Is Calcification of Intracranial Arteries Important and How

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 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 intracranial carotid calcification 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 lumen9; 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 calcification is associated with unstable plaque features that predispose to distal embolism. This study by Bos and colleagues4 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 inwhite individuals. The study indicates that intracranial carotidcalcification isamajor risk factor for stroke inwhite individuals but does not establish a pathophysiologic causal relationshipbetweenthe two.Establishing thatwill require further prospective studies that correlate the association between intracranial arterial calcification and stenosis more clearly, identifyatheroscleroticplaque featuresassociatedwith calcification thatmay be associatedwith a high risk for distal embolism, and classify ischemic strokes that occur in patientswith intracranial carotid calcification according to size, location (cortical or subcortical), vascular territory, and thecoexistenceofotherpotential causesof stroke.Muchworkneeds to be done. Related article page 405 Opinion