Multiple Potential Risks for Stroke

Clinicians are always hoping to identify a single unifying diagnosis, but, in fact, many patients have more than one medical problem. Individuals seem to accumulate diseases (and different drug prescriptions) as they age. Physicians who care for elderly patients are well aware that multiple coexisting diagnoses are the rule rather than the exception.

Some risk factors predispose to multiple different pathogens and pathological processes and identifying them depends on the thoroughness and duration of the search. Genetic composition, lifestyle factors, and multiple exposures to potential pathogenetic elements over time help explain the coexistence of multiple different and often unrelated medical problems. Few problem-oriented lists in patients older than 70 years are short; probably none include single entries.

It should come as no surprise to physicians that patients with risk factors for atherosclerosis often have coronary artery disease, peripheral vascular occlusive disease, and strokes. The major risk factors that predispose to atherosclerosis (hypertension, cigarette smoking, diabetes, hyperlipidemia, sedentary lifestyle, obesity) promote plaque formation and occlusive disease in the coronary and limb arteries, aorta, and cervicocranial arteries. Hypertension also predisposes the penetrating arteries of the brain to develop degenerative changes, such as medial hypertrophy, fibrinoid degeneration, and luminal narrowing. Hypertension and atherosclerosis are true systemic diseases that affect arteries and arterioles throughout the body. Patients with risk factors for atherosclerosis, especially those with advanced age, would be expected to show multiple cardiac, aortic, extracranial, intracranial, and penetrating artery occlusive lesions that pose a risk for stroke.

In this issue of THE JOURNAL, Barnett and colleagues from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group¹ report on the nature of strokes that occurred during follow-up among patients with severe carotid artery occlusive disease. Among 2885 patients in NASCET, 749 patients had 1039 strokes during an average follow-up of 5 years. Many strokes were not explained by underlying carotid artery disease but instead were due to embolism of cardiac origin and penetrating artery disease.¹ The proportion of cardioembolic strokes in the territory of symptomatic carotid arteries was 12.0% in patients with 60% to 69% carotid artery stenosis and 6.9% in those with 70% to 99% stenosis. When strokes that developed on the side of the brain in the supply area of arteries that were severely stenosed but asymptomatic at study entry were studied, fully 40% were not attributable to the carotid artery stenosis.² In NASCET, patients with known cardiac sources of embolism at the time of randomization were excluded, nearly half the patients with strokes did not have echocardiograms, and relatively few patients had transesophageal echocardiograms (TEEs). Aortic atheromatosis, now known to be an important cause of strokes, as well as many potential cardiac sources undoubtedly were not sought or detected in NASCET because of the infrequency of TEEs. In a previous report from NASCET, about one third of patients with severe extracranial carotid artery disease also had intracranial occlusive disease.³

Studies from the Lausanne Stroke Registry, a large prospective database of first strokes, also show a high frequency of multiple potential coexisting causes of stroke. Moncayo and colleagues⁴ recently reported that among more than 3500 patients with first ischemic strokes entered into the Lausanne Stroke Registry, evaluation showed that at least 2 potential causes of brain infarction were present in 250 patients (7%). This is probably a minimum figure, considering that half of the patients did not have echocardiograms. In a prior study from the Lausanne Stroke Registry, among 159 patients with atrial fibrillation without valvular heart disease who had carotid artery territory strokes, 22 (14%) had a cardiac source of embolism other than atrial fibrillation, and 107 (67%) had an abnormal internal carotid artery ipsilateral to the stroke (>50% stenosis in 11%) as determined by ultrasonography.⁵ The multiple potential etiologies were clinically important since a follow-up study of patients with first stroke in the Lausanne Stroke Registry showed that 46 (38%) of 121 recurrent strokes had a different etiology than the initial index stroke.⁶ Wilson and Jamieson⁷ reviewed their experience with patients who had high-grade internal carotid artery stenosis or occlusion and also had cardiac and aortic evaluation. Potential cardiac or aortic sources of emboli were present in 54% of patients; aortic arch plaques greater than 4 mm in diameter were found in 26% of patients with severe internal carotid artery occlusive disease.

