Christian Foerch

Serum S100B Predicts a Malignant Course of Infarction in Patients With Acute Middle Cerebral Artery Occlusion

Background and Purpose— Early predictors of infarct volume may improve therapeutic decisions in patients with acute cerebral ischemia. We investigated whether measurements of serum astroglial protein S100B can predict a malignant course of infarction in acute middle cerebral artery (MCA) occlusion. Methods— We included 51 patients (24 women, mean age 69.1±12.4 years) admitted within 6 hours after stroke symptom onset caused by proximal MCA occlusion, as shown by magnetic resonance angiography (n=39), intra-arterial angiography (n=4), or transcranial duplex sonography (n=8). Blood samples were drawn at hospital admission and 8, 12, 16, 20, and 24 hours after symptom onset. Serum S100B concentrations were determined using a fully automated immunoluminometric assay. A malignant course of infarction was defined as the occurrence of clinical signs of cerebral herniation within the first 7 days of treatment or the clinical decision to perform decompressive hemicraniectomy caused by critical space-occupying swelling as detected by repeated neuroimaging. Results— Sixteen patients developed malignant infarction (31%). Beginning with the 12-hour value, mean S100B serum concentrations were significantly higher in patients with a malignant course compared with those without (12 hours 1.23±1.24 versus 0.29±0.45 μg/L; 16 hours 1.80±1.65 versus 0.38±0.53 μg/L; 20 hours 1.90±1.53 versus 0.44±0.48 μg/L; and 24 hours 2.41±1.59 versus 0.57±0.66 μg/L; all P <0.001). A 12-hour S100B value >0.35 μg/L predicted malignant infarction with 0.75 sensitivity and 0.80 specificity. A 24-hour value >1.03 μg/L provided 0.94 sensitivity and 0.83 specificity. Conclusions— The serum marker S100B can predict a malignant course of infarction in proximal MCA occlusion. This finding may improve the identification and monitoring of patients at particularly high risk for herniation.

Serum glial fibrillary acidic protein as a biomarker for intracerebral haemorrhage in patients with acute stroke

Background: Biomarkers of stroke are an evolving field of clinical research. A serum marker which can differentiate between haemorrhagic and ischaemic stroke in the very early phase would help to optimise acute stroke management. Objective: To examine whether serum glial fibrillary acidic protein (GFAP) identifies intracerebral haemorrhage (ICH) in acute stroke patients. Methods: A pilot study assessing 135 stroke patients admitted within six hours after symptom onset. Diagnosis of ICH (n = 42) or ischaemic stroke (n = 93) was based on brain imaging. GFAP was determined from venous blood samples obtained immediately after admission, using a research immunoassay. Results: GFAP was detectable in the serum of 39 patients (34 of 42 (81%) with ICH, and five of 93 (5%) with ischaemic stroke). Serum GFAP was substantially raised in patients with ICH (median 11 ng/l, range 0 to 3096 ng/l) compared with patients with ischaemic stroke (median 0 ng/l, range 0 to 14 ng/l, p<0.001). Using receiver operating characteristic curve analysis, a cut off point of 2.9 ng/l provided a sensitivity of 0.79 and a specificity of 0.98 for the identification of ICH in acute stroke (positive predictive value 0.94, negative predictive value 0.91; p<0.001). Conclusions: Serum GFAP can reliably detect ICH in the acute phase of stroke. Further evaluation of the usefulness of GFAP as an early diagnostic marker of ICH is now required, with the aim of optimising cause specific emergency management.

Difference in recognition of right and left hemispheric stroke

Symptoms of cerebrovascular events differ depending on the hemisphere in which the lesion arises, thereby affecting disease recognition and management. We aimed to establish whether left and right hemispheric strokes are unequally distributed in inpatients. We obtained data from a large hospital-based stroke registry in Germany. 11,328 patients (56%) had left hemispheric events and 8769 (44%) had right-sided lesions (p<0.0001). Age, stroke severity, and time from symptom onset to admission were significantly associated with left hemispheric stroke, suggesting a selection effect. Difficulties in recognition of symptoms due to right hemispheric stroke challenge efforts to optimise stroke management, particularly in the critical early hours of stroke.

