Functional: Neuromodulation

Background

• Neurostimulation: the use of electrical stimuli on nerves and muscles to achieve immediate clinical responses in neurogenic conditions of pelvic organ dysfunction
• Neuromodulation: the use of electrical stimuli on nerves to alter neurotransmission processes in non-neurogenic and neurogenic conditions

Neurophysiology of Electrical Stimulation For Storage And Emptying Disorders

• The acquired and unique ability to void volitionally is due to either negative feedback (inhibition of voiding) or positive feed-forward (induction of voiding) influences of supraspinal inputs from the pontine micturition center on this sacral micturition reflex pathway.
  • Bladder afferent nerve signaling sends information about pain and bladder fullness to the brain that will in turn initiate the micturition reflex.
    • Any loss of either central supraspinal inhibitory influences or increased sensitization of bladder afferent signaling can lead to unmasking of involuntary voiding.
      • Bladder overactivity may be in part mediated by the loss of voluntary control of the voiding reflex and, furthermore, emergence of primitive voiding reflexes.
      • In certain states of neurologic or inflammatory disease of the bladder, the previously silent C fibers may emerge and trigger the micturition reflex. Accordingly, blockade of this pathway by electrical neuromodulation, similar to pharmacologic blockade by capsaicin (a C-fiber blocker), may suppress detrusor overactivity (DO)
• Reflexes That Promote Bladder Storage [note that this description is slightly different than CW11 Chapter 69 description]
  • Guarding reflex
    • Guards or prevents urine loss from times of cough or other physical stress that would normally trigger a micturition episode.
    • Under somatic influence
    • Suprapontine input from the brain turns off the guarding reflex during micturition to allow efficient and complete emptying.
  • Bladder afferent reflex
    • Promotes continence during periods of bladder filling and is quiet during micturition (similar to the guarding reflex)
    • Works through sacral interneurons that then activate storage through pudendal nerve efferent pathways directed toward the urethral sphincter.  
    • Under sympathetic tone
• Reflexes That Promote Bladder Emptying
  • Signals from the bladder that may modulate the need to void with fullness, pain, pressure, or stretch may elicit bladder afferent activity through the Aδ or even C fibers.
    • These bladder afferent nerve fibers then synapse with both parasympathetic efferents (bladder-bladder reflex) and parasympathetic urethral efferents (bladder-urethral) reflex.
  • The urge to void may then be translated as an initial activity (inhibitory) of the bladder-urethral reflex to allow the pressure in the urethral outlet to drop immediately before a bladder contraction ensues and simultaneously permit the bladder-bladder reflex to allow a smooth bladder contraction to occur as the reflex is maintained throughout the entire void
• Putative Mechanism of Action of Sacral Neuromodulation
  • Activation of somatic sacral afferent inflow at the sacral root level that in turn affects the storage and emptying reflexes in the bladder and central nervous system accounts for the positive effects of neuromodulation on both storage and emptying functions of the bladder
• Putative Mechanism of Action of Sacral Neuromodulation in Overactive Bladder
  • Inhibition by electrical neuromodulation may, in part, modulate the sensory outflow from the bladder through the ascending pathways to the pontine micturition center, thereby preventing involuntary contractions
  • By modulating the micturition reflex circuit but allowing voluntary voiding to occur, sacral neuromodulation may affect and improve the abnormal bladder sensations, involuntary voids, and detrusor contractions but still maintain normal bladder sensations and voluntary voiding patterns.
• Putative Mechanism of Action of Sacral Neuromodulation in Urinary Retention
  • Sphincteric activity can be turned off by brain pathways to allow efficient and complete bladder emptying.
  • If the suprasacral pathways are altered, the guarding and urethral reflexes still exist and cannot be turned off. This may cause retention, as in the spinal cord–injured patient who in turn has detrusor-sphincter dyssynergia resulting in urinary retention. Thus, inhibition of the guarding reflexes may allow urinary retention states to be improved

