Diagnosis and Treatment of Acute Ischemic Stroke: An Update
Published
Jun 25, 2019
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Carolina García Alfonso
https://orcid.org/0000-0002-1712-0434
Andrea Estefania Martínez Reyes
Valentina García
Andres Ricaurte Fajardo
Isabel Torres
Juliana Coral Casas
https://orcid.org/0000-0002-1712-0434
Andrea Estefania Martínez Reyes
Valentina García
Andres Ricaurte Fajardo
Isabel Torres
Juliana Coral Casas
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Abstract
Acute stroke is the second cause of death worldwide, generating high costs in its treatment and recovery, as well as a great socioeconomic impact, being the main cause of long-term disability. Although, the simple computerized tomography (CT) scan of the brain is still the neuroimage recommended by the international guidelines for the initial evaluation and decision making on the management of the patient with suspected stroke, recent years have witnessed extraordinary advances in the timely and early diagnosis of stroke, with new tools, from the standardization of cerebral angiotomography as an initial study, to perfusion techniques which allows to establish the nucleus of the area and the potentially salvageable surrounding area, as well as, therapies that give the patient support to the functionality and quality of life in the medium and long term. Taking into account the above, it is of vital importance an update on the available methods and on the different options available according to the case of each patient for acute stroke, with a practical clinical approach and applicable real health scenario in Colombia.
Keywords
acute cerebrovascular accident, brain infarction, stroke, thrombolysis, thrombolytic therapyataque cerebrovascular agudo, ictus, infarto cerebral, terapia trombolítica, trombólisis
References
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3. Mikulik R, Wahlgren N. Treatment of acute stroke: an update. J Intern Med. 2015;278:145-65.
4. Maldonado N, Kazmi S, Suárez J. Update in the management of acute ischemic stroke. Crit Care Clin. 2014;30:673-97.
5. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:146-603.
6. Pradilla AG, Vesga BE, León-Sarmiento FE. Estudio neuroepidemiológico nacional (Epineuro) colombiano. Rev Panam Salud Pública. 2003;14:104-11.
7. Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol. 2011;10:471.
8. Lin MP, Liebeskind DS. Imaging of ischemic stroke. Continuum (NY). 2016;22:1399-423.
9. Jordan JD, Powers WJ. Cerebral Autoregulation and Acute Ischemic Stroke. Am J Hypertens. 2012;25:946-50.
10. Aries MJH, Elting JW, De Keyser J, Kremer BPH, Vroomen PCAJ. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. Stroke. 2010;41:2697-704.
11. Faraci FM. Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol. 2006;100:739-43.
12. Deb P, Sharma S, Hassan KM. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology. 2010;17:197.
13. Zarco L, González F, Coral J. Tratamiento actual del ataque cerebrovascular isquémico (ACV) agudo. Univ Méd (Bogotá). 2008;49:467-98.
14. Sierra C, Coca A, Schiffrin EL. Vascular mechanisms in the pathogenesis of stroke. Curr Hypertens Rep. 2011;13:200-7.
15. Lu GW, Liu HY. Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioning. J Appl Physiol. 2001;91:1193-8.
16. Love S. Oxidative stress in brain ischemia. Brain Pathol. 1999;9:119-31.
17. Dugan LL, Choi DW. Excitotoxicity, free radicals, and cell membrane changes. Ann Neurol. 1994;35:S17-21.
18. Brott T, Jr HPA, Olinger CP, Marler JR, Barsan WG, Biller J, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864-70.
19. Angosto MC. Bases moleculares de la apoptosis. Académica Número la Real Acad Nac Farm. 2003;69:36-64.
20. Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med. 2003;348:1365-75.
21. Bandera E, Botteri M, Minelli C, Sutton A, Abrams KR, Latronico N. Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke. 2006;37:1334-9.
