Alcohol Intoxication and Traumatic Spinal Cord Injury

Alcohol Intoxication and Traumatic Spinal Cord Injury

C H A P T E R 5 Alcohol Intoxication and Traumatic Spinal Cord Injury: Basic and Clinical Science C.L. Crutcher, II, J. Veith, G.C. Tender Louisiana ...

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5 Alcohol Intoxication and Traumatic Spinal Cord Injury: Basic and Clinical Science C.L. Crutcher, II, J. Veith, G.C. Tender Louisiana State University Health Science Center, New Orleans, LA, United States


intoxication and its effects on the pathophysiology of SCI, and alcohol intoxication and its impact on clinical SCI patients.

Traumatic spinal cord injury (SCI) victims often suffer permanent neurological damage. Depending on the anatomical level of injury, SCI patients may be left paraplegic or quadriplegic. The incidence of traumatic SCI in the United States is 54 cases per million annually, with about 17,000 new cases per year (National Spinal Cord Injury Statistical Center, 2015). The incidence of traumatic SCI worldwide is 10.4 to 83 cases per million annually (Wyndaele & Wyndaele, 2006). The most common causes of SCI, in descending order of frequency, are: traffic accidents, work, sports and recreation, falls, and violence (Devivo, 2012). Traumatic SCI can be separated into two components: the primary injury and the secondary injury. The primary injury encompasses the inciting mechanism, such as physical spinal cord compression, and the secondary injury involves downstream pathological processes, such as ischemia and altered cellular metabolism. Alcohol intoxication is a major risk factor for traumatic SCI and is present in up to 34% of cases (Levy et al., 2004). The lifetime prevalence of alcohol abuse disorders in the United States is 17.8% (Hasin, Stinson, Ogburn, & Grant, 2007). Alcohol use is the third leading cause of mortality from modifiable risky behaviors in the United States (Mokdad, Marks, Stroup, & Gerberding, 2004). Many SCI patients have higher rates of preinjury alcohol abuse than the general population (Kolakowsky-Hayner et al., 1999). Alcohol intoxicated patients often present with more severe injuries in the trauma population (Waller, Hill, Maio, & Blow, 2003). Basic science and clinical science research has investigated alcohol intoxication and its influence on traumatic SCI. This chapter is a review of the pertinent literature regarding pathophysiology of SCI, alcohol

Addictive Substances and Neurological Disease

PATHOPHYSIOLOGY OF TRAUMATIC SPINAL CORD INJURY An acute SCI can be divided into two components, the primary and secondary injury. The primary injury typically consists of compression, contusion, distraction, or transection of the neural tissue, blood vessels, or supporting tissues as a direct result of a traumatic event. Common causes of primary injury include herniated disks, fractures and/or dislocations of the spine, and bullets or other sharp penetrating objects. The secondary injury involves edema, hemorrhage, ischemia, inflammation, and injury to neuronal cells and their membranes. Over 25 secondary mechanisms of SCI have been described (Oyinbo, 2011). See Table 5.1 for a list of major secondary injury mechanisms. Secondary injury to the spinal cord involves a complex cascade of vascular, cellular, and inflammatory events.

VASCULAR INJURY Immediately following an SCI, there are changes in the local and systemic blood flow. Experimental SCI models demonstrate that there is a local reduction in vascularity and blood flow at the site of trauma, contributing to spinal cord ischemia (Figley, Khosravi, Legasto, Tseng, & Fehlings, 2014; Yeo et al., 1984; Yeo, Payne, Hinwood, & Kidman, 1975). Within 30 min of trauma, local spinal cord microvasculature experiences


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40 TABLE 5.1


Major Secondary Mechanisms of Spinal Cord Injury

Major Secondary Injury Mechanisms • Vascular compromise

Ischemia/reperfusion injury Hemorrhage Neurogenic shock Vasospasm

• Membrane dysfunction

Increased membrane permeability Fluid accumulation and edema Altered ionic homeostasis Lipid peroxidation

• Cellular dysfunction

Apoptosis/programmed cell death Astroglial scar formation Cavitation Chromatolysis Altered myelination demyelination Altered energy utilization and production Oligodendrocyte apoptosis

