Stroke and Traumatic Brain Injury: Qatar Clinical Neuroscience Conference

Journal Articles

Immunology of stroke

Iadecola C, Anrather J. Stroke research at a crossroad: asking the brain for directions. Nat Neurosci. 2011;14(11):1363-8.

Iadecola C, Anrather J. The immunology of stroke: from mechanism to translation. Nat Med. 2011;17(7):796-808.

Iadecola C, Zhang F, Casey R, et al. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci. 1997;17(23):9157-64.

Kunz A, Abe T, Hochrainer K, et al. Nuclear factor-kappaB activation and postischemic inflammation are suppressed in CD36-null mice after middle cerebral artery occlusion. J Neurosci. 2008;28(7):1649-58.

Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181-98.

Ridder DA, Schwaninger M. NF-kappaB signaling in cerebral ischemia. Neuroscience. 2009;158(3):995-1006.

Cerebral collaterals and acute stroke

Nambiar V, Sohn SI, Almekhlafi MA, et al. CTA collateral status and response to recanalization in patients with acute ischemic stroke. AJNR Am J Neuroradiol. 2013. [Epub ahead of print.]

Parthasarathy R, Kate M, Rempel JL, et al. Prognostic evaluation based on cortical vein score difference in stroke. Stroke. 2013;44(10):2748-54.

Terpolilli NA, Kim S-W, Thal SC. Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circ Res. 2012;110:727-38.

Imaging in transient ischemic attacks

Albers GW, Caplan LR, Easton JD et al. Transient ischemic attack-proposal for a new definition. N Engl J Med. 2002;347(21):1713-16.

Asdaghi N, Hameed B, Saini M, et al. Acute perfusion and diffusion abnormalitites predict early new MRI lesions 1 weeks after minor stroke and transient ischemic attack. Stroke. 2011;42(8):2191-5.

Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke. 2009;40(6):2276-93.

Gladstone DJ, Kapral MK, Fang J, et al. Management and outcomes of transient ischemic attacks in Ontario. CMAJ. 2004;170(7):1099-104.

Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA. 2000;284(22):2901-6.

Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007;369(9558):283-92.

Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6(11):361-9.

Rothwell PM, Giles MF, Flossmann E, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet. 2005;366(9479):29-36.

Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic stroke. N Engl J Med. 2013;369(1):11-9.

Teleneurology for acute stroke

Carr BG, Branas CC, Metlay JP, et al. Access to emergency care in the United States. Ann Emerg Med. 2009;54(2):261-9.

Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characterisitcs, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation. 2011;123(7):750-8.

Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA. 2000;283(9):1151-8.

Katzan IL, Hammer MD, Furlan AJ. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke. 2003:34(3);799-800.

Lansberg MG, Schrooten M, Bluhmki E, et al. Treatment time-specific number needed to treat estimates for tissue plasminogen activator therapy in acute stroke based on shifts over the entire range of the modified Rankin Scale. Stroke. 2009;40(6):2079-84.

Muller-Barna P, Schwamm LH, Haberl RL. Telestroke increases use of acute stroke therapy. Curr Opin Neurol. 2012;25(1):5-10.

Nelson RE, Saltzman GM, Skalabrin EJ, et al. The cost-effectiveness of telestroke in the treatment of acute ischemic stroke. Neurology. 2011;77(17):1590-8.

Schwab S, Vatankhah B, Kukla C, et al. Long-term outcome after thrombolysis in telemedical stroke care. Neurology. 2007;69(9):898-903.

Schwamm LH, Holloway RG, Amarenco P, et al. A review of the evidence for the use of telemedicine within stroke systems of care: a scientific statement from the American Heart Association/American Stroke Association. Stroke. 2009;40(7):2616-34.

Schwamm LH, Rosenthal ES, Hirshberg A, et al. Virtual TeleStroke support for the emergency department evaluation of acute stroke. Acad Emerg Med. 2004;11(11):1193-7.

Silva GS, Farrell S, Shandra E, et al. The status of telestroke in the United States: a survey of currently active stroke telemedicine programs. Stroke. 2012;43(8):2078-85.

Joint Commission
The Joint Commission accredits and certifies more than 20 500 health care organizations and programs in the United States. Joint Commission accreditation and certification is recognized nationwide as a symbol of quality that reflects an organization's commitment to meeting certain performance standards.

TEMPIS (Germany)
TEMPIS is a telemedical network founded in 2003 by two specialized stroke centers and 12 (now 15) regional hospitals in eastern Bavaria/Germany to provide modern stroke management and advanced stroke expertise in non-urban areas.

Pregnancy-related stroke

Cipolla MJ, Vitullo L, McKinnon J. Cerebral artery reactivity changes during pregnancy and the postpartum period: a role in eclampsia? Am J Physiol Heart Circ Physiol. 2004;286(6):H2127-32.

Cipolla MJ. Cerebrovascular function in pregnancy and eclampsia. Hypertension. 2007;50(1):14-24.

Cross JN, Castro PO, Jennett WB. Cerebral strokes associated with pregnancy and the puerperium. Br Med J. 1968;3(5612):214-8.

Kuklina EV, Tong X, Bansil P, et al. Trends in pregnancy hospitalizations that included a stroke in the United States from 1994 to 2007: reasons for concern? Stroke. 2011;42(9):2564-70.

Sharshar T, Lamy C, Mas JL. Incidence and causes of strokes associated with pregnancy and puerperium. A study in public hospitals of Ile de France. Stroke in Pregnancy Study Group. Stroke. 1995;26(6):930-6.

Wiebers DO, Whisnant JP. The incidence of stroke among pregnant women in Rochester, Minn, 1955 through 1979. JAMA. 1985;254(21):3055-7.

Subarachnoid hemorrhage

Al-Shahi Salman R, Sudlow CL. Case fatality after subarachnoid haemorrhage: declining, but why? Lancet Neurol. 2009;8(7):598-9.

Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med. 2006;355(9):928-39.

Greving JP, Wermer MJ, Brown RD, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol. 2014;13(1):59-66.

