Pathophysiology and Therapy for SCI/TBI 21 Traumatic and : 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 (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 (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 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 and , 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 three funiculi; each is subdivided into groups of longitudinal tracts. The spinal cord remains primarily a longitudinal structure, lacking The main objectives in the the three-dimensional complexity of the ce- management of the severely head- rebral hemispheres during maturation.7 The injured patient are to treat the appreciation of these developmental neu- complications of TBI and to limit ronal differences may assist in the treatment secondary CNS damage. of persons with neurotrauma. 24 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 1999

proposed that ischemia is probably the great- O2 saturation and CPP should be optimized to est factor contributing to secondary damage maximize oxygen delivery.12 Monitoring ce- in TBI. Hypoxia, which results from is- rebral perfusion is a complex issue due to the chemia, disrupts aerobic oxidative respira- fact that posttraumatic CBF alterations are tion. The following mechanisms have been often heterogeneous. Regional CBF may be

proposed as disruptive to cell membranes: elevated and depressed in some parts of the Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 progressive loss of phospholipids, brain.13 This same concept also applies to cytoskeletal abnormalities, reactive oxygen ICP monitoring. species, lipid breakdown products, and loss of intracellular amino acids. Prolonged is- Pressure dynamics chemia contributes to permanent damage of In the person with brain injury, the Monro- the cell membrane, irreversible injury, and Kellie doctrine establishes that within the cell death. Key events in any ischemic le- confines of the cranium, ICP is governed by sions include energy depletion and activation three factors: brain parenchymal volume, of anaerobic glucolysis. Cytoskeletal integ- volume of cerebrospinal fluid (CSF), and rity and homeostatic mechanisms are dis- cerebral blood volume (CBV).4 The relation- rupted and contribute to the cellular death ship between intracranial volume and ICP because of the presence of excess calcium, can be expressed as the pressure volume sodium, and chloride.11 Hypoxia and index (PVI). PVI is the volume that must be perfusional status play a significant role in adjusted from the craniospinal axis to raise or the secondary injury process in TBI and SCI. decrease the ICP 10-fold.14,15 In reality, PVI After an ischemic insult, the complex may not be of practical value, but it illustrates buildup of metabolic products, such as free the importance of the “pressure phenom- radicals, dysregulation of calcium, and exci- ena.” Under normal circumstances, PVI is 26 tatory neurotransmitters, contributes to dis- mL of fluid. To change the ICP from 1 to 10, ruption of neuronal cellular integrity. 26 mL of fluid must be added. However, this The morphological and biochemical same volume (an additional 26 mL) will also changes due to tissue ischemia and hypoxic raise the ICP from 10 to 100 mm Hg. injury have been more clearly defined in Cerebral parenchymal volume (CPV) in- humans and animals, especially in regard to creases after due to the cerebral

cardiac muscle. Oxygen (O2) delivery de- edema resulting in increased ICP. To com- pends primarily on the O2 content of the pensate, CSF is initially displaced from the arterial blood and cerebral blood flow (CBF), cranium and, subsequently, changes in CBV measured in mm/100 g of brain tissue per occur. The arteriolar system, with one third minute. Arterial O2 content is dependent on of the total CBV, is responsible for autoregu-

the level of hemoglobin (Hgb) and O2 satura- lation. Autoregulation allows the blood ves- tion. Cerebral blood flow (CBF) is a major sels to change in diameter in response to determinant of adequate cerebral oxygen- metabolic effect.9 Because autoregulation is ation. Cerebral perfusion pressure (CPP) is compromised in moderate and severe is- the difference between mean arterial pres- chemia, CBF varies passively with perfusion sure (MAP) and ICP.4 Based on this formula, pressure.16 Careful appreciation of potential Pathophysiology and Therapy for SCI/TBI 25

