There is growing concern regarding the prevalence and

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1 Stroke Symptoms in Individuals Reporting No Prior Stroke or Transient Ischemic Attack Are Associated With a Decrease in Indices of Mental and Physical Functioning George Howard, DrPH; Monika M. Safford, MD; James F. Meschia, MD; Claudia S. Moy, PhD; Virginia J. Howard, MSPH; LeaVonne Pulley, PhD; Camilo R. Gomez, MD; Martha Crowther, PhD Background and Purpose Stroke symptoms in the absence of recognized stroke are common, but potential associated dysfunctions have not been described. Methods We assessed quality-of-life measures using the Physical and Mental Component Summary scores of the Short Form 12 (PCS-12 and MCS-12) in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Differences in mean PCS-12 and MCS-12 scores were assessed among participant groups symptoms-free (n ); history of stroke symptoms but free of stroke/transient ischemic attack (n 3404); history of stroke (n 1491); and history of transient ischemic attack (n 818). Results Participants with symptoms (but no diagnosis) had average PCS-12 scores 5.5 (95% CI: 5.2 to 5.9) points lower than those without symptoms, a difference similar to transient ischemic attack (6.0; 95% CI: 5.3 to 6.7) and over one half the effect of stroke (8.4; 95% CI: 8.0 to 9.0). MCS-12 scores were 2.7 (95% CI: 2.4 to 3.0) points lower for those with symptoms, 0.5 for transient ischemic attack (95% CI: 0.0 to 1.1), and 1.6 for stroke (95% CI: 1.2 to 2.0). Differences in demographic and vascular risk factors, health behaviors, physiological measures, and indices of socioeconomic status did not fully explain these differences. Those reporting history of weakness or numbness had larger current decrements in physical functioning, and those reporting history of inability to express themselves or understand language had larger current decrements in mental functioning. Conclusions Individuals with clinically consistent symptoms but no stroke diagnosis have a lower quality of life than those without symptoms. The difference in physical functioning is substantial with a smaller decline in mental functioning. Apart from so-called silent stroke, there appear to be many individuals with possibly symptomatic cerebrovascular disease either stroke or transient ischemic attack who are not being diagnosed. Furthermore, these symptomatic but undiagnosed strokes may not be benign. (Stroke. 2007;38: ) Key Words: cerebrovascular disorders cohort studies health-related quality of life There is growing concern regarding the prevalence and implications of silent cerebral infarction in the general population. So-called silent infarctions are those that are found on brain imaging in individuals who have not had a clinically apparent stroke. The prevalence of these silent infarctions increases from approximately 11% between ages 55 and 65 years 1 to nearly 50% in individuals over age 85 years. 2 Although it is estimated that there are 4 million prevalent clinically diagnosed strokes, it has been estimated that there are as many as 10 million prevalent silent strokes in the United States. 3 Just as silent myocardial infarctions are associated with subsequent risk of a clinically pronounced myocardial infarction, 4 these silent cerebral infarctions also appear to be associated with substantial increased risk of cognitive decline 5,6 and subsequent clinically pronounced stroke. 7 9 In addition, there is a rich literature documenting the association of subcortical ischemic vascular dementia and organic neuropsychiatric symptoms Although not clinically recognized, some silent strokes may nevertheless be associated with changes in a person s health state. Even relatively mild declines that do not rise to the level of clinical detection could nonetheless result in Received November 20, 2006; final revision received January 2, 2007; accepted January 8, From the Department of Biostatistics (G.H.), School of Public Health, University of Alabama at Birmingham, Birmingham, Ala; the Deep South Center on Effectiveness at the Birmingham VA Medical Center and the Division of Preventive Medicine (M.M.S.), University of Alabama at Birmingham, Birmingham, Ala; the Mayo Clinic (J.F.M.), Jacksonville, Fla; the National Institute of Neurological Disorders and Stroke, National Institutes of Health (C.S.M.), Bethesda, Md; the Department of Epidemiology (V.J.H., L.P.), School of Public Health, University of Alabama at Birmingham, Birmingham, Ala; the Department of Health Behavior (L.P.), University of Arkansas Health Science University, Little Rock, Ark; the Alabama Neurological Institute (C.R.G.), Birmingham, Ala; and the Department of Health Behavior (M.C.), School of Public Health, University of Alabama at Birmingham, Birmingham, Ala. Correspondence to George Howard, DrPH, Professor and Chair, Department of Biostatistics, School of Public Health, 1665 University Blvd, University of Alabama at Birmingham, Birmingham, AL ghoward@uab.edu 2007 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Howard et al Quality of Life in Those With Only Stroke Symptoms 2447 clinically important deficits in mental and physical functioning. As such, some silent strokes may in fact be whispering stroke, that is, they could have clinically consistent symptoms that fail to result in a diagnosis of stroke or transient ischemic attack (TIA) either through the symptoms being insufficiently pronounced or persistent to raise concerns in the participant; or if clinical care was sought, the symptoms were not sufficiently defined to result in a diagnosis of stroke. Nevertheless, these symptoms could still be associated with potential subclinical deficits detected by systematic testing, and these subclinical deficits could be associated with a substantial population-level public health burden. Rose observed that modest changes in a large proportion of the population can have a larger impact on the public health than dramatic changes in a smaller high-risk populations. 13 A large proportion of the general population undergoing these subclinical deficits that could be caused by whispering strokes may pose a significant public health burden through a shift of a substantial proportion of the population to lower levels of health status. That is, although we do not know whether the study participants with these symptoms failed to seek care for the symptoms, or if they did seek care, the clinician did not make a clinical diagnosis of stroke, these symptoms could be associated with a shift in the functioning for a large proportion of the population that would be associated with a substantial public health burden. REasons for Geographic And Racial Differences in Stroke (REGARDS) is a large national cohort of black and white individuals over age 45 years. We have previously reported that 7% of this population reported a clinical history of stroke or TIA, and another 18% reported a history of major stroke signs and symptoms without a doctor having told them they have had a stroke. 14 The Framingham Stroke Risk Function, 15 a summary index of stroke risk factor levels, was a major predictor of the presence of such symptoms. 14 The group of individuals with stroke symptoms but no diagnosis of stroke had odds of cognitive impairment approximately one third higher than those without either symptoms or a stroke diagnosis. 16 Although cognitive impairment is an important reflection of debility, 17 little is known about other dimensions of health in such individuals, including the impact of physical and mental health functioning on their quality of life, making it difficult to assess the potential public health burden. This report continues the investigation of the potential public health impact of undiagnosed strokes among those reporting only symptoms (but not clinical stroke itself). We assessed average physical and mental functioning among these participants and compared them with participants who reported no symptoms of TIA or stroke; those reporting a history of TIA only; and those reporting a history of stroke. Methods Analysis was based on data from the REGARDS study, a national longitudinal cohort study of black and white individuals over age 45 years. Recruitment began in January 2003 and is ongoing. Twenty percent of the sample was selected from the buckle of the Stroke Belt (coastal plain region of NC, SC, and Ga), 30% from the Stroke Belt states (remainder of NC, SC, and Ga plus Ala, Miss, Tenn, Ark, and La), and the remaining 50% from the other 48 contiguous United States. Within each region, individuals were recruited from commercially available lists of residents using a combination of mail and telephone contact. For those agreeing to participate, demographic information, medical history, including prior diagnosis of high blood pressure, family history, and indices of cognitive function and quality of life were obtained by computer-assisted telephone interview. After the computer-assisted telephone interview, physical measures were collected at an in-home examination, including blood pressure, blood and urine samples, electrocardiogram, and an inventory of current medications. This report uses participants with both the computerassisted telephone interview and in-home visit data. Informed consent was obtained from all participants. Defined according to standards proposed by Morton et al, 18 the cooperation (participation) rate (percent agreeing to be interviewed among known eligible candidates contacted) was over 60%. 