Neuroma-in-continuity

[Bessie Murrillo]

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A neuroma-in-continuity is a neuroma that results from failure of the regenerating nerve growth cone to reach peripheral targets. It occurs within an intact nerve in response to internally damaged fascicles, resulting in a distal portion of the nerve that no longer functions properly. Management of neuromas-in-continuity is challenging. Chemical methods, and microsurgical techniques including fascicular ligation, and burying into muscle and bone have been reported to prevent neuroma-in-continuity formation. The purpose of this article is to present novel techniques for neuroma-in-continuity management, and to discuss the related literature.

A neuroma-in-continuity is a neuroma resulting from a nerve injury in which internal neuronal elements are partially disrupted (with a variable degree of disruption to the endoneurium and perineurium) while the epineurium typically remains intact. The portion of injured axons are misdirected and embedded in connective tissue, which may give rise to local neuroma pain and a distal nerve deficit. The lesion may result from a multitude of injury mechanisms, and clinical presentation is often variable depending on the nerve affected. Clinical, electrodiagnostic, and imaging examinations are helpful in assessing the extent and degree of the lesion. If no clear evidence of recovery is identified within 3-4 months post-injury, the patient may benefit from operative exploration. Surgical management options include neurolysis, neuroma resection, nerve grafting, and nerve transfer, or a combination of modalities. A primary consideration of surgery is the possibility of further downgrading nerve function in the pursuit of more, thereby highlighting the need to carefully weigh the advantages and disadvantages prior to surgical intervention. The objective of this review article is to describe the current understanding of the pathophysiology of neuroma-in-continuity lesions, and to review the approach to the affected patient including clinical evaluation, ancillary testing, and intraoperative assessment and treatment options.

There is a focal area of hypoechoic thickening, loss of fascicular pattern of the median nerve in the mid-forearm scar region. The nerve shows continuity. The short-axis image shows the involvement of full thickness of the nerve. There is no perineural collection.

An adult male had a penetrating metal injury to the left volar mid-forearm region. He developed weakness of the fingers innervated by the median nerve. Nerve conduction study also suggested median neuropathy. Ultrasound shows a traumatic neuroma-in-continuity involving the median nerve at the scar region.

Background. Common peroneal nerve (CPN) injuries are generally common but they are uncommon due to gunshot injuries and are associated with poor motor outcomes. Managing neuroma-in-continuity is still challenging because there are currently no accepted standards for deciding on the most effective course of treatment or estimating the time needed for repair. Treatment options for a neuroma-in-continuity include neurolysis, neuroma resection with interposition, end-to-side nerve grafting, and bypass grafting.

Case presentation. A 40-year-old man presented with findings of complete right foot drop due to an 8-month-old firearm injury to his right distal thigh. Following baseline investigations, imaging, and anaesthesia fitness, he underwent surgical exploration under general anaesthesia. A neuroma-in-continuity was found in the CPN, resected, and an end-to-end nerve repair was performed. Along with the neuroma-in-continuity, a bullet fragment was also removed. The neurological status remained unchanged postoperatively.

Conclusion. Regardless of the cause of the lesion, patients should be urged to seek surgical therapy if there is no spontaneous recovery within four months after the CPN injury. Sharp injuries and knee dislocations have a better chance of recovery than crush injuries and gunshot wounds.

Peripheral nerve transection and neuroma-in-continuity injuries are associated with permanent functional deficits, often despite successful end-organ reinnervation. Axonal misdirection with non-specific reinnervation, frustrated regeneration and axonal attrition are believed to be among the anatomical substrates that underlie the poor functional recovery associated with these devastating injuries. Yet, functional deficits associated with axonal misdirection in experimental neuroma-in-continuity injuries have not yet been studied. We hypothesized that experimental neuroma-in-continuity injuries would result in motor axon misdirection and attrition with proportional persistent functional deficits. The femoral nerve misdirection model was exploited to assess major motor pathway misdirection and axonal attrition over a spectrum of experimental nerve injuries, with neuroma-in-continuity injuries simulated by the combination of compression and traction forces in 42 male rats. Sciatic nerve injuries were employed in an additional 42 rats, to evaluate the contribution of axonal misdirection to locomotor deficits by a ladder rung task up to 12 weeks. Retrograde motor neuron labeling techniques were utilized to determine the degree of axonal misdirection and attrition. Characteristic histological neuroma-in-continuity features were demonstrated in the neuroma-in-continuity groups and poor functional recovery was seen despite successful nerve regeneration and muscle reinnervation. Good positive and negative correlations were observed respectively between axonal misdirection (p

