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Jul.22.2022

Ischemic Stroke

Synopsis

Key Points

  • Ischemic stroke is an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction
  • Initial physical examination includes a focused neurologic examination, which enables the examiner to obtain a baseline NIH Stroke Scale score. Evaluation must proceed quickly; immediately involve neurologist or stroke team so that patient does not lose eligibility for time-limited treatments
  • CT scan (without contrast) is initial imaging modality of choice (in most facilities) to exclude acute hemorrhage; MRI is an alternative r1
  • If large vessel infarct is suspected and endovascular mechanical thrombectomy is considered, perform CT angiography or magnetic resonance angiography to image intracranial vessels; this imaging must not delay administration of IV thrombolytic therapy to eligible patients r1
  • IV recombinant tissue plasminogen activator is first line therapy and is administered to patients who meet eligibility criteria within 3 hours of symptom onset. This window of time may be stretched to 4.5 hours for some patients who meet eligibility criteria r1
  • Offer endovascular mechanical thrombectomy in addition to IV thrombolytic therapy to eligible patients with infarct attributable to an occluded internal carotid artery or proximal middle cerebral artery, NIH Stroke Scale score of 6 or higher, and good prestroke function
  • Selected patients with other causative occlusions who do not meet these criteria also may benefit from endovascular treatment
  • Acute ischemic stroke has variable prognosis, based on location and size of the infarct. IV administration of recombinant tissue plasminogen activator and endovascular mechanical thrombectomy improve functional outcomes but increase risk of intracranial bleeding
  • Early recognition and management of stroke complications, including cerebral edema and intracranial bleeding, help prevent further brain damage

Urgent Action

  • Urgent management of airway, ventilation, and circulation is vital in patients who have decreased levels of consciousness
  • Implement institutional stroke code for patients with acute ischemic stroke to administer recombinant tissue plasminogen activator within 3 hours of symptom onset, after appropriate screening, with the following goals: r2
    • Within 20 minutes of patient arrival: perform CT scan (without contrast) r1
    • Determine eligibility for thrombolytic therapy
    • Within 3 hours of symptom onset (4.5 hours in selected patients): administer IV recombinant tissue plasminogen activator r1
    • Door-to-needle goal for thrombolytic therapy is within 60 minutes; a 45-minute goal is considered reasonable r1r2
  • For most patients, the only laboratory test result that must be reviewed before administering a thrombolytic agent is fingerstick (or blood-drawn) glucose level
  • Selected patients (ie, those with possible bleeding diathesis and those suspected or known to be on anticoagulants) must have their coagulation study results reviewed before being given IV thrombolysis
  • If anticipating endovascular therapy, obtain imaging of intracranial vessels with either CT or magnetic resonance angiography during initial brain imaging, if possible r1

Pitfalls

  • After taking initial history, obtain head CT without contrast if ischemic stroke is suspected. Do not waste time waiting for results of other recommended diagnostic testing before initiating thrombolytic therapy in eligible patients, with the following exceptions: r1
    • All patients: the only laboratory result required in all patients before thrombolytic therapy is initiated is blood glucose level; fingerstick blood draw is acceptable
    • Patients with known or suspected bleeding diathesis or anticoagulant use: review coagulation studies and platelet count to ascertain eligibility before proceeding
  • IV thrombolytic therapy has proven clinical benefit for both severe stroke symptoms and mild (but disabling) stroke symptoms. Do not exclude patients when NIH Stroke Scale score is low but a functionally disabling deficit (eg, isolated aphasia) is present r1

Terminology

Clinical Clarification

  • Ischemic stroke is brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathologic, neuroimaging, and/or clinical evidence of permanent injury

Classification

  • By an underlying cause r3
    • Lacunar stroke caused small vessel occlusive disease
    • Nonlacunar stroke causes
      • Cardioembolism
      • Large artery atherosclerosis
      • Other known causes
      • Cryptogenic (undetermined cause)
        • Includes embolic stroke of unknown source

Diagnosis

Clinical Presentation

History

  • Clinical presentation is variable, depending on area of brain involved
  • Symptoms usually occur abruptly c1
    • Confusion c2
    • Difficulty finding or forming words c3c4
    • Slurred speech c5
    • Visual symptoms; may include decreased vision or loss of vision in 1 or both eyes or double vision c6c7c8
    • Numbness of face, arm, or leg c9c10c11c12
    • Weakness of face, arm, or leg c13c14c15
    • Difficulty walking, with loss of balance or coordination; may indicate brainstem or cerebellar lesion c16c17c18
    • Headache c19
    • Nausea with vomiting c20c21
  • Time of symptom onset is the most important factor in patient history and should be sought so that eligibility for time-limited thrombolytic and endovascular therapies can be determined r1
    • Time of onset is defined as the last time patient was at baseline (ie, asymptomatic) state
    • If patient lives alone and is uncertain of time of symptom onset, it may be helpful to do some creative questioning regarding television programs being watched when symptoms appeared (eg, check time of airing) or cell phone conversations or text messages sent before or after symptoms occurred (eg, check time stamp on phone)
    • For patients who awaken with stroke symptoms, time of onset is the time patient was last awake without symptoms
    • Commonly, stroke symptoms are preceded by a brief period of similar symptoms that completely resolved before recurring
      • For these patients, for purposes of determining therapeutic eligibility, time of onset is defined as time at which the current set of symptoms began

Acute stroke symptoms in a young patient with neck pain and headache suggest carotid or vertebral dissection as the cause c22c23

Note comorbid conditions and medications that may affect decision to administer thrombolytic therapy, including: r1

  • Current use of warfarin
  • Current use of direct thrombin inhibitors or direct factor Xa inhibitors
  • Head trauma or stroke within past 3 months
  • Myocardial infarction within past 3 months
  • Gastrointestinal or urinary tract bleeding within past 21 days
  • Recent (within past 14 days) major trauma or major surgery, especially cranial or spinal surgery
  • Diagnostic dural or intra-arterial puncture in noncompressible location within past 7 days
  • History of ischemic stroke
  • History of intracranial hemorrhage
  • History of intracranial aneurysm or vascular malformation
  • Bleeding or clotting disorder
  • Systemic malignancy
  • Diabetes
  • Pregnancy

Symptoms that suggest alternative diagnoses include:

  • Fever or recent infection
  • Seizures
  • Psychiatric disorders

Physical examination

  • Decreased level of consciousness requires urgent attention to ABCs (airway, breathing, and circulation) c24
  • Focused neurologic examination allows rapid calculation of NIH Stroke Scale score
    • NIH Stroke Scale forms a baseline to follow disease course, predict prognosis, and assess eligibility for thrombolytic therapy
      • Detailed instructions and scoring are available at NIH/National Institute of Neurological Disorders and Stroke website r4
      • Determine score by the sum of the following variables; a varied number of points are awarded for each response (eg, 0 for normal response): r4
        • Level of consciousness: alert, drowsy, obtunded, or unresponsive c25c26c27c28
        • Response to 2 orientation questions: answers neither, 1, or both correctly c29c30
        • Response to 2 commands: performs neither, 1, or both correctly
        • Gaze: normal horizontal movement, partial gaze palsy, or complete gaze palsy c31
        • Visual fields: no visual field defect, partial hemianopia, complete hemianopia, or bilateral hemianopia c32c33c34
        • Facial movement: normal, minor weakness, partial weakness, or complete unilateral palsy c35c36
        • Motor function in arm (both right and left): no drift, drift before 5 seconds, fall before 5 seconds, no effort against gravity, or no movement c37c38
        • Motor function in leg (both right and left): no drift, drift before 5 seconds, fall before 5 seconds, no effort against gravity, or no movement
        • Limb ataxia: none, present in 1 limb, or present in 2 limbs c39
        • Sensory: none, mild, or severe loss c40c41c42
        • Language: normal, mild aphasia, severe aphasia, or mute c43
        • Articulation: normal, mild dysarthria, or severe dysarthria c44
        • Inattention/extinction: absent, mild, or severe c45
      • NIH Stroke Scale.Instructions: Administer stroke scale items in the order listed. Record performance in each category after each subscale examination. Do not go back and change scores. Follow directions provided for each examination technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the examination and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). NIH source document includes images.From the National Institute of Neurological Disorders and Stroke: NIH Stroke Scale. NIH website. Accessed August 5, 2020. https://catalog.ninds.nih.gov/pubstatic//NDS-636/NDS-636.pdf
        InstructionsScale definition
        1a. Level of consciousness
        The investigator must choose a response if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, 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 totally unresponsive, flaccid, and areflexic.
        Score:
        1b. Level of consciousness questions
        The patient is asked the month and his/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 will score 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 1. It is important that only the initial answer be graded and that the examiner not “help” the patient with verbal or non-verbal cues0 = Answers both questions correctly.

        1 = Answers 1 question correctly.

        2 = Answers neither question correctly.
        Score:
        1c. Level of consciousness commands
        The patient is asked to open and close the eyes and then to grip and release the nonparetic hand. Substitute another 1-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 (ie, follows none, 1, or 2 commands). Patients with trauma, amputation, or other physical impediments should be given suitable 1-step commands. Only the first attempt is scored.0 = Performs both tasks correctly.

        1 = Performs 1 task correctly.

        2 = Performs neither task correctly.
        Score:
        2. Best gaze
        Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be 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 will be 1. If a patient has an isolated peripheral nerve paresis (CN III, IV, or VI), score a 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 1 or both eyes, but forced deviation or total gaze paresis is not present.
        2 = Forced deviation, or total gaze paresis is not overcome by the oculocephalic maneuver.
        Score:
        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 patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11.0 = No visual loss.

        1 = Partial hemianopia.
        2 = Complete hemianopia.
        3 = Bilateral hemianopia (blind including cortical blindness).
        Score:
        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 symmetrical 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 1 or both sides (absence of facial movement in the upper and lower face).
        Score:
        5. Motor arm
        The limb is placed in the appropriate position: extend the arms (palms down) 90° (if sitting) or 45° (if supine). Drift is scored if the arm falls before 10 seconds. 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.0 = No drift; limb holds 90° (or 45°) for full 10 seconds.

        1 = Drift; limb holds 90° (or 45°), but drifts down before full 10 seconds; does not hit bed or other support.

        2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90° (or 45°), drifts down to bed, but has some effort against gravity.

        3 = No effort against gravity; limb falls.
        4 = No movement.