Elevated Serum S100B Levels Indicate a Higher Risk of Hemorrhagic Transformation After Thrombolytic Therapy in Acute Stroke

Background and Purpose— Intracerebral hemorrhage constitutes an often fatal sequela of thrombolytic therapy in patients with ischemic stroke. Early blood–brain barrier disruption may play an important role, and the astroglial protein S100B is known to indicate blood–brain barrier dysfunction. We investigated whether elevated pretreatment serum S100B levels predict hemorrhagic transformation (HT) in thrombolyzed patients with stroke. Methods— We retrospectively included 275 patients with ischemic stroke (mean age of 69±13 years; 46% female) who had received thrombolytic therapy within 6 hours of symptom onset. S100B levels were determined from pretreatment blood samples. Follow-up brain scans were obtained 24 hours after admission, and HT was classified as either hemorrhagic infarction (1, 2) or parenchymal hemorrhage (1, 2). Results— HT occurred in 80 patients (29%; 45 hemorrhagic infarction, 35 parenchymal hemorrhage). Median S100B values were significantly higher in patients with HT (0.14 versus 0.11 &mgr;g/L; P=0.017). An S100B value in the highest quintile corresponded to an OR for any HT of 2.87 (95% CI: 1.55 to 5.32; P=0.001) in univariate analysis and of 2.80 (1.40 to 5.62; P=0.004) after adjustment for age, sex, symptom severity, timespan from symptom onset to hospital admission, vascular risk factors, and storage time of serum probes. A pretreatment S100B value above 0.23 &mgr;g/L had only a moderate sensitivity (0.46) and specificity (0.82) for predicting severe parenchymal bleeding (parenchymal hemorrhage 2). Conclusions— Elevated S100B serum levels before thrombolytic therapy constitute an independent risk factor for HT in patients with acute stroke. Unfortunately, the diagnostic accuracy of S100B is too low for it to function in this context as a reliable biomarker in clinical practice.

Experimental Model of Warfarin-Associated Intracerebral Hemorrhage

Background and Purpose— Future demographic changes predict an increase in the number of patients with atrial fibrillation. As long-term anticoagulation for the prevention of ischemic strokes becomes more prevalent, the burden of warfarin-associated intracerebral hemorrhage (W-ICH) is likely to grow. However, little is known about the clinical aspects and pathophysiologic mechanisms of W-ICH. This study describes the development of a mouse model of W-ICH in which hematoma growth and outcomes can be correlated with anticoagulation parameters. Methods— CD-1 mice were treated with warfarin (2 mg/kg per 24 hours) added to drinking water. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum. Hemorrhagic blood volume was quantified by means of a photometric hemoglobin assay 2 and 24 hours after hemorrhage induction. Neurologic outcomes were assessed on a 5-point scale. Results— The international normalized ratio in nonanticoagulated mice was 0.8±0.1. After 24 (W-24) and 30 (W-30) hours of warfarin pretreatment, international normalized ratio values increased to 3.5±0.9 and 7.2±3.4, respectively. Compared with nonanticoagulated mice, mean hemorrhagic blood volume determined 24 hours after hemorrhage induction was found to be 2.5-fold larger in W-24 mice (P=0.019) and 3.1-fold larger in W-30 mice (P<0.001, n=10 per group). Mortality at 24 hours after hemorrhage induction was 0% in nonanticoagulated mice, 10% in W-24 mice, and 30% in W-30 mice. Hematoma enlargement between 2 and 24 hours after hemorrhage induction was −1.4% for nonanticoagulated mice, 22.9% for W-24 mice, and 62.2% for W-30 mice. Conclusions— This study characterizes the first experimental model of W-ICH. It may be helpful in gaining further insights into the pathophysiology of W-ICH and may be used for testing the efficacy of treatment strategies, such as hemostatic therapy, in this severe subtype of stroke.

