Grade 1 or ‘ding’ con -
cussions in high school athletes. Am J Sports Med . January–February 2004;32(1):47–54. 142. De Beaumont L, Henry LC, Gosselin N. Long-term functional alterations in sports con -
cussion. Neurosurg Focus . 2012;33(6):E8:1–7. 143. K oh JO, Cassidy JD, Watkinson EJ. Incidence of concussion in contact sports: A sys -
tematic review of the evidence. Brain Inj . October 2003;17(10):901–917. 144. Anderson T, Heitger M, Macleoud AD. Concussion and mild head injury. Pract Neurol. 2006;6:342–357.195 DMSO in Basic Neuroprotection
 145. Ma R, Miller CD, Hogan MV , Diduch BK, Carson EW, Miller MD. Sports-related con -
cussion: Assessment and management. J Bone Joint Surg Am . 2012;94(17):1618–1627. 146. Jordan BD. The clinical spectrum of sport-related traumatic brain injury. Nat Rev 
Neurol. April 2013;9(4):222–230. 147. Nariai T, Inaji M, Tanaka Y , Hiura M, Hosoda C, Ishii K, Ohno K. PET molecular imag -
ing to investigate higher brain dysfunction in patients with neurotrauma. Acta Neurochir 
Suppl. 2013;118:251–254. 148. Stern RA, Rile y DO, Daneshvar DH, Nowinski CJ, Cantu RC, McKee AC. Long-term 
consequences of repetitive brain trauma: Chronic traumatic encephalopathy. PM R . October 2011;3(10 Suppl 2):S460–S467. 149. Giza CC, Ho vda DA. The neurometabolic cascade of concussion. J Athl Train  
2001;36:228–235. 150. Signoretti S, Lazzarino G, Tavazzi B, Vagnozzi R. The pathophysiology of concussion. PM R . October 2011;3(10 Suppl 2):S359–S368. 151. Fineman I, Ho vda DA, Smith M, Yoshino A, Becker DP. Concussive brain injury is 
associated with a prolonged accumulation of calcium: A 45Ca autoradiographic study. Brain Res . 1993;624:94–102. 152. Golding EM, Steenberg ML, Contant CF Jr, Krishnappa I, Robertson CS, Bryan RM Jr. 
Cerebrovascular reactivity to CO(2) and hypotension after mild cortical impact injury. Am J Physiol . October 1999;277(4 Pt 2):H1457–H1466. 153. Grindel SH. Epidemiology and pathoph ysiology of minor traumatic brain injury. Curr 
Sports Med Rep . February 2003;2(1):18–23. 154. K olias AG, Guilfoyle MR, Helmy A, Allanson J, Hutchinson PJ. Traumatic brain injury 
in adults. Pract Neurol . August 2013;13(4):228–35. 155. Shah KR, West M. The effect of concussion on cerebral uptake of 2-deoxy-D-glucose in 
rat. Neurosci Lett . 1983;40:287–291. 156. Echemendia RJ, Iv erson GL, McCrea M, Macciocchi SN, Gioia GA, Putukian M, 
Comper P. Advances in neuropsychological assessment of sport-related concussion. Br J Sports Med . April 2013;47(5):294–298. 157. Katayama Y , Becker DP, Tamura T, Hovda DA. Massive increases in extracellular potas -
sium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg . 1990;73:889–900. 158. Mark LP , Prost RW, Ulmer JL, Smith MM, Daniels DL, Strottmann JM, Brown WD, 
Hacein-Bey L. Pictorial review of glutamate excitotoxicity: Fundamental concepts for neuroimaging. AJNR Am J Neuroradiol . November–December 2001;22(10):1813–1824. 159. Mullan S, Jaf ar J, Hanlon K, Brown FD. Dimethyl sulfoxide on the management of 
postoperative hemiplegia. In Cerebral Arterial Spasm , ed. R.H. Wilkins. Williams & 
Wilkins, Baltimore, MD, 1980; pp. 646–653. 160. Jacob SW , de la Torre JC. Pharmacology of dimethyl sulfoxide in cardiac and CNS dam -
age. Pharmacol Rep . March–April 2009;61(2):225–235. 161.  de la Torre JC. Treatment of head injury in mice, using a fructose 1,6-diphosphate and 
dimethyl sulfoxide combination. Neurosurgery . August 1995;37(2):273–279. 162. Mark ov AK. Hemodynamics and metabolic effects of fructose 1,6-diphosphate 
in ischemia and shock: Experimental and clinical observations. Ann Emerg Med . 1986;15:1470–1477. 163. F arias LA, Smith EE, Markov AK. Prevention of ischemic-hypoxic brain injury and 
death in rabbits with fructose-1, 6-diphosphate. Stroke. 1990;21:606–613. 164. Mark ov AK, Lehan P, Figueroa A: Improvement of left ventricular function with fructose 
1,6-diphosphate in clinical coronary artery disease. Eur Heart J . 1994;15(Suppl):277. 165. Hall ED, Yonkers P, McCall JM, Braughler JM. Effects of the 21-aminosteroid U74006F 
on experimental head injury in mice. J Neurosurg . 1988;68:456–461.196 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
 166. Sutton RL, Lescaudron L, Stein DG. Beha vioral consequences of moderate and severe 
cortical contusion in the rat. Soc Neurosci Abstr . 1990;16:777. 167. Marcel GA. Red cell deformability: Physiological, clinical and pharmacological aspects. J Med 1979;10:409–416. 168. Heckler FR, Markov A, White TZ, Jone EW. Effect of fructose 1,6-diphosphate on 
canine hind limbs subjected to tourniquet ischemia. J Hand Surg . 1983;8:622–623. 169. Benesh R, Benesh RE. The effect of organic phosphates from the human erythro -
cyte on the allosteric properties of hemoglobin. Biochem Biophys Res Commun . 1967;26:162–167. 170. Benesh R, Benesh RE. Intracellular or ganic phosphates as regulators of oxygen release 
by hemoglobin. Nature . 1969;221:618–622. 171. Beharry S, Bragg PD. Interaction of beef-heart mitochondrial F1-A TPase with immobi -
lized ATP in the presence of dimethyl sulfoxide. J Bioenerg Biomembr . 1992;24:507–514. 172.  de la Torre JC, Hill PK. Ultrastructural studies on formation of brain edema and its treat -
ment following experimental brain infarction in monkeys. In Dynamics of Brain Edema , 
eds. H. Pappius, W. Feindel. Springer-Verlag, Berlin, Germany, 1976; pp. 306–314. 173. Bickler PE, Buck LT. Effects of fructose-1,6-bisphosphate on glutamate release 
and ATP loss from rat brain slices during hypoxia. J Neurochem . October 
1996;67(4):1463–1468. 174. Espanol MT , Litt L, Hasegawa K, Chang LH, Macdonald JM, Gregory G, James TL, 
Chan PH. Fructose-1,6-bisphosphate preserves adenosine triphosphate but not intracel-
lular pH during hypoxia in respiring neonatal rat brain slices. Anesthesiology . February 
1998;88(2):461–472. 175. Cárdenas A, Hurtado O, Leza JC, Lorenzo P, Bartrons R, Lizasoain I, Moro MA. Fructose-
1,6-bisphosphate inhibits the expression of inducible nitric oxide synthase caused by oxygen-glucose deprivation through the inhibition of glutamate release in rat forebrain 
slices. Naunyn Schmiedebergs Arch Pharmacol . September 2000;362(3):208–212. 176. W elch G, Loscalzo J. Nitric oxide and the cardiovascular system. J Cardiovasc Surg . 1994;9:361–371. 177. Rosamond W, Flegal K, Furie K. Heart disease and stroke statistics—2008 update: A 
report from the American heart association statistics committee and stroke statistics sub -
committee. Circulation . 2008;117(4):e25–e46. 178. Braeuninger S, Kleinschnitz C, Niesw andt B, Stoll G. Focal cerebral ischemia. Methods 
Mol Biol . 2012;788:29–42. 179. Campbell BC, Donnan GA, Da vis SM. Vessel occlusion, penumbra, and reperfusion—
Translating theory to practice. Front Neurol . 2014;5:194–195. 180. Ramos-Cabrer P , Campos F, Sobrino T, Castillo J. Targeting the ischemic penumbra. Stroke. January 2011;42(1 Suppl):S7–S11. 181.  de la Torre JC, Fortin T, Park GA, Pappas BA, Richard MT. Brain blood flow resto -
ration ‘rescues’ chronically damaged rat CA1 neurons. Brain Res . September 24, 
1993;623(1):6–15. 182. W atson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD. Induction of repro -
ducible brain infarction by photochemically initiated thrombosis. Ann Neurol . 1985;17:497–504. 183. O’Brien MD, Waltz AG. Transorbital approach for occluding the middle cerebral artery 
without craniectomy. Stroke. 1973;4:201–206. 184. K oizumi J, Yoshida Y , Nakazawa T, Ooneda G. Experimental studies of ischemic brain 
