Mr Muhammad Adeel Akhtar
BSc, MBBS, MRCSEd, Dip SEM (UK), PG Dip CAOS, MD (Res), MFCI, MFSEM, MFSTEd, FFSTEd, FEBOT, FRCSEd (Trauma & Orthopaedics)
Consultant Trauma and Orthopaedic Surgeon with Special interest in Lower Limb Arthroplasty, Arthroscopy, Trauma and Sports Injuries, NHS Fife.
Honorary Clinical Senior Lecturer, Deanery of Clinical Sciences, College of Medicine & Veterinary Medicine, University of Edinburgh.
Honorary Clinical Senior Lecturer, School of Medicine, University of St Andrews.
Ethan Gilmour
BSc, Medical Student, St Andrews University, Scotland.
Background
Amputees may experience chronic pain that limits their use of prostheses and affects their quality of life (1). Pain may be experienced in the residuum or in the amputated limb as phantom limb pain. It is thought to be caused by a complex interaction of multiple factors such as abnormal activity of severed nerves and restructuring of the cortical representation of the limb (2).
Pain in the residuum may be due to the nerves severed during amputation. When nerves are severed, the ends attempt to repair the damage by growing towards each other. In the case of amputation, loss of the distal limb results in the presence of only one severed nerve ending. This causes the growth to be directionless and disorganised, which results in the formation of a neuroma. Neuromas consist of scar and nerve tissue formed into a cluster at the severed nerve ending. Neuromas may cause intense pain either spontaneously or in response to a stimulus. The traditional treatment has been to excise the neuroma and then bury the nerve end deep in muscle or bone tissue (1).
Targeted muscle re-innervation.
Targeted muscle re-innervation (TMR), reported by Dumanian in 2002(1), is a procedure that can be carried out at the time of amputation or osseointegration (2). TMR was initially performed to allow increased prosthesis control, primarily in shoulder disarticulations and above elbow amputations (2). The procedure involves the connection of severed mixed or sensory nerves onto motor nerves. The nerves and target muscles involved differ depending on the level of amputation. In the upper limb, the median, ulnar and radial nerves (3) can be transferred.
An important consideration when identifying target muscles is whether the muscle is superficial or deep, as this affects the strength of signal detected by surface electromyography (sEMG). These signals may be detected, measured and used to control prosthetic limbs (myo-electric prostheses).
A second consideration is the level of function of the muscle, as the removal of normal motor innervation causes any residual function to be lost. Muscles severed during amputation are the most appropriate targets (4).
The transfer distance should be kept to a minimum to reduce tension on the nerve.
The target muscle can be divided to give more separate motor units providing an increased number of muscle signals for electromyography. An example of this is Biceps Brachii which can be divided into its medial and lateral heads. When this is performed an adipo-fascial flap can be incorporated as a physical barrier to reduce cross talk between muscle groups and provide clearer signals for electromyography (3).
TMR can also be used for the treatment or prevention of neuromas (1,5,6). This intervention is based on the premise that attaching the cut nerve end to a motor unit may prevent abnormal re-growth and neuroma formation. A common phrase summarizing this is “somewhere to go and something to do”.
The following are the principles of TMR. Any neuromas present should be excised before transfer. The previous innervation to the muscle is severed, to prevent multiple innervations and disrupted signals for electromyography. The proximal stumps of any motor nerves are buried in muscle tissue to avoid neuroma formation. The distal stump of the previous nerve to the muscle is the transfer target, and the nerve is joined directly onto it.
Once TMR has been carried out, the patient undergoes rehabilitation to train voluntary, specific, repeatable contraction of the newly innervated muscle which will improve the ability to use myo-electric prostheses. It takes between 3 and 6 months for the muscles to become fully re-innervated, and for EMG signals to be detectable (7,8).
Once this has been confirmed the patient can be fitted with a more advanced prosthesis for maximum functionality (4). Following TMR it has been observed that the remaining sensory nerve fibres begin to reinnervate the skin overlying the new innervation site (4). It has been hypothesised that this may allow for the transfer of sensory stimuli from prosthesis to these reinnervated areas by means such as haptic feedback (i.e via the sense of touch). Another method which has been investigated for transfer of sensation is surgically implanting electrodes on the distal ends of sensory nerves to allow for direct stimulation of the nerve (9).
Literature Review.
Since its inception in 2002, the utilization of TMR has expanded for increasing the number of available signals for electromyography. TMR has been carried out at a variety of amputation levels, either for EMG signal creation, treatment and prevention of neuromas, or both.
