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Peripheral nervous system surgery: Travelling through no man's land to new horizons
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.250732
Contemporary peripheral nervous system (PNS) surgery is only an intermittent stop between the past and the future.[1] The times are changing, and so are the pathogenesis and management of peripheral nerve injuries and diseases.[2],[3] Not only is our understanding and knowledge of these injuries and diseases broader and more profound, but their patterns, mechanisms and extent have also changed, leading to a different distribution of these ailments in populations, and even to different syndromes.[4] Many factors have influenced this development through time, and there are still other factors in sight, awaiting their time to be considered as being influential in determining the outcome of peripheral nerve surgery. Hence, progress in the development of repair methods and techniques continues in an unrestrained fasion. In order to achieve mastery, it is essential to assess the accumulated experiences of the past, adhere to modern recommendations, implement all the available technical advances, and embrace upcoming prospects and challenges.
The beginnings Peripheral nerve surgery dates back to the times of Hippocrates, who was the first to mention nerve injuries, instructing his pupils not to overstretch the arm when treating dislocation, in order to avoid nerve injury. Hippocrates never mentioned nerve repair in his known works. However, in the book, “Wonders of Surgeons”, Surgeon Ibrahim quoted the words of Hippocrates that were related to the first nerve repair: “When the caravan I travelled together with stayed overnight on the bank of the Tigris River, a thief attempted to steal a horse. However, the owner of the horse stabbed him in the leg and caused splitting of a nerve over the ankle region. Upon encountering the accident, I cleaned off the wound and applied bandage at proximal and distal sides. I pin-pointed the two cut ends of the nerve and united them by using a woman's hair as suture material and then I closed the wound. However, although the man did not limp while walking, a lump persisted in the wound.”[5],[6] Galen of Pergamon, one of the most accomplished medical researchers of antiquity, who significantly influenced the development of neurology, distinguished between motor nerves (issuing from the anterior parts of the brain) and sensory nerves (issuing from the posterior brain regions). Regarding nerve repair, he concluded that repair of a severed nerve might lead a patient to develop epilepsy, and therefore, he discouraged nerve repair unless it was absolutely necessary. Galen was one of the first to transect a nerve to assess the result. He sectioned the recurrent laryngeal nerve in oxen and pigs and recognized that hoarseness was a consequence of this action.[7] Avicenna was the first to recommend epineural end-to-end anastomosis with sutures. Gabriele Ferrara was the first to describe suturing of the stumps of a transected nerve as well as the nerve-end dissection technique, with a detailed portrayal of the equipment that he used for conducting peripheral nerve surgery.[8] The potential of a nerve to regenerate was first indicated by William Cumberland Cruikshank in 1776. He cut a section from the vagus nerve of dogs and after some weeks found what he believed to be a new growth of the nerve filing in the gap. His manuscript, however, was neglected by the Royal Society until 1795, when the paper was finally published.[9] Early development Since the second half of the nineteenth century, a body of literature on nerve regeneration and nerve repair strategies began to accumulate, starting with the milestone observations of Augustus Waller in 1850.[10] Waller described for the first time the progressive axonal disorganization, occurring downstream to nerve transection and also involving the myelin sheaths of Schwann. Paget, in 1947, was the first to report functional recovery after primary repair of the median nerve in a young patient. There were also attempts to use autografts, as well as tubularized bones in the past, although these did not result in functional improvements in humans.[10] Nerve transfers, also referred to as “neurotization”, were introduced by Tuttle in 1913 and popularized by Narakas three decades ago. Nerve transfers have since been the primary mechanisms for repair in brachial plexus (BP) avulsion injuries.[11],[12]
“The art in the skill and the skill in the art” The development of brachial plexus surgery, with the help of neurophysiological diagnostic procedures and intraoperative monitoring, has led to better approaches and techniques, especially with regard to nerve transfers and grafting procedures. With advancements in the surgical management, in the recognition of importance of cortical plasticity, and in motor-re-education and perioperative rehabilitation, nerve transfers have been resulting in improved functional outcomes in patients with nerve injuries.[13],[14] The Oberlin and Somsak procedures are important nerve transfer procedures for ensuring proximal brachial plexus repair, especially when double and triple transfers are used. Asian authors have, in addition, often favored the contralateral C7 transfer.[13],[15] There are also advanced graft repair procedures that use viable proximal nerve stumps as donors. These procedures allow for the restoration of priority functions – elbow flexion and shoulder abduction (the latter provides stability), although their results are usually inferior to nerve transfers.