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Neuromodulation: past, present, and future
Urol Clin N Am 32 (2005) xv–xvi
Introduction
Neuromodulation: Past, Present, and Future The concept of in vivo nerve stimulation to alter physiologic processes that cause symptoms originated in the nineteenth century. Advances in technology permitted this approach to bloom in the late twentieth century for the treatment of neuromuscular disorders, pain, and urologic conditions. Pioneering work by Tanagho, Brindley, and Schmidt led to clinical trials of implantable devices to treat genitourinary disorders including erectile dysfunction, urinary incontinence, interstitial cystitis, and urinary retention. Recently added to this list is use for fecal incontinence. However, clinical use often preceded a thorough understanding of the mechanisms whereby these devices improve such a wide array of conditions. Neuromodulation has expanded beyond the laboratory and academic centers to community practice. The adoption of these methods by community urologists reflects the frustration of patients and physicians with current behavioral and pharmacologic regimens for urge incontinence, pelvic pain, and retention. Indeed, patients often plead for anything that has the hope of relieving these very bothersome symptoms. A more complete understanding of the sites, transmitters, and pathways regulating the genitourinary tract permits testable hypotheses regarding how stimulation of peripheral autonomic and somatic nerves—as well as areas within the central nervous system—improve conditions such as urge urinary incontinence. Complicating this understanding has been the realization that nerves change their function and sometimes signaling methods in response to disease, injury, and even repeated electrical stimulation. These alterations have been generically termed neural plasticity. Simplistically, it has been thought that stimulation of sacral nerves leads to release of neurotransmitters that inhibit bladder function, a model used to explain efficacy of acupuncture. In addition, long-term changes as inferred from increased production of proto-oncogene products and
neurotrophins has been postulated. However, the universal observation that discontinuation of nerve stimulation after years of functioning results in the immediate return of symptoms indicates this modality works acutely. Thus long-term plasticity triggered by stimulation may be unlikely. In clinical trials the finding that certain areas of the brain exhibit increased activity correlating with efficacy implies that supraspinal sites play an important role in addition to spinal sites. Advances on two fronts will allow improvements in our ability to stimulate nerves and produce desirable effects on genitourinary function. First, more detailed neurophysiologic information is needed to design devices targeting plasticity in neural pathways. For example, if changes in Na/K channels in bladder afferents occur in response to inflammation, injury, or obstruction of the lower urinary tract and contribute to increased afferent activity, it may be possible to set parameters that reverse or improve the environment for nerve function. Knowledge of how magnetic and electrical fields alter cellular function is needed. Second, advances in technology, including nanotechnology, will allow miniaturization of devices and improved acceptance among clinicians and patients. It is possible that multimodal therapies that combine neuromodulation with neurotoxins or small-molecule drug therapies may be desirable in some conditions. For example, botulinum toxin A may be needed to transiently reduce neurotransmitter release, whereas subsequent nerve stimulation could prevent return of overactivity. It appears intuitively obvious that insights into pathophysiology and risk factors may identify those patients that are best served by neuromodulation. Risk/benefit and cost/benefit ratios must be carefully weighed for patients undergoing implantation of neuromodulatory devices. Given the enthusiastic reports in the literature for devices
0094-0143/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ucl.2004.11.001
urologic.theclinics.com
xvi
INTRODUCTION
such as InterStim (Medtronic) in patients failing behavioral and pharmacologic therapies, one wonders why this approach has not been more widely used. Data on durability and ideal candidates are now appearing from pioneering sites. Yet largescale randomized studies—especially comparator studies with different modes of neuromodulation— are needed instead of relatively small numbers of patients from a large number of institutions. A national registry would clarify these issues. Although the best patients for implantation are still debatable, and prescreening is often required, some individuals seem to fare poorly in the long term. These patients include those with chronic pain, complete lesions (in cord-injured patients), or neurologic disease. Such failures provide insight into the mechanisms that prevent neuromodulation from working in expected ways.
This issue of the Urologic Clinics of North America tackles some of these issues and reviews a growing world experience. It features a group of highly distinguished experts in the field who relate their experiences with this modality. The current enthusiasm is tempered by the realization that neuromodulation is not a panacea; therefore, further advances are needed before this approach has more widespread appeal.
