Intractable Overactive Bladder: Neuromodulation and Botulinum Toxin Therapy
Mary T. McLennan
SACRAL NEUROMODULATION
Indications
Tanagho and Schmidt introduced sacral neuromodulation in 1981 (1). Medtronic (Medtronic Inc., Minneapolis, MN) received initial approval to market Interstim therapy for the treatment of urge incontinence in 1997. The indications were expanded in 1999 to include frequency/urgency syndromes and nonobstructive urinary retention.
Most insurance companies do not approve this as first-line therapy. The latest Medicare recommendations involve the following criteria:
Symptoms must be present for at least 12 months and have resulted in significant disability (i.e., limiting ability to work or participate in activities outside the home).
Other methods of conservative therapy have failed.
Conservative therapy must be documented.
Pharmacological (two different medications)
Behavioral (pelvic floor exercises, behavioral modification, biofeedback, timed voids, fluid management)
Successful test stimulation, defined as a 50% reduction in symptomatology during a 3- to 5-day percutaneous test stimulation and symptom return when the stimulation is removed.
Pathophysiology
The mechanism of action is uncertain, but the effect appears to be by modulating afferent fibers. In the case of frequency/urgency/urge incontinence syndromes, stimulation of afferent input to S3 activates spinal inhibitory pathways (2,3). Stimulation of sensory afferents from the pelvic floor can also inhibit the detrusor either at the spinal level or via neural pathways. Idiopathic urinary retention is thought to be secondary to increased pelvic floor muscle activity (4). Continuous contraction of the pelvic floor is believed to cause detrusor inhibition. Based on the cat model, overactivity of the urethral sphincter results in detrusor hypotonia and suppression of bladder sensation. Fowler et al described the so-called Fowler syndrome where the patient has an atonic detrusor and absent sensation of fullness (5). The same group later reported that successful neuromodulation resulted in a return of bladder perception and normal detrusor contraction, presumably secondary to interfering with the increased afferent activity of the urethral sphincter (6). More recently this same group was able to demonstrate that this effect does appear to be the result of an afferent mediated response (7).
In patients with chronic pain, for example interstitial cystitis, it is felt that abnormal nonmyelinated C-afferent fibers are the basis for pain (8). Sacral neuromodulation acts by the afferent system once again and may be effective by modulating the C-afferent fibers. Other investigators have suggested that proximal activation of afferent fibers and peripheral nerves can lead to effective pain relief by exerting an inhibitory effect on the dorsal root (9).
Evaluation
The patient should undergo the standard urogynecological evaluation. This should include a detailed history focusing on medical and neurological risk factors, as certain conditions are relative contraindications to implantation (i.e., known neurological disease). Aggravating factors (i.e., fluid intake, medications, and mobility) need to be assessed. Symptomatology needs to be detailed, including length of symptoms, pad use, degree of disruption to activities of daily living, and amount of frequency, urgency, and urge incontinent episodes. In the case of urinary retention, the amount voided versus the amount obtained by self-catheterization needs to be documented. Previous failed therapies, including duration of trial, must be noted. Standard examination including a directed neurological examination, postvoid residual, and urinalysis is performed. Further studies may be performed as indicated (i.e., uncertain diagnosis, hematuria without infection, increased postvoid residual or symptoms of incomplete emptying, risk factors for bladder cancer). Urodynamics is not a necessity.
Currently most centers do not perform electrodiagnosis prior to implantation. Mastropietro et al presented work on the electrodiagnostic features of responders and nonresponders. An increased bladder-anal and clitoral-anal reflex sensory threshold correlated with improved outcome (10).
A baseline voiding diary for a minimum of 3 days is required to assess eligibility. This provides the basis on which the 50% improvement during test stimulation is assessed. Medtronic provides a standardized diary. It is worthwhile using their diary, as results can then be compared between centers.