22. Staykov D, Gupta R. Hemicraniectomy in malignant middle cerebral artery infarction. Stroke. 2011;42:513-6.
23. Simard JM, Chen M, Tarasov K V., Bhatta S, Ivanova S, Melnitchenko L, et al. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke. Nat Med. 2006;12:433-40.
24. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. 2016;36:513-38.
25. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment. Stroke. 1993;24:35-41.
26. Alexandru R, Terecoasă EO, Tiu C. Etiologic classification of ischemic stroke: Where do we stand? Clin Neurol Neurosurg. 2017;159:93-106.
27. Molina-Seguin J, Vena AB, Colàs-Campàs L, Benalbdelhak I, Purroy F. Revisión sistemática de las características y pronóstico de los sujetos que sufren un ictus criptogénico no lacunar de mecanismo embólico. Neurología. 2018;66:325-30.
28. Pare JR, Kahn JH. Basic neuroanatomy and stroke syndromes. Emerg Med Clin North Am. 2012;30:601-15.
29. Wintermark M, Sanelli PC, Albers GW, Bello JA, Derdeyn CP, Hetts SW, et al. Imaging recommendations for acute stroke and transient ischemic attack patients: a joint statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery. J Am Coll Radiol. 2013;20:828-32.
30. Southerland AM. Clinical evaluation of the patient with acute stroke. Continuum. 2017;23:40-61.
31. Birenbaum D, Bancroft LW, Felsberg GJ. Imaging in acute stroke. West J Emerg Med. 2011;12:67-76.
32. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 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. 2018:46-110.
33. Hill M, Rowley HA, Adler F, Eliasziw M, Furlan A, Higashida RT. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using ASPECTS. Stroke. 2003;34:1925-31.
34. Vilela P, Rowley HA. Brain ischemia: CT and MRI techniques in acute ischemic stroke. Eur J Radiol. 2017;96:162-72.
35. Bouchez L, Sztajzel R, Vargas MI, et al. CT imaging selection in acute stroke. Eur J Radiol. 2017;96:153-61.
36. Martinon E, Lefevre PH, Thouant P, Osseby GV, Ricolfi F, Chavent A. Collateral circulation in acute stroke: assessing methods and impact: a literature review. J Neuroradiol. 2014;41:97-107.
37. Hao Y, Yang D, Wang H, Zi W, Zhang M, Geng Y, et al. Predictors for symptomatic intracranial hemorrhage after endovascular treatment of acute ischemic stroke. Stroke. 2017;48:1203-9. https://doi.org/10.1161/STROKEAHA.116.016368.
38. Havenon A, Mlynash M, Kim-Tenser MA, et al. DEFUSE 3: Good collaterals are associated with reduced ischemic core growth but not neurologic outcome. Stroke. 2019;50(3):632-8.
39. Brozici M, van der Zwan A, Hillen B. Anatomy and functionality of leptomeningeal anastomoses: a review. Stroke. 2003;34:2750-62.
40. Donnan GA, Davis SM. Neuroimaging, the ischaemic penumbra, and selection of patients for acute stroke therapy. Lancet Neurol. 2002;1:417-25.
41. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct- DAWN. N Engl J Med. 2018; 378:11-21.
42. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutiérrez S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging-DEFUSE 3. N Engl J Med. 2018;708-18.
43. Srinivasan A, Goyal M, al Azri F, Lum C. State-of-the-art imaging of acute stroke. RadioGraphics. 2006;26:S75-95.
44. Cockroft KM, Prestigiacomo CJ, Duffis EJ, Gandhi CD. Cerebral angiography: surgical endovascular neuroradiology. New York: Thieme; 2015.
45. Jayaraman MV, Grossberg JA, Meisel KM, Shaikhouni A, Silver B. The clinical and radiographic importance of distinguishing partial from near-complete reperfusion following intra-arterial stroke therapy. Am J Neuroradiol. 2013;34:135-9.
46. Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, et al. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients with Acute Ischemic Stroke Regarding Endovascular Treatment. Stroke. 2015;46:3020-35.
47. Pahs L, Droege C, Kneale H, Pancioli A. A novel approach to the treatment of orolingual angioedema after tissue plasminogen activator administration. Ann Emerg Med. 2016;68:345-8.
48. Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24:6-46.
49. Gobin YP, Starkman S, Duckwiler GR, Grobelny T, Kidwell CS, Jahan R, et al. MERCI 1: A phase 1 study of mechanical embolus removal in cerebral ischemia. Stroke. 2004;35:2848-53.
50. Po Sit S, Langer D, Stingele R. The penumbra pivotal stroke trial: Safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40:2761-8.
51. Costalat V, MacHi P, Lobotesis K, Maldonado I, Vendrell JF, Riquelme C, et al. Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the solitaire device: A prospective 50-patient single-center study: Timing, safety, and efficacy-RECOST. Stroke. 2011;42:1929-35.
52. Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): A randomised, parallel-group, non-inferiority trial. Lancet. 2012;380:1241-9.
53. Berkhemer O, Fransen PS, Beumer D, Lingsma H. A Randomized trial of intraarterial treatment for acute ischemic stroke - MR CLEAN. N Engl J Med. 2015;372:2747-57.
54. Campbell BCV, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection-EXTEND-IA. N Engl J Med. 2015;372:1009-18.
55. Demchuk AM, Goyal M, Menon BK, Eesa M, Ryckborst KJ, Kamal N, et al. Endovascular treatment for small core and anterior circulation proximal occlusion with emphasis on minimizing CT to recanalization times (ESCAPE) trial: methodology. Int J Stroke. 2015;10:429-38.
56. Molina CA, Chamorro A, Rovira À, de Miquel A, Serena J, Roman LS, et al. REVASCAT: A randomized trial of revascularization with SOLITAIRE FR® device vs. best medical therapy in the treatment of acute stroke due to anterior circulation large vessel occlusion presenting within eight-hours of symptom onset. Int J Stroke. 2015;10:619-26.
57. Guzik A, Bushnell C. Stroke epidemiology and risk factor management. Continuum (Minneap Minn). 2017;23:15-39.
58. Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-59.
2. Arauz A, Ruiz-Franco A. Enfermedad vascular cerebral. Rev Fac Med (Méx.). 2012;55(3):11-21.
3. Mikulik R, Wahlgren N. Treatment of acute stroke: an update. J Intern Med. 2015;278:145-65.
4. Maldonado N, Kazmi S, Suárez J. Update in the management of acute ischemic stroke. Crit Care Clin. 2014;30:673-97.
5. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:146-603.
6. Pradilla AG, Vesga BE, León-Sarmiento FE. Estudio neuroepidemiológico nacional (Epineuro) colombiano. Rev Panam Salud Pública. 2003;14:104-11.
7. Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol. 2011;10:471.
8. Lin MP, Liebeskind DS. Imaging of ischemic stroke. Continuum (NY). 2016;22:1399-423.
9. Jordan JD, Powers WJ. Cerebral Autoregulation and Acute Ischemic Stroke. Am J Hypertens. 2012;25:946-50.
10. Aries MJH, Elting JW, De Keyser J, Kremer BPH, Vroomen PCAJ. Cerebral autoregulation in stroke: a review of transcranial Doppler studies. Stroke. 2010;41:2697-704.
11. Faraci FM. Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol. 2006;100:739-43.
12. Deb P, Sharma S, Hassan KM. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology. 2010;17:197.
13. Zarco L, González F, Coral J. Tratamiento actual del ataque cerebrovascular isquémico (ACV) agudo. Univ Méd (Bogotá). 2008;49:467-98.
14. Sierra C, Coca A, Schiffrin EL. Vascular mechanisms in the pathogenesis of stroke. Curr Hypertens Rep. 2011;13:200-7.
