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CHAPTER 167: Stroke Syndromes 1119 Stroke Syndromes Steven Go INTRODUCTION AND EPIDEMIOLOGY In the United States, 795,000 people experience strokes annually (one stroke every 40 seconds and one death from stroke every 4 minutes).1 Of these events, 77% are primary strokes, whereas 23% represent recurrent strokes. 1 In addition to the human costs, the financial implications of stroke are enormous—strokes accounted for an estimated $33.9 billion of total expenditures in the United States in 2012 to 2013. 1 Despite these grim statistics, from 2004 to 2014, the age-adjusted stroke death rate fell 28.7%. 1 With the growing use of stroke units, thrombolysis, mechanical retrieval, and the ever-expanding treatment time window, there is potential for improving patient outcomes. PATHOPHYSIOLOGY AND ANATOMY Stroke is generally defined as any disease process that interrupts blood flow to the brain. Injury is related to the loss of oxygen and glucose substrates necessary for high-energy phosphate production and the pres ence of mediators of secondary cellular injury. Subsequent factors, such as edema and mass effect, may exacerbate the initial insult. An understanding of the diagnosis and treatment of stroke begins with a working knowledge of the relevant vascular supply and neuro anatomy of the brain. The arterial supply to the brain is illustrated in Figures 167-1 and 167-2. The vascular supply is divided into anterior and posterior circula tions. Clinical findings in stroke are determined by the location of the lesion(s) (Table 167-1), but the degree of collateral circulation may cause variations in the specific clinical symptoms and their severity. Stroke results from two major mechanisms: ischemia and hemor rhage. Ischemic strokes account for 87% of all strokes and are categorized by cause: thrombotic, embolic, or hypoperfusion related. Hemorrhagic strokes are subdivided into intracerebral (accounting for 10% of all strokes) and nontraumatic subarachnoid hemorrhage (accounting for 3% of all strokes) 1 (Table 167-2). The final common pathway for all of these mechanisms is altered neuronal perfusion. Neurons are exquisitely sensitive to changes in cerebral blood flow and die within minutes of complete cessation of perfusion—hence, the current treatment emphasis on rapid reperfusion strategies. PREHOSPITAL CARE The early detection of stroke must begin with the general public. In general, stroke knowledge among laypersons remains suboptimal, especially in the elderly, 2 the poorly educated, 2 and minority populations. 3 This has led to mass media initiatives to raise stroke awareness4; however, the effectiveness of these initiatives is often short lived.4-6 Three of the more commonly used prehospital tools are the Cincinnati Prehospital Stroke Scale, 7 the Los Angeles Prehospital Stroke Screen, 8 and the Melbourne Ambulance Stroke Screen9 (Table 167-3). With the increasing usage of endovascular thrombectomy for emergent large-vessel occlusion, numerous attempts have been made to derive prehospital tools to detect emergent large-vessel occlusion in order to aid in patient routing to comprehensive stroke centers. 10-16 However, at this time, no published scale has demonstrated both high speci ficity and sensitivity for detection of emergent large-vessel occlusion,17,18 and the assessment of these scales in actual prehospital use has been limited.

ssel occlusion in order to aid in patient routing to comprehensive stroke centers. 10-16 However, at this time, no published scale has demonstrated both high speci ficity and sensitivity for detection of emergent large-vessel occlusion,17,18 and the assessment of these scales in actual prehospital use has been limited. 18 Therefore, routine use of these emergent large-vessel occlusion scales in the prehospital setting awaits further validation. Time is a critical component in the care of stroke patients. EMS per sonnel should quickly ascertain the time of onset of the patient’s symptoms, giving particular attention to bystander accounts to clarify details, because stroke patients may be difficult historians. Family members and/ or witnesses to the event should be urged to come to the ED as soon as possible to provide further medical information to the treating physician. Time at the scene should be limited. EMS personnel should rapidly stabilize the patient’s condition and transport the patient to the closest facility best able to emergently and properly treat the patient’s stroke. In some cases, it may be necessary to bypass closer, but less capable, facilities in order to increase the chances of the patient receiving the best CHAPTER Broca’s area Sensory cortex Auditory area Motor cortex Contraversive eye center Wernicke’s aphasia area Visual cortex Post. parietal a. Ant. parietal a. Rolandic a. Prerolandic a. Lateral oribitofrontal a. Sup. division middle cerebral a. Temporopolar a. Middle cerebral a. Inf. division middle cerebral a. Angular a. Post. temporal a. Visual radiation Ant. temporal a. FIGURE 167-1. Cerebral hemisphere, lateral aspect. Note the branches and distribution of the middle cerebral artery and the principal regions of cerebral localization. The middle cerebral artery bifurcates into a superior and inferior division. a. = artery; ant. = anterior; inf. = inferior; post. = posterior; sup. = superior. [Modified with permission from Fauci AS, Braunwald E, Kasper DL, et al: Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill Professional; 2008.] Tintinalli_Sec14_p1101-1186.indd 1119 8/2/19 12:08 PM

erior division. a. = artery; ant. = anterior; inf. = inferior; post. = posterior; sup. = superior. [Modified with permission from Fauci AS, Braunwald E, Kasper DL, et al: Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill Professional; 2008.] Tintinalli_Sec14_p1101-1186.indd 1119 8/2/19 12:08 PM 1120 SECTION 14: Neurology TABLE 167-1 Anterior and Posterior Circulation of the Brain Circulation Major Arteries Major Regions of Brain Supplied Anterior (internal carotid system) Ophthalmic Optic nerve and retina Anterior cerebral Frontal pole Anteromedial cerebral cortex Anterior corpus callosum Middle cerebral Frontoparietal lobe Anterotemporal lobe Posterior (vertebral system) Vertebral Brainstem Posteroinferior cerebellar Cerebellum Basilar Thalamus Posterior cerebral Auditory/vestibular structures Medial temporal lobe Visual occipital cortex Medial rolandic a. Sensory cortex Post. parietal a. Splenial a. Lateral posterior choroidal a. Post. thalamic a. Parietooccipital a. Visual cortex Striate area along calcarine sulcus Calcarine a. Post. temporal a. Medial posterior choroidal a. Hippocampal a. Ant. temporal a. Post. cerebral a. Penetrating thalamosubthalamic paramedian a. Post. communicating a. Medial orbitofrontal a. Ant. cerebral a. Frontopolar a. Callosomarginal a. Medial prerolandic a. Secondary motor area Pericallosal a. Motor cortex FIGURE 167-2. Cerebral hemisphere, medial aspect. Note the branches and distribution of the anterior cerebral artery, posterior cerebral artery, and the principal regions of cerebral localization. a. = artery; ant. = anterior; post. = posterior. [Reproduced with permission from Fauci AS, Braunwald E, Kasper DL, et al: Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill Professional; 2008.] possible care, especially if a patient may be a candidate for endovascular therapy. However, the decision-making process for determining the ideal destination remains complex. For example, one must weigh the known harms from delays in administration of IV thrombolytics 20 if a patient bypasses a primary stroke center versus the potential harm from delays in thrombectomy 21 that can be caused by the “drip and ship to a comprehensive stroke center” approach in patients who turn out to have an emergent large-vessel occlusion. At the time of this writing, the 2018 American Heart Association (AHA)/American Stroke Association (ASA) acute ischemic stroke recommendations 19 are being modified to better address this difficult issue. 22 Therefore, the development of local EMS stroke routing policies should involve EMS directors, ED medi cal directors, stroke center directors, and healthcare policy officials to determine how best to utilize the specific resources available in that particular community. CLINICAL FEATURES The diagnosis of stroke in the ED rests on the bedrock of a focused, accurate history and physical examination. 23 The clinical presentation of stroke can range from the obvious (facial droop, arm drift, abnormal speech) to the subtle (generalized weakness, lightheadedness, vague sensory changes, altered mental status). Women account for slightly more than half of strokes in the United States, 24 and very modest gender differences exist in terms of presenting signs and symptoms.25-27 In general, women tend to report more severe, but diffuse, nontraditional symp toms compared to the more traditional symptoms typically reported by men, 26 but evidence of these distinctions is limited ( Table 167-4).  HISTORY The timing of symptom onset, the presence of associated symptoms, and the medical history may point toward a particular mechanism of stroke.

t diffuse, nontraditional symp toms compared to the more traditional symptoms typically reported by men, 26 but evidence of these distinctions is limited ( Table 167-4).  HISTORY The timing of symptom onset, the presence of associated symptoms, and the medical history may point toward a particular mechanism of stroke. For example, sudden onset of symptoms suggests an embolic or hemorrhagic stroke, whereas a stuttering or waxing and waning deficit suggests a thrombotic or hypoperfusion-related stroke. A history of Valsalva maneuver immediately preceding a thunderclap headache or sudden onset of symptoms suggests a ruptured cerebral aneurysm, whereas a recent history of neck trauma or manipulation suggests cervical artery dissection. Risk factors for vessel thrombus include hypertension, diabetes mellitus, and coronary atherosclerotic disease. In contrast, atrial fibrillation, valvular replacement, or recent myocardial infarction suggests embolism. Transient neurologic deficits occurring in the same vascular distribution suggest underlying vascular disease consistent with a thrombotic stroke, whereas transient deficits involving different vas cular distributions suggest embolism. Although adjunctive history can be helpful in determining the type of stroke, exhaustive or unduly prolonged attempts to elicit nonessential history should not delay therapy. Accurately determine the time of symptom onset. Time of onset is frequently misreported as the time a patient was discovered with symptoms or the time of awakening (if symptoms were noted upon awakening). Tintinalli_Sec14_p1101-1186.indd 1120 8/2/19 12:08 PM

mpts to elicit nonessential history should not delay therapy. Accurately determine the time of symptom onset. Time of onset is frequently misreported as the time a patient was discovered with symptoms or the time of awakening (if symptoms were noted upon awakening). Tintinalli_Sec14_p1101-1186.indd 1120 8/2/19 12:08 PM CHAPTER 167: Stroke Syndromes 1121 TABLE 167-2 Stroke Classification Stroke Type Mechanism Major Causes Clinical Notes Ischemic Thrombotic Narrowing of a damaged vascular lumen by an in situ process—usually clot formation Atherosclerosis Vasculitis Arterial dissection Polycythemia Hypercoagulable state Infection (human immunodeficiency virus infection, syphilis, trichinosis, tuberculosis, aspergillosis) Symptoms often have gradual onset and may wax and wane. Common cause of transient ischemic attack. Embolic Obstruction of a normal vascular lumen by intravascular material from a remote source Valvular vegetations Mural thrombi Paradoxical emboli Cardiac tumors (myxomas) Arterial-arterial emboli from proximal source Fat emboli Particulate emboli (IV drug use) Septic emboli Typically sudden in onset. Account for 20% of ischemic strokes. Hypoperfusion Low–blood flow state leading to hypoperfusion of the brain Cardiac failure resulting in systemic hypotension Diffuse injury pattern in watershed regions. Symptoms may wax and wane with hemodynamic factors. Hemorrhagic Intracerebral Intraparenchymal hemorrhage from previously weakened arterioles Hypertension Amyloidosis Iatrogenic anticoagulation Vascular malformations Cocaine use Intracranial pressure rise causes local neuronal damage. Secondary vasoconstriction mediated by blood breakdown products or neuronal mechanisms (diaschisis) can cause remote perfusion changes. Risks include advanced age, history of stroke, and tobacco or alcohol use. More common in those of Asian or African descent. Nontraumatic subarachnoid Hemorrhage into subarachnoid space Berry aneurysm rupture Vascular malformation rupture May be preceded by a sentinel headache (“warning leak”). TABLE 167-3 Prehospital Stroke Scales Cincinnati Prehospital Stroke Scale (If any of the three items are abnormal, sensitivity = 66%, specificity = 87% for acute stroke.) 1. Facial droop (abnormal: one side of face does not move as well as other side) 2. Arm drift (abnormal: one arm does not move or one arm drifts down compared with the other) 3. Speech (abnormal: slurred, inappropriate words or mute) Los Angeles Prehospital Stroke Screen (If answers to all items 1–6 are “Yes” or “Unknown,” sensitivity = 91% [95% confidence interval (CI) 76%–98%], specificity = 97% [95% CI 93%–99%] for acute stroke.) 1. Age >45 y 2. No history of seizure disorder 3. New onset of neurologic symptoms in last 24 h 4. Patient ambulatory at baseline (prior to event) 5. Blood glucose level of 60–400 milligrams/dL 6. Obvious asymmetry in any of the following examinations: facial smile/grimace, grip, arm strength Melbourne Ambulance Stroke Screen (If answers to all items 1–4 are “Yes” PLUS at least one of 5–8 is present, sensitivity = 90% [95% CI 81%–96%], specificity = 74% [95% CI 53%–88%] for acute stroke.) 1. Age >45 y 2. No history of seizure/epilepsy 3. Not wheelchair-bound/bedridden at baseline 4. Blood glucose 50–400 milligrams/dL 5. Unilateral facial droop 6. Unilateral hand grip weakness 7. Unilateral arm drift 8. Abnormal speech The time of onset is defined as the last known time when the patient’s condition was at their baseline (i.e., “last known well” time).

