RECAPEM

Update on Management of Acute Ischemic Stroke in The Emergency Department

December 12, 2020 via Shahriar Lahouti

CONTENTS

Abbreviation: AIS, acute ischemic stroke; CAA, cerebral amyloid angiopathy; CVA, cerebrovascular accident; CVT, cerebral vein thrombosis; DWI, diffusion-weighted imaging; EVT, endovascular therapy; FLAIR, fluid-attenuated inversion recovery; ICH, intracranial hemorrhage; IV-tPA; intravenous tissue plasminogen activator (alteplase in our discussion) NCCT, noncontrast computed tomography; CTA, CT angiography; LVO, large vessel occlusion; MRI, magnetic resonance imaging; MRA, MR angiography; MT, mechanical thrombectomy;

Preface

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Cerebrovascular disease encompasses a variety of medical conditions that affect the cerebral circulation and brain function. Stroke is generally defined as any disease process that interrupts blood flow to the brain. In the following discussion acute ischemic stroke and transient ischemic attack are reviewed in the light of recent guidelines.

Anatomy and Pathophysiology

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An understanding of the diagnosis and treatment of stroke begins with a clinical knowledge of the relevant vascular supply and neuroanatomy of the brain (see following slides).

The significance of grasping pathophysiologic classification (figure 1) is that each type of stroke has a different presentation, treatment and prognosis. Acute cerebrovascular syndrome (ACVS) is a constellation of signs and symptoms that are caused by any acute vascular pathology (arterial or venous) that injures the central nervous system tissues. Arterial CVA is classified broadly into two major types; ischemic (≈68%) and hemorrhagic (≈32%)1. Ischemic stroke (the main focus of this discussion) has three main subtypes; thrombotic, embolic and hypoperfusion.

 

The vascular supply is divided into anterior and posterior circulations (figure 2). Clinical findings in ischemic stroke are determined by the location of the lesion, but the degree of collateral circulation may cause variations in the specific clinical symptoms and their severity. The clinical findings in acute ischemic stroke (AIS) is summarized in the following table (figure 3).

 

Clinical Presentation of Ischemic Stroke

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Acute ischemic stroke and transient ischemic attack (TIA) are medical emergencies that occur as a result of disruption in blood flow to the brain, and originate from a similar pathophysiologic process along the spectrum of acute cerebrovascular syndrome. The core feature of ischemic cerebrovascular accidents is abrupt onset of focal neurologic deficit (FND). However the reverse is not true, that is to say not all neurological signs and symptoms with sudden onset of FND are ischemic (see DDx below). One may distinguish ischemic vascular accidents from other disease processes by investigating certain historical and clinical features (figure 4).

NATURE OF SYMPTOMS: The symptoms and signs in ischemic attack are ‘negative’ in nature (i.e. loss of normal brain function) hence called “Neurologic Deficit”; as opposed to positive or irritative phenomena, which usually have a non-vascular cause (e.g. migraine, seizure, radiculopathy, etc).

  • Negative symptoms may include loss of vision, hearing, feeling, or ability to move a part of the body
  • Positive symptoms suggest active discharge from the central nervous system including visual (eg, bright lines, shapes, objects), auditory (eg, tinnitus), somatosensory (eg, paresthesia), or motor (eg, jerking movements).

ONSET: Thrombotic stroke has a gradual onset while embolic stroke and SAH have an abrupt onset. Most patients with ‘ICH’ have gradual onset (sometimes they may have abrupt onset with maximal deficit severity at the very beginning).

The negative symptoms in ischemic vascular accidents may involve one or more modality or function (e.g. motor +/- sensory). The key feature is that it all happens simultaneously at the very onset of attack (while for example in migraine aura the symptoms typically progresses from one modality to another; i.e. after the visual symptoms clear, paresthesia begins. when paresthesia is clear, aphasia or other cortical function abnormalities may develop).

COURSE & PROGRESSION:The neurologic deficits in thrombotic stroke have stuttering (wax and waning) patterns. ‘ICH’ has progressive patterns and severity of signs and symptoms progress over time. Deficits in patients with embolic stroke may suddenly resolve (since endogenous plasminogen activator may lyse the clot).

FOCAL SYMPTOMS: Denotes dysfunction at anatomically localized brain area. In the context of ischemic events the focal signs and symptoms are negative in nature; called ‘FND’ such as unilateral motor or sensory deficit. For example a focal ischemic insult at the frontal lobe cannot cause bilateral motor deficit or any sensory deficit. Examples for non-focal deficit may include altered level of consciousness, bilateral motor or sensory deficit, amnesia2.

Since focal neurologic deficit can be caused by different pathophysiologic processes (ischemic stroke, hemorrhage, local effect of a mass lesions such as tumor or an enlarging cerebral artery aneurysm, herniation syndromes etc) it is more helpful to consider ‘FND’ in correlation with a vascular territory.

VASCULAR TERRITORY:The negative symptoms of ischemic vascular accident should usually correlate with a specific vascular territory. Ischemic vascular insult can happen in two distinct cerebral circulation (anterior vs. posterior circulation). It can happen in large vessels of the corresponding cerebral circulation or in small “penetrating branches” of the vessels (lacunar stroke). The distinguishing signs and symptoms are mentioned in figure 3.

