Michael Goertler

Early Neurobehavioral Outcome After Stroke Is Related to Release of Neurobiochemical Markers of Brain Damage

BACKGROUND AND PURPOSE The study aimed to investigate the predictive value of neurobiochemical markers of brain damage (protein S-100B and neuron-specific enolase [NSE]) with respect to early neurobehavioral outcome after stroke. METHODS We investigated 58 patients with completed stroke who were admitted to the stroke unit of the Department of Neurology at Magdeburg University. Serial venous blood samples were taken after admission and during the first 4 days, and protein S-100B and NSE were analyzed by the use of immunoluminometric assays. In all patients, lesion topography and vascular supply were analyzed and volume of infarcted brain areas was calculated. The neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale (NIHSS) on admission, at days 1 and 4 on the stroke unit, at day 10, and at discharge from the hospital. Comprehensive neuropsychological examinations were performed in all patients with first-ever stroke event and supratentorial brain infarctions. Functional outcome was measured with the Barthel score at discharge from the hospital. RESULTS NSE and protein S-100B concentrations were significantly correlated with both volume of infarcted brain areas and NIHSS scores. Patients with an adverse neurological outcome had a significantly higher and significantly longer release of both markers. Neuropsychological impairment was associated with higher protein S-100B release, but this did not reach statistical significance. CONCLUSIONS Serum concentrations and kinetics of protein S-100B and NSE have a high predictive value for early neurobehavioral outcome after acute stroke. Protein S-100B concentrations at days 2 to 4 after acute stroke may provide valuable information for both neurological status and functional impairment at discharge from the acute care hospital.

Risk of Stroke, Transient Ischemic Attack, and Vessel Occlusion Before Endarterectomy in Patients With Symptomatic Severe Carotid Stenosis

Background and Purpose— We aimed to identify and determine the clinical relevance of parameters predictive of stroke recurrence and vessel occlusion before carotid endarterectomy. Methods— One hundred forty-three consecutive patients (105 men; mean age, 66.1±8 years) with symptomatic severe carotid artery stenosis were prospectively followed up until carotid endarterectomy. Patients had suffered an ischemic vascular event in the ipsilateral anterior circulation 9.6 days (median; range, 0 to 92 days) before presentation and assessment of stenosis. Admission examination included medical history, neurological status, extracranial and transcranial Doppler/duplex sonography, CT/MRI, ECG, and routine laboratory examination. All patients were reevaluated in the same way the day before surgery (without CT/MRI) and at recurrence of an ischemic event (including CT/MRI). Results— The end point of follow-up after 19.0 days (median; range, 0 to 118) was carotid endarterectomy in 120 patients, ipsilateral recurrent ischemia in 15 patients (7 transient events and 8 disabling strokes, with carotid occlusion in 4), and (asymptomatic) carotid occlusion in 8 patients. An exhausted cerebrovascular reactivity as determined by a Doppler CO2 test in the middle cerebral artery ipsilateral to the stenosis was the only independent predictive parameter for disabling stroke (odds ratio [OR], 9.7; 95% confidence interval [CI], 2.1 to 44.1;P =0.003). Stroke rate in patients with exhausted reactivity was 27% per month compared with 5.2% in those with normal reactivity. Progression of stenosis toward occlusion was observed in 12 patients and correlated with decreased poststenotic peak systolic velocity (OR, 0.75; 95% CI, 0.62 to 0.90;P =0.002), poststenotic arterial narrowing (OR, 22.7; 95% CI, 3.6 to 141.6;P =0.001), and very severe stenosis (OR, 13.6; 95% CI, 2.2 to 83.7;P =0.005). In patients without hemodynamic compromise, occlusion was not associated with increased stroke risk. Conclusions— Patients with recently symptomatic high-grade carotid artery stenosis and ipsilateral hemodynamic compromise are at high risk for early disabling stroke. Assessment of the hemodynamic status is recommended after diagnosis of severe carotid stenosis in symptomatic patients to further investigate and evaluate whether these patients may benefit from early endarterectomy.

Feasibility and validity of transcranial duplex sonography in patients with acute stroke

Objectives: To evaluate in a prospective multicentre setting the feasibility of transcranial colour coded duplex sonography (TCCS) for examination of the middle cerebral artery (MCA) in patients with acute hemispheric stroke, and to assess the validity of sonographic findings in a subgroup of patients who also had a correlative angiographic examination. Methods: TCCS was performed in 58 consecutive patients within six hours of the onset of a moderate to severe hemispheric stroke. Ultrasound contrast agent (Levovist) was applied if necessary. Thirty two patients also had computed tomography angiography (n=13), magnetic resonance angiography (n=18), or digital subtraction angiography (n=1). In 14 of these patients, both the sonographic and corresponding angiographic examination were performed within six hours of stroke onset (mean time difference between TCCS and angiography 0.8 hours). Eighteen patients, in whom angiography was carried out more than 24 hours after stroke onset, had a follow up TCCS for method comparison (mean time difference 6.1 hours). Results: Initial unenhanced TCCS performed 3.4 (SD 1.2) hours after the onset of symptoms depicted the symptomatic MCA mainstem in 32 patients (55%) (13 occlusions, one stenosis, 18 patent arteries). After signal enhancement, MCA status could be determined in 54 patients (93%) (p<0.05), showing an occlusion in 25, a stenosis in two, and a patent artery in 27 patients. In 31 of the 32 patients who had correlative angiography, TCCS and angiography produced the same diagnosis of the symptomatic MCA (10 occlusions, three stenoses, 18 patent arteries); TCCS was inconclusive in the remaining one. Conclusion: TCCS is a feasible, fast, and valid non-invasive bedside method for evaluating the MCA in an acute stroke setting, particularly when contrast enhancement is applied. It may be a valuable and cost effective alternative to computed tomography and magnetic resonance angiography in future stroke trials.

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.

Release of neurobiochemical markers of brain damage is related to the neurovascular status on admission and the site of arterial occlusion in acute ischemic stroke.

OBJECTIVES The study aimed at an analysis of the kinetics of protein S100B and neuron-specific enolase (NSE) and their relation to the site of arterial occlusion in patients with acute ischemic stroke. METHODS We investigated 32 consecutive patients admitted within 6 h after stroke onset. Serial venous blood samples were taken hourly between 1 and 6 h, and at 12, 18, 24, 48, 72, 96, and 120 h after stroke onset. The neurovascular status was assessed on admission and monitored by repetitive extracranial and transcranial duplex sonography. In all patients, infarct volume was calculated. The neurological deficit was quantified by the National Institutes of Health stroke scale score, and functional outcome after 3 months was assessed with the modified Rankin Scale. RESULTS Patients with normal flow velocities in basal cerebral arteries at admission showed significantly less S100B release than those with main stem or multiple branch occlusions (p<0.01). S100B cut-off values of 0.15 microg/l (between 6 and 18 h), 0.21 microg/l (between 24 and 48 h) and 0.5 microg/l (from 72 to 120 h) differentiated best between patients with initially normal and pathological sonographic vessel findings. The release of S100B and NSE was highly correlated with the severity of the corresponding neurological deficit as well as with the final infarct volume. S100B concentrations from 6 h on were associated with the functional outcome. S100B values 48 h after stroke above 0.2 microg/l indicated a poor functional status 3 months after stroke. CONCLUSIONS Protein S100B may serve as a monitoring parameter in acute ischemic stroke, especially with respect to the neurovascular status. Furthermore, S100B obtains additional information about functional outcome.

Rapid Decline of Cerebral Microemboli of Arterial Origin After Intravenous Acetylsalicylic Acid

BACKGROUND AND PURPOSE The present study investigated the influence of the antiplatelet agent acetylsalicylic acid (ASA) on cerebral microembolism as detected by transcranial Doppler sonography (TCD). METHODS Nine patients with recent transient ischemic attack or minor stroke of arterial origin were investigated. Eight had not received an antiplatelet or anticoagulant medication before TCD, and in 1 patient a preexisting ASA medication (100 mg/d) had not been changed since the onset of stroke symptoms. An initial 1-hour TCD monitoring was extended for an additional 2.5 hours after an intravenous bolus injection of 500 mg ASA and was repeated for 1 hour on the following day. RESULTS Microembolic signals (MES) were detected in all patients only on the symptomatic side. After the ASA bolus injection, a significant drop of the MES rate was found in 7 patients, all without previous medication, starting 30 minutes after the application (mean per hour=25.1 [range, 6 to 66] versus mean per hour=6.4 [range, 0 to 14]). In 3 of these patients, platelet aggregation tests were performed that demonstrated normal aggregation before bolus injection and inhibited aggregability as early as 30 minutes after bolus injection. The rate of MES remained unchanged in 1 patient without antiplatelet medication. The ninth patient, who had suffered an ischemic event on ASA, showed only a transient decrease of MES frequency. CONCLUSIONS In patients with recent stroke of arterial origin, intravenous ASA can rapidly reduce cerebral microemboli as detected by TCD. Microemboli might be a useful parameter to monitor early effects of antiplatelet therapy.

Release of brain–type and heart–type fatty acid–binding proteins in serum after acute ischaemic stroke

This study aimed at an analysis of the release of Braintype and Heart–type Fatty Acid– Binding Proteins (B–FABP and HFABP) in acute ischaemic stroke and their potential value as neurobiochemical markers of brain damage.We investigated 42 consecutive patients admitted within 6 hours after ischaemic stroke. Serial venous blood samples were taken hourly between 1 to 6 hours, and at 12, 18, 24, 48, 72, 96, and 120 hours after stroke onset. In all patients lesion topography was assessed and infarct volume was calculated. The neurological deficit was quantified by the National Institutes of Health stroke scale score, and functional outcome was assessed with the modified Rankin Scale 3 months after stroke.H–FABP and B–FABP concentrations showed peak values already 2 to 3 hours after stroke onset and remained elevated up to last measurements at 120 hours.Unlike BFABP, early H–FABP concentrations were significantly associated with the severity of the neurological deficit and the functional outcome. High H–FABP release was associated with large infarction on CT.Our study shows for the first time quantitative data of serum BFABP and H–FABP being elevated early in acute ischaemic stroke indicating that especially H–FABP might have the potential to be a rapid marker of brain damage and clinical severity. As both FABPs indicate damage to neuronal and glial tissue but are not specific for cerebral infarction, further investigations are needed to better understand the prolonged release of both in ischaemic stroke which is in contrast to the transient increase after myocardial infarction and can not be explained by their renal extraction.

Predictive value of the Essen Stroke Risk Score and Ankle Brachial Index in acute ischaemic stroke patients from 85 German stroke units

Background: Risk stratification can contribute to individualised optimal secondary prevention in patients with cerebrovascular disease. Objective: To prospectively investigate the prediction of the Essen Stroke Risk Score (ESRS) and a pathological Ankle Brachial Index (ABI) in consecutive patients hospitalised with acute ischaemic stroke or transient ischaemic attack (TIA) in 85 neurological stroke units throughout Germany. Methods: 852 patients were prospectively documented on standardised case report forms, including assessment of ESRS and ABI. After 17.5 months, recurrent cerebrovascular events, functional outcome or death could be assessed in 729 patients predominantly via central telephone interview. Results: After discharge from the documenting hospital, recurrent stroke occurred in 41 patients (5.6%) and recurrent TIA in 15 patients (2.1%). 52 patients (7.1%) had died, 33 (4.5%) from cardiovascular causes. Patients with an ESRS ⩾3 (vs <3) had a significantly higher risk of recurrent stroke or cardiovascular death (9.7% vs 5.1%; odds ratio (OR) 2.00, 95% confidence interval (CI) 1.08 to 3.70) and a higher recurrent stroke risk (6.9% vs 3.7%; OR 1.93, 95% CI 0.95 to 3.94). Patients with an ABI ⩽0.9 (vs >0.9) had a significantly higher risk of recurrent stroke or cardiovascular death (10.4% vs 5.5%; OR 2.00, 95% CI 1.12 to 3.56) and a higher recurrent stroke risk (6.6% vs 4.6%; OR 1.47, 95% CI 0.76 to 2.83). Conclusion: Our prospective follow-up study shows a significantly higher rate of recurrent stroke or cardiovascular death and a clear trend for a higher rate of recurrent stroke in patients with acute cerebrovascular events classified as high risk by an ESRS ⩾3 or a pathological ABI.