        UN = Amputation or joint fusion, explain:
        Score 5a (left arm):

        Score 5b (right arm):
        6. Motor leg
        The limb is placed in the appropriate position: hold the leg at 30° (always tested supine). Drift is scored if the leg falls before 5 seconds. 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.0 = No drift; leg holds 30° position for full 5 seconds.

        1 = Drift; leg falls by the end of the 5-second period but does not hit the bed.

        2 = Some effort against gravity; leg falls to bed by 5 seconds but has some effort against gravity.

        3 = No effort against gravity; leg falls to bed immediately.

        4 = No movement.

        UN = Amputation or joint fusion, explain:
        Score 6a (left leg):

        Score 6b (right leg):
        7. Limb ataxia
        This item is aimed at finding evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, ensure testing is done in 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 nose from extended arm position.0 = Absent.

        1 = Present in 1 limb.
        2 = Present in 2 limbs.
        UN = Amputation or joint fusion, explain:
        Score:
        8. Sensory
        Sensation or grimace to pinprick when tested, or withdrawal from 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 accurately check for hemisensory loss. A score of 2, “severe or total sensory loss,” should only be given 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 = 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 the affected side; or there is a loss of superficial pain with pinprick, but patient is aware of being touched.

        2 = Severe or total sensory loss; patient is not aware of being touched in the face, arm, and leg.
        Score:
        9. Best language
        A great deal of information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name the items on the attached naming sheet, and to read from the attached list of sentences. Comprehension is judged from responses here, as well as to all of the commands in the preceding general neurological exam. If visual 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 = 3) will automatically score 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 1-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. Reduction of speech and/or comprehension, however, 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 the listener. Range of information that can be exchanged is limited; listener carries burden of communication. Examiner cannot identify materials provided from patient response.

        3 = Mute, global aphasia; no usable speech or auditory comprehension.
        Score:
        10. Dysarthria
        If patient is thought to be normal, an adequate sample of speech must be obtained by asking patient to read or repeat words from the attached 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 the explanation for this choice. Do not tell the patient why he/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.

        UN = Intubated or other physical barrier, explain:
        Score:
        11. Extinction and inattention (formerly Neglect)
        Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable.0 = No abnormality.

        1 = Visual, tactile, auditory, spatial, or personal inattention, or extinction to bilateral simultaneous stimulation in 1 of the sensory modalities.
        2 = Profound hemi-inattention or extinction to more than 1 modality; does not recognize own hand or orients to only 1 side of space.
        Score:
  • Typical patterns of a left (ie, dominant) hemispheric stroke include right hemiparesis, right-sided sensory loss, right-sided visual defect with abnormal right conjugate gaze, dysarthria, and aphasia c46c47c48c49c50c51
  • Typical patterns of a right (ie, nondominant) hemispheric stroke include left hemiparesis, left-sided sensory loss, left-sided visual defect with abnormal left conjugate gaze, neglect of left visual field, inattention to left-sided stimuli, and dysarthria c52c53c54c55c56c57c58
  • Typical patterns of a brainstem or cerebellar stroke include sensory loss in all limbs, gait ataxia, bilateral visual field defects, nystagmus, dysconjugate gaze, and amnesia c59c60c61c62c63c64
  • Cardiorespiratory examination may find signs of cardiac disease or dysrhythmia (eg, irregular pulse, cardiac murmurs, pulmonary rales, pedal edema) c65c66c67c68c69c70
  • Carotid artery pulsations and/or peripheral pulses may be decreased with atherosclerotic vascular disease c71c72
  • Skin examination may find signs of coagulopathies or platelet disorders (eg, petechiae, ecchymosis), trauma, or embolic lesions (ie, Osler nodes, Janeway lesions) c73c74c75c76

Causes and Risk Factors

Causes

Common causes
  • Atherosclerotic carotid artery disease (accounts for approximately 10%-15% of ischemic strokes) r5c77
  • Lacunar strokes may be caused by either small emboli or occlusion of small vessels from lipohyalinosis; hypertension is a major contributor to this r6c78c79
  • Cardiac embolism, most commonly from atrial fibrillation and less often from mural thrombi in patients with dilated left ventricle c80
  • Noncardiac embolism (eg, air embolism, cholesterol embolism, embolization of plaque from an extracranial to an intracranial artery) c81c82c83

Less common causes

  • Cervicocerebral arterial dissection c84
  • Primary hypercoagulable state c85
  • Hypotension, which may cause ischemia in the watershed zones between 2 adjacent arterial territories or may cause global cerebral ischemia c86
  • Moyamoya disease c87
  • Vasculitis c88

Risk factors and/or associations

Age
  • Risk increases with age r7c89
Sex
  • Lifetime risk of stroke in men (24.7%) is not significantly different than in women (25.1%) on a global scale r8c90c91
Genetics
  • Family history of stroke is a risk factor; however, no specific genetic factor has been established r7c92
    • Genetic influence is primarily on the basis of influence on individual risk factors
  • Certain forms of hereditary cerebral small-vessel disease are associated with stroke at a younger age r9
Ethnicity/race
  • Age-adjusted incidence of first ischemic stroke per 1000 was 1.91 in Black, 1.49 in Hispanic, and 0.88 in non-Hispanic White individuals r10c93c94c95c96c97
Other risk factors/associations
  • Transient ischemic attack (eg, in a review of several trials, 23% of strokes had history of transient ischemic attack) r11c98
  • Patients with so-called silent cerebrovascular disease have 2 to 3 times increased relative risk of acute ischemic stroke r12
    • Silent cerebrovascular disease is defined as evidence of cerebrovascular disease visible on brain scans in asymptomatic patients
      • Silent brain infarcts
      • MRI white matter hyperintensities of presumed vascular origin r6
  • Atrial fibrillation c99
  • Hypertension c100
  • Dyslipidemia c101
  • Diabetes mellitus c102
  • Myocardial infarction c103
  • Fibromuscular dysplasia (risk factor for arterial dissection) c104c105
  • Obesity/overweight c106c107
  • Cigarette smoking c108
  • Alcohol consumption c109
  • Illicit drug use c110
  • Mitral valve stenosis c111
  • Low serum potassium level (risk level is questionable) c112
  • Use of estrogen-containing contraceptives c113
  • Use of estrogen plus progestin or estrogen alone in postmenopausal women c114c115
  • Migraine c116
  • Obstructive sleep apnea c117

Diagnostic Procedures

Primary diagnostic tools

  • Immediate steps
    • Time is critical so that patient does not lose eligibility for time-limited treatment options
    • Use of prehospital stroke scales for initial triage in community or emergency department setting may aid in rapid, accurate detection of stroke. Cincinnati Prehospital Stroke Scale has highest sensitivity in community settings, whereas ROSIER scale (recognition of stroke in the emergency room) is preferred in emergency department r1r13r14
    • Perform emergency brain CT (without contrast enhancement) on arrival to hospital (within 20 minutes) if ischemic stroke is suspected r1
      • Primarily done to exclude acute intracerebral hemorrhage rather than to document ischemic changes
    • If patient otherwise meets criteria for endovascular therapy, use a noninvasive intracranial vascular study—usually CT angiography or magnetic resonance angiography—during initial imaging evaluation to identify large vessel occlusion r1
      • May be done before obtaining serum creatinine level in patients without history of renal impairment
      • Do not delay administering IV recombinant tissue plasminogen activator (if indicated) to obtain or review these additional studies, which may be postponed until after alteplase administration
    • Use history, physical examination, and neurologic examination (ie, NIH Stroke Scale score) to assess stroke severity and eligibility for thrombolytic and endovascular therapies r1c118c119
      • NIH Stroke Scale scores range from 0 to 42 points, which are interpreted as follows (note that various sources use slightly different categorization cutoffs): r1r15c120
        • No stroke: 0 points
        • Minor stroke: 1 to 4 points
        • Moderate stroke: 5 to 19 points
        • Severe stroke: 20 points or more
    • Perform routine initial laboratory testing, including chemistry panels, CBC, coagulation studies, cardiac troponin levels, and pregnancy tests for women of childbearing age. Only assessment of blood glucose level must precede initiation of IV alteplase in all patients r1c121c122c123c124c125c126c127c128c129c130
      • Exception: if patient is known to be taking anticoagulants or to have a bleeding diathesis, check coagulation test and platelet count results before proceeding, as elevated results may preclude use of thrombolytic agents
        • If taking warfarin: review prothrombin time, INR, and activated partial thromboplastin time
        • If taking direct thrombin inhibitors or direct factor Xa inhibitors: review thrombin time and ecarin clotting time (if available)
        • If bleeding diathesis is suspected: review coagulation test and platelet count results
    • All patients with suspected stroke: obtain ECG and place on continuous cardiac monitoring in the emergency department; continue after admission. Do not wait for review of initial ECG before starting IV recombinant tissue plasminogen activator, if indicated r1c131
  • Obtain additional imaging, if indicated
    • Do not delay administering IV alteplase in eligible patients to obtain additional neuroimaging r1
    • In patients who are potential candidates for mechanical thrombectomy: r1
      • Obtain noninvasive intracranial vascular imaging, usually CT angiography or magnetic resonance angiography (if not already performed)
      • Obtain extracranial vascular imaging (carotid and vertebral arteries)by either CT or magnetic resonance angiography (preferred) or by carotid ultrasonography (less sensitive)
        • In patients who are potential candidates for mechanical thrombectomy, imaging of extracranial carotid and vertebral arteries—in addition to providing information about intracranial circulation—provides useful information about patient eligibility and for endovascular procedural planning
      • Obtain additional brain imaging (eg, CT perfusion) and/or diffusion-weighted MRI with or without perfusion to help select patients for mechanical thrombectomy
        • Recommended specifically for selecting patients with large vessel occlusion in anterior circulation who present 6 to 24 hours from time of onset (last time patient known to be well)
          • Not routinely recommended for selecting patients for treatment within 6-hour window
        • It may be reasonable to incorporate collateral flow status into clinical decision-making in some candidates to determine eligibility for mechanical thrombectomy
    • Obtain noninvasive imaging of carotid arteries (eg, carotid ultrasonography, CT, or magnetic resonance angiography) within 24 hours of hospital admission in patients with nondisabling stroke involving the carotid territory who may be candidates for carotid endarterectomy or stenting. Goal is to treat eligible patients within 48 to 72 hours r1
    • In patients who are ineligible for mechanical thrombectomy, imaging of extracranial carotid and vertebral arteries may be delayed until inpatient evaluation r1
    • Consider chest radiography only if underlying cardiac, pulmonary, or pulmonary vascular disease is suspected. Do not unnecessarily delay thrombolytic therapy for chest radiography r1c132
    • Obtain echocardiography if cardioembolism is suspected; however, this can be obtained nonemergently to guide secondary prevention r16c133

