Ischemic Stroke

Stroke is classified as cryptogenic when one of the following occurs:

• The diagnostic evaluation is incomplete.

• No cause is identified despite an extensive evaluation.

• There is more than one probable cause (eg, atrial fibrillation and ipsilateral carotid stenosis).

Embolic stroke of undetermined source (ESUS), a subcategory of cryptogenic stroke, is diagnosed when no source has been identified after sufficient diagnostic evaluation has excluded lacunar stroke, major cardioembolic sources, and ipsilateral steno-occlusive vessel disease (> 50% occlusion). Recent evidence suggests that symptomatic nonstenotic carotid disease with < 50% occlusion may be an important a cause of stroke (1).

Emboli may lodge anywhere in the cerebral arterial tree.

Emboli may originate as cardiac thrombi, especially in the following conditions:

• Atrial fibrillation

• Rheumatic heart disease (usually mitral stenosis)

• Post–myocardial infarction

• Vegetations on heart valves in bacterial or marantic endocarditis

• Atrial myxoma

• Prosthetic heart valves

• Mechanical circulatory assist devices (eg, left ventricular assist device, or LVAD [2])

Other sources include clots that form after open-heart surgery and atheromas in neck arteries or in the aortic arch. Rarely, emboli consist of fat (from fractured long bones), air (in decompression sickness), or venous clots that pass from the right to the left side of the heart through a patent foramen ovale with shunt (paradoxical emboli). Emboli may dislodge spontaneously or after invasive cardiovascular procedures (eg, catheterization). Rarely, thrombosis of the subclavian artery results in embolic stroke in the vertebral artery or its branches.

Ischemic stroke can also result from lacunar infarcts. These small (≤ 1.5 cm) infarcts result from nonatherothrombotic obstruction of small, perforating arteries that supply deep cortical structures; the usual cause is lipohyalinosis (degeneration of the media of small arteries and replacement by lipids and collagen). Emboli may cause lacunar infarcts. Lacunar strokes >1.5 cm in patients without cardiovascular risk factors (eg, hypertension, diabetes, smoking) suggest a central embolic source.

Lacunar infarcts tend to occur in patients with diabetes or poorly controlled hypertension.

Large-vessel atherosclerosis can affect intracranial or extracranial arteries.

Atheromas, particularly if ulcerated, predispose to thrombi. Atheromas can occur in any major cerebral artery and are common at areas of turbulent flow, particularly at the carotid bifurcation. Partial or complete thrombotic occlusion occurs most often at the main trunk of the middle cerebral artery and its branches but is also common in the large arteries at the base of the brain, in deep perforating arteries, and in small cortical branches. The basilar artery and the segment of the internal carotid artery between the cavernous sinus and supraclinoid process are often occluded.

Less common causes of stroke include vascular inflammation secondary to disorders such as acute or chronic meningitis, vasculitic disorders, and syphilis; dissection of intracranial arteries or the aorta; hypercoagulability disorders (eg, antiphospholipid syndrome, hyperhomocysteinemia, underlying malignancy); hyperviscosity disorders (eg, polycythemia, thrombocytosis, hemoglobinopathies, plasma cell disorders); and rare disorders (eg, fibromuscular dysplasia, moyamoya disease, Binswanger disease).

In children, sickle cell disease is a common cause of ischemic stroke.

Any factor that impairs systemic perfusion (eg, carbon monoxide toxicity, severe anemia or hypoxia, polycythemia, hypotension) increases risk of all types of ischemic strokes. A stroke may occur along the borders between territories of arteries (watershed areas); in such areas, blood supply is normally low, particularly if patients have hypotension and/or if major cerebral arteries are stenotic.

1. 1. Ospel JM, Kappelhof M, Ganesh A, et al: Symptomatic non-stenotic carotid disease: current challenges and opportunities for diagnosis and treatment. J Neurointerv Surg jnis-2022-020005, 2023.. doi: 10.1136/jnis-2022-020005 Online ahead of print.