ASSOCIATED SYMPTOMS: Certain associated symptoms can suggest specific stroke subtypes:

Altered level of consciousness: Despite that differential diagnosis of altered level of consciousness is broad, When other clinical presentations are suggestive for stroke, reduced alertness can be caused by the following process:

  • Elevated ICP secondary to ICH, SAH, CVT, massive embolic or thrombotic stroke (a large hemispheric infarct are typically followed by edema that can progress to coma).
  • Posterior circulation large arteries thrombotic or embolic stroke (In particular, ischemia involving the tegmentum of the pons can cause loss of consciousness)
  • Thalamic or pontine hemorrhage

👉Patients with signs and symptoms of systemic hypoperfusion (i.e. shock state) can present with altered level of consciousness, pallor, sweating, tachycardia or severe bradycardia, and low blood pressure. The neurologic signs are typically bilateral, although they may be asymmetric when there is preexisting cerebral vascular occlusive disease.

Seizure: occurrence of seizure within the acute phase of stroke suggests a cortical lesion. It is most commonly seen with SAH, ICH (lobar ICH), CVT and rarely may be seen with ischemic stroke (brain embolism).

Headache: Presence of headache is often more consistent with other diagnosis (ICH, SAH, CVT) rather than ischemic stroke (rarely some patients may have headaches in the prodromal period before thrombotic strokes).

Vomiting: It is more suggestive for elevated intracranial pressure (ICH, SAH, CVT) or may be seen in patients with posterior circulation large artery ischemia.

Fever: Raise the possibility of endocarditis and embolic stroke.

Chest pain: Patients with aortic dissection (type A) may develop acute ischemic stroke which is preceded by sudden onset of chest pain. Rarely patients with extensive atherosclerosis may develop ‘AIS’ and acute myocardial infarction simultaneously!

Neck pain: It may suggest cervicocerebral arterial dissection.

Elevated ICP: Global symptoms of elevated ICP include headache, depressed global consciousness and vomiting. Focal symptoms of elevated ICP may be caused by local effects in patients with mass lesions or by herniation syndromes (e.g. subfalcine, central transtentorial, uncal transtentorial, upward cerebellar, cerebellar tonsillar/foramen magnum, and transcalvarial).

Signs of elevated ICP include CN VI palsies, papilledema. Nowadays bedside ultrasound is widely available, and elevated ICP can be easily identified. Ocular sonography can provide a noninvasive measure of optic nerve sheath diameter, which has been found to correlate with ICP. A number of studies have found that diameters of 5 to 6 mm have the ability to discriminate between normal and elevated ICP in patients with intracranial hemorrhage and traumatic brain injury (more on this here).

The etiologies of elevated ‘ICP’ is discussed here. For the purpose of this discussion, presence of intracranial hypertension may suggest hemorrhagic infarction or a massive ischemic infarct.

DURATION:The duration of neurologic deficit has traditionally been used to separate ‘TIA’ from infarction.

Typically the signs and symptoms of TIA last less than 1-2 hours (by classic ‘time-based’ definition < 24 hours). However with the advent of neuroimaging it has been shown that time is not reliable to distinguish ‘TIA’ from stroke as 33% of patients whose neurologic symptoms have lasted for less than 24 hours and have been resolved by the time of evaluation shown to have evidence of brain tissue infarction in diffusion-weighted MRI. These patients are at a higher risk of developing full blown ischemic infarction.

In the ‘tissue-based’ definition, TIA is a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia; without acute infarction3. The clinical significance of the ‘tissue-based” definition relies in two facts:

  1. All patients suspected of having acute cerebrovascular syndrome should have early neuroimaging4.
  2. Patients with acute cerebrovascular syndrome (brief and spontaneously resolving) whose neuroimaging shows evidence of infarction have higher risk of developing ischemic CVA within the next 48hours.

 

Physical Exam:

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.

In cases where time-sensitive treatment decisions must be made, the initial assessment may be very brief and performed in parallel to other interventions.

NIHSS SCORE:The National Institutes of Health Stroke Scale is widely used to assess neurological deficits in stroke patients in a structured manner. It provides a general measure of neurologic deficits using 11 items to produce a score of 0 to 42. Higher scores predict a larger lesion size, greater stroke severity, and worsened short- and long-term outcomes. All patients should have the ‘NIHSS’ calculated, as it is a widely accepted measure of stroke severity. Generally, this should be performed after initial stabilization and neuroimaging.

Notably, the ‘NIHSS’ is a tool designed for research and is good at revealing the potential for stroke in the anterior circulation but is not as reliable for the posterior circulation.

Differential Diagnosis

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The history and physical examination should be used to distinguish between other disorders in the differential diagnosis of stroke (figure 5) . As examples, seizures, syncope, migraine, and hypoglycemia can mimic acute ischemia. The most difficult cases involve patients with focal signs and altered level of consciousness. It is important to ask the patient or a relative whether the patient takes insulin or oral hypoglycemic agents, has a history of a seizure disorder or drug overdose or abuse, medications on admission, recent trauma, or hysteria.

Delineatingthe duration of attack is helpful to distinguish ischemic accidents from certain other diseases with paroxysmal nature (e.g. migraine, seizure).