[16] Artificial grafts and conduits Ongoing discoveries in neuroscience and biomaterial engineering hold promise for the development of allografts and conduits. They have the potential for surpassing nerve autografts in clinical efficacy.[17] Artificial nerve conduits have emerged as an alternative to autologous nerve grafting for the repair of short-segment peripheral nerve defects. However, the clinical results are inferior in comparison to that obtained with autologous nerve grafts. Understanding the complex biological reactions that take place during peripheral nerve regeneration will allow researchers to develop a nerve conduit with physical and biological properties similar to those of an autologous nerve graft that supports nerve proliferation and stimulates the regeneration in both short and long nerve defects.[18] Permeability, flexibility, strength, fabrication design, lumen diameter, and the internal frame- work, influence the quality of synthetic nerve conduits. The permeability of the conduit allows the supportive cells to acquire nutrients and oxygen. Different techniques such as cutting holes in the walls, fiber spinning, rolling of meshes, and adding sugar or salt crystals have been utilized to make the conduits permeable.[18] There is also a possibility for improvement in the outcome with the use of cell therapy (Schwann cells, olfactory ensheating cells or stem-cells) in addition to the addition of conduits.[19] Composite photocross-linkable gelatin/tropoelastin hydrogel adhesives were developed from the two naturally derived polymers, gelatin-methacryloyl and methacryloyl-substituted tropoelastin. Mechanical properties exhibited by the materials are tunable by varying their ratio. In addition, composite hydrogels exhibited a 15–fold higher adhesive strength to nerve tissue ex vivo compared to fibrin controls. Furthermore, the composites were shown to support essential cellular components for nerve regeneration (including Schwann cell viability and proliferation, neurite extension and glial cell participation) in vitro. This phenomenon showed that the composites may be used as clinically relevant biomaterials to regenerate nerves and reduce the need for microsurgical suturing during nerve reconstruction.[20] Augmentation of regeneration The peripheral nerve exhibits a much larger capacity for regeneration than the structures of the central nervous system. The glia surrounding the peripheral nerve respond rapidly to nerve injury by clearing debris from the injury site, supplying essential growth factors and providing structural support, all of which enhances neuronal regeneration.[21] Phototherapy Laser phototherapy was applied as a supportive factor for accelerating and enhancing axonal growth and regeneration after injury, or after a reconstructive peripheral nerve procedure. Results of the experimental study on denervated muscles suggest that laser treatment can restore function of the peripheral nerve to a substantial degree, when initiated at the earliest possible postinjury stage.[22] These findings could have direct therapeutic applications on preserving the function of denervated muscle after a peripheral nerve injury.[23] Electrical stimulation Electrical stimulation has the ability, as shown both in animal and in human experiments, to accelerate substantially axon outgrowth from the proximal to the distal nerve stumps, so that muscle reinnervation occurs significantly earlier. Low-intensity electrical stimulation has been shown to improve nerve regeneration, probably due to an increased production of brain-derived neurotrophic factors (BDNFs) and neural growth factors, and a subsequent enhancement of myelin production. This method may be complemented with specific exercise to further improve nerve regeneration or muscle preservation.[24] There are also other methods to stimulate nerve regeneration; however, these have not attained significant clinical benefits so far.[25] Quality of life: Beyond useful functional recovery The majority of studies in the literature focus solely on motor recovery when reporting on outcome after surgery for brachial plexus injuries. However, during recovery, the individuals who have undergone surgery often go through a mentally, physically, and emotionally challenging process, including the occurrence of pain, scarring, and the inability to perform routine tasks. Satisfactory motor recovery is only a check-point in the overall outcome, while these patients remain disabled.[14] Only a few studies dealt with quality of life, functional outcome, pain, and the patients' satisfaction. To this end, it is important to consider not only muscle strength, but also other aspects of recovery, to develop specific methods to assess every aspect, in order to understand the whole effect of a brachial plexus injury, as well as to treat every patient individually and learn the effects of surgical treatment on all aspects of recovery.[14] Limitations Lack of evidence-based guidelines and randomized controlled trials Peripheral nerve surgery lacks evidence-based recommendations, probably due to the limited number of these cases, as well as due to the lack of a systematic approach and unity in order to perform randomized controlled trials in the field.[26] The recommendations applicable to peripheral nerve surgery are based on rather small-scale studies, performed on a limited number of patients. Surgeons therefore, strongly favor an individualised approach and patient specific surgery in order to reach the best possible results.