Wolfgang Lalouschek

Is Elevated Mean Platelet Volume Associated With a Worse Outcome in Patients With Acute Ischemic Cerebrovascular Events

Background and Purpose— Increased mean platelet volume (MPV), indicating higher platelet reactivity, is associated with an increased risk of myocardial infarction. Higher levels of MPV have been found in patients with acute ischemic stroke than in control subjects. Data from smaller studies regarding an association between MPV and stroke severity and outcome have been controversial. If such an association exists, MPV might help to identify patients at increased risk of a severe course of acute cerebrovascular disease. Methods— Within a multicenter, cross-sectional study nested in a cohort, we analyzed the relation between MPV and stroke severity as determined by the modified Rankin Scale after 1 week in 776 patients with acute ischemic stroke or transient ischemic attack. By multivariate logistic regression modeling, we determined the influence of MPV on stroke severity, adjusting for potential confounding factors. Results— Patients within the highest quintile of MPV had a significantly higher risk of suffering a severe stroke, defined as modified Rankin Scale score of 3 to 6, compared with patients within the lowest quintile (odds ratio = 2.6; 95% confidence interval, 1.6 to 4.1; P <0.001). This association remained significant after adjustment for possible confounding factors (odds ratio = 2.2; 95% confidence interval, 1.2 to 4.0; P = 0.013). Conclusions— Our results indicate that an elevated MPV is associated with a worse outcome for acute ischemic cerebrovascular events independent of other clinical parameters.

Inflammation and Carotid Artery—Risk for Atherosclerosis Study (ICARAS)

Background—Compelling evidence suggests that inflammation is fundamentally involved in the pathogenesis of atherosclerosis; however, temporal correlation between inflammation and morphological features of atherosclerosis progression has not been demonstrated unequivocally. Methods and Results—We prospectively studied 1268 consecutive patients who were initially asymptomatic with respect to carotid artery disease. Patients underwent serial carotid ultrasound investigations at baseline and after a follow-up interval of a median of 7.5 months (range 6 to 9 months), with measurement of carotid flow velocities and categorization of carotid arteries as 0% to 29%, 30% to 49%, 50% to 69%, 70% to 89%, or 90% to 99% stenosed or occluded. High-sensitivity C-reactive protein (hs-CRP) and serum amyloid A (SAA) were measured at baseline and follow-up. Progression of carotid atherosclerosis was found in 103 (8.1%) of 1268 patients. Hs-CRP and SAA, respectively, at baseline (P=0.004 and P=0.014) and follow-up (P<0.001 and P<0.001) and the change from baseline to follow-up (P<0.001 and P<0.001) were significantly associated with progressive atherosclerosis. Adjusted ORs (95% CI) for atherosclerosis progression with increasing quintiles of baseline hs-CRP were 1.65 (0.71 to 3.84), 1.87 (0.8 to 4.37), 3.32 (1.49 to 7.39), and 3.65 (1.65 to 8.08), and with increasing quintiles of baseline SAA, they were 0.86 (0.38 to 1.92), 0.99 (0.49 to 1.99), 1.72 (0.91 to 3.28), and 2.28 (1.24 to 4.20), respectively, compared with the lowest quintiles. Conclusions—These findings supply evidence for a close temporal correlation between inflammation and morphological features of rapidly progressive carotid atherosclerosis, which suggests that elevation or increase of the inflammatory biomarkers hs-CRP and SAA identifies the presence of active atherosclerotic disease.

Effect of pretreatment with statins on the severity of acute ischemic cerebrovascular events

