Ischemic Stroke




Acute ischemic stroke carries the risk of morbidity and mortality. Since the advent of intravenous thrombolysis, there have been improvements in stroke care and functional outcomes. Studies of populations once excluded from thrombolysis have begun to elucidate candidates who might benefit and thus should be engaged in the process of shared decision-making. Imaging is evolving to better target the ischemic penumbra salvageable with prompt reperfusion. Availability and use of computed tomography angiography identifies large-vessel occlusions, and new-generation endovascular therapy devices are improving outcomes in these patients. With this progress in stroke treatment, risk stratification tools and shared decision-making are fundamental.


Key points








  • Tissue plasminogen activator (tPA) (Alteplase) is an treatment approved for treatment of acute ischemic stroke for patients who meet inclusion criteria and who are treated in the appropriate setting.



  • The risk of symptomatic hemorrhagic conversion in properly selected patients can be less than 2% with no increase in disability or mortality; conversely, the risk can be greater than 15% in patients with significant comorbidities.



  • A decision not to use tPA in the appropriate setting is acceptable, but clinical decision-making must be well supported in the medical record.



  • The earlier the treatment for acute ischemic stroke, the better the outcome.



  • Exclusion criteria for tPA have been revised: minor strokes, severe strokes, age, and seizures must be placed in context of risk/benefit.






Introduction


The 3 broad categories of stroke are ischemic (87%), hemorrhagic (10%), and subarachnoid hemorrhage (3%). The specific definition is brain, spinal cord, or retinal cell death secondary to infarction. Of ischemic strokes, 60% are thrombotic, and 40% are embolic. The brain in ischemic stroke has a core infarct area and ischemic penumbra. The penumbra represents an area that may be salvaged with prompt reperfusion. The neurologic deficit can be devastating, and stroke remains the leading cause of disability and fourth most common cause of death in the United States.


In the United States, approximately 795,000 people suffer a stroke annually, 77% of which are new strokes and 23% are recurrent. The lifetime risk of stroke from age 55 to 75 years is 20% in women and 15% in men. Approximately 10% of patients with an acute ischemic stroke (AIS) die within 1 year, and 20% to 25% of patients remain severely disabled.


There have been advances in prevention, diagnosis, and therapy over the past 22 years since the National Institute of Neurologic Disorders and Stroke (NINDS) trial was published demonstrating a higher likelihood of having a favorable clinical outcome at 3 months when tPA (Alteplase) was administered versus placebo. Since then, several other studies and data base analyses have supported the benefit of tPA within the appropriate time window, and its use is recommended by all major societies, including the American College of Emergency Physicians, the American Stroke Association (ASA), and the American Academy of Neurology. This review provides a summary of guideline recommendations with a primary focus on the advances in thrombolytic inclusion/exclusion criteria, diagnostic neuroimaging, and management of large vessel occlusion (LVO).




Introduction


The 3 broad categories of stroke are ischemic (87%), hemorrhagic (10%), and subarachnoid hemorrhage (3%). The specific definition is brain, spinal cord, or retinal cell death secondary to infarction. Of ischemic strokes, 60% are thrombotic, and 40% are embolic. The brain in ischemic stroke has a core infarct area and ischemic penumbra. The penumbra represents an area that may be salvaged with prompt reperfusion. The neurologic deficit can be devastating, and stroke remains the leading cause of disability and fourth most common cause of death in the United States.


In the United States, approximately 795,000 people suffer a stroke annually, 77% of which are new strokes and 23% are recurrent. The lifetime risk of stroke from age 55 to 75 years is 20% in women and 15% in men. Approximately 10% of patients with an acute ischemic stroke (AIS) die within 1 year, and 20% to 25% of patients remain severely disabled.


There have been advances in prevention, diagnosis, and therapy over the past 22 years since the National Institute of Neurologic Disorders and Stroke (NINDS) trial was published demonstrating a higher likelihood of having a favorable clinical outcome at 3 months when tPA (Alteplase) was administered versus placebo. Since then, several other studies and data base analyses have supported the benefit of tPA within the appropriate time window, and its use is recommended by all major societies, including the American College of Emergency Physicians, the American Stroke Association (ASA), and the American Academy of Neurology. This review provides a summary of guideline recommendations with a primary focus on the advances in thrombolytic inclusion/exclusion criteria, diagnostic neuroimaging, and management of large vessel occlusion (LVO).




