Publications by authors named "Benjamin Hotter"

30 Publications

  • Page 1 of 1

Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P.

Neuromuscul Disord 2021 02 28;31(2):123-133. Epub 2020 Nov 28.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University Munich, Munich, Germany; Medical Genetics Centre, Bayerstr. 3-5, 80335 Munich, Germany. Electronic address:

More than 80 genes are known to be associated with Charcot-Marie-Tooth disease (CMT). Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families. Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment. The patients harbored ten different variants in LRSAM1, seven of which were novel. Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging. The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant. Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance. Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein. In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy. ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2020.11.011DOI Listing
February 2021

Transfer RNA fragments replace microRNA regulators of the cholinergic poststroke immune blockade.

Proc Natl Acad Sci U S A 2020 12 7;117(51):32606-32616. Epub 2020 Dec 7.

The Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, 9190401 Jerusalem, Israel;

Stroke is a leading cause of death and disability. Recovery depends on a delicate balance between inflammatory responses and immune suppression, tipping the scale between brain protection and susceptibility to infection. Peripheral cholinergic blockade of immune reactions fine-tunes this immune response, but its molecular regulators are unknown. Here, we report a regulatory shift in small RNA types in patient blood sequenced 2 d after ischemic stroke, comprising massive decreases of microRNA levels and concomitant increases of transfer RNA fragments (tRFs) targeting cholinergic transcripts. Electrophoresis-based size-selection followed by qRT-PCR validated the top six up-regulated tRFs in a separate cohort of stroke patients, and independent datasets of small and long RNA sequencing pinpointed immune cell subsets pivotal to these responses, implicating CD14 monocytes in the cholinergic inflammatory reflex. In-depth small RNA targeting analyses revealed the most-perturbed pathways following stroke and implied a structural dichotomy between microRNA and tRF target sets. Furthermore, lipopolysaccharide stimulation of murine RAW 264.7 cells and human CD14 monocytes up-regulated the top six stroke-perturbed tRFs, and overexpression of stroke-inducible tRF-22-WE8SPOX52 using a single-stranded RNA mimic induced down-regulation of immune regulator Z-DNA binding protein 1. In summary, we identified a "changing of the guards" between small RNA types that may systemically affect homeostasis in poststroke immune responses, and pinpointed multiple affected pathways, which opens new venues for establishing therapeutics and biomarkers at the protein and RNA level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2013542117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768686PMC
December 2020

External Validation of Five Scores to Predict Stroke-Associated Pneumonia and the Role of Selected Blood Biomarkers.

Stroke 2021 01 7;52(1):325-330. Epub 2020 Dec 7.

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Center for Stroke Research Berlin, NeuroCure Clinical Research Center and Department of Neurology, Charité University Hospital Berlin, Germany (B.H., S.H., L.U., A.M.).

Background And Purpose: Several clinical scoring systems as well as biomarkers have been proposed to predict stroke-associated pneumonia (SAP). We aimed to externally and competitively validate SAP scores and hypothesized that 5 selected biomarkers would improve performance of these scores.

Methods: We pooled the clinical data of 2 acute stroke studies with identical data assessment: STRAWINSKI and PREDICT. Biomarkers (ultrasensitive procalcitonin; mid-regional proadrenomedullin; mid-regional proatrionatriuretic peptide; ultrasensitive copeptin; C-terminal proendothelin) were measured from hospital admission serum samples. A literature search was performed to identify SAP prediction scores. We then calculated multivariate regression models with the individual scores and the biomarkers. Areas under receiver operating characteristic curves were used to compare discrimination of these scores and models.

Results: The combined cohort consisted of 683 cases, of which 573 had available backup samples to perform the biomarker analysis. Literature search identified 9 SAP prediction scores. Our data set enabled us to calculate 5 of these scores. The scores had area under receiver operating characteristic curve of 0.543 to 0.651 for physician determined SAP, 0.574 to 0.685 for probable and 0.689 to 0.811 for definite SAP according to Pneumonia in Stroke Consensus group criteria. Multivariate models of the scores with biomarkers improved virtually all predictions, but mostly in the range of an area under receiver operating characteristic curve delta of 0.05.

Conclusions: All SAP prediction scores identified patients who would develop SAP with fair to strong capabilities, with better discrimination when stricter criteria for SAP diagnosis were applied. The selected biomarkers provided only limited added predictive value, currently not warranting addition of these markers to prediction models. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01264549 and NCT01079728.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.120.031884DOI Listing
January 2021

Withholding or withdrawing life support in long-term neurointensive care patients: a single-centre, prospective, observational pilot study.

J Med Ethics 2020 May 5. Epub 2020 May 5.

Department of Neurology and Stroke and Hertie Institute of Clinical Brain Reseach, University Hospital Tübingen, Tübingen, Germany

Purpose: Scarce evidence exists regarding end-of-life decision (EOLD) in neurocritically ill patients. We investigated the factors associated with EOLD making, including the group and individual characteristics of involved healthcare professionals, in a multiprofessional neurointensive care unit (NICU) setting.

Materials And Methods: A prospective, observational pilot study was conducted between 2013 and 2014 in a 10-bed NICU. Factors associated with EOLD in long-term neurocritically ill patients were evaluated using an anonymised survey based on a standardised questionnaire.

Results: 8 (25%) physicians and 24 (75%) nurses participated in the study by providing their 'treatment decisions' for 14 patients at several time points. EOLD was 'made' 44 (31%) times, while maintenance of life support 98 (69%) times. EOLD patterns were not significantly different between professional groups. The individual characteristics of the professionals (age, gender, religion, personal experience with death of family member and NICU experience) had no significant impact on decisions to forgo or maintain life-sustaining therapy. EOLD was patient-specific (intraclass correlation coefficient: 0.861), with the presence of acute life-threatening disease (OR (95% CI): 18.199 (1.721 to 192.405), p=0.038) and low expected patient quality of life (OR (95% CI): 9.276 (1.131 to 76.099), p=0.016) being significant and independent determinants for withholding or withdrawing life-sustaining treatment.

Conclusions: Our findings suggest that EOLD in NICU relies mainly on patient prognosis and not on the characteristics of the healthcare professionals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/medethics-2019-106027DOI Listing
May 2020

Unmet Need for Social and Emotional Support and Lack of Recalled Screening Is Associated with Depression in the Long-Term Course After Stroke.

