Ramona Schuppner

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany – A national case collection:

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0–3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.

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.

Active at night, sleepy all day - Sleep disturbances in patients with hepatitis C virus infection

BACKGROUND & AIMS More than 50% of patients with chronic hepatitis C with only mild liver disease complain about chronic fatigue, daytime sleepiness and poor sleep quality. The aim of the present study was to characterize and objectify the sleep disturbances in hepatitis C virus-infected patients. METHODS Twenty-five women who had been infected with hepatitis C virus contaminated anti-D immunoglobulin in 1978/79 and 22 age-matched female healthy controls underwent actigraphy over a period of 5 days to measure motor activity and thereby sleep-wake-rhythm and in addition completed questionnaires for depression, health-related quality of life, fatigue and sleep, and a sleep diary. Liver cirrhosis, a history of neurological or psychiatric disease, history of intravenous drug abuse, shift work, or current medication with effect upon the central nervous system were exclusion criteria. RESULTS The patients achieved higher scores for depression, fatigue and sleep disturbances and lower quality of life scores than the healthy controls. Actigraphy showed higher nocturnal activity and worse sleep efficiency in the patients, while the 24-h activity level did not differ between groups. Fatigue and quality of life scores correlated with bad sleep quality and daytime sleepiness. CONCLUSIONS Our data indicate that chronic fatigue is associated with bad sleep quality and increased nocturnal activity in HCV-infected patients suggesting an alteration of sleep architecture behind fatigue in HCV-associated encephalopathy.

Temporal Pattern of Cytotoxic Edema in the Perihematomal Region After Intracerebral Hemorrhage A Serial Magnetic Resonance Imaging Study

Background and Purpose— Knowledge about cytotoxic edema (CE) in intracerebral hemorrhage is still limited. We aimed to analyze its presence, temporal pattern, and prognostic meaning. Methods— Twenty-one patients with primary intracerebral hemorrhage underwent magnetic resonance imaging at days 1, 3, and 7 after symptom onset. CE was identified using diffusion-weighted imaging. Hematoma and perihematomal edema volumes were measured on fluid-attenuated inversion recovery images. National Institutes of Health Stroke Scale score was assessed at admission and with each magnetic resonance imaging. Clinical outcome was assessed by modified Rankin scale at 90 days. Results— CE appeared in half of the patients within the first 24 hours. The apparent diffusion coefficient values decreased until day 3 and were significantly reversed from days 3 through 7 (P<0.01). Patients with CE showed significantly faster perihematomal edema growth from day 0 to 1 (P=0.036) than those without. Larger 3-day perihematomal edema volume (P=0.02) and presence of CE on day 3 (P=0.07) were associated with poor clinical outcome. Conclusions— CE is associated with stroke severity, perihematomal edema volume, and poor outcome. It is considered to indicate ongoing neuronal injury and, thus, might emerge as new treatment target.

The temporal dynamics of plasma fractalkine levels in ischemic stroke: association with clinical severity and outcome

BackgroundThe chemokine fractalkine (CX3CL1, FKN) is involved in neural-microglial interactions and is regarded as neuroprotective according to several in vivo studies of inflammatory and degenerative states of the brain. Recently, an association with outcome in human ischemic stroke has been proposed. In this study, we aimed to investigate the temporal pattern of FKN levels in acute ischemic stroke in relation to stroke severity and outcome.MethodsFKN levels were measured in plasma specimens of fifty-five patients with acute ischemic stroke. Blood was available for time points 6 hours (h), 12 h, 3 days (d), 7 d and 90 d after stroke onset. Clinical outcome was evaluated using the modified Rankin Scale (mRS) at 7 d and 90 d.ResultsThe time course of FKN significantly differs depending on stroke severity, with higher FKN levels linked to a lower severity. FKN levels in patients with moderate to severe strokes differ significantly from controls. In outcome analysis, we found an association of dynamics of FKN with clinical outcome. Decrease of FKN is pronounced in patients with worse outcome. Multivariate analysis including stroke severity and stroke etiology revealed that deltaFKN between 6 h and 3 d is independently associated with mRS at 90 d. In addition deltaFKN is inversely correlated with the extent of brain damage, as measured by S100B.ConclusionsFKN dynamics are independently associated with stroke outcome. Further studies might give insight on whether FKN is actively involved in the inflammatory cascade after acute ischemic stroke.

Blood–cerebrospinal fluid barrier dysfunction in patients with neurological symptoms during the 2011 Northern German E. coli serotype O104:H4 outbreak

ARTICLE Sir, we read with great interest the recently published article by Magnus et al. (2012) describing the neurological symptoms in patients with a complicated Shiga toxin–producing Escherichia coli infection. This article is of great relevance owing to the large number of 104 cases with neurological sequelae out of a cohort of 217 patients of this rare disease. These 104 patients were subjected to neurological, neuroradiological, neurophysiological, CSF and neuropathological examinations. CSF analysis was performed in 10 patients due to haemolytic uremic syndrome–associated thrombocytopaenia in many others. The only CSF abnormality reported was a slight protein elevation (600–1200 mg/l) in three patients. During the outbreak of Shiga toxin–producing E. coli in 2011, we also had the opportunity to be involved in the treatment of 52 patients (Weissenborn et al. , 2012). Five female patients with severe neurological symptoms (Table 1) were subjected to CSF analysis. In contrast to the report of Magnus et al. …

Neurological Sequelae in Adults After E coli O104: H4 Infection-Induced Hemolytic-Uremic Syndrome.