Data from the Harvard Stroke Registry, the Stroke Data Bank, and the New England Medical Center Registries indicate that multiple potential stroke etiologies are even more frequent than reported in NASCET and the Lausanne Stroke Registry.^{8 - 10} Among 407 patients in the New England Medical Center Posterior Circulation Registry, 82 (20%) had 2, and 8 (2%) had 3 potential etiological explanations for posterior circulation ischemia. Analyses have shown that coronary artery disease with myocardial infarction, peripheral limb artery occlusive disease, and extracranial vascular occlusive disease often coexist.^{11 - 12} During follow-up of patients who present with brain ischemia, mortality is more often due to myocardial infarction than subsequent stroke.⁸ Echocardiographic and extracranial ultrasonographic evaluations of patients with coronary artery disease reveal a high frequency of coexisting atherosclerotic lesions within the aorta and the carotid arteries. Strokes, encephalopathy, and cognitive and behavioral abnormalities following coronary artery bypass graft (CABG) surgery are most often related to cardiac abnormalities and aortic atheromatosis.^{13 - 14}

The frequent coexistence of more than 1, and sometimes multiple, potential risk conditions for stroke and coronary artery disease is an important fact. Unfortunately, there is no single way to prevent all causes of brain ischemia. Studies that combine patients with brain ischemia by tempo and severity (eg, transient ischemic attacks and minor strokes) alone rather than by etiology and stroke mechanism show that the most promising single agents for stroke prevention are only about 25% to 30% effective.¹⁵ The reason for this ineffectiveness is directly related to the diverse causes of brain ischemia. Penetrating artery disease, cardiogenic embolism, intra-arterial embolism arising from extracranial plaques, emboli arising from protruding aortic atheroma, and hypoperfusion related to stenosis of an intracranial artery are all quite different pathophysiologic entities. Even within embolism of cardiac origin, the material that embolizes varies greatly and includes calcium from heart valves, myxomatous material, bacteria, fibrous strands, white platelet-fibrin thrombi, and red thrombi. Effective medical prophylaxis of patients with cerebral embolism of cardiac origin depends on the biologic material that embolizes, not the source from which the emboli originate.^{16 - 18}

How should this knowledge of the frequent coexistence of multiple potential etiologies of stroke affect the evaluation and treatment of individual patients? First, all patients who have myocardial, limb, or brain ischemia or who have evidence of atherosclerosis based on imaging studies deserve assessment of potential risk factors, such as hypertension, diabetes, smoking, and lifestyle factors, and modification of these risks when possible. Second, patients with atherosclerosis who have had brain or myocardial ischemia should have an evaluation of their coronary arteries, aorta, and extracranial and intracranial arteries. This assessment can be performed quite safely using modern cardiac, ultrasonographic, and magnetic resonance imaging capabilities. Images of the aorta can now be obtained using extracranial ultrasonographic probes.^{19 - 20} Therapeutic strategies should then be instituted for each of the potential risks identified, when clinically feasible. Clinicians should carefully weigh the risk-benefit ratio of each strategy. Some treatments, such as drugs that modify platelet function and anticoagulation therapy, might be effective against more than 1 of the lesions found, whereas other treatments, such as carotid endarterectomy and intracranial and extracranial angioplasty, are effective only for the occlusive lesions treated. Some treatments that might benefit 1 lesion (eg, CABG) might pose a risk for patients with severe extracranial and intracranial occlusive disease. Third, patients should have a TEE with evaluation of the heart and the aorta before undergoing CABG surgery.

In patients with stroke, atherosclerosis remains the most common underlying disorder. Physicians need to consider the entire patient after thorough evaluation before deciding on the optimum treatment strategies to prevent initial or recurrent stroke.