This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lammie, G. A. Articles by Dennis, M. S. Search for Related Content PubMed PubMed Citation Articles by Lammie, G. A. Articles by Dennis, M. S. Related Collections Pathophysiology Embolic stroke Pathology of Stroke

(Stroke. 1999;30:1319-1325.)
© 1999 American Heart Association, Inc.

Original Contributions

Recently Occluded Intracranial and Extracranial Carotid Arteries

Relevance of the Unstable Atherosclerotic Plaque

G. Alistair Lammie, MD, MRCPath; Peter A. G. Sandercock, MD, FRCP Martin S. Dennis, MD, FRCP

From the Departments of Pathology (G.A.L.) and Clinical Neurosciences (P.A.G.S., M.S.D.), Edinburgh University, Edinburgh, Scotland.

Correspondence and reprint requests to Dr G.A. Lammie, Neuropathology Laboratory, Alexander Donald Bldg, Western General Hospital, Crewe Road, Edinburgh, Scotland EH4 2XU. E-mail al{at}skull.dcn.ed.ac.uk

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background and Purpose—It is now widely accepted that thrombotic coronary artery occlusion usually follows rupture of an unstable atherosclerotic plaque. The significance of such instability in arteries supplying the brain is less well appreciated. We therefore describe the clinical and pathological features of recent, symptomatic internal carotid artery occlusion to examine the pathogenetic role of plaque instability at both extracranial and intracranial sites.

Methods—Cases were selected from a consecutive series of 188 adult neuropathology autopsies. In 90 of these, the principal neuropathological abnormality was cerebral infarction, in 14 cases due to recent occlusion of 1 or more segments of the internal carotid artery. In each case, a full systemic, cardiovascular, and neuropathological autopsy was performed. Plaque instability was assessed by the presence or absence of a large, necrotic, lipid core; a thin, fibrous cap; and superficial inflammation.

Results—Of the 14 cases, 3 showed extracranial (carotid sinus), 7 intracranial, and 4 both extracranial and intracranial carotid artery occlusion. In 6 of the 7 occluded carotid sinuses, thrombus overlay an ulcerated, unstable, atherosclerotic plaque. In 1 extracranial and all 11 intracranial occlusions, there was either no atheroma or a mildly stenotic, stable, fibrous plaque, and in these cases, the cause of occlusion was embolism (8 cases), giant-cell arteritis (1 case), and unknown (3 cases).

Conclusions—Coronary-type rupture of an unstable atherosclerotic plaque is the usual cause of fatal occlusion of the carotid sinus, but other causes usually underlie intracranial carotid occlusion. The nature and consequences of intracranial atherosclerosis require further study.

Key Words: atherosclerosis • carotid artery • occlusion • pathology • stroke

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
It is now widely accepted that thrombotic occlusion of the coronary arteries usually follows rupture or endothelial erosion of an unstable, atherosclerotic plaque.^{1 2 3} Clinicopathological study of postmortem coronary arteries has defined the unstable plaque as having a large core of extracellular lipid and/or necrotic cellular debris overlain by a thin, eccentric, fibrous cap, with evidence of inflammation.^{2 3 4 5} There are relatively few pathological studies of thrombosed internal carotid arteries (ICAs), and the relevance to the brain of the coronary paradigm of plaque instability remains unclear, despite the fact that occlusion of at least the cervical portion of the ICA is an important cause of stroke.^{6 7 8 9} We therefore describe the clinical and pathological features in 14 consecutive autopsy cases of fatal ICA occlusion to investigate its pathogenesis at both intracranial and extracranial sites and to examine the pathogenetic role of plaque instability.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Cases were selected from a consecutive series of 188 adult neuropathology autopsies referred to 1 of the authors (G.A.L.) over a 3-year period in the Neuropathology Laboratory, University of Edinburgh, beginning in October 1994. These 188 cases included referrals for a range of proven and suspected neuropathologies, with a relatively high proportion of stroke cases reflecting the authors' research interests. In 118 cases the principal neuropathological abnormality was cerebrovascular (44, regional infarction; 39, lacunar or small cortical infarcts; 6, global or border zone ischemia; 1, venous infarction; 16, primary intracerebral hemorrhage; 11, subarachnoid hemorrhage; and 1, primary intraventricular hemorrhage).

