Neurogenic Bladder: Selected Treatments

Number: 0852

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Aetna considers enterocystoplasty (augmentation cystoplasty) medically necessary for the treatment of neurogenic bladder that is refractory to medication. 

Aetna considers the following interventions experimental and investigational for the treatment of neurogenic bladder because their effectiveness for this indication has not been established (not an all-inclusive list):

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:
51960 Enterocystoplasty, including intestinal anastomosis

CPT codes not covered for indications listed in the CPB:

Peripheral lidocaine application (neural therapy), Genital nerve stimulation - no specific code:
38206 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous
38232 Bone marrow harvesting for transplantation; autologous
38241 Hematopoietic progenitor cell (HPC); autologous transplantation
51700 Bladder irrigation, simple, lavage and/or instillation
64555 Percutaneous implantation of neurostimulator electrode array; peripheral nerve (excludes sacral nerve) [peripheral neuromodulation]
64575 Incision for implantation of neurostimulator electrode array; peripheral nerve (excludes sacral nerve) [peripheral neuromodulation]
64585 Revision or removal of peripheral neurostimulator electrode array
64635 Destruction by neurolytic agent, paravertebral facet joint nerve(s), with imaging guidance (fluoroscopy or CT); lumbar or sacral, single facet joint
+64636 Destruction by neurolytic agent, paravertebral facet joint nerve(s), with imaging guidance (fluoroscopy or CT); lumbar or sacral, each additional facet joint (List separately in addition to code for primary procedure)
90867 Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; initial, including cortical mapping, motor threshold determination, delivery and management
90868 Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent delivery and management, per session
90869 Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment; subsequent motor threshold re-determination with delivery and management
97813 Acupuncture, 1 or more needles; with electrical stimulation, initial 15 minutes of personal one-on-one contact with the patient
+97814     each additional 15 minutes of personal one-on-one contact with the patient, with re-insertion of needle(s)

HCPCS codes not covered for indications listed in the CPB:

Instillation of neomycin-polymyxin or Oxybutynin - no specific code:
A4595 Electrical stimulator supplies, 2 lead, per month, (e.g., TENS, NMES)
A4630 Replacement batteries, medically necessary transcutaneous electrical stimulator, owned by patient
E0720 Transcutaneous electrical nerve stimulation (tens) device, two lead, localized stimulation
E0730 Transcutaneous electrical nerve stimulation (tens) device, four or more leads, for multiple nerve stimulation
E0731 Form fitting conductive garment for delivery of tens or nmes (with conductive fibers separated from the patient's skin by layers of fabric)
J1580 Injection, garamycin, gentamicin, up to 80 mg
J1800 Injection, propranolol hcl, up to 1 mg

ICD-10 codes covered if selection criteria are met:
G83.4 Cauda equina syndrome
N31.0 - N31.9 Neuromuscular dysfunction of bladder

Background

A neurogenic bladder is the loss of normal bladder function caused by damage to part of the nervous system.  It may result from a disease, an injury, or a birth defect affecting the brain, spinal cord, or nerves leading to the bladder, its outlet (the opening into the urethra from the bladder), or both. 

Intravesical transurethral bladder stimulation is a diagnostic and rehabilitative technique for the neurogenic bladder.  The ultimate goal of the treatment is to create conscious micturition control.  The technique combines direct electrical stimulation of bladder receptors with visual biofeedback using patient observance of a water manometric representation of the detrusor response.  The bladder is catheterized, and a slow-fill cystometrogram is performed.  At the end of the cystometrogram, the bladder is emptied.  This emptied volume is defined as the bladder capacity.  The measured pressure at the end of the cystometrogram when bladder capacity is reached is defined as the bladder capacity pressure.  Following the initial cystometrogram, the bladder is filled to half capacity.  An initial 15-minute bladder observation period is followed by a 90-minute therapy session.  Observations during the first treatment are used in setting initial parameters for future stimulation.  Patients are usually treated with 20 out-patient sessions (a series) during which periodic adjustments are made depending on the response of the bladder to stimulation.  Following the first series, a cystometrogram is performed, and the bladder is allowed to rest for approximately 3 to 6 months.  At the next visit, a cystometrogram is repeated, and a subsequent course of stimulation sessions (5 to 15) is administrated for 1 to 2 weeks.  Medications that may affect bladder dynamics are routinely discontinued a few days before urodynamic studies and during bladder stimulation therapy.  The program is multi-staged, and not all patients require full therapy.  Once the training process is completed, no additional therapy is usually necessary, and the results are permanent. 

Boone et al (1992) conducted a prospective, randomized, sham controlled and blinded study on the efficacy of intravesical transurethral electrotherapy in treating urinary incontinence in the myelodysplastic child.  A total of 31 children completed the protocol.  Of the patients completing the study, 13 were randomly selected to serve as an internal sham control having the electrocatheter placed without activating the stimulator.  These patients were subsequently treated with a 3-week course of electrotherapy.  The remaining 18 patients completing the study were randomly selected to undergo 2 3-week courses of intravesical bladder stimulation.  Urodynamic studies were performed before and after each treatment series.  Detailed daily questionnaires were submitted to each participant covering subjective improvement in urinary continence and any development of bladder sensory awareness.  Analysis of urodynamic data and questionnaires failed to reveal any statistically significant increase in bladder capacity, development of detrusor contractions, improvement in detrusor compliance, or the acquisition of bladder sensation allowing timely intermittent catheterization and preventing urinary incontinence. 

Lyne and Bellinger (1993) reported on a study of patients with neurovesical dysfunction that were treated with transurethral electrical bladder stimulation.  A total of 17 patients (2.5 years to 20 years) completed the series.  All patients demonstrated detrusor contraction during therapy, and 88 % had sensation of contractions, usually developing later in therapy. 

