Carlos S. Kase

Stroke Severity in Atrial Fibrillation The Framingham Study

BACKGROUND AND PURPOSE Stroke occurring with atrial fibrillation (AF) is more likely to be fatal or more severe than non-AF stroke based on clinical series, but data from prospective epidemiological studies are sparse and inconsistent. METHODS Over 40-year follow-up of the original 5070 Framingham cohort, 501 initial ischemic strokes, including 103 with AF, were analyzed. Stroke severity was rated as none, mild, moderate, severe, or fatal. Since 1981, functional status indicated by the Barthel index has been evaluated acutely and at 3, 6, and 12 months. Severity and functional status of AF strokes were compared with non-AF strokes using chi 2 test and Students t test. Thirty-day mortality was assessed by logistic regression analyses. RESULTS AF was associated with increased stroke severity (P = .048). Thirty-day mortality was greater in AF strokes than in non-AF strokes (25% versus 14%). The multivariate-adjusted odds ratio for 30-day mortality for AF subjects was 1.84 (95% confidence interval, 1.04 to 3.27). Since 1981, follow-up was available for 150 initial ischemic strokes, including 30 with AF. Compared with the non-AF group, the AF group had poorer survival and more recurrences during 1 year of follow-up. The AF subjects had lower mean Barthel index scores acutely (29.6 versus 58.6, P < .001) and at 3 months (P = .005), 6 months (P = .003), and 12 months (P = .130) after stroke among survivors. CONCLUSIONS Ischemic stroke associated with AF was nearly twice as likely to be fatal as non-AF stroke. Recurrence was more frequent, and functional deficits were more likely to be severe among survivors. Since stroke is usually the initial manifestation of embolism in AF, prevention is critical to reducing disability and mortality.

An Updated Definition of Stroke for the 21st Century A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Despite the global impact and advances in understanding the pathophysiology of cerebrovascular diseases, the term “stroke” is not consistently defined in clinical practice, in clinical research, or in assessments of the public health. The classic definition is mainly clinical and does not account for advances in science and technology. The Stroke Council of the American Heart Association/American Stroke Association convened a writing group to develop an expert consensus document for an updated definition of stroke for the 21st century. Central nervous system infarction is defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury. Central nervous system infarction occurs over a clinical spectrum: Ischemic stroke specifically refers to central nervous system infarction accompanied by overt symptoms, while silent infarction by definition causes no known symptoms. Stroke also broadly includes intracerebral hemorrhage and subarachnoid hemorrhage. The updated definition of stroke incorporates clinical and tissue criteria and can be incorporated into practice, research, and assessments of the public health.

The influence of gender and age on disability following ischemic stroke: the Framingham study ☆

The magnitude of disability among elderly stroke survivors is substantial. There have been few community-based estimates of the contribution gender and older age make to stroke-related disability and outcome. Using the original Framingham Study cohort, we documented gender-specific neurological deficits and disability differences in stroke survivors at six months post-stroke. Logistic regression analyses were performed to estimate odds ratios, comparing men and women, and adjusting for age, and age and stroke subtype. Age and gender-matched controls were then compared to distinguish stroke-related disability from disability associated with general aging. Results showed that almost half (43%) of all elderly stroke survivors in the cohort had moderate to severe neurological deficits. In the crude analyses, women were more dependent in ADLs (33.9% vs 15.6%), less likely to walk unassisted (40.3% vs 17.8%), and living in nursing homes (34.9 % vs 13.3%). After adjusting for age and stroke subtype, it was older age that accounted for the severity of disability. When compared to age and gender-matched controls, stroke cases were significantly more disabled in all domains studied. In this elderly cohort, more women experienced initial strokes and were more disabled at 6 months post-stroke than men. However, older age at stroke onset, not gender or stroke subtype, was associated with greater disability. Health care providers need to understand that strokes occur later in life for women and that because of age, women are at greater risk for disability and institutionalization.