OBJECTIVE Treatment with statins reduces the risk of ischemic stroke among patients at increased risk for vascular disease. Recent experimental data suggest neuroprotective properties of statins in acute cerebral ischemia. We investigated whether a premedication with statins is associated with a better outcome in patients with acute ischemic cerebrovascular events. METHODS Within a cross-sectional study, nested in a cohort we identified 1691 patients with a recent ischemic stroke or transient ischemic attack. Clinical severity of the vascular event was evaluated by the modified Rankin Scale (mRS) after 1 week. By means of multivariate logistic regression modeling, we determined the influence of prior statin use on stroke severity with adjustment for potential confounding factors. RESULTS Severe stroke, defined as a modified Rankin Scale of 5 or 6 (n=231; 14%), was less frequent in patients receiving statin treatment before the event (6% vs. 14%, OR=0.37; 95% CI 0.19 to 0.74; p=0.004). This association remained significant after adjustment for confounding factors. We found a significant interaction between the presence of diabetes and the effect of pretreatment with statins on stroke outcome. Of the patients with diabetes, none of those on statin treatment but 16% of those without a statin had a bad outcome. After exclusion of the group of diabetic patients with prior statin medication, the protective effect was reduced and not statistically significant anymore. CONCLUSIONS Pretreatment with statins seems to be associated with reduced clinical severity in patients with acute ischemic cerebrovascular events, particularly in patients with diabetes.

Headache at Stroke Onset in 2196 Patients With Ischemic Stroke or Transient Ischemic Attack

Background and Purpose— Headache is a common symptom in acute ischemic and hemorrhagic stroke, but many aspects of its association with other clinical factors are controversial. Methods— We analyzed characteristics of headache symptoms at stroke onset and associations between headache at stroke onset and at several clinical parameters in 2196 patients experiencing ischemic stroke or transient ischemic attack within a multicenter hospital-based stroke registry. Results— Five hundred eighty-eight (27%) patients experienced headache at stroke onset. In a multivariate analysis, headache at stroke onset was positively associated with female sex, history of migraine, younger age, cerebellar stroke (but not with other brain stem locations), and blood pressure values on admission <120 mm Hg systolic and <70 mm Hg diastolic. It showed no significant association with stroke severity measured by the modified Rankin Scale at days 5 to 7 after the event, presumed etiology, or time of day. Conclusions— Our results, derived from a large number of systematically documented patients with acute ischemic cerebrovascular events, show no association of headache with stroke etiology or outcome. Our results indicate that the previously described association of headache with vertebrobasilar stroke is mainly because of its association with cerebellar stroke. We could confirm previously described associations of headache at stroke onset with younger age and a history of migraine, implicating a careful evaluation of young patients with a focal neurological deficit and a history of migraine to avoid misclassification as “complicated migraine.”

Structural and serum surrogate markers of cerebrovascular disease in obstructive sleep apnea (OSA): association of mild OSA with early atherosclerosis.

AbstractThere is increasing evidence of a causal interaction between obstructive sleep apnea (OSA) and cerebrovascular disease. The aim of the study was to elucidate the relationship between the polysomnographically (PSG) measured severity of OSA and carotid atherosclerosis determined by ultrasonography and serum surrogate markers. 147 patients (102 males, 45 females) referred to our sleep laboratory for evaluation of snoring and sleep–disordered breathing were investigated. Carotid atherosclerosis was evaluated by serum analysis of high-sensitivity C–reactive protein (hs–CRP) and fibrinogen and four sonographic indices: intima–media thickness (IMT) of the common carotid artery (CCA), IMT from bulb to internal carotid artery (Bulb–ICA), combined IMT measurements from all segments and a plaque score (PlaS). Pearson correlation analysis, intergroup comparison (ANOVA), covariance analysis and a multiple regression were performed to assess the association between surrogate markers and respiratory variables. 44 patients had no OSA (apnea–hypopnea index AHI < 5/h), 27 mild (AHI 5–15), 25 moderate (AHI 15–30) and 51 severe OSA (AHI > 30). After adjusting for potential confounders, significant differences between the controls and all three OSA groups were observed in the CCA–IMT (p = 0.032) and in the PlaS between the controls and the severe group (p = 0.034). Multiple regression revealed the AHI as an independent predictor of CCA–IMT (p = 0.001) and combined IMT (p = 0.001), whereas the percentage of total sleep time with an oxygen saturation below 90 % was associated with Bulb–ICA IMT (p = 0.018) and hs–CRP (p = 0.015). OSA is associated with higher surrogate levels of cerebrovascular disease. Even mild OSA seems to predispose to early atherosclerosis.