edema. I: A new experimental model of cerebral embolism in rats in which recirculation 
can be introduced in the ischemic area. Jpn J Stroke . 1986;8:1–8. 185. O’Collins VE, Macleod MR, Donnan GA, Howells DW. Evaluation of combina -
tion therapy in animal models of cerebral ischemia. J Cereb Blood Flow Metab . 2012;32(4):585–597.197 DMSO in Basic Neuroprotection
 186. T amura A, Graham DI, McCulloch J, Teasdale GM. Focal cerebral ischaemia in the 
rat:  1. Description of technique and early neuropathological consequences following 
middle cerebral artery occlusion. J Cereb Blood Flow Metab . 1981;1:53–60. 187. Long a EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery 
occlusion without craniectomy in rats. Stroke. 1989;20:84–91. 188. Kanemitsu H, Nakagomi T, Tamura A, Tsuchiya T, Kono G, Sano K. Differences in 
the extent of primary ischemic damage between middle cerebral artery coagulation and intraluminal occlusion models. J Cereb Blood Flow Metab . 2002;22:1196–1204. 189. K ong LQ, Xie JX, Han HB, Liu HD. Improvements in the intraluminal thread technique 
to induce focal cerebral ischaemia in rabbits. J Neurosci Methods . 2004;137:315–319. 190. Baskaya MK, Dogan A, Dempsey RJ. Application of endovascular suture occlu -
sion of middle cerebral artery in gerbils to obtain consistent infarction. Neurol Res . 1999;21:574–578. 191. Freret T, Bouet V , Toutain J, Saulnier R, Pro-Sistiaga P, Bihel E, Mackenzie ET, Roussel 
S, Schumann-Bard P, Touzani O. Intraluminal thread model of focal stroke in the non-human primate. J Cereb Blood Flow Metab . 2008;28:786–796. 192. Durukan A, Tatlisumak T. Acute ischemic stroke: Overview of major experimental 
rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol 
Biochem Behav. 2007;87(1):179–197. 193. Bacig aluppi M, Comi G, Hermann DM. Animal models of ischemic stroke. Part two: 
Modeling cerebral ischemia. Open Neurol J . 2010;4:34–38. 194. Carmichael ST. Rodent models of focal stroke: Size, mechanism, and purpose. NeuroRx . July 2005;2(3):396–409. 195. Liu F , McCullough LD. Middle cerebral artery occlusion model in rodents: Methods and 
potential pitfalls. J Biomed Biotechnol . 2011;2011:464701. doi: 10.1155/2011/464701. 196. Armstead WM, Ganguly K, Kiessling JW. Signaling, delivery and age as emerging 
issues in the benefit/risk ratio outcome of tPA for treatment of CNS ischemic disorders. J Neurochem. 2010;113(2):303–312. 197. Zi vin JA, Fisher M, DeGirolami U, Hemenway CC, Stashak JA. Tissue plas -
minogen activator reduces neurological damage after cerebral embolism. Science . 1985;230:1289–1292. 198. NINDS tSTSG. The National Institute of Neurological Disorders and Stroke rt-PA 
Stroke Study Group Tissue plasminogen activator for acute ischemic stroke. N Engl J 
Med. 1995;333:1581–1587. 199. Audebert HJ, Sa ver JL, Starkman S, Lees KR, Endres M. Prehospital stroke care: New 
prospects for treatment and clinical research. Neurology. July 30, 2013;81(5):501–508. 200. Hainsw orth AH, Markus HS. Do in vivo experimental models reflect human cerebral 
small vessel disease? A systematic review. J Cereb Blood Flow Metab . December 
2008;28(12):1877–1891. 201. Fisher M, Feuerstein G, Ho wells DW, Hurn PD, Kent TA, Savitz SI, Lo EH, STAIR 
Group. Update of the stroke therapy academic industry roundtable preclinical recom -
mendations. Stroke. June 2009;40(6):2244–2250. 202. Donnan GA, Da vis SM, Parsons MW, Ma H, Dewey HM, Howells DW. How to make 
better use of thrombolytic therapy in acute ischemic stroke. Nat Rev Neurol . June 14, 
2011;7(7):400–409. 203. Dirnagl U. Bench to bedside: The quest for quality in experimental stroke research. J Cereb Blood Flow Metab . 2006;26:1465–1478. 204. Philip M, Benatar M, Fisher M, Sa vitz SI. Methodological quality of animal studies 
of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke . 2009;40:577–581. 205. Rossi J. Nonhuman primate research: The wrong way to understand needs and necessity. Am J Bioeth . 2009;9:21–23.198 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
 206. Marshall JW , Cummings RM, Bowes LJ, Ridley RM, Green AR. Functional and histo -
logical evidence for the protective effect of NXY-059 in a primate model of stroke when 
given 4 hours after occlusion. Stroke. 2003;34:2228–2233. 207. Marshall JW , Green AR, Ridley RM. Comparison of the neuroprotective effect of clo -
methiazole, AR-R15896AR and NXY-059 in a primate model of stroke using histologi-cal and behavioural measures. Brain Res . 2003;972:119–126. 208. Shuaib A, Lees KR, Lyden P et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med . 2007;357:562–571. 209.  de la Torre JC, Surgeon JW. Dexamethasone and DMSO in experimental transorbital 
cerebral infarction. Stroke. November–December 1976;7(6):577–583. 210. Karaça M, Kiliç E, Yazici B, Demir S, de la Torre JC. Ischemic stroke in elderly patients 
treated with a free radical scavenger-glycolytic intermediate solution: A preliminary pilot trial. Neurol Res . January 2002;24(1):73–80. 211. W illmore LJ, Rubin JJ. The effect of tocopherol and dimethyl sulfoxide on focal edema 
and lipid peroxidation induced by isocortical injection of ferrous chloride. Brain Res . April 2, 1984;296(2):389–392. 212a. Demchenk o IT, Boso AE, Bennett PB, Whorton AR, Piantadosi CA. Hyperbaric 
oxygen reduces cerebral blood flow by inactivating nitric oxide. Nitric Oxide . 2000;4(6):597–608. 212b. T omiyama Y , Jansen K, Brian JE Jr, Todd MM. Hemodilution, cerebral O2 delivery, 
and cerebral blood flow: A study using hyperbaric oxygenation. Am J Physiol . April 
1999;276(4 Pt 2):H1190–H1196. 212. Little JR, Spetzler RF, Roski RA, Selman WR, Zabramski J, Lesser RP. Ineffectiveness 
of DMSO in treating experimental brain ischemia. Ann NY Acad Sci . 1983;411:269–277. 213. Fukuda S, del Zoppo GJ. Models of focal cerebral ischemia in the nonhuman primate. ILAR J . 2003;44(2):96–104. 214.  de Crespign y AJ, D’Arceuil HE, Maynard KI et al. Acute studies of a new primate 
model of reversible middle cerebral artery occlusion. J Stroke Cerebrovasc Dis . March–
April 2005;14(2):80–87. 215. Cook DJ, Tymianski M. Nonhuman primate models of stroke for translational neuropro -
tection research. Neurotherapeutics . April 2012;9(2):371–379. 216. Asplund K. Randomized clinical trials of hemodilution in acute ischemic strok e. Acta 
Neurol Scand Suppl . 1989;127:22–30. 217. Carson S, McDonagh M, Russman B, Helf and M. Hyperbaric oxygen therapy for stroke: 
A systematic review of the evidence. Clin Rehabil . December 2005;19(8):819–833. 218. McGra w CP. Treatment of cerebral infarction with dimethyl sulfoxide in the mongolian 
gerbil. Ann NY Acad Sci . 1983;411:278–285. 219. Shimizu S, Simon RP, Graham SH. Dimethylsulfoxide (DMSO) treatment reduces 
infarction volume after permanent focal cerebral ischemia in rats. Neurosci Lett . December 19, 1997;239(2–3):125–127. 220. Bardutzk y J, Meng X, Bouley J, Duong TQ, Ratan R, Fisher M. Effects of intravenous 
dimethyl sulfoxide on ischemia evolution in a rat permanent occlusion model. J Cereb 
Blood Flow Metab. August 2005;25(8):968–977. 221. Gilboe DB, Kintner D, Fitzpatrick JH, Emoto SE, Esanu A, Braquet PG, Bazan NG. Recovery of postischemic brain metabolism and function following treatment with a free radical scavenger and platelet-activating factor antagonists. J Neurochem . 1991;56:311−319. 222. Nakahiro M, Arakawa O, Narahashi T, Ukai S, Kato Y , Nishinuma K, Nishimura T. 