autoregulation abnormalities is key to post- therapy may be more effective than continu- traumatic CNS management. ous fusion.20–22 Mannitol increases intravas- cular volume and has an immediate plasma- Management of ICP expanding effect. Mannitol reduces the Aggressive treatment of elevated ICP has relative concentration of hematocrit, thereby become critical to acute brain injury manage- decreasing blood viscosity, and increases Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 ment. The normal ICP is 0–15 torr. Effective both CBF and cerebral oxygen delivery.23,24 management of elevated ICP (defined as The osmotic effect of mannitol is delayed for >20–25 torr) has been shown to have signifi- 15–30 minutes until gradients are estab- cant impact on outcome.17–19 Based on the lished. Because mannitol is excreted entirely formula, CPP = MAP - ICP, a decrease in ICP in the urine, a risk of renal failure exists when results in an increase in CPP (if MAP is serum osmolarity exceeds 320 mOsm. A maintained). The basis of ICP management reverse osmotic effect is possible because includes ventricular drainage, sedation and mannitol can penetrate into the brain.25 This paralysis, mannitol, hyperventilation, and reverse osmotic shift may be more common barbiturate therapy. with continuous infusion. An additional ben- efit of mannitol is that it may also act as a free Ventricular drainage radical scavenger agent.26 Glycerol, which is An important management technique for metabolized by the liver, can be used in the treatment of ICP is the ventricular cath- patients with severe renal dysfunction. eter that allows the clinician not only to monitor ICP but to effectively treat it by Hyperventilation draining CSF either continuously or inter- Hyperventilation remains a highly effec- mittently. tive, acute treatment for increased ICP via changes in CBV.27 However, studies have Sedation and paralysis demonstrated that prophylactic treatment Short acting, reversible agents are prefer- with hyperventilation is not beneficial.28 In able for sedation in this population. This some cases, vasoconstriction obtained with intervention allows the clinician to manage hyperventilation causes the CBF to drop be- ICP effectively by titration and to avoid low ischemic levels. Thus, hyperventilation overtreatment. Intravenous morphine sul- should not be used for an extended period of fate, benzodiazepines, propofol (Diprivan), time and pCO2 should not be reduced below and nondepolarizing neuromuscular block- 28 mm Hg. Evidence-based guidelines for ing agents such as pancuronium (Pavulon) the treatment of the severely head-injured are commonly used. Opioids have secondary patient from the Brain Trauma Foundation29 effects, which may be of benefit. have advocated against the prophylactic use of hyperventilation. The use of jugular Mannitol venous oxygen saturation and CBF monitor- Doses of 0.25–1.0 g/kg are useful for the ing to identify cerebral ischemia (evolving control of ICP after severe head injury. Lim- from the use of hyperventilation) have also ited data suggest that intermittent bolus been recommended. 26 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 1999

Barbiturates exist among those persons with head trauma, because the accuracy of the neurologic ex- Barbiturates remain a topic of consider- amination during distraction may be im- able debate. The prophylactic use of barbitu- paired. Tator et al.32 reported neurological rates has been discouraged. The proposed deterioration in 8.1% of cases after traction. mechanisms of action for barbiturates are The role and timing of surgical interven- Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 reduction in cerebral metabolic rate of O2 and tion remain somewhat controversial. In a modulation of excitotoxic mechanisms. recent multicenter retrospective study ex- Most neuro-intensivists are concerned with amining the role and timing of surgery in the potential deleterious effects of lowering acute SCI in 36 North American centers, blood pressure, specifically with regard to Tator and colleagues32 found there was little CPP. Barbiturates combined with a vaso- agreement on optimum timing of decom- pressor agent to assist in the maintenance of pressive surgery. Even more unsettling is CPP may be more beneficial. This combina- the lack of consistent and definitive evi- tion therapy in patients with refractory cases dence that surgical intervention leads to of elevated ICP or inadequate CPP needs improved neurological recovery. Surgical further investigation.30,31 reduction has been associated with neuro- logic improvement in certain experiments SCI in animals despite the lack of consistent benefits in humans.35 Reduction appears as a Spinal stabilization possible option in 70%–80% of cases.36 After initial resuscitation of the person Heiden et al.37 demonstrated no neurologi- after injury, radiological evaluation of the cal improvement regardless of the timing or spine should be established. Tator et al.32 type of surgical intervention. However, recommended MR imaging to quantify the Mirza et al.38 retrospectively reviewed out- extent and severity of spinal cord compres- comes of 43 persons with cervical spinal sion. Their review also highlighted the lack injury with neurologic deficits and felt that of uniformity in imaging assessment, be- early surgery (within 3 days) may well im- cause only about half of the patients under- prove neurologic recovery. The decision of went MR imaging. Current surgical and non- surgical management was based on un- surgical interventions focus on promoting stable fracture pattern or neurologic com- stabilization and restoring alignment. Al- pression as determined by the treating phy- though a variety of options are available, the sician. There was no statistically significant use of Gardner-Wells tongs remains popular. difference in the rate of complications be- Overdistraction must be avoided, especially in upper cervical spine injuries with signifi- cant anterior and posterior column instabil- Even more unsettling is the lack of ity.33 General recommendations discuss dis- consistent and definitive evidence that traction forces of 5 lb per cervical vertebral surgical intervention leads to improved level; however, some have recommended neurological recovery. forces as high as 100 lb.34 Clear concerns Pathophysiology and Therapy for SCI/TBI 27