Laboratory

  • Do not delay thrombolytic therapy while awaiting test results unless specifically indicated, except blood glucose level, which is obtained immediately at the bedside r1
  • Blood glucose level r1c134
    • Hypoglycemia may mimic stroke; hyperglycemia is related to poor outcomes
    • Quickly correct hypoglycemia by administering dextrose
  • CBC with platelet count r1c135
    • Abnormal results (eg, polycythemia, leukocytosis, thrombocytopenia, thrombocytosis) may indicate cause of stroke
    • If platelet count is unknown, do not withhold thrombolytic therapy with a recombinant tissue plasminogen activator; however, if platelet count is known, do not use thrombolytic therapy if platelet count is lower than 100,000 cells/mm³
  • Blood chemistry (ie, levels of electrolytes, creatinine, and BUN) r2c136
    • Provides baseline information about renal function, metabolic state, and acid-base balance
  • Prothrombin time/INR r1c137c138
    • Measurement is indicated in all patients
    • Except in patients known to be taking anticoagulants or suspected of having a bleeding diathesis, do not withhold thrombolytic therapy with a recombinant tissue plasminogen activator pending test results r1
    • Thrombolytic therapy is not recommended if INR is higher than 1.7 or prothrombin time is longer than 15 seconds r1
  • Activated partial thromboplastin time c139
    • Measurement is indicated in all patients r1r2
    • Do not withhold thrombolytic therapy with a recombinant tissue plasminogen activator pending test results, except in patients known to be taking anticoagulants or suspected of having a bleeding diathesis r1
  • Thrombin time and ecarin clotting time r1c140c141
    • Measurement indicated in patients taking direct thrombin inhibitors or direct factor Xa inhibitors
    • Thrombin time is a sensitive indicator of thrombin inhibition
    • Ecarin clotting time may not be readily available, but it has a linear relationship with direct thrombin inhibitor levels
    • There are no specific guidelines regarding cut-point levels for thrombin time or ecarin clotting time for administration of thrombolytic therapy
  • Cardiac troponin levels r1c142c143
    • Measurement indicated in all patients; used as prognostic factor
    • Cardiac biomarker levels may be elevated in patients with ischemic stroke
    • Increased stroke severity and mortality risk are associated with elevated troponin T level
    • Troponin I level may increase owing to an acute ischemic stroke alone or may indicate an acute comorbid coronary syndrome r17
    • Rarely rises above 2 nanograms/mL in the setting of acute ischemic stroke alone r17
  • Lipid profile r1c144
    • Obtain fasting or nonfasting plasma lipid profile to document baseline LDL cholesterol and estimate atherosclerotic cardiovascular disease risk in patients aged 20 years and older who are not already on lipid-lowering therapy
  • Pregnancy test
    • Indicated in all women of childbearing age c145
    • If patient is pregnant, first carefully evaluate risks and potential benefits; only then administer thrombolytic therapy with a recombinant tissue plasminogen activator r1

Imaging

  • CT of head
    • CT without contrast is initial imaging modality of choice r1c146
      • Perform within 20 minutes of presentation, before starting thrombolytic therapy
      • Uses
        • Differentiate ischemic from hemorrhagic stroke
        • Determine presence of cerebral edema
        • Assess location, severity, and prognosis of stroke and assess eligibility for mechanical thrombectomy
          • Use ASPECTS (Alberta Stroke Program Early CT Score) to determine eligibility for endovascular therapy r18
            • 2 standardized regions of middle cerebral artery territory are evaluated:
              • Basal ganglia level: thalamus, basal ganglia, and caudate
              • Supraganglionic level: corona radiata and centrum semiovale
            • Abnormality must be visible on at least 2 consecutive cuts
            • Subtract 1 point from 10 for any evidence of early ischemic change for each of the defined regions
              • Normal CT finding receives ASPECTS of 10 points
              • A score of 0 indicates diffuse involvement throughout middle cerebral artery territory
        • May help to exclude other nonvascular conditions (eg, neoplasm)
    • CT angiography r1c147
      • Indicated if endovascular mechanical thrombectomy is considered
      • Aids in noninvasive assessment of extracranial and intracranial vasculature and in detection of stenosis or occlusion
      • Very high specificity and sensitivity for detecting intracranial occlusions
      • Better than ultrasonography for differentiating extracranial carotid high-grade stenosis from occlusion
    • CT perfusion imaging adds additional information but is not routine r19c148
      • Provides information about regional cerebral hemodynamics, including cerebral blood flow, cerebral blood volume, and mean transit time
      • Permits delineation of the ischemic penumbra outside the core infarct
      • Patient with a small core and a large penumbra is most likely to benefit from reperfusion therapies
      • Salvageable brain tissue typically has a prolonged mean transit time, a moderately reduced cerebral blood flow, and a nearly normal or even increased cerebral blood volume owing to autoregulatory vasodilation
  • MRI of head c149
    • Alternative to CT (without contrast) for initial imaging r1
      • Also has role in guiding selection of stroke secondary prevention in some patients (eg, those with patent foramen ovale who may be candidates for mechanical closure)
    • Uses r2
      • Helps to assess cause, subtype, location, duration, and severity of stroke
      • Helps to detect brainstem and cerebellar lesions, differentiate acute from chronic ischemia, and identify subclinical satellite lesions
    • Magnetic resonance angiography r1c150
      • Aids in noninvasive assessment of intracranial and extracranial vasculature
      • Indicated if endovascular mechanical thrombectomy or intra-arterial fibrinolysis is considered
      • Can identify other causes of stroke (eg, arterial dissection, venous thrombosis, vasculitis, fibromuscular dysplasia)
    • MRI with diffusion-weighted imaging adds additional information but is not routine r1
      • Hyperintensity or restricted diffusion on this imaging mode is indicative of acute cerebral ischemia and is often apparent within minutes of the ischemic event
      • More sensitive than CT for detecting chronic hemorrhage, new infarction, and small vessel infarctions
      • As sensitive as CT for detecting acute hemorrhage
      • MRI with perfusion-weighted imaging can detect impaired perfusion and may identify ischemic tissue that can be salvaged more than 3 hours after symptom onset
      • Useful for selecting patients who may benefit from mechanical thrombectomy between 6 and 24 hours after time last known to be well
      • May be useful for selecting patients among those who awake with symptoms or those with unclear time of onset more than 4.5 hours from time last known to be well who may benefit from IV alteplase within 4.5 hours of stroke recognition
  • Carotid Doppler ultrasonography r2c151
    • Safe screening technique for imaging carotid bifurcation and measuring blood velocities
    • Limited ability to image extracranial vasculature proximal or distal to bifurcation
    • Screen patients with non-disabling stroke involving carotid territory who are candidates for carotid revascularization within 24 hours of admission r1
  • Echocardiography r20c152
    • Indicated when a cardiac cause of stroke is suspected
    • Helps to detect valvular heart disease, aortic arch atheroma, cardiac masses, endocarditis, prosthetic thrombosis, and patent foramen ovale r16
    • Predicts embolic risk in the presence of atrial fibrillation
  • Radiography of chest r1c153
    • Indicated only if underlying cardiac, pulmonary, or pulmonary vascular disease is suspected
    • Should not delay thrombolytic therapy unless intrathoracic pathology is suspected

Functional testing

  • ECG c154
    • Perform at time of presentation; do not delay performing head CT or administering thrombolytic therapy, if indicated r1
    • Continuous cardiac monitoring should begin in the emergency department and continue for at least the first 24 hours of hospitalization to detect arrhythmias (eg, atrial fibrillation) r1

Differential Diagnosis

Most common

  • Transient ischemic attack c155d1
    • Transient neurologic dysfunction resulting from focal brain, retinal, or spinal cord ischemia without infarction on brain imaging
    • Symptoms persist for fewer than 24 hours with rapid resolution of focal neurologic deficit
    • Clinical examination findings are within reference range between episodes of transient ischemic attack
    • Transient ischemic attack persisting for longer than 1 hour may be associated with abnormal findings on MRI with diffusion-weighted imaging
  • Migraine with aura c156d2
    • Usually, patient has history of headache preceded by aura
    • Headache, when present, is associated with prostration, nausea, vomiting, phonophobia, and photophobia
    • Aura may present as gradual onset of neurologic symptoms (eg, unilateral numbness or weakness) and may be present without headache, making the 2 conditions clinically indistinguishable
    • Diagnosis is usually based on history and clinical findings; brain imaging with CT or MRI is necessary to differentiate the conditions if there is no history of previous migraine with aura or if clinical suspicion is high
  • Hypoglycemia c157d3
    • Occurs most commonly in people with diabetes as a result of overtreatment, when serum glucose levels are lower than 70 mg/dL d4
    • Symptoms include anxiety, sweating, tremors, nausea, weakness, palpitations, convulsions, and confusion, progressing to stupor and coma
    • Focal neurologic deficits may be present
    • Low serum glucose level with resolution of symptoms after administering glucose confirms diagnosis
  • Intracranial hemorrhage c158
    • Hemorrhage within the brain parenchyma or into the epidural, subdural, or subarachnoid space
    • Sudden onset of symptoms, including:
      • Severe headache
      • Nausea or vomiting
      • Confusion or altered mentation
      • Decreased level of consciousness
      • Focal sensory and motor deficits
    • Cannot be differentiated from ischemic stroke without imaging
    • Evidence of hemorrhage within or around the brain on imaging studies confirms diagnosis
  • Hypertensive encephalopathy c159
    • Rapidly evolving severe hypertension (usually higher than 200/130 mm Hg) associated with neurologic symptoms, including: d5
      • Headache
      • Nausea or vomiting
      • Seizures
      • Impaired vision
      • Cortical blindness
      • Dizziness
      • Confusion, stupor leading to coma
    • Changes in mental status are characteristic findings
    • Focal neurologic signs may be present
    • Presence of papilledema, cotton-wool exudates, and retinal hemorrhage on funduscopy
    • Evidence of cerebral edema on imaging
    • Diagnosis is made by exclusion
  • Wernicke encephalopathy c160
    • Neuropsychiatric condition caused by thiamine deficiency, manifesting with: d6
      • Ataxia
      • Ophthalmoplegia
      • External rectus palsy
      • Nystagmus
      • Confusion
    • History of alcohol use disorder is common d7
    • Optic disk edema and retinal hemorrhages on funduscopy
    • Low blood thiamine and erythrocyte thiamine transketolase levels on laboratory evaluation
    • Diagnosis is based on history and clinical findings
    • Clinical improvement and elevation of erythrocyte thiamine transketolase levels after parenteral thiamine administration confirms diagnosis
  • Central nervous system tumor c161
    • Gradual onset and progression of symptoms, including:
      • Seizures
      • Headache
      • Nausea or vomiting
      • Progressive neurologic deficits
      • Change in personality
      • Gait disturbance
      • Cognitive impairment
    • Papilledema may be present on funduscopy
    • Presence of structural lesions, degeneration, or enhancing focal lesions on CT or MRI support diagnosis
  • Central nervous system abscess c162
    • Intracerebral infection developing into a space-occupying lesion
    • Presents with focal neurologic deficit, headache, and fever
    • History of endocarditis, drug use disorder, and medical device implant should arouse suspicion
    • Leukocytosis and elevated erythrocyte sedimentation rate on laboratory evaluation indicate infection
    • Evidence of brain abscess and midline shift on CT or MRI confirm diagnosis d8
  • Postictal suppression of cortical activity c163
    • After a seizure, the motor cortex may remain in a suppressed state for several hours, mimicking acute stroke
    • Diagnosis is based on history (particularly if the seizure was witnessed) and negative findings on imaging studies d9
  • Psychogenic disorders
    • Panic disorder, anxiety disorder, or conversion reactions may mimic ischemic stroke, mainly in children or adolescents c164c165c166
    • Anxiety disorder may present with anxiety, worry, irritability, headache, dizziness, motor symptoms, and insomnia
    • Conversion disorder may present with sensory/motor symptoms or psychogenic seizure
    • Panic attack presents with intense fear/apprehension and respiratory, cardiac, and neurologic symptoms
    • Diagnosis is based on history and clinical examination
      • Absence of objective neurologic findings
      • Inconsistent neurologic examination
      • Nonvascular distribution of neurologic findings

