Journal of Neurotrauma

Trauma victims with cervical spinal cord injuries should be managed by proper immobilization and immediate reduction of spinal cord fractures to anatomical alignment. Patients must be stabilized medically, and a thorough neurologic and radiographic evaluation must precede any surgical intervention. Treatment must be individualized and depends on the level and severity of injury. New pharmacotherapies under intensive investigation offer some hope of recovery of function to patients with spinal cord injuries. Recent clinical trials with methylprednisolone indicate that the sensory and motor outcome of patients subject to trauma with spinal cord injuries improved when they received high doses within 8 hr of injury. Clinical trials are being proposed with tirilizad, a member of a new family of drugs, the 21-aminosteroids. This agent, which may be even more effective than methylprednisolone, has none of the side effects associated with other steroids.

The generation of oxygen radicals and the process of lipid peroxidation have become a focus of attention for investigators in the fields of central nervous system (CNS) injury and stroke (e.g., ischemia). While absolute proof for their involvement in the pathophysiology of traumatic and ischemic damage to the CNS remains to be established, numerous recent studies have provided considerable support for the occurrence of free radical and lipid peroxidation reactions in the injured or ischemic CNS. Furthermore, the use of antioxidants and free radical scavengers in the treatment of experimental and clinical CNS trauma and ischemia has provided convincing support for the involvement of oxygen radicals and lipid peroxidation in these conditions. In this report we will review some of the history behind the hypothesis for an involvement of oxygen radical-mediated lipid peroxidation in the pathophysiology of CNS injury and look at some of the more recent work conducted in this area.

Calcium ions initiate and regulate responses of central nervous tissues to injury. Calcium ions entering injured cells will activate phospholipases, disrupt mitochondrial electron transport, and release free radicals. Neurons normally possess a large reservoir of substances to bind calcium, as well as calcium-activated proteins that protect phospholipids and free radical scavengers. However, calcium entry can initiate a stereotyped injury response. Injured cells release potassium and neurotransmitters that depolarize neighboring cells and cause further calcium entry. Free radical and phospholipase attack of membranes cause lipid peroxidation, generating more free radicals and releasing arachidonic acid. Cyclo-oxygenase and lipo-oxygenase convert arachidonic acid to prostaglandins and leukotrienes, eicosanoids that cause edema and vasoconstriction. Why have neurons, the longest-lived and most important cells of the body, evolved these elaborate autodestructive mechanisms? The calcium-activated injury response may serve a protective purpose. Potassium and neuro-transmitter release spreads the calcium load over many cells. Membrane breakdown floods extracellular fluids with phosphates and phosphatides that bind calcium ions. Lowering extracellular calcium activity efficiently reduces the driving force for calcium entry into surviving cells. Edema and vasoconstriction resulting from eicosanoids slow calcium diffusion from blood and surrounding tissues, reducing the probability of "calcium paradox" when calcium returns. The tissue rapidly eliminates moribund cells that would otherwise consume precious metabolic resources. The possibility that the injury response may be protective has important therapeutic implications.

Bradykinin, a nine-amino-acid peptide formed from a large precursor polypeptide (kininogen) by the action of the enzyme kallikrein (kininogenase), is the initial mediator of inflammation, and, in particular, bradykinin induces pain and alters vascular permeability. Bradykinin is one of the first compounds produced at the site of tissue injury and subsequently initiates a cascade of reactions that produce the cardinal features of inflammation. We will explore the role that bradykinin plays in various types of neuronal injury. In particular, we will focus on the role that bradykinin and other kinins play in brain and spinal cord trauma, in the pathophysiology of subarachnoid and intraparenchymal hemorrhage and ischemia, and in the initiation of nociceptive pain. This role suggests that bradykinin antagonists may be clinically useful in the therapeutic management of neurosurgical patients.

Following traumatic brain injury, cells that are not directly, and thereby irreversibly damaged are subjected to ionic fluxes including potassium and calcium. This injury-induced ionic flux is a result of both neuronal firing via direct mechanical stimulation of the neurons as well as the activation of ligand-gated ion channels primarily associated with excitatory amino acids (e.g. glutamate). This ionic destabilization places enormous energy demands on these cells in order to activate pumping mechanisms to reinstate normal ionic balance. The primary fuel used to acquire this energy is glucose, which results in a period of hyperglycolysis leading to the accumulation of lactate. This acute period of increased glucose metabolism lasts only during the acute period, after which these same cells exhibit a state of chronic metabolic depression for both glucose and oxygen. This metabolic derangement may prevent the necessary energy production for maintaining cellular protein synthesis which is inhibited following traumatic brain injury.

This injury-induced metabolic derangement is not uniform throughout all regions. Some structures are more or less affected presumably due to their proximity to the site of trauma and/or to the extent to which they have a preponderance to being more vulnerable to insult. Within these affected regions, the metabolic dysfunction indicates that cells are functionally compromised in their ability to respond to both normal physiologic and pathophysiologic challenges. This results in the expression of neurological deficits and an enhanced vulnerabil-ity of these cells to a second insult, both of which dissipate as normal metabolic function returns over time.