In 14 of the 90 cases with cerebral infarction, there was recent occlusion of 1 or more segments of the carotid artery at autopsy. In all 14 cases, a full neuropathological postmortem study was performed at gross and microscopic levels, and all significant cerebrovascular pathology was documented. Occluded arteries were serially sectioned at 5-mm intervals or less. Brain infarcts were dated histologically,¹⁰ and arterial territories were defined¹¹ according to published maps. Hypertension was defined as a documented clinical history of hypertension, either untreated or treated, or autopsy evidence of concentric left ventricular hypertrophy without other cause. Potential causes of cerebral infarction and potential cardiac sources of embolism were defined according to published criteria¹² and further refined by the results of autopsy. The key features of an unstable atherosclerotic plaque were defined as being a large, necrotic, lipid core; a thin, fibrous cap; and superficial inflammation, as in the coronary circulation.^{2 3 4 5}

	Results

Top Abstract Introduction Methods Results Discussion References

 
Clinical and Autopsy Findings
All 14 patients were white, whose age at death ranged from 32 to 87 years. In 13 of the 14 cases, carotid occlusion was associated with clinical features consistent with carotid territory stroke, and in the remaining case (case 11), the patient presented with a brain stem stroke caused by simultaneous basilar artery occlusion. Poststroke survival ranged from <1 day to 12 weeks, and the cause of death in each case was attributed, either directly or indirectly, to the stroke. Thus, 5 patients died as a result of brain swelling secondary to cerebral infarction, and in 1, death was due to brain stem infarction. The remaining 8 patients died from complications of stroke; in 5 cases, bronchopneumonia; and in 3, deep venous thrombosis and subsequent pulmonary embolus. Therefore, all 14 cases could reasonably be classified as fatal stroke.

Of the 14 cases, 3 showed only extracranial carotid occlusion (cases 1 through 3); 7, only intracranial occlusion (cases 8 through 14); and 4, both extracranial and intracranial occlusion (cases 4 through 7). In all 7 cases with extracranial carotid occlusion, this involved the carotid sinus; in 6 cases, occlusion extended a short distance up the proximal internal carotid artery (ICA), and in 2 cases (cases 4 and 7), involvement of the distal segment of the common carotid artery was noted. Of the 11 intracranial carotid occlusions, 1 involved the siphon alone (case 5); 4, the supraclinoid segment (cases 7, 9, 11, and 12); and 6, both segments. There was extension into contiguous branches of the circle of Willis in 8 of the 11 cases; in 6 cases this involved the middle cerebral artery, in 1 case the middle and anterior cerebral arteries, and in 1 case the middle and posterior cerebral arteries.

The resulting pattern of brain infarction corresponded to all or part of the combined middle and anterior cerebral artery territories (cases 1, 2, 3, 7, and 13), the middle cerebral artery territory alone (cases 4, 9, 10, and 14), the anterior/middle cerebral artery border zone territory (case 5), the anterior choroidal artery territory (case 8), and multiple anterior circulatory loci (cases 6, 11, and 12). The histological age of each infarct corresponded, at least focally, with the clinical stroke onset. Relevant clinical and autopsy findings are summarized in Table 1.

View this table: [in this window] [in a new window]   Table 1. Clinical and Autopsy Features

Underlying Vessel Wall Pathology
In 6 of the 7 occluded extracranial carotid segments (cases 1 through 6), thrombus focally overlay ulcerated, unstable, atherosclerotic plaque (Figure 1). In each, there was a large necrotic, lipid core that occupied at least 80% of the plaque cross-sectional area, which was covered by a uniformly or focally thin, fibrous cap (Figure 1A). Superficial plaque monocytes and foam cells were present in each of these 6 plaques but in varying proportions and numbers (Figure 1B). The underlying plaque was between 50% and 95% stenotic. In 2 cases, there was evidence of intraplaque hemorrhage comprising a relatively pure population of red blood cells, and in 5, of intraplaque thrombus, with evidence of a fibrin "scaffold" and enmeshed platelets as well as red blood cells.

View larger version (100K): [in this window] [in a new window]   Figure 1. Right carotid sinus from case 4 showing features of atheromatous plaque instability. A, Low-power view showing a large, necrotic core with cholesterol clefts (*), a focally thin, fibrous cap (thin arrow), and an adherent microthrombus (thick arrowhead). Elsewhere there was evidence of cap ulceration and occlusive thrombus. Hematoxylin and eosin stain, x44. B, High-power view showing infiltration of the fibrous cap by small, mononuclear cells and foam cells. The lumen at this point is patent (top). Hematoxylin and eosin stain, x220.

