Publications by authors named "Michael G Hennerici"

210 Publications

Five-Year Prognosis After TIA or Minor Ischemic Stroke in Asian and Non-Asian Populations.

Neurology 2021 01 12;96(1):e54-e66. Epub 2020 Oct 12.

From the Department of Neurology and Stroke Center (T.H., H.C., J.L., P.C.L., P.-J.T., P.A.), Bichat Hospital, AP-HP and INSERM LVTS-U1148, DHU FIRE, Université Paris-Diderot, Sorbonne-Paris Cité, France; Center for Brain and Cerebral Vessels (S.U.), Sanno Hospital and Sanno Medical Center, International University of Health and Welfare, Tokyo, Japan; Department of Medicine and Therapeutics (L.K.S.W.), Chinese University of Hong Kong, Prince of Wales Hospital; Department of Neurology (T.H., K.K.), Tokyo Women's Medical University, Japan; Université Lille (J.L.), Centre Hospitalier Universitaire Lille, Équipe d'Accueil 2694-Santé Publique: Épidémiologie et Qualité des Soins, Lille, France; Stanford Stroke Center (G.W.A.), Department of Neurology and Neurological Sciences, Stanford University Medical Center, CA; Cerebrovascular Disease Service (L.R.C.), Beth Israel Deaconess Medical Center, Harvard University, Boston, MA; Melbourne Brain Centre (G.A.D.), Royal Melbourne Hospital, University of Melbourne, Parkville, Australia; Department of Neurosciences (J.M.F.), Service of Neurology, Hospital Santa Maria, University of Lisbon, Portugal; Department of Neurology (M.G.H.), Universitäts Medizin Mannheim, Heidelberg University, Germany; Stroke Unit, Department of Neurology (C.M.), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Spain; Stroke Prevention Research Unit (P.M.R.), Nuffield Department of Clinical Neuroscience, University of Oxford, UK; Department of Cardiology (P.G.S.), Bichat Hospital, AP-HP, Paris, France; National Heart and Lung Institute Imperial College (P.G.S.), Institute of Cardiovascular Medicine and Science Royal Brompton Hospital, London, UK; Department of Biostatistics (É.V.), Université Paris-Diderot, Sorbonne-Paris Cité, Fernand Widal Hospital, AP-HP, Paris, France.

Objective: To determine long-term vascular outcomes of Asian patients who experienced TIA or minor ischemic stroke and to compare the outcomes of Asian patients with those of non-Asian patients, in the context of modern guideline-based prevention strategies.

Methods: This is a subanalysis of the TIAregistry.org project, in which 3,847 patients (882 from Asian and 2,965 from non-Asian countries) with a recent TIA or minor ischemic stroke were assessed and treated by specialists at 42 dedicated units from 14 countries and followed for 5 years. The primary outcome was a composite of cardiovascular death, nonfatal stroke, and nonfatal acute coronary syndrome.

Results: No differences were observed in the 5-year risk of the primary outcome (14.0% vs 11.7%; hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.88-1.37; = 0.41) and stroke (10.7% vs 8.5%; HR, 1.17; 95% CI, 0.90-1.51; = 0.24) between Asian and non-Asian patients. Asian participants were at higher risk of intracranial hemorrhage (1.8% vs 0.8%; HR, 2.23; 95% CI, 1.09-4.57; = 0.029). Multivariable analysis showed that the presence of multiple acute infarctions on initial brain imaging was an independent predictor of primary outcome and modified Rankin Scale score of >1 in both Asian (HR, 1.91; 95% CI, 1.11-3.29; = 0.020) and non-Asian (HR, 1.39; 95% CI, 1.02-1.90; = 0.037) patients.

Conclusion: The long-term risk of vascular events in Asian patients was as low as that in non-Asian patients, while Asian participants had a 2.2-fold higher intracranial hemorrhage risk. Multiple acute infarctions were independently associated with future disability in both groups.

Classification Of Evidence: This study provides Class I evidence that among people who experienced TIA or minor stroke, Asian patients have a similar 5-year risk of cardiovascular death, stroke, and acute coronary syndrome as non-Asian patients.
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http://dx.doi.org/10.1212/WNL.0000000000010995DOI Listing
January 2021

Medicine 4.0: New Technologies as Tools for a Society 5.0.

J Clin Med 2020 Jul 12;9(7). Epub 2020 Jul 12.

Pôle M.I.R.N.E.D. et Service du Service de Médecine Interne, Diabète et Maladies Métaboliques Hôpitaux Universitaires de Strasbourg, Faculté de Médecine-Université de Strasbourg, 1 porte de l'Hôpital, 67000 Strasbourg, France.

Are new technologies in the medicine sector a driver to support the development of a society 5.0? Innovation pushes the artisan to become smart and lean, customer-oriented but within a standardized environment of production, maintaining and ensuring the quality of the product. An artisan is a user and innovator, as an essential part of the industrial chain. In the healthcare sector, the doctor is the industrial artisan, and medicine can be considered as an example of a smart tool, strongly tailored, that embeds the innovation of materials, nano-devices, and smart technology (e.g., sensors and controllers). But how much of society is ready to host smart technology "on board", becoming "on life", constantly connected with remote controls that allow us to monitor, gather data, and, in any case, act, with preventive healthcare solutions? After a short overview of the medicine sector, a preliminary, tentative link between technological innovation and the healthcare sector allows us to adopt several outlooks on how to change research, always more transdisciplinary, combining science with social science in order to remain human-centered.
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http://dx.doi.org/10.3390/jcm9072198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408705PMC
July 2020

Stroke in COVID-19 and SARS-CoV-1.

Cerebrovasc Dis 2020 26;49(3):235-236. Epub 2020 May 26.

Department of Neurology, Universitätsmedizin Mannheim, Mannheim, Germany.

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http://dx.doi.org/10.1159/000508370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316642PMC
August 2020

Open Questions in Acute Stroke Management and Stroke Prevention.