15. Lu GW, Liu HY. Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioning. J Appl Physiol. 2001;91:1193-8.
16. Love S. Oxidative stress in brain ischemia. Brain Pathol. 1999;9:119-31.
17. Dugan LL, Choi DW. Excitotoxicity, free radicals, and cell membrane changes. Ann Neurol. 1994;35:S17-21.
18. Brott T, Jr HPA, Olinger CP, Marler JR, Barsan WG, Biller J, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20:864-70.
19. Angosto MC. Bases moleculares de la apoptosis. Académica Número la Real Acad Nac Farm. 2003;69:36-64.
20. Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med. 2003;348:1365-75.
21. Bandera E, Botteri M, Minelli C, Sutton A, Abrams KR, Latronico N. Cerebral blood flow threshold of ischemic penumbra and infarct core in acute ischemic stroke: a systematic review. Stroke. 2006;37:1334-9.
22. Staykov D, Gupta R. Hemicraniectomy in malignant middle cerebral artery infarction. Stroke. 2011;42:513-6.
23. Simard JM, Chen M, Tarasov K V., Bhatta S, Ivanova S, Melnitchenko L, et al. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke. Nat Med. 2006;12:433-40.
24. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. 2016;36:513-38.
25. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment. Stroke. 1993;24:35-41.
26. Alexandru R, Terecoasă EO, Tiu C. Etiologic classification of ischemic stroke: Where do we stand? Clin Neurol Neurosurg. 2017;159:93-106.
27. Molina-Seguin J, Vena AB, Colàs-Campàs L, Benalbdelhak I, Purroy F. Revisión sistemática de las características y pronóstico de los sujetos que sufren un ictus criptogénico no lacunar de mecanismo embólico. Neurología. 2018;66:325-30.
28. Pare JR, Kahn JH. Basic neuroanatomy and stroke syndromes. Emerg Med Clin North Am. 2012;30:601-15.
29. Wintermark M, Sanelli PC, Albers GW, Bello JA, Derdeyn CP, Hetts SW, et al. Imaging recommendations for acute stroke and transient ischemic attack patients: a joint statement by the American Society of Neuroradiology, the American College of Radiology and the Society of NeuroInterventional Surgery. J Am Coll Radiol. 2013;20:828-32.
30. Southerland AM. Clinical evaluation of the patient with acute stroke. Continuum. 2017;23:40-61.
31. Birenbaum D, Bancroft LW, Felsberg GJ. Imaging in acute stroke. West J Emerg Med. 2011;12:67-76.
32. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 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. 2018:46-110.
33. Hill M, Rowley HA, Adler F, Eliasziw M, Furlan A, Higashida RT. Selection of acute ischemic stroke patients for intra-arterial thrombolysis with pro-urokinase by using ASPECTS. Stroke. 2003;34:1925-31.
34. Vilela P, Rowley HA. Brain ischemia: CT and MRI techniques in acute ischemic stroke. Eur J Radiol. 2017;96:162-72.
35. Bouchez L, Sztajzel R, Vargas MI, et al. CT imaging selection in acute stroke. Eur J Radiol. 2017;96:153-61.
36. Martinon E, Lefevre PH, Thouant P, Osseby GV, Ricolfi F, Chavent A. Collateral circulation in acute stroke: assessing methods and impact: a literature review. J Neuroradiol. 2014;41:97-107.
37. Hao Y, Yang D, Wang H, Zi W, Zhang M, Geng Y, et al. Predictors for symptomatic intracranial hemorrhage after endovascular treatment of acute ischemic stroke. Stroke. 2017;48:1203-9. https://doi.org/10.1161/STROKEAHA.116.016368.
38. Havenon A, Mlynash M, Kim-Tenser MA, et al. DEFUSE 3: Good collaterals are associated with reduced ischemic core growth but not neurologic outcome. Stroke. 2019;50(3):632-8.
39. Brozici M, van der Zwan A, Hillen B. Anatomy and functionality of leptomeningeal anastomoses: a review. Stroke. 2003;34:2750-62.
40. Donnan GA, Davis SM. Neuroimaging, the ischaemic penumbra, and selection of patients for acute stroke therapy. Lancet Neurol. 2002;1:417-25.
41. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct- DAWN. N Engl J Med. 2018; 378:11-21.
42. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutiérrez S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging-DEFUSE 3. N Engl J Med. 2018;708-18.
43. Srinivasan A, Goyal M, al Azri F, Lum C. State-of-the-art imaging of acute stroke. RadioGraphics. 2006;26:S75-95.
44. Cockroft KM, Prestigiacomo CJ, Duffis EJ, Gandhi CD. Cerebral angiography: surgical endovascular neuroradiology. New York: Thieme; 2015.
45. Jayaraman MV, Grossberg JA, Meisel KM, Shaikhouni A, Silver B. The clinical and radiographic importance of distinguishing partial from near-complete reperfusion following intra-arterial stroke therapy. Am J Neuroradiol. 2013;34:135-9.
46. Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, et al. 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients with Acute Ischemic Stroke Regarding Endovascular Treatment. Stroke. 2015;46:3020-35.
47. Pahs L, Droege C, Kneale H, Pancioli A. A novel approach to the treatment of orolingual angioedema after tissue plasminogen activator administration. Ann Emerg Med. 2016;68:345-8.
48. Frontera JA, Lewin JJ 3rd, Rabinstein AA, Aisiku IP, Alexandrov AW, Cook AM, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24:6-46.
49. Gobin YP, Starkman S, Duckwiler GR, Grobelny T, Kidwell CS, Jahan R, et al. MERCI 1: A phase 1 study of mechanical embolus removal in cerebral ischemia. Stroke. 2004;35:2848-53.
50. Po Sit S, Langer D, Stingele R. The penumbra pivotal stroke trial: Safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40:2761-8.
51. Costalat V, MacHi P, Lobotesis K, Maldonado I, Vendrell JF, Riquelme C, et al. Rescue, combined, and stand-alone thrombectomy in the management of large vessel occlusion stroke using the solitaire device: A prospective 50-patient single-center study: Timing, safety, and efficacy-RECOST. Stroke. 2011;42:1929-35.
52. Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): A randomised, parallel-group, non-inferiority trial. Lancet. 2012;380:1241-9.
53. Berkhemer O, Fransen PS, Beumer D, Lingsma H. A Randomized trial of intraarterial treatment for acute ischemic stroke - MR CLEAN. N Engl J Med. 2015;372:2747-57.
54. Campbell BCV, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection-EXTEND-IA. N Engl J Med. 2015;372:1009-18.
55. Demchuk AM, Goyal M, Menon BK, Eesa M, Ryckborst KJ, Kamal N, et al. Endovascular treatment for small core and anterior circulation proximal occlusion with emphasis on minimizing CT to recanalization times (ESCAPE) trial: methodology. Int J Stroke. 2015;10:429-38.
56. Molina CA, Chamorro A, Rovira À, de Miquel A, Serena J, Roman LS, et al. REVASCAT: A randomized trial of revascularization with SOLITAIRE FR® device vs. best medical therapy in the treatment of acute stroke due to anterior circulation large vessel occlusion presenting within eight-hours of symptom onset. Int J Stroke. 2015;10:619-26.
57. Guzik A, Bushnell C. Stroke epidemiology and risk factor management. Continuum (Minneap Minn). 2017;23:15-39.
58. Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-59.
How to Cite
García Alfonso, C., Martínez Reyes, A. E., García, V., Ricaurte Fajardo, A., Torres, I., & Coral Casas, J. (2019). Diagnosis and Treatment of Acute Ischemic Stroke: An Update. Universitas Medica, 60(3), 1–17. https://doi.org/10.11144/Javeriana.umed60-3.actu
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