Dimethyl sulfoxide (DMSO) blocks GABA-induced current in rat dorsal root ganglion neurons. Neurosci Lett . 1992;138:5−8. 223. Sa wada M, Sato M. The effect of dimethyl sulfoxide on the neuronal excitability and 
cholinergic transmission in Aplysia ganglion cells. Ann NY Acad Sci . 1975;243:337−357.199 DMSO in Basic Neuroprotection
 224. Sa ver JL. Number needed to treat estimates incorporating effects over the entire range 
of clinical outcomes: Novel derivation method and application to thrombolytic therapy 
for acute stroke [published correction appears in Arch Neurol . 2004;61(10):1599]. Arch 
Neurol. 2004;61(7):1066–1070. 225. The National Institute of Neurological Disorders and Strok e rt-PA Stroke Study 
Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med . 1995;333(24):1581–1587. 226. Laha RK, Dujovny M, Barrionuevo PJ, DeCastro SC, Hellstrom HR, Maroon JC. Protective effects of methylprednisolone and dimethyl sulfoxide in experimental middle cerebral artery embolectomy. J Neurosurg . 1978;49:508−516. 227. Demopoulos HB, Flamm E, Yoder M. Mechanisms of barbiturate protection of isch -
emic endothelium. A scanning electron microscopy study. Am Assoc Neurrol Surg. 1979;19:35–36. 228. Miller TR. Costs associated with gunshot wounds in Canada in 1991. CMAJ . November 
1, 1995;153(9):1261–1268. 229. Sorani MD, Morabito D, Rosenthal G, Giacomini K, Manle y G. Characterizing the 
dose–response relationship between mannitol and intracranial pressure in traumatic brain injury patients using a high-frequency physiological data collection system. J Neurotrauma . 2008;25(4):291–298. 230. Bro wn FD, Johns L, Mullan S. Dimethyl sulfoxide therapy following penetrating brain 
injury. Ann NY Acad Sci . 1983;411:245–252. 231. Marmarou A, Saad A, Aygok G, Rigsbee M. Contribution of raised ICP and hypotension 
to CPP reduction in severe brain injury: Correlation to outcome. Acta Neurochir Suppl . 2005;95:277–280. 232. Struchen MA, Hannay HJ, Contant CF , Robertson CS. The relation between acute phys -
iological variables and outcome on the glasgow outcome scale and disability rating scale 
following severe traumatic brain injury. J Neurotrauma . 2001;18:115–125. 233. Manle y G, Knudson MM, Morabito D, Damron S, Erickson V , Pitts L. Hypotension, 
hypoxia, and head injury: Frequency, duration, and consequences. Arch Surg . 2001;136:1118–1123. 234. Pigula F A, Wald SL, Shackford SR, Vane DW. The effect of hypotension and hypoxia on 
children with severe head injuries. J Pediatr Surg . 1993;28:310–14. 235. Haddad SH, Arabi YM. Critical care management of severe traumatic brain injury in 
adults. Scand J Trauma Resusc Emerg Med. 2012;20:12–29. 236. U.S. Census Bureau, Population Di vision. December 2012. Table 2. Projections of the 
Population by Selected Age Groups and Sex for the United States: 2015 to 2060 (NP2012-T2). 237. V iswanathan M, Kim SK, Berdichevsky A, Guarente A. A role for SIR-2.1 regulation of 
ER stress response genes in determining C. elegans life span. Dev Cell . 2005;9:605–615. 238. Kampk otter A, Nkwonkam CG, Zurawski RF, Timpel C, Chovolou Y . Investigations of 
protective effects of the flavonoids quercetin and rutin on stress resistance in the model 
organism Caenorhabditis elegans. Toxicology . 2007;234:113–123. 239. W ang G, Huang C, Wang Y , Guo Q, Jiang H, Wen J. Changes in expression of  c yclooxygenase-2 
in the spinal dorsal horn after intrathecal p38MAPK inhibitor SB203580 on neuropathic pain in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban . July 2013;38(7):686–690. 240.  de la Torre JC. Alzheimer’s disease: How does it start? J Alzheimers Dis . December 
2002;4(6):497–512. 241.  de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer’s 
disease? Neurol Res . June 1993;15(3):146–153. 242.  de la Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, 
dogma, and dialectics. Lancet Neurol . 2004;3:184–190. 243.  de la Torre JC. Critical threshold cerebral hypoperfusion causes Alzheimer’s disease. Acta Neuropathol . 1999;98:1–8.200 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
 244. Stürchler -Pierrat C, Abramowski D, Duke M et al. Two amyloid precursor protein trans -
genic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA . 1997;94:13287–13292. 245. McGo wan E, Eriksen J, Hutton M. A decade of modeling Alzheimer’s disease in trans -
genic mice. Trends Genet . 2006;22:281–289. 246. Da vies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s dis -
ease. Lancet . 1976;2:1403. 247. Ebert U, Kirch W. Scopolamine models of dementia: Electroencephalogram findings 
and cognitive performance. Eur J Clin Invest . 1998;28:944–949. 248. Ser geant N, Buée L. TAU models. In Animal Models of Dementia , eds. P.P. De Deyn, D. 