Characterisation of the Diagnostic Window of Serum Glial Fibrillary Acidic Protein for the Differentiation of Intracerebral Haemorrhage and Ischaemic Stroke

Background: The rapid differentiation between intracerebral haemorrhage (ICH) and ischaemic stroke (IS) using biomarker testing would allow the prehospital, cause-specific management of stroke patients. Based on single measurements made during the acute phase of stroke, the value of serum glial fibrillary acidic protein (GFAP) was reported to be higher in ICH patients than in IS patients. The aim of the present study was to characterise the diagnostic window of serum GFAP for differentiating between ICH and IS. Methods: 63 stroke patients admitted within 6 h of symptom onset were prospectively included. ICH (n = 18) and IS (n = 45) were diagnosed using brain imaging. Blood sampling was scheduled for 1, 2, 3, 4, 6, 12, 24 and 48 h after stroke onset (if applicable), and serum GFAP was measured using an ELISA test. Results: For the first 24 h after stroke, median GFAP values in IS patients remained below the detection limit. Between 2 and 6 h of stroke onset, serum GFAP was significantly higher in ICH patients than in IS patients (p < 0.001 for all 4 time points). According to a receiver operating characteristic curve analysis, the overall diagnostic accuracy of GFAP in differentiating between ICH and IS was >0.80 within the 2- to 6-hour time window. Two hours after stroke onset, serum GFAP values were significantly correlated with ICH volume (r = 0.755, p = 0.007). Conclusions: The time window between 2 and 6 h after stroke onset is best for using GFAP to differentiate between ICH and IS. In the very early phase (i.e. <2 h), sensitivity for detecting ICH is low, thus hampering the application of GFAP as a near-patient test in the prehospital phase.

Invited Article: Searching for oracles?: Blood biomarkers in acute stroke

Emerging data suggest that a wide array of measurable biomarkers in blood may provide a novel window into the pathophysiology of stroke. In this review, we survey the state of progress in the field. Three specific questions are assessed. Can biomarkers augment the clinical examination and powerful brain imaging tools to enhance the accuracy of the diagnostic process? Can biomarkers be used to help triage patients for thrombolytic therapy? Can biomarkers help predict patients who are most susceptible to malignant infarction? Many encouraging molecular candidates have been found that appear to match the known cascades of neurovascular injury after stroke. However, whether these putative biomarkers may indeed have direct clinical utility remains to be quantitatively validated. Larger clinical trials are warranted to establish the sensitivity and specificity of biomarkers for routine use in clinical stroke.

Plasma and Brain Matrix Metalloproteinase-9 After Acute Focal Cerebral Ischemia in Rats

Background and Purpose— Plasma levels of matrix metalloproteinase-9 (MMP-9) have been proposed to be a useful biomarker for assessing pathological events in brain. Here, we examined the temporal profiles of MMP-9 in blood and brain using a rat model of acute focal cerebral ischemia. Methods— Plasma and brain levels of MMP-2 and MMP-9 were quantified at 3, 6, 12, and 24 hours after permanent middle cerebral artery occlusion in male Sprague-Dawley rats. Infarct volumes at 24 hours were confirmed with 2,3,5-triphenyl-tetrazolium-chloride staining. Results— In plasma, zymographic bands were detected between 70 and 95 kDa corresponding to pro-MMP-2, pro-MMP-9, and activated MMP-9. A higher 135-kDa band was also seen that is likely to be NGAL-conjugated MMP-9. After ischemia, there were no significant changes in pro-MMP-2, but plasma levels of pro-MMP-9 steadily increased over the course of 24 hours. Activated MMP-9 levels in plasma were significantly elevated only at 24 hours. Plasma NGAL-MMP-9 complexes showed a transient elevation between 3 to 6 hours, after which levels decreased back down to pre-ischemic baselines. In brain homogenates, pro-MMP-2, pro-MMP-9, and activated MMP-9 were seen but no NGAL-MMP-9 bands were detected. Compared to the contralateral hemisphere, MMP-2 and MMP-9 levels in ischemic brain progressively increased over the course of 24 hours. Overall levels of MMP-9 in plasma and brain were significantly correlated, especially at 24 hours. Plasma levels of pro-MMP-9 at 24 hours were correlated with final infarct volumes. Conclusions— Elevated plasma levels of MMP-9 appear to be correlated with brain levels within 24 hours of acute cerebral ischemia in rats. Further investigation into clinical profiles of MMP-9 in acute stroke patients may be useful.