Decter et al (1994) published a follow-up report on the use of transurethral electrical stimulation in patients with neurogenic bladder.  Since 1989, they performed 64 series in 25 patients with neurogenic bladders.  A cystometrogram was performed before each series of stimulation to monitor progress, and impressions of the stimulation were obtained by a questionnaire.  The initial evaluation cystometrogram before stimulation revealed that 18 patients (72 %) had bladder contractions.  After electrical bladder stimulation, 24 patients (96 %) manifested contractions.  Before stimulation, only 3 children sensed the contractions, while during stimulation 50 % of the patients perceived the contractions.  A cystometogram performed before each series demonstrated a greater than 20 % increase in the age adjusted bladder capacity in 6 of the 18 patients (33 %) with serial studies.  Improvements in the end filling pressure defined by clinically significant decrease were observed in 5 of these patients (28 %).  The authors concluded that transurethral electrical bladder stimulation is a time-consuming, labor intensive technique, and the limited urodynamic benefits the patients achieved did not materially alter the daily voiding regimen.  As a result, the authors were not enrolling any new patients into the program.

Cheng et al (1996) published the results of their continuing study (since 1984) on the use of intravesical transurethral bladder stimulation in children with neurogenic bladder.  The authors examined data from multiple institutions and compared it to their own experience.  A total of 335 patients had adequate and accurate pretreatment and post-treatment urodynamic studies, and were reviewed in the study.  Bladder capacity and bladder capacity pressure were determined for each patient before and after therapy.  Overall, 53 % of patients had increased bladder capacity of 20 % or greater after treatment, which represented a 63 % increase from pre-treatment values.  The increase occurred in an average of 1.9 years.  Further analysis of the patients revealed that in 90 % intravesical storage pressures were decreased or maintained within a safe range (less than 40 cm. water).  Evaluation of patients who did not respond to bladder stimulation with a 20 % or greater increase in bladder capacity revealed that they had nearly normal bladder capacity before therapy.  According to the authors, bladder stimulation is effective in increasing bladder capacity without significantly elevating storage pressure in a majority of patients.  The technique is safe and effective in improving bladder compliance, and the program can be reproduced elsewhere.  However many other institutions have conducted similar trials with mixed regard to the efficacy of the treatment modality, and that, to date, clinical experience with bladder stimulation has been too limited to permit identification of the cases that will succeed or fail with the therapy.    

Hagerty et al (2007) evaluated their 22-year experience with intravesical electrotherapy in patients with neurogenic bladder.  The charts of 405 patients who received intravesical electrotherapy were reviewed.  Cystometrograms were performed at the start of each treatment series.  Bladder capacity and pressure were determined for each patient before and after therapy.  Patients were also questioned regarding the sensation of bladder filling.  From 1985 to 2006, a total of 372 patients with an average age of 5.5 years (range of 0 to 43) had follow-up information available and were included for evaluation.  Patients received a median of 29 treatment sessions (range of 2 to 197).  Mean patient follow-up was 6.6 years (range of 0 to 19.7).  Of the 372 patients, 286 (76.9 %) had a 20 % or greater increase in bladder capacity after treatment.  In this subset of patients bladder storage pressure at capacity was normal (less than 40 cm water) in 74.4 % (213 of 286).  Of the 17.2 % of patients (64 of 372) who had no change in bladder capacity 81.21 % (52 of 64) had normal bladder storage pressures after treatment.  Bladder sensation was developed and sustained in 61.6 % of patients (229 of 372), including 33.6 % in the first series. 

It is written in the 2011 textbook Wein: Campbell-Walsh Urology, intravesical electrotherapy, an old technique, which has been has been resurrected with some interesting and promising results is certainly controversial. 

Enterocystoplasty, also called augmentation cystoplasty, is an enlargement of the bladder with a patch of small or large intestine or stomach.  Clean intermittent catheterization is necessary after the procedure.

Acupuncture

Zhang et al (2014) stated that neurogenic bladder is one of the most common complications following spinal cord injury (SCI). In China, acupuncture therapy is a common treatment for neurogenic bladder due to SCI, but its safety and effectiveness remain uncertain. These researchers described a protocol for a systematic review to investigate the safety and effectiveness of acupuncture for neurogenic bladder due to SCI. A total of 8 databases will be searched from their inception: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, the China National Knowledge Infrastructure (CNKI), the VIP database, the Wanfang database, the China Doctoral Dissertations Full-text Database (CDFD) and the China Master's Theses Full-text Database (CMFD). Any clinical randomized controlled trials (RCTs) and the first period of randomized cross-over studies related to acupuncture for neurogenic bladder due to SCI will be included. Outcomes will include change in urinary symptoms, urodynamic tests, clinical assessment and quality of life (QOL). The incidence of adverse events will be assessed as the safety outcome. Study selection, data extraction and quality assessment will be performed independently by 2 reviewers. Assessment of risk of bias, data synthesis and subgroup analysis will be carried out using Review Manager soft-ware. The authors noted that ethics approval is not required since this is a protocol for a systematic review. They stated that the findings of this systematic review will be disseminated via peer-reviewed publications and conference presentations.

Yang and colleagues (2019) will examine the effectiveness of acupuncture combined with rehabilitation training (RT) for the treatment of patients with neurogenic bladder (NB) secondary to SCI.  These researchers will conduct a comprehensive literature search from the following data-bases from the inceptions to the present with no language limitation: PubMed, Embase, Cochrane Library, SinoMed, Web of Science, Allied and Complementary Medicine Database, VIP, WANGFANG, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure.  Furthermore, they will also search gray literature, including dissertations and conference proceedings.  RevMan V.5.3 software will be used for the study selection, assessment of bias of bias, and data synthesis.  This study will synthesize the available evidence of RT combined with acupuncture for NB secondary to SCI, including episodes of urinary incontinence, urinary retention, urinary tract infection, bladder overactivity, QOL, and AEs.  The authors concluded that this study will examine if acupuncture combined with RT is safe and effective for the treatment of NB secondary to SCI.

Other Electrical Stimulation Therapies

McGee et al (2015) noted that electrical stimulation (ES) for bladder control is an alternative to traditional methods of treating NLUTD resulting from SCI. These investigators discussed the neurophysiology of bladder dysfunction following SCI and the applications of ES for bladder control following SCI, spanning from historic clinical approaches to recent pre-clinical studies that offer promising new strategies that may improve the feasibility and success of ES therapy in patients with SCI. Electrical stimulation provides a unique opportunity to control bladder function by exploiting neural control mechanisms. The understanding of the applications and limitations of ES for bladder control has improved due to many pre-clinical studies performed in animals and translational clinical studies. Techniques that have emerged as possible opportunities to control bladder function include pudendal nerve stimulation and novel methods of stimulation, such as high frequency nerve block. The authors concluded that further development of novel applications of ES will drive progress towards effective therapy for SCI. The optimal solution for restoration of bladder control may encompass a combination of efficient, targeted ES, possibly at multiple locations, and pharmacological treatment to enhance symptom control.