14 Study methods were reviewed and approved by the Institutional Review Boards at the collaborating institutions. Additional methodological details are provided elsewhere. 19 The outcome variables for this report were the Physical Component Summary score of the Short Form 12 (PCS-12) score, reflecting physical functioning, and the Mental Component Summary score of the Short Form 12 (MCS-12) score, reflecting mental functioning. 20 These well-validated and widely used indices have scores of 0 to 100 with 100 representing perfect health. These scores have been standardized so that the mean score of the general population is 50 points with a standard deviation of 10 points. Relatively small differences in these scores are associated with substantial health impacts. For example, type 2 diabetes is associated with a 5-point decrement in PCS scores, and those with a 5-point decrement are associated with a one third increase in the probability of being hospitalized within the subsequent 6 months. 21 The text for the SF-12 questions are provided in Table 1; the PCS-12 and MCS-12 scores were developed with differential weighting of these questions contributing to each scale. The primary independent variable, positive stroke signs and symptoms, was assessed using the Questionnaire for Verifying Stroke-Free Status (QVSS) Although neurological symptoms may arise from conditions other than stroke, the QVSS is a 6-item validated questionnaire proposed to identify patients with stroke in the general population and has been shown to have high sensitivity (0.97) but modest specificity (0.60). 25 Analyses were performed relating the PCS-12 and MCS-12 scores to symptoms reported on one or more of the QVSS items and also to each of the 6 individual QVSS questions. The text for the QVSS is provided in Table 1. Variables that could potentially confound the relationship between stroke signs and symptoms and the measures of physical and mental health functioning were categorized into 4 broad classes. Demographic variables included age, sex, and race (black or white). Cerebrovascular disease risk factors were hypertension (systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg or self-reported use of antihypertensive medications), diabetes (fasting glucose 126 mg/dl or nonfasting glucose 200 mg/dl or self-reported use of medications), smoking status (never versus past versus current use of cigarettes), high-density lipoprotein cholesterol level, low-density lipoprotein cholesterol level, previous heart disease (self-reported myocardial infarction, coronary artery bypass graft, angioplasty, or stenting), and atrial fibrillation (selfreport or electrocardiographic evidence). Measures of fitness include body mass index and regular exercise (the question How many times per week do you engage in intense physical activity, enough to work up a sweat? categorized into never, 1 to 3 times per week, and 4 or more times a week). Measures of socioeconomic status were household income (less than $20 K, $20 K to $35 K, $35 K to 75 K, and $75 K or more) and education (less than high school graduate, high school graduate, some college, or college graduate or more). This report is based on the REGARDS cohort assembled by March 2006 numbering at that time participants. These participants were categorized into 4 mutually exclusive groups: (1) those selfreporting a history of stroke ( Were you ever told by a physician that you had a stroke? ); (2) those not reporting a stroke but selfreporting a TIA ( Were you ever told by a physician that you had a

3 2448 Stroke September 2007 TABLE 1. Short Form 12 Scale Underlying the Primary Outcome of Physical Functioning (PCS) and Mental (MCS) Functioning and the QVSS Establishing Stroke Symptoms Short Form In general, would you say that your health is excellent, very good, good, fair, or poor? 2. Now I am going to read a list of activities that you might do during a typical day. As I read each item, please tell me if your health now limits you a lot, limits you a little, or does not limit you at all in these activities. Moderate activities such as moving a table, pushing a vacuum cleaner, bowling, or playing golf. Does your health now limit you a lot, a little, or not at all in these activities? 3. Climbing several flights of stairs? Does your health now limit you a lot, limit you a little, or not limit you at all in climbing several flights of stairs? 