Hans Worthmann

The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome.

Background: Early inflammation has been suggested as an important factor contributing to unfavorable prognosis after acute ischemic stroke. The present study aimed to clarify the temporal dynamics of discrete inflammatory markers/mediators for future mechanism-targeting anti-inflammatory strategies in ischemic brain damage. Methods: Blood samples of 69 patients with transient ischemic attack or ischemic stroke were taken upon admission and at time points 6, 12 and 24 h, as well as 3 and 7 days after symptom onset for analysis of monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), interleukin-6 (IL-6), C-reactive protein (CRP) and the brain damage marker S100B. Clinical scores (modified Rankin Scale, National Institute of Health Stroke Scale) were assessed on day 90. Results: MCP-1, MMP-9, TIMP-1, IL-6, CRP and S100B showed significantly different time courses depending on stroke outcome. While the levels of IL-6, MCP-1 and MMP-9 increased already a few hours after symptom onset, CRP and S100B gradually rose commencing at 12–24 h. TIMP-1 demonstrated an extended plateau. By multiple linear regression analysis IL-6, MCP-1, TIMP-1 and S100B were determined to be independently related to clinical outcome scores at specific time points. Conclusions: Our data show important differences in the early time course of several potential markers for the complex network of inflammation and brain damage after ischemic stroke depending on stroke outcome. This must be considered for any therapeutical approach using anti-inflammatory treatment.

Hepatitis C virus infection and the brain

There is growing evidence that hepatitis C virus (HCV)-infection may affect the brain. About half of the HCV-infected patients complain of chronic fatigue irrespective of their stage of liver disease or virus replication rate. Even after successful antiviral therapy fatigue persists in about one third of the patients. Many patients, in addition, report of deficits in attention, concentration and memory, some also of depression. Psychometric testing revealed deficits in attention and verbal learning ability as characteristic for HCV-afflicted patients with normal liver function. Magnetic resonance spectroscopic studies showed alterations of the cerebral choline, N-acetyl-aspartate, and creatine content in the basal ganglia, white matter and frontal cortex, respectively. Recently, pathologic cerebral serotonin and dopamine transporter binding and regional alterations of the cerebral glucose utilisation compatible with alterations of the dopaminergic attentional system were observed. Several studies detected HCV in brain samples or cerebro-spinal fluid. Interestingly, viral sequences in the brain often differed from those in the liver, but were closely related to those found in lymphoid tissue. Therefore, the Trojan horse hypothesis emerged: HCV-infected mononuclear blood cells enter the brain, enabling the virus to reside within the brain (probably in microglia) and to infect brain cells, especially astrocytes.

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.

Contrast Extravasation on Computed Tomography Angiography Predicts Clinical Outcome in Primary Intracerebral Hemorrhage: A Prospective Study of 139 Cases

Background and Purpose— Several retrospective studies suggested that contrast extravasation on CT angiography predicts hematoma expansion, poor outcome, and mortality in primary intracerebral hemorrhage. We aimed to determine the predictive value of contrast extravasation on multidetector CT angiography for clinical outcome in a prospective study. Methods— In 160 consecutive patients with spontaneous intracerebral hemorrhage admitted within 6 hours of symptom onset, noncontrast CT and multidetector CT angiography were performed on admission. A follow-up noncontrast CT was done at 24 hours. Multidetector CT angiography images were analyzed to identify the presence of contrast extravasation. Clinical outcome was assessed by modified Rankin Scale on discharge and at 90 days. Results— A total of 139 patients with primary intracerebral hemorrhage were included in the final analysis. Contrast extravasation occurred in 30 (21.6%) patients. The presence of contrast extravasation was associated with increased hematoma expansion (P<0.0001), in-hospital mortality (P=0.008), prolonged hospital stay (P=0.006), poor outcome on discharge (P=0.025), increased 3-month mortality (P=0.009), and poor clinical outcome (P<0.0001). In multivariate analysis, contrast extravasation was a promising independent predictor (OR, 10.5; 95% CI, 3.2–34.7; P<0.0001) for 90-day poor clinical outcome followed by the presence of intraventricular hemorrhage (OR, 3.4; 95% CI, 1.5–7.7; P=0.003) and initial hematoma volume (OR, 1.0; 95% CI, 1.0–1.1; P=0.013). Conclusions— The presence of contrast extravasation on multidetector CT angiography in patients with hyperacute-stage intracerebral hemorrhage is an independent and strong factor associated with poor outcome. Any patient with intracerebral hemorrhage with such sign on multidetector CT angiography should be monitored intensely and treated accordingly.

