Opinion
EDITORIAL
Is Calcification of Intracranial Arteries Important and How? Marc I. Chimowitz, MBChB; Louis R. Caplan, MD
Intracranial atherosclerosis is a well-recognized and common cause of stroke in Asian, black, and Hispanic individuals. 1,2 Recent studies showed that intracranial occlusive disease is also a more common cause of Related article page 405 stroke in white individuals than previously thought. 3 In this issue of JAMA Neurology, Bos and colleagues4 provide evidence that intracranial carotid artery calcification is an important risk factor for stroke in an elderly white Dutch population. As part of the prospective, population-based Rotterdam study, the authors followed up 2323 individuals to determine the incidence of stroke (parenchymal brain hemorrhage or ischemic) after they had nonenhanced computed tomography (CT) scanning that imaged the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. The authors used calcification volume in these arteries as an indicator of atherosclerosis and correlated this with the risk for all stroke and ischemic stroke. They found that larger intracranial carotid calcification volume was independently associated with all stroke and that intracranial carotid calcification was a more important risk factor for stroke than aortic arch calcification or extracranial carotid calcification. The apparent discrepancy between the importance of intrac ranial c arotid c alc ific ation as a major risk factor for stroke in this study and the low frequency of stroke caused by intracranial atherosclerosis in most studies of white patients is largely explained by the different design of these studies. Prior studies identified consecutive patients with stroke and determined the frequency of proximal intracranial atherosclerotic arterial stenosis. In the current study, intracranial carotid calcification (not stenosis) was measured and correlated with subsequent stroke regardless of the territory of the stroke. Data on the size, location (cortical or subcortical), and vascular territory of brain infarcts were not collected. While the current study suggests that intracranial carotid artery calcification is an important, previously seldom considered, risk factor for subsequent stroke in any vascular territory in white patients, the study did not show that the intracranial vascular lesions were the cause of the strokes. Many of the ischemic strokes in this study were almost surely not caused by intracranial carotid atherosclerosis because the strokes were either in a different vascular territory or were caused by other vascular diseases (eg, coexisting penetrating artery disease,5 a cardiac source of embolism). Moreover, at least 11% of the strokes in the study were hemorrhagic and no causal relationship has been established between
intracranial arterial calcification and parenchymal brain hemorrhage. Recent interest in calcification of arteries has been spurred on by the strong association between coronary calcification detected by cardiac CT and the risk for future cardiac events.6 The situation appears to be different in relation to carotid artery disease in the neck where the presence of heavy calcification on spiral CT has been correlated with stable, noninflammatory, asymptomatic plaques.7 Whether intracranial arterial calcification is also associated with stable plaque that is unlikely to cause a distal stroke is unknown. What is known is that severe stenosis of an intracranial artery is strongly associated with a high risk for stroke distal to the stenosis in patients presenting with a transient ischemic attack or stroke. 8 If the presence of severe intracranial carotid calcification implied coexistent severe arterial stenosis of the artery, that would provide some evidence of a potential causal link between calcification and risk for stroke attributable to the affected artery. However, the relationship between calcification of the intracranial carotid artery and coexistent stenosis is unsettled. Older pathological studies found that heavy calcification of the carotid siphon did not necessarily indicate stenosis of the lumen 9 ; however, a more recent neuroimaging study showed that the positive predictive value of severe carotid siphon calcification on CT for a stenosis of greater than 50% on angiography was 86% using bone window measurements.10 It is also possible that intracranial carotid calcification may cause stroke without the presence of coexistent stenosis if c alc ific ation is assoc iated with unstable plaque features that predispose to distal embolism. This study by Bos and colleagues 4 raises important questions about the role of calcification in the pathophysiology of intracranial atherosclerosis and should reawaken interest in intracranial atherosclerosis as a cause of stroke in white individuals. The study indicates that intracranial carotid calcification is a major risk factor for stroke in white individuals but does not establish a pathophysiologic causal relationship between the two. Establishing that will require further prospective studies that correlate the association between intracranial arterial calcification and stenosis more clearly, identify atherosclerotic plaque features associated with calcification that may be associated with a high risk for distal embolism, and classify ischemic strokes that occur in patients with intracranial carotid calcification according to size, location (cortical or subcortical), vascular territory, and the coexistence of other potential causes of stroke. Much work needs to be done.
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JAMA Neurology April 2014 Volume 71, Number 4
Copyright 2014 American Medical Association. All rights reserved.