2. 2. Caprio FZ, Sorond FA: Cerebrovascular disease: Primary and secondary stroke Prevention. Med Clin North Am 103 (2):295–308, 2019. doi: 10.1016/j.mcna.2018.10.001 Epub 2018 Nov 28.

Neuroimaging with CT or MRI is done first to exclude intracerebral hemorrhage, subdural or epidural hematoma, and a rapidly growing, bleeding, or suddenly symptomatic tumor. CT evidence of even a large anterior circulation ischemic stroke may be subtle during the first few hours; changes may include effacement of sulci or the insular cortical ribbon, loss of the gray-white junction between cortex and white matter, and a dense middle cerebral artery sign. Within 6 to 12 hours of ischemia, medium-sized to large infarcts start to become visible as hypodensities; small infarcts (eg, lacunar infarcts) may be visible only with MRI.

Diffusion-weighted MRI (highly sensitive for early ischemia) can be done immediately after initial CT neuroimaging.

Images of Ischemic Stroke

Hypoxic Ischemic Brain Injury and Cerebral Edema

This image shows a noncontrast CT in a patient with hypoxic brain injury and cerebral edema. Note the loss of gray-white matter differentiation (circle), hypoxic-ischemic damage to the basal ganglia (arrows), and effacement of the sulci.

... read more

© 2017 Elliot K. Fishman, MD.

Insular Ribbon Loss

This CT scan shows effacement of the sylvian fissure and insular ribbon (straight arrows) on the infarcted side of brain compared with the normal insular ribbon (curved arrows).

... read more

By permission of the publisher. From Geremia G, Greenlee W. In Atlas of Cerebrovascular Disease. Edited by PB Gorelick and MA Sloan. Philadelphia, Current Medicine, 1996.

Middle Cerebral Artery Infarct

A large lucent infarction is seen in the area of brain supplied by the right middle cerebral artery.

By permission of the publisher. From Furie K, et al: Cerebrovascular disease. In Atlas of Clinical Neurology. Edited by RN Rosenberg. Philadelphia, Current Medicine, 2002.

Ischemic Stroke in the Left Middle Cerebral Artery (CT)

This noncontrast head CT scan shows a hyperdense left middle cerebral artery. This finding indicates a focal clot in the left middle cerebral artery (arrow).

... read more

Image courtesy of Ji Y. Chong, MD.

Acute Ischemic Stroke in the Left Insular and Frontal Lobes (MRI)

This MRI scan shows an area of restricted diffusion consistent with an acute ischemic stroke in the left insular and frontal lobes.

... read more

Image courtesy of Ji Y. Chong, MD.

Lacunar Infarct

This CT scan shows a low-density, well-defined lacunar infarct (arrow) within the basal ganglia.

By permission of the publisher. From Geremia G, Greenlee W. In Atlas of Cerebrovascular Disease. Edited by PB Gorelick and MA Sloan. Philadelphia, Current Medicine, 1996.

Hypoxic Ischemic Brain Injury and Cerebral Edema

This image shows a noncontrast CT in a patient with hypoxic brain injury and cerebral edema. Note the loss of gray-white matter differentiation (circle), hypoxic-ischemic damage to the basal ganglia (arrows), and effacement of the sulci.

... read more

© 2017 Elliot K. Fishman, MD.

Insular Ribbon Loss

This CT scan shows effacement of the sylvian fissure and insular ribbon (straight arrows) on the infarcted side of brain compared with the normal insular ribbon (curved arrows).

... read more

By permission of the publisher. From Geremia G, Greenlee W. In Atlas of Cerebrovascular Disease. Edited by PB Gorelick and MA Sloan. Philadelphia, Current Medicine, 1996.

Middle Cerebral Artery Infarct

A large lucent infarction is seen in the area of brain supplied by the right middle cerebral artery.

By permission of the publisher. From Furie K, et al: Cerebrovascular disease. In Atlas of Clinical Neurology. Edited by RN Rosenberg. Philadelphia, Current Medicine, 2002.

Ischemic Stroke in the Left Middle Cerebral Artery (CT)

This noncontrast head CT scan shows a hyperdense left middle cerebral artery. This finding indicates a focal clot in the left middle cerebral artery (arrow).

