Felix Fluri

Copeptin: A Novel, Independent Prognostic Marker in Patients with Ischemic Stroke

Early prediction of outcome in patients with ischemic stroke is important. Vasopressin is a stress hormone. Its production rate is mirrored in circulating levels of copeptin, a fragment of provasopressin. We evaluated the prognostic value of copeptin in acute stroke patients.

Thrombolysis in Stroke Mimics: Frequency, Clinical Characteristics, and Outcome

Background and Purpose— Intravenous thrombolysis for acute ischemic stroke is usually based on clinical assessment, blood test results, and CT findings. Intravenous thrombolysis of stroke mimics may occur but has not been studied in detail. Methods— We determined frequency, clinical characteristics, and outcome of mimic patients versus patients with stroke treated with intravenous thrombolysis using data of a prospective, single-center thrombolysis data bank. Results— Among 250 patients, 243 (97.2%) had strokes and 7 (2.8%) were mimics. Seizure was the most frequent diagnosis among mimics. There was a trend toward lower National Institutes of Health Stroke Scale scores in mimics (9.9±4.2) compared with strokes (13.7±5.4; P=0.06). Global aphasia without hemiparesis was the presenting symptom in 3 (42.9%) mimics versus 8 (3.3%) strokes (P=0.002). Orolingual angioedema, symptomatic intracranial hemorrhage, and asymptomatic intracranial hemorrhage occurred in 3 (1.2%), 13 (5.3%), and 30 (12.3%) patients with stroke, but were absent in mimics. After 3 months, 6 (85.7%) mimics and 86 (35.4%) strokes had a modified Rankin Scale score of 0 to 1 (P=0.01). Conclusions— Only few patients receiving intravenous thrombolysis did eventually have a final diagnosis other than stroke, ie, mostly seizures. Their outcome was favorable. Although clinical features differed between the stroke and the mimic groups, the differences were not distinctive enough to allow assigning individual patients to either of the groups. Multimodal neuroimaging or electroencephalographic recordings may be helpful for this assignment. However, their potential benefit has to be weighed against the potential harm of delayed thrombolysis.

Animal models of ischemic stroke and their application in clinical research

This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models.

Intravenous Thrombolysis in Stroke Attributable to Cervical Artery Dissection

Background and Purpose— Intravenous thrombolysis (IVT) for stroke seems to be beneficial independent of the underlying etiology. Whether this is also true for cervical artery dissection (CAD) is addressed in this study. Methods— We used the Swiss IVT databank to compare outcome and complications of IVT-treated patients with CAD with IVT-treated patients with other etiologies (non-CAD patients). Main outcome and complication measures were favorable 3-month outcome, intracranial cerebral hemorrhage, and recurrent ischemic stroke. Modified Rankin Scale score ≤1 at 3 months was considered favorable. Results— Fifty-five (5.2%) of 1062 IVT-treated patients had CAD. Patients with CAD were younger (median age 50 versus 70 years) but had similar median National Institutes of Health Stroke Scale scores (14 versus 13) and time to treatment (152.5 versus 156 minutes) as non-CAD patients. In the CAD group, 36% (20 of 55) had a favorable 3-month outcome compared with 44% (447 of 1007) non-CAD patients (OR, 0.72; 95% CI, 0.41 to 1.26), which was less favorable after adjustment for age, gender, and National Institutes of Health Stroke Scale score (OR, 0.50; 95% CI, 0.27 to 0.95; P=0.03). Intracranial cerebral hemorrhages (asymptomatic, symptomatic, fatal) were equally frequent in CAD (14% [7%, 7%, 2%]) and non-CAD patients (14% [9%, 5%, 2%]; P=0.99). Recurrent ischemic stroke occurred in 1.8% of patients with CAD and in 3.7% of non-CAD-patients (P=0.71). Conclusion— IVT-treated patients with CAD do not recover as well as IVT-treated non-CAD patients. However, intracranial bleedings and recurrent ischemic strokes were equally frequent in both groups. They do not account for different outcomes and indicate that IVT should not be excluded in patients who may have CAD. Hemodynamic compromise or frequent tandem occlusions might explain the less favorable outcome of patients with CAD.