Cerebrovasc Dis 2019 10;47(5-6):205-206. Epub 2019 Sep 10.

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http://dx.doi.org/10.1159/000502991DOI Listing
May 2020

Non-cardioembolic stroke/transient ischaemic attack in Asians and non-Asians: A post-hoc analysis of the PERFORM study.

Eur Stroke J 2019 Mar 24;4(1):65-74. Epub 2018 Aug 24.

Department of Neurology and Stroke Center, Hôpital Bichat, APHP and Université Paris-Diderot-Sorbonne, Paris, France.

Introduction: We aimed to compare the characteristics and vascular outcomes between Asian and non-Asian patients with non-cardioembolic stroke/transient ischaemic attack receiving antiplatelet monotherapy and to identify population-specific predictors for recurrent events.

Patients And Methods: We conducted a post-hoc analysis of data from the PERFORM study, in which 19,100 patients (mean age, 67.2 years; male, 63%; 2178 Asian and 16,922 non-Asian patients) with non-cardioembolic ischaemic stroke/transient ischaemic attack were randomised to aspirin or terutroban and followed for two years. The primary outcome was a composite of major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke and cardiovascular death).

Results: There was no difference in major adverse cardiovascular events risk between Asian and non-Asian populations (11.1% vs. 10.5%; p = 0.39). However, Asian patients were at significantly higher risk of intracranial haemorrhage (2.4% vs. 1.3%; hazard ratio (HR) 1.87; 95% confidence interval (CI) 1.34-2.60; p < 0.001) and major bleeding (5.4% vs. 4.1%; HR 1.30; 95% CI 1.04-1.61; p = 0.02). Stroke risk was significantly higher in Asian than in non-Asian populations among patients with lacunar stroke (7.4% vs. 4.5%; p = 0.02). In multivariable analysis, diastolic blood pressure (HR per 5 mm Hg 1.08; 95% CI 1.01-1.16; p = 0.03) and diabetes (HR 1.36; 95% CI 1.22-1.52; p < 0.001) were independent predictors of major adverse cardiovascular events for Asian and non-Asian patients, respectively. Compared with non-Asian patients, Asian patients had significantly higher risk of haemorrhagic events when given antiplatelet monotherapy for secondary prevention after non-cardioembolic stroke/transient ischaemic attack. Lacunar stroke and elevated diastolic blood pressure were more associated with recurrence risk in Asian patients.
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http://dx.doi.org/10.1177/2396987318797245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533862PMC
March 2019

Editorial.

Cerebrovasc Dis 2019 21;47(1-2). Epub 2019 Mar 21.

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http://dx.doi.org/10.1159/000499327DOI Listing
March 2019

Risks of Acute Stroke Treatment in Patients with Cardiac Disease.

Cerebrovasc Dis 2018 18;46(5-6). Epub 2019 Jan 18.

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http://dx.doi.org/10.1159/000496627DOI Listing
June 2019

Five-Year Risk of Stroke after TIA or Minor Ischemic Stroke.

N Engl J Med 2018 Jun 16;378(23):2182-2190. Epub 2018 May 16.

From Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Neurology and Stroke Center (P.A., P.C.L., L.M.T., J.L., P.-J.T.), and the Department of Cardiology (P.G.S.), Bichat Hospital, INSERM Laboratory for Vascular Translational Science-Unité 1148, Département Hospitalo-Universitaire Fibrose Inflammation Remodelage, Université Paris-Diderot, Sorbonne-Paris Cité, and AP-HP, Department of Biostatistics, Université Paris-Diderot, Sorbonne-Paris Cité, Fernand Widal Hospital (É.V.), Paris, and Université Lille, Centre Hospitalier Universitaire Lille, Équipe d'Accueil 2694-Santé Publique: Épidémiologie et Qualité des Soins, Lille (J.L.) - all in France; the Stanford Stroke Center, Department of Neurology and Neurological Sciences, Stanford University Medical Center, Stanford, CA (G.W.A.); the Department of Neurology, Hôtel-Dieu de France, Saint Joseph University, Beirut, Lebanon (H. Abboud); the Stroke Unit, San Camillo Hospital, Rome (S.A.); Ärztliche Leitung der Klinik für Neurologie, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin (H. Audebert), Klinik für Neurologie, Allgemeines Krankenhaus Celle, Celle (W.H.), and the Department of Neurology, Universitäts Medizin Mannheim, Heidelberg University, Heidelberg (M.G.H.) - all in Germany; Shaare Zedek Medical Center, Jerusalem, Israel (N.M.B.); the Cerebrovascular Disease Service, Beth Israel Deaconess Medical Center, Harvard University, Boston (L.R.C.); Serviço de Neurologia, Hospital de Santo António-Centro Hospitalar do Porto, Porto (M.C.), and the Department of Neurosciences, Service of Neurology, Hospital Santa Maria, University of Lisbon, Lisbon (J.M.F.) - both in Portugal; the Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia (G.A.D.); the Stroke Unit and Neurology Service, University Hospital José Eleuterio González, Universidad Autónoma de Nuevo León, Monterrey, Mexico (F.G.-R.); the Neurovascular Research Unit and Health Research Board, Stroke Clinical Trials Network Ireland, University College Dublin, Dublin (P.J.K.); the Comprehensive Stroke Center, Palacký University and University Hospital Olomouc (M.K.), and the Department of Nursing, Faculty of Health Science, Palacký University (D.Š), Olomouc, Czech Republic; the Department of Neurology, Kaohsiung Medical University Chung-Ho Memorial Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan (H.-F.L.); the Stroke Unit, Department of Neurology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona (C.M.), the Stroke Unit, Hospital Universitari Arnau de Vilanova, Universitat de Lleida, Lleida (F.P.), and the Stroke Unit, Department of Neurology, Albacete University Hospital, Universidad de Castilla-La Mancha, Albacete (T.S.) - all in Spain; the Department of Neurology, Nowon Eulji Medical Center, Eulji University, Seoul, South Korea (J.M.P.); the Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford (P.M.R.), and the National Heart and Lung Institute Imperial College, Institute of Cardiovascular Medicine and Science Royal Brompton Hospital, London (P.G.S.) - both in the United Kingdom; the International University of Health and Welfare, Center for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Center, Tokyo (S.U.); the Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing (Y.W.); and the Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong (L.K.S.W.).

