Restoring bladder function using motor and sensory nerve transfers: a cadaveric feasibility study

Abstract

OBJECTIVE

Bladder dysfunction after nerve injury has a variable presentation, and extent of injury determines whether the bladder is spastic or atonic. The authors have proposed a series of 3 nerve transfers for functional innervation of the detrusor muscle and external urethral sphincter, along with sensory innervation to the genital dermatome. These transfers are applicable to only cases with low spinal segment injuries (sacral nerve root function is lost) and largely preserved lumbar function. Transfer of the posterior branch of the obturator nerve to the vesical branch of the pelvic nerve provides a feasible mechanism for patients to initiate detrusor contraction by thigh adduction. External urethra innervation (motor and sensory) may be accomplished by transfer of the vastus medialis nerve to the pudendal nerve. The sensory component of the pudendal nerve to the genitalia may be further enhanced by transfer of the saphenous nerve (sensory) to the pudendal nerve. The main limitations of coapting the nerve donors to their intrapelvic targets are the bifurcation or arborization points of the parent nerve. To ensure that the donor nerves had sufficient length and diameter, the authors sought to measure these parameters.

METHODS

Twenty-six pelvic and anterior thigh regions were dissected in 13 female cadavers. After the graft and donor sites were clearly exposed and the branches identified, the donor nerves were cut at suitable distal sites and then moved into the pelvis for tensionless anastomosis. Diameters were measured with calipers.

RESULTS

The obturator nerve was bifurcated a mean ± SD (range) of 5.5 ± 1.7 (2.0–9.0) cm proximal to the entrance of the obturator foramen. In every cadaver, the authors were able to bring the posterior division of the obturator nerve to the vesical branch of the pelvic nerve (located internal to the ischial spine) in a tensionless manner with an excess obturator nerve length of 2.0 ± 1.2 (0.0–5.0) cm. The distance between the femoral nerve arborization and the anterior superior iliac spine was 9.3 ± 1.8 (6.5–15.0) cm, and the distance from the femoral arborization to the ischial spine was 12.9 ± 1.4 (10.0–16.0) cm. Diameters were similar between donor and recipient nerves.

CONCLUSIONS

The chosen donor nerves were long enough and of sufficient caliber for the proposed nerve transfers and tensionless anastomosis.

Micturition is controlled by a neural circuit involving the brain, spinal cord, inferior mesenteric ganglia, and peripheral nerve plexus that functions to coordinate urine storage and voiding.^1,2 When this circuit is damaged, the patient can develop neurogenic bladder dysfunction.^3,4 This has a variable presentation depending on the location of the injury and its severity. Neurogenic bladder dysfunction can be broadly classified into 2 main types: spastic bladder with detrusor sphincter dyssynergia, which generates high pressures with low volumes and associated outlet obstruction; or flaccid bladder, which results in large volumes and a typically low-pressure system with an incompetent sphincter.

The proposed transfers in this communication are specific to rare injuries that result in loss of all sacral nerve root function with sparing of most lumbar-source nerves. This would occur in cauda equina injuries at the L5–S1 level or with resection of sacral tumors that require sacrifice of the associated sacral nerves. In these clinical cases, a flaccid, lower motor neuron–injured bladder would be the most common scenario. Patients with such bladder dysfunction have increased risk of long-term urological complications, including nephrolithiasis, infection, renal failure, and bladder cancer.^3–5 Modern management of bladder dysfunction includes clean intermittent self-catheterization, urinary diversion via a conduit to the bowel, pharmacotherapy, or use of an indwelling suprapubic or urethral catheter.³ Although these interventions significantly decrease the morbidity related to urinary tract complications, patients experience embarrassment, social isolation, and complications related to these interventions that decrease their quality of life.⁴ In a systemic review of the health priorities of spinal cord injury patients, the top priorities included restoration of bowel and bladder function, restoration of upper-extremity motor function, and recovery of sexual function.⁶