Molyneux A, Kerr R, Stratton I, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002;360(9342):1267-74.

Molyneux AJ, Kerr RS, Birks J, et al. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol. 2009;8(5):427-33.

Rinkel GJ. Intracranial aneurysm screening: indications and advice for practice. Lancet Neurol. 2005;4(2):122-8.

Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362(9378):103-10.

Current therapy for TBI

Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993;34(2):216-22.

Chesnut RM, Temkin N, Carney N, et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med. 2012;367(26):2471-81.

Downard C, Hulka F, Mullins RJ, et al. Relationship of cerebral perfusion pressure and survival in pediatric brain-injured patients. J Trauma. 2000;49(4):654-8.

Peterson E, Chesnut RM. Static autregulation is intact in majority of patients with severe traumatic brain injury. J Trauma. 2009;67(5):944-9.

Robertson CS, Valadka AB, Hannay HJ, et al. Prevention of secondary ischemic insults after severe head injury. Crit Care Med. 1999;27(10):2086-95.

Rosner MJ, Rosner SD, Johnson AH. Cerebral perfusion pressure: management protocol and clinical results. J Neurosurg. 1995;83(6):949-62.

Sviri GE, Aaslid R, Douville CM, et al. Time course for autoregulation recovery following severe traumatic brain injury. J Neurosurg. 2009;111(4):695-700.

Hypothermia for TBI

Hartings JA, Strong AJ, Fabricius M, et al. Spreading depolarizations and late secondary insults after traumatic brain injury. J Neurotrauma. 2009;26(11):1857-66.

Popp E, Sterz F, Bottiger BW. Therapeutic hypothermia after cardiac arrest. Anaesthesist. 2005;54(2):96-106.

Rumana CS, Gopinath SP, Uzura M, et al. Brain temperature exceeds systemic temperature in head-injured patients. Crit Care Med. 1998;26(3):562-7.

Hyperosmolar therapy for brain edema

Battison C, Andrews PJ, Graham C, Petty T. Randomized, controlled trial on the effect of a 20% mannitol solution and a 7.5% saline/6% dextran solution on increased intracranial pressure after brain injury. Crit Care Med. 2005;33(1):196-202.

Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. II. Hyperosmolar therapy. J Neurotrauma. 2007;24(Suppl 1):S14-20.

Bulger EM, May S, Brasel KJ, et al. Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. JAMA. 2010;304(13):1455-64.

Froelich M, Ni Q, Wess C, et al. Continuous hypertonic saline therapy and the occurrence of complications in neurocritically ill patients. Crit Care Med. 2009;37(4):1433-41.

Härtl R, Ghajar J, Hochleuthner H, Mauritz W. Hypertonic/hyperoncotic saline reliably reduces ICP in severely head-injured patients with intracranial hypertension. Acta Neurochir Suppl. 1997;70:126-9.

Lazaridis C, Neyens R, Bodle J, DeSantis SM. High-osmolarity saline in neurocritcal care: systematic review and meta-analysis. Crit Care Med. 2013;41(5):1353-60.

Lescot T, Degos V, Zouaoui A, et al. Opposed effects of hypertonic saline on contusions and noncontused brain tissue in patients with severe traumatic brain injury. Crit Care Med. 2006;34(12):3029-33.

Mirski AM, Denchev ID, Schnitzer SM, Hanley FD. Comparison between hypertonic saline and mannitol in the reduction of elevated intracranial pressure in a rodent model of acute cerebral injury. J Neurosurg Anesthesiol. 2009;12(4):334-44.

Oddo M, Levine JM, Frangos S, et al. Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension. J Neurol Neurosurg Psychiatry. 2009;80(8):916-20.

Rockswold GL, Solid CA, Paredes-Andrade E, et al. Hypertonic saline and its effect on intracranial pressure, cerebral perfusion pressure, and brain tissue oxygen. Neurosurgery. 2009;65(6):1035-41.

Schurer L, Dautermann C, Härtl R, et al. Treatment of hemorrhagic hypotension with hypertonic/hyperoncotic solutions: effects on regional cerebral blood flow and brain surface oxygen tension. Eur Surg Res. 1992;24(1):1-12.

Wakai A, McCabe A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev. 2013;8:CD001049.

Pediatric TBI

Anderson V, Godfrey C, Rosenfeld JV, Catroppa C. 10 years outcome from childhood traumatic brain injury. Int J Dev Neurosci. 2012;30(3):217-24.

Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury. Clin Sports Med. 2011;30(1):33-48.

Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344(8):556-63.

Diaz-Arrastia R, Kochanek PM, Bergold P, et al. Pharmacotherapy of traumatic brain injury; state of the science and the road forward: report of the Department of Defense Neurotrauma Pharmacology Workgroup. J Neurotrauma. 2014;31(2):135-58.

Harmon KG, Drezner JA, Gammons M, et al. American Medical Society for Sports Medicine position statement: concussion in sport. Br J Sports Med. 2013;47(1):15-26.

Hutchison JS, Frndova H, Lo TY, Guerguerian AM. Impact of hypotension and low cerebral perfusion pressure on outcomes in children treated with hypothermia therapy following severe traumatic brain injury: a post hoc analysis of the Hypothermia Pediatric Head Injury. Dev Neurosci. 2010;32(5-6):406-12.

Kochanek PM, Carney N, Adelson PD, et al. Guidelines for the acute management of severe traumatic brain injury in infants, children, and adolescents — second edition. Pediatr Crit Care Med. 2012;13(S1):S1-82.

Maruta J, Suh M, Niogi SN, et al. Visual tracking synchronization as a metric for concussion screening. J Head Trauma Rehabil. 2010;25(4):292-305.

McCrory P, Meeuwisse W, Johnston K, et al. Consensus statement on concussion in sport: the 3rd International Conference on Concussion in Sport held in Zurich, November 2008. Br J Sports Med. 2009;43(Suppl 1):i76-90.

Pineda JA, Leonard JR, Mazotas IG, et al. Effect of implementation of a paediatric neurocritical care programme on outcomes after severe traumatic brain injury: a retrospective cohort study. Lancet Neurol. 2013;12(1):45-52.