In the 1 remaining occluded extracranial carotid artery (case 7) and in 7 of the 11 occluded intracranial segments (cases 4 through 10), there was underlying atherosclerosis, which was <50% stenotic and either fibrous or fibrocalcific (Figure 2). In none of the 11 occluded intracranial carotids nor in the occluded sinus in case 7 was there evidence of hemorrhage, ulceration, or fissuring, and none had a significant lipid, necrotic core or superficial plaque inflammation.

View larger version (116K): [in this window] [in a new window]   Figure 2. An occluded right carotid siphon (case 8) in which red blood cell–rich thrombus (top) overlies a stable, paucicellular fibrous plaque (bottom), with no evidence of a necrotic core, inflammation, or ulceration. Hematoxylin and eosin stain, x220.

In case 11 there was focal segmental giant-cell arteritis on multiple segments of the circle of Willis and intracranial ICAs. In case 12, both intracranial ICAs and proximal middle cerebral arteries were occluded by a mixture of vascularized fibrous tissue and recent organizing and organized thrombus. The occluded intracranial vessel walls in cases 13 and 14 appeared histologically normal. These pathological findings are summarized in Table 2.

View this table: [in this window] [in a new window]   Table 2. Pathology of Thrombosed Carotid Artery and Proposed Mechanism of Occlusion

Mechanism of Occlusion
The mechanism of occlusion in 6 of the 7 occluded extracranial carotids (cases 1 through 6) was ulceration of unstable carotid sinus atherosclerotic plaque with subsequent thrombosis. In cases 3 and 5, this event appeared to have been coincident with and was possibly precipitated by postoperative hypotension. In each of these 6 cases, the thrombus was of mixed type histologically (platelets, fibrin, and red blood cells), in 3 with a distally propagating red blood cell–rich "tail." In 3 cases with extracranial carotid occlusion, there was also ipsilateral siphon occlusion (cases 4 through 6) by thrombus, histologically similar to the main stem or tail of the sinus thrombus, and in these cases, siphon occlusion was assumed to be embolic from the ipsilateral sinus.

In the 1 remaining case with sinus occlusion (case 7), there was simultaneous contralateral siphon occlusion, both presumed in the absence of other demonstrable causes, to be due to paradoxical embolism from autopsy-verified deep leg vein thrombosis through a large patent foramen ovale. In this and all other cases with intracranial carotid occlusion, the occluded segment was either histologically normal or <50% stenosed by fibrous or fibrocalcific stable, atherosclerotic plaque.

Of the 7 cases with solely intracranial occlusion, a probable mechanism was determined in 3: cardiac embolism (case 8, histologically verified left atrial thrombus), artery-to-artery embolus (case 9, ulcerated unstable aortic arch and carotid sinus atherosclerosis), and paradoxical embolus (case 10, atrial septal defect, deep venous thrombosis, and multiple pulmonary emboli). In 4 of the total of 8 cases assumed to be embolic, there was a pattern of multiple cortical microinfarcts elsewhere in the brain, which provided further evidence in support of this mechanism.

In case 11 there were multiple intracranial thromboses in the circle of Willis due to giant-cell arteritis, which had been unsuspected during life, and death followed brain stem infarction due to basilar artery occlusion. The etiopathogenesis of bilateral intracranial carotid occlusions in case 12, giving a radiological and pathological picture characteristic of the so-called moyamoya syndrome, is obscure. The details of this case and the possible contribution of the underlying primary oxalosis are discussed elsewhere.¹³

The underlying mechanisms of occlusion in cases 13 and 14 are unknown. In neither was there an obvious cardiac or arterial source of embolus detected during life or at autopsy. In case 13, autopsy revealed bilateral extracranial vertebral artery dissections and evidence of fibromuscular dysplasia, but neither was present in the occluded intracranial arteries. In case 14, there was a history of insulin-dependent diabetes mellitus. In neither case was there significant atherosclerosis. Both patients had a prior history of migraine, an exacerbation of which appeared to herald the onset of the fatal stroke. A possible relation between stroke and migraine in these 2 patients is therefore intriguing, although neither case fulfilled strict criteria for migrainous stroke.¹⁴

