Overactive bladder (OAB), a concept proposed by the International Continence Society (ICS), is a syndrome characterized by symptoms of urinary urgency, often accompanied by urinary frequency and nocturia, with or without urge incontinence, and its etiology is not well understood. The etiology is not well understood, which makes its diagnosis and treatment difficult. An epidemiological survey showed that about 33 million adults worldwide have OAB symptoms [1], and the quality of life of OAB patients is significantly reduced. It can be seen that the high clinical prevalence of OAB seriously affects the work and life of patients.
In the new guidelines for the diagnosis and treatment of OAB, the treatment of OAB mainly includes behavioral training, pharmacological treatment, and other treatment options if the above treatments are ineffective, including botulinum toxin injection, bladder instillation of capsaicin analogs, and neuromodulation techniques. stimulation (SNS) and sacral never neuromodulation (SNM) have provided a new way of treatment for OAB. In this paper, we intend to introduce the pathogenesis of OAB and the progress of sacral never neuromodulation technique for the treatment of OAB.
I. Possible pathogenesis of OAB and the feasibility of neuromodulation
Urinary activity is divided into two different cycles, namely the storage phase and the voiding phase. The characteristic abnormality of OAB is the shortened interval of this cycle. For a normal voiding activity, the following four conditions must be present.
(1) A normal central nervous system;
(2) normal autonomic nerves and a coordinated sympathetic and parasympathetic nervous system;
(3) normal bladder anatomy and physiological activity;
(4) normal urethral anatomy and physiological activity. These four components form a unified whole, and disorders in any one of them will lead to abnormal voiding activity and corresponding clinical symptoms.
The neuromodulatory mechanisms associated with human voiding activity are complex, and many issues remain to be elucidated: for example, the relationship between the vegetative nervous system and voiding, the synaptic connection between sympathetic and parasympathetic, and the fact that sympathetic alpha receptors can have the same effect as parasympathetic M receptors on different parts of the detrusor. The external urethral sphincter, which is predominantly innervated by somatic motor nerves, is also innervated by vegetative nerves. In addition, how mental factors influence voiding activity needs to be further investigated.
The spinal cord center is the low-level center for voiding control and is also the necessary route for afferent and efferent transmission from the brain and subcortical centers. The pelvic ganglion acts as a filter in voiding regulation [3]. The parasympathetic neurons that innervate the bladder and posterior urethra are located in the middle lateral column of the spinal cord from S2 to 4. The synaptic connections between the axons of the anterior pelvic ganglion neurons and the postganglionic neurons distributed in the bladder can be located both in the ganglia of the pelvic plexus and in the bladder wall. Physiological activities such as urination, defecation, penile erection, and ejaculation are all related to the sympathetic coordination between the pelvic and trunk nerves.
The pathogenesis of OAB is unknown and there are several theories, currently the following four are considered.
(1) Instability of the detrusor muscle: caused by a non-neurogenic etiology, abnormal contraction of the detrusor muscle during the storage phase causes the corresponding clinical symptoms;
(2) Bladder sensory hypersensitivity: the urge to urinate occurs at smaller bladder volumes;
(3) Abnormal function of the urethra and pelvic floor muscles;
(4) other causes: e.g. abnormal psychiatric behavior, hormonal metabolism disorders, etc. [4].?
Bladder sensory allergy and OAB is a hot topic of discussion in recent years. When bladder sensory hypersensitivity is present, frequent afferent impulses reaching the pontocerebral voiding center inevitably lead to the production of frequent urges to urinate at a smaller bladder capacity. Current studies have shown that sensory nerves and their receptors located within the bladder wall play an important role in the formation of bladder sensory function [5]. The afferent nerve fibers of bladder sensation contain myelinated Aδ fibers and unmyelinated C fibers. Once the excitation threshold of Aδ fibers is reduced, premature transmission of excitation to the voiding center leads to OAB symptoms such as urinary frequency; when inflammation occurs in the lower urinary tract, C fibers that sense chemical stimuli become excited, again producing OAB symptoms. Abnormal expression of purinergic receptor subtype (P2X3) receptors in nerve endings located in the submucosa of the bladder may lead to OAB symptoms. Capsaicin receptors, which are sensitive to capsaicin, are also abundantly expressed in afferent nerve fibers within the tissue of the bladder forceps and in the submucosal plexus [6].
The process of secondary OAB should include at least 2 main components.