Stroke assessment and differential diagnosis


The assessment for stroke often starts with prehospital measures by emergency medical services (EMS). Activation of EMS is recommended by the ASA based on evidence showing activation improves door-to-needle times, and thus may be related to improved outcomes (Class I; Level B evidence, see “Applying Classification of Recommendations and Level of Evidence” at reference 12 for grading scheme ). As EMS plays a crucial role in stroke timelines, the emergency physician (EP) must be aware of prehospital history, assessment tools, and interventions.


The prehospital history emphasizes time of symptom onset, history of diabetes, prior stroke, seizures, hypoglycemia, hypertension, and atrial fibrillation. Additional history aids in the assessment for tPA eligibility, including medications such as antiplatelet/anticoagulants, surgeries within the past 3 months, and head or other major trauma.


The history is performed in conjunction with assessment tools for stroke. In the prehospital setting, the 2 most commonly used tools are the Los Angeles (LAPSS) and Cincinnati Prehospital Stroke Screen (CPSS) (Class I; Level B evidence ). Both screens activate stroke notification if any point is abnormal. The LAPSS includes asymmetry of facial smile/grimace, grip, and arm strength/drift. The CPSS assesses for unilateral facial droop, unilateral arm drift, and slurred speech. Given advancements in LVO management, Perez de la Ossa and colleagues developed the Rapid Arterial Occlusion Evaluation (RACE) scale as a prehospital tool to assess stroke severity and possibly identify LVO with the premise that patients identified as high risk of LVO are best transferred to a stroke center with endovascular capabilities. The RACE scale was derived from National Institutes of Health Stroke Scale (NIHSS) items that highly correlate with LVO. The scale encompasses 5 items rated in score 0 to 2, including facial palsy, arm motor function, leg motor function, head and gaze deviation, and aphasia or agnosia. In the validation study, a score of ≥5 showed sensitivity 0.85, specificity of 0.68, positive predictive value of 0.42, and negative predictive value of 0.94 for LVO. Despite the promising data, further study is warranted to further validate scales for LVO risk stratification.


Focused prehospital measures include standard ABCs, intravenous (IV) access, cardiac monitoring, and correction of hypoglycemia. Given that hypoglycemia can be a stroke mimic, fingerstick glucose should be checked by EMS (Class I; Level B evidence ), and if less than 60 mg/dL, the patient should be given 50 mL of 50% dextrose.


On arrival to the emergency department (ED), the EP should perform the history, physical examination, and stabilizing measures. As thrombolysis is a time-sensitive therapy, these measures should be accomplished as part of a coordinated team approach, shown in Table 1 . History should address signs and symptoms of stroke mimics, discussed in Box 1 .



Table 1

Emergency department care timeline

























Action Time
Door to physician ≤10 min
Door to stroke team ≤15 min
Door to computed tomography (CT) initiation ≤25 min
Door to CT interpretation ≤45 min
Door to drug (≥80% compliance) ≤60 min
Door to stroke unit admission ≤3 h


Box 1





  • Central nervous system (CNS) abscess



  • CNS tumor



  • Drug toxicity



  • Hypertensive encephalopathy



  • Hypoglycemia/Hyperglycemia



  • Migraine with aura (complicated migraine)



  • Seizure with postictal paresis, aphasia, or neglect



  • Psychogenic



  • Wernicke encephalopathy



  • Head trauma



  • Multiple sclerosis, degenerative neurologic disorders



  • Intracranial hemorrhage



  • Systemic infection



  • Syncope



Ischemic stroke mimics


The ED stroke assessment encompasses the standardized NIHSS. This scale, which ranges from 0 to 42, assists in categorizing stroke into “mild” (1–5), “moderate” (6 and 13), and “severe” (>13). Lower scores are associated with a smaller risk of hemorrhagic conversion after tPA and overall better outcomes. “Mild” strokes can still be associated with significant disability, and the score alone should not be used as the sole determinate for thrombolytic eligibility. Physical examination may localize the lesion, assisting radiology interpretation, further explored in Table 2 . The physical examination must also evaluate for signs of head or other body trauma, signs of seizure, dysrhythmia, or stigmata of coagulopathy.



