- Email: [email protected]
Embolization of calcific thrombi after tissue plasminogen activator treatment
Case Report
Embolization of Calcific Thrombi After Tissue Plasminogen Activator Treatment Brett M. Kissela, MD, Rashmi U. Kothari, MD, Thomas A. Tomsick, Daniel Woo, MD, and Joseph Broderick, MD
MD,
Background and purpose: Embolic stroke has been reported after thrombolysis in cardiac patients but has not yet been documented after thrombolytic therapy for acute ischemic stroke. Description of cases: Patient 1 had a calcific embolus in the right M1 region on head computed tomography (CT) scan when treated with tissue plasminogen activator (tPA). Repeat imaging within hours showed distal migration of calcific fragments into the M2 region. Patient 2 had a calcific embolus in the right M1 region, as well as distal calcific emboli in multiple vascular distributions on initial head CT scan. She was treated with intravenous tPA but became unresponsive within 2 hours. Repeat imaging showed new calcium-density signal in the basilar artery. Conclusions: We present 2 cases of radiographically evident, calcific embolization after tPA therapy for acute ischemic stroke. Emboli with a calcific component may lyse with tPA, but such patients should be carefully monitored for distal or recurrent embolization. Key Words: Thrombolysis—Acute stroke—Calcium—Embolus. Copyright © 2001 by National Stroke Association
Embolic stroke with calcified thrombus may be caused by the release of calcium from sources such as calcified cardiac valves.1-4 In such patients, it is possible that thrombolysis would not be effective. Embolic ischemic stroke has been associated with tissue plasminogen activator (tPA) use in patients with valvular thrombus5-11 or acute myocardial infarction (AMI)12-19 caused by liberation of thrombus. To date, the use of tPA for the acute treatment of ischemic stroke has not been associated with definitive evidence of embolic phenomena. In a stroke patient, embolic phenomena
From the Departments of Neurology and Radiology, University of Cincinnati, OH; and the Borgess Research Institute, Kalamazoo, MI. Received September 13, 2000; accepted March 9, 2001. Address reprint requests to Brett M. Kissela, MD, Department of Neurology, University of Cincinnati, 231 Albert Sabin Way, ML0525, Cincinnati, OH 45267-0525. Copyright © 2001 by National Stroke Association 1052-3057/01/1003-0009$35.00/0 doi:10.1053/jscd.2001.25467
caused by thrombolytic treatment with tPA use may be difficult to discern from the etiologic cause of the stroke. We present 2 cases involving calcific emboli and the use of tPA in acute stroke.
Description of Cases Case 1 A 74-year-old man presented with sudden onset of left arm and leg weakness, left facial droop, and slurred speech. His National Institute of Health Stroke Scale (NIHSS) score was 16. A noncontrast head computed tomography (CT) scan was performed that showed a calcium-density signal in the right middle cerebral artery (MCA) territory, M1 region (Fig 1). The patient was treated at 2 hours and 30 minutes after the onset of symptoms with 75 mg of intravenous tPA (8 mg bolus and 67 mg infusion). Within hours, his symptoms had completely resolved. Repeat imaging was performed and
Journal of Stroke and Cerebrovascular Diseases, Vol. 10, No. 3 (May-June), 2001: pp 135-138
135
B.M. KISSELA ET AL.
136
Figure 1. Noncontrast head CT scan performed on patient 1 during initial evaluation. Note the calcium-density signal in the right MCA, M1 region.
Figure 3. Carotid duplex image of the right internal carotid artery, the most likely source of calcific emboli as the origin of the patient’s stroke. The plaque seen is irregular, hetergenous, moderately echogenic, and calcified. A 50% to 60% stenosis was reported.
showed that the calcium-density signal had migrated into the Sylvian fissure (Fig 2). His workup was significant for a carotid Doppler study showing 50% to 60% stenosis bilaterally but with a right internal carotid artery plaque that was irregular, heterogenous, moderately echogenic,
and calcified (Fig 3). This plaque was believed to be the most likely origin for the patient’s stroke because echocardiography was unremarkable. He underwent carotid endarterectomy without complication and was discharged without neurologic deficit. Case 2
Figure 2. Noncontrast head CT scan performed on patient 1 after treatment with tPA. The calcium-density signal has migrated into the Sylvian fissure, in the M2 region of the right MCA.