tween the two groups. The authors proposed inflammatory activity and reduced mineralo- that surgical management allowed better corticoid activity.43 Animal studies demon- stabilization than what was possible with strated that dosing regimens that were cen- tong traction and immobilization. Immobi- tered on inhibition of posttraumatic spinal lization effects were compared to five phar- cord lipid peroxidation could result in tissue macological agents in a cohort assembled preservation and promote functional recov- Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 by Ducker and colleagues. 39 They found ery.44 In addition to finding steroids to be an that conservative treatment (immobiliza- effective antioxidant, extensive studies have tion) was associated with better outcomes, noted the importance of steroids in modifica- which were defined as motor index score tion of neuronal excitability, synaptic trans- (based on the American Spinal Cord Injury mission,45 maintenance of aerobic metabo- Association standard) and Frankel Impair- lism,46,47 tissue blood flow,48 and restoration ment Scale. Katoh and Masry40 demon- in calcium dysregulation.49 The basis for glu- strated the recovery of conservatively cocorticoid treatment was founded on the treated persons with cervical SCI. How- effectiveness of this class in treating edema ever, nonsurgical intervention of the un- associated with brain tumors.43 stable spine raises the issue of continued The National Acute Spinal Cord Injury motion and detrimental consequences to the Study (NASCIS) was established in 1975 to healing neuronal tracts.38 Furthermore, the examine acute pharmacological therapies. numerous deletorious effects of immobili- NASCIS I compared high-dose (1,000-mg zation and bed rest are well known and are infusion) versus low-dose (100 mg) methyl- not readily acceptable.41 Surgical practice prednisolone for 10 days. This study failed also has a geographic variation. European to demonstrate a difference between high- investigators favored a nonoperative ap- and low-dose steroid. This is attributed to proach, maintaining patients in tongs and the inadequate dose of steroid. The associa- traction for 6 weeks or more, to allow for tion of steroids with a higher rate of compli- spontaneous fusion.42 Controversy exists cations caused researchers to conclude that regarding specific surgical techniques. The steroids were not beneficial.50 No placebo outcomes of anterior versus posterior ap- control group was used in NASCIS I. proaches also have not been resolved. The NASCIS II was completed in 1990 and recent retrospective study by Tator and col- demonstrated that high-dose methylpred- leagues32 confirms the need for a random- nisolone given within 8 hours of injury ized controlled trial to assess the role and resulted in a clinical difference in neuro- the timing of surgical intervention. logic recovery.51 NASCIS III evaluated 499 persons with traumatic SCI presenting Neuroprotective therapy within 8 hours and resulted in the following Glucocorticosteroids have been studied in recommendations: patients who are initi- well-designed trials in acute and chronic spi- ated on high-dose methylprenisolone nal cord pathologies since the 1960s. Meth- within 3 hours of injury should be main- ylprednisolone is a synthetic glucocorticoid tained on the treatment for 24 hours; how- that was developed for its enhanced anti- ever, if steroid therapy is initiated between 28 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 1999

3 to 8 hours after injury, therapy should be Areas for Future Investigation continued for 48 hours unless there are com- plicating medical factors.52 A one-year fol- Considerable enthusiasm has evolved low-up study revealed no superiority of over the potential of reducing secondary in- tirilazad mesylate (a 21-amino steroid) over jury by blocking or inhibiting certain path-

