Silent MRI infarcts and the risk of future stroke
The cardiovascular health study
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Abstract
Background: Silent infarcts are commonly discovered on cranial MRI in the elderly. Objective: To examine the association between risk of stroke and presence of silent infarcts, alone and in combination with other stroke risk factors. Methods: Participants (3,324) in the Cardiovascular Health Study (CHS) without a history of stroke underwent cranial MRI scans between 1992 and 1994. Silent infarcts were defined as focal lesions greater than 3 mm that were hyperintense on T2 images and, if subcortical, hypointense on T1 images. Incident strokes were identified and classified over an average follow-up of 4 years. The authors evaluated the risk of subsequent symptomatic stroke and how it was modified by other potential stroke risk factors among those with silent infarcts. Results: Approximately 28% of CHS participants had evidence of silent infarcts (n = 923). The incidence of stroke was 18.7 per 1,000 person-years in those with silent infarcts (n = 67) compared with 9.5 per 1,000 person-years in the absence of silent infarcts. The adjusted relative risk of incident stroke increased with multiple (more than one) silent infarcts (hazard ratio 1.9 [1.2 to 2.8]). Higher values of diastolic and systolic blood pressure, common and internal carotid wall thickness, and the presence of atrial fibrillation were associated with an increased risk of strokes in those with silent infarcts (n = 53 strokes). Conclusion: The presence of silent cerebral infarcts on MRI is an independent predictor of the risk of symptomatic stroke over a 4-year follow- up in older individuals without a clinical history of stroke.
Silent infarct is a term commonly used to describe lesions that share neuroimaging characteristics with cerebral infarctions but without any recognized clinical symptoms. Silent infarcts are frequent in neuroimages of the elderly, occurring in 10 to 38% of cases.1-4⇓⇓⇓ The clinical importance of these lesions is unclear. Previous studies suggest that silent infarcts are associated with measurable neurologic dysfunction3,5⇓ and have many of the same risk factors as clinically evident stroke.3,6,7⇓⇓
Because silent infarcts are often incidental findings on cranial imaging performed for other reasons, the practical question for clinicians is whether they portend a high possibility for future clinical stroke. Clinicopathologic studies have revealed subcortical infarcts with the same pathology as symptomatic infarcts yet without any apparent clinical correlate.8 If the etiology of silent and symptomatic infarcts were the same, then one would expect the rate and risk factors for recurrent stroke to be similar for both. Indeed, at least one report indicates that silent infarcts are a risk factor for future stroke.9
The Cardiovascular Health Study (CHS) is a prospective, multicenter study of older adults followed for the development of stroke and cardiovascular disease. As part of the study, 3,660 participants underwent MRI scan of the brain. We analyzed the results of these imaging studies to determine the following: 1) Are silent infarcts an independent risk factor for subsequent symptomatic stroke in the elderly? 2) If so, among those with silent infarcts, are there certain factors that identify subgroups at particularly high risk for incident stroke? and 3) How does the presence of a silent infarct affect the risk of stroke in those with other traditional stroke risk factors?
Methods.
CHS cohort, evaluations, and definitions.
CHS participants were recruited from a random sample of the Health Care Financing Administration Medicare eligibility lists in four US communities: Forsyth County, NC; Sacramento County, CA; Washington County, MD; and Allegheny County (Pittsburgh), PA. Eligible and consenting participants underwent an extensive baseline evaluation including standard questionnaires, physical examination, and laboratory testing. Parts of the baseline evaluation have been repeated at various times since the initial examinations were conducted. Further details of study design, definitions, and methods were published elsewhere.10
Cranial MRI scans were performed between June 1992 and June 1994. Participants without contraindications and who consented underwent imaging using a standard protocol.11,12⇓
Imaging data were sent to a single reading center for interpretation by neuroradiologists trained in CHS protocol and without knowledge of the subjects’ demographic or clinical profile.
