Neurotrauma

There is increasing evidence that most forms of traumatic brain damage are not immediate, i.e. rather it is a process and not an event that is set into motion by mechanical loading of neurones and their axons, and the vascular system. One of the principal determinants of outcome after injury may well be an ability of nerve cells and their processes to modulate ionic fluxes including Ca2+ through membrane defects generated by mechanical injury, the activation of voltage dependent channels and through receptor mediator channels, such as those associated with the NMDA receptor and possibly non-NMDA receptors. If the cell is capable of binding sequestering, exchanging or pumping Ca2+ then restoration of pre-traumatic levels of intracellular free Ca2+ will occurr. Lf these functions are compromised then a series of enzyme and gene activation may begin. These and other processes singly or in combination will produce acute cell death (necrosis) or delayed cell death (apoptosis). The outcome following head injury is therefore a product of many factors including the genome of the patient. Prospects for improved outcome after closed head injury will require a better understanding of the mechanisms of injury and the types and time course of the ensuing pathology (4). Not only should it then be possible to reduce mortality by prevention or avoidance of head injury, given that it has now been established that the principal mechanisms of brain damage are either contact or acceleratioddeceleration, but also reduce the amount of disability in survivors by various neuroprotective therapies. From a clinical point of view treatment is directed at the type of damage diagnosed and, in particular, as to whether the neurological condition of the patient is due to a focal mass lesicn or diffuse injury to the brain. The detection and management of mass lesions is of paramount importance given the urgent need for surgical evacuation in order to prevent raised intracranial pressure, internal herniation and compression of the brain stem. Such focal brain injuries result from localised damage and accoiir t for approximately 50 per cent of patients with severe head injuries and some two-thirds of deaths associatec. with head injury. In contrast diffuse brain injuries x e associated with widespread dysfunction, which may be functional as in the case of concussion or may involve structural damage as occurs in prolonged traumatic: coma without mass lesions. It is now recognised that the principal pathology in these patients is widespread damage to axons, a condition that is described as diffuse axonal injury. The diffuse brain injuries which account for about 40 per cent of cases with severe injurie: and for about one-third of deaths due to head injury .are the most frequent cause of persisting neurological disability in survivors (3). Although the nature and distribution of damage after head injury is diverse there is increasing evidence that apolipoprotein E (rtpoE) polymorphism is a putative susceptibility risk f x t o r for the effects of head injury. The mechanisms by which apoE influences outcome following brain injury is not clear but there is increasing evidence that apoE allelic variation modulates the development and outcome of several diseases of the central nervous system. Axonal injury in short-surviving head injury Axonal injury results from mechanical distortion of the brain and in its most severe form is the cause of death from catastrophic injuries to the brain in patients who either die at t;ie scene of the accident or before reaching hospital. Lesser amounts of mechanical loading are thought to be responsible for a clinical spectrum that ranges from concussion to post-traumatic coma to the vegetative state. Given the different responses by the various cellular elements of the brain to mechanical distortion, it is likely that the functional deficit is the result of a combination of injuries sustained by axons, dendrites. cell bodies, preand post-synaptic terminals and receptors. and by astrocytes. Particular attention has been given to darnage to axons. especially as laboratory models have now clearly demonstrated that only at the greatest levels of injury do axons become sheared or disconnected, that is undergo primary axotomy. Rather, non-disruptively injured axons under, 00 a sequence of changes which culminate in secondary axotomy, a process that has been studied extensively by electronmicroscopy and immunohistochemistry both in animal models and in Man (6). Laboratory studies have indicated a common sequence of morphological response by axons in response to mechanical loading comprising in sequence focal changes in the structure and permeability of the axolemma, swelling of axonal mitochondria, the development of so-called nodal blebs andor focal decrease in the internodal axonal diameter, loss of axonal microtubules and changes of the intraaxonal relationships of neurofilaments, involution of the internodal