COVID-19-associated stroke

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parul Pahal, M.B.B.S[2], Moises Romo M.D.

Synonyms and keywords: COVID-19, SARS-CoV-2, stroke, CT scan, cerebrovascular disease, TPA, alteplase

Overview

Cerebral hemorrhage or cerebral ischemia disrupts cerebral perfusion and can lead to an acute neurologic condition, called stroke. Cerebrovascular complications have been reported in severe Coronavirus Disease 2019 (COVID-19). However, neurological complications are not very common in rapidly spreading COVID-19 which is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The presenting complaints in majority of stroke patients reported in different studies were respiratory complaints (shortness of breath, cough) and non-specific constitutional symptoms such as fever, malaise, etc., and stroke developed later in the course of the disease. This is thought to be due to COVID-19-associated coagulopathy. However, there are few case reports and studies that have mentioned specific neurological presenting complaints such as altered mental status, limb weakness, and aphasia. Various non-pulmonary features are being reported as the COVID-19 understanding is unfolding with the spike of cases and continuously rising number of cases globally.

To view general COVID-19 section, click here.

Historical Perspective

  • Stroke was first recognized by Hippocrates, in the fourth century BC, almost 2,400 years ago, and it was reffered to as Apoplexy, a Greek medical literature term, which means 'struk down by violence'. Later, renaissance anatomists, in mid-16th century A.D., explained the pathophysiology of stroke, differentiating the causes as bleeding or blockage of A cerebral artery.
  • Mao et al., in his study, first reported neurological symptoms in COVID-19 patients hospitalized in Wuhan, China from January 16, 2020, to February 19, 2020. Neurological symptoms were reported in 78 patients out of 214 COVID-19 positive hospitalized patients with COVID-19 in Wuhan, China. The stroke patients reported specifically were 14. In this study, patients with cardiovascular risk factors who presented with severe systemic symptoms were at higher risk of stroke.
  • Yaghi et al. retrospectively examined stroke patients admitted across different locations of NYU Langone hospital in New York. In this study, the incidence of 0.9% was observed in laboratory confirmed COVID-19 positive patients included in this study. Stroke diagnosis was proved by imaging, and cryptogenic stroke was seen in most of these patients. The mortality was much higher in stroke patients who were COVID-19 positive.

To view historical perspective of COVID-19 section, click here.

Classification

  • There is no specific classification established for 'Stroke in COVID-19 patients'.
  • It is same as the general classification of stroke.[1]


To view classification of COVID-19 section, click here.

Pathophysiology

  • Further investigations should be done to better understand the mechanism of Stroke in patients with COVID-19.

To view pathophysiology COVID-19 section, click here.

Causes

Differentiating COVID-19-associated stroke from other Diseases

  • For further information about the differential diagnosis, click here.
  • To view the differential diagnosis of COVID-19, click here.

Epidemiology and Demographics

Prevalence of stroke in patients with COVID-19
Date of publication Country Author Number of patients Severe infection Neurological symptoms Acute Cerebrovascular disease Ischemic/Hemorrhagic Stroke
April 10, 2020 Wuhan, China Mao et al.[3] 214 88 patients (41.1%), Mean age-58.2 years 78 patients (36.4%) 5 among severe [5.7%] infection group vs 1 [0.8%]) in non-severe group Ischemic-4, Hemorrhagic-1
May 29, 2020 Wuhan, China Qin et al. (Retrospective cohort study) 1875 461 severe on admission 50 patients ie. 15 among severe and 35 among mild on admission (Median age-70 years), 30 males and 20 females Ischemic-90%, Hemorrhagic-10%
May 20, 2020 New York Yaghi et al.[4] (Retrospective cohort study) 3556 Stroke at the time of admission-14/32 (43.8%), eventually developed stroke during hospitalization-18 (56.2%) 32 patients (0.9%) Ischemic stroke- 32
April 28, 2020 New York city Oxley et al. 5 Large vessel stroke-5, Mean age-<50 years
July 12, 2020 New York Valderrama et al. 1 (52-year old male) Ischemic stroke
Prevalence of COVID-19-associated stroke varies in different studies