Since the discovery of nerve growth factor (NGF) nearly 40 years ago, extensive studies have elaborated the trophic relationship between a neuron and its end organ. Much evidence has accumulated that depicts the crucial role of neurotrophic factors in determining neuronal survival both during development and after injury. The molecular events by which trophic factors determine whether an individual neuron lives or dies are poorly understood. The function of active protein synthesis as a prerequisite for neuronal death has led to the hypothesis that all neurons contain a mechanism to self-destruct or a phenomenon of programmed cell death. The loss of trophic support may, therefore, lead to the initiation of this so called "suicide" program within individual cells. Recently, multiple other trophic factors have been discovered. At least two of these factors, brain-derived neurotrophic factor and neurotrophin-3, appear related to members of the same gene family as the prototypic neurotrophic factor, nerve growth factor. Other metabolic factors, such as intracellular calcium, may be instrumental in determining the dependence of individual neurons on specific trophic support. A "set-point" hypothesis has been described concerning the relationship between intracellular calcium and the NGF dependency of embryonic neurons in cell culture. Changes in calcium metabolism may be an important determinant in altering trophic dependence and naturally occurring cell death. Neurotrophic factors also influence the reaction of the neuron to axotomy and subsequent axonal regeneration. Exogenously supplied trophic factors may prevent neuronal loss after axotomy when supplied at the site of injury. Both NGF and FGF have been shown to enhance early regeneration across gaps within silicone chambers. After axotomy, NGF and the NGF receptor are both increased in the Schwann cell within the distal nerve segment; such changes may be important in providing neurotropic support for growing axons.

Understanding these neurotrophic agents may allow one to control better the fate of individual neurons during development or after injury. The ability to alter the neuronal response to injury and to trophic factor deprivation has potential clinical significance. By understanding mechanisms associated with neuronal death, one may gain insight into the causes of neurodegenerative disorders characterized by neuronal loss and develop possible therapeutic strategies to ameliorate neuronal loss. Any agent able to mitigate the disastrous sequelae after neuronal trauma may have clinical utility.

The occurrence of astrocytic swelling in response to CNS trauma is reviewed. This response occurs rapidly and appears earlier than the reactive astrocytic response to neuronal and axonal injury. Astrocytic swelling is viewed as an exaggerated pathologic extension of normal astrocytic functions, such as regulation of extracellular ion levels and brain pH. Potential deleterious consequences of swelling, such as failure of ion homeostasis mechanisms, impaired uptake of neurotransmitters, and release of excitotoxic amino acids, are discussed. Possible pharmacologic interventions are reviewed showing that inhibition of such swelling or prevention of some of its potential deleterious consequences by an anion transport inhibitor, L-644,711, may have beneficial effects in head trauma.

Disruption of myelinated nerve fibers usually constitutes the most significant damage contributing to chronic neurologic deficits in severe spinal cord injuries. Inflammatory responses form one facet of a wide array of pathologic phenomena that combine to produce this damage. The therapeutic importance of inflammation is amplified by its delayed time-course and the number of different approaches that may be taken to its modulation. The response to trauma involves two significant waves of cellular infiltration: the first, dominated by polymorphonuclear leukocytes, peaks within a few hours; the second, by macrophages, begins after 1-2 days and reaches a peak at 5-7 days. Secondary demyelination of surviving nerve fibers and delayed loss of axons coincide with the macrophage response, and may be an example of "bystander damage" caused by the cytotoxic products of activated phagocytes. We know relatively few details of this delayed pathologic change, even in animal models. In particular, it is difficult to separate potential beneficial effects of macrophages in removing cellular debris, stimulating tissue revascularization and repair of the central nervous system environment, from the potential destructive effects associated with their phagocytic activity and their stimulation of scar formation through the release of factors that induce proliferation of peripheral cellular components within the injured spinal cord.

Traumatic neural injury is often accompanied by demyelination. The factors that determine the ability of the CNS to remyelinate are examined as well as the origin of the cells responsible for the remyelination. Evidence is presented that suggests that both a precursor-type oligodendrocyte as well as an oligodendrocyte that previously formed a myelin sheath are able to remyelinate in the CNS. A key determinant of the success of remyelination is the ability for either cell type to proliferate before remyelination. We have developed a method to isolate the oligodendrocyte from the mature CNS and studied the mitotic potential of these adult oligodendrocytes in vitro. In contrast to neonatal oligodendrocytes, the adult oligodendrocytes respond weakly to soluble and particulate mitogens. However, when cocultured with neurites, the adult oligodendrocytes demonstrate a more vigorous mitotic response, which may be related to the ability of the neurite to upregulate receptors which transduce the mitotic signal. Since we have identified fibroblast growth factor as a mitogen associated with the axonal plasma membrane that stimulates neonatal oligodendrocytes to divide, we have examined the redistribution of membrane-associated fibroblast growth factor in an in vitro model of neuronal injury. After neuritic injury, fibroblast growth factor containing membrane vesicles were redistributed to the surface of cocultured oligodendrocytes. After invasion of macrophages to a site of neural injury, enzymes secreted by macrophages can release extracellular stores of fibroblast growth factor into the vicinity. This burst of mitotic potential may preferentially stimulate astrocyte rather than oligodendrocyte division, leading to glial scarring and a subsequent failure of remyelination. Other factors to be considered in the potential for remyelination after injury are astrocyte-derived factors that inhibit myelination and the proteins in oligodendrocytes that prevent axonal regrowth indirectly influencing remyelination potential. Thus, provided the oligodendrocyte can gain access to relevant mitogens either in the axonal plasma membrane or in a soluble form and undergo a wave of proliferation, there is good potential for remyelination after neural injury. However, if axonal regrowth is inhibited and astrocytes preferentially are stimulated to divide and form a glial scar, the prognosis for remyelination is poor.