... read more

Image courtesy of Ji Y. Chong, MD.

Acute Ischemic Stroke in the Left Insular and Frontal Lobes (MRI)

This MRI scan shows an area of restricted diffusion consistent with an acute ischemic stroke in the left insular and frontal lobes.

... read more

Image courtesy of Ji Y. Chong, MD.

Lacunar Infarct

This CT scan shows a low-density, well-defined lacunar infarct (arrow) within the basal ganglia.

By permission of the publisher. From Geremia G, Greenlee W. In Atlas of Cerebrovascular Disease. Edited by PB Gorelick and MA Sloan. Philadelphia, Current Medicine, 1996.

For cardiac causes, testing typically includes ECG, telemetry or Holter monitoring, serum troponin, and transthoracic or transesophageal echocardiography. Implantable cardiac monitors are useful for detecting underlying atrial arrhythmias in patients with cryptogenic stroke (1).

For vascular causes, testing may include magnetic resonance angiography (MRA), CT angiography (CTA), carotid and transcranial duplex ultrasonography, and conventional angiography. The choice and sequence of testing is individualized, based on clinical findings. MRA, CTA, and carotid ultrasonography all show the anterior circulation; however, MRA and CTA provide better images of the posterior circulation than carotid ultrasonography. In general, CTA is preferred to MRA because motion artifacts are avoided. Usually, CTA or MRA should be done urgently but should not delay treatment with IV tPA if it is indicated.

Effects of Thrombectomy After Stroke (Arteriogram)

Image

Image courtesy of Ji Y. Chong, MD.

For blood-related causes (eg, thrombotic disorders), blood tests are done to assess their contribution and that of other causes. Routine testing typically includes complete blood count (CBC), metabolic panel, prothrombin time/partial thromboplastin time (PT/PTT), fasting blood glucose, hemoglobin A1C, and lipid profile.

1. 1. Sanna T , Diener H-C., Passman RS, et al: Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 370:2478–2486, 2014. doi: 10.1056/NEJMoa1313600

Guidelines for early management of stroke are available from the American Heart Association and American Stroke Association. Patients with acute ischemic strokes are usually hospitalized.

Supportive measures such as the following may be needed during initial evaluation and stabilization.

• Airway support and ventilatory assistance if decreased consciousness or bulbar dysfunction compromises the airway

• Supplemental oxygen only if needed to maintain oxygen saturation > 94%

• Correction of hyperthermia (temperature > 38° C) by using an antipyretic medication and identifying and treating the cause of hyperthermia

• Treatment of hypoglycemia (blood glucose < 60 mg/dL)

• Treatment of hyperglycemia to lower blood glucose to 140 to 180 mg/dL while closely monitoring for hypoglycemia

Perfusion of an ischemic brain area may require a high blood pressure (BP) because autoregulation is lost; thus, BP should not be decreased except in the following cases:

• There are signs of other end-organ damage (eg, aortic dissection, acute myocardial infarction, pulmonary edema, hypertensive encephalopathy, retinal hemorrhages, acute renal failure).

If BP is ≥ 220 mm Hg systolic or ≥ 120 mm Hg diastolic on 2 successive readings 15 minutes apart, lowering BP by 15% in the 24 hours after stroke onset is reasonable.

For patients who are eligible for acute reperfusion therapy, BP is treated to decrease it to < 180/105 mm Hg before starting IV thrombolysis with one of the following:

Patients with presumed thrombi or emboli may be treated with one or a combination of the following:

• tPA, thrombolysis-in-situ, and/or mechanical thrombectomy

• Antiplatelet medications

• Anticoagulants

aspirin-induced or nonsteroidal anti-inflammatory drug (NSAID)-induced asthma or urticaria, other hypersensitivity to aspirin

Recombinant tPA). Some experts recommend using tPA up to 4.5 hours after symptom onset (see Expansion of the Time Window for Treatment of Acute Ischemic Stroke With Intravenous Tissue Plasminogen Activator); however, between 3 hours and 4.5 hours after symptom onset, additional exclusion criteria apply (see table ). Thus, tPA must be given within 4.5 hours of symptom onset—a difficult requirement. Because the precise time of symptom onset may not be known, clinicians must start timing from the moment the patient was last observed to be well.