Treatment

Goals

  • Start treatment for eligible patients as quickly as possible r1
    • Door-to-needle goal for thrombolytic therapy is within 60 minutes; within 45 minutes is best
    • Start thrombolytic therapy within 3 hours of symptom onset, if possible (may be administered within 4.5 hours with decreased benefit)
    • Begin endovascular therapy (with mechanical thrombectomy) as early as possible but within 6 hours; may be considered in select patients up to 24-hour window
    • Technical goal of thrombectomy is reperfusion to an mTICI 2b/3 angiographic result (on the modified treatment in cerebral infarction scale) to maximize probability of a good functional clinical outcome
  • Prevent complications; recognize and manage existing ones
  • Arrange rehabilitation to preserve or improve function
  • Prevent recurrence

Disposition

Admission criteria

Admit all patients to a specialized stroke unit, if available r21

Patients with onset of stroke symptoms more than 24 hours before admission may be admitted to a general hospital ward, unless they meet criteria for ICU or neurologic ICU admission

Criteria for ICU admission
  • After IV or intra-arterial thrombolytics or mechanical thrombectomy r22
  • Hemispheric stroke with concern about impending mental status decline and loss of protective airway reflexes r22
  • Basilar thrombosis or top-of-the-basilar syndrome (tip-of-the-basilar syndrome) r22
  • Blood pressure augmentation required for a documented area of hypoperfusion r22
  • IV blood pressure or heart rate control required r22
  • Required neurologic evaluation every 1 to 2 hours owing to symptom fluctuation or suspected ongoing ischemia r22
  • Worsening neurologic status r22
  • After interventional neuroradiology procedure r22

Recommendations for specialist referral

  • Urgent consultation with a neurologist is advised for all patients with suspected stroke
  • If available, arrange for patient to be evaluated immediately by multidisciplinary stroke team for thrombolytic and endovascular therapy eligibility. This may be initiated by what is called stroke code in some institutions r13
  • Consult with neurosurgeon or vascular surgeon about use of carotid endarterectomy for patient with carotid stenosis or occlusion
  • Consult with cardiologist about evaluation and management of coexisting cardiac conditions
  • Refer to rehabilitative services for occupational therapy, physical therapy, and speech therapy once stable

Treatment Options

Initial emergency department/hospital management

  • General supportive care
    • Monitor and correct hypoxia, hypo- or hyperglycemia, and hyperthermia; correction may be associated with improved outcomes r23
      • Supplemental oxygen is not recommended in nonhypoxic patients; use supplemental oxygen only to maintain saturation higher than 94% (94%-96% recommendedr24) r1
      • Intubation may be required in patients with decreased respiratory drive owing to cerebral edema or hemispheric stroke
        • Also recommended for those who have bulbar dysfunction that causes airway compromise
      • Treat hyperglycemia to achieve blood glucose target of 140 to 180 mg/dL (must be less than 400 mg/dL to proceed to thrombolytic therapy); treat hypoglycemia if below 60 mg/dL (must be higher than 50 mg/dL to proceed to thrombolytic therapy) r1
      • If patient is febrile, administer antipyretics to maintain body temperature lower than 38°C r1r25
      • There is no role for therapeutic hypothermia r26
    • Correct hypotension and hypovolemia to maintain systemic perfusion r1
      • Optimal blood pressure and parenteral fluid type and volume are unknown
    • Position patient
      • Patients traditionally were placed flat in bed for the first 24 hours unless there was risk of aspiration or suspected increased intracranial pressure; however, a recent trial showed no significant 90-day disability difference between lying flat and sitting up with head elevated at least 30° r27
    • Do not administer any oral medications until patient is screened for swallowing dysfunction. Administer medications by alternative routes r1
  • Acute blood pressure management
    • Goal blood pressure
      • Optimal blood pressure in acute stroke is unknown; in general:
        • There may be an association between worse outcomes and lower blood pressures, but not all studies confirm this
        • No studies have addressed treatment of low blood pressure in patients with stroke; benefits and harms of crystalloids versus colloids to treat hypotension are unknown r1
      • If patient is eligible for reperfusion therapies
        • Lower blood pressure to less than 185/110 mm Hg before thrombolytic therapy and maintain at less than 180/105 mm Hg for 24 hours afterward r1r28
          • Exact blood pressure at which risk of hemorrhage after thrombolysis increases is unknown. These recommendations are based on target blood pressures used in randomized controlled trials of IV thrombolytic therapy
          • No specific minimum systolic blood pressure is recommended with thrombolytic therapy, but systolic pressures between 141 and 150 mm Hg have been associated with optimal mortality and functional outcomes r29
        • For patients undergoing mechanical thrombectomy, it is recommended to maintain blood pressure below 180/105 mm Hg during thrombectomy and for 24 hours afterward r30
        • Choice of blood pressure treatment for patients eligible for thrombolytic therapy
          • Fast-acting, rapidly reversible agents are recommended
            • Recommended treatments include labetalol, nicardipine, clevidipine, and sodium nitroprusside r1
              • Other options may be appropriate for patients with comorbid conditions that may benefit from acute reductions in blood pressure (eg, acute coronary event, acute heart failure, aortic dissection, preeclampsia, eclampsia)
              • If blood pressure is not maintained at 185/110 mm Hg or lower, do not administer alteplase
              • During and after thrombolytic therapy, maintain blood pressure at 180/105 mm Hg or lower
      • If the patient is not eligible for thrombolytic therapy and has very high blood pressure (higher than 220 mm Hg systolic or 120 mm Hg diastolic) careful blood pressure reduction is reasonable r1r28r30
        • May be lowered by 15% within 24 hours of symptom onset; watch for worsening of neurologic function
        • Acute lowering (in the first 24 hours) is not necessary if blood pressure is lower than 220/120mmHg, unless the patient has another condition that requires it (eg, acute coronary syndrome, aortic dissection, hypertensive encephalopathy) r30
        • Blood pressure management is more permissive to promote collateral vessel perfusion

Begin reperfusion therapy for eligible patients (those who meet all general eligibility criteria and do not have contraindications) as soon as possible