[26] Due to the restricted number of patients, even the industry financed trials are small case series or in-vitro and animal models; there are only limited clinical experiments.[3],[27] Hand function restoration Brachial plexus injuries affect the hand function in different ways. Deficits may resemble those of a radial nerve palsy or those of an associated, high medio-ulnar paralysis. A related analysis shows that active extension of the wrist is paramount in all procedures to gain quality results.[28] Brachial plexus palsies of C7-T1 result in the complete loss of hand function, including finger and thumb flexion and extension as well as intrinsic muscle function. The task of reanimating such a hand remains challenging, and so far, there has been no reliable neurological reconstructive method for restoring hand function.[29] The authors aimed to establish a reliable strategy to reanimate the paralyzed hand. Two patients had sustained C7-T1 complete lesions. In the first stage of the operative procedure, a supinator motor branch to posterior interosseous nerve transfer was performed with brachialis motor branch transfer to the median nerve to restore finger and thumb extension and flexion. In the second stage, the intact brachioradialis muscle was used for abductorplasty to restore thumb opposition. Both patients regained good finger extension and flexion. Thumb opposition was also attained, and the overall hand function was satisfactory. The described strategy proved effective and reliable in restoring hand function after the C7-T1 brachial plexus palsies.[29] Neuropathic pain and painful syndromes Along with a partial or complete loss of sensory and motor function, peripheral nerve injury may be followed by various pain syndromes. Pain may be limited to the sensory distribution of the injured nerve or may have a more diffuse character, gradually spreading in a non-segmental distribution.[30] The mechanism of painful nerve injury is frequently related to laceration, drug injection, iatrogenic damage, contusion, compression, or traction, whereas missile-caused trauma is a rare cause of pain, especially in civilian practice.[30] There are different treatment modalities, including drug therapy, nerve surgery, sympatholysis, and the dorsal root entry zone (DREZ) operation, which may be used as a single treatment or in combination for final pain relief. Non-invasive therapies should usually be exhausted before the consideration of surgical therapy, and patients should undergo preoperative general and psychological screening.[31]
Cell therapy Stem cells Stem cells have been shown to have the potential to help regenerate lost neurons, increase glial support cells and make the microenvironment around the nerve injury site more favorable. A number of studies have highlighted the ability of stem cells from a variety of sources to differentiate into Schwann cells as the starting material for these constructs.[32] The selection of ideal stem cells has long been debated in the field of regenerative medicine; stem cells should be easily accessible, expand rapidly in culture, be able to survive in vitro and integrate into host tissue, and be amenable to transfection and expression of exogenous genes. Mesenchymal stem cells can differentiate into many kinds of cell types including Schwann cells. Since there are limitations related to the use of Schwann cells in nerve injuries, it is necessary to know about the substitute cell types. So far, different sources of mesenchymal stem cells exist. Thus, various types of stem cells include the embryonic stem cells, bone-marrow derived stem cells, adipose-derived stem cells, etc. The existence of their beneficial effects on nerve regeneration after injury has also been confirmed.[32] On the other hand, neural stem cells, besides being able to differentiate into neurons and Schwann-like cells, secrete various neurotrophic factors, including brain-derived neurotrophic factor, fibroblast growth factor, nerve growth factor, insulin-like growth factor and hepatocyte growth factor; and promote regeneration of the axonal myelin sheath, angiogenesis, and immune regulation.[33] Stem cells may be injected directly around the nerve stumps or around a bridging nerve graft, injected into the lumen of a nerve conduit, suspended in a scaffold, injected into a neuromuscular junction, or administered systemically. Regardless of their mode of administration, their transplantation still remains in the pre-clinical stage and has yet to make significant headways into clinical practice. Cell banks may provide benefits for future applications of stem cell therapy.[33] Schwann cells and olfactory ensheating cells Transplantation of glial cells is a very promising therapy for peripheral nerve injuries. The olfactory nerve is constantly having a turn-over of cells throughout life, which means olfactory ensheathing cells are continuously stimulating neural regeneration, whilst Schwann cells only promote regeneration after direct injury to the peripheral nervous system (PNS). A thorough understanding of the mechanisms is crucial for the development of future therapies using transplantation of peripheral glia to treat neural injuries and/or disease.