An 80-year-old woman presented with sudden onset of left upper extremity weakness, left upper extremity sensory loss with extinction to double simultaneous stimulation, and mild dysarthria. She was also somnolent although easily arousable. Her NIHSS score was 7. A noncontrast head CT scan was performed and showed calcium-density signal in the right MCA territory, M1 region (Fig 4). There was also evidence of calcific emboli in the distal branches of multiple vascular territories. She was treated at approximately 2 hours and 45 minutes with 60 mg of intravenous tPA (6 mg bolus and 54 mg infusion). Within 2 hours after tPA treatment, the patient became unresponsive and required intubation for airway protection. A repeat noncontrast head CT scan was obtained that showed a new calcium-density signal in the basilar artery (Fig 5). No hemorrhage was noted. The patient had a carotid doppler study that showed bilateral internal carotid artery calcific plaques with less than 50% stenosis. She also had a transthoracic echocardiogram that was significant for a calcified aortic valve and mitral annulus. She never experienced any neurologic recovery and died when life support was withdrawn 5 days after onset of symptoms.
EMBOLIZATION OF CALCIFIC THROMBI
Figure 4. Noncontrast head CT scan performed on patient 2 during initial evaluation. Note the calcium-density signal in the right MCA, M1 region.
137
the setting of lytic use for thrombosis seen on prosthetic valves. Pape et al.5 described a patient who received tPA for a mobile thrombus seen on a St. Jude prosthetic mitral valve and subsequently developed a fatal left hemisphere stroke 45 minutes into the tPA infusion. Autopsy showed a left middle cerebral artery embolus. Roudaut et al.6 reported 4 fatal strokes and 6 transient ischemic attacks among 64 patients with prosthetic valve thrombosis treated with thrombolytic therapy, some of whom were treated more than once. In other studies, 2 of 88 patients had cerebral infarcts, and 3 had transient neurologic deficits attributable to cerebral embolism.7-11 These reports have led some investigators to recommend that thrombolysis not be performed on patients with thrombus on a prosthetic valve unless they are hemodynamically unstable and require immediate treatment. Some investigators have hypothesized that thrombolysis for AMI may also lead to an increased incidence of embolic ischemic stroke, above and beyond the increased stroke incidence seen in the first weeks to months. In the prethrombolytic era, the incidence of stroke after AMI ranged between 0.9% to 2.4%,12-14 with 60% of these strokes occurring in the first 4 days. In the era of thrombolysis for AMI, the incidence of ischemic stroke in patients treated with thrombolysis has been 0.7% to 1.8%,15-19 although this must be interpreted with caution because many patients who would be at high risk for embolic stroke are excluded from thrombolytic therapy.17
Discussion Calcific emboli can occur after cardiac interventions1-2 or spontaneously,2-4 as occurred in the first patient, leading to ischemic stroke. Strokes caused by such emboli may still be amenable to thrombolytic treatment, presumably because associated thrombus is dissolved, leading to the restoration of flow despite residual calcium. This is what happened in the case of patient 1 when movement of the calcium on follow-up CT scan was associated with the recovery of neurologic function. In contrast, the release of emboli with thrombolytic therapy for acute ischemic stroke could account for clinical worsening in a small number of patients. In support of this concept, we present radiographic and clinical evidence of a new embolic event in our second patient that was almost certainly caused by the use of tPA, given the temporal correlation of worsening with tPA administration. Clinical deterioration could also occur from distal embolization of a proximal embolus, although the opposite was shown in patient 1. To date, the use of tPA for the acute treatment of ischemic stroke has not been associated with definitive evidence of embolic phenomena, but embolic stroke after tPA use for cardiac indications has been reported previously. The most frequent occurrence of embolic stroke after thrombolysis for cardiac indications has occurred in
Figure 5. Follow-up noncontrast head CT scan performed on patient 2 after treatment with tPA and subsequent clinical deterioration. Note a new calcium-density signal in the basilar artery, anterior to the pons.