Background: After a transient ischemic attack (TIA) or minor stroke, the long-term risk of stroke and other vascular events is not well known. In this follow-up to a report on 1-year outcomes from a registry of TIA clinics in 21 countries that enrolled 4789 patients with a TIA or minor ischemic stroke from 2009 through 2011, we examined the 5-year risk of stroke and vascular events.

Methods: We evaluated patients who had had a TIA or minor stroke within 7 days before enrollment in the registry. Among 61 sites that participated in the 1-year outcome study, we selected 42 sites that had follow-up data on more than 50% of their enrolled patients at 5 years. The primary outcome was a composite of stroke, acute coronary syndrome, or death from cardiovascular causes (whichever occurred first), with an emphasis on events that occurred in the second through fifth years. In calculating the cumulative incidence of the primary outcome and secondary outcomes (except death from any cause), we treated death as a competing risk.

Results: A total of 3847 patients were included in the 5-year follow-up study; the median percentage of patients with 5-year follow-up data per center was 92.3% (interquartile range, 83.4 to 97.8). The composite primary outcome occurred in 469 patients (estimated cumulative rate, 12.9%; 95% confidence interval [CI], 11.8 to 14.1), with 235 events (50.1%) occurring in the second through fifth years. At 5 years, strokes had occurred in 345 patients (estimated cumulative rate, 9.5%; 95% CI, 8.5 to 10.5), with 149 of these patients (43.2%) having had a stroke during the second through fifth years. Rates of death from any cause, death from cardiovascular causes, intracranial hemorrhage, and major bleeding were 10.6%, 2.7%, 1.1%, and 1.5%, respectively, at 5 years. In multivariable analyses, ipsilateral large-artery atherosclerosis, cardioembolism, and a baseline ABCD score for the risk of stroke (range, 0 to 7, with higher scores indicating greater risk) of 4 or more were each associated with an increased risk of subsequent stroke.

Conclusions: In a follow-up to a 1-year study involving patients who had a TIA or minor stroke, the rate of cardiovascular events including stroke in a selected cohort was 6.4% in the first year and 6.4% in the second through fifth years. (Funded by AstraZeneca and others.).
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http://dx.doi.org/10.1056/NEJMoa1802712DOI Listing
June 2018

Synergistic Strategies to Promote Stroke Research.

Cerebrovasc Dis 2018 26;45(3-4):I-II. Epub 2018 Apr 26.

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http://dx.doi.org/10.1159/000489054DOI Listing
March 2019

The Challenge of Interdisciplinary Stroke Cooperation: Time for a Change!

Cerebrovasc Dis 2018 14;45(1-2):I-II. Epub 2018 Mar 14.

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http://dx.doi.org/10.1159/000488100DOI Listing
March 2019

Off-label use of IV t-PA in patients with intracranial neoplasm and cavernoma.

Ther Adv Neurol Disord 2018 5;11:1756285617753423. Epub 2018 Feb 5.

Department of Neurology, UniversitätsMedizin Mannheim, University of Heidelberg, Mannheim, Germany.

Background: The safety of systemic thrombolysis in patients with intracranial tumor and cavernoma are unknown. So far evidence is limited to a number of case reports and few case series or unspecified data based on population-based analysis. Our aim was to comprehend the risk of systemic thrombolysis in these patients.

Methods: Patients with additional evidence of intracranial tumor or cavernoma who received IV tissue plasminogen activator (t-PA) treatment at our comprehensive stroke center over a period of 7 years were identified in our stroke database and compared to the same number of matched control subjects without any evidence of intracranial tumor and cavernoma. Clinical history and imaging patterns before and after t-PA therapy were individually reviewed for each patient.

Results: Thirty-four patients with additional evidence of meningioma (19/34), cavernoma (13/34) or malignant intracranial neoplasm (2/34) were identified. The incidence of secondary intracranial hemorrhage observed showed no difference between control subjects (9/34, 26%) and patients (6/34, 18%; = 0.56). Symptomatic hemorrhage in patients with meningioma or cavernoma could not be observed. Likewise, the prevalence of stroke mimics showed no difference between patients (8/34, 24%) and control subjects (5/34, 15%; = 0.54). However, both patients with malignant intracranial neoplasm presented with a stroke mimic and intracranial hemorrhage was observed in one of them.

Conclusions: In compliance with existing evidence, treatment in patients with meningioma and cavernoma appears to be safe and reasonable, while the therapy should be avoided in patients with malignant intracranial neoplasm with blood-brain barrier disruption.
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http://dx.doi.org/10.1177/1756285617753423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808960PMC
February 2018

Arterial Spin Labeling Cerebral Perfusion Magnetic Resonance Imaging in Migraine Aura: An Observational Study.

J Stroke Cerebrovasc Dis 2018 May 10;27(5):1262-1266. Epub 2018 Jan 10.

Department of Neurology, Universitätsmedizin Mannheim, University of Heidelberg, Mannheim, Germany; Department of Neurology, Klinikum Kempten, Kempten, Germany.

Background: Changes in cerebral perfusion during migraine with aura (MA) have been assessed mainly using dynamic susceptibility contrast (DSC) magnetic resonance perfusion imaging. A contrast agent-free method to assess these changes would be desirable. We assessed changes in cerebral perfusion during MA using arterial spin labeling (ASL) perfusion magnetic resonance imaging.

Methods: We investigated 4 patients with a standardized protocol including ASL perfusion imaging during MA (n = 2) or early headache phase (n = 2) and asymptomatic follow-up. Semiquantitative evaluation was done using a region of interest (ROI) within hypoperfused or hyperperfused areas and corresponding ROIs in the contralateral hemisphere. Relative ratios of mean perfusion in the corresponding ROIs were calculated. DSC imaging was done at initial time points and compared visually with ASL findings.