Table 2

Stroke syndromes































Distribution Deficits
Anterior cerebral artery (ACA) Paratonic rigidity, abulia: lack of initiative
Contralateral motor (more commonly lower extremity)
Contralateral sensory (more commonly lower extremity)
Gait apraxia
Middle cerebral artery (MCA) Homonymous hemianopia
Neglect (nondominant)
Aphasia: Wernicke, Broca
Contralateral motor (more commonly face and upper extremity, more than lower extremity but can have frank hemiplegia)
Contralateral sensory
Penetrating; also known as lacunar Dysarthria
Internal capsule: contralateral pure motor
Thalamus: contralateral pure sensory
Cerebellar: ipsilateral ataxia
Posterior cerebral artery (PCA) Occipital cortex (visual): homonymous hemianopia, macula sparing, visual perseverations
Cranial nerve (CN) III palsy: paresis of vertical eye movements
Alexia without agraphia
Cerebral peduncle, midbrain: motor, sensory, choreoathetosis
Thalamus: spontaneous pain
Vertebrobasilar Dizziness, nausea, vomiting, coma
CN palsies, diplopia
Dysarthria, dysphagia, hiccups
Motor deficit crossed sensory deficit: ipsilateral face and contralateral body involvement
Limb/gait ataxia
Anterior spinal artery Caudal medulla (CN XII): tongue deviates ipsilateral
Contralateral motor deficit
Contralateral proprioception
Posterior inferior cerebellar artery (PICA) Vertigo, vomiting, nystagmus
Ipsilateral Horner syndrome: ptosis, anhidrosis, miosis
CN IX-X deficit: dysphagia, hoarseness, decreased gag
Contralateral limb and ipsilateral face pain, temperature
Ipsilateral ataxia, dysmetria
Anterior inferior cerebellar artery (AICA) Vertigo, vomiting, nystagmus
CN VII deficit: decreased lacrimation
CN V: decreased corneal reflex, ipsilateral Horner syndrome
Facial motor, pain, and temperature


In addition to initial stabilization ensuring brain oxygenation and perfusion, blood glucose assessment and reassessment is fundamental. Diagnostic tests should include an electrocardiogram, imaging, complete blood count, basic metabolic panel, coagulation panel (prothrombin time, partial thromboplastin time, international normalized ratio), and troponin (Class I; Level C evidence ). Of these studies, the only result required before tPA is glucose determination. Therapy should not be delayed for coagulation or platelet studies unless there is suspected bleeding abnormality or thrombocytopenia, history of anticoagulation use, or anticoagulation use is uncertain. In retrospective reviews, the rate of unsuspected coagulopathy or thrombocytopenia in ischemic stroke is very low, comprising 0.4% with unsuspected coagulopathy and 0.3% with unsuspected thrombocytopenia.


An essential step before tPA is neuroimaging. Door to imaging times include 25 minutes to initiation of imaging and 45 minutes to interpretation. Commonly, head noncontrast computed tomography (NCCT) is the imaging modality of choice, however MRI is an option. In the case of suspected LVO, advanced imaging using IV contrast should be performed. Additional imaging should not delay the administration of tPA if the patient is eligible (Class I; Level A evidence ).


Use of contrast in both MRI and CT is relatively contraindicated in patients with impaired renal function. In computed tomography (CT), contrast can cause contrast-induced nephropathy (CIN), defined as an absolute increase in serum creatinine of greater than 0.5 mg/dL or greater than 25% above baseline within 48 to 72 hours after contrast administration. In patients with no known renal disease, the risk of CIN is approximately 2% with no reported cases needing hemodialysis. Therefore, in patients with no known renal disease, practitioners should not wait for serum creatinine measurements before scanning. Interestingly, a study by Davenport and colleagues stratified patients receiving IV contrast by stable estimated glomerular filtration rate (eGFR); contrast was nephrotoxic in patients with eGFR less than 30 (CKD stage 4–5) and did not appear to be nephrotoxic in adults with eGFR greater than 45 (CKD stage 3A and above). In MRI, contrast in those with eGFR less than 30 is associated with gadolinium-induced nephrogenic systemic fibrosis or dermatosis.




Advances in inclusion and exclusion criteria


The Food and Drug Administration (FDA) contraindications for tPA were largely based on the 1995 NINDS trial. The derivation of the trial’s inclusion and exclusion criteria arose from expert opinion, cardiac literature on thrombolysis, and basic science publications. Controversies over the tPA contraindications led to extensive research culminating in a February 2016 ASA Scientific Statement revising the inclusion and exclusion criteria for AIS (note: this is independent of the FDA-approved package insert inclusion/exclusion criteria).


The benefits of tPA have been published in trials demonstrating improved rates of disability after treatment, based on disability scores. Despite this, many patients do not receive tPA despite presenting within the treatment time window due to an exclusion criterion. The changes in the 2016 ASA Statement address these barriers. The FDA approved tPA (Alteplase) for treatment within 3 hours from time of symptom onset, shown in Table 3 . The extended time window to 4.5 hours is endorsed by all major societies involved in stroke care for patients meeting inclusion criteria after shared decision making on risks and benefits ; however, use beyond 3 hours is not FDA approved, see Table 4 .



