Transcobalamin 2 variant associated with poststroke homocysteine modifies recurrent stroke risk.

OBJECTIVES: The Vitamin Intervention for Stroke Prevention trial found an association between baseline poststroke homocysteine (Hcy) and recurrent stroke. We investigated genes for enzymes and cofactors in the Hcy metabolic pathway for association with Hcy and determined whether associated single nucleotide polymorphisms (SNPs) influenced recurrent stroke risk. METHODS: Eighty-six SNPs in 9 candidate genes (BHMT1, BHMT2, CBS, CTH, MTHFR, MTR, MTRR, TCN1, and TCN2) were genotyped in 2,206 subjects (83% European American). Associations with Hcy measures were assessed using linear regression models assuming an additive genetic model, adjusting for age, sex, and race and additionally for baseline Hcy when postmethionine load change was assessed. Associations with recurrent stroke were evaluated using survival analyses. RESULTS: Five SNPs in the transcobalamin 2 (TCN2) gene were associated with baseline Hcy (false discovery rate [FDR]-adjusted p = 0.049). TCN2 SNP rs731991 was associated with recurrent stroke risk in the low-dose arm of the trial under a recessive model (log-rank test p = 0.009, hazard ratio 0.34). Associations with change in postmethionine load Hcy levels were found with 5 SNPs in the cystathionine ß-synthase (CBS) gene (FDR-adjusted p < 0.031). CONCLUSIONS: TCN2 variants contribute to poststroke Hcy levels, whereas variants in the CBS gene influence Hcy metabolism. Variation in the TCN2 gene also affects recurrent stroke risk in response to cofactor therapy.

Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis.

Joubert syndrome (JS) is an autosomal recessive disorder, consisting of mental retardation, cerebellar vermis aplasia, an irregular breathing pattern, and retinal degeneration. Nephronophthisis (NPHP) is found in 17-27% of these patients, which was designated JS type B. Mutations in four separate genes (AHI1, NPHP1, CEP290/NPHP6, and MKS3) are linked to JS. However, missense mutations in a new ciliary gene (RPGRIP1L) were found in type B patients. We analyzed a cohort of 56 patients with JS type B who were negative for mutations in three (AHI1, NPHP1, and CEP290/NPHP6) of the four genes previously linked to the syndrome. The 26 exons encoding RPGRIP1L were analyzed by means of PCR amplification, CEL I endonuclease digestion, and subsequent sequencing. Using this approach, four different mutations in the RPGRIP1L gene in five different families were identified and three were found to be novel mutations. Additionally, we verified that missense mutations are responsible for JS type B and cluster in exon 15 of the RPGRIP1L gene. Our studies confirm that a T615P mutation represents the most common mutation in the RPGRIP1L gene causing disease in about 8-10% of JS type B patients negative for NPHP1, NPHP6, or AHI1 mutations.

Statin treatment and adherence to national cholesterol guidelines after ischemic stroke.

BACKGROUND: National cholesterol guidelines have defined high vascular risk individuals as those who could potentially benefit most from statin therapy. The authors aimed to determine the rate of statin use, its predictors, and the achievement of national guideline target lipid goals among ischemic stroke survivors. METHODS: The authors abstracted data from the Vitamin Intervention for Stroke Prevention (VISP) study database from the United States and Canada to incorporate into algorithms for initiating statin therapy according to the National Cholesterol Education Program (NCEP) guidelines for high-risk individuals. The authors applied these algorithms to all study subjects. Univariate as well as multivariate associations for target lipid levels and statin implementation were then evaluated utilizing pertinent demographic, clinical, and laboratory data. RESULTS: Of 2,894 subjects in the analysis dataset, 38% were women; 71% were recruited in the United States and 29% in Canada. Of 769 high-risk subjects, 262 (34%) had a low-density lipoprotein (LDL) level > or =130 mg/dL and 124 of these (47%) were not on statin. Among those high-risk persons on statin treatment, only 42% had an LDL < or =100 mg/dL. Subjects in the overall cohort were more likely to be on a statin if they were treated in the United States or had a history of hypertension or coronary artery disease. CONCLUSIONS: Approximately one out of three guideline-eligible high vascular risk ischemic stroke patients in this study had low-density lipoprotein cholesterol concentrations above qualifying levels for pharmacologic therapy, but half of these patients were not taking a statin, and of those receiving statin treatment, less than half were within recommended lipid goals.