Electrical Stimulation for Storage Disorders

• Criteria for Selection of Patients
  • Sacral neuromodulation is frequently attempted in patients in whom traditional conservative measures (e.g., bladder retraining, pelvic floor biofeedback, and medications) have failed and before more invasive surgical procedures (e.g., enterocystoplasty and urinary diversion)
  • There are no defined preclinical factors, such as urodynamic findings, that can predict which patients will or will not respond to sacral neuromodulation.
  • Contraindications:
    • Absolute (4):
      1. Significant anatomic abnormalities in the spine or sacrum that may present challenges to gaining access
      2. Cognitive dysfunction in patients who cannot manage their device or judge the clinical outcome
      3. Physical limitations that prevent the patient from achieving normal pelvic organ function, such as functional urinary incontinence
      4. Non-compliance
    • Relative (2):
      1. Pregnancy
         • Potential for teratogenicity or abortion from the effect of electrical stimulation is not known; no adverse effects of electrical stimulation on pregnant rats
         • Termination of pregnancy is not advised for prospective mothers when electrical stimulation has been performed unknowingly in early pregnancy.
         • Females with electrical stimulation devices for pelvic health conditions who become pregnant may simply turn off their devices during pregnancy.
      2. MRI
         • At present, contraindicated to perform MRI of a patient with an implantable neurostimulator system, if the MRI is looking at spinal cord segments or anything below the head
         • Recent changes in the manufacturer recommendations do allow for head MRI to be performed with an InterStim in situ, but clearance requires several factors including having the device turned off and use of a 1.5-Tesla magnet or lower
         • For patients who have InterStim devices in place, we advocate removal of the device in preparation for elective MRI based on current manufacturer recommendations. After the MRI procedure, a new neuroelectrode and generator may be placed.
         • Anecdotal reports of patients safely undergoing the study (MRI) with the InterStim implant in place have occurred, but patients should have the devices turned off in anticipation.
• Electrical Stimulation of the Bladder
• Sacral Rhizotomy
  • In most cases, bilateral anterior and posterior sacral rhizotomy or conusectomy converts an overactive detrusor to an areflexic one.
    • This alone may be inappropriate therapy because it also adversely affects the rectum, anal and urethral sphincters, sexual function, and the lower extremities.
    • In an attempt to leave sphincter and sexual function intact, selective motor nerve section can increase bladder capacity by abolishing only the motor supply responsible for involuntary contractions
      • Partial or selective procedures are considered only in such patients who retain some sensation or have excellent reflex erections.
        • To enhance the clinical response and minimize side effects, differential sacral rhizotomy always should be preceded by stimulation and blockade of the individual sacral roots with cystometric and sphincterometric control.
      • Posterior rhizotomy decreases the reflex activity of the detrusor and improves bladder compliance
      • There is still controversy about the role of anterior rhizotomy for treatment of DO; unintended effects on pelvic and lower extremity sensory or motor functions may occur with disastrous medical and legal sequelae.
    • Advantages of bilateral posterior sacral rhizotomy in treatment of voiding dysfunction after SCI:
      1. Abolishing reflex incontinence
      2. Improving compliance
      3. Abolishing striated sphincter dyssynergia without altering resting tone
    • For optimal bladder emptying to be achieved, sacral anterior root stimulation with posterior rhizotomies of S2, S3, and S4 would be required.
      • The S3 anterior (ventral) root provides the dominant motor innervation of the human bladder.

Sacral Neuromodulation

Indications

• FDA-approved indications for sacral nerve stimulation (SNS):
  1. Non-obstructive urinary retention
  2. Urinary urge incontinence
  3. Urinary urgency-frequency syndrome
  4. Chronic fecal incontinence
• Not FDA-approved in patients with urologic or gastrointestinal symptoms arising from a known neuropathy, such as multiple sclerosis, Parkinson's disease, a congenital neuropathic anomaly, post-traumatic spinal cord injury, and/or pelvic nerve injury arising from pelvic surgery.
• Clinical trials are ongoing for its use in interstitial cystitis, chronic prostatitis (i.e., chronic pelvic pain), and idiopathic constipation failing traditional treatment modalities.