. Not wheelchair-bound/bedridden at baseline 4. Blood glucose 50–400 milligrams/dL 5. Unilateral facial droop 6. Unilateral hand grip weakness 7. Unilateral arm drift 8. Abnormal speech The time of onset is defined as the last known time when the patient’s condition was at their baseline (i.e., “last known well” time). Quickly exclude as many stroke mimics as possible (Table 167-5).28-30 After likely stroke mimics are excluded, if acute stroke is still the most likely diagnosis and if the symptom onset is within the recommended time limits for thrombolytic therapy, elicit information pertaining to inclusion and exclusion criteria for the administration of thrombolytics in acute ischemic stroke. 19,31  PHYSICAL EXAMINATION Assessment of airway, breathing, and circulation is the top priority. Next, the goals of examination are to confirm the diagnosis of stroke, exclude stroke mimics, and identify comorbidities. Fever should prompt an investigation for potential infection. CNS infections (meningitis, encephalitis) may mimic a stroke, or an infection such as aspiration pneumonia or a urinary tract infection may be a complication of the stroke. Evaluate for Tintinalli_Sec14_p1101-1186.indd 1121 8/2/19 12:08 PM

ify comorbidities. Fever should prompt an investigation for potential infection. CNS infections (meningitis, encephalitis) may mimic a stroke, or an infection such as aspiration pneumonia or a urinary tract infection may be a complication of the stroke. Evaluate for Tintinalli_Sec14_p1101-1186.indd 1121 8/2/19 12:08 PM 1122 SECTION 14: Neurology TABLE 167-4 Selected Stroke Symptoms Traditional symptoms Sudden numbness or weakness of face, arm, or leg—especially unilateral * Sudden aphasia Sudden dysarthria* Sudden memory deficit or spatial orientation or perception difficulties Sudden visual deficit or diplopia* Sudden dizziness, gait disturbance, or ataxia* Sudden severe headache with no known cause Nontraditional symptoms Impaired consciousness or syncope† Generalized weakness† Altered mental status† Dysphagia† Shortness of breath Sudden pain in the face, chest, arms, or legs Seizure Falls or accidents Sudden hiccups Sudden nausea Sudden fatigue Sudden palpitations *More common in men. †More common in women. TABLE 167-5 Stroke Mimics Disorder Distinguishing Clinical Features Seizures/postictal paralysis (Todd’s paralysis) Transient paralysis following a seizure, which typically disappears quickly; can be confused with transient ischemic attack. Seizures can be secondary to a cerebrovascular accident. Syncope No persistent or associated neurologic symptoms. Meningitis/ encephalitis Fever, immunocompromised state may be present, meningismus, detectable on lumbar puncture. Complicated migraine History of similar episodes, preceding aura, headache. Brain neoplasm or abscess Focal neurologic findings, signs of infection, detectable by imaging. Epidural/subdural hematoma History of trauma, alcoholism, anticoagulant use, bleeding disorder; detectable by imaging. Subarachnoid hemorrhage Sudden onset of severe headache. * Hypoglycemia Can be detected by bedside glucose measurement, history of diabetes mellitus. Hyponatremia History of diuretic use, neoplasm, excessive free water intake. Hypertensive encephalopathy Gradual onset; global cerebral dysfunction, headache, delirium, hypertension, cerebral edema. Hyperosmotic coma Extremely high glucose levels, history of diabetes mellitus. Wernicke’s encephalopathy History of alcoholism or malnutrition; triad of ataxia, ophthal moplegia, and confusion. Labyrinthitis Predominantly vestibular symptoms; patient should have no other focal findings; can be confused with cerebellar stroke. Drug toxicity (lithium, phenytoin, carbamazepine) Can be detected by particular toxidromes and elevated blood levels. Phenytoin and carbamazepine toxicity may present with ataxia, vertigo, nausea, and abnormal reflexes. Bell’s palsy Neurologic deficit confined to isolated peripheral seventh nerve palsy; often associated with younger age. Ménière’s disease History of recurrent episodes dominated by vertigo symptoms, tinnitus, deafness. Demyelinating disease (multiple sclerosis) Gradual onset. Patient may have a history of multiple episodes of neurologic findings in multifocal anatomic distributions. Conversion disorder No cranial nerve findings, nonanatomic distribution of findings (e.g., midline sensory loss), inconsistent history or examination findings. *Although subarachnoid hemorrhage is a type of stroke, it has special considerations in terms of diagnosis and management. See Chapter 166, “Spontaneous Subarachnoid and Intracerebral Hemorrhage.” meningismus, signs of emboli (Janeway lesions and Osler nodes), and bleeding diatheses (ecchymoses or petechiae). A funduscopic examination may identify signs of papilledema (suggesting a mass lesion, cerebral vein thrombosis, or hypertensive crisis) or preretinal hemorrhage (consistent with subarachnoid hemorrhage).

” meningismus, signs of emboli (Janeway lesions and Osler nodes), and bleeding diatheses (ecchymoses or petechiae). A funduscopic examination may identify signs of papilledema (suggesting a mass lesion, cerebral vein thrombosis, or hypertensive crisis) or preretinal hemorrhage (consistent with subarachnoid hemorrhage). Assess for findings suggestive of possible cardiac or vascular disease, such as rales, an S 3 gallop, or carotid bruit. Use a validated stroke severity scale to assess the neurologic status of the patient. The National Institutes of Health Stroke Scale (NIHSS)32 is the most widely used scale for documenting the severity of a stroke . The NIHSS is an 11-category (15-item) neurologic evaluation (score range of 0 to 42) that is rapid (5 to 10 minutes), has a high interrater reliability, 33,34 and provides a baseline score that is useful in predicting patient outcomes35,36 (Table 167-6). An Adobe Acrobat (pdf) file of the NIHSS, as well as detailed instructions for its use, are readily available for download from the National Institute of Neurological Disorders and Stroke (NINDS) website (https:// www.ninds.nih.gov/sites/default/files/NIH_Stroke_Scale.pdf). In addition, NIHSS calculators are available on the internet 37 and for use with mobile devices.38,39 An important caveat is that the NIHSS is weighted toward the detection of anterior circulation strokes as opposed to posterior circulation strokes.40,41 This is because common symptoms of posterior strokes (cranial nerve deficits and ataxia) receive fewer points, and ataxia is often scored as absent by raters if weakness is present. In addition, the NIHSS has a bias toward detection of left hemisphere strokes. 42 A modified NIHSS, which omits the redundant and least reliable items, produces clinical results similar to those for the full NIHSS 43 and is easier to use (score range of 0 to 31); however, this scale has not been as widely validated as the full NIHSS and is not in common use. Important scoring rules for proper use of the NIHSS 44 are as follows: Score what you see, not what you think; score the first response, not the best response, except item 9 (best language); and do not coach. (See Video: NIH Stroke Scale.)  ISCHEMIC STROKE SYNDROMES ANTERIOR CEREBRAL ARTERY INFARCTION Occlusion of the anterior cerebral artery is uncommon (0.5% to 3% of all strokes 45), but when unilateral occlusion occurs, it can cause contralateral sensory and motor symptoms in the lower extremity, with sparing of the hands and face. In addition, a left-sided lesion is typically associated with akinetic mutism and transcortical motor aphasia (a nonfluent aphasia with greatly reduced spontaneous speech, but with retained auditory comprehension and repetition ability), whereas right-sided infarction can result in confusion and motor hemineglect. Bilateral occlusion can cause a combination of the above symptoms but was particularly associated with mutism, incontinence, and poor outcome in one small series. MIDDLE CEREBRAL ARTERY INFARCTION The middle cerebral artery is the vessel most commonly involved in stroke, and clinical findings can be quite variable, depending on exactly where the lesion is located and which brain hemisphere is dominant. (In right-handed patients and in up to 80% of left-handed patients, the left hemisphere is dominant.) A middle cerebral artery stroke typically presents with hemiparesis, facial plegia, and sensory loss contralateral to the affected cortex. These deficits variably affect the face and upper extremity more than the lower extremity. If the dominant hemisphere is involved, aphasia (receptive, expressive, or both) is often present.

cerebral artery stroke typically presents with hemiparesis, facial plegia, and sensory loss contralateral to the affected cortex. These deficits variably affect the face and upper extremity more than the lower extremity. If the dominant hemisphere is involved, aphasia (receptive, expressive, or both) is often present. If the nondominant hemisphere is involved, inattention, neglect, extinction on double-simultaneous stimulation, dysarthria without aphasia, and constructional apraxia (difficulty in drawing complex two-dimensional Tintinalli_Sec14_p1101-1186.indd 1122 8/2/19 12:08 PM

cerebral artery stroke typically presents with hemiparesis, facial plegia, and sensory loss contralateral to the affected cortex. These deficits variably affect the face and upper extremity more than the lower extremity. If the dominant hemisphere is involved, aphasia (receptive, expressive, or both) is often present. If the nondominant hemisphere is involved, inattention, neglect, extinction on double-simultaneous stimulation, dysarthria without aphasia, and constructional apraxia (difficulty in drawing complex two-dimensional Tintinalli_Sec14_p1101-1186.indd 1122 8/2/19 12:08 PM CHAPTER 167: Stroke Syndromes 1123 TABLE 167-6 National Institutes of Health Stroke Scale (NIHSS) Instructions Scale Definition 1a. Level of consciousness (LOC)* The investigator must choose a response if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, or orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement (other than reflexive posturing) in response to noxious stimulation. 0 = Alert; keenly responsive. 1 = Not alert, but arousable by minor stimulation to obey, answer, or respond. 2 = Not alert; requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). 3 = Responds only with reflex motor or autonomic effects or is totally unre sponsive, flaccid, and areflexic. 1b. LOC questions The patient is asked the month and his or her age. The answer must be correct—there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions are given a score of 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not secondary to aphasia are given a score of 1. It is important that only the initial answer be graded and that the examiner not “help” the patient with verbal or nonverbal cues. 0 = Answers both questions correctly. 1 = Answers one question correctly. 2 = Answers neither question correctly. 1c. LOC commands The patient is asked to open and close the eyes and then to grip and release the nonparetic hand. Substitute another one-step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime) and the result scored (i.e., follows no, one, or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 0 = Performs both tasks correctly. 1 = Performs one task correctly. 2 = Performs neither task correctly. 2. Best gaze Only horizontal eye movements are tested. Voluntary or reflexive (oculocephalic) eye movements are scored, but caloric testing is not done. If the patient has a conjugate deviation of the eyes that can be overcome by voluntary or reflexive activity, the score is 1. If a patient has an isolated peripheral nerve paresis (cranial nerve III, IV, or VI), the score is 1. Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, preexisting blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis not overcome by the oculoce phalic maneuver. 3. Visual Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as normal.

l gaze paresis not overcome by the oculoce phalic maneuver. 3. Visual Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia, is found. If the patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a score of 1, and the results are used to respond to item 11. 0 = No vision loss. 1 = Partial hemianopia. 2 = Complete hemianopia. 3 = Bilateral hemianopia (blind including cortical blindness). 4. Facial palsy* Ask—or use pantomime to encourage—the patient to show teeth or raise eyebrows and close eyes. Score symmetry of grimace in response to noxious stimuli in the poorly responsive or noncomprehending patient. If facial trauma/bandages, orotracheal tube, tape, or other physical barriers obscure the face, these should be removed to the extent possible. 0 = Normal symmetric movements. 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). 3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face). 5. Motor arm The limb is placed in the appropriate position: extend the arms (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm falls before 10 s. (Count out loud and use fingers to show the patient the count.) The aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the nonparetic arm. Only in the case of amputation or joint fusion at the shoulder, the examiner should record the score as untestable (UN) and clearly write the explanation for this choice. 5a. Left arm 5b. Right arm 0 = No drift; limb holds 90 (or 45) degrees for full 10 s. 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 s; does not hit bed or other support. 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some effort against gravity. 3 = No effort against gravity; limb falls. 4 = No movement. 6. Motor leg The limb is placed in the appropriate position: hold the leg at 30 degrees (the patient is always tested supine). Drift is scored if the leg falls before 5 s. (Count out loud and use fingers to show the patient the count.) The aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the nonparetic leg. Only in the case of amputation or joint fusion at the hip, the examiner should record the score as untestable (UN) and clearly write the explanation for this choice. 6a. Left leg 6b. Right leg 0 = No drift; leg holds 30-degree position for full 5 s. 1 = Drift; leg falls by the end of the 5-s period but does not hit bed. 2 = Some effort against gravity; leg falls to bed by 5 s, but has some effort against gravity. 3 = No effort against gravity; leg falls to bed immediately. 4 = No movement. (Continued) Tintinalli_Sec14_p1101-1186.indd 1123 8/2/19 12:08 PM

full 5 s. 1 = Drift; leg falls by the end of the 5-s period but does not hit bed. 2 = Some effort against gravity; leg falls to bed by 5 s, but has some effort against gravity. 3 = No effort against gravity; leg falls to bed immediately. 4 = No movement. (Continued) Tintinalli_Sec14_p1101-1186.indd 1123 8/2/19 12:08 PM 1124 SECTION 14: Neurology TABLE 167-6 National Institutes of Health Stroke Scale (NIHSS) Instructions Scale Definition 7. Limb ataxia* This item is aimed at finding evidence of a unilateral cerebellar lesion. Test with the patient’s eyes open. In case of visual defect, ensure that testing is done in the intact visual field. The finger-nose-finger and heel-shin tests are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN) and clearly write the explanation for this choice. In case of blindness, test by having the patient touch the nose from an extended arm position. 0 = Absent. 1 = Present in one limb. 2 = Present in two limbs. 8. Sensory† Sensation or grimace to pinprick when tested, or withdrawal from a noxious stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is scored as abnormal, and the examiner should test as many body areas (arms [not hands], legs, trunk, face) as needed to check accurately for hemisensory loss. A score of 2, “severe or total sensory loss,” should be given only when a severe or total loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will therefore probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a score = 3) are automatically given a 2 on this item. 0 = Normal; no sensory loss. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on affected side, or there is loss of superficial pain with pinprick, but patient is aware of being touched. 2 = Severe to total sensory loss; patient is not aware of being touched on face, arm, and leg.* 9. Best language A great deal of information about comprehension is obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the test picture, to name the items on the test naming sheet, and to read from the test list of sentences. Comprehension is judged from responses here as well as responses to all of the commands in the preceding general neurologic examination. If vision loss interferes with the tests, ask the patient to identify objects placed in the hand, repeat, and produce speech. The intubated patient should be asked to write. The patient in a coma (item 1a score = 3) automatically scores 3 on this item. The examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the patient is mute and follows no one-step commands. 0 = No aphasia; normal. 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. However, reduction of speech and/or comprehension makes conversation about provided materials difficult or impossible. For example, in conversation about provided materials, examiner can identify picture or naming card content from patient’s response. 2 = Severe aphasia; all communication is through fragmentary expression; great need for inference, questioning, and guessing by listener. Range of information that can be exchanged is limited; listener carries burden of communication.

erials, examiner can identify picture or naming card content from patient’s response. 2 = Severe aphasia; all communication is through fragmentary expression; great need for inference, questioning, and guessing by listener. Range of information that can be exchanged is limited; listener carries burden of communication. Examiner cannot identify materials provided from patient’s response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria* If the patient is thought to be normal, an adequate sample of speech must be obtained by asking the patient to read or repeat words from the test list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the patient is intubated or has other physical barriers to producing speech, the examiner should record the score as untestable (UN) and clearly write an explanation for this choice. Do not tell the patient why he or she is being tested. 0 = Normal. 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. 2 = Severe dysarthria; patient’s speech is so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/ anarthric. 11. Extinction and inattention Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe vision loss preventing visual double simultaneous stimulation and the responses to cutaneous stimuli are normal, the score is 0. If the patient has aphasia but does appear to attend to both sides, the score is 0. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Because the abnormality is scored only if present, the item is never scored as untestable. 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction in more than one modality; patient does not recognize own hand or orients to only one side of space. *Items not included in the modified NIHSS. 43 †Scale for item 8 is compressed to two elements (0 = normal; 1 = abnormal) for modified NIHSS. 43 Source: National Institute of Neurological Disorders and Stroke (NINDS) website (https://www.ninds.nih.gov/sites/default/files/NIH_Stroke_Scale.pdf). Accessed September 11, 2018. or three-dimensional figures) may occur. A homonymous hemianopsia and gaze preference toward the side of the infarct may also be seen, regardless of the side of the infarction. POSTERIOR CEREBRAL ARTERY INFARCTION (DISTAL POSTERIOR CIRCULATION) The classic symptoms and signs of posterior circulation strokes include ataxia, nystagmus, altered mental status, and vertigo, but presentation can sometimes be rather subtle. 47 Crossed neurologic deficits (e.g., ipsilateral cranial nerve deficits with contralateral motor weakness) may indicate a brainstem lesion. According to an analysis of a large stroke registry, 48 symptoms of posterior cerebral artery involvement include unilateral limb weakness, dizziness, blurry vision, headache, and dysarthria. Common presenting signs include visual field loss, unilateral limb weakness, gait ataxia, unilateral limb ataxia, cranial nerve VII signs, lethargy, and sensory deficits.48 Visual field loss, classically described as contralateral homonymous hemianopsia and unilateral cortical blind ness, is thought to be specific for distal posterior circulation stroke because the visual centers of the brain are supplied by the posterior cerebral artery.