Ragan DK, McKinstry R, Benzinger T, et al. Alterations in cerebral oxygen metabolism after traumatic brain injury in children. J Cereb Blood Flow Metab. 2013;33(1):48-52.

Rivara FP, Koepsell TD, Wang J, et al. Disability 3, 12, and 24 months after traumatic brain injury among children and adolescents. Pediatrics. 2011;128(5):e1129-38.

Robertson CL, Clark RS, Dixon CE, et al. No long-term benefit from hypothermia after severe traumatic brain injury with secondary insult in rats. Crit Care Med. 2000;28(9):3218-23.

Ropper AH, Gorson KC. Clinical practice. Concussion. N Engl J Med. 2007;356(2):166-72.

Vascular dementia

Chi NF, Chien LN, Ku HL, et al. Alzheimer disease and risk of stroke: a population-based cohort study. Neurology. 2013;80(8):705-11.

Iadecola C, Davisson RL. Hypertension and cerebrovascular dysfunction. Cell Metab. 2008;7(6):476-84.

Iadecola C. Cerebrovascular effects of amyloid-beta peptides: mechanisms and implications for Alzheimer's dementia. Cell Mol Neurobiol. 2003;23(4-5):681-9.

Iadecola C. The pathobiology of vascular dementia. Neuron. 2013;80(4):844-66.

Jackman K, Iadecola C. Neurovascular regulation in the ischemic brain. Antiox Redox Signal. 2014. [Epub ahead of print.]

Knecht S, Wersching H, Lohmann H, et al. High-normal blood pressure is associated with poor cognitive performance. Hypertension. 2008;51(3):663-8.

Tolppanen AM, Lavikainen P, Solomon A, et al. Incidence of stroke in people with Alzheimer disease: a national register-based approach. Neurology. 2013;80(4):353-8.

Young CN, Cao X, Guruju MR, et al. ER stress in the brain subfornical organ mediates antiogensin-dependent hypertension. J Clin Invest. 2012;122(11):3960-4.

Clinical Trials

Hypothermia for TBI

HOPES
The Hypothermia for Patients requiring Evacuations of Subdural hematoma trial aims to find out if therapeutic hypothermia improves outcomes following TBI that requires surgery.

NABISH-I
Clifton GL, Miller ER, Choi SC et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344(8):556-63.

NABISH-II
Clifton GL, Valadka A, Zygun D, et al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol. 2011;10(2):131-19.

Stroke

CHANCE
Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-9.

CREST
Brott TG, Hobson RW, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010;363(1):11-23.

CURE
Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.

IMS-III
Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903.

FAST-MAG
Saver JL, Kidwell C, Eckstein M, Starkman S. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial. Stroke. 2004;35(5):e106-8.

Meta-analysis of IV t-PA Therapy
Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010;375(9727):1695-1703.

PHANTOM-S
Weber JE, Rozanski M, Waldschmidt C, et al. PHANTOM-S: the prehospital acute neurological therapy and optimization of medical care in stroke patients — study. Int J Stroke. 2012;7(4):348-53.

POINT
The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke trial is a randomized, double-blind, multicenter clinical trial to determine whether clopidogrel 75 mg/day (after a loading dose of 600 mg) is effective in improving survival free from major ischemic vascular events.

SAMMPRIS
Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365(11):993-1003.

SPS3
Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367(9):817-25.

Websites

American Stroke Association

American Heart Association

Brain Injury Association of America

Global Neurotrauma Research

National Institute of Neurological Disorders and Stroke. Traumatic Brain Injury Information Page.

National Stroke Association

Stroke Center: Trials Registry

The Brain Trauma Foundation

Sponsors

Presented by

A recent epidemiological survey identified stroke and traumatic brain injury (TBI) as the most prevalent causes of adult-onset brain disorders in the U.S. While stroke primarily affects the elderly, TBI is the most common cause of childhood death and disability, with half of patients under 18 years old. In March 2014, clinical experts in stroke and TBI met in Doha, Qatar, to share current and future practices in the diagnosis, imaging, management, and treatment of these conditions.

Stroke

Stroke is the second leading cause of death in the world and the leading cause of permanent disability. As the population ages, the number of stroke patients is increasing, despite the declining incidence of stroke over the past 30 years. Risk factors for stroke include demographic characteristics such as age and gender, behaviors like smoking, and medical conditions like hypertension.

Stroke is classified into two categories. Ischemic stroke results from a blockage in the vessels that supply the brain with blood and is further classified according to the origin of the blood clot. Hemorrhagic stroke results from a ruptured blood vessel that disrupts blood flow to part of the brain.

Ischemic stroke is more common and results from a loss of blood to the brain caused by an obstructed blood vessel. Hemorrhagic stroke is characterized by bleeding in the brain caused by weakened blood vessels. (Image courtesy of Matthew E. Fink)

Ischemia activates a series of harmful pathways that lead to neuronal death. Protective pathways such as collateral flow, inflammation, decreased protein synthesis, and increased antioxidant production are activated to mitigate damage. Costantino Iadecola and Ashfaq Shuaib described processes that could be targeted to find new treatments for stroke. Iadecola described the conflicting role of inflammation in stroke as both a cause of damage and a critical component of tissue repair. Shuaib discussed the role of collateral blood flow in mitigating neurological damage.

Early treatment after stroke is critical to restore blood flow to the affected area and prevent permanent brain damage. David Chiu discussed recent trials in stroke demonstrating the benefits of early therapy to prevent neurological damage and recurrent stroke. Shuaib stressed the importance of early imaging in patients experiencing transient ischemic attacks (TIAs) to inform proper treatment and management decisions. Lee Schwamm showed how telemedicine can improve stroke care in small and/or rural hospitals that may not have a dedicated neurological staff on-site. Finally, Matthew E. Fink described pregnancy-related stroke and subarachnoid hemorrhage.