Relationship of periodontal disease and edentulism to stroke/TIA.

Periodontitis has been shown to increase the systemic inflammatory response, which has been implicated in atherosclerosis and cerebrovascular events. We hypothesized an association between periodontitis or edentulism and Stroke/TIA in the ARIC Study. Data on 9415 dentate and 1491 edentulous adults included demographics, cardiovascular outcomes, lifestyle, laboratory measures, and, for 6436 of the dentate, a dental examination. The dependent variable was Stroke/TIA, and the exposure was extent (%) of attachment level 3+ millimeters (AL). Quartiles of AL and edentulism were compared for Stroke/TIA using odds ratios (OR) and 95% confidence intervals (CI), and confounders were controlled by logistic regression. Stroke/TIA was prevalent in 13.5% of periodontal examinees, 15.6% of dentate non-examinees, and 22.5% of edentulous persons. The highest quartile of AL (OR 1.3, CI 1.02-1.7) and edentulism (OR 1.4, CI 1.5-2.0) were associated with Stroke/TIA.

Vitamin Intervention for Stroke Prevention (VISP) trial: rationale and design.

Elevated plasma levels of homocyst(e)ine [H(e)] are surprisingly common and strongly associated with endothelial dysfunction and a marked increase in vascular risk. Treatment with a combination of folic acid, pyridoxine (vitamin B6) and cobalamin (vitamin B12) reduces plasma H(e) levels in most cases, restores endothelial function, and regresses carotid plaque, but there is no evidence that such treatment will reduce clinical events. The Vitamin Intervention for Stroke Prevention (VISP) study is a double-masked, randomized, multicenter clinical trial designed to determine if, in addition to best medical/surgical management, high-dose folic acid, vitamin B6, and vitamin B12 supplements will reduce recurrent stroke compared to lower doses of these vitamins. Patients at least 35 years old with a nondisabling ischemic stroke within 120 days, and screening plasma H(e) > the 25th percentile of benchmark population data are eligible. Secondary endpoints are myocardial infarction or fatal coronary heart disease. This paper describes the design and rationale of the study.

Effect of contralateral occlusion on long-term efficacy of endarterectomy in the asymptomatic carotid atherosclerosis study (ACAS). ACAS Investigators.

BACKGROUND AND PURPOSE: The Asymptomatic Carotid Atherosclerosis Study (ACAS) established the effectiveness of prophylactic carotid endarterectomy, for patients in good health who had stenosis >/=60%, if conducted by surgeons with a surgical morbidity and mortality of <3%. This secondary analysis was performed to determine whether the presence of contralateral cervical carotid occlusion alters the efficacy of asymptomatic ipsilateral carotid endarterectomy. METHODS: One hundred sixty-three participants who had a baseline contralateral occlusion documented by Doppler ultrasound (77 medical, 86 surgical) were compared with 1485 participants with a patent contralateral carotid artery (748 medical, 737 surgical) for the risk of a combined end point of perioperative (30-day) death or stroke or long-term (5-year) ipsilateral stroke. RESULTS: For those without contralateral occlusion, surgery was associated with a 6.7% absolute reduction in the 5-year risk (95% CI, 2.1% to 11.4%), while for those with a contralateral occlusion, surgery was associated with a 2.0% absolute increase in risk (95% CI, -9.3% to 5.2%), which was a statistically significant difference in the effect of surgery (P:=0.047). This difference is primarily attributable to low long-term risk for medically managed patients with contralateral occlusion. CONCLUSIONS: While this post hoc analysis should be interpreted with caution, the findings suggest that endarterectomy in asymptomatic subjects with contralateral occlusion provides no long-term benefit (and may be harmful) in preventing stroke and death. These findings were a result of the benign course of medically treated subjects.

Low mini-mental status predicts mortality in asymptomatic carotid arterial stenosis. Asymptomatic Carotid Atherosclerosis Study investigators.

OBJECTIVE: To determine whether carotid endarterectomy is superior to best medical therapy in preserving cognition, and whether low Mini-Mental State Examination (MMSE) scores predict TIA, stroke, myocardial infarction, or death. METHODS: Subjects participating in the Asymptomatic Carotid Atherosclerosis Study were administered the MMSE at periodic intervals. Group means were calculated at randomization, 1 and 3 months later, and every 6 months thereafter. The group means were compared by treatment and over time. A proportional hazard regression model incorporating postrandomization MMSE score as a predictor variable was used to estimate risk of death, stroke, or other outcome events. RESULTS: There was no intergroup difference in mean MMSE score during 5 years of observation. For individual patients, the relationship between a low postrandomization score on the MMSE and increased risk of death was significant (p

The global burden of disease study: implications for neurology.