  • The incidence of stroke in hospitalized COVID-19 patients is reported to be 0.9–2%.majority of them being ischemic subtype. The mortality in COVID-19 positive stroke patients is reported to be 39%[3].
  • A New York study published in May reported that the proportion of these strokes seem to be higher in younger men.[4] Most of these strokes are large vessel ischemic strokes and are catastrophic.
  • In a single center retrospective study conducted in Wuhan by Qin C. et al. which included 1875 laboratory-confirmed COVID-19 patients from january 27th, 2020, to March 5th, 2020, 50 patients had history of stroke. The median age of this study group was 63 years, with stroke patients relatively older(70 years) when compared to non-stroke patients (62 years).[6]
  • Stroke is one of the neurological manifestations in patients with severe infection. There is limited information on COVID-19 patients with stroke who survived.

To view epidemiology and demographics of COVID-19 section, click here.

Risk Factors

  • According to one of the study conducted in New York, Stroke in COVID-19 infected patients is seen in relatively young patients as compared to with non COVID-19 patients.[4]
  • However, due to disparities in the stroke prevalence in different studies, no clear association has been established.


To view risk factors of COVID-19 section, click here.

Screening


To view screening of COVID-19 section, click here.

Natural History, Complications, and Prognosis


To view natural history, complications and prognosis of COVID-19 section, click here.

Diagnosis

Diagnostic Study of Choice

History and Symptoms

  • The majority of patients with COVID-19-associated stroke initially presented with respiratory symptoms (e.g. cough, shortness of breath etc) and constitutional features. These patients developed cerebrovascular signs and symptoms later in the course of disease.
  • The following table summarizes the signs and symptoms found in 5 patients with COVID-19 infection that later acquiered a stroke:[8][9]
Patient no. Onset of neurologic symptoms
Age and Gender
Neurologic Signs & Symptoms
1 On Admission 73-year old, Male Respiratory distress, fever, and altered mental status
2 On Admission 83-year old, Female Fever, slurring of speech, facial droop, and reduced oral intake [8]
3 On Admission 80-year old female Left sided weakness, altered mental status, one week history of frequent falls [8]
4 On Admission 88-year old, Female An 15 minute episode of weakness and numbness of right arm and word finding difficulty [8]
5 On Admission 58-year old, Male Dense Right-sided weakness and acute onset aphasia
Reported cases of patients with COVID-19 infection and symptoms suggestive of stroke.

Most common symptoms

Less common symptoms


Physical Examination

Physical examination of patients with stroke depending on vessel involved
Vessel involved Physical examination
Anterior cerebral artery
Middle cerebral artery
  • Most common site of infarction
Posterior cerebral artery[17]
Vertebrobasilar artery Midbrain
  • Contralateral decreased motor strength
  • Deviation of eye downwards and outwards-ipsilateral 3rd nerve palsy
Medulla
  • Impaired gag reflex
  • Uvula deviated to the opposite side of lesion
  • Ptosis
  • Miosis
  • Enophthalmos
  • Ipsilateral impaired pain, touch and temperature sensation on the upper half of the face
  • Contralateral decreased motor strength and sensory loss
  • Romberg's sign
  • Deviation of the tongue to the side of the lesion-hypoglossal nerve
  • Contralateral decreased motor strength
  • Contralateral loss of position sense, vibration and two point discrimination
Pons
Cerebellum