nerve VII signs, lethargy, and sensory deficits.48 Visual field loss, classically described as contralateral homonymous hemianopsia and unilateral cortical blind ness, is thought to be specific for distal posterior circulation stroke because the visual centers of the brain are supplied by the posterior cerebral artery. Light-touch and pinprick sensation deficits, loss of ability to read (alexia) without agraphia, inability to name colors, recent memory loss, unilateral third nerve palsy, and hemiballismus have also been reported. Motor dysfunction, although common, is typically minimal, which can keep some patients from realizing they have had a stroke. BASILAR ARTERY OCCLUSION (MIDDLE POSTERIOR CIRCULATION) Occlusion of the basilar artery most commonly presents with symp toms of unilateral limb weakness, dizziness, dysarthria, diplopia, and headache. 48 The most common presenting signs are unilateral limb (Continued) Tintinalli_Sec14_p1101-1186.indd 1124 8/2/19 12:08 PM

ILAR ARTERY OCCLUSION (MIDDLE POSTERIOR CIRCULATION) Occlusion of the basilar artery most commonly presents with symp toms of unilateral limb weakness, dizziness, dysarthria, diplopia, and headache. 48 The most common presenting signs are unilateral limb (Continued) Tintinalli_Sec14_p1101-1186.indd 1124 8/2/19 12:08 PM CHAPTER 167: Stroke Syndromes 1125 weakness, cranial nerve VII signs, dysarthria, Babinski sign, and oculo motor signs.48 Dysphagia, nausea or vomiting, dizziness, and Horner’s syndrome are positively correlated with basilar artery occlusion.48 Basilar artery occlusion can also rarely cause locked-in syndrome, which occurs with bilateral pyramidal tract lesions in the ventral pons and is characterized by complete muscle paralysis except for upward gaze and blinking. Basilar artery occlusions have a high risk of death and poor outcomes. 49,50 VERTEBROBASILAR INFARCTION (PROXIMAL POSTERIOR CIRCULATION) Patients with vertebrobasilar infarction most commonly present with symptoms of dizziness, nausea or vomiting, headache, dysphagia, unilateral limb weakness, and unilateral cranial nerve V symptoms. Common presenting signs include unilateral limb ataxia, nystagmus, gait ataxia, cranial nerve V signs, limb sensory deficit, and Horner’s syndrome. 48 For further discussion of vertigo, see Chapter 170, “Vertigo. ” CEREBELLAR INFARCTION Patients with cerebellar infarction can present with very nonspecific symptoms and can present with dizziness (with or without vertigo), nausea and vomiting, gait instability, headache, limb ataxia, dysarthria, dysmetria, nystagmus, hearing loss, and intractable hiccups. 51 Mental status may vary from alert to comatose. Because up to 25% of noncon trasted head CTs can be normal in cerebellar infarction, 52 if the initial noncontrasted head CT is unremarkable, obtain an emergent diffusionweighted MRI when this diagnosis is suspected . A CT angiogram or magnetic resonance angiogram is useful to characterize any vascular lesion once the diagnosis is made. The clinical presentation and course of cerebellar infarction can be frustratingly difficult to predict, but the clinician must remain vigilant to the possibility of rapid deterioration secondary to increased brainstem pressure caused by cerebellar edema. Therefore, extremely close serial examinations (especially looking for gaze palsy and altered mental status) and prompt neurologic and neurosurgical bedside consultations are needed. Obtain early neurosurgical consultation for patients with cerebellar infarction. Cerebellar edema can lead to rapid deterioration with herniation, and consultation is required to determine the need for emergency posterior fossa decompression in these patients. Acute obstructing hydrocephalus or symp tomatic mass effect requires rapid treatment of elevated intracranial pressure with hyperosmolar therapy (mannitol or hypertonic saline) and emergent surgical decompression. LACUNAR INFARCTION Lacunar infarcts are pure motor or sensory deficits caused by infarction of small penetrating arteries and are commonly associated with chronic hypertension and increasing age. The presentation is variable based on the location and size of the lesions. The prognosis is generally consid ered more favorable than for other stroke syndromes. CAROTID AND VERTEBRAL ARTERY DISSECTION Carotid or vertebral artery dissection (collectively referred to as “cervical artery dissection”) is an uncommon entity (2.6 to 2.9 per 100,000 annually in the general population) that is a major cause of stroke (up to 20% prevalence) in young adults and the middle-aged. 53 A history of neck trauma in the days to weeks prior to presentation is a prominent risk factor. The trauma is usually minor 54 (e.g., manipulative therapy of the neck 55-57 or sport-related trauma 58).

the general population) that is a major cause of stroke (up to 20% prevalence) in young adults and the middle-aged. 53 A history of neck trauma in the days to weeks prior to presentation is a prominent risk factor. The trauma is usually minor 54 (e.g., manipulative therapy of the neck 55-57 or sport-related trauma 58). Other associated conditions include hypertension, 59 large-vessel arteriopathies, 60 history of migraine,61 and heritable connective tissue disease.62 The typical first symptom of patients with carotid or vertebral artery dissection is unilateral headache (68%), neck pain (39%), or face pain (10%),63 which can precede other symptoms by hours to days (median, 4 days).64 New-onset headache or neck pain of unclear etiology is such an important symptom that imaging of the neck vessels is recommended by some as part of initial evaluation. 65 Symptoms may be transient or persistent. The median time between an initial presentation of neck pain and the development of other neurologic symptoms is 14 days, but if headache is the first symptom, other neurologic symptoms follow within a median time of 15 hours.  CAROTID ARTERY DISSECTION The headache is most commonly in the frontotemporal region and, due to its variable quality and severity, may mimic subarachnoid hemor rhage (i.e., “thunderclap” headache), temporal arteritis, or preexisting migraine. A partial Horner’s syndrome (miosis and ptosis) has traditionally been linked to carotid artery dissection, but in reality, it occurs in only about 25% of patients and is a sign accompanying other disorders besides stroke. 66 Associated cranial nerve palsies have been reported in 12% of carotid artery dissections. 67 Carotid dissection can progress to cause cerebral ischemia or, rarely, retinal infarction.  VERTEBRAL ARTERY DISSECTION Vertebral artery dissection commonly presents with dizziness/vertigo (58%), headache (51% to 65%), and neck pain (46% to 66%). 63,68 Both headache and neck pain can be unilateral or bilateral. 63 The headache is typically occipital, but can rarely present with pain on an entire side of the head or in the frontal region. 69 Other symptoms and signs may include unilateral facial paresthesia, dizziness, vertigo, nausea/emesis, diplopia and other visual disturbances, ataxia, limb weakness, numb ness, dysarthria, and hearing loss. Cervical radiculopathy (typically a peripheral motor deficit at the C5 level) is a rare presentation (1%) and can also involve multiple levels and sensory findings. 70 Untreated vertebral artery dissection may result in infarction in regions of the brain supplied by the posterior circulation. CT/CT angiography and MRI/magnetic resonance angiography are the diagnostic modalities of choice for suspected carotid, vertebral, or basi lar artery dissection and have similar test performance characteristics. The choice of study is usually determined by immediate availability and patient stability. The sensitivity of color duplex US for the detection of cervical artery dissection is comparatively low (approximately 92%) and may miss important vascular lesions. 72,73  TREATMENT OF CAROTID AND VERTEBRAL ARTERY DISSECTION Cervical artery dissection can cause ischemic stroke via a thromboem bolic process, or a decreased blood flow secondary to the vascular lesion itself, or from a mixed mechanism. 74 If a patient with cervical artery dissection presents with the symptoms of acute ischemic stroke, treat them similarly to any other stroke patient. Although no large-scale randomized trials regarding systemic thrombolysis in cervical artery dissection have yet been published, a meta-analysis of 10 observational studies (n = 846) concluded that thrombolysis was equally efficacious in stroke from cervical artery dissection as in stroke from other causes.

ke patient. Although no large-scale randomized trials regarding systemic thrombolysis in cervical artery dissection have yet been published, a meta-analysis of 10 observational studies (n = 846) concluded that thrombolysis was equally efficacious in stroke from cervical artery dissection as in stroke from other causes. Furthermore, the study determined that thrombolysis in cervical artery dissection caused no increased incidence of harm when compared to its use in stroke from other causes. 75 Therefore, consider the administra tion of IV thrombolytic therapy in all eligible patients with stroke from cervical artery dissection . The efficacy of endovascular therapy for cervical artery dissection–related stroke is unclear because the benefits of endovascular therapy have been shown only for the anterior circulation (see later section “Endovascular Therapy”), and there is a paucity of published data to direct care in these patients. For example, after excluding many studies for low quality, a 2017 meta-analysis studying this issue was able to include only 16 retrospective case reports or small case series, which had “an overall high risk of bias. ” 76 Although the outcome trend in the included data was favorable for endovascular therapy, the lack of high-quality randomized data makes drawing definitive conclusions difficult. Therefore, if a patient with cervical artery dissection–related stroke qualifies for consideration of endovascular therapy, discuss with a stroke neurointerventionalist at a comprehensive stroke center to help determine the best course of action. In cervical artery dissection patients who are not candidates for thrombolysis or endovascular therapy, the two major medical choices Tintinalli_Sec14_p1101-1186.indd 1125 8/2/19 12:08 PM

therapy, discuss with a stroke neurointerventionalist at a comprehensive stroke center to help determine the best course of action. In cervical artery dissection patients who are not candidates for thrombolysis or endovascular therapy, the two major medical choices Tintinalli_Sec14_p1101-1186.indd 1125 8/2/19 12:08 PM 1126 SECTION 14: Neurology for treatment are anticoagulation or antiplatelet therapy. Historically, carotid and vertebral artery dissection has been traditionally treated with IV heparin followed by warfarin (to maintain an INR of 2.0 to 3.0). This treatment has persisted despite the absence of high-quality randomized controlled trials comparing anticoagulation with other potentially more effective treatment modalities. 77 In 2012 and 2015, meta-analyses of nonrandomized trials found no difference in patient outcomes between antiplatelet therapy and anticoagulation. 78,79 In 2015, the Cervical Artery Dissection in Stroke Study was published. 80 The Cervical Artery Dissection in Stroke Study was the first randomized trial comparing antiplatelet agents (aspirin, dipyridamole, or clopidogrel alone or in combination [determined by the individual clinician]) to anticoagulation (heparin [either unfractionated heparin or therapeutic low-molecular-weight heparin] followed by warfarin) in acute cervical artery dissection. The Cervical Artery Dissection in Stroke Study found no difference in patient outcomes between the two treatment modalities. An important caveat is that based on previous estimates of recurrent stroke prevalence, the planned study size was small (n =250). However, during the trial, it was discovered that the prevalence of recurrent stroke in both the control and study groups was far lower than expected and there were no deaths. Based on these data, the authors determined the study lacked the power to detect a difference between the two treatment modalities and that the revised sample size to do so (n = 10,000) made further investigation unfeasible. 81 Therefore, pend ing the availability of new randomized controlled trial data, administer either anticoagulant or antiplatelet therapy in the ED if the patient is not a candidate for IV thrombolysis . Select the specific therapy in conjunction with appropriate specialist consultation.  HEMORRHAGIC STROKE SYNDROMES Spontaneous intracerebral hemorrhage may be clinically indistinguishable from ischemic infarction, but the two conditions are distinct clinical entities in terms of management, with higher levels of morbidity and mortality for hemorrhage than for ischemic infarction. 82,83 Therefore, perform CT to differentiate between the two. Headache, nausea, and vomiting often precede the neurologic deficit, and the patient’s condition may quickly deteriorate (see Chapter 166, “Spontaneous Subarachnoid and Intracerebral Hemorrhage”). Cerebellar hemorrhage may be clinically indistinguishable from cerebellar infarction. The same clinical presentation and management considerations detailed earlier in this chapter apply (see earlier section “Cerebellar Infarction”). Subarachnoid hemorrhage is typically characterized by a severe occipital or nuchal headache. Patient history includes the recent sudden onset of a maximal-intensity headache in many cases. Careful history taking may reveal activities associated with a Valsalva maneuver, such as defecation, sexual activity, weight lifting, or coughing, at stroke onset. For further information, see Chapter 166, “Spontaneous Subarachnoid and Intracerebral Hemorrhage. ”  STROKE DIAGNOSIS Mimics (Table 167-5)28-30 can often be distinguished from stroke by careful history taking and physical examination, bedside tests, observation, and appropriate imaging.

, or coughing, at stroke onset. For further information, see Chapter 166, “Spontaneous Subarachnoid and Intracerebral Hemorrhage. ”  STROKE DIAGNOSIS Mimics (Table 167-5)28-30 can often be distinguished from stroke by careful history taking and physical examination, bedside tests, observation, and appropriate imaging. However, it can be difficult to distinguish conditions with focal transient symptoms (e.g., seizure) from transient ischemic attack (TIA). INITIAL DIAGNOSTIC EVALUATION The classic mantra, “ time is brain,”84 explains the current AHA/ASA stroke guidelines Class IB recommendation to enact “an organized protocol for the emergency evaluation of patients with suspected stroke” in which the primary goal is to achieve a door-to-needle time of ≤60 minutes of ED arrival in ≥50% of acute ischemic stroke patients who are treated with thrombolytics. 19 Based on performance data in hospitals participating in the “Get with the Guidelines—Stroke” initiative (i.e., median door-to-needle time 56 minutes; 30% treated in ≤45 minutes), 85 it seems likely that the recommended door-to-needle time goal will decrease in the future. Creation of a multidisciplinary stroke team is recommended, along with implementation of quality improvement initia tives to “safely increase IV thrombolytic treatment. ” 19 The culture of the institution should be aligned to encourage rapid diagnosis and treatment of stroke. Train triage personnel to suspect stroke and to quickly activate a stroke critical pathway that includes specific standing orders and pro cedures. Implement the critical pathway immediately upon that patient’s arrival, beginning in the triage area. Notify the emergency physician, the ED charge nurse, and the CT and laboratory technicians immediately when acute stroke is suspected. Do not delay the workup because ED beds are overcrowded or the emergency physician is currently otherwise engaged. ED core interventions are listed in Table 167-7. 19,86-98 Nonessential testing and procedures (including IV starts and blood draws) should not delay performing brain imaging within 20 minutes of the patient’s arrival. A summary of time goals is listed in Table 167-8.19 BRAIN IMAGING Obtain emergency non–contrast-enhanced CT for suspected acute stroke upon arrival. Most acute ischemic strokes are not visualized by a noncontrast brain CT in the early hours of a stroke. 23 Therefore, the utility of the first brain CT is primarily to exclude intracranial bleeding, abscess, tumor, and other stroke mimics, as well as to detect current contraindications to thrombolytics (e.g., “extensive regions of clear hypoattenuation”). The CT scan should be interpreted by the most expert interpreter available as soon as it is completed. The identification of subtle hem orrhage and early cerebral infarction requires expertise. In hospitals without on-site experts, telemedicine consultation is an option. Studies have shown fair to excellent interobserver agreement in CT readings between telemedicine stroke neurologists and neuroradiologists, 99,100 and telemedicine was associated with faster head CT interpretation in a cohort of 19 rural critical access hospitals. 101 In one retrospective study (n = 1659), even when there were differing CT interpretations between telemedicine stroke neurologists and overreading neuroradiologists in patients who received thrombolytics, there was no association with thrombolysis-related symptomatic intracranial hemorrhage. Diffusion-weighted MRI is superior to non–contrast-enhanced CT or other types of MRI (T1/T2 weighted, fluid-attenuated inversion recovery) in the detection of acute infarction.