A scoring system (FABS) is proposed for screening and stratifying stroke mimics from acute cerebral ischemia and to identify patients who may require magnetic resonance imaging to confirm or refute a diagnosis of stroke in the emergency setting 5. This scoring system includes 6 variables with 1 point for each variable, if present:

  • Absence of Facial droop
  • Negative history of Atrial fibrillation
  • Age <50 years
  • Systolic Blood pressure <150 mm Hg at presentation
  • History of Seizures
  • Isolated Sensory symptoms without weakness at presentation

FABS score ≥3 could identify patients with stroke mimic with sensitivity of 90% and specificity of 91% The negative predictive value and positive predictive value were reported as 93% and 87% respectively.

It seems to be reliable in stratifying stroke mimics from acute cerebral ischemia cases among patients in whom the head CT was negative for any acute findings. It can help clinicians consider advanced imaging for further diagnosis.

 

Approach To Diagnosis and Management

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The classic mantra, time is brain explains the current AHA/ASA stroke guidelines recommendation to enact “an organized protocol for the emergency evaluation of patients with suspected stroke”. A door-to-needle time of ≤60 minutes is the benchmark for achieving rapid treatment with intravenous alteplase6. The in-hospital timeline is shown below (figure 6).

 

Medical Stabilization

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AIRWAY: All patients with suspected acute stroke should be assessed immediately upon arrival for airway compromise 6. Patients who are unable to clear oral secretions or maintain airway stability should be immediately intubated ( neurocritical care intubation).

BREATHING: Provide supplemental O2 if oxygen saturation is <94%. Supplemental O2 is not recommended in non-hypoxic patients with ‘AIS’ 6.

CIRCULATION: All patients with suspected acute stroke should be assessed immediately upon arrival for hemodynamic stability 6.

  • Hypotension with evidence of poor perfusion (shock state) can mimic stroke especially in elderly patients and should be appropriately managed.
  • Hypertension: Patients with cerebrovascular accidents frequently have high blood pressure. The approach to blood pressure management in ‘AIS’ is inherently different from the approach in acute hemorrhagic stroke. For this reason, a neuroimaging study (CT or MRI) is critical to help guide blood pressure therapy in patients with acute stroke.
  • IV Access: Obtain peripheral intravenous (IV) access and avoid unnecessary lines, and ABG sinceminor vascular trauma in patients with ischemic CVA who are deemed to be candidates for thrombolysis may become a real problem.
  • Initiate labwork

DISABILITY: Perform a focused neurological exam and obtain a point-of-care glucose.

  • The focused exam is structured around relevant data gathered during the medical history and is catered to the differential diagnosis. The examiner should be focused on determining whether (1) there is a lesion and (2) where the lesion is localized.

👉ECG: Baseline ECG assessment is recommended in patients presenting with “AIS” but should not delay initiation of IV alteplase in selected patients.

👉Nothing by mouth (NPO) to protect against aspiration

👉Nonessential testing and procedures should not delay performing brain imaging within 25 minutes of the patient’s arrival 6.

 

Brain imaging: Determination of Stroke Major Types

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All patients suspected for ‘AIS’ and ‘TIA’ (determined to be stable) should be taken immediately for neuroimaging (Non-contrast head CT +/- other modalities)6. Brain and neurovascular imaging plays a crucial role in acute stroke by 7 8:

  • Differentiating ischemia from hemorrhage (Is there an ICH at NCCT that is a contraindication to IV-tPA or EVT, or is there a large well-established hypoattenuating infarct?)
  • Excluding stroke mimics, such as tumor
  • Assessing the status of large cervical and intracranial arteries (Is there a proximal LVO seen at CTA that can be treated with EVT?)
  • Estimating the volume of brain tissue that is irreversibly infarcted (ie, infarction core)
  • Estimating the extent of potentially salvageable brain tissue that is at risk for infarction (ie, ischemic penumbra)

The approach to imaging may differ according to individual patient characteristics (eg, time from stroke onset, potential candidate for reperfusion therapies) and local availability of stroke expertise and imaging capabilities.

  • For example in patients suspected of ‘TIA’ who are asymptomatic (time is not brain) by the time of presentation to the hospital it may be reasonable to obtain brain MRI initially if available.

However when a patient is a potential candidate for IV-tPA based on clinical characteristics and initial head CT, do not delay thrombolytic administration while waiting to perform more advanced imaging such as CTA.

NONCONTRAST HEAD CT: It is the most common imaging modality used for triage of ‘AIS’; since it is widely available, rapid, and can easily detect ‘ICH’. Most ‘AIS’ are not visualized by a non-contrast brain CT in the early hours of a stroke.Therefore, the utility of the first brain CT is primarily to exclude ‘ICH’, abscess, tumor, and other stroke mimics, as well as to detect current contraindications to thrombolytics (e.g. extensive regions of clear hypoattenuation)7.

👉Minor ischemic changes (ie, early signs of infarction) on CT are not a contraindication to treatment; these include subtle or small areas of hypodensity, loss of gray-white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery sign (figure 6). In patients with a hyperdense MCA sign, IV-tPA can be beneficial.

👉IV-tPA is not beneficial in the presence of extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT and is not recommended6 (figure 7). Severe hypoattenuation is defined as obvious hypodensity which represents irreversible injury6. These patients have a poor prognosis despite IV-tPA.

BRAIN MRI: Standard brain MRI protocols that include conventional T1-weighted, T2-weighted, FLAIR, DWI and the apparent diffusion coefficient (ADC) map; can reliably diagnose both ‘AIS’ and acute hemorrhagic stroke in emergency settings.

