Neuromodulation for Restoration of Urinary and Bowel Control
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.302457
Source of Support: None, Conflict of Interest: None
Keywords: Blepharospasm, hemifacial spasm, microvascular decompression, neuromodulation, oro-mandibular dystonia
Control of the lower urinary tract is a complex, multilevel process that involves the peripheral and central nervous systems. Patients with spinal cord diseases or injuries present with multiple bladder and bowel problems. The commonest are urinary, urgency, frequency, urge incontinence, retention and/or fecal incontinence.
Sacro Neuro Modulation (SNM) has become a well-established treatment modality in recent years for patients with refractory non-obstructive chronic urinary retention, urgency-frequency syndrome and urgency incontinence.
The experimental and established “off-label” applications of SNM have also encompassed chronic pelvic pain syndrome including chronic prostatitis and bladder pain syndromes.
Neuromodulation in urology is not a novel concept but certainly one that has lagged in dissemination. Though the first reports of neurostimulation to empty bladder came in 1970s’, it was only in 1988 that Schmidt and Tanagho restarted discussion and supplication of neuromodulation and electrical stimulation of sacral nerve in urology. In 1981, Department of Urology, University of California at San Francisco initiated a clinical program pertaining to the efficacy of neurostimulation. In 1982, Schmidt and Tanagho proposed that intraspinal extradural segments, sacral roots, can be stimulated electrically especially in canines, in conjunction with selective neurotomy to make the stimulus a pure autonomic effect on the bladder wall itself.
The word “neurostimulation” was recoined to “neuromodulation” as experts felt that electrical currents do not only stimulate but rather modulate the messages carried by different nerves involved in the micturition process. A multi-center trial was conducted by Urosystems, Inc. from 1985-92. In 1994, Medtronic CE mark, for InterStim® in Europe for treatment of management of chronic functional disorders of the pelvis and lower urinary and intestinal tract was approved. FDA granted Medtronic approval of the InterStim System for treatment of urge incontinence in the US in September 1997. In April, 1999 - FDA approved the InterStim System for treatment of symptoms of urgency-frequency and urinary retention. In October 2000, Medtronic Commercial Release for SNS-Bowel was approved. Later TWIN was launched in November 2002. In October 2002, the Tined lead was launched and N’Vision programmer was launched in the official market in Europe.
Control of micturition
Bladder afferents project to the sacral parasympathetic nucleus where they synapse both with preganglionic neurons and with local interneurons (not shown). Other inputs ascend to relay primarily in the periaqueductal gray. Some ascending projections terminate in the parabrachial nucleus (PBN), which relays bladder afferent input to the insular cortex via the thalamus. The sacral parasympathetic nucleus located at the S2–S4 levels activates parasympathetic neurons in the pelvic ganglia via nicotinic receptors (nAChR). Parasympathetic ganglion neurons release acetylcholine (ACh), which promotes detrusor contraction via M3 receptors and inhibits norepinephrine (NE) release from sympathetic terminals via presynaptic M2 receptors; parasympathetic neurons also release nitric oxide (NO), which relaxes the urethral smooth muscle. Preganglionic sympathetic neurons (PSN) located at the L1-L2 spinal segments activate neurons in the hypogastric ganglia; these neurons release NE, which inhibits the detrusor muscle via 3 receptors, contracts the bladder neck via 1 receptors, and presynaptically inhibits parasympathetic transmission via 2 receptors. The motoneurons of the Onuf nucleus at S2-S4 segments project via the pudendal nerve to elicit contraction of the external urethral sphincter via nAChRs. Neurons of the sacral cord receiving A bladder afferent input and project to the periaqueductal gray, which relays this information to the pontine micturition center, triggering the micturition reflex. The pontine micturition center activates sacral preganglionic neurons and inhibits, via interneurons, the Onuf nucleus motoneurons. Storage reflexes (not shown) are stimulated during bladder filling and are integrated at the level of the lumbosacral spinal cord. The hypothalamus insula, dorsal anterior cingulate, and lateral prefrontal cortex are involved in the behavioral control of micturition; the medial prefrontal cortex exerts a tonic inhibition on the periaqueductal gray and may be involved in the decision as to whether or not to initiate voiding.
MICTURITION CYCLE: Begins with an empty bladder. As bladder fills, proprioceptive nerve endings in detrusor send sensation of filling (stretch) to ascending pathway of spinal cord. As sensation of filling increases, motor cortex inhibits cholinergic receptors and stimulates b and a receptors and external sphincter. When the voluntary decision to void is confirmed, the message to relax the external sphincter descends the motor pathway. Following relaxation of external sphincter, quick message to stimulate cholinergic receptors and inhibit b receptors in the bladder to initiate a detrusor contraction is sent. Onset of detrusor contraction with message to inhibit a receptors and internal urethral sphincter and the urethra opens for voiding. When the bladder is empty, bladder neck closes and micturition cycle begins again.