Results: In all patients, regional perfusion changes were detected in the acute phase. These abnormalities did not respect the boundaries of major cerebral vascular territories but overlapped onto adjoining regions. During MA, adjacent hypoperfused and hyperperfused areas were found, whereas during headache, regional hyperperfusion only was observed. Perfusion abnormalities normalized on follow-up.

Conclusions: ASL perfusion imaging is a contrast agent-free method suitable for assessment of reversible perfusion changes during or immediately after MA.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.12.002DOI Listing
May 2018

Does being physically active prevent future disability in older people? Attenuated effects when taking time-dependent confounders into account.

BMC Geriatr 2017 12 21;17(1):290. Epub 2017 Dec 21.

Department of Neurology, Universitäts Medizin Mannheim, Mannheim, Germany.

Background: Causal experimental evidence that physical activity prevents disability in older people is sparse. Being physically active has nonetheless been shown to be associated with disability-free survival in observational studies. Observational studies are, however, prone to bias introduced by time-dependent confounding. Time-dependent confounding occurs when an exposure (e.g. being physically active at some time-point) potentially affects the future status of a confounder (such as depression sometime later), and both variables have an effect on latter outcome (i.e. disability). "Conventional" analysis with e.g. Cox-regression is the mainstay when analyzing longitudinal observational studies. Unfortunately, it does not provide unbiased estimates in the presence of time-dependent confounding. Marginal structural models (MSM) - a relatively new class of causal models - have the potential to adequately account for time-dependent confounding. Here we analyze the effect of older people being physically active on disability, in a large long-term observational study. We address time-dependent confounding by using marginal structural models and provide a non-technical practical demonstration of how to implement this type of modeling.

Methods: Data is from 639 elderly individuals ascertained in the European multi-center Leukoaraiosis and Disability study (LADIS), followed-up yearly over a period of three years. We estimated the effect of self-reported physical activity on the probability to transit to instrumental disability in the presence of a large set of potential confounders. We compare the results of "conventional" modeling approaches to those estimated using marginal structural models, highlighting discrepancies.

Results: A "conventional" Cox-regression-like adjustment for salient baseline confounders signals a significant risk reduction under physical activity for later instrumental disability (OR 0.62, 95% CI 0.44-0.90). However, given MSM estimation, the effect is attenuated towards null (OR 1.00, 95% CI 0.57-1.76).

Conclusions: Contrary to most reports, we did not find that physical activity in older people prevents future instrumental disability, when taking time-dependent confounding into account. This result may be due to the characteristics our particular study population. It is, however, also conceivable that previous evidence neglected the effect of this type of bias. We suggest that analysts of longitudinal observational studies consider marginal structural models as a further modeling approach.
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http://dx.doi.org/10.1186/s12877-017-0657-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740527PMC
December 2017

Diurnal Variation of Intravenous Thrombolysis Rates for Acute Ischemic Stroke and Associated Quality Performance Parameters.

Front Neurol 2017 21;8:341. Epub 2017 Jul 21.

Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany.

Introduction: Based on data from the Baden-Wuerttemberg stroke registry, we aimed to explore the diurnal variation of acute ischemic stroke (IS) care delivery.

Materials And Methods: 92,530 IS patients were included, of whom 37,471 (40%) presented within an onset-to-door time ≤4.5 h. Daytime was stratified in 3-h time intervals and working vs. non-working hours. Stroke onset and hospital admission time, rate of door-to-neurological examination time ≤30 min, onset-/door-to-imaging time IV thrombolysis (IVT) rates, and onset-/door-to-needle time were determined. Multivariable regression models were used stratified by stroke onset and hospital admission time to assess the relationship between IVT rates, quality performance parameters, and daytime. The time interval 0:00 h to 3:00 h and working hours, respectively, were taken as reference.

Results: The IVT rate of the whole study population was strongly associated with the sleep-wake cycle. In patients presenting within the 4.5-h time window and potentially eligible for IVT stratification by hospital admission time identified two time intervals with lower IVT rates. First, between 3:01 h and 6:00 h (IVT rate 18%) and likely attributed to in-hospital delays with the lowest diurnal rate of door-to-neurological examination time ≤30 min and the longest door-to-needle time Second, between 6:01 h and 15:00 h (IVT rate 23-25%) compared to the late afternoon and evening hours (IVT rate 27-29%) due to a longer onset-to-imaging time and door-to-imaging time. No evidence for a compromised stroke service during non-working hours was observed.

Conclusion: The analysis provides evidence that acute IS care is subject to diurnal variation which may affect stroke outcome. An optimization of IS care aiming at constantly high IVT rates over the course of the day therefore appears desirable.
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http://dx.doi.org/10.3389/fneur.2017.00341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519519PMC
July 2017

Predictors of Outcome in Acute Stroke Patients: Are They Reliable and Potentially Useful?

Cerebrovasc Dis 2017 12;44(1-2):I-II. Epub 2017 Jul 12.

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http://dx.doi.org/10.1159/000479121DOI Listing
December 2018

Differences in Characteristics and Outcomes Between Asian and Non-Asian Patients in the TIAregistry.org.

Stroke 2017 07 5;48(7):1779-1787. Epub 2017 Jun 5.