Traumatic brain injury

TBI is caused by sudden trauma to the brain during an incident such as a fall or motor vehicle accident. The sudden motion can cause the brain to move and twist within the skull, damaging brain tissue. TBI usually causes brain swelling, or edema, which can increase intracranial pressure (ICP) and decrease cerebral perfusion pressure (CPP), the pressure gradient that causes blood flow in the brain. Signs and symptoms of TBI include headache, fatigue, vomiting, increased sensitivity to light, irritability, and sleep problems. While the damage and symptoms of TBI are reversible in some patients, for others symptoms persist. There is currently no reliable method to determine which patients will experience ongoing symptoms.

Since little can be done to treat the initial injury, current therapies for TBI focus on mitigating the secondary effects of injury, such as increased ICP, hypotension, ischemia, fever, and seizures, to allow the brain time to heal itself. Treatment is focused on monitoring ICP and CPP. Randall Matthew Chesnut provided a historical perspective, describing how the guidelines for ICP and CPP monitoring evolved, and presented data from recent trials suggesting that the current thresholds may not be appropriate in all cases. Chesnut called for a more individualized approach to treating TBI that takes into account the underlying reasons for increased ICP and decreased CPP, which can vary among patients.

Neeraj Badjatia and Roger Härtl presented clinical evidence for the use of hypothermia and hyperosmolar therapy to decrease ICP and mitigate neuronal damage. Barry Kosofsky and Jose A. Pineda Soto focused on the unique needs and characteristics of pediatric TBI, with Kosofsky providing his approach for managing sports-related TBI in children.

Speakers:
Costantino Iadecola, Weill Cornell Medical College
Ashfaq Shuaib, University of Alberta, Canada

Highlights

• Inflammation is a cause of tissue damage but is also critical to tissue repair in stroke patients.
• Good collateral blood flow can mitigate ischemic damage in stroke patients and identify patients who may respond to thrombolytic therapy outside the recommended time window.
• In patients with poor collateral blood flow, therapeutic interventions may be able to activate collateral circulation during acute stroke.

Inflammation in ischemic stroke

Ischemic stroke triggers several harmful pathways within neurons that result in apoptosis, inflammation, oxidative stress, and excitotoxicity. In turn, the brain attempts to minimize damage by activating protective pathways that increase collateral flow, decrease protein synthesis to save energy, and engage antioxidant defenses. Costantino Iadecola of Weill Cornell Medical College and Ashfaq Shuaib of the University of Alberta respectively discussed inflammation and collateral flow as means to understand the pathology of stroke, identify patients most likely to respond to therapy, and develop new therapies.

Inflammation has positive and negative effects in stroke patients. After the initial ischemic injury, a series of mechanisms result in the production of reactive oxygen species (ROS) and eventually inflammation. During the acute phase of stroke, inflammation can increase ICP and lead to secondary injury. However, within days to weeks after stroke, inflammation is critical to tissue repair.

During the acute phase of stroke, inflammation causes an increase in ICP and can result in secondary injury. However, in later phases inflammation is vital to repair damaged tissue. (Image courtesy of Costantino Iadecola)

Iadecola discussed the molecular mechanisms that promote inflammation after stroke. Briefly, ischemia-induced apoptosis releases cell fragments that bind to and activate CD36, a receptor involved in innate immunity that is found on the surface of microglia, macrophages, and endothelial cells. Activation of CD36 results in the expression of several inflammatory genes, including the immunological form of nitric oxide synthase (iNOS), which downregulates mitochondrial activity and DNA synthesis via the production of nitric oxide (NO) and is upregulated following stroke.

According to Iadecola, the molecules involved in inflammation provide attractive therapeutic targets; however, therapeutic strategies should focus on the downstream effectors of inflammatory damage and should be carefully timed as the negative effects of inflammation manifest during acute phases of the disease.

Collateral circulation in ischemic stroke

Collateral circulation is another mechanism the brain uses to minimize damage after stroke. Blood flow is maintained in the brain via a network of collateral arteries (several arteries that supply the same area with blood). Approximately one-third of people are born with poor collateral flow, which decreases universally with age and is negatively affected by hypertension and diabetes. Shuaib stressed the importance of evaluating collateral flow during acute stroke to assess treatment response and prognosis. In patients with good collateral flow, ischemic damage progresses more slowly because blood can reach the affected area of the brain via collateral vessels. These patients may benefit from thrombolytic therapy administered after the recommended 4-hour time window.

Intra-cranial collaterals. (Image courtesy of Ashfaq Shuaib)

The SENTIS (Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke) trial investigated whether collateral flow can be enhanced via transient aortic occlusion in patients experiencing stroke. The goal of aortic occlusion is to divert blood from the lower limbs to the brain, thereby increasing cerebral blood flow (CBF) and improving collateral flow. The trial used the CoAxia NeuroFlo catheter to partially occlude the aorta for 45 minutes. Among 515 patients randomized to undergo either aortic occlusion or conventional treatment, aortic occlusion did not decrease disability but was associated with a significantly lower rate of mortality—particularly among elderly patients over 70 years old, patients who had moderately severe stroke, and patients who were treated within 5 hours of stroke.

Speakers:
David Chiu, Houston Methodist Hospital Neurological Institute
Ashfaq Shuaib, University of Alberta, Canada
Lee Schwamm, Harvard Medical School; Massachusetts General Hospital

Highlights

• Early treatment is critical to prevent neurological damage and reduce the risk of recurrent stroke.
• In patients experiencing transient ischemic attacks, early, detailed MR imaging can identify those at risk for recurrent stroke.
• Telemedicine can connect primary stroke centers with smaller hospitals to increase and improve treatment in stroke patients.

Benefits of early treatment in acute stroke

In the emergency room, one of the first tests performed in stroke patients is a CT scan to identify the stroke as ischemic or hemorrhagic. For ischemic stroke, thrombolytic therapy may be indicated to break up the blood clot and restore blood flow to the affected region. Thrombolytic therapy can be dangerous in hemorrhagic stroke because it can increase the risk of further hemorrhage. Current guidelines recommend administering thrombolytic therapy no more than 4.5 hours after the onset of symptoms, when the risk of hemorrhage generally begins to outweigh the benefit of therapy.

