Introduction

Neuromodulation uses electrical or chemical modulation to affect the physiologic response of an organ. Using electrical stimulation to control voiding dysfunction was first described by Tanagho and colleagues in 1989. Those initial reports of success in treating voiding dysfunction refractory to traditional methods have led to significant research over the past 2 decades. This article discusses the physiology, indications, methods, and results of available neuromodulation techniques for the treatment of bladder and bowel dysfunction.

Bladder dysfunction in the form of urinary urge, urinary frequency, and urgency incontinence are commonly described as overactive bladder (OAB). The International Continence Society defines OAB as a symptomatic syndrome suggestive of lower urinary tract dysfunction. It is estimated that 33.3 million adults suffer from OAB in the United States and as the population of aging adults continues to grow this number is likely to increase. Treatment modalities typically begin with noninvasive measures, like behavioral modification, pelvic floor physical therapy, and pharmacologic therapies. In the past, surgical options, including augmentation enterocystoplasty, detrusor myectomy, bladder denervation, and urinary diversion, were commonly performed.

FI is defined as the involuntary loss of flatus or stool. This experience can be a humiliating and life-altering event for patients. The exact prevalence of this condition is unknown, but published rates have ranged from 1% to 2% to as high as 11% to 15%. The problem is multifactorial, and current treatments result in modest overall success. FI may be secondary to many causes, categorized by having structurally intact but weak anal sphincters (such as rectal prolapse, constipation, neuropathy, and inflammatory bowel disease) or structurally defective sphincters (congenital malformations and obstetric, surgical, and traumatic injury). Traditional nonsurgical treatment options have included dietary and pharmacologic stool modification, antimotility agents, biofeedback, injectable bulking agents, and radiofrequency application to the anal sphincter, all with results falling short of desired goals. The initial surgical management of FI secondary to anal sphincter trauma traditionally has been either direct sphincter repair or, more commonly, overlapping sphincter repair. Long-term success rates are poor, ranging from 35% to 50%. Advanced options have included placement of an artificial bowel sphincter, dynamic graciloplasty, and fecal diversion. These methods are invasive, technically challenging, and fraught with complications, limiting their widespread use.

For 15 years, sacral neuromodulation (SNM) has been Food and Drug Administration (FDA) approved for the treatment of urinary urgency and frequency, urgency incontinence, and nonobstructive urinary retention. During that time, many investigators have observed improvement in bowel dysfunction in patients with sacral neuromodulators. These observations and further studies have resulted in the recent FDA approval of SNM for FI. Neuromodulation has gained acceptance as a treatment modality for bladder and bowel dysfunction. It offers a minimally invasive, reversible method with low morbidity when other first-line treatment options have failed.

The physiology of neuromodulation

The exact neural mechanisms responsible for the effects of electrical neuromodulation on the lower urinary tract and bowel are unknown. Prior to discussing how neuromodulation works, the normal micturition pathway is reviewed briefly. Normal detrusor function relies on a balance between excitatory and inhibitory pathways to maintain continence and the ability to volitionally void. Baseline activity of the sympathetic system provides storage and continence by inhibiting detrusor contractions and maintaining sphincter tone. Parasympathetic activation stimulates detrusor contraction, sphincter relaxation, and ultimately micturition. This balance between sympathetic and parasympathetic nervous systems is under suprasacral control. Bladder afferent signaling relays information about fullness, pressure, stretch, and pain, initiating voiding through multiple reflex pathways. Supraspinal input from the pontine micturition center and cerebral cortex on these sacral reflex pathways control voiding in a voluntary manner. The pontine micturition center provides negative feedback to inhibit voiding and promote continued storage and positive input leading to the induction of voiding. This complex system to maintain control of voiding can be altered by loss of supraspinal inhibitory control or increased sensitization to bladder afferent signals, both contributing to involuntary voiding.

The control of sensory input to the central nervous system (CNS) is thought to work through a gate-control mechanism. The gate-control theory states that noxious stimuli perception does not entirely depend on the A-delta and C-fiber sensory nerves transmitting information to the CNS but on the pattern of peripheral nerve activity. A-delta bladder afferent nerve fibers project to the pontine nuclei to provide inhibitory and excitatory input to reflexes controlling bladder and sphincter function. Afferent C-fibers within the bladder are normally thought to be mechano-insensitive and unresponsive and are thus referred to as silent C-fibers. These normally inactive C-fibers may be sensitized by neurologic diseases, inflammation, infection, or normal bladder functions, such as distention, thus causing activation of involuntary micturition reflexes and OAB. Sensory input from large myelinated pudendal nerve fibers may modulate erroneous bladder input conveyed by A-delta or C-fiber afferents at the gate control level of the spinal cord. OAB may then be attributed to a deficiency of the inhibitory control systems involving pudendal afferent nerves.