Joussain and Denys (2015) stated that management of LUTD in neurological diseases remains a priority because it leads to many complications such as incontinence, renal failure and decreased QOL. A pharmacological approach remains the first-line treatment for patients with NLUTD, while ES has been proposed as second-line treatment. However, clinicians must be aware of the indications, advantages and side effects of the therapy. This report provided an update on the 2 main ES therapies for NLUTD:
  1. inducing direct bladder contraction with the Brindley procedure and
  2. modulating LUT physiology (sacral neuromodulation, tibial posterior nerve stimulation or pudendal nerve stimulation).
These investigators stated that ES could be proposed for NLUTD as second-line treatment after failure of oral pharmacologic approaches. Nevertheless, further investigations are needed for a better understanding of the mechanisms of action of these techniques and to confirm their effectiveness. Other electrical investigations, such as deep-brain stimulation and repetitive transcranial magnetic stimulation, or improved sacral anterior root stimulation, which could be associated with non-invasive and highly specific de-afferentation of posterior roots, may open new fields in the management of NLUTD.

Transcutaneous Electrical Nerve Stimulation

Gross and colleagues (2016) stated that transcutaneous electrical nerve stimulation (TENS) is a promising therapy for non-neurogenic LUTD and might also be a valuable option in patients with an underlying neurological disorder. These investigators systematically reviewed all available evidence on the safety and effectiveness of TENS for treating neurogenic LUTD.  The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement.  After screening 1,943 articles, 22 studies (2 RCTs, 14 prospective cohort studies, 5 retrospective case series, and 1 case report) enrolling 450 patients were included; 11 studies reported on acute TENS and 11 on chronic TENS.  In acute TENS and chronic TENS, the mean increase of maximum cystometric capacity ranged from 69 ml to 163 ml and from 4 ml to 156 ml, the mean change of bladder volume at first detrusor over-activity from a decrease of 13 ml to an increase of 17 5ml and from an increase of 10 ml to 120 ml, a mean decrease of maximum detrusor pressure at first detrusor over-activity from 18 cm H20 to 72 cm H20 and 8 cm H20, and a mean decrease of maximum storage detrusor pressure from 20 cm H20 to 58 cm H2O and from 3 cm H20 to 8 cm H2O, respectively.  In chronic TENS, a mean decrease in the number of voids and leakages per 24 hours ranged from 1 to 3 and from 0 to 4, a mean increase of maximum flow rate from 2 ml/s to 7 ml/s, and a mean change of post-void residual from an increase of 26 ml to a decrease of 85 ml.  No TENS-related serious adverse events have been reported.  Risk of bias and confounding was high in most studies.  The authors concluded that although preliminary data suggested TENS might be safe and effective for treating neurogenic LUTD, the evidence base is poor and more reliable data from well-designed RCTs are needed to make definitive conclusions.

In a meta-analysis, Parittotokkaporn et al (2021) examined the effectiveness of TENS for the treatment of neurogenic bladder dysfunction secondary to SCI.  These investigators carried out a systematic search of Medline, Embase, Web of Science, Scopus, and Cochrane libraries up to February 2021 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.  All RCTs that studied TENS for neurogenic bladder in a SCI population were included.  The primary outcomes of interest were MCC and maximum detrusor pressure during filling (Pdet, max).  Meta-analysis was conducted with RevMan v5.3.  A total of 6 RCTs involving 353 subjects were included.  Meta-analysis showed that TENS significantly increased MCC (standardized mean difference [SMD] of 1.11, 95 % CI: 0.08 to 2.14, p = 0.03, I2 = 54 %) in acute SCI.  No benefits were observed for maximum Pdet.  TENS was associated with no major AEs.  The authors concluded that TENS may be a safe and effective intervention for neurogenic bladder dysfunction following SCI.  Moreover, these researchers stated that more studies the form of adequately powered, randomized, sham-controlled studies are needed to confirm these findings; and further investigation is needed to determine optimal stimulation parameters and duration of the treatment.

The authors stated that the main drawback of this meta-analysis was the quality of the RCTs and the small sample sizes of participants, which could increase the risk of type 2 errors.  Furthermore, due to inconsistencies in reported outcomes, only certain studies could be pooled for meta-analysis.  Heterogeneity (as measured by I2 value) of subgroup analysis could not be measured as too few studies being pooled, in particular for the outcomes of MCC.  Interventions, including such parameters as the site, dose, and duration of stimulation, were not standardized and varied widely between studies, reflecting variation in TENS protocols.

In a systematic review, Silva et al (2022) examined the benefits and harms of electrical stimulation (EE), alone or in association with other interventions, compared with sham and other interventions, for the treatment of neurogenic bladder dysfunction in myelomeningocele.  This review was carried out following the methodological recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.  These investigators conducted a search in the following electronic databases: Medline, Cochrane Central Register of Controlled Trials, Embase, LILACS, and PEDro; RCTs that examined any EE in children diagnosed with myelomeningocele and neurogenic bladder and/or UI were included and reported.  When comparing EE versus sham groups, some estimated effects showed a wide CI, probably due to the small sample size of the included studies.  This indicated an imprecision in these findings.  Regarding the safety of this intervention and safety of the lower urinary tract, no AEs resulting from EE were reported.  All the included studies have examined the effectiveness of EE compared with sham, but different EE parameters and electrode positions among studies made it impossible to conduct a meta-analysis.  The authors concluded that based on very low certainty evidence, the findings of this systematic review suggested no difference between EE and sham to improve UI in children with myelomeningocele.  However, the small sample size and the imprecision arising from the wide CIs must be considered.  These investigators noted that the small number of studies published to-date on the effects of EE for children with myelomeningocele was considered an impacting clinical practice limitation, a fact that denotes the need for future RCTs with greater methodological rigor, as recommended by the CONSORT statement, to support the use of this intervention in clinical practice.