Test Stimulation Phase
Peripheral Nerve Evaluation
When initially marketed, the initial test phase was called the peripheral nerve evaluation (PNE). With the advent of the tined lead, this phase is less commonly done and therefore will be described only briefly. In the office, the patient is placed in the prone position with pillows under the abdomen to flatten the back and under the knees to elevate the lower limbs. The skin and subcutaneous tissue and periostium are infiltrated with a Xylocaine or Xylocaine/bicarbonate solution (1% Xylocaine with 8.4% bicarbonate in a ratio of 10 to 1) over the S3 foramen. The addition of bicarbonate decreases stinging and burning from the highly acidic Xylocaine. For the average-sized patient, a 3-inch 22-gauge spinal needle is inserted into the foramen. The operator needs to be aware of the sacral anatomy. The orientation of S4 to the skin surface is approximately 90 degrees, but it is only 60 degrees at S3 (Fig. 12.1). The spinal needle probes the bone and then drops into the foramen, a movement that has a distinct feel. The insulated spinal needle is connected to the temporary stimulator (Fig. 12.2). The parameters are preset at a stimulation frequency of 10 Hz, pulse duration 210 microseconds, and current of 0.5 to 20 milliamps. An appropriate S3 response is plantar flexion of the ipsilateral great toe and contraction of the levator ani, causing deepening of the groove between the buttocks, the so-called bellows response (11). Toe flexion is not requisite. S4 stimulation results in appropriate sensation for the patient but no motor response. The patient typically reports a pulling sensation in the vagina and/or rectum or a vibrating or tingling sensation in the vagina or rectum. An S2 response would involve plantar flexion and an eversion of the foot and a withdrawal-type “clamp” of the rectum. This is not desirable.
When an appropriate response is obtained, a 3057 PNE test electrode wire is threaded through the sheath of the spinal needle. It is important for the patient to avoid bending, as this may dislodge the wire. The lead is attached to the temporary stimulation device (Fig. 12.3). The patient adjusts the voltage of the stimulation by turning a simple dial. She should feel the response at all times, but it should be comfortable. The patient should be made aware that the intensity may vary and may have to be adjusted accordingly depending on her position and activity. Direct comparison is made between a 3-day diary done during the PNE and the one performed before stimulation to determine if there has been at least a 50% improvement in symptoms to qualify for permanent implantation. Successful response for the test stimulation phase is reported at a mean of 55% (range 28% to 83%) (Table 12.1) (6,12, 13, 14, 15, 16, 17, 18, 19, 20).
Incorrect placement is a reason for failure of test phase. Janknegt et al surgically implanted 10 nonresponders and noted that 8 obtained a positive response, indicating inappropriate positioning was the reason for failure (21). Benson reported on the addition of electrodiagnosis (22). A ring electrode located on a Foley catheter is placed in the urethra. The muscle response from the urethral sphincter is recorded. He reported a positive response rate of 80%. Of the responders, 46% did not have a bellows response, 74% no toe response, and 46% no vaginal/sensation response, the responses typically looked for when relying on perineal and extremity visualization.
 FIGURE 12.1 ● Needle orientation for test stimulation. |
Because of the number of failures and lead migration during the test phase resulting in fewer numbers of patients being eligible for the permanent implantation, the technique changed in 2003. Currently, the actual implantable electrode is placed and used for the test phase—the so-called staged implant.
 FIGURE 12.2 ● Temporary stimulator. |
Staged Implant
The initial test phase is now done in the operating room, at which time the tined lead is placed (Fig. 12.4). This first stage typically runs between 1 and 4 weeks, with most physicians doing a patient trial for a minimum of 2 weeks. The time may be particularly important in patients with interstitial cystitis, as their condition will often wax and wane, and it may take an extended period of time to determine the effectiveness of the therapy.
There is no evidence that bilateral lead placement is advantageous (see later discussion), so most physicians will place one lead into the sacral foramina that appears to have the best motor response at the time of initial placement. The patient is placed in an identical position as in the older PNE phase. It is very important that the anesthesiologist be informed to avoid long-acting muscle relaxants, as these may interfere with the elicitation of an electromyographic (EMG) response from the anal sphincter/toe/foot. The patient must be adequately supported with chest rolls, arm supports, and pillows under the knees to avoid nerve injury and pressure necrosis. The feet are left exposed to determine the toe or foot response as deemed appropriate. The buttocks are taped apart so that the anal sphincter is readily apparent.