axolemma, separation of the axolemma from the internal aspect of the myelin sheath to form periaxonal spaces, the occurrence of so-called axonal swellings, the development of so-called myelin intrusions and finally axonal disconnection to form so-called degeneration or axonal bulbs. The initial axonal changes are thought to be similar in Man 'and certainly immunocytochemical studies in Man for XF-L and (APP have provided novel information concerning the time course of damage to axons after head injury. For example, it has been possible to label axons by (-APP between 1.75 and 2 hours after head injury and clear examples of axonal disconnection may be found between 6 and 12 hours (1, 8). The use of these techniques which are more sensitive than classical silver stains have also demonstrated an apparent continued recruitment of damaged axons up to 24 hours and they may persist for up to 99 days after the initial injury. Such findings provide additional support for the concept that the reactive axon demonstrate a spectrum of progressive pathology rather than there being a single posttraumatic time course that culminates in axonal disconnection between 12 to 24 hours after injury. It has been suggested that the most likely initiating abnormality in axons is the creation of traumatic cell membrane defects that have recently been referred to as mechanoporation (20). There is a transient depolarisation of the axon that allows ionic t'lus t o occ'iiixiti at higher levels of injury the damaged axon becomss permeable to extracellular tracers (10. 1 1 j . Measuremmt of changes in intracellular Ca2+. in isolated axons (,2) and in endothelial cell culture 12 I ) subjectsd to defor-mation have demonstrated transient increascs in cellulnr Ca2+, that parallel the amount of tissue deformation. I n mild cases intracellular Ca?+ levels have become normal after seconds to minutes, but at more severe Icvzls of injury without tissue disruption intracellular Ca?+ may rise to such high levels that it hccomes injurious to the cell. The changes in ionic concentration in certain nerve fibres may activate calmodulin which in turn disrupts the internal cyto-architecture with a loss of microtubules (5 ) . The resulting disorganisation causes focal accumulation of membranous organelles that may progress with the formation of axonal swellings. Earlier studies of secondary axotomy had suggested that trauma acted principally to induce misalignment of the intra-axonal cytoskeleton which in turn impaired axonal transport resulting in axonal swelling and axoto-my (13). While this may be true after mild injuryin a greater level of injury there are changes in both the intra-axonal cytoskeleton and related axolemma ( 1 0). In particular there was rapid compaction of neurofilaments and side-arm loss (10, 11). It is now quite clear that changes in axons are heterogeneous, thereby raising the distinct possibility that the hypothesis are not mutually exclusive and that dependmg on many factors a number of changes may be initiated that reflect a particular mechanisms that has been activated. Furthermore, since there is now clear evidence for a time course extending over several hours of the development of axonal pathology after non-disniptive axonal injury, there is potential for the development of therapeutic strategies to minimise such pathology and thus improve the long-term outcome for the head-injured patient. Clinico-pathological correlations have shown that the clinical findings in a patient are a product of the total number of axons damaged, the summary of the axonal damage, and their anatomical location. Axonal injury is almost always present after head injury and because of its frequency and importance a more full undcrstanding of its pathobiology is required before further improvement in the care of head-injured patients can occur. Influence of apolipoprotein E on outcome One of the most import post functions of apolipoprotein E (apoE) is as a lipid transport protein i 12). Apolipoprotein E is synthesised principally by ilstro___ _ _ __ . . 1286 Plenary Lecture PL5 1 cytes where it is packaged with cholesterol and phospholipid to form lipidprotein complexes which are then released into the extracellular space and internalised into neurones via apoE receptors. By this mechanism cholesterol and phospholipids are transported to neurones to allow the maintenance and repair of cell membranes, the growth of neurites and synaptogenesis. In Man there are three common alleles of apoE gene designated (2, (3 and (4 which encode three isoforms of the protein (E2, E3 and E4) and in vitro data indicate substantial differences in the behaviour of these isoforms. The apoE (4 allele is the most important genetic determinant of susceptibility to Alzheimer’s disease and acts synergistically with a history of a previous head injury (7). Additional evidence linking a history of head injury and Alzheimer’s disease comes from the studies of boxers who have developed Deme