Van Dam. Springer Science + Business Media, New York, 2010; pp. 449–468. 249. Castañé A, Theobald DE, Robbins TW. Selective lesions of the dorsomedial striatum 
impair serial spatial reversal learning in rats. Behav Brain Res . 2010;210:74–83. 250. Le vitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a 
Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature . 1995;377:351–354. 251.  de la Torre JC, Fortin T, Park G, Butler K, Kozlowski P, Pappas B, de Socarraz H, 
Saunders J. Chronic cerebrovascular insufficiency induces dementia-like deficits in aged 
rats. Brain Res . 1992;582:186–195. 252.  de la Torre JC, Nelson N, Sutherland RJ, Pappas BA. Reversal of ischemic-induced 
chronic memory dysfunction in aging rats with a free radical scavenger-glycolytic inter -
mediate combination. Brain Res . 1998;779:285–288. 253.  de la Torre JC, Nelson N, Sutherland RJ. Combined fructose 1,6-diphosphate-dimethyl 
sulfoxide reverses chronic memory deficits in brain ischemic rats. In Neurochemistry , 
eds. A. Teelken, J. Korf, Plenum Press, New York, 1997; pp. 173–176. 254. Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, van Duijn 
CN, Van Broeckhoven C, Grobbee DE. Atherosclerosis, apolipoprotein E, and preva -
lence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet. January 18, 
1997;349(9046):151–154. 255.  v an Oijen M, de Jong FJ, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM. Atherosclerosis and risk for dementia. Ann Neurol . May 2007;61(5):403–410. 256. Johnson DK, Morris JC, Galvin JE. Verbal and visuospatial deficits in dementia with 
Lewy bodies. Neurology. October 25, 2005;65(8):1232–1238. 257. Iachini I, Ia varone A, Senese VP, Ruotolo F, Ruggiero G. Visuospatial memory in 
healthy elderly, AD and MCI: A review. Curr Aging Sci . March 2009;2(1):43–59. 258. F arkas E, Institóris A, Domoki F, Mihály A, Luiten PG, Bari F. Diazoxide and dimethyl 
sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain dam -
age after carotid artery occlusion. Brain Res . May 22, 2004;1008(2):252–260. 259. Markv artova V , Cendelin J, V ozeh F. Effect of dimethyl sulfoxide in cerebellar mutant 
Lurcher mice. Neurosci Lett . May 24, 2013;543:142–145. 260. Porras-Garcia E, Cendelin J, Dominguez-del-T oro E, V ozeh F, Delgado-Garcia JM. Purkinje cell loss affects differentially the execution acquisition and prepulse inhi -
bition of skeletal an facial motor responses in Lurcher mice. Eur. J. Neurosci. 2005;21:979–988. 261. Caddy KW , Biscoe TJ. Structural and quantitative studies on the normal C3H and 
Lurcher mutant mouse. Philos Trans R Soc Lond B Biol Sci . 1979;287(1020):167–201. 262. Barcal J, Cendelín J, K orelusová I, T ůma J, V ozeh F. Glutamate receptor block in 
Lurcher mutant mice during ontogeny and its effect on hippocampal long-term potentia -
tion. Prague Med Rep . 2010;111(2):127–134. 263.  deLara CM, Jenner TJ, Townsend KM, Marsden SJ, O’Neill P. The effect of dimethyl 
sulfoxide on the induction of DNA double-strand breaks in V79-4 mammalian cells by 
alpha particles. Radiat Res . October 1995;144(1):43–49.201 DMSO in Basic Neuroprotection
 264. Cig arrán S, Barrios L, Caballín MR, Barquinero JF. Effect of DMSO on radia -
tion-induced chromosome aberrations analysed by FISH. Cytogenet Genome Res . 2004;104(1–4):168–172. 265. Gre gersen N, Bross P, Vang S, Christensen JH. Protein misfolding and human disease. Annu Rev Genomics Hum Genet . 2006;7:103–124. 266. Araka wa T, Ejima D, Kita Y , Tsumoto K. Small molecule pharmacological chaperones: 
From thermodynamic stabilization to pharmaceutical drugs. Biochim Biophys Acta . 2006;1764(11):1677–1687. 267. P app E, Csemely P. Chemical chaperones: Mechanisms of action and potential use. In 
Molecular Chaperones in Health and Disease . Handbook of Experimental Pharmacology, 
V ol. 172, Gadstel, M (Ed. ), Springer-Verlag, Berlin, Heidelberg, 2006; pp. 405–416. 268. Curt A, Ellaway PH. Clinical neurophysiology in the prognosis and monitoring of trau -
matic spinal cord injury. Handb Clin Neurol. 2012;109:63–75. 269. Shields CB, Ping Zhang Y , Shields LB, Burke DA, Glassman SD. Objective assessment 
of cervical spinal cord injury levels by transcranial magnetic motor-evoked potentials. Surg Neurol . November 2006;66(5):475–483. 270.  de la Torre JC. Spinal cord injury. Review of basic and applied research. Spine . 1981;6(4):315–335. 271. Hurlbert RJ. Methylprednisolone for acute spinal cord injury: An inappropriate standard 
of care. J Neurosurg . 2000;93:1–7. 272. Hurlbert RJ, Hamilton MG. Meth ylprednisolone for acute spinal cord injury: 5-year 
practice reversal. Can J Neurol Sci . March 2008;35(1):41–45. 273. Hurlbert RJ, Moulton R. Why do you prescribe methylprednisolone for acute spinal 
cord injury? A Canadian perspective and a position statement. Can J Neurol Sci . August 
2002;29(3):236–239. 274. P andya KA, Weant KA, Cook AM. High-dose methylprednisolone in acute spinal cord 
injuries: Proceed with caution. Orthopedics. May 2010;33(5):327–331. 275. Kajihara K, Ka wanaga H, de la Torre JC, Mullan S. Dimethyl sulfoxide in the treatment 
of experimental acute spinal cord injury. Surg Neurol . January 1973;1(1):16–22. 276. Mullan S, de la Torre JC, Kajihara K, Kawanaga HM. Use of dimethyl sulfoxide in exper -
imental head and spinal cord injuries. J Neurol Neurosurg Psychiat . 1973;36:153–154. 277.  de la Torre JC, Kajihara K, Rowed DW, Kawanaga HM, Mullan JF. Modification of 
experimental head and spinal cord injury. Trans Amer Neurol Assoc . 1973;97:230–233. 278. Goldsmith HS. Application of the omentum to brain and spinal cord. In The Omentum, 
Application to Brain and Spinal Cord, ed. H.S. Goldsmith. Forefront Publishing, Wilton, CT, 2000; pp. 25–43. 279. Goldsmith HS. Can the standard treatment of acute spinal cord injury be impro ved? Perhaps the time has come. Neurol Res . 2007;29;16–20. 280. Zileli M, Ovul I, Dalbasti T. Effects of methyl prednisolone, dimethyl sulphoxide and 
naloxone in experimental spinal cord injuries in rats. Neurol Res . 1988;10:232–235. 281. Ruck er NC, Lumb WV , Scott RJ. Combined pharmacologic and surgical treatments for 
acute spinal cord trauma. Ann NY Acad Sci . 1983;411:191–199. 282. Gelderd JB, Fife WP, Bowers DE, Deschner SH, Welch DW. Spinal cord transection in 
rats: The therapeutic effects of dimethyl sulfoxide and hyperbaric oxygen. Ann NY Acad 
Sci. 1983;411:218–233. 283. Shi R, Qiao X, Emerson N, Malcom A. Dimethylsulfoxide enhances CNS neuronal 
plasma membrane resealing after injury in low temperature or low calcium. J Neurocytol . September–October 2001;30(9–10):829–839. 284. T uran NN, Akar F, Budak B, Seren M, Parlar AI, Sürücü S, Ulus AT. How DMSO, 
a widely used solvent, affects spinal cord injury. Ann Vasc Surg . January 2008; 
2(1):98–105.202 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
 285. Blokhina O, Virolainen E, Fagerstedt KV . Antioxidants, oxidative damage and oxygen 
deprivation stress: A review. Ann Bot . January 2003;91 Spec No:179-94. 286. Szabó C, Ohshima H. DN A damage induced by peroxynitrite: Subsequent biological 
effects. Nitric Oxide . October 1997;1(5):373–385. 287. Erecinska M, Silv er IA. ATP and brain function. J Cereb Blood Flow Metab . 1989;9:2–19. 288. Clark e DD, Sokoloff L. Circulation and energy metabolism of the brain. In Basic 
Neurochemistry , eds. G.J. Siegel, B.W. Agranoff, R.W. Albers, P.B. Molinoff. Raven 
Press, New York, 1994; pp. 645–680. 289. Le vine JM, Cohen ND, Heller M et al. Efficacy of a metalloproteinase inhibitor in spinal 
cord injured dogs. PLoS One . 2014;9(5):e96408. 290. Sharp K, Yee KM, Steward O. A re-assessment of the effects of treatment with an epi -
dermal growth factor receptor (EGFR) inhibitor on recovery of bladder and locomotor 
function following thoracic spinal cord injury in rats. Exp Neurol . 2012;233:649–659.203
9DMSO in Clinical 
Neuroprotection
OVERVIEW OF CLINICAL TRAUMATIC BRAIN INJURY
Head injuries in humans can involve trauma to the scalp, skull, or brain. They can be 
described as mild, moderate, or severe (Figure 9.1). Head injuries can be penetrating where the skull is broken, or closed, where the brain may be injured but the skull remains intact. Penetrating injuries are generally caused by auto accidents, blows to the head, 
and gunshot wounds. Closed head injuries are caused mainly by vehicular accidents, acts of violence, falls, and sports-related trauma. 1 The severity of closed head injuries 
range from mild concussions to disabling brain trauma leading to total incapacitation or death. Traumatic brain injuries typically involve young adult men. Brain trauma can damage tissue at the site of impact or at the opposite poles of 
impact due to sudden acceleration–deceleration movement of the brain, which acts like a mass of jelly moving forward and backward inside the skull. This type of brain injury is called a coup–contercoup injury because damage occurs at the site 
of impact and on the direct, opposite side as the brain moves forward and backward. Symptoms after a traumatic brain injury vary according to the severity of the injury as well as what part of the brain is affected and whether the injury is localized to one part of the brain or is diffuse. Symptoms can range from a simple headache with no loss of consciousness (LOC) to fatigue, dizziness, nausea, and vomiting, to severe cognitive impairment, mood changes resulting in confusion, restlessness, agitation,
2 
to motor-sensory deficits involving speech, vision, muscle coordination, and coma.3
Focal and diffuse cerebral injuries are descriptive ways to classify the extent of 
structural or functional damage to the brain. As the term implies, focal injury occurs in a specific brain location (Figure 9.1), while diffuse injury can involve more wide -