Several recent trials have demonstrated the importance of early thrombolytic therapy to prevent neurological dysfunction and recurrent events in ischemic stroke patients. If administered within 90 minutes of symptom onset, thrombolytic therapy is 18.5 times more likely to be beneficial than harmful; if administered 360 minutes after symptom onset, it is more likely to cause harm than benefit.

David Chiu of Houston Methodist Hospital Neurological Institute described several studies of treatment regimens after stroke. In the IMS III (Interventional Management of Stroke III) trial, adding intra-arterial endovascular therapy (intra-arterial delivery of thrombolytic therapy to the clot site or mechanical removal of the clot via a thrombectomy device) to intravenous thrombolytic therapy conferred no significant advantage in mortality or in incidence of intracerebral hemorrhage. However, the analysis demonstrated the importance of early therapy: every 30-minute delay in intra-arterial therapy decreased the likelihood of a good clinical outcome by 10%. Chiu asserted that future trials in acute stroke should target earlier time windows.

Chiu also described two clinical trials comparing the efficacy of dual antiplatelet therapy (aspirin and clopidogrel) to aspirin monotherapy. Antiplatelet therapies prevent blood clot formation and are often used to prevent recurrent stroke. In the SPS3 (Secondary Prevention of Small Subcortical Strokes) study, which initiated therapy 2 weeks after the initial stroke, 8 years of follow-up demonstrated no difference in the rate of recurrent stroke. In contrast, a study in China called CHANCE, which initiated therapy within 24 hours of symptom onset, found a 32% lower risk of recurrent stroke in the dual therapy group compared to the aspirin monotherapy group. A similar study, the POINT (Platelet-Oriented Inhibition in New TIA and minor ischemic stroke) trial, is underway in the U.S. to determine whether similar results can be achieved in a different patient population.

Benefits of early imaging in transient ischemic attacks

Ashfaq Shuaib discussed the importance of early imaging in patients with transient ischemic attacks (TIAs), brief (less than one-hour) episodes in which there is a temporary lack of blood flow to a confined region of the brain. Approximately 10.5% of TIA patients experience a second stroke, half within 2 days. However, early treatment can reduce the risk of recurrent stroke by 80%.

Scoring systems based on age, diabetes status, duration of TIA, weakness, speech impairment, and blood pressure can help identify patients at high risk of recurrent stroke, but Shuaib also stressed the necessity of early CT and MR imaging. CT scans, standard for acute stroke patients, are ubiquitous and fast. However, Shuaib recommended that clinicians also perform MR imaging because it is more accurate and can detect ischemic stroke earlier, which is especially important for patients experiencing brief ischemic episodes.

Shuaib recommended performing MR imaging in the ER to determine when to admit patients and/or administer aggressive treatment. For infarctions that are below the detection of standard diffusion-weighted MRI technology, he recommended more sensitive MRI techniques, such as diffusion-tensor imaging (DTI) and perfusion-weighted imaging (PWI).

One outstanding question in the field is how long patients should receive therapy. To help answer this question, Shuaib is currently involved in a study comparing 10-day and 30-day treatment of dual antiplatelet therapy to investigate whether treatment duration can be reduced in patients experiencing TIAs.

PWI can predict recurrent stroke in patients with TIA. Acute diffusion-weighted imaging (DWI) detects a region of infarction (left). At the same time, acute PWI detects a perfusion deficit in a different region of the brain (center). Seven days later, an infarction is detected in the same region of the brain by DWI (right). (Image courtesy of Ashfaq Shuaib)

Reducing the time to treatment: telemedicine in stroke care

Although the importance of early stroke treatment has been demonstrated in several clinical studies, many patients do not receive timely therapy. In a pooled analysis of 6 trials of neuroprotective therapies for acute stroke, only 0.2% of patients were treated within the first hour of brain ischemia, whereas 92.3% were treated after 3 hours. Because up to 70% of stroke patients arrive at hospital by ambulance, engaging paramedics in stroke treatment can significantly reduce the time to treatment. New models of care in which ambulances are equipped with CT scanners are being investigated in Berlin, Germany, and in Houston, Texas.

Lee Schwamm described the TeleStroke program at Massachusetts General Hospital, which uses telemedicine to provide stroke patients with high-quality, timely care. Physicians at certified stroke centers evaluate patients via video, review CT or MRI scans, and perform neurological exams, such as the NIH Stroke Scale (NIHSS). A primary purpose of TeleStroke is to determine whether a patient meets the requirements for thrombolytic therapy. Eligibility depends on CT and MRI scans, neurological function, and the time since symptom onset. Not all hospitals have the experienced personnel needed to evaluate such criteria.

Schwamm advocated a "hub and spoke" model of telemedicine, with the TeleStroke system located at a hub hospital, often an academic medical center or large tertiary hospital, and close-by spoke hospitals that can call for consultation and transfer patients if necessary. In a study by Schwamm of 38 hospitals with a TeleStroke program, 80%–90% of spoke hospitals were either rural or small hospitals.

Treatment and evaluation of acute stroke patients via telemedicine is cost-effective, and several studies show both that telemedicine increases the use of thrombolytic therapy and that thrombolytic therapy administered based on evaluation via telemedicine is as effective and well tolerated as therapy administered at a certified stroke center.

Speaker:
Matthew E. Fink, Weill Cornell Medical College

Highlights

• Although representing a small fraction of strokes, subarachnoid hemorrhages significantly contribute to the cost and mortality rate of stroke.
• Pregnancy is a risk factor for stroke that may be overlooked by many hospitals. The risk of pregnancy-related stroke may be higher in older women.

Aneurismal subarachnoid hemorrhage

Approximately 2%–4% of healthy people have a benign, unruptured aneurysm, a ballooning of a weakened region of a blood vessel. If left untreated, aneurysms can rupture, causing hemorrhagic stroke. Subarachnoid hemorrhage (SAH) occurs in the area between the brain and the thin tissues that cover it.