In this study, a cerebral infarct by MRI was defined as an area of abnormal signal in a vascular distribution that lacked mass effect.3,4⇓ Infarcts of the cortical gray and deep nuclear regions had to be brighter on spin density and T2-weighted images than normal gray matter. The requirement for hyperintensity on spin density–weighted images was intended to distinguish small deep nuclear region infarcts from dilated perivascular spaces. Infarcts in the white matter were similarly defined, except that they had to be hypointense on T1-weighted images to distinguish them from diffuse white matter disease. A MRI infarct was considered a silent infarct if there was no self-report of TIA or stroke at baseline and no incident TIA or stroke before the MRI that was performed as part of the study. Only infarcts 3 mm or greater were identified and classified according to size (maximum of the anterior-posterior, right to left, and rostral-caudal dimensions), number (one, more than one), and location (cortical, subcortical). An infarct that involved the cortex, even if it spanned subcortical regions as well, was termed cortical. If the infarct had no cortical locations, it was considered subcortical. The category of cortical + subcortical refers to multiple infarcts, at least one of which was cortical and one subcortical. Reproducibility studies have documented good agreement both within and between readers for lesions 3 mm or greater, but less so for lesions less than 3 mm.11 In this article, a silent MRI lacunar infarct was defined as exclusively subcortical and less than 20 mm in each of the measured dimensions.
Possible symptomatic cerebrovascular events after the study MRI scan were identified during follow-up yearly examinations and at interim 6-month phone contacts.
In addition, hospital records from all nonstroke hospitalizations were reviewed for ICD codes 430 through 438 identifying cerebrovascular disease. Detailed information was collected for all potential events as described previously.13 This information was presented to a stroke adjudication committee made up of neurologists from each site along with a neuroradiologist and a clinician from the Coordinating Center. The adjudication committee determined whether a TIA or stroke had occurred and classified a stroke type as ischemic, hemorrhagic, or uncertain. Using prespecified definitions, the committee further divided ischemic stroke into four subtypes: cardioembolic, atherosclerotic, lacunar, and other uncertain subtype.13 In brief, cardioembolic required a potential source of cardiac emboli to be identified; atherosclerotic, greater than 70% stenosis of the relevant carotid artery; and lacunar, a clinical presentation and imaging consistent with a lacunar syndrome. The term stroke is subsequently used in this report to denote an adjudicated cerebral infarct, intracerebral hemorrhage, or subarachnoid hemorrhage. Only the first (incident) stroke for each participant during the study period was included in the analysis.
Statistical methods.
Analysis was conducted using SPSS 10.0 for Windows. Clinical data were obtained from information available at the clinic visit closest in time to the MRI. The median length of follow-up was 4.2 years from the time of the MRI scan.
The first question was approached by analyzing whether, after controlling for known risk factors for stroke, the presence of silent infarcts was significantly associated with risk of future stroke. After controlling for age, sex, and selected stroke risk factors, separate Cox proportional hazard functions were run to examine the additional influence on incident stroke risk of the presence of silent infarcts, their location, and the number of silent infarcts. For these models, selection of the optimal set of stroke risk factors was made by employing forward and backward stepwise proportional hazard functions (using liberal criteria of 0.10 to enter and 0.15 to remove) with 20 stroke risk factors previously identified in the CHS cohort.14 These risk factors were selected because they were significantly associated with the risk of stroke in bivariate and multivariate analyses and included self-report of hypertension, systolic blood pressure, diastolic blood pressure, use of hypertensive medicine, use of any diuretics, self-reported aspirin use in past 2 weeks, American Diabetes Association diabetic status, high-density lipoprotein cholesterol, fasting glucose, fasting insulin, creatinine, factor VII, atrial fibrillation on EKG, left ventricular hypertrophy on EKG, EKG left ventricular mass, common carotid artery wall thickness, internal carotid artery wall thickness, maximum internal carotid stenosis, and history of myocardial infarction or congestive heart failure before the MRI scan.
For the second question, among the group of participants who had a silent infarct, the significance of risk of stroke from each of a variety of potential risk factors was evaluated using Cox proportional hazard functions. Each of these Cox models contained only a single potential risk factor. To further explore associations between stroke risk and the significant risk factors, stroke rates (per 1,000 person-years) were calculated by quartile for each risk factor.