uroradiologists in patients who received thrombolytics, there was no association with thrombolysis-related symptomatic intracranial hemorrhage. Diffusion-weighted MRI is superior to non–contrast-enhanced CT or other types of MRI (T1/T2 weighted, fluid-attenuated inversion recovery) in the detection of acute infarction. 102,103 However, CT’s superior rapid availability, MRI’s patient-specific contraindications (lack of cooperation, claustrophobia, metallic implants or pacemak ers, and diminished access to the patient), the relative inexperience in some practitioners in interpreting MRI scans in acute stroke, and costeffectiveness 102 work in CT’s favor for this indication. Therefore, in the vast majority of EDs, a non–contrast-enhanced CT is the most readily available imaging study and is the only imaging study necessary prior to administration of thrombolytics. 19 An emerging exception to this general rule is in the case of patients in whom time of stroke symptom onset is uncertain. One trial found that patients with ischemic stroke seen with diffusion-weighted MRI, but no hyperintensity of the parenchyma seen on fluid-attenuated inversion recovery, benefited from IV thrombolytic therapy 104 (see later section “Thrombolysis: Indications, Exclusions, Dosage, and Complications”). Nevertheless, even in these patients, non– contrast-enhanced CT is still the imaging mode of first choice.  VASCULAR IMAGING With the advent of endovascular therapies, identifying the presence of intracranial large-vessel stenosis or occlusion is important for therapeutic decisions. CT angiography or magnetic resonance angiography can detect these lesions. If a patient is a possible candidate for endovascular therapy, vascular imaging (typically CT angiography of the head and neck) is recommended concurrently with the initial head CT; however, these additional studies should not delay thrombolytic administration. 19 In other words, if a patient is a candidate based on the initial CT, do not delay thrombolytic administration while waiting to perform CT angiography or to receive the results of CT angiography . Therefore, if an Tintinalli_Sec14_p1101-1186.indd 1126 8/2/19 12:08 PM

dies should not delay thrombolytic administration. 19 In other words, if a patient is a candidate based on the initial CT, do not delay thrombolytic administration while waiting to perform CT angiography or to receive the results of CT angiography . Therefore, if an Tintinalli_Sec14_p1101-1186.indd 1126 8/2/19 12:08 PM CHAPTER 167: Stroke Syndromes 1127 TABLE 167-7 Core ED Interventions for Suspected Acute Stroke Intervention/Evaluation Rationale/Discussion All patients Assessment of airway, breathing, circulation Immediate life threats must be addressed before other interventions are undertaken. Actively manage airway if necessary. Establish IV access IV access is necessary for possible thrombolytic therapy. ( Do not delay brain imaging for prolonged IV access attempts. ) Pulse oximetry To detect hypoxia. Oxygen administration (if hypoxia is present) Routine oxygen supplementation is not indicated in stroke 86 and should be given only to keep oxygen saturation >94%. Cardiac monitoring Dysrhythmias, especially atrial fibrillation, are not infrequent in acute stroke and may predict 3-month mortality.87,88 Prophylactic administration of antiarrhythmic agents is not indicated. Bedside glucose determination To rapidly rule out hypoglycemia mimicking stroke. Treat hypoglycemia (<60 milligrams/dL) with IV dextrose. This is the only laboratory test result required prior to thrombolytic therapy 19 unless the patient is taking oral anticoagulation therapy or heparin, or if there is a strong suspicion of thrombocytopenia or other bleeding diatheses 19 (see Table 167-11). Noncontrasted brain CT or MRI To exclude intracerebral hemorrhage, other contraindications to IV thrombolytics, or stroke mimics. (See discussion in “Brain Imaging” section of this chapter.) ECG Acute coronary syndrome, dysrhythmias (especially atrial fibrillation), ECG changes, and abnormal cardiac biomarkers are frequently associated with acute stroke.89,90 ECG abnormalities and abnormal troponin T levels may also predict short-term and 3-mo mortality.87,91 A large study (n = 9180) of consecutive stroke patients revealed that 2.3% suffered a subsequent myocardial infarction, with 64.9% morbidity/mortality compared with 35.8% in the entire cohort. 92 A 2016 meta-analysis (n = 52,098) determined that one third of ischemic stroke patients with no previous cardiac history had >50% coronary stenosis. There was also a 3% overall risk of having an myocadiac infarction within a year of an acute stroke. CBC including platelet count To detect polycythemia, thrombocytosis, or thrombocytopenia. Coagulation studies To detect preexisting coagulopathy in hemorrhagic stroke or when thrombolytics are being considered in circumstances where there is a strong suspicion of the possibility of a coagulopathy (see Table 167-11). Electrolyte levels To detect electrolyte-imbalance stroke mimics (particularly Na + and Ca2+). Cardiac biomarker levels See “ECG” earlier in this table. A 2018 study also found that an elevated B-type natriuretic peptide within 48 hours was associated with a pure cardiac stroke mechanism (odds ratio 4.35; 95% confidence interval 2.59–7.29; P < .5) and may be useful in detecting cardiac etiologies of ischemic stroke. Nothing by mouth (NPO) order To protect against aspiration. Strict bed rest in the ED To protect against falls and seizures (in the period immediately after stroke).

ardiac stroke mechanism (odds ratio 4.35; 95% confidence interval 2.59–7.29; P < .5) and may be useful in detecting cardiac etiologies of ischemic stroke. Nothing by mouth (NPO) order To protect against aspiration. Strict bed rest in the ED To protect against falls and seizures (in the period immediately after stroke). In patients who can maintain oxygenation, supine position has been suggested to possibly improve patient outcomes by enhancing cerebral blood flow 95; however, a large (n = 11,093) cluster-randomized, crossover trial found no difference in stroke patient outcomes between lying flat for 24 hours and head of bed elevation to at least 30 degrees.96 However, significant methodologic concerns about this study have been raised, and optimal head positioning for stroke remains controversial.97 That said, it is probably reasonable to consider raising the head of the bed to 15 to 30 degrees in patients at risk for hypoxia, airway compromise, aspiration, or suspected increased intracranial pressure. Selected patients Chest radiograph Routine chest radiography in asymptomatic patients is not recommended and should be reserved only for situations where a cardiopulmonary contraindication to thrombolytics is suspected or if immediate management would be significantly impacted by chest radiograph findings. 98 Urinalysis To detect infectious stroke mimics or stroke-associated infections. Pregnancy test (if female of childbearing age) Pregnancy influences diagnosis and management considerations. Toxicology screen and/or blood alcohol level (if ingestion suspected) To detect stroke mimics as well as potential causes of stroke such as ingestion of a sympathomimetic (e.g., cocaine, methamphetamine, phencyclidine). Lumbar puncture (if infection or subarachnoid hemorrhage suspected) To detect stroke mimics. 2018 American Heart Association/American Stroke Association guidelines recommend that based on consensus expert opinion (Class IIb; Level of evidence: C-EO), IV thrombolysis may be considered in patients who have undergone lumbar puncture in the preceding 7 d. indicated CT angiography is not done with the initial head CT, it is reasonable to administer thrombolytics after the noncontrasted CT and then return the patient to the CT scanner for CT angiography to minimize door-to-needle time. 19 It is important to realize that in patients with no history of renal insufficiency, it is not necessary to have a serum creatinine result prior to performing contrasted studies for stroke, because these studies are not associated with significantly increased risk of acute kidney injury. 105-107  PERFUSION STUDIES In acute ischemic stroke, the area of irreversible brain infarct ( core) is surrounded by ischemic tissue that may potentially be salvageable, regardless of the time of onset of symptoms. The size of this penumbra region cannot be ascertained clinically, so perfusion CT and diffusionweighted MRI/fluid-attenuated inversion recovery can be used to mea sure the size of the penumbra and to guide further therapy for patients who fall outside the time ranges for thrombolysis or where the time of symptom onset is unclear. 108 However, to date, there are only two major positive studies in these particular patients that used perfusion TABLE 167-8 AHA/ASA Time Recommendations for Acute Ischemic Stroke Presenting to the ED Intervention Time Goal (from ED arrival) Activation of stroke team Immediately upon arrival Start of brain imaging ≤20 minutes Administration of IV thrombolytics ≤60 minutes (secondary goal ≤45 minutes) Abbreviation: AHA/ASA = American Heart Association/American Stroke Association. Tintinalli_Sec14_p1101-1186.indd 1127 8/2/19 12:08 PM

e Goal (from ED arrival) Activation of stroke team Immediately upon arrival Start of brain imaging ≤20 minutes Administration of IV thrombolytics ≤60 minutes (secondary goal ≤45 minutes) Abbreviation: AHA/ASA = American Heart Association/American Stroke Association. Tintinalli_Sec14_p1101-1186.indd 1127 8/2/19 12:08 PM 1128 SECTION 14: Neurology TABLE 167-9 Management of Hypertension Before Administration of Recombinant Tissue Plasminogen Activator (rtPA) or in Patients Awaiting Thrombectomy If the patient is a candidate for rtPA therapy, the target arterial blood pressures are systolic blood pressure ≤185 mm Hg and diastolic blood pressure ≤110 mm Hg. Drug Comments Labetalol, 10–20 milligrams IV over 1–2 min, may repeat ×1 Use with caution in patients with severe asthma, severe chronic obstructive pulmonary disease, congestive heart failure, diabetes mellitus, myasthenia gravis, concurrent calcium channel blocker use, hepatic insufficiency. May cause dizziness and nausea. Nicardipine infusion, 5 milligrams/h, titrate up by 2.5 milligrams/h at 5- to 15-min intervals; maximum dose: 15 milligrams/h; when desired blood pressure attained, reduce to 3 milligrams/h Use with caution in patients with myocardial ischemia, concurrent use of fentanyl (hypotension), congestive heart failure, hypertrophic cardiomyopathy, portal hypertension, renal insufficiency, hepatic insufficiency (may need to adjust starting dose). Contraindicated in patients with severe aortic stenosis. Can cause headache, flushing, dizziness, nausea, reflex tachycardia. Clevidipine infusion, 1–2 milligrams/h, titrate up by doubling dose every 2–5 min; maximum dose: 21 milligrams/h Use with caution in patients with congestive heart failure. Can cause reflex tachycardia atrial fibrillation, and systemic hypotension. Contraindicated in patients with severe aortic stenosis, allergies to soy or eggs, and lipid metabolism disorders (e.g., pathologic hyperlipidemia, lipoid nephrosis, or acute pancreatitis with hyperlipidemia). Alternative agents such as hydralazine or enalaprilat may be considered if clinically appropriate. If the target arterial blood pressures for rtPA administration cannot be reached with these initial measures, then the patient is no longer a candidate for rtPA therapy . studies to select candidates for endovascular therapy in their protocols (see later section “Endovascular Therapy”): the Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention (DAWN) trial 109 and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution trial (DEFUSE 3). 110 Therefore, the current AHA/ASA guidelines do not recommend routine use of perfusion studies in all stroke patients . Rather, they primarily advocate using perfusion studies in the context of strict adherence to DAWN and DEFUSE 3’s inclusion and exclusion criteria when treating patients outside of clinical trials. 19 This point has become an issue of debate because of the publication of positive studies on patients who awaken with stroke symptoms (“wake-up strokes”) that used CT perfusion to aid in selecting patients for thrombolytic therapy. 104,111,112 These studies and clinician feedback caused the AHA/ASA to withdraw the portion of their 2018 guidelines that suggested using perfusion studies in selecting patients for endovascular therapy in <6 hours was not beneficial. 22 Therefore, at this time, the best use of perfusion studies in acute stroke remains somewhat unsettled, but it is likely to be pivotal in the management of patients with unknown or prolonged last known well times 113 and in patients with TIA (see later section “TIA Risk Stratification and Disposition”).

t beneficial. 22 Therefore, at this time, the best use of perfusion studies in acute stroke remains somewhat unsettled, but it is likely to be pivotal in the management of patients with unknown or prolonged last known well times 113 and in patients with TIA (see later section “TIA Risk Stratification and Disposition”).  GENERAL TREATMENT OF ACUTE ISCHEMIC STROKE STANDARD TREATMENT Initial ED stabilization and interventions are listed in Table 167-7. 19,86-98 Many of these interventions are consensus based. Not all patients will be eligible for thrombolytics, so it is important to follow general treatment principles for all patients. Dehydration can contribute to worsened outcomes in ischemic stroke patients secondary to increased blood viscosity, hypotension, renal impairment, and venous thromboembolism. 114,115 However, routine volume expansion and hemodilution do not improve outcomes in stroke patients.116 Therefore, correct dehydration if present with IV crystalloid fluids, but do not overcorrect. For euvolemic patients, provide maintenance fluids. Routine oxygen supplementation is not indicated in stroke 86 and should be given only if necessary to keep oxygen saturation >94% . Hyperbaric oxygenation treatment is of no benefit.117 Fever is associated with increased morbidity and mortality in stroke,118 possibly due to fever-related inflammatory response,118 increased metabolic demands, and free radical production. 119 Identify the source of fever and treat the underlying cause (e.g., infection). While it is tradi tional to treat the fever itself with acetaminophen, strong evidence of favorable outcomes as a result of doing this remains elusive. 120,121 Avoid ibuprofen for temperature regulation, as it has been shown to not lower temperature in these patients 122 and may be associated with risk of bleeding. In addition, physical cooling measures should be considered second-line therapies only, 123 as their benefit has not been established.124 Admit all acute stroke patients to monitored care units familiar with the care of stroke patients, preferably to specialized stroke units at des ignated stroke centers. The use of stroke units has been associated with decreased complications and length of stay, improved daily function, decreased rate of discharge to long-term care facilities, and increased likelihood of being able to live at home in the long term—with the benefit being independent of thrombolytic use. 125-127 If a patient with acute stroke presents to a facility that lacks these resources, consider transferring the patient to a higher level of care after the patient’s condition has stabilized and IV thrombolytics have been given, as indicated—the “drip and ship” model. Emergent, early consultation with an experienced stroke physi cian at the accepting institution is desirable in these circumstances. BLOOD PRESSURE CONTROL IN STROKE The optimal blood pressure for acute ischemic stroke victims is unknown; however, based on consensus opinion, the current AHA/ASA acute stroke guidelines 19 recommend that hypotension and hypovolemia be corrected with either colloids or crystalloids 128 to maintain organ perfusion; however, there is no specific target blood pressure for patients not eligible for reperfusion therapy. Conversely, based on the blood pressure guidelines used in randomized controlled trials of thrombolytics, blood pressure control is considered essential prior to, during, and after thrombolytic therapy. A systolic blood pressure >185 mm Hg or a diastolic blood pressure >110 mm Hg is a contraindication to the use of thrombolytics 19 because elevated blood pressure (both before and after thrombolysis) 129,130 is associated with increased risk for hemorrhagic transformation of ischemic stroke.