spread regions of the brain (Figure 9.1, arrows). An example of a focal injury is an epidural or subdural hematoma where a blood clot forms on the surface of the brain (epidural) or below the epidural membrane, typically as a result of a blow to the head. Diffuse axonal injuries can follow a mild or moderate head injury, and recovery 
is often possible when the lesions are few and diffusivity is contained. 4,5 Diffuse 
axonal injuries are generally caused by acceleration–deceleration of the head, which may or may not contact any external object in particular since the injury can occur from violent brain shaking. This shaking within the skull can burst blood vessels and severely injure brain tissue. One of the outcomes of diffuse injuries involves the 
shearing of axonal tracts and tissue white matter that result as brain tissues of differ -
ent densities slide over each other much like tectonic plates under the earth slipping 
past each other and colliding to create earthquakes. Diffuse axonal injuries rarely 204 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
induce death, but they can be devastating as the cause of permanent vegetative state 
and they are considered the most significant determinant of morbidity in patients with brain trauma. 6 It is estimated that only 10% of people affected by severe diffuse 
axonal injury regain consciousness and only a small percentage of these will attain near-normal recovery of neurological function. 7 Significant improvement after 1 year 
is rare.8
Diffuse axonal injuries are maybe difficult to detect by imaging techniques 
unless ventricular hemorrhage, abnormal foci, or multiple petechial hemorrhages are detected (Figure 9.1). These injuries frequently involve the frontal and inferior temporal lobes and the brainstem but spare major damage to basic life functions that control cardiac and respiratory systems. Often, the diagnosis of diffuse axonal injury is made when the patient’s symptoms are disproportionate to the imaging findings. 9
The treatment of focal or diffuse brain trauma is aimed at immediate measures 
to reduce swelling inside the brain and prevent secondary damage and a deadly outcome. Brain swelling creates dangerous increases in intracranial pressure (ICP) because the cranial vault is a rigid container and the tissue, with nowhere to go except to squeeze through the foramen magnum, can be compressed to quickly diminish cerebral perfusion and establish ischemia and brain infarction. 10 The herniated brain 
tissue coning  through the foramen magnum can also put fatal pressure on regions of 
the brainstem, which are vital to life.11
Brain trauma can affect cerebral autoregulation. Cerebral autoregulation is a 
homeostatic mechanism that maintains a constant level of cerebral blood flow (CBF) 
MildSeverity of traumatic brain injury
Moderate
Severe
FIGURE 9.1  (See color insert.) A mild head injury refers to the severity of the initial 
blunt trauma, which is generally a concussion affecting the scalp or the skull and involves brief (<30 min) changes in mental status or consciousness as opposed to a severe injury, which results in extended LOC, coma, and posttraumatic amnesia (PTA) lasting days, months, or years. This injury has a high risk of mortality. LOC after a moderate head injury does not generally exceed 6 h, and PTA may extend up to 24 h. A moderate-to-severe head injury can result in an epidural hematoma, subdural hematoma, or intraparenchymal hemorrhage.205 DMSO in Clinical Neuroprotection
in the presence of changing cerebral perfusion pressures (CPPs). Autoregulation 
fails when the mean arterial pressure (MAP) falls below 60 mmHg or rises above 150 mmHg. When cerebral autoregulation fails, the chances for survival are consid -
ered poor. A gold standard for measuring cerebral autoregulation is not available at the present time, and a search of the literature shows considerable divergence in the methods used. This fact is not surprising given that cerebral autoregulation is more a concept than a physically measurable entity. However, neuromonitoring of cerebral autoregulation is essential in guiding therapy and assessing the metabolic require -
ment of the cerebral tissues at a time of physiological crisis. 12
Because the primary damage cannot be controlled due to the fact that a direct 
mechanical injury has already occurred, prevention of secondary damage is the pri -
mary goal of neurocritical care and treatment. Secondary damage develops within hours or sometimes days and is dependent on whether treatment can reverse or minimize impaired cerebrovascular autoregulation, cerebral metabolic dysfunc -
tion, tissue edema, inflammation, and inadequate brain oxygenation. 13–15 Figure 9.2 
summarizes the initial clinical approach to the patient sustaining a severe head injury as recommended by a joint section on neurotrauma and critical care from the American Association of Neurological Surgeons. 16 The chronological order of 
this approach can vary according to the circumstances of the head injury. These guidelines can also be used for moderate and even mild head injuries when deemed appropriate. Extended tissue destruction spreading from the primary site of head trauma is the 
first pathophysiological stage characterizing secondary brain damage. The extended tissue damage will kill more brain cells as it spreads through the brain tissue mainly from impaired cerebral perfusion, growing edema, and as cytotoxic free radicals and excitatory neurotransmitters are released. Basic clinical approach to th e
head-injur ed patien t
Provide oxygenation/ventilation (when n eeded )
Reduce IC P
Restore CBF
Maintain normal blo od pressure
Identi fy associa ted injuries
Prevent se condary brain damage
FIGURE 9.2  Emergency approach to the head-injured patient includes oxygenation to 
prevent hypoxemia, reduction of high ICP, prevention of low CBF that is associated with poor outcome, and prevention of systolic blood pressure drop below 90 mmHg, ruling out secondary injuries and providing treatment to prevent secondary damage. (From American Association of Neurological Surgeons, J. Neurotrauma , 24, S-1, 2007. )206 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
This pathologic process will progress if untreated and further involve cellular 
DNA fragmentation and inhibition of DNA repair.17 The final outcome from this 
tissular cataclysm is the obliteration of vascular and cellular structures leading to 
necrotic or programmed cell death.17 The clinical outcome of uncontrolled second -
ary damage following brain trauma will likely result in severe neurologic impair -
ment or death.11
The most commonly used method for grading the severity of brain injury is the 
Glasgow coma score (GCS), a neurological scale that attempts to provide an objective and reliable way of quantifying a person’s conscious level following traumatic brain injury and a possible prediction of outcome. The GCS is used primarily because it is simple and has a relatively high degree of interobserver reliability, but it should be used only after any needed resuscitative measures are applied. Developed by Teasdale and Jennett,
18 the GCS scale classifies patients with mild, 
moderate, or severe head injuries using three aspects of neurologic function: eye opening, verbal response, and motor response. The presence or absence of these functions is scored using a scale ranging from 3 to 15, which correspond to a mild injury (13–15), moderate injury (9–12), and severe injury (3–8). 18 The GCS allows 
serial evaluations of patients’ progress and can also provide an assessment of the value of a given treatment. The difference between a GCS of 3–4 and 7–8 can mean the difference between permanently poor outcome (3–4) to potentially good recov -
ery and moderate disability. Patients arriving at the hospital with a GCS of 3 and bilateral, fixed dilated pupils have little chance of survival as opposed to patients with the same GCS score and reactive pupils. It has been argued that the motor response of the GCS yields similar prediction 
rates of outcome as the summed GCS score due to the fact the motor component is not only linearly related to survival but also preserves almost all the predictive power of the GCS. 19,20
Using the motor component of the GCS also allows intubated patients to be evalu -
ated without the verbal response of the GCS. It appears then that the best motor response is probably the most significant predictor of outcome. Besides the GCS motor response, other classifications of injury severity focus on the duration of post -
traumatic amnesia (PTA) and duration of LOC. The PTA correlates with the overall severity of the injury and can be assessed with the Galveston orientation and amne -
sia test (GOAT) or the orientation log (O-Log). 21
The guidelines recommended for the clinical management of patients (Figure 9.2) 
and the GCS are particularly useful in patients with severe brain trauma who clearly benefit from prompt and effective emergency care because most of the pathology that determines long-term outcome will be present in the first hours after a head injury. 22 
Therefore, a concise, clear, and practical approach to the evaluation and treatment of patients with severe brain trauma is necessary to avoid delays in management and to minimize secondary brain damage. In the general U.S. population, roughly 1.7 million brain injuries are reported annu -
ally, leading to more than 52,000 deaths. 23 The majority of these injuries are minor 
bumps on the head that require no treatment, but even mild head injuries can lead to lifelong disability or even death. Beyond the effects of acute injury, troubling new 207 DMSO in Clinical Neuroprotection
findings indicate that even minor brain injury can predispose to neurodegeneration 
and dementia in later life.24
American involvement in recent wars indicates that as many as 320,000 U.S. 