Matthew E. Fink of Weill Cornell Medical College discussed treatment and care for aneurismal SAH. There are approximately 30 000 cases of SAH in the U.S. each year. Unlike that of other types of stroke, the incidence of SAH has remained relatively stable over the past 30 years, at 10.5 per 100 000 person years. Although SAH represents a small fraction of strokes, it contributes significantly to the morbidity and mortality of stroke. SAH has one of the highest mortality rates of any naturally occurring disease, with an acute fatality rate of up to 51%, compared to 5% for myocardial infarction. In addition, 46% of survivors have long-term cognitive dysfunction and approximately one-third will require lifelong care.

Fink stressed the importance of proper screening and prevention for SAH and called for genetic studies of high-risk groups to better understand its causes. The PHASES aneurysm risk score published early 2014 in Lancet Neurology was developed from a meta-analysis of six trials of unruptured cranial aneurysm in 8000 patients. The score takes into account the size and location of the aneurysm as well as patient characteristics such as age, hypertension, and nationality. While the score can be used to eliminate high-risk aneurysms, the risks of complications due to therapy increase with age; therefore, a small aneurysm in an older patient may not be worth treating.

Increasing probability of aneurysm rupture based on PHASES risk score. (Image courtesy of Matthew E. Fink)

Among patients with SAH, 25% die as a direct result of the hemorrhage. Other causes of death include vasospasm, rebleeding, hydrocephalus, intracerebral hematoma, surgical complications, and medical complications. According to Fink, all these conditions are either preventable or treatable and there is significant opportunity for physicians to reduce the morbidity and mortality associated with hemorrhage. Fink argued for a multidisciplinary approach that includes neurologists, neurosurgeons, anesthesiologists, and critical care and emergency medical specialists.

Treatment for SAH includes early surgery (within 12 hours of arrival at the hospital) to eliminate the aneurysm and prevent rebleeding. Other therapies include CSF drainage, hemodilution, intravascular volume expansion, induced arterial hypertension, inotrope infusion, and calcium channel blockers. In a study by Fink at the Neurological Institute of New York, the 30-day mortality rate in patients after SAH decreased from 50% to less than 20% after these therapies were instituted in the late 1980s.

Pregnancy-related stroke

Blood clotting factors increase during normal pregnancy, putting pregnant women at risk of thromboembolitic complications, including venous thrombosis, pulmonary embolism, subarachnoid hemorrhage, cerebral infarction, and myocardial infarct. While the risk of stroke in the U.S. has generally decreased over time, from 1994–5 to 2006–7 the risk of pregnancy-related stroke increased by 47% and 83% during antepartum and postpartum periods, respectively. The primary reason for this trend is a higher rate of childbirth at older ages; another reason is the increased prevalence of diseases such as hypertension, heart disease, diabetes, and obesity. Women who experience a pregnancy-related stroke are not at increased risk of stroke in the future.

Most cases of pregnancy-related stroke occur postpartum or peripartum, defined as the two days before and one day following delivery. The risk of ischemic stroke increases 2-fold during pregnancy, 9-fold during the postpartum period, and 34-fold during the peripartum period. While risk of brain hemorrhage does not increase during pregnancy, there are 95- and 47-fold increased risks for intracranial hemorrhage (ICH) and SAH, respectively, during the peripartum period, and 12- and 2-fold increased risks during the postpartum period.

According to Fink, pregnancy-related stroke is often missed because it is relatively rare and may not be accompanied by the usual warning signs, such as blurry vision or dizziness or sudden weakness, numbness, or paralysis. Furthermore, the types of stroke that occur during pregnancy and postpartum differ from the most common types in the general population. For example, hemorrhagic stroke is more common than ischemic stroke in pregnant women, and carotid atherosclerosis, which is the most common cause of stroke among elderly patients, is rare. Fink recommended prenatal screening for thrombophilias, such as factor V Leiden mutation and elevated factor VIII levels. These conditions affect blood coagulation, increasing the risks of blood clot formation, ischemic stroke, and cerebral venous thrombosis. He also recommended aggressive blood pressure management in pregnant patients.

Diagnostic evaluation and treatment for pregnancy-related and other types of stroke are similar. However, Fink highlighted special considerations for women experiencing stroke during pregnancy, based on potential risk to the fetus. MRI should be avoided during the first trimester and warfarin treatment for ischemic stroke should be avoided during the first and second trimesters. Although thrombolytic therapy is not approved in pregnant patients, many centers use it because the drug does not cross the placenta, and no fetal injury has been reported.

Because the incidence of pregnancy-related stroke is rare, a single medical center may only encounter one case per year. Fink stressed the importance of creating a prospective registry of pregnancy-related stroke cases to collect sufficient data for future studies.

Speakers:
Randall Matthew Chesnut, University of Washington; Harborview Medical Center
Roger Härtl, Weill Cornell Medical College
Neeraj Badjatia, University of Maryland School of Medicine

Highlights

• Current guidelines provide thresholds for ICP and CPP in patients experiencing TBI; however, a more individualized approach may be warranted.
• Current guidelines recommend the use of mannitol to decrease ICP in TBI patients. The data for hypertonic saline are not robust enough to provide any recommendation for its use.
• Although hypothermia has been shown to reduce ICP, randomized trials have failed to demonstrate a benefit in TBI patients.

Pathophysiology of TBI

Traumatic brain injury can result from a sudden blow to the head. As the head experiences abrupt acceleration or deceleration, contact between the frontal cortex and the skull can damage brain tissue. The motion also stretches the fibers that connect the cortex to the brain stem, causing further damage. TBI leads to brain swelling, which results in increased intracranial pressure (ICP), decreased cerebral perfusion pressure (CPP), decreased CBF, ischemia, and edema, all of which can exacerbate the initial injury.

In TBI, the initial brain injury results in a series of secondary insults, such as increased ICP and decreased CPP and CBF. Current treatments focus on managing these secondary insults as opposed to treating the brain injury itself. (Image courtesy of Roger Härtl)

Signs and symptoms of TBI can be physical, cognitive, and emotional. Physical symptoms include headaches, light sensitivity, noise sensitivity, nausea, vomiting, fatigue, numbness, tingling, and impaired vision and balance. Cognitive problems include impairments in concentration, memory, and attention. Emotional problems include irritability, sadness, and nervousness. Patients may also experience sleep problems, including drowsiness or trouble falling asleep.