Major drawbacks of MRI are that it is not readily available and its use may be limited by contraindications (e.g. metal implant or pacemakers) or patient intolerance (i.e. claustrophobia). Newer ultrafast MRI protocols can reduce acquisition times from the 15 to 20 min required for conventional MRI to 5 min or less.

👉Brain MRI with DWI is superior to NCCT for the detection of acute infarction9. It is the diagnostic gold standard in acute cerebrovascular syndrome to differentiate TIA from infarction and non-ischemic mimics. Up to 30% of suspected TIA patients with clinical resolution of symptoms will show a rule-in infarction on MRI (figure 9).

Moreover DWI can provide prognostic information in patients with ‘TIA’ 10 11 (more on this below).

DWI-FLAIR mismatch: It refers to evidence of a hyperintense lesion on DWI consistent with acute infarction but no corresponding signal abnormality on the FLAIR images (figure 10). This mismatch indicates that the stroke is relatively acute (ie, within 4.5 h), since insufficient time has passed for development of hyperintense signal on FLAIR, a sign of vasogenic edema. In some trials this DWI-FLAIR mismatch has been used to select patients for treatment with IV-tPA when the time of stroke onset is unwitnessed or unknown12.

VASCULAR IMAGING:

With the advent of endovascular therapies, identifying the presence of intracranial large-vessel occlusion is important for therapeutic decisions. CTA or MRA can detect these lesions7 (figure 11). If a patient is a possible candidate for EVT, vascular imaging is recommended concurrently with the initial head CT; however, these additional studies should not delay thrombolytic administration.

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.

PERFUSION STUDY:

In acute ischemic stroke, the area of irreversible brain infarct (core) is surrounded by ischemic tissue (penumbra) that may potentially be salvageable (figure 12), regardless of the time of onset of symptoms.

Perfusion study (Multimodal CT or MRI) can provide crucial information about the volume of tissue that is irreversibly damaged (infarction core) and the volume of tissue that is critically hypoperfused but potentially salvageable with reperfusion (ischemic penumbra)7. This will guide further therapy for patients who fall outside the time ranges for thrombolysis or where the time of symptom onset is unclear

 

Reperfusion Therapy

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Ischemic CVA is a time-sensitive diagnosis (time is brain⏳) and the most important factor in successful reperfusion therapy of ‘AIS’ is early reperfusion for appropriate candidates.

The immediate goal of reperfusion treatment for ‘AIS’ is to salvage regions of the brain that are ischemic but not yet infarcted. The long term goal is to reduce stroke-related disability and mortality.The options for reperfusion therapy are intravenous thrombolytics and mechanical thrombectomy.

 

Intravenous Alteplase (tPA)

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At the current time, alteplase is the only approved thrombolytic agent for ‘AIS’ treatment (if patients meet eligibility criteria).

BENEFIT: Several studies have shown the potential benefit of IV-tPA if administered within 4.5 hours of ischemic stroke symptom onset.13 14 It has been shown that earlier thrombolytic treatment was associated with reduced mortality and symptomatic intracranial hemorrhage and higher rates of independent ambulation at discharge.

RISK OF ICH: Using the National Institute of Neurological Disorders and Stroke (NINDS) definition for symptomatic intracranial hemorrhage (any hemorrhagic transformation temporally related to any neurologic worsening15); IV-tPA is associated with increased risk of symptomatic intracranial hemorrhage (5-7%)14. However this definition of ICH may be overly inclusive because it captures even small petechial hemorrhages associated with minimal neurologic deterioration that are unlikely to have altered long-term functional outcome.

In contrast by using a more clinically sensible definition of symptomatic intracerebral hemorrhage (including only those hemorrhages which are associated with clinical worsening of ≥4 points on NIHSS score16), the rate of symptomatic intracranial hemorrhage was reported as 1.8% in other studies17 .

Although several variables can affect the outcome (e.g. size and site of the clot 18 19, clot age and composition20, age, sex, stroke severity 21 22), the only factor that has been shown to be independently associated with response to treatment is ‘TIME-TO-TREATMENT’. 13 14 23

DECISION MAKING:

All adult patients with a clinical diagnosis of ‘AIS’ should be rapidly screened for treatment with IV-tPA. Simultaneously, patients with suspected ‘AIS’ involving the anterior circulation should be evaluated for mechanical thrombectomy.

BENCHMARK: A door-to-needle time of ≤60 minutes is the benchmark for achieving rapid treatment with IV-tPA (figure 6).

CONTRAINDICATION FOR THROMBOLYTIC: Assess for presence of contraindication for thrombolytic (figure 14)6.

The potential risks should be discussed during IV-tPA eligibility deliberation and weighed against the anticipated benefits during decision making.

A number of clinical issues may complicate the decision to use reperfusion therapy for ’AIS’. These are discussed here.

Hematologic considerations6

In most cases, the results of routine laboratory tests including coagulation parameters and platelet count are not required to proceed with intravenous alteplase treatment. IV-tPA should not be delayed while results are pending unless one of the following conditions is present:

  • Clinical suspicion of a bleeding abnormality or thrombocytopenia
  • Current or recent use of anticoagulants (eg, heparin, warfarin, direct oral anticoagulants [DOACs])
  • Use of anticoagulants is not known

Alteplase could be considered when appropriate laboratory tests such as aPTT, INR, clotting time, thrombin time,

or direct factor Xa activity assays are normal or when the patient has not taken a dose of these ACs for >48 h and renal function is normal.