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401
Opinion Editorial
ARTICLE INFORMATION Author Affiliations: Department of Neurosciences, Medical University of South Carolina, Charleston (Chimowitz); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Caplan). Corresponding Author: Marc I. Chimowitz, MBChB, Medical University of South Carolina Stroke Program, 19 Hagood Ave, Harborview Office Tower, Ste 501, Charleston, SC 29425 ([email protected]). Published Online: February 17, 2014. doi:10.1001/jamaneurol.2013.6224. Conflict of Interest Disclosures: None reported. REFERENCES 1. Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2013;12(11):1106-1114.
402
2. Caplan LR, Wityk RJ, Glass TA, et al. New England Medical Center Posterior Circulation registry. Ann Neurol. 2004;56(3):389-398. 3. Mazighi M, Labreuche J, Gongora-Rivera F, Duyckaerts C, Hauw JJ, Amarenco P. Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke. 2008;39(4):1142-1147. 4. Bos D, Portegies MLP, van der Lugt A, et al. Intracranial carotid artery atherosclerosis and the risk of stroke in whites: the Rotterdam Study [published online February 17, 2014]. JAMA Neurol. doi:10.1001 /jamaneurol.2013.6223. 5. Hong NR, Seo HS, Lee YH, et al. The correlation between carotid siphon calcification and lacunar infarction. Neuroradiology. 2011;53(9):643-649.
7. Shaalan WE, Cheng H, Gewertz B, et al. Degree of carotid plaque calcification in relation to symptomatic outcome and plaque inflammation. J Vasc Surg. 2004;40(2):262-269. 8. Kasner SE, Chimowitz MI, Lynn MJ, et al; Warfarin Aspirin Symptomatic Intracranial Disease Trial Investigators. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation. 2006;113(4):555-563. 9. Fisher CM, Gore I, Okabe N, White PD. Calcification of the carotid siphon. Circulation. 1965;32(4):538-548. 10. Woodcock RJ Jr, Goldstein JH, Kallmes DF, Cloft HJ, Phillips CD. Angiographic correlation of CT calcification in the carotid siphon. AJNR Am J Neuroradiol. 1999;20(3):495-499.
6. Peters SA, Bakker M, den Ruijter HM, Bots ML. Added value of CAC in risk stratification for cardiovascular events: a systematic review. Eur J Clin Invest. 2012;42(1):110-116.
JAMA Neurology April 2014 Volume 71, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/18/2015
jamaneurology.com
EDITORIAL
Is Calcification of Intracranial Arteries Important and How? Marc I. Chimowitz, MBChB; Louis R. Caplan, MD
Intracranial atherosclerosis is a well-recognized and common cause of stroke in Asian, black, and Hispanic individuals. 1,2 Recent studies showed that intracranial occlusive disease is also a more common cause of Related article page 405 stroke in white individuals than previously thought. 3 In this issue of JAMA Neurology, Bos and colleagues4 provide evidence that intracranial carotid artery calcification is an important risk factor for stroke in an elderly white Dutch population. As part of the prospective, population-based Rotterdam study, the authors followed up 2323 individuals to determine the incidence of stroke (parenchymal brain hemorrhage or ischemic) after they had nonenhanced computed tomography (CT) scanning that imaged the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. The authors used calcification volume in these arteries as an indicator of atherosclerosis and correlated this with the risk for all stroke and ischemic stroke. They found that larger intracranial carotid calcification volume was independently associated with all stroke and that intracranial carotid calcification was a more important risk factor for stroke than aortic arch calcification or extracranial carotid calcification. The apparent discrepancy between the importance of intrac ranial c arotid c alc ific ation as a major risk factor for stroke in this study and the low frequency of stroke caused by intracranial atherosclerosis in most studies of white patients is largely explained by the different design of these studies. Prior studies identified consecutive patients with stroke and determined the frequency of proximal intracranial atherosclerotic arterial stenosis. In the current study, intracranial carotid calcification (not stenosis) was measured and correlated with subsequent stroke regardless of the territory of the stroke. Data on the size, location (cortical or subcortical), and vascular territory of brain infarcts were not collected. While the current study suggests that intracranial carotid artery calcification is an important, previously seldom considered, risk factor for subsequent stroke in any vascular territory in white patients, the study did not show that the intracranial vascular lesions were the cause of the strokes. Many of the ischemic strokes in this study were almost surely not caused by intracranial carotid atherosclerosis because the strokes were either in a different vascular territory or were caused by other vascular diseases (eg, coexisting penetrating artery disease,5 a cardiac source of embolism). Moreover, at least 11% of the strokes in the study were hemorrhagic and no causal relationship has been established between