Risk Manag Healthc Policy 2020 1;13:285-293. Epub 2020 Apr 1.

Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Purpose: Details on adequate care and prevalence of depression in long-term stroke aftercare are limited. We aimed to determine long-term depression rates after stroke and to test for an association between depression and inadequate screening, socio-economic complications and lack of sub-optimal care.

Patients And Methods: In this cross-sectional study, 57 patients were re-invited into the clinic 2-3 years after stroke. Patients were interviewed about recalled screening concerning depression and unmet needs. Depression, the patient's social situation, and confounders were assessed by standardized scores.

Results: In our study, 20% (n = 11) of patients were classified as depressed by the HDRS-17 score result. However, only 36% of all patients recalled to have been previously screened for depression and only 43% of those patients also recalled out-patient screening. Patients classified as depressed reported significantly lower recalled screening rates (9% vs 43%; p = 0.036) and higher rates of self-reported unmet need with emotional problems (72% vs 18%; p < 0.001). Depression in our study was further associated with a worse socio-economic situation, fewer social contacts, unmet needs with regard to emotional problems and higher rates of recommendations to apply for additional social support.

Conclusion: Our data suggest that systematic out-patient screening for depression is lacking in stroke aftercare. Furthermore, the high rate of unmet emotional needs, the poor socio-economic situation and the higher rates of recommendations for social counselling and application for benefits suggest an undersupply of care in the out-patient setting that is more prominent in patients with depression and warrants further studies to investigate the underlying causes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/RMHP.S228265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131991PMC
April 2020

Inflammatory and stress markers predicting pneumonia, outcome, and etiology in patients with stroke: Biomarkers for predicting pneumonia, functional outcome, and death after stroke.

Neurol Neuroimmunol Neuroinflamm 2020 05 25;7(3). Epub 2020 Feb 25.

From the Charité - Universitätsmedizin Berlin (B.H., S.H., L.U., A.M.), Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Center for Stroke Research Berlin, NeuroCure Clinical Research Center and Department of Neurology, Berlin; Friedrich Loeffler Institute of Medical Microbiology (L.U.), University Medicine Greifswald, Greifswald, Germany; Neurovascular Research Laboratory (J.M., A.B.), Vall d'Hebron Institut de Recerca, Barcelona; Stroke Research Program (J.M.), Institute of Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville; Department of Neurology (J.M.), Hospital Universitario Virgen Macarena, Spain; and Department of Medical Immunology (C.M.), Charité University Medicine and Labor Berlin - Charité Vivantes GmbH, Berlin, Germany.

Objective: Prognosis of stroke is negatively affected by complications, in particular stroke-associated pneumonia (SAP). We hypothesized that inflammatory and stress biomarkers predict SAP during hospitalization and outcome 3 months after stroke.

Methods: We pooled the clinical data of 2 acute stroke studies with identical assessment: the STRoke Adverse outcome is associated WIth NoSoKomial Infections (STRAWINSKI) and PREDICT studies. Measurement of biomarkers (ultrasensitive procalcitonin [PCTus]; midregional pro-adrenomedullin; midregional pro-atrial natriuretic peptide [MRproANP]; ultrasensitive copeptin [CPus]; C-terminal pro-endothelin) was performed from serum samples drawn on the first 4 days of hospital admission.

Results: The combined cohort consists of 573 cases with available backup samples to perform the analysis. SAP was associated with increased admission and maximum levels of all biomarkers. Furthermore, all biomarkers were associated with death and correlated with functional outcome 3 months after stroke. The multivariate logistic regression model retained ultrasensitive CPus and PCTus beyond clinical risk factors for predicting SAP, improving the receiver operating characteristic area under the curve (AUC) from 0.837 to 0.876. In contrast, the biomarkers did not improve the prediction of death and functional outcome in the multivariate model. Cardioembolic strokes were significantly associated with higher values of all biomarkers, whereas discrimination was best for MRproANP (AUC = 0.811 for maximum value).

Conclusions: The tested biomarkers are associated with SAP and poor functional outcome. However, these biomarkers only slightly improve prediction of SAP and do not improve long-term outcome prediction over clinical parameters. MRproANP showed the best discrimination for identifying cardioembolic stroke, warranting further studies to confirm our finding.

Clinical Trial Registration: clinicaltrials.gov NCT01264549 and NCT01079728.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051196PMC
May 2020

Social work support and unmet social needs in life after stroke: a cross-sectional exploratory study.

BMC Neurol 2019 Sep 6;19(1):220. Epub 2019 Sep 6.

Center for Stroke Research Berlin, Charité University Medicine Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Background: Stroke patients are often affected by long-term disabilities with needs concerning social issues. There is relatively little consideration of social recovery of patients and the support required to return to work, receive social benefits, participate in daily life activities, maintain contact with family and friends and to organize financial affairs. In our study we aimed to investigate if existing tools record social needs adequately. We analyzed the current provision of social support provided in long-term care after stroke and whether unmet social needs were associated with quality of life, caregiver burden, overall function and degree of disability.

Methods: Our analysis is part of the Managing Aftercare of Stroke study (MAS-I), a cross-sectional exploratory study of patient needs 2-3 years after initial stroke. Assessment tools included the Nikolaus-score (social situation), the EuroQoL (quality of life), the German Burden Scale for Family Caregivers (caregiver burden), the modified Rankin Scale (disability / dependence), Stroke Impact Scale (function and degree of disability) and the Stroke Survivor Needs Questionnaire (unmet needs).

Results: Overall 57 patients were included in MAS-I, with ten patients classified in urgent need of socio-economic support according to the Nikolaus-score. Patients with lower than normal Nikolaus-score had a higher degree of disability. Thirty percent of all patients had never received professional social support. Social worker contact happened mostly during the stay in acute hospital or rehabilitation institution. Only four patients (11%) reported long-term support after discharge. Apart from social worker contact during acute care, 43% of patients had unmet needs in the long-term aftercare. Forty percent of all patients included in MAS-I were recommended for social work intervention after an in-depth analysis of their situation. Finally, we saw that unmet social needs were associated with lower quality of life and higher caregiver burden.

Conclusions: Our data suggest significant unmet needs in social care in long-term stroke patients. Screening tools for unmet social needs such as the Nikolaus-score do not holistically report patients' needs.

Trial Registration: Clinicaltrials.Gov NCT02320994 . Registered 19 December 2014 (retrospectively registered).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-019-1451-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729017PMC
September 2019

High-resolution diffusion-weighted imaging identifies ischemic lesions in a majority of transient ischemic attack patients.