Because of the epidemiological transition, the global burden of illness has changed. Several factors have contributed to this change, including improvements in maternal and child health, increasing age of populations, and newly recognized disorders of the nervous system. It is now evident that neurologic disorders have emerged as priority health problems worldwide. This is reflected in the Global Burden of Disease Study, jointly published by the World Health Organization and other groups. The proportionate share of the total global burden of disease resulting from neuropsychiatric disorders is projected to rise to 14.7% by 2020. Although neurologic and psychiatric disorders comprise only 1.4% of all deaths, they account for a remarkable 28% of all years of life lived with a disability. This study provides compelling evidence that one cannot assess the neurologic health status of a population by examining mortality statistics alone. Health ministries worldwide must prioritize neurologic disorders, and neurologists must be prepared to provide care for increased numbers of people individually and in population groups.

Hyperbaric oxygen decreases infarct size and behavioral deficit after transient focal cerebral ischemia in rats.

Cerebral hypoxia is a major component of immediate and secondary cell damage caused by ischemia. Hyperbaric oxygen (HBO) is a potent means to increase the amount of oxygen dissolved in blood plasma. The effectiveness of HBO in clinical and experimental cerebral ischemia, however, is controversial. We sought to determine whether treatment with HBO initiated early after focal cerebral ischemia-onset protects the brain when experimental conditions such as brain temperature are controlled. Male Wistar rats (n=57) underwent reversible filament occlusion of the right middle cerebral artery (MCA) for 75 min. Animals were awakened after filament introduction and assessed for presence of forelimb paresis. Rats then underwent a 60-min course of either 100% O(2) at 1.0 atmosphere absolute (ata; control group), HBO 1.5 ata, or HBO 2.5 ata in a customized HBO chamber allowing physiological monitoring and pericranial temperature control. The filament was then removed. Seven days after ischemia, rat behavior was scored from 3-18 (18=normal) and brains were removed for histological analysis of infarct volume. Rats treated with HBO 2.5 ata had better mean+/-standard deviation (S.D.) behavioral scores (14+/-2; p<0.05) than control (10+/-3) or HBO 1.5-ata-treated animals (11+/-3). Similarly, total infarct volumes (mean+/-S.D.) were smaller in animals receiving HBO at 2.5 ata (76+/-65 mm(3); p<0.05) compared to control (129+/-83 mm(3)) and HBO 1.5-ata (119+/-68 mm(3))-treated groups. Cortical infarction occurred less frequently in HBO 2. 5-ata-treated than in control animals (44% vs. 71%; p<0.05). We conclude that HBO can improve outcome after temporary focal ischemia when treatment is started early after ischemia-onset but HBO dose appears important. Potential mechanisms include enhanced oxygen supply to marginally perfused cells.

Prevalence and anatomic characteristics of infarct-like lesions on MR images of middle-aged adults: the atherosclerosis risk in communities study.

BACKGROUND AND PURPOSE: MR imaging has revealed putative evidence of subclinical cerebrovascular disease (CVD) as reflected by white matter signal changes and infarct-like lesions (ILLs). Nonetheless, the prevalence of this condition in the general population has been defined only to a limited extent. We herein report the prevalence and anatomic characteristics of ILLs seen on cranial MR images obtained as part of a population-based study of cardiovascular disease in middle-aged adults. These results are contrasted to those of previous similar studies, particularly those of an elderly population in the Cardiovascular Health Study (CHS). METHODS: This Atherosclerosis Risk in Communities (ARIC) cohort consists of a probability sample of community-living persons who were 55 to 72 years old at the time of MR examination. MR imaging of 1890 participants was performed at two ARIC field centers, based on a common protocol. MR studies were evaluated by trained readers at the MR Reading Center using original digital data displayed on a high-resolution workstation. The measures of lesion size, anatomic location, and signal intensity were collected. The definition for an ILL was a non-mass, hyperintense region with an arterial vascular distribution on spin-density and T2-weighted images. RESULTS: Two hundred ninety participants had ILLs, for an overall prevalence of 15.3%. Eighty-two percent of participants with ILLs had lesions that were 3 mm or larger in maximal dimension, although 87% of these lesions were 20 mm or smaller in maximal dimension. The prevalence of ILLs increased with age, from 7.9% in the 55- to 59-year-old age group to 22.9% in the 65- to 72-year-old age group (P < .001). Lesion prevalence was greater in black (20.7%) than in white persons (10.2% [P < .0001]), but did not differ significantly between male and female participants. The basal ganglia and thalamic region was the most commonly affected anatomic site, accounting for 78.9% of the lesions. CONCLUSION: Considering that the prevalence of self-reported stroke or transient ischemic attack in ARIC participants is 1.5%, these results suggest that there is significantly more subclinical than clinical CVD in the general population. Furthermore, the prevalence of this subclinical disease increases with age, and is greater in black persons. ILLs are dominated by "lacunae" in the basal ganglia and thalamus. These results are, in general, similar to those of a comparable study of elderly participants in the CHS, except for a 60% lower prevalence of ILLs in this younger population.

