Michael T. Wunderlich

Release of Glial Tissue–Specific Proteins After Acute Stroke A Comparative Analysis of Serum Concentrations of Protein S-100B and Glial Fibrillary Acidic Protein

Background and Purpose This study was aimed at the comparative analysis of serum concentrations of glial fibrillary acidic protein (GFAP) and protein S-100B in patients with acute stroke. Methods We investigated 32 patients with stroke symptoms consistent with cerebral ischemia in the anterior territory of vascular supply. Serial venous blood samples were taken after admission to the hospital and during the first 4 days after onset of stroke. Evaluation of lesion topography and volume of infarcted brain area was based on cranial CT data. The patients’ clinical status was consecutively evaluated by the National Institutes of Health Stroke Scale (NIHSS) and the Barthel Index score at discharge from the hospital. Results Protein S-100B and GFAP release was found to be significantly correlated (r =0.96;P <0.001). The release of both biochemical markers was associated with the volume of brain lesions (S-100B:r =0.957, P <0.0001; GFAP:r =0.955, P <0.0001) and the neurological status at discharge from the hospital (S-100B:r =0.821, P =0.0002; GFAP:r =0.717, P =0.0003). The highest correlation between both S-100B and GFAP serum concentration and Barthel score was calculated at the last time of blood sampling, 4 days after stroke onset (S-100B:r =0.621, P <0.001; GFAP:r =0.655, P <0.001). The release of both astroglia derived proteins differed between different subtypes of stroke. GFAP was found to be a more sensitive marker of brain damage in patients with smaller lacunar lesions or minor strokes. Conclusions Our results indicate that postischemic release patterns of GFAP and S-100B protein may allow insight into the underlying pathophysiology of acute cerebral infarcts and may be used as a valuable tool of clinical stroke treatment.

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.

Neurobehavioral Outcome Prediction After Cardiac Surgery: Role of Neurobiochemical Markers of Damage to Neuronal and Glial Brain Tissue

BACKGROUND AND PURPOSE The goal of the present study was to investigate the predictive value of neurobiochemical markers of brain damage (protein S-100B and neuron-specific enolase [NSE]) with respect to the short- and long-term neuropsychological outcomes after cardiac surgery with cardiopulmonary bypass (CPB). METHODS We investigated 74 patients who underwent elective CABG or valve replacement surgery and who showed no severe neurological deficits after surgery. Patients were investigated with a standardized neurological examination and a comprehensive neuropsychological and neuropsychiatric assessment 1 to 2 days before surgery, 3 and 8 days after surgery, and 6 months later. Serial venous blood samples were taken preoperatively and 1, 6, 20, and 30 hours after skin closure. Protein S-100B and NSE were analyzed with immunoluminometric assays. RESULTS Patients with severe postoperative neuropsychological disorders showed a significantly higher and longer release of neurobiochemical markers of brain damage. Patients who presented with a delirium according to DSM-III-R criteria 3 days after surgery had significantly higher postoperative S-100B serum concentrations. Multivariate analysis (based on postoperative NSE and S-100B concentrations and age of patients, type of operation, length of cross-clamp and perfusion time, and intraoperative and postoperative oxygenation) identified NSE and S-100B concentrations 6 to 30 hours after skin closure as the only variables that contributed significantly to a predictive model of the neuropsychological outcome. NSE, but not S-100B, release was significantly higher in patients undergoing valve replacement surgery. CONCLUSIONS Postoperative serum concentrations and kinetics of S-100B and NSE have a high predictive value with respect to the early neuropsychological and neuropsychiatric outcome after cardiac surgery. The analysis of NSE and S-100B release might allow insight into the underlying pathophysiology of brain dysfunction, thus providing a valuable tool to monitor and evaluate measures to improve cardiac surgery with CPB.

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.

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.

Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke.

This study aimed at an analysis of glial fibrillary acidic protein (GFAP) in acute ischemic stroke, its association with the neurovascular status and its potential value as monitoring parameter. In 53 consecutive patients, serial venous blood samples were taken on admission, 6, 12, 18, 24, 48, 72, 96, and 120 h after stroke onset. The neurovascular status was assessed by repetitive extracranial and transcranial duplex sonography. Neurologic deficits were quantified by the National Institutes of Health stroke scale, and functional outcome was assessed with the modified Rankin Scale. Mean GFAP values were elevated from admission on with highest levels 48 h after stroke onset. GFAP release was highly correlated with severity of neurologic deficits and infarct volume. In patients with persistent middle cerebral artery occlusion, GFAP increased significantly compared with patients with normal sonographic findings (P = 0.019) and recanalization after thrombolysis resulted in a significant reduced increase (P = 0.038). GFAP concentrations were associated with the functional outcome after 3 months. Release kinetics of GFAP are associated with patients clinical deficits and infarct volume, depend on the neurovascular status on admission and on early recanalization after thrombolysis, and may be used as an additional predictor of the early course and functional outcome.