Matched Case-Control Study on Factor V Leiden and the Prothrombin G20210A Mutation in Patients With Ischemic Stroke/Transient Ischemic Attack Up to the Age of 60 Years

Background and Purpose— The role of the factor V Leiden mutation (FVL) and the G20210A mutation of the prothrombin (factor II [FII]) gene for arterial thrombosis is not clear. Methods— We investigated the prevalence of these mutations in 468 patients with an acute stroke or transient ischemic attack (TIA) before the age of 60 years and in a healthy control population individually matched for age and gender. We also analyzed interactions between the mutations, gender, standard vascular risk factors, and stroke risk. Results— The prevalence of the FVL did not differ significantly between patients and control subjects. However, we found a significant interaction between the FVL, smoking, and risk of stroke in women: female smokers without FVL had a somewhat increased risk of stroke of 2.6 (95% CI, 1.5 to 4.6; P=0.001) compared with nonsmoking noncarriers of the FVL. Stroke risk was markedly higher in female smokers who had the FVL (OR, 8.8; 95% CI, 2.0 to 38.0; P=0.004) after multivariate adjustment. No such interaction was observed in men. In contrast, the frequency of the FII G20210A mutation was significantly higher in male patients compared with controls (6% versus 1%; adjusted OR, 6.1; 95% CI, 1.3 to 28.3; P=0.021). In females, the prevalence of the mutation was 3% in both groups. We found no significant interactions of the FII G20210A mutation with other vascular risk factors and stroke risk. Conclusions— Our data indicate a highly increased risk of ischemic cerebrovascular events in women up to 60 years who smoke and have FVL. We also found evidence for an increased risk of stroke/TIA in men who have the FII G20210A mutation but not in women in this age group.

A Meta-Analysis of Candidate Gene Polymorphisms and Ischemic Stroke in 6 Study Populations: Association of Lymphotoxin-Alpha in Nonhypertensive Patients

Background and Purpose— Ischemic stroke is a multifactorial disease with a strong genetic component. Pathways, including lipid metabolism, systemic chronic inflammation, coagulation, blood pressure regulation, and cellular adhesion, have been implicated in stroke pathophysiology, and candidate gene polymorphisms in these pathways have been proposed as genetic risk factors. Methods— We genotyped 105 simple deletions and single nucleotide polymorphisms from 64 candidate genes in 3550 patients and 6560 control subjects from 6 case–control association studies conducted in the United States, Europe, and China. Genotyping was performed using the same immobilized probe typing system and meta-analyses were based on summary logistic regressions for each study. The primary analyses were fixed-effects meta-analyses adjusting for age and sex with additive, dominant, and recessive models of inheritance. Results— Although 7 polymorphisms showed a nominal additive association, none remained statistically significant after adjustment for multiple comparisons. In contrast, after stratification for hypertension, 2 lymphotoxin-alpha polymorphisms, which are in strong linkage disequilibrium, were significantly associated among nonhypertensive individuals: LTA 252A>G (additive model; OR, 1.41 with 95% CI, 1.20 to 1.65; P=0.00002) and LTA 26Thr>Asn (OR, 1.19 with 95% CI, 1.06 to 1.34; P=0.003). LTA 252A>G remained significant after adjustment for multiple testing using either the false discovery rate or by permutation testing. The 2 single nucleotide polymorphisms showed no association in hypertensive subjects (eg, LTA 252A>G, OR, 0.93; 95% CI, 0.84 to 1.03; P=0.17). Conclusions— These observations may indicate an important role of LTA-mediated inflammatory processes in the pathogenesis of ischemic stroke.

Influence of Socioeconomic Status on Mortality After Stroke. Retrospective Cohort Study

Background and Purpose— Low socioeconomic status is associated with increased morbidity and mortality from stroke. The purpose of this study was to investigate the association between 4 independent measures of socioeconomic status and mortality of patients with acute ischemic stroke and transient ischemic attack. Methods— Socioeconomic status was assessed by taking into account levels of education, occupation, occupational status, and income. The end point was overall mortality. We used Cox proportional hazard models to adjust for age, sex, and severity of stroke on admission. Results— A total of 2606 stroke patients were followed up for a median of 2.5 years. Unskilled workers had a hazard ratio of 1.87 for death after stroke (95% CI, 1.37 to 2.55) and skilled workers had a hazard ratio of 1.61 (95% CI, 1.23 to 2.11) compared with white-collar workers. Of 4 income groups, patients with the second lowest level of income had a hazard ratio of 1.60 (95% CI, 1.10 to 2.33) and patients with the third lowest level of income had a hazard ratio of 1.71 (95% CI, 1.25 to 2.32) compared with patients with the highest income. The hazard ratio for death after stroke for early retired patients was 1.75 (95% CI, 1.01 to 3.04) compared with stroke patients in the active workforce at the time of the event. Conclusions— Socioeconomic status is associated with survival of patients with acute stroke after adjustment for age, sex, and severity of stroke. The influence of socioeconomic status seems to continue to affect the outcome largely independent of stroke severity.