Our goal is to develop surgical solutions that can functionally reinnervate the lower urinary tract in the case of a low injury affecting the sacral nerve roots. We have demonstrated in a canine model that detrusor reinnervation after sacral ventral root transection can be achieved by transfer of a somatic nerve source, such as the genitofemoral, femoral, and obturator nerve branches, to the vesical branch of the pelvic nerve (also known by surgeons in the nerve-sparing literature as the vesical branch of the inferior hypogastric plexus), as evidenced by increased bladder pressure with electrical stimulation of those nerves after transfer.^7–9 Although this results in a hybrid synapse, i.e., a parasympathetic target innervated by somatic cholinergic fibers, both our work and that of others have shown that this provides functional bladder contraction. As expected, a nerve with more motor axons provides a more robust detrusor contraction.⁹ However, the transfer decision must be balanced against the loss of function that may result from sacrifice of the donor nerve. Ideally, a nerve transfer to initiate detrusor contraction would result in minimal lower-extremity functional loss yet drive effective contraction.

Restoration of urinary continence also depends on a functional external urethral sphincter.³ This would require the transfer of a different motor nerve that could provide tonic motor input to the sphincter. This must be a different nerve than that used for bladder reinnervation to avoid cocontraction of the detrusor and sphincters and therefore bladder outlet obstruction. We propose a series of 3 nerve transfers that would result in separate restoration of detrusor and external urethral sphincter muscle function, along with sensory reinnervation of the genital region (Fig. 1).

FIG. 1.

Nerve transfer options—both donors and targets—for bladder reinnervation. Figure is available in color online only.

Our approach utilizes the transfer of motor nerves to restore both bladder emptying (detrusor contraction) and continence (external urinary sphincter contraction), as well as possible transfer of a sensory nerve to further enhance sensation in the pudendal nerve dermatome. First, we propose that transfer of the posterior branch of the obturator nerve to the vesical branch of the pelvic nerve provides a feasible mechanism for patients to initiate detrusor muscle contraction. The vesical branch of the pelvic nerve carries the parasympathetic outflow from the S2–4 nerve roots to the bladder wall and is distinct from the prostatic branch of the pelvic nerve that provides innervation for erection.¹⁰ The obturator nerve provides motor innervation to the medial compartment of the thigh and is largely responsible for thigh adduction.¹¹ It originates in the lumbar plexus with contributions from L2 to L4, bifurcates into anterior and posterior divisions, and then exits the pelvis through the obturator foramen into the medial compartment of the thigh. The anterior branch provides innervation to the adductor longus, adductor brevis, and gracilis muscles, as well as sensation to the distal medial thigh; the posterior division innervates the obturator externus muscle and portions of the adductor brevis and adductor magnus muscles.

There are several functional reasons that this posterior division of the obturator nerve was chosen as the preferred donor for detrusor activation. First, this is a predominantly motor nerve that is near the pelvic plexus. If this nerve is used as the source, the patient would be able to initiate detrusor contraction with sustained adduction of the thigh. This was felt to be more sustainable with typical micturition in a sitting or squatting position. When the posterior division of the obturator nerve is lost, gait is unlikely to be significantly compromised because 1) there are several other lateral rotators of the hip that can be activated in place of the obturator externus and 2) the adductor brevis and adductor magnus are innervated by the anterior branch of the obturator nerve and sciatic nerve, respectively, and can provide the necessary adduction.^12,13