4. During the past 4 weeks, have you accomplished less than you would like as a result of your physical health? 5. During the past 4 weeks, were you limited in the kind of work or other regular daily activities you do as a result of your physical health? 6. During the past 4 weeks, have you accomplished less than you would like as a result of any emotional problems such as feeling depressed or anxious? 7. During the past 4 weeks, did you not do work or other regular daily activities as carefully as usual as a result of any emotional problems such as feeling depressed or anxious? 8. During the past 4 weeks, how much did pain interfere with your normal work, including both work outside the home and housework? Did it interfere not at all, a little bit, moderately, quite a bit, or extremely? 9. During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities like visiting with friends or relatives? Has it interfered all of the time, most of the time, some of the time, a little of the time, or none of the time? 10. How much of the time during the past 4 weeks have you felt calm and peaceful? Would you say all of the time, most of the time, a good bit of the time, some of the time, a little of the time, or none of the time? 11. How much of the time during the past 4 weeks did you have a lot of energy? Would you say all of the time, most of the time, a good bit of the time, some of the time, a little of the time, or none of the time? 12. How much of the time during the past 4 weeks did you feel downhearted and blue? Would you say all of the time, most of the time, a good bit of the time, some of the time, a little of the time, or none of the time? QVSS 1. Have you ever had sudden painless weakness on one side of your body? 2. Have you ever had sudden numbness or a dead feeling on one side of your body? 3. Have you ever had sudden painless loss of vision in one or both eyes? 4. Have you ever suddenly lost one half of your vision? 5. Have you ever suddenly lost the ability to understand what people were saying? 6. Have you ever suddenly lost the ability to express yourself verbally or in writing? Responses to each question are yes, no, don t know/not sure, or refused ministroke or TIA, also known as a transient ischemic attack? ); (3) those not reporting a stroke or TIA but reporting stroke symptoms by the QVSS; and (4) those not reporting stroke, TIA, or stroke symptoms. The 156 (0.71%) participants who refused to answer these questions or answered don t know to stroke history or symptoms were removed from the analysis, providing participants in this analysis. The relationship between stroke signs and symptoms and the PCS-12 and MCS-12 was evaluated in a set of incremental linear regression models. First, crude associations were estimated followed by subsequent adjustment for: (1) demographic factors (age and race gender strata); (2) further adjustment for cerebrovascular disease risk factors (hypertension, diabetes, smoking status, highdensity lipoprotein cholesterol level, low-density lipoprotein cholesterol level, previous heart disease, and atrial fibrillation); (3) additional adjustment for indices of physical fitness (body mass index and exercise); and finally (4) additional adjustment for measures of socioeconomic status (education and income). Two sets of models were fit within this structure. In the first set of models, we examined the differences in the mean PCS-12 and MCS-12 scores between the 4 mutually exclusive groups defined by history of stroke, TIA, stroke symptoms, or none. Additional analyses assessed the differences in mean PCS-12 and MCS-12 between those participants who were symptom-free and those with each of the 6 individual signs and symptoms reflected by the QVSS questions (ie, a specific sign or symptom). Results A description of the study population by stroke/tia/symptom status group is provided in Table 2 (differences between groups P for all variables). By design, the population overrepresented blacks (from 38.9% among those with no symptoms or diagnosis to 51.7% for those with a history of stroke) and was approximately one half female (from 47.9% for those with a history of stroke to 57.7% for those with a history of TIA). Generally, risk factors were more prevalent, exercise was less prevalent, and socioeconomic status indices were lower across the spectrum from asymptomatic with no history of stroke/tia, to symptoms without history of stroke/ TIA, to history of TIA, and finally to history of stroke. Measures of health functioning were reflective of the anticipated scores from a general population sample (anticipated mean of 50 and SD of 10) with the mean of the PCS-12 decreasing across the strata described and MCS-12 scores being lower (particularly for those with symptoms but without a history of stroke or TIA). Figure 1A shows the estimated difference (with 95% confidence limits) for the PCS-12 score between participants not reporting stroke symptoms and without a history of stroke