A significant amount of research has focused on the effect of SNM on afferent sensory nerve fibers with the dominant theory that electrical stimulation of these somatic afferent fibers modulates voiding and continence reflex pathways in the CNS. The success of electrical neuromodulation for OAB may result from the restoration of the balance between bladder inhibitory and excitatory control systems. Electrical stimulation modulates the afferent sensory input of the bladder on the pontine center, thereby inhibiting involuntary contractions. Neuromodulation may also remedy OAB by the alteration of afferent signals delivered to the spinal cord that effect activity and basal tone of the pelvic floor.

The physiology of neuromodulation

The exact neural mechanisms responsible for the effects of electrical neuromodulation on the lower urinary tract and bowel are unknown. Prior to discussing how neuromodulation works, the normal micturition pathway is reviewed briefly. Normal detrusor function relies on a balance between excitatory and inhibitory pathways to maintain continence and the ability to volitionally void. Baseline activity of the sympathetic system provides storage and continence by inhibiting detrusor contractions and maintaining sphincter tone. Parasympathetic activation stimulates detrusor contraction, sphincter relaxation, and ultimately micturition. This balance between sympathetic and parasympathetic nervous systems is under suprasacral control. Bladder afferent signaling relays information about fullness, pressure, stretch, and pain, initiating voiding through multiple reflex pathways. Supraspinal input from the pontine micturition center and cerebral cortex on these sacral reflex pathways control voiding in a voluntary manner. The pontine micturition center provides negative feedback to inhibit voiding and promote continued storage and positive input leading to the induction of voiding. This complex system to maintain control of voiding can be altered by loss of supraspinal inhibitory control or increased sensitization to bladder afferent signals, both contributing to involuntary voiding.

The control of sensory input to the central nervous system (CNS) is thought to work through a gate-control mechanism. The gate-control theory states that noxious stimuli perception does not entirely depend on the A-delta and C-fiber sensory nerves transmitting information to the CNS but on the pattern of peripheral nerve activity. A-delta bladder afferent nerve fibers project to the pontine nuclei to provide inhibitory and excitatory input to reflexes controlling bladder and sphincter function. Afferent C-fibers within the bladder are normally thought to be mechano-insensitive and unresponsive and are thus referred to as silent C-fibers. These normally inactive C-fibers may be sensitized by neurologic diseases, inflammation, infection, or normal bladder functions, such as distention, thus causing activation of involuntary micturition reflexes and OAB. Sensory input from large myelinated pudendal nerve fibers may modulate erroneous bladder input conveyed by A-delta or C-fiber afferents at the gate control level of the spinal cord. OAB may then be attributed to a deficiency of the inhibitory control systems involving pudendal afferent nerves.

A significant amount of research has focused on the effect of SNM on afferent sensory nerve fibers with the dominant theory that electrical stimulation of these somatic afferent fibers modulates voiding and continence reflex pathways in the CNS. The success of electrical neuromodulation for OAB may result from the restoration of the balance between bladder inhibitory and excitatory control systems. Electrical stimulation modulates the afferent sensory input of the bladder on the pontine center, thereby inhibiting involuntary contractions. Neuromodulation may also remedy OAB by the alteration of afferent signals delivered to the spinal cord that effect activity and basal tone of the pelvic floor.

Sacral neuromodulation

The InterStim Therapy System (Medtronic, Minneapolis, MN, USA) is the only FDA-approved device for sacral nerve stimulation as a means to treat refractory urinary urgency, frequency, incontinence, and nonobstructive urinary retention. The device has also received recent FDA approval for treatment of FI. This device consists of a tined quadripolar lead that is inserted percutaneously through the S3 sacral foramen and attached to a permanent implantable pulse generator (IPG). Electrical stimulation is transmitted through the IPG to the lead in proximity to the sacral nerve roots at S3, thereby modulating bladder function. The device has several parameters that can be adjusted, including pulse width, frequency, and energy level. Transcutaneous programming can be used to adjust which leads are positive and negative, giving physicians the ability to trial several settings and adjust parameters to optimize patient outcomes. Patients are equipped with a handheld remote that allows 4 different programs with different stimulation settings to be used.

Indications for bladder dysfunction

Patient selection for SNM is a process in evolution and parameters to predict patient successes derived from prospective trials are limited. Patients undergoing initial test stimulation generally have symptoms that are refractory to behavioral modification and medical therapy for OAB. In the authors’ experience, failure to have relief of symptoms after a trial of behavioral therapy and 2 anticholinergic medications is sufficient to consider offering patients SNM therapy. It is also important to consider the high rate of medication discontinuation with medical therapy for OAB, thus patients who cannot tolerate anticholinergic medications should be given consideration for SNM therapy.