To restore continence, ideally the external urinary sphincter should be reinnervated. The femoral nerve is large with many motor and sensory branches available as nerve transfer donors. The femoral nerve also originates in the lumbar plexus with L2–4 contributions yet exits the pelvis more anteriorly and laterally than the obturator nerve. The femoral nerve passes under the inguinal ligament and arborizes to the target muscles in the anterior compartment of the thigh. Given that there are many anterior compartment muscles that initiate knee extension, selection of a single motor branch is unlikely to dramatically impact gait function. Transfer of the nerve from the vastus medialis (a medial branch of the femoral nerve) to the pudendal nerve target allows for motor innervation of the external urinary sphincter. Of note, the pudendal nerve, prior to its exit from the pelvis, presents as a 2-fascicle nerve, of which 1 fascicle is predominantly motor and the other predominantly sensory. This allows for modality-specific transfer to better target sensory fibers to sensory targets. The sensory components of the pudendal nerve, which branch to become the inferior rectal nerve, perineal nerve, and dorsal nerve of the penis or clitoris, are responsible for innervation of the genitalia. Therefore, these may be restored by transfer of the saphenous nerve to this component of the pudendal nerve. The saphenous nerve is a cutaneous sensory branch originating from the femoral nerve that normally innervates the medial thigh and calf. It is a large sensory nerve with abundant sensory axons and is anatomically convenient for reinnervation of the sensory component of the pudendal nerve.¹⁴ Our considered donors and potential targets for transfer are summarized in Fig. 1.

In our experience, ample distal nerve is available for transfer from the anterior and medial compartments of the leg to pelvic targets.^9,14 If more donor nerve is required, dissection and neurolysis can be continued distally. Ideally, and as we propose, the sensory and motor donor nerves should be nearby to minimize morbidity when harvesting these branches. The branches to the vastus medialis and saphenous nerves both project medially and course through different planes but can be accessed through the same incision. The main limitation to reaching pelvic targets is the bifurcation or arborization point of the parent nerve.

Thus, the objective of this cadaveric study was to assess the anatomical feasibility of nerve transfers from the posterior division of the obturator nerve to the vesical branch of the pelvic nerve, as well as nerve transfers from the vastus medialis branch of the femoral nerve to the pudendal nerve. Therefore, to determine the approximate amount of distal dissection needed to transfer branches of the femoral and obturator nerves, we measured how the nerves coursed through the anterior and/or medial thigh compartments. We measured the location of the proximal arborization points from known bony landmarks to assist with surgical planning. From the arborization points, we measured the distances to fixed intrapelvic bony targets and recipient nerves. In addition, we measured the diameter of each nerve (donor and target) to assess coaptation feasibility.

Methods

In compliance with the St. Louis University School of Medicine and the Practical Anatomy and Surgical Education center policies, human cadavers were made available for dissection by us. Twenty-six pelvic and anterior thigh regions in 13 female cadavers were dissected. Each cadaver was inspected to ensure that the anatomy of the pelvic floor and anterior thigh had not been damaged during preparation. If a region or a cadaver was not intact, it was removed from the cohort.

Careful dissection was performed to expose the nerve, bone, and muscle landmarks. The anterior superior iliac spine (ASIS) and ischial spine (IS) were used as a fixed frame of reference for measurements, external and internal localization, and preoperative planning. The ASIS is a readily identifiable external bony landmark and is useful for incision planning. The IS serves as an external and internal landmark and is immediately proximal to the pudendal nerve and vesical branch of the pelvic nerve.

In each cadaver, dissection began with an anterior pelvic approach to identify the vesical branches of the pelvic nerve, pudendal nerve, obturator nerve, bladder vasculature (including the superior and inferior vesical vessels), and ureter (Fig. 2). Upon locating the important intrapelvic targets, we opened the anterior and medial thigh regions to identify the obturator and femoral nerves and their branches, including the vastus medialis and the saphenous nerves (Fig. 3).

FIG. 2.