The treatment should be discontinued if the result of the laboratory results were:

  • PLT< 100.000
  • INR>1.7
  • PTT>40s

👉In otherwise eligible patients who were taking antiplatelet drug monotherapy or combination therapy before the stroke, IV alteplase is recommended.

Rapidly improving stroke symptoms: It should be considered an exclusion for reperfusion therapy only for patients who improve to the degree that any remaining deficits are non-disabling 24.

Severity of stroke: Large infarcts are defined as those that involve more than one ­third of the ‘MCA’ territory or more than one ­half of the ‘PCA’ territory based upon neuroimaging with CT or MRI.Though less reliable, large infarct size can also be defined clinically (eg, NIHSS score >15). It is worth mentioning here that although the severity of neurologic deficit on ‘NIHSS score’ is associated with intracranial hemorrhage 25; stroke severity alone cannot be used to select or exclude patients for intravenous thrombolysis 14 6 .

  • Minor stroke:is defined as low points on NIHSS scoring system (NIHSS ≦5 score) in the absence of persistent disabling neurologic deficit. Any of the following should be considered disabling deficits
    • Complete hemianopia: ≥2 on the National Institutes of Health Stroke Scale (NIHSS) question 3
    • Severe aphasia: ≥2 on NIHSS question 9
    • Visual extinction: ≥1 on NIHSS question 11
    • Any weakness limiting sustained effort against gravity: ≥2 on NIHSS question 5 or 6
    • Any deficits that lead to a total NIHSS >5
    • Any remaining deficit considered potentially disabling by the patient, family, or the treating practitioner
    • For patients with an NIHSS score of 0 to 5, a clearly disabling deficit has also been defined as one that would prevent the patient from performing basic activities of daily living (ie, bathing, walking, toileting, and eating) or returning to work26

Imaging: Minor ischemic changes (ie, early signs of infarction) on CT are not a contraindication to treatment; these include subtle or small areas of hypodensity, loss of gray-white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery sign. In the presence of extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT intravenous thrombolytic is not recommended.

Seizure at onset: IV alteplase is reasonable in patients with a seizure at the time of onset of acute stroke if evidence suggests that residual impairments are secondary to stroke and not a postictal phase.

Dural puncture: IV alteplase may be considered for patients who present with AIS, even in instances when they may have undergone a lumbar dural puncture in the preceding 7 days.

SPECIFIC SITUATIONS:

By time:

  • Unwitnessed stroke onset and “wake-up” stroke: When the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal. For patients whose stroke symptoms are first noted upon awakening from sleep, the last time known to be normal may be the time they went to bed (if the patient can report this reliably) or the last time seen normal by a friend or family member. Such patients are not eligible for alteplase treatment unless the time last known to be normal is less than 4.5 hours. Imaging-based selection of patients with unknown stroke onset time for intravenous alteplase treatment is under investigation.When there is an ischemic parenchymal brain lesion on magnetic resonance imaging (MRI) diffusion-weighted imaging but no corresponding hyperintensity on fluid-attenuated inversion recovery (FLAIR), an imaging mismatch correlates with a stroke onset time of 4.5 hours or less27
  • Although several small studies have shown promising results for imaging-based selection of patients for intravenous alteplase administration when time is not known, additional trials are needed to determine the efficacy and safety of this treatment 28.
  • 3-4.5 hours: For otherwise eligible patients, the benefit of IV alteplase extends to 4.5 hours.However there are additional exclusion criteria for this time window (age >80 years old, an NIHSS score >25, a combination of previous stroke and diabetes, and oral anticoagulant use regardless of INR). However, these are not considered as absolute contraindications to intravenous alteplase treatment in the 3- to 4.5-hour time window, and alteplase is still beneficial in these patients.
  • 4.5-6 hours: Patients within 4.5 to 6 hours from stroke symptom onset should not receive intravenous alteplase because harm may exceed benefit, but they should be evaluated to determine if they are candidates for mechanical thrombectomy.
  • Beyond 6 hours: IV alteplase is not considered as a therapeutic option. However, mechanical thrombectomy using imaging-based selection (CTA, MRA) of patients with anterior circulation stroke who have were last known to be normal or at neurologic baseline 6 to 24 hours before treatment
  • Beyond 24 hours: Patients beyond 24 hours from ischemic CVA symptoms are not eligible for either IV thrombolytic or mechanical thrombectomy.

Age ≧80 years:They still benefit from IV-tPA treatment despite a higher mortality rate compared with younger patients. For otherwise eligible patients, age is not a contraindication for treatment. However age 80 years is a relative contraindication in the 3-to 4.5-hour time window.

Concurrent acute myocardial infarction: For patients presenting with concurrent “AIS” and acute MI, treatment with IV-tPA at the dose appropriate for cerebral ischemia, followed by percutaneous coronary angioplasty and stenting if indicated, is reasonable.

Preexisting disability: Preexisting disability does not seem to independently increase the risk of ICH after IV alteplase, but it may be associated with less neurological improvement and higher mortality. Therapy with IV alteplase for acute stroke patients with preexisting disability (mRS score ≥2) may be reasonable, but decisions should take into account relevant factors, including quality of life, social support, place of residence, need for a caregiver, patients’ and families’ preferences, and goals of care.