Circulating damage marker profiles support a neuroprotective effect of erythropoietin in ischemic stroke patients

The German Multicenter EPO Stroke Trial, which investigated safety and efficacy of erythropoietin (EPO) treatment in ischemic stroke, was formally declared a negative study. Exploratory subgroup analysis, however, revealed that patients not receiving thrombolysis most likely benefited from EPO during clinical recovery, a result demonstrated in the findings of the Göttingen EPO Stroke Study. The present work investigated whether the positive signal on clinical outcome in this patient subgroup was mirrored by respective poststroke biomarker profiles. All patients of the German Multicenter EPO Stroke Trial nonqualifying for thrombolysis were included if they (a) were treated per protocol and (b) had at least two of the five follow-up blood samples for circulating damage markers drawn (n = 163). The glial markers S100B and glial fibrillary acid protein (GFAP) and the neuronal marker ubiquitin C-terminal hydrolase (UCH-L1) were measured by enzyme-linked immunosorbent assay in serum on d 1, 2, 3, 4 and 7 poststroke. All biomarkers increased poststroke. Overall, EPO-treated patients had significantly lower concentrations (area under the curve) over 7 d of observation, as reflected by the composite score of all three markers (Cronbach α = 0.811) and by UCH-L1. S100B and GFAP showed a similar tendency. To conclude, serum biomarker profiles, as an outcome measure of brain damage, corroborate an advantageous effect of EPO in ischemic stroke. In particular, reduction in the neuronal damage marker UCH-L1 may reflect neuroprotection by EPO.

Asymmetric Dimethyarginine as Marker and Mediator in Ischemic Stroke

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is known as mediator of endothelial cell dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia, arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. Accordingly, clinical studies found evidence that increased ADMA levels are associated with a higher risk of cerebrovascular events. After the acute event of ischemic stroke, levels of ADMA and its analog symmetric dimethylarginine (SDMA) are elevated through augmentation of protein methylation and oxidative stress. Furthermore, cleavage of ADMA through dimethylarginine dimethylaminohydrolases (DDAHs) is reduced. This increase of dimethylarginines might be predictive for adverse clinical outcome. However, the definite role of ADMA after acute ischemic stroke still needs to be clarified. On the one hand, ADMA might contribute to brain injury by reduction of cerebral blood flow. On the other hand, ADMA might be involved in NOS-induced oxidative stress and excitotoxic neuronal death. In the present review, we highlight the current knowledge from clinical and experimental studies on ADMA and its role for stroke risk and ischemic brain injury in the hyperacute stage after stroke. Finally, further studies are warranted to unravel the relevance of the close association of dimethylarginines with stroke.

Prognostic value of blood interleukin-6 in the prediction of functional outcome after stroke: A systematic review and meta-analysis

We aimed to quantify the association of blood interleukin-6 (IL-6) concentrations with poor outcome after stroke and its added predictive value over clinical information. Meta-analysis of 24 studies confirmed this association with a weighted mean difference of 3.443 (1.592-5.294) pg/mL, despite high heterogeneity and publication bias. Individual participant data including 4112 stroke patients showed standardized IL-6 levels in the 4th quartile were independently associated with poor outcome (OR=2.346 (1.814-3.033), p<0.0001). However, the additional predictive value of IL-6 was moderate (IDI=1.5%, NRI=5.35%). Overall these results indicate an unlikely translation of IL-6 into clinical practice for this purpose.

Association of Molecular Markers With Perihematomal Edema and Clinical Outcome in Intracerebral Hemorrhage