William D. Steers, MD, FACS Hovey Dabney Professor & Chair Department of Urology University of Virginia School of Medicine Box 800422 Charlottesville, VA 22908, USA
Introduction
Neuromodulation: Past, Present, and Future The concept of in vivo nerve stimulation to alter physiologic processes that cause symptoms originated in the nineteenth century. Advances in technology permitted this approach to bloom in the late twentieth century for the treatment of neuromuscular disorders, pain, and urologic conditions. Pioneering work by Tanagho, Brindley, and Schmidt led to clinical trials of implantable devices to treat genitourinary disorders including erectile dysfunction, urinary incontinence, interstitial cystitis, and urinary retention. Recently added to this list is use for fecal incontinence. However, clinical use often preceded a thorough understanding of the mechanisms whereby these devices improve such a wide array of conditions. Neuromodulation has expanded beyond the laboratory and academic centers to community practice. The adoption of these methods by community urologists reflects the frustration of patients and physicians with current behavioral and pharmacologic regimens for urge incontinence, pelvic pain, and retention. Indeed, patients often plead for anything that has the hope of relieving these very bothersome symptoms. A more complete understanding of the sites, transmitters, and pathways regulating the genitourinary tract permits testable hypotheses regarding how stimulation of peripheral autonomic and somatic nerves—as well as areas within the central nervous system—improve conditions such as urge urinary incontinence. Complicating this understanding has been the realization that nerves change their function and sometimes signaling methods in response to disease, injury, and even repeated electrical stimulation. These alterations have been generically termed neural plasticity. Simplistically, it has been thought that stimulation of sacral nerves leads to release of neurotransmitters that inhibit bladder function, a model used to explain efficacy of acupuncture. In addition, long-term changes as inferred from increased production of proto-oncogene products and
neurotrophins has been postulated. However, the universal observation that discontinuation of nerve stimulation after years of functioning results in the immediate return of symptoms indicates this modality works acutely. Thus long-term plasticity triggered by stimulation may be unlikely. In clinical trials the finding that certain areas of the brain exhibit increased activity correlating with efficacy implies that supraspinal sites play an important role in addition to spinal sites. Advances on two fronts will allow improvements in our ability to stimulate nerves and produce desirable effects on genitourinary function. First, more detailed neurophysiologic information is needed to design devices targeting plasticity in neural pathways. For example, if changes in Na/K channels in bladder afferents occur in response to inflammation, injury, or obstruction of the lower urinary tract and contribute to increased afferent activity, it may be possible to set parameters that reverse or improve the environment for nerve function. Knowledge of how magnetic and electrical fields alter cellular function is needed. Second, advances in technology, including nanotechnology, will allow miniaturization of devices and improved acceptance among clinicians and patients. It is possible that multimodal therapies that combine neuromodulation with neurotoxins or small-molecule drug therapies may be desirable in some conditions. For example, botulinum toxin A may be needed to transiently reduce neurotransmitter release, whereas subsequent nerve stimulation could prevent return of overactivity. It appears intuitively obvious that insights into pathophysiology and risk factors may identify those patients that are best served by neuromodulation. Risk/benefit and cost/benefit ratios must be carefully weighed for patients undergoing implantation of neuromodulatory devices. Given the enthusiastic reports in the literature for devices
0094-0143/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ucl.2004.11.001
urologic.theclinics.com
xvi
INTRODUCTION
such as InterStim (Medtronic) in patients failing behavioral and pharmacologic therapies, one wonders why this approach has not been more widely used. Data on durability and ideal candidates are now appearing from pioneering sites. Yet largescale randomized studies—especially comparator studies with different modes of neuromodulation— are needed instead of relatively small numbers of patients from a large number of institutions. A national registry would clarify these issues. Although the best patients for implantation are still debatable, and prescreening is often required, some individuals seem to fare poorly in the long term. These patients include those with chronic pain, complete lesions (in cord-injured patients), or neurologic disease. Such failures provide insight into the mechanisms that prevent neuromodulation from working in expected ways.
This issue of the Urologic Clinics of North America tackles some of these issues and reviews a growing world experience. It features a group of highly distinguished experts in the field who relate their experiences with this modality. The current enthusiasm is tempered by the realization that neuromodulation is not a panacea; therefore, further advances are needed before this approach has more widespread appeal.
William D. Steers, MD, FACS Hovey Dabney Professor & Chair Department of Urology University of Virginia School of Medicine Box 800422 Charlottesville, VA 22908, USA