  • The use of stroke scales helps to measure the degree of neurological impairment, ease communication, may help select patients candidates for fibrinolytic or mechanical therapy, permits the evaluation of changing clinical status, and identifies those patients at higher risk for complications (eg. intracerebral hemorrhage).
  • The National Institutes of Health Stroke Scale (NIHSS) is a tool used to measure the neurologic impairment caused by a stroke in a quantitative manner.[24] The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.
National Institutes of Health Stroke Scale (NIHSS)
Tested item Title Response and score
1A Level of consciousness 0—Alert
1—Drowsy
2—Obtunded
3—Coma/unresponsive
1B Orientation questions (2) 0—Answers both correctly
1—Answers 1 correctly
2—Answers neither correctly
2 Gaze 0—Normal horizontal movements
1—Partial gaze palsy
2—Complete gaze palsy
3 Visual fields 0—No visual field defect
1—Partial hemianopia
2—Complete hemianopia
3—Bilateral hemianopia
4 Facial movement 0—Normal
1—Minor facial weakness
2—Partial facial weakness
3—Complete unilateral palsy
5 Motor function (arm)

a. Left

b. Right

0—No drift
1—Drift before 10 s
2—Falls before 10 s
3—No effort against gravity
4—No movement
6 Motor function (leg)

a. Left

b. Right

0—No drift
1—Drift before 5 s
2—Falls before 5 s
3—No effort against gravity
4—No movement
7 Limb ataxia 0—No ataxia
1—Ataxia in 1 limb
2—Ataxia in 2 limbs
8 Sensory 0—No sensory loss
1—Mild sensory loss
2—Severe sensory loss
9 Language 0—Norma
1—Mild aphasia
2—Severe aphasia
3—Mute or global aphasia
10 Articulation of words 0—Norma
1—Mild dysarthria
2—Severe dysarthria
11 Extinction or inattention 0—Absent
1—Mild loss (1 sensory modality lost)
2—Severe loss (2 modalities lost)
Adapted from Lyden et al., 1994 American Heart Association, Inc.
  • The pre-stroke Modified Rankin Score (mRS) is an estimated score used to assess the patient’s pre-stroke level of function. An estimated mRS should be abstracted from current medical record documentation about the patient’s ability to perform activities of daily living prior to the hospitalization for the acute ischemic stroke event.[25]
Alberta stroke program early CT score (ASPECTS)
Area affected Score
Subganglionic Nuclei: M1 - Frontal operculum   1
M2 - Anterior temporal lobe 1
M3 - Posterior temporal lobe 1
Supraganglionic Nuclei: M4  - Anterior MCA    1
M5  - Lateral MCA   1
M6  - Posterior MCA    1
Basal Ganglia: C - Caudate 1
L - Lentiform Nucleus     1
I - Insula 1
IC - Internal Capsule 1
Adapted from The University of Calgary ASPECT score in Accute stroke, 2020
Pre-Stroke Modified Rankin Score (mRS)
Score Item tested
0 The patient had no residual symptoms.
1 The patient had no significant disability; able to carry out all activities.
2 The patient had slight disability; unable to carry out all activities but able to look after self without daily help.
3 The patient had moderate disability; requiring some external help but able to walk without the assistance of another individual.
4  The patient had moderately severe disability; unable to walk or attend to bodily functions without assistance of another individual.
5 The patient had severe disability; bedridden, incontinent, requires continuous care.
6 Unable to determine (UTD) from the medical record documentation.
Adapted from Specifications Manual for Joint Commission National Quality Measures, 2018


Laboratory Findings

  • Patients with stroke associated to COVID-19 will have a positive test for COVID-19 confirmed either through molecular tests, nucleic acid amplification test, or serological testing.

Ultrasound

X-ray

  • Head x-rays can help rule out foreign metal objects in the head before performing an MRI, detect skull fractures, and identify intracranial calcifications that may serve as hallmarks for brain structural changes in countries with poor access to more specific imaging tests.
  • There is no evidence of usefulness of chest x-ray in the acute setting of stroke.[7]

CT scan

MRI

  • MRI of the head before IV alteplase administration to exclude microbleeds is not recommended.[7]
  • Multimodal MRI of the head should be done in patients who present within 24 hours of the initiation of symptoms.[27]
  • In patients who wake up with clinical symptoms of stroke of unknown onset (more than 3 hours?), an MRI with diffusion-positive FLAIR may be useful for selecting those who can benefit from IV alteplase administration.[7]

Electrocardiogram


  • To view diagnosis of COVID-19 section, click here.

