Pudendal neuromodulation for urinary and fecal incontinence and sphincter dyssynergia

SUMMARY / ABSTRACTSpinal cord injury (SCI) frequently produces severe, life-long bladder and bowel dysfunction that results in urinary (UI) and fecal incontinence (FI), as well as sphincter dyssynergia that results in urinary retention and fecal impaction. Current standard of care for incontinence consists of modestly effective drugs, complicated surgery, or adult diapers. Bladder and bowel voiding require multiple-times-daily catheterization of the bladder and regular digital extraction of feces for most SCI individuals. Diapers are odiferous, catheters induce frequent urinary tract infections, and digital bowel programs are time-consuming and stigmatizing for the individual and/or their caregiver. For most people with SCI, bladder and bowel dysfunction impacts their professional and social lives more than their inability to walk.Our Phase 1 STTR application, in anesthetized preparations, determined electrical pulse characteristics (e.g. 3T, 100 usec, 10-30 Hz), which when applied to the pudendal (PUD) nerve, stimulated efferent and afferent fibers to produce, respectively, sustained contractions (rt1 hour) of the urethral and anal sphincters and inhibition of bladder activity with increased bladder capacity. Bladder leak point pressures were also markedly increased. These physiological effects should significantly reduce UI and FI when replicated in patients. In addition, the same electrodes and stimulator that were used to stimulate the PUD nerve were also able to block the PUD nerve by switching from low frequency to kHz high frequency (constant duty cycle) pulses that prevented sphincter contractions.In Aim 1 of this Phase 2 SBIR application, chronic SCI preparations are first tested to confirm that they respond to the above pulse characteristics similarly to our Phase 1 study in spinal intact studies. For Aim 2, a translational study is performed in which an implantable pulse generator (IPG), is interfaced with electrodes placed bilaterally on the pudendal nerves of chronic SCI preparations for 2 months. During this time, the IPG is used to stimulate the PUD nerve when “Storage” of urine and feces is desired and then switched to block the PUD nerve when “Voiding” of urine and feces is desired. The IPG uses a remote control to switch between Storage Mode and Voiding Mode. Effectiveness in controlling UI and FI episodes is assessed by comparing the number and volume/weight of episodes on test days, with versus without, activation of Storage Mode. Effectiveness for controlling sphincter dyssynergia is assessed by measuring drug-induced voiding efficiency and subjective ratings of Credé difficulty on test days, with versus without, activation of Voiding Mode. At the end of the study sphincters are evaluated for signs of sphincter muscle hypertrophy and increases in fatigue- resistant muscle fibers. Finally, in preparation for FDA discussions, we will assess different preparations in consideration of GLP safety studies.