methylprednisolone administered for 24 ways. If effective neuroprotective therapy Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 hours.53 Of interest, Heary et al.,54 in a retro- became a reality, it would provide a mean- spective analysis, noted that steroids did not ingful intervention for the neurotrauma pa- improve neurologic outcome among persons tient. As the knowledge base regarding the with gunshot wounds to the spine. In addi- exact sequence of events in secondary injury tion, steroid therapy was associated with grows, the opportunity to minimize second- more complications. ary injury develops. Topics that are central to Gangliosides are complex acidic glycolip- the discussion of the pathophysiology of ids in high concentrations in the CNS. There CNS pathology are excitotoxic mechanisms, is evidence supporting the facilitative role of calcium dysregulation, apoptosis, and induc- gangliosides in neuronal regeneration.55,56 tion of lipid peroxidation. Each issue will be Geisler et al.57 explored the neuroprotective elaborated in the following sections. role of GM-1 ganglioside in a small, random- ized trial with 37 patients. In this study, GM- Apoptosis 1 was noted to enhance recovery of neuro- Apoptosis (programmed cell death) is the logic function after a year. process of activating autodestructive mecha- nisms leading to physiologic cell death. Cel- Perfusional Issues lular shrinkage and genomic fragmentation characterize this process. Phagocytes subse- The role of maintaining adequate cerebral quently engulf cells. Regulated protein se- perfusion has been well demonstrated in per- quences are also required.59 Apoptosis is dif- sons with , , ferentiated from necrosis by its characteristic and TBI. Of specific concern is the tendency morphological features of cell shrinkage for persons with SCI to develop relative (chromatin condensation, formation of cyto- hypotension secondary to loss of normal au- plasmic blebs and apoptotic bodies, phago- toregulation mechanisms. In a pilot study, cytosis of apoptotic cells by neighboring Vale et al.58 evaluated the role of aggressive cells, and a lack of inflammation) that are blood pressure management and found that it best seen with electron microscopy.2,60–62 optimizes the potential for neurological re- Apoptosis can be triggered by many exog- covery. Volume expansion and intentional enous stimuli and is dependent, in part, on blood pressure augmentation may serve to gene activation and new protein synthesis. maintain adequate spinal cord blood flow Substances such as heat- proteins, and to preserve neuronal function. This area oncogenes, and bacterial toxins can induce deserves further investigation; the role of apoptosis by activating a number of genes. hyperdynamic therapy has not been ad- Apoptosis-specific genes that stimulate or equately evaluated. inhibit cell death have been identified in the Pathophysiology and Therapy for SCI/TBI 29

development of the nematode C. elegans. overexcitation.64 Choi65,66 has suggested that Many of the genes have homologues in mam- excitotoxic cellular damage occurs via two mals (e.g., ced-3,4 and bcl-2 are induced in mechanisms: an influx of sodium (Na+) and the nematodes and mammals, respectively) calcium (Ca++) that leads to neuronal swell- Even though apoptosis is known to be ing; and Ca++-induced activation of critical in many normal biologic functions degradative enzymes with delayed cellular Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 such as embryogenesis and the endometrial damage. Ubiquitous excitatory neurotrans- cell cycle of menstruation, it is believed to be mitters, such as glutamate, have been found involved in the secondary injury after me- to be among the most prevalent neurotrans- chanical SCI and TBI.61 Emery and col- mitters in the CNS. Although glutamate leagues61 evaluated apoptosis and the spatial binds to most EAA receptors, various and temporal expression of apoptotic cells in ligands have been used to characterize EAA the spinal cords of 15 patients who died after subtypes. The NMDA receptor includes a a traumatic SCI. Using histologic and complex receptor-mediated voltage-depen- nuclear staining techniques, they found dent monovalent and divalent cation chan- apoptotic cells at the edges of the and nel.67 Even though NMDA or glutamate will in adjacent white matter. open the ion channel, it must overcome a were identified with characteristic apoptotic voltage-dependent blockade by magnesium nuclei. Apoptosis occurs in human SCI and (Mg++).68,69 Opening of an ion channel thus greatly contributes to the secondary patho- leads to an influx of Ca++ and Na+ and, in genesis of SCI.61 Data have shown that exchange, an efflux of potassium (K+). In apoptosis occurs after TBI as well. Apoptosis addition, activation of the NMDA receptor appears to involve excessive calcium entry requires glycine binding.70 Modulation of and activation of caspase-3 (a cysteine pro- the NMDA receptor has also been demon- tease). The effect of various potential thera- strated by zinc (Zn), which also binds to a peutic agents on apoptosis requires addi- distinctive site and is thought to inhibit tional focus. Even though they are glycine binding.71 potentially beneficial against some second- Additional classes of EAA receptors in- ary injury processes, Pohl et al.63 have sug- clude the kainate (KA) and AMPA receptors. gested that N-methyl-d-aspartate (NMDA) These are collectively referred to as the non- antagonists may increase the intensity of NMDA receptors. Activation of these recep- apoptotic damage. Caspase inhibitors may tors occurs in a non-voltage-dependent man- be helpful in the reducing the extent of ner, allowing the exchange of monovalent apoptosis. ions (influx of Na+ and the efflux of K+).11 AMPA and KA may also, however, be per- Excitotoxic mechanisms meable to Ca++ in some special circum- Delayed neuronal cell loss and dysfunc- stances.72 tion after neurotrauma is the result of second- Although many studies have measured the ary injury. These events are thought to result change in amino acid levels after SCI, few from the dysregulation of excitatory amino have evaluated the role of EAA in secondary acids (EAA) with subsequent pathologic injury. Watanabe et al.73 studied changes in 30 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 1999