Demyelination in white matter tracts has been observed in experimental and human spinal cord injury. The pathophysiology of demyelinated axons depends, in part, on their ion channel organization. Myelinated axons display a complementary distribution of sodium channels (clustered in the nodal axon membrane) and fast potassium channels (in the internodal axon membrane). The low density of sodium channels in the internodal axon membrane will impede conduction after demyelination. Moreover, “unmasked" potassium channels will tend to clamp the axon membrane close to Ek, interfering with conduction in demyelinated axons. Pharmaco-logic blockade of these potassium channels can increase the safety factor for conduction in demyelinated axons.

Restoration of conduction in demyelinated axons, so that action potentials can traverse the zone without myelin, appears to underly clinical remissions in patients with multiple sclerosis and may occur in some patients with spinal cord injury. At a cellular level, conduction through demyelinated axon regions can be facilitated by several mechanisms, including remyelination, development of excitability in demyelinated regions (which requires an adequate density of sodium channels), and impedance matching. Astrocytes have been shown to establish a specific relationship with sodium channel-rich regions of the axon membrane, and may play a role in the deployment and/or maintenance of sodium channels within the demyelinated axon membrane.

Calcium influx appears to play a critical role in the cascade of events leading to secondary injury after spinal cord trauma. Recent observations suggest the hypothesis that myelin damage in spinal cord trauma may be mediated, at least in part, by influx of calcium into an intracellular compartment. As the route of calcium entry is identified and characterized, it may be possible to design strategies that will limit secondary injury after CNS trauma. The deleterious effects of calcium in injured white matter accumulate gradually, which suggests the potential reversibility of dysfunction in spinal cord tracts if treated early after trauma.

The neural circuitry of the lumbar spinal cord can generate alternating extension and flexion of the hindlimbs. The hindlimbs of adult cats with complete transection of the spinal cord at a low thoracic level (T12-T13) can perform full weight-supporting locomotion on a treadmill belt moving at a range of speeds. Some limitations in the locomotor capacity can be associated with a deficit in the recruitment level of the fast extensors during the stance phase and the flexors during the swing phase of a step cycle. The level of locomotor performance, however, can be enhanced by daily training on a treadmill while emphasizing full weight-support stepping and by providing appropriately timed sensory stimulation, loading, and/or pharmacologic stimulation of the hindlimb neuromuscular apparatus. Furthermore, there appears to be an interactive effect of these interven-tions. For example, the maximum treadmill speed that a spinal adult cat can attain and maintain is significantly improved with daily full weight-supporting treadmill training, but progressive recruitment of fast extensors becomes apparent only when the hindlimbs are loaded by gently pulling down on the tail during the stepping. Stimulation of the sural nerve at the initiation of the flexion phase of the step cycle can likewise markedly improve the locomotor capability. Administration of clonidine, in particular in combination with an elevated load, resulted in the most distinct and consistent alternating bursts of electromyographic activity during spinal stepping. These data indicate that the spinal cord has the ability to execute alternating activation of the extensor and flexor musculature of the hindlimbs (stepping) and that this ability can be improved by several interventions such as training, sensory stimulation, and use of some pharmacologic agents. Thus, it appears that the spinal cord, without supraspinal input, is highly plastic and has the potential to "learn," that is, to acquire and improve its ability to execute full weight-supporting locomotion on a treadmill belt.

Spinal cord injury models continue to be used to learn more about the pathophysiology of injury as well as potential therapeutic interventions. Most researchers now rely on rat models of injury with injury produced by impact, compression, or even photochemical techniques. A number of laboratories have confirmed that reproducible and graded injury can be produced in the rat with outcome monitored by behavioral, neurophysiologic, and morphologic analyses. Biochemical, physiologic, and pharmacologic studies with these models are being used to further define factors that contribute to chronic injury and thus may be the subject of therapeutic intervention. In addition, a new approach to therapy is being explored via implantation of cells into the injured spinal cord. Cell suspensions can be implanted in clinically relevant injury models without exacerbating the effects of injury and with some indications of beneficial effect. The potential usefulness of such an approach is just beginning to be evaluated.

