Degeneration and regeneration of the nervous system

Nerve regeneration is a complex biological phenomenon. In the peripheral nervous system, nerves can regenerate on their own if injuries are small. Larger injuries must be surgically treated, typically with nerve grafts harvested from elsewhere in the body. Spinal cord injury is more complicated, as there are factors in the body that inhibit repair. Unfortunately, a solution to completely repair spinal cord injury has not been found. Thus, bioengineering strategies for the peripheral nervous system are focused on alternatives to the nerve graft, whereas efforts for spinal cord injury are focused on creating a permissive environment for regeneration. Fortunately, recent advances in neuroscience, cell culture, genetic techniques, and biomaterials provide optimism for new treatments for nerve injuries. This article reviews the nervous system physiology, the factors that are critical for nerve repair, and the current approaches that are being explored to aid peripheral nerve regeneration and spinal cord repair.

Neural tissue engineering: strategies for repair and regeneration.

Functional recovery from peripheral nerve injury and repair depends on a multitude of factors, both intrinsic and extrinsic to neurons. Neuronal survival after axotomy is a prerequisite for regeneration and is facilitated by an array of trophic factors from multiple sources, including neurotrophins, neuropoietic cytokines, insulin-like growth factors (IGFs), and glial-cell-line-derived neurotrophic factors (GDNFs). Axotomized neurons must switch from a transmitting mode to a growth mode and express growth-associated proteins, such as GAP-43, tubulin, and actin, as well as an array of novel neuropeptides and cytokines, all of which have the potential to promote axonal regeneration. Axonal sprouts must reach the distal nerve stump at a time when its growth support is optimal. Schwann cells in the distal stump undergo proliferation and phenotypical changes to prepare the local environment to be favorable for axonal regeneration. Schwann cells play an indispensable role in promoting regeneration by increasing their synthesis of surface cell adhesion molecules (CAMs), such as N-CAM, Ng-CAM/L1, N-cadherin, and L2/HNK-1, by elaborating basement membrane that contains many extracellular matrix proteins, such as laminin, fibronectin, and tenascin, and by producing many neurotrophic factors and their receptors. However, the growth support provided by the distal nerve stump and the capacity of the axotomized neurons to regenerate axons may not be sustained indefinitely. Axonal regenerations may be facilitated by new strategies that enhance the growth potential of neurons and optimize the growth support of the distal nerve stump in combination with prompt nerve repair.

The cellular and molecular basis of peripheral nerve regeneration.

Background: The purpose of this study was to determine the prevalence, cause, severity, and patterns of associated injuries of limb peripheral nerve injuries sustained by patients with multiple injuries seen at a regional Level 1 trauma center. Methods: Patients sustaining injuries to the radial, median, ulnar, sciatic, femoral, peroneal, or tibial nerves were identified using a prospectively collected computerized database, maintained by Sunnybrook Health Science Centre, and a detailed chart review was undertaken. Results: From a trauma population of 5,777 patients treated between January 1, 1986, and November 30, 1996, 162 patients were identified as having an injury to at least one of the peripheral nerves of interest, yielding a prevalence of 2.8%. These 162 patients sustained a total of 200 peripheral nerve injuries, 121 of which were in the upper extremity. The mean patient age was 34.6 years (SEM ± 1.1 year), and 83% of patients were male. The mean injury severity score was 23.1 (±0.90), and the mean length of hospital stay was 28 days (±1.8). Conclusions: Motor vehicles crashes predominated (46%) as the cause of injury. The most frequently injured nerve was the radial nerve (58 injuries), and in the lower limb, the peroneal nerve was most commonly injured (39 injuries). Diagnosis of a peripheral nerve injury was made within 4 days of admission to Sunnybrook Health Science Centre in 78% of the cases. Surgery was required to treat 54% of patients. Head injuries were the most common associated injury, occurring in 60% of patients. Other common associated injuries included fractures and dislocations. The present report aims to aid in identification and treatment of peripheral nerve injuries.

Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries.

umeroscapular arthrodesis is a well-established operative procedure that involves fusion of the humeral head to the glenoid. In some procedures, the fusion also includes an acromiohumeral arthrodesis. Humeroscapular arthrodesis is commonly called “shoulder arthrodesis,” and we use that term in this paper for simplicity. Indications for this procedure early in the twentieth century included the treatment of residual glenohumeral destruction resulting from tuberculosis and the treatment of upper-extremity paralysis resulting from poliomyelitis. Additional historical indications included osteoarthritis, rheumatoid arthritis, irreparable injury of the rotator cuff, and severely comminuted fracture of the proximal aspect of the humerus. The advent of shoulder arthroplasty has resulted in a marked reduction in the number of shoulder arthrodeses performed, although there are instances when arthrodesis is favored over joint-replacement arthroplasty. This article reviews the indications for shoulder arthrodesis, the pertinent features of the preoperative evaluation, the controversial issue of the desirable position of the arthrodesis, the various techniques for shoulder arthrodesis, and the management of complications.