A: Illustration of the intrapelvic nerves of interest. The left field of view shows the obturator nerve (dashed red line) and the vesical branch of the pelvic nerve (the red line indicates the axotomy point) in their original positions. The right field of view shows neurolysis of the obturator divisions and reflection for coaptation with the vesical branch (red arrow). B: Intrapelvic dissection of the obturator nerve (pubic symphysis is indicated by the blue arrow). C: Careful splitting of the obturator at the obturator foramen (blue arrow). D: Proximal extension and transection of the posterior division. E: Aligning the posterior division of the obturator nerve adjacent to the ureter bundle with the vesical branch of the pelvic nerve (red vessel loop). F: Size comparison of the obturator nerve (in forceps) with the vesical branch of pelvic nerve (red vessel loop). © Margaret Sten, published with permission.

FIG. 3.

A: Illustration of the donor nerves and landmarks. The dashed lines indicate the measured distances for preoperative planning (ASIS and the greater trochanter of the femur to the femoral nerve arborization) and the distance from the femoral nerve arborization to the intrapelvic coaptation site. B: Key branches of the femoral nerve are color highlighted to correspond with the labeled nerves in panel A. The black dashed line indicates the inguinal ligament. n. = nerve. © Margaret Sten, published with permission.

After the graft and donor sites were clearly exposed and the nerve branches identified, the donor nerves were cut at suitable distal sites and then reflected into the pelvis or perineum. Care was taken to ensure tensionless coaptation between the donor and recipient nerves.

We measured the distance from the obturator canal to the bifurcation of the obturator nerve by using a flexible ruler with centimeter markers (Fig. 2). The posterior division of the obturator nerve was cut at an internal site of the obturator foramen. This division was then carefully neurolysed away from the anterior division, proximally, to enable adequate mobilization and to ensure tensionless repair. This branch was stripped away from the rest of the obturator nerve as far proximally as it would easily separate. We halted dissection after separating these divisions became a little more challenging, and this location was determined to be the site of bifurcation. This freed branch was then reflected toward the IS for measurement. The excess nerve length of the posterior division of the obturator nerve beyond the IS was measured. The posterior division was then brought proximal to the ureter, where the vesical branch of the pelvic nerve emerges from the inferior hypogastric plexus and courses parallel to the posterolateral aspect of the ureter onto the bladder wall (Fig. 2).

We then reflected the femoral branches superiorly and, similar to the procedure for the obturator nerve, allowed these to separate from the main femoral trunk as far as they would easily separate. Once this became less facile, we stopped dissection and determined that this was the point of bifurcation. We then measured the distance from the ASIS and the greater trochanter of the femur to the arborization site. This site marked the point at which we would pivot the selected branches because further neurolysis proximal to this point would be more difficult and potentially cause morbidity in the remaining femoral branches. We then transposed the femoral nerve branches of interest under the inguinal ligament and into the pelvis. To determine how much nerve would be required in the thigh region, we measured the distance from the arborization to the IS within the pelvis (the distance necessary for distal exposure and harvesting). We then moved these branches adjacent to the pudendal nerve trunk at its location within the pelvis just prior to its exit. The diameter of each nerve (donor and recipient) was measured at the site of coaptation with Vernier calipers (model 536-121, Mitutoyo Vernier Pointed Jay Caliper).

Parametric data calculations were performed, including determination of mean ± SD (range) values, with Microsoft Excel.

Results

Confirming our prior observations, the vesical branch of the pelvic nerve and the pudendal nerve trunk were in reasonable proximity to the IS within the pelvic region in all cadavers. The obturator nerve bifurcated a mean of 5.5 cm from the obturator canal entrance (Table 1). The more proximally the obturator bifurcated, the easier it was to bring to the target nerve. The mean amount of excess obturator nerve was 2.0 cm. In every cadaver, we were able to bring the posterior division of the obturator to the vesical branch of the pelvic nerve in a tension-free manner (Fig. 2).

TABLE 1.