Tissue Engineering

Zhang and Liao (2014) stated that bladder augmentation with enterocystoplasty is the gold standard therapy for neurogenic bladder. The presence of gastrointestinal segments in the urinary tract has been associated with many complications. These researchers investigated an alternative approach using small intestinal submucosa as scaffold for reconstruction. They selected 8 candidates with poor bladder capacity and compliance for small intestinal submucosa cystoplasty. Candidate age ranged from 14 to 54 years, and included 6 patients with myelomeningoceles and 2 patients with SCI. Serial urodynamics, cystograms, ultrasonography and serum analyses were used to assess the outcomes of surgery. Follow-up range was 11 to 36 months (mean of 12). Compared to the pre-operative findings there were significant increases in maximum bladder capacity (p < 0.05) at the 3 and 12-month follow-up (170.1 ± 75.7 ml pre-operatively, 365.6 ± 68.71 ml at 3 months and 385.5 ± 52.8 ml at 12 months), an increase in bladder compliance (p < 0.01) at the 12-month follow-up (5.9 ± 4.0 ml/cm H2O pre-operatively and 36.3 ± 30.0 ml/cm H2O at 12 months) and a decrease in maximum detrusor pressure (p < 0.05) at the 12-month follow-up (43.6 ± 35.7 cm H2O pre-operatively and 15.1 ± 7.6 cm H2O at 12 months). Bowel function returned promptly after surgery. No metabolic consequences were noted and no urinary calculi were observed. Renal function was preserved. The authors concluded that small intestinal submucosa can be used as a scaffold for rebuilding a functional bladder; tissue engineering technology provides a potentially viable option for genitourinary reconstruction in patients with neurogenic bladder.

Taweel and Seyam (2015) stated that neurogenic bladder dysfunction due to SCI poses a significant threat to the well-being of patients. Incontinence, renal impairment, urinary tract infection, stones, and poor QOL are some complications of this condition. The majority of patients will require management to ensure low pressure reservoir function of the bladder, complete emptying, and dryness. Management typically begins with anti-cholinergic medications and intermittent catheterization. Patients who fail this treatment because of inefficacy or intolerability are candidates for a spectrum of more invasive procedures. Endoscopic managements to relieve the bladder outlet resistance include sphincterotomy, botulinum toxin injection, and stent insertion. In contrast, patients with incompetent sphincters are candidates for trans-obturator tape insertion, sling surgery, or artificial sphincter implantation. Coordinated bladder emptying is possible with neuromodulation in selected patients. Bladder augmentation, usually with an intestinal segment, and urinary diversion are the last resort. The authors stated that tissue engineering is promising in experimental settings; however, its role in clinical bladder management is still evolving.

Alpha-Blockers

Kroll and colleagues (2016) evaluated the usefulness of selective alpha 1-blockers in children with neurogenic urinary tract dysfunctions (neurogenic bladder) and increased leak point pressure (LPP).  A total of 14 children aged 6 to 16 years with neurogenic bladder and LPP greater than 40 cm H₂O were enrolled in the study.  All patients received a selective alpha 1-blocker, Cardura (doxazosin mesylate), for 6 to 8 weeks with an initial dosage of 0.03 mg/kg.  During the observation period the continuation of oral anti-cholinergics, clean intermittent catheterization (CIC), observation of "urinary dryness" and urinary incontinence periods were recommended.  Patients were scheduled for a follow-up visit and urodynamic investigation after 6 to 8 weeks after the doxazosin therapy was started.  In 4 patients, urine leakage occurred at lower pressures; in 9 patients, no significant changes in urine leak point pressures were detected; in 3 patients, there was a significant increase in the bladder capacity; in 1 patient, deterioration in continence was noted.  The differences both in LPP and LPV before and after the treatment were not statistically significant.  The authors concluded that their observations were consistent with the conclusions from other studies and showed no evident effectiveness of doxazosin in children with neurogenic bladder.

Beta-Agonists

Wollner and Pannek (2016) stated that in patients with NLUTD due to SCI, neurogenic detrusor overactivity (NDO) can cause both deterioration of the upper urinary tract and urinary incontinence.  Anti-muscarinic treatment is frequently discontinued due to side effects or lack of efficacy, whereas injection of onabotulinumtoxin into the detrusor is a minimally invasive procedure with risks of urinary retention, infection and hematuria.  Myrbetriq (mirabegron), a new beta-3 agonist, is a potential new agent for treatment of NDO.  In a retrospective chart analysis, these researchers evaluated the effectiveness of mirabegron in SCI patients with NLUTD.  A total of 15 patients with NDO were treated with mirabegron for a period of at least 6 weeks.  Significant reduction of the frequency of bladder evacuation per 24 hours (8.1 versus 6.4, p = 0.003), and of incontinence episodes per 24 hours (2.9 versus 1.3, p = 0.027) was observed.  Furthermore, These researchers observed improvements in bladder capacity (from 365  to 419 ml), compliance (from 28 to 45 ml/cm H(2)0) and detrusor pressure during storage phase (45.8  versus 30 cm H(2)0).  At follow-up, 9/15 patients were satisfied with the therapy, 4/15 reported side effects (3 × aggravation of urinary incontinence, 1 × constipation).  The authors concluded that mirabegron may evolve as an alternative in the treatment of NDO.  They observed improvements in urodynamic and clinical parameters.  However, these investigators stated that due to the limited number of patients and the retrospective nature of the study, prospective, placebo-controlled studies are needed to ascertain the value of beta-agonists in patient with NLUTD.

In a systematic review, Helou and colleagues (2020) examined the use of mirabegron in patients with neurogenic bladder.  These researchers reviewed the literature using 4 data-bases (Medline via PubMed, Scopus, Cochrane, and Embase).  Articles examining mirabegron in neurogenic bladder patients were collected, and assessment of the drug's efficacy was reviewed according to clinical and urodynamic parameters.  A total of 7 studies were selected and 302 patients with NB were evaluated, ranging from 15 to 66 patients per study.  All of the patients had received anti-muscarinics as a previous treatment modality.  Mirabegron was used as a 2nd-line treatment after anti-muscarinics lacked efficacy or caused adverse effects.  The duration of the treatments ranged from 4 to 12 weeks.  Reported in 2 studies each, bladder compliance and maximal cystometric capacity were the most commonly improved urodynamic parameters.  In the majority of the studies, positive outcomes were reported for clinical scores.  Furthermore, analysis of the IPSS sub-scores revealed an improvement of storage symptoms as opposed to voiding symptoms.  In all of the studies, mirabegron was well-tolerated.  The authors concluded that mirabegron appeared to be an effective treatment in the management of neurogenic bladder unresponsive to anti-muscarinics, especially in patients presenting with storage symptoms.  Moreover, these researchers stated that there is still no evidence concerning the use of mirabegron as a 1st-line therapy for neurogenic bladder.