Many physicians initially place the spinal needle under fluoroscopy; however, for those not attuned to using fluoroscopy, it can sometimes be
difficult to determine the exact positioning, and the bony landmarks are still very useful. The position of the sciatic notch and the drop-off of the coccyx are the most consistent landmarks. For the patient who has a larger body mass index (BMI), the drop-off coccyx may be easier to palpate than the notch. It is important for the individual physician to determine how many fingerbreadths above the drop-off the S3 foramen is located (approximately three to four). The midline is marked and then the approximate location of S3 is 1.5 fingerbreadths lateral to the midline. A spinal needle similar to the old test stimulation needle is then placed at a 60-degree angle and advanced into S3. Attachment to the test stimulator confirms placement, as evidenced by contraction of the anal sphincter with elevation of the pelvis with or without plantar flexion of the great toe. If there is any doubt as to whether it is an S3 response, needles can be placed above or below the initial foramina to determine an S2 response. Fluoroscopy is often useful at this time, especially the lateral view to determine how far up on the sacrum the spinal needles are located.
difficult to determine the exact positioning, and the bony landmarks are still very useful. The position of the sciatic notch and the drop-off of the coccyx are the most consistent landmarks. For the patient who has a larger body mass index (BMI), the drop-off coccyx may be easier to palpate than the notch. It is important for the individual physician to determine how many fingerbreadths above the drop-off the S3 foramen is located (approximately three to four). The midline is marked and then the approximate location of S3 is 1.5 fingerbreadths lateral to the midline. A spinal needle similar to the old test stimulation needle is then placed at a 60-degree angle and advanced into S3. Attachment to the test stimulator confirms placement, as evidenced by contraction of the anal sphincter with elevation of the pelvis with or without plantar flexion of the great toe. If there is any doubt as to whether it is an S3 response, needles can be placed above or below the initial foramina to determine an S2 response. Fluoroscopy is often useful at this time, especially the lateral view to determine how far up on the sacrum the spinal needles are located.
 FIGURE 12.3 ● Test stimulation phase. |
TABLE 12.1 Success with PNE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 FIGURE 12.4 ● Tined lead. |
After confirmation of an S3 response, a wire is then placed down the spinal needle into the foramina. A small incision is placed from the spinal needle down 0.5 cm to allow for easier placement of the plastic introducer. The rest of the placement is very similar to placing a central line (i.e., the use of the Saldinger technique). Once the wire is through the foramina, the spinal needle is removed. A wider introducer with a plastic covering is then inserted over the wire and through the foramina. There is a distinctive “pop” or give as this goes through the foramina. Fluoroscopy confirms that the plastic sheath is deep enough in the foramina. There is a small radiopaque ring at the tip of the sheath, and this should be just beyond the bony plate.
 FIGURE 12.5 ● The lead (left) is now placed though the introducer (right). |
With a twist of the needle, the inside metal introducer is removed, leaving the plastic sheath in place. Through this plastic sheath, a tined lead is passed (Fig. 12.5). The lead has four electrodes similar to the previous one, with the exception that electrode 1 is now wider to compensate for small degrees of lead movement that may occur postoperatively. The lead is passed down through the plastic sheath to the level of the first mark on the lead. This ensures that the electrodes are beyond the end of the plastic sheath but that the barbs of the tined lead are still within the plastic sleeve and not activated.