Ann Neurol 2019 09 31;86(3):452-457. Epub 2019 Jul 31.

Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany.

Transient ischemic attack (TIA) is defined as focal neurological deficit caused by ischemia resolving within 24 hours. In a secondary analysis of a large monocentric cohort of 446 TIA patients, we explored the frequency and determinants of diffusion-weighted imaging (DWI) lesions on high-resolution magnetic resonance imaging. Overall, 240 (54%) of all TIA patients presented with DWI lesions. These patients had higher National Institute of Health Stroke Scale and ABCD2 scores and presented more frequently with vessel occlusion and perfusion deficits, but had similar functional outcome at 3 months. Taken together, high-resolution DWI provides evidence of ischemic brain injury in the majority of TIA patients. ANN NEUROL 2019;86:452-457.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25551DOI Listing
September 2019

Identifying unmet needs in long-term stroke care using in-depth assessment and the Post-Stroke Checklist - The Managing Aftercare for Stroke (MAS-I) study.

Eur Stroke J 2018 Sep 19;3(3):237-245. Epub 2018 Apr 19.

Center for Stroke Research Berlin and Department of Neurology, Charité University Hospital Berlin, Berlin, Germany.

Introduction: Detailed data on the long-term consequences and treatment of stroke are scarce. We aimed to assess the needs and disease burden of community-dwelling stroke patients and their carers and to compare their treatment to evidence-based guidelines by a stroke neurologist.

Methods: We invited long-term stroke patients from two previous acute clinical studies ( = 516) in Berlin, Germany to participate in an observational, cross-sectional study. Participants underwent a comprehensive interview and examination using the Post-Stroke Checklist and validated standard measures of: self-reported needs, quality of life, overall outcome, spasticity, pain, aphasia, cognition, depression, secondary prevention, social needs and caregiver burden.

Results: Fifty-seven participants (median initial National Institutes of Health Stroke Scale score 10 interquartile range 4-12.75) consented to assessment (median 41 months (interquartile range 36-50) after stroke. Modified Rankin Scale was 2 (median; interquartile range 1-3), EuroQoL index value was 0.81 (median; interquartile range 0.70-1.00). The frequencies for disabilities in the major domains were: spasticity 35%; cognition 61%; depression 20%; medication non-compliance 14%. Spasticity ( = 0.008) and social needs ( < 0.001) had the strongest impact on quality of life. The corresponding items in the Post-Stroke Checklist were predictive for low mood ( < 0.001), impaired cognition ( = 0.015), social needs ( = 0.005) and caregiver burden ( = 0.031). In the comprehensive interview, we identified the following needs: medical review (30%), optimization of pharmacotherapy (18%), outpatient therapy (47%) and social work input (33%).

Conclusion: These results suggest significant unmet needs and gaps in health and social care in long-term stroke patients. Further research to develop a comprehensive model for managing stroke aftercare is warranted. clinicaltrials.gov NCT02320994.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2396987318771174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453198PMC
September 2018

Results of Robotic Thymectomy Performed in Myasthenia Gravis Patients Older Than 60 Years at Onset.

Ann Thorac Surg 2019 09 15;108(3):912-919. Epub 2019 Mar 15.

Department of Surgery, Competence Center of Thoracic Surgery, Charité University Hospital Berlin, Berlin, Germany. Electronic address:

Background: Data are limited on the safety and efficacy of robotic thymectomy in patients with myasthenia gravis (MG) older than 60 years at onset.

Methods: Patients older than 60 years at MG onset who underwent robotic thymectomy in Charite Universitaetsmedizin Berlin between 2003 and 2017 were potentially eligible for inclusion. The main outcomes were perioperative complications and clinical outcome according to the Myasthenia Gravis Foundation of America Post-Intervention Status.

Results: Sixty-eight (25 women, 43 men) of 580 patients with MG who underwent robotic thymectomy were eligible for perioperative analyses (median age at MG onset 67 years, range: 61 to 85 years). The perioperative morbidity rate was 13.2%, and the only perioperative death was due to aortic dissection. Fifty-one patients were available for further analysis with a median follow-up time of 60 months (range: 12 to 263 months). The complete stable remission rate was 7.8%, the improvement rate was 68.6%, and the overall mortality rate was 11.8%. Compared with preoperative use, the mean daily dose of corticosteroid agents was significantly reduced at the last follow-up (17.6 ± 23.6 mg versus 2.6 ± 6.1 mg, p = 0.0001) without increased use of azathioprine (35.9 ± 61.9 mg versus 42.7 ± 59 mg, p = 0.427). After excluding 2 patients seronegative for the anti-acetylcholine receptor antibody, 10 of 49 seropositive patients achieved "good outcome" (including four complete stable remissions, three pharmacologic remissions, and three minimal manifestations 0) which was predicted by being free of concomitant disease (odds ratio 7.307, 95% confidence interval: 1.188 to 44.937, p = 0.032) and Myasthenia Gravis Foundation of America classification I before thymectomy (odds ratio 6.696, 95% confidence interval: 1.259 to 35.620, p = 0.026).

Conclusions: Robotic thymectomy seems to be safe and effective in patients with MG older than 60 years at onset with a statistically significant steroid-sparing effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.athoracsur.2019.02.016DOI Listing
September 2019

IL-6 Plasma Levels Correlate With Cerebral Perfusion Deficits and Infarct Sizes in Stroke Patients Without Associated Infections.

Front Neurol 2019 15;10:83. Epub 2019 Feb 15.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany.

