Key points

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 .

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.

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 .

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 6

American Heart Association (AHA) guidelines inclusion and exclusion criteria less than 4.5 h

Inclusion
Diagnosis of ischemic stroke causing measurable neurological deficit Onset of symptoms within 3.0–4.5 h

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