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Occlusion of the cervical ICA, while sometimes asymptomatic,¹⁵ is an important cause of stroke.^{6 7 8 9} However, in contrast to coronary artery occlusion, there has been a relative paucity of necropsy data regarding carotid sinus thrombosis. Fisher^{6 7} suggested that atherosclerosis was the likely pathological cause of occlusive carotid sinus thrombosis, and he confirmed Chiari's earlier observation that thrombosis at this site is often preceded by plaque ulceration.⁷ This concept has subsequently been confirmed by others, and carotid sinus plaque rupture has been associated with sites at which a thin, fibrous cap overlies a large necrotic core,¹⁶ as in the coronary circulation. There are rather more data, although much conflicting, concerning nonocclusive carotid plaque morphology and its prognostic value regarding the development of neurological symptoms. These data are based mainly on pathology studies of carotid endarterectomy specimens, in some of which neurological symptoms have been correlated with lipid, necrosis-rich plaques¹⁷ or with thin, fibrous caps, foam cell cap infiltration, and plaque rupture.¹⁸ Such observations clearly support the potential relevance of coronary-type plaque instability in the carotid sinus, and aspects of this literature have been the subject of recent review.¹⁹ However, there remain very few autopsy studies of thrombotic occlusion of the cervical ICA: most predate the modern concept of the unstable atherosclerotic plaque, and in some, the importance of intimal rupture is disputed.²⁰ Our observations suggest that fatal carotid sinus occlusion almost always follows rupture of an unstable atherosclerotic plaque, in a manner directly analogous to coronary artery occlusion.^{1 2 3 4 5}

It has become increasingly apparent in the coronary circulation that the degree of stenosis per se is a poor predictor of the propensity of the plaque to rupture.²¹ Similarly, whereas high-grade stenosis is widely held to be closely related to stroke and transient ischemic attacks,²² it has been argued that the nature of the plaque in this situation may also be at least as important.²³ Thus, although thrombotic sinus occlusion is often reported in relation to tight stenosis,^{9 16 24} 1 serial-section study of 11 cases of recent thrombotic ICA occlusion suggested that in nearly half, there was only moderate (<60%) stenosis.²⁰ In our cases, the preexisting degree of stenosis ranged from 50% to 95%, suggesting that it is plaque instability, often but not necessarily in association with a tight stenosis, that is the essential precursor to thrombotic occlusion.

It should be emphasised that whereas our observations do suggest that similar plaque features may promote plaque ulceration and thrombosis in carotid and coronary arteries, the clinical significance may well be different at the 2 sites, and in the carotid, this phenomenon remains ill understood. It is possible, for example, that asymptomatic plaque complications may be more frequent in the carotid than in the coronary circulation. This subject merits further study.

In contrast to the carotid sinus, atherosclerotic narrowing and occlusive thrombosis of the intracranial ICA are considered relatively rare, at least in whites. The intracranial portion of the ICA is by convention divided into petrous, cavernous (together constituting the siphon), and supraclinoid or T segments. Although the intracranial ICA commonly harbors some atherosclerosis, particularly in its cavernous and supraclinoid segments,^{25 26} this is more often calcific^{25 26 27 28} and less often severely stenotic^{24 25 26 27 29} than in the sinus. Perhaps in large part due to this phenomenon, intracranial ICA thrombosis is considered to be significantly less common than in the neck, its frequency in autopsy studies of carotid occlusion ranging from 0% to 30%.^{7 9 24 26 27 30} Furthermore, whereas intracranial carotid thrombosis has been attributed to atherosclerosis,⁹ it has also been suggested that thrombus in this region is more likely to be embolic,^{8 9 24 31 32 33 34} perhaps due to clotting abnormalities,³⁵ or, by implication, nonatherosclerotic vessel disease.³⁶ Thrombi also appear to develop in less severely stenosed lumens in the distal compared with the proximal ICA.⁹

Despite these various claims, intracranial atherosclerosis and occlusion remain underresearched, both in the carotid siphon and in other intracranial arteries. Understanding the nature and consequences of intracranial atherosclerosis is, however, potentially important, not the least because it may be a marker of severe cerebrovascular and systemic atherosclerosis elsewhere. Furthermore, it has an unexplained tendency to be more severe in blacks, Asians, and Orientals,^{37 38 39} and some have suggested it has a worse prognosis than extracranial disease.^{40 41 42}

Our findings suggest that fatal thrombotic occlusion of the intracranial ICA is usually not due directly to underlying atherosclerosis. The same may also be true for contiguous arteries on the circle of Willis. Thus, in 1 careful autopsy study of middle cerebral artery occlusion, only 2 of a series of 47 infarcts were considered to be caused by in situ thrombosis due to underlying atherosclerosis.⁴³ In the occluded intracranial carotid artery, we suggest that where there is underlying atheroma, it is usually fibrous or fibrocalcific and lacks any of the hallmarks of plaque instability. Similarly, whereas cases of "atherosclerotic" circle of Willis thrombus are recorded, they are more commonly related to less severely stenotic disease than at the sinus⁴⁴ or have been associated with stable, fibrous,⁴⁵ or nonruptured⁴⁴ plaques, thus casting doubt on a causal role for atheroma in these cases also. Some authors have suggested that thrombosis in arteries on the circle of Willis may complicate ulceration of fibrous plaques⁴⁵ or may even be a consequence of intramural hemorrhage,⁴⁰ while in others, in situ thrombus could be seen without either plaque rupture or intraplaque hemorrhage.⁴⁶ Finally, it should be emphasised that the posterior circulation may not necessarily conform to this pattern. In 1 thorough autopsy study of vertebrobasilar occlusions, a high proportion were associated with and presumed to be caused by tightly stenotic atherosclerotic plaques, although the nature of the underlying plaques was not detailed.⁴⁷ Differing frequencies of cardiac emboli, as well as discrepancies in the severity of atherosclerosis between anterior and posterior circulations, may underlie such observations.