138
A more telling statistic is the number of strokes that occurred in the first 24 hours because these are more likely attributable to liberation of emboli. In the thrombolysis in myocardial infarction-2 trial, there were 29 strokes (0.74% of all patients treated with thrombolysis), of which 9 (31%) occurred within the first 24 hours.16 In summary, we present 2 cases of calcific embolization after tPA therapy for acute ischemic stroke. Emboli with a calcific component may lyse with tPA, but such patients should be carefully monitored for distal or recurrent embolization. Despite this possibility, tPA therapy within the first 3 hours remains the best (and currently only) therapy for acute ischemic stroke.
References 1. Kirk GR, Johnson JK. Computed tomography detection of a cerebral calcific embolus following coronary catheritication. J Neuroimaging 1994;4:241-242. 2. Vernhet H, Torres GF, Laharotte JC, et al. Spontaneous calcific cerebral emboli from calcified aortic valve stenosis. J Neuroradiol 1993;20:19-23. 3. Shanmugam V, Chhablani R, Gorelick PB. Spontaneous calcific cerebral embolus. Neurology 1997;48:538-539. 4. Stein JH, Soble JS. Thrombus associated with mitral valve calcification. A possible mechanism for embolic stroke. Stroke 1995;26:1697-1699. 5. Pape LA, Love DG, Gore JM. Massive thromboembolic stroke and death after fibrinolytic therapy of St. Jude prosthetic mitral valve thrombosis: Documentation by transthoracic Doppler echocardiography. Am Heart J 1994;128:406-409. 6. Roudaut R, Labbe T, Lorient-Roudaut M-F, et al. Mechanical cardiac valve thrombosis: Is fibrinolysis justified? Circulation 1992;86:II8-II15 (suppl). 7. Amann FW, Kiowski W, Pfisterer M, et al. Fibrinolytic treatment in thrombotic obstruction of a tilting disc prosthesis. Am Heart J 1986;112:1084-1088.
B.M. KISSELA ET AL. 8. Ledain LD, Ohayon JP, Colle JP, et al. Acute thrombotic obstruction with disc valve prostheses: Diagnostic considerations and fibrinolytic treatment. J Am Coll Cardiol 1986;7:743-751. 9. Witchitz S, Veyrat C, Moisson P, et al. Fibrinolytic treatment of thrombus on prosthetic heart valves. Br Heart J 1980;44:545-554. 10. Dzavik V, Cohen G, Chan KL. Role of transesophageal echocardiography in the diagnosis and management of prosthetic valve thrombosis. J Am Coll Cardiol 1991;18: 1829-1833. 11. Silber H, Khan SS, Matloff JM, et al. The St. Jude valve: Thrombolysis as the first line of therapy for cardiac valve thrombosis. Circulation 1993;87:30-37. 12. Thompson PL, Robinson JS. Stroke after myocardial infarction: Relation to infarct size. Br Med J 1978;2:457-459. 13. Behar S, Tanne D, Abinader E, et al. Cerebrovascular accident complicating acute myocardial infarction: Incidence, clinical significance, and short- and long-term mortality rates. Am J Med 1991;91:45-50. 14. Komrad MS, Coffey CE, Coffey KS, et al. Myocardial infarction and stroke. Neurology 1984;34:1403-1409. 15. Gore JM, Sloan M, Price TR, et al. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study (TIMI). Circulation 1991;83:448-459. 16. Sloan MA, Price TR, Terrin ML, et al. Ischemic cerebral infarction after rt-PA and heparin therapy for acute myocardial infarction: The TIMI II pilot and randomized clinical trial combined experience. Stroke 1997;28:11071114. 17. O’Connor CM, Califf RM, Massey EW, et al. Stroke and acute myocardial infarction in the thrombolytic era: Clinical correlates and long-term prognosis. J Am Coll Cardiol 1990;16:533-540. 18. Stafford PJ, Strachan CJL, Vincent R, et al. Multiple microemboli after disintegration of clot during thrombloysis for acute myocardial infarction. Br Med J 1989; 299:1310-1312. 19. Maggioni AP, Franzosi MG, Farina ML, et al. Cerebrovascular events after myocardial infarction: Analysis of the GISSI Trial. BMJ 1991;302:1428-1431.