Diagnostic Accuracy of Plasma Glial Fibrillary Acidic Protein for Differentiating Intracerebral Hemorrhage and Cerebral Ischemia in Patients with Symptoms of Acute Stroke

BACKGROUND Glial fibrillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke. GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. In this study the diagnostic accuracy of plasma GFAP was determined in a prospective multicenter approach. METHODS Within a 1-year recruitment period, patients suspected of having acute (symptom onset<4.5 h before admission) hemispheric stroke were prospectively included into the study in 14 stroke centers in Germany and Switzerland. A blood sample was collected at admission, and plasma GFAP was measured by use of an electrochemiluminometric immunoassay. The final diagnosis, established at hospital discharge, was classified as ICH, ischemic stroke, or stroke mimic. RESULTS The study included 205 patients (39 ICH, 163 ischemic stroke, 3 stroke mimic). GFAP concentrations were increased in patients with ICH compared with patients with ischemic stroke [median (interquartile range) 1.91 μg/L (0.41-17.66) vs 0.08 μg/L (0.02-0.14), P<0.001]. Diagnostic accuracy of GFAP for differentiating ICH from ischemic stroke and stroke mimic was high [area under the curve 0.915 (95% CI 0.847-0.982), P<0.001]. A GFAP cutoff of 0.29 μg/L provided diagnostic sensitivity of 84.2% and diagnostic specificity of 96.3% for differentiating ICH from ischemic stroke and stroke mimic. CONCLUSIONS Plasma GFAP analysis performed within 4.5 h of symptom onset can differentiate ICH and ischemic stroke. Studies are needed to evaluate a GFAP point-of-care system that may help optimize the prehospital triage and management of patients with symptoms of acute stroke.

Pretreatment With Antiplatelet Agents Is Not Independently Associated With Unfavorable Outcome in Intracerebral Hemorrhage

Background and Purpose— This study investigated the effect of preexisting antiplatelet therapy on mortality and functional outcome in patients with intracerebral hemorrhage (ICH). Methods— Our analysis was based on a large, country-wide stroke registry in Germany. All parameters relevant to this analysis, including age, prehospital status (according to the modified Rankin Scale, mRS), International Classification of Diseases–based diagnosis, and pretreatment with antiplatelet agents or oral anticoagulants, were recorded prospectively. Main outcome measures were in-hospital mortality rate and functional status at hospital discharge (mRS). Results— Over a 2-year period, 1691 patients with ICH (ICD-10: I61) were documented (48% female; mean age, 72±12 years). At symptom onset, 26% were taking antiplatelet agents, and 12% were taking oral anticoagulants. By univariate logistic regression, pretreatment with antiplatelet drugs or anticoagulants was found to be a significant predictor of in-hospital mortality (odds ratio [OR], 1.42; P=0.008; OR, 1.53; P<0.001) and of an unfavorable functional outcome (defined as mRS >2 or death; OR, 1.33, P=0.039; OR, 1.51; P<0.001). However, after adjustment for age and prehospital status, antiplatelet pretreatment was no longer an independent risk factor of in-hospital death (OR, 1.12; P=0.490) or unfavorable functional outcome (OR, 0.97; P=0.830), whereas the influence of pretreatment with oral anticoagulants remained significant (OR, 1.45; P<0.001; OR, 1.42; P=0.009). Conclusions— In contrast to oral anticoagulants, pretreatment with antiplatelet agents is not an independent risk factor of mortality and unfavorable outcome in patients with ICH.