Genomewide Association Studies of Stroke

BACKGROUND The genes underlying the risk of stroke in the general population remain undetermined. METHODS We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Gender Differences in Stroke Incidence and Poststroke Disability in the Framingham Heart Study

Background and Purpose— Stroke is emerging as a major public health problem for women, as it is for men. Controversy persists regarding gender differences in stroke incidence, severity, and poststroke disability. Methods— Participants in the Framingham Original (n=5119; 2829 women) and Offspring (n=4957, 2565 women) cohorts who were 45 years and stroke-free were followed to first incident stroke. Gender-specific outcome measures were adjusted for the Framingham Stroke Risk Profile components. Results— We observed 1136 incident strokes (638 in women) over 56 years of follow-up. Women were significantly (P<0.001) older (75.1 versus 71.1 years for men) at their first-ever stroke, had a higher stroke incidence above 85 years of age, lower at all other ages, and a higher lifetime risk of stroke at all ages. There was no significant difference in stroke subtype, stroke severity, and case fatality rates between genders. Women were significantly (P<0.01) more disabled before stroke and in the acute phase of stroke in dressing (59% versus 37%), grooming (57% versus 34%), and transfer from bed to chair (59% versus 35%). At 3 to 6 months poststroke women were more disabled, more likely to be single, and 3.5 times more likely to be institutionalized (P<0.01). Conclusions— These results from the Framingham Heart Study (FHS) support the existence of gender-differences in stroke incidence, lifetime risk (LTR) of stroke, age at first stroke, poststroke disability, and institutionalization rates. Prestroke disability and sociodemographic factors may contribute to the high rate of institutionalization and poorer outcome observed in women.

Precursors of extracranial carotid atherosclerosis in the Framingham Study

To investigate cardiovascular risk factors and carotid atherosclerosis, we related previously measured risk factors to carotid atherosclerosis as determined by duplex ultrasonography in the Framingham Study cohort. Risk factors measured prospectively on 1,116 cohort members, ages 66 to 93, were related to the severity of carotid atherosclerosis measured by carotid ultrasonography performed during biennial examination no. 20 (1988 to 1990). The degree of carotid atherosclerosis was expressed as a percent carotid stenosis and, for statistical analysis, subjects were divided into four groups according to percent carotid stenosis. The prevalence of significant carotid stenosis in the general population was low–7% in women and 9% in men. A multivariate logistic regression model showed that age, cigarette smoking, systolic blood pressure, and cholesterol were independently related to carotid atherosclerosis. Alcohol consumption was also significant in men, but not in women. In addition, our results indicate that both current and former smoking in both sexes was related to the degree of carotid atherosclerosis.

Migraine, headache, and the risk of stroke in women A prospective study

Background: Migraine and headache in general have been associated with subsequent risk of stroke, primarily in retrospective case-control studies. Prospective data evaluating the association between specific headache forms and stroke are sparse. Methods: A prospective cohort study was conducted among 39,754 US health professionals age 45 and older participating in the Women’s Health Study with an average follow-up of 9 years. Incident stroke was self-reported and confirmed by medical record review. Results: A total of 385 strokes (309 ischemic, 72 hemorrhagic, and 4 undefined) occurred. Compared with nonmigraineurs, participants who reported migraine overall or migraine without aura had no increased risk of any stroke type. Participants who reported migraine with aura had increased adjusted hazards ratios (HRs) of 1.53 (95% CI 1.02 to 2.31) for total stroke and 1.71 (95% CI 1.11 to 2.66) for ischemic stroke but no increased risk for hemorrhagic stroke. Participants with migraine with aura who were <55 years old had a greater increase in risk of total (HR 1.75; 95% CI 1.02 to 3.00) and ischemic (HR 2.25; 95% CI 1.30 to 3.91) stroke. Compared with participants without headache, headache in general and nonmigraine headache were not associated with total, ischemic, or hemorrhagic stroke. Conclusions: In these prospective data, migraine was not associated with total, ischemic, or hemorrhagic stroke. In subgroup analyses, we found increased risks of total and ischemic stroke for migraineurs with aura. The absolute risk increase was, however, low, with 3.8 additional cases per year per 10,000 women.

Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: The PROACT II trial

Objective: To analyze the frequency, clinical characteristics, and predictors of symptomatic intracerebral hemorrhage (ICH) after intraarterial (IA) thrombolysis with recombinant pro-urokinase (r-proUK) in acute ischemic stroke. Method: The authors conducted an exploratory analysis of symptomatic ICH from a randomized, controlled clinical trial of IA thrombolysis with r-proUK for patients with angiographically documented occlusion of the middle cerebral artery within 6 hours from stroke onset. Patients (n = 180) were randomized in a ratio of 2:1 to either 9 mg IA r-proUK over 120 minutes plus IV fixed-dose heparin or IV fixed-dose heparin alone. As opposed to intention to treat, this analysis was based on “treatment received” and includes 110 patients given r-proUK and 64 who did not receive any thrombolytic agent. The remaining six patients received out-of-protocol urokinase and were excluded from analysis. The authors analyzed centrally adjudicated ICH with associated neurologic deterioration (increase in NIH Stroke Scale [NIHSS] score of ≥4 points) within 36 hours of treatment initiation. Results: Symptomatic ICH occurred in 12 of 110 patients (10.9%) treated with r-proUK and in two of 64 (3.1%) receiving heparin alone. ICH symptoms in r-proUK–treated patients occurred at a mean of 10.2 ± 7.4 hours after the start of treatment. Mortality after symptomatic ICH was 83% (10/12 patients). Only blood glucose was significantly associated with symptomatic ICH in r-proUK–treated patients based on univariate analyses of 24 variables: patients with baseline glucose >200 mg/dL experienced a 36% risk of symptomatic ICH compared with 9% for those with ≤200 mg/dL (p = 0.022; relative risk, 4.2; 95% CI, 1.04 to 11.7). Conclusions: Symptomatic ICH after IA thrombolysis with r-proUK for acute ischemic stroke occurs early after treatment and has high mortality. The risk of symptomatic ICH may be increased in patients with a blood glucose >200 mg/dL at stroke onset.

Secular trends in stroke incidence and mortality. The Framingham Study.

Background: The reduction in US stroke mortality has been attributed to declining stroke incidence. However, evidence is accumulating of a trend in declining stroke severity. Methods: We examined secular trends in stroke incidence, prevalence, and fatality in Framingham Study subjects aged 55–64 years in three successive decades beginning in 1953, 1963, and 1973. Results: No significant decline in overall stroke and transient ischemic attack incidence or prevalence occurred. In women, but not men, incidence of completed ischemic stroke declined significantly. Stroke severity, however, decreased significantly over time. Stroke with severe neurological deficit decreased in later decades, with a fall in rates of severe stroke cases in which patients were unconscious on admission to the hospital. There was no substantial change in the case mix of infarcts and hemorrhages and no decline in hemorrhage to account for the decline in severity. The proportion of isolated transient ischemic attacks increased significantly over the 30 years studied, yielding an apparent and significant decline in case–fatality rates in men only. Conclusions: Secular trends in stroke incidence and fatality did not follow a clear or definite pattern of decline. While a significant decline in stroke severity occurred over three decades, incidence of infarction fell only in women. The decline in total case fatality rates occurred only in men and resulted largely from an increased incidence of isolated transient ischemic attacks. The severity of completed stroke was significantly lower in the later decades under study.

Dementia After Stroke

Background and Purpose— Identification of risk factors for dementia after stroke is best performed in comparison with stroke-free controls, because older subjects at high risk for stroke also have a substantial risk of dementia in the absence of stroke. Previous case-control studies were hospital-based. We used a nested case-control design to prospectively evaluate these risk factors in the community-based Framingham Study cohort. Methods— We compared 212 subjects who were free of dementia in January 1982 and sustained a first stroke after this date, with 1060 age- and sex-matched, stroke- and dementia-free controls. We calculated 10-year risks of dementia (by Diagnostic and Statistical Manual of Mental Disorders, Volume IV criteria) developing in cases and controls and also estimated the hazard ratios within subgroups defined by exposure to various demographic factors (age, gender, education), stroke-related features (right or left hemisphere, stroke type, second stroke), stroke risk factors (hypertension, diabetes, atrial fibrillation, smoking) and apolipoprotein E genotype. Results— Dementia developed in 19.3% of cases and 11.0% of controls. Baseline stroke doubled the risk of dementia (hazard ratio [HR]: 2.0; 95% confidence interval [CI]: 1.5 to 3.1) and adjustment for age, sex, education, and exposure to individual stroke risk factors did not diminish the risk (HR: 2.4; 95% CI: 1.6 to 3.7). The HR was higher in younger subjects (age younger than 80 years [HR: 2.6; 95% CI: 1.5 to 4.5]), apolipoprotein E 3/3 homozygotes (HR: 3.4; 95% CI: 2.0 to 5.8), and high school graduates (HR: 2.4; 95% CI: 1.5 to 3.9). Conclusion— Stroke increases a subjects risk of dementia as compared with age- and sex-matched controls. Primary and secondary prevention of stroke should significantly decrease the risk of all dementia.