Therapy for severe TBI

According to Randall Matthew Chesnut of the University of Washington and Harborview Medical Center, there is a mismatch between the pathophysiology of brain injury and current treatments. Current strategies such as ICP and CPP monitoring aim to treat the symptoms of brain injury while giving the brain time to heal itself and avoiding secondary injuries. Chesnut described some of these treatments.

Current TBI treatments do not address the pathophysiology of brain injury. (Image courtesy of Randall Matthew Chesnut)

After the initiation of ICP monitoring, the mortality rate for TBI decreased from 50% to between 18% and 36%. However, as Chesnut pointed out, correlation must not be confused with causation. A randomized trial comparing a protocol that monitored ICP and a protocol that did not failed to reveal a difference in efficacy. Chesnut asserted that advances in rehabilitation, imaging, trauma surgery, emergency care, and pre-hospital care may have also contributed to the decrease in mortality.

Current guidelines recommend maintaining ICP below 20 mm Hg. However, Chesnut argued that this threshold, developed in the 1960s and 1980s when care was managed differently, may not be as relevant today. In a case study, a patient whose ICP rarely fell within the acceptable range, increasing to as high as 60 mm Hg, showed no neurological changes. By day 7, the patient's ICP had fallen to within the acceptable range. This unusual case illustrates that the threshold for treating ICP can be tailored to individual patients. Chesnut emphasized that treatment modification should be done carefully and under close observation.

With regard to CPP, higher pressure is often thought to be better. However, in a retrospective review of pediatric patients with TBI, among patients with CPP above 40 mm Hg no correlation was found between increased CPP and improved mortality, suggesting a threshold effect. In a 1997 study, Chesnut showed that patients who did not receive CPP management but had no hypotension did as well as those who received CPP management. The major advantage of CPP management may be to reduce cerebral ischemia, but high CPP is not necessarily better because it carries a risk of damaging the blood–brain barrier and of toxicity caused by vasopressors and hypervolemia. Chesnut recommended keeping CPP within a normal range to normalize CBF, rather than focusing only on increasing CPP, but stressed that cerebral hypotension must be avoided.

Chesnut cautioned that there are no "magic numbers" with regard to TBI; the goal of current strategies is to allow the brain time to heal itself while avoiding secondary injuries. In the future, he hopes for more targeted therapies that address the pathophysiology of TBI and primary brain injury instead of secondary effects like ICP and CPP.

Hyperosmolar therapy for TBI

Roger Härtl of Weill Cornell Medical College described the use of mannitol and hypertonic saline to decrease ICP. Both substances are unable to cross the blood–brain barrier, creating an osmotic effect that draws fluid out of the brain. In a case-controlled study, Härtl compared mannitol and hypertonic saline treatment in over 3000 patients with severe TBI over 10 years. Hypertonic saline was the more effective treatment for lowering cumulative and daily ICP; however, although the treatment reduced the number of days spent in the ICU, it did not reduce 2-week mortality.

There are no recommendations for the use of hypertonic saline in the adult guidelines for TBI because current data are not sufficiently robust. Härtl asserted that it is difficult to draw conclusions and make recommendations based on the current studies comparing mannitol and hypertonic saline, which include a small number of patients and vary in study design and in the concentrations and combinations of mannitol and hypertonic saline used.

Hypothermic therapy for TBI

In TBI patients, increased ICP and inflammation can cause brain temperature to be elevated as much as 4°C above body temperature. Clinicians may induce hypothermia at the time of injury in an effort to decrease ICP. Mild hypothermia—a body temperature of to 32°C–34°C—has produced neuroprotective effects in several ischemic brain injury models.

Neeraj Badjatia of the University of Maryland School of Medicine reviewed clinical trials investigating the efficacy of hypothermia in brain injury. Although two clinical trials, NABISH-I and NABISH-II, failed to show any improvement in disability among patients with TBI, a meta-analysis of several studies revealed hypothermia treatment reduced the risk of poor neurological outcomes and death. Badjatia hypothesized that the application of a fixed duration of hypothermia, regardless of whether ICP had returned to normal, may have contributed to the failure of previous trials. He is optimistic that hypothermia may benefit patients after brain injury, because it has been demonstrated to reduce ICP. Two ongoing trials, EUROTHERM and HOPES, are investigating the efficacy of hypothermia therapy when ICP is used to determine when body temperature should be returned to normal.

Speakers:
Jose A. Pineda Soto, Washington University School of Medicine; St. Louis Children's Hospital
Barry Kosofsky, Weill Cornell Medical College

Highlights

• TBI is the leading cause of childhood death and disability in the U.S.
• The primary causes of TBI in children are motor vehicle accidents and sports injuries.
• Current guidelines for TBI treatment in children focus on preventing secondary brain injury.

Guidelines and treatment for pediatric TBI

Of the 1.74 million people who suffer from TBI each year, half are under the age of 18. In the U.S., TBI is the leading cause of childhood death and disability. The most common causes of TBI among children are motor vehicle accidents and sports injuries. Children who experience significant TBI can demonstrate delayed development in IQ, language, motor function, and memory. Several characteristics of children differentiate pediatric TBI from adult TBI. Children's brains are more plastic than adults' brains, which may enable children to recover more completely, though often less quickly, but may also make them more vulnerable to injury. Specifically, infants and children have higher brain water content, decreased brain myelination, and less neck strength, all of which render infants' brains more susceptible to mechanical damage.

Jose A. Pineda Soto of Washington University School of Medicine and St. Louis Children's Hospital reviewed guidelines for the treatment of pediatric TBI. The current guidelines by the Brain Trauma Foundation target secondary injuries, such as hypotension, intracranial hypertension, fever, and seizures. In a retrospective study at his institution, Pineda investigated the success of the recommended approach, finding a 70% decrease in mortality in pediatric TBI patients after the guidelines were applied. In particular, the guideline-recommended implementation of earlier and more aggressive ICP monitoring and treatment was related to better outcomes. He is currently investigating how other variables, including CPP, MAP, CVP, glucose, and temperature management, impact pediatric outcomes.