Technique

• Sacral nerve stimulation (SNS) by the InterStim procedure is performed in 2 stages:
  • Stage I: clinical trial of a temporary or permanent lead for external stimulation
  • Stage II: implantation of a subcutaneous implantable pulse generator (IPG)

Stage I

• During the initial introduction of sacral neuromodulation therapy, patients undergo a percutaneous nerve evaluation by the placement of a unilateral percutaneous lead in the S3 foramen
  • Whereas some physicians still prefer to perform the first stage by a percutaneous nerve evaluation approach, many have adopted a permanent tined lead placement
• Insert figure
• Procedure
  • The location of the S3 foramen is approximated by measuring 9 cm cephalad to the drop-off of the sacrum and 1-2 cm lateral to the midline on either side.
  • The nerve is tested for the appropriate S3 motor response:
    • Test stimulation is repeated on each electrode, and the responses are observed.
    • Sacral nerve responses

Nerve root	Motor	Sensory
S2	Plantarflexion of the entire foot with lateral rotation and clamp movement of the anal sphincter	Leg and thigh
S3	Plantar flexion of the great toe§ AND Bellows reflex (anal wink. contraction of the perineal area, which represents contraction of the levator muscles)	Parasthesias or sensation of pulling of rectum, scrotum, or vagina
S4	Bellows reflex only	Sensation of pulling in the rectum only

• An S3 response should be noted on ≥2 of the electrodes
  • A sensory response is not needed to confirm proper placement if the correct S3 motor response is observed, although this is debatable.
    • Although controversial, proper localization of the device may be improved if one can localize the stimulation at the time of lead positioning to sensation of the vagina-rectum juncture in females and perineoscrotal area in males
  • When a motor response is absent despite correct placement:
    1. Ensure that the patient has muscle twitches and is not under neuromuscular blockade.
    2. After confirming lack of neurmuscular blockage, raising the conscious level of the patient during the procedure and detecting the correct sensory response will confirm proper localization
    • A clinical response may still be obtained during the screening trial period despite the absence of the motor response
  • Follow-up
    • Changes in LUTS and postvoid residuals (PVRs) are recorded in a detailed bladder diary
      • If improvement is minimal or absent, revision or bilateral percutaneous lead placement may be attempted.
      • If > 50% improvement in symptoms of urgency/frequency or urgency urinary incontinence is attained, a permanent IPG is implanted
    • The length of the trial with the external pulse generator may vary slightly from patient to patient, by the indication, and by the surgeon’s practice preference.
      • In patients with urgency/frequency and urgency urinary incontinence, a 1-2-week trial is generally adequate.
      • For retention, a longer trial of 3-4 weeks or more may be necessary before a desired clinical response is obtained.

Stage II

• Entails placement of the IPG

Outcomes

• At 6 months, SNS improved:
  1. Number of daily voids (16.9 ± 9.7 to 9.3 ± 5.1)
  2. Volume voided (118 ± 74 mL to 226 ± 124 mL)
  3. Degree of urgency (rank score of 2.2 ± 0.6 to 1.6 ± 0.9)
  4. Quality-of-life measures (SF-36)

Bilateral Stimulation and Neuromodulation

• The current technique for sacral neuromodulation involves a unilateral lead at the S3 nerve foramen to achieve results in cases of urgency, frequency, urgency urinary incontinence, and idiopathic nonobstructive urinary retention.
• Bilateral stimulation has been suggested as an alternative, particularly in failed unilateral lead placements, for potential salvage or added benefit as the bladder receives bilateral innervation

Selective Nerve Stimulation

Posterior Tibial Nerve Stimulation (PTNS)

• Posterior tibial nerve is a mixed sensory and motor nerve
  • Contains fibers originating from spinal roots L4 through S3 that modulate the somatic and autonomic nerves to the pelvic floor muscles, bladder, and urinary sphincter.
• Efficacy
  • Improves OAB symptoms with magnitude to anti-muscarinics, but PTNS has a better adverse event profile.★
  • Clinical trials of PTNS have been performed in detrusor overactive conditions with and without pelvic pain and urinary retention. Although clinical trials have produced variable results, PTNS is minimally invasive, demonstrates efficacy, and is easily applicable and well tolerated in all the LUT conditions studied.
  • One of the major limitations of this therapy is the need for continued and repeated sessions
• Indications
  • 2019 AUA OAB Guidelines★
    • May be offered as third-line treatment in a carefully selected patient population, characterized by moderately severe baseline incontinence and frequency and willingness to comply with the PTNS protocol.
      • Patients must also have the resources to make frequent office visits both during the initial treatment phase and to obtain maintenance treatments in order to achieve and maintain treatment effects.
  • FDA-approved for OAB treatment★
• Adverse events (2):★
  • Painful sensation during stimulation that did not interfere with treatment
  • Minor bleeding at the insertion site