Background and Purpose— Perihematomal edema contributes to secondary brain injury in intracerebral hemorrhage (ICH). Increase of matrix metalloproteinases (MMPs) and growth factors is considerably involved in blood–brain barrier disruption and neuronal cell death in ICH models. We therefore hypothesized that increased levels of these molecular markers are associated with perihematomal edema and clinical outcome in ICH patients. Methods— Fifty-nine patients with spontaneous ICH admitted within 24 hours of symptom onset were prospectively investigated. Noncontrast CT was performed on admission for diagnosis of ICH and quantification of initial hematoma volume. MRI was performed on day 3 to evaluate perihematomal edema. Concentrations of MMP-3, MMP-9, as well as vascular endothelial growth factor and angiopoietin-1 on admission were determined by enzyme-linked immunosorbent assays. Clinical outcome was assessed by modified Rankin Scale at 90 days. Results— Increased MMP-3 levels were independently associated with perihematomal edema volume (P<0.05). Cytotoxic edema surrounding the hematoma was seen in 36 (61%) cases on 3-day MRI. Cytotoxic edema did not correlate with the level of any of the biomarkers studied. Levels of MMP-3 ≥12.4 ng/mL and MMP-9 ≥192.4 ng/mL but not vascular endothelial growth factor and angiopoietin-1 predicted poor clinical outcome at 90 days (modified Rankin Scale >3) independent of stroke severity and hematoma volume at baseline (odds ratio, 25.3, P=0.035; odds ratio, 68.9, P=0.023; respectively). Conclusions— MMPs 3 and 9 seem to be significantly involved in secondary brain injury and outcome after primary ICH in humans, and thus should be further evaluated as targets for therapeutic strategies in this devastating disorder.

Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke

Background and Purpose— Recently, we reported high seroprevalence (age-dependent up to >19%) of N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1) autoantibodies in both healthy and neuropsychiatrically ill subjects (N=4236). Neuropsychiatric syndrome relevance was restricted to individuals with compromised blood–brain barrier, for example, apolipoprotein E4 (APOE4) carrier status, both clinically and experimentally. We now hypothesized that these autoantibodies may upon stroke be protective in individuals with hitherto intact blood–brain barrier, but harmful for subjects with chronically compromised blood–brain barrier. Methods— Of 464 patients admitted with acute ischemic stroke in the middle cerebral artery territory, blood for NMDAR1 autoantibody measurements and APOE4 carrier status as indicator of a preexisting leaky blood–brain barrier was collected within 3 to 5 hours after stroke. Evolution of lesion size (delta day 7–1) in diffusion-weighted magnetic resonance imaging was primary outcome parameter. In subgroups, NMDAR1 autoantibody measurements were repeated on days 2 and 7. Results— Of all 464 patients, 21.6% were NMDAR1 autoantibody–positive (immunoglobulin M, A, or G) and 21% were APOE4 carriers. Patients with magnetic resonance imaging data available on days 1 and 7 (N=384) were divided into 4 groups according to NMDAR1 autoantibody and APOE4 status. Groups were comparable in all stroke-relevant presenting characteristics. The autoantibody+/APOE4− group had a smaller mean delta lesion size compared with the autoantibody−/APOE4- group, suggesting a protective effect of circulating NMDAR1 autoantibodies. In contrast, the autoantibody+/APOE4+ group had the largest mean delta lesion area. NMDAR1 autoantibody serum titers dropped on day 2 and remounted by day 7. Conclusions— Dependent on blood–brain barrier integrity before an acute ischemic brain injury, preexisting NMDAR1 autoantibodies seem to be beneficial or detrimental.

Neurologic manifestations of E coli infection–induced hemolytic-uremic syndrome in adults

Objective: To describe the neurologic and neuroradiologic complications of Shiga toxin producing Escherichia coli infection (STEC)–associated hemolytic-uremic syndrome (HUS) in adults. Methods: All 52 adult patients with STEC O104:H4 infection cared for at Hannover Medical School during the outbreak in Germany through May–July 2011 are considered in this observational study. Forty-three of the 52 patients underwent a standard neurologic diagnostic procedure including clinical examination, Mini-Mental State Examination, and Glasgow Coma Scale Score. Thirty-six patients underwent EEG, and 26 had cerebral MRI, 9 of them repeatedly. Case records of 9 patients who had not been seen by a neurologist were analyzed retrospectively. Results: Forty-eight of the 52 patients had HUS. All but 1 of these showed neurologic symptoms. Focal neurologic signs like double vision, difficulties in finding words, or hyperreflexia were present in 23, additional deficits in orientation, attention, memory, or constructive abilities in 9, and marked impairment of consciousness in 15. MRI showed brainstem, midbrain, thalamus, corpus callosum, and white matter lesions in half of the patients, predominantly in diffusion-weighted images. The extent of MRI lesions did not correlate with clinical symptoms. General slowing but no focal alteration was found in half of the patients examined by EEG. Conclusion: Our findings suggest a toxic-metabolic pathology behind the neurologic impairment instead of multiple infarction due to microthrombosis. Future studies should aim to clarify if early antibiotic therapy or bowel cleansing might help to decrease the rate of neurologic complications in STEC-HUS.