(1) The initiating cause acts on the detrusor muscle ;
(2) the eventual unstable contraction of the tissue of the detrusor muscle. How neuromodulation acts on the excitability of the detrusor muscle and the detrusor muscle in the above two major links is a hot topic of current clinical and basic research [7]. It involves the neuromodulation of excitability of the detrusor muscle and the regulation of excitation transmission between detrusor cells. Excitation of one or several nerves by stimulation and modulation of sacral nerves can affect the activity of another or several pelvic floor nerve pathways, so SNS or SNM can be used to treat lower urinary tract dysfunction by excitation or inhibition of these nerve roots.
II. SNM technique for OAB
The mechanism of action of neuromodulation techniques for the treatment of neurogenic bladder is mainly by electrical stimulation, using electrical currents with specific parameters to stimulate the pelvic tissue organs or the nerve fibers and nerve centers innervating them, in order to improve urinary storage or voiding function by direct action on the effector organ, or by influence on the activity of the nerve pathways. A variety of neuromodulation techniques have been practiced over the years for the treatment of OAB, the main ones being.
(1) Electrical stimulation of the voiding center;
(2) electrical stimulation of the bladder (intravesical electrical stimulation or direct electrical stimulation of the bladder method) [8];
(3) Peripheral electrical stimulation and modulation, including sacral nerve root electrical stimulation, pubic nerve electrical stimulation, pelvic floor muscle electrical stimulation and dorsal penile nerve electrical stimulation;
(4) other electrical stimulation techniques, such as body surface electrical stimulation, spinal cord electrical stimulation, pelvic nerve electrical stimulation, and Chinese medicine acupuncture. Stimulation of the dermal nerves of the lower extremities and the skin of the perineum, vagina, and penis has been used clinically to treat urge incontinence with some efficacy [9], but the long-term results are mostly unsatisfactory. Because trans-S3 neuromodulation therapy is convenient for electrode fixation, the site of the buried electrical stimulation generator is stable, and it is not easy to damage other functions of the nerve in that area, so currently trans-S3 sacral neuromodulation therapy is the most common route.
1., NM technology development history: electrical stimulation began in 1954 with Boyce intravesical implantation of electrical stimulation in the bladder wall and in 1963 with Caldwell for urinary incontinence [10]. in the late 1980s, Schmidt et al [11] found that sacral nerve root stimulation could inhibit uncoordinated neural reflexes, laying the foundation for the maturation of neuromodulation and SNS technology. The clinical efficacy of implantable SNM treatment was confirmed through studies reported by several medical centers after Shaker et al. used it in patients with intractable urge incontinence disease in 1998 and Schmidt et al. used it in patients with chronic urinary retention in 1999 [12], and it received clinical treatment approval from both the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH), and subsequently began The clinical efficacy of the SNM technology was confirmed, and the clinical treatment was approved by FDA and NIH, and then started to be applied in clinical practice.
2, SNM technology mechanism of action: electrical stimulation produces therapeutic effects through nerve activity, muscle contraction and the coupling of nerve excitation and muscle contraction, which can cause muscle contraction, activate nerve reflexes and regulate some functions of the central nervous system.
SNM excites the afferent fibers in the sacral nerve roots with low voltage, and then acts on the pelvic organs of urination and defecation through the spinal cord and cerebral bridge reflexes to regulate and balance their storage and urinary functions. It can restore the normal balance relationship between excitation and inhibition within the urinary control system and improve the two opposite symptoms of urinary dysfunction, namely urge incontinence and urinary retention.
3. surgical approach: patients with OAB who are refractory, cannot tolerate medication, have pelvic floor dysfunction, including non-obstructive urinary retention and incomplete bladder emptying, are suitable for SNM. treatment will be divided into 2 phases [13]: pilot testing and permanent implantation. After the trial conditioning, a voiding diary will be recorded for 3-7 d and compared with the preoperative voiding diary or the status of the voiding diary after the stimulator is turned off; if there is a 50% objective improvement in the number of urgency incontinence, urinary frequency and urgency symptoms, a significant improvement in subjective symptoms, and a significant reduction in residual urine, the trial conditioning is effective and permanent implantation of a pacemaker may be considered [14]. A permanent sacral nerve root modulator called the Interstim system has been developed and produced in the United States. The US FDA currently adopts 3 categories of absolute indications for Interstim.
(1) Refractory urge urinary incontinence ;
(2) Refractory urinary frequency and urgency syndrome;
(3) non-obstructive chronic urinary retention.
Sacral nerve testing: All patients record a voiding diary for 5 d prior to sacral nerve testing. testing can be performed in the operating room or on an outpatient basis with the patient in a prone position and the operator marking the position of the right and left S2, S3 and S4 sacral foramina on the body surface with a marker. The patient’s sensory and motor responses are different for S2, S3 and S4 nerve roots: S2 nerve roots usually do not produce sensory responses, but motor responses include anterior-posterior contractions of the anal sphincter and perineum (called clamp responses) and rotational movements of the legs; S3 nerve roots have sensory responses of vaginal or rectal contractions (called clamp responses) and rotational movements of the legs. The motor responses include contractions of the anal sphincter and perineum (the so-called “bellows-like” response) and the plantarflexion reflex of the NFDC3 toe; S4 may have a rectal pulling sensation and also produces a “bellows-like” response (but not as much as S3). response (but not as much as S3), and motor response of the legs and toes.