This paper describes historical and current experimental models used to develop our current understanding of the biomechanics and pathophysiology of traumatic spinal cord injury; the advantages and limitations of current experimental models; considerations for selecting an appropriate injury model based on experimental objectives; and key physiological factors in the spinal cord injury response that may interact with the injury response and alter the outcome. All of the above must be considered in the development and selection of an appropriate experimental injury model that meets specific needs.

Various experimental models have been developed to study spinal cord injury and the pathophysiological and physical mechanisms responsible for tissue damage and loss of function. Such modeling may involve inherently different biomechanical variables with alternative outcomes and purposes. There is not, therefore, a single "ideal" experimental injury model just as there is no "stereotypical" clinical spinal cord injury. Instead, the goals and objectives of the research dictate specific requirements on the model. In all cases, however, both physical and physiological aspects of the model should be considered, and measured if possible, to ensure interlaboratory comparability and possible clinical relevance. Also, experimental techniques, especially anesthesia, and surgical procedures, should be carefully reviewed for interactions with the injury response or potential therapeutic interventions to ensure validity of interpretation.

It is hoped that data correlating physical spinal cord injury parameters with functional outcome will ultimately be combined with data on vertebral injury and spinal failure mechanics to further our understanding of clinical injury. Such approaches should lead to interventions that reduce the incidence and severity of traumatic human spinal cord injury.

Brain missile wounding (BMW) affects brainstem and medullary cardiorespiratory functions leading to immediate systemic hypertension, bradycardia, and apnea. Secondary complications may also occur because of subsequent changes in systemic and intracranial physiological variables. To delineate the immediate and secondary effects of BMW, we monitored changes in several cerebral and cardiorespiratory parameters in pentobarbital-anesthetized spontaneously breathing cats before wounding and up to 90 min afterward. Total and regional cerebral blood flow (rCBF) and cardiac output (CO) were measured (microsphere technique) and arterial blood was sampled for pH, PO₂ and PCO₂ once before BMW and one to four times afterward. Mean arterial blood pressure (MABP), intracranial pressure (ICP), cerebral perfusion pressure (CPP=MABP – ICP), electrocardiogram (ECG), heart rate (HR), and electroencephalogram (EEG) were continuously recorded. Respiratory frequency (f), tidal volume (V_t), and ventilation (V) were recorded during each flow measurement and periodically throughout the experiment. Four unwounded cats served as controls and 15 cats were wounded at 1.4 J fronto-occipitally through an intact cranium.

Unwounded cats showed no significant changes in any physiological variable measured during a 100 min experimentation period. Four wounded cats survived a 90 min post-BMW period and had only a transient brainstem effect including a 50% increase in MABP concurrently with 50% reductions in the f and HR. Nonsurvivors (11 of 15) lived from 1 to 41 min after wounding. These cats initially demonstrated similar changes in MABP, f, and HR to survivors, but these variables remained unstable, possibly indicating a persisting brainstem damage. Apnea accounted for death in 10 of 11 nonsurvivors. Although the primary brainstem effect might have existed in all nonsurvivors, it appears that only one cat died from reduced respiration alone. Others had one or several postwounding secondary complications: abruptly increased ICP producing a negative CPP, extreme reductions in CO or CBF and ventilation. Cardiac arrest occurred once. Thus, post-BMW mortality cannot be consistently ascribed to the impairment of a single physiological variable.

Free radicals have been implicated in the injury that occurs to brain tissue in response to ischemia and reperfusion insults. Confirmatory in vivo studies have been limited by the difficulty in measuring free radicals in brain tissue. This review discusses potential mechanisms for free radical production in brain tissue and the evidence supporting the therapeutic efficacy of free radical scavengers. Free radicals may be produced during ischemia/reperfusion as a result of multiple mechanisms involving normal regulatory systems of intra-/ extracellular metabolism. For example, metabolism of free fatty acids by the cyclo-oxygenase pathway and adenine nucleotides by xanthine oxidase has been proposed to produce free radical adducts during reperfusion. Therapeutic strategies aimed at decreasing brain injury from free radical production include administration of free radical scavengers at the time of reperfusion. Pharmacologic interventions for protection from free radical injury in brain are hindered because of limited access to the site of free production.