From the APHP, Department of Neurology and Stroke Center, Bichat Hospital, INSERM LVTS-U1148, DHU FIRE, Université Paris-Diderot, Sorbonne-Paris Cité, France (T.H., L.S., P.C.L., P-J.T., P.A.); Clinical Research Center for Medicine, International University of Health and Welfare, Center for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Center, Tokyo, Japan (S.U.); Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital (L.K.S.W.); Stanford Stroke Center, Department of Neurology and Neurological Sciences, Stanford University Medical Center, CA (G.W.A.); Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel (N.M.B.); Cerebrovascular Disease Service, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA (L.R.C.); The Florey Institute of Neuroscience and Mental Health, the University of Melbourne, Parkville, VIC, Australia (G.A.D.); Department of Neurosciences, Hospital Santa Maria, University of Lisbon, Portugal (J.M.F.); Department of Neurology, Universitäts Medizin Mannheim, Heidelberg, Germany (M.G.H.); Université de Lille, CHU Lille, EA 2694-Santé publique: épidémiologie et qualité des soins, France (J.L.); Stroke Unit, Department of Neurology, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Spain (C.M.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, United Kingdom (P.M.R.); APHP, Department of Cardiology, INSERM LVTS-U1148, DHU FIRE, Université Paris-Diderot, Sorbonne-Paris Cité, Hôpital Bichat, France, and NHLI Imperial College, ICMS Royal Brompton Hospital, London, United Kingdom (P.G.S.); APHP, Department of Biostatistics, Université Paris-Diderot, Sorbonne-Paris Cité, Fernand Widal Hospital, France (É.V.).

Background And Purpose: This study provides the contemporary causes and prognosis of transient ischemic attack (TIA) and minor stroke in Asians and the direct comparisons with non-Asians.

Methods: The TIAregistry.org enrolled 4789 patients (1149 Asians and 3640 non-Asians) with a TIA or minor ischemic stroke within 7 days of onset. Every participating facility had systems dedicated to urgent intervention of TIA/stroke patients by specialists. The primary outcome was a composite of cardiovascular death, nonfatal stroke, and nonfatal acute coronary syndrome.

Results: Approximately 80% of patients were evaluated within 24 hours of symptom onset. At 1 year, there were no differences in the rates of composite cardiovascular events (6.8% versus 6.0%; =0.38) and stroke (6.0% versus 4.8%; =0.11) between Asians and non-Asians. Asians had a lower risk of cerebrovascular disease (stroke or TIA) than non-Asians (adjusted hazard ratio, 0.79; 95% confidence interval, 0.63-0.98; =0.03); the difference was primarily driven by a lower rate of TIA in Asians (4.2% versus 8.3%; <0.001). Moderately severe bleeding was more frequent in Asians (0.8% versus 0.3%; =0.02). In multivariable analysis, multiple acute infarcts (=0.005) and alcohol consumption (=0.02) were independent predictors of stroke recurrence in Asians, whereas intracranial stenosis (<0.001), ABCD score (<0.001), atrial fibrillation (=0.008), extracranial stenosis (=0.03), and previous stroke or TIA (=0.03) were independent predictors in non-Asians.

Conclusions: The short-term stroke risk after a TIA or minor stroke was lower than expected when urgent evidence-based care was delivered, irrespective of race/ethnicity or region. However, the predictors of stroke were different for Asians and non-Asians.
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http://dx.doi.org/10.1161/STROKEAHA.117.016874DOI Listing
July 2017

The effect of adipose tissue-derived stem cells in a middle cerebral artery occlusion stroke model depends on their engraftment rate.

Stem Cell Res Ther 2017 04 26;8(1):96. Epub 2017 Apr 26.

Department of Neurology, Universitätsmedizin Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany.

Background: In the field of experimental stem cell therapy, intra-arterial (IA) delivery yields the best results concerning, for example, migrated cell number at the targeted site. However, IA application also appears to be associated with increased mortality rates and infarction. Since many rodent studies systemically apply 1 × 10 cells, this could also be a consequence of engrafted cell number. The aim of this study was therefore to investigate the effect of different doses of adipose tissue-derived stem cells (ASCs) on engraftment rates and stroke outcome measured in vivo using 9.4-T high-field magnetic resonance imaging (MRI).

Methods: Male Wistar rats (n = 43) underwent a middle cerebral artery occlusion (MCAo) for 45 or 90 min, followed by IA delivery of either saline or 1 × 10, 3 × 10, or 5 × 10 ASCs pre-labelled with very small superparamagnetic iron oxide particles (VSOPs). MRI (9.4-T) analysis was performed 48 h and 9 days post-MCAo. Lesion volumes were assessed by analysis of T2-weighted images and cell signal tracking showing cell engraftment and active cell migration by an improved T2*-analysis.

Results: The ASC-derived signal intensity increased in the affected hemisphere 48 h post MCAo with injected cell number (p < 0.05). The analysis of stroke volumes revealed an increased infarction after injection of 1 × 10 ASCs compared to controls or application of 5 × 10 ASCs (p < 0.05). At 9 days post-MCAo, injection of 3 × 10 ASCs resulted in reduced infarct volumes (p < 0.05). Correspondingly, MRI analysis revealed no changes in cell numbers between both MRI examinations but showed active ASC migration to the site of infarction.

Conclusion: Our results confirm that IA injection is an efficient way of targeting damaged brain tissue but its usefulness strongly depends on the right dose of delivered stem cells since this factor has a strong influence on migration rate and infarct volume, with better results for doses below 1 × 10 cells. Future challenges will include the determination of therapeutic doses for best cellular engraftment and stroke outcome.
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http://dx.doi.org/10.1186/s13287-017-0545-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407025PMC
April 2017

Update on Intracerebral Hemorrhages.

Cerebrovasc Dis 2017 18;43(3-4):I-I. Epub 2017 Mar 18.

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http://dx.doi.org/10.1159/000465899DOI Listing
March 2017

Symptomatic Patients Remain at Substantial Risk of Arterial Disease Complications Before and After Endarterectomy or Stenting.

Stroke 2017 04 13;48(4):1005-1010. Epub 2017 Mar 13.