We confirm that the majority of fatal occlusive intracranial ICA thrombi are likely embolic^{8 9 24 31 32 33 34} and emphasise that these emboli may arise not only in the heart and aorta but also in the ipsilateral carotid sinus^{6 34} or paradoxically, in the venous circulation. However, it should be emphasised that this selected autopsy series is unlikely to be representative of the entire spectrum of carotid disease and may underestimate other common sources of emboli, such as atrial fibrillation.

In a significant proportion of patients with intracranial carotid artery occlusion, careful clinical work-up may fail to identify a possible cause during life. This study illustrates how subsequent autopsy may reveal an unexpected predisposing factor or vasculopathy, for example, intracranial giant-cell arteritis.⁴⁸ Nevertheless, a relatively high proportion of intracranial occlusion cases remains in the "cause unknown" category even after autopsy, particularly in younger patients.^{9 48} Indeed, in the 3 comparatively young cases in this series (cases 12 through 14), the cause remained uncertain even after thorough postmortem examination.

In conclusion, our observations suggest that coronary-type plaque instability usually underlies fatal thrombotic carotid sinus occlusion. Future studies should focus on the relevance of nonocclusive plaque instability at the carotid sinus and its relation to stenosis and cerebral emboli, as well as to atherosclerosis elsewhere in the body, both stable and unstable. Detection of unstable carotid plaque by noninvasive radiographic means remains a research priority. We also suggest that fatal intracranial carotid artery occlusion rarely follows this coronary paradigm and that further pathology study is required to determine the nature and consequences of intracranial atheroma.

	Acknowledgments

 
G.A.L. is funded by the Medical Research Council. The authors are grateful to Angela Penman for typing the manuscript and Charles Warlow for constructive criticism.

Received February 23, 1999; revision received April 8, 1999; accepted April 23, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Constantinides P. Plaque fissures in human coronary thrombosis. J Atheroscler Res. 1966;6:1–17.

2. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death and crescendo angina. Br Heart J. 1985;53:363–373.[Free Full Text]

3. Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage and smooth muscle content. Br Heart J. 1993;69:377–381.[Abstract/Free Full Text]

4. Van der Wal AC, Becker AE, Van der Loos CM, Das PK. Site of initial rupture or erosion of thrombosed coronary atherosclerotic plaques is characterised by an inflammatory process irrespective of dominant plaque morphology. Circulation. 1994;89:36–44.[Abstract/Free Full Text]

5. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of acute coronary artery disease and acute coronary syndromes. N Engl J Med. 1992;326:242–250.[Medline] [Order article via Infotrieve]

6. Fisher CM. Occlusion of the internal carotid artery. AMA Arch Neurol Psychiatry. 1951;65:346–377.[Medline] [Order article via Infotrieve]

7. Fisher CM. Occlusion of the carotid arteries: further experiences. AMA Arch Neurol Psychiatry. 1954;72:187–204.[Medline] [Order article via Infotrieve]

8. Blackwood W, Hallpike JF, Kocen RS, Mair WGP. Atheromatous disease of the carotid arterial system and embolism from the heart in cerebral infarction: a morbid anatomical study. Brain. 1969;92:897–910.[Free Full Text]

9. Castaigne P, Lhermitte F, Gautier J-C, Escourolle R, Derouesne C. Internal carotid artery occlusion: a study of 61 instances in 50 patients with post mortem data. Brain. 1970;93:231–258.[Free Full Text]

10. Chuaqui R, Tapia J. Histologic assessment of the age of recent brain infarcts in man. J Neuropathol Exp Neurol. 1993;52:481–489.[Medline] [Order article via Infotrieve]

11. Kalimo H, Kaste M, Haltia M. Vascular diseases. In: Graham DI, Lantos PL, eds. Greenfield's Neuropathology. 6th ed. London, England: Arnold; 1997;1:316–317.