Treatment

Early assesment

  • The initial assesment goals of ischemic stroke may include the following:[28]


 
 
 
 
 
 
 
 
 
 
 
 
1) Airway

2) Breathing

3) Circulation
 
1) O2 administration at SpO2<94%

2) Ventilatory assisstance is provided to patients who have difficulty breathting

3) IV fluids or vasopressors are given to maintain hemodynamic stability
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early Diagnosis
 
History and PE

1) Help assess the severity of neurological deficit
2) Give clue to the underlying cause

3) Determine the site of infarction
 
Initial diagnostic tests

1) Noncontrast brain CT or brain MRI
2) Blood glucose
3) Oxygen saturation
4) Serum electrolytes/renal function tests
5) Complete blood count, including platelet count
6) Markers of cardiac ischemia
7) Prothrombin time/INR
8) Activated partial thromboplastin time

9) ECG
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early assessment of ischemic stroke
 
 
 
 
Reperfusion therapy
 
Medical
r-tPA in eligible patients within 3-4.5 hours of onset of symptoms
 
Surgical
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptomatic relief
 
1) Fever
2) Headache
3) Shortness of breath
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prognosis
 
1)NIHSS scoring
2)Glassgow coma scale
 
 
 
 
 
 


Medical therapy

  • The reported cases of treatment for COVID-19-associated stroke have followed the same guidelines as patients with no COVID-19 infection. The following recommendations are mainly based on the current guidelines of management for stroke of the AHA 2019.
  • IV alteplase is always preferred over mechanical thrombectomy when there are no contraindications.
  • The usefulness of anticoagulants such as thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) is not well established in the acute setting of stroke.
  • The use of thrombolysis via ultrasound waves concomitant to IV fibrinolysis is not recommended.
  • High-intensity statin therapy should be initiated in patients younger than 75 with clinical ASCVD, to achieving a reduction in LDL-C levels of at least 50%.
  • In patients older than 75 years of age with clinical ASCVD, it is reasonable to initiate moderate or high-intensity statin therapy after reviewing adverse effects and drug interactions.[7]
  • Risk and beneffits should be discussed before initiation of statin therapy to weight ASCVD risk reduction against the potential for statin-associated side effects.[7]
  • Continuation of statin therapy during the acute period of ischemic stroke is reasonable among patients already taking statins.


Summarized management of ischemic stroke
Medical treatment Drug class Recommendations
Acute Long-Term
Reperfusion therapy Tissue plasminogen activator (t-PA)
  • None
Antithrombotic agents Antiplatelet agents
  • Oral administration of aspirin (initial dose is 325 mg) is recommended within 24 to 48 hours after stroke onset in most patients[29]
  • Aspirin is contraindicated in patients with ischemic stroke within 24 hours of t-PA administration[29]
  • DAPT therapy (aspirin and clopidogrel) is recommended for 90 days in patients with symptomatic intracranial large artery disease
  • Long term therapy with clopidogrel or aspirin extended release dipyridamole may be used for secondary prevention of non cardioembolic stroke
Anticoagulants
  • Parenteral or oral anticoagulation is not recommended within 48 hours of onset of ischemic stroke[35]
  • Oral anticoagulants may be used for secondary prevention of ischemic stroke in patients with atrial fibrillation or other cardioembolic disease[36]
Antilipid therapy Statins
  • Among patients already taking statins at the time of onset of ischemic stroke, continuation of statin therapy during the acute period is reasonable[29]
  • Long term management of ischemic stroke with high intensity statins may be recommended for patients with atherosclerotic disease
  • Patients who cannot tolerate high intensity dose, medium or low intensity statins may prove beneficial
Antihypertensive therapy Intravenous antihypertensives

(Labetolol, nitroprusside)