amino acid levels and the extent of injury in acceptable for humans.77 Several NMDA incomplete cervical SCI in rats. They discov- antagonist agents have also been explored. ered that glutamate and aspartate began to Selfotel (formerly a Ciba-Geigy decrease immediately after injury, and they [Broomfield, CO] product), Cerostat (Cam- found no other changes in other amino acid bridge Pharmaceuticals, Cambridge, MA),

levels. Their findings suggest that EAAs are and EAA-494 (Sandoz, East Hanover, NJ) Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 released at the site of primary injury and that have been developed as direct glutamate the histopathological changes observed in (NMDA) antagonists.78 Cerostat has yielded the white matter are a result of autoclastic less than efficacious results. Selfotel has mechanisms. been evaluated in phase III trials in North Takeda and colleagues74 examined EAA’s America and Europe and has been suspended relationship to SCI in an in vitro spinal cord because early data did not support significant preparation and found that an overactivation benefit in humans.9 A potential limitation of of NMDA receptors in the spinal cord can all of these agents is the need to administer cause protein degradation and osmotic dis- them within hours after the injury. turbances. They proposed that NMDA re- ceptors play a key role in the death of Calcium regulation essential for the generation of neurogenesis Voltage-dependent calcium (Ca++) chan- of locomotion. The lack of integration in nels, together with the structurally similar brain stem networks, central pattern genera- Na+ channels, are embedded in the lipid layer tors in the spinal cord, and sensorimotor of cells. Various Ca++ channel subtypes exist; circuits is believed to cause paralysis. L-type and N-type channels play prominent Yanase et al.75 attempted to clarify the role roles in TBI. Potential therapies are directed of NMDA receptors in acute SCI by studying at a blockade of these channels.79 The perme- the pathological change in intraspinal micro- ability of these channels has a great impact on circulation after acute SCI in rabbits. NMDA feedback mechanism of excitoxic activation receptor antagonist MK-801 greatly im- and cellular death.80 Excess or inappropriate proved recovery and decreased edema at the activation of the Na+ and Ca++ channels re- site of injury. They concluded that the sec- sults in activity harmful to cellular stability. ondary injury to SCI was mediated by the Voltage-dependent Na+ channels in axons NMDA receptors in the early postinjury time and nerve terminals initiate glutamate re- frame. Glutamate antagonists also appear to lease by propagating depolarization to the possess neuroprotective effects in experi- vesicular site. Presynaptic voltage-activated mental SCI.76 Ca++ channels are ungated in response to the Although NMDA antagonist agents have depolarization. The elevation of cytoplasmic shown great promise in the animal model of Ca++ levels in the nerve terminals initiates the brain injury, they have yet to prove effective- process of exocytosis of glutamate.81 ness in clinical trial.9 MK-801 (Fidia, Italy) Overactivation of the Na+ channels results in was the prototypical NMDA antagonist. trains of action potentials invading the pen- Even though MK-801 was valuable in the umbra, which causes extensive glutamate animal model, its side-effect profile was un- release. Increased energy supplies are neces- Pathophysiology and Therapy for SCI/TBI 31