after thrombolytic therapy. A systolic blood pressure >185 mm Hg or a diastolic blood pressure >110 mm Hg is a contraindication to the use of thrombolytics 19 because elevated blood pressure (both before and after thrombolysis) 129,130 is associated with increased risk for hemorrhagic transformation of ischemic stroke. Elevated pretreatment blood pressure is common (20%), 131 and a strategy of active management of elevated blood pressure as opposed to watchful waiting may increase the proportion of patients able to receive thrombolysis. 131,132 Therefore, if a patient is a candidate for thrombolytics, lower blood pressure to meet these entry parameters. An approach to management of arterial hypertension is detailed in Table 167-9 19 and Table 167-10. 19 If the target arterial blood pressures cannot be reached with these measures, then the patient is no longer a candidate for thrombolytic therapy. Similarly, based on randomized controlled trials of intraarterial therapy, the same blood pressure goal of ≤185/110 mm Hg is recommended for those who are candidates for intra-arterial therapy. 19 Preliminary studies also suggest that less favorable outcomes after thrombectomy are also associated with elevated baseline blood pressures. HYPERGLYCEMIA The current AHA/ASA guidelines recommend the maintenance of blood glucose between 140 milligrams/dL (7.77 mmol/L) and 180 milligrams/dL (9.99 mmol/L). 19 Avoid and treat hypoglycemia (<60 milligrams/dL Tintinalli_Sec14_p1101-1186.indd 1128 8/2/19 12:08 PM

associated with elevated baseline blood pressures. HYPERGLYCEMIA The current AHA/ASA guidelines recommend the maintenance of blood glucose between 140 milligrams/dL (7.77 mmol/L) and 180 milligrams/dL (9.99 mmol/L). 19 Avoid and treat hypoglycemia (<60 milligrams/dL Tintinalli_Sec14_p1101-1186.indd 1128 8/2/19 12:08 PM CHAPTER 167: Stroke Syndromes 1129 TABLE 167-10 Management of Hypertension During and After Administration of Thrombolytics or Other Acute Reperfusion Therapy Blood Pressure Monitoring Frequencies Time After Start of rtPA Infusion Frequency of Blood Pressure Monitoring 0–2 h Every 15 min 3–8 h Every 30 min 9–24 h Every 60 min Drug Treatment of Hypertension During and After Administration of Thrombolytics or Other Acute Reperfusion Therapy If systolic blood pressure is >180–230 mm Hg or diastolic blood pressure is >105–120 mm Hg Labetalol, 10 milligrams IV followed by infusion at 2–8 milligrams/min. Nicardipine infusion, 5 milligrams/h, titrate up by 2.5 milligrams/h at 5- to 15-min intervals; maximum dose 15 milligrams/h. Clevidipine infusion, 1–2 milligrams/h, titrate up by doubling dose every 2–5 min; maximum dose 21 milligrams/h. If blood pressure is not controlled by above measures or if diastolic blood pressure >140 mm Hg Consider sodium nitroprusside infusion (0.5–10 micrograms/kg/min). Continuous arterial monitoring advised; use with caution in patients with hepatic or renal insufficiency. Increases intracranial pressure. Pregnancy category C. [3.33 mmol/L]). Remember that both hypoglycemia and hyperglycemia are important stroke mimics. Hyperglycemia is common in acute stroke, 134,135 and glycemic control has been recommended based on data that associate less favorable outcomes with hyperglycemia. 136-138 However, data to support improved outcomes with tight glycemic control are lacking,139,140 and hypoglycemia must be avoided because it is associated with brain dysfunction.140 ANTIPLATELET THERAPY The current AHA/ASA guidelines recommend the adminis tration of oral (or by rectum if swallowing impairment is present) aspirin within 24 to 48 hours after stroke onset unless thrombolytics have been given within the prior 24 hours. 19 No antiplatelet agent (including aspirin) should be given within 24 hours of receiving thrombolytic therapy . When the results of the International Stroke Trial 141 and the Chinese Acute Stroke Trial142 are combined (40,000 patients), these studies demonstrate significant reduction in mortality and morbidity rates (at 4 weeks and 6 months) when aspirin (dose 160 to 300 milligrams) is administered to acute ischemic stroke patients within 48 hours. 143 The benefit seems due mainly to reduction of recurrent stroke. Aspirin is cost-effective and adds no risk to the outcome of ischemic stroke. 143 In eligible patients with aspirin contraindications, it might be reasonable to consider alter native antiplatelet drugs, but evidence for their efficacy is limited. 19 In terms of combination antiplatelet therapy, the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial found that mild stroke patients who received clopidogrel along with aspirin within 24 hours had fewer recurrent strokes (hazard ratio 0.68; 95% confidence interval [CI], 0.57 to 0.81; number needed to treat = 29) 144,145 and better functional outcomes (1.7% absolute reduction of poor functional outcome; 95% CI, 0.03% to 3.42%; number needed to treat = 59) 146 in 90 days than patients who received aspirin alone. However, the CHANCE study patients had mild, nondisabling strokes or TIAs, and the study was performed entirely in China. Therefore, these results await wider external validation before they can be recommended routinely. Antiplatelet therapy is contraindicated in acute hemor rhagic stroke.

s who received aspirin alone. However, the CHANCE study patients had mild, nondisabling strokes or TIAs, and the study was performed entirely in China. Therefore, these results await wider external validation before they can be recommended routinely. Antiplatelet therapy is contraindicated in acute hemor rhagic stroke.  THROMBOLYSIS BACKGROUND NINDS STUDY The National Institutes of Health/NINDS study 147 was a randomized double-blind trial comparing IV alteplase with placebo. The drug was administered within 3 hours of symptom onset, with approximately one half of patients treated within 90 minutes. Outcomes were measured using four different neurologic outcome scales (including the NIHSS) and a global statistic. Although there was no difference in the treatment and control groups at 24 hours, at 3 months, the odds ratio (OR) for a favorable outcome in treated patients was 1.7 (95% CI, 1.2 to 2.61; P = .008), an 11% to 13% absolute risk reduction benefit (number needed to treat = 8 to 9 for tPA <3 hours). Put another way, 31% to 50% of the patients receiving alteplase (depending on the scale used) had a favorable outcome at 3 months compared with 20% to 38% of patients given placebo. Benefit was found regardless of ischemic stroke subtype and was sustained 1 year after therapy. Symptomatic intracerebral hemorrhage attributable to thrombolytics occurred in 6.4% of patients in the alteplase group (45% mortality), whereas symptomatic intracerebral hemorrhage occurred in 0.6% of those in the placebo group (50% mortality). Despite this increased rate of intracerebral hemorrhage, the mortality rate at 3 months was not significantly different for the treatment and placebo groups (17% vs. 21%, respectively; P = .30), and the percentage of patients left severely disabled was lower among those receiving thrombolytics. 147 The NINDS trial represented the first randomized placebo-controlled trial that showed benefit of IV alteplase in acute stroke. Prior trials using different thrombolytic agents, different dosing of thrombolytics, or different treatment windows failed to show benefit or showed harm. Based largely on the NINDS data, in 1996, the U.S. Food and Drug Administration approved the use of IV alteplase in acute ischemic stroke within 3 hours of stroke onset. Concerns have been raised about the NINDS trial results. 148,149 The NINDS trial, although well designed, was relatively small and studied 624 patients total, 312 of whom received alteplase. As a result of chance, there existed an imbalance in baseline stroke severity between the two groups that apparently favored the thrombolytic group. Therefore, the NINDS investigators commissioned an independent reanalysis of the data 150 in 2004 that took this imbalance into account. This reanalysis found that, despite the imbalance, the originally described benefit of alteplase held. The authors concluded that “these findings support the use of alteplase to treat patients with acute ischemic stroke within 3 hours of onset. ” 150 However, they did concede the need to collect further data to determine which particular stroke subgroups would benefit or be harmed. In 2009, a graphic reanalysis of the NINDS trial data set was published, 151 which showed very small differences in the treatment and placebo group outcomes, with a slight favoring of thrombolytic treat ment. Therefore, the authors concluded that the reported NINDS results could have resulted from confounding alone. However, the methodology of this reanalysis was challenged in a subsequent graphic reanalysis of the NINDS data that supported the original results, 152 although these critiques have also been challenged in turn.

herefore, the authors concluded that the reported NINDS results could have resulted from confounding alone. However, the methodology of this reanalysis was challenged in a subsequent graphic reanalysis of the NINDS data that supported the original results, 152 although these critiques have also been challenged in turn. 153 Finally, the reliability of one of the primary measures of stroke disability in NINDS and subsequent trials, the modified Rankin scale, has been questioned. SUBSEQUENT THROMBOLYTIC TRIALS The European Cooperative Acute Stroke Study III (ECASS III) demon strated efficacy with an expansion of the treatment window to 4.5 hours.31 The OR favored treated patients (OR 1.34; 95% CI, 1.02 to 1.76), and the post hoc analysis, which adjusted for confounding variables, yielded similar statistical results (OR 1.42; 95% CI, 1.02 to 1.98). Although the incidence of intracerebral hemorrhage was higher in the treated group than the placebo group (27% vs. 17%) and the incidence of symptomatic hemorrhage was also higher in the treated group (2.4% vs. 0.2%; 7.9% vs. 3.5% when the NINDS definition of symptomatic hemorrhage was used), mortality was similar in both groups (7.7% in the rtPA group and 8.4% in the control group). Based on these data, AHA/ASA issued a 2009 scientific advisory 155 that recommended thrombolytics should be administered to eligible patients who present between 3 and 4.5 hours of an acute stroke, as long as they meet the ECASS III criteria (see Table 167-11). However, Tintinalli_Sec14_p1101-1186.indd 1129 8/2/19 12:08 PM

d on these data, AHA/ASA issued a 2009 scientific advisory 155 that recommended thrombolytics should be administered to eligible patients who present between 3 and 4.5 hours of an acute stroke, as long as they meet the ECASS III criteria (see Table 167-11). However, Tintinalli_Sec14_p1101-1186.indd 1129 8/2/19 12:08 PM 1130 SECTION 14: Neurology (Continued) TABLE 167-11 Summary of American Heart Association (AHA)/American Stroke Association (ASA) 2018 Inclusion/Exclusion Criteria for IV Alteplase in Acute Ischemic Stroke Inclusion Criteria Onset of symptoms <3 h prior to thrombolytic administration Defined as the time the patient was last known well or last known to be at their neurologic baseline. Measurable diagnosis of acute ischemic stroke Use of NIHSS score recommended. There is no upper or lower limit of NIHSS score for thrombolytics, as benefit may be seen with both mild but disabling stroke symptoms 170 as well as in very severe strokes.158 Early improvement with residual moderate impairment and potential disability is not a contraindication. Age ≥18 y No upper age limit for <3 h last known well time administration. Onset of symptoms from 3 to 4.5 h prior to rtPA administration Must meet the above inclusion criteria, plus these additional inclusion criteria: Age ≤80 y No history of diabetes mellitus and prior stroke NIHSS score ≤25 Not taking oral anticoagulants No brain imaging evidence of ischemic injury involving greater than one third of the middle cerebral artery territory Exclusion Criteria Last known well time >3 or 4.5 hours Acute intercranial hemorrhage or history of intracranial hemorrhage Symptoms and signs suggestive of subarachnoid hemorrhage CT brain imaging that exhibits extensive regions of clear hypoattenuation (obvious hypodensity) Prior ischemic stroke or severe head trauma within 3 months Acute posttraumatic brain infarction that occurs during acute in-hospital phase Intracranial/intraspinal surgery within 3 months GI malignancy or GI bleeding within 21 days Pretreatment systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg despite therapy (see Table 167-9) Platelet count <100,000/mm 3 If patient has no history of thrombocytopenia, thrombolytics may be given before this lab result is available; however, stop thrombolytics if the platelet count is <100,000/mm 3. INR >1.7 or activated PTT >40 s, or prothrombin time >15 s If patient is not taking oral anticoagulant or heparin, thrombolytics may be given before this lab result is available; however, stop thrombolytics if these lab tests come back elevated above normal limits. Oral anticoagulant use in and of itself is not a contraindication, but these labs should be checked prior to administration of thrombolytics if the patient is taking oral anticoagulants or heparin. Use of low-molecular-weight heparin within preceding 48 h Current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (such as activated PTT, INR, platelet count, and ecarin clotting time [ECT]; thrombin time; or appropriate factor Xa activity assays) Thrombolytics may be given before coagulopathy labs results available if the patient has not received a dose of these agents for >48 h and if renal function is normal. Thrombolytics may be given if the appropriate coagulopathy laboratory tests are not elevated. Current use of glycoprotein IIb/IIIa receptor inhibitors Current infective endocarditis Known or suspected aortic arch dissection Intra-axial intracranial neoplasm Blood glucose level <50 milligrams/dL (2.7 mmol/L) The glucose level should be normalized prior to thrombolytic administration.

tory tests are not elevated. Current use of glycoprotein IIb/IIIa receptor inhibitors Current infective endocarditis Known or suspected aortic arch dissection Intra-axial intracranial neoplasm Blood glucose level <50 milligrams/dL (2.7 mmol/L) The glucose level should be normalized prior to thrombolytic administration. Selected Additional Recommendations for Various Conditions Arterial puncture of noncompressible artery <7 d The safety and efficacy of thrombolytics in this condition are unclear. Arteriovenous malformation The safety and efficacy of thrombolytics with this condition are unclear; however, thrombolytics may be considered in the case of severe stroke with unruptured/untreated intracranial arteriove nous malformation. Dural puncture Dural puncture (<7 d) is not a contraindication. Eye hemorrhage Diabetic retinal hemorrhage or other ophthalmologic hemorrhage is not a contraindication, but the benefits of thrombolytics must be weighed against the potential threat to sight. Major surgery or major trauma (not involving the head) within preceding 14 d rtPA may be carefully considered if the benefits outweigh risks. Malignancy Extra-axial intracranial neoplasm is not a contraindication. The safety and efficacy of thrombolytic administration in systemic malignancy are unclear. Menstruation Menstruation and menorrhagia without clinically significant anemia are not contraindications. Clinically significant anemia due to these processes mandates an emergent consultation with a gynecologist prior to thrombolytic administration Tintinalli_Sec14_p1101-1186.indd 1130 8/2/19 12:08 PM

cy are unclear. Menstruation Menstruation and menorrhagia without clinically significant anemia are not contraindications. Clinically significant anemia due to these processes mandates an emergent consultation with a gynecologist prior to thrombolytic administration Tintinalli_Sec14_p1101-1186.indd 1130 8/2/19 12:08 PM CHAPTER 167: Stroke Syndromes 1131 based on trial data and unpublished data from the U.S. manufacturer of alteplase (Genentech), the U.S. Food and Drug Administration has denied approval for this indication 156; therefore, alteplase administration >3 hours after symptom onset is still considered off label in the United States.157 In contrast, the European Medicines Agency has approved use from 3 to 4.5 hours after symptom onset. In 2012, the third International Stroke Trial (IST-3) 158 was published, making it the largest (n = 3035 patients) randomized controlled trial for ischemic stroke to date. Patients in the treatment group were given the standard dose of thrombolytics up to 6 hours after stroke onset, with 72% of patients receiving thrombolytics after 3 hours. The exclusion criteria were loosened, including eliminating any upper age limit and the broadening of the acceptable blood pressure range prior to thrombolytics (systolic 90 to 220 mm Hg; diastolic 40 to 130 mm Hg). 159 The trial showed no difference at 6 months in the primary outcome measure, Oxford Handicap Score (0 to 2; alive and independent): 37% versus 34% (OR 1.13; 95% CI, 0.95 to 1.35; P = .181) in the treatment versus control groups, respectively. However, a secondary ordinal analysis showed a favorable shift in Oxford Handicap Scores (indicating less disability) in the treatment group at 6 months. Although symptomatic intracranial hemorrhage occurred in 7% of treated patients versus 1% of controls (P <.0001) and 11% of deaths occurred within 7 days in treated patients versus 7% in controls (P <.001), mortality at 6 months was the same (27%) in both treatment and control groups. The favorable shift in Oxford Handicap Score in treated patients appeared to last at least 18 months and was associated with higher overall self-reported health, with no increased mortality. 160 Interestingly, a subgroup analysis in the IST-3 revealed that patients receiving thrombolytics between 3 and 4.5 hours after symptom onset actually had a nonstatistical trend toward a worse functional outcome compared with controls than patients receiving thrombolytics less than 3 hours and from 4.5 to 6 hours after symptom onset. In 2014, a Cochrane systematic review and meta-analysis (27 trials, 10,187 patients) concluded that thrombolytic-treated stroke patients were less likely to be dead or dependent than controls, and that early treatment was better than late treatment, with possible benefit up to 6 hours after symptom onset. 161 This benefit held despite increased symptomatic intracranial hemorrhage and more early and late deaths. In 2016, a group of nonneurologists and nonemergency physicians published a systematic review and meta-analysis (26 trials, 10,431 patients) that concluded that although thrombolysis was associated with marginally improved functional outcomes, it also increased early mortality and symptomatic intracranial hemorrhage rates. 154,162 These authors urgently called for further randomized controlled trials to be performed to help resolve this continuing controversy. In 2015, the American College of Emergency Physicians gave a Level B (moderate clinical certainty) recommendation for IV thrombolytics both in the below 3 hour and in the 3 to 4.5 hour treatment windows.

