Femke Mathot

General introduction 15 1 potassium channels. 14 As a response to an action potential that is send off from the neuron, these sodium channels open, causing an influx of positive sodium ions that rejuvenate the action potential. Through this mechanism, myelin helps to prevent action potentials from decaying during their travel down the entire length of the axon. 15 The transmitted action potentials are also accelerated by the presence of myelin. Because nodes of Ranvier are not myelinated, the action potentials only slow down at each node, leading to saltatory conduction; ‘jumping’ propagation of the action potential from node to node. 16 Unmyelinated axons lack the insulating layer of myelin, resulting in less rapid and less efficient transmission of action potentials. 17, 18 Based on the level of myelination and the conduction velocity, nerve fibers can be divided into three classes by Erlanger and Gasser 19 : group A) heavily myelinated fibers, group B) moderately myelinated fibers, group C) unmyelinated fibers. Group A fibers contain fibers responsible for somatic motoric control, proprioception, vibration, light touch and fast pain. Autonomic nerve fibers belong to group B. Pressure, slow pain, crude touch and temperature are transmitted by group C fibers. The thicker the axon, the thicker the myelin sheath and the faster the nerve conduction velocity. 20 The importance of adequate levels of myelin for each type of nerve fiber is emphasized by diseases like multiple sclerosis, which is caused by demyelination of the central nervous system. 21 Presence of myelinating cells (Schwann cells) at the site of a nerve injury is therefore hypothesized to be crucial for adequate peripheral nerve regeneration. PATHOPHYSIOLOGY OF NERVE REGENERATION Seddon, later supplemented by Sunderland, refined a classification concerning the severity of peripheral nerve injury. Grade I, neuropraxia, includes the loss of the myelin sheath, without damage to the axon. When the myelin sheath and the axon are damaged but the nerve casings (endoneurium, perineurium, epineurium) are still intact, one speaks of a grade II nerve injury, axonotmesis. In grade III, (endoneurium) and grade IV (endoneurium and perineurium), the connective tissues surrounding the axons are additionally injured. Grade V is a complete transection of the nerve (myelin, axon, endoneurium, perineurium, epineurium), neurotmesis. 22, 23 Grade VI is a later proposed addition to the classification and describes different grades of injury along the course of the nerve. 24 In large axon injuries or injuries close to the neuron cell body, neuron death can occur. In cases with axonal injury distant from the neuron, axons are able to regenerate. Considering their complex composition, injured peripheral nerves require complex recovery processes to restore their function. This starts with Wallerian degeneration; damaged cells die by apoptosis and axonal and myelin debris distal to the injury is phagocytosed by activated macrophages. 25 Part of the damaged and nearby lying Schwann Cells change their gene and protein expression, resulting in non-myelinating, proliferating Schwann Cells. 26, 27 Wallerian degeneration blends into nerve regeneration when the neurons, macrophages and Schwann