Pudendal Nerve

• Because the bladder afferent reflex works through sacral interneurons that then activate storage through pudendal nerve efferent pathways directed toward the urethral sphincter, the pudendal nerve is a logical target for developing neuromodulation therapies
• Neurophysiologic studies reveal that SNS works for bladder storage disorders by a similar inhibition of the micturition reflex as a result of electrical stimulation of sensory afferent fibers, in particular by depolarization of Aα and Aγ somatomotor fibers that affect the pelvic floor and external sphincter and thus inhibit detrusor activity. Because many of the sensory afferent nerve fibers contained in the sacral spinal nerves originate in the pudendal nerve, the pudendal nerve afferents are important targets for neuromodulating the inhibitory reflex on the micturition reflex
• Direct pudendal nerve neuromodulation stimulates more pudendal afferents than SNS provides and may do so without the side effects of off-target stimulation of leg and buttock muscles.

Dorsal Genital Nerve

• (dorsal nerve of the penis in males, clitoral nerve in females)
• The terminal and most superficial branches of the pudendal nerve
• Found at the level of the symphysis pubis.
• Afferent nerves that carry sensory information from the glans of the penis or clitoris.
• Proximally, the dorsal genital nerves form a component of the pudendal nerve and then the sacral spinal roots.
• Contributes to the pudendal-pelvic nerve reflex that has been proposed as a mechanism of bladder inhibition.
  • Whereas squeezing the glans penis or manipulation of the clitoris is clinically known to help suppress bladder contractions as observed in behaviors of voiding avoidance, direct electrical stimulation of these organs does not produce a significant effect on the micturition reflex as measured by urodynamics during the storage phase. However, direct dorsal genital nerve electrical stimulation in experimental and clinical studies appears promising in producing an inhibition of the micturition reflex

Transcutaneous Electrical Stimulation

• Other methods of electrical stimulation have been used that seem to occupy a place midway between anal, vaginal, or perineal stimulation and sacral root stimulation

OnabotulinumtoxinA vs. Sacral Neuromodulation in Overactive Bladder

• The increasing use of OBTX in the therapy for OAB has yielded questions to how to decide whether to use OBTX or sacral neuromodulation in patients with refractory OAB.
• At present, patients with emptying disorders or those at risk for urinary retention who do not want to catheterize would not be ideal candidates for OBTX. Furthermore, these patients need to be aware of the re-treatment intervals approximately every 6 months and this may aid in decision making. On the contrary, if someone has neurogenic conditions, is not willing to undergo an implant (permanent), or may need future MRIs, sacral neuromodulation becomes a less attractive option.