For the third question, stroke rates were calculated for combinations of each of five traditional cerebrovascular or cardiovascular risk factors. For each risk factor, Cox proportional hazard functions were used to obtain confidence levels of hazard ratios for incident strokes in the presence of silent infarcts; the risk factor and the joint combination of the two; unadjusted and adjusted for age at MRI, sex, race, smoking status; coronary heart disease status at MRI; and the other traditional risk factors. Finally, the significance of interactions was examined directly by separate Cox models for stroke risk, which included the main effects of silent infarcts and each risk factor plus their interaction, unadjusted and adjusted as noted.
Results.
Of the CHS cohort of 5,888, a total of 3,660 participants underwent cranial MRI imaging. As a group, those who were scanned were significantly younger, more educated, more likely never to have smoked, and healthier than those who were not scanned, as detailed previously.4,5⇓ For the current analyses, 284 subjects (7.8%) were excluded based on adjudicated stroke or TIA before the MRI. An additional 52 (1.4%) were excluded due to a self-report at baseline (but not thereafter) of prior stroke or TIA, leaving a total of 3,324 participants, 923 (28%) of whom had silent infarcts on MRI.
There were 159 total clinical strokes (table 1), 67 occurring among the 923 participants with a silent infarct on MRI (7.3%) and 92 occurring in the 2,401 participants without silent infarcts (3.8%). The incidence of stroke was much higher in participants with than without silent infarcts (18.7 vs 9.5/1,000 person-years), hazard ratio 1.5 (1.1 to 2.1).
Distribution of characteristics of silent infarcts, rates of incident strokes per 1,000 person-years, and hazard ratios for incident strokes post-MRI as a function of infarct characteristics
After controlling for age and sex, eight of 20 factors were selected as being independently associated with the risk of incident stroke post-MRI: systolic blood pressure, diastolic blood pressure, fasting insulin, presence of atrial fibrillation on EKG, left ventricular hypertrophy on EKG, common carotid artery wall thickness, internal carotid artery wall thickness, and history of myocardial infarction before the MRI scan. Controlling for age, sex, and these eight selected risk factors, separate Cox proportional hazard functions were run to examine the additional influence of the presence, location, and number of silent infarcts on the risk of incident stroke post-MRI. A significant excess risk of stroke was associated with the presence of silent infarcts. In addition, the location and number of infarcts were each independently associated with incident stroke risk. Having multiple silent infarcts appeared to almost double the risk of subsequent stroke compared with those without silent infarcts. In a stepwise model, once number of silent infarcts entered (controlling for other factors), the location did not approach significance.
The group of 67 participants with silent infarcts and a subsequent stroke had significantly higher systolic and diastolic blood pressures, greater internal and common carotid wall thicknesses, and higher prevalence of EKG atrial fibrillation than participants with silent infarcts but no incident stroke or those without a silent infarct (table 2). Table 3 displays the stroke rates seen with increasing quartile of each of these five risk factors in the presence or absence of silent infarcts. Participants with silent infarcts in the highest quartile of each risk factor or with atrial fibrillation had the greatest elevation in stroke rate.
Descriptive statistics and associations between incident strokes and potential risk factors among those with (n = 923) and without (n = 2,401) silent infarcts
Number of incident strokes and incident stroke rates per 1,000 person-years as a function of selected* risk factors and presence of silent infarcts
The results of how several recognized cardiovascular and cerebrovascular risk factors are associated with rate of stroke in participants with and without silent infarcts can be found on the Neurology Web site (go to www.neurology.org and scroll down the Table of Contents to find the title link for this article). Participants with a self-reported history of hypertension and silent infarct had a higher risk of stroke compared with participants with neither hypertension or subclinical infarction (21.9 vs 8.6/1,000 person-years), hazard ratio 2.2 (1.4 to 3.3). A history of diabetes was also associated with an increased risk of stroke in combination with subclinical infarction, hazard ratio 2.5 (1.3 to 4.5). Participants with either a history of myocardial infarction or congestive heart failure before the MRI had an increased risk of stroke independent of the presence or absence of silent infarcts. The risk of stroke was increased among participants with atrial fibrillation and silent infarcts (hazard ratio, 6.9 [2.8 to 17.5]). Five of the 22 participants with both atrial fibrillation and silent infarcts went on to sustain an incident stroke for a rate of 68 per 1,000 person-years. Among the 64 participants with atrial fibrillation and no silent infarcts, there were seven strokes for a rate of 30.1 per 1,000 person years. No interaction between the five risk factors and silent infarcts was found to be significant in the Cox models.