We aimed to investigate several blood-based biomarkers related to inflammation, immunity, and stress response in a cohort of patients without stroke-associated infections regarding their predictive abilities for functional outcome and explore whether they correlate with MRI markers, such as infarct size or location. We combined the clinical and radiological data of patients participating in two observational acute stroke cohorts: the PREDICT and 1000Plus studies. The following blood-based biomarkers were measured in these patients: monocytic HLA-DR, IL-6, IL-8, IL-10, LBP, MRproANP, MRproADM, CTproET, Copeptin, and PCT. Multiparametric stroke MRI was performed including T2, DWI, FLAIR, TOF-MRA, and perfusion imaging. Standard descriptive sum statistics were used to describe the sample. Associations were analyzed using Fischer's exact test, independent samples test and Spearmans correlation, where appropriate. Demographics and stroke characteristics were as follows: 94 patients without infections, mean age 68 years (SD 10.5), 32.2% of subjects were female, median NIHSS score at admission 3 (IQR 2-5), median mRS 3 months after stroke 1 (IQR 0-2), mean volume of DWI lesion at admission 5.7 ml (SD 12.8), mean FLAIR final infarct volume 10 ml (SD 14.9), cortical affection in 61% of infarctions. Acute DWI lesion volume on admission MRI was moderately correlated to admission/maximum IL-6 as well as maximum LBP. Extent of perfusion deficit and mismatch were moderately correlated to admission/maximum IL-6 levels. Final lesion volume on FLAIR was moderately correlated to admission IL-6 levels. We found IL-6 to be associated with several parameters from acute stroke MRI (acute DWI lesion, perfusion deficit, final infarct size, and affection of cortex) in a cohort of patients not influenced by infections. www.ClinicalTrials.gov, identifiers NCT01079728 and NCT00715533.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2019.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384225PMC
February 2019

Generalization after ocular onset in myasthenia gravis: a case series in Germany.

J Neurol 2018 Dec 17;265(12):2773-2782. Epub 2018 Sep 17.

Department of Surgery, Competence Center of Thoracic Surgery, Charité University Hospital Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Background And Purpose: Approximately, 50% of myasthenia gravis (MG) patients initially present with purely ocular symptoms. Of these, about 60% will develop secondary generalized MG, typically within 2 years. Risk factors for secondary generalization are still controversial. In this study, we reviewed clinical parameters, thymic pathologies and medical treatments of MG patients with purely ocular symptoms at onset to investigate risk factors for secondary generalization.

Methods: In this monocentric retrospective study, we reviewed consecutive patients who underwent robotic thymectomy between January 2003 and October 2017 in Charite Universitaetsmedizin Berlin. We used univariate and multivariate Cox proportional hazards regression models to identify factors associated with secondary generalization. Survival curves were plotted using Kaplan-Meier method and log-rank tests were performed to analyze the association between corticosteroids use and secondary generalization in subgroups defined by anti-AChR antibody status and thymic pathology.

Results: One hundred and eighty of 572 MG patients who underwent robotic thymectomy were eligible for inclusion, of whom 110 (61.1%) developed a secondary generalized MG over a mean follow-up time of 23.6 months. The presence of a thymoma (HR 1.659, 95% CI (1.52-2.617), P = 0.029) was the only risk factor for secondary generalization in our series. Treating with corticosteroids was associated with a lower conversion rate in ocular myasthenia patients with thymic hyperplasia (n = 55, P = 0.028), but not with other thymic pathologies including thymoma and normal or atrophic thymus.

Conclusions: The conversion rate in ocular myasthenia was high in our series, predicted by the presence of a thymoma. Our findings suggest that corticosteroids can prevent secondary generalization in ocular myasthenia patients with thymic hyperplasia, which requires further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-018-9056-8DOI Listing
December 2018

Selection bias in clinical stroke trials depending on ability to consent.

BMC Neurol 2017 Dec 4;17(1):206. Epub 2017 Dec 4.

Center for Stroke Research Berlin, Charité University Hospital Berlin, Charitéplatz 1, 10115, Berlin, Germany.

Background: Clinical trials are the hallmark of evidence-based medicine, but recruitment is often challenging, especially in stroke trials investigating patients not being able to give informed consent. In some nations, ethics committees will not approve of inclusion in a clinical study via consent of a legal representative. The ethical dilemma of including or excluding those patients has not been properly addressed, as there is little data on the effect of stroke characteristics on the ability to give informed consent.

Methods: To examine differences between patients able and unable to consent at inclusion to an acute stroke trial, we conducted a post-hoc analysis of monitoring records from a multicentric interventional trial. These records listed patients who gave informed consent by themselves and those who needed a legal representative to do so. This exemplary STRAWINSKI trial aimed at improving stroke outcome by biomarker-guided antibiotic treatment of stroke associated pneumonia and included patients within 40 h after stroke onset, suffering from MCA infarctions with an NIHSS score > 9 at admission. Standard descriptive and associative statistics were calculated to compare baseline characteristics and outcome measures between patients who were able to consent and those who were not.

Results: We identified the person giving consent in 228 out of 229 subjects. Patients with inability to consent were older (p < 0.01), suffered from more left-hemispheric (p < 0.01) and more severe strokes (NIHSS, p < 0.01), were more likely to die during hospitalisation (p < 0.01) or have unfavourable outcome at discharge (mRS, p < 0.01), to develop fever (p < 0.01) and tended to be more susceptible to infections (p = 0.06) during the acute course of the disorder.

Conclusions: Demographics, stroke characteristics and outcomes significantly affect stroke patients in their ability to consent. Where selection criteria and primary outcome measures of a trial are significantly affected by ability to consent, excluding patients unable to consent might be unethical.

Trial Registration: URL http://www.clinicaltrials.gov . Unique identifier: NCT01264549 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-017-0989-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716230PMC
December 2017

Author Response.

Neurology 2016 Mar;86(9):880

View Article and Find Full Text PDF

Download full-text PDF

Source
March 2016

Adult hemophagocytic lymphohistiocytosis causing multi organ dysfunction in a patient with multiple autoimmune disorders: when the immune system runs amok.

Clin Case Rep 2016 Feb 16;4(2):165-70. Epub 2015 Dec 16.

Neurological Intensive Care Unit Department of Neurology Charité - Universitätsmedizin Berlin 10117 Berlin Germany.

We report a case of several autoimmune disorders eventually presenting as severe multi organ dysfunction syndrome caused by adult hemophagocytic lymphohistiocytosis (HLH). Clinical and laboratory tests might lead to fatal misinterpretation without awareness of its diagnostic evaluation, as HLH shares common features with sepsis and immune-mediated systemic inflammatory response syndromes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736532PMC
February 2016

Reliability of Two Diameters Method in Determining Acute Infarct Size. Validation as New Imaging Biomarker.

PLoS One 2015 8;10(10):e0140065. Epub 2015 Oct 8.

Center for Stroke Research Berlin (CSB), Department of Neurology, Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.