Embolization of Calcific Thrombi After Tissue Plasminogen Activator Treatment Brett M. Kissela, MD, Rashmi U. Kothari, MD, Thomas A. Tomsick, Daniel Woo, MD, and Joseph Broderick, MD
MD,
Background and purpose: Embolic stroke has been reported after thrombolysis in cardiac patients but has not yet been documented after thrombolytic therapy for acute ischemic stroke. Description of cases: Patient 1 had a calcific embolus in the right M1 region on head computed tomography (CT) scan when treated with tissue plasminogen activator (tPA). Repeat imaging within hours showed distal migration of calcific fragments into the M2 region. Patient 2 had a calcific embolus in the right M1 region, as well as distal calcific emboli in multiple vascular distributions on initial head CT scan. She was treated with intravenous tPA but became unresponsive within 2 hours. Repeat imaging showed new calcium-density signal in the basilar artery. Conclusions: We present 2 cases of radiographically evident, calcific embolization after tPA therapy for acute ischemic stroke. Emboli with a calcific component may lyse with tPA, but such patients should be carefully monitored for distal or recurrent embolization. Key Words: Thrombolysis—Acute stroke—Calcium—Embolus. Copyright © 2001 by National Stroke Association
Embolic stroke with calcified thrombus may be caused by the release of calcium from sources such as calcified cardiac valves.1-4 In such patients, it is possible that thrombolysis would not be effective. Embolic ischemic stroke has been associated with tissue plasminogen activator (tPA) use in patients with valvular thrombus5-11 or acute myocardial infarction (AMI)12-19 caused by liberation of thrombus. To date, the use of tPA for the acute treatment of ischemic stroke has not been associated with definitive evidence of embolic phenomena. In a stroke patient, embolic phenomena
From the Departments of Neurology and Radiology, University of Cincinnati, OH; and the Borgess Research Institute, Kalamazoo, MI. Received September 13, 2000; accepted March 9, 2001. Address reprint requests to Brett M. Kissela, MD, Department of Neurology, University of Cincinnati, 231 Albert Sabin Way, ML0525, Cincinnati, OH 45267-0525. Copyright © 2001 by National Stroke Association 1052-3057/01/1003-0009$35.00/0 doi:10.1053/jscd.2001.25467
caused by thrombolytic treatment with tPA use may be difficult to discern from the etiologic cause of the stroke. We present 2 cases involving calcific emboli and the use of tPA in acute stroke.
Description of Cases Case 1 A 74-year-old man presented with sudden onset of left arm and leg weakness, left facial droop, and slurred speech. His National Institute of Health Stroke Scale (NIHSS) score was 16. A noncontrast head computed tomography (CT) scan was performed that showed a calcium-density signal in the right middle cerebral artery (MCA) territory, M1 region (Fig 1). The patient was treated at 2 hours and 30 minutes after the onset of symptoms with 75 mg of intravenous tPA (8 mg bolus and 67 mg infusion). Within hours, his symptoms had completely resolved. Repeat imaging was performed and
Journal of Stroke and Cerebrovascular Diseases, Vol. 10, No. 3 (May-June), 2001: pp 135-138
135
B.M. KISSELA ET AL.
136
Figure 1. Noncontrast head CT scan performed on patient 1 during initial evaluation. Note the calcium-density signal in the right MCA, M1 region.
Figure 3. Carotid duplex image of the right internal carotid artery, the most likely source of calcific emboli as the origin of the patient’s stroke. The plaque seen is irregular, hetergenous, moderately echogenic, and calcified. A 50% to 60% stenosis was reported.
showed that the calcium-density signal had migrated into the Sylvian fissure (Fig 2). His workup was significant for a carotid Doppler study showing 50% to 60% stenosis bilaterally but with a right internal carotid artery plaque that was irregular, heterogenous, moderately echogenic,
and calcified (Fig 3). This plaque was believed to be the most likely origin for the patient’s stroke because echocardiography was unremarkable. He underwent carotid endarterectomy without complication and was discharged without neurologic deficit. Case 2
Figure 2. Noncontrast head CT scan performed on patient 1 after treatment with tPA. The calcium-density signal has migrated into the Sylvian fissure, in the M2 region of the right MCA.
