afferent activity, resulting in increased efferent signaling 1 Consequently, voluntary control of micturition is compromised 1 13 Reference: 1. Leng WW, Morrisroe SN. Urol Clin N Am. 2006;33:

Leading Theories in Mechanism of Action for Medtronic Sacral Neuromodulation 14

Restoring Balance May Help OAB Patients 15 References: 1. Chancellor MB, Chartier-Kastler EJ. Neuromodulation. 2000;3(1): Leng WW, Morrisroe SN. Urol Clin N Am. 2006;33: The goal of Sacral Neuromodulation (SNM) is to modulate the abnormal involuntary reflexes of the lower urinary tract and restore voluntary control. 1,2 Medtronic SNM Infection, inflammation, anatomic abnormalities Involuntary Reflex Mechanisms Voluntary Micturition Control Neurological diseases

How Does Sacral Neuromodulation Work? Sacral Neuromodulation electrically stimulates somatic afferent nerves in a sacral spinal root and sends signals to the CNS that may restore normal bladder function 1 Activation of somatic afferent nerves alters bladder sensory pathways and inhibits reflex bladder hyperactivity 1 16 Reference: 1. Leng WW, Morrisroe SN. Urol Clin N Am. 2006;33:

Neurostimulator Implant Site Medtronic Sacral Neuromodulation sends electrical stimulation to the sacral nerve via the InterStim ® System, which includes an implanted neurostimulator and lead The sacral nerve, in particular, influences pelvic floor behavior and is believed to modulate neural reflexes 1 17 References: 1. Buback D. AORN J. 2001;73(1):

Production of Action Potentials Modulate CNS Processing of Bladder Afferent Input The neurostimulator provides an electrical charge to an area near the sacral nerve, resulting in altered neural activity This stimulation likely depolarizes the nerve, causing an action potential 1 The signal propagates impulses along the axon as if the neuron had naturally fired an action potential 1 18 Reference: 1. Johnson M. Watson T, ed. Electrotherapy: Evidence-Based Practice. 12th ed. Elsevier; 2008:

Modulation of Abnormal Afferent Activity within CNS The action potentials induced by electrical stimulation are thought to alter abnormal sensory input from the bladder 1,2 Efferent pathways are uninhibited so as not to suppress voluntary voiding 3 Unlike other therapies that target the bladder, bladder regulation occurs without directly influencing the bladder or sphincter muscles 4 19 References: 1. Johnson M. Evidence-Based Practice. 12th ed. Philadelphia, PA: Elsevier; 2008: Chancellor MB, Chartier-Kastler EJ. Neuromodulation. 2000;3(1): Leng WW, Chancellor MB. Urol Clin N Am. 2005;32: van der Pal F, Heesakkers JPFA, Bemelmans BLH. Curr Opin Urol. 2006;16:

Normalization of Brain Activity in OAB Patients 1 20 Reference: 1. Blok BFM, Goen J, Bosch JLHR, et al. BJU Int. 2006;98: Areas involved in micturitionAreas involved in awareness and urge

Conclusions OAB is a common problem with a prevalence that is expected to increase A healthy LUT is a result of a balance between sensory and motor signaling Sensory signals convey information on bladder fullness via the sacral nerve and may be altered in OAB patients Medtronic Sacral Neuromodulation delivers electrical stimulation to the sacral nerve which is thought to modulate abnormal sensory signaling Sacral Neuromodulation is correlated with more normal patterns of brain activation in OAB patients Further research into the mechanisms of action of SNM may provide insights into the pathophysiology of OAB and lead to future improvements in neuromodulation therapies 21

Sacral Neuromodulation Mechanism of Action Current scientific evidence supports the following concepts on the effect of SNM in OAB patients: Production of action potentials that modulate central nervous system (CNS) processing of bladder afferent input Modulation of abnormal afferent (sensory) activity Normalization of brain activity Restoration of bladder function 22

Important Safety Information InterStim ® Therapy for Urinary Control is indicated for the treatment of urinary retention and the symptoms of overactive bladder, including urinary urge incontinence and significant symptoms of urgency-frequency alone or in combination, in patients who have failed or could not tolerate more conservative treatments. The following Warning applies only to InterStim Therapy for Urinary Control: Warning: This therapy is not intended for patients with mechanical obstruction such as benign prostatic hypertrophy, cancer, or urethral stricture. InterStim ® Therapy for Bowel Control is indicated for the treatment of chronic fecal incontinence in patients who have failed or are not candidates for more conservative treatments. Contraindications for Urinary Control and for Bowel Control: Diathermy. Patients who have not demonstrated an appropriate response to test stimulation or are unable to operate the neurostimulator. Precautions/Adverse Events: For Urinary Control: Safety and effectiveness have not been established for bilateral stimulation; pregnancy, unborn fetus, and delivery; pediatric use under the age of 16; or for patients with neurological disease origins such as multiple sclerosis. For Bowel Control: Safety and effectiveness have not been established for bilateral stimulation; pregnancy, unborn fetus, and delivery; pediatric use under the age of 18; or for patients with progressive, systemic neurological diseases. For Urinary Control and for Bowel Control: The system may be affected by or adversely affect cardiac devices, electrocautery, defibrillators, ultrasonic equipment, radiation therapy, MRI, theft detectors/screening devices. Adverse events include pain at the implant sites, new pain, lead migration, infection, technical or device problems, adverse change in bowel or voiding function, and undesirable stimulation or sensations, including jolting or shock sensations. For full prescribing information, please call Medtronic at and/or consult Medtronic’s website at Product technical manual must be reviewed prior to use for detailed disclosure. USA Rx Only. Rev