Prognostic Value of Copeptin One-Year Outcome in Patients With Acute Stroke

Background and Purpose— An accurate long-term outcome prediction may improve management of stroke patients. We investigated the ability of copeptin to predict 1-year outcome in stroke patients. Methods— In this preplanned post hoc analysis, the National Institutes of Health Stroke Scale score and copeptin levels were measured on admission in a cohort of patients with ischemic stroke. The primary end point was functional outcome (modified Rankin Scale score <3 or 3–6) after 1 year. The secondary end point was all-cause mortality. Results— Of 362 patients, 341 (94.2%) completed the 1-year follow-up, 146 (43%) patients had an unfavorable functional outcome, and 66 (20%) died. Multivariate logistic-regression analysis adjusted for age and National Institutes of Health Stroke Scale score showed that copeptin was an independent predictor of functional outcome (odds ratio=4.00; 95% CI, 1.94–8.19) and death (odds ratio=2.68; 95% CI, 1.24–5.82). The area under the receiver operating characteristic curve of copeptin was 0.72 (95% CI, 0.67–0.77) for functional outcome and 0.74 (95% CI, 0.69–0.78) for mortality. Copeptin improved the area under the receiver operating characteristic curve of the National Institutes of Health Stroke Scale score for functional outcome from 0.70 (95% CI, 0.64–0.74) to 0.76 (95% CI, 0.71–0.82; P=0.002) and for mortality from 0.74 (95% CI, 0.69–0.78) to 0.78 (95% CI, 0.71–0.85; P=0.04). Conclusions— Copeptin levels are a useful, complementary tool to predict functional outcome and mortality 1 year after stroke. Clinical Trial Registration— ISCTRN 00390962; clinicaltrials.gov No. NCT00390962.

Mannose-Binding Lectin Deficiency is Associated with Smaller Infarction Size and Favorable Outcome in Ischemic Stroke Patients

Background The Mannose-binding lectin (MBL) pathway of complement plays a pivotal role in the pathogenesis of ischemia/reperfusion (I/R) injury after experimental ischemic stroke. As comparable data in human ischemic stroke are limited, we investigated in more detail the association of MBL deficiency with infarction volume and functional outcome in a large cohort of patients receiving intravenous thrombolysis or conservative treatment. Methodology/Principal Findings In a post hoc analysis of a prospective cohort study, admission MBL concentrations were determined in 353 consecutive patients with an acute ischemic stroke of whom 287 and 66 patients received conservative and thrombolytic treatment, respectively. Stroke severity, infarction volume, and functional outcome were studied in relation to MBL concentrations at presentation to the emergency department. MBL levels on admission were not influenced by the time from symptom onset to presentation (p = 0.53). In the conservative treatment group patients with mild strokes at presentation, small infarction volumes or favorable outcomes after three months demonstrated 1.5 to 2.6-fold lower median MBL levels (p = 0.025, p = 0.0027 and p = 0.046, respectively) compared to patients with more severe strokes. Moreover, MBL deficient patients (<100 ng/ml) were subject to a considerably decreased risk of an unfavorable outcome three months after ischemic stroke (adjusted odds ratio 0.38, p<0.05) and showed smaller lesion volumes (mean size 0.6 vs. 18.4 ml, p = 0.0025). In contrast, no association of MBL concentration with infarction volume or functional outcome was found in the thrombolysis group. However, the small sample size limits the significance of this observation. Conclusions MBL deficiency is associated with smaller cerebral infarcts and favorable outcome in patients receiving conservative treatment. Our data suggest an important role of the lectin pathway in the pathophysiology of cerebral I/R injury and might pave the way for new therapeutic interventions.

Transient ischemic attack versus transient ischemic attack mimics : frequency, clinical characteristics and outcome

Background: There is insufficient evidence regarding which clinical features are best suited to distinguish between transient ischemic attack (TIA) and disorders mimicking TIA (TIA mimics). Methods: We compared the frequency, clinical characteristics and outcome of patients with TIA and TIA mimics in a prospective, single-center emergency department cohort over 2 years. Results: Of 303 patients, 248 (81.8%) had a TIA and 55 (18.2%) had TIA mimics. Epileptic seizures (26/55; 43.7%) and migraine attacks (13/55; 23.6%) were the most common TIA mimics. In patients presenting with unilateral paresis, TIA mimics were less likely than in patients without unilateral paresis [odds ratio (OR) 0.35, 95% confidence interval (CI) 0.17–0.68]. Memory loss (OR 9.17, 95% CI 2.89–32.50), headache (OR 3.71, 95% CI 1.07–12.78) and blurred vision (OR 2.48, 95% CI 0.90–6.59) increased the odds of TIA mimics. Once these clinical features were taken into account, neither aphasia, dysarthria, sensory loss, blood pressure values nor the duration of symptoms were found to improve explanation of the underlying status. At 3 months, stroke, recurrent TIA and myocardial infarction were absent in patients with TIA mimics but occurred in 13 (5.2%), 20 (8.1%) and 3 (1.2%) TIA patients, respectively. Conclusions: About 1 in every 5 patients with suspected TIA had a TIA mimic. Paresis suggested TIA, while other clinical variables used in risk assessment scores after TIA were not shown to distinguish between the two entities. Patients with TIA mimics had a better short-term prognosis.