An 80-year-old woman presented with sudden onset of left upper extremity weakness, left upper extremity sensory loss with extinction to double simultaneous stimulation, and mild dysarthria. She was also somnolent although easily arousable. Her NIHSS score was 7. A noncontrast head CT scan was performed and showed calcium-density signal in the right MCA territory, M1 region (Fig 4). There was also evidence of calcific emboli in the distal branches of multiple vascular territories. She was treated at approximately 2 hours and 45 minutes with 60 mg of intravenous tPA (6 mg bolus and 54 mg infusion). Within 2 hours after tPA treatment, the patient became unresponsive and required intubation for airway protection. A repeat noncontrast head CT scan was obtained that showed a new calcium-density signal in the basilar artery (Fig 5). No hemorrhage was noted. The patient had a carotid doppler study that showed bilateral internal carotid artery calcific plaques with less than 50% stenosis. She also had a transthoracic echocardiogram that was significant for a calcified aortic valve and mitral annulus. She never experienced any neurologic recovery and died when life support was withdrawn 5 days after onset of symptoms.
EMBOLIZATION OF CALCIFIC THROMBI
Figure 4. Noncontrast head CT scan performed on patient 2 during initial evaluation. Note the calcium-density signal in the right MCA, M1 region.
137
the setting of lytic use for thrombosis seen on prosthetic valves. Pape et al.5 described a patient who received tPA for a mobile thrombus seen on a St. Jude prosthetic mitral valve and subsequently developed a fatal left hemisphere stroke 45 minutes into the tPA infusion. Autopsy showed a left middle cerebral artery embolus. Roudaut et al.6 reported 4 fatal strokes and 6 transient ischemic attacks among 64 patients with prosthetic valve thrombosis treated with thrombolytic therapy, some of whom were treated more than once. In other studies, 2 of 88 patients had cerebral infarcts, and 3 had transient neurologic deficits attributable to cerebral embolism.7-11 These reports have led some investigators to recommend that thrombolysis not be performed on patients with thrombus on a prosthetic valve unless they are hemodynamically unstable and require immediate treatment. Some investigators have hypothesized that thrombolysis for AMI may also lead to an increased incidence of embolic ischemic stroke, above and beyond the increased stroke incidence seen in the first weeks to months. In the prethrombolytic era, the incidence of stroke after AMI ranged between 0.9% to 2.4%,12-14 with 60% of these strokes occurring in the first 4 days. In the era of thrombolysis for AMI, the incidence of ischemic stroke in patients treated with thrombolysis has been 0.7% to 1.8%,15-19 although this must be interpreted with caution because many patients who would be at high risk for embolic stroke are excluded from thrombolytic therapy.17
Discussion Calcific emboli can occur after cardiac interventions1-2 or spontaneously,2-4 as occurred in the first patient, leading to ischemic stroke. Strokes caused by such emboli may still be amenable to thrombolytic treatment, presumably because associated thrombus is dissolved, leading to the restoration of flow despite residual calcium. This is what happened in the case of patient 1 when movement of the calcium on follow-up CT scan was associated with the recovery of neurologic function. In contrast, the release of emboli with thrombolytic therapy for acute ischemic stroke could account for clinical worsening in a small number of patients. In support of this concept, we present radiographic and clinical evidence of a new embolic event in our second patient that was almost certainly caused by the use of tPA, given the temporal correlation of worsening with tPA administration. Clinical deterioration could also occur from distal embolization of a proximal embolus, although the opposite was shown in patient 1. To date, the use of tPA for the acute treatment of ischemic stroke has not been associated with definitive evidence of embolic phenomena, but embolic stroke after tPA use for cardiac indications has been reported previously. The most frequent occurrence of embolic stroke after thrombolysis for cardiac indications has occurred in
Figure 5. Follow-up noncontrast head CT scan performed on patient 2 after treatment with tPA and subsequent clinical deterioration. Note a new calcium-density signal in the basilar artery, anterior to the pons.
