The physiology of neuromodulation

The exact neural mechanisms responsible for the effects of electrical neuromodulation on the lower urinary tract are unknown. A significant amount of research has focused on the effect of sacral neuromodulation (SNM) on afferent sensory nerve fibers, with the dominant theory being that electrical stimulation of these somatic afferent fibers modulates voiding and continence reflex pathways in the central nervous system (CNS). The control of sensory input to the 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 mechanoinsensitive and unresponsive and thus referred to as silent C-fibers. These normally inactive C-fibers may be sensitized by inflammation or infection, thus causing activation of involuntary micturition reflexes and detrusor overactivity. 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. Detrusor hyper-reflexia then may be attributed to a deficiency of the inhibitory control systems involving pudendal afferent nerves. The success of electrical neuromodulation for detrusor hyper-reflexia may result from the restoration of the balance between bladder inhibitory and excitatory control systems. The stimulation of urethral afferents to facilitate the micturition reflex and stimulation of the dorsal nerve of the clitoris to inhibit bladder activity have been demonstrated in animal models for SNM.

Another theory behind the effectiveness for SNM for hyper-reflexia is that electrical neuromodulation may alter cortical sensory areas of the brain. Blok and colleagues used positron emission tomography (PET) to evaluate regional cerebral blood flow in patients with chronic SNM and those patients with recently activated SNM. Their findings demonstrated activation of different areas of the cerebral cortex among patients with chronic and acute SNM. This finding also implies that the brain undergoes neuroplasticity during periods of long-term SNM in the areas of detrusor hyperactivity, awareness of bladder filling, the urge to void, and the timing of micturition. Other studies have used changes in somatosensory-evoked potentials before and after SNM to illustrate the cortical effects of SNM.

Neuromodulation also has been used effectively for the treatment of nonobstructive urinary retention, and while the mechanism of action is not entirely clear, experimental data shed some light in this area. One such study by Schultz-Lampel and colleagues investigated the effects of direct sacral nerve stimulation on detrusor contractility in cats. Their data suggested that sacral nerve stimulation at low frequencies resulted in detrusor contractions. An associated rebound effect was noted with increasing amplitude of detrusor contractions with cessation of the sacral stimulus. The authors suggest that this rebound effect may be attributed to the sacral stimulus, enabling previously inhibited bladder efferent activity and thus allowing a bladder contraction. Neuromodulation also may remedy sphincter dyssynergia and the inability to void by the alteration of afferent signals delivered to the spinal cord that affect activity and basal tone of the pelvic floor.

Sacral nerve stimulation

Sacral nerve stimulation long has been a reliable form of neuromodulation for various types of lower urinary tract dysfunction including overactive bladder and nonobstructive urinary retention. These two therapeutic indications make it an attractive option for treating patients with neurogenic bladder. Lombardi and colleagues described their experience with SNM in patients with an incomplete SCI suffering from neurogenic lower urinary tract symptoms with a mean follow-up of 61 months. They divided their study population into two groups, with one group consisting of patients with urinary retention (n = 13) and the other group consisting of patients with overactive bladder symptoms (n = 11). In the urinary retention group 9 of 13 (69%) patients reported a 50% improvement in baseline voiding parameters, with a significant decrease in the number of catheterizations and a significant increase in the frequency of void and voided volume. At the conclusion of the study, 38% of patients no longer required catheterization for bladder emptying. Among the patients with overactive bladder symptoms, an 80% reduction in daytime frequency was observed, with 3 out of 7 subjects with previous urge incontinence remaining completely dry during the study period. This study illustrates the dual efficacy of SNM for the spectrum of voiding dysfunction found in SCI patients. Other trials of SNM for neurogenic bladder have been less promising. Hohenfellner and colleagues described their experience with SNM among patients with neurogenic bladder dysfunction. Their patient population consisted of patients with bladder storage failure due to detrusor hyper-reflexia (n = 15), failure to empty due to detrusor areflexia (n = 11), and combined bladder hypersensitivity and detrusor areflexia (n = 1), with a mean follow-up of 89 months. In eight patients (30%), symptoms of lower urinary tract dysfunction were attenuated by 50% for 54 months (range 11–96 months). After this time period, all implants became ineffective, except in one patient. This study illustrates that while SNM may be effective for neurogenic bladder dysfunction, the results may be temporary.

Sacral nerve stimulation

Sacral nerve stimulation long has been a reliable form of neuromodulation for various types of lower urinary tract dysfunction including overactive bladder and nonobstructive urinary retention. These two therapeutic indications make it an attractive option for treating patients with neurogenic bladder. Lombardi and colleagues described their experience with SNM in patients with an incomplete SCI suffering from neurogenic lower urinary tract symptoms with a mean follow-up of 61 months. They divided their study population into two groups, with one group consisting of patients with urinary retention (n = 13) and the other group consisting of patients with overactive bladder symptoms (n = 11). In the urinary retention group 9 of 13 (69%) patients reported a 50% improvement in baseline voiding parameters, with a significant decrease in the number of catheterizations and a significant increase in the frequency of void and voided volume. At the conclusion of the study, 38% of patients no longer required catheterization for bladder emptying. Among the patients with overactive bladder symptoms, an 80% reduction in daytime frequency was observed, with 3 out of 7 subjects with previous urge incontinence remaining completely dry during the study period. This study illustrates the dual efficacy of SNM for the spectrum of voiding dysfunction found in SCI patients. Other trials of SNM for neurogenic bladder have been less promising. Hohenfellner and colleagues described their experience with SNM among patients with neurogenic bladder dysfunction. Their patient population consisted of patients with bladder storage failure due to detrusor hyper-reflexia (n = 15), failure to empty due to detrusor areflexia (n = 11), and combined bladder hypersensitivity and detrusor areflexia (n = 1), with a mean follow-up of 89 months. In eight patients (30%), symptoms of lower urinary tract dysfunction were attenuated by 50% for 54 months (range 11–96 months). After this time period, all implants became ineffective, except in one patient. This study illustrates that while SNM may be effective for neurogenic bladder dysfunction, the results may be temporary.