The first SNM device made commercially available was the InterStim (Medtronics, USA). It was first approved in 1997 by FDA for use in refractory OAB. In 1999, FDA approved it for urgency, frequency and Non Obstructive Urinary Retention (NOUR). By now, more than 50000 units have been implanted. SNM is dedicated to the S3 foramina targeting the S3 nerve root, identified as most relevant containing sensory fibers from the pelvic floor and parasympathetic neural fibers affecting the detrusor muscle of the bladder.
Mechanism of action of SNM: The goal is to restore the patient's voluntary control and facilitate normal voiding and continence. The theories are complex and are perhaps in part due to the sophisticated interaction of the higher central voiding centers in the brain, spinal cord and peripheral nervous system in facilitating the function of the lower urinary tract. The therapeutic effect of SNM are thought to arise through electrical stimulation of both afferent and efferent neuronal components in the pelvic viscera and connecting interspinal interneurons. The stimulator provides an electrical charge in close proximity to the sacral nerve roots, regenerating propogational axonal action potentials in the region. This in turn stimulates the somatic afferents which modulate higher center control of micturition (prefrontal cortex and insula) by restoring normal bladder function and suppressing reflex bladder activity (OAB). This is achieved through adaptive neuronal plasticity and thus, an intact neural system (at least distally) is a neural requirement of SNM to successfully restore bladder function. It does not have any direct effects on urethral resistance.
Successful voiders ↑ activity dorsomedial pons
Unsucccessful voiders ↑ activity ventro lateral pons
Several studies have proved that SNM has modulatory effects on the brain. Utilizing PET and functional MRI, researches identified decreased function in orbitofrontal cortex, angulate gyrus and thalamus, and stimulatory effects on the dorsolateral prefrontal cortex. SNM corresponded to preimplantation increased activity in the angulate and inferior frontal gyri, insula and thalamus. Such patterns of activity preimplantation were shown to predict response to SNM in females of OAB.
On a neurophysiological level, OPIOID receptors are shown to be inhibited by SNM and this inhibitory effect is augmented by tramadol and other opioid agonsists. Blockage of beta-2 receptors showed the opposite response during SNM.
OAB and Refractory OAB (Wet and Dry): Overactive bladder can be attributed to four different specific etiologies:
Indications: The FDA, ICS, EAU and AUA have suggested the following indications of SNM
It is theorized that SNM moderates the normal micturition reflex by stimulating the somatic afferent inhibition of sensory processing of the bladder within the spinal cord and stimulation of alpha myelinated afferent fibers and unmyelinated C fibers in S3 and S4 nerve roots. As a rule, conservative options should be exhausted by giving an adequate trial before consideration of a third-line treatment. Other nonapproved applications of SNM include neurogenic lower urinary tract symptoms, pediatrics and adolescents and even in contraindicated situations including continued SNM in pregnancy in urological conditions
Post SNM: Increased voided volumes and decreased urgency is seen. OAB wet >44 years female (17%) efficacy, OAB wet >64 years male (15.6%) efficacy. Substantial efficacy in patients with mix urinary incontinence or solitary SUI.
Prediction of Effect: Evidence suggests that there is no single UDS parameter or grading that can predict SNM. In urodynamic evaluation preoperatively, anatomic and functional obstruction, neurogenic “high risk” and acontractile bladder must be excluded. No clear prognostic value has been shown yet for pre-neuromodulation urodynamic parameters, except a complete acontractile bladder More women tended to receive implants than men. Number of urge incontinence episodes per day improved more in men than in women. Severity of the incontinence improved more in women than in men. This gender discrimination is perhaps explained by the anatomical difference of the distal urinary tract in men and women
Preoperative Assessment: Counselling and preoperative assessment is important. One stage versus staged implant surgery must be decided. ICS recommends that pre-operative urodynamic testing is not mandatory but phase testing is highly recommended prior to embarking on surgical implantation of SNM Implantable Pulse Generator (IPG). Bladder compliance and response rate has a negative correlation in SNM. Thus, patients with low compliance are highly unlikely to have a successful SNM trial. Counseling about unsuccessful trial should be done preoperatively. It is not necessary to do urodynamics postimplantation.