[21] Olfactory ensheating cells are pluripotent, displaying Schwann-cell and astrocyte-like properties, with the ability to phagocytose degenerating axons, create channels to guide new axonal regeneration and produce a variety of neurotrophic factors, including nerve growth factor (NGF), brain derived neurotropic factor (BDNF), platelet-derived growth factor, and neuropeptide Y, enhancing the injured axonal survival. Experimental work indicates that transplantation of olfactory ensheathing cells at the time of surgical nerve repair can enhance regeneration and functional outcome. Although olfactory ensheathing cells present a better option, autologous cells are very complicated to reach and collect, therefore the use of Schwann cells looks like a more appropriate method, regardless of their inferior features.[34] Gene therapy Gene therapy can be defined as the introduction of a foreign therapeutic gene into living cells to treat a disease. This foreign gene is termed a transgene, whose expression is driven by a so-called promoter. The most efficient way to insert a transgene into a cell is with the use of a viral vector. This is a specially modified virus that has lost its capacity to replicate but maintains the ability to attach to and enter into cells, delivering a transgene to the cell nucleus. The studied potential vectors include herpes simplex, adenovirus, lentivirus, and adeno-associated viral vectors. The adeno-associated viral vectors have been shown to be the most reliable vectors that serve as a gene delivery platform. The main targets for gene therapy in peripheral nerve injury are Schwann cells, fibroblasts, and denervated muscles. The aim of gene therapy is to obtain a sort of transcriptional reprogramming so that more neurotrophic factors, cell adhesion or extracellular matrix molecules, and transcription factors are produced. As the gene delivery technology approaches a state of clinical readiness, the time when gene therapy will become an integral part of the armory of nerve surgeons is fast approaching.[35] Robotic surgery The use of a robot makes it possible to perform microsurgical procedures in very narrow corridors with telemanipulation and minimally invasive techniques. The technique also achieves a higher magnification and eliminate the surgeons' tremor. The endoscopic, robotic-assisted approach allows for the safe dissection and identification of the supraclavicular structures of the brachial plexus. The reconstruction of the upper trunk with a nerve graft was successfully completed using an epineural microsurgical suture technique performed exclusively with the aid of a robot. There were no instances of inadvertent macroscopic damage to the vascular and nervous structures involved. The ability to perform a minimally invasive procedure to explore and repair a brachial plexus injury may provide a new option in the acute management of these injuries.[36] Oberlin procedure was performed in four cases presenting with elbow flexion paralysis, 8 months after injury using a da Vinci-S robot. The open technique was used in 3 cases, and the mini-invasive approach in the last one; however, in the latter case, there was a need for converting the procedure to an open technique because of the difficulty in visualizing the operative field. After one year, all of the patients recovered elbow flexion. No sensory or motor deficits were found in the ulnar nerve territory.[37] In another series of six patients with total deltoid muscle paralysis, a da Vinci-S robot was used to perform the Somsak procedure. In two cases, an endoscopic procedure was tried under carbon dioxide insufflation; however, as with the Oberlin procedure, the conversion to an open technique was needed. In almost all of the patients, the deltoid function against resistance was obtained, and the average shoulder abduction was 112 degrees. No weakness of elbow extension was observed.[38] As can be seen from this overview, the supraclavicular exploration and graft repair, as well as Oberlin and Somsak procedures are possible with the use of da Vinci robots. The development of specific retractors and instruments, as well as the usage of a higher insufflation pressure, may improve the mini-invasive technique. Bionic reconstruction For patients with global brachial plexus injuries with lower root avulsions, who have no alternative treatment, bionic reconstruction offers a means to restore hand function. The first-time bionic reconstruction, a combined technique of selective nerve and muscle transfers, elective amputation, and prosthetic rehabilitation to regain hand function, was used by Aszmann et al., who included three patients with complete brachial plexus palsy after injury in their study and successfully enabled prosthetic hand use in all three patients.[39] The two-stage treatment included (1) identification and repair to achieve useful electromyographic signals for prosthetic control (followed by specific rehabilitation), (2) amputation of the hand and replacement with the bionic prosthesis.[39] Artificial intelligence Researchers have recently developed an artificial neural network capable of predicting the outcome of different tissue-engineered peripheral nerve grafts used in research applications. Using over 30 independent variables to describe tissue-engineering materials, artificial neural networks were trained to predict the success of various grafts. After application of the validation data, the predictive accuracy of artificial neural networks was 92.59% and 90.85% for the ratio of the actual length to the critical length and the critical regeneration length, respectively.