Physical activity and ischemic stroke risk. The atherosclerosis risk in communities study.

BACKGROUND AND PURPOSE: The relationship between physical activity and stroke is inconclusive according to the 1996 US Surgeon General's Report on Physical Activity and Health. Therefore, this study examined the relationship between physical activity and ischemic stroke risk among 14 575 Atherosclerosis Risk in Communities Study participants aged 45 to 64 years free of self-reported stroke and coronary heart disease at baseline. METHODS: Eligible potential stroke hospitalizations were identified from ongoing hospital surveillance and from hospitalizations reported by the cohort study participants. All strokes were validated by hospitalization records. Physical activity was measured as sport, leisure (nonsport), and work with the use of the Baecke questionnaire. Multivariable Poisson and Cox proportional hazards models were used to determine the association of differing levels of physical activity with ischemic stroke incidence. RESULTS: During an average of 7.2 years of follow-up, 189 incident ischemic strokes occurred. Ischemic stroke incidence rates were highest in the lowest quartile of sport, leisure, and work scores. The hazard rate ratios with 95% CIs for ischemic stroke for the highest quartile compared with the lowest quartile of activity adjusted for age, sex, race-center, education, and smoking, were sport 0.83 (0.52, 1.32), leisure 0.89 (0.57, 1.37), and work 0.69 (0.47, 1.00). Further adjustment for factors that likely were intermediate variables (hypertension, diabetes, fibrinogen, and body mass index) between physical activity and stroke attenuated the associations. CONCLUSIONS: Our findings suggest that physical activity was weakly associated with a reduced risk of ischemic stroke among middle-aged adults. The association may be due to links between physical activity and other risk factors or due to chance.

Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association.

OBJECTIVE: To establish, in a single resource, up-to-date recommendations for primary care physicians regarding prevention strategies for a first stroke. PARTICIPANTS: Members of the National Stroke Association's (NSA's) Stroke Prevention Advisory Board and Cedars-Sinai Health System Department of Health Services Research convened on April 9, 1998, in an open meeting. The conference attendees, selected to participate by the NSA, were recognized experts in neurology (9), cardiology (2), family practice (1), nursing (1), physician assistant practices (1), and health services research (2). EVIDENCE: A literature review was carried out by the Department of Health Services Research, Cedars-Sinai Health System, Los Angeles, Calif, using the MEDLINE database search for 1990 through April 1998 and updated in November 1998. English-language guidelines, statements, meta-analyses, and overviews on prevention of a first stroke were reviewed. CONSENSUS PROCESS: At the meeting, members of the advisory board identified 6 important stroke risk factors (hypertension, myocardial infarction [MI], atrial fibrillation, diabetes mellitus, blood lipids, asymptomatic carotid artery stenosis), and 4 lifestyle factors (cigarette smoking, alcohol use, physical activity, diet). CONCLUSIONS: Several interventions that modify well-documented and treatable cardiovascular and cerebrovascular risk factors can reduce the risk of a first stroke. Good evidence for direct stroke reduction exists for hypertension treatment; using warfarin for patients after MI who have atrial fibrillation, decreased left ventricular ejection fraction, or left ventricular thrombus; using 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors for patients after MI; using warfarin for patients with atrial fibrillation and specific risk factors; and performing carotid endarterectomy for patients with stenosis of at least 60%. Observational studies support the role of modifying lifestyle-related risk factors (eg, smoking, alcohol use, physical activity, diet) in stroke prevention. Measures to help patients improve adherence are an important component of a stroke prevention plan.

