Targeted muscle reinnervation in the lower extremity

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Introduction

Targeted muscle reinnervation (TMR) is a nerve transfer of a proximal nerve, either mixed or sensory, into a distal motor nerve. Initially described by Dumanian and Kuiken, TMR was first used to help gain more dynamic and intuitive control over upper extremity myoelectric prosthetics. These first cohorts of patients were incidentally found to have decreased neuroma pain and phantom limb pain (PLP). TMR in the lower extremity is currently most commonly used to prevent or treat symptomatic neuromas and PLP after amputation. While still poorly understood, some studies have demonstrated how TMR can restore normal cellular morphology in the peripheral nervous system (PNS) as well as restore cortical mapping in the central nervous system (CNS). Preventing or minimizing pain in patients with lower extremity neuromas or major limb amputations is critical to maximizing physical functional ability. While functional TMR has not been employed in the lower extremity compared to the upper extremity because of the disparity in complexity of prosthetics, in the future TMR could allow for more advanced knee and ankle joint control of prosthetics.

This chapter will describe indications, workup, technical principles, operative techniques, and outcomes for TMR in the lower extremity.

Physiology of targeted muscle reinnervation

After the initial proximal and distal axonal degeneration following a nerve injury, any proximal discontinuous axons will sprout in an attempt to reinterface with the more distal axonal tract. When the sprouting axons connect to a distal segment or target organ, neurotrophic factors are released that result in pruning of the excess axons and cessation of the axonal sprouting. In cases where sprouting axons fail to reach a target or become trapped in surrounding scar tissue, the axons will continue to sprout and create a neuroma. In some patients, these neuromas can become quite symptomatic, causing severe, radiating pain in the distribution of the nerve. In patients with amputations, the neuroma may be a peripheral origin for PLP. Neuromas are not the exclusive cause of PLP, as PLP likely results from pathology in both the CNS and PNS, though its mechanism is still poorly understood.

Dumanian et al . demonstrated that the involved axons in a neuroma are sensory, not motor, axons. This finding is consistent with the finding that motor nerves do not form symptomatic neuromas at the donor site when performing free muscle flaps. TMR therefore focuses on isolating the involved sensory axons and providing them a new continuous circuit to prevent the maladaptive axonal sprouting process causing pain.

With TMR, the affected sensory or mixed nerve is freshly cut to healthy axons and then interfaced with a willing distal motor nerve. The donor motor nerve is completely transected to create a denervated muscle, willing to accept reinnervation. This is why TMR transfers are best performed in an end-to-end fashion as opposed to an end-to-side fashion. Once interfaced, the axons of the sensory or mixed nerve regenerate and form connections with the motor end plates and sensory organelles within the muscles to provide axonal continuity once again.

Dumanian et al . demonstrated in a rabbit model that TMR restores near-normal axon count, size, and degree of myelination in the sensory nerve, and that muscle function persists in the donor motor nerve in 95% of transfers. In addition to potentially causing more normal neural cytoarchitecture, TMR has been demonstrated with an fMRI study to minimize the maladaptive cortical reorganization that may contribute to PLP following a major extremity amputation. TMR, clinically, appears to work despite large axonal mismatches between recipient and donor nerves, even though there are no dedicated studies to support this. One theory is the new axonal continuity of some of the sensory axons may induce axonal pruning of the surrounding discontinuous sensory axons. Another theory is the large area of surrounding denervated muscle from the more proximal transection of the motor nerve creates multiple motor units willing to accept new innervation, similar to the mechanism of an RPNI.

In amputees, the newly reinnervated target muscles create new end effectors for the more proximally cut peripheral nerves. With the appropriate myoelectric prosthetic, these surface signals can be detected, amplified, and then translated for more advanced volitional control of prosthetics. This has mostly been done with the currently more advanced upper extremity prosthetics but could similarly be applied to lower extremity prosthetics in the future.

Indications for targeted muscle reinnervation in the lower extremity

There are three primary indications for TMR in the lower extremity: (1) primary prevention of development of symptomatic neuromas and PLP in patients undergoing an amputation; (2) secondary management of symptomatic neuromas and/or PLP in patients with an existing amputation; and (3) adjunctive management to surgical excision of symptomatic neuromas. As myoelectric prosthetics in the lower extremity catch up to those made for the upper extremity, one may see a greater role of TMR in enhancing patients’ use of more advanced and active prostheses.

All patients undergoing primary major lower extremity amputations should be considered candidates for primary TMR. The only contraindication is if the patient is critically ill, requiring intensive preoperative monitoring, such that any additional time under anesthesia places the patient at undue risk. TMR can be performed primarily at the time of amputation in patients undergoing an amputation for limb-threatening ischemia and/or infection. One should discuss the possibility of surgery under sedation with perineural catheters with the patient, anesthesia team, and amputation team. Patients with lower extremities that preoperatively are completely paralyzed and insensate, such as from a spinal cord injury, have limited benefits from TMR. Patients, both amputees and non-amputees, with evidence of a symptomatic neuroma and/or PLP in the distribution of a named nerve should be considered candidates for TMR. Careful preoperative physical examination and diagnostics should be conducted to make sure there are not other causes of the patient’s pain and to be evaluated for evidence of CRPS and/or centralization of the patient’s peripheral nerve pain.

General concepts and principles

Certain guiding principles should be followed when performing TMR nerve transfers to optimize functional outcomes and limit donor site morbidity. These are similar to described principles of nerve and tendon transfers.