S3 is mainly responsible for the function of anal raphe and has less influence on the motor function of the lower limbs, so the electrode is usually placed at the level of S3, but the final decision of where to place the test electrode is made by the response of each sacral nerve. After the sacral foramen is selected, the guide core of the puncture sleeve is withdrawn, the test electrode is inserted, and the puncture needle is withdrawn. The electrodes were properly secured outside the body and connected to a pulse generator, tested for 3-7 d, and a voiding diary was recorded for 5 d. The results were compared between the pre-test and test periods. If there is a significant (>50%) objective improvement and/or a significant subjective improvement, a permanent implantation procedure may be considered.
Permanent implantation: The implantation is performed under general anesthesia (without inotropic drugs) in the prone position. The puncture sleeve test described above is repeated first. The most appropriate sacral foramen is found (i.e., the desired response). A subsacral median incision, 6-10 cm long, is made, and the skin, subcutaneous tissue, and lumbodorsal fascia are incised layer by layer to separate the paraspinal muscles on the side of the retained puncture sleeve and expose the sacral periosteum. The permanent electrode is inserted into the selected sacral foramen while the puncture sleeve is withdrawn, and a test is performed to adjust the appropriate insertion depth, which should ensure that at least three of the four electrode contacts (0, 1, 2 and 3 electrode contacts) have the desired motor response (the “bellows-like” response of the anal raphe and the plantarflexion reflex of the NFDC3 toe).
The permanent electrode is fixed to the sacral periosteum at the selected insertion depth to ensure that the electrode does not migrate, at which point it should be retested to confirm that the electrode has not migrated. A separate incision is made in the lateral abdominal wall at the level of the posterior superior iliac crest, approximately 5-7 cm long, and the skin and subcutaneous tissue are incised. The neuromodulator is inserted and the permanent electrode is connected to the neuromodulator with an extension lead. The incision is closed layer by layer and a postoperative frontal and lateral x-ray of the sacrum is taken to see if the electrode is correctly positioned. 1 week later the neuromodulator is turned on using the physician’s remote controller to set the appropriate stimulation parameters and patterns. Patients were taught to use the patient remote controller to turn the regulator on and off and to adjust the stimulation intensity. A diary of urination before and after implantation and adverse reactions after implantation are recorded.
In recent years, a minimally invasive percutaneous dentate stimulation lead puncture implantation technique has emerged, which uses an inverted dentate lead design to ensure that the stimulation lead does not migrate postoperatively. The implantation is performed under local anesthesia, and the patient is able to cooperate and complain about the perceptual response, which improves the efficacy by helping to select the optimal implantation site.
4, Interstim efficacy and complications: there are many treatments for OAB with predominantly frequent, urgent and urge incontinence symptoms, mainly for patients with recalcitrant OAB due to the high price of electrical stimulation neuromodulation. the therapeutic efficacy of Interstim is based on a correct test stimulation, which allows for a long-term and is reversible device implantation.?
In recent years, the long-term efficacy of sacral nerve stimulation neuromodulation for OAB has been increasingly reported, and it is increasingly recognized by physicians and patients as an important treatment for OAB that has failed to respond to drug therapy. There are hundreds of reports on the efficacy, including several multicenter clinical trials. The results vary widely depending on the equipment, the operator, the number of cases enrolled, the criteria used to determine efficacy, and the length of follow-up. The overall effectiveness rate generally ranges from 40% to 75%. Overall analysis seems to indicate that SNS is relatively effective for refractory urge incontinence and refractory urinary frequency and urgency syndrome.
A prospective, randomized, multicenter clinical study of SNS showed [16] that at 6 months after SNS, 77% of patients with urge incontinence randomized to SNS implantation were completely free of heavy leakage, compared with only 8% of the unimplanted control group; in this group, clinical outcomes persisted for up to 18 months, at which point 52% of patients in the implanted group achieved complete dryness, 24% of In this group, 52% of the implanted patients achieved complete dryness and 24% of those with incontinence had >50% improvement. Similarly, the average number of voids per day in patients with refractory urinary urgency decreased significantly at 6 months after SNS compared to the unimplanted control group, with a significant decrease of 56% in the implanted group compared to 4% in the control group; residual urine volume was also significantly lower in patients with chronic urinary retention, with a 69% residual-free rate in the implanted group compared to 9% in the control group.