Furthermore, UpToDate reviews on “Chronic complications of spinal cord injury and disease” (Abrams and Wakasa, 2020), and “Patient education: Neurogenic bladder in adults (The Basics)” (UpToDate, 2020) do not mention mirabegron as a management / therapeutic option.

Bulking Agents

In a review on “Management options for sphincteric deficiency in adults with neurogenic bladder”, Myers et al (2016) stated that bulking agents have a very poor success as either a primary or secondary treatment of neurogenic intrinsic sphincteric deficiency.

Radiofrequency Ablation of Sacral Nerves

Jo and colleagues (2016) noted that little research has been expended on the use of bipolar radio-frequency (RF) ablation of sacral nerves in SCI patients with NDO, and no study has been undertaken to demonstrate its long-term effect.  In a prospective, randomized controlled feasibility study, these researchers examined the effect of bipolar RF ablation of the 2nd and 3rd sacral nerves over 2 years in SCI patients with NDO.  A total of 10 SCI patients with NDO were recruited.  These patients were randomly assigned to 2 groups:
  1. the intervention group (n = 5), and
  2. the control group (n = 5).
Control group members received optimized conventional treatment.  International Consultation on Incontinence Questionnaire (ICIQ), 3-day voiding diary, and the urinary incontinence QOL scale (I-QOL) data were obtained at baseline and at 6, 12, and 24 months after intervention.  Urodynamic study (UDS) was performed at baseline and 24 months after intervention.  In the intervention group, percutaneous bipolar RF neurotomy was performed on both S2 and S3 nerves in each patient.  Frequency of urinary incontinence and ICIQ and IQOL scores showed significant effects for time and for the group x time interaction (p < 0.05).  Daily mean volume of urinary incontinence showed only a significant group effect.  In UDS parameters, comparisons of values at baseline and at 24 months revealed all variables showed significant intergroup differences (p < 0.05).  The authors concluded that percutaneous bipolar RF ablation of sacral nerves S2 and S3 effectively reduced urinary incontinence and improved QOL in SCI patients with NDO and the effects lasted over 2 years.  The main drawback of this study was its small sample size (n = 10).

Temporary Urethral Stents

Matillon and colleagues (2016) stated that temporary prosthetic sphincterotomy is a possible treatment for neurologic detrusor sphincter dyssynergia (DSD).  In a prospective, non-comparative, single-center study, these researchers verified the feasibility and effectiveness of the urethral stent (US) Temporary ALLIUM BUS "BULBAR URETHRAL STENT".  This study included patients over 18 years, with a neurologic DSD proved urodynamically for which medical treatment was not indicated or failed.  The primary end-point was the percentage of patients who had a voiding method considered as improved or much improved at 1 month and the feasibility of the procedure.  From January to June 2015, a total of 7 patients, (mean age of 47.9 years [24 to 76]) were prospectively enrolled.  One patient was lost to sight at 1 month and therefore excluded.  The median follow-up was 8.1 months (1 to 10).  All procedures were technically successful.  At 1 month, there were 57 % of grade 2 complications (Clavien-Dindo), 1 of 6 patients had a migration of the US.  At 1 month, QOL and the urologic situation was considered good in 3 patients, unchanged in 2 patients and decreased in 1 patient.  The study was stopped after the inclusion of 7 patients.  At the date of the latest news, 5 of 6 patients had a migrated or an explanted US.  The authors concluded that the temporary urethral stent ALLIUM BUS did not appear to be a possible surgical alternative for the treatment of DSD.

Autologous Mesenchymal Stem Cells (Cellular Therapy)

Mahajan and colleagues (2016) stated that neurogenic bladder is a term applied to a mal-functioning urinary bladder due to neurologic dysfunction or insult emanating from internal or external trauma, disease, or injury.  These investigators reported on a case of neurogenic bladder following laminectomy procedure and long-standing diabetes mellitus with neuropathy treated with autologous mesenchymal stem cells (cellular therapy).  In this single-case study, the authors highlighted differentiation potential and paracrine effects of mesenchymal stem cells on bladder function.  Moreover, they stated that regular follow-up to monitor progression/improvement of the condition is mandatory; and further trials and novel routes of administration are needed to improve the effectiveness of cellular therapy in various conditions.

Peripheral Lidocaine Application (Neural Therapy)

Tamam and colleagues (2017) stated that many agents and treatments are used in the treatment of NDO in patients with multiple sclerosis (MS), but no study has been conducted on the use of peripheral lidocaine application (neural therapy [NT]) on MS patients.  These investigators evaluated the effects of local administration of lidocaine on NDO in MS patients.  For each patient lidocaine was injected at each session.  Sessions were held once-weekly for 5 weeks.  At each session, T10-L1 urogenital segment intradermal injections, Frankenhauser, and sacral epidural injections were given.  Patients had clinical and urodynamic assessment 1 month before and 3, 9, and 12 months after NT.  In addition, MS QOL inventory (MSQL-54) and bladder control scale (BLCS) was performed for patients.  A total of 28 patients were included in the study (8 men, 20 women; average age of 31.7 ± 8.1 years).  The injection therapy significantly improved volume at first involuntary bladder contraction (FCV), Pdet, max, maximal cystometric bladder capacity (MCC) after 3 months.  Also, the MSQL-54 and BLCS scores were improved with treatment.  However, these improvements reached a maximum 3 months after treatment, but from the 9 month a regression was observed in the parameters, and after 12 months the findings were seen to be slightly above their basal levels.  The authors concluded that these findings suggested that NDO treatment (peripheral lidocaine application) in MS patients could be an effective treatment, which is easy and has very few side effects, and is cost effective.