Background: In order to select patients most likely to benefit for thrombolysis and to predict patient outcome in acute ischemic stroke, the volumetric assessment of the infarcted tissue is used. However, infarct volume estimation on Diffusion weighted imaging (DWI) has moderate interrater variability despite the excellent contrast between ischemic lesion and healthy tissue. In this study, we compared volumetric measurements of DWI hyperintensity to a simple maximum orthogonal diameter approach to identify thresholds indicating infarct size >70 ml and >100 ml.

Methods: Patients presenting with ischemic stroke with an NIHSS of ≥ 8 were examined with stroke MRI within 24 h after symptom onset. For assessment of the orthogonal DWI lesion diameters (od-values) the image with the largest lesion appearance was chosen. The maximal diameter of the lesion was determined and a second diameter was measured perpendicular. Both diameters were multiplied. Od-values were compared to volumetric measurement and od-value thresholds identifying a lesion size of > 70 ml and > 100 ml were determined. In a selected dataset with an even distribution of lesion sizes we compared the results of the od value thresholds with results of the ABC/2 and estimations of lesion volumes made by two resident physicians.

Results: For 108 included patients (53 female, mean age 71.36 years) with a median infarct volume of 13.4 ml we found an excellent correlation between volumetric measures and od-values (r2 = 0.951). Infarct volume >100 ml corresponds to an od-value cut off of 42; > 70 ml corresponds to an od-value of 32. In the compiled dataset (n = 50) od-value thresholds identified infarcts > 100 ml / > 70 ml with a sensitivity of 90%/ 93% and with a specificity of 98%/ 89%. The od-value offered a higher accuracy in identifying large infarctions compared to both visual estimations and the ABC/2 method.

Conclusion: The simple od-value enables identification of large DWI lesions in acute stroke. The cutoff of 42 is useful to identify large infarctions with volume larger than 100 ml. Further studies can analyze the therapeutic utility of this new method.

Trail Registration: ClinicalTrials.org NCT00715533.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140065PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598169PMC
May 2016

Natural course of total mismatch and predictors for tissue infarction.

Neurology 2015 Sep 31;85(9):770-5. Epub 2015 Jul 31.

From the Center for Stroke Research Berlin, Charité University Hospital Berlin, Germany.

Objective: We longitudinally assessed patients presenting with total mismatch and hypothesized that hypoperfusion intensity ratio (HIR), severity of stroke, and occlusion of blood vessel are predictors of tissue fate.

Methods: Patients with suspected stroke or TIA admitted to our emergency department between September 2008 and October 2012 with suspected stroke or TIA were eligible to participate in the ongoing stroke imaging study 1000Plus. Patients received acute and follow-up stroke MRI, basic demographics were collected, and stroke severity was rated according to the NIH Stroke Scale (NIHSS). Inclusion criteria for the substudy were total mismatch on admission examination and available follow-up.

Results: We identified 23 patients with total mismatch: median age 70 years (interquartile range 66-78), 10 female (43.5%). Infarction was found on follow-up diffusion-weighted imaging (median lesion size 1.3 mL) in 9 patients (39.1%). Infarction was correlated with NIHSS at admission (p = 0.026) and HIR (p = 0.015) but not with vessel occlusion. Clinical outcome as measured by last recorded NIHSS score and modified Rankin Scale score at discharge was significantly worse in patients with infarction on follow-up.

Conclusion: Final infarction is frequently seen in patients with total mismatch. Clinical presentation at admission and severity of hypoperfusion measured by HIR, but not occlusion of the supplying vessel, predict tissue fate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000001889DOI Listing
September 2015

Relative FLAIR Signal Intensities over Time in Acute Ischemic Stroke: Comparison of Two Methods.

J Neuroimaging 2015 Nov-Dec;25(6):964-8. Epub 2015 Feb 16.

Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Germany.

Background And Purpose: Visibility of lesions on fluid attenuated inversion recovery (FLAIR) images appears indicative of the time window in acute ischemic stroke. We compared two published methods for calculation of relative FLAIR signal intensities (rSI) regarding their association with time from symptom onset in a longitudinal fashion.

Methods: We prospectively included patients receiving serial MRI examinations between 4.5 and 35 hours from symptom onset. FLAIR rSI was determined using two methods: a whole regions-of-interest (ROI) method and a hotspot method, selecting only a single area of visually highest signal. Signal intensity (rSI) was calculated relative to the contralateral side for each time point.

Results: We included 21 patients with 3-6 MRI examinations on the first 2 days after stroke onset. FLAIR rSI determined with both methods shows a linear association with time from onset, although the hotspot results showed higher variability. Both methods with their previously published thresholds are reliable for identifying patients outside the 4.5 hours time window.

Conclusion: Both methods show a similar performance, and might be a suitable help for the visual assessment of FLAIR lesion visibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jon.12224DOI Listing
December 2016

Early time course of FLAIR signal intensity differs between acute ischemic stroke patients with and without hyperintense acute reperfusion marker.

Cerebrovasc Dis 2014 30;37(2):141-6. Epub 2014 Jan 30.

Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: In animal models of stroke, the time course of blood-brain barrier (BBB) disruptions has been elaborately studied. In human patients, leakage of gadolinium into cerebrospinal fluid (CSF) space, visualized on MRI fluid attenuated inversion recovery (FLAIR) images, is considered a sign of BBB disruptions. It was termed 'hyperintense acute reperfusion marker' (HARM) and was associated with hemorrhages. However, the time course of the leakage is unknown and difficult to study in human patients. Also, the association of HARM with signal intensities and enhancement in the parenchyma on FLAIR images has not been thoroughly researched.

Methods: We analyzed imaging data of acute ischemic stroke patients who underwent repetitive MRI examinations within the first 36 h after the time of symptom onset. HARM was evaluated on FLAIR images. Regions of interest (ROI) of the hyperintensities on diffusion-weighted imaging (DWI) were determined for each time point and mirrored to the contralateral side. The ROI were furthermore corrected for CSF-filled space, using apparent diffusion coefficient (ADC) images. The corrected ROI were used to determine mean signal intensities of the lesions relative to the contralateral side on FLAIR, ADC and B0 images for each time point.

Results: The 18 included patients (5 females; median age: 69 years; median NIHSS score: 5) received 3-5 MRI examinations on the first day and 1-2 examinations on day 2 after stroke. Eight of the patients (44.4%) showed HARM on at least 1 examination. In 6 of these patients, HARM was already seen at the second examination, at the earliest 3.5 h after symptom onset. The HARM-positive patients had higher relative signal intensities (rSI) on FLAIR images in the parenchyma corresponding to the DWI-positive tissue compared with the HARM-negative patients. This difference between groups was statistically significant for the 2nd and 3rd examination (medians of 4.31 and 6.37 h from symptom onset, p < 0.001 and p = 0.005, respectively). No significant difference in rSI between groups was seen for ADC or B0 images.

