STROKE: The Cutting Edge: 2017 i THE CUTTING EDGE

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STROKE: The Cutting Edge is published by AHC Media, a Relias Learning company

Executive Editor: Leslie G. Coplin AHC Media Editorial Group Manager: Terrey L. Hatcher Senior Accreditations Officer: Lee Landenberger

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ISBN: 978-1-941481-36-3

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Clinical Cardiology Alert ED Management Internal Medicine Alert Neurology Alert OB/GYN Clinical Alert

ii STROKE: The Cutting Edge: 2017 ACCREDITATION INFORMATION

ACCREDITATION STATEMENT Relias Learning is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Relias Learning, LLC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Provider approved by the California Board of Registered Nursing, Provider #CEP13791, for 8 Contact Hours.

CREDIT DESIGNATION Relias Learning designates this enduring material for a maximum of 8.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity has been approved for 8.0 nursing contact hours using a 60-minute contact hour.

ACTIVITY OBJECTIVES After reading STROKE: The Cutting Edge: 2017, the participant will be able to: 1. Discuss current scientific research and data regarding the diagnosis and treatment of stroke; 2. Discuss the pathogenesis and treatment of stroke; 3. Explain the basic science of brain function as it applies to stroke; 4. Cite new information regarding new drugs for stroke and new uses for traditional drugs; 5. Identify nonclinical issues of importance for health care providers who treat stroke patients. 6. Discuss advances in neurointerventional treatment.

Physicians and nurses participate in this CME/CE activity by reading the articles, using the provided references for further research, and studying the relevant questions at the end of the book. Participants will then be directed to a website, where they will complete an online assessment to show what they’ve learned. They must score 100 on the assessment in order to complete the activity, but they are allowed to answer the questions multiple times if needed. After they have successfully completed the assessment, they will be directed to an online activity evaluation form. Once that is submitted, they will receive their credit letter.

TARGET AUDIENCE This activity is intended for for neurologists, emergency medicine physicians and nurses, Joint Commission-certified stroke center personnel, psychiatrists, and ENTs.

EXPIRATION DATE March 31, 2020

PHYSICIAN EDITOR Matthew Fink, MD Louis and Gertrude Feil Professor in Clinical Neurology and Chairman, Department of Neurology, Weill Cornell Medical College; Neurologist-in-Chief, New York Presbyterian Hospital

PEER REVIEWER Amre M. Nouh, MD Director of the Stroke Center, Hartford Hospital; Assistant Professor and Associate Residency Program Director, Department of Neurology, University of Connecticut

NURSE PLANNER Donna Avanecean, MS, RN, FNP-C, CNRN, DNP-c Movement Disorders/DBS Program, Department of Neurosurgery, Yale University

FINANCIAL DISCLOSURES In order to reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, Dr. Fink, Dr. Nouh, and Dr. Avanecean report no financial relationships relevant to this field of study.

Editorial and Production: Ms. Coplin, Ms. Hatcher, and Mr. Landenberger report no financial relationships relevant to this field of study.

Authors: Financial disclosure information for authors can be found at the beginning of their respective articles. This publication does not receive commercial support.

STROKE: The Cutting Edge: 2017 iii TABLE OF CONTENTS

Module 1: Prevention and Risk Factor Reduction (1 hour) Preventing 90% of Stroke with 10 Modifiable Risk Factors...... 1 A New Risk Score for Stroke in Atrial Fibrillation...... 2 Effects of Aspirin on Risk of Early Recurrent Stroke After Transient Ischemic Attack and Ischemic Stroke...... 4 Headaches in the Elderly: A Non-specific Marker for Stroke Risk...... 6 Migraine with Aura and Systemic Right-to-Left Shunt: Risk for Stroke?...... 8 Contraception, Migraines, and Stroke...... 10 Arterial Ischemic Stroke Prevention and Risk Factor Management...... 13 Proceedings from the 2017 International Stroke Conference...... 31 Stroke Alert: A Review of Current Stroke Literature...... 33 CME Test: Module 1...... 35

Module 2: Prehospital and Emergency Care (1 hour) Functional Outcomes in Acute Ischemic Stroke Patients Receiving Prehospital Thrombolysis in Mobile Stroke Units...... 38 New Mobile Stroke Unit Programs Aim to Improve Outcomes...... 40 Proceedings from the 2017 International Stroke Conference...... 44 Stroke Alert: A Review of Current Stroke Literature...... 45 CME Test: Module 2...... 46

Module 3: Neuroimaging for Stroke (1 hour) Blood-brain Barrier Breakdown in RCVS...... 48 Proceedings from the 2017 International Stroke Conference...... 50 CME Test: Module 3...... 51

Module 4: Large Vessel Ischemic Stroke Treatment (1 hour) Intravenous Glyburide to Reduce Brain Swelling in Large Hemispheric Infarction...... 53 Proceedings from the 2017 International Stroke Conference...... 55 Stroke Alert: A Review of Current Stroke Literature...... 57 CME Test: Module 4...... 59

Module 5: Acute Endovascular Treatment (1 hour) Proceedings from the 2017 International Stroke Conference...... 60 A Review of Current Stroke Literature...... 62 CME Test: Module 5...... 63

iv STROKE: The Cutting Edge: 2017 TABLE OF CONTENTS

Module 6: In-hospital Management of Stroke (1 hour) RESCUEicp: A Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension...... 65 Proceedings from the 2017 International Stroke Conference...... 67 A Review of Current Stroke Literature...... 69 CME Test: Module 6...... 71

Module 7: and AVMs (1 hour) Proceedings from the 2017 International Stroke Conference...... 73 A Review of Current Stroke Literature...... 74 CME Test: Module 7...... 75

Module 8: Stroke Rehabilitation (1 hour) Stroke: Rehabilitation and Recovery...... 77 Proceedings from the 2017 International Stroke Conference...... 87 CME Test: Module 8...... 88.