Given the relatively high rate of stroke in participants with silent infarct and atrial fibrillation, we examined the type of subsequent stroke that occurred in participants that had silent infarcts (table 4). Five of 10 participants with a cortical silent infarct sustained an incident cardioembolic stroke. Even in participants with only silent subcortical infarcts, one fourth subsequently had a cardioembolic stroke.
Distribution of incident stroke types as a function of presence of silent infarcts
Discussion.
In the CHS, a community-based elderly cohort, the presence of silent MRI infarcts was an independent risk factor for future stroke. Of the 3,324 participants without history of stroke who underwent MRI scanning in the early years of the study, 28% had one or more silent infarcts. Participants with silent infarcts were twice as likely as those without to experience a subsequent symptomatic stroke.
Fisher,8 in his clinicopathologic studies of lacunes, proposed that subcortical infarcts not associated with obvious symptoms were silent simply because they occurred in clinically ineloquent regions of the brain. If it is assumed that silent and symptomatic infarcts have a common pathogenesis, then the rate of clinically evident strokes in those with silent infarcts should approximate previously reported stroke recurrence rates. In fact, one might expect an even higher chance of incident stroke in those with silent infarcts because they may not receive the type of medical intervention for secondary prevention given individuals who present with stroke.
Reported recurrence rates for cerebral infarcts are quite variable in the literature, perhaps influenced by the cohort studied, types of stroke considered, and means of ascertainment. For example, some studies describe stroke recurrence rates as high as 25 to 37% at 5 years.15-17⇓⇓ However, lower rates of recurrence have been seen, particularly if one considers subcortical infarcts or minor strokes.18,19⇓ A recent study of minor stroke, defined as having minor or no disability within 30 days of stroke onset, found an average annual recurrence rate of 1.5%.20 A population based series in Malmö, Sweden, reported a rate of 2.0%.21 Although not exactly comparable with stroke recurrence rates, in the CHS, 7.3% of participants with silent infarcts had a symptomatic stroke during the 4 years of follow-up, which averages out to approximately 1.8% per year. This rate is similar to the only other prospective study of stroke occurrence in those with silent infarcts in which the annual incident stroke rate was 2.8%.9
Cerebral infarct subtype may be anticipated to have an association with chance of recurrence. Cortical infarcts, presumably more often caused by a cardioembolic mechanism or large-vessel atherosclerotic disease, might be expected to have a higher rate of future stroke.22 Although the numbers of silent infarcts solely involving the cortex in the CHS was small, there did not appear to be any difference in risk of incident stroke compared with subcortical lesions. Rather, the only infarct characteristic that was associated with an increased risk of subsequent stroke was the number of silent infarcts present, regardless of location.
Among the CHS cohort with silent infarcts, we examined whether there may be other factors that are associated with increased risk of subsequent stroke. Although not having a statistical interaction with silent infarcts, the small group of participants with atrial fibrillation and silent infarcts had a particularly high rate of stroke. Moreover, half of the incident ischemic strokes in participants with silent cortical infarcts were classified as cardioembolic. In a earlier small series of patients with atrial fibrillation, the presence of silent infarcts was a predictor of incident symptomatic stroke.23 Considering individuals with other traditional stroke risk factors such as history of hypertension or diabetes, the presence of silent infarcts did not raise the relative risk of stroke any more than the additive relative risk of each individual factor. However, the combination of hypertension or diabetes with silent infarcts resulted in a risk of clinical stroke ranging between 2% and 3% per year.