Technique: Fluoroscopic guidance is required for percutaneous nerve evaluation (PNE). Ultrasound-guided PNE has been tried but is not that popular. Preoperative antibiotic administration is recommended (Amoxycillin or broad-spectrum cephalosporin or Clindamycin + vancomycin).
The PNE is done under local anesthesia or sedation. NO MUSCLE RELAXATION is used. The tined lead is placed in the S3 foramina. The PNE can be done in the OT (Right, Left or both), or as an office procedure. The patient lies prone. Very obese patients or ones with anatomical variations or previous sacral scars may preclude office PNE. Patients exhibit and experience typical sensory and motor responses. The two-staged procedure depends on a 2–4 weeks arbitrary period of testing for improved responses in patients planned for implantation. Voiding diary must be used in order to evaluation efficacy when/after testing. Patient should return towards baseline voiding behavior after completion of test stimulation
Before the advent of the Tined Lead, the leads were put by open surgery, in the foramina and stimulated.
SNM device consists of a tined lead connected to a stimulator (IPG) by insulated cords. The latest IPG (InterStim II) is connected to a quadripolar deflected lead tip tined lead. The tines allow for anchorage of the lead and prevent displacement. The quadripolar lead contains four electrical stimulation contact regions or electrodes, which are used to designate four different programmable changes on each region to provide possible combinations of modulatory charges,,
The IPG is a battery dependent neuromodulator that delivers electrical stimulation transmitted via the lead. It has an embedded antenna that receives signals from the operator remote controllers. The battery lasts from 3 years to 5 years.
The IPG is implanted in a subcutaneous pocket on the same side as the tined lead is placed in the S3 foramina. Sterility of the IPG is to be maintained at all times. Programming is done after IPG implantation when the patient is fully awake
Control – Patient programmer allows patients to adjust levels of stimulation, within physician-set limits, and also to turn stimulation on and off.
Empowerment – Patient programmer lets patients feel more in charge of the management of their condition.
Effectiveness – Patient programmer allows effective bladder or bowel control.
If there is pain at the IPG and if pain remains with bipolar stimulation:
1 - check risk of infection
2 - check for allergic reaction (silicon pocket, use allergic kit from Medtronic)
3 - check if IPG's position is too superficial
In case of pain in the genital area, bowel:
1 - check risk of infection.
If patient complains of pain in the leg:
1 - if pain in 2 legs: other issue
2 - if pain in the same leg of the lead, reposition of the electrode to be considered.
SNM uses a continuous stimulation protocol. Other forms of electrical neuromodulation for OAB, like PTNS, use stimulation for 30 min per 1 or 2 weeks. The effectiveness of this PTNS protocol suggests that intermittent SNM stimulation might have a beneficial effect on OAB symptoms. Indeed, a prospective randomized crossover trial showed no difference of the effects between continuous and cyclic stimulation with 16 s on and 8 s off. Another prospective cohort study in 19 patients demonstrated no difference between SNM for 8 h on and 16 h off and continuous SNM. Closed-loop neurostimulation is also a future possibility for SNM in idiopathic OAB. In such a stimulation protocol the electrical stimulation is only necessary just before the OAB symptoms are present. The start of the stimulation could be set on the basis of a certain bladder volume at which the first sensation is perceived by the patient or at the point that the bladder pressure increases. Both parameters – bladder volume and increased bladder pressure – could be measured directly by a microchip on the bladder or indirectly by measurement of afferent pelvic nerve activity.
3. Direct Pudendal Nerve Stimulation: Placement of both a sacral and pudendal tined lead in Alcock's canal, continuous stimulation is delivered to both nerves thus prospects of improving continence and increasing blader capacity in neurogenic patients.
4. PTNS: Percutaneous tibial nerve stimulation (PTNS) is an alternative modality of neuromodulation altering pelvic function. The tibial nerve shares a common origin with the sacral nerve innervating the pelvic floor and bladder. Thus, stimulating this peripheral nerve can result in alterations of pelvic pain, along with bladder and bowel function. PTNS uses a 34 G needle inserted 3–5 cm above the medial malleolus, connected to an external electrical stimulation device. Patients attend 10–12 weekly treatment sessions lasting 30 minutes, followed by monthly sessions to maintain the efficacy of the PTNS. Direct pudendal neuromodulation has been described to treat some UCPPS. PTNS can indeed modulate the voiding and storage function of the bladder leading to an overall subjective improvement of symptoms in about 60% of the patients and 47%–56% improvement of FVC parameters with sustainable outcome on the long run. The placebo effect (subjective improvement measured by patients who actually received sham treatment) is about 21% and may be even higher in children. This might be explained by the regular visits, peer-grouping, and/or the weekly attention paid to their problem by the caregivers. PTNS seems not to be cost-effective as a primary treatment compared to antimuscarinics, but is a good treatment option in refractory OAB or when antimuscarinics are not tolerated. Although PTNS is minimally invasive and not costly, it is time-consuming. Therefore, new techniques with implants are being explored and show initially promising results. PTNS has a “carry over” effect.