Oxygen radical-mediated lipid peroxidation appears to be a critical factor in posttraumatic neuronal degeneration. Thus, numerous studies have evaluated the neuroprotective efficacy of pharmacologic agents with lipid antioxidant activity in models of spinal cord and brain injury. Intensive pretreatment of animals with the endogenous lipid peroxyl radical scavenger alpha tocopherol (i.e., vitamin E) has been shown to decrease posttraumatic spinal cord ischemia and to enhance chronic neurologic recovery. However, the slow CNS tissue uptake of vitamin E requires chronic dosing, making it an impractical agent for the treatment of acute neural injury. The glucocorticoid steroid methylprednisolone has been shown to possess significant antioxidant efficacy and, when administered to animals or humans in antioxidant dosages, improves chronic neurologic recovery after spinal cord injury. This activity of methylprednisolone is independent of the steroid's glucocorticoid receptor-mediated actions. Novel antioxidant 21-aminosteroids have been developed that are devoid of glucocorticoid activity but have greater antioxidant efficacy than methylprednisolone. One of these, U74006F or tirilazad mesylate, has been shown to be effective in animal models of brain and spinal cord injury and is currently undergoing phase II clinical trials. Compounds that combine the amino functionality of the 21-aminosteroids with the peroxyl radical scavenging chromanol portion of vitamin E (i.e., 2-methylaminochro- mans) have also recently shown promise as neuroprotective agents. The consistent benefit afforded by antioxidant compounds adds further support to the concept that lipid peroxidation is an important therapeutic target for acute pharmacologic neuroprotection.

Research into traumatic brain injury (TBI), focusing on changes in energy metabolism, cerebrovascular dysfunction, and brain parenchymal morphology, has not produced complete descriptions of mechanisms mediating the pathophysiology of TBI. New studies indicate that neurochemical alterations mediate important components of brain physiology associated with TBI, and these alterations may be responsive to pharmacologic therapy. We discuss rodent models of TBI, review current experimental evidence of muscarinic cholinergic and excitatory amino acid (EAA) receptor involvement in its pathophysiology, and address issues relevant to the interpretation of these data.

Axonal injury appears to be a feature common to all traumatic brain injuries, and has been linked to much of the morbidity seen in head-injured patients. We consider how such axonal injury contributes to morbidity and also sets the stage for CNS reorganization postinjury. Efforts should continue to determine the correlates of such reorganization and to find therapeutic strategies to expedite it.

Although the mechanisms underlying secondary or delayed damage after traumatic injury to the central nervous system (CNS) are poorly understood, delayed neuronal injury may result from pathologic changes in the brain's endogenous neurochemistry. These neurochemical changes may include the overactivation of neurotransmitter release systems, changes in presynaptic or postsynaptic receptor binding, or the pathologic release or synthesis of autodestructive injury factors. Identification of such factors and the timing of the neurochemical cascade after CNS injury provides a window of opportunity for treatment with pharmacologic agents that modify synthesis, release, receptor binding, or physiologic activity with subsequent limitation of damage and disability. Over the past decade, a number of experimental studies have reported that modification of postinjury events by pharmacologic manipulation can promote functional recovery in a variety of animal models of CNS injury. This article summarizes the recent work suggesting that endogenous opioid peptides, catecholamines, and magnesium all play a role in the pathophysiologic cascade after brain injury and that pharmacologic manipulation of these endogenous systems may improve functional outcome after brain injury.

Remarkable advances have been made in pharmacologic treatments of acute and chronic spinal cord injury. The recent National Acute Spinal Cord Injury Study (NASCIS) showed that very high dose methylprednisolone given within 8 hr after injury improves neurologic recovery. The mechanism is believed to be inhibition of lipid peroxidation. Many other drugs have been claimed to be beneficial in animal studies, including other lipid peroxidation inhibitors, free radical scavengers, opiate receptor blockers, NMDA receptor blockers, calcium channel blockers, inhibitors of arachidonic acid metabolism, and protease inhibitors. In chronic spinal cord injury, much progress also has been made. Myelin was found to possess factors that inhibit axonal regeneration. Blocking these factors enhances spinal cord regeneration. Monosialic gangliosides (GM1) were recently found to improve neurologic recovery in spinal-cord-injured patients. Given as late as 48-72 hr after injury, the mechanism of action is not well understood. However, the GM1 results give hope that recovery mechanisms can be manipulated pharmacologically. Nonregenerative therapy for chronic spinal cord injury is also being developed. Several drugs, including 4-aminopyridine and baclofen, respectively blockers of potassium channels and GABA-B receptors, improve conduction in demyelinated axons. These drugs may be useful for identifying patients who might benefit from remyelination therapy. Finally, NASCIS has complicated acute spinal cord injury studies. To bring a drug to clinical trial, an investigator must now determine the optimal treatment dose, timing, and duration over a range of injury severities, in comparison and combination with methylpred- nisolone. This requirement has so increased the scale of drug testing that multicenter laboratory trials may be necessary.

After trauma to the nervous system, the peripheral nervous system and the central nervous system (CNS) behave differently from each other. In the peripheral nervous system, regenerative sprouts often elongate and grow over long distances to reestablish functional connections. In the CNS, regenerative sprouts do not elongate beyond 1 mm. Tissue culture and biochemical experiments have demonstrated the presence of inhibitors of neurite growth, proteins with molecular weights 35 and 250 kDa (NI-35, NI-250) which exclusively occur in CNS myelin. Their neutralization leads to long-distance fiber regeneration in spinal cord and brain of the rat.