4 Howard et al Quality of Life in Those With Only Stroke Symptoms 2449 TABLE 2. Description of Study Population by Symptomatic Status Strata Asymptomatic, No Stroke/TIA or TIA relative to: (1) those reporting symptoms only, (2) those with a history of TIA, and (3) those with a history of stroke. Compared with those reporting no symptoms, participants reporting symptoms had a 5.5 (95% CI: 5.2 to 5.9) point lower PCS-12 score, a difference that was similar to a 6.0 (95% CI: 5.3 to 6.7) point lower score for those with a TIA and approximately two thirds of the 8.5 (95% CI: 8.0 to 9.0) point decrement observed for participants with a history of stroke. Adjustment for demographics, cerebrovascular disease risk factors, exercise and body mass index, and socioeconomic status only partially attenuated these effects with similar relationships maintained among those reporting symptoms only, those with a history TIA, and those with a Symptomatic, No Stroke/TIA History of TIA History of Stroke N Demographic factors Black, % Female, % Age (mean SD) Cerebrovascular risk factors Hypertensive, % Diabetic, % Cigarette smoking Never, % Past, % Current, % High-density lipoprotein (mean SD) Low-density lipoprotein (mean SD) Heart disease, % Atrial fibrillation, % Fitness measures Weekly exercise level None, % to 3, % or more, % Body mass index (mean SD) Socioeconomic status indices Income $20 K, % $20 K to $35 K, % $35 K to $75 K, % $75 K, % Education Less than high school, % High school graduate, % Some college, % College, % Outcomes PCS-12 (mean SD) MCS-12 (mean SD) history of stroke. In the fully adjusted model, those with symptoms had PCS-12 scores 3.5 (95% CI: 3.1 to 3.9) points below those without symptoms, whereas those with a history of TIA were 3.7 (95% CI: 3.0 to 4.4) lower and those with a history of stroke were 5.6 (95% CI: 5.1 to 6.2) lower. With the exception of those reporting symptoms only and those with a history of TIA (0.21 P 0.66 across models), differences between any two strata were significant (P ), suggesting that regardless of adjustment for covariates, physical functioning was highest among those without symptoms or history of TIA or stroke, was intermediate for those reporting either symptoms or history of TIA, and was poorest for those reporting history of stroke.

5 2450 Stroke September 2007 Figure 2. Estimated mean (95% CI) difference between population with each of the six stroke symptoms compared with the population without history of stroke, TIA, or stroke symptoms after adjustment for demographic factors (age, race, sex), stroke risk factors (hypertension, diabetes, high-density lipoprotein, low-density lipoprotein, cigarette smoking, atrial fibrillation), fitness measures (exercise and body mass index), and socioeconomic status (income and education). Figure 1. A, The difference in PCS-12 between individuals free of stroke, TIA, and stroke symptoms as compared with patients with history of stroke (light dashed line: ----),those who are stroke-free but with a history of TIA (dark dashed line: ----), and those free of stroke and TIA but with stroke symptoms (dark solid line: ). Estimated mean differences (and 95% CI) are shown in crude (unadjusted analysis), and after incremental adjustment for demographic factors (age, race, sex), stroke risk factors (hypertension, diabetes, high-density lipoprotein, lowdensity lipoprotein, cigarette smoking, atrial fibrillation), fitness measures (exercise and body mass index), and socioeconomic status (income and education). B, Similar estimated differences for MCS-12. The differences in average mental health functioning (MCS-12) between groups of participants with and without stroke symptoms were smaller but still significant (P ) than those observed for physical functioning (see Figure 1B). Unadjusted, participants with stroke symptoms had an average MCS-12 score 2.7 (95% CI: 2.4 to 3.0) points lower than those without symptoms. These differences were only slightly attenuated to 2.1 (95% CI: 1.8 to 2.4) points after adjustment for demographic factors, risk factors, measures of fitness, and indices of socioeconomic status. The difference between participants with and without symptoms was significantly (P ) larger than: (1) the difference between those without symptoms but a history of TIA (crude difference 