Nerve repair: Bridging the gap from “limp” to “limb”
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.250712
Source of Support: None, Conflict of Interest: None
The first alleged nerve coaptation was performed by a Persian physician named Avicenna. Before that, the field of peripheral nerves (PN) was “noli me tangere” in Latin, that is, “touch me not,” considering that touching the injured nerves produced seizures. The field of peripheral nerve surgery has grown leaps and bounds recently over the last couple of decades. With the advent of advanced diagnostic tools, surgical microscopes and microinstruments, with refinements in microsurgical techniques, along with better understanding of the nerve regeneration process, have changed the face of the game.
In the earlier century, nerve injuries were categorized as compression, contusion, laceration or division lesions. In 1943, Seddon introduced the first classification system based on nerve fibre and nerve trunk pathology in three categories: neurapraxia, axonotmesis and neurotmesis. This classification was followed by that of Sunderland who further subdivided the same spectrum into five grades based on histological features. Then a newer classification system of nerve injury was proposed by Millesi based on the severity of reactive nerve fibrosis. He proposed three types from A to C, depending on the extent of fibrosis involving the epineurium, interfascicular epineurium and endoneurium, respectively.
Over the years, the potential of the regenerative capacity of peripheral nerves due to the presence of an intact soma has been explored with significant amount of success. It has been observed that the initial process of Wallerian degeneration of axonal components rapidly leads to recruitment and activation of non-neuronal cells which contribute to the regeneration process. On this plot, a large number of advanced researches are being undertaken to get a breakthrough in the process of nerve regeneration and recovery.
In their article, “Recent advances in nerve repair” Ramachandran et al., have given an elaborate overview of all the aspects of nerve injury right from the diagnosis to management with emphasis on recent advances and nerve transfers. To add to that, the importance of careful history taking and physical examination cannot be overemphasised in a case of nerve injury, as they provide the key information. It is imperative to know the type of pain, attribute the deficits to peripheral nerves, localise the probable lesion, and the most important of all, assess the severity of injury as neurapraxia, axonotmesis or neurotmesis. Only in rare cases can all of these questions be sufficiently answered on history and clinical examination alone. However, clinical assessment forms the basis for rational decisions about the necessity and timing of additional diagnostic testing. The clinical testing also is an important tool for testing the status of reinnervation during the follow-up period. The Hoffmann-Tinel's sign is one of the clinical tests which may give information regarding the speed and extent of recovery. Nonetheless, in many clinical situations, electrodiagnostic and imaging studies may be necessary to provide additional relevant information.
Electromyography (EMG) and nerve conduction studies (NCS) are recommended after 4-6 weeks of injury in view of the ongoing Wallerian degeneration. Contrary to the authors' view, there are a few instances where certain tests can be useful in the acute setting, preferably within 4 days of injury during which the Wallerian degeneration has not set in. The presence of motor unit action potentials (MUAPs) on EMG in the acute setting suggests an incomplete lesion and so neurotmesis is ruled out, which further may assist in decision making regarding the timing of surgical intervention. Similarly, studying the transition of compound muscle action potential (CMAP) in NCS from normal to low can reliably localize the nerve lesion.
High resolution ultrasound (HRU) has got a significant role to play before, during and after nerve surgery. Ultrasound can be used to detect the location of proximal and distal nerve stumps before surgery and the location can be marked on the skin preoperatively to minimise the incision, tailor the procedure better and also save time that otherwise would be needed for search for the nerve stumps. During surgery, the HRU can reliably be used to assess the severity of the underlying nerve injury and the type and grade of nerve fibrosis. During monthly evaluations postoperatively, the HRU examinations may pick up signs of failed neuro-regeneration earlier than may be detected by the electrodiagnostic procedures and thus ascertain the need for surgical revision. Magnetic resonance imaging has an established role during the management of PN injuries. The most obvious MRI sign of a complete nerve transection is the detection of an end-bulb neuroma, while an incomplete nerve lesion might show a neuroma-in-continuity (NIC). The presence of a pseudomeningocele may indicate a preganglionic root avulsion injury. Recently, diffusion tensor imaging (DTI) has created quite an interest. In some animal studies, it is shown that the tracked fibres terminate at the point of axonal discontinuity within hours after the occurrence of traumatic nerve injury, while the fibres may extend distal to the located injury and show an increase in the fractional anisotropy (FA) in case of nerve regeneration. Interestingly, MRI of the muscles may also predict the severity of denervation of a muscle. Normal muscle tissue presents with an intermediate signal on T1 weighted and T2 weighted sequences, while in acute nerve injury, a marked increase in the T2 relaxation time can be observed as early as 5 days after an axonotmesis or neurotmesis. These MRI findings can be correlated with the amount of spontaneous activity on EMG, and with the size of the MUAPs. The main advantage of this sequence is that, as compared to EMG, it is painless and can visualize the whole cross-section of an extremity. Its lower sensitivity to axonotmesis and its inability to detect neurapraxia are its limitations.