Complications and Troubleshooting of Sacral Neuromodulation

• Categorized as percutaneous test stimulation vs post-implant complications

Test stimulation

1. Lead migration (most common, 12%)
2. Technical problems
3. Pain

Post-implantation

• Pain (15% at 12 months)
• Pocket (IPG) Discomfort
  • Classified as pocket vs. output related
    • Pocket-related causes of discomfort include infection, pocket location (waistline), pocket dimension (too tight, too loose), seroma, and erosion
    • Output-related causes include sensitivity to unipolar stimulation (if this mode is used) or current leak.
  • See CW11 Figure 81-10 for Troubleshooting Algorithm for Implantable Pulse Generator Site Discomfort
  • Diagnosis and Evaluation
    • Turn off the device and ask the patient if the discomfort is still present to differentiate pocket-related from output-related causes
      • If the discomfort disappears, device output is probably causing discomfort.
        • Output-related
          • If the stimulation program is unipolar, switch to bipolar and see whether that eliminates discomfort.
            • Some patients are sensitive to the unipolar mode of stimulation, because the positive pole is the neurostimulator.
          • Another possibility is leakage of fluid into the connector.
            • This somehow creates a short circuit whereby the current from the device follows this fluid pathway out to the patient’s tissue.
            • Most patients report this as a burning sensation. Even though current is following this fluid out to the patient’s tissue, some of the current also may be getting to the electrodes as well, so some patients feel both burning in the pocket and stimulation in the perineum.
            • Reprogramming around this can be tried by using different electrode combinations.
              • If reprogramming is unsuccessful, the patient is asked if the “burning” sensation is tolerable (it will not harm the patient’s tissues); if it is not tolerable, a revision may be necessary to dry out the connection sites
        • Pocket-related
          • If the discomfort persists, the cause is not related to the device output.
          • In the absence of clinical signs of infection, pocket-related causes such as pocket size, seroma, and erosion must be considered.
• Surgical revision
  • Performed in 33% of cases to resolve an adverse event.
    • This included relocation of the neurostimulator because of pain at the subcutaneous pocket site and revision of the lead for suspected migration.
    • At the time of this study, the generator was implanted in the lower abdomen. This profile of complications has changed dramatically with use of the InterStim II generator and posterior (gluteal) pocket location.
  • Explant of the system was performed in 10% for lack of efficacy
• Infection
  • Management: explantation of the whole system.
    • To date, no preoperative or perioperative antibiotic regimen has been decided to be best and should otherwise be left to surgeon discretion.
      • Antibiotic consideration should otherwise be targeted toward skin site pathogens and methicillin-resistant Staphylococcus aureus.
• Decreased or absent response after a successful interval
  • See CW11 Figure 81-8 in Campbell's Urology for Diagnostic Algorithm and Troubleshooting for Recurrent Symptoms
  • When the patient presents with recurrent symptoms, evaluation of the stimulation perception is necessary. The possibilities are that the patient perceives:
    • The stimulation in a wrong location compared with baseline
    • No stimulation
    • Intermittent stimulation
    • Documentation of the exact location and amplitudes of the best stimulation parameters should be done early after successful implantation, to set as a baseline so when changes occur, the baseline can be noted.
  • Impedance measurement is used to check the integrity of the system when a patient presents with a sudden or gradual disappearance of stimulation
    • Impedance describes the resistance to the flow of electrons through a circuit.
      • The electrical circuit in this context starts at the neurostimulator’s circuitry and goes through the connectors to the extension wires, through the extension connector to the lead wires, through the lead’s electrodes to the patient’s tissue, and back either through another electrode and up the same path to the circuitry (bipolar) or to the neurostimulator case and into the circuitry (unipolar).
      • Most measurements of impedance fall within the 400- to 1500-ohm range.
        • If there is too much resistance, no current will flow (open).
        • If there is too little resistance, excessive current flow results in diminished battery longevity (short).
    • Open circuits
      • Can be caused by a fractured lead or extension wires and loose connections
        • If the circuit is broken somehow, electrons cannot flow
      • Impedance measurements are high (>4000 ohms)
        • Unipolar measurements are most useful for identifying open circuits because they take one lead wire measurement at a time, immediately identifying which connection or wire has the problem.
      • Patients generally feel no stimulation if an open circuit is present
    • Short circuits
      • Can be caused by body fluid intrusion into the connectors or crushed wires that are touching each other
        • Electrons always will follow the path of least resistance
      • Impedance measurements are low (<50 ohms) (short = low)
        • Bipolar measurements are most useful for identifying short circuits
      • Patients may or may not feel stimulation, or stimulation may not be present in the correct area (i.e., the generator site) or may vary in strength (i.e., a surging sensation).
  • The intraoperative algorithm for management of impedance problems includes initial testing of impedances; most physicians bypass intraoperative electrodiagnostics and just change the lead to avoid any continued problems postoperatively.
  • Wrong Location
    • If the patient reports that the stimulation location or pattern has changed, it is best to go back to each unipolar setting and map where the patient feels the stimulation.
      • The device is set to 0−, case+ and the patient is asked where she or he feels the sensation; next it is set to 1−, case+ and the patient again is asked about the sensation; next it is set to 2−, case+ and finally to 3−, case+.
      • If these combinations do not confirm the target area, the next step is to start programming bipolar combinations.
      • When those are exhausted, sometimes increasing the pulse width widens the stimulation area
      • If the programming possibilities are exhausted, revision for lead repositioning or relocation to the other side may be necessary.
  • No Stimulation
    • The obvious is checked first: the device parameters must be set high enough, an inadvertent on-off is checked (set magnet switch off to avoid inadvertent magnet activations), and whether the IPG is nearing the end of its life is checked.
    • Next, impedance readings are performed, paying close attention to unipolar impedances. These impedances measure one lead wire with the case, so it is easy to isolate a problem. Using unipolar impedances, it is possible to tell which lead wires are still intact and which ones are not, as mentioned previously. Programming of the electrodes is then continued with acceptable impedance measurements.
    • Bipolar measurements are checked to rule out short circuits as well (very low impedance measurements). If programming around the malfunctioning lead does not restore the stimulation, the patient will often need to undergo revision.
  • Intermittent Stimulation
    • Again, inadvertent on-off is checked.
    • Intermittent stimulation can be caused by either a loose connection or positional sensitivity. If a loose connection is suspected, palpating the connection site and re-creating the intermittency is a good clue as to where the problem lies.
    • Taking impedances while the patient reports the stimulation intermittently determines whether the problem is positional (acceptable impedances are still present) or mechanical (when the patient feels stimulation go off, the impedances are high).
    • With positional sensitivity, the lead position shifts when a patient moves in a certain direction (e.g., the patient reports that the stimulation goes away on standing). The lead position may have moved farther from the nerve during standing, and the amplitude may just need to be increased.
    • Intermittent stimulation represents a challenging dilemma to troubleshoot.