This study had 2 major drawbacks:
  1. small sample size (n = 28), and
  2. improvement was not sustained beyond 3 months.
These preliminary findings need to be further investigated in well-designed studies.

Peripheral Neuromodulation

Schneider et al (2015) stated that tibial nerve stimulation (TNS) is a promising therapy for non-neurogenic lower urinary tract dysfunction (LUTD) and might also be a valuable option for patients with an underlying neurological disorder. These investigators systematically reviewed all available evidence on the safety and effectiveness of TNS for treating neurogenic lower urinary tract dysfunction (NLUTD). The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. After screening 1943 articles, 16 studies (4 RCTs, 9 prospective cohort studies, 2 retrospective case series, and 1 case report) enrolling 469 patients (283 women and 186 men) were included; 5 studies reported on acute TNS and 11 on chronic TNS. In acute and chronic TNS, the mean increase of maximum cystometric capacity ranged from 56 to 132 ml and from 49 to 150 ml, and the mean increase of bladder volume at first detrusor over-activity ranged from 44 to 92 ml and from 93 to 121 ml, respectively. In acute and chronic TNS, the mean decrease of maximum detrusor pressure during the storage phase ranged from 5 to 15 cm H2O and from 4 to 21 cm H2O, respectively. In chronic TNS, the mean decrease in number of voids per 24 hours, in number of leakages per 24 hours, and in post-void residual ranged from 3 to 7, from 1 to 4, and from 15 to 55 ml, respectively. No TNS-related adverse events have been reported. Risk of bias and confounding was high in most studies. The authors concluded that although preliminary data of RCTs and non-RCTs suggested TNS might be safe and effective for treating NLUTD, the evidence base is poor, derived from small, mostly non-comparative studies with a high risk of bias and confounding. They stated that more reliable data from well-designed RCTs are needed to reach definitive conclusions.

Barboglio Romo and Gupta (2017) noted that peripheral  and sacral neuromodulation are minimally invasive surgical procedures that are 3rd-line therapeutic options for the treatment of patients with idiopathic over-active bladder syndrome.  There has been interest in their effectiveness in the management of neurogenic lower urinary tract dysfunction (NLUTD).  Contemporary data suggested promising outcomes for urinary and bowel symptoms in carefully selected patients with SCI and/or MS.  The authors reviewed the current literature regarding urinary and bowel outcomes in patients with NLUTD and discussed contemporary studies that suggested that treatment during particular stages of neurologic injury may prevent long-term urinary sequelae.

Furthermore, an UpToDate review on “Chronic complications of spinal cord injury and disease” (Abrams and Wakasa, 2017) states that “SCI produces bladder dysfunction, often referred to as the neurogenic bladder.  Other complications can result from this, including infections, vesicoureteral reflux, renal failure, and renal calculi.  Clean intermittent catheterization, supplemented by medications as needed is the usual initial treatment.  Some patients require a chronic indwelling catheter.  Botulinum toxin and sacral nerve modulators are being investigated as alternative treatment options”.

Tudor and colleagues (2020) examined the safety, efficacy and impact on QOL of percutaneous tibial nerve stimulation (PTNS) in neurological patients reporting overactive bladder symptoms.  In this retrospective evaluation over 18 months at a tertiary healthcare center, patients finding 1st-line treatments for overactive bladder ineffective or intolerable underwent a standard 12-week course of PTNS.  Symptoms were evaluated using standardized ICIQ and bladder diaries.  Of 74 patients (52 women, 22 men, mean age of 56 years), 49 (66.2 %) patients had neurological disorder [19 (25.7 %) MS and 30 (40.5 %) other neurological conditions] and 25 (33.8 %) idiopathic overactive bladder.  Overall for the entire cohort significant improvements were recorded after 12 weeks in the following domains: 24-hour frequency on bladder diary - 1.67 (- 3.0, 0.33) (p = 0.002), number of incontinent episodes on bladder diary - 0.0 (- 1, 0) (p = 0.01), incontinence severity on bladder diary 0 (- 0.33, 0) (p = 0.007), OAB symptoms - 3 (- 11.5, 5) (p = 0.01), and QOL - 16 (- 57, 6.5) (p = 0.004).  There were no significant differences in outcomes between patients with idiopathic and neurogenic overactive bladder.  The authors concluded that PTNS appeared to be a possible promising alternative for patients with neurological disorder reporting overactive bladder symptoms who found 1st-line treatments either ineffective or intolerable.  Moreover, they stated that a properly designed study is needed to address safety and efficacy.

Genital Nerve Stimulation

Bourbeau and colleagues (2019) stated that neurogenic bladder dysfunction, including NDO is one of the most clinically significant problems for persons with SCI, affecting health and QOL.  Genital nerve stimulation (GNS) can acutely inhibit NDO-related reflex bladder contractions and increase bladder capacity.  However, it is unknown if GNS can improve urinary continence or help meet individuals' bladder management goals during sustained use, which is needed for GNS to be clinically effective.  In a pilot feasibility study, these researchers examined the effectiveness of home GNS for individuals with SCI and NDO.  Subjects maintained voiding diaries during a 1-month control period without stimulation, 1 month with at-home GNS, and 1 month after GNS.  Urodynamic and QOL assessments were conducted after each treatment period, and a satisfaction survey was taken at study completion.  Subjects included 5 men with SCI and NDO.  The primary outcome measure was leakage events per day; secondary outcome measures included self-reported subject satisfaction, bladder capacity, and stimulator use frequency.  GNS reduced the number of leakage events from 1.0 ± 0.5 to 0.1 ± 0.4 leaks per day in the 4 subjects who reported incontinence data.  All study participants were satisfied that GNS met their bladder goals; wanted to continue using GNS; and would recommend it to others.  The authors concluded that short-term at-home GNS reduced urinary incontinence and helped subjects meet their bladder management goals.  They stated that these data helped to form the design of a long-term clinical trial testing of GNS as an approach to reduce NDO.