STROKE: The Cutting Edge | Module 1: Prevention and Risk Factor Reduction v STROKE: THE CUTTING EDGE Module 1: Prevention and Risk Factor Reduction

vi Module 1: Prevention and Risk Factor Reduction | STROKE: The Cutting Edge ABSTRACT & COMMENTARY Preventing 90% of Stroke with 10 Modifiable Risk Factors

By Joseph E. Scherger, MD, MPH, Vice President, Primary Care, Eisenhower Medical Center; Clinical Professor, Keck School of Medicine, University of Southern California.

Dr. Scherger reports no financial relationships relevant to this field of study.

SYNOPSIS: Controlling 10 modifiable risk factors would prevent 90.7% of , according to results from a 32-country study.

SOURCE: O’Donnell MJ, Chin SL, Rangarajan S, et al. Global and regional effects of modifiable risk factors associated with acute stroke in 32 countries. Lancet 2016; Jul 15 doi: http//dx.doi.org/10.1016/S0140-6736(16)30506-2. [Epub ahead of print].

he INTERSTROKE investigators from 32 countries An argument can be made about personal responsibility in Asia, the Americas, Europe, Australia, the Middle in avoiding preventable chronic illness and events such as TEast, and Africa conducted a case-control study of stroke. Individuals are in charge of their own lifestyle deci- patients suffering acute stroke compared with controls. sions. However, one also can make an argument that these Researchers compared 13,447 acute stroke cases (10,388 risk factors are a public health problem, with culture and with ischemic stroke and 3,059 with hemorrhagic stroke) environment leading to poor health choices. In his book Fat with 13,472 matched controls. The investigators identified Chance, Robert Lustig from the University of California, 10 modifiable risk factors that may have prevented 90.7% of San Francisco makes this argument forcefully.1 Lustig points strokes. to the ill effects of added sugars and high fructose corn syr- The most important modifiable risk factor is hyperten- up leading to obesity, type 2 diabetes, metabolic syndrome, sion. Eliminating high blood pressure would reduce stroke and fatty liver, with the food industry largely to blame by risk by 48%. There were regional variations, with hyper- hooking the population on these addictive sweets. The pub- tension causing about 39% of strokes in North America, lic health response has been lukewarm at best. Australia, and Western Europe, and nearly 60% of strokes Science is coming together with medical practice to put in Southeast Asia. The other modifiable risk factors, with more focus on modifiable risk factors in chronic disease obvious overlap in many patients are: and preventing major events such as stroke. Had this study zz Physical inactivity: 36% been conducted 20 years ago, smoking would have been zz Hyperlipidemia: 27% a much greater factor. We have the resources to become zz Poor diet: 23% much healthier worldwide by adopting healthy lifestyles and zz Obesity: 19% protecting the environment. The public is becoming better zz Smoking: 12% educated in this area, and those businesses that sell unhealthy zz Heart disease: 9% products are beginning to feel the effect. Physicians, especial- zz Alcohol: 6% ly those in primary care, should be “captains” in the battle zz Diabetes: 4% against the poor health choices that surround us every day. zz Stress: 6% Reference Commentary 1. Lustig R. Fat Chance: Beating the Odds Against Sugar, Processed Food, Stroke is the third leading cause of death and a major Obesity, and Disease. New York: Penguin Group; 2012. cause of disability, and as this study shows is highly pre- ventable. Unhealthy lifestyle leads to more than 90% of all strokes worldwide. The same could be said of heart disease and many cancers. Most instances of poor health and pre- mature demise are self-inflicted.

STROKE: The Cutting Edge | Module 1: Prevention and Risk Factor Reduction 1 Arterial Ischemic Stroke Prevention and Risk Factor Management

Michael P. Lerario, MD, Department of Neurology, Weill Cornell Medical College, New York; New York- Presbyterian/Queens Hospital, Flushing, NY

Alan Z. Segal, MD, Department of Neurology, Weill Cornell Medical College, New York

Drs. Lerario and Segal report no financial relationships relevant to this field of study.

troke is a common problem, affecting nearly 800,000 pressure control, including many different agents such people annually in the United States.1 Domestically, it as angiotensin-converting enzyme inhibitors, angiotensin is the fifth most common cause of death and a leading receptor blockers, calcium channel blockers, and diuretics.3 S 1 cause of significant long-term disability. Stroke costs the The choice of agent is less crucial than the successful lower- United States an estimated $34 billion each year.1 Given this ing of blood pressure. In general, blood pressure treatment extraordinary burden on the health of the American popula- should be targeted to a normal blood pressure of < 140/90 tion, appropriate stroke prevention measures could dramati- mmHg.3 However, recent evidence suggests a more aggres- cally improve our quality and length of life. sive goal of systolic < 120 mmHg may be beneficial for The widespread institution of screening, risk factor modi- the primary prevention of cardiovascular events.4 Although fication, and treatment of known cardiac and cerebrovascu- these data applied to a composite outcome of stroke, lar disease is paramount to the health of our nation. The fol- myocardial infarction, heart failure, and vascular death, they lowing article discusses the best evidence-based practice for confirm that “pre-hypertension” (diastolic 80-90 and systolic stroke diagnosis, prevention, and risk factor management. 120-140) contributes to increased stroke risk. Where strong data are absent, usual practice and expert con- Hypercholesterolemia is another important stroke risk fac- sensus are accepted and noted as such. tor. Low-density liporprotein (LDL) cholesterol in patients with a prior stroke should be < 70 mg/dL. Cholesterol low- Stroke Epidemiology ering is particularly important in patients with a prior history There are nearly 800,000 strokes in the United States each of atherosclerotic disease, in which case the American Heart year, with 130,000 associated deaths.1,2 Although stroke is Association (AHA) recommends titrating statins to the the second leading cause of death worldwide, it is only the maximum tolerated dosage (high-intensity statin) rather than fifth most likely cause in the United States.1,2 Because of specific LDL goals.5 Large cohorts of patients with prior the major disability associated with stroke, the overall cost myocardial infarction, such as the Heart Protection Study, to this country is substantial. Up to 30% of patients who have shown that control of lipids not only prevents future survive a stroke will require institutional care.2 Mortality heart attack but specifically lowers stroke rates by about from stroke varies according to ethnicity, with blacks twice 25%.6 as likely to suffer a stroke and more likely to die compared Obstructive sleep apnea (OSA) approximately doubles to whites.2 The “stroke belt” in the southeastern United the risk of stroke when compared to controls, and stroke States has the highest national stroke mortality.2 Stroke risk rates increase steadily with OSA severity.7 The mechanism increases with age, but 34% of stroke affects individuals by which OSA results in cerebral embolism is not entirely younger than 65 years of age.2 The overall stroke incidence certain; however, it is known that sleep-disordered breath- is expected to rise in the near future as the population ages, ing increases the development of atrial fibrillation, a potent despite recent advances in risk factor reduction, which has stroke risk factor.8 The treatment for OSA is quite effective. reduced the per capita incidence of strokes. There are gen- Continuous positive airway pressure (CPAP) therapy has der differences in stroke rates as well.Women are 50% more been shown to be effective in reducing stroke risk to equal likely than men to have a stroke, particularly due to a high patients with no history of sleep-disordered breathing.7 incidence in white elderly females.2 Diabetes is known to confer excess risk of stroke inde- pendent of blood pressure.9 Specific stroke mechanisms, Modifiable Stroke Risk Factors such as large artery atherosclerotic disease or small vessel Hypertension is the most important modifiable stroke ischemia, are associated with poor glucose control.9 Despite risk factor. Multiple trials have shown the benefit of blood stroke being a known vascular complication of diabetes,