Conclusion: HARM does not only represent a contrast medium leakage from the pial system into the CSF space. It is accompanied by a markedly increased rSI in the early ischemic lesion on FLAIR images, which is likely due to parenchymal enhancement. The lack of differences on B0 images excludes a pure T2 effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000357422DOI Listing
November 2014

Impact of selection criteria on recruitment in an interventional stroke trial.

Cerebrovasc Dis 2013 30;36(5-6):344-50. Epub 2013 Oct 30.

Center for Stroke Research, Charité University Hospital Berlin, Berlin, Germany.

Background: Randomized controlled clinical trials are the gold standard for scientific evaluation of clinical diagnostic and treatment concepts. Frequently, recruitment of participants is slower than expected, especially in acute conditions with a short time frame for inclusion. Simple prediction models have been proposed to extrapolate recruitment rates. We hypothesized a significant overestimation of recruitment when ignoring interdependence of selection criteria, leading to an insufficient representation of reality by available models. We proposed that slight modifications to inclusion criteria might augment recruitment without causing selection bias.

Methods: We analyzed recruitment in an acute intervention trial of acute ischemic stroke initiated by our facility. Frequencies of selection criteria were recorded and analyzed individually as well as cumulatively. We then amended the trial protocol by moderate modifications to the selection criteria. The main outcome criterion was the rate of recruited over screened patients, with the goal of increasing recruitment fourfold without adding unacceptable selection bias. A previously presented prediction model was applied to our trial and compared with actual recruitment. Data were compared between screening periods at recruitment prior to and after the implementation of the amendments.

Results: The impact of typical as well as novel inclusion criteria such as age limits, imaging-based definition of pathology, time between onset and presentation as well as inability to consent were quantified. Age restriction, definition of index event and late arrival after ictus were identified as the most challenging modifiable selection criteria. Amending those criteria increased recruitment by a factor of 4.1. Inability to consent was a significant exclusion criterion gaining impact with the target population. The selection criteria had a cumulative rather than separate recruitment-limiting impact. A previously presented model did not predict recruitment sufficiently.

Conclusion: We describe frequencies of selection criteria in a typical cohort of patients suffering from acute cerebrovascular events, and their cumulative impact. These data may help to better understand recruitment limitations and allow designing future trials more effectively. Ability to consent especially is a major contributor to trial exclusion, strongly interfering with the targeted trial population of ischemic stroke. Tentative prescreening phases before site or trial initiation should be considered. No predictive statistical models of recruitment have been established so far.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000355493DOI Listing
October 2014

Validity of negative high-resolution diffusion-weighted imaging in transient acute cerebrovascular events.

Stroke 2013 Sep 11;44(9):2598-600. Epub 2013 Jul 11.

Department of Neurology, Charité University Hospital Berlin, Berlin, Germany.

Background And Purpose: A significant amount of strokes are reported to be diffusion-weighted imaging (DWI) negative in acute imaging. We attempted to quantify the rate of false-negative high-resolution (hr) DWI and to identify a valid screening tool to guide follow-up MRI to diagnose infarction initially not visible on hrDWI.

Methods: An a priori-defined post hoc analysis of a prospective 3T MRI cohort of acute cerebrovascular events imaged within 24 hours of ictus. Basic demographics, risk factors, National Institute of Health Stroke Scale, and imaging parameters were recorded.

Results: Of 151 patients with negative acute hrDWI, 63 received follow-up scans depicting infarction in 7 cases (11.1%). Persistence of clinical symptoms as established by National Institute of Health Stroke Scale on the following day was strongly associated with infarction on follow-up MRI (odds ratios, 17.5; 95% confidence interval, 2.83-108.12). Negative predictive value of follow-up National Institute of Health Stroke Scale was 0.96.

Conclusions: Infarcts are frequently invisible on initial hrDWI, but we may well trust in negative hrDWI in completely transient cerebrovascular events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.113.001594DOI Listing
September 2013

GABAB receptor antibodies in paraneoplastic cerebellar ataxia.

J Neuroimmunol 2013 Mar 14;256(1-2):94-6. Epub 2013 Jan 14.

Division of Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany.

Autoantibodies to the gamma-aminobutyric acid-B (GABAB) receptor were recently described in patients with limbic encephalitis presenting with early or prominent seizures. We report on a 64-year-old man with malignant melanoma who during adjuvant therapy with interferon (IFN)-alpha developed cerebellar ataxia. Indirect immunofluorescence on brain tissue sections revealed high-titer (1:20,000) IgG1 serum autoantibodies to the cerebellar molecular and granular layer, which were confirmed to be directed against GABAB receptor in a cell-based assay. This case highlights cerebellar ataxia in the absence of seizures as a clinical manifestation of GABAB receptor autoimmunity and extends the spectrum of tumors underlying this condition to malignant melanoma. IFN-alpha therapy may have contributed to the development of autoimmunity in this patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneuroim.2012.12.006DOI Listing
March 2013

Automated vs manual delineations of regions of interest- a comparison in commercially available perfusion MRI software.

BMC Med Imaging 2012 Jul 18;12:16. Epub 2012 Jul 18.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, Germany.

Background: In perfusion magnetic resonance imaging a manual approach to delineation of regions of interest is, due to rater bias and time intensive operator input, clinically less favorable than an automated approach would be. The goal of our study was to compare the performances of these approaches.

Methods: Using Stroketool, PMA and Perfscape/Neuroscape perfusion maps of cerebral blood flow, mean transit time and Tmax were created for 145 patients with acute ischemic stroke. Volumes of hypoperfused tissue were calculated using both a manual and an automated protocol, and the results compared between methods.

Results: The median difference between the automatically and manually derived volumes was up to 210 ml in Perfscape/Neuroscape, 123 ml in PMA and 135 ml in Stroketool. Correlation coefficients between perfusion volumes and radiological and clinical outcome were much lower for the automatic volumes than for the manually derived ones.

Conclusions: The agreement of the two methods was very poor, with the automated use producing falsely exaggerated volumes of hypoperfused tissue. Software improvements are necessary to enable highly automated protocols to credibly assess perfusion deficits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2342-12-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423015PMC
July 2012

ABCD(2) as a screening tool for cerebral infarction on stroke MRI?