The (-174) G/C polymorphism in the interleukin-6 gene is associated with the severity of acute cerebrovascular events.

BACKGROUND AND PURPOSE Elevated plasma levels of interleukin-6 (IL-6) are associated with an increased risk and worse outcome of acute vascular events. A common G/C promoter polymorphism at nt (-174) of the IL-6 gene has been shown to affect basal IL-6 levels. Consequently, the IL-6 genotype may be associated with risk and outcome of ischemic stroke (IS). We investigated the statistical association between this polymorphism and cerebrovascular events, as well as the clinical outcome in patients with symptoms before the age of 60. METHODS We examined 214 patients of 60 years or less with acute ischemic stroke or transient ischemic attack (TIA) and 214 age- and sex-matched healthy control subjects for the (-174) IL-6 G/C polymorphism by mutagenic separated polymerase chain reaction (MS PCR). Clinical severity of the vascular event was evaluated by validated scales at predefined points of time. RESULTS In the total group of patients, the genotype and allele frequencies in the patient group (38% GG, 45% GC, 17% CC; allelic frequency: 60% G, 40% C) did not differ significantly from the control group. However, individuals homozygous for the (-174)G variant had significantly worse scores on the NIH Stroke Scale (NIHSS) already on admission and 1 week after the event. Also, patients with severe disability 1 week and 3 months after the event (Rankin Scale (RS) 4 or 5; NIH Stroke Scale> or =6) were significantly more often carriers of the GG genotype. In a multivariate analysis, the IL-6 (-174)GG genotype was significantly associated with severe disability after 1 week (RS 4-5; odds ratio (OR)=3.2, 95% CI: 1.5-6.6; p=0.002; NIHSS> or =6; OR=4.2, 95% CI: 1.6-11.1). CONCLUSIONS The (-174)GG-genotype of the IL-6 gene is associated with severe stroke in young patients with acute cerebrovascular events. Further studies with larger patient groups are warranted to confirm these findings.

Polymorphisms of the inflammatory system and risk of ischemic cerebrovascular events.

Abstract Background: Chronic and acute infections are associated with an increased risk of stroke. The inflammatory response can be influenced by functional polymorphisms in components of the immune system. We hypothesized that these polymorphisms may also modulate the risk of ischemic cerebrovascular events. Methods: We determined the frequency of polymorphisms in tumor necrosis factor-α[(TNF-α) G(–376)A, G(–244)A, G(–238)A, G(–308)A], Toll-like receptor 4 [(TLR4) Gly299Asp and Thr399Ile], interleukin-1-receptor antagonist [(IL-1-RA) intron 2 variable-number tandem repeat], monocyte differentiation antigen CD14 receptor C(–260)T, and interleukin-6 [(IL-6) G(–174)C] genes in 404 patients with acute stroke or transient ischemic attack before the age of 60years and in 415 healthy individuals. We also tested for interactions between genotypes, recent febrile episodes and stroke risk. Results: None of the polymorphisms was associated with an increased risk of stroke after adjustment for age and gender. Following multivariate adjustment, carriers of the TNF-α (–308)A allele, the IL-1-RA 2* allele or the IL-6 (–174)C allele appeared to have an increased risk of stroke in association with a febrile episode prior to strokes. Conclusion: In our study none of the investigated polymorphisms of the inflammatory system was associated with the risk of acute cerebrovascular events before the age of 60years. However, post-hoc analyses indicate that some polymorphisms seem to contribute to the risk of stroke in combination with fever. Clin Chem Lab Med 2006;44:918–23.