STROKE: The Cutting Edge | Module 1: Prevention and Risk Factor Reduction 13 mimic stroke include seizure with postictal deficits, migraine aura, conversion disorder, encephalopathy from metabolic Table 2. TOAST Classification System disturbances, intracranial tumors or infections, hyperten- of Stroke Subtypes sive encephalopathy, Bell’s palsy, , Prevalence of Stroke Stroke Subtype spinal or nerve disorders, peripheral vertigo, and syncope. Subtype32 The discrimination of a true vascular event from a mimic is important in terms of treatment and follow-up. Whereas Large artery atherosclerosis 15.5% TIA is a known risk factor for subsequent stroke, the risk of future vascular events after the diagnosis of a mimic is Cardioembolism 27.8% negligible.23,24 The ABCD2 score may be helpful in making the diagnosis of a non-vascular event. Lower scores on this scale are associated with mimics, rather than true TIAs, and Small vessel occlusion 18.1% have a low likelihood of future stroke.24 Nevertheless, this Stroke of other determined differentiation between mimic and true stroke may not be as 4.2% important in the acute setting, since it has been deemed safe etiology to treat mimics with intravenous (IV) tissue plasminogen Stroke of undetermined etiology activator. The risk of symptomatic Two or more identified causes 34.4% following IV thrombolysis has been demonstrated to be 1% Negative evaluation or less.22,25 . Lacunar stroke refers to the pathophys- Stroke Mechanisms iological, clinical, and radiographic findings observed in Causes of Stroke. Ischemic stroke, the damage to neuro- small vessel disease. A lacunar stroke is the result of arterial nal tissue as a result of reduced cerebral blood flow, can obstruction of a single deep, penetrating vessel that supplies be a common endpoint due to many conditions. The main the subcortical structures of the brain, such as the capsule, causes of stroke are due to either thrombosis or embolism basal ganglia, thalamus, and paramedian .26,29 of a cerebral artery. Thrombosis refers to a local occlusive Such arterial obstruction is associated with the pathological process formed in situ within the artery. The site of ob- changes occurring in response to chronic hypertension or struction may occur either within a large intra- or extracra- diabetes, including microatheroma or lipohyalinosis.26 Lipo- nial artery (which is typically the result of atherosclerosis) hyalinosis refers to the degenerative change in small blood or within a small penetrating artery (which typically is due vessels due to the accumulation of lipid within the vessel to chronic vessel changes from hypertension).26,27 On the wall.26 other hand, embolism refers to thrombus that travels from Since the affected arteries are small, the resultant strokes the site of formation and lodges within distal vessels. The (known as lacunes) also are small. These irregular cavitary source of embolism either may be a proximal artery, the lesions typically are < 1.5 centimeters in diameter.30 Radio- heart, or paradoxically from the venous system in the case graphically, lacunar strokes appear as small infarcts in typical of a patent foramen ovale (PFO).26,27 Embolic strokes tend subcortical structures, with MRI being more sensitive than to cause symptoms that are abrupt and maximal at onset.26 CT for detecting these lesions.26 (See Figure 1.) The imaging Additionally, embolism often leads to cortical infarction in findings of a small, deep infarct in the absence of other the cerebral surface of an arterial territory and is more likely possible stroke etiologies is strongly supportive of a lacu- to be associated with hemorrhagic conversion.28 nar etiology. Larger areas of infarction, known as giant or TOAST Classification System.There have been many super lacunes, may imply thrombosis or embolism of the attempts to categorize mechanisms of stroke for clinical proximal branch from which the penetrating artery arises; and research purposes. A commonly used classification for instance, a lenticulostriate territory stroke could result schema for stroke subtype is known as the TOAST system.27 from a nonocclusive embolus to the middle cerebral artery.26 (See Table 2.) The TOAST system has inherent limitations, Therefore, subcortical strokes > 1.5 centimeters in size may namely the large number of stroke patients who resultantly necessitate a diagnostic evaluation aimed at finding an em- are classified as cryptogenic (i.e., having undetermined eti- bolic source of stroke, including echocardiography, teleme- ology). The TOAST investigators did not require aggressive try, and noninvasive angiography of the head and neck. diagnostic testing, by today’s standards, prior to categoriz- Lacunar infarcts clinically present as one of several classic ing a patient as cryptogenic; for instance, transesophageal syndromes, with the following being the most common: echocardiogram and extended arrhythmia monitoring were pure motor weakness, pure sensory loss, mixed sensorim- not required. Nevertheless, it is a useful tool for research otor, ataxia hemiparesis, and dysarthria-clumsy hand syn- purposes and for conceptualizing stroke mechanism in a dromes.31 The symptoms of lacunar stroke often fluctuate simplified manner. over the acute course of the disease, hence the name “stut-

STROKE: The Cutting Edge | Module 1: Prevention and Risk Factor Reduction 15 Figure 1. MRI Displaying Typical Imaging Characteristics of Acute Lacunar Infarctions

Note small, deep infarctions in the left paramedian pons (A) and right thalamus (B).