12. Bogousslavsky J, Van Melle G, Regli F, for the Lausanne Stoke Registry Group. The Lausanne Stroke Registry: analysis of 1000 consecutive patients with first stroke. Stroke. 1988;19:1083–1092.[Abstract/Free Full Text]

13. Lammie GA, Wardlaw JM, Dennis MS. Thrombo-embolic stroke, moya-moya phenomenon and primary oxalosis. Cerebrovasc Dis. 1998;8:45–50.[Medline] [Order article via Infotrieve]

14. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8:13–28.

15. Hennerici M, Hulsbomer HB, Hefter K, Lammerts D, Rautenberg W. Natural history of asymptomatic extracranial disease: results of a long term prospective study. Brain. 1987;110:771–791.

16. Ogata J, Masuda J, Yutani C, Yamaguchi T. Rupture of atheromatous plaque as a cause of thrombotic occlusion of stenotic internal carotid artery. Stroke. 1990;21:1740–1745.[Abstract/Free Full Text]

17. Feeley TM, Leen EJ, Colgan MP, Moore DJ, Hourihane DOB, Shanik GD. Histologic characteristics of carotid artery plaque. J Vasc Surg. 1991;13:719–724.[Medline] [Order article via Infotrieve]

18. Carr S, Farb A, Pearce WH, Virmani R, Yao JST. Atherosclerotic plaque rupture in symptomatic carotid artery stenosis. J Vasc Surg. 1996;23:755–766.[Medline] [Order article via Infotrieve]

19. Gronholdt M-LM. Ultrasound and lipoproteins as predictors of lipid-rich, rupture-prone plaques in the carotid artery. Arterioscler Thromb Vasc Biol. 1999;19:2–13.[Abstract/Free Full Text]

20. Torvik A, Svindland A, Lindboe CF. Pathogenesis of carotid thrombosis. Stroke. 1989;20:1477–1483.[Abstract/Free Full Text]

21. Ambrose JA, Tannenbaum MA, Alexopoulos D, Monsen CS, Weiss M, Borriw S, Gorlin R, Fuster V. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol. 1988;12:56–62.[Abstract]

22. European Carotid Surgery Trialists Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998;351:1379–1387.[Medline] [Order article via Infotrieve]

23. Bornstein NM, Norris JW. The unstable carotid plaque. Stroke. 1989;20:1104–1106.[Free Full Text]

24. Rodda RA. The arterial patterns associated with internal carotid disease and cerebral infarcts. Stroke. 1986;17:69–75.[Abstract/Free Full Text]

25. Samuel KC. Atherosclerosis and occlusion of the internal carotid artery. J Pathol Bacteriol. 1956;71:391–401.[Medline] [Order article via Infotrieve]

26. Schwartz CJ, Mitchell JRA. Atheroma of the carotid and vertebral arterial systems. BMJ. 1961;2:1057–1063.

27. Fisher CM, Gore I, Okabe N, White PD. Atherosclerosis of the carotid and vertebral arteries: extracranial and intracranial. J Neuropathol Exp Neurol. 1965;24:455–476.

28. Fisher CM, Gore I, Okabe N, White PD. Calcification of the carotid siphon. Circulation. 1965;32:538–547.[Free Full Text]

29. Choi SS, Crampton A. Atherosclerosis of arteries of neck: post mortem angiographic and pathologic study. Arch Pathol. 1961;72:379–385.[Medline] [Order article via Infotrieve]

30. Hultquist GT. Uber thrombose und embolie der arteria carotis und hierbei vorkommende Gehirnveranderungen. Stockholm, Sweden: Norstedt; 1942:1–399.

31. Torvik A, Jorgensen L. Thrombotic and embolic occlusions of the carotid arteries in autopsy material, 1: prevalence, location and associated disease. J Neurol Sci. 1964;1:24–39.

32. Wiener LM, Berry RG, Kundin J. Intracranial circulation in carotid occlusion. Arch Neurol. 1964;2:554–561.

33. Fieschi C, Bozzao L. Transient embolic occlusion of the middle cerebral and internal carotid arteries in cerebral apoplexy. J Neurol Neurosurg Psychiatry. 1969;32:236–240.[Free Full Text]

34. Levy R, Duyckaerts C, Hauw JJ. Massive infarcts involving the territory of the anterior choroidal artery and cardioembolism. Stroke. 1995;26:609–613.[Abstract/Free Full Text]

35. Caplan LR. Cerebrovascular disease: larger artery occlusive disease. In: Appel S, ed. Current Neurology. Chicago, Ill: Chicago Yearbook Medical: 1988;8:179–226.