Although tPA can cause fatal or other symptomatic brain hemorrhage, patients treated with tPA strictly according to protocols still have a higher likelihood of functional neurologic recovery. Only clinicians experienced in stroke management should use tPA to treat patients with acute stroke; inexperienced physicians are more likely to violate protocols, resulting in more brain hemorrhages and deaths. When tPA is given incorrectly (eg, when given despite the presence of exclusion criteria), risk of hemorrhage due to tPA is high mainly for patients who have had stroke; risk of brain hemorrhage is very low (about 0.5%; 95% confidence interval of 0 to 2.0% [1]) for patients who have had a stroke mimic (eg, hemiplegic migraine, certain CNS infections, postictal paralysis, functional neurologic disorders). If experienced clinicians are not available on site, consultation with an expert at a stroke center (including video evaluation of the patient [telemedicine]), if possible, may enable these clinicians to use tPA. Because most poor outcomes result from failure to strictly adhere to the protocol, a checklist of inclusion and exclusion criteria should be used.

Before treatment with tPA, the following are required:

• Brain hemorrhage must be excluded by CT

• Systolic BP must be < 185 mm Hg

• Diastolic BP must be < 105 mm Hg

• Blood glucose must be > 50 mg/dL

Dose of tPA is 0.9 mg/kg IV (maximum dose 90 mg); 10% is given by rapid IV injection over 1 minute, and the remainder by constant infusion over 60 minutes. Vital signs are closely monitored for 24 hours after treatment. Any bleeding complications are aggressively managed. Anticoagulants and antiplatelet medications are not used within 24 hours of treatment with tPA.

2

34]):

• Recent major surgery or procedure (eg, coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels)

• Cerebrovascular disease

• Recent intracranial hemorrhage

• Recent gastrointestinal or genitourinary bleeding

• Recent trauma

• Hypertension (systolic BP > 175 mm Hg or diastolic BP > 110 mm Hg

• Acute pericarditis

• Subacute bacterial endocarditis

• Hemostatic defects including those due to severe hepatic or renal disease

• Significant hepatic dysfunction

• Pregnancy

• Hemorrhagic diabetic retinopathy or other hemorrhagic ophthalmic conditions

• Septic thrombophlebitis or occluded arteriovenous cannula at an infected site

• Advanced age (> 77 years)

Thrombolysis-in-situ (angiographically directed intra-arterial thrombolysis) of a thrombus or embolus is almost obsolete except when a clot is too distal to be accessed by catheters (eg, distal A2 [anterior cerebral artery distal to the anterior communicating artery]).

Mechanical thrombectomy (angiographically directed intra-arterial removal of a thrombus or embolus by a stent retriever device) is standard of care in large stroke centers for patients with recent large-vessel occlusion in the anterior circulation.

Mechanical thrombectomy had previously been restricted to use within 6 hours of symptom onset in patients with internal carotid artery or middle cerebral artery occlusion. However, at comprehensive stroke centers, clinical and/or imaging findings that suggest a substantial amount of tissue at risk of infarction (penumbra) may justify later treatment. For example, the volume of infarcted tissue and at-risk underperfused tissue (ischemic penumbra) can be identified using perfusion CT or perfusion MRI. A sizeable mismatch between the infarct and at-risk volume identified by diffusion-weighted or perfusion-weighted imaging suggests that substantial penumbra is still potentially salvageable. In the DEFUSE 3 trial, benefit was evident up to 16 hours after symptom onset in patients with a small infarct and a larger penumbra; both findings are based on imaging criteria (5). In the DAWN trial, benefit was evident up to 24 hours after symptom onset in patients with a large mismatch between infarct volume based on imaging and severity of the clinical deficit based on clinical criteria (6); this finding suggests that salvageable penumbra is present.