Electrical Stimulation For Emptying Disorders

Electrical Stimulation to the Nerve Roots

• The detrusor is usually innervated primarily by S3 and to a smaller extent by S2 or S4.
• Erectile stimulation is chiefly by S2, with a small contribution from S3 and none from S4.
• Rectal stimulation is by means of all three roots equally.
• The current Brindley stimulator uses the principle of post-stimulus voiding
  • Relaxation time of the striated sphincter after a stimulus train is shorter than the relaxation time of the detrusor smooth muscle. When interrupted pulse trains are used, voiding is achieved between the pulse trains because of the sustained high intravesical pressure.
  • Post-stimulus voiding has a few shortcomings because voiding occurs in spurts at above-normal bladder pressures; when the stimulus parameters are not properly adjusted the detrusor pressures can become too high, putting the upper tracts at risk; and movement of the lower limbs occurs during stimulation because the nerve roots also contain fibers innervating leg musculature, and this movement can be cumbersome for the patient.
• Electrical stimulation of the ventral sacral roots with some techniques to reduce detrusor hyperactivity and obviate striated sphincter dyssynergia has become an accepted treatment modality for LUTD in patients with SCI.

Transurethral Electrical Bladder Stimulation (TEBS)

• Facilitates emptying by establishing conscious control of the initiation and completion of a micturition reflex
• Only patients with an incomplete central or peripheral nerve lesions and with receptors still capable of reactivity and with a detrusor still capable of contractility will benefit from this technique.
  • Patients with incomplete lesions have at least some nerve pathways between the bladder and the cerebral centers but are too weak to be efficient under normal circumstances. TEBS in this situation is hypothesized to activate specific mechanoreceptors in the bladder wall.
• Children with congenital neurogenic bladder dysfunction who have never experienced the urge to void require a biofeedback system to realize the nature and meaning of this new sensation induced by TEBS.
• Transurethral electrical stimulation has fallen out of favor for the most part.

Sacral Neuromodulation of Emptying Disorders

• Has been successful in patients with:
  • Idiopathic nonobstructive retention
  • Retention secondary to deafferentation of the bladder after hysterectomy
  • Fowler syndrome

Percutaneous Tibial Nerve Stimulation for Emptying Disorders

• PTNS also has been studied in the setting of nonobstructive urinary retention

Questions

1. What the putative mechanism of action of neuromodulation?
2. What are the contraindications to neuromodulation?

Answers

1. What the putative mechanism of action of neuromodulation?
2. What are the contraindications to neuromodulation?

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 81