• Other

intraparenchymal hemorrhage acts as a catalyst for bloodebrainespinal cord barrier (BBSCB) breakdown, plasma membrane breakdown, and free radical production (Losey, Young, Krimholtz, Bordet, & Anthony, 2014; Sadrzadeh, Anderson, Panter, Hallaway, & Eaton, 1987). Anderson examined the effects of alcohol on traumatic SCI using ferrets. The animals were intoxicated to a level of 100 mg/dL. The study demonstrated that intoxicated animals had larger amounts of iron accumulation at the injury site and in adjacent tissue when compared to the non-intoxicated controls. Iron accumulation at the site on injury was suggested to represent either hemorrhage or vascular congestion (Anderson, 1986). Other studies have shown that intoxicated animals have much larger areas of hemorrhage and surrounding edema when compared to non-intoxicated subjects (Flamm et al., 1977). Free iron derived from hemoglobin potentiates secondary SCI by inhibiting sodiumepotassium ATPase (Naþ/Kþ ATPase) activity and catalyzes peroxidation of central nervous system lipids (Sadrzadeh et al., 1987). Therefore, the initial injury that causes hemorrhage initiates a cyclical cascade of secondary injury mechanisms that are selfpropagating and are exacerbated by alcohol.

Injury due to excitotoxic neurotransmitters Excessive cytokine release and immune response Inflammation Increased oxidative stress Cytokine production Free radical formation

vasospasm that results in reduced blood flow (Dohrmann & Allen, 1975). Systemically, the mean arterial pressure temporarily increases, followed by an extended period of hypoperfusion. The heart rate and peripheral vascular resistance also decrease (Guha & Tator, 1988). The combination of these effects results in spinal cord hypoperfusion, which leads to further spinal cord ischemia. Direct contusion of the spinal cord leads to development of intraparenchymal hemorrhage (Choo et al., 2007). Congestion of the microvasculature of the gray matter with erythrocytes, followed by endothelial injury, further contribute to hemorrhage formation within the spinal cord (Dohrmann, Wagner, & Bucy, 1971). The spinal cord tissue adjacent to these sites of hemorrhage demonstrates increased susceptibility to ischemic damage further contributing to the initial SCI (Tator & Fehlings, 1991). In addition to the direct injury to the spinal cord tissue caused by the contusion,

MEMBRANE DYSFUNCTION AND EDEMA FORMATION The BBSCB is an anatomical and physiological barrier preventing the passage of certain substances from the systemic blood circulation into the extracellular fluid space of the brain and spinal cord. The BBSCB is semipermeable and highly selective. The BBSCB is composed of astrocyte-induced tight junctions of the basement membrane around capillaries. The BBSCB prevents passage of large and hydrophilic molecules, large proteins, and other toxic substances into the central nervous system. Certain substances such as glucose or specific proteins may be transported selectively across the BBSCB by simple diffusion, simple diffusion through an aqueous channel, facilitated diffusion, or active transport through protein channels. Examinations of spinal cords after experimental transection demonstrate increased bloodebrain barrier breakdown due to increased transendothelial transport of proteins (Noble & Wrathall, 1987). This increased leakage of intravascular content contributes to spinal cord edema and worsens functional outcome (Leonard, Thornton, & Vink, 2015). Furthermore, direct spinal cord contusion leads to both temporary and permanent increases in cellular membrane permeability that is proportional to the degree of contusion (Simon, Sharif, Tan, & LaPlaca, 2009).