sary to reestablish the Na+/K+ gradient as energy stores are further depleted. The re- Calcium channel blockers are known sulting loss of intracellular Ca++ homeostasis to affect vasodilation and have been results in a rise in Ca++ that leads to excessive shown to increase spinal cord blood release of glutamate, which propagates a flow in animal models. 82 self-reinforcing cycle of cell death. In addi- Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 tion, Ca++ increases the production of free radicals that damage cell membranes.83 Intra- cellular Ca++ liberates calpain, which is in- agent (whole blood, angiotensin, or adrena- volved in propagation of protease-dependent line) or with saline as a control. Nimodipine cytoskeletal destruction.84 The presence of was later added. They found that the groups high levels of Ca++ results in ion gradient that were given pressor agents alone showed disturbances leading to further excitotoxic increased mean systemic arterial blood pres- release and cellular swelling. sure (MSAP), but no improvement in SCBF The dihydropyridine calcium channel was noted as compared to the control group. blocker, nimodipine (Bayer, Germany), has When the nimodipine was added later, SCBF received a great deal of . was improved only in the adrenaline-treated Nimodipine has been approved for the treat- group, where MSAP was maintained above ment of vasospasm associated with sub- 100 mm Hg. They concluded that SCBF can arachnoid hemorrhage in humans. The drug be increased by nimodipine if MSAP can appears to function directly by acting as a also be maintained; however, their study did neuronal protective agent rather than by hav- not address the effects of nimodipine on ing an effect on vasospasm.85 The efficacy of recovery after SCI. nimodipine in the treatment of brain injury Fehlings et al.90 found that a combination has been reported by Teasdale in the British of nimodipine and dextran improved SCBF /Finnish Co-operative Head Injury Trial after a compression injury at the T1 spinal Group and by Braakman in the European cord in rats, whereas no improvement was Study Group on Nimodipine in Severe Head seen in the placebo/saline-, placebo/dextran-, Injury.86,87 The latter initiative noted no ben- or nimodipine/saline-treated groups. Also, eficial overall effect except in patients with they found improvement in axonal function traumatic subarachnoid hemorrhage.87 A re- in both motor tracts and somatosensory tracts cent trial in Europe demonstrated that with the nimodipine/dextran combination. nimodipine is effective in improving out- They concluded that posttraumatic SCBF come after traumatic subarachnoid hemor- improves the function of injured spinal cord rhage.88 axons, which confirms that posttraumatic Calcium channel blockers are known to ischemia greatly contributes to the pathogen- affect vasodilation and have been shown to esis of acute SCI. increase spinal cord blood flow (SCBF) in Pointillart et al.91 evaluated the improve- animal models. Guha et al.89 studied the ef- ment in axonal function in baboons treated fects of nimodipine on SCBF by treating post with the calcium channel blocker nimodipine cervical-cord-injured rats with a pressor after compression of the spinal cord. They 32 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 1999

discovered that nimodipine increased SCBP cals. Superoxide dismutase (SOD) catalyzes and that axonal function improved as mea- the conversion of superoxide radicals to

sured by somatosensory evoked potentials. H2O2. SOD is a powerful oxygen radical The development of the conotoxin class of scavenger. It is quickly metabolized in the neuroprotective agents has stirred a great peripheral system and thus requires the con-

deal of interest. These agents are developed jugation of polyethelene glycol (PEG) to Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 from the venom of a killer snail. Conotoxins prolong its active life.96 Preliminary results appear to block the influx of calcium via N- with PEG-SOD in humans appeared favor- type calcium channels. A unique N-type cal- able; however, a more recent trial has indi- cium channel blocker, SNX-III (Neurex; cated that the had not reached Parke Davis, Morris Plains, NJ), appears to statistical significance in achieving im- be effective when administered up to 24 proved outcomes.97 Although there was no hours after experimental stroke induction in statistical significance in neurologic out- animals.92 However, a recent clinical trial has come, the agent was well tolerated. More been suspended due to concern with favorable outcomes and no increase in mor- conotoxin-associated hypotension. tality were noted. Glutathione peroxidase catalyzes the re- Free-radical formation 94 duction of H2O2 into water. Other endog- Free radicals are highly reactive particles enous antioxidants include: alpha-toco- that accumulate in sequential fashion from pherol (vitamin E), alpha lipopoic acid,

molecular O2 via single electron reductions. retinoic acid (vitamin A), and ascorbic acid They are extremely chemically reactive.93 (vitamin C). Iron appears to catalyze the Free radicals have unpaired electrons and production of free radicals and the lipid seek to bind with protein or lipid membranes. peroxidation process.95 Oxygen radical formation often leads to cel- Methylprednisolone is believed to influ- lular membrane damage. Sources of free ence free-radical formation. As previously radicals include: neutrophils, nitric oxide, stated, this agent has shown efficacy in human calcium entry, and mitochondrial damage. SCI.51–53 Several trials of high-dose corticos-

The initial O2 radical in the sequence is the teroids for the treatment of brain injury con- superoxide radical. In biologic systems, this ducted during the 1980s did not show signifi- species has a short half-life and is usually in cant benefits. Two significant trials failed to a charged form in acidic environments. In- demonstrate marked improvement in out- creased levels of free radicals cause a loss of comes among persons with head injury.99,100 autoregulation, ischemia, and membrane High-dose steroids are not a part of the guide- lipid peroxidation.94–98 The finding that cer- lines for the management of severe TBI.29 tain neural recovery processes may be facili- Tirilizad (Pharmacia Upjohn, Kalamazoo, tated in part by the presence of some free MI) is a 21- aminosteroid lacking glucocorti- radicals97 raises additional complicating in- coid effects, yet it inhibits lipid peroxidation. terest. A trial of Tirilizad was terminated prema- Natural enzymes under physiologic con- turely due to an excess mortality in the experi- ditions provide protection against free radi- mental group. This altered mortality rate ap- Pathophysiology and Therapy for SCI/TBI 33

pears to be due to a selection bias in the study, because there was a larger number of patients Hypothermia has long been noted to in the severe injury group who received medi- have a protective effect on central cation.101 Tirilizad also has not yet shown neurologic dysfunction. increased efficacy as compared to high-dose 52 methylprednisolone in traumatic SCI. Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021