138
A more telling statistic is the number of strokes that occurred in the first 24 hours because these are more likely attributable to liberation of emboli. In the thrombolysis in myocardial infarction-2 trial, there were 29 strokes (0.74% of all patients treated with thrombolysis), of which 9 (31%) occurred within the first 24 hours.16 In summary, we present 2 cases of calcific embolization after tPA therapy for acute ischemic stroke. Emboli with a calcific component may lyse with tPA, but such patients should be carefully monitored for distal or recurrent embolization. Despite this possibility, tPA therapy within the first 3 hours remains the best (and currently only) therapy for acute ischemic stroke.
References 1. Kirk GR, Johnson JK. Computed tomography detection of a cerebral calcific embolus following coronary catheritication. J Neuroimaging 1994;4:241-242. 2. Vernhet H, Torres GF, Laharotte JC, et al. Spontaneous calcific cerebral emboli from calcified aortic valve stenosis. J Neuroradiol 1993;20:19-23. 3. Shanmugam V, Chhablani R, Gorelick PB. Spontaneous calcific cerebral embolus. Neurology 1997;48:538-539. 4. Stein JH, Soble JS. Thrombus associated with mitral valve calcification. A possible mechanism for embolic stroke. Stroke 1995;26:1697-1699. 5. Pape LA, Love DG, Gore JM. Massive thromboembolic stroke and death after fibrinolytic therapy of St. Jude prosthetic mitral valve thrombosis: Documentation by transthoracic Doppler echocardiography. Am Heart J 1994;128:406-409. 6. Roudaut R, Labbe T, Lorient-Roudaut M-F, et al. Mechanical cardiac valve thrombosis: Is fibrinolysis justified? Circulation 1992;86:II8-II15 (suppl). 7. Amann FW, Kiowski W, Pfisterer M, et al. Fibrinolytic treatment in thrombotic obstruction of a tilting disc prosthesis. Am Heart J 1986;112:1084-1088.
B.M. KISSELA ET AL. 8. Ledain LD, Ohayon JP, Colle JP, et al. Acute thrombotic obstruction with disc valve prostheses: Diagnostic considerations and fibrinolytic treatment. J Am Coll Cardiol 1986;7:743-751. 9. Witchitz S, Veyrat C, Moisson P, et al. Fibrinolytic treatment of thrombus on prosthetic heart valves. Br Heart J 1980;44:545-554. 10. Dzavik V, Cohen G, Chan KL. Role of transesophageal echocardiography in the diagnosis and management of prosthetic valve thrombosis. J Am Coll Cardiol 1991;18: 1829-1833. 11. Silber H, Khan SS, Matloff JM, et al. The St. Jude valve: Thrombolysis as the first line of therapy for cardiac valve thrombosis. Circulation 1993;87:30-37. 12. Thompson PL, Robinson JS. Stroke after myocardial infarction: Relation to infarct size. Br Med J 1978;2:457-459. 13. Behar S, Tanne D, Abinader E, et al. Cerebrovascular accident complicating acute myocardial infarction: Incidence, clinical significance, and short- and long-term mortality rates. Am J Med 1991;91:45-50. 14. Komrad MS, Coffey CE, Coffey KS, et al. Myocardial infarction and stroke. Neurology 1984;34:1403-1409. 15. Gore JM, Sloan M, Price TR, et al. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study (TIMI). Circulation 1991;83:448-459. 16. Sloan MA, Price TR, Terrin ML, et al. Ischemic cerebral infarction after rt-PA and heparin therapy for acute myocardial infarction: The TIMI II pilot and randomized clinical trial combined experience. Stroke 1997;28:11071114. 17. O’Connor CM, Califf RM, Massey EW, et al. Stroke and acute myocardial infarction in the thrombolytic era: Clinical correlates and long-term prognosis. J Am Coll Cardiol 1990;16:533-540. 18. Stafford PJ, Strachan CJL, Vincent R, et al. Multiple microemboli after disintegration of clot during thrombloysis for acute myocardial infarction. Br Med J 1989; 299:1310-1312. 19. Maggioni AP, Franzosi MG, Farina ML, et al. Cerebrovascular events after myocardial infarction: Analysis of the GISSI Trial. BMJ 1991;302:1428-1431.