From APHP, Department of Neurology and Stroke Center, Bichat Hospital, INSERM LVTS-U1148, DHU FIRE, Université Paris-Diderot, Sorbonne-Paris Cité, France (C.H., P.C.L., L.S., J.L., P.-J.T., P.A.); Stanford Stroke Center, Department of Neurology and Neurological Sciences, Stanford University Medical Center (G.W.A.); Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel (N.M.B.); Department of Neurosciences (Neurology), Hospital Santa Maria, University of Lisbon, Portugal (J.M.F.); Cerebrovascular Disease Service, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA (L.R.C.); The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia (G.A.D.); Department of Neurology, UMM University Heidelberg, Germany (M.G.H.); Stroke Unit, Department of Neurology, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Spain (C.M.); Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, UK (P.M.R.); APHP, Department of Cardiology, INSERM LVTS-U1148, DHU FIRE, Université Paris-Diderot, Sorbonne-Paris Cité, Hôpital Bichat, Paris, France; and NHLI Imperial College, ICMS Royal Brompton Hospital London, UK (P.G.S.); Clinical Research Center for Medicine, International University of Health and Welfare, Center for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Center, Tokyo, Japan (S.U.); APHP, Department of Biostatistics, Université Paris-Diderot, Sorbonne-Paris Cité, Fernand Widal hospital, Paris, France (É.V.); and Department of Medicine & Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR (K.S.L.W.).

Background And Purpose: After carotid endarterectomy (CEA) or carotid artery stenting (CAS) in patients with transient ischemic attack or minor ischemic stroke, recurrent stroke risk falls to a low rate on modern medical treatment.

Methods: We used data from 4583 patients with recent transient ischemic attack or minor stroke enrolled in the TIAregistry.org to perform a nested case-control analysis to evaluate pre- and post-CEA/CAS risk. Cases were defined as patients with a CEA/CAS during the 1-year follow-up period. For each case, 2 controls with a follow-up time greater than the time from qualifying event to CEA/CAS were randomly selected, matched by age and sex. Primary outcome was defined as major vascular events (MVE, including stroke, cardiovascular death, and myocardial infarction).

Results: The median delay from symptom onset of qualifying event to CEA/CAS was 11 days (interquartile range, 6-23). Overall, patients with CEA/CAS had a higher 1-year risk of MVE than other patients (14.8% versus 5.8%; adjusted hazard ratio, 2.40; 95% confidence interval, 1.61-3.60; <0.001). During the matched preprocedural period, MVE occurred in 14 (7.5%) cases and in 13 (3.5%) controls, with an adjusted odds ratio =2.46 (95% confidence interval, 1.07-5.64; =0.03). In the postprocedural period, the risk of MVE was also higher in cases than in controls (adjusted <0.03).

Conclusions: Patients with CEA/CAS had a higher 12-month risk of MVE, as well as during pre- and postprocedural periods. These results suggest that patients in whom CEA/CAS is anticipated are likely to be an informative population for inclusion in studies testing new antithrombotic strategies started soon after symptom onset.
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http://dx.doi.org/10.1161/STROKEAHA.116.015171DOI Listing
April 2017

Specificities of Ischemic Stroke Risk Factors in Arab-Speaking Countries.

Cerebrovasc Dis 2017 15;43(3-4):169-177. Epub 2017 Feb 15.

Hotel Dieu de France, Saint Joseph University, Beirut, Lebanon.

Background: Stroke is largely preventable, and therefore, a better understanding of risk factors is an essential step in reducing the population stroke rate and resulting disease burden in Arab countries.

Summary: We performed 2 separate analyses in 2 similar populations of patients with noncardioembolic ischemic stroke. This first involved 3,635 patients in the Outcomes in Patients with TIA and Cerebrovascular disease (OPTIC) registry (followed for 2 years), with baseline collection of the usual risk factors and 5 socioeconomic variables (unemployment status, residence in rural area, living in fully serviced accommodation, no health-insurance coverage, and low educational level). The second involved patients in the PERFORM trial (n = 19,100 followed up for 2 years), with baseline collection of the usual risk factors and 1 socioeconomic variable (low educational level). The primary outcome was a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death. Stroke risk factors were more prevalent in patients in Arab countries. The incidence of major cardiovascular events (MACE; age- and gender-adjusted) was higher in Arab countries (OPTIC, 18.5 vs. 13.3%; PERFORM, 18.4 vs. 9.7%; both p ≤ 0.0001). These results remained significant after adjustment on risk factors and were attenuated in OPTIC after further adjustment on socioeconomic variables (hazard ratio 1.24; 95% CI 0.98-1.55; p = 0.07). Key Messages: Patients with ischemic stroke living in Arab countries had a lower mean socioeconomic status, a much higher prevalence of diabetes mellitus, and a higher rate of MACE compared with patients from non-Arab countries. This finding is partly explained by a higher prevalence of risk factors and also by a high prevalence of poverty and low educational level.
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http://dx.doi.org/10.1159/000454776DOI Listing
December 2017

Diagnostic and Prognostic Relevance of Magnetic Resonance Imaging and Electrophysiological Findings in Acute Spinal Ischemia.

J Stroke Cerebrovasc Dis 2017 Mar 12;26(3):459-464. Epub 2017 Jan 12.

Department of Neurology, University Hospital Mannheim, University of Heidelberg, Heidelberg, Germany.

Objective: Our purpose was to classify the rare entity of spontaneous spinal ischemia with clinical, magnetic resonance-tomographic, and electrophysiological parameters to determine criteria for outcome prediction.

Methods: We analyzed the stroke registry database of the University Hospital Mannheim, Germany, from 2004 to 2010 for patients with a diagnosis of vascular spinal cord ischemia.

Results: Ten patients were identified (mean age 65 years [range 50-83], 5 women). In 5 patients an etiology was found. Spinal diffusion-weighted magnetic resonance imaging revealed acute ischemia in 7 patients at initial imaging and this diagnosis was confirmed during the first week in the remaining 3 patients. Electrophysiological studies showed abnormal motor evoked potentials (MEPs) in 8 patients and abnormal somatosensory evoked potentials (SSEPs) in 7 patients. After rehabilitation, 5 patients had regained walking ability, whereas 5 patients stayed wheelchair bound. All patients with unfavorable outcome (American Spinal Injury Association (ASIA) Impairment score [AIS] score of ≤C) showed severe pyramidal tract lesions in MEPs during the first week. All patients with normal MEPs had an excellent outcome (AIS of E, P < .05).