Progressive stimulation of the four individual electrodes is then performed to determine the optimal position of the lead. The lead can be adjusted deeper or more superficially by gently moving the plastic outer sheath and lead together. It is very important not to move the lead itself; otherwise, the tines may be activated prematurely and the lead cannot be readjusted after that. Ideally, at least two electrodes should give an EMG response. It is preferable to obtain a good motor response from electrode 1, as this is the widest electrode. If anything, the leads tend to be pulled back, so it is preferable to obtain a response from the more superficial leads 3, 2, and 1 as opposed to 0 and 1. This means that in the event that the lead is pulled back slightly, response may be lost in electrodes 2 or 3 but allows for 1 and 0 to pick up.
When ideal placement is confirmed, a lateral film is taken. This film is then left on the one side of the fluoroscopy viewer and under live view; an attempt is made to remove the outer plastic sheath while leaving the electrode configuration in the same position as the initial film. The lead is then tunneled to the buttock on the side selected for the programmer (IPG). A small pocket is fashioned to accommodate the interconnection piece. A special tunneling device is provided with the kit that enables smooth passage. A boot is placed over this wire, the interconnection lead attached to the electrode, and the boot secured in place with suture to minimize the risk of any fluid leaking into the connection area. The tunneling device is used again to tunnel from the buttock incision to the opposite side where the temporary lead exits. It is important to place the exit site as far away as possible from the future site of the IPG and the lead to minimize the risk of infection.
The operative sites are irrigated with sterile water. The incisions are closed. The buttock incision is typically closed in two layers to minimize the risk of seroma or hematoma, which increases the risk of infection. Sterile dressings are then applied and a large bio-occlusive dressing is placed over the whole area. Patients are typically covered with a broad spectrum of antibiotic for several days to a week after the procedure. The exteriorized wire is then connected to the patient programmer. The handheld temporary programmer is then set to the electrode configuration that was felt to be the optimal response in the operating room. The patient is then allowed to adjust the intensity of stimulation. The temporary programmer does allow for reprogramming between the different electrodes should an optimal response not be obtained initially. Success rates for this test stimulation have typically been higher than for the original PNE (see Table 12.1) (23,24).
Permanent Implantation
Stage 2: Implantation of the IPG
Assuming there is greater than a 50% reduction of symptoms, the patient is eligible for the second stage, which is the much shorter of the two procedures. This can be done with the patient in the prone position but is also easily achieved with the patient in the lateral position. This latter position is quicker, as one can avoid the padding required for the prone position. The site where the buttock incision was made for the first stage is placed uppermost. This incision is then opened, the connection piece disconnected, the bulkier end of the wire cut, and the exteriorized portion of the wire pulled out through the skin. It is important not to drag the exterior wire back through the pocket. The pocket is then enlarged to accommodate the IPG. Once hemostasis is achieved, the wire is attached to the IPG, which is then placed in the pocket. Impedance values are then obtained to ensure all the connections are appropriate, and the device can then be programmed to the electrode combination that was determined to be the best during the first stage. Ideally, the impedance should be less than 2,000 Ω. The pocket is then closed with a subcutaneous suture and then either subcuticular or interrupted skin sutures (Fig. 12.6).
Postoperative Care
Some physicians will place the patient on broadspectrum antibiotics for several days up to a week. The patient may adjust the intensity of the stimulation with the telemetry unit (Fig. 12.7). Patients need to be informed that the stimulation may need to be increased or decreased over the next several weeks depending on the amount of edema and trauma to the area. They should avoid twisting or bending and lifting for 4 to 6 weeks to minimize the risk of lead movement.
Predictors for Successful Implantation
Patient selection for permanent implantation is based largely on the successful test stimulation (i.e., successful stage 1 implantation). Several authors have sought to determine if any clinical characteristics are predictive of a successful trial stimulation. Scheepens et al noted that patients who were older, had longer duration of complaints, and a neurogenic bladder were more likely to have an unsuccessful test (25). In addition, patients with urinary retention were less likely to have successful stimulation compared to patients with urge incontinence. The history of disc surgery increased the likelihood of a positive test. The authors, however, concluded by saying that a test stimulation phase is still necessary to determine objectively whether the patient can be successfully implanted.