  • Used to control high blood pressure in patients with BP>185/110 mmHg before starting t-PA[29]
  • Long term oral antihypertensives may be used after 24 hours of ischemic stroke in patients having history of hypertension
Oral antihypertensive therapy
  • Long term oral antihypertensives may be used after 24 hours of ischemic stroke in patients having history of hypertension
Antihyperglycemic agents Insulin
  • May be used to control blood glucose between range of 140-180 mg/dl since hyperglycemia is associated with worst outcome in patients with acute ischemic stroke[29]
  • Long term oral antidiabetic may be used for secondary prevention of ischmeic stroke in patients with diabetes mellitus


Alteplase

Tenecteplase

Antiplatelet therapy

  • Administration of aspirin is recommended in patients with AIS within 24 to 48 hours after onset. For those treated with IV alteplase, aspirin administration is generally delayed until 24 hours later.
  • The dose of aspirin is usually between 160-300mg daily.
  • IV aspirin administration within 90 minutes after the start of IV alteplase is associated with symptomatic intracranial hemorrhage, for which co administration is discouraged but benefits should be assessed in each individual case.[7]
  • Dual antiplatelet therapy with aspirin and clopidogrel (75 mg/d, with a loading dose of 600mg) may be started within 24 hours after symptom onset and continued for 21 days in patients with no cardioembolic ischemic stroke.
  • Aspirin should not substitute IV alteplase or mechanical thrombectomy in patients eligible for these therapies.[7]

Surgery

  • The usefulness of emergency carotid endarterectomy, carotid angioplasty and stenting in the absence of an intracranial clot is not well established.[7]

Mechanical thrombectomy with a stent retriever

  • Patients should receive mechanical thrombectomy with a stent retriever if they meet all the following criteria:
    1. Prestroke mRS score of 0 to 1
    2. Causative occlusion of the internal carotid artery or MCA segment 1 (M1)
    3. Age ≥18 years
    4. NIHSS score of ≥6
    5. ASPECTS of ≥6; and
    6. Treatment can be initiated within 6 hours of symptom onset

Aspiration thrombectomy

  • Direct aspiration thrombectomy as first-pass mechanical thrombectomy is recommended as noninferior to stent retriever for patients who meet all the following criteria:
    1. Prestroke mRS score of 0 to 1;
    2. Causative occlusion of the internal carotid artery or M1;
    3. Age ≥18 years;
    4. NIHSS score of ≥6;
    5. ASPECTS ≥6; and
    6. Treatment initiation within 6 hours of symptom onset.

Intra arterial fibrinolysis

Other aspects of management

Primary Prevention

Secondary Prevention

To view treatment of COVID-19 section, click here.