1860--neurology was there.

The year 1860 was a beginning of social, political, and medical upheaval in the United States. The Civil War over states' rights, which would last for 4 years and change the political landscape of the United States forever, had its roots in that year. American neurology was conceived and gestated by the Civil War because of the collaboration between William A. Hammond (1828-1900) and Silas Weir Mitchell (1829-1914), who became the founders of American neurology. Thus, 1860 serves as a pivotal point from which to view the precursors of American neurology and the later war and postwar developments.

Recurrent carotid stenosis : results of the asymptomatic carotid atherosclerosis study.

BACKGROUND AND PURPOSE: We sought to determine the incidence of recurrent carotid stenosis in patients in the Asymptomatic Carotid Atherosclerosis Study (ACAS) who had undergone carotid endarterectomy and were prospectively followed with Doppler ultrasound for up to 5 years. METHODS: The ACAS database was interrogated to determine the rate of recurrent carotid stenosis (>/=60%) based up angiogram-validated Doppler data, with a 90% and a 95% positive predictive value, as well as information concerning the technologists' interpretation of percent stenosis. These 3 parameters are reported for each of 3 time intervals: within 3 months of operation (residual disease), between 3 and 18 months (early restenoses), and between 18 and 60 months (late restenosis). RESULTS: Of the 825 patients randomized to the surgical arm of the study, 720 actually underwent carotid endarterectomy, and 645 had complete ultrasound data. The aggregate incidence of residual and recurrent carotid stenosis for all time intervals ranged from 12.7% to 20.4%, depending on the positive predictive value confidence level desired. Residual disease occurred in 4.1% to 6.5%; true, early restenosis was found in 7.6% to 11.4%; and late restenosis occurred in 1.9% to 4.9%. None of the traditional risk factors showed a statistically significant effect on recurrent stenosis. The use of patch angioplasty closure reduced overall risk of restenosis from 21.2% to 7.1%, from 16.7% to 4.6%, and from 27.4% to 8.2%, depending on the PPV confidence level desired (P<0.001). Of the 136 patients judged to have recurrent stenosis, only 8 (5.9%) underwent reoperation (only 1 for symptoms). There was no correlation between late stroke and recurrent stenosis. CONCLUSIONS: Carotid endarterectomy is a durable procedure with a low rate of true restenosis, particularly when patch angioplasty is used to close the arteriotomy.

Cigarette smoking and other risk factors for silent cerebral infarction in the general population.

BACKGROUND AND PURPOSE: Silent cerebral infarctions (SCIs) have a prevalence between 10% and 40% in the transient ischemic attack population and have been associated with increased mortality and morbidity; however, little is known about the prevalence and risk factors for SCI in the general population. This report focuses on the role of cigarette smoking and other risk factors for SCI in the general population. METHODS: MRI scans were performed on 1737 participants selected from the general population as part of the Atherosclerosis Risk in Communities Study. Smoking status and other major cerebrovascular risk factors were assessed, and associations between smoking status and SCIs were established with the use of ANCOVA. RESULTS: Overall, the prevalence of SCI in this population aged 55 to 70 years was 11%. Cigarette smoking had an ordered association (P=0.029) with the presence of SCI, with the odds ratio (OR) of nonsmoking participants exposed to environmental tobacco smoke being 1.06 (95% confidence interval [CI], 0.64 to 1.75) times as great as for nonsmokers not exposed; the OR of past smokers was 1.16 (95% CI, 0.74 to 1.83) times greater, and the OR of current smokers was 1.88 (95% CI, 1.13 to 3.13) times greater. An increased prevalence was also noted among black, older, and hypertensive participants. CONCLUSIONS: This report is among the first to examine the risk factors for SCI in the general population and finds a relatively high overall prevalence (11%). There is an ordered relationship between increasing exposure to cigarette smoke and the presence of SCI that parallels the relationship between smoking and carotid atherosclerosis. The magnitude of the association with smoking is substantial compared with the effect of hypertension and other traditional cerebrovascular risk factors. The reduction in prevalence of SCI between current and past smokers and the trend that increased pack-years of smoking is related to increased prevalence of SCI are both additional arguments for smoking avoidance and cessation.