Table 3

Noncontrast CT findings in acute stroke






















Imaging Finding Description
Dense middle cerebral artery (MCA)/MCA dot sign Increased density in a major cerebral artery
Dot: distal MCA branches in the sylvian fissure
Hypodensity of lentiform nucleus Loss of definition between the putamen and globus pallidus
Insular ribbon sign Loss of definition of the gray-white interface in the lateral margins of the insula
Loss of gray/white differentiation Loss of distinction between gray and white matter, especially between the basal ganglia and internal capsule or insular or frontoparietal cortex and underlying white matter
Hypodensity Cytotoxic edema and increased water content, commonly quantified by increased Hounsfield Units


Table 4

American Heart Association (AHA) Guidelines Exclusion Criteria less than 3 hours













































AHA 2013 Update AHA 2016
Significant head trauma in previous 3 mo
Prior stroke in previous 3 mo Removed: The potential for increased risk of symptomatic intracranial hemorrhage is not well established (Class IIB; Level B) however should be weighted against anticipated benefits (Class I; Level C)
Symptoms suggest subarachnoid hemorrhage Subarachnoid hemorrhage
Arterial puncture at noncompressible site in previous 7 d
History of previous intracranial hemorrhage Removed: Warning for recent intracranial hemorrhage
History of intracranial neoplasm Modified: Contraindicated in intra-axial intracranial neoplasm (Class III; Level C). Probably recommended in extra-axial intracranial neoplasm (Class IIA; Level C)
History of arteriovenous malformation or aneurysm Modified: Increased risk of intracranial hemorrhage; however, may be considered in severe neurologic deficits and high likelihood of morbidity and mortality (Class IIB; Level C)
Intracranial or intraspinal surgery within 3 mo
Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg) Current severe uncontrolled hypertension
No specific values
Active internal bleeding
Infective endocarditis
Acute bleeding diathesis
Platelet count <100,000 mm 3
Heparin within 48 h with elevated activated partial thromboplastin time
Use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated laboratory tests
Current use of anticoagulation with international normalized ratio >1.7 or prothrombin time >15 s

Data from Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44(3):870–947; and Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016;47(2):581–641.


Modifications in exclusion criteria span 2 broad categories of patients: those at risk of hemorrhage and those with stroke mimics. High risk of hemorrhage includes prior stroke in the preceding 3 months, prior intracranial hemorrhage (ICH), and postsurgical patients. The data are lacking on the specific risks and time relation after these events. In the case of prior ICH, the risk likely corresponds to the volume of encephalomalacia from the previous ICH, if the stroke is in the same vascular territory, and how recently the ICH took place. Nevertheless, studies have found only a handful of patients who were given tPA with prior ICH. For prior stroke ≤3 months, studies by Karlinski and colleagues suggest no increase in symptomatic ICH (sICH) if readministering tPA. Based on these limited data, tPA is still considered potentially harmful in the cases of prior stroke and prior ICH (Class III; Level B evidence). However, for prior stroke ≤3 months, the potential risks and benefits of tPA should be discussed during the decision-making process (Class I; Level C evidence) ( Tables 5–7 ).



Table 5

American Heart Association (AHA) guidelines exclusion criteria less than 3 h

































Relative Exclusion
AHA 2013 Update AHA 2016
Blood glucose concentration <50 mg/dL Removed: It is reasonable to consider tissue plasminogen activator (tPA) after glycemic management (dextrose) and neurologic reexamination within 15 min
Computed tomography demonstrates multilobar infarction (hypodensity >one-third cerebral hemisphere)
AHA 2013 Class III, Level A
Removed: There is insufficient evidence to identify a threshold of hypoattenuation. However, tPA in extensive regions of clear hypoattenuation is not recommended (Class III; Level A)
Minor or rapidly improving stroke symptoms Removed
Pregnancy
Seizure at onset with postictal residual neurologic deficits Removed (Class IIa; Level C)
Major surgery or serious trauma within previous 14 d Removed: tPA may be considered with risks of bleeding weighted against severity and potential disability (Class IIb; Level C)
Gastrointestinal or urinary tract hemorrhage within previous 21 d Gastrointestinal or urinary tract hemorrhage
Acute myocardial infarction (MI) within previous 3 mo Modified: Reasonable if MI was non–ST-elevation MI (STEMI) (Class IIa: Level C) or STEMI involving the right or inferior myocardium (Class IIa; Level C) or STEMI involving left anterior myocardium (Class IIb; Level C)

Data from Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44(3):870–947; and Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016;47(2):581–641.

Dec 1, 2017 | Posted by in Uncategorized | Comments Off on Ischemic Stroke
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