Distances measured between nerve branch points and/or bony landmarks

Structure	Value (cm)
ASIS to femoral nerve arborization	9.3 ± 1.8 (6.5–15.0)
IS to femoral nerve arborization	12.9 ± 1.4 (10.0–16.0)
Greater trochanter to femoral nerve arborization	14.5 ± 0.7 (13.8–15.2)
Obturator canal entrance to obturator proximal bifurcation	5.5 ± 1.7 (2.0–9.0)
Obturator length beyond IS after neurolysis & translation	2.0 ± 1.2 (0.0–5.0)
Distance from femoral nerve arborization to distal harvested saphenous nerve	31.1 ± 1.25 (27.9–34.5)

Values are mean ± SD (range).

The distance from the first arborization of the femoral nerve in the anterior thigh to the ASIS was 9.3 cm. The distance from this arborization point to the IS within the pelvis was 12.9 cm. To confirm the potential to progressively dissect and gain donor nerve length, we determined that the length of saphenous nerve available for harvest beyond femoral arborization (31.1 cm) was over twice the length required (12.9 cm) to reach the IS.

The donors and recipient nerve branches had similar diameters, with the largest motor donor being the obturator and the largest sensory donor being the saphenous (Table 2).

TABLE 2.

Nerve diameters (donors and recipients)

Nerve	Value (mm)
Lateral femoral cutaneous nerve	1.8 ± 0.6 (1.0–2.6)
Obturator nerve	2.6 ± 0.8 (1.3–3.9)
Pudendal nerve	2.0 ± 0.1 (1.9–2.1)
Saphenous nerve	2.0 ± 0.7 (1.2–3.1)
Vastus lateralis nerve branch	1.9 ± 0.0 (1.9–1.9)
Vastus medialis nerve branch	1.8 ± 0.4 (1.4–2.3)
Anterior vesical branch of pelvic nerve	2.1 ± 0.2 (1.9–2.3)

Values are mean ± SD (range).

Discussion

This study builds on earlier anatomical feasibility studies with increased consideration for patient recovery and function. We can envision that sustained activation of the donor nerve must be feasible to achieve sustained contraction of the detrusor muscle. In a dog model, we explored the use of a femoral nerve branch as a donor nerve for reinnervating the bladder.⁹ We now realize that a patient would have to initiate knee extension to activate a femoral nerve branch for detrusor muscle contraction, which may prove very tiring and uncomfortable, especially when sitting on a toilet. In contrast, an obturator nerve branch would be activated by adduction of the thigh, which is much more achievable while sitting or standing, and would likely lead to few mobility issues (as described in the introduction). Use of the obturator nerve as a preferred reinnervating motor nerve donor to the vesical branch of the pelvic nerve would have some key advantages. The obturator nerve is a robust source of motor axons, redundantly innervates many medial compartment muscles, has low comorbidity associated with harvesting, and has demonstrated feasibility of activation for voiding and now surgical feasibility in humans (surgical feasibility was already shown in dogs).^7,12 The cumulative nerve transfer proposal is delineated in Table 3.

TABLE 3.

Proposed reinnervation strategy

Target	Terminal Nerve	Nerve Root Origin	Primary Function	Reinnervating Nerve	Nerve Root Origin	Proposed Outcome
Detrusor muscle	Anterior vesical branch of pelvic nerve	S2–4	Contraction of bladder	Posterior division of obturator	L2–4	Bladder contraction w/ thigh adduction
Genital dermatome	Pudendal nerve	S2–4	Somatic sensation	Saphenous nerve	L2–4	Increased sensation
External urinary sphincter	Pudendal nerve	S2–4	Somatic control of external urinary sphincter	Branch to vastus medialis	L2–4	Increased sphincter tone

Common considerations with such transfers are the potential for inadvertent activation with walking. In our preliminary studies, we found that sustained tonic activation is required to generate adequate intravesical pressure. The phasic activation that occurs with walking is unlikely to generate the responses required. Additionally, volitional activation of the external sphincter is typically utilized when the tone of the internal sphincter is insufficient. A patient is unlikely to maintain contraction in this sphincter after nerve transfer. Instead, we hope that this reinnervation would result in improved bulk and tone to the sphincter and therefore provide additional resistance, and that volitional activation would be required only when a full bladder is perceived. This has yet to be demonstrated, as such clinical scenarios cannot be confirmed until they are applied to patients. Finally, sensory transfers typically result in sensation that, at least initially, is perceived in the distribution from which the nerve was transferred. In this case, touching the genitalia would be perceived in the medial thigh and leg. This is typically good for protective sensation, but optimal sexual sensation may not be recovered.