Eicasanoids and cytokines dynorphins could induce limb paralysis in Loss of membrane integrity results in free mice. Dynorphin antagonists were found to fatty acid formation. Breakdown of these be protective. fatty acids results in the formation of prostag- McIntosh et al.104 have reported that landins and leukotrienes, which are powerful dynorphins worsened brain injury in rats, inflammatory agents. The role of the cellular whereas Vink and colleagues105 demon- inflammatory processes is now being appre- strated that pretreatment with kappa receptor ciated in CNS insults. Nonsteroidal anti- antagonists improved injury. In contrast, inflammatory agents (NSAIDS; such as in- Hall and colleagues106 have shown that treat- domethacin) and glucocorticoid steroids ment with the kappa receptor agonist has inhibit these by-products. improved injury in mice. Such discrepancies The role of cytokines in CNS injury re- are felt to be secondary to the role of various mains an interesting area of investigation. kappa isoreceptors.107 Interleukins are ubiquitous in the CNS. They Generation of nitric oxide can occur as a augment and modulate the bioactivity of result of intracellular calcium release. Nitric many cell types. IL1, IL2, and IL6 have been oxide functions as a free-radical variant and shown to have a modulating effect in human decreases neuronal survival.108 In one is- neurotrauma. Kossman et al.101 have shown chemic model, activation of the NMDA re- that IL6 affects the release of neurotrophic ceptor leads to nitric oxide formation. Nitric factors, while Rothwell102 has demonstrated oxide may influence protein kinase C, further that IL1 appears to mediate experimentally exacerbating excitatory amino acid release induced neurodegeneration. and cellular damage. Thyrotropin-releasing hormone (TRH) in Other areas the treatment of persons with neurotrauma Recent evidence supports the theorem that has raised much interest. TRH is a tripeptide several opioid receptor subtypes exist: mu, that has many physiologic and biochemical delta, and kappa. Opioids appear to have a actions. TRH and its analogs have been modulating effect on glutamate release. In shown to antagonize the effects of endog- addition, potentiation of certain opiod recep- enous opioids, platelet-activating factor, and tors has shown variable effects on outcome excitotoxins. Experimental studies have after experimental brain injury. The role of shown a benefit in both the SCI and TBI these receptors in secondary injury is not yet models. Pitts et al.109 evaluated 20 persons clear. Faden103 has shown that dynorphin is with SCI and felt that TRH was beneficial in elevated at the site of injury and that a small incomplete injury group. 34 TOPICS IN SPINAL CORD INJURY REHABILITATION/FALL 1999

Hypothermia has long been noted to have sion, but it was associated with improved a protective effect on central neurologic dys- outcomes on the Glasgow Outcome Scale at function. Moderate hypothermia typically 3 and 6 months.117 means surface cooling to 32–33ºC.110 The The National Acute Brain Injury Study: mechanisms of hypothermia have been pos- Hypothermia (NABIS:H) is an ongoing