Expendable motor target

Motor nerve transection will lead to loss of function in at least a portion of the affected muscle, and therefore motor targets must be carefully selected to minimize loss of function. In amputees, the muscles lose their native function and instead function primarily to provide soft-tissue padding over the bony stump. Motor targets to muscles that are smaller in caliber and contribute less to soft-tissue padding should be preferentially selected. For example, smaller, deeper muscles like the extensor digitorum longus (EDL) and tibialis posterior (TP) should be chosen over muscles like the tibialis anterior (TA), gastrocnemius, and soleus, which are more critical in maintaining optimal peritibial padding. In non-amputees, one should consider choosing a neuromuscular unit donor that provides a less critical function. For instance, preserving the TA – the primary ankle dorsiflexor – is preferred over preserving the EDL, which is a much weaker ankle dorsiflexor, and loss of toe extension is better tolerated. If one has to use a more critical motor nerve, one should ensure that muscle has redundant proximal innervation or perform an intramuscular dissection to use just a branch of the motor nerve, preserving the rest of the muscle’s function.

Anatomic feasibility of transfer

The proximal nerve and the distal motor target must be within close enough proximity to allow for a tension-free coaptation. If possible, it is advantageous for the motor target to be in the same anatomic compartment as the proximal nerve to avoid scarring and entrapment from crossing fascial planes or septae. When performing a TMR transfer on a superficial nerve, it is important to transpose the nerve subfascially and release the fascia at the transition point to prevent the development of an entrapment site. For instance, the saphenous and sural nerves are superficial to fascia at the level of a below-knee amputation (BKA), and these nerves either need to be accessed distally and transposed subfascially or accessed more proximally where they are subfascial.

Axonal capture

A motor target with an adequate size match to the proximal nerve is rarely available in TMR nerve transfers. This has not been associated with worse outcomes, as some axonal continuity at the coaptation site may cause the release of neurotropic factors that may suppress the surrounding discontinuous axons from sprouting. However, there are methods to overcome this size mismatch and prevent “axonal escape” from the proximal nerve stump. Both recipient and donor nerves should be sharply cut to healthy nerve fascicles, and the nerves can be cut to preserve a larger cuff of epineurium relative to the encased axons. Properly placed epineurial sutures and use of fibrin glue can help direct the axons of the larger sensory or mixed nerve down the sheath of the donor motor nerve. If there is a significant size mismatch at the TMR site, the entire coaptation can be anchored to the muscle at the target neuromuscular junction, which surrounds the coaptation with muscle for any escaping axons to embed into. This technique can be augmented by elevating a flap or completely free graft of muscle to wrap around the coaptation to provide a TMR and regenerative peripheral nerve interface (RPNI) dual effect.

Nerve transposition with proximal transfer

When possible, the sensory/mixed nerve should be transposed proximally to allow for relocation of the nerve transfer away from the contact surface. This is especially important when performing TMR in amputees. Even with a perfect nerve coaptation or direct repair after injury, a painful Tinel is often felt at the repair site, which for amputees can be particularly painful and prevent optimal use of their prosthetic.

Maintain proximal nerve function

TMR transfers should be performed at a level that maintains the nerve’s more proximal functions. For example, the sural nerve provides lateral foot and ankle and the majority of posterior leg sensation. Performing a very proximal transfer sacrifices posterior leg sensation, which is the critical, weight-bearing portion of a BKA stump in most posterior-based BKA flaps. In non-amputees, patients have to understand that they are choosing a chance of lesser pain in exchange for permanent numbness in that nerve’s distribution.

Evaluate proximal compression points

Known proximal compression points of the involved nerve should be assessed for signs of clinical entrapment. The double-crush phenomenon describes the finding that nerves of pathology at one anatomic location may be predisposed to having pathology at another location. This risk increases in patients with systemic peripheral neuropathies such as diabetic polyneuropathy. For example, patients with superficial peroneal nerve (SPN) neuromas should be evaluated for common peroneal nerve (CPN) compression at the fibular head.

Targeted muscle reinnervation in primary amputations

Overview

TMR should be offered to all patients undergoing major lower extremity amputations above the ankle. Physiologically addressing the major sensory and mixed nerves at the time of amputation prevents or minimizes severity of pain secondary to symptomatic neuromas and PLP. Primary prevention or minimization of pain may help prevent centralization of chronic pain and/or development of chronic regional pain syndrome (CRPS), both of which tend to linger when TMR is performed secondarily for stump neuromas and/or PLP. Patients undergoing an amputation for any reason – trauma, oncologic resection, ischemia, infection, etc. – are all candidates. The previous notion that patients with diabetes and/or vascular disease do not benefit in the same way is incorrect. In the future, TMR may enable more advanced myoelectric prosthetics, as it has in the upper extremity.

Perioperative evaluation and multidisciplinary care

As discussed in Chapter 6.1 , patients should be counseled preoperatively about the risks and benefits of TMR. It is important to counsel patients that, while TMR has been demonstrated to reduce frequency and severity of residual limb pain (RLP) and PLP, patients should still expect some degree of pain post-amputation. There are some risks specific to TMR. A usable motor target may not be identified in all cases, causing one to resort to more traditional traction neurectomy and muscle implantation. The TMR transfer may not work, and a symptomatic neuroma and PLP may still develop.

The importance of coordinating with the surgeons performing the amputation and the anesthesiologist cannot be understated. If one is not the surgeon performing the amputation, it is important to be willing to share block time and/or be readily available to perform the TMR once the osteotomies are completed. Preoperative indwelling nerve catheters are crucial in helping block the immediate central pain experience of the nerve transections and to allow surgeries to be performed under regional anesthesia in comorbid patients.

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