Neural tissue transplantation has become recognized widely as a powerful experimental tool for studying structure-function relationships, development, plasticity, and capacities for regeneration in the adult CNS. In addition, this area of investigation has generated considerable interest in approaches that might be applicable to a variety of catastrophic neurological disorders. In this regard, attention has been given to neural tissue grafting as a potential therapeutic strategy in various forms of neurodegenerative disease. More recently, however, other investigations have begun to focus on the possible application of peripheral and central neural tissue transplants for promoting repair in forms of CNS trauma. This review highlights various neural transplantation approaches that have been explored primarily in the context of injury to the adult CNS, with emphasis on spinal cord injury. An overview is presented of the evolution of this area of research in terms of emerging biological perspectives, technological advances, and experimental modelling. Discussion centers on progress that has been made and a variety of theoretical and practical issues that remain to be resolved.

Neuroimaging with CT and MRI is a basis for decision making in individual head-injured patients and also provides a classification of patients according to severity of damage, patterns of injury, pathophysiologic mechanisms and prognosis. Such classifications can be based on the intracranial lesions identified: subdural, extradural, and intracerebral hematomas, contusions, and shearing lesions, or indirect indications of raised intracranial pressure and brain swelling: shift, obliteration of the third ventricle and basal cisterns, and signs of ischemia. The appropriate classification for early diagnosis and acute decision making may differ from the assessment of severity of damage, prognosis and late sequelae. Parallel systems of classification, suitable for these purposes, are proposed.

This review summarizes currently available epidemiologic, clinical, pathologic, and outcome data in patients with moderate head injury (MHI, GCS 9–12). This important subset comprises about 20% of head injuries in the United States. Affected patients usually are young, and most injuries are due to vehicular accidents. Current evidence (mortality rate and outcome) from various studies suggests an apparent dichotomy within the MHI category (9-10 vs 11-12). The fomer is more in keeping with the favorable subgroup of severe head injuries, and the latter is more appropriate to the mild head injury group. Should there be a reclassification based on this dichotomy? This is obviously important for clinical management and prognostication in these patients. The experimental evidence for a pathologic and biochemical substrate of MHI is reviewed. It is becoming increasing evident that biochemical mediators of secondary neuronal injury in MHI are at least as important as those attributed to severe head injury, but MHI may be more amenable to therapy. It may be prudent, therefore, to direct further effort to this subgroup of patients. Although additional study is required, the pattern of recovery in MHI as determined by extant neurobehavioral studies is analyzed.

The authors review acute and delayed traumatic intracerebral hemorrhages. Based on recent experimental and clinical data, these injuries' clinical presentation, pathologic characteristics, and treatment are discussed. A description of traumatic hemorrhage based on biomechanics is emphasized.

Management of cerebral gunshot injuries has changed considerably since Cushing's (1916) and Matson's (1948) classification schemes, developed during World War I and World War II, respectively. These military injuries are characterized by either very high mass, low-velocity shrapnel wounds or by high muzzle velocity missiles causing extensive destruction of tissue. The preponderance of low muzzle velocity weapons seen in clinical practice and the availability of computed tomographic (CT) evaluation within minutes after presentation has altered the range of prognostic indicators available to the neurosurgeon and the amount of relative importance placed on each factor. Raimondi and Samuelson (1970) noted this difference in wound ballistics and offered a classification scheme based on initial neurologic assessment. No well-defined classification system for civilian craniocerebral gunshot wounds has been proposed that evaluates and integrates clinical, laboratory, and neuroradiologic data. A retrospective study was performed on all 62 civilians with gunshot wounds to the head admitted to the University of Virginia Hospital between December, 1984, and November, 1990. The patient population consists of 86% males and 14% females, with an age range of 10–72 years; 60% self-inflicted wounds and 32% patients who died en route or immediately upon arrival at the hospital. The overall mortality rate was 55% at 1 week postinjury. Although we have demonstrated an association between some previously defined factors and prognosis in civilian injury, such as admission Glasgow Coma Scale (GCS) (p = 0.001) and initial pupillary response (p < 0.001), we have also defined other significant predictors of outcome including abnormal coagulation states on admission (p < 0.001) and the neuroradiologic examination. Parameters for heads assessed using CT for statistical significance included number and type of intracerebral planes crossed (midsagittal, p < 0.004; midcoronal, p = 0.859; horizontal midventricular, p < 0.002; all three planes crossed, p = 0.017), ventricular involvement (p = 0.024), presence of intracerebral hemorrhage (p = 0.013), and estimation of volume of contused brain on initial evaluation (p < 0.001).

The introduction of structural imaging of the brain by computed tomography (CT) scans and magnetic resonance imaging (MRI) has further refined classification of head injury for prognostic, diagnosis, and treatment purposes. We describe a new classification scheme to be used both as a research and a clinical tool in association with other predictors of neurologic status.

Selected neurophysiologic studies can supplement clinical examination in assessing residual motor function after spinal cord or head injury. The ability of polyelectromyographic recording to detect subclinical suprasegmental control is illustrated in paraplegic patients after spinal cord injury. Excitatory or inhibitory modulation of segmental motor activity in a subpopulation of patients with clinically complete motor paralysis suggests residual connection across the lesion. This observation is consistent with the pathologic finding that complete transection of the spinal cord is rare after spinal cord injury. A preliminary study of motor-evoked potentials also indicates their potential value as an objective measure of the functional status of descending pathways. Neurophysiological assessment of subclinical residual motor function may be useful in understanding the role of suprasegmental input in the manifestation of spasticity, in objectively documenting recovery of function after injury, and may aid in the development of more specific restorative measures. Our limited experience in head-injured patients also suggests the potential usefulness of these tools in supplementing clinical evaluation.

How effectively the survivor of CNS trauma can function in society is the ultimate clinical outcome. Many victims of spinal cord injury (SCI) and traumatic brain injury (TBI) are frequently left with permanent impairment. Measurements of impairment, and the direct relationship to the functional loss and resultant disability, should be the gold standard for determining the effectiveness of interventions.

The primary impairments in SCI are motor and sensory loss while those in TBI are neurobehavioral disorders. Classifications for impairment are reasonably well defined in SCI and several approaches are gaining wide acceptance. We hope that internationally agreed upon standards will be forthcoming within the year. The functional independence measure (FIM), which was developed in the past 6-7 years, will be added to the standards. It shows good reliability for SCI as an overall assessment and some of the specific categories of self-care and mobility. An extension of the FIM is needed for more precise measurement of function in quadriplegic subjects.

Classification of impairment in TBI has been more difficult. While the Glasgow Outcome Scale has gained international acceptance for almost 10 years, it has limitations in gradations from the moderate disability to the good recovery groups. The Disability Rating Scale (DRS) has shown good reliability, better precision than the Glasgow Outcome Scale, and greater reliability than other measures. An extension of the FIM, called the functional assessment measure (FAM), and the DRS are currently being tested by regional TBI centers in the United States. Functional assessment measures should be available within the next several years.

Organized neurosurgery has developed and promoted a national educational program for adolescents to reduce the number of head and spinal cord injuries sustained by this group of young people. The program has been adopted widely, with over 1,000,000 teenagers exposed to it since its inception in 1986. Preliminary data suggest that the program has had a favorable impact on the knowledge and attitudes of young people regarding head and spinal cord injuries, risk-taking behavior, and incidence of injuries.

More than half of all brain trauma is caused by motor vehicle crashes. Prevention strategies that reduce the likelihood of motor vehicle crashes or injuries to occupants will also prevent brain trauma. Many effective strategies have yet to be applied on a large scale. Roadway design improvements such as removal of fixed objects from roadsides, widening roadside recovery zones, installing dividers between opposing lanes of traffic, and replacing fixed utility poles with breakaway designs, have been effective in reducing crashes and injuries. Driver measures of documented benefit include the 55 mph speed limit, safety belt use laws, 21 year legal drinking age, administrative license suspension for drinking drivers, and driving curfews and postponement of licensure for teenagers.

Motor vehicle safety has improved greatly since the National Highway Traffic Safety Administration began regulating vehicle design. Significant design requirements include lap and shoulder belts in front seat positions, and, more recently, automatic safety belts or air bags in front seat positions, head restraints in front seat positions, reinforcing side and roof beams, and the center-mounted brake light.

The most significant future advance will be the provision of full front seat air bags in all passenger vehicles. As much as one-quarter of brain trauma can be prevented or reduced in severity by this measure alone. Further safety requirements should include head restraints in rear positions, a-pillar, b-pillar, and roof padding, antilock brakes, and a vehicle rollover standard.

Raised intracranial pressure (ICP) occurs at some time in 50-75% of severely head injured patients. Measurement of ICP alone is not sufficient. Arterial pressure must also be monitored: the important physiological variable is cerebral perfusion pressure. Detailed analysis of the ICP recording yields valuable information on the nature and cause of ICP, with implications for appropriate therapy. Additional measurements of importance include brain electrical activity, arterial and jugular venous oxygen saturation, and blood flow velocity in major intracranial arteries measured by transcranial Doppler sonography. These assessments not only add information about the cause of intracranial hypertension (vascular vs. nonvascular) but also help to regulate therapy, providing early warning that a treatment for reducing the ICP is actually producing global brain ischemia. In the management of raised ICP, all correctable factors must first of all be dealt with, then a choice made between hypnotic drugs and osmotic therapy according to whether the cause of raised ICP is, respectively, vascular or nonvascular.

This article reviews the progress made by the Traumatic Coma Data (TCD) bank participants in studying the influence of raised intracranial pressure (ICP) on outcome in head-injured patients and summarizes new concepts of the pathophysiologic mechanisms involved in ICP rise.