0.5 with 95% CI: 0.0 to 1.1; with no attenuation after adjustment for confounders to a difference of 0.6 with 95% CI: 0.1 to 1.2); and (2) the difference between those without symptoms and those with a history of stroke (crude difference 1.6 with 95% CI: 1.2 to 2.0; with only modest attenuation by adjustment for confounders to a difference of 1.0 with 95% CI: 0.5 to 1.0). In analysis restricted to participants who were stroke- and TIA-free (n ), the associations between individual QVSS stroke symptoms and PCS-12 and MCS-12 scores are shown in Figure 2 (fully adjusted model only). Even after adjustment for all factors in the full model, a positive response for each of the 6 individual QVSS symptoms was associated with a significant difference in both the PCS-12 and the MCS-12 scores. For the questions on one-sided weakness and one-sided numbness, the PCS-12 score was approximately one half a SD lower for those with symptoms (approximately 5 points lower), a larger difference than was observed for the MCS-12 score (difference of approximately 2 to 3 points). Compared with other QVSS symptoms, reporting loss of vision was associated with a relatively small difference of approximately 2 points in both the PCS-12 and the MCS-12 scores. Reporting loss of one half of the visual field was associated with a significant, but relatively small, impact on the MCS-12 score (differences of only approximately 1 point) but a larger difference in the PCS-12 score of 3 points. The largest differences in MCS-12 scores were observed for those reporting an inability to understand or an inability to express oneself, in which the effect on the MCS-12 and PCS-12 scores was similar and substantial (differences of 4 to 5 points). Discussion This report strengthens the evidence that subtle deficits that could represent symptomatic but undiagnosed strokes, or whispering strokes, are associated with a large public health burden. Approximately 18% 14 of the general population without history of stroke or TIA reported a history of one or more of these stroke symptoms. Using the same screening instrument for stroke symptoms, we have previously reported that this population is at increased risk of cognitive impair-

6 Howard et al Quality of Life in Those With Only Stroke Symptoms 2451 ment. 16 This report strengthens that observation by documenting an association between stroke symptoms in the absence of diagnosed stroke or TIA with a decrease in both physical and mental health-related quality of life. That these symptoms are occurring among the population at increased risk for stroke, 14 and that when they occur, they are associated with a decline in cognitive functioning, 16 and are now associated with lower physical and mental functioning, suggests that a large proportion of these symptoms might be attributable to small strokes. The resulting magnitude of functional decline among this large proportion of the general population represents a substantial public health burden. According to published estimates, the impact of a 5-point decline in health-related quality of life in 18% of the population could translate into a public health burden on the same order of magnitude as that imposed by type 2 diabetes. 21 In addition to the public health impact, on the individual level, screening for potential cognitive impairment and reduced quality of life could be warranted along with any appropriate interventions. Current literature refers to the infarctions identified by MRI in the absence of clinical stroke as silent cerebral infarctions. 1,2 We do not have MRI studies in the REGARDS cohort and cannot confirm that those with stroke symptoms do indeed have infarction on cerebral imaging. However, it may be reasonable to assume that there is considerable overlap between those with whispering symptoms and those with silent infarctions. Many studies have documented a substantial increased risk for subsequent clinical stroke among those with silent infarctions. Individuals with these silent infarctions have been shown to be at higher risk for more rapid cognitive decline, 5,6 for subsequent clinically recognized stroke, and death. 