Conservative Medical Treatment and Intravenous Thrombolysis in Acute Stroke from Carotid T Occlusion

Background: We aimed to analyse the course of early recanalization and corresponding functional outcome in patients with an acute occlusion of the carotid T who were treated conservatively or underwent intravenous thrombolysis. Methods: Forty-two patients with an acute occlusion of the carotid T within 6 h were recruited from consecutive admissions to a neurological department participating in the Duplex Sonography in Acute Stroke study. All patients underwent a standardized admission and follow-up procedure. Colour-coded duplex sonography was performed on admission, 30 min after thrombolysis, and at 6 and 24 h after onset of symptoms. Recanalization of the carotid T was classified as complete, partial and absent. Functional outcome was rated with the modified Rankin scale (mRS) at 3 months as favourable (mRS 0–2) or poor (mRS 3–6). Results: Within 6 h, complete or partial recanalization occurred in 1 of 27 patients treated conservatively and in 6 of 15 thrombolysed patients. Intravenous thrombolysis predicted early recanalization also after adjustment for age, sex, cardioembolic stroke aetiology and time to treatment (adjusted odds ratio, OR, 39.7; 95% confidence interval, CI, 2.0–801.7; p = 0.016). An early recanalization was the only selected predictor of a favourable outcome (OR, 13.6; 95% CI, 1.0–179.0; p = 0.047) at regression analysis, and was achieved in 3 thrombolysed patients but in none with conservative medical treatment. Conclusions: In patients treated conservatively, functional outcome is poor and early recanalization rarely occurs. The latter can be achieved by intravenous thrombolysis with a rate comparable to that found at an intra-arterial approach without major intracranial bleeding complications. Early recanalization is associated with a better functional outcome.

Sequential analyses of neurobiochemical markers of cerebral damage in cerebrospinal fluid and serum in CNS infections

Objective –  To elucidate the relation between release patterns and cerebrospinal fluid/serum concentrations of neurobiochemical markers of cerebral damage and their potential value as monitoring parameters in central nervous system infections.

Carotid endarterectomy in a patient with persistent proatlantal artery.

Accessible online at: www.karger.com/ced On admission, a 37-year-old man presented with an acute right-sided sensorimotor hemiparesis and nonfluent aphasia (NIH Stroke Scale score 11) persisting for more than 12 h. As cerebrovascular risk factors, the patient exhibited untreated arterial hypertension and chronic nicotine abuse (42 pack-years). Cranial computer tomography revealed a left-sided posterior border zone infarction. An electrocardiogram on admission, subsequent ECG monitoring and transthoracic echocardiography indicated no significant pathological findings. Extracranial color-coded duplex sonography revealed an occlusion of the left internal carotid artery (ICA) directly after the bifurcation. About 1.5 cm more distally, a high-frequency flow signal in projection on the lumen of the left ICA ( fig. 1 ) was detected. Transcranial duplex sonography showed a diminished blood flow velocity of the left middle and anterior cerebral arteries. The left vertebral artery was hypoplastic. Digital subtraction angiography confirmed the extracranial occlusion of the left ICA. Furthermore, it revealed a persistent proatlantal intersegmental artery originating from the V 3 segment of the vertebral artery and discharging into the ICA distally from the carotid occlusion ( fig. 2 ). In addition, the patient presented a fetal blood supply type (with hypoplastic P 1 segments), i.e. the posterior arteries were supplied by the intracranial distal internal artery via the posterior communicating arteries. An additional hypoplasia of the right A 1 segment made an anterior cross-flow impossible and led to the critical situation that the entire left hemisphere was supplied only by the persistent intersegmental proatlantal artery. Fluctuation and slight deterioration of the patient’s neurological symptoms despite hypertensive systolic blood pressure values between 160 and 200 mm Hg and additional small-sized infarcts of terminal vessels demarcated in a follow-up cranial computer tomography emphasized the critical hemodynamic situation. A revascularization procedure was seen as indicated. The patient underwent thrombendarterectomy (TEA) of the occluded left ICA 6 days after the onset of stroke symptoms. Afterwards, the neurological deficits did not improve in general but fluctuations were no longer observed and the patient could be transferred to a Cerebrovasc Dis 2007;23:458–459