rgently called for further randomized controlled trials to be performed to help resolve this continuing controversy. In 2015, the American College of Emergency Physicians gave a Level B (moderate clinical certainty) recommendation for IV thrombolytics both in the below 3 hour and in the 3 to 4.5 hour treatment windows. 163 Subsequently, although the Canadian Association of Emergency Physicians “strongly recommended” IV thrombolytics in the below 3 hour window, as a result of data from the IST-3 158 and other data,164 the Canadian Association of Emergency Physicians issued a conditional recommendation against the use of thrombolytic therapy beyond 3 hours of symptom onset.165 Others recently raised similar concerns,149,166 some of which prompted a review of alteplase for ischemic stroke by the United Kingdom Medicines and Healthcare Products Regulatory Agency. This review eventually upheld the decision to endorse the use of IV alteplase for stroke up to 4.5 hours.  THROMBOLYSIS: INDICATIONS, EXCLUSIONS, DOSAGE, MONITORING, AND COMPLICATIONS Indications The decision to administer thrombolytics must be made rapidly and accurately. There must be careful identification of the time of symptom onset, defined as the last moment the patient was known to be at baseline (i.e., last known well time) . Taking the patient and family chronologically through the events immediately prior to the stroke is particularly helpful in unclear cases. Thrombolytic use in stroke is not currently recommended by AHA/ASA when the time of onset cannot be reliably determined. As of this writing, the AHA/ASA recommend that strokes recognized upon awakening (up to approximately 25% to 30% of strokes 168,169) should be clocked from the time at which the patient was last known to be without symptoms. However, after the current AHA/ASA guidelines 19 were published, the landmark Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (W AKE-UP) trial results were published. 104 W AKE-UP was a randomized con trolled multicenter European trial that recruited patients who awoke with stroke symptoms or who were not considered candidates for IV thrombolysis with a last known well time of >4.5 hours. These patients underwent MRI with diffusion-weighted imaging and fluid-attenuated inversion recovery. If in the judgment of the treating physician, there was evidence of an acute ischemic stroke on diffusion-weighted MRI, but no parenchymal hyperintensity on fluid-attenuated inversion recovery, the patients were considered to have a diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch consistent with a recent stroke and the patients were offered enrollment into the study. A total of 503 patients were randomly assigned to either a standard dose of alteplase or placebo, and there were no significant differences in demographic qualities, stroke severity (median NIHSS of 6), or median time of thrombolysis to symptom onset between the groups. Average last known well time for both groups was about 10 hours, and the aver age time from symptom recognition to treatment was about 3 hours for both groups. At 90 days after treatment, 53.3% of the alteplase group had minimal disability (modified Rankin scale score of 0 or 1) compared with 41.8% of the placebo group (adjusted OR 1.61; 95% CI, 1.09 to 2.36; P = .02). The median 90-day modified Rankin scale score of the alteplase group was 1, whereas in the placebo group, it was 2 (adjusted common OR 1.62; 95% CI, 1.17 to 2.23; P = .003). However, 4.1% of patients who received alteplase died within 90 days compared with 1.2% of patients in the control group (OR 3.38; 95% CI, 0.92 to 12.52; P = .07), with 50% of the deaths in the treatment group being unrelated to the acute stroke.

roup, it was 2 (adjusted common OR 1.62; 95% CI, 1.17 to 2.23; P = .003). However, 4.1% of patients who received alteplase died within 90 days compared with 1.2% of patients in the control group (OR 3.38; 95% CI, 0.92 to 12.52; P = .07), with 50% of the deaths in the treatment group being unrelated to the acute stroke. In a similar vein, 2.0% of the alteplase patients suffered a symptomatic TABLE 167-11 Summary of American Heart Association (AHA)/American Stroke Association (ASA) 2018 Inclusion/Exclusion Criteria for IV Alteplase in Acute Ischemic Stroke Myocardial infarction Acute myocardial infarction is not a contraindication to rtPA. Recent (<3 months) non–ST-segment elevation myocardial infarction is not a contraindication to rtPA. Recent (<3 months) ST-segment elevation myocardial infarction involving the left anterior, right, or inferior myocardium is not a contraindication to rtPA. Other cardiac conditions Consult a cardiologist prior to rtPA administration for other cardiac conditions such as pericarditis, heart chamber thromboses, and cardiac tumors. Pregnancy rtPA may be considered for pregnant women with moderate to severe stroke. The administration of rtPA at <14 d postpartum remains controversial. Seizure at onset Seizure at onset is not a contraindication to rtPA if residual impairments are thought secondary to stroke and not postictal phenomenon. Unruptured intracranial aneurysm An aneurysm <10 mm in size is not a contraindication to rtPA. rtPA administration with an aneurysm ≥10 mm size is controversial. Abbreviation: NIHSS = National Institutes of Health Stroke Scale. (Continued) Tintinalli_Sec14_p1101-1186.indd 1131 8/2/19 12:08 PM

not postictal phenomenon. Unruptured intracranial aneurysm An aneurysm <10 mm in size is not a contraindication to rtPA. rtPA administration with an aneurysm ≥10 mm size is controversial. Abbreviation: NIHSS = National Institutes of Health Stroke Scale. (Continued) Tintinalli_Sec14_p1101-1186.indd 1131 8/2/19 12:08 PM 1132 SECTION 14: Neurology intracerebral hemorrhage compared with 0.4% in the placebo group (OR 4.95; 95% CI, 0.57 to 42.87; P = .15). This trial had several limitations, including the exclusion of patients eligible for mechanical thrombec tomy, adults >80 years old, and patients with NIHSS score of >25 and/ or large middle cerebral artery lesions. In addition, the trial was stopped early (about 300 patients short of planned enrollment) due to cessation of funding. Had these limitations not been present, the numerical trends toward increased harm in the treatment group may well have been statistically significant. Although these important results await further confirmation by larger trials, W AKE-UP is a landmark trial that has the potential to change practice in the near future, especially when mechanical thrombectomy is not a viable option; however, its results should be considered preliminary at this time. To achieve optimal outcomes, the patient must be evaluated carefully for indications and exclusions for IV thrombolytic therapy (Table 167-11), and the findings must be documented meticulously, preferably on computerized or preprinted assessment forms. The decision to admin ister thrombolytics is made by assessing multiple factors, including the numerical NIHSS score. A score between 4 and 22 is commonly used as one of the criteria for thrombolytic administration. However, some patients may have a lower NIHSS score, yet have a potentially disabling condition (e.g., aphasia, hemianopia, gait disturbance). Some studies have also shown benefit with thrombolysis in minor strokes, 170,171 but further data are needed to be conclusive.172,173 Nevertheless, interpret an NIHSS score in the total context of the individual patient when making treatment decisions. A bedside blood glucose is required prior to thrombolysis; how ever, do not withhold thrombolysis because other laboratory results are still pending unless there is reason to suspect a pathologic or iatrogenic coagulopathy. Administer thrombolytic therapy to eligible patients even if endovascular therapies are being considered. Exclusions In the previous AHA/ASA stroke guidelines,155,174 the exclusion criteria hewed very closely to the conservative criteria used by the NINDS and ECASS III trials. However, in the current recommenda tions, 19 several of the previous exclusion/relative exclusion criteria from the 2013 guidelines156 have been eliminated or modified based on recent data and expert consensus.157 In addition, the practical clinical validity of the ECASS III criteria for administration of thrombolytics from 3 to 4.5 hours has been challenged, because positive outcomes have been demonstrated in patients who would not have qualified for treatment in ECASS III. However, the current AHA/ASA guidelines still list them as part of the inclusion criteria for thrombolytics from 3 to 4.5 hours (Table 167-11), but they note the ongoing controversy. Therefore, carefully consider the treatment risks versus anticipated benefits of proposed rtPA therapy, especially if any of the relative contraindications are present prior to administration of the drug. When faced with such patients, obtain emergency consultation with a physician with acute stroke expertise, whether on-site or via telemedicine, because local expert treatment varies and patient care decisions should be individualized. Dosage As of this writing, only alteplase is FDA approved for treatment of acute ischemic stroke.

ith such patients, obtain emergency consultation with a physician with acute stroke expertise, whether on-site or via telemedicine, because local expert treatment varies and patient care decisions should be individualized. Dosage As of this writing, only alteplase is FDA approved for treatment of acute ischemic stroke. However, the treatment options may include tenecteplase in some situations, especially outside the US. Alteplase and tenecteplase have different dosages. Therefore, use the full brand or generic name (alteplase, tenecteplase) when ordering. Do not use abbreviations (rtPA, TNK, etc) to avoid medication errors. As doses also vary for the clinical indication (stroke, STEMI, PE), make sure the dose you select is the dose appropriate for the clinical indication. 175 The standard total dose of alteplase is 0.9 milligram/kg IV , with a maximum dose of 90 milligrams; administer 10% of the dose as a bolus over 1 minute, with the remaining amount infused over 60 minutes. Recent data from Asian trials have suggested that low-dose alteplase in acute ischemic stroke results in comparable patient outcomes, with less morbidity and mortality. 176 However, at the time of this writing, these preliminary results await large-scale confirmation in non-Asian populations; therefore, the above standard alteplase dose remains recommended. The dose of tenecteplase is weight-based,: <60 kg: 30 milligrams; 60-70 kg: 40 milligrams; 80-90 kg 45 milligrams; >90 kg, 50 milligrams for patients > 90 kg. The maximum dose is 50 milligrams. Tenecteplase is given as a single IV bolus over 5-10 seconds. Monitoring and Complications Perform blood pressure and neurologic checks every 15 minutes for 2 hours after starting the infusion. Table 167-10 outlines the emergent management of hypertension during and after administration of thrombolytics. Admit patients to a specialized stroke unit (if available) or an intensive care unit familiar with the use of thrombolytic drugs and neurologic monitoring. If post-rtPA bleeding is suspected, halt drug administration and perform an emergent CT. Order a CBC with platelet count, coagulation studies, fibrinogen level, and typing and cross-match for packed red blood cells, cryoprecipitate or fresh frozen plasma, and platelets. Emergent neurology, neurosurgery, and hematology consultations, as needed, are appropriate. Be prepared to treat the possible side effect of orolingual angioedema (reported incidence approximately 0.2% to 17%). 177-179 Patients taking angiotensinconverting enzyme inhibitors appear to be at higher risk for this com plication (adjusted OR 3.9; 95% CI, 1.6 to 9.7).180 Middle cerebral artery infarction has also been previously reported to be a risk factor, but this has been challenged by more recent data. 181 If orolingual angioedema occurs, discontinue thrombolysis 19 and treat angioedema similarly to other causes of angioedema (see Chapter 14, “ Allergy and Anaphylaxis”). Consider administration of icatibant, which has been reported to be efficacious in thrombolytic-associated angioedema in a handful of case reports. 182,183 Administration of plasma-derived C1 esterase inhibitor has also been suggested to be of value, given its efficacy in angiotensin-converting enzyme inhibitor–associated angioedema.19,184 The role of angioedema prophylaxis in this setting is unknown, but there has been at least one reported case of successful IV thrombolysis for recurrent stroke in a patient with history of previous thrombolytic-associated angioedema, using simultaneous administration of prednisolone, ranitidine, and clemastine.