While drawing strength from having standardized cranial MRI and longitudinal clinical data on more than 3,300 community-dwelling elderly participants, some limitations of this study need to be mentioned. Inherent in this and similar studies is the lack of direct pathologic confirmation that the lesions on MRI scans that we designated as cerebral infarcts are indeed those and not some other pathologic process. Moreover, the decision whether a participant had a silent infarct depended on the participants self-report of an event or one documented in the medical records. Previous studies suggest that self-report may underestimate the number of people who may have had a TIA or stroke.24 The CHS cohort may not be representative of the general population older than 65 years of age, those who participated being generally healthier than those who did not. In addition, the CHS participants completing the MRI examination were on average younger, more educated, and healthier than those who did not. Finally, given the large number of risk factors examined and the relatively small number of strokes that occurred in various subgroups, associations (or lack thereof) between particular risk factors, silent infarcts and future stroke must be interpreted cautiously because we cannot be sure some of the findings simply represent noise in the data set.
The results of our exploratory analysis suggest that silent infarcts in the elderly may confer a higher risk of subsequent stroke. If this finding can be substantiated in future work, then the discovery of a silent infarct should engender the same type of careful evaluation and treatment considerations applied to individuals with symptomatic infarcts. Further investigation is needed to determine whether more aggressive treatment of stroke risk factors such as hypertension, diabetes, and atrial fibrillation in those with silent infarcts can actually decrease the occurrence of future stroke. Similarly, the value of performing cranial MRI scanning on elderly patients with atrial fibrillation to screen for silent infarcts remains unanswered by this study.
Appendix
Participating Institutions and Principal Staff: Forsyth County, NC, Wake Forest University School of Medicine: Gregory Burke, Sharon Jackson, Alan Elster, Curt Furberg, Gerardo Heiss, Dalane Kitzman, Margie Lamb, David Lefkowitz, Mary Lyles, Cathy Nunn, Ward Riley, John Chen, Beverly Tucker; Forsyth County, NC, Wake Forest University School of Medicine ECG Reading Center: Farida Rautaharju, Pentti Rautaharju; Sacramento County, CA, University of California, Davis: William Bonekat, Charles Bernick, Michael Buonocore, Mary Haan, Calvin Hirsh, Lawrence Laslett, Marshall Lee, John Robbins, William Seavey, Sharene Theroux, Richard White; Washington County, MD, The Johns Hopkins University: M. Jan Busby-Whitehead, Joyce Chabot, George Comstock, Adrian Dobs, Linds Fried, Joel Hill, Steven Kittner, Shiriki Kumanyika, David Levine, Joao Lima, Neil Powe, Thomas Price, Jeff Williamson, Moyses Szklo, Melvyn Tockman; Washington County, MD, The Johns Hopkins University MRI Reading Center: Norman Beauchamp, R. Nick Bryan, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Naiyer Iman, Michael Kraut, Cynthia Quinn, Grace Lee, Carolyn Meltzer, Larry Schertz, Earl Steinberg, Scott Wells, Linda Wilkins, Nancy Yue; Allegheny County, PA, University of Pittsburgh: Steven Goldstein, Diane Ives, Charles Jungreis, Lewis Kuller, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne Smith, Sidney Wolfson; Echocardiography Reading Center (Baseline)–University of California, Irvine: John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, Retha Webb; Ultrasound Reading Center, New England Medical Center, Boston: Daniel O’Leary, Joseph Polak, Laurie Funk; Central Blood Analysis Laboratory, University of Vermont: Elaine Cornell, Mary Cushman, Russell Tracy; Pulmonary Reading Center, University of Arizona: Paul Enright; Coordinating Center, University of Washington, Seattle: Alice Arnold, Annette Fitzpatrick, Richard Kronmal, Bruce Psaty, David Siscovick, Will Lonstreth, Patricia Wahl, David Yanez, Paula Diehr, Corinne Dulberg, Bonnie Lind, Thomas Lumley, Ellen O’Meara, Jennifer Nelson, Charles Spiekerman; NHLBI Project Office: Diane Bild, Teri Manolio, Peter Savage, Patricia Smith.
Acknowledgments
Supported by contracts N01-HC-85079–NO1-HC-85086, N01-HC35129, and N01-HC15103 from the National Heart, Lung, and Blood Institute.
Footnotes
-
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the October 9 issue to find the title link for this article.
*See the Appendix on page 1228 for a list of the members of the Cardiovascular Health Study Collaborative Research Group.
- Received February 22, 2001.
- Accepted June 12, 2001.
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