36. Silverstein A, Hollin S. Occlusion of the supraclinoidal portion of the internal carotid artery. Neurology. 1963;13:679–685.

37. Gorelick PB, Caplan LR, Hier DB, Parker SL, Patel D. Racial differences in the distribution of anterior circulation occlusive disease. Neurology. 1984;34:54–59.[Abstract/Free Full Text]

38. Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: a review. Stroke. 1986;17:648–655.[Free Full Text]

39. Leung SY, Ng THK, Yuen ST, Lauder IJ, Ho FCS. Pattern of cerebral atherosclerosis in Hong Kong Chinese: severity in intracranial and extracranial vessels. Stroke. 1993;24:779–786.[Abstract/Free Full Text]

40. Craig D, Meguro K, Watridge C, Robertson JT, Barnett HJM, Fox AJ. Intracranial internal carotid artery stenosis. Stroke. 1982;13:825–828.[Abstract/Free Full Text]

41. Marzewski DJ, Furlan AJ, St Louis P, Little JR, Modic MT, Williams G. Intracranial internal carotid artery stenosis: long-term prognosis. Stroke. 1982;13:821–824.[Abstract/Free Full Text]

42. Wechsler LR, Kistler JP, Davis KR, Kaminski MJ. The prognosis of carotid siphon stenosis. Stroke. 1986;17:714–718.[Abstract/Free Full Text]

43. Lhermitte F, Gautier JC, Derouesne C. Nature of occlusions of the middle cerebral artery. Neurology. 1970;20:82–88.[Free Full Text]

44. Sadoshima S, Fukushima T, Tanaka K. Cerebral artery thrombosis and intramural hemorrhage. Stroke. 1979;10:411–414.[Abstract/Free Full Text]

45. Constantinides P. Pathogenesis of cerebral artery thrombosis in man. Arch Pathol. 1967;83:422–428.[Medline] [Order article via Infotrieve]

46. Ogata J, Masuda J, Yutani C, Yamaguchi T. Mechanisms of cerebral artery thrombosis: a histopathological analysis of eight necropsy cases. J Neurol Neurosurg Psychiatry. 1994;57:17–21.[Abstract/Free Full Text]

47. Castaigne P, Lhermitte F, Gautier JC, Escourolle R, Derouesne C, Der Agopian P, Popa C. Arterial occlusions in the vertebro-basilar system: a study of 44 patients with post-mortem data. Brain. 1973;96:133–154.[Free Full Text]

48. Adams JH, Graham DI. Twelve cases of fatal cerebral infarction due to arterial occlusion in the absence of atheromatous stenosis or embolism. J Neurol Neurosurg Psychiatry. 1967;30:479–488.[Free Full Text]

This article has been cited by other articles:

				J. N. Redgrave, P. Gallagher, J. K. Lovett, and P. M. Rothwell Critical Cap Thickness and Rupture in Symptomatic Carotid Plaques: The Oxford Plaque Study Stroke, June 1, 2008; 39(6): 1722 - 1729. [Abstract] [Full Text] [PDF]

				S. Kinlay, G. G. Schwartz, A. G. Olsson, N. Rifai, M. Szarek, D. D. Waters, P. Libby, P. Ganz, and for the Myocardial Ischemia Reduction with Aggress Inflammation, Statin Therapy, and Risk of Stroke After an Acute Coronary Syndrome in the MIRACL Study Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 142 - 147. [Abstract] [Full Text] [PDF]

				J.N.E. Redgrave, J.K. Lovett, P.J. Gallagher, and P.M. Rothwell Histological Assessment of 526 Symptomatic Carotid Plaques in Relation to the Nature and Timing of Ischemic Symptoms: The Oxford Plaque Study Circulation, May 16, 2006; 113(19): 2320 - 2328. [Abstract] [Full Text] [PDF]

				O Y Bang, P H Lee, S R Yoon, M A Lee, I S Joo, and K Huh Inflammatory markers, rather than conventional risk factors, are different between carotid and MCA atherosclerosis J. Neurol. Neurosurg. Psychiatry, August 1, 2005; 76(8): 1128 - 1134. [Abstract] [Full Text] [PDF]

				J.K. Lovett, J.N.E. Redgrave, and P.M. Rothwell A Critical Appraisal of the Performance, Reporting, and Interpretation of Studies Comparing Carotid Plaque Imaging With Histology Stroke, May 1, 2005; 36(5): 1085 - 1091. [Abstract] [Full Text] [PDF]