Salminger (10) published the results of 30 patients with either transhumeral amputation or shoulder disarticulations. After a mean follow up of 5.3 years, patients were assessed using 3 functional outcome measures, namely the Action Research Arm Test, Southampton Hand Assessment Procedure, and the Clothespin-relocation test. They reported viable EMG signals were present in all patients at follow up, with prosthesis use being between 3 and 10 hours per day in a sub-group of 10 of the 13 patients fitted with a prosthesis. Functional measures were only performed pre-operatively in 2 patients for comparison, and while they showed improvement, the small number of patients and lack of comparison for other patients limits the validity of any conclusions. Interestingly, despite 11 patients’ main indication for TMR being neuroma pain, no results on post-operative pain were reported. The reason for this is not discussed, which raises potential concerns about reporting bias. This study also reported an abandonment rate of 32% for the rehabilitation programme, so a potential target for future research could be to identify areas where the programme can be modified to make the process easier. The study also identified prosthetic factors to be a major reason for abandonment. The utility of the prosthesis & improvement of function is vital to continued usage.
A randomised control trial investigating TMR was carried out by Dumanian et al. (6). This trial included 28 patients with both upper and lower limb amputations presenting with chronic pain. It compared the effectiveness of TMR for reducing both residual and phantom limb pain with the standard care protocol (neuroma excision and burying). Patients were blinded to treatment for 1 year until follow up. In the case of persisting pain in controls, patients were then offered TMR.
Assessment used a 0-11 pain scale and PROMIS forms for pain intensity, behaviour, and interference. The results after 1 year follow up showed trends in favour of TMR for both residual and phantom limb pain, but statistical significance was not achieved. However the change in TMR patients was above the level of clinical importance therefore still demonstrating effectiveness. At the final follow up, 72% of patients who received TMR reported mild or absent phantom limb pain, whereas only 40% of the control group reported this. For residual limb pain the percentages were 67% and 27% for TMR and control populations, respectively. Function was also assessed using the Neuro-Quality of Life for lower limb amputees, which resulted in lack of difference at 1 year but showed improvement in score at the last follow up time point when crossover patients were included.
This study is limited by the number of patients, though this was reported to be due to issues with patient recruitment for randomisation. The study benefits from the randomised control trial design, which improves the validity of the results, as well as the clinical relevance. The follow up period is also acceptable; however, it would be useful to investigate the effects of TMR over a longer period.
Multiple studies reporting outcomes for both concurrent and delayed TMR (7,8), have reported patients experiencing phantom limb pain in the post-operative period but mainly resolving after 3-6 months. Bowen et al. (7) presented the results of 22 patients who received TMR either concurrent to amputation (18) or delayed (4). This study correlated the timeframe of this phantom pain with the time before muscle twitches appear in re-innervated muscles at 3 months, suggesting a potential causal relationship. However, due to a small sample size, further research is required to determine whether this is a consequence of the TMR physiological process or the surgical procedure itself. Despite this lack of certainty of a cause, the short clinical duration before resolution in most patients, suggests this is unlikely to be a significant issue or contraindication to the procedure but should be included in pre-operative counselling.
Both Pierrie et al.(11) and Michno et al.(8) reported voluntary contraction with detectable EMG signals present between 3 and 6 months post-operatively, reporting on 1 bilateral upper and lower limb amputee treated concurrently and 11 patients treated with delayed TMR, respectively. Both also reported that patients experienced either an absence of pain or a lessening of severity. Of the 11 patients reported in the Michno article, 5 continued to experience neuroma related pain due to untreated neuromas being discovered later. This suggests that there is room for improvement in the pre-operative assessment procedure to prevent any neuromas from being missed, and thus eliminating the need for a second TMR operation.
Alexander et al. (2) reported on 31 oncologic amputees treated for prevention of pain with concurrent TMR, which represents the largest single TMR population in this report. The control group consisted of 58 amputees, in whom amputation was also carried out for oncological reasons. The control group was acquired from a survey which allowed the authors to match indication for amputation for the control group, however it also introduces a risk of bias, and uncertainty as to the level of true representation of the population of oncological amputees. Results were compared after a minimum of 1 year follow up and 4 of 6 neuroma showed improvement in symptom frequency and severity. Significant improvements were also reported in assessed PROMIS measures for both residual and phantom limb pain in the TMR group, when compared with the control group. A secondary outcome was a comparison of pre- and postoperative opioid use which also showed an improvement, with a reduction of patients using opioids from 56% pre-operatively to 26%, then 22% at 3 months and 1 year follow up, respectively. The authors also found an opportunity to improve their protocol, as they discovered that in 2 patients pure sensory nerves formed neuromas which led to re-operation. Since this finding they have included sensory nerves in TMR procedures. These sensory neuromas may also be the cause of the neuromas found in the study by Michno et al. (8) thus suggesting that this may be a notable advance in preventing recurrence of symptoms and reducing the need for secondary TMR.