Eur Neurol 2012 27;67(5):315-20. Epub 2012 Apr 27.

Center for Stroke Research Berlin, Charité University Hospital Berlin, Berlin, Germany.

Background: The newly proposed transient ischemic attack (TIA) definition demands for MRI exclusion of infarction. Due to limited resources other tools than MRI predicting tissue infarction would be valuable. We hypothesized that ABCD(2) risk score is a valid screening tool for diffusion-weighted imaging (DWI) lesions.

Methods: TIA patients were prospectively enrolled in an observational MRI study to receive acute and follow-up stroke MRI. ABCD(2) scores were calculated, and sociodemographics and risk factors were recorded.

Results: One hundred and thirty-two TIA patients were enrolled over nine months. Five patients were excluded due to different diagnosis. Forty-five of the 127 remaining patients showed acute ischemic lesions on DWI. Median ABCD(2) scores for DWI-negative and -positive patients were 4 and 5, respectively. Ordinal, trichotomized and dichotomized ABCD(2) were significantly associated to DWI. Univariate analysis of single score items and other risk factors demonstrated unilateral weakness, duration of symptoms and smoking as predictive for DWI restrictions. In multivariate analysis unilateral weakness remained significant.

Conclusions: High-risk ABCD(2) score due to the impact of hemiparesis is associated with the occurrence of DWI lesions but is still not accurate enough for a reliable differentiation of cerebrovascular events with and without MRI lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000336267DOI Listing
August 2012

The potential of microvessel density in prediction of infarct growth: a two-month experimental study in vessel size imaging.

Cerebrovasc Dis 2012 15;33(4):303-9. Epub 2012 Feb 15.

Center for Stroke Research Berlin, Charité-University Medicine Berlin, Berlin, Germany.

Objectives: Vessel size imaging is a novel technique to evaluate pathological changes of the microvessel density quantity Q and the mean vessel size index (VSI). As a follow-up study, we assessed these parameters for microscopic description of ischemic penumbra and their potentials in predicting lesion growth.

Methods: Seventy-five patients with a perfusion-diffusion mismatch were examined within 24 h from symptom onset. We defined three regions of interest: the initial infarct (INF), the ischemic penumbra (IPE), and the healthy region (HEA) symmetric to the IPE. For 23 patients with a 6th-day follow-up, IPE regions were divided into areas of infarct growth and areas of oligemia.

Result: The median values of Q and VSI were: for INF 0.29 s(-1/3) and 15.8 μm, for IPE 0.33 s(-1/3) and 20.6 μm and for HEA 0.36 s(-1/3) and 17.4 μm. The Q in the IPE was significantly smaller than in HEA, and VSI was significantly larger. The Q with a threshold of 0.32 s(-1/3) predicted the final infarction with a sensitivity of 69% and a specificity of 64%.

Conclusions: The reduced Q and increased VSI in the IPE confirmed our previous pilot results. Although Q showed a trend to identify the severity of ischemia in an overall voxel population, its potential in predicting infarct growth needs to be further tested in a larger cohort including a clear status of reperfusion and recanalization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000335302DOI Listing
July 2012

Search for a map and threshold in perfusion MRI to accurately predict tissue fate: a protocol for assessing lesion growth in patients with persistent vessel occlusion.

Cerebrovasc Dis 2011 15;32(2):186-93. Epub 2011 Aug 15.

Center for Stroke Research Berlin (CSB), Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.

Background: The MRI-based mismatch concept has been used to estimate the risk of infarction in ischemic stroke. Based on multiple studies on magnetic resonance perfusion imaging, it seems unlikely that any perfusion parameter threshold will provide a reliable prediction of radiological or clinical outcome for all patients. The goal of our study was to find a minimally biased yet maximally useful perfusion postprocessing protocol which would offer the treating physician a useful estimate of tissue fate.

Methods: One hundred and forty-five acute ischemic stroke patients, admitted within 24 h after stroke to the Charité-University Medicine Hospital in Berlin between March 2008 and November 2009, were included in this study. Using three different software packages (Perfscape/Neuroscape, PMA and Stroketool), maps of mean transit time, cerebral blood flow (CBF) and T(max) were created. Three different thresholds were applied on each parameter map and subsequent volumes of hypoperfused tissue were calculated.

Results: Overall, the maps and thresholds giving the least amount of overestimation of the final infarct volume were T(max) 8 s in Perfscape/Neuroscape, CBF 20 ml/100 g/min in PMA and CBF 15% (of the highest value on the scale for a given patient) in Stroketool. In patients with persistent vessel occlusion, a CBF map with a restrictive threshold showed volumes of tissue at definite risk of infarction in up to 100% of patients. The additional use of a CBF map with a high threshold enabled identification of patients without penumbras.

Conclusions: No combination of software, map and threshold was able to give a reliable estimate of tissue fate for either all patients or any subgroup of patients. However, in patients with vessel occlusion, combination of a CBF map with a low and a high threshold can enable calculation of the minimum volume of brain tissue that will inevitably be lost if the occlusion persists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000328663DOI Listing
January 2012

Fully automated postprocessing carries a risk of substantial overestimation of perfusion deficits in acute stroke magnetic resonance imaging.

Cerebrovasc Dis 2011 22;31(4):408-13. Epub 2011 Feb 22.

Center for Stroke Research Berlin, Charité - University Medicine Berlin, Germany.

Background And Purpose: Due to the risk of rater bias and time restrictions in clinical practice, an automated approach to delineation of hypoperfused tissue in patients with acute ischemic stroke would be preferred to a manual one. We tested the hypothesis that existing software solutions, on account of numerous artifacts, produce hypoperfused tissue even in a cohort of patients with no ischemia.

Methods: Thirty-nine patients, all admitted for exclusion of cerebral ischemia or hemorrhage and without a final diagnosis of stroke imaged between September 2008 and May 2009 were included in the study. Using 3 different software packages (PerfScape/NeuroScape, PMA and Stroketool), perfusion maps of mean transit time, cerebral blood flow and T(max) were created for each patient. Three different thresholds were applied to each parameter map, and subsequent volumes of hypoperfused tissue were calculated.