				J.K. Lovett, P.J. Gallagher, L.J. Hands, J. Walton, and P.M. Rothwell Histological Correlates of Carotid Plaque Surface Morphology on Lumen Contrast Imaging Circulation, October 12, 2004; 110(15): 2190 - 2197. [Abstract] [Full Text] [PDF]

				C Kremer, T Schaettin, D Georgiadis, and R W Baumgartner Prognosis of asymptomatic stenosis of the middle cerebral artery J. Neurol. Neurosurg. Psychiatry, September 1, 2004; 75(9): 1300 - 1303. [Abstract] [Full Text] [PDF]

				J. P.J. Halcox and J. E. Deanfield Beyond the Laboratory: Clinical Implications for Statin Pleiotropy Circulation, June 1, 2004; 109(21_suppl_1): II-42 - II-48. [Abstract] [Full Text] [PDF]

				J. F. Arenillas, J. Alvarez-Sabin, C. A. Molina, P. Chacon, J. Montaner, A. Rovira, B. Ibarra, and M. Quintana C-Reactive Protein Predicts Further Ischemic Events in First-Ever Transient Ischemic Attack or Stroke Patients With Intracranial Large-Artery Occlusive Disease Stroke, October 1, 2003; 34(10): 2463 - 2468. [Abstract] [Full Text] [PDF]

				T. Vainas, H. A.J.M. Kurvers, W. H. Mess, R. d. Graaf, R. Ezzahiri, J. H.M. Tordoir, G.-W. H. Schurink, C. A. Bruggeman, and P. J.E.H.M. Kitslaar Chlamydia pneumoniae Serology Is Associated With Thrombosis-Related but Not With Plaque-Related Microembolization During Carotid Endarterectomy Stroke, May 1, 2002; 33(5): 1249 - 1254. [Abstract] [Full Text] [PDF]

				D. Tanne, A. Shotan, U. Goldbourt, M. Haim, V. Boyko, Y. Adler, L. Mandelzweig, and S. Behar Severity of Angina Pectoris and Risk of Ischemic Stroke Stroke, January 1, 2002; 33(1): 245 - 250. [Abstract] [Full Text] [PDF]

				J. F. Arenillas, C. A. Molina, J. Montaner, S. Abilleira, M. A. Gonzalez-Sanchez;, and J. Alvarez-Sabin Progression and Clinical Recurrence of Symptomatic Middle Cerebral Artery Stenosis: A Long-Term Follow-Up Transcranial Doppler Ultrasound Study Stroke, December 1, 2001; 32(12): 2898 - 2904. [Abstract] [Full Text] [PDF]

				D. J. Fitzgerald Vascular biology of thrombosis: The role of platelet-vessel wall adhesion Neurology, September 1, 2001; 57(90002): S1 - 4. [Abstract] [Full Text]

				J. Bogousslavsky and J. R. Leclerc Platelet glycoprotein IIb/IIIa antagonists for acute ischemic stroke Neurology, September 1, 2001; 57(90002): S53 - 57. [Abstract] [Full Text]

				D. A. Bluemke, A. E. Stillman, K. G. Bis, T. M. Grist, R. A. Baum, R. D’Agostino, E. S. Malden, J. A. Pierro, and E. K. Yucel Carotid MR Angiography: Phase II Study of Safety and Efficacy for MS-325 Radiology, April 1, 2001; 219(1): 114 - 122. [Abstract] [Full Text]

				J. Plutzky and P. M. Ridker Statins for Stroke: The Second Story? Circulation, January 23, 2001; 103(3): 348 - 350. [Full Text] [PDF]

				P.M. Rothwell The Interrelation between carotid, femoral and coronary artery disease Eur. Heart J., January 1, 2001; 22(1): 11 - 14. [PDF]

				R. Cote, C. Wolfson, S. Solymoss, A. Mackey, J. R Leclerc, D. Simard, F. Rouah, F. Bourque, and B. Leger Hemostatic Markers in Patients at Risk of Cerebral Ischemia Stroke, August 1, 2000; 31(8): 1856 - 1862. [Abstract] [Full Text] [PDF]

				N. J. Thomas Reply to the Editor: J. Thorac. Cardiovasc. Surg., June 1, 2000; 119(6): 1296 - 1296. [Full Text]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lammie, G. A. Articles by Dennis, M. S. Search for Related Content PubMed PubMed Citation Articles by Lammie, G. A. Articles by Dennis, M. S. Related Collections Pathophysiology Embolic stroke Pathology of Stroke