A B

tering lacune.” Although lacunar strokes comprise nearly contributing to the higher rate of 20% of strokes,32 they have the lowest in-hospital mortality with reperfusion associated with embolic strokes.28 of the subtypes.33 There are many potential causes of cerebral cardioem- Cardioembolic Stroke. Cerebral embolism occurs when bolism. (See Table 3.) Whether a stroke can be attributed particulate material from a proximal source travels through to a cardioembolic source requires the identification of a the arterial system to lodge within a downstream cerebral ar- known cardiac risk factor for embolic stroke, as well as the tery. Emboli to the brain are most often composed of mural exclusion of other etiologies, such as large artery atheroscle- thrombi or platelet aggregates and most often travel to the rosis or lacunar infarct, based on dedicated neuroimaging.27 anterior circulation (particularly the middle cerebral artery The probability of a stroke being attributed to an identified territory), given that these arteries accept the majority of ce- cardiac risk factor depends on how strongly that risk factor rebral blood flow.26 Although an embolic etiology accounts is associated with ischemic stroke.27 The most common for up to 70% of stroke cases,26 probable or definite evi- high-risk sources of cardioembolism include valvular heart dence of cardiac embolism is demonstrated in only 25-30% disease, the formation of an intracardiac thrombus (e.g., of ischemic strokes.32 In other instances, the source of em- recent myocardial infarction or atrial fibrillation), ventricular bolus may be a proximal large artery, the venous circulation or septal aneurysms, and cardiomyopathies. Three specific in the case of a PFO, or unknown (cryptogenic).27 A cardiac cardiac sources of stroke, including atrial fibrillation, PFO, source is implied if the emboli result in bilateral infarcts, and aortic arch atheroma, are discussed in depth below. particularly if cortical and in multiple vascular territories.28 Atrial Fibrillation as a Stroke Risk Factor. Atrial fibril- (See Figure 2.) For example, a potential cardioembolic etiolo- lation is the most common sustained cardiac arrhythmia, gy of stroke would be inferred from an MRI demonstrating occurring in 1-2% of the general population, and is even simultaneously occurring left middle cerebral artery and more prevalent in aging populations.35 Atrial fibrillation can right posterior cerebral artery acute transcortical infarctions. lead to left atrial or atrial appendage thrombus formation, These emboli tend to be evanescent, and obstruction of which can serve as a source of embolism. The arrhythmia is an intracranial artery may recanalize spontaneously,34 likely a very strong risk factor for stroke, increasing this risk by as

16 Module 1: Prevention and Risk Factor Reduction | STROKE: The Cutting Edge monitoring on cardioembolic stroke recurrence due to the References known superiority of anticoagulation to antiplatelets in me- 1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and dium- to high-risk atrial fibrillation patients. However, this Stroke Statistics—2015 Update: A report from the American has yet to be proven definitively. In the meantime, a standard Heart Association. Circulation 2015;131:e29-322. 2. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and approach is to monitor cryptogenic stroke patients for at Stroke Statistics—2016 Update: A Report From the American least 30 days, while treating them with antiplatelet therapy, Heart Association. Circulation 2016;133:e38-e360. unless atrial fibrillation is discovered.107 3. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the In addition to extended arrhythmia monitoring, it has prevention of stroke in patients with stroke and transient isch- been suggested that additional advanced diagnostic tech- emic attack: a guideline for healthcare professionals from the niques be used to uncover other potential stroke etiologies American Heart Association/American Stroke Association. Stroke in cryptogenic patients who have otherwise unremarkable 2014;45:2160-2236. 60 4. Wright JT, Williamson JD, Whelton PK, et al. A randomized trial routine stroke evaluations. Such testing could include the of intensive versus standard blood-pressure control. N Engl J Med measurement of D-dimer and screening for occult ma- 2015;373:2103-2116. lignancy to rule out cancer-related coagulopathy. Aortic 5. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA pathology such as atherosclerosis also may embolize to the guideline on the treatment of blood cholesterol to reduce athero- brain and is best visualized using transesophageal echocar- sclerotic cardiovascular risk in adults: A report of the American diography. Interatrial shunts, including PFO and atrial septal College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S1-45. defects, should be tested for with bubble studies either 6. Group HPSC. MRC/BHF Heart Protection Study of cholesterol using echocardiography or transcranial Doppler. Advanced, lowering with simvastatin in 20,536 high-risk individuals: A ran- high-resolution vascular wall imaging, with or without domised placebo-controlled trial. Lancet 2002;360:7-22. contrast, also may detect arterial plaques with ulceration 7. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea or other high-risk elements that could serve as a source of as a risk factor for stroke and death. N Engl J Med 2005;353: embolism. 2034-2041. 8. Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea.Circulation 2004;110: Conclusion 364-367. Given the frequency of stroke occurrence, and the high 9. Barrett-Connor E, Khaw KT. Diabetes mellitus: An independent rates of resultant death and disability, an evidence-based risk factor for stroke? Am J Epidemiol 1988;128:116-123. prevention strategy is one of the largest weapons in a 10. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short- clinican’s armamentarium against stroke. With time, we are term prognosis of transient ischemic attack in a population-based learning more about the importance of precise risk factor study. Stroke 2005;36:720-723. 11. Redgrave JN, Coutts SB, Schulz UG, et al. Systematic review of management, the role of statins for atherosclerotic disease, associations between the presence of acute ischemic lesions on and the use of targeted antithrombotic therapy based on the diffusion-weighted imaging and clinical predictors of early stroke underlying mechanism of stroke. Whereas large artery ath- risk after transient ischemic attack. Stroke 2007;38:1482-1488. erosclerotic and small vessel disease responds to antiplatelet 12. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation agents, anticoagulation has been found to be superior in of transient ischemic attack: a scientific statement for healthcare certain high-risk cardiac conditions, such as atrial fibrilla- professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular tion. The recent expansion of oral anticoagulants to include Surgery and Anesthesia; Council on Cardiovascular Radiology and factor Xa and direct thrombin inhibitors has significantly Intervention; Council on Cardiovascular Nursing; and the Inter- improved the overall risk/benefit profile of the medical disciplinary Council on Peripheral Vascular Disease. The Ameri- therapy for patients with nonvalvular atrial fibrillation. can Academy of Neurology affirms the value of this statement as Surgical options also vary by stroke subtype and mechanism. an educational tool for neurologists. Stroke 2009;40:2276-2293. Although symptomatic cervical carotid stenosis is amena- 13. Prabhakaran S, Chong JY, Sacco RL. Impact of abnormal diffu- sion-weighted imaging results on short-term outcome following ble to revascularization with stenting or endarterectomy, transient ischemic attack. Arch Neurol 2007;64:1105-1109. stenting of intracranial atherosclerosis has proven harmful 14. Ovbiagele B, Kidwell CS, Saver JL. Epidemiological impact in the in clinical trials. Patients with unexplained stroke after a United States of a tissue-based definition of transient ischemic standard diagnostic evaluation, particularly if young, should attack. Stroke 2003;34:919-924. have advanced testing to evaluate for rarer causes of stroke. 15. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation If a cryptogenic stroke appears embolic on neuroimaging, and refinement of scores to predict very early stroke risk after such patients may benefit from extended cardiac monitoring transient ischaemic attack. Lancet 2007;369:283-292. 16. Amarenco P, Lavallée PC, Labreuche J, et al. One-year risk of or empiric anticoagulation, although randomized trial data stroke after transient ischemic attack or minor stroke. N Engl J are needed to demonstrate improved clinical outcomes with Med 2016;374:1533-1542. such practice. 17. Olivot JM, Wolford C, Castle J, et al. Two aces: Transient ischemic attack work-up as outpatient assessment of clinical evaluation and safety. Stroke 2011;42:1839-1843.