Recently, evidence for the efficacy of mechanical thrombectomy in patients with posterior circulation strokes has been growing (7).

In the past, clinical trials restricted mechanical thrombectomy to patients with an NIHSS score > 6; however, recent evidence supports the usefulness of mechanical thrombectomy in patients with an NIHSS < 6 (8).

Current evidence supports the use of mechanical thrombectomy with IV thrombolysis (bridging therapy) for all patients who are otherwise eligible for thrombolysis (9). It should not be used as an alternative to IV recombinant tPA for patients with acute ischemic stroke if they are eligible for tPA. Devices used to remove thrombi are being improved, and recent models reestablish perfusion in 90 to 100% of patients.

Effects of Thrombectomy After Stroke (Arteriogram)

Image

Image courtesy of Ji Y. Chong, MD.

Oral antiplatelet medications are used in acute stroke treatment to reduce the risk of recurrent disabling stroke. The following may be used:

10).

aspirin alone for reducing risk of stroke in the first 90 days and does not increase risk of hemorrhage (11). However, prolonged (eg, > 3 months) use of clopidogrel plus aspirin is avoided because it has no advantage over aspirin

Anticoagulation

Usually, anticoagulation is avoided in the acute stage because risk of hemorrhage (hemorrhagic transformation) is higher, especially with large infarcts.

Supportive care is continued during convalescence:

• Controlling hyperglycemia and fever can limit brain damage after stroke, leading to better functional outcomes.

• Screening for dysphagia before patients begin eating, drinking, or receiving oral medications can help identify patients at increased risk of aspiration; it should be done by a speech-language pathologist or other trained health care practitioner.

• Enteral nutrition if needed should be started within 7 days of admission after an acute stoke.

• Intermittent pneumatic compression (IPC) for deep venous thrombosis prophylaxis is recommended for immobile stroke patients without contraindications.

• Measures to prevent pressure ulcers are started early.

• Physical therapy to help maximize function and prevent sarcopenia and joint contractures

Long-term management also focuses on prevention of recurrent stroke (secondary prevention). Modifiable risk factors (eg, hypertension, diabetes, smoking, alcohol use disorder, dyslipidemia, obesity) are treated. Reducing systolic BP may be more effective when the target BP is < 120 mm Hg rather than the typical level (< 140 mm Hg). The timeline for reducing BP to these levels should be determined based on the each patient's health status and risk of recurrent stroke or other cardiovascular events.

Depression often occurs after a stroke and may interfere with recovery. Treatment of depression may aid in recovery, Clinicians should ask patients whether they are feeling sad or have lost interest or pleasure in doing formerly enjoyable activities. Clinicians should also ask family members whether they have noticed any signs of depression in the patient.

Extracranial carotid endarterectomy or stenting is indicated for patients with recent nondisabling, submaximal stroke attributed to an ipsilateral carotid obstruction of 70 to 99% of the arterial lumen or to an ulcerated plaque if life expectancy is at least 5 years. In other symptomatic patients (eg, patients with TIAs), endarterectomy or stenting with antiplatelet therapy is indicated for carotid obstruction of ≥ 60% with or without ulceration if life expectancy is at least 5 years. These procedures should be done by surgeons and interventionists who have a successful record with the procedure (ie, morbidity and mortality rate of < 3%) in the hospital where it will be done. If carotid stenosis is asymptomatic, endarterectomy or stenting is beneficial only when done by very experienced surgeons or interventionists, and that benefit is likely to be small. For many patients, carotid stenting with an emboli-protection device (a type of filter) is preferred to endarterectomy, particularly if patients are ≥ 70 years and have a high surgical risk. Carotid endarterectomy and stenting are equally effective for stroke prevention. In the periprocedural period, myocardial infarction is more likely after endarterectomy, and recurrent stroke is more likely after stenting.

Extracranial vertebral angioplasty and/or stenting can be used in certain patients with recurrent symptoms of vertebrobasilar ischemia despite optimal medical treatment and a vertebral artery obstruction of 50 to 99%.

