A roadmap for advancing neurostimulation approaches for bladder and bowel function after spinal cord injury

Introduction

Neurogenic bladder and bowel dysfunction following spinal cord injury (SCI) strongly and adversely affect quality of life. Bladder and bowel management can be complicated, time consuming, require caregiver assistance, and impact social life, independence, and dignity. Individuals with SCI report that improving bladder and bowel function are high priorities [1,2,3]. However, there remains a large, unmet, clinical need.

To accelerate bladder and bowel research in SCI, the Craig H. Neilsen Foundation held a workshop in March 2017 [4]. One identified priority was to examine existing and emerging neurostimulation approaches. Here, we define neurostimulation as the application of electrical stimulation, alone or in combination with another intervention, to provide targeted activation or inhibition of neural circuits to modulate physiological functions.

Individuals from research, clinical care, industry, patient advocacy, and funding agencies formed a working group to create a roadmap for advancing neurostimulation approaches in this area of autonomic function. Acknowledging the need for input from the community, a Consumer Advisory Board was also formed of six volunteer members of the North American Spinal Cord Injury Consortium who themselves have SCI. Recruitment took into account diversity in gender, level of injury, duration since injury, and SCI community involvement to provide perspectives from the lived experience.

At this time, neurostimulation should not be considered the optimal therapy for the majority of individuals with SCI. However, considering the drawbacks of multiple daily catheterizations and the continuing frequency of urinary tract infections in people with SCI, as well as the difficulty of compliance with anticholinergic medicines due to side effects, neurostimulation has a strong scientific rationale and provides a promising area for further development.

The purpose of this work is to discuss advancement and translation of neurostimulation approaches for neurogenic bladder and bowel function. We discuss users’ bowel and bladder priorities and attitudes toward neurostimulation approaches. Emerging and existing neurostimulation technologies with near-term clinical potential are briefly reviewed. Opportunities and challenges for clinical translation are outlined, and recommendations to address these challenges are discussed. Collectively, these sections provide a roadmap to guide the advance of neurostimulation approaches to improve or restore bladder and bowel function for individuals with SCI. This roadmap has taken into account agencies, institutions, cultural factors, and socioeconomic factors that apply in the United States and Canada, and some of the discussion may not apply equally in other countries.

Characterization of need

There is great variation in spinal cord lesions, and thus also in the functions, strategies, and needs for management among individuals with SCI. Neurostimulation approaches need to be flexible to address the varying combinations of dysfunctions that individuals experience. Treatment must meet functional goals as defined by the user and be individualized; dynamic to adapt to change as the user ages; and socially acceptable. Treatment must produce a predictable, reliable means of managing an individual’s bladder and/or bowel with as much user independence and as little time as possible. The field would benefit from a deeper understanding of the specific bladder and bowel needs and priorities of individuals with SCI in order to define better specific targets for bladder and bowel functional recovery.

A recent survey asked individuals with SCI about how they manage their neurogenic bladder and bowel, their needs and priorities for their bladder and bowel functions, and their attitudes toward neurostimulation approaches to improve or restore these functions [5]. Respondents’ top priorities for restoring bladder function were being able to empty their bladder without catheters, maintaining urinary continence, and being free of medical complications, such as urinary tract infections or episodes of autonomic dysreflexia. Top priorities for restoring bowel function were maintaining fecal continence, having increased predictability in their bowel routine, and having a reduced time to complete their bowel emptying routine. Most respondents indicated that they were very likely to adopt an implanted or external neurostimulation system to improve their bladder or bowel function. However, one key study limitation was that it was not clear how representative these respondents were of the population of individuals with SCI. Understanding the needs and priorities of individuals with SCI will help drive advancement of existing or emerging approaches to meet these needs. Therefore, further study of the needs and preferences of individuals with SCI should be done.

Existing or emerging neurostimulation approaches for control of bladder and bowel function

Neurostimulation is a growing field that has the potential to improve or restore bladder or bowel function for individuals with SCI [6]. This document is intended to highlight research approaches with high potential for translation in the near future, but does not intend to support, promote, or endorse particular products.

Bladder and bowel emptying

Sacral anterior root stimulation has been effective for improving bladder and bowel emptying in several thousand persons with SCI [7, 8]. Sensory deafferentation (posterior rhizotomy) is usually required to prevent reflex contractions of the bladder and external urethral sphincter. This rhizotomy irreversibly eliminates reflex erection, reflex micturition, and any remaining pelvic sensation.

An experimental approach, demonstrated in animals, electrically blocks signal conduction in the pudendal nerves or sacral roots and can reversibly reduce sphincter contractions [9, 10]. This approach achieved bladder voiding comparable to that when stimulation was combined with rhizotomy and may mitigate the need for posterior rhizotomy in the future.

