Pathophysiology and Therapy for SCI/TBI 21 Traumatic Brain Injury and Spinal Cord Injury: Pathophysiology and Acute Therapeutic Strategies Ross D. Zafonte, Benton T. Giap, William M. Coplin, and Pedrang Pangilian Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 The cellular cascades of damage to the central nervous system (CNS) are becoming increasingly clear. The foundation of evidence is based primarily on animal models. Although there is a growing body of knowledge of therapeutics for traumatic brain injury (TBI) and spinal cord injury (SCI), the literature is scanty in addressing therapeutic intervention for both. It is unclear why current treatment protocols are proven to be effective in one neurotrauma subpopulation and not efficacious in another group. For instance, methylpred- nisolone has been noted to be associated with worse outcome in penetrating SCI, yet to be beneficial in other traumatic SCI causes. This article will review the anatomical basis, common pathophysiological processes, and therapeutics for TBI and SCI. A broad overview of current beliefs regarding management techniques and novel neuroprotective therapies, which may eventually influence functional outcome, will be presented for the rehabilitation professional. Key words: pathophysiology, spinal cord injury, traumatic brain injury DVANCES IN basic neurobiology range of function and structure. Reversible research have added much to the injury, irreversible injury, and cell death can Aknowledge base of the pathophysiol- be considered progressive stages of dysfunc- ogy of traumatic brain injury (TBI) and spi- tion when exogenous stimuli are greater than nal cord injury (SCI). It is well recognized the adaptive response.2 Cell death is the final that there are primary and secondary injuries and ultimate result of cellular injury. The of the central nervous system (CNS) after a traumatic insult. Primary injury consists of Ross D. Zafonte, DO, is Interim Chairman and Asso- the initial neurochemical damage, which oc- ciate Professor, Department of Physical Medicine and Rehabilitation, Wayne State University, Detroit, curs at initial impact. This phase can only be Michigan. modified by injury prevention. Secondary injury is progressive cellular damage, which Benton T. Giap, MD, is Traumatic Brain Injury Fel- is a result of degradative biochemical pro- low, Rehabilitation Institute of Michigan, Department cesses that are set in motion at the time of the of Physical Medicine and Rehabilitation, Wayne State University, Detroit, Michigan. injury. Considerable research effort has been directed toward clarifying the time course William M. Coplin, MD, is Assistant Professor, De- and nature of the biochemical cascades, partments of Neurological Surgery and Neurology, which underlie secondary injury.1 Novel and Medical Director of Neurotrama Center/Detroit pharmacological therapies are currently be- Receiving Hospital, Wayne State University, Detroit, Michigan. ing developed, all geared at inhibiting and limiting the extent of secondary injury. Cells Pedrang Pangilian, MD, Wayne State University, have a number of adaptations, such as atro- Detroit, Michigan. phy, hypertrophy, hyperplasia, and metapla- Top Spinal Cord Inj Rehabil 1999;5(2):21–40 sia to stressors, to maintain a fairly narrow © 1999 Thomas Land Publishers, Inc. 21 22 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 1999 causes of most cell injury can be catego- tions; however, the clinical implications rized into one the following: hypoxia, have not yet been fully realized. physical agents, chemical and drugs, infec- Adequate perfusion to the penumbra re- tious agents, immunological reactions, ge- gion can potentially preserve neuronal cell netic derangements, and nutritional imbal- function after a CNS insult.4 The penumbra ance. However, death of cells occurs by two contains cells that are at risk unless Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 distinct processes, necrosis and apoptosis. reperfusion is reestablished within a certain In necrosis, there is a rapid decline in the window. The focus of recent investigations ability of the cell to maintain homeostasis has been on neuroprotective agents that can and it quickly becomes swollen and disinte- ameliorate damage to the penumbra. Treat- grates, releasing its contents and initiating ment programs based on the maintenance of an inflammatory chain reaction.2 cerebral perfusion and control of intracranial Apoptosis, or programmed cell death, oc- pressure (ICP) have proven to be of critical curs in a more orderly fashion because this importance to the functional outcome of the is a gene-regulated