In a recent study assessing the role of patient age, Amundsen et al noted that cure rates, defined as no daily incontinent episodes, were significantly greater in patients under the age of 55 (65% vs. 37%) (26). Though there was no difference in comorbidities between the two age groups, they noted that individuals with three or more chronic conditions had a lower chance of cure. Both groups, however, had a statistically significant improvement in the number of incontinent episodes, quality of life, pad usage, and voiding frequency. Of note, the two groups may have not been comparable, as detrusor contractions on formal urodynamic
testing were noted in 80% of the younger patients as opposed to 60% in the older patients. These results were reported for the older technique of outpatient test stimulation (PNE) followed by surgical placement of the leads. In their initial study of these older patients, the same group noted a 48% response rate to the test stimulation, which is lower than most reported rates of successful test stimulation (27). It would be interesting to reassess those patients who failed the initial test stimulation with the now two-staged procedure. It is possible that these older patients had more orthopaedic abnormalities, which made spinal needle placement more difficult, and fluoroscopy may have been useful. Certainly in other groups, it has been shown that the two-staged approach does result in a greater percentage of successful test stimulations.
testing were noted in 80% of the younger patients as opposed to 60% in the older patients. These results were reported for the older technique of outpatient test stimulation (PNE) followed by surgical placement of the leads. In their initial study of these older patients, the same group noted a 48% response rate to the test stimulation, which is lower than most reported rates of successful test stimulation (27). It would be interesting to reassess those patients who failed the initial test stimulation with the now two-staged procedure. It is possible that these older patients had more orthopaedic abnormalities, which made spinal needle placement more difficult, and fluoroscopy may have been useful. Certainly in other groups, it has been shown that the two-staged approach does result in a greater percentage of successful test stimulations.
 FIGURE 12.6 ● Implantable pulse generator and lead in place. |
 FIGURE 12.7 ● Patient telemetry unit. |
Results
Frequency, Urgency, and/or Urge Incontinence
A recent Medline search to 2005 reveals that there continues to be only three randomized control trials evaluating Interstim in patients with frequency, urgency, and/or incontinence (overactive bladder). There have been no additional ones since 2000. Schmidt et al randomized 34 patients with urge incontinence to immediate implantation and 42 patients to delayed implantation (28). At 6 months, 47% of the implanted group were dry and 29% had a greater than 50% improvement. There was a significant reduction in leaks per day and pad usage. Once stimulation was deactivated, the number of incontinent episodes increased back to baseline. Hassouna et al randomized 51 patients with frequency/urgency: 25 to immediate implantation and 26 to delayed implantation (3). At 6 months
there was a statistically significant reduction in number of voids per day (16.9 +/− 9.7 to 9.3 +/− 5.1), volume per void (118 mL +/− 74 to 226 mL +/− 124), and degree of urgency (rank 2.2 +/− 0.6 to 1.6 +/− 0.9). Efficacy was sustained at 12 and 24 months. Weil et al randomized 21 patients to immediate implantation and 23 to continuation of conservative therapy (20). At 6 months the control group was eligible to cross over. Fifty-six percent were dry and 75% had greater than a 90% improvement. Implanted patients exhibited improved quality-of-life measures (physical function and emotional role) compared with controls.
there was a statistically significant reduction in number of voids per day (16.9 +/− 9.7 to 9.3 +/− 5.1), volume per void (118 mL +/− 74 to 226 mL +/− 124), and degree of urgency (rank 2.2 +/− 0.6 to 1.6 +/− 0.9). Efficacy was sustained at 12 and 24 months. Weil et al randomized 21 patients to immediate implantation and 23 to continuation of conservative therapy (20). At 6 months the control group was eligible to cross over. Fifty-six percent were dry and 75% had greater than a 90% improvement. Implanted patients exhibited improved quality-of-life measures (physical function and emotional role) compared with controls.