Posterior circulation stroke: If otherwise eligible for IV-tPA, they should receive the treatment. Mechanical thrombectomy is beneficial for select patients with ‘AIS’ caused by a proximal intracranial arterial occlusion in the anterior circulation, but trials that established the benefit of mechanical thrombectomy largely excluded patients with posterior circulation infarcts. However, endovascular interventions for vertebrobasilar occlusions, including mechanical thrombectomy, may be treatment options for stroke centers with appropriate expertise.

Arterial dissection: Patients with cervicocephalic arterial dissection will benefit from reperfusion therapy (IV-tPA, and/or MT) if otherwise eligible 29. This does not include aortic dissection wherein tPA is absolutely contraindicated.

  • Patients with cervicocerebral arterial dissection who are not candidates for reperfusion therapy, benefit from antiplatelet or antithrombotic agents, though the superiority of antithrombotic drugs over antiplatelet has not been shown 30.

 

Mechanical Thrombectomy (MT)

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Patients with ‘AIS’ due to proximal large artery occlusion may not respond well to IV-tPA and eligibility for ‘MT’ should be considered simultaneously while evaluating for IV-tPA treatment. It is indicated for patients with ‘AIS’ due to a large artery occlusion in the anterior circulation who can be treated within 24 hours of the time last known to be well (ie, at neurologic baseline), regardless of whether they receive IV-tPA for the same ischemic stroke event.

Patients with ischemic stroke from large vessel occlusion should receive IV-tPA without delay, if eligible, even if ‘MT’ is being considered 6 . ‘MT’ treatment should then be started as quickly as possible31, and should not be delayed to assess the response to IV-tPA.

Patient selection:

General criteria: All patients should meet the general criteria for ‘MT’ which include:

  • ‘MT’ can be performed within 24h of the symptom onset at a stroke center with appropriate expertise in the use of stent retrievers
  • Vascular imaging(e.g. CTA) shows proximal large artery occlusion in the anterior circulation
  • Persistent disabling neurologic deficit
  • A small infarct core (ie, limited signs of early ischemic change) on neuroimaging and absence of hemorrhage

Specific criteria: For patient selection within a certain time window certain eligibility criteria should be met.

Within the 6hours: For patients who can be treated within 6 hours of the symptom onset, the following criteria for ‘MT’ is adapted and modified from MR CLEAN trial 32:

  • Age ≧18 y
  • Pre-stroke disability score {modified Rankin Scale (mRS) score of ≤1}
  • NIHSS score ≧ 6 or or any persistent neurologic deficit that is potentially disabling
  • ASPECTS score ≥6 on noncontrast brain CT or DWI-MRI (figure 16)
  • Intracranial arterial occlusion of the distal intracranial ICA, or the M1 or M2 segments of the MCA, or the A1 or A2 segments of ACA, demonstrated with CTA, MRA,

6 to 24 hours: The DEFUSE 333and DAWN34 trials selected patients for treatment beyond 6 hours using imaging-based criteria which are mentioned in the following figure (figure 15).

 

Initial Management of Acute Ischemic Stroke

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Intravenous alteplase administration: “Time is brain.” The sooner IV-tPA treatment is initiated after ischemic stroke (in eligible patients), the more likely it is to be beneficial. Before initiating treatment make sure that the following conditions are met 6:

  1. The diagnosis is acute ischemic stroke
  2. Treatment is commencing within the required 4.5 hour time window after the onset of symptoms, defined as the time last seen normal or at baseline
  3. There is a persistent, measurable neurologic deficit
  4. Eligibility criteria are met
  5. Serum glucose must be checked to rule out hypoglycemia as a cause of neurologic deficit.
  6. The noncontrast head CT or brain MRI is without hemorrhage or other contraindication
  7. Blood pressure parameters are met
  8. Two intravenous lines, preferably large bore, are in place
  9. Accurate body weight has been determined

All patients who have received IV alteplase for acute ischemic stroke should be admitted to an intensive care unit or dedicated stroke unit for at least 24 hours of close neurologic and cardiac monitoring 6.

Blood pressure management: The approach to blood pressure management in acute ischemic stroke is inherently different from hemorrhagic stroke (will be discussed separately). The blood pressure targets 6 for patients with acute ischemic stroke and therapeutic options are shown in figure below.

If patients with acute ischemic stroke who are otherwise eligible for reperfusion therapy, the blood pressure should be acutely controlled to the level below 185/110mm Hg (otherwise the patient cannot receive reperfusion therapy) 6. The blood pressure should be closely monitored during the treatment and within 24hours post-treatment (figure 7).

👉Generally reversible and titratable agents are best option, since they allow rapid and safe titration to the goal blood pressure (e.g. nicardipine, clevidipine, labetalol). However in patients who have comorbid conditions (e.g. aortic dissection, acute myocardial infarction, preeclampsia/eclampsia) different therapeutic regimens may be considered.

In patients who are not candidate for reperfusion therapy, the blood pressure should not be treated acutely unless the hypertension is extreme (SBP>220 or DBP>120 mmHg), or the patient has active ischemic coronary disease, heart failure, aortic dissection, hypertensive encephalopathy, or pre-eclampsia/eclampsia. When treatment is indicated, cautious lowering of blood pressure by approximately 15% during the first 24 hours after stroke onset is suggested.