Urinary and fecal continence

Continent storage of urine and stool is often impaired following SCI because there are unwanted reflex bladder and bowel contractions and the descending signals for inhibiting the bladder and bowel are compromised. Electrical stimulation of other inhibitory reflex pathways may prevent or stop unwanted activity and improve urinary and fecal continence.

Several studies have shown that transcutaneous stimulation of the genital nerves via surface electrodes strongly inhibits bladder activity in women and men with SCI [11]. A recent comparison showed that this form of stimulation suppressed detrusor contractions and increased bladder capacity in individuals with chronic SCI whereas electrical stimulation of the skin over the tibial nerves, sacrum or lower spine did not [12]. There is also evidence of its effects on neurogenic bowel dysfunction [13].

Implanted sacral root neuromodulation via the sacral foramina was reported to improve bladder and bowel control in patients with acute SCI if done while the detrusor was still areflexic [14]. A clinical trial has been designed to test this further [15]. However, there is little evidence that this approach improves bladder and bowel control for individuals with chronic SCI.

Epidural stimulation of the lumbosacral spinal cord is an emerging approach to improve bladder and bowel control in individuals with SCI [16, 17]. Early studies are being conducted in individuals with SCI, especially in conjunction with rehabilitation, that are showing promising results. A framework was outlined for conducting the research needed to define an effective epidural stimulation procedure [18]. Nonsurgical alternatives to epidural stimulation, including transcutaneous electrical and magnetic stimulation, have also shown promising results.

The ultimate goal of neurostimulation is to restore synergic function of the bladder, bowel and sphincters, and this has not yet been reliably achieved.

Opportunities and challenges to advancing neurostimulation approaches for neurogenic bladder and bowel function

There are significant opportunities for improving neurogenic bladder and bowel function using neurostimulation. These include our growing understanding of the needs and preferences of individuals with SCI, existing and emerging neurostimulation technologies, and the successful commercialization of neurostimulation devices designed for other neurological conditions. In spite of these opportunities, there is a dearth of neurostimulation devices for SCI. This is probably because there are particular challenges in SCI that differ from those in other disabilities, and challenges for developing devices that exceed those for developing medications and other therapies. These challenges include the limited integration of stakeholders in this area, the academic framework of bioengineering research that may not strongly incentivize translation to clinical application, particular regulatory and reimbursement issues for medical devices, and commercializing devices in the small market of SCI. Figure 1 summarizes these issues.

Fig. 1: Roadmap for advancing neurostimulation approaches for neurogenic bladder and bowel function.
figure1

Stakeholders need to be better integrated and translational research needs to be incentivized toward clinical impacts. We should carefully consider targets for recovery of bladder and bowel function, and existing and emerging approaches to meet those targets. Some neurostimulation approaches have demonstrated some potential for clinical impact and could be advanced. Finally, a clear vision for clinical adoption, simultaneous with a plan for regulatory and reimbursement strategies, are critical to advance neurostimulation approaches.

Integration of stakeholders

Getting an effective device into clinical practice in SCI requires integration of different stakeholders to define a problem, identify a solution, conduct a clinical trial, and make a device clinically available and commercially viable. Individuals with SCI have a unique perspective on priorities but have not been well-represented in this process; they are typically not included in research except as study participants. Regulatory agencies, reimbursement specialists, and commercial manufacturers are often not included until late in this process, as discussed below. Improved integration of stakeholders can result in improved problem definition and solution identification, improved conduct of clinical trials testing an intervention, and improved ability to define and evaluate success of an intervention.

Individuals with SCI are now forming and joining organizations that reach out to other stakeholders, and professional societies are increasingly seeking participation from individuals with SCI. Some funding agencies are actively encouraging inclusion of individuals with SCI as members of the research team and the review process. For example, the National Advisory Board on Medical Rehabilitation Research includes six members representing individuals with disabilities [19]. The FDA encourages the use of “patient-reported outcomes” (PROs) and “patient preferences” in regulatory studies [20]. Companies have long known the value of market research but this has not always informed researchers. There are also information resources, such as the Spinal Cord Injury Research Evidence (SCIRE) Project, providing current and credible information for all stakeholders [21]. Successful integration of all stakeholders can lead to greater success on the translational pathway.

Translation pathway

Academic research is not incentivized to support clinical translation as strongly as discovery science. For most researchers, especially in academic institutions, there may not be a clear funding path to translate and commercialize technologies. The grant review process may tend to reward innovation and new scientific knowledge, but less so validation and refinement of existing technologies. Funding agencies have many mechanisms available to support translational research projects, but academic institutions do not necessarily reward these activities, and the publication rate may be lower for translational research than discovery research. Stakeholders should familiarize themselves with these opportunities and the review process should reflect the stage of translation and the goals of the mechanisms.