7 9 Those with whispering symptoms could potentially represent a similar high-risk group, which REGARDS will examine in the future. Clearly, some proportion of these symptoms may not be related to small stroke or could be related to stroke-mimic diseases. However, if confirmed in longitudinal studies, our findings suggest that the QVSS could potentially be used to detect individuals who could be targeted for special intervention for stroke prevention. Clearly, this approach has much greater feasibility than the prospect of screening using brain imaging. This report has many strengths, including the large national sample with systematic evaluation of physical and mental functioning and identification of those with history of stroke, TIA, and stroke symptoms. In addition, the evaluation of the REGARDS cohort is sufficiently detailed to account for many potential confounding factors in the assessment of the relationship between stroke symptoms and quality-of-life measures. An important weakness is the reliance on selfreported stroke and TIA, in which these findings would be substantially strengthened by the addition of imaging studies. Like other studies relying on self-reported stroke, we are somewhat reassured that the impact of stroke is likely sufficiently large to have reasonable reliability in self-reports; however, an unknown proportion of stroke survivors may not recall receiving a diagnosis, nor are reported events confirmed by medical record review or imaging in our study. The QVSS also has greater sensitivity than specificity, detecting symptoms that might not have been caused by stroke. Like other cross-sectional studies, this report may be subject to recall bias, specifically those participants with lower physical or mental health functioning may be more likely to remember and report previous stroke symptoms. It would have been interesting to have brain imaging on those participants experiencing symptoms to establish if these whispering strokes had a pathological basis. However, had the assessment of these symptoms been sufficiently complete to include imaging, then it is likely that the underlying stroke would have been detected and resulted in a diagnosis of stroke. Hence, the need to have imaging is a circular argument; if imaging were available to confirm that the undiagnosed whispering stroke was in fact a stroke, then the majority of these events would not be undiagnosed. The focus of this article is on the associated deficits of undiagnosed strokes that result from exactly this lack of an adequate assessment. Like in all cross-sectional studies, we cannot be assured of the direction of causation between the symptoms and the quality-of-life measures, and it is possible that processes used to recruit the REGARDS cohort could have introduced systematic biases. In particular, there is the possibility that those same individuals who tend to report stroke symptoms could also be more likely to provide responses associated with lower measures of health-related quality of life. Finally, we note that issues have been raised regarding the validity of the Short Form scales in stroke populations. 25 Importantly, these concerns are applicable to the assessment of correlates of quality-of-life measures within the stroke population and are not generally applicable to analyses in which the general population (in which the Short Form scales are well validated) are compared with a disease population (patients with stroke in our case). When coupled with previous reports from the REGARDS cohort, these findings suggest that stroke symptoms as assessed by the QVSS are quite common in the general population, are associated with clinically important declines in physical and mental functioning, and may often be associated with whispering strokes. If confirmed, because previous stroke is a powerful prognostic factor for subsequent stroke, our findings suggest that a large proportion of the adult population may be at high risk for subsequent larger clinically diagnosed stroke. The methods we used for detection are easily applied in practice, opening the door to widespread implementation in primary care and public health programs. Acknowledgments The authors acknowledge the participating investigators and institutions: University of Alabama at Birmingham (Study PI, Data Coordinating Center, Survey Research Unit): George Howard, Leslie McClure, Virginia Howard, Libby Wagner, Virginia Wadley, Rodney Go, Ella Temple, Margaret Stewart; University of Vermont (Central Laboratory): Mary Cushman; Wake Forest University Medical Center (ECG Reading Center): Ron Prineas; University of Cincinnati (Neuro-Epidemiology, Stroke Validation, Medical Monitoring): Brett Kissela, Dawn Kleindorfer, Joseph Broderick; Alabama Neurological Institute (Stroke Validation Center, Medical Monitoring): Camilo Gomez, David Rhodes, Susanna Bowling, Sean Orr; University of Arkansas for Medical Sciences (Survey Research): LeaVonne Pulley; Examination Management Services Inc (In-Home Visits): Andra Graham; National Institute of Neurological Disorders and Stroke, National Institutes of Health (Funding Agency): Claudia Moy.