intracranial arterial calcification and parenchymal brain hemorrhage. Recent interest in calcification of arteries has been spurred on by the strong association between coronary calcification detected by cardiac CT and the risk for future cardiac events.6 The situation appears to be different in relation to carotid artery disease in the neck where the presence of heavy calcification on spiral CT has been correlated with stable, noninflammatory, asymptomatic plaques.7 Whether intracranial arterial calcification is also associated with stable plaque that is unlikely to cause a distal stroke is unknown. What is known is that severe stenosis of an intracranial artery is strongly associated with a high risk for stroke distal to the stenosis in patients presenting with a transient ischemic attack or stroke. 8 If the presence of severe intracranial carotid calcification implied coexistent severe arterial stenosis of the artery, that would provide some evidence of a potential causal link between calcification and risk for stroke attributable to the affected artery. However, the relationship between calcification of the intracranial carotid artery and coexistent stenosis is unsettled. Older pathological studies found that heavy calcification of the carotid siphon did not necessarily indicate stenosis of the lumen 9 ; however, a more recent neuroimaging study showed that the positive predictive value of severe carotid siphon calcification on CT for a stenosis of greater than 50% on angiography was 86% using bone window measurements.10 It is also possible that intracranial carotid calcification may cause stroke without the presence of coexistent stenosis if c alc ific ation is assoc iated with unstable plaque features that predispose to distal embolism. This study by Bos and colleagues 4 raises important questions about the role of calcification in the pathophysiology of intracranial atherosclerosis and should reawaken interest in intracranial atherosclerosis as a cause of stroke in white individuals. The study indicates that intracranial carotid calcification is a major risk factor for stroke in white individuals but does not establish a pathophysiologic causal relationship between the two. Establishing that will require further prospective studies that correlate the association between intracranial arterial calcification and stenosis more clearly, identify atherosclerotic plaque features associated with calcification that may be associated with a high risk for distal embolism, and classify ischemic strokes that occur in patients with intracranial carotid calcification according to size, location (cortical or subcortical), vascular territory, and the coexistence of other potential causes of stroke. Much work needs to be done.
jamaneurology.com
JAMA Neurology April 2014 Volume 71, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/18/2015
401
Opinion Editorial
ARTICLE INFORMATION Author Affiliations: Department of Neurosciences, Medical University of South Carolina, Charleston (Chimowitz); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Caplan). Corresponding Author: Marc I. Chimowitz, MBChB, Medical University of South Carolina Stroke Program, 19 Hagood Ave, Harborview Office Tower, Ste 501, Charleston, SC 29425 ([email protected]). Published Online: February 17, 2014. doi:10.1001/jamaneurol.2013.6224. Conflict of Interest Disclosures: None reported. REFERENCES 1. Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2013;12(11):1106-1114.
402
2. Caplan LR, Wityk RJ, Glass TA, et al. New England Medical Center Posterior Circulation registry. Ann Neurol. 2004;56(3):389-398. 3. Mazighi M, Labreuche J, Gongora-Rivera F, Duyckaerts C, Hauw JJ, Amarenco P. Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke. 2008;39(4):1142-1147. 4. Bos D, Portegies MLP, van der Lugt A, et al. Intracranial carotid artery atherosclerosis and the risk of stroke in whites: the Rotterdam Study [published online February 17, 2014]. JAMA Neurol. doi:10.1001 /jamaneurol.2013.6223. 5. Hong NR, Seo HS, Lee YH, et al. The correlation between carotid siphon calcification and lacunar infarction. Neuroradiology. 2011;53(9):643-649.
7. Shaalan WE, Cheng H, Gewertz B, et al. Degree of carotid plaque calcification in relation to symptomatic outcome and plaque inflammation. J Vasc Surg. 2004;40(2):262-269. 8. Kasner SE, Chimowitz MI, Lynn MJ, et al; Warfarin Aspirin Symptomatic Intracranial Disease Trial Investigators. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation. 2006;113(4):555-563. 9. Fisher CM, Gore I, Okabe N, White PD. Calcification of the carotid siphon. Circulation. 1965;32(4):538-548. 10. Woodcock RJ Jr, Goldstein JH, Kallmes DF, Cloft HJ, Phillips CD. Angiographic correlation of CT calcification in the carotid siphon. AJNR Am J Neuroradiol. 1999;20(3):495-499.
6. Peters SA, Bakker M, den Ruijter HM, Bots ML. Added value of CAC in risk stratification for cardiovascular events: a systematic review. Eur J Clin Invest. 2012;42(1):110-116.
JAMA Neurology April 2014 Volume 71, Number 4
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/18/2015
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