.19,184 The role of angioedema prophylaxis in this setting is unknown, but there has been at least one reported case of successful IV thrombolysis for recurrent stroke in a patient with history of previous thrombolytic-associated angioedema, using simultaneous administration of prednisolone, ranitidine, and clemastine. 185 History of angioedema to thrombolytics and use of angiotensinconverting enzyme inhibitors are not designated by the ASA/AHA as explicit contraindications to IV thrombolysis 19; however, if these factors are present, specifically discuss them as part of informed consent.  ENDOVASCULAR THERAPY There is intense interest in endovascular therapies, primarily intra-arterial thrombolysis and mechanical clot disruption/extraction. Potential advantages of endovascular therapies include an expanded treatment window, a treatment for patients with non–time-based contraindications to IV thrombolysis, an ability to specifically evaluate the occluded vascular territory, use of lower total doses of thrombolytic drugs, and the pos sibility of mechanical clot disruption. However, early randomized trials of mechanical endovascular therapy with primarily intra-arterial thrombolysis or first-generation endovascular devices did not show benefit. 186-189 Subsequently, in 2015, five pivotal multicenter trials regarding intraarterial thrombectomy in acute ischemic stroke were published. The Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), 190 the Extending the Time for Thrombolysis in Emergency Neurological Deficits– Intra-Arterial (EXTEND-IA) trial, 191 the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial, 192 the Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial, 193 and the Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset (REV ASCAT) trial 194 were the first prospective, randomized trials to demonstrate the efficacy of intra-arterial thrombectomy with IV thrombolysis with second-generation devices in acute ischemic stroke. In 2016, an additional randomized trial, Thrombecto mie des Artères Cerebrales (THRACE), 195 was published, the results of which were consistent with those of the previous studies. MR CLEAN190 was the largest trial (n = 502) and the only trial of this group that was not stopped prematurely for efficacy. It compared intraarterial treatment (thrombolysis, thrombectomy, or both) with usual medical therapy for patients with anterior circulation proximal occlusions within 6 hours of stroke onset (91% of the control group received IV rtPA). The inclusion criteria included adults >18 years old (no upper Tintinalli_Sec14_p1101-1186.indd 1132 8/2/19 12:08 PM

ent (thrombolysis, thrombectomy, or both) with usual medical therapy for patients with anterior circulation proximal occlusions within 6 hours of stroke onset (91% of the control group received IV rtPA). The inclusion criteria included adults >18 years old (no upper Tintinalli_Sec14_p1101-1186.indd 1132 8/2/19 12:08 PM CHAPTER 167: Stroke Syndromes 1133 TABLE 167-12 Results of Eight Positive Randomized Trials of Mechanical Intra-Arterial Treatment in Acute Anterior Stroke Trial No. Upper Age Limit (y) Endovascular Treatment Time Inclusion Criteria mRS (0–2) at 90 d * (treatment vs. controls) Mortality† (treatment vs. controls) Symptomatic Intracranial Hemorrhage † (treatment vs. controls) MR CLEAN 190 502 None Retrievable stent +/– intra-arterial thrombolysis or intra-arterial thrombolysis alone Ability to undergo endovascular treatment within 6 h 32.6% vs. 19.1% OR = 2.16 (95% CI, 2.39–3.38) NNT = 8 18.9% vs. 18.4% 7.7% vs. 6.4% EXTEND-IA 191 70 None Solitaire FR stent retriever IV thrombolysis <4.5 h of stroke onset 71% vs. 40% OR = 4.2 (95% CI, 1.4–12) NNT = 4 9% vs. 20% 0% vs. 6% ESCAPE 192 316 None Retrievable stent Within 12 h of stroke onset 53% vs. 29.3% Rate ratio = 1.8 (95% CI, 1.4–2.4) NNT = 5 10.4% vs. 19% 3.6% vs. 2.7% SWIFT PRIME193 196 80 Solitaire stent retriever Within 6 h of stroke onset 60% vs. 35% Risk ratio = 1.70 (95% CI, 1.23–2.33) NNT = 4 9% vs. 12% 0% vs. 3% REVASCAT 194 206 80 Solitaire stent retriever Within 8 h of stroke onset 43.7% vs. 28.2% OR = 2.1 (95% CI, 1.1–4.0) NNT = 7 18.4% vs. 15.5% 1.9% vs. 1.9% THRACE 195 414 80 Various stent retriever devices IV thrombolysis within 4 h and thrombectomy within 5 h of stroke onset 53% vs. 42% OR = 1.55 (95% CI, 1.05–2.30) NNT = 9 12% vs. 13% 2% vs. 2% DAWN 109 206 None Trevo stent retriever Within 6–24 h of last known well time 49% vs. 13% OR = 6.25 (95% CI, 3.11–12.54) NNT = 3 19% vs. 18% 6% vs. 3% DEFUSE 3110 182 90 Various FDA-approved thrombectomy devices Within 6–16 h of last known well time 45% vs. 17% OR = 4.01 (95% CI, 2.02–8.02) NNT = 4 14% vs. 26% 7% vs. 4% Abbreviations: CI = confidence interval; DAWN = Diffusion-Weighted Imaging or Computerized Tomography Perfusion Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention; DEFUSE 3 = Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke; ESCAPE = Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times; EXTEND-IA = Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial; FDA = U.S. Food and Drug Administration; MR CLEAN = Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; mRS = modified Rankin scale; NNT = number needed to treat; OR = adjusted odds ratio; REVASCAT = Randomized Trial of Revascularization with Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset; SWIFT PRIME = Solitaire FR with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke; THRACE = Thrombectomie des Artères Cerebrales. *Treatment efficacy differences in each trial are statistically significant. †Differences in mortality and symptomatic intracranial hemorrhage in each trial were not statistically significant. age limit) and an NIHSS score ≥2. Major findings included significant 90-day functional benefit in treatment versus controls (90-day modified Rankin scale score of 0 to 2: 32.6% vs. 19.1%, respectively [OR 2.16; 95% CI, 1.39 to 3.38]; number needed to treat = 7).

rrhage in each trial were not statistically significant. age limit) and an NIHSS score ≥2. Major findings included significant 90-day functional benefit in treatment versus controls (90-day modified Rankin scale score of 0 to 2: 32.6% vs. 19.1%, respectively [OR 2.16; 95% CI, 1.39 to 3.38]; number needed to treat = 7). With intra-arterial treatment, there was no significant increase in symptomatic ICH (7.7% vs. 6.4%), but there was a higher incidence of vessel perforation (0.9%) and dissection (1.7%), and 5.6% of patients had an ischemic stroke in a different vascular distribution within 90 days versus 0.4% in controls. However, despite these findings, there was no statistical difference in mortality (18.9% vs. 18.4%). An important limitation of this study is that although the disease severity was similar in the treatment and control groups, the control group had relatively poor outcomes in terms of the modified Rankin scale. This reflects the rather broad inclusion criteria of the study, which may allow greater generalizability of the results. The results of the other five trials cited are largely consistent with MR CLEAN, and these trials were all stopped early during interim safety analyses because of efficacy of the treatment arm ( Table 167-12). Based on the data from the previously discussed six trials, in 2015, the AHA/ASA issued a new Class IA recommendation 196 that patients receive endovascular therapy with a stent retriever if they meet all of the inclusion criteria in Table 167-13. A subsequent pooled analysis (n =1287) for the first five random ized positive trials found that a modified Rankin scale score of 0 to 2 at 90 days was present in 46% of patients in the endovascular treatment group versus 26.5% of controls (number needed to treat = 5.1), with no significant difference in 90-day mortality or symptomatic intracranial hemorrhage. 197 A 2016 Cochrane systematic review and meta-analysis of 10 trials of endovascular therapy, including the previous negative trials, concluded the following: “Moderate to high quality evidence suggests that compared with medical care alone in a selected group of patients endo vascular thrombectomy as add-on to intravenous thrombolysis performed within six to eight hours after large vessel ischaemic stroke in the anterior circulation provides beneficial functional outcomes, without increased detrimental effects. ” Tintinalli_Sec14_p1101-1186.indd 1133 8/2/19 12:08 PM

d group of patients endo vascular thrombectomy as add-on to intravenous thrombolysis performed within six to eight hours after large vessel ischaemic stroke in the anterior circulation provides beneficial functional outcomes, without increased detrimental effects. ” Tintinalli_Sec14_p1101-1186.indd 1133 8/2/19 12:08 PM 1134 SECTION 14: Neurology In 2018, two important studies, the DAWN trial 109 (n = 206) and the DEFUSE 3 trial 110 (n = 182) compared endovascular therapy plus standard treatment with standard treatment alone in patients with late presenting stroke (6 to 24 hours and 6 to 16 hours last known well time, respectively) and evidence of potentially reversible ischemia (a mismatch between clinical symptoms and infarct size and a penumbra of ≥15 mL, respectively; Table 167-12). Both trials were multicenter, randomized, open-label trials with blinded outcome assessment, and both were stopped early because of the loss of clinical equipoise in favor of the treatment group. DAWN found that the percentage of patients with functional outcome at 90 days (modified Rankin scale score of 0 to 2) with thrombectomy was 49% compared with 13% in the control group (an adjusted difference of 33% [95% CI, 21% to 44%]; posterior probability of superiority >0.999). Similarly, DEFUSE 3 found that thrombectomy patients had a better distribution of dis ability scores at 90 days than controls (OR 2.77; 95% CI, 1.63 to 4.70; P <.001). The percentage of thrombectomy patients compared with controls who had a modified Rankin scale score of 0 to 2 at 90 days was 45% versus 17%, respectively (risk ratio 2.67; 95% CI, 1.60 to 4.48; P <.001). In both trials, the mortality and morbidity outcomes in both the treatment and control groups were statistically equal. Although these results support the notion of extending the window for acute treatment of stroke, an important caveat is that the AHA/ASA recom mends thrombectomy in the >6 hour window only if the strict inclu sion/exclusion criteria for DAWN or DEFUSE 3 are followed . The inclusion and exclusion criteria of both trials are complex and lengthy but are readily available online. 199,200 Despite the encouraging results of all of these recent endovascular therapy trials, the current availability of endovascular treatment modalities remains rather limited at most primary stroke centers, which may circumscribe widespread use. Nevertheless, although all eligible stroke patients should be considered for IV thrombolysis as a first-line therapy, also consider emergent consultation with a neurointerventionalist for adjunctive endovascular therapy in patients who meet the criteria listed in Table 167-13 and in patients who meet the DAWN or DEFUSE 3 criteria.199,200  OTHER TREATMENT MODALITIES Therapeutic hypothermia, induced hypertension, endovascular thera pies, carotid endarterectomy/stenting, and emergency hemicraniectomy for massive infarcts are modalities that are being studied, but as of this writing, benefits are unproven. Mild therapeutic hypothermia is associated with improved neu rologic outcomes in comatose patients who survive cardiopulmonary arrest.

lar thera pies, carotid endarterectomy/stenting, and emergency hemicraniectomy for massive infarcts are modalities that are being studied, but as of this writing, benefits are unproven. Mild therapeutic hypothermia is associated with improved neu rologic outcomes in comatose patients who survive cardiopulmonary arrest. 202 Consequently, there is much interest in the potential benefit of induced hypothermia in acute stroke, both alone and in combination with neuroprotective strategies 203 and endovascular therapy.204 However, hypothermia’s efficacy has not been firmly established, and it may be associated with increased risk of pneumonia.205 Therefore, its use is considered experimental at this time.19 Animal data206 and preliminary trials have suggested that implementing drug-induced hypertension in an effort to increase blood flow to the ischemic penumbra may benefit outcomes from acute ischemic stroke, 207-209 with recent increased interest given penumbra-based endovascular interventions.210 However, there are insufficient data to recommend this modality outside of clinical trials at this time. 19 Patients with a massive middle cerebral artery infarct are less favor able candidates for thrombolytic therapy and have an 80% mortality rate. Massive middle cerebral artery infarct is commonly associated with space-occupying cerebral edema and may be amenable to decompressive craniectomy. A 2007 pooled analysis of data from three European trials (Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery [DECIMAL], 211 Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery [DESTINY], 212 and Hemicraniectomy After Middle Cerebral Artery Infarction With Life-Threatening Edema Trial [HAMLET]) 213 showed that decompressive hemicraniectomy was associated with better outcomes than medical therapy. 214 However, the overall efficacy of this approach remains in question. For example, in 2014, the Hemicraniec tomy and Durotomy upon Deterioration Infarction-Related Swelling (HeADDFIRST) pilot trial 215 found no statistical difference in the 180-day mortality between the medically managed patients in this trial (40%) and the patients who underwent hemicraniectomy plus medical treatment (34%). Ultimately, several recent meta-analyses of hemicraniectomy versus medical treatment for large middle cerebral artery infarction concluded that although decompressive craniectomy results in reduced mortality, most survivors are left with severe or very severe disability. 216-218 Therefore, the decision to perform surgery must be made on an individual case-by-case basis.  TRANSIENT ISCHEMIC ATTACK TIA is defined as follows: “a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. ” 219 This tissue-based definition recognizes that although TIA symptoms typically last <1 to 2 hours, duration of symptoms is an unreliable discriminator between TIA and infarction because about 33% of TIAs have signs of infarction on MRI. 220 View a TIA as analogous to unstable angina—that is, an ominous harbinger of a potential future vascular event. In fact, the adjusted OR for stroke <1 month after TIA is 30.4 (95% CI, 10.4 to 89.4), 221 and the overall 90-day stroke risk after TIA is about 9.2% to 9.5%. 136-138 Some data suggest that 50% of these subsequent events occur within 2 days after presentation to the ED. 136 Published risk factors associated with increased risk for subsequent stroke include hypertension, diabetes mellitus, symptom duration of ≥10 minutes, weakness, and speech impairment.

s about 9.2% to 9.5%. 136-138 Some data suggest that 50% of these subsequent events occur within 2 days after presentation to the ED. 136 Published risk factors associated with increased risk for subsequent stroke include hypertension, diabetes mellitus, symptom duration of ≥10 minutes, weakness, and speech impairment. 136 A study of admitted patients found increased risk with male sex, age ≥65 years, hyperlipid emia, and dysarthria.139 TIA DIAGNOSIS The initial considerations and workup of TIA are very similar to those of acute stroke (see earlier section “Stroke Diagnosis”), including the emphasis on seeking mimics that can simulate TIA (Table 167-5). Pay particular attention to performing an ECG in these patients to detect atrial fibrillation, given its association with cardioembolic stroke and the fact its associated stroke risk can be mitigated in many patients. An unsettled issue in the initial workup involves brain imaging. Although a noncontrasted CT is still the initial imaging study of choice (primarily to rule out stroke mimics), it cannot reliably predict risk of subsequent stroke. 222 However, it has been shown that positive findings on diffusionweighted MRI have predictive value for subsequent early stroke risk in TIA patients, 223 as does cervical vascular imaging by magnetic reso nance angiography.224 Furthermore, a large meta-analysis225 of 41 studies (n = 2541) determined that although Doppler US has test characteristics slightly inferior to magnetic resonance angiography in detecting 70% to 99% carotid stenosis (sensitivity of 89% [95% CI, 85% to 92%] and 94% TABLE 167-13 AHA/ASA Indications for Endovascular Therapy With a Stent Retriever196 •   Prestroke mRS score 0 to 1 •   Acute ischemic stroke receiving IV rtPA within 4.5 h of onset according to guidelines from professional medical societies •   Causative occlusion of the ICA or proximal MCA (M1) •   Age ≥18 y •   NIHSS score of ≥6 •   ASPECTS of ≥6 •   Treatment can be initiated (groin puncture) within 6 h of symptom onset All 7 criteria need to be met for stent retriever endovascular therapy to be indicated. Abbreviations: AHA/ASA = American Heart Association/American Stroke Association; ASPECTS = Alberta Stroke Program Early CT Score; ICA = internal carotid artery; MCA (M1) = sphenoidal (horizontal) segment of the middle cerebral artery; mRS = modified Rankin scale; NIHSS = National Institutes of Health Stroke Scale; rtPA = recombinant tissue plasminogen activator. Tintinalli_Sec14_p1101-1186.indd 1134 8/2/19 12:08 PM