5. TTNS: Transcutaneous posterior tibial nerve stimulation (TPTNS) is a simple, non-invasive, safe and low-cost intervention with promising effectiveness, directly targeting urgency or mixed UI. It uses a portable transcutaneous electrical nerve stimulation (TENS) machine to stimulate the posterior tibial nerve using surface electrodes placed adjacent to the medial malleolus. It does not require the resident to actively engage in order to receive the intervention, and so is suitable for those who are physically and cognitively frail. It is comfortable to use and promotes dignified care, as only access to the resident's ankle is required. It has been shown in randomized controlled trials (RCTs) to reduce UI in community-living older women and adults with neurogenic bladder dysfunction (including multiple sclerosis, Parkinson's and stroke). Although the exact mechanism of action has yet to be fully understood, TPTNS is believed to restore the balance between excitatory and inhibitory bladder functioning by modulating the signal traffic to and from the bladder through the sacral plexus. It is hypothesized that stimulating afferent sacral nerves in the lower extremities increases the inhibitory stimuli to the efferent pelvic nerve, suppresses bladder afferent nerve activity, reduces detrusor contractility and increases bladder capacity, and by these means TPTNS reduces the sensation of urgency and the frequency of micturition, thus enabling improved bladder control. These mechanisms may also reduce the volume of urine retained in the bladder after voiding.
6. TENS: Transcutaneous electrical nerve stimulation (TENS) is a non-invasive peripheral stimulation technique used to relieve pain. During TENS pulsed electrical currents are delivered across the intact surface of the skin to activate underlying nerves. Patients can self-administer TENS and titrate dosage as required because there is no potential for overdose and there are few side effects or drug interactions. Maximal analgesia occurs when TENS generates a strong but non-painful electrical paraesthesia beneath the electrodes. Effects are generally rapid in onset and offset so patients are encouraged to administer TENS as needed and throughout the day
7. Dorsal Genital Stimulation Stimulation of pudendal afferents has been shown to be effective in animal studies and in studies of neurogenic detrusor overactivity. The DGN carries sensory information from the glans of the penis or clitoris and forms a component of the pudendal nerve. Previous results in laboratory animals revealed prolonged suppression of the parasympathetic micturition reflex after stimulation of the DGN. The mechanism of action of DGN stimulation to treat bladder overactivity is thought to be inhibition of the bladder by pudendal afferent stimulation. Somatic inputs via the pudendal nerve reduce the output of the parasympathetic efferent innervation of the bladder by direct post-synaptic inhibition and possibly by pre-synaptic inhibition of bladder afferents. Somatic inputs increase the sympathetic outflow to the bladder (via the hypogastric n.) which inhibits the excitatory parasympathetic input to the bladder at the level of the vesical ganglia and directly inhibits the smooth muscle of the bladder wall.
Neurogenic Lower Urinary Tract Dysfunction: Neurological diseases that have documented voiding dysfunction elements include SCI, MS, PD, CVA and diabetic neuropathy. The concept of neural remodeling as a hypothesized effect of SNM has also been studied as a potential role in neurogenic LUTD, particularly in spinal shock
ICS recommends SNM as an option for control of urinary symptoms in patients with neurological conditions who are at low risk of developing upper tract deterioration from controlled voiding.
Mastrich Series through kind courtesy, Dr. Ernest Weil Multiple Sclerosis: Though not FDA approved, neuromodulation has been tried for bladder overactivity in these patients. It has however not shown any benefit for MS patients with hypoactive urinary bladder or retention
Chronic Pelvic Pain Syndrome, Interstitial Cystitis and Bladder Pain Syndromes: Bilateral stimulation efficacy in these conditions have been demonstrated. Chronic urologic pain, be it bladder pain syndrome, prostatitis, or some other form of urologic chronic pelvic pain syndrome (UCPPS), may present in a variety of symptoms and severities. A multimodal approach, as outlined in this supplement, is generally required to manage these difficult-to-treat conditions. One option available may be to electrically alter the afferent pain signals within the pelvis through sacral neuromodulation (SNM). The bladder and pelvic floor are innervated via sacral nerve roots, which transmit afferent sensory signals up to the brain. The S3 sacral nerve root is most specifically associated with sensory function of the detrusor and pelvic floor muscles. In addition to afferent sensory and efferent motor nerves responsible for bladder and bowel function, pain signals are transmitted through C-fibres and Ad-fibers that travel along the same path.