Researchers who have achieved important scientific discoveries may either lack the desire to translate these findings, or may not have the skillset, resources, or expertise to navigate an unfamiliar process. Improving integration with other stakeholders, can help ameliorate some of these issues.

The translational pathway is also challenging because funding agencies may not support the level of de-risking sought by commercial entities. While funding for Phase I or Early Feasibility Studies may be relatively straightforward, Phase II trials may be significantly harder to fund. Achieving a sufficient level of evidence for effectiveness can be particularly challenging within the field of spinal cord medicine because of the small size and great heterogeneity of the population. The limited number of potential study participants can make recruitment for a study challenging if there are only a few study sites, especially if studies are competing for a pool of potential participants. Coordination with other research centers, funding agencies, and advocacy groups could help address this challenge. Clinical trials of medical devices typically require fewer subjects than pharmaceutical trials, but the surgery required for implanting neurostimulators can deter research participants. Several advocacy groups together support a database of SCI clinical trials that individuals with SCI can navigate (https://scitrials.org/), which could result in increased research participation.

Regulatory and reimbursement strategies

Understanding the requirements and processes to receive regulatory approval for a neurostimulation device is complex and time consuming, particularly if it is implanted for life. Regulatory agencies, such as the FDA’s Center for Devices and Radiological Health, can provide guidance, and some funding agencies provide support for efforts to achieve regulatory approval. There are particular ethical challenges associated with the lifetime support of devices, including analysis of risk, informed consent, and posttrial responsibilities, and work with individuals with SCI to assess potential risks and benefits [22].

Identifying a reimbursement strategy is more complicated and less understood than the regulatory strategy. Not only must the medical community agree that the device is safe and effective, but the cost-benefit balance must be competitive with other treatment options. The reimbursement rate may be based on existing device or procedure codes, not on the cost of the intervention, which can be challenging for device manufacturers. Early engagement with national bodies that control reimbursement for devices and their long term support is important.

Commercialization

The SCI market is small. While neurostimulation can be profitable for some disorders, it is challenging in the small market of SCI. Sacral anterior root stimulation has been shown in several studies to be cost-effective for restoring bladder and bowel function after SCI. A study conducted for implantable sacral anterior root stimulation in the USA projected that an implanted neuroprosthesis would greatly reduce the cost of managing neurogenic bladder and bowel [23]. While this study showed cost savings for healthcare delivery, it did not necessarily extend to commercial sustainability for a company providing this device. Many other factors determine the clinical acceptance of a technique in SCI. A device must demonstrate value not only to the patient but also to the payer, the providers in the supply chain, and the manufacturer and distributors. Understanding the cost-effectiveness of neurostimulation devices and developing strategies for sustainably serving the small SCI market may improve opportunities for commercialization of neurostimulation devices for people living with SCI.

To understand and improve the likelihood of success of an approach, the research team should engage with business development managers, knowledge transfer specialists, and potential industry partners early in translation. There should be a vision for creating clinical adoption and market awareness of the intervention to ensure healthcare delivery. An intervention must demonstrate significant value to the consumer by providing a large or critically important clinical benefit at acceptable costs.

A potential opportunity for facilitating translation and commercialization of neurostimulation approaches for bladder and bowel function is to adapt or reuse existing technologies to treat new indications. Several companies are making their technologies available through public–private partnerships via funding mechanisms supported by the NIH. These companies offer FDA-regulated devices for use in new research activities that could cover additional new indications for bladder or bowel function. In a for-profit model of healthcare delivery, market forces may ultimately determine if there is a commercialization pathway for new devices or for leveraging existing devices.

Conclusion

Persons with SCI are interested in adopting neurostimulation approaches for improving bladder and bowel function. Several neurostimulation approaches could advance the field in the short term. Existing stimulation devices from other indications might be used for the neurogenic bladder and bowel. Neurostimulation might be used to inhibit unwanted contraction of the bladder and to block unwanted contraction of the sphincters, as well as to promote both storage and emptying of the bladder and bowel.

Translating these existing and emerging techniques into clinical practice requires stakeholders to collaborate across traditional academic, regulatory, and commercial boundaries, and to identify early the obstacles and solutions unique to SCI, bladder and bowel function, and medical devices.

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Funding

This work was supported in part by the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service RX001962. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

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Correspondence to Dennis Bourbeau.

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KT and BGS are co-authors and they work for Dignify Therapeutics Inc. and for Radiometer, respectively. These roles may present real or perceived conflicts of interest.

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Bourbeau, D., Creasey, G., French, J. et al. A roadmap for advancing neurostimulation approaches for bladder and bowel function after spinal cord injury. Spinal Cord 58, 1227–1232 (2020). https://doi.org/10.1038/s41393-020-00544-x

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