👉Pain and anxiety both can cause elevated blood pressure. Before initiating antihypertensive medications make sure that pain and anxiety have been adequately treated especially among intubated patients.

Be Prepared: In patients undergoing fibrinolytic therapy, physicians should be prepared to treat potential emergent adverse effects, including bleeding complications and angioedema that may cause partial airway obstruction 6.

Symptomatic intracerebral hemorrhage should be suspected in any patient who develops sudden neurologic deterioration, a decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in blood pressure after thrombolytic therapy is administered, especially within the first 24 hours of treatment. The management of patients with symptomatic ICH (figure 19) and angioedema (figure 20) are mentioned below.

Systemic bleeding: Mild systemic bleeding usually occurs in the form of oozing from intravenous catheter sites, ecchymoses (especially under automated blood pressure cuffs), and gum bleeding; these complications do not require cessation of treatment 6. More serious bleeding, such as from the gastrointestinal or genitourinary system, may require discontinuation of alteplase depending on the severity. Rarely, patients who suffer stroke after a recent myocardial infarction can develop bleeding into the pericardium, resulting in life-threatening tamponade. Consequently, patients who become hypotensive after alteplase should be evaluated with urgent echocardiography6.

Fever: Hyperthermia (temperature > 38C)contributes to neuronal injury 6 in patients with acute stroke via several different mechanisms (more on this here). Besides treatment of fever, make sure to search for and exclude certain conditions including meningitis, subdural empyema, brain abscess, infective endocarditis and more common problems such as urinary tract infection, pneumonia.

Hypo/hyperglycemia: Both conditions (hypoglycemia and hyperglycemia) can mimic cerebrovascular accidents and also can cause neuronal injury through multiple mechanisms6.

  • Hypoglycemia ( blood sugar < <60 mg/dL) should be corrected.
  • Hyperglycemia is common in patients with acute stroke and is associated with poor functional outcome. It may be due to preexisting diabetes, newly diagnosed diabetes or stress hyperglycemia. Recent guidelines suggest to keep serum glucose in the range of 140 to 180 mg/dL. However several studies have shown that tight control of glucose with intravenous insulin does not improve functional outcome in patients with acute ischemic stroke.

Swallowing assessment: Dysphagia is common in patients with acute stroke and is associated with development of aspiration pneumonia. It is important to keep the patient ‘NPO’ (nothing by mouth) to protect against aspiration until the swallowing function is evaluated 6.

Antiplatelet therapy: Administration of aspirin (dose 160 to 300 mg) 6 is recommended in patients with AIS within 24 to 48 hours after onset. For those treated with IV alteplase, aspirin administration is generally delayed until 24 hours later. Note that aspirin, if and when indicated, can be given rectally if swallowing assessment is not performed or the patient has dysphagia

  • Dual antiplatelet therapy (DAPT): In patients presenting with minor noncardioembolic ischemic stroke (NIHSS score ≤5) who did not receive IV-tPA, treatment with dual antiplatelet therapy (aspirin and clopidogrel) started within 24 hours after symptom onset and continued for 21 days is effective in reducing recurrent ischemic stroke for a period of up to 90 days from symptom onset35

Prophylaxis for deep vein thrombosis: VTE prophylaxis with thigh-length intermittent pneumatic compression (IPC), starting at admission, for patients within 72 hours of acute ischemic stroke onset who have restricted mobility is recommended in addition to routine care (hydration and aspirin) 6.

  • Pharmacologic VTE prophylaxis can be administered for select patients within 48 hours of acute ischemic stroke onset who have restricted mobility. Exceptions include patients with TIA or minor stroke who are being treated with dual antiplatelet therapy (DAPT) and patients receiving full-dose heparin or oral anticoagulation for another indication. Option may include subcutaneous LMWH (e.g. enoxaparin 40mg daily) or subcutaneous low-dose unfractionated heparin (5000 units two to three times daily)

Statin therapy: The utility of statin therapy during the acute phase of ischemic stroke is less well-studied; however several studies have shown that long-term intensive statin therapy is associated with a reduced risk of recurrent ischemic stroke and cardiovascular events. Therefore for patients with acute ischemic stroke starting statin treatment as soon oral medications can be used safely seems reasonable 36.

 

Determining The Stroke Subtypes

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Treatment of patients with ‘AIS’ involves several phases. The initial phase of management includes medical stabilization and reperfusion therapy (IV-tPA and/or MT) if eligible.

The next phase of management includes determining the pathophysiology of the ‘AIS’ via performing a more comprehensive evaluation, so that secondary prevention of stroke could be implemented as soon as possible.

As already discussed (figure 4), the pathophysiology of the “AIS” and “ TIA”can be classified into (TOAST classification system 37):

  • Large artery atherosclerosis
  • Cardioembolism
  • Small-vessel occlusion
  • Stroke of other determined etiology
  • Stroke of undetermined etiology
    • Two or more causes identified
    • Negative evaluation
    • Incomplete evaluation

Determining the pathophysiology of ischemic stroke and “TIA” is typically accomplished by performing a comprehensive evaluation including:

  • Cardiac monitoring for possible occult atrial fibrillation
  • Echocardiography (TTE/TEE) to identify the possible source of cardioembolism (figure 4).
  • Vascular study (Duplex ultrasound of neck, CTA or MRA of neck and head arteries) to determine the status of major cerebral vessels.
  • Blood test including hypercoagulable studies in select patients.