Cauda Equina Syndrome: Cases have been reported with improvement in bladder and bowel symptoms in many cases of Cauda Equina Syndrome.
Paediatric SNM: Sacral neuromodulation should be considered for children with dysfunctional elimination syndrome whose symptoms are refractory to maximum medical therapy understanding that the risk of reoperation is >50%. Elimination of the trial period reduces the number of general anesthetics without sacrificing outcomes. In a pediatric population sacral neuromodulation is effective for bladder and bowel dysfunction and should be considered before irreversible surgery.
Future Directions: The future directions in the field of SNM include Rechargeable IPGs and MRI compatible systems. Due to the system-oriented, and not organ-oriented, approach, SNM not only treats urinary disorders, but may also have a beneficial effect on bowel and sexual dysfunction as well as on pelvic pain. Most of the clinical therapies aimed at functional bladder disorders are not specifically targeted to the micturition reflex areas, but influence cortical and subcortical brain areas, which, in turn, modulate the micturition reflex components. Examples of such therapies are pelvic floor physiotherapy, biofeedback, transcutaneous electrical nerve stimulation, posterior tibial nerve stimulation and SNM. Currently, there is no effective behavioral, chemical or electrical treatment which works directly and specifically on the central components of the micturition reflex. The central components of the micturition reflex consist of sacral spinal interneurons and their ascending sensory pathway to the periaqueductal gray (PAG) and the pontine micturition center (PMC) in the caudal brainstem, and the PMC and its descending motor pathway to the sacral cord
Closed loop neuromodulation
Current sacral neuromodulation therapy uses open-loop electrical stimulation to alleviate symptoms, which limits battery life and can lead to neural habituation. Neural recordings from bladder sensory afferents suggested that SNM causes a shift in the relationship between bladder sensory neuron firing rates and bladder pressure, which is consistent with the hypothesis that SNM works by reducing bladder afferent activity. Pre-clinical and clinical pilot studies have demonstrated that sensory feedback-based, or closed-loop, stimulation of relevant nerves may offer greater clinical benefit by driving bladder function only when necessary, leading to increased bladder capacity.
Cardiac Pacemaker: It can be concluded that InterStim sacral neuromodulation appears to be safe in patients with cardiac pacemakers programmed using bipolar settings. Continuous cardiac monitoring and pacemaker telemetry are recommended during programming, as well as testing using maximal sacral nerve stimulation, to ensure that no inhibition or interference occurs
In patients with functional bowel disorders such as gastroparesis, functional dyspepsia, gastroesophageal reflux, fecal incontinence or constipation, not responding to maximal medical treatment, bowel lavage or biofeedback therapy, can now be treated with SNM which has evolved as a treatment for fecal incontinence and constipation.
SNM causes direct stimulation of the anal sphincter and causes changes in rectal sensations and several CNS areas. Inflammatory Bowel Disorders are a contraindication for SNM at present. A morphologically intact anal sphincter is NOT a prerequisite for success in the treatment of fecal incontinence with SNM. An anal sphincter defect of less than 33%can be successfully treated with SNM without repair.
In case of combination of diffuse structural damage of anal sphincter and pudendal neuropathy, researchers have achieved an 80% success of over 6 months with SNM. The evolution of SNM is evolving and is a research subject of great interest.
OUR EXPERIENCE: We have an experience of over 20 patients in last 11 years. These include patients of refractory OAB, chronic NOUR and Cauda Equina Syndrome. We do a two-staged procedure in view of the high cost and abide by the AUA, EAU and ICS guidelines. Our long-term results for neuropathic OAB are awaited.
I thank my colleagues in the neuro-urology clinic, Dr. Joy Desai, Dr. Paresh Doshi, and my partner in SNM procedures, Dr. Preeti Doshi. I am grateful to Professor Ernest Weil, formerly of the University of Mastrich and Dr. S. N. Katrak, Professor Emeritus, Jaslok Hospital for guiding me in the field of neuro-urology. I thank Dr. Arun Shah, Director, Neurology, Sir H.N. Hospital for including me in the multiple sclerosis clinic. I am grateful to my resident colleagues, Dr. Abhishek Ghosh, Dr. Hussain Shaikh and Dr. Amitkumar Polara to help me prepare the article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.