Traumatic brain injury (TBI) often causes disturbances of the cerebrovascular circulation, which contribute to the infliction of secondary injury, although the complex nature of the mechanisms involved is not fully understood. First, the role of ischemia in TBI is still controversial. Despite experimental and pathologic data suggesting important interactions between ischemia and trauma, evidence for posttraumatic ischemia with CBF measurements in patients so far had eluded most investigators. Recent data, however, indicate that low CBF and ischemia probably only occur within the first few hours after injury, yet have important impact on neurologic status and outcome. Similarly, the clinical significance of posttraumatic hyperemia is unclear. A relationship between raised intracranial pressure (ICP) and hyperemia has been suspected, but reports have not been consistent, possibly due to a dissociation between CBF and CBV in head-injured patients. Measurements of CBV in the acute stage of severe head injury now have confirmed this concept, and also suggest that increased CBV may contribute to brain stiffness and elevated ICP. Impairment of cerebrovascular CO2 reactivity and autoregulation often occurs after TBI. Although no correlation with the severity of injury or outcome has been established, it is obvious that diminished adaptive responses of the cerebral vasculature render the brain more vulnerable to additional systemic insults, such as derangements of blood pressure, altered rheology, or hypoxia. The posttraumatic status of vascular reactivity and autoregulation also has important implications with regard to the treatment of high ICP, in particular for the use of hyperventilation and pharmacologic management of blood pressure, which are discussed in detail.

A reduced cerebral blood flow (CBF) and a widened arteriovenous oxygen difference (AVDO2) almost always have been associated with a poor neurologic outcome. The literature on this relationship is reviewed. A logistic regression analysis model of the effect of CBF on neurologic outcome was developed, which was adjusted for various confounding factors. CBF remained significantly associated with neurologic outcome despite these adjustments.

This review discusses recent programs in early and late neurobehavioral recovery from closed head injury (CHI). The research on early recovery has encompassed the relationship of localized brain lesions to the duration of impaired consciousness and features of posttraumatic amnesia. Of the research on late neurobehavioral outcome of CHI, studies emanating from the Traumatic Coma Data Bank are reviewed in detail, including analysis of acute neurologic indices in relation to recovery of memory, information processing speed, and other cognitive measures. Recent studies concerning the neurobehavioral outcome of CHI in children are discussed as are investigations of behavioral disturbance, psychosocial outcome, and family variables. The review concludes with an assessment of recent studies concerning the efficacy of rehabilitation directed toward the cognitive sequelae of CHI and preliminary trials to evaluate the potential use of psychoactive drugs in the postacute management of head injured patients.

The patient with head injury must overcome central and systemic insults. In addition to the head injury itself, the patient suffers a systemic metabolic response to injury. Both of these insults can affect the patient's ability to survive and recover. During the past decade, investigators have described the systemic metabolic result identified by hypermetabolism, hypercatabolism, the acute-phase response, decreased immunocompetence, hyperglycemia, increased counterregulatory hormone levels, increased ventricular fluid and serum cytokine levels, and altered gastric function. During the next decade, investigators will attempt to modulate this response by manipulating the types of nutrients administered, use of pharmacologic and physiological agents, and administration of growth factors.

In 1990, the Second National Acute Spinal Cord Injury Study reported that high-dosage methylprednisolone improves neurologic recovery in spinal-injured humans. The study showed that patients who received the drug within 8 hr after injury improved, whereas those who received the drug later did not. The drug significantly increased recovery even in severely injured patients who were admitted with no motor or sensory function below the lesion, contradicting a long-held dogma that such patients would not recover. Some researchers, however, have questioned the stratification of the patient population, the use of summed neurologic change scores, and the absence of functional assessments. The stratification by injury severity and treatment time was planned a priori and based on objective criteria. Detailed analyses revealed no differences between groups attributable to stratification or randomization. While multivariate analyses of the summed neurologic scores were used, the conclusions were corroborated by other analytical approaches that did not rely on summed scores. For example, treatment with methylprednisolone more than doubled the probability that patients would convert from quadriplegia or paraplegia to quadriparesis or paraparesis, analgesia to hypalgesia, and anesthesia to hypesthesia. The treatment also significantly improved neurologic scores in lumbosacral segments, indicating that beneficial effects were not limited to segments close to the lesion site. The treatment did not significantly affect mortality or morbidity. The study strongly suggests that methylprednisolone has significant beneficial effects in human spinal cord injury, that these effects occur only when the drug is given within 8 hr, and that it helps even in patients with severe spinal cord injuries. These conclusions have important implications for spinal cord injury care and research.

Spinal cord injury is typically a devastating injury with no or only limited neurologic recovery. Recent papers have reported enhancement of neurologic recovery following spinal cord injury with both methylprednisolone and GM-1 ganglioside. This paper provides additional details of the GM-1 study and a further analysis of recovery of motor function for each of the ten neurologic levels assessed in the study. This additional analysis provides further evidence that the largest enhanced recovery of motor function in the GM-1 treatment group occurred in the muscles of the lower extremities and is consistent with the enhanced recovery occurring in the white matter tracts passing through the level of injury.