The role of intraoperative electrophysiology can be considered in two major categories: (a) “monitoring” an intact nerve function during a manipulation inside the nerve; and, (b) “diagnosing” the functional integrity of the lesioned fascicles of a peripheral nerve. For monitoring, somatosensory evoked potential (SSEP) and electromyographic potential (EMG) from the target muscle supplied by the motor nerve, while directly stimulating the nerve fascicles, are preferred over motor evoked potential (MEP). Specifically, designed stimulation-integrated microdissectors aid in performing the microsurgical steps of fascicular resection and in simultaneously stimulating the fascicles. The method of choice for an intraoperative diagnosis is to measure the nerve conduction velocity by means of recording the compound nerve action potential (cNAP) across a nerve lesion. It helps in recognizing partial lesions of nerves and in replacing only those fascicles that do not show conduction. This technique is called the split repair.
There is no debate that nerve reconstruction performed as early as possible strongly improves the prognosis and optimizes the condition for functional recovery. This is because there is a persistent reduction in the quality of motor recovery 6 months after injury. A sharp transection injury within a clean wound requires immediate repair, while in the majority of cases, a wait-and-see attitude and an early secondary nerve reconstruction is advisable, as mentioned by the authors. The authors have elaborated the surgical options for nerve coaptation in details; however, a few facts need to be further discussed.
The main principle of nerve surgery is to perform a tension-free repair and achieve an optimal adaptation of the nerve ends and fascicles. Whenever needed, the contused nerve stumps are required to be trimmed back to the healthy epineurium and a visible fascicular structure. The importance of a bloodless field should not be overlooked, especially for the neurosurgeons who, unlike plastic surgeons, are not used to it. The use of a proximal tourniquet should be considered, whenever required. But while using it, one should be aware that the nerve blood supply expires within 15–45 minutes distal to the tourniquet. However, it recovers rapidly after opening of the cuff within a few minutes. For hemostasis, a small tipped bipolar coagulator or sponges dipped in a solution of 1:100,000 epinephrine in 10 ml of saline should be used.
The authors have discussed in detail about the three types of end-to-end neurorrhaphy: epineurial, perineurial and group fascicular. To add to that, all three procedures should always be initiated with the preparation of the nerve ends, as discussed earlier. Transverse cuts, 1 mm distant from each other, should progressively be made with a sharp instrument like a blade or a pair of microscissors until an area of healthy fascicles without fibrotic tissue is reached. Hemostasis is always imperative as discussed, because bleeding can lead to excessive fibrosis and distortion of the nerve architecture. The visualization of the normal-appearing fascicular pattern on the cut nerve surfaces can also be effective in helping in the correct realignment of peripheral nerve stumps in areas along with running vessels on the surface. One should, however, remember that the fascicular topography usually changes after 1–2 cm of neural trimming. The groups of fascicles can usually be opposed as closely as possible even though the repair is done at the epineurial level. End-to-end neurorrhaphy is without any doubt superior to other techniques.
Considering the end-to-side neurorrhaphy, whether the receptor nerve should be coapted to the donor nerve through an epineurotomy or a perineurotomy is still a controversial issue. Although some experimental studies have revealed that no difference was detected whether or not a nerve window at the coaptation site was made,, some other investigators claim that after a perineurotomy, there is a greater degree of axonal damage to the donor nerve which enhances the axonal regeneration with better histological results., Further large, multicentric animal as well as human randomised studies are needed to come to a conclusion regarding this issue. Practically, in the majority of cases, it will provide only a limited sensory recovery. As of now, one should consider it as a therapeutic option only in cases of failure of other attempts of nerve repair or when other approaches are not feasible, especially when protective sensibility is a reasonable goal to achieve.
In cases of nerve grafting, the graft should always be harvested after exposure of the injured nerve. This is because the extent of the lesion can be defined as well as the size of the defect can be measured. Then, the size and number of grafts required can be calculated. To release tension on the suture lines, the length of the grafts should be about 15–20% greater than the measured gap, as mentioned by the author, because they always present with some shrinkage owing to a relative initial hypovascularization and dessication.
The classical approach of nerve harvesting involves making the skin incision along the entire course of the graft, carefully dissecting and transecting the nerve, and preparing it for autologous transplantation. But this approach makes the nerve harvest a cumbersome and a major operation. In order to minimize the trauma, endoscopic techniques have been introduced. Although being minimally invasive, the endoscopic nerve harvesting is time consuming. In order to facilitate a faster harvesting of the donor nerve, another simpler and minimally invasive option is the nerve stripper. With the use of the nerve stripper, the entire length of the nerve up to its origin from the popliteal fossa can be dissected and stripped off. The entire procedure takes around 10–20 min, which is significantly less when compared to endoscopic harvesting.