STROKE: The Cutting Edge | Module 1: Prevention and Risk Factor Reduction 27 CME/CE QUESTIONS

To earn credit for this module, log in to to take the post-test.

1. Which of the following has NOT been identified as a 7. In the study by Champaloux et al, the risk of modifiable risk factor for stroke? stroke in women with migraine without aura using a. Diabetes combined hormonal contraceptives and women with b. Vigorous exercise migraine without aura not using combined hormonal c. Poor diet contraceptives was roughly equivalent. d. Smoking a. True b. False 2. Which of the following is the greatest risk factor for causing acute stroke? 8. Which of the following is not a modifiable stroke risk a. Hypertension factor? b. Smoking a. Hypertension c. Obesity b. Age d. Diabetes c. Obstructive sleep apnea d. Diabetes 3. New research suggests which of the following tests may add significantly to the estimation of stroke risk 9. Which is not a recent criticism of the ABCD2 score in atrial fibrillation? for stratifying stroke risk following transient ischemic a. NT-proBNP attack? b. High-sensitivity troponin a. It does not include an assessment for high-risk c. Both stroke mechanisms such as carotid stenosis or d. Neither atrial fibrillation. b. It overestimates stroke risk. 4. Aspirin administered orally after a transient ischemic c. It was not designed to triage patients from the attack: emergency department. a. should be given at least five days after the onset d. It cannot be used to differentiate true stroke from of symptoms. stroke mimic. b. should be given as soon as possible after the onset of symptoms. 10. Which score on the CHA2DS2-VASc scale typically c. should be given at least three days after the onset warrants anticoagulation for stroke prevention in of symptoms. atrial fibrillation patients at average bleeding risk? d. should never be given. a. 0 b. 1 5. Which statement best describes headache and the c. 2 elderly? d. 3 a. Headaches are not indicators of disease risk. b. Headache prevalence decreases with age. 11. Which diagnostic tests would be recommended for a c. Both migraine without and with aura increase patient suspected of having primary central nervous stroke risk. system vasculitis? d. Tension-type headache is a rare cause of a. Lumbar puncture headache. b. Cerebral angiogram c. Brain biopsy 6. The presence of a spontaneous right-to-left shunt in d. All of the above a migraineur in the general population is associated with an increased risk of which of the following? 12. Evidence-based management for secondary a. Silent posterior circulation infarcts stroke prevention in patients with intracranial b. White matter lesions atherosclerosis includes all of the following except: c. Symptomatic cerebral ischemia a. intracranial stenting. d. Persistence of migraine attacks over time b. short-term dual antiplatelet therapy. e. Increased mean attack frequency c. strict blood pressure control. d. intensive LDL lowering with a statin medication.