Pediatric sports injuries

There are approximately 35 million youth athletes in the U.S. at risk for sports-related concussion or TBI. Sports concussions can be particularly difficult to treat because there is no clear evidence or research to support treatment guidelines in children. Most sports-related head injuries are mild and reversible. However, as Barry Kosofsky of Weill Cornell Medical College explained, 20%–30% of injuries falling into the mild TBI category may result in ongoing symptoms, such as headache, attention and memory deficits, and emotional problems. Unfortunately, current diagnostic tests such as MRI, neuropsychology, and EEG are unable to differentiate between patients who will have persistent symptoms and those who will recover. Kosofsky stressed the need for biomarkers that can identify patients at risk for ongoing brain damage.

In patients with TBI there is a need for actionable biomarkers that can predict the ability of intervention to improve functional outcomes and reduce neurological damage. (Image courtesy of Barry Kosofsky)

In the absence of such biomarkers, Kosofsky outlined his approach to treating children experiencing TBI and concussion. Cognitive and neuropsychiatric assessments, such as ImPACT, a test used to determine when an athlete can return to the field, are not very reliable. If a patient has not fully recovered from the initial brain injury, there is an increased risk of subsequent injury. Kosofsky recommended a graded approach in which the patient slowly returns to mental and then to physical exercise. If an increase in mental or physical activity causes symptoms, the patient should return to previous activity levels for 2 to 3 days and should not attempt to "power through" a headache. Eventually, the patient can return to the field and then gradually increase physical activity.

Speakers:
Glen Prusky, Weill Cornell Medical College; Burke Medical Research Institute
Costantino Iadecola, Weill Cornell Medical College

Highlights

• Diabetes causes neuronal dysfunction, possibly resulting from defects in mitochondrial function.
• Therapies that restore mitochondrial function may reverse the effects of neuronal damage in diabetes.
• The vasculature plays a key role in dementia, including in Alzheimer's disease.

Neuronal dysfunction in a mouse model of diabetes

Patients with diabetes are at increased risk of stroke, dementia, and Parkinson's disease. Glen Prusky of Weill Cornell Medical College and Burke Medical Research Institute described his work to elucidate the effect of diabetes on the nervous system in a mouse model. Prusky measures neurological dysfunction in mice by monitoring the visuomotor response. Briefly, researchers monitor deficits in the mouse's ability to track a rotating visual stimulus.

To monitor neuronal dysfunction in mice, Prusky assesses deficits in head/neck motions in response to a rotating visual stimulus. (Image courtesy of Glen Prusky)

In a mouse model, diabetes resulted in defects in the visuomotor response, which appear before other symptoms of diabetes, such as weight gain and abnormal glucose levels. Because mitochondrial dysfunction is a marker of several neurological disorders, Prusky administered a peptide called MTP-131 that increases ATP production while reducing the production of reactive oxygen species (ROS) in the mitochondria. In control animals, MTP-131 had no effect on visuomotor function; however, in diabetic mice, it increased visuomotor function to normal levels. The effect of MTP-131 was restricted to visuomotor function—it had no effect on weight or glucose levels.

Prusky hopes to identify behavioral markers of nervous system dysfunction in the early stages of metabolic disease, contending that agents that improve mitochondrial efficiency, such as MTP-131, are promising candidates for treating such neuronal dysfunction.

Hypertension and dementia

Costantino Iadecola discussed the link between hypertension and dementia. Normally, the brain maintains a stable CBF despite changes in blood pressure by changing the diameter of blood vessels through a process known as autoregulation. Hypertension promotes hardening of the artery walls and plaque buildup, which can interfere with autoregulation.

Hypertension has several deleterious effects on cerebral blood vessels. It can lead to blockages in the carotid arteries and result in ischemia and infarction. (Image courtesy of Costantino Iadecola)

For every 10 mm Hg increase in blood pressure, there is a significant decline in cognitive ability—even for blood pressure values that are considered normal. However, blood pressure must be managed with care. High blood pressure causes remodeling of the blood vessels; therefore, a decrease in blood pressure could decrease the supply of blood to the brain, resulting in ischemia.

The role of the vasculature in Alzheimer's disease

Alzheimer's disease is the most common form of dementia and is most commonly associated with the deposition of amyloid plaques comprised of Aβ peptide. Aβ peptide can damage neurons, but it has also been shown to damage blood vessels. Iadecola described the role of the brain's vasculature in Alzheimer's disease. In a mouse model of Alzheimer's disease, CBF decreased before any sign of neuronal dysfunction, which increased the susceptibility to ischemic injury. When researchers induced an ischemic stroke in Alzheimer's disease mice, the mice suffered from a greater decrease in blood flow and a higher infarction volume than non-Alzheimer's disease mice.

Can inflammatory pathways be targeted to reduce damage in stroke patients?

Increased collateral flow was not shown to provide a benefit with regard to disability after stroke but did decrease mortality—will this treatment find a place in the clinic?

How can we best determine who is likely to benefit from thrombolytic therapy, especially after the recommended 4.5-hour time window?

What is the appropriate duration of antiplatelet therapy for stroke and TIA patients?

How can we best identify pregnant patients who are at risk for stroke?

What aspects of brain injury pathology should be targeted to reduce damage and improve function?

Can targeting mitochondrial dysfunction decrease neuronal damage in patients with metabolic disorders?

How much does ICP monitoring contribute to decreased morality in TBI patients? What effects do other treatment and monitoring variables have?

Under what conditions might hypothermia reduce brain damage and improve function in patients with TBI?

How do mannitol and hypertonic saline treatments compare in patients with TBI?

What biomarkers can predict which patients are likely to have persistent symptoms following mild TBI?

How can we develop a personalized, targeted approach to ICP and CPP management that takes into account the underlying pathology of the injury?