Conclusions: Diffusion-weighted imaging (DWI) is a useful tool to confirm acute spinal ischemia suspected in patients within the first days after symptom onset. Poor outcome was associated with severe electrophysiological abnormalities in MEPs and SSEPs. Normal MEPs were significantly predictive of an excellent prognosis. A multimodal diagnostic approach combining DWI and electrophysiological evaluation facilitates the prediction of the individual clinical outcome.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.12.031DOI Listing
March 2017

Posterior versus Anterior Circulation Stroke in Young Adults: A Comparative Study of Stroke Aetiologies and Risk Factors in Stroke among Young Fabry Patients (sifap1).

Cerebrovasc Dis 2017 14;43(3-4):152-160. Epub 2017 Jan 14.

Department of Neurology, University Medicine, Ernst Moritz Arndt University, Greifswald, Germany.

Background: Although 20-30% of all strokes occur in the posterior circulation, few studies have explored the characteristics of patients with strokes in the posterior compared to the anterior circulation so far. Especially data on young patients is missing.

Methods: In this secondary analysis of data of the prospective multi-centre European sifap1 study that investigated stroke and transient ischemic attack (TIA) patients aged 18-55 years, we compared vascular risk factors, stroke aetiology, presence of white matter hyperintensities (WMH) and cerebral microbleeds (CMB) between patients with ischaemic posterior circulation stroke (PCS) and those having suffered from anterior circulation stroke (ACS) based on cerebral MRI.

Results: We diagnosed PCS in 612 patients (29.1%, 407 men, 205 women) and ACS in 1,489 patients (70.9%). Their age (median 46 vs. 47 years, p = 0.205) and stroke severity (modified Rankin Scale: both 2, p = 0.375, Barthel Index 90 vs. 85, p = 0.412) were similar. PCS was found to be more frequent among the male gender (66.5 vs. 60.1% with ACS, p = 0.003). Vertebral artery (VA) dissection was more often the cause of PCS (16.8%) than was carotid artery dissection of ACS (7.9%, p < 0.001). Likewise, small vessel disease (Trial of Org 10172 in Acute Stroke Treatment [TOAST] = 3, PCS: 14.7%, ACS: 11.8%) and stroke of other determined aetiology (TOAST = 4, PCS: 24.5%, ACS: 16.0%) were more frequent in those with PCS. Furthermore, patent foramen ovale (PFO; PCS: 31.1%, ACS: 25.4%, p = 0.029) was more often detected in patients with PCS. In contrast, large-artery atherosclerosis (TOAST = 1, PCS: 15.4%, ACS: 22.2%) and cardio-embolic stroke (TOAST = 2, PCS: 15.6%, ACS: 18.0%) were less frequent in those with PCS (p < 0.001) as were preceding cerebrovascular events (10.1 vs. 14.1%, p = 0.014), TIA (4.8 vs. 7.7%, p = 0.016) and smoking (53.2 vs. 61.0%, p = 0.001). The presence, extent, and location of WMH and CMB did not differ between the 2 groups.

Conclusions: Our data suggested a different pattern of aetiology and risk factors in young patients with PCS compared to those with ACS. These findings especially call for a higher awareness of VA dissection and potentially for more weight of a PFO as a risk factor in young patients with PCS. Clinical trial registration-URL: http://www.clinicaltrials.gov; NCT00414583.
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http://dx.doi.org/10.1159/000454840DOI Listing
December 2017

The Intracranial-B2LEED3S Score and the Risk of Intracranial Hemorrhage in Ischemic Stroke Patients Under Antiplatelet Treatment.

Cerebrovasc Dis 2017 14;43(3-4):145-151. Epub 2017 Jan 14.

Université Paris Diderot, Paris, France.

Background: Chronic antiplatelet therapy in the post-acute phase of non-cardioembolic ischemic stroke is limited by the risk of intracranial hemorrhage (ICH) complications.

Methods: We developed an ICH risk score based on the PERFORM trial cohort (n = 19,100), which included patients with a non-cardioembolic ischemic stroke or transient ischemic attack, and externally validated this score in one contemporary trial of very similar size and inclusion criteria, the PRoFESS trial (n = 20,332 patients). Outcome was ICH over 2 years. A Cox proportional-hazard regression analysis identified risk factors. Discrimination was quantified with c-statistics and calibration was assessed by comparing predicted and observed ICH risk in PERFORM and PRoFESS.

Results: ICH occurred within 2 years in 263 (1.4%) patients in PERFORM trial and in 246 (1.2%) patients in PRoFESS trial. A 13-point score based on 9 items (Intracranial-B2LEED3S score - low body mass index, blood pressure, lacune, elderly, Asian ethnicity, coronary artery or cerebrovascular disease history, dual antithrombotic agent or oral anticoagulant, gender) was derived from the PERFORM trial. In PERFORM, the observed 2-year ICH risk varied from 0.75% in low-risk (score ≤2) to 2.44% in high-risk patients (score ≥5) with an acceptable calibration but a low discrimination both in PERFORM (c-statistic 0.64, 95% CI 0.61-0.68) and on external validation in PRoFESS (0.58, 95% CI 0.55-0.62).

Conclusion: The Intracranial-B2LEED3S score helps identify patients who are at a high risk of bleeding. However, other variables need to be identified to improve the score (e.g., microbleeds) (Clinical Trial Registration Information ISRCTN66157730). URL: http://www.isrctn.com/ISRCTN66157730?totalResults=5&pageSize=10&page=1&searchType=basic-search&offset=3&q=&filters=conditionCategory%3ACirculatory+System%2CrecruitmentCountry%3ATaiwan%2CrecruitmentCountry%3AAustria&sort=.
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http://dx.doi.org/10.1159/000453459DOI Listing
December 2017

Patent Foramen Ovale and Cryptogenic Strokes in the Stroke in Young Fabry Patients Study.

Stroke 2017 01 29;48(1):30-35. Epub 2016 Nov 29.