troops in Iraq and Afghanistan have suffered head injuries mostly from improvised explosive devices (IEDs). 25 Many of these blast injuries, while not immediately life 
threatening, can have a long-term impact that fosters personality changes, impulse-control problems, and dementia in later life. 25 It may also explain the high incidence 
of suicide among veterans returning home from combat.26
HEAD INJURY IN CHILDREN
Head injury occurs frequently in children and accounts for approximately 500,000 emergency department visits annually in the United States. Nearly 75% of these inju -
ries are ultimately diagnosed as mild in severity, and the vast majority of cases will have no long-term neurological sequelae. However, even mild head injuries will sus -
tain intracranial damage and long-term consequences. 27 Although it is a challenge to 
triage children with a mild head injury with respect to possible intracerebral lesions on CT scanning, several indices such as admission GCS score, focal neurological deficits, and fractures detected by skull radiography have been found reliable predic -
tors of positive findings when CT is performed. 28
Diagnosing severe traumatic brain injury in children is most important because 
long-term neurodisability and death can quickly follow and early neurosurgical intervention and/or pharmacotherapy may improve the outcome. 29 Children who sur -
vive severe traumatic brain injury are at high risk for problems in behavior, adaptive functioning, and educational performance. 30
COST AND CONSEQUENCES OF TRAUMATIC BRAIN INJURY
According to the World Health Organization, traumatic brain injury is a problem that affects 10 million people annually worldwide. 31 Among these, 5.3 million Americans 
live with long-term disabilities related to traumatic brain injury.32
In the United States, traumatic brain injury–associated direct and indirect costs 
have been estimated to be more than 76.5 billion dollars a year.33 This cost does 
not include 11  years of warfare in Iraq and Afghanistan, where, according to a Congressional Research Service report into military casualty statistics, approxi -
mately 300,000 troops have experienced some form of brain trauma. 25
Aside from cognitive and physical disability problems encountered by most peo -
ple with traumatic brain injury, this injury is believed to be a risk factor in the devel -
opment of Alzheimer’s disease, sometimes occurring decades after the trauma.34 It 
is now clear that a history of brain trauma predisposes the individual 2–4 times to an increased risk of Alzheimer’s disease when compared to individuals with no history of brain trauma. 35
The long-term neuropathologic process evolving after single traumatic brain event 
of sufficient severity to produce LOC is poorly understood, but it has been specu -
lated that chronic cerebral hypoperfusion may play a major role.36 This conclusion 208 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
is supported by arterial spin-labeling magnetic resonance imaging (MRI) of people 
with a prior moderate-to-severe traumatic brain injury who showed cerebral hypo -
perfusion in regions of the brain such as the posterior cingulate cortex, later asso -
ciated with neuropathological changes, characteristic of Alzheimer’s dementia.37 
Reduced CBF during aging is known to be a marker for cognitive impairment prior to the onset of Alzheimer’s dementia. 38,39
CHRONIC TRAUMATIC ENCEPHALOPATHY
Boxers who have had repeated blows to the head for years were shown to have cere -
bral hemodynamic impairment affecting cerebral perfusion, and these changes were associated with a higher incidence of neurocognitive dysfunction corresponding to a lack of sustained attention, difficulty concentrating on tasks at hand, disorientation, and not remembering newly learned material when compared to a similar group without a history of brain trauma. 40 Originally, this type of injury was described as 
punch drunk  by Martland in 1927 and later given the more descriptive term demen -
tia pugilistica by Millspaugh.41
The realization was slow in coming that the same repetitive type of head knock -
ing in boxers could also occur in players of other contact sports such as football, soccer, lacrosse, rugby, and hockey. This brain injury is now known as chronic traumatic encephalopathy (CTE). At the beginning, CTE may be asymptomatic or start slowly with symptoms initially involving problems in memory and concentra -
tion. Months and years after the initial symptoms of concussion have faded, new symptoms occur as gradual degeneration of brain function occurs with episodes of disorientation, confusion, dizziness, severe neurocognitive disturbances, and dementia. Although early diagnosis of CTE is often difficult due to an absence of bleeding 
or major structural abnormalities on a CT scan, grossly, CTE in the final stages is characterized by the enlargement of the ventricles and atrophy of the hippocampus, amygdala, and frontal, temporal, parietal, and entorhinal cortices. 42 Histologically, 
there is significant neuronal loss and increase of reactive glial cells usually accom -
panied by neurofibrillary tangle formation in the hippocampus and entorhinal cor -
tex, two regions associated with learning and memory and the primary targets for Alzheimer’s disease pathologic lesions. 42,43
These findings suggest that structural brain lesions, both focal and diffuse, are 
the primary contributors to the abnormal cerebral perfusion changes seen in chronic traumatic brain injury and CTE and that CBF quantitation may serve as an early marker to assess the degree of damage to neurons and their synapses. Besides neuroimaging measurements of CBF, neurocognitive tests designed 
to assess mental status are now used to complement any structural or physiologi -
cal brain abnormality in people at risk of CTE. These tests can evaluate decision-making ability, reaction time, attention, and memory of an athlete after sustaining 
a concussion or following repetitive knocks to the head from the participation of 
sports-related activities. The goal of these measures is to identify and prevent further damage to the brain in athletes from the particular sport activity before it becomes irreversible if head pounding is continued or ignored.209 DMSO in Clinical Neuroprotection
TREATING TRAUMATIC BRAIN INJURY
The initial focus of managing an acute traumatic brain injury is to stabilize the 
injured person in order to minimize complications from secondary damage. This approach generally follows the clinical guidelines outlined in Figure 9.1. Mild traumatic brain injuries usually require no treatment other than rest and 
over-the-counter pain relievers to treat a headache. However, it is estimated that up to 3% of mild head injuries progress to more serious consequence, so careful evaluation of the injury and its potential to worsen is mandatory. Most mild head injuries may not require hospitalization and can be closely monitored at home by a responsible caretaker given written instructions for any persistent worsening of initial symptoms or new symptoms. For moderate-to-severe traumatic brain injuries, the general rule is to stabilize the 
patient to minimize secondary damage such as the development of plateau waves. Plateau waves during traumatic brain injury are abrupt increases of ICP above 40 mmHg that can be due to lower CBF, cardiac output, and brain tissue oxygen -
ation. These plateau waves can be controlled when CPP and oxygenation can be restored in head-injured patients. 44
This can be done initially with intravenous (IV) fluids to maintain the patient in 
a state of euvolemia or mild hypervolemia.45 Fluid resuscitation has replaced the old 
rule of fluid restriction since hypovolemia has been shown to reduce cardiac output. When cardiac output is decreased following brain trauma, there is often a reduction in cerebral perfusion that may cause an increase in cerebral edema and ICP. 36 Thus, 
fluid restriction is contraindicated in patients with raised ICP and brain edema. The brain trauma patient may also require sedation to prevent agitation as well as pain medication as required. The preferred treatment for increased ICP is currently the use of osmotherapy, 
such as mannitol and hypertonic saline. 46 This treatment however is problematic 
especially when it is extended for long periods of time since it has been shown to promote electrolyte abnormalities, especially hypernatremia. 47 Other adverse effects 
after osmotherapy are associated with cardiac failure, bleeding diathesis, and phle -
bitis. No benefits of small-volume resuscitation with hypertonic saline have been shown in patients with traumatic brain injury. 48
Consequently, in adults, there is insufficient evidence to support the use of hyper -
tonic saline or mannitol for managing ICP because of the risks of severe hypernatre -
mia, and caution has been advised with the combined use of mannitol and hypertonic saline. 49 Careful control of fluid balance, electrolyte status, and serum osmolarity 
(<320 mmol/L) is mandatory when hypertonic agents are used. Many prehospital care systems use advanced-level prehospital care providers in 
the belief that prevention or early correction of these insults will improve patient outcomes. The main goal of prehospital management is to prevent hypoxia and hypotension, 