Other important considerations for our reinnervation proposal are time to recovery and bladder rehabilitation. After extent of sacral injury is confirmed by loss of volitional and reflex contractions with urodynamic testing and loss of innervation to the pudendal innervated muscles is confirmed with electromyography, and if the possibility of sacral reinnervation is precluded by the confirmed zone of injury, we would enroll the patient in preoperative planning and ideally complete the transfer within 1 year of injury to limit detrusor atrophy. We have shown the feasibility of providing donor nerves to graft sites in this study, although after coaptation the axons must grow to their distal targets, which could require several months. After the axons have reached their distal targets, bladder rehabilitation would be possible. There may be a significant delay in coordinated contraction until detrusor muscle bulk is recovered. Additionally, detrusor contraction needs to be coordinated with internal and external sphincter relaxation. If there is aberrant innervation and contraction, this may necessitate intervention by urology and gynecology specialists. We envision patients will need significant assistance to tune the tone of their urinary sphincters to match the tone of the detrusor and therefore allow for controlled micturition. We see restoration of genital sensation as a part of bladder rehabilitation and patient function. We hope that providing a primary sensory nerve for growth into the pudendal dermatome may provide patients with increased sensation for feedback about micturition and potentially increased sexual function.

Our study was limited to only female cadavers. We do not expect these measurements to vary considerably between female and male specimens, but we intend to confirm our findings in a small cohort of male cadavers.

Conclusions

Our proposed transfers were technically feasible, with adequate donor length to ensure tensionless coaptation. The main limitation to achieving tensionless coaptation is the distance from the arborization or split point to the recipient nerve. Thus, our approach focused on measuring the constraining features of nerve transfers. This was more important for obturator nerve branch transfer than for either donor branches from the femoral nerve, for which we need only to extend the exposure and harvest more distally to obtain sufficient length. Our proposed nerve transfers allow for reinnervation of several components of the micturition pathway and directly address the quality-of-life issues that patients most frequently have. We hope that considering these functions as part of a surgical feasibility assessment will allow for a more complete clinical translation.

Acknowledgments

Drs. Johnston and Bazarek received support from NREF. Drs. Barbe and Ruggieri received support from NIH (no. 1R21NS123206).

Disclosures

Dr. De is a consultant for Laborie Medical Technologies, Luca Biologics, Consumer Medical/Alight, Glycologix, and Cambridge Medical Experts; owns stock in ERYP and Doximity; and receives non–study-related clinical or research support from NIDDK.

Author Contributions

Conception and design: Brown, Johnston, De, Lemos, Ruggieri, Barbe. Acquisition of data: Brown, Johnston, McIntyre, De, Lemos, Ruggieri, Barbe. Analysis and interpretation of data: Brown, Johnston, Bazarek, McIntyre, De, Lemos, Ruggieri, Barbe. Drafting the article: Brown, Johnston, Bazarek, Sten, McIntyre. Critically revising the article: Brown, Johnston, Bazarek, Sten, McIntyre, Fine, De, McGovern, Ruggieri, Barbe. Reviewed submitted version of manuscript: Brown, Johnston, De, McGovern, Ruggieri, Barbe. Approved the final version of the manuscript on behalf of all authors: Brown. Statistical analysis: Brown, Johnston, Barbe. Administrative/technical/material support: Brown, Johnston, Lemos, Ruggieri, Barbe. Study supervision: Brown, Johnston, Ruggieri, Barbe.