  • Thrombolysis with an IV recombinant tissue plasminogen activator for eligible patients. Door-to-needle time of 60 minutes is the goalr2; 2019 guidelines suggested 45 minutes may be achievable. Give this treatment even if considering endovascular therapiesr1
    • A 2020 study reported that among patients aged 65 years or older with acute ischemic stroke who were treated with tissue plasminogen activator, shorter door-to-needle times were associated with lower all-cause mortality and lower all-cause readmission at 1 year r31
    • Owing to the proven benefit and need to expedite treatment, when a patient cannot provide consent (eg, has aphasia or confusion) and a legally authorized representative is not immediately available to provide proxy consent, it is justified to proceed with IV thrombolysis in an otherwise eligible adult patient with a disabling acute ischemic stroke r1
    • If inhouse expertise is unavailable, telestroke networks may be helpful for triaging patients who are eligible for thrombolysis or interfacility transfer for acute mechanical thrombectomy
    • First line therapy: alteplase administered as soon as possible r1
      • IV tenecteplase may be reasonable as an alternative to IV alteplase in patients who are eligible for both IV fibrinolysis and mechanical thrombectomy and in those with minor neurologic impairment and no major intracranial occlusion
    • Eligibility and timing
      • When it can be administered within 3 hours of stroke symptom onset or from baseline status (time last known to be well), offer alteplase to all otherwise eligible patients aged 18 years or older who have a quantifiable neurologic deficit r1
        • Equally recommended for patients aged 80 years or older r32
        • Recommended for both severe stroke symptoms and mild but disabling stroke symptoms r32
          • There is increased risk of hemorrhagic transformation with severe stroke symptoms, but there is still proven clinical benefit for these patients when treatment is administered in 3-hour time window
        • Not recommended for otherwise eligible patients with mild nondisabling stroke
      • When it can be administered in the 3- to 4.5-hour window, offer alteplase to all otherwise eligible patients aged 18 to 80 years r1
        • Lower-level evidence suggests that for patients older than 80 years presenting in the 3- to 4.5-hour window, IV alteplase is safe and can be as effective as it is in younger patients r32
        • In this time window, patient must meet these additional criteria:
          • NIH Stroke Scale score 25 or lower (benefit uncertain with higher score)
          • No imaging evidence of ischemic injury involving more than one-third of middle cerebral artery territory
          • No history of either diabetes mellitus or prior ischemic stroke; however, lower-level evidence suggests that IV alteplase may be as effective as treatment given to this population in the 0- to 3-hour window
          • Not taking any oral anticoagulants; however, for patients taking warfarin who have an INR of 1.7 or lower and present in the 3- to 4.5-hour window, IV alteplase appears safe and may be beneficial
      • When it can be administered within 4.5 hours of stroke symptom recognition, alteplase also may be beneficial in otherwise eligible patients aged 18 to 80 years who awaken with stroke symptoms or who have unclear time of onset and have diffusion-weighted MRI findings of a lesion involving less than one-third of the middle cerebral artery territory and no visible signal change on FLAIR (fluid-attenuated inversion recovery) r1
      • European guidelines recommend intravenous thrombolysis with alteplase for all patients with acute stroke symptoms less than 4.5 hours in duration r32
        • Also recommended for patients presenting from 4.5 to 9 hours after known onset time or those with stroke symptoms on awakening from sleep, and with CT or MRI evidence of core/perfusion mismatch, and for whom mechanical thrombectomy is either not indicated or not planned r32
    • Contraindications to alteplase r1
      • Mild nondisabling stroke
      • Hypertension that cannot be lowered to under 185/110 mm Hg r32
      • CT showing acute intracranial hemorrhage
      • CT showing extensive regions of clear hypoattenuation (these patients have a poor prognosis despite IV alteplase; severe hypoattenuation defined as obvious hypodensity represents irreversible injury)
      • Ischemic stroke within past 3 months
      • Severe head trauma within past 3 months
        • Do not administer IV alteplase to patient with posttraumatic infarction that occurs during the acute in-hospital phase of management of head trauma
      • Intracranial/spinal surgery within previous 3 months
      • Earlier history of intracranial hemorrhage
      • Symptoms and signs most consistent with a subarachnoid hemorrhage
      • Patients with structural gastrointestinal malignancy or gastrointestinal bleeding event within 21 days of stroke event are considered high risk
      • Coagulopathy
        • Platelet count lower than 100,000 cells/mm³
          • In patients without history of thrombocytopenia, can initiate treatment with IV alteplase before platelet count is available, but discontinue alteplase if platelet count is lower than 100,000 cells/mm³
        • Any of the following: INR higher than 1.7, prothrombin time greater than 15 seconds, or activated partial thromboplastin time greater than 40 seconds
          • In patients who have not recently used oral anticoagulants or heparin, initiate treatment with IV alteplase before coagulation test results are available, but discontinue treatment if INR is higher than 1.7 or prothrombin time is abnormally elevated by local laboratory standards
      • Concomitant medications
        • Abciximab
        • IV aspirin: do not administer within 90 minutes of starting IV alteplase
        • Direct thrombin inhibitors or direct factor Xa inhibitors: do not administer alteplase unless laboratory test results (eg, activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, appropriate direct factor Xa activity assays) are within reference range or unless patient has not received a dose of these agents for more than 48 hours
        • Low-molecular-weight heparin: do not administer alteplase to patients who have received a full treatment dose (not prophylactic dose) of low-molecular-weight heparin within the previous 24 hours
      • Known intra-axial intracranial neoplasm
      • Known or suspected aortic arch dissection
      • Symptoms consistent with infective endocarditis
      • Contraindications to alteplase.Data from Powers WJ et al: Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 50(12):e344-418, 2019.
        Category of contraindicationContraindication
        General
        Time of symptom onsetTime of symptom onset is unclear or was not witnessed in a patient whose last known time at baseline state is more than 3 to 4.5 hours prior
        Symptom onset was greater than 3 to 4.5 hours prior
        More than 4.5 hours since time of stroke symptom onset or when patient was last known to be well/at baseline
        Hypo- and hyperglycemiaDo not administer alteplase until hypoglycemia corrected to greater than 50 mg/dL and hyperglycemia corrected to less than 400 mg/dL
        Blood pressure Hypertension that cannot be lowered to less than 185/110 mm Hg
        Alternative or comorbid critical diagnosisPatient presentation suggests subarachnoid hemorrhage
        Known or suspected aortic arch dissection
        Symptoms consistent with infective endocarditis
        Imaging
        CT revealsAcute intracranial hemorrhage
        Extensive regions of clear hypoattenuation
        Past medical history and comorbidities
        Recent history, within past 3 monthsPrior ischemic stroke
        Severe head trauma 
        Intracranial/spinal surgery
        Known historyIntracranial hemorrhage
        ComorbidityIntra-axial intracranial neoplasm
        Patients with structural gastrointestinal malignancy or recent gastrointestinal bleeding event within 21 days of their stroke event should be considered high risk
        Coagulopathy/anticoagulant use
        Platelets Less than 100,000 cells/mm³
        INR and prothrombin timeINR greater than 1.7;
        Prothrombin time greater than 15 seconds (or abnormal by local standards); 
        and/or greater than 40 seconds     
        Warfarin usePatients with a history of warfarin use, unless INR is 1.7 or less and/or a prothrombin time is less than 15 seconds, in which case treatment may be reasonable
        Direct thrombin inhibitors or direct factor Xa inhibitorsUnless laboratory tests such as activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal, or the patient has not received a dose of these agents for greater than 48 hours
        Low-molecular-weight heparin Patients who have had full treatment dose (not prophylactic dose) within the previous 24 hours
    • Other eligibility considerations
      • Warfarin: IV alteplase appears safe and may be beneficial for patients taking warfarin who have an INR of 1.7 or lower and present in the 3- to 4.5-hour window r1
      • Hypo- and hyperglycemia may mimic acute stroke presentations; do not administer alteplase until hypoglycemia is corrected to higher than 50 mg/dL and hyperglycemia corrected to lower than 400 mg/dL r1
        • European guidelines do not recommend withholding alteplase in patients with blood glucose greater than 400 mg/dL despite the risk of poor functional outcome in such patients r32
      • Dural puncture: may consider IV alteplase for patients who present with acute ischemic stroke, even when they have undergone a lumbar dural puncture in the preceding 7 days r1
      • Arterial puncture: safety and efficacy of administering IV alteplase to patients who present with acute ischemic stroke who have had an arterial puncture of a noncompressible blood vessel in the 7 days preceding stroke symptoms are uncertain r1
      • Recent major trauma: in patients with acute ischemic stroke and recent major trauma (within 14 days) not involving the head, carefully consider IV alteplase, but weigh risks of bleeding from injuries related to trauma against severity and potential disability from ischemic stroke r1
      • Recent major surgery: consider using IV alteplase in carefully selected patients presenting with acute ischemic stroke who have undergone a major surgery in the preceding 14 days, but weigh potential increased risk of surgical site hemorrhage against anticipated benefits r1
      • Past gastrointestinal/genitourinary bleeding (more than 21 days prior): literature reports low bleeding risk with IV alteplase administered in the setting of past gastrointestinal/genitourinary bleeding. Administering IV alteplase in this patient population may be reasonable (alteplase administration within 21 days of a gastrointestinal bleeding event is not recommended) r1
      • Menstruation: IV alteplase is probably indicated in women who present with acute ischemic stroke who are menstruating and do not have a history of menorrhagia. Warn patients that alteplase treatment could increase menstrual flow r1
        • Consider IV alteplase because potential benefits probably outweigh serious bleeding risks even in patients with recent history of or active menorrhagia who do not have clinically significant anemia or hypotension
        • When there is history of or recent active vaginal bleeding that causes clinically significant anemia, emergency consultation with a gynecologist is indicated before making a decision about IV alteplase
      • Cervical dissections r1
        • Intracranial: usefulness and hemorrhagic risk of alteplase with known or suspected associated intracranial arterial dissection remain unknown, uncertain, and not well established
        • Extracranial: when stroke is suspected to be associated with extracranial cervical arterial dissection, alteplase is reasonably safe when given within 4.5 hours and probably recommended
      • Cerebral microbleeds
        • In otherwise eligible patients who have previously demonstrated a small number (1-10) of cerebral microbleeds on MRI, administer IV alteplase r1
        • In otherwise eligible patients who have previously demonstrated a high burden of cerebral microbleeds (more than 10) on MRI, IV alteplase may be associated with increased risk of intracranial hemorrhage and benefits of treatment are uncertain; however, IV alteplase may be reasonable if there is potential for significant benefit r1
      • Unruptured intracranial aneurysm: with a known small or moderate (less than 10 mm) unruptured and unsecured intracranial aneurysm, IV alteplase is probably recommended r1
      • Extra-axial intracranial neoplasm: alteplase treatment is probably recommended for patients with acute ischemic stroke who harbor an extra-axial intracranial neoplasm r1
      • Acute or recent myocardial infarction r1
        • Acute myocardial infarction: for patients presenting with concurrent acute ischemic stroke and acute myocardial infarction, treat with IV alteplase at the dose appropriate for cerebral ischemia and follow with percutaneous coronary angioplasty and stenting, if indicated
        • Recent myocardial infarction (within 3 months):
          • Non–ST elevation myocardial infarction: treat ischemic stroke with IV alteplase
          • ST elevation myocardial infarction involving the right or inferior myocardium: treat ischemic stroke with IV alteplase
          • ST elevation myocardial infarction involving the left anterior myocardium: treat ischemic stroke with IV alteplase
      • Procedural stroke: depending on eligibility criteria, treat ischemic stroke complications of cardiac or cerebral angiographic procedures with IV alteplase r1
      • Systemic malignancy: patients with systemic malignancy and life expectancy longer than 6 months may benefit from IV alteplase if other contraindications (eg, coagulation abnormalities, recent surgery, systemic bleeding) do not coexist r1
      • Pregnancy or postpartum period r1
        • During pregnancy: consider administering IV alteplase when anticipated benefits of treating moderate or severe stroke outweigh anticipated increased risks of uterine bleeding
        • Early postpartum period (less than 14 days after delivery): safety and efficacy of IV alteplase have not been well established
      • Ophthalmic conditions: can use IV alteplase in patients presenting with acute ischemic stroke who have a history of diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions, but weigh potential increased risk of vision loss against anticipated benefits of reduced stroke-related neurologic deficits r1
      • Sickle cell disease: IV alteplase can be beneficial for adults presenting with an acute ischemic stroke who have known sickle cell disease r1
      • Illicit drug use: drug use can contribute to incident stroke; IV alteplase may be used in patients with illicit drug use–associated acute ischemic stroke if they have no other exclusions r1
      • Conditions that mimic stroke (eg, postictal paresis, migraine): risk of symptomatic intracranial hemorrhage in patients with these conditions is quite low. Recommended to start IV alteplase rather than delaying treatment to pursue additional diagnostic studies r1
  • Endovascular therapy with mechanical thrombectomy is recommended for eligible patients; reduced time from symptom onset to reperfusion with endovascular therapies is highly associated with better clinical outcomes r33r34r35r36r37r38
    • Mechanical thrombectomy with stent retrievers is the recommended first line therapy ahead of intra-arterial fibrinolysis r1
      • Intra-arterial fibrinolysis within 6 hours of stroke symptom onset may be considered in selected patients with contraindications to IV alteplase; however, outcomes are unknown
    • Administer IV alteplase to eligible patients even if considering mechanical thrombectomy r1
    • Do not postpone endovascular therapy to await/monitor for clinical response after administering IV alteplase r1r39
    • Eligibility and timing
      • Patients should receive mechanical thrombectomy with a stent retriever if treatment can be initiated (groin puncture) within 6 hours of symptom onset and they meet all the following criteria:
        • Prestroke modified Rankin Scale score of 0 to 1 r1
          • Although benefits are uncertain, may be considered for patients who have prestroke modified Rankin Scale score greater than 1 and causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1); additional randomized trial data are needed
        • Causative occlusion of the internal carotid artery or middle cerebral artery segment 1 (M1) r1
          • Although benefits are uncertain, also may be considered for patients who have 1 of the following:
            • Causative occlusion of the middle cerebral artery segment 2 (M2) or middle cerebral artery segment 3 (M3)
            • Causative occlusion of the anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries
        • Patient aged 18 years or older
          • Meta-analysis of 5 randomized controlled trials showed favorable effect with mechanical thrombectomy over standard care across all patient age subgroups including those aged 70 years or older (number of patients in these trials who were aged 90 years or older was very small) r40
        • NIH Stroke Scale score of 6 or greater r1
          • Although benefits are uncertain, may be considered for patients who have prestroke NIH Stroke Scale score less than 6 and causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1); additional randomized control trial data are needed
        • ASPECTS (Alberta Stroke Program Early CT Score) of 6 or greater r1
          • Although benefits are uncertain, may be considered for patients who have ASPECTS (Alberta Stroke Program Early CT Score) less than 6 and causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1); additional randomized trial data are needed
      • If treatment can be initiated (groin puncture) within 6 to 16 hours of time last known to be well, mechanical thrombectomy is recommended in selected patients with both of the following: r1
        • Large vessel occlusion in the anterior circulation
        • Meeting other eligibility criteria from DAWNr41 or DEFUSE 3r42 trial
      • If treatment can be initiated (groin puncture) within 16 to 24 hours of time last known to be well, mechanical thrombectomy is reasonable in selected patients with both of the following: r1
        • Large vessel occlusion in the anterior circulation
        • Meeting other eligibility criteria from DAWN r41trial
    • Salvage intra-arterial thrombolysis may be used to achieve desired mTICI 2b/3 angiographic result (on the modified treatment in cerebral infarction scale) r1
    • Outcomes with endovascular thrombectomy surpass those of standard IV thrombolytic therapy r43
      • Functional outcomes in patients with acute anterior circulation ischemic stroke and large artery occlusion are superior to those attained with standard therapy r44
      • Neurologic outcomes are superior 3 months after treatment in patients who receive endovascular treatment in addition to IV thrombolysis r45
      • For patients with severe stroke, adding endovascular interventions improves functional outcome and health-related quality of life at 12 months compared with IV thrombolytic therapy alone r46