The loss of cellular membrane continuity leads to a loss of ionic homeostasis and edema formation due to a leaky plasma membrane and ion channel dysfunction. The cells of the central nervous system utilize several different ion channels to maintain homeostasis and ionic equilibrium. Sodium and calcium concentrations are two main ionic components of merit in the discussion regarding SCI. The sodiumepotassium channel (Naþ/ Kþ ATPase) and the sodiumecalcium exchanger (NCX), among others, are two principal ion exchangers that maintain osmotic and ionic homeostasis. The Naþ/Kþ ATPase normally functions to exchange three extracellular potassium ions for two intracellular sodium ions. Similarly, the NCX removes one intracellular calcium ion in exchange for three extracellular sodium ions. NCX is one of the most important methods for removing intracellular calcium and maintaining calcium homeostasis (DiPolo & Beauge, 2006). Sodiumepotassium channel malfunction after SCI is evident as early as 5 min post contusion in the experimental SCI model (Clendenon, Allen, Gordon, & Bingham, 1978). Experimental studies show that increased intracellular sodium concentrations contribute to cytotoxic edema formation (Lemke & Faden, 1990), intracellular pH alterations (Agrawal & Fehlings, 1996), and calcium homeostasis derangement (Blaustein & Lederer, 1999; Tomes & Agrawal, 2002). Agrawal and Fehlings (1996) have demonstrated that increased intracellular sodium concentrations post SCI correlate with worsened traumatic axonal injury and that prevention of intracellular acidosis by blocking the sodiumehydrogen exchanger had neuroprotective effects. This suggests that increased intracellular acidosis has a negative impact in traumatic SCI. Experimental animals pretreated with alcohol have more extensive white matter edema, and evidence of tissue loss when compared to non-intoxicated controls (Brodner, Van Gilder, & Collins, 1981). Although there are no experimental studies that examine alcohol intoxication and its impact on Naþ/Kþ ATPase and NCX in the setting of traumatic SCI, alcohol has been studied in nontraumatic models. Alcohol treated animals have altered Naþ/Kþ ATPase activity resulting in intracellular sodium accumulation (Blachley, Johnson, & Knochel, 1985). Additionally, studies have shown that ethanol exposed animals have higher levels of lactate (Halt, Swanson, & Faden, 1992) and oxygen consumption than nonalcohol treated animals (Blachley et al., 1985). It is possible that alcohol exposure puts the neural tissue in an altered physiological state that exacerbates the secondary mechanisms after SCI. Calcium influx is evident within 45 min of experimental SCI (Happel et al., 1981). In the setting of experimental SCI, the increased sodium concentration causes the NCX to reverse direction and contribute to calcium


influx rather than efflux (DiPolo & Beauge, 2006; Li, Jiang, & Stys, 2000). Alcohol exposure to microsomes and synaptosomes from murine neural tissue causes a release of calcium from intracellular storage and an increase in resting calcium concentration (Daniell, Brass, & Harris, 1987; Daniell & Harris, 1989). Increased intracellular calcium concentration post SCI leads to mitochondrial dysfunction, free radical and reactive oxygen species (ROS) formation, and phospholipase oxygenation (Young, 1992). Mitochondrial dysfunction and ROS formation occurs within the first hour after SCI, in conjunction with calcium influx (Azbill, Mu, BruceKeller, Mattson, & Springer, 1997). Excess intracellular calcium also promotes activation of proteases with resulting membrane breakdown and initiation of cellular apoptosis, also known as programmed cell death (Ray, Matzelle, Wilford, Hogan, & Banik, 2001; Shields, Schaecher, Hogan, & Banik, 2000). Alcohol exposure increases the resting calcium concentration in neural tissue potentially exacerbating these deleterious effects of excess calcium in traumatic SCI.

INFLAMMATION AND IMMUNEMEDIATED RESPONSE TO SPINAL CORD INJURY Inflammation and immune-mediated responses to SCI have been identified as key elements in secondary SCI. After traumatic SCI, the site is invaded by leukocytes, neutrophils, and monocytes (Bao et al., 2009). These cells contribute to the release of proinflammatory cytokines and free radical production. In experimental rat studies, pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-a), interleukin-1 beta (IL-1b), and interleukin-6 (IL-6) expression, have been shown to increase after SCI (Yang et al., 2005). Increased production of cytokines after SCI contributes to apoptosis and increased production of free radical species (Wang, Kong, Qi, Ye, & Song, 2005; Yune et al., 2003). Exogenous cytokine administration during in vitro studies has shown that early exposure, within 1 day of injury, leads to increased recruitment and activation of macrophages and microglial cells. The size of tissue loss appears greater in the cytokine treated spinal cords compared to controls, but the difference is not statistical. The same study demonstrated that late exposure, 4 days after injury, had increased macrophage recruitment and decreased microglial activation. The animals that were exposed to exogenous cytokines 4 days after injury had reduced tissue loss at 7 days when compared to controls. This suggests a possible protective effect with late exposure to cytokines (Klusman & Schwab, 1997). In human subjects, traumatic SCI patients have higher neutrophil and monocyte free radical production,