STROKE: The Cutting Edge | Module 1: Prevention and Risk Factor Reduction 35 New Mobile Stroke Unit Programs Aim to Improve Outcomes

By Dorothy Brooks, Editor, ED Management

Ms. Brooks reports no financial relationships relevant to this field of study.

veryone knows that shortening the time to treatment says. “The only way we can do it even faster is to do it in the is key to improving outcomes in stroke patients. field.” EHowever, some experts believe that continued prog- Initially, stakeholders were hesitant to approve the project ress in this area requires a bold approach and new thinking because of all the rules, regulations, and bureaucracy, but on how care can be delivered optimally. For example, a Fink persisted in pushing the concept. number of medical centers are experimenting with the use “I was convinced that this was really the next phase in of mobile stroke units (MSU), ambulance-like vehicles that treating patients with acute stroke because if we could cut are equipped with the necessary technology and expertise to down the time to treatment, it was going to result in saving bring brain-saving treatment to the patient. lives and increasing the number of people making a full Although the units are deployed in several states, including recovery,” Fink notes. “To me, that was a really important Texas, Ohio, Colorado, Tennessee, and New York, investiga- goal.” tors at these pioneering sites are experimenting with all the The turning point came in 2015 when a hospital board different parameters, everything from how, when, and where member bought into the MSU approach, convinced others the units should be deployed to how the MSUs should inter- on the merits of the idea, and offered to underwrite the face ideally with hospitals and EDs. Further, some sites are project. “Then we were off and running,” Fink adds. experimenting with larger, more robust units equipped with However, Fink notes that building the MSU and getting the technology to perform more sophisticated diagnostics all the physicians on board with the innovation was the and potentially more care delivery in the prehospital envi- easy part. Much more difficult was the process of working ronment. through all the regulatory agencies and receiving appropriate approvals from both the state and the city. Cut Through Red Tape “We had to integrate [the MSU approach] with the 911 In October 2016, New York Presbyterian/Weill Cornell EMS fire department system, which runs all of the -am Medical Center in New York became the first medical center bulances in New York City,” Fink explains. “We have the on the East Coast to deploy an MSU. It’s a project that Mat- largest EMS system in the country.” thew Fink, MD, the neurologist-in-chief of the Division of Stroke and Critical Care Neurology at the hospital, has been Integrate with EMS championing since 2013. With all the approvals finally in hand, the MSU began de- “The very first ambulance like this was developed in Ham- ploying on Oct. 3, 2016, in what is phase one of the project. burg, Germany, in 2003,” Fink explains. “I heard about it on During this period, a neurologist is on board the MSU along my trips there and was very intrigued because the European with two paramedics and a CT technologist. Also on board model of emergency medical service is different than the is a portable CT scanner that can image a patient’s brain to American model. In Europe, doctors often go out on the determine if the patient is suffering a stroke. ambulances and they do more treatment in the field than we When someone calls 911, the dispatcher will ask a few do.” questions based on the Cincinnati Prehospital Stroke Scale. With good results observed in Europe from use of the If the answers suggest that the probability of stroke is high, MSUs, Fink concluded that his center should offer this capa- then the dispatcher will send both a basic life support unit bility. and the MSU to the scene. “We have worked very hard to initiate treatment of “We also monitor all the radio chatter on the EMS radio stroke as fast as possible, and we have done very well, but channel so if we hear of a case that we are not called for but we have come to the point where we have done it as fast as we think it sounds like a stroke, then we will dispatch the we possibly can when patients [are brought] to the ED,” he stroke unit ourselves,” Fink explains. “We have what is called

40 Module 2: Prehospital and Emergency Care | STROKE: The Cutting Edge STROKE ALERT A Review of Current Stroke Literature

By Matthew E. Fink, MD, FAAN, Professor and Chairman, Department of Neurology, Weill Cornell Medical College; Neurologist-in-Chief, New York Presbyterian Hospital

Dr. Fink reports he is a retained consultant for Procter & Gamble and Pfizer.

Which Patients with TIA Are at High Risk Dual Antiplatelet Therapy Appears More Effective for a Recurrent Cerebral Vascular Events? Than Single Therapy

SOURCE: Yaghi S, Rostanski SK, Boehme AK, et al. Imaging SOURCE: Ge F, Lin H, Liu Y, et al. Duel antiplatelet therapy parameters and recurrent cerebral vascular events in patients after stroke or transient ischemic attack – how long to treat? The with minor stroke or transient ischemic attack. JAMA Neu- duration of aspirin plus clopidogrel in stroke or transient isch- rol 2016;73:572-578. emic attack: A systematic review and meta-analysis. Eur J Neu- rol 2016;23:1051-1057. ecurrent cerebral vascular events (RCVEs) are one of Rthe main determinants of outcome in patients after mi- he CHANCE study showed that the combination of nor strokes and transient ischemic attacks (TIAs). The risk Taspirin and clopidogrel was superior to aspirin alone for of recurrence is highest within 90 days and is particularly reducing the risk of stroke in the first 90 days after a TIA or high in the first 48 hours. A number of scoring systems have minor ischemic stroke (N Engl J Med 2013;369:11-19). In been developed to attempt a prediction and stratify high-risk its 2014 guidelines, the American Heart Association recom- from low-risk patients. However, the scores have been lim- mended that the combination of aspirin and clopidogrel can ited because they were derived from mostly non-neurologist be initiated within 24 hours for a minor ischemic stroke or diagnosed TIA samples and their applicability to patients TIA and continued for 90 days. However, the CHANCE seen by current neurology stroke teams is questionable. The trial was performed in China with a discrete ethnic popula- objective of this study is to determine predictors of early tion, and it was not clear if the optimal duration of treat- recurrent cerebral vascular events among patients with TIA ment should be 90 days or longer. In ischemic heart disease, or minor stroke, defined as an NIHSS of 0 to 3. This ret- treatment with dual antiplatelet therapy beyond one year is rospective cohort study was conducted at two tertiary care the standard of care in patients who have coronary stents, centers, Columbia University in New York, and Tulane Uni- and this question has been unanswered in patients with versity in New Orleans, from 2010 until 2014. All patients transient ischemic attack or stroke. Therefore, the authors were diagnosed with a TIA or minor stroke by a neurologist performed a comprehensive literature review and meta-anal- when they presented to the emergency department. The ysis, and identified nine randomized controlled trials that primary outcome was a recurrent neurological event un- included 21,923 patients. In review of these trials, short- explained by any other medical condition. Of 1,258 total term dual antiplatelet therapy significantly reduced the risk patients, 71 had recurrent events. In a multivariate model of of ischemic stroke recurrence by 41% and major vascular prediction for recurrent infarct, the significance predictors events by 30%, without an increased risk of intracranial were 1) infarcts on neuroimaging (CT or diffusion-weighted hemorrhage. Prolonged treatment beyond 90 days reduced MRI), with an odds ratio of 1.75, and 2) large vessel disease the risk of ischemic stroke recurrence by 12% and major etiology, with an odds ratio of 6.69. When both predictors vascular events by 10%. However, the risk of major bleeding were present, there was a further increase in the risk of and intracranial hemorrhage was increased in those patients patients to have recurrent cerebral vascular events. When treated for a longer term. Therefore, it appears that short- neither predictor was present, the rate of recurring events term dual antiplatelet therapy appears to be superior to was extremely low (up to 2%). Patients who had recurrent prolonged treatment. However, this difference in outcome events were less likely to be discharged to home. needs to be confirmed by further well-designed randomized clinical trials.