These studies suffer from a number of epidemiological problems, most notably patient dropout. Schmidt initially implanted 86 patients, but 6-month data was reported on only 58 patients (58/86 = 67%) (28). Similarly, Weil et al randomized 21 patients to immediate implantation, but only 16 patients were evaluable at 6 months (20). Long term, the dropout numbers are even greater, with 36% of the original patients evaluable at 18 months (28). This raises the concern about the potential of significant bias, since it is possible that those lost patients represented a disproportionate number of treatment failures.
Observational trials have produced similar results. Cure rates range from 26% to 68%, with greater than 50% improvement in 4% to 85% (Table 12.2) (1,3,13,15,16,19,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44). Long-term results have typically shown lower success rates, with a certain percentage noting failure with time. At a mean follow-up of 30.8 months, Janknegt et al noted more than 50% improvement in 30% of the 96 patients (37); Siegel 59% at 3 years (41); Elhilali 45% at a mean of 6.45 years (39); and Aboseif 77% at 24 months (42).
With increasing time, it has become obvious that surgical revision rates are higher than initially reported (Table 12.3). Explantation rates range from 1.4% to 22% and replacement/relocation rates range from 1.4% to 54%. Dasgupta noted a 54% revision rate in 26 retention patients, with the most common reasons being loss of efficacy, discomfort, and leg pain (45). The total number of operations often exceeds the numbers of patients in the particular study; for example, Weil reported a total of 57 reoperations in 36 patients (16). Recently Elhilali reported on 41 of 52 patients available for long-term follow-up (39). Of the 22 patients with urgency and frequency, at a mean of 6.45 years, 2/22 (9.1%) had the device removed and 3/22 (13.6%) stopped using it. Of the six urge incontinent patients, 2/6 were explanted and 1/6 stopped using it. Additionally, 1/9 retention patients stopped using the device. Thus, the overall removal rate was 5/41 (22%), with an additional 22% stopping using the device. This is an important consideration in view of the expense of the device. Therefore, it is important to choose patients well and to stress to them that this is not a “oneshot deal” but a life-long commitment during which time they may require multiple operations and that efficacy may change with time.
Retention
Most studies reporting on success with urinary retention have small numbers of patients. This is not surprising, as this condition is typically less common than overactive bladder. In the only randomized control trial, Jonas et al enrolled 177 patients with urinary retention refractory to standard therapy (46). Sixty-eight patients had successful peripheral nerve evaluations; 37 of these patients were randomly assigned to immediate implantation and 31 patients to delayed implantation. Results were reported on 29 of the implanted patients and 22 controls. Of the remaining 17 patients, 6 had not yet been enrolled, 3 were lost to follow-up, and 8 did not complete the voiding diary. At 6 months, 69% of those treated were voiding normally without catheterization and 14% had greater than a 50% reduction in postvoid residual. Results were sustained at 18 months. Observational data has consistently shown higher cure rates for this condition compared to overactive bladder, with cure rates of 65% to 97%. An additional 11% to 33% of patients required minimal catheterization (once per day). The effect appears to be well sustained long term, especially when compared to the long-term results for overactive bladder patients (Table 12.4) (23,30,31,34, 41,42,45, 46, 47).
Interstitial Cystitis
Interstitial cystitis is still not an approved indication for implantation. These patients are typically implanted because of their complaints of frequency and urgency. Several small series have been published detailing the success in patients with refractory or end-stage disease. Unlike studies of frequency and urgency, these studies typically report quality-of-life measures, and most use a pain scale assessment (47, 48, 49, 50, 51, 52).
The largest study to date, by Whitmore et al, found significant improvement in frequency, pain, and quality-of-life measures (48). More than 76% of the 33 patients reported more than 50% improvement. Smaller studies have reported similar findings, with all showing a significant decrease in pain and improved quality of life. Improvement rates from 76% to 96% were reported (Table 12.5). Peters at al noted that in 21 narcotic-dependent end-stage patients, 4/18 stopped all narcotics, and the mean decrease in morphine equivalents was from 81.6 to 52.0 mg/day (30%) (52).
TABLE 12.2 Success Rate for Treatment of Urge Incontinence (UI), Frequency, Urgency | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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