The autografts can be further classified into trunk grafts, cable grafts and vascularized nerve grafts. Trunk grafts are composed of mixed motor and sensory fibres. They have poor functional results due to the presence of the mixed nerve, and the large diameter of the nerve which inhibits the ability to properly revascularize the centre of the graft. Cable grafts are several sections of small nerve grafts aligned in parallel to connect the fascicular groups. Vascularized nerve grafts have the advantage that there is no period of ischemia while harvesting them, as compared to non-vascularized grafts.
In addition to installation of allografts that the authors have discussed, there are other biological conduits in use such as autologous veins, arteries, muscles, and heterogeneous collagen tubes (composed of denatured skeletal muscle or muscle basal lamina, veins, and polyglycolic acid (PGA)–collagen tubes). There are advantages in using a vein conduit because the tissue composition of veins is similar to that of the nerve tissue. Also the muscle–vein-combined graft conduits have broadly been devised by tissue engineering and may be effectively employed for repair of segmental nerve injuries. All these conduits provide support for the nerve for the short time and then degrade to innocuous products after complete nerve regeneration.
A few synthetic degradable polymers, although being less biocompatible relative to biopolymers, may offer opportunities for a tailored degradation and control of mechanical strength, porosity and microstructural properties. These include polyglycolic acid (PGA), polylactic acid (PLA), poly(ε-caprolactone) [PCL], polylactic acid-co-glycolic acid (PLGA), and polyurethanes (PUs). Some authors have also tried nonbiodegradable polymers such as methacrylate-based hydrogels, silicone, polystyrene and polytetrafluoroethylene but only in preclinical models., There are a few blends of natural ploymers with synthetic ones, called hybrid polymers, that have been devised but are not in clinical usage. In a nutshell, an autograft is still considered the gold standard, but in the right situations, either conduits or acellular allografts may also achieve equivalent results, making them excellent options for facilitating nerve regeneration.
A technique described in the beginning of the twentieth century, muscular neurotisation, entails surgical insertion of peripheral nerves directly into denervated muscles. This procedure is only indicated when no distal nerve stump is available for neural coaptation, or when the lesion involves the neuromuscular junction. Experimentally, it was shown that the implantation of a normal nerve near denervated motor end plates reinnervates this site, and that those axons which do not have a contact with these persistent motor end plates will induce new ones in previously denervated areas of a muscle. However, clinically it restores significantly less function when compared with other techniques, leaving areas of the target muscle denervated. In the majority of studies, the entire nerve has been implanted into the target muscle, which might be the reason for the persistent areas of denervation where growing axons could not have reached. To overcome this problem, Brunelli showed the splitting of the donor nerve into multiple fascicles and implanting them separately and widely across the area of a muscle. However, no consensus has been reached regarding this controversy. Nerve root repair and re-implantation has recently been described as a new technique but needs to be studied more for the surgeons to come to a definitive conclusion.
The use of fibrin glue in nerve surgery is still considered off-label. It is believed that the artificial “clot” created by the glue protects the repair from the scar tissue and allows healing to occur. The structural integrity of the nerve anastomosis is preserved for about 3 weeks by the antifibrinolytic component of the sealant. However, it is to be kept in mind that the glue cannot be used as a substitute to the sutures and a fine suturing technique. A few experimental works have also tested other suture-free methods such as laser welding of nerve ends; there methods have failed to be adopted in actual clinical practice.,
After the intervention, it is always uncertain if the nerve anastomosis will result in successful functional recovery. The regeneration process is to be followed up carefully by means of serial clinical examinations at 6-weekly intervals. One should be aware that the protection sensitivity usually returns spontaneously but the ability of tactile discrimination returns in only a limited number of cases. To support recovery of the latter, the institution of aggressive and purposeful sensory reintegration programs are necessary. The initiation of the relearning process must be started immediately after the nerve reconstruction. Considering the rehabilitation of motor function, the rehabilitative physical therapy is usually started after 3 weeks of surgery to prevent undue stretch over the anastomoses. During the initial 3 weeks, the limb should be immobilised.
On an average, a follow-up period of 6 months is considered before an unequivocal functional successful outcome may be established. Despite the fact that the current treatment strategies demonstrate some success, further efforts need to be carried out with the goal to simultaneously potentiate axonal regeneration, increase neuronal survival, modulate central reorganization, and inhibit or reduce target organ atrophy.
Peripheral nerve surgery is a neurosurgical subspecialty which has recently gained worldwide acceptance both amongst neurosurgeons as well as patients because of enormous advancements that have taken place in this field and the significantly improved results. More and more neurosurgeons should opt for this subspecialty. The authors of the study in focus should be commended for their efforts in covering the majority of aspects of this vast topic and also for the comprehensive clarity of thoughts shared.