AbstractIn an outbreak of shiga toxin-producing Escherichia coli infections and associated hemolytic-uremic syndrome (STEC O104:H4) in Germany in the year 2011 neurological complications in adult patients occurred unexpectedly frequent, ranging between 48% and 100% in different patient groups. Few is known about the long-term effects of such complications and so we performed follow-up exams on 44 of the patients treated for STEC-HUS at Hannover Medical Scool in this observational study. Standardized follow-up exams including neurological and neuropsychological assessments, laboratory testing, magnetic resonance imaging (MRI), and EEG were carried out. Subgroups were examined 2 (n = 34), 7 (n = 22), and 19 (n = 23) months after disease onset. Additionally, at the 19-month follow-up, quality of life, sleep quality, and possible fatigue were assessed.Nineteen months after disease onset 31 patients were reassessed, 22 of whom still suffered from symptoms such as fatigue, headache, and attention deficits. In the neuropsychological assessments only 39% of the patients performed normal, whereas 61% scored borderline pathological or lower. Upon reviewal, the follow-up data most prominently showed a secondary decline of cognitive function in about one-quarter of the patients. Outcome was not related to treatment or laboratory data in the acute phase of the disease nor length of hospitalization. Prognosis of STEC-HUS associated brain dysfunction in adults with regard to severity of symptoms is mostly good; some patients however still have not made a full recovery. Patients’ caretakers have to be aware of possible secondary decline of brain function as was observed in this study.

Monocyte Subsets and Related Chemokines in Carotid Artery Stenosis and Ischemic Stroke

Carotid stenosis (CS) is an important cause of ischemic stroke. However, reliable markers for the purpose of identification of high-risk, so-called vulnerable carotid plaques, are still lacking. Monocyte subsets are crucial players in atherosclerosis and might also contribute to plaque rupture. In this study we, therefore, aimed to investigate the potential role of monocyte subsets and associated chemokines as clinical biomarkers for vulnerability of CS. Patients with symptomatic and asymptomatic CS (n = 21), patients with cardioembolic ischemic strokes (n = 11), and controls without any cardiovascular disorder (n = 11) were examined. Cardiovascular risk was quantified using the Essen Stroke Risk Score (ESRS). Monocyte subsets in peripheral blood were measured by quantitative flow cytometry. Plaque specimens were histologically analyzed. Furthermore, plasma levels of monocyte chemotactic protein 1 (MCP-1) and fractalkine were measured. Intermediate monocytes (Mon2) were significantly elevated in symptomatic and asymptomatic CS-patients compared to controls. Mon2 counts positively correlated with the ESRS. Moreover, stroke patients showed an elevation of Mon2 compared to controls, independent of the ESRS. MCP-1 levels were significantly higher in patients with symptomatic than in those with asymptomatic CS. Several histological criteria significantly differed between symptomatic and asymptomatic plaques. However, there was no association of monocyte subsets or chemokines with histological features of plaque vulnerability. Due to the multifactorial influence on monocyte subsets, the usability as clinical markers for plaque vulnerability seems to be limited. However, monocyte subsets may be critically involved in the pathology of CS.

ADAMTS-13 Activity Predicts Outcome in Acute Ischaemic Stroke Patients Undergoing Endovascular Treatment

BACKGROUND Endovascular treatment improves outcome in patients with acute ischaemic stroke due to large vessel occlusion in general. But outcome in some of these patients is jeopardized by recanalization failure or bleeding. OBJECTIVES This study aimed to determine a possible association of mediators of inflammation and haemostasis (C-reactive protein, interleukin-6, matrix metalloproteinase-9, monocyte chemoattractant protein-1, asymmetric dimethylarginine [ADMA], symmetric dimethylarginine, von Willebrand factor and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 13 [ADAMTS-13]) with the post-intervention grade of reperfusion, complications and clinical outcome in patients who underwent endovascular treatment of ischaemic stroke. PATIENTS/METHODS Forty-one patients with acute ischaemic stroke due to large vessel occlusion were prospectively enrolled into the study. Peripheral venous blood was taken prior to treatment and 24 hours and 3, 7 and 90 days after symptom onset. The post-intervention grade of reperfusion was determined using the modified Treatment in Cerebral Infarction (mTICI) score. Clinical outcome on day 90 was assessed using the modified Rankins scale (mRS). RESULTS Low ADAMTS-13 activity (p = 0.009) and missing of statin therapy (p = 0.038) on admission were independently associated with unfavourable outcome (mRS: 5-6). Patients with unsuccessful reperfusion (mTICI: 0-1) showed higher ADMA levels on admission (p = 0.018). However, this association could not be confirmed in the binary logistic regression analysis. CONCLUSION Low ADAMTS-13 activity is a predictor of unfavourable outcome in patients with ischaemic stroke undergoing endovascular therapy. Further studies are warranted to elucidate the clinical and potential therapeutic role of ADAMTS-13 in acute ischaemic stroke.

Systemic inflammation and immune cell phenotypes are associated with neuro-psychiatric symptoms in patients with chronic inflammatory liver diseases

Chronic inflammatory liver diseases are frequently associated with neuropsychiatric and cognitive dysfunctions. We hypothesized that symptomatic patients may show altered levels of soluble inflammatory mediators (SIMs) as well as changes in immune cell phenotypes.