However sometimes despite a thorough evaluation, the etiology of ischemic stroke is not well-defined; hence called cryptogenic stroke. It is defined as brain infarction that is not attributable to a source of definite cardioembolism, large artery atherosclerosis, or small artery disease despite a thorough vascular, cardiac, and serologic evaluation 38.

  • The pathophysiology of cryptogenic stroke is likely heterogeneous. Proposed mechanisms include cardiac embolism secondary to occult paroxysmal atrial fibrillation, aortic atheromatous disease or other cardiac sources, paradoxical embolism from atrial septal abnormalities such as patent foramen ovale, hypercoagulable states, and preclinical or subclinical cerebrovascular disease.
  • It has been shown that a significant proportion of cryptogenic strokes adhere to embolic infarct topography on brain imaging.
  • Cryptogenic stroke is a diagnosis of exclusion.
  • The acute management of cryptogenic stroke is similar to that of other ischemic stroke subtypes.

 

Secondary Prevention

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Once the pathophysiology of the ischemic event is identified, then decision on treatment regimen for secondary prevention of ischemic attack can be made which include medical treatment (antiplatelets or antithrombotic agents) or vascular intervention (i.e. carotid revascularization). The general approach for secondary prevention of ischemic events in patients with ‘AIS’ and ‘TIA’ is provided in the following algorithm (figure 21). Keep in mind that this algorithm is intended to provide a general picture of using antiplatelet and antithrombotic drugs and the outlined steps may vary among patients. Refer to guidelines for the chosen drug and dosage in the selected patient 6 38.

 

Disposition

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Admission:

Almost all ‘AIS’ patients with persistent neurologic deficits, in addition to high-risk TIA patients, should be admitted to the hospital 6.

Patients receiving reperfusion therapies should be admitted to institutions with neurosurgical capabilities in the event of (HT) warranting emergency intervention.

Patients in extremis or with signs of increased intracranial pressure (hydrocephalus, midline shift, altered mental status, seizures) should be cared for in an intensive care unit (preferably one with neurocritical care expertise).

Discharge:

Some patients with ‘TIA’ may be discharged home if certain criteria are met. As discussed earlier, the definition of ‘TIA’ has evolved to ‘tissue-based’ and virtually all patients who have a suspected TIA require urgent evaluation due to the high stroke risk associated with TIA as defined by this new definition.

The appropriate initial evaluation of ‘TIA’ may include basic laboratory studies that are suggested by the history and physical examination,EKG, brain imaging, and neurovascular imaging.

The nature and tempo of the symptoms and signs and a negative brain imaging (DWI-MRI) for infarction can suggest the brain ischemia i.e. ‘TIA’ as the cause of the patient’s signs and symptoms. However many other non-vascular etiologies can mimic ‘TIA’ which have been discussed earlier.

Upon clinical diagnosis of ‘TIA’, risk stratification should be performed to identify those patients who are at higher risk of developing ischemic stroke and therefore benefit from hospital admission and possible urgent intervention or treatment. It has been shown that the most clinically used prediction tool for risk stratification (ABCD2 score 39 ) does not provide an accurate estimate of stroke risk and clinical decisions based on an ABCD2 score cut-off are subject to significant misclassification error. Clinical judgment and integrating certain clinical and imaging features are more accurate in predicting risk of cerebrovascular events 40.

Symptom-based risk stratification identifies patients with high or moderate risk as:

  • High risk symptoms: Unilateral weakness (face, arm, leg), slurred speech
  • Moderate risk symptoms: Presence of any of the following symptoms and (absence of motor or language disturbance): Hemi-sensory deficits, monocular visual loss, hemi-visual field deficit, or presence of posterior circulation signs and symptoms(e.g. Dysarthria, diplopia, ataxia)

Time from symptom onset to health care presentation risk stratification41

  • High risk: < 48h
  • Moderate risk: 48 hours to 2 weeks
  • Low risk: more than 2 weeks

Other clinical features associated with high risk ‘TIA’ include:

  • Known significant carotid stenosis
  • Patient with diabetes
  • Crescendo TIA
  • Large ischemic stroke in the past
  • Suspected embolic source (e.g. AF, DCM, valvular heart disease, recent acute myocardial infarction)
  • Positive initial DWI-MRI imaging for infarction 42 43 44

After comprehensive evaluation, some patients without high risk feature who meet all of the following criteria may be safely discharged home :

  • The patient’s symptoms are completely resolved and they have not been stuttering or crescendo-like, suggesting an unstable process.
  • Neuroimaging is reassuring.
  • Vessel imaging of the head and neck does not reveal new significant/critical large vessel stenosis or occlusion warranting immediate intervention.
  • The patient does not have evidence of a clear and unaddressed cardioembolic etiology (such as atrial fibrillation).
  • Early specialty follow-up (preferably with a vascular neurologist) can be arranged.

 

Going further:

Post Peer Reviewed By: Mojtaba Chardoli. MD, Darab Zohri. MD

 

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Shahriar Lahouti

Founder, Chief Editor
I am Shahriar Lahouti and RECAP EM is my primary FOAMed project. The philosophy of RECAP EM is to promote critical thinking and enlightening the mindsets with most rational, current evidence towards a safer practice.

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