DIAS I: Duplex-Sonographic Assessment of the Cerebrovascular Status in Acute Stroke A Useful Tool for Future Stroke Trials

Background and Purpose A number of controlled trials have evaluated the benefit of intravenous thrombolysis in acute stroke with inconsistent results. None of these studies assessed the initial vascular status or provided information regarding the recanalization rate after therapy. Further trials need to clarify whether certain subgroups might possibly benefit more than others from intravenous thrombolysis. Therefore, a fast and valid method for assessment of cerebrovascular status is needed. In this multicenter study, we evaluated the potentials and limitations of color-coded duplex sonography (TCCS) for cerebrovascular status assessment in acute stroke patients before and after therapy. Furthermore, we compared the recanalization rate for patients referred to thrombolytic and conservative medical therapy. Methods Fifty-eight patients suffering from hemispheric stroke were enrolled consecutively in 8 centers. Duplex sonography was performed on admission, 2 hours after start of therapy, and 24 hours after onset of symptoms. Therapy was started within 6 hours. Results Intravenous thrombolysis was performed in 18 patients, conservative medical therapy in 39 patients, and early thromboendarterectomy in 1 patient. The middle cerebral artery (MCA) mainstem was patent in 29 patients (53.7%), occluded in 25 (46.3%), and was not assessable in 4 patients. Recanalization of the occluded MCA after 2 and 24 hours was diagnosed in 50% and 78% of the patients treated with rtPA and in 0% and 8% in the conservatively treated patients. Conclusions Intravenous thrombolysis is highly effective in restoring blood flow after MCA occlusion. TCCS is suitable for assessment of the cerebrovascular status in acute stroke and therefore might define therapeutically relevant subgroups of patients in future stroke trials on the basis of their vascular pathology.

Cessation of embolic signals after antithrombotic prevention is related to reduced risk of recurrent arterioembolic transient ischaemic attack and stroke

Objectives: To evaluate the reduction of embolic signals after the initiation of an antithrombotic secondary prevention in patients with recent arterioembolic stroke and to determine the predictive value of decreased microembolism on the risk of early stroke recurrence. Methods: Eighty six consecutive patients (55 men, 31 women; mean age 60.6 years) with a non-disabling arterioembolic ischaemic event in the anterior circulation within the last 30 days and a medium grade or high grade stenosis (≥50%) of the ipsilateral carotid or middle cerebral artery underwent 1 hour transcranial Doppler monitoring as part of the admission examinations. Antithrombotic secondary prevention was started after completion of admission. Patients in whom embolic signals were detected underwent a second monitoring within 4 days (mean time 1.8 days). All patients were followed up prospectively to evaluate the relation between presence and persistence of embolic signals and the risk of recurrent transient ischaemic attack (TIA) and stroke within the next 6 weeks. Results: In 44 patients, embolic signals were detected at admission, a mean 5.4 days (range 0 to 21 days) after the initial event. Twenty five were positive for embolic signals also at the second monitoring, in 19 signals had ceased. Forty two patients without embolic signals at admission served as controls. During follow up, six ischaemic events (two stroke, three TIA, one amaurosis fugax) occurred in 25 patients with persisting embolic signals but none in 19 patients in whom signals had ceased by the second monitoring. One patient in the control group had a TIA. The incidence of a recurrent event was 0.45 per 30 patient-days if embolic signals persisted compared with 0.015 if signals could not be detected or had ceased. Persistence of embolic signals was an independent predictor of a recurrent TIA or stroke (adjusted odds ratio 37.0; 95% confidence interval (95% CI) 3.5 to 333; p<0.003). Cessation and decrease of embolic signals was associated with the administration of antiplatelet agents but not with anticoagulation with intravenous heparin (p<0.001). Conclusions: Rapid cessation of embolic signals detected in patients with recently symptomatic arterial stenosis decreases increased risk of an early ischaemic recurrence. Effect of antithrombotic agents on embolic signals might serve as a marker for their efficacy on preventing stroke recurrence.