mechanism. This route TBI survivor. Although the foundation of of cell death is less destructive to the sur- acute SCI management consists of correcting rounding cells despite the fact that the cell anatomical abnormalities (i.e., spinal stabili- shuts off its biochemical processes and in- zation) and minimizing secondary damage creases its production of free radicals. with neuroprotective agents, recent evidence Apoptosis occurs as a normal process dur- suggests that adequate perfusion to the spinal ing which abnormal and defective cells are cord after injury is also an important factor. removed.3 Correction of systemic parameters such as In SCI and TBI, a physical agent (me- hypoxia, hypotension, and hyperglycemia is chanical trauma such as impact trauma, com- critical to the current concept of limiting pression, stretch, or transection) is usually secondary injury. The roles of posttraumatic the initial inciting incident. This primary genetic expression and programmed cell injury is usually instantaneous and irrevers- death process in recovery are important areas ible. However, brain and spinal cord function of investigation.5 continue to decline after the mechanical trauma. This has lead to a concept of second- Anatomical Considerations ary trauma, which is injury or loss of function after the initial trauma.4 Secondary injury The CNS is traditionally viewed as consist- patterns include posttraumatic changes, loss ing of the spinal cord and the brain. This is a of energy metabolism, edema, and release of simplistic view of the CNS. Although they cytotoxic substances. The mechanism of sec- both derived from the neural plate, the brain ondary trauma could possibly be one or a and spinal cord have distinct anatomical orga- combination of the aforementioned mecha- nizational complexity.6 Thus, for the sake of nisms of cell injury. The potential for treating limiting heterogeneity that potentially con- TBI and SCI by limiting the secondary injury founds results, most laboratory models of is intriguing and has vast clinical implica- induced SCI and brain injury are studied sepa- Pathophysiology and Therapy for SCI/TBI 23 rately. Such models were criticized on the Current Treatment Paradigms of TBI basis that they were poor replications of actual and SCI injuries. In designing and studying the thera- peutic effects of neuroprotective agents, most The basis for effective treatment of any investigators have relied on animal models pathology depends upon the comprehensive that sustain a particular mechanism of injury. understanding of the cellular-molecular- Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 Because the pathophysiology of SCI shares structural disturbances that need to be modi- certain features with other mechanical and fied. Substantial progress has been made ischemic insults to the CNS, perhaps certain when the complex cascades of injury are therapy can be useful for a number of cerebral better defined. An important principle in this insults as well.7,8 definition is the evaluation of the potential During development, the nervous system positive and negative consequences of arises from the ectoderm layer. The rostral blocking or enhancing any particular path- aspects form three primitive vesicles: way. Despite recent advances, most phase III prosencephalon, mesenecephalon, and trials for severely head-injured patients have rhomencephalon. The prosencephalon de- failed. Recent well-intended trials have velops into the cerebral hemispheres (telen- failed to identify therapeutics that are un- cephalon). The telencephalon undergoes tre- equivocally efficacious. Doppenberg and mendous changes to become a Bullock9 recommended that trial designs tar- three-dimensional entity, influencing the get pathophysiological mechanisms in this configuration of surrounding structures. The heterogeneous population instead of using a other major derivative of the prosencephalon blanket or one-size-fits-all approach. includes the diencephalon, which gives rise to the thalamus and the hypothalamus.6,7 TBI The mammalian spinal cord serves as a conduit for 20 million nerve fibers and func- The main objectives in the management of tions as the relay system for the brain and the the severely head-injured patient are to treat body. The spinal cord consists of the internal the complications of TBI (e.g., increased gray matter, made up of nerve cell bodies, ICP) and to limit secondary CNS damage. glia, and dendrites. The external white matter Vital to this concept is the maintenance of is made up of primarily myelinated fibers. adequate cerebral oxygenation. Miller et al.10 The white matter is further divided into