tulated to include reduction of cerebral me- multicenter project that examines the role of Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 tabolism,111 stabilization of cell mem- systemic hypothermia in the treatment of branes,112 and suppression of the build-up of severe head injury. Outcome assessments excitotoxic amino acids after insults.113 Hy- include the Glasgow Outcome Scale and pothermia reduced ICP and CBF during the neuropsychological evaluations with a sur- cooling period.110 Shiozaki and colleagues114 prising high follow-up rate. However, no noted reduced ICP and increased CPP, de- significant improvement is noted in the treat- creased CBF, arteriojugular venous oxygen ment group.118 difference, and cerebral metabolic rate of Dixon and colleagues119 examined the oxygen with mild hypothermia. Shapiro et therapeutic effects of moderate hypothermia al.115 showed that the combined therapy of (32ºC) in Sprague-Dawley rats with induced barbiturates and conventional hypothermia parietal injury. Hypothermia significantly may effectively control intracranial hyper- resulted in less motor and spatial tension in patients with severe head injury. performance deficits as compared to the two Prior work had been limited by conventional control groups—one group that was main- cooling (less than 30ºC) resulting in tained at normothermia and the other group arrhythmias and coagulopathy.116 Recent de- that was a surgical procedures group. No velopments have allowed a safer initiation of differences were noted in the volumes of hypothermic therapy, and many of these hippocampal layers in three groups. complications can be prevented. Marion et The therapeutic potential of hypothermia al. 110 recently reported improved outcomes on SCI has been explored in both humans and in 40 patients with severe closed head injury animals. In animal models of spinal cord is- who were treated with moderate hypother- chemia, Wakamatsu et al.120 noted that moder- mia, which consisted of cooling blankets and ate hypothermic treatment resulted in im- cold saline gastric lavage within 10 hours proved neurologic function as compared to after injury. Both groups had similar inci- intrathecal tetracaine (a sodium channel dence of systemic complications blocker) in rabbits subjected to ischemic spi- (arrythmias, coagulopathies, and pulmonary nal cord injury. The mechanism of complications). In a later randomized, con- neuroprotection may be related to inhibition trolled trial with 82 patients with severe head of glutamate release. Farooque and col- injury (Glasgow Scale score of 3–7), leagues121 studied the effects of moderate hy- patients in the treatment group were cooled pothermia on extracellular lactic acids and to 33ºC for a mean of 10 hours, maintained at amino acids in rats with experimentally 32–33ºC for 24 hours, and then rewarmed. transected spinal cord and noted no significant Hypothermia did not benefit the group with a differences in hypothermic and normother- score of 3–4 on admis- mic subjects in the levels of arginine, taurine, Pathophysiology and Therapy for SCI/TBI 35

glutamine, glycine, tyrosine, lactic acid, and effective in limiting lipid peroxidation, as pyruvate. However, the mean level of lactate measured by the tissue content of malonil tended to be lower and recovery was quicker dialdehyde. De Haan and colleagues126 found in hypothermic animals. The result of their a significant reduction in the histopathologic study does not suggest that moderate hypoth- damage in rabbits in the mild hypothermic ermia attenuates extracellular accumulation group (4º epidural temperature decrease) and Downloaded from http://meridian.allenpress.com/tscir/article-pdf/5/2/21/1985042/fc2l-7jlc-gcpl-42ap.pdf by guest on 29 September 2021 of excitatory amino acids, but instead it raises in the group with both mild hypothermia and the possibility that hypothermia may prolong aminosteroid U-74389G. There was a sig- the duration of glutamate receptor nificant reduction in the incidence of overactivation. Kakinohana and colleagues122 and neurologic deficits in the hy- evaluated the effects of postischemic spinal pothermic group that was not demonstrated tissue on neurologic function after aortic oc- in the group that received 21-aminosteroid at clusion. Three treatment arms consisted of the normothermic condition. various protocols of step-wise or immediate intrathecal cooling and reperfusion. The re- Conclusion sults indicated that immediate reperfusion (0– 15 minutes) represented the critical period that The pathophysiology of neurotrauma is has the greatest impact in terms of complex. The secondary processes of SCI neuroprotection. Hypothermia, when initi- and TBI have much in common. State-of- ated in this critical window, showed signifi- the-art research has lead to clinical trials cant therapeutic response, with the highest assessing the effects of various efficiency at 27ºC. Spinal cord ischemia is a neuroprotective agents. At present, there is substantial concern during and after aortic no adequate therapy for SCI and TBI. Much . In a recent review, Robertazzi and more work is needed to further define the Cunningham123 postulated that the etiology of complex cascades of the secondary injury spinal cord ischemia during aortic cross- process. The pathophysiological heteroge- clamping consists of a series of cascades, neity of the neurotrauma population will re- which include proximal hypertension, in- quire experimental designs to target the spe- crease in cerebrospinal pressure, peri- cific pathways that are disrupted. The timing, operative hypotension, and inadequate perfu- dose response, and safety profiles of many sion. Matsumoto et al.124 found that experimental agents pose further therapeutic hypothermia offered a distinct advantage challenges. The rehabilitation professional against SCI in mammals subjected to occlu- needs to keep aware of the developments sion of the aorta. with neuroprotective agents because these Tuzgen and colleagues125 noted that epidu- agents are likely to influence outcomes in ral cooling of the traumatized spinal cord is persons with neurotrauma in the near future.

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