Stroke Program Early CT Score; ICA = internal carotid artery; MCA (M1) = sphenoidal (horizontal) segment of the middle cerebral artery; mRS = modified Rankin scale; NIHSS = National Institutes of Health Stroke Scale; rtPA = recombinant tissue plasminogen activator. Tintinalli_Sec14_p1101-1186.indd 1134 8/2/19 12:08 PM CHAPTER 167: Stroke Syndromes 1135 [95% CI, 88% to 97%] and specificity of 84% [95% CI, 77% to 89%] and 93% [95% CI, 89% to 96%], respectively), 225 Doppler US still performs well enough (negative likelihood ratio of 0.13, compared to 0.06 for MRA) 225 to be useful in helping to risk-stratify TIA patients in the ED.226 Due to its relatively low specificity (84%), confirm any positive Dop pler US findings with magnetic resonance angiography or CT angiography. As a screening test, CT angiography lagged behind the other two modalities in detecting extracerebral carotid stenosis in TIA patients (sensitivity 77% [95% CI, 68% to 84%], specificity 95% [95% CI, 91% to 97%], negative likelihood ratio 0.24), 225 despite its utility in detect ing intracranial vascular lesions. 227 Based on these and similar data, in 2016, the American College of Emergency Physicians recommended 226 that suspected TIA patients should receive a noncontrasted head CT in the ED, and when feasible, physicians should obtain diffusion-weighted MRI and cervical vascular imaging. These recommendations reference a growing trend to attempt to use clinical characteristics plus imaging to selectively manage some TIA patients as outpatients (see later section “TIA Risk Stratification and Disposition”). TIA TREATMENT Treatment of TIA primarily focuses on prevention of subsequent stroke.  ANTIPLATELET AGENTS After TIA, the use of aspirin to prevent future vascular events is historically well accepted. Current practice includes dipyridamole plus aspirin (reasonable as a first choice), clopidogrel, and aspirin alone. The selec tion of a particular antiplatelet regimen is a multifactorial decision based on comorbid conditions, bleeding risk, prior drug use, and cost. A very large meta-analysis (>88,000 patients) 228 concluded that aspi rin plus dipyridamole was superior to aspirin alone for prevention of vascular events after stroke or TIA. Aspirin plus dipyridamole was associated with more hemorrhagic events than dipyridamole (relative risk 1.83; 95% CI, 1.17 to 2.81) but was associated with fewer hemorrhagic events than aspirin and clopidogrel (relative risk 0.38; 95% CI, 0.25 to 0.56). However, the previously mentioned CHANCE trial (n = 5170) found that the combination of clopidogrel and aspirin was superior to aspirin alone for reducing the risk of stroke in the first 90 days without increasing the risk of hemorrhage. 144 These positive outcomes were found to have persisted at 1-year follow-up. 145 The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke trial is currently in progress to investigate this comparison as well.  ANTICOAGULATION Adjusted-dose oral anticoagulation with warfarin has been the histori cal therapy of choice for stroke prevention in patients with nonvalvular atrial fibrillation and TIA; however, an assessment of warfarin antico agulation for stroke prevention in the United States demonstrated a dismal rate of optimal anticoagulation control. 230 This has led to mul tiple randomized controlled trials of novel anticoagulants, which have been shown to have equivalent efficacy but with less risk of intracranial hemorrhage compared to warfarin. 231 The risk of recurrent stroke in the presence of atrial fibrillation without anticoagulation is low, prob ably <5% over the next 48 hours; moreover, the risk of hemorrhagic transformation of an acute stroke is also greatest in the first 48 hours.

cy but with less risk of intracranial hemorrhage compared to warfarin. 231 The risk of recurrent stroke in the presence of atrial fibrillation without anticoagulation is low, prob ably <5% over the next 48 hours; moreover, the risk of hemorrhagic transformation of an acute stroke is also greatest in the first 48 hours. Consequently, in the setting of acute atrial fibrillation, anticoagula tion therapy typically should not be started in the ED but should be initiated in the inpatient setting. Multiple studies have demonstrated that, although unfractionated heparin may help prevent recurrent stoke, its potential benefits are outweighed by the increased risk of intracranial hemorrhage. Multiple studies of low-molecular-weight heparin and heparinoids have found similarly disappointing results. A Cochrane systematic review of 24 randomized trials (23,748 patients) found no net benefit of anticoagulants in acute stroke. 232 In addition, a meta-analysis of seven trials focused specifically on anticoagulant use in acute cardiothrombotic stroke and found no overall benefit. 233 Therefore, the use of unfractionated heparin, lowmolecular-weight heparin, or heparinoids for emergent treatment of a specific stroke subtype or TIA cannot be recommended based on available evidence, even in the presence of atrial fibrillation.234  ENDARTERECTOMY In TIA patients with medically treated high-grade internal carotid artery lesions, carotid endarterectomy should be performed promptly, because surgical benefit is greatest within 2 weeks of the TIA. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) 236 and the International Carotid Stenting Study (ICSS) 237 suggest that carotid stenting may be a viable alternative to endarterectomy, with similar functional outcomes up to 10 years, 237,238 despite a small increase in nondisabling stroke in stented patients in the ICSS trial. 237 Carotid stenting may be especially useful in patients <70 years old 236 or in patients with higher surgical risks.239 On the other hand, the evidencebased role of emergent or urgent carotid endarterectomy/stenting in acute stroke is still not conclusively defined. TIA RISK STRATIFICATION AND DISPOSITION Because TIAs frequently precede acute strokes, much work has been done in attempting to develop TIA risk stratification tools in an effort to identify which low-risk patients may safely be discharged from the ED and worked up as outpatients. The most frequently studied of these tools is the Age, Blood pressure, Clinical characteristics, Duration, and Diabetes (ABCD 2) scoring system. 240 In 2007, the ABCD 2 scoring system was developed to incorporate and replace two previous scoring scales (California score and ABCD score). 240 Johnston et al 240 initially reported 2-day risks of subsequent stroke as 1% (ABCD 2 score 0 to 3), 4.1% (score 4 to 5), and 8.1% (score 6 to 7). The 7-day stroke risks were 1.2% (ABCD 2 score 0 to 3), 5.9% (score 4 to 5), and 11.7% (score 6 to 7). Despite these initial promising data, subsequent published studies produced conflicting conclusions as to the ABCD2 score’s utility for predicting subsequent stroke after TIA. 241-243 The interrater reliability and accuracy of the ABCD2 score have been challenged, especially with nonspecialists in actual use.244-247 A large meta-analysis (>16,000 patients)248 found inadequate positive and negative likelihood ratios (1 to 2 and 0.5 to 1, respectively) to be of practical use when deciding stroke risk in a given patient. Overall, the ABCD 2 score identified high-risk patients poorly and had only modest success in predicting low-risk patients, and the study authors cautioned against solely relying on the ABCD score to risk-stratify patients.

and 0.5 to 1, respectively) to be of practical use when deciding stroke risk in a given patient. Overall, the ABCD 2 score identified high-risk patients poorly and had only modest success in predicting low-risk patients, and the study authors cautioned against solely relying on the ABCD score to risk-stratify patients. 248 In an attempt to improve accuracy of ABCD2, the presence of two or more TIA events at 7 days (ABCD3) and diffusion-weighted MRI (ABCD 3-I) have been added to the original scoring system. One study did demonstrate the superiority of these new scales to predict stroke. 249 However, the addition of these two data points limits the usefulness of these scales in the ED during initial presentation. Although use of the ABCD 2 score had been recommended previously by major guidelines, 219 based on the most current literature, the American College of Emergency Physicians issued an updated clinical policy 226 in 2016. This clinical policy recommends that current risk stratification instruments such as ABCD2 should not be used to identify TIA patients who can be safely discharged home .226 Specifically, “the ABCD2 does not sufficiently identify the short-term risk for stroke to use alone as a risk-stratification instrument. ”226 A 13-factor Canadian TIA score250 has been developed that has shown initial promising results; however, it has yet to be validated for general use. In light of the difficulty in precisely identifying TIA patients who are safe to send home from the ED, some experts have recommended that most TIA patients be hospitalized to monitor and educate them, begin antiplatelet therapy (unless contraindicated), rapidly treat subsequent stroke, assess stroke risk factors, implement preventive measures, and perform endarterectomy in appropriate patients. However, as a result of cost resource utilization concerns, there is great interest in developing ED-based strategies for safely managing TIAs as outpatients as opposed to standard admission. Numerous studies have been published exploring this issue. 226 Although these studies have largely shown that the use of special ED-directed TIA protocols results in decreased resource use with no increased risk of subsequent stroke, most have compared admission with extensive ED observation Tintinalli_Sec14_p1101-1186.indd 1135 8/2/19 12:08 PM

published exploring this issue. 226 Although these studies have largely shown that the use of special ED-directed TIA protocols results in decreased resource use with no increased risk of subsequent stroke, most have compared admission with extensive ED observation Tintinalli_Sec14_p1101-1186.indd 1135 8/2/19 12:08 PM 1136 SECTION 14: Neurology protocols or prompt referral to dedicated TIA clinics. A representative example is a 2007 randomized controlled trial 251 (n = 151) that demon strated that lower-risk patients (i.e., those without the following factors: abnormality on initial head CT, abnormal ECG, abnormal lab values, known possible embolic source [atrial fibrillation, cardiomyopathy, or valvulopathy], known carotid stenosis, previous large stroke, or cre scendo TIAs) can be safely discharged after a 12-hour ED observation period that includes continual cardiac and serial clinical monitoring, coupled with a thorough initial evaluation (including neurology con sultation, carotid imaging, and echocardiography). More recent studies have also included diffusion-weighted MRI in their protocols. 252 Many of these studies lack sufficient controls and are relatively small, and there is no consensus on which specific protocol or approach is optimal. In addition, many of the proposed algorithms require resources that are not readily available in most EDs. However, there is general support for the use of these types of protocols by the American College of Emergency Physicians. 226 The approach to the disposition of a specific patient must be individualized and may depend not only on medical factors, but also the patient’s social situation, as well as the healthcare resources available at the particular treating institution.  SPECIAL POPULATIONS STROKE OR TIA WITH CONCURRENT ACUTE MYOCARDIAL INFARCTION The co-occurrence of acute myocardial infarction and acute stroke has implications for acute treatment in the ED, but strong evidencebased treatment recommendations are lacking. Troponin elevation in acute ischemic stroke is not uncommon (prevalence, 0% to 34% 253), is associated with multiple disease processes (e.g., acute coronary syn drome, congestive heart failure, renal failure, myopericarditis, chronic obstructive pulmonary disease, pulmonary embolism, sepsis, atrial fibrillation 254,255), and is independently associated with worse all-cause mortality.256 Troponin elevation in acute stroke is most probably secondary to acute coronary syndrome if other obvious causes are excluded, especially if typical ECG findings for acute coronary syndrome are present. 257 Concomitant acute stroke and acute myocardial infarction due to paradoxical embolus traversing a patent foramen ovale has been well described in the literature. 258,259 Type A aortic dissection has also been reported to present with simultaneous stroke and myocardial infarction. Simultaneous acute ischemic stroke and myocardial infarction can be therapeutically problematic because treating one condition with a pro cedure may delay a time-dependent indicated procedure for the other. In addition, there are some therapies for acute myocardial infarction (e.g., heparin) that are contraindicated in acute stroke. There are no published controlled trials directly addressing these complex patients. Nonethe less, based on expert consensus, the 2018 AHA/ASA guidelines gave a Class IIa (moderate) recommendation: “For patients presenting with concurrent AIS [acute ischemic stroke] and acute MI [myocardial infarction], treatment with IV alteplase at the dose appropriate for cerebral ischemia, followed by percutaneous coronary angioplasty and stenting if indicated is reasonable.

delines gave a Class IIa (moderate) recommendation: “For patients presenting with concurrent AIS [acute ischemic stroke] and acute MI [myocardial infarction], treatment with IV alteplase at the dose appropriate for cerebral ischemia, followed by percutaneous coronary angioplasty and stenting if indicated is reasonable. ” 19 Regardless of the treatment strategy chosen, the risks and benefits of the various therapeutic approaches must be carefully weighed in this situation in order to pri oritize the various proposed interventions, depending on the clinical condition of the patient. 261 Obtain emergent neurology and cardiology consults on these patients, but do not delay thrombolysis for stroke if the patient qualifies. SICKLE CELL DISEASE Stroke afflicts both adults and children with sickle cell disease, with an overall prevalence of 3.8% 262 compared to the overall prevalence of 2.7% (age ≥20 years) in the general population in the United States. 1 Sickle cell disease is the most common cause of ischemic stroke in children. Patients homozygous for hemoglobin S have the highest incidence of stroke (0.61 in 100 patient-years), but all genotypes are at increased risk. 262 The highest incidence of hemorrhagic stroke in these patients occurs from ages 20 to 29.262 Cerebral aneurysms and arterial abnormalities also occur with increased frequency in patients with sickle cell disease, and careful evaluation for subarachnoid hemorrhage is mandated for patients pre senting with headache and neurologic findings. Initial management is similar to that for stroke patients without sickle cell disease, but care should also be taken to treat the underlying sickle cell disease with oxygen administration, hydration, and pain control, if necessary. The presence of sickle cell disease has not been found to significantly affect safety or outcomes in stroke patients treated with IV thrombolysis and is not considered a contraindication to thrombolytic therapy in eligible patients.19 Therefore, if patients with sickle cell disease otherwise qualify, administer IV thrombolysis. Despite a paucity of high-quality evidence, expert consensus also recommends emergent exchange packed red blood cell transfusion in sickle cell patients with acute ischemic stroke, with the goal of reduc ing hemoglobin S levels to <30%, 264 along with a target goal to achieve a total hemoglobin level of 10 grams/dL (but no higher in order to avoid hyperviscosity). 265-267 The same therapy has been recommended in hemorrhagic stroke in order to reduce vasospasm and secondary ischemic infarction. 264 Exchange transfusion appears to reduce the incidence of subsequent ischemic stroke in children compared with simple transfusion. 268 However, if exchange transfusion is not readily available, consider a simple packed red blood cell transfusion in these patients while preparations for exchange transfusion are being made. Emergent consultation with a hematologist and a stroke neurologist is in order for these patients, and admission to a comprehensive stroke center is indicated. YOUNG ADULTS Strokes in young adults (age 18 to 50 years) are increasing in incidence.269,270 Possible causes include an increasing prevalence of some traditional cardiovascular risk factors 271 (e.g., hyperlipidemia, 272 diabetes, 273,274 obesity275), increasing rates of recreational drug use,276 and better awareness and diagnosis of stroke in this age group.269,277 In this group, cervical arterial dissection accounts for 20% of all ischemic strokes and may often be preceded by only minor trauma. The young adult with a cardioembolic event may have mitral valve prolapse, rheumatic heart disease, or para doxical embolism 259 as the originating cause.

stroke in this age group.269,277 In this group, cervical arterial dissection accounts for 20% of all ischemic strokes and may often be preceded by only minor trauma. The young adult with a cardioembolic event may have mitral valve prolapse, rheumatic heart disease, or para doxical embolism 259 as the originating cause. Migrainous stroke (infarc tion associated with typical migraine attack among those with established recurrent migraines) is also a possibility in this age group. Some members of this population are at risk for ischemic stroke from substance abuse. Heroin, cocaine, amphetamines, and other sympathomimetic drugs are often implicated. 276 Patients who have human immunodeficiency virus and a recent CD4 cell count <200 cells/mm3 are also at increased risk for ischemic stroke (rate ratio 2.5; 95% CI, 1.3 to 4.6),278 as are young adults who survive cancer.279 Studies suggest that younger stroke victims have more favorable morbidity and mortality rates than elders after undergoing stroke treatments such as IV thrombolysis, 280 thrombectomy,281 and decompressive surgery for large middle cerebral artery strokes. 282 Therefore, treat these patients aggressively. Acknowledgments: The author gratefully acknowledges Karen Manley for her steadfast manuscript support, as well as Amanda Augustine, Ashley Borden, Jarrett Gardner, Ryan Jacobsen, Liliya Kraynov, Sean Mark, and Charles Spencer for their insightful suggestions. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec14_p1101-1186.indd 1136 8/2/19 12:08 PM