7 2452 Stroke September 2007 Source of Funding The research reported in this article was supported by cooperative agreement NS from the National Institute of Neurological Disorders and Stroke. None. Disclosures References 1. Howard G, Wagenknecht LE, Cai J, Cooper L, Kraut MA, Toole JF. Cigarette smoking and other risk factors for silent cerebral infarctions in the general population. Stroke. 1998;29: Bryan RN, Wells SW, Miller TJ, Elster AD, Jungreis CA, Poirier VC, Lind BK, Manolio TA. Infarct-like lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly data from the Cardiovascular Health Study. Radiology. 1997;202: Leary MC, Saver JL. Annual incidence of first silent stroke in the United States: a preliminary estimate. Cerebrovasc Dis. 2003;16: Cohn PF. Should silent ischemia be treated in asymptomatic individuals? Circulation. 1990;82(suppl II): Schmidt WP, Roesler A, Kretzschmar K, Ladwig KH, Junker R, Berger K. Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population. JAm Geriatr Soc. 2004;52: Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348: Mosley TH Jr, Knopman DS, Catellier DJ, Bryan N, Hutchinson RG, Grothues CA, Folsom AR, Cooper LS, Burke GL, Liao D, Szklo M. Cerebral MRI findings and cognitive functioning: the Atherosclerosis Risk in Communities study. Neurology. 2005;64: Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2005;34: Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, Hubbard LD, Mosley TH. Atherosclerosis Risk in Communities Study. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA. 2002;288: Knopman DS. Dementia and cerebrovascular disease. Mayo Clin Proc. 2006;81: Gorelick PB. William M. Feinberg Lecture: Cognitive vitality and the role of stroke and cardiovascular disease risk factors. Stroke. 2005;36: Roman GC, Sachdev P, Royall DR, Bullock RA, Orgogozo JM, Lopez-Pousa S, Arizaga R, Wallin A. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci. 2004;226: Rose G. Mass prevention: population-directed approach. Acta Cardiol Suppl. 1988;29: Howard VJ, McClure LA, Meschia JF, Pulley L, Orr SC, Friday GH. The high prevalence of stroke symptoms among persons without a diagnosis of stroke or TIA in a general population: the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study. Arch Intern Med. 2006; 166: Wolf PA, D Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke. 1991;22: Wadley VG, McClure LA, Howard VJ, Unverzagt FW, Go RC, Moy CS, Crowther MR, Gomez CR, Howard G. Cognitive status, stroke symptom reports, and modifiable risk factors among individuals with no history of stroke or TIA in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Stroke. 2007;38: Joshi S, Morley JE. Cognitive impairment. Med Clin North Am. 2006; 90: Morton LM, Cahill J, Hartge P. Reporting participation in epidemiologic studies: a survey of practice. Am J Epidemiol. 2006;163: Howard VJ, Cushman M Pulley LV, Gomez CR, Go RC, Prineas RJ, Graham A, Moy CS, Howard G. The REasons for Geographic and Racial Differences in Stroke (REGARDS) study: objectives and design. Neuroepidemiology. 2005;25: Ware JE Jr, Durner-Bowker DM, Kosinski M, Gandek B. SF-12v2. How to Score Version 2 of the SF-12 Health Survey. Boston: Quality Metric; Ware JE. Applications of Health Outcomes Evaluation Methods. Available at: HarvardOutcomesApp pdf. Accessed June 16, Meschia JF, Brott TG, Chukwudelunzu FE, Hardy J, Brown RD Jr, Meissner I, Hall LJ, Atkinson EJ, O Brien PC. Verifying the stroke-free phenotype by structured telephone interview. Stroke. 2000;31: Jones WJ, Williams LS, Meschia JF. Validating the questionnaire for verifying stroke-free status (QVSFS) by neurological history and examination. Stroke. 2001;32: Meschia JF, Lojacono MA, Miller MJ, Brott TG, Atkinson EJ, O Brien PC. Reliability of the questionnaire for verifying stroke-free status. Cerebrovasc Dis. 2004;17: Hobart JC, Williams LS, Moran K, Thompson AJ. Quality of life measurement after stroke: uses and abuses of the SF-36. Stroke. 2002;33: