Tissue Plasminogen Activator for Acute Ischemic Stroke in Patients With Unruptured Cerebral Aneurysms Luis D’Olhaberriague, MD, PhD, Nishit Joshi, MD, Seement Chaturvedi, MD, Panayiotis Mitsias, MD, William Coplin, MD, Christopher A. Lewandowski, MD, Suresh C. Patel, MD, and Steven R. Levine, MD
Intracranial hemorrhage (ICH) is the most feared complication of thrombolytic therapy for acute ischemic stroke. There are limited data on the risks of thrombolysis in patients with asymptomatic intracranial aneurysm. We report 2 adults with signs of hemispheric ischemia who were successfully treated with intravenous tissue plasminogen activator (t-PA), despite the presence of asymptomatic intracranial aneurysm. The presence of an asymptomatic intracranial aneurysm may not necessarily preclude a good outcome from acute ischemic stroke treated with rt-PA. Selected patients harboring incidental, unruptured intracranial aneurysm may benefit from thrombolytics. Key Words: Ischemic stroke—Intracranial aneurysm— Tissue plasminogen activator—Thrombolysis.
Intracranial hemorrhage (ICH) is the most dreaded complication of thrombolytic therapy for acute ischemic stroke. Trials on thrombolysis for stroke1,2 excluded patients with current ICH, a history of past ICH, or clinical presentation suggestive of subarachnoid hemorrhage (SAH). The issue of asymptomatic aneurysm and thrombolysis for stroke is far more complex. In the National Institute of Neurological Disorders and Stroke (NINDS) recombine tissue plasminogen activator (rt-PA) trial, asymptomatic aneurysms were not an explicit exclusion.1 In turn, the American Academy of Neurology,3 the American Heart
From the Department of Neurology, Wayne State University/ Detroit Medical Center, Stroke Program, Detroit, MI; and the Departments of Neurology, Emergency Medicine, and Diagnostic Radiology (Division of Neuroradiology), Center for Stroke Research, Henry Ford Hospital and Health Sciences Center, Detroit, MI. Received December 29, 1999; accepted January 19, 2000. Supported in part by Grant No. NS 23393 from the National Institutes of Health, Bethesda, MD. Address reprint requests to Luis D’Olhaberriague, MD, PhD, Wayne State University-Detroit Medical Center, Stroke Program, Department of Neurology, University Health Center 6-E, 4201 Sant Antoine, Detroit, MI 48201. Copyright r 2000 by National Stroke Association 1052-3057/00/0904-0006$3.00/0 doi:10.1053/jscd.2000.7213
Association,4 and the European ad hoc Consensus Group5 do not mention asymptomatic aneurysm in their statements on thrombolysis for stroke. Not withstanding all these, the Federal Drug Administration (FDA) approved tissue plasminogen activator (t-PA) package insert of Alteplase (Genentech, S. San Francisco, CA) includes the presence of an intracranial aneurysm as a contraindication for thrombolysis for myocardial infarction, stroke, and pulmonary embolism. Guidelines for coronary thrombolysis consider an absolute contraindication any history of ICH.7 The medical community now has to apply the NINDS rt-PA Stroke Trial results to the ‘‘real world,’’ to test not only the efficacy, but the effectiveness of thrombolysis in stroke.8 Among the possible problems related to the generalization of thrombolysis in the community include the immediate availability of physicians trained in reading emergency computed tomography (CT) scans of ischemic stroke patients and the fact that some vascular lesions may not appear on CT or magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA). Patients harboring incidental asymptomatic intracranial aneurysm pose a specific, unresolved question. We now report 2 patients with acute ischemic stroke successfully treated with intravenous t-PA despite the presence of an incidental asymptomatic intracranial aneurysm.
Journal of Stroke and Cerebrovascular Diseases, Vol. 9, No. 4 ( July-August), 2000: pp 181-184
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matter distinction at the basal ganglia/internal capsule level and a large interhemispheric, round, hyperdense, anterior lesion, suggesting an aneurysm of the anterior communicating artery (AComA) (Fig 2A). Conventional cerebral angiography confirmed the presence of an AComA aneurysm that received supply from both anterior cerebral arteries (Fig 2B). Transesophageal echocardiogram did not show a source of emboli, and he was discharged home on ticlopidine 250 mg twice daily with an NIHSS score 1. No short-term or long-term bleeding complications were noted and his 3-month NIHSS score was 1.
Figure 1. Conventional cerebral angiogram showing a left intracavernous carotid aneurysm (patient 1).
Case Reports Patient 1 A 37-year-old woman with a history of untreated hypertension and cigarette smoking presented to the emergency room of Detroit Receiving Hospital with a sudden onset of dysarthria and right-sided weakness of 45 minutes duration. Her admission blood pressure was 175/100 mm Hg. On neurological examination, she had dysarthria, right-sided ataxia, and mild right-sided weakness (her National Institutes of Health Stroke Scale [NIHSS] score was 6). The patient was treated with 0.9 mg/kg of intravenous t-PA. Her MRI showed diffuse white matter changes and her intracranial time-of-flight MRA did not show any specific vascular lesion. Carotid duplex and transesophageal echocardiogram were normal. Laboratory evaluation showed mild hyperhomocysteinemia of 21 µmol/L (normal range, 3 to 14 µmol/L). Conventional cerebral angiography (Fig 1) showed a left intracavernous carotid aneurysm, which was 5 mm in diameter. No short-term or long-term bleeding complications were noted and her 3-month NIHSS score was 2. Patient 2 A 79-year-old hypertensive man presented with the sudden onset of left hemiplegia. He was taken to a local community hospital. His initial blood pressure was 170/84 mm Hg. He was alert, and there was left hemiplegia, left hemineglect, and right gaze preference (NIHSS score, 16). After a head CT, which was read as normal, he received 0.9 mg/kg of intravenous t-PA within 90 minutes after the onset of his symptoms. His blood pressure increased to 191/90 mm Hg, therefore, he received 10 mg of intravenous labetolol. He was then transferred to Henry Ford Hospital. On admission, he was alert and awake, ignoring his current medical problem and showing a left face and arm hemiparesis and hypesthesia (NIHSS score, 5). On review of the initial CT, there was loss of grey/white
Figure 2. (A) A CT scan showing a large interhemispheric, round, hyperdense, anterior lesion, suggesting an aneurysm of the anterior communicating artery (patient 2). (B) Left carotid angiogram (frontal projection) shows anterior communicating artery aneurysm (patient 2).
t-PA IN PATIENTS WITH CEREBRAL ANEURYSMS
Discussion The cases we present here represent the common practice of giving acute thrombolytic therapy for ischemic stroke, where pretreatment cerebral angiography is neither required nor customarily performed. The aneurysm of patient 1 was not detected by noninvasive tests, including MRA, until angiography was performed. Although aneurysm size is a well-established risk factor for aneurysm rupture,9,10 patient 1 had a small aneurysm, but the second patient had a large one. Whereas the prevalence of asymptomatic intracranial aneurysm in the general population is approximately 1%,11 higher rates were found in some series. For example, in the North American Symptomatic Carotid Endarterectomy Trial, 3.2% of patients had intracranial aneurysms.12 Therefore, it is expected that there will be a similar frequency of intracranial aneurysm, which may or may not be evident on CT, in candidates for t-PA for ischemic stroke. In the clinical trials of intravenous thrombolysis for ischemic stroke,1,2 patients were excluded if they had a history of ICH. However, patients with intracranial aneurysm were not explicitly excluded. Whether investigators in these trials might have excluded patients with asymptomatic aneurysm large enough to be evident on head CT is unknown. After coronary thrombolysis, ICH has been reported in 0.5% to 1.5% of patients.7,13,14 In the study of Gore et al,15 of 3,924 patients, 33 (0.84%) had ICH and 4 (0.10%) had subdural hematomas. No single case of SAH was reported. In the study of Uglietta et al,13 13 of 1,696 (0.77%) patients had ICH related to coronary thrombolysis with t-PA (24% were SAH). In all cases, except 1 with SAH, there was associated parenchymal hematoma. This radiological pattern suggests coagulopathy rather than aneurysmal rupture as the mechanism of the hemorrhage. There was a single case of SAH with intraventricular hemorrhage and no hematoma, in which the authors speculated a ruptured aneurysm as a possible mechanism. Neither an angiogram nor an autopsy were performed. The expected frequencies of aneurysm in the studies of Gore et al15 and Uglietta et al13 would have been 118 and 59, respectively. Therefore, neither the frequency of hemorrhages found (far below the expected number of aneurysms) nor their radiological features are suggestive of aneurysmal SAH. As data on angiograms in these patients were not reported and head CT is not required in the guidelines for coronary thrombolysis,7 it cannot be ruled out that some of these ICH or SAH could have actually been related to undetected aneurysm. In general, after coronary thrombolysis, a very low frequency of subarachnoid hemorrhage due to rupture of berry aneurysms has been reported.14 On the other hand, fusiform aneurysms16 have been associated with ischemic phenomena and might be the source of artery-to-artery embolism. It is not known whether thrombolytic therapy may increase the risk of artery-to-artery embolism in this setting. In general,
183
higher dosages, hypofibrinogenemia, hypertension, increasing activated partial thromboplastin time prolongation, delayed treatment, a history of dementia, increased age, low platelet count, hyperglycemia, and amyloid angiopathy1,2,4,7,13,14 are risk factors for thrombolysisrelated ICH. In the NINDS rt-PA Stroke Trial,17 only pretreatment NIH stroke score and edema/mass effect on initial CT were independently associated with ICH, and review of baseline CT scans failed to detect any asymptomatic aneurysm (Dr S.C. Patel, personal communication, April, 1999). A recommendation regarding a hypothetical modification of the current guidelines on the use of intravenous t-PA in ischemic stroke patients with asymptomatic, incidental, intracranial aneurysm cannot, and should not, be made based on 2 isolated observations, as was the case of our patients. The presence or suspicion of such an aneurysm may not preclude good outcome in carefully selected cases, but until further data is gathered, clinicians should be cautious. Treating physicians should also be aware of the conflicting guidelines in this area with regard to the package insert and the formulations from expert panels.3-6 Further safety data on the use of t-PA in acute stroke patients with undetected aneurysm is necessary. Acknowledgment: The authors acknowledge the Publications Committee of the NINDS rt-PA Trial for permission to refer to original data from the Trial.
Note Added in Proof After finishing this article, Lagares et al18 reported on a case of intracranial hemorrhage secondary to coronary thrombolysis in a patient who harbored a brain aneurysm, stressing the potential risks of thrombolysis in patients with aneurysms.
References 1. The National Institute of Neurological Disorders and Stroke rt-PA Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:15811587. 2. Hacke W, Kaste M, Fieschi C, et al. Randomised doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European Australasian Acute Stroke Study Investigators. Lancet 1998;352:1245-1251. 3. Practice advisory: Thrombolytic therapy for acute ischemic stroke—summary statement. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996;47:835-839. 4. Adams HP Jr, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: A supplement to the guidelines for the management of patients with acute ischemic stroke. Stroke 1996;27:1711-1718. 5. The European ad hoc Consensus Group. European Strategies for Early Intervention in Stroke. Cerebrovasc Dis 1996;6:315-324.
L. D’OLHABERRIAGUE ET AL.
184 6. Physicians Desk Reference 1999. Montvale: Medical Economics, 1999:1059. 7. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA Guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1996;28: 1328-1428. 8. Furlan AJ, Kanoti G. When is thrombolysis justified in patients with acute ischemic stroke? A bioethical perspective. Stroke 1997;28:214-218. 9. The International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms. Risk of rupture and risks of surgical intervention. N Engl J Med 1998;339:1725-1733. 10. Juvela S. Prevalence and risk factors in spontaneous intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage. Arch Neurol 1996;53:734-740. 11. Schievnik WI. Intracranial aneurysms. N Engl J Med 1997;336:28-39. 12. Barnett HJM, Eliaziw M, Meldrum HE. The identification by imaging methods of patients who might benefit
13.
14.
15.
16.
17.
18.
from carotid endarterectomy. Arch Neurol 1995;52:827831. Uglietta JP, O’Connor CM, Byoko OB, et al. CT patterns of intracranial hemorrhage complicating thrombolytic therapy for acute myocardial infarction. Radiology 1991; 181:555-559. Sloan MA, Price TR. Intracranial hemorrhage following thrombolytic therapy for acute myocardial infarction. Semin Neurol 1991;11:385-398. Gore JM, Sloan M, Price TR, et al. and the TIMI investigators. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the thrombolysis in myocardial infarction study. Circulation 1991;83:448-459. Pessin MS, Chimowitz MI, Levine SR, et al. Stroke in patients with fusiform vertebrobasilar aneurysms. Neurology 1989;39:16-21. The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997;28:2109-2118. Lagares A, Gomez PA, Lobato RD, et al. Cerebral aneurysm after r-tPA thrombolysis for acute myocardial infarction. Surg Neurol 1999;52:623-626.
Intracranial hemorrhage (ICH) is the most feared complication of thrombolytic therapy for acute ischemic stroke. There are limited data on the risks of thrombolysis in patients with asymptomatic intracranial aneurysm. We report 2 adults with signs of hemispheric ischemia who were successfully treated with intravenous tissue plasminogen activator (t-PA), despite the presence of asymptomatic intracranial aneurysm. The presence of an asymptomatic intracranial aneurysm may not necessarily preclude a good outcome from acute ischemic stroke treated with rt-PA. Selected patients harboring incidental, unruptured intracranial aneurysm may benefit from thrombolytics. Key Words: Ischemic stroke—Intracranial aneurysm— Tissue plasminogen activator—Thrombolysis.
Intracranial hemorrhage (ICH) is the most dreaded complication of thrombolytic therapy for acute ischemic stroke. Trials on thrombolysis for stroke1,2 excluded patients with current ICH, a history of past ICH, or clinical presentation suggestive of subarachnoid hemorrhage (SAH). The issue of asymptomatic aneurysm and thrombolysis for stroke is far more complex. In the National Institute of Neurological Disorders and Stroke (NINDS) recombine tissue plasminogen activator (rt-PA) trial, asymptomatic aneurysms were not an explicit exclusion.1 In turn, the American Academy of Neurology,3 the American Heart
From the Department of Neurology, Wayne State University/ Detroit Medical Center, Stroke Program, Detroit, MI; and the Departments of Neurology, Emergency Medicine, and Diagnostic Radiology (Division of Neuroradiology), Center for Stroke Research, Henry Ford Hospital and Health Sciences Center, Detroit, MI. Received December 29, 1999; accepted January 19, 2000. Supported in part by Grant No. NS 23393 from the National Institutes of Health, Bethesda, MD. Address reprint requests to Luis D’Olhaberriague, MD, PhD, Wayne State University-Detroit Medical Center, Stroke Program, Department of Neurology, University Health Center 6-E, 4201 Sant Antoine, Detroit, MI 48201. Copyright r 2000 by National Stroke Association 1052-3057/00/0904-0006$3.00/0 doi:10.1053/jscd.2000.7213
Association,4 and the European ad hoc Consensus Group5 do not mention asymptomatic aneurysm in their statements on thrombolysis for stroke. Not withstanding all these, the Federal Drug Administration (FDA) approved tissue plasminogen activator (t-PA) package insert of Alteplase (Genentech, S. San Francisco, CA) includes the presence of an intracranial aneurysm as a contraindication for thrombolysis for myocardial infarction, stroke, and pulmonary embolism. Guidelines for coronary thrombolysis consider an absolute contraindication any history of ICH.7 The medical community now has to apply the NINDS rt-PA Stroke Trial results to the ‘‘real world,’’ to test not only the efficacy, but the effectiveness of thrombolysis in stroke.8 Among the possible problems related to the generalization of thrombolysis in the community include the immediate availability of physicians trained in reading emergency computed tomography (CT) scans of ischemic stroke patients and the fact that some vascular lesions may not appear on CT or magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA). Patients harboring incidental asymptomatic intracranial aneurysm pose a specific, unresolved question. We now report 2 patients with acute ischemic stroke successfully treated with intravenous t-PA despite the presence of an incidental asymptomatic intracranial aneurysm.
Journal of Stroke and Cerebrovascular Diseases, Vol. 9, No. 4 ( July-August), 2000: pp 181-184
181
182
L. D’OLHABERRIAGUE ET AL.
matter distinction at the basal ganglia/internal capsule level and a large interhemispheric, round, hyperdense, anterior lesion, suggesting an aneurysm of the anterior communicating artery (AComA) (Fig 2A). Conventional cerebral angiography confirmed the presence of an AComA aneurysm that received supply from both anterior cerebral arteries (Fig 2B). Transesophageal echocardiogram did not show a source of emboli, and he was discharged home on ticlopidine 250 mg twice daily with an NIHSS score 1. No short-term or long-term bleeding complications were noted and his 3-month NIHSS score was 1.
Figure 1. Conventional cerebral angiogram showing a left intracavernous carotid aneurysm (patient 1).
Case Reports Patient 1 A 37-year-old woman with a history of untreated hypertension and cigarette smoking presented to the emergency room of Detroit Receiving Hospital with a sudden onset of dysarthria and right-sided weakness of 45 minutes duration. Her admission blood pressure was 175/100 mm Hg. On neurological examination, she had dysarthria, right-sided ataxia, and mild right-sided weakness (her National Institutes of Health Stroke Scale [NIHSS] score was 6). The patient was treated with 0.9 mg/kg of intravenous t-PA. Her MRI showed diffuse white matter changes and her intracranial time-of-flight MRA did not show any specific vascular lesion. Carotid duplex and transesophageal echocardiogram were normal. Laboratory evaluation showed mild hyperhomocysteinemia of 21 µmol/L (normal range, 3 to 14 µmol/L). Conventional cerebral angiography (Fig 1) showed a left intracavernous carotid aneurysm, which was 5 mm in diameter. No short-term or long-term bleeding complications were noted and her 3-month NIHSS score was 2. Patient 2 A 79-year-old hypertensive man presented with the sudden onset of left hemiplegia. He was taken to a local community hospital. His initial blood pressure was 170/84 mm Hg. He was alert, and there was left hemiplegia, left hemineglect, and right gaze preference (NIHSS score, 16). After a head CT, which was read as normal, he received 0.9 mg/kg of intravenous t-PA within 90 minutes after the onset of his symptoms. His blood pressure increased to 191/90 mm Hg, therefore, he received 10 mg of intravenous labetolol. He was then transferred to Henry Ford Hospital. On admission, he was alert and awake, ignoring his current medical problem and showing a left face and arm hemiparesis and hypesthesia (NIHSS score, 5). On review of the initial CT, there was loss of grey/white
Figure 2. (A) A CT scan showing a large interhemispheric, round, hyperdense, anterior lesion, suggesting an aneurysm of the anterior communicating artery (patient 2). (B) Left carotid angiogram (frontal projection) shows anterior communicating artery aneurysm (patient 2).
t-PA IN PATIENTS WITH CEREBRAL ANEURYSMS
Discussion The cases we present here represent the common practice of giving acute thrombolytic therapy for ischemic stroke, where pretreatment cerebral angiography is neither required nor customarily performed. The aneurysm of patient 1 was not detected by noninvasive tests, including MRA, until angiography was performed. Although aneurysm size is a well-established risk factor for aneurysm rupture,9,10 patient 1 had a small aneurysm, but the second patient had a large one. Whereas the prevalence of asymptomatic intracranial aneurysm in the general population is approximately 1%,11 higher rates were found in some series. For example, in the North American Symptomatic Carotid Endarterectomy Trial, 3.2% of patients had intracranial aneurysms.12 Therefore, it is expected that there will be a similar frequency of intracranial aneurysm, which may or may not be evident on CT, in candidates for t-PA for ischemic stroke. In the clinical trials of intravenous thrombolysis for ischemic stroke,1,2 patients were excluded if they had a history of ICH. However, patients with intracranial aneurysm were not explicitly excluded. Whether investigators in these trials might have excluded patients with asymptomatic aneurysm large enough to be evident on head CT is unknown. After coronary thrombolysis, ICH has been reported in 0.5% to 1.5% of patients.7,13,14 In the study of Gore et al,15 of 3,924 patients, 33 (0.84%) had ICH and 4 (0.10%) had subdural hematomas. No single case of SAH was reported. In the study of Uglietta et al,13 13 of 1,696 (0.77%) patients had ICH related to coronary thrombolysis with t-PA (24% were SAH). In all cases, except 1 with SAH, there was associated parenchymal hematoma. This radiological pattern suggests coagulopathy rather than aneurysmal rupture as the mechanism of the hemorrhage. There was a single case of SAH with intraventricular hemorrhage and no hematoma, in which the authors speculated a ruptured aneurysm as a possible mechanism. Neither an angiogram nor an autopsy were performed. The expected frequencies of aneurysm in the studies of Gore et al15 and Uglietta et al13 would have been 118 and 59, respectively. Therefore, neither the frequency of hemorrhages found (far below the expected number of aneurysms) nor their radiological features are suggestive of aneurysmal SAH. As data on angiograms in these patients were not reported and head CT is not required in the guidelines for coronary thrombolysis,7 it cannot be ruled out that some of these ICH or SAH could have actually been related to undetected aneurysm. In general, after coronary thrombolysis, a very low frequency of subarachnoid hemorrhage due to rupture of berry aneurysms has been reported.14 On the other hand, fusiform aneurysms16 have been associated with ischemic phenomena and might be the source of artery-to-artery embolism. It is not known whether thrombolytic therapy may increase the risk of artery-to-artery embolism in this setting. In general,