Intracranial major artery angioplasty and/or stenting may be effective in patients when optimal treatment with medications has been ineffective. Key factors to consider are patient characteristics (eg, control of risk factors, adherence to the medication regimen), timing of the procedure (> 3 weeks after the stroke), and the interventionist's experience. Recent evidence indicates that the rate of periprocedural adverse events can be acceptably low after percutaneous transluminal angioplasty and stenting when these factors are considered (12).

Endovascular closure of a patent foramen ovale plus use of antiplatelet therapy is recommended for patients < 60 years with an embolic stroke of undetermined cause despite extensive evaluation (13, 14).

Oral antiplatelet medications are used to prevent subsequent noncardioembolic (atherothrombotic, lacunar, cryptogenic) strokes (secondary prevention). The following may be used:

aspirinaspirin

aspirin, if started during acute treatment, is given for only a short time (eg, < 3 weeks) because it has no advantage over aspirinaspirin

Oral anticoagulants

13

Statins

1. 1. Tsivgoulis G, Zand R, Katsanos AH, et al: Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis. Stroke 46 (5):1281–1287, 2015. doi: 10.1161/STROKEAHA.115.009012

2. 2. Menon BK, Singh N, Sylaja, PNLancet 25;401(10377):618–619, 2023. doi: 10.1016/S0140-6736(22)02633-2 Epub 2023 Feb 9.

3. 3. Frank B, Grotta JC,.Alexandrov AV, et al: Thrombolysis in stroke despite contraindications or warnings? Stroke 44 (3):727–733, 2013. doi: 10.1161/STROKEAHA.112.674622 Epub 2013 Feb 6.

4. 4. Highlights of prescribing information for alteplase. Accessed 6/17/23.

5. 5. Albers GW, Marks MP, Kemp S, et al: Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 378 (8):708–718, 2018. doi: 10.1056/NEJMoa1713973 Epub 2018 Jan 24.

6. 6. Nogueira RG, Jadhav AP, Haussen DC, et al: Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 378 (1):11–21, 2018. doi: 10.1056/NEJMoa1706442 Epub 2017 Nov 11.

7. 7. Jovin TG, Li C, Wu L, et al: Trial of thrombectomy 6 to 24 hours after stroke due to basilar-artery occlusion. N Engl J Med 2022; 387:1373-1384, 2022. doi: 10.1056/NEJMoa2207576

8. 8. Abecassis IJ, Almallouhi E, Chalhoub R, et al: Outcomes after endovascular mechanical thrombectomy for low compared to high National Institutes of Health Stroke Scale (NIHSS): A multicenter study. Clin Neurol Neurosurg 225:107592, 2023. doi: 10.1016/j.clineuro.2023.107592 Epub 2023 Jan 13.

9. 9. Masoud HE, de Havenon A, Castonguay AC, et al: 2022 Brief practice update on intravenous thrombolysis before thrombectomy in patients with large vessel occlusion acute ischemic stroke: A statement from Society of Vascular and Interventional Neurology Guidelines and Practice Standards (GAPS) Committee. Stroke. Vasc Interv Neurol 2 (4) 2022. doi: 10.1161/SVIN.121.000276

10. 10. Zheng-Ming C, CAST (Chinese Acute Stroke Trial) Collaborative Group: Lancet 349 (9065):1641–1649, 1997.

11. 11. Hao Q, Tampi M, O'Donnell M, et alBMJ 363:k5108, 2018. doi: 10.1136/bmj.k5108

12. 12. Alexander MJ, Zauner A, Chaloupka JC, et al: WEAVE Trial: Final results in 152 on-label patients. Stroke 50 (4):889–894, 2019. doi: 10.1161/STROKEAHA.118.023996

13. 13. Powers WJ, Rabinstein AA, Ackerson T, 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):3331–3332, 2019. doi: 10.1161/STROKEAHA.119.027708 Epub 2019 Oct 30.

14. 14. Kavinsky CJ, Szerlip M, Goldsweig AM, et al: SCAI guidelines for the management of patent foramen ovale. Standards and guidelines 1 (4), 100039, 2022. doi: 10.1016/j.jscai.2022.100039