Other initial treatment considerations

  • Aspirin
    • Recommended to administer aspirin within 24 to 48 hours after onset of acute ischemic stroke if intracranial hemorrhage has been excluded on follow-up brain CT or MRI r1r21
    • For patients with minor ischemic stroke (nondisabling and NIH Stroke Scale score of 3 or less) who did not receive IV alteplase, dual antiplatelet therapy with aspirin and clopidogrel beginning within 24 hours is recommended to prevent early secondary stroke r1r3r47r48r49
      • Treat for 21 days with dual antiplatelet therapy (aspirin and clopidogrel), then continue with aspirin alone; some experts suggest shorter duration of dual therapy to minimize bleeding risks r47r49r50
      • Dual antiplatelet therapy is no more effective than a single agent for ischemic stroke prevention and increases the risk of bleeding if initiated later after stroke or continued for longer duration r47
      • European guidelines also recommend dual antiplatelet therapy with aspirin and ticagrelor for 30 days for patients with non-cardioembolic mild to moderate ischemic stroke in the past 24 hours (weaker recommendation) r47r51
      • Do not use dual antiplatelet therapy in patients with major stroke owing to increased risk of intracranial bleeding r49
    • For those treated with IV alteplase, generally delay aspirin administration until 24 hours later r1
    • In patients unsafe or unable to swallow, rectal or nasogastric administration is appropriate r21
    • Safety and benefit confirmed by a large Cochrane review of aspirin trials r52
    • Aspirin is not a substitute for acute stroke treatment in patients who are eligible for IV thrombolysis or mechanical thrombectomy r1
    • Continue aspirin or initiate alternative antithrombotic agent 2 weeks after stroke or discharge (whichever is sooner) r21
  • Deep venous thrombosis prophylaxis
    • In immobile patients with stroke who do not have contraindications, intermittent pneumatic compression in addition to routine care (aspirin and hydration) is recommended (do not use elastic compression stockings) r1
    • Benefit of prophylactic-dose subcutaneous unfractionated or low-molecular-weight heparin in immobile patients with acute ischemic stroke is not well established r1
      • Appears to decrease risk of deep venous thrombosis in hospitalized patients with acute ischemic stroke but increases risk of intracranial bleeding r53
  • Emergency carotid endarterectomy or carotid angioplasty
    • Use of emergent or urgent carotid endarterectomy is not well established r1
    • Stroke specialists may consider carotid endarterectomy when clinical indicators or brain imaging suggest a small infarct core with large territory at risk (eg, penumbra), compromised by inadequate flow from a critical carotid stenosis or occlusion
  • Urgent anticoagulation r1
    • Not recommended for preventing early recurrent stroke, halting neurologic worsening, or improving outcomes
    • Meta-analyses confirm the lack of benefit of urgent anticoagulation r54r55
    • Usefulness of argatroban, dabigatran, or other thrombin inhibitors to treat patients with acute ischemic stroke is not well established; further clinical trials are needed r1
    • Safety and usefulness of factor Xa inhibitors to treat acute ischemic stroke are not well established; further clinical trials are needed r1
    • Optimal medical management of patients with radiologic evidence of nonocclusive, intraluminal thrombus (eg, cervical carotid, vertebrobasilar arteries) remains uncertain r1
    • Usefulness of urgent anticoagulation in patients with severe stenosis of an internal carotid artery ipsilateral to an ischemic stroke is not well established r1
  • Neuroprotective or neurorehabilitative agents
    • Various drugs with neuroprotective properties have been studied in preclinical or clinical trials in ischemic stroke; however to date, none has demonstrated consistent benefits r56r57r58r59
      • The Stroke Preclinical Assessment Network in the United States will evaluate several promising neuroprotective agents for efficacy as adjuncts to endovascular thrombectomy r58
    • Agents that stimulate endogenous neuroplasticity may help reduce disability after stroke
      • European guideline recommends considering cerebrolysin (30 ml/day IV for at least initial 10 days after stroke) in conjunction with early motor rehabilitation; citalopram may also be beneficial r60

Secondary prevention of stroke

  • Effective secondary prevention requires timely identification of stroke mechanism and modifiable risk factors r3
  • Antihypertensive therapy d5
    • Unless contraindicated, initiate antihypertensive therapy after the first several days in patients with blood pressure higher than 140/90 mm Hg; resume antihypertensive therapy in treated patients with known hypertension r1
    • Individualize pharmacologic therapy based on pharmacologic properties, mechanism of action, and specific patient characteristics; a thiazide diuretic, an ACE inhibitor, or an angiotensin receptor blocker may be beneficial r3r28
    • Reasonable blood pressure goals: systolic below 130 mm Hg and diastolic below 80 mm Hg r3r28
  • Antiplatelet therapy
    • Continue antiplatelet drugs during remaining hospitalization and after discharge for secondary prevention in patients with noncardioembolic stroke r21r47
    • Individualize drug therapy with aspirin, clopidogrel, or aspirin-dipyridamole r3
    • Dual antiplatelet therapy with aspirin and clopidogrel is not recommended for long-term secondary prevention after stroke r3
    • Dual antiplatelet therapy with aspirin and clopidogrel for 21 through 90 days beginning within 24 hours is recommended to prevent early secondary stroke in patients with minor ischemic stroke (nondisabling and NIH Stroke Scale score of 3 or less) who did not receive IV alteplase r3r47
  • Statin therapy d10
    • Recommended for secondary prevention of stroke; may also improve functional outcomes after acute stroke r1
    • According to 2021 guideline, administer atorvostatin 80 mg daily to patients with LDL cholesterol greater than 100 mg/dL and without known coronary artery disease or cardiac causes of embolism r3
      • Administer statin therapy (plus ezetimibe if needed) to patients with atherosclerotic disease with goal of reducing LDL cholesterol to lower than 70 mg/dL r3
      • In patients at very high risk (stroke plus one other major atherosclerotic cardiovascular disease event or stroke and multiple high-risk conditions) whose LDL cholesterol remains above 70 mg/dL despite maximally tolerated statin therapy and ezitimibe may be treated with a PCSK9 inhibitor r3
    • 2019 guidelines recommended patients aged 75 years or younger with clinical atherosclerotic cardiovascular disease receive high-intensity statin therapy (goal of reducing LDL cholesterol levels by 50% or more) r1r61
      • Moderate-intensity statin therapy (goal of reducing LDL cholesterol levels by 30%-49%) is appropriate if high-intensity therapy is contraindicated or not tolerated r1r61
      • Consider adding ezetimibe to maximally tolerated statin therapy in patients at very high risk (multiple major atherosclerotic cardiovascular disease events or 1 major atherosclerotic cardiovascular disease event and multiple high-risk conditions) and those with suboptimal response to maximally tolerated statin therapy r1r61
      • Patients older than 75 years with clinical atherosclerotic cardiovascular disease may be given high-intensity or moderate-intensity statin therapy depending on potential benefits, risks, drug interactions, and patient frailty and preferences r1r61
    • Continue statin therapy in patients who were already receiving it at time of stroke r1
    • For patients who are eligible, consider starting statin therapy in the hospital r1
  • Oral anticoagulation
    • Long-term oral anticoagulation is indicated for patients with nonvalvular atrial fibrillation, mechanical heart valves, dilated cardiomyopathy, or rheumatic valve disease r3r62d11
      • Warfarin, dabigatran, rivaroxaban, or apixaban may be used r63
  • Smoking cessation r3d12
    • Advise all patients to avoid exposure to tobacco smoke; advise those who use tobacco to quit (at each contact)
    • May receive assistance in quitting through referral to smoking cessation program or via pharmacotherapy
  • Revascularization for carotid artery stenosis
    • Carotid endarterectomy is recommended for patients who have suffered a stroke within 6 months and have ipsilateral severe carotid artery stenosis (70%-99% by noninvasive imaging), provided that mortality and morbidity risk is less than 6% r3
      • Also recommended in patients with moderate carotid stenosis (50%-69%) depending on their age, sex, and comorbidities
      • Carotid artery stenting may be considered as an alternative in patients younger than 70 years with symptomatic (50%-99%) carotid stenosis and for patients with comorbidities that increase the risks of surgery r3r5
      • When revascularization is indicated for nondisabling stroke, it is recommened to perform within 2 weeks of the index stroke r3r5
    • Revascularization is not recommended if degree of carotid stenosis is less than 50% r3
  • Left atrial appendage occlusion r64
    • Transcatheter left atrial appendage occlusion is an emerging alternative for stroke prophylaxis in selected patients with nonvalvular atrial fibrillation who are ineligible for long-term anticoagulation r3r65