Copyright: 2013 Alant et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Axonal misdirection is strictly not expected to follow pure axonotmetic (Sunderland Grade 2 or crush) injuries in which full functional recovery usually occurs [5,6]. This is thought to be because of preservation of endoneurial connective tissue integrity, which helps axons to regenerate accurately and efficiently to the original targets. In contrast, unrepaired transection injuries (Sunderland Grade 5) are not expected to recover any significant function, although rodents are known to be able to regenerate axons across substantial transection gaps [7,8]. Unrepaired transection injuries should represent the extreme of axonal misdirection, provided that the regeneration gap is bridged.

In order to effectively investigate the relationship between axonal misdirection and functional deficit, the gap in experimental data between minimal and extreme nerve injuries needed to be bridged. These intermediate sub-transection (Sunderland Grade: 3 - endoneurial and 4: - endo- and perineurial disruption) injuries that result in neuroma-in-continuity (NIC) formation are the most challenging clinically and have previously been elusive to experimental investigation because of the lack of an appropriate animal model. Recently a clinically relevant traumatic NIC model was presented that showed some promise to bridge this gap [9]. Although sciatic nerve NIC injuries were associated with functional deficits discernable from crush injuries, this model was not mechanistically validated by the unequivocal demonstration of quantitative data to support the histological and functional findings.

We hypothesized that experimental NIC injuries would result in motor axon misdirection and attrition with persistent functional deficits. We show how the NIC, femoral and sciatic nerve injury models were exploited to demonstrate 1) axonal misdirection and attrition of motor neurons with motor pathway projections in NIC injuries, similar to transection injuries; 2) for the first time, a direct correlation between the degree of motor axon misdirection and behavioral deficit, with inclusion of the NIC injury spectrum; 3) a negative correlation between functional recovery and the degree of attrition of motor neurons projecting into motor pathways. We hereby demonstrate how this small animal NIC model (with some refinement), can help to expose otherwise elusive substrates of nervous system injuries to experimental investigation and possible therapeutic manipulation.

Male Lewis rats were used in these experiments (Charles River Laboratories International Inc., St-Constant, QC, Canada). The study protocol was approved by the University of Calgary Animal Care Committee and adhered strictly to the Canadian Council on Animal Care guidelines (protocol M08124).

All efforts were made to minimize suffering and animals were maintained in a temperature and humidity controlled environment with standard rat chow (Purina, Mississauga, ON, Canada), water ad libitum and a 12:12h light:dark cycle. Surgical procedures were performed under inhalation anesthetic (Isoflurane, Pharmaceutical Partners of Canada Inc., Richmond Hill, ON, Canada) using standard microsurgical and aseptic technique and an operating microscope. Buprenorphine (0.03mg/kg) subcutaneous injections followed by jello with buprenorphine were used for peri- and post-operative analgesia. Surgical procedures were well tolerated by all animals, with no complications observed. Animals were sacrificed at study termination, under deep inhalation anesthesia with intra-peritoneal Somnitol (Bimeda-MTC, Cambridge, ON, Canada) followed by trans-cardiac perfusion with saline and 2% paraformaldehyde.

Selective and variable disruption of the internal nerve architecture of a nerve would potentially result in proportional axonal misdirection and attrition. We first set out to investigate to what degree we could induce misdirection within an injured nerve without disruption of its gross epineurial continuity. We applied the newly developed NIC injury model to the femoral nerve misdirection model, which is favorably suited and established to investigate axonal misdirection [10]. The rodent femoral nerve terminates in a motor (quadriceps) and a cutaneous division (saphenous and thigh skin) of similar size [10]. Following a more proximal injury, the motor neurons with axons that are misdirected into the cutaneous division can be back labeled by various techniques to estimate the degree of misdirection [11].

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