Current concepts review

This study reports a rat model of chronic nerve compression. The sciatic nerves of adult male Sprague Dawley rats were bonded with 1-cm lengths of tubing with varying internal diameters. Histological and electrical studies as well as studies to assess the blood-nerve barrier function were carried out at one through six months. With marked compression of the sciatic nerve, profound electrical changes were noted as early as one month, and histological findings were those of degeneration and regeneration. In the rats with minimal compression, nerve conduction studies remained normal. The earliest findings were alterations in the blood-nerve barrier, followed by histological changes in the large myelinated fibers at the periphery of the fascicles and changes about the nodes of Ranvier. This model appears to be a valid one with which to study other aspects of both the pathophysiology and treatment of chronic nerve compression.

Chronic nerve compression--an experimental model in the rat.

Selected Basic Considerations, Mechanisms and Pathology of Injury, Clinical and Electrical Evaluation, Grading Results, Nerve Action Potential Recordings, Operative Care and Techniques, Radial Nerve, Median Nerve, Ulnar Nerve, Combined Upper Extremity Nerve Injuries, Lower Extremity Nerves, Brachial Plexus Anatomy and Physiology, Lacerations to Brachial Plexus, Gunshot Wounds to Brachial Plexus, Stretch Injuries to Brachial Plexus, Birth Palsies, Thoracic Outlet Syndrome, Accesory Nerve, Reconstructive Procedures, Pain of Nerve Origin, Tumors Involving Nerve.

Nerve Injuries: Operative Results for Major Nerve Injuries, Entrapments, and Tumors

This study reports the degree of spontaneous regeneration that will occur in the sciatic nerve of a rat 5 months after complete resection of the nerve. In 30 animals, the sciatic nerve was excised. Histological assessment at 5 months revealed evidence of regeneration for a variable distance (mean 23.7 mm +/- 6.4 mm). Histological sections were studied at 1-cm intervals along the length of the nerve. Evidence of compartmentation with "minifascicle" formation was noted. The orientation of the nerve fibers was parallel to the long axis of the nerve. This study assessing spontaneous regeneration is meant to serve as a control for other studies evaluating the effect of factors that may influence nerve regeneration in the rat model.

Histologic assessment of nerve regeneration in the rat.

While compression neuropathy is a common clinical problem, the opportunity to study human nerve material is rare. A histological assessment of the superficial radial nerve of four human cases with entrapment syndrome is reported. Changes in the perineurium and the endoneurial microvessels as well as the presence of Renaut bodies were the earliest histological abnormalities noted. Connective tissue changes included epineurial and perineurial fibrosis. Nerve fibre pathology varied from fascicle to fascicle. The myelinated and unmyelinated fibre populations responded differently to this compression. In the myelinated fibre population, marked thinning of the myelin was noted. In the unmyelinated fibre population, a shift in the fibre histogram due to a new population of very small fibres was observed suggesting degeneration with subsequent regeneration of this fibre population.

Chronic human nerve compression – a histological assessment

In a primate model a histologic assessment of neuroma formation is reported. Three experimental groups were defined. Transected sensory nerves left adjacent to the incisional wound in an area of movement (wrist) were considered the control group. In the "proximally cut" group the same sensory nerves were positioned well proximal to the incisional wound. In the "muscle-implantation" group these nerves were placed in adjacent muscles. At 6 months a histologic assessment of the neuroma formation in the three experimental groups was carried out. Implantation of the sensory nerve into muscle significantly altered the regenerative potential of that nerve. The muscle completely surrounded the sensory nerve. The minimal neuroma that formed had significantly less scar tissue and contained nerve fibers that were of a smaller diameter and decreased density than either the control or the proximally cut group. There were no histologic differences between these latter two groups. However, regeneration into the overlying skin that was noted in the control neuromas was not seen in those nerves which had been proximally cut.

Alan R. Hudson

Papers

Chronic nerve compression--an experimental model in the rat.

Nerve Injuries: Operative Results for Major Nerve Injuries, Entrapments, and Tumors

Histologic assessment of nerve regeneration in the rat.

Chronic human nerve compression – a histological assessment

Alteration of neuroma formation by manipulation of its microenvironment.