References

  1. ↑ Theofanidis, Dimitrios (2015). "From Apoplexy to Brain Attack, a Historical Perspective on Stroke to Date". Journal of Nursing & Care. 04 (01). doi:10.4172/2167-1168.1000e121. ISSN 2167-1168.
  2. ↑ Paniz‐Mondolfi, Alberto; Bryce, Clare; Grimes, Zachary; Gordon, Ronald E.; Reidy, Jason; Lednicky, John; Sordillo, Emilia Mia; Fowkes, Mary (2020). "Central nervous system involvement by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2)". Journal of Medical Virology. 92 (7): 699–702. doi:10.1002/jmv.25915. ISSN 0146-6615.
  3. ↑ 3.0 3.1 3.2 Mao, Ling; Jin, Huijuan; Wang, Mengdie; Hu, Yu; Chen, Shengcai; He, Quanwei; Chang, Jiang; Hong, Candong; Zhou, Yifan; Wang, David; Miao, Xiaoping; Li, Yanan; Hu, Bo (2020). "Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China". JAMA Neurology. 77 (6): 683. doi:10.1001/jamaneurol.2020.1127. ISSN 2168-6149.
  4. ↑ 4.0 4.1 4.2 4.3 Yaghi, Shadi; Ishida, Koto; Torres, Jose; Mac Grory, Brian; Raz, Eytan; Humbert, Kelley; Henninger, Nils; Trivedi, Tushar; Lillemoe, Kaitlyn; Alam, Shazia; Sanger, Matthew; Kim, Sun; Scher, Erica; Dehkharghani, Seena; Wachs, Michael; Tanweer, Omar; Volpicelli, Frank; Bosworth, Brian; Lord, Aaron; Frontera, Jennifer (2020). "SARS-CoV-2 and Stroke in a New York Healthcare System". Stroke. 51 (7): 2002–2011. doi:10.1161/STROKEAHA.120.030335. ISSN 0039-2499.
  5. ↑ Tsivgoulis, Georgios; Katsanos, Aristeidis H.; Ornello, Raffaele; Sacco, Simona (2020). "Ischemic Stroke Epidemiology During the COVID-19 Pandemic". Stroke. 51 (7): 1924–1926. doi:10.1161/STROKEAHA.120.030791. ISSN 0039-2499.
  6. ↑ 6.0 6.1 Qin, Chuan; Zhou, Luoqi; Hu, Ziwei; Yang, Sheng; Zhang, Shuoqi; Chen, Man; Yu, Haihan; Tian, Dai-Shi; Wang, Wei (2020). "Clinical Characteristics and Outcomes of COVID-19 Patients With a History of Stroke in Wuhan, China". Stroke. 51 (7): 2219–2223. doi:10.1161/STROKEAHA.120.030365. ISSN 0039-2499.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 7.20 7.21 7.22 7.23 7.24 7.25 7.26 7.27 7.28 7.29 7.30 7.31 7.32 7.33 7.34
  8. ↑ 8.0 8.1 8.2 8.3 Avula, Akshay; Nalleballe, Krishna; Narula, Naureen; Sapozhnikov, Steven; Dandu, Vasuki; Toom, Sudhamshi; Glaser, Allison; Elsayegh, Dany (2020). "COVID-19 presenting as stroke". Brain, Behavior, and Immunity. 87: 115–119. doi:10.1016/j.bbi.2020.04.077. ISSN 0889-1591.
  9. ↑
  10. ↑
  11. ↑
  12. ↑
  13. ↑ 13.0 13.1 13.2
  14. ↑ 14.0 14.1
  15. ↑
  16. ↑
  17. ↑
  18. ↑
  19. ↑
  20. ↑
  21. ↑
  22. ↑
  23. ↑ 23.0 23.1
  24. ↑
  25. ↑
  26. ↑
  27. ↑ 27.0 27.1 27.2 27.3 27.4
  28. ↑ Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM; et al. (2013). "Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association". Stroke. 44 (3): 870–947. doi:10.1161/STR.0b013e318284056a. PMID 23370205.
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM; et al. (2013). "Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association". Stroke. 44 (3): 870–947. doi:10.1161/STR.0b013e318284056a. PMID 23370205.
  30. ↑ Lansberg MG, O'Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE; et al. (2012). "Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e601S–36S. doi:10.1378/chest.11-2302. PMC 3278065. PMID 22315273.
  31. ↑ "Position Statement on the Use of Intravenous Thrombolytic Therapy in the Treatment of Stroke". American Academy of Emergency Medicine. Retrieved 2008-01-25.
  32. ↑ Prabhakaran S, Ruff I, Bernstein RA (2015). "Acute stroke intervention: a systematic review". JAMA. 313 (14): 1451–62. doi:10.1001/jama.2015.3058. PMID 25871671.
  33. ↑ Wardlaw JM, Murray V, Berge E, del Zoppo GJ (2014). "Thrombolysis for acute ischaemic stroke". Cochrane Database Syst Rev. 7: CD000213. doi:10.1002/14651858.CD000213.pub3. PMC 4153726. PMID 25072528.
  34. ↑ Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E; et al. (2014). "Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials". Lancet. doi:10.1016/S0140-6736(14)60584-5. PMID 25106063.
  35. ↑ Paciaroni M, Agnelli G, Micheli S, Caso V (2007). "Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials". Stroke. 38 (2): 423–30. doi:10.1161/01.STR.0000254600.92975.1f. PMID 17204681. ACP JC synopsis
  36. ↑ Hart RG, Pearce LA, Aguilar MI (2007). "Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation". Ann. Intern. Med. 146 (12): 857–67. PMID 17577005.
  37. ↑


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