because these systemic insults are prone to induce secondary brain damage. 50 When 
patient status was recorded by trained paramedics at the scene of injury before hospital admission, oxygen saturation below 90% was found in half of all cases reviewed and hypotension was present in about 25% of head injury patients. 51,52 210 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
Trauma renders the brain more vulnerable to these secondary insults,52 and hypoxia 
and hypotension are strongly associated with poor outcome.53
Consequently, the introduction of a prehospital system capable of normalizing 
oxygenation and blood pressure has been associated with improved outcome.54,55 To 
our knowledge however, only one randomized control led trial (RCT) has compared 
physician and nonphysician teams in prehospital brain trauma management.55 This 
single RCT supported the value of trained paramedical personnel able to perform bag-valve-mask ventilation, apply external compression for hemorrhage, intubate orally without adjuvant neuromuscular blockade, and establish IV lines to adminis -
ter crystalloid or other solutions. 56
Are there pharmacological treatments now clinically available that will stop and 
reverse the pathology that follows a moderate or severe traumatic brain injury? In a word, no. 57
This grim conclusion is supported by the sobering fact that the best and worst 
hospitals in the United States report similar morbidity and mortality rates of patients admitted with moderate-to-severe traumatic brain injuries. 58 This finding stresses the 
predictably poor outcome in this group of patients and the lack of an effective treat -
ment or intervention to control the catastrophic sequelae associated with this injury. Lu et al.59 conducted a comprehensive literature review of RCTs in adults sustain -
ing a traumatic brain injury over the past 30 years. RCTs are the gold standard of clinical trials due to their rigorous way of determining whether a cause–effect rela -
tion exists between treatment and outcome. Lu et al. 59 dramatically discovered that of 55 acute-phase trials of interventions 
for traumatic brain injury, 40 showed either no effect or adverse effects when used on brain trauma patients. These acute-phase trials were defined as interventions that occurred within 24 h following injury to the brain. 59 The few trials with lim -
ited effectiveness in treating brain trauma patients were nonpharmacological and included early nutritional therapy, cognitive rehabilitation, and physical rehabili -
tation. Treatments such as decompressive craniotomy, hyperventilation, therapeu -
tic hypothermia, and osmotic pharmacotherapy led to either ineffective or mixed results. 59
For example, decompressive craniotomy, hyperosmotic therapy including manni -
tol or hypertonic saline, and hypothermia have shown inconsistent effects, with some studies reporting positive results
60,61 and others reporting negative or no results.62–64
Lu’s review59 of 32 RCTs examining drugs targeting neuronal excitotoxicity 
such as magnesium, insulin, or corticosteroids and drugs blocking lipid peroxida -
tion either failed to show a positive treatment effect or led to adverse effects. Of the 32 clinical RCTs, only 3 drugs showed positive treatment effects for acute trau -
matic brain injury, including 1 involving methylphenidate, a dopamine agonist and psychostimulant. 65
However, a recent Cochrane Central Register analysis of 20 traumatic brain injury 
RCTs using dopamine agonists including methylphenidate showed no trend toward 
efficacy and safety when measures of cognitive and neuropsychological function 
were applied.66 One major concern of these RCTs was the high risk of bias involved 
in each investigation, which consisted mainly of selection reporting bias and the lack of information to determine the efficacy of randomization. 66 This search analysis of 211 DMSO in Clinical Neuroprotection
the relevant literature concluded that dopamine agonists such as methylphenidate, 
amantadine, and bromocriptine cannot be recommended as part of the acute treat -
ment regimen to preserve cognitive function following traumatic brain injury.66
The other two drugs found to have efficacy in the review of Lu et al.59 of brain 
trauma treatments were the calcium channel antagonist nimodipine and progester -
one, a reproductive hormone involved in pregnancy and the menstrual cycle. The activities of progesterone and DMSO in traumatic brain injury (TBI) are discussed in detail in the “DMSO Compared to Progesterone for Traumatic Brain Injury” sec -
tion. This section includes two most recent clinical trials reported in December 2014, showing no benefit to patients treated for TBI using progesterone. As for the calcium channel blockers, Harders et al. 67 reported on a prospective, ran -
domized, double-blind, placebo-controlled study of nimodipine on 123 patients to treat subarachnoid hemorrhage secondary to traumatic brain injury and found that 6 months after this treatment, significantly less unfavorable results in terms of severe disability, vegetative state, or death resulted when compared to a placebo-treated group. Again, however, a systematic review of RCTs using calcium channel blockers, 
including nimodipine for acute traumatic head injury, showed considerable uncer -
tainty over its effects. The use of nimodipine after blunt head injury revealed an increase in adverse reactions suffered by the group receiving this treatment, a finding that implies the drug is harmful for some patients. 68
With regard to progesterone, two RCTs, reported in 2007–2008, showed positive 
data for this drug. In the first trial, 159 randomized patients were randomized to receive progesterone (N = 82) or a placebo (N = 77) within 8 h of injury. All patients were evaluated after 3 and 6 months of follow-up. Improved neurological outcome and lower mortality rate were reported for the progesterone-treated group at both time points. 69
The second trial using progesterone was a randomized, double-blind, placebo-
controlled trial consisting of 100 adult brain trauma patients who were treated within 11 h of injury with a postresuscitation GCS of 4–12. After 30 days postinjury, only moderately injured patients (GCS 9–12) showed lower mortality rate than placebo and possible  signs of benefit when compared to the placebo group. The mortality 
rate reduction was marginally significant when the treatment group was compared with placebo. 70 Stein et al.71 theorized that the possible mechanisms of progesterone 
neuroprotection may lie in its ability to lower brain edema and downregulate the inflammatory cascade associated with traumatic-induced brain swelling. More recently, a Cochrane Injuries Group’s Specialised Register analyzed 3 small 
RCTs involving 315 people treated with progesterone or placebo for traumatic brain injury and concluded that progesterone may improve the neurologic outcome of patients with traumatic brain injury but cautioned that evidence for effectiveness remains insuf -
ficient. 72 This Cochrane analysis recommended that multicenter RCTs are needed to 
examine whether any benefit for head injury is provided by progesterone therapy.72
DMSO IN TRAUMATIC BRAIN INJURY
Although much has been learned in the past 25  years about the cellular and molecular pathologies associated with traumatic brain injury, the hunt for effec -
tive treatments has been a historical disappointment. This failure to find an 212 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
effective treatment for traumatic brain injury may have more to do with choice of 
the experimental model than with the choice of what end points may be relevant to the human injury. For example, there are two major flaws in correlating the effectiveness of a ther -
apy for brain trauma using small animals as the injury model. The first flaw is that the animal models used to test potential treatments for head injury, such as rats, cats, rabbits, sheep, pigs, and mice,
73 all have cerebrovascular supplies that are inherently 
dissimilar to humans or nonhuman primates and this dissimilarity creates a variable tolerance when trauma is applied to their brains. Human and nonhuman primate brain is highly organized and lacks the col -
lateralization of cerebral vessels found in small mammals, so its vulnerability to brain trauma or ischemia is much greater than that of small mammals. The second major flaw may be an inherent ineffectiveness of the treatment being tested. These two experimental flaws may help explain why dramatic therapeutic responses often reported as breakthroughs in the head injury field using small animals sub -
jected to head injury later are shown to have almost zero correlation to the human counterpart. Consequently, extrapolations relating the success of these therapies in small ani -
mal models to humans are at best uncertain and impossible to predict. To complicate matters, traumatic brain injury in humans can result in focal 
pathology due to the formation of hematomas and vessel infarction, or diffuse injury involving spreading edema, activation of inflammatory cytokines, release of excit -
atory neurotransmitters, and diffuse axonal injury. 74 Some but not all of the patho -