The results of Sielgel et al [17] showed that after 3 years of implantation of the Interstim device, 59% of patients with urge incontinence had sustained significant improvement and 46% had complete resolution of their incontinence symptoms. The results of a study by van Kerrebroeck et al [18], who reported 152 patients with urge incontinence, urinary frequency, and urinary retention treated with the SNM technique at 17 medical centers worldwide (with a follow-up of up to 5 years), showed a decrease in leakage events from (9.6 ± 6.0) to (3.9) per d to (3.9 ± 4.0) events/d, frequency events from (19.3 ± 7.0) events/d to (14.8 ± 7.6) events/d, and an increase in urine output from (92.3 ± 52.8) ml/d to (165.2 ± 147.7) ml/d; no quality of life or irreversible complications occurred.
Also the Interstim technique is useful in patients with refractory OAB after stress urinary incontinence surgery; Sherman et al [16] reported that 65% of a group of patients who responded to test stimulation and underwent permanent electrode implantation also achieved improvement in their symptoms.
There is a certain rate of complications associated with SNS implantation. The more frequently reported complications are pain or infection. The incidence of displacement of the electrical pulse generator is 33%. Common complications also include pain at the location of the lead (25%), lead-related complications such as lead displacement (16%), poor wound healing (7%); 9% of patients have to remove the electrode for various reasons, and the incidence of these complications is gradually decreasing with the continuous improvement of technology [19].
5, the current situation of domestic application: at present, doctors in China have started to use percutaneous SNS technology to treat OAB, and in recent years they have also adopted Tined Lead electrode under C-arm machine to perform percutaneous minimally invasive puncture implantation into S3 sacral foramen for sacral nerve modulation practice. The technique is designed as an inverted tooth-shaped electrode, which is minimally invasive and ensures that the stimulating electrode is not displaced after surgery; the operation is performed under local anesthesia, and the implantation can be tested at the same time, which creates conditions for permanent implantation in phase II and is more suitable for the national conditions of China, and has a better? prospect.
In 2007, Tang Hua et al [20] reported that after 40 weeks of using the percutaneous SNM technique (using acupuncture needles to puncture at the S3 nerve foramen and sending pulses with a computerized random pulse acupuncture device) in female OAB patients, the patients’ quality of life was analyzed by urination diaries, patient symptoms and psychological scores of depression and anxiety before and after treatment for any improvement. In 23 patients, the number of daily urination was significantly reduced, the average volume of urination was increased, and the degree of urgency was reduced; in 9 patients, the symptoms improved slightly, but the efficacy was not significant. The psychological scores of depression and anxiety before and after treatment were also significantly improved in those with significantly improved symptoms. Further work was done to compare SNM with other treatment modalities, including the use of capsaicin analogs and tolterodine, and the results showed that the SNM technique not only improved the lower urinary tract symptoms of OAB, but also had mild side effects [21].
It should be said that this is a new attempt and a preliminary work of sacral neuromodulation therapy technique in combination with our national conditions, and we hope it can be an inspiration for our domestic colleagues.
6, Development prospect: although SNM has only been proven to be used for urge incontinence, urinary urgency, urinary frequency syndrome and non-obstructive urinary retention, Interstim is already being investigated for other neurogenic pelvic floor disorders, including chronic pelvic pain syndrome, interstitial cystitis, defecation difficulties, irritable bowel syndrome and chronic constipation, but its safety and efficacy need to be further studies.
SNM is an effective and clinically feasible technique for the minimally invasive treatment of OAB, offering hope for people with refractory OAB who have failed conventional treatment. However, it is expensive and the stimulator needs to be replaced regularly due to the 7-10 year battery life limit, which may affect its widespread use in China. In addition, there is a learning curve for the surgical technique. It is hoped that cooperation and communication can be strengthened by continuously expanding clinical cases, reducing the price of materials and equipment, and developing affordable localized products to benefit more patients.
III. Summary
A survey on the incidence of OAB in six European countries showed that 16.6% of 16,776 respondents had OAB, and the incidence of OAB increased with age, but the difference between men and women was not statistically significant [22]. Stewart et al [23] conducted a telephone survey of 5204 people over 18 years of age in the United States and showed that the prevalence of OAB was 16.0% (394/2469) in men and 16.9% (463/2735) in women.
Among the conventional treatments for OAB, behavioral training and medication have been effective, but due to the complexity of the etiology, some patients still have to undergo specific treatment modalities, which include the application of SNM techniques. There are still many uncharted spaces in this field waiting to be explored, and we hope that colleagues will join us in following the development of this field to provide better treatment pathways for patients.