Copeptin adds prognostic information after ischemic stroke Results from the CoRisk study

Objective: To evaluate and validate the incremental value of copeptin in the prediction of outcome and complications as compared with established clinical variables. Methods: In this prospective, multicenter, cohort study, we measured copeptin in the emergency room within 24 hours from symptom onset in 783 patients with acute ischemic stroke. The 2 primary end points were unfavorable functional outcome (modified Rankin Scale score 3–6) and mortality within 90 days. Secondary end points were any of 5 prespecified complications during hospitalization. Results: In multivariate analysis, higher copeptin independently predicted unfavorable outcome (adjusted odds ratio 2.17 for any 10-fold copeptin increase [95% confidence interval {CI}, 1.46–3.22], p < 0.001), mortality (adjusted hazard ratio 2.40 for any 10-fold copeptin increase [95% CI, 1.60–3.60], p < 0.001), and complications (adjusted odds ratio 1.93 for any 10-fold copeptin increase [95% CI, 1.33–2.80], p = 0.001). The discriminatory accuracy, calculated with the area under the receiver operating characteristic curve, improved significantly for all end points when adding copeptin to the NIH Stroke Scale score and the multivariate models. Moreover, the combination of copeptin with a validated score encompassing both the NIH Stroke Scale and age led to a net reclassification improvement of 11.8% for functional outcome and of 37.2% for mortality. Conclusions: In patients with ischemic stroke, copeptin is a validated blood marker that adds predictive information for functional outcome and mortality at 3 months beyond stroke severity and age. Copeptin seems to be a promising new blood marker for prediction of in-hospital complications.

Copeptin, Procalcitonin and Routine Inflammatory Markers–Predictors of Infection after Stroke

Background Early predictors for the development of stroke-associated infection may identify patients at high risk and reduce post-stroke infection and mortality. Methods In 383 prospectively enrolled acute stroke patients we assessed time point and type of post-stroke infections (i.e. pneumonia, urinary tract infection (UTI) other infection (OI)). Blood samples were collected on admission, and days 1, and 3 to assess white blood cells (WBC), monocytes, C-reactive protein (CRP), procalcitonin (PCT), and copeptin. To determine the magnitude of association with the development of infections, odds ratios (OR) were calculated for each prognostic blood marker. The discriminatory ability of different predictors was assessed, by calculating area under the receiver operating characteristic curves (AUC). Prognostic models including the three parameters with the best performance were identified. Results Of 383 patients, 66 (17.2%) developed an infection after onset of stroke. WBC, CRP, copeptin and PCT were all independent predictors of any infection, pneumonia and UTI developed at least 24 hours after measurements. The combination of the biomarkers WBC, CRP and copeptin (AUC: 0.92) and WBC, CRP and PCT (AUC: 0.90) showed a better predictive accuracy concerning the development of pneumonia during hospitalization compared to each marker by itself (p-Wald <0.0001). Conclusion Among ischemic stroke patients, copeptin, PCT, WBC and CRP measured on admission were predictors of infection in general, and specifically for pneumonia and UTI within 5 days after stroke. The combination of these biomarkers improved the prediction of patients who developed an infection.

Stress hormones predict cerebrovascular re-events after transient ischemic attacks

Background: TIA is a strong predictor of subsequent stroke. The hypothalamic stress hormone copeptin is an accurate prognostic marker in acute ischemic stroke. This study assessed prognostic reliability of 2 distinct stress hormones, copeptin and cortisol, for the risk stratification of re-events in patients with TIA. Methods: We conducted a prospective study in patients admitted to the emergency department with a TIA. Clinical risk scoring using the ABCD2 score was determined and both hormones were measured in plasma on admission. The primary endpoint was a cerebrovascular re-event within 90 days. Results: We included 107 consecutive patients with TIA. Re-events occurred in 10 patients (9%). Copeptin levels were higher in patients with a re-event compared with patients without re-event (p = 0.02), in contrast to cortisol (p = 0.53). Copeptin revealed a higher area under the receiver operating characteristics curve (AUC) to predict re-events compared to the ABCD2 score (AUC of 0.73 vs 0.43; p < 0.01) and improved its prognostic accuracy (AUC of combined model of 0.77; p = 0.002). Conclusion: Measurement of plasma copeptin but not cortisol levels in patients with TIA provides additional prognostic information beyond the ABCD2 clinical risk score alone. If confirmed in future studies, routine copeptin measurement may be an additional tool for risk stratification and targeted resource allocation after TIA.