logical processes are easy to create in a small animal model but difficult to clinically assess posttrauma after a treatment is delivered due to the variability and tolerance associated with each animal species. From this perspective, DMSO had a distinct advantage when it was first tested 
for traumatic brain injury in the early 1970s because nonhuman primates were used. For reasons discussed in Chapter 8, using nonhuman primates, whose brains very closely resemble human brain, means that the injury will closely reflect the human injury and if the treatment works in the nonhuman primate, it is also likely to work in people. 75–78 The only caveat in the use of a nonhuman primate is that human trau -
matic brain injury is more complex than the controlled laboratory injury monkeys experience. The results of these brain injury studies showed DMSO had a dramatic positive 
effect on ICP, CPP, cerebral metabolic rate of oxygen, CBF, and survival. 75–78
CPP is defined as the net pressure gradient that drives CBF to perfuse the brain. It is generally measured as the MAP minus ICP (MAP − ICP). CPP in adults is normally between 70 and 100 mmHg, while the normal ICP ranges from 5 to 15 mmHg. 79,80
It is important that CPP be maintained at narrow limits during trauma to the 
brain, because if it is too low, it can contribute to both brain ischemia and irreversible 
brain damage and if it is too high, it can raise ICP and increase the risk of complica -
tions or death.79 One standard technique of lowering ICP after brain trauma in people 
is to induce controlled hyperventilation in order to maintain PaCO2 at the low end of 
normal, that is, 35–40 mmHg.79213 DMSO in Clinical Neuroprotection
The basic studies on the use of DMSO for traumatic brain injury previously 
reported in monkeys75–78 led to several pilot clinical trials using IV DMSO on head-
injured patients. One early study by Waller et al.81 tested DMSO on 11 adult patients 
with high ICP and a GCS score of 4–6 following brain trauma or subarachnoid 
hemorrhage. All 11 patients had failed to respond to standard therapy and were con-sidered to be on the verge of dying. DMSO was given as a rapid bolus intravenously in a 40% or 10% solution at 1 g/kg. This dose was repeated every 6 h as needed to maintain the ICP below 20 mmHg. 81
In all patients, DMSO effectively increased diuresis and reduced the ICP where 
standard therapy had failed. DMSO treatment showed that three patients who were expected to die survived with good recovery; the other eight patients died despite their initial normalization of the intracranial hypertension, which could not be con -
trolled after several days. 81
The ability of DMSO to maintain CPP above 60 mmHg as shown by 
Brown et al.77,78 after severe brain trauma may explain the benefit seen in Waller’s 
et al.81 results on patients with lethal ICPs. This conclusion has support from a pre -
liminary study showing the importance of maintaining CPP from sinking too low in the presence of high ICP. 77
The findings from the study by Waller et al.81 indicated that aggressive manage -
ment to keep CPP above 60 mmHg can lead to good neurological outcomes despite the presence of extremely high ICP. Such a process may work by lowering cerebro -
vascular resistance, which will increase CBF to supply low perfusion brain regions where undamaged but dysfunctional penumbral brain cells at risk of dying can be rescued. A study by Marshall et al. 82 was reported several years after the Waller et al.81 
clinical trial using DMSO for intractable, severe head injury. Six patients refractory to barbiturate and other standard treatments were given 10% DMSO intravenously at a dose of 1 g/kg. 82 Because of difficulties with fluid overload reflected by elec-
trolyte disturbances and increased pulmonary wedge pressure, DMSO was titrated against ICP and readministered as a 20% solution. DMSO was observed to rapidly lower ICP below 20 mmHg  in all but one patient within an average of 6 h, three patients responding after 3–4 h and the rest after 12–18 h. It was not clear from this report how many of the six patients died when ICP could no longer be controlled, but it must be assumed that poor survival resulted. 82 Both at 10% and 20% DMSO 
volumes, electrolyte disturbances involving hypernatremia developed in all patients treated. These investigators reported that DMSO was a rapid and effective agent  in 
lowering uncontrolled ICP where standard therapy had failed but were also dis -
couraged from handling DMSO because they needed to use special plastic IV bags and IV tubing that were not made of polyvinyl chloride. 82 The reason for 
not using polyvinyl chloride tubing and IV bags is that DMSO is known to leach this plastic when it comes in contact with it. 76 However, this problem can be 
readily overcome by using glass dispensing IV bottles and teflon IV tubing or teflon catheters. 83 The electrolyte problems encountered in the Marshall et al.82 
study were likely due to the high IV volumes given at 10% and 20% solutions at a concentration of 1 g/kg.214 Dimethyl Sulfoxide (DMSO) in Trauma and Disease
A brief communication by Gumerlock and Neuwelt83 shortly following the clini -
cal study by Marshall et al.82 involved five closed head injury patients treated with 
IV DMSO for increased ICP. DMSO 20% solution was given at 100 mg/kg as an 
initial bolus followed by repeated hourly infusions of 100 mg/kg tapering off as ICP was lowered. A rapid response was observed after the DMSO bolus and ICP was reduced to normal levels using this regimen. 83 The aftermath of these treatments 
with DMSO consisted of two outcomes. The first outcome involved two children given IV DMSO. The first was a 1(1/2)-year-old girl admitted with a GCS score of 7 (severe) and an ICP of 30 mmHg. This patient received DMSO for 84 h after being unresponsive to mannitol treatment and recovered slowly over a 3-week period when she was discharged from the hospital. Her electrolytes during treatment remained normal, including serum sodium values. 83
The second patient was a 7-year old child admitted with a GCS of 5 (severe) and 
ICP of 25 mmHg.83 Using the same aforementioned regimen, DMSO was given for 
36 h and ICP was controlled during that time. The patient recovered after 8 weeks and was discharged from the hospital. Serum electrolytes remained normal during treatment, including sodium values. The remaining three patients were adults rang -
ing in age from 17 to 52  years old who were admitted with GCS scores of 3–5 (severe). 83 Two of these three patients had ICPs above 50 mmHg. Although all three 
patients initially responded to the DMSO regimen used before, the ICP escaped con -
trol and all three died. The sodium values in these DMSO nonresponders ranged from 159 to 172 mmol/L. 83
Although the number of patients in this trial was small, it is of interest to note 
that age and ICP values may have played a role in the response and final outcome to DMSO and to the elevated serum sodium concentrations.
Dimethyl_Sulfoxide_(DMSO)_in_Trauma_and_Disease_[2015].txt
Summarize the following text section accurately and concisely. Maintain specific details and numerical information, and use anti-repetition mechanisms:

        Grade 1 or ‘ding’ con -
cussions in high school athletes. Am J Sports Med. January–February 2004;32(1):47–54. 142. De Beaumont L, Henry LC, Gosselin N. Long-term functional alterations in sports con -
cussion. Neurosurg Focus. 2012;33(6):E8:1–7. 143. K oh JO, Cassidy JD, Watkinson EJ. Incidence of concussion in contact sports: A sys -
tematic review of the evidence. Brain Inj. October 2003;17(10):901–917. 144. Anderson T, Heitger M, Macleoud AD. Concussion and mild head injury. Pract Neurol. 2006;6:342–357. 195 DMSO in Basic Neuroprotection
 145. Ma R, Miller CD, Hogan MV, Diduch BK, Carson EW, Miller MD. Sports-related con -
cussion: Assessment and management. J Bone Joint Surg Am. 2012;94(17):1618–1627. 146. Jordan BD. The clinical spectrum of sport-related traumatic brain injury. Nat Rev 
Neurol. April 2013;9(4):222–230. 147. Nariai T, Inaji M, Tanaka Y, Hiura M, Hosoda C, Ishii K, Ohno K. PET molecular imag -
ing to investigate higher brain dysfunction in patients with neurotrauma. Acta Neurochir 
Suppl. 2013;118:251–254. 148. Stern RA, Rile y DO, Daneshvar DH, Nowinski CJ, Cantu RC, McKee AC. Long-term 
consequences of repetitive brain trauma: Chronic traumatic encephalopathy. PM R. October 2011;3(10 Suppl 2):S460–S467. 149. Giza CC, Ho vda DA. The neurometabolic cascade of concussion. J Athl Train  
2001;36:228–235. 150. Signoretti S, Lazzarino G, Tavazzi B, Vagnozzi R. The pathophysiology of concussion.
Prevention of secondary damage and minimizing the risk of mortality.
What is the primary goal of treating traumatic brain injury?
To classify the severity of head injury and predict the likelihood of survival.
What is the Glasgow Coma Scale (GCS) used for?
Shearing of axonal tracts and tissue white matter, leading to permanent disability.
What is the primary damage in diffuse axonal injury?
To prevent hypoxia and hypotension, as these insults can induce secondary brain damage.
What is the primary focus of prehospital care in managing traumatic brain injury?
To prevent secondary damage and maintain cerebral perfusion pressure.
What is the primary goal of using DMSO in traumatic brain injury?