higher free radical production from leukocytes, higher concentration of oxidative enzymes, and proinflammatory factors, transcription factor nuclear factor kappa B (NF-kB) and cyclooxygenase-2 (COX-2) than their nonespinal cord injured and able bodied controls. There is also evidence that the heightened inflammatory state in SCI patient increases oxidative stress and leads to worsening lipid peroxidation (Bao et al., 2009). COX 2 is responsible for the enzymatic conversion of arachidonic acid into breakdown products such as thromboxanes, prostacyclins, and prostaglandins. Resnick et al. suggest that COX 2 production leads to worse functional outcome. The authors studied COX 2 mRNA and protein expression after spinal cord contusion injury. They found that the study group that was administered selective COX 2 inhibitors had better functional outcomes when compared to the nontreated group (Resnick, Graham, Dixon, & Marion, 1998). Research regarding alcohol intoxication and inflammation after traumatic SCI is lacking. Recent research in traumatic brain injury has revealed that acute alcohol intoxication delays the resolution of inflammation and inflammatory markers IL-1b, IL-6, and TNF-a after traumatic injury (Teng & Molina, 2014). Alcohol intoxication may have a similar effect in spinal cord tissue. Alcohol treated subjects have higher levels of free fatty acid and thromboxane levels than that their sober counterparts (Halt et al., 1992). The higher concentration of thromboxane represents a heightened inflammatory state as well as contributing to spinal cord hypoperfusion (Tempel & Martin, 1992). Prolonged exposure to pro-inflammatory molecules can lead to increased cytokine production, greater tissue loss, and greater free radical damage.

FREE RADICAL FORMATION AND LIPID PEROXIDATION Free radicals are molecules with an unpaired electron that are highly reactive to oxygen molecules, DNA, and certain enzymes. ROS are a specific type of free radicals that has the unpaired electron on the oxygen atom. Increased iron concentration after experimental SCI can act as a catalyst for the formation of some ROS (Liu, Liu, Sun, Alcock, & Wen, 2003) and lipid peroxidation (Zhang, Scherch, & Hall, 1996). Free radicals can cause damage to plasma membranes in the form of lipid peroxidation. Lipid peroxidation of fatty acids can generate more free radicals leading to further damage and decreased neuron viability (Porter, Caldwell, & Mills, 1995; Zhang et al., 1996). Free radical formation contributes to increased oxidative stress, lipid damage, nucleic acid damage, mitochondrial damage, and initiation of apoptosis (Xu

et al., 2005). Increased calcium concentrations, as discussed earlier, catalyze lipid peroxidation leading to further membrane damage (Braughler, Duncan, & Chase, 1985). After experimental contusion injury to the spinal cord, there is evidence of dose-related membrane phospholipid hydrolysis (Demediuk, Daly, & Faden, 1989a) and ROS production (Luo, Li, Robinson, & Shi, 2002). Additionally, macrophages, as discussed earlier, are recruited to the site of injury as early as 6 h after contusion and produce the ROS, nitric oxide (Satake et al., 2000). After experimental spinal cord contusion, examination of injured tissue reveals decreased levels of phospholipids and cholesterol, and increased in free fatty acids (FFA) (Demediuk et al., 1989a). Arachidonic acid is a key FFA released after spinal cord trauma. Increased arachidonic acid exposure increases intracellular calcium concentrations, increases oxidative stress, and decreases cell viability (Toborek et al., 1999). Alcohol treated subjects also have higher levels of free fatty acid and thromboxane levels than that of their sober counterparts (Halt et al., 1992). This offers further support that alcohol intoxication contributes to increased lipid peroxidation and plasma membrane damage.

EXCITATORY NEUROTRANSMITTERS Immediately after experimental SCI there is an increase in release of excitatory neurotransmitters from injured neurons (Demediuk, Daly, & Faden, 1989b; Farooque, Hillered, Holtz, & Olsson, 1996; Panter, Yum, & Faden, 1990). Glutamate is one of the most abundant excitatory neurotransmitters in the spinal cord. Glutamate stimulates N-methyl-D-Aspartate (NMDA), kinate, and a-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) receptors. The net result of glutaminergic stimulation of NMDA receptors is a net influx of calcium ions. Experimentally, excessive concentrations of glutamate similar to levels experienced during traumatic SCI has been shown to cause damage to local neurons (Liu, Xu, Pan, & McAdoo, 1999), to cause damage to supporting cells of the central nervous system (Xu, Hughes, Ye, Hulsebosch, & McAdoo, 2004), and to cause functional impairments in rats (Xu, Hughes, Zhang, Cain, & McAdoo, 2005). NMDA and AMPA-mediated calcium influx lead to mitochondria depolarization and cytotoxicity and increased cell death (Sen, Joshi, Joshi, & Joshi, 2008; Urushitani et al., 2001). The devastating effects of glutamate excito-toxicity are also linked to apoptosis (Xu, Liu, Hughes, & McAdoo, 2008). Alcohol treated rats have significantly less aspartate and glutamate in their neural tissue after SCI when compared to saline infused rats (Halt et al., 1992). The




decreased concentration of excitatory amino acids within the neural tissue suggest that the cells release more excitatory amino acids upon injury. As stated foregoing, increased exposure to these excitatory neurotransmitters leads to increased intracellular calcium, which contributes to cellular apoptosis, mitochondrial dysfunction, free radical formation, and ultimately decreased cell viability.