183
higher dosages, hypofibrinogenemia, hypertension, increasing activated partial thromboplastin time prolongation, delayed treatment, a history of dementia, increased age, low platelet count, hyperglycemia, and amyloid angiopathy1,2,4,7,13,14 are risk factors for thrombolysisrelated ICH. In the NINDS rt-PA Stroke Trial,17 only pretreatment NIH stroke score and edema/mass effect on initial CT were independently associated with ICH, and review of baseline CT scans failed to detect any asymptomatic aneurysm (Dr S.C. Patel, personal communication, April, 1999). A recommendation regarding a hypothetical modification of the current guidelines on the use of intravenous t-PA in ischemic stroke patients with asymptomatic, incidental, intracranial aneurysm cannot, and should not, be made based on 2 isolated observations, as was the case of our patients. The presence or suspicion of such an aneurysm may not preclude good outcome in carefully selected cases, but until further data is gathered, clinicians should be cautious. Treating physicians should also be aware of the conflicting guidelines in this area with regard to the package insert and the formulations from expert panels.3-6 Further safety data on the use of t-PA in acute stroke patients with undetected aneurysm is necessary. Acknowledgment: The authors acknowledge the Publications Committee of the NINDS rt-PA Trial for permission to refer to original data from the Trial.
Note Added in Proof After finishing this article, Lagares et al18 reported on a case of intracranial hemorrhage secondary to coronary thrombolysis in a patient who harbored a brain aneurysm, stressing the potential risks of thrombolysis in patients with aneurysms.
References 1. The National Institute of Neurological Disorders and Stroke rt-PA Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:15811587. 2. Hacke W, Kaste M, Fieschi C, et al. Randomised doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European Australasian Acute Stroke Study Investigators. Lancet 1998;352:1245-1251. 3. Practice advisory: Thrombolytic therapy for acute ischemic stroke—summary statement. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996;47:835-839. 4. Adams HP Jr, Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: A supplement to the guidelines for the management of patients with acute ischemic stroke. Stroke 1996;27:1711-1718. 5. The European ad hoc Consensus Group. European Strategies for Early Intervention in Stroke. Cerebrovasc Dis 1996;6:315-324.
L. D’OLHABERRIAGUE ET AL.
184 6. Physicians Desk Reference 1999. Montvale: Medical Economics, 1999:1059. 7. Ryan TJ, Anderson JL, Antman EM, et al. ACC/AHA Guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1996;28: 1328-1428. 8. Furlan AJ, Kanoti G. When is thrombolysis justified in patients with acute ischemic stroke? A bioethical perspective. Stroke 1997;28:214-218. 9. The International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms. Risk of rupture and risks of surgical intervention. N Engl J Med 1998;339:1725-1733. 10. Juvela S. Prevalence and risk factors in spontaneous intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage. Arch Neurol 1996;53:734-740. 11. Schievnik WI. Intracranial aneurysms. N Engl J Med 1997;336:28-39. 12. Barnett HJM, Eliaziw M, Meldrum HE. The identification by imaging methods of patients who might benefit
13.
14.
15.
16.
17.
18.
from carotid endarterectomy. Arch Neurol 1995;52:827831. Uglietta JP, O’Connor CM, Byoko OB, et al. CT patterns of intracranial hemorrhage complicating thrombolytic therapy for acute myocardial infarction. Radiology 1991; 181:555-559. Sloan MA, Price TR. Intracranial hemorrhage following thrombolytic therapy for acute myocardial infarction. Semin Neurol 1991;11:385-398. Gore JM, Sloan M, Price TR, et al. and the TIMI investigators. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the thrombolysis in myocardial infarction study. Circulation 1991;83:448-459. Pessin MS, Chimowitz MI, Levine SR, et al. Stroke in patients with fusiform vertebrobasilar aneurysms. Neurology 1989;39:16-21. The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997;28:2109-2118. Lagares A, Gomez PA, Lobato RD, et al. Cerebral aneurysm after r-tPA thrombolysis for acute myocardial infarction. Surg Neurol 1999;52:623-626.