[40] Although preliminary, the results of this investigation highlight the potential role of machine learning in the analysis and development of tissue-engineering strategies for peripheral nerve repair. The biomechanics of the upper extremities are particularly complex, involving multivariate nonlinear relationships that are theoretically amenable to modelling by machine learning. Artificial neural networks have been used to develop automated controllers for a variety of neuroprostheses, including those that are used to restore hand grasp and wrist control along with more proximal upper extremity function. The results highlight the potential for artificial neural networks, in the development of neuroprosthetic controllers for the hand and wrist.[41] Along with the examples presented above, machine learning has the potential to provide additional innovations in hand and nerve surgery. For example, using databases containing information derived from sensorial mapping following peripheral nerve repair, patterns of regrowth could be used to develop an algorithm capable of prognosticating the degree of sensory and motor restoration based on location, mechanism of nerve injury, and physical examination findings.[42] Interdisciplinary networks Nowadays, sound networking and information spread could be managed via the internet and via specific platforms to interconnect those who care for patients and work together. Overcoming educational, medical and geographic barriers, it is mandatory to incorporate rehabilitation, psychology and other “life sciences”. Attaining relief of symptoms for the individual should be the highest common goal.[43]
As it is well known, education is the most powerful tool and weapon to combat the manifestations of nerve injury. The permanent need for continuous medical education and for determininig methods that lead to an improvement in the abilities to understand the philosophy of surgical treatment of peripheral nervous system disorders is more than obvious in 21st century. The World Federation of Neurosurgical Societies (WFNS) Peripheral Nerve Surgery Committee was formed through an enormous effort of a small group of enthusiastic neurosurgeons, with three Serbian neurosurgeons being an integral part of it. It was started as an endeavor to regain an elevated position for peripheral nerve surgery on the international neurosurgical armamentarium. The first World Congress of Brachial Plexus and Peripheral Nerve Surgery was held in New Delhi, India in 2016 organized by the Indian Society for Peripheral Nerve Surgery; the second will be organized in Mexico City, in October 2019, together with the 4th Theoretical and Practical International Course in Peripheral Nerve and Brachial Plexus Surgery as a joint effort between Mexican neurosurgeons, plastic and orthopedic surgeons, together with worldwide group of surgeons renowned in performing peripheral nerve surgery as a major surgical activity. The previous international hands-on cadaver courses in peripheral nerve and brachial plexus surgery, organized by the WFNS Peripheral Nerve Surgery Committeein Leon, Spain in 2016, Belgrade, Serbia in 2017, and Frankfurt, Germany in 2018, proved to be very successful. After Mexico City, the next courses are planned as follows: 2020 in Rio de Janeiro, Brazil; 2021 in Dubai, UAE; and 2022 in Rovigo and Venice, Italy. Meanwhile, the Copenhagen Peripheral Nerve Surgery Course 2018 culminated in a Video Atlas, which is to be published by the end of 2018. The Narakas International Symposium on brachial plexus and peripheral nerve surgery has a long history and tradition; the 21st symposium is going to be held at Leiden Nerve Center in Leiden, Netherlands in May 2019. The 24th Sunderland Society Meeting will be held in Israel in November 2019. The Belgrade school of peripheral nerve surgery – which has developed over the past thirty years due to the expertise and devotion of Dr. Miroslav Samardžić, the founding father of modern peripheral nerve surgery at the Clinic of Neurosurgery, Clinical Center of Serbia, and Dr. Zoran Roganović, the most prominent neurosurgeon in Serbian Military Surgery – has meanwhile received significant visibility on the world map of neurosurgery. It is with a sense of pride and responsibility that I represent it nowadays in my capacity as Vice President of the WFNS Peripheral Nerve Surgery Committee and Chairman of the European Association of Neurological Surgery (EANS) Peripheral Nerve Section.[1] The EANS Section of Peripheral Nerve Surgery was founded with my personal efforts, with the focus on reestablishing the multidisciplinary and transdisciplinary nature of peripheral nerve surgery. The first business meeting was held in Belgrade, Serbia, in November 2017 during the 2nd Theoretical and Practical International Course in Peripheral Nerve and Brachial Plexus Surgery, and we are looking forward to the first Peripheral Nerve Surgery Session at the EANS Congress in Brussels 2018. In addition to the obvious neurosurgical influence on the development of peripheral nerve surgery, surgeons of other specialties (especially plastic and orthopedic surgeons) are also making a significant impact on the discipline. Therefore, a natural sequence of events would be the formation of a transdisciplinary subspeciality that will help to establish the nerve surgeon. This could be achieved by utilizing consecutive educational programs, in order to achieve mastery in the art of peripheral nerve surgery.
Peripheral nerve surgery has had a rich past, an accomplished present, and definitely a bright future. Over the recent years, peripheral nerve surgery has had a very steep progression line and is reaching its peak progress velocity in the present times. More is yet to come, and new horizons are within reach.
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