Preoperative evaluation often includes a careful history and physical examination with pelvic examination, including assessment of pelvic floor musculature and support. It is important to evaluate these patients for infectious, malignant, or anatomic conditions that might be the root cause of their symptoms. Thus, urine culture, cytology, and cystoscopy may aid in making an accurate diagnosis. Urodynamics may assist in the diagnosis of detrusor overactivity when the clinical symptoms are unclear. Urodynamics are not required for every patient prior to SNM, especially if patients have a clear history of urge incontinence. There is limited data to support which patients urodynamics will provide predictive value about the potential benefit from neuromodulation. Groenendijk and colleagues demonstrated that patients with urinary urge incontinence without detrusor overactivity had as much or more success with SNM therapy as those patients who had urinary urge incontinence and urodynamic findings of detrusor overactivity. A voiding diary chronicling voiding frequency, voided volumes, associated urgency, and incontinence episodes per day is important part of the evaluation to adequately assess improvement after the test stimulation.

Implantation methods

Prior to permanent generator implantation, patients undergo a temporary trial to determine if they benefit from stimulation. During the test period, patients repeat a voiding diary, with emphasis on voiding frequency, voided volumes, and episodes of incontinence. Patients are considered to have a positive response to therapy if they have a 50% or better improvement in their symptoms, such as a decrease in incontinent episodes per day or an increase in voided volumes. Patients who have at least a 50% improvement are candidates for IPG placement.

There are 2 trial stimulation techniques commonly used, a monopolar percutaneous nerve evaluation (PNE) or staged placement of a quadripolar lead. PNE is performed in the office under local anesthesia, usually without fluoroscopic guidance, inserting a fine monopolar wire through the third sacral foramen. Correct lead placement is determined by a levator ani motor response, plantar flexion of the ipsilateral great toe, and induction of perineal sensory activation. The temporary lead is fixed to the skin with an adhesive dressing and stimulation is delivered through an external device for 3 to 5 days. Advantages to this approach include avoiding multiple trips to the operating room, associated anesthetic risks, and cost. The reliability of the PNE at predicting long-term success has been questioned. The temporary lead with its single stimulation point can be easily dislodged from its position in the sacral foramen, leading to an inaccurate test period. If a patient has a successful PNE test, it may not predict robust long-term outcomes with a permanent implant. Bosch and Groen reported that 28% of patients who started with a percutaneous lead and went on to receive a permanent tined lead and IPG did not experience the same efficacy that was experienced during the test period, suggesting that the placement of the tined lead after PNE did not replicate the exact anatomic position of the PNE or that the short test period may not accurately reflect the clinical response.

Staging SNM using a permanent quadripolar lead and IPG was first described by Janknegt and colleagues in 1997. The patient is positioned prone in the operating room under sedation with a local anesthetic injected in the overlying skin of the insertion site. The quadripolar tined lead is placed through a small incision into the S3 foramen with fluoroscopic guidance. Anterior to posterior fluoroscopic images as well as cross-table lateral images of the lead should be taken and saved. These confirm accurate positioning and serves as reference at a later date if a patient should lose efficacy of the therapy and lead migration is suspected. Placement in the S3 foramen is confirmed by several indictors, including fluoroscopic position and motor and sensory response. A typical motor response is identification of a levator bellow and/or greater toe flexion with stimulation. Sensory response is typically perceived as a tapping or pulsation in the rectal, perineal, scrotal or vaginal region. Obtaining an accurate sensory response while patients are under sedation is not always easy and a recent study demonstrated that sensory response is not necessary when placing a sacral lead. A test period of 2 weeks using a staged approach is ideal to assess whether there is an adequate response to therapy.

Literature on the efficacy of the 2-stage procedure suggests that this technique is more dependable in identifying responders to therapy than the PNE technique. Borawski and colleagues evaluated 30 patients aged 55 years and older with refractory urge incontinence randomized to either PNE or a staged technique. The likelihood of progressing to IPG was significantly greater in the staged cohort (15 of 17 patients; 88%) compared with the PNE group (6 of 13 patients; 46%). A formal cost analysis comparing PNE to staged implantation has not been performed. Baxter and Kim reported on Medicare physician reimbursement rates in California in 2009. Unilateral staged implantation performed in the operating room reimbursed $742.73 with subsequent IPG paying $1055.85 for a total compensation of $1798.58. Unilateral office-based PNE trial reimbursed $1792.62 and, if successful, an additional $1055.85 for the IPG placement for a total of $2848.47, perhaps providing a financial incentive for physicians to perform this less-sensitive measure for a trial period.