Drug therapy

  • Thrombolytics r1
    • Alteplase (first line therapy) c167
      • Alteplase Solution for injection; Adults: 0.9 mg/kg (Max: 90 mg) IV over 60 minutes with initial 10% of the total dose given as bolus over 1 minute within 3 hours, or 4.5 hours for select patients, of stroke symptom onset or baseline well state.
    • Tenecteplase (alternative for selected patients) r66c168
      • Tenecteplase Solution for injection; Adults: 0.25 mg/kg (Max: 25 mg) or 0.4 mg/kg (Max: 40 mg) IV as a single dose within 4.5 or 6 hours, respectively for select patients, of stroke symptom onset.
  • Antiplatelet agents r1c169
    • Aspirin c170
      • Aspirin Oral tablet; Adults: 160 to 325 mg PO once daily.
        • Patients with minor stroke (NIH Stroke Scale score of 3 or less) who did not receive IV alteplase may be given aspirin in combination with clopidogrel for up to 21 days to prevent early secondary stroke; aspirin monotherapy can be continued thereafter r49r50
    • Clopidogrel c171
      • Clopidogrel Bisulfate Oral tablet; Adults: 300 or 600 mg PO once, followed by 75 mg PO once daily.
        • May be used short-term with aspirin for prevention of early secondary stroke in patients with minor noncardioembolic stroke (NIH Stroke Scale score of 3 or less) who did not receive IV alteplase r49r67
    • Aspirin, extended-release dipyridamole r3r67
      • Aspirin, Dipyridamole Oral capsule, extended-release; Adults: Aspirin 25 mg/dipyridamole 200 mg PO twice daily.
  • Antihypertensives for initial management of blood pressure higher than 185/110 mm Hg in patients otherwise eligible for thrombolytic therapy r1c172
    • Labetalol c173c174
      • Intermittent dosage
        • Labetalol Hydrochloride Solution for injection; Adults: 10 to 20 mg IV. May repeat dose once.
      • Continuous infusion dosage (if systolic blood pressure greater than 180-230 mm Hg or diastolic blood pressure greater than 105-120 mm Hg)
        • Labetalol Hydrochloride Solution for injection; Adults: 1 to 8 mg/minute continuous IV infusion until goal blood pressure is attained then transition to oral labetalol. Usual total dose: 50 to 200 mg. Max cumulative dose: 300 mg.
    • Nicardipine c175c176
      • Nicardipine Hydrochloride Solution for injection; Adults: 5 mg/hour continuous IV infusion, initially. Titrate by 2.5 mg/hour every 5 to 15 minutes until goal blood pressure is attained. Max: 15 mg/hour. Reduce to 3 mg/hour after response achieved.
    • Clevidipine c177
      • Clevidipine Emulsion for injection; Adults: 1 to 2 mg/hour continuous IV infusion, initially. Double dose every 90 seconds until the blood pressure approaches goal, then increase by less than double every 5 to 10 minutes as needed. Max: 32 mg/hour or 1,000 mL/24 hours due to lipid load restrictions. Max duration: 72 hours.
    • Sodium nitroprusside (if blood pressure not controlled with listed agents or diastolic blood pressure higher than 140 mm Hg) c178
      • Sodium Nitroprusside Solution for injection; Adults: 0.3 to 0.5 mcg/kg/minute continuous IV infusion, initially. Titrate by 0.5 mcg/kg/minute every 5 minutes until desired effect or blood pressure cannot be further reduced without compromising organ perfusion. Max: 10 mcg/kg/minute for 10 minutes.

Nondrug and supportive care

Overview

  • Nothing by mouth until swallowing is assessed; hydrate with IV fluids r1
  • All patients should undergo formal dysphagia screening test as soon as possible after admission r68
    • Formal swallowing screening test (eg, water swallow test or multiple-consistency tests) before allowing patient to take anything by mouth has been shown to reduce rates of post-stroke pneumonia and decrease risk of early mortality r68
    • Additional testing (eg, videofluoroscopy, fiberoptic endoscopic evaluation) by a speech-language pathologist is indicated if dysphagia is present
  • If swallowing is intact, start enteral diet within 7 days of admission after an acute stroke r1
  • If swallowing is impaired, initially use nasogastric tubes for feeding, starting within the first 7 days. Place percutaneous gastrostomy tubes in patients with longer anticipated persistent inability to swallow safely (longer than 2-3 weeks) r1
  • Oral hygiene protocols with use of chlorhexidine gel or rinse are reasonable to reduce risk of aspiration pneumonia after stroke (when combined with routine swallowing assessment) r1
  • Routine placement of an indwelling bladder catheter is not recommended r1
  • Mobilization is recommended after 24 to 48 hours if patient is stable. Observe carefully for worsening neurologic status during transition from recumbent to sitting to standing r1c179
    • Do not perform high-dose, very early mobilization within 24 hours of stroke onset because it can reduce odds of a favorable outcome at 3 months r1
  • Use of intermittent pneumatic compression stockings is recommended to reduce risk of deep vein thrombosis in immobile patients with no contraindications r1
    • Do not use elastic compression stockings
    • Prophylactic anticoagulation with subcutaneous heparin does not have significant effect on mortality or functional status
  • Early physical, occupational, and speech rehabilitation services help patients return home earlier r69c180c181c182
Procedures
Endovascular mechanical thrombectomy c183
General explanation
  • Manual mechanical thrombectomy involves inserting a catheter through the femoral artery and advancing it to the occluded site. A stent retriever is advanced and used to remove the clot r2
  • Typically performed under conscious sedation; general anesthesia also may be appropriate
Indication
  • Patients who meet these eligibility criteria: r1
    • Can have treatment initiated via groin puncture within 6 hours of symptom onset
      • For selected patients with large vessel occlusion of anterior circulation who meet additional criteria, window of time can be extended to 24 hours
    • Have prestroke functional ability modified Rankin Scale score of 0 to 1
      • May be considered for patients who have prestroke modified Rankin Scale score higher than 1 and causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1)
    • Have causative occlusion of the internal carotid artery or proximal middle cerebral artery (M1)
    • Are aged 18 years or older
    • Have NIH Stroke Scale score of 6 or more
    • Have ASPECTS (Alberta Stroke Program Early CT Score) of 6 or more
  • May benefit or be reasonable for some carefully selected patients with other causative occlusions r1
    • Causative occlusion of M2 or M3 portion of middle cerebral arteries, anterior cerebral arteries, vertebral arteries, basilar artery, or posterior cerebral arteries
    • Prestroke modified Rankin Scale score higher than 1, Alberta Stroke Program Early CT Score lower than 6, or NIH Stroke Scale score lower than 6 and causative occlusion of internal carotid artery or proximal middle cerebral artery (M1)
Contraindications
  • Any patient who does not meet all inclusion criteria
Complications
  • Access-site problems (eg, vessel or nerve injury, access-site hematoma, groin infection) r70
  • Device-related complications (eg, vasospasm, arterial perforation and dissection, device detachment or misplacement) r70
  • Embolization to new or target vessel territory r70
  • Intracerebral hemorrhage r70
  • Postoperative hemorrhage r70
  • Pseudoaneurysm r70
Interpretation of results
  • Adequate reperfusion is judged with use of a reperfusion score r1
    • mTICI score (modified treatment in cerebral infarction score) is the current assessment tool of choice and predicts clinical outcomes
    • mTICI 2b/3 is the threshold for adequate reperfusion in recent clinical trials

Comorbidities

  • Urgent treatment of the following comorbidities is required in patients with acute ischemic stroke:

Special populations

  • Pregnant patients
    • Risk of pregnancy-related ischemic stroke ranges from 4 to 26 per 100,000 deliveries r71
    • Diagnose as for nonpregnant population; perform CT (without contrast) without delay r72r73
    • Thrombolysis is not contraindicated during pregnancy r72r73
      • However, pregnant and lactating patients may be at higher risk for complications during thrombolytic therapy
      • Treat with IV alteplase providing the potential benefit exceeds risks of severe uterine bleeding
      • Maintain blood pressure from 140 to 160 mm Hg systolic and 90 to 110 mm Hg diastolic during treatment with IV alteplase r72
    • Mechanical thrombectomy may not be contraindicated in carefully selected patients r72
    • Secondary prevention of stroke in pregnant patients is complicated by need to balance risk of recurrent stroke against risk of adverse effects on developing fetus r71
      • In presence of high-risk condition that would require anticoagulation outside pregnancy, it is reasonable to treat with low-molecular-weight or unfractionated heparin until end of first trimester, then with warfarin until near delivery, at which time heparin is resumed
      • In the presence of a lower-risk condition that would be treated with antiplatelet therapy outside of pregnancy, consider treating with either low-molecular-weight or unfractionated heparin or not treating during first trimester
  • Patent foramen ovale
    • Approximately 23% to 30% of the general population has patent foramen ovale or the pro–patent foramen ovale form (ie, normally closed but subject to opening under higher pressures), which allows communication between the left and right atria. Under some circumstances, this defect may allow venous or right atrial thrombus to enter arterial circulation and cause stroke r74
    • Presence of patent foramen ovale is not associated with increased risk of stroke in the general population; however, patients with cryptogenic stroke are more likely than the general population to have patent foramen ovale r75
    • Secondary prevention of stroke in patients with patent foramen ovale is controversial r75
      • Options include anticoagulation, antiplatelet therapy alone, and closure of patent foramen ovale with short-term or long-term antiplatelet therapy
      • Prior studies had not found benefit for patent foramen ovale closure; however, more recent data show patent foramen ovale closure does reduce risk of recurrent stroke relative to antiplatelet therapy alone r76r77
      • 2018 guidelines suggest patent foramen ovale closure and antiplatelet therapy over long-term anticoagulation therapy or antiplatelet therapy alone; anticoagulation therapy is preferred if patent foramen ovale closure is contraindicated or declined r75r78

Monitoring

  • Follow up with CT or MRI 24 hours after thrombolytic therapy before starting anticoagulants or antiplatelet agents r1

Complications and Prognosis

Complications

  • Early recognition and management of acute stroke complications help prevent further brain injury
    • Cerebral edema c191c192
      • Patients with large territorial supratentorial infarctions are at high risk for complicating brain edema and increased intracranial pressure
      • Consider early transfer of patients who are at risk for malignant brain edema to institution with neurosurgical expertise r1
      • Decline in level of consciousness is most common presentation; timing varies r79
        • This symptom is more commonly caused by displacement of midline structures (eg, thalamus, brainstem) than by globally increased intracranial pressure
        • Edema peaks 3 to 4 days after stroke
        • In some patients, may be delayed up to day 10, corresponding to infarction and edema of penumbral area surrounding ischemic tissue
        • Less commonly, early reperfusion of a large volume stroke can cause accelerated edema within the first 24 hours (malignant edema)
      • Other physical signs include ipsilateral pupillary dysfunction, varying degrees of mydriasis, and worsening motor function
      • Confirm with CT (preferred; without contrast) or MRI
      • Manage with medical efforts to reduce intracranial pressure while consulting with neurosurgeon r79
        • Raise head of bed 20° to 30°
        • Provide brief, moderate hyperventilation as a bridge to more definitive therapy
        • Osmotic therapy with mannitol r1r79
      • Drains and decompressive surgery may be needed r1
        • Can manage acute hydrocephalus that may develop secondary to ischemic stroke by placing ventricular drain c193
        • Suboccipital craniectomy may be indicated in patients with large cerebellar strokes causing obstructive hydrocephalus or brainstem compression
        • Decompressive hemicraniectomy may be indicated in patients with massive hemispheric infarctions and declining levels of consciousness (convincing evidence of improved mortality and functional outcome, especially in patients younger than 60 years who can be treated within 48 hours of stroke onset) r80
    • Intracranial hemorrhage r1c194
      • Presents clinically with worsening neurologic symptoms, decreasing mental status, headache, increased blood pressure and pulse, and vomiting
      • May develop within 12 to 24 hours of IV thrombolytic therapy
      • Also may occur in patients who did not receive thrombolytic therapy, especially those who have had more severe strokes, are older, and have a cardioembolic pathogenesis
      • If suspected: r1
        • Stop infusion of alteplase
        • Obtain CBC, prothrombin time (INR), activated partial thromboplastin time, fibrinogen level, and type and crossmatch
        • Obtain emergency nonenhanced head CT
        • Administer reversal agents
          • Cryoprecipitate (includes factor VIII): 10 units infused over 10 to 30 minutes (onset in 1 hour, peaks in 12 hours); administer additional dose for fibrinogen level of less than 200 mg/dL r1
          • Tranexamic acid 1000 mg IV infused over 10 minutes or ε-aminocaproic acid 4 to 5 g over 1 hour, followed by 1 g IV until bleeding is controlled (peak onset in 3 hours) r1
        • Obtain neurosurgery and hematology consults
        • Provide supportive care, including managing systemic and intracranial pressure
        • Further management depends on size and location of hemorrhage and patient's medical and neurologic status
    • Orolingual angioedema associated with IV alteplase administration r1c195
      • Uncommon; manage as follows:
        • Maintain airway
        • Endotracheal intubation may not be necessary if edema is limited to anterior tongue and lips. If needed, awake fiberoptic intubation is optimal
          • Cricothyroidotomy is rarely needed and is also problematic after IV alteplase
        • Discontinue alteplase infusion (and hold any ACE inhibitors)
        • Administer IV methylprednisolone 125 mg
        • Administer IV diphenhydramine 50 mg
        • Administer famotidine 20 mg IV
        • If there is further increase in angioedema, administer epinephrine (0.1%) 0.3 mL subcutaneously or by nebulizer 0.5 mL
        • Additional treatments that may be beneficial (have been successfully used in hereditary angioedema and ACE inhibitor–related angioedema):
          • Icatibant, a selective bradykinin β₂ receptor antagonist, 3 mL (30 mg) subcutaneously in abdominal area; additional injection of 30 mg may be administered at 6-hour intervals, not to exceed 3 injections total in 24 hours
          • Plasma-derived C1 esterase inhibitor (20 units/kg)
    • Seizures
      • Manage seizures that occur after ischemic stroke with anticonvulsants, as would be given for any other acute neurologic condition r1c196
      • Prophylactic anticonvulsants are not recommended
  • Long-term complications after stroke
    • Immobilized patients are at increased risk for developing deep vein thrombosis and pulmonary embolism; anticoagulant prophylaxis for deep vein thrombosis is recommended in these patients c197c198
    • Spasticity; managed with stretching exercises, drugs, and casts c199
    • Chronic immobility may predispose these patients to decubitus ulcers (ie, pressure sores, bedsores); regular dressing and treatment of infection may be required c200
    • Depression occurs in approximately 30% of patients after stroke r81c201
    • Poststroke cognitive impairment is common and may be disabling r82c202
    • Ongoing functional impairments; refer to appropriate rehabilation services r83c203c204
    • Dysphagia r68c205
    • Risk of falls r83c206

Prognosis

  • Prognosis for acute ischemic stroke varies based on location and size of infarct
  • IV thrombolytic therapy with recombinant tissue plasminogen activator improves neurologic and functional outcome of patients with ischemic stroke treated within 4.5 hours after symptom onset, but it is not associated with a mortality benefit r1
  • Endovascular therapy using stent retrievers additionally improves outcomes for ischemic stroke resulting from large vessel occlusion; clinical outcome improves with increasing degree of vessel recanalization r1
  • Symptomatic intracerebral hemorrhage is a complication of IV thrombolysis in a small percentage of patients (3.3% in recent meta-analysis; 6% in other studies); mortality rate may be 50% if this occurs r84

Screening and Prevention

Screening c207

At-risk populations

  • Patients with atherosclerotic carotid artery disease
    • Atherosclerotic carotid artery disease is a major cause of ischemic stroke r5
    • Risk factors for carotid artery stenosis include older age, male sex, hypertension, smoking, hypercholesterolemia, diabetes, and heart disease; however, there is no means of determining who is at increased risk of stroke when carotid artery stenosis is present r85
    • Screening for carotid artery stenosis is not recommended in asymptomatic adults (ie, those without a history of transient ischemic attack, stroke, or other neurologic signs or symptoms referable to the carotid arteries) r85

Screening tests

  • Screening modalities for carotid artery stenosis include carotid duplex ultrasonography (DUS), magnetic resonance angiography, and computed tomography angiography r85

Prevention

  • General recommendations for primary prevention of cardiovascular disease r86
    • Perform 10-year atherosclerotic cardiovascular disease risk estimation using a risk estimator tool for adults who are aged 40 to 75 years and are being evaluated for cardiovascular disease prevention; for adults aged 20 to 39 years, it is reasonable to assess traditional risk factors at least every 4 to 6 years
      • A free risk calculator with advice based on recent American College of Cardiology/American Heart Association guidelines is available from the American College of Cardiology (available as web download or app) r87
    • All adults should consume a healthy diet that emphasizes vegetables, fruits, nuts, whole grains, lean vegetarian or animal protein, and fish and minimizes trans fats, processed meats, refined carbohydrates, and sweetened beverages
    • For adults who are overweight or obese, counseling and caloric restriction are recommended for achieving and maintaining weight loss
    • Adults should engage in at least 150 minutes per week of accumulated moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity c208
    • For adults with type 2 diabetes mellitus, making lifestyle changes and meeting exercise recommendations are crucial. Metformin is first line therapy, followed by consideration of a sodium-glucose cotransporter 2 inhibitor or a glucagon-like peptide-1 receptor agonist
    • Advise patients to stop smoking, if necessary. Refer active smokers to counseling in combination with drug therapy (using nicotine replacement, bupropion, or varenicline) c209d12
    • Advise patients that aspirin should be used infrequently in routine primary prevention of atherosclerotic cardiovascular disease owing to lack of net benefit
    • Statin therapy is first line treatment for primary prevention of atherosclerotic cardiovascular disease in patients with elevated LDL cholesterol levels (190 mg/dL or higher), with diabetes mellitus (patients aged 40-75 years), and at sufficient atherosclerotic cardiovascular disease risk (determined by clinician-patient risk discussion)
    • Nonpharmacologic interventions are recommended for all adults with elevated blood pressure or hypertension. For those requiring pharmacologic therapy, target blood pressure is generally lower than 130/80 mm Hg
  • Consider low-dose rivaroxaban plus aspirin for efficacious antithrombotic therapy for primary as well as secondary prevention of stroke in patients with atherosclerosis r88
  • In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than those who received placebo; most patients were already receiving proven secondary prevention therapies r89
  • Surgical procedures to improve carotid artery blood flow, including carotid endarterectomy (CEA), carotid artery angioplasty, and stenting or transartery revascularization, may be indicated in patient with carotid artery stenosis r85
    • European guidelines recommend carotid endarterectomy in patients with 60% or greater asymptomatic carotid artery stenosis who are considered to be at increased risk of stroke despite best medical therapy r5
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