Yeh and colleagues (2019) noted that few studies have examined the effects of changing the amplitude of dorsal GNS on the inhibition of NDO in individuals with SCI.  These researchers examined the acute effects of changes in GNS amplitude on bladder capacity gain in individuals with SCI and NDO.  Cystometry was used to evaluate the effects of continuous GNS on bladder capacity during bladder filling.  The cystometric trials were conducted in a randomized sequence of cystometric fills with continuous GNS at stimulation amplitudes ranging from 1 to 4 times of threshold (T) required to elicit the genito-anal reflex.  The bladder capacity increased minimally and maximally by approximately 34 % and 77 %, respectively, of the baseline bladder capacity at 1.5 T and 3.2 T, respectively.  Stimulation amplitude and bladder capacity were significantly correlated (R = 0.55, P = 0.01).  The authors concluded that the findings of this study demonstrated a linear correlation between the stimulation amplitude ranging from 1 to 4T and bladder capacity gain in individuals with SCI in acute GNS experiments.  However, GNS amplitude out of the range of 1 to 4 T might not be exactly a linear relationship due to sub-threshold or saturation factors.  The authors concluded that further research is needed to examine this issue.  Moreover, these researchers stated that these results may be critical in laying the groundwork for understanding the effectiveness of acute GNS in the treatment of NDO.

Electro-Acupuncture

Zhang and colleagues (2019) examined the effect of electro-acupuncture on the morphological change of the bladder tissue and the protein expression levels of NGF, TrkA, p-TrkA, AKT, and p-AKT in the bladder tissue of rats with neurogenic bladder (NGB) following supra-sacral SCI and explored its partial mechanism of action.  A total of 80 female Sprague-Dawley rats were randomly divided into blank group, model group, electro-acupuncture group, model / siNGF group, and electro-acupuncture / siNGF group according to random number table method with 16 rats in each group; 80 NGB models after supra-sacral SCI were established by adopting a modified spinal cord transection method.  Electro-acupuncture intervention was conducted on the 19th day after modeling.  The bladder function was detected by bladder weight, urine output, serum BUN, and urine protein.  After treatment for 7 consecutive days, the rats were killed and the bladder tissues were removed rapidly for microscopic observation of morphological change after hematoxylin and eosin stain and for determination of the protein expression levels of NGF, TrkA, p-TrkA, AKT, and p-AKT via Western blot analysis.  The transcription of NGF was measured by reverse-transcription polymerase chain reaction (rt-PCR).  After treatment, compared with the blank group, the bladder weight of model and electro-acupuncture groups were significantly increased (p < 0.05).  Compared with the model group, the bladder weight of the electro-acupuncture group was decreased (p > 0.05).  Compared with the blank group, the urine output of the model group was increased (p < 0.05).  Compared with the blank group, the urine output of the electro-acupuncture group was increased (p > 0.05).  Compared with the blank group, the serum BUN of the model group was increased (p < 0.05).  Compared with the blank group, the serum BUN of the electro-acupuncture group was increased (p > 0.05).  Compared with the blank group, the urine protein of the model group was increased (p < 0.05).  Compared with the blank group, the urine protein of the electro-acupuncture group was increased (p > 0.05).  The expression of NGF, p-TrkA, and p-AKT in the model and electro-acupuncture groups was obviously higher than that in the blank group (p < 0.05).  The expression of NGF, p-TrkA, and p-AKT in the electro-acupuncture group was higher than that in the model group.  The expression of TrkA and AKT were unchanged in blank, model, and electro-acupuncture groups (p > 0.05).  After tail vein injection with siNGF lentivirus, the expression of NGF in the model/siNGF group and electro-acupuncture/siNGF group was significantly decreased (p < 0.05); and the protein level of p-AKT and p-TrkA was significantly lower than that of the model and electro-acupuncture groups (p < 0.05).  The authors concluded that sacral electro-acupuncture therapy could improve the expression of both NGF/TrkA signaling and AKT signaling in the local nerve of the damaged spinal cord, inhibit apoptosis of the damaged spinal cord, protect nerve cells, and promote the recovery of the damaged nerve.  At the same time, electro-acupuncture can promote the coordination of micturition reflex and improve NGB function following SCI.

Fesoterodine

Walter and colleagues (2018) noted that managing and preventing risk factors associated with cardiovascular and cerebrovascular impairment is well studied in able-bodied individuals.  However, individuals with SCI at or above the spinal segment T6 are prone to experience autonomic dysreflexia (AD) but also to suffer from NDO.  Treatment of NDO would not only improve lower urinary tract function (UTI) but could also reduce the severity and frequency of life-threatening episodes of AD.  Fesoterodine, an anti-muscarinic drug, has been successfully employed as a 1st-line treatment for detrusor over-activity in individuals without an underlying neurological disorder.  These investigators described the protocol of a trial that will examine the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with SCI.  This phase-II, open-label exploratory, non-blinded, non-randomized, single-center study will examine the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with chronic SCI at or above T6.  During screening, these researchers will interview potential candidates (with a previous history of NDO and AD) and evaluate their injury severity.  At baseline, these investigators will perform cardiovascular and cerebrovascular monitoring [blood pressure (BP), heart rate (HR) and cerebral blood flow (CBF) velocity] during urodynamics (UDS) and 24-hour ambulatory BP monitoring (ABPM) during daily life to evaluate severity and frequency of AD episodes (i.e., maximum increase in systolic BP).  The primary outcome is a reduction of artificially induced (during UDS) and spontaneous (during daily life) episodes of AD as a display of treatment efficacy.  To answer this, these researchers will repeat UDS and 24-hour ABPM during the last cycle of the treatment phase (12 weeks overall, i.e., 3 cycles of 4 weeks each).  At the end of each treatment cycle, participants will be asked to answer standardized questionnaires (AD symptoms and QOL) and present bladder and bowel diaries, which will provide additional subjective information.