STROKE: The Cutting Edge | Module 4: Large Vessel Ischemic Stroke Treatment 57 CME/CE QUESTIONS

To earn credit for this module, log in to ______to take the post-test.

1. Which of the following statements is true? a. Intravenous glyburide did not reduce edema in large hemispheric infarction as measured by decreased midline shift. b. Intravenous glyburide resulted in increased concentrations of metalloproteinase 9, a biomarker of brain edema. c. Adverse reactions were more common in patients receiving intravenous glyburide compared to patients receiving placebo. d. There was a strong trend towards poorer functional outcomes in patients receiving intravenous glyburide compared to patients receiving placebo. e. None of the above

2. In secondary stroke prevention, a single-agent antiplatelet medication is just as effective in reducing recurrent stroke or TIA as dual antiplatelet treatments. a. True b. False

3. In patients who present with transient ischemic attack or minor stroke, the period of time with the highest risk of recurrence is the first 48 hours following the initial event. a. True b. False

4. Following acute ischemic stroke, treatment with a single antiplatelet agent is just as efficacious as treatment with dual antiplatelet medications, and carries a lower risk of intracranial hemorrhage. a. True b. False

58 Module 4: Large Vessel Ischemic Stroke Treatment | STROKE: The Cutting Edge Proceedings from the 2017 International Stroke Conference

By Matthew E. Fink, MD, FAAN, Feil Professor and Chairman, Department of Neurology, and Assistant Dean of Clinical Affairs, Weill Cornell Medical College; Neurologist-in-Chief, New York Presbyterian Hospital

Dr. Fink reports he is a consultant for Procter & Gamble.

Message from the Editor: This article is based on personal included pool data from 1,764 patients, using CT perfusion interactions as a participant at the International Stroke Con- imaging to define the ischemic core volume and determine ference in Houston, Feb. 22-24, 2017. All interpretations the relationship of ischemic core volume to functional out- and opinions are exclusively those of the author. come following endovascular thrombectomy. Ischemic core was calculated by a fully automated computerized system General Anesthesia in Endovascular Reperfusion from Phillips imaging. The ischemic core was defined as Stroke Trials a reduction of cerebral blood flow > 30% of blood flow Bruce Campbell from the University of Calgary, repre- to normal brain. The endovascular group and the control senting the HERMES collaboration, presented the effect of group were well matched for baseline characteristics, includ- general anesthesia on outcomes in five endovascular reper- ing median NIHSS of 17, initial median ASPECTS score fusion stroke trials that were reported in 2015, using pooled of 8, percent that received alteplase, and baseline median data. A logistic regression model was developed and adjust- ischemic core volume of 10 mL in the endovascular group ed for variables, which included age, sex, stroke severity on and 9 mL in the control group. In the control group that re- the NIH stroke scale, time from symptom onset to random- ceived IV tPA, there was a rapid drop-off in functional inde- ization, baseline ASPECT score, baseline site of occlusion, pendence (mRS 0-2) as the ischemic core volume increased, and whether the patient received alteplase prior to undergo- from 50% recovery when there was a core volume close to 0 ing endovascular treatment. About 25% of patients received down to 10% as the ischemic core approached 70 mL. With general anesthesia, and there were no significant differences endovascular therapy, the curve shifted upward, showing in the baseline characteristics between the two groups. tPA 70% functional recovery with an ischemic core of 0, and was administered in 88% of the general anesthesia group as much as 30% functional recovery with an ischemic core and about 80% of the group that did not receive general of 70 mL, and a straight-line relationship between those anesthesia. Functional outcome was shown to be significant- two points. The differences between the two groups were ly better (mRS 0-2) in the group that did not receive general highly significant after adjustment for all other variables. If anesthesia, with an odds ratio of 2.62 in favor of no anes- full reperfusion was accomplished, the curve shifted upward thesia resulting in improved outcomes (statistically signifi- again, and functional independent outcome improved a step cant, P < 0.001). In patients who underwent thrombectomy, further. In patients who had ischemic cores > 70 mL, there there was a 50% return to functional independence in those was no statistically significant benefit or difference between who were treated without general anesthesia, compared to treatment with intravenous tPA compared to endovascu- only a 36% recovery to functional independence in those lar thrombectomy. In conclusion, ischemic core volume is who were treated with general anesthesia. There was an correlated with worse outcome, and ischemic core volume > improvement in terms of early recovery, return to normal 70 mL does not seem to favor endovascular thrombectomy function, and reduced mortality in patients who were treated over intravenous thrombolysis. with thrombectomy without general anesthesia, all statistical- ly significant. In conclusion, neurological outcomes are bet- Contact Aspiration of Intracranial Clot ter in patients who were treated without general anesthesia, vs. Stent-retriever and there were more complications associated with general Bertrand Lapergue, from Versailles, France, presented anesthesia, particularly an increased risk of pneumonia. the results of the ASTER trial, comparing the addition of contact aspiration of intracranial clot vs. stent-retriever as CT Perfusion Imaging the initial intervention for recanalization in patients with In a second presentation, Bruce Campbell presented data acute . The investigators aimed to as- from seven recent trials of endovascular therapy, which certain whether contact aspiration was more efficient as a

60 Module 5: Acute Endovascular Treatment | STROKE: The Cutting Edge Stroke: Rehabilitation and Recovery

Joel Stein, MD, Simon Baruch Professor and Chair, Department of Rehabilitation and Regenerative Medicine, Columbia University College of Physicians and Surgeons; Professor and Chair, Department of Rehabilitation Medicine, Weill Cornell Medical College; and Physiatrist-in-Chief, NewYork-Presbyterian Hospital, New York

Dr. Stein reports he receives grant/research support from Tyromotion, GMBH and Myomo, Inc.; and he has developed online CME materials for QuantiaMD.