From the Department of Neurology, Medical Campus Lake Constance, Klinikum Friedrichshafen, Germany (R.H.); Department of Neurology, University of Ulm, Ulm, Germany (R.H.); Department for Biostatistics and Clinical Epidemiology (U.G.) and Center for Stroke Research (U.G.), Charité-Universitätsmedizin Berlin, Germany; Department of Internal Medicine II, Katharinen Hospital, Unna, Germany (F.W.); Department of Neurology, Austin Health and Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia (V.T.); Department of Neurology, Justus Liebig University Giessen, Germany (C.T.); Department of Neurology (C.E., F.F.) and Clinical Division of Neuroradiology, Vascular and Interventional Radiology, Department of Radiology (C.E.), Medical University of Graz, Austria; Department of Neurology, University of Mannheim, Germany (M.W., M.G.H.); Department of Neurology and Stroke Service, The Adelaide and Meath Hospital, incorporating the National Children's Hospital, Dublin, Ireland (D.J.H.M.); Department of Clinical Neurosciences, Royal Free Campus, UCL Institute of Neurology, London, United Kingdom (D.J.H.M.); Academic Unit of Neurology, School of Medicine, Trinity College Dublin, Ireland (D.J.H.M.); Department of Neurology, Helsinki University Central Hospital, Finland (J.P., T.T.); Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sweden (T.T.); Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden (T.T.); Department of Neurology, University Medicine Greifswald, Ernst Moritz Arndt University of Greifswald, Germany (C.K., B.v.S.); Department of Epidemiology and Biometrics, University of Tübingen, Germany (P.M.); Department of Neurology, New York University School of Medicine (E.K.); Department of Clinical Sciences, Section of Neurology, Lund University, Sweden (B.N.); and Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock, Germany (A.R.).

Background And Purpose: A patent foramen ovale (PFO) is disproportionately prevalent in patients with cryptogenic stroke. Without alternative explanations, it is frequently considered to be causative. A detailed stratification of these patients may improve the identification of incidental PFO.

Methods: We investigated the PFO prevalence in 3497 transient ischemic attack and ischemic stroke patients aged 18 to 55 years in the prospective multicenter SIFAP1 study (Stroke in Young Fabry Patients 1) using the ASCO classification. Patients without an obvious cause for transient ischemic attack/stroke (ASCO 0) were divided into subgroups with and without vascular risk factors (ASCO 0+ and 0-). In addition, we looked for PFO-related magnetic resonance imaging lesion patterns.

Results: PFO was identified in 25% of patients. Twenty percent of patients with a definite or probable cause of transient ischemic attack/stroke (≥1 grade 1 or 2 ASCO criterion; n=1769) had a PFO compared with 29% of cryptogenic stroke patients (ASCO 0 and 3; n=1728; P<0,001); subdivision of cryptogenic strokes revealed a PFO in 24% of 978 ASCO 3 patients (n.s. versus ASCO 1 and 2) and a higher prevalence of 36% in 750 ASCO 0 cases (P<0.001 versus ASCO 3 and versus ASCO 1 and 2). PFO was more commonly observed in ASCO 0- (n=271) than in ASCO 0+ patients (n=479; 48 versus 29%; P<0.001). There was no PFO-associated magnetic resonance imaging lesion pattern.

Conclusions: Cryptogenic stroke patients demonstrate a heterogeneous PFO prevalence. Even in case of less conclusive diseases like nonstenotic arteriosclerosis, patients should preferentially be considered to have a non-PFO-mediated stroke.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.
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http://dx.doi.org/10.1161/STROKEAHA.116.013620DOI Listing
January 2017

Access, timing and frequency of very early stroke rehabilitation - insights from the Baden-Wuerttemberg stroke registry.

BMC Neurol 2016 Nov 16;16(1):222. Epub 2016 Nov 16.

Department of Neurology, Klinikum Kempten-Oberallgaeu, Kempten, Germany.

Background: While the precise timing and intensity of very early rehabilitation (VER) after stroke onset is still under discussion, its beneficial effect on functional disability is generally accepted. The recently published randomized controlled AVERT trial indicated that patients with severe stroke might be more susceptible to harmful side effects of VER, which we hypothesized is contrary to current clinical practice. We analyzed the Baden-Wuerttemberg stroke registry to gain insight into the application of VER in acute ischemic stroke (IS) and intracerebral hemorrhage (ICH) in clinical practice.

Methods: 99,753 IS patients and 8824 patients with ICH hospitalized from January 2008 to December 2012 were analyzed. Data on the access to physical therapy (PT), occupational therapy (OT), and speech therapy (ST), the time from admission to first contact with a therapist and the average number of therapy sessions during the first 7 days of admission are reported. Multiple logistic regression models adjusted for patient and treatment characteristics were carried out to investigate the influence of VER on clinical outcome.

Results: PT was applied in 90/87% (IS/ICH), OT in 63/57%, and ST in 70/65% of the study population. Therapy was mostly initiated within 24 h (PT 87/82%) or 48 h after admission (OT 91/89% and ST 93/90%). Percentages of patients under therapy and also the average number of therapy sessions were highest in those with a discharge modified Rankin Scale score of 2 to 5 and lowest in patients with complete recovery or death during hospitalization. The outcome analyses were fundamentally hindered due to biases by individual decision making regarding the application and frequency of VER.

Conclusions: While most patients had access to PT we noticed an undersupply of OT and ST. Only little differences were observed between patients with IS and ICH. The staff decisions for treatment seem to reflect attempts to optimize resources. Patients with either excellent or very unfavorable prognosis were less frequently assigned to VER and, if treated, received a lower average number of therapy sessions. On the contrary, severely disabled patients received VER at high frequency, although potentially harmful according to recent indications from the randomized controlled AVERT trial.
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http://dx.doi.org/10.1186/s12883-016-0744-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112693PMC
November 2016

Editorial.

Cerebrovasc Dis 2016 28;42(5-6):512-513. Epub 2016 Oct 28.

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http://dx.doi.org/10.1159/000452636DOI Listing
September 2018