ALCOHOL INTOXICATION AND THE EFFECTS ON PRECLINICAL SPINAL CORD INJURY The effect of alcohol intoxication on the severity of traumatic SCI has been a point of interest within the scientific community. There are numerous preclinical studies demonstrating that alcohol intoxication leads to worse traumatic SCI when compared to nonintoxicated controls. This section of the chapter focuses on alcohol intoxication and its detrimental effects on traumatic SCI outcomes.

ALCOHOL INTOXICATION AND INJURY SEVERITY In general trauma, alcohol intoxicated patients present to the hospital with more severe injuries than sober patients (Waller et al., 2003). In a small study, intoxicated patients who presented with positive blood alcohol were more likely present with more severe neurological injury or quadraparesis (Forchheimer, Cunningham, Gater, & Maio, 2005). Patient with cervical SCI are more likely to have consumed alcohol compared to patients with other levels of SCI (Garrison et al., 2004). Patient with cervical SCI are more likely to present with paralysis of all four extremities than thoracic or lumbar injuries due to the anatomy of the spinal cord. More recent research has shown that after controlling for injury severity, alcohol intoxication had no effect on 1-year mortality, or degree of functional impairment at 6 weeks, 6 months, or 1 year after SCI in patients who survive to hospital admission (Furlan & Fehlings, 2013). Although injury severity is unaffected by degree of alcohol intoxication, intoxicated patients are more likely to suffer from in-hospital medical complications such as pneumonia, deep vein thrombosis and pulmonary embolism, urinary tract infections, and skin complications (Crutcher, Ugiliweneza, Hodes, Kong, & Boakye, 2014).

ALCOHOL USE AND SPINAL CORD INJURY PATIENTS ALCOHOL AND FUNCTIONAL OUTCOMES Experimental traumatic SCI outcomes are routinely evaluated by measuring compound action potentials, measuring somatosensory evoked potentials, testing reflexes, or evaluating voluntary limb movement. Alcohol intoxicated animals have significantly diminished neurological recovery after contusion SCI and have a significantly higher mortality than non-intoxicated study animals (Halt et al., 1992). Four to six weeks from injury, alcohol treated animals are significantly less likely to be able to support their own weight and walk without difficulty when compared to sober study subjects (Flamm et al., 1977; Halt et al., 1992). During surgery, monitored evoked potentials are permanently lost more often in the alcohol intoxicated animals, and those intoxicated animal are more often left permanently paralyzed when compared to non-intoxicated animals (Flamm et al., 1977). Flamm et al. (1977) suggest that the immediate loss of evoked potentials results from a synergistic effect of alcohol and trauma where damages to membrane-bound Naþ/Kþ ATPase impair axon impulse transmission capabilities.

Up to 96% of patients with SCI report preinjury alcohol use, with 57% of users identifying as heavy users (Kolakowsky-Hayner et al., 1999). Acute SCI patients often require intense physical and occupational rehabilitation to recover some degree of functional independence. Patients with significant histories of drinking problems have lower functional independence upon rehabilitation admission and discharge than patients without a significant drinking history (Bombardier, Stroud, Esselman, & Rimmele, 2004).

CONCLUSION Traumatic SCI often has devastating and permanent neurological consequences. There are about 17,000 cases of traumatic SCI every year. Up to 96% of SCI patients report preinjury alcohol use. Alcohol intoxication has been shown to have deleterious effects on experimental SCI severity. Alcohol intoxication and exposure primes spinal cord cells for injury and promotes a milieu to enhance and propagate many secondary injury mechanisms. Alcohol intoxication worsens the degree of




vascular insult, inflammation and immune-mediated response, excitatory neurotransmitter damage, free radical damage, edema formation, and membrane dysfunction. In human SCI, alcohol intoxication has no impact on the severity on injury. Intoxicated patients, however, suffer more complications and have lower functional independence than sober patients.

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