Rehabilitation is a critical component of stroke treatment, and cognitive abilities and strategies. Both recovery and as most stroke survivors are left with significant neurolog- compensation are crucial concepts in rehabilitation and key ical impairments and other sequelae, such as spasticity and therapeutic approaches; interventions must be balanced to pain. Approximately 40% of stroke patients are left with address patient goals and efficiently deploy the available moderate functional impairment and 15%-30% with severe rehabilitation resources.2 disability.1 Stroke rehabilitation aims to reverse these impair- Over the last several decades, a significant amount of ments to the extent possible, maximize functionality through research has been conducted to further elucidate how best the use of compensatory approaches, prevent complications, to provide comprehensive stroke rehabilitation. Currently, it and manage comorbidities. This article reviews the basic is comprised of several key components, including assess- principles of rehabilitation, current practices, and evidence ment, goal setting, treatment of functional and psychosocial supporting various aspects of stroke rehabilitation. impairments, and prevention of complications. Patients are reassessed at regular intervals to evaluate progress, and treat- Role of Primary Care Physician ment plans are adjusted accordingly. Ideally, rehabilitation With millions of stroke survivors in the United States, pri- begins immediately following stroke and often becomes a mary care physicians often are faced with providing care to long-term element in the lives of these patients. Assessment these individuals and, thus, need to be able to identify com- and treatment should begin in the setting of acute hospi- mon post-stroke rehabilitation issues. Post-stroke depression talization, and depending on the needs of the individual, can occur at any time after stroke, and it is important that continued rehabilitation may transition to the appropriate primary care physicians recognize this as a treatable and inpatient or outpatient setting. reversible condition, rather than a “natural” consequence of National and international guidelines have been developed disability after stroke. Monitoring range of motion to iden- to provide resources for health care providers with the latest tify developing contracture and/or spasticity is important evidence-based practices, such as the American Heart As- so that referral can be made to a rehabilitation physician if sociation (AHA) Guidelines published in 2016.3 The AHA these occur. Lastly, addressing the stroke survivor’s mobility, grading system for level of evidence and strength of recom- ability to perform activities of daily living (ADL), and any mendation are referenced in this article where applicable.3 deterioration in functional status are critical to making time- (See Table 1.) Adherence to stroke rehabilitation guidelines is ly referrals to rehabilitation services when needed. When associated with improved patient functional outcomes.4 these issues are identified early, the primary care physician In an effort by the Joint Commission and the AHA, can prevent the progression of debilitating consequences by certification has been developed using current guidelines initiating treatment or referring to appropriate specialists for and established standards of care to identify both Primary further evaluation and management. Stroke Centers and Comprehensive Stroke Centers. The rehabilitation requirements for Primary Stroke Center certi- Rehabilitation fication include the ability to assess for rehabilitation needs Functional improvement in rehabilitation is accom- and refer for appropriate post-acute care. Comprehensive plished through a combination of neurological recovery Stroke Centers also must have a rehabilitation service led and adoption of compensatory techniques and equipment. by a physician with expertise in neurorehabilitation, and the Improved functional independence may be attained by service must include therapists, nurses, and social workers reducing impairment directly (i.e., via neural recovery using with an expertise in addressing the rehabilitation needs of cerebral plasticity to overcome neuronal loss) or through stroke patients.5,6 Complete guidelines can be found on the compensation for impairment by using remaining physical Joint Commission’s website.5

STROKE: The Cutting Edge | Module 8: Stroke Rehabilitation 77 Figure 1. Transcranial Magnetic Stimulation

This technique is used both as a tool for investigating brain physiology during stroke recovery, and also as a potential therapy to enhance motor recovery.

Photo courtesy of Dr. Joel Stein. confirm this hypothesis for an upper limb exercise interven- including pharmacotherapy to facilitate plasticity and the tion.11 Overall, there is insufficient evidence to make specif- use of non-invasive brain stimulation. (See Figure 1.) Even if ic recommendations regarding the optimal level of intensity ultimately adopted, these novel therapies are likely to serve of rehabilitation services. Determining intensity level as an adjunctive role to conventional physical and occupational well as duration of therapy is often greatly impacted by the therapy, rather than obviate the need for traditional forms mental and physical tolerance of the patient to participate of rehabilitation. in therapy, and therefore, programs must be individualized Conventional stroke rehabilitation includes repetitive task based on the multidisciplinary team’s assessment and plan training; however, effects of specific interventions may gen- of care. eralize poorly to related tasks. Emphasis should be placed on task- or context-specific training, which has been found Motor Rehabilitation effective in improving upper and lower extremity motor Many stroke patients suffer from muscle weakness and function.12 impaired motor control, with resultant functional deficits. Constraint-induced movement therapy (CIMT) is another Multiple therapeutic methods have been developed to aid type of repetitive task training, involving forced use of the stroke patients with improving motor function. These affected limb by “constraining” use of the non-paretic limb. methods typically involve repeated practice of movements A randomized trial found benefit in upper limb use after as a foundation, and vary greatly from simple task-specif- CIMT training, and it is considered a “reasonable” treat- ic training to more complex methods, using virtual reality ment for suitable stroke survivors (AHA Class IIa, Level of or advanced robotics. Additional therapeutic options have Evidence A).13 The durability of this benefit is unknown, emerged recently and are still currently being studied, however, and additional research is required to define opti-

STROKE: The Cutting Edge | Module 8: Stroke Rehabilitation 79