Risk with magnetic resonance imaging after implant—when is it safe?

As the use of sacral nerve stimulators becomes more popular worldwide, there are important safety considerations, especially with regards to magnetic resonance imaging (MRI). MRI is an important diagnostic tool for multiple medical and neurologic disorders. MRI is currently contraindicated in patients with implantable devices. The possible hazards of performing MRI with an implantable device such as a sacral neuromodulator include device movement, dislocation of the neurostimulator, excessive heat to the nerve, changes in programming, and damage to the neurostimulator components. Elkelini and Hassouna retrospectively reviewed histories of six patients who underwent a total of eight MRI examinations with sacral neuromodulation. Five examinations were of the brain, while three other examinations were of the cervical and thoracic vertebrae using a magnetic resonance system operating at a static magnetic field strength of 1.5 T. No patients reported any unusual symptoms during the examination, and imaging was not affected by the pulse generator located away from the imaged anatomic area. The pulse generators were turned off before MRI examination and when interrogated after the examination, no malfunctions were found. There was no change in the perception of stimulus once the pulse generator was reactivated, and follow-up voiding diaries revealed no changes in voiding parameters. Although the author’s findings are encouraging, the routine use of MRI with an implanted device such as Interstim (Medtronic, Minneapolis, Minnesota) still should be used with caution.

Complications of sacral neuromodulation

Complications from SNM have been well described and are usually minor adverse events. The rate of complication ranges from 12% to 53% depending on the examined series. A recent article by White and colleagues followed patients receiving SNM for urinary urge/frequency, urge incontinence, and urinary retention to record the incidence of adverse events and determine if there are predictive factors predisposing patients to adverse events. At a mean follow-up of 37 months, 30% of patients had experienced adverse events. Lead migration, lack of efficacy, and trauma were the most common adverse events. Significant predictors of adverse events included a history of trauma, a change in body mass index class, enrollment in a pain clinic, the duration of follow-up, and a history of adverse events.

Pudendal neuromodulation for neurogenic bladder

The pudendal nerve is a peripheral nerve that is composed mainly of afferent sensory fibers from sacral nerve roots S1, S2, and S3. Most afferent sensory fibers are contributed by S2 (60%) and S3 (35%) according to afferent activity mapping procedures. Consequently, the pudendal nerve is a major contributor to bladder afferent regulation and bladder function. Pudendal nerve entrapment often leads to significant voiding dysfunction, including urinary incontinence and detrusor hyper-reflexia. Because the pudendal nerve carries such a large percentage of afferent fibers, neuromodulation of the pudendal nerve is an attractive option for refractory detrusor hyper-reflexia. Opisso and colleagues compared patient-controlled pudendal nerve stimulation with automatic stimulation to treat neurogenic detrusor overactivity. A total of 17 patients with neurogenic detrusor overactivity underwent three cystometric filling trials. The first cystometry was used to determine bladder capacity. The second cystometry was done with automatic electrical stimulation of the pudendal nerve when the bladder reached a threshold pressure of 10 cm H ₂ O above the mean detrusor pressure. The third filling cystometry was done with patients controlling the pudendal stimulation and asked to begin stimulation when they could sense the onset of an uninhibited bladder contraction. Automatic and patient-controlled pudendal nerve stimulation resulted in greater bladder capacity in all subjects and inhibited more than an average of 2 detrusor contractions per filling. The authors suggest that based on their findings patients with neurogenic detrusor overactivity may be able to use patient-controlled stimulation of the pudendal nerve to increase bladder capacity and prevent uninhibited detrusor contractions. Spinelli and colleagues described their experience with pudendal nerve stimulation using a device with a quadrapolar tined lead placed at Alcock canal in 15 patients with neurogenic bladder. In this study, the average number of incontinent episodes among this group of patients decreased from seven to three episodes per day. Eight patients became continent during the screening phase of the study, and four patients had a greater than 50% improvement in the number of incontinent episodes experienced per day. Urodynamic evaluation in seven patients revealed a significant increase in detrusor capacity and a decrease in maximum detrusor pressure. The authors suggest that based on these preliminary data, pudendal nerve stimulation is an effective therapeutic alternative for neurogenic overactive bladder patients who are nonresponders to antimuscarinic drugs and in whom traditional sacral neuromodulation has had poor results. The authors also point out that the minimally invasive nature of pudendal nerve stimulation using the quadrapolar tined lead is an attractive alternative to more invasive procedures such as bladder augmentation. Currently at the authors’ institution, the most common indication for pudendal neuromodulation is for patients who have had failure of sacral neuromodulation. The placement of the lead is done via a posterior approach and requires electrophysiologic monitoring of the pudendal nerve action potentials intraoperatively to confirm pudendal stimulation.