Results: The median volume of hypoperfused tissue for all the subjects was 92.9 ml (interquartile range, IQR: 13.3-323.4 ml) when calculated by PerfScape/NeuroScape, 30.42 ml (IQR: 13.9-71.4 ml) when calculated by PMA and 78.71 ml (IQR: 40.3-140.8 ml) when calculated by Stroketool. The volumes derived via the different software applications mostly showed only a weak-to-moderate association with each other (Spearman's correlation coefficient between 0.02 and 0.76).

Conclusions: Although automated protocols show promise, the programs Stroketool, PerfScape and PMA require substantial improvement in order to be able to automatically and reliably differentiate between patients with a credible region of ischemia-related hypoperfusion and those without.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000323212DOI Listing
June 2011

Hyperintense acute reperfusion marker on FLAIR is not associated with early haemorrhagic transformation in the elderly.

Eur Radiol 2010 Dec 21;20(12):2990-6. Epub 2010 Jul 21.

Department of Neurology, Center for Stroke Research Berlin-CSB, Charité, Universitätsmedizin Berlin, Berlin, Germany.

Objectives: The hyperintense acute reperfusion marker (HARM) has been described as a predictor for haemorrhagic transformation (HT) in acute ischaemic stroke. We hypothesised that this phenomenon is not present in the elderly.

Methods: It was possible to assess 47/84 consecutive patients aged 80 and over with diagnosed ischaemic stroke or transient ischaemic attack (TIA). MRI was performed within 24 h of onset of symptoms with follow-up MRI within a further 48 h.

Results: Of 47 included patients, 19 showed HARM; it was only seen on follow-up examination. Ten of the 47 patients underwent thrombolysis with recombinant tissue plasminogen activator (rt-PA); 4 of them showed HARM, and 1 of those showed HT. HARM was found in three out of eight patients with haemorrhagic transformation on baseline and/or follow-up MRI. We did not observe an association between HARM and early HT either in the whole group or in the patients who received thrombolysis.

Conclusion: HARM was not associated with HT in the elderly after ischaemic stroke, independent of treatment. While it may indicate dysfunction of the blood-brain barrier (BBB), it does not necessarily amount to HT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-010-1881-9DOI Listing
December 2010

Prospective study on the mismatch concept in acute stroke patients within the first 24 h after symptom onset - 1000Plus study.

BMC Neurol 2009 Dec 8;9:60. Epub 2009 Dec 8.

Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Background: The mismatch between diffusion weighted imaging (DWI) lesion and perfusion imaging (PI) deficit volumes has been used as a surrogate of ischemic penumbra. This pathophysiology-orientated patient selection criterion for acute stroke treatment may have the potential to replace a fixed time window. Two recent trials - DEFUSE and EPITHET - investigated the mismatch concept in a multicenter prospective approach. Both studies randomized highly selected patients (n = 74/n = 100) and therefore confirmation in a large consecutive cohort is desirable. We here present a single-center approach with a 3T MR tomograph next door to the stroke unit, serving as a bridge from the ER to the stroke unit to screen all TIA and stroke patients. Our primary hypothesis is that the prognostic value of the mismatch concept is depending on the vessel status. Primary endpoint of the study is infarct growth determined by imaging, secondary endpoints are neurological deficit on day 5-7 and functional outcome after 3 months.

Methods And Design: 1000Plus is a prospective, single centre observational study with 1200 patients to be recruited. All patients admitted to the ER with the clinical diagnosis of an acute cerebrovascular event within 24 hours after symptom onset are screened. Examinations are performed on day 1, 2 and 5-7 with neurological examination including National Institute of Health Stroke Scale (NIHSS) scoring and stroke MRI including T2*, DWI, TOF-MRA, FLAIR and PI. PI is conducted as dynamic susceptibility-enhanced contrast imaging with a fixed dosage of 5 ml 1 M Gadobutrol. For post-processing of PI, mean transit time (MTT) parametric images are determined by deconvolution of the arterial input function (AIF) which is automatically identified. Lesion volumes and mismatch are measured and calculated by using the perfusion mismatch analyzer (PMA) software from ASIST-Japan. Primary endpoint is the change of infarct size between baseline examination and day 5-7 follow up.

Discussions: The aim of this study is to describe the incidence of mismatch and the predictive value of PI for final lesion size and functional outcome depending on delay of imaging and vascular recanalization. It is crucial to standardize PI for future randomized clinical trials as for individual therapeutic decisions and we expect to contribute to this challenging task.

Trial Registration: clinicaltrials.gov NCT00715533.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2377-9-60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224745PMC
December 2009

Monocyte migration: a novel effect and signaling pathways of catestatin.

Eur J Pharmacol 2008 Nov 21;598(1-3):104-11. Epub 2008 Sep 21.

Department of Internal Medicine 1, Medical University of Innsbruck, Innsbruck, Austria.

Several members of the neuropeptide family exert chemotactic actions on blood monocytes consistent with neurogenic inflammation. Furthermore, chromogranin A (CgA) containing Alzheimer plaques are characterized by extensive microglia activation and such activation induces neuronal damage. We therefore hypothesized that the catecholamine release inhibitory peptide catestatin (hCgA(352-372)) would induce directed monocyte migration. We demonstrate that catestatin dose-dependently stimulates chemotaxis of human peripheral blood monocytes, exhibiting its maximal effect at a concentration of 1 nM comparable to the established chemoattractant formylated peptide Met-Leu-Phe (fMLP). The naturally occurring catestatin variants differed in their chemotactic property insofar as that the Pro370Leu variant was even more potent than wild type, whereas the Gly364Ser variant was less effective. Specificity of this effect was shown by inhibition of catestatin-induced chemotaxis by a specific neutralizing antibody. In addition, catestatin mediated effect was blocked by dimethylsphingosine and treatment with endothelial differentiation gene (Edg)-1 and Edg-3 antisense RNA as well as by incubation with pertussis toxin and genistein indicating involvement of tyrosine kinase receptor-, G-protein- and sphingosine-1-phosphate signaling. Catestatin also stimulated Akt- and extracellular signal related kinase (ERK)-phosphorylation and catestatin-induced chemotaxis was blocked by blockers of phosphoinositide-3 (PI-3) kinase and nitric oxide as well as by inhibition of the mitogen-activated protein kinases (MAPK) system indicating involvement of these signal transduction pathways. In summary, our data indicate that catestatin induces monocyte chemotaxis by activation of a variety of signal transduction pathways suggesting a role of this peptide as an inflammatory cytokine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2008.09.016DOI Listing
November 2008