TMR with muscle transfer.
Muscle transfers can be utilised in conjunction with TMR to provide additional targets if there are insufficient number of viable muscles for EMG to provide ideal control of a myo-electric prosthesis. Lu et al. (12) detailed their technique for performing a serratus anterior transfer for use with TMR and presented the results of a procedure carried out in a trans-humeral amputee. Individual sections of the muscle are isolated and transferred along with their respective neuro-vascular pedicle to the residuum. They are then sutured in place and a peripheral nerve is attached. Due to a lack of method for patient recruitment and the inclusion of only a single patient, this paper suffers from a significant risk of bias, however its main aim was to present the technique and it is likely that future research will be carried out to provide more robust evidence for adaptation of this technique. This procedure is designed for a specific subset of patients who otherwise could not achieve the same number of EMG signals.
Conclusion.
Most of the papers reporting the outcomes of TMR are limited by the small population size and low evidence level, suggesting a high risk of bias. Despite these limitations, these articles independently concluded that TMR was an effective treatment option. TMR represents a new method of treating neuroma and phantom limb pain.
Previous methods have attempted to minimise the symptoms of neuroma rather than giving the damaged nerves something useful to do again. TMR on the other hand gives the transferred nerves a distal target and a purpose. It is hoped that disorganised growth, and neuroma formation can be prevented. An increase in EMG signal quantity and quality may reduce prosthesis abandonment by increasing the function of myoelectric prostheses.
TMR may prove to be a significant advance in the management of amputee rehabilitation. It has the potential, should enough evidence and acceptance be accrued, for concurrent TMR to become part of the standard treatment plan for amputation; and for delayed TMR to become the standard treatment for neuromas or phantom limb pain.
References
- Chappell AG, Jordan SW, Dumanian GA. Targeted Muscle Reinnervation for Treatment of Neuropathic Pain. Clin Plast Surg. 2020;47(2):285-93.
- Alexander JH, Jordan SW, West JM, Compston A, Fugitt J, Bowen JB, et al. Targeted muscle reinnervation in oncologic amputees: Early experience of a novel institutional protocol. J Surg Oncol. 2019;120(3):348-58.
- Mioton LM, Dumanian GA. Targeted muscle reinnervation and prosthetic rehabilitation after limb loss. J Surg Oncol. 2018;118(5):807-14.
- Morgan EN, Kyle Potter B, Souza JM, Tintle SM, Nanos GP, 3rd. Targeted Muscle Reinnervation for Transradial Amputation: Description of Operative Technique. Tech. 2016;20(4):166-71.
- Lanier ST, Jordan SW, Ko JH, Dumanian GA. Targeted Muscle Reinnervation as a Solution for Nerve Pain. Plast Reconstr Surg. 2020;146(5):651e-63e.
- Dumanian GA, Potter BK, Mioton LM, Ko JH, Cheesborough JE, Souza JM, et al. Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees: A Randomized Clinical Trial. Ann Surg. 2019;270(2):238-46.
- Bowen JB, Ruter D, Wee C, West J, Valerio IL. Targeted Muscle Reinnervation Technique in Below-Knee Amputation. Plast Reconstr Surg. 2019;143(1):309-12.
- Michno DA, Woollard ACS, Kang NV. Clinical outcomes of delayed targeted muscle reinnervation for neuroma pain reduction in longstanding amputees. J Plast Reconstr Aesthet Surg. 2019;72(9):1576-606.
- Ortiz-Catalan M, Mastinu E, Sassu P, Aszmann O, Branemark R. Self-Contained Neuromusculoskeletal Arm Prostheses. N Engl J Med. 2020;382(18):1732-8.
- Salminger S, Sturma A, Roche AD, Mayer JA, Gstoettner C, Aszmann OC. Outcomes, Challenges, and Pitfalls after Targeted Muscle Reinnervation in High-Level Amputees: Is It Worth the Effort? Plast Reconstr Surg. 2019;144(6):1037e-43e.
- Pierrie SN, Gaston RG, Loeffler BJ. Targeted Muscle Reinnervation for Prosthesis Optimization and Neuroma Management in the Setting of Transradial Amputation. J Hand Surg [Am]. 2019;44(6):525.e1-.e8.
- Lu D, Myers H, Bruscino-Raiola F. Pedicled Serratus Anterior Flap as an Alternative Muscle Target for Targeted Muscle Reinnervation in Transhumeral Amputees. J Hand Surg [Am]. 2019;44(11):997.e1-.e6.