Intravesical Instillation of Gentamicin, Neomycin-Polymyxin or Oxybutynin

Honda and colleagues (2019) stated that children with spinal cord disorders can present with NGB.  A bladder with low compliance may cause urinary incontinence (UI), which negatively impacts QOL and renal function.  Long-term high pressure NGB can increase the risk of deterioration in renal function.  Anti-muscarinic pharmacotherapy with CIC is currently considered one of the most effective treatments for these patients.  However, some patients do not respond to oral medication or have unacceptable adverse events (AEs), which may result in medical withdrawal for these patients.  Intravesical oxybutynin has been used in the treatment of NGB with less AEs compared with oral medication.  However, an important issue with this treatment is retention of the solution in the bladder.  Moreover, as yet no data are available on the very long-term use and outcome of modified intravesical oxybutynin therapy.  These investigators reported on the safety, efficacy, and side effects of long-term modified intravesical oxybutynin therapy in children with NGB.  Modified intravesical oxybutynin (1.25 mg/5 ml, twice-daily) was administered to 4 children (3 boys and 1 girl) with NGB (detrusor over-activity and/or low compliance bladder), who were previously unresponsive to or experienced intolerable AEs from oral medications.  Results of pre-treatment cystometrograms were compared to those from follow-up urodynamic studies.  Anti-cholinergic AEs, occurrence of UTI, and degree of incontinence during this treatment were also evaluated.  After 1 year, bladder compliance improved in 3 of the 4 patients.  After 3 years, detrusor over-activity was undetectable in all patients.  Bladder compliance at 3 years and 10 years after initiation of therapy was similar for 3 patients, and they are continuing modified intravesical oxybutynin therapy; 1 patient discontinued therapy at 118 months due to worsening of bladder compliance and upper UTI.  No anti-cholinergic systemic AEs were observed in any of the patients.  The authors concluded that the findings of this study suggested that modified intravesical oxybutynin was an effective and relatively safe long-term therapeutic option for children with NGB.  These preliminary findings need to be validated by well-designed studies.

The authors stated that this study had several drawbacks.  First, in all retrospective analyses, there were inherent limitations.  Second, the pooled sample size (n = 4) was not powered to demonstrate the safety or efficacy of long-term modified intravesical oxybutynin therapy in children with NGB.  Third, the ideal study would be a prospective, randomized, placebo controlled trial.  Challenges and limitations of trial design for pediatric patients with refractory NGB included patient heterogeneity, and the small number of patients in whom traditional urotherapy failed.

Huen and colleagues (2019) noted that recurrent UTIs are common in patients with NGB performing CIC treated with or without oral antibiotic prophylaxis.  These researchers examined if daily neomycin-polymyxin or gentamicin bladder instillations reduce the rate of symptomatic UTIs, the need for oral antibiotic prophylaxis, emergency department (ED) visits for UTI, and in-patient hospitalizations for UTI in patients with NGB on CIC.  The y examined resistance patterns in urine microorganisms in patients treated with antibiotic bladder instillations.  These investigators retrospectively reviewed the records of all-age patients cared for in the pediatric urology clinic with NGB on CIC having symptomatic UTIs and on daily intravesical instillations of neomycin-polymyxin or gentamicin between 2013 and 2017.  Symptomatic UTIs were defined as a positive urine culture with greater than 10,000 colony forming units/ml associated with 1 or more of the following patient complaints: cloudy / foul-smelling urine, fevers, chills, increase in bladder spasms, pain, urinary leakage, or physician decision for antibiotic treatment.  Multidrug-resistant organisms were resistant to 2 or more classes of antibiotics.  A total of 52 patients with a median age of 14.5 years and 192 distinct urine cultures were identified; 90.4 % and 9.6 % of patients received neomycin-polymyxin and gentamicin instillations, respectively.  After initiation of intravesical antibiotics, the rate of symptomatic UTIs was reduced by 58 % (incidence rate ratio [IRR]: 0.42, 95 % confidence interval [CI]: 0.31 to 0.56; p < 0.001), the rate of ED visits was reduced by 54 % (IRR: 0.46, 95 % CI: 0.30 to 0.71; p < 0.001), and the rate of in-patient hospitalizations for UTI was reduced by 39 % (IRR: 0.61, 95 % CI: 0.37 to 0.98; p = 0.043).  Fewer patients received oral antibiotic prophylaxis after initiation of antibiotic instillations (odds ratio [OR]: 0.12, 95 % CI: 0.02 to 0.067; p = 0.016).  There was a trend toward a decrease in multi-drug resistance and no change in gentamicin resistance in urine microorganisms.  The authors concluded that this study described a feasible alternative treatment for patients with NGB on CIC who had persistent UTIs despite oral antibiotic prophylaxis, and for some patients, it may suggest a possibility of discontinuing oral prophylaxis.  These researchers stated that limitations of this trial included a retrospective design with a small cohort of patients (n = 4) and varying dosages of neomycin-polymyxin.

Guidelines from the European Association of Urology (2016) state that, to reduce detrusor overactivity, antimuscarinics can also be administered intravesically  The guidelines state that the efficacy, safety and tolerability of intravesical administration of 0.1% oxybutynin hydrochloride compared to its oral administration for treatment of neurogenic bladder has been demonstrated in a randomized controlled study  The guidelines state that this approach may reduce adverse effects because the antimuscarinic drug is metabolised differently and a greater amount is sequestered in the bladder, even more than with electromotive administration.

Transcranial Magnetic Stimulation

In a systematic review, Nardone and colleagues (2019) examined the usefulness of motor evoked potentials (MEPs) for exploring the integrity of striated sphincters and pelvic floor motor innervation in normal subjects and of repetitive transcranial magnetic stimulation TMS (rTMS) in patients with NB dysfunction.  These researchers carried out a literature search using PubMed and Embase.  They identified, reviewed and discussed 11 articles matching the inclusion criteria.  The authors concluded that the assessment of MEPs could represent a useful tool in the examination of patients with urologic disorders.  High-frequency rTMS could improve detrusor contraction and/or urethral sphincter relaxation in patients with MS and bladder dysfunction.  Low-frequency (LF) rTMS appeared to be an effective treatment of neurogenic lower urinary tract dysfunctions in subjects with Parkinson's disease (PD) and possibly other neurodegenerative disorders.  Furthermore, rTMS might have the potential to restore bladder and bowel sphincter function after incomplete SCI.  These investigators noted that LF rTMS could also relieve some symptoms of bladder pain syndrome and chronic pelvic pain.  These researchers stated that the clinical applicability of MEPs appeared to be questionable, since a poor reproducibility was detected for all pelvic floor muscles.  Furthermore, the use of rTMS in this field is emerging and the results of a few preliminary studies should be replicated in controlled, randomized studies with larger sample sizes.

References

The above policy is based on the following references:

Enterocystoplasty

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Other Experimental Interventions

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