Benjamin Hotter | Charité - Universitätsmedizin Berlin / Charité Medical University Berlin (original) (raw)

Papers by Benjamin Hotter

Clinical Case Reports, 2015

We report a case of several autoimmune disorders eventually presenting as severe multi organ dysf... more 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.

Eur Neurol, 2012

Background: The newly proposed transient ischemic attack (TIA) definition demands for MRI exclusi... more 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 ABCD2 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

PLOS ONE, 2015

In order to select patients most likely to benefit for thrombolysis and to predict patient outcom... more 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. 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. 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. 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. ClinicalTrials.org NCT00715533.

Neurology, 2015

We longitudinally assessed patients presenting with total mismatch and hypothesized that hypoperf... more 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. 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. 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. 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.

Journal of neuroimaging : official journal of the American Society of Neuroimaging, Jan 16, 2015

Visibility of lesions on fluid attenuated inversion recovery (FLAIR) images appears indicative of... more 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. 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. 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 i...

Journal of Neuroimmunology, 2013

Autoantibodies to the gamma-aminobutyric acid-B (GABAB) receptor were recently described in patie... more 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.

European Radiology, 2010

Objectives The hyperintense acute reperfusion marker (HARM) has been described as a predictor for... more 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.

European Neurology, 2012

The newly proposed transient ischemic attack (TIA) definition demands for MRI exclusion of infarc... more 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. 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. 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. 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.

European Journal of Pharmacology, 2008

Several members of the neuropeptide family exert chemotactic actions on blood monocytes consisten... more 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.

Cerebrovascular Diseases, 2012

Vessel size imaging is a novel technique to evaluate pathological changes of the microvessel dens... more 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. 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. 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%. 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.

Cerebrovascular Diseases, 2011

Due to the risk of rater bias and time restrictions in clinical practice, an automated approach t... more 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. 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. 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). 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.

Cerebrovascular Diseases, 2013

Randomized controlled clinical trials are the gold standard for scientific evaluation of clinical... more 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. 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. 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. 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.

Cerebrovascular Diseases, 2011

The MRI-based mismatch concept has been used to estimate the risk of infarction in ischemic strok... more 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. 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. 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. 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.

Cerebrovascular Diseases, 2012

white matter disease and hemorrhagical transformation as well as with stroke severity (NIHSS), st... more white matter disease and hemorrhagical transformation as well as with stroke severity (NIHSS), stroke etiology and thrombolysis rate were analyzed. Results: FVH were detectable in 75 (89.3%) patients. The median number of FVH was 4 (IQR 2-7). Patients with FVH 1 4 presented with more severe strokes due to NIHSS (p = 0.021), had larger initial DWI lesions (p = 0.008), perfusion deficits (p = 0.001) and mismatch volumes/ratios (p = 0.005). The final infarct volume was larger (p = 0.005), and hemorrhagic transformation was more frequent (p = 0.029) in these patients. Conclusions: The presence of FVH indicates larger ischemic areas in brain parenchyma predominantly caused by proximal anterior circulation vessel occlusion. A high count of FVH might be a further surrogate marker for initial ischemic mismatch and stroke severity.

Cerebrovascular Diseases, 2014

CSF-filled space, using apparent diffusion coefficient (ADC) images. The corrected ROI were used ... more 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 B 0 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 B 0 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 B 0 images excludes a pure T2 effect.

BMC Neurology, 2009

The mismatch between diffusion weighted imaging (DWI) lesion and perfusion imaging (PI) deficit v... more 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

Aktuelle Neurologie, 2009

Clinical Case Reports, 2015

We report a case of several autoimmune disorders eventually presenting as severe multi organ dysf... more 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.

Eur Neurol, 2012

Background: The newly proposed transient ischemic attack (TIA) definition demands for MRI exclusi... more 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 ABCD2 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

PLOS ONE, 2015

In order to select patients most likely to benefit for thrombolysis and to predict patient outcom... more 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;70 ml and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;100 ml. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 70 ml and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 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. 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 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;100 ml corresponds to an od-value cut off of 42; &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 70 ml corresponds to an od-value of 32. In the compiled dataset (n = 50) od-value thresholds identified infarcts &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 100 ml / &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 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. 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. ClinicalTrials.org NCT00715533.

Neurology, 2015

We longitudinally assessed patients presenting with total mismatch and hypothesized that hypoperf... more 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. 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. 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. 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.

Journal of neuroimaging : official journal of the American Society of Neuroimaging, Jan 16, 2015

Visibility of lesions on fluid attenuated inversion recovery (FLAIR) images appears indicative of... more 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. 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. 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 i...

Journal of Neuroimmunology, 2013

Autoantibodies to the gamma-aminobutyric acid-B (GABAB) receptor were recently described in patie... more 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.

European Radiology, 2010

Objectives The hyperintense acute reperfusion marker (HARM) has been described as a predictor for... more 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.

European Neurology, 2012

The newly proposed transient ischemic attack (TIA) definition demands for MRI exclusion of infarc... more 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. 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. 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. 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.

European Journal of Pharmacology, 2008

Several members of the neuropeptide family exert chemotactic actions on blood monocytes consisten... more 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.

Cerebrovascular Diseases, 2012

Vessel size imaging is a novel technique to evaluate pathological changes of the microvessel dens... more 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. 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. 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%. 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.

Cerebrovascular Diseases, 2011

Due to the risk of rater bias and time restrictions in clinical practice, an automated approach t... more 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. 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. 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&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s correlation coefficient between 0.02 and 0.76). 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.

Cerebrovascular Diseases, 2013

Randomized controlled clinical trials are the gold standard for scientific evaluation of clinical... more 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. 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. 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. 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.

Cerebrovascular Diseases, 2011

The MRI-based mismatch concept has been used to estimate the risk of infarction in ischemic strok... more 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. 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. 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. 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.

Cerebrovascular Diseases, 2012

white matter disease and hemorrhagical transformation as well as with stroke severity (NIHSS), st... more white matter disease and hemorrhagical transformation as well as with stroke severity (NIHSS), stroke etiology and thrombolysis rate were analyzed. Results: FVH were detectable in 75 (89.3%) patients. The median number of FVH was 4 (IQR 2-7). Patients with FVH 1 4 presented with more severe strokes due to NIHSS (p = 0.021), had larger initial DWI lesions (p = 0.008), perfusion deficits (p = 0.001) and mismatch volumes/ratios (p = 0.005). The final infarct volume was larger (p = 0.005), and hemorrhagic transformation was more frequent (p = 0.029) in these patients. Conclusions: The presence of FVH indicates larger ischemic areas in brain parenchyma predominantly caused by proximal anterior circulation vessel occlusion. A high count of FVH might be a further surrogate marker for initial ischemic mismatch and stroke severity.

Cerebrovascular Diseases, 2014

CSF-filled space, using apparent diffusion coefficient (ADC) images. The corrected ROI were used ... more 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 B 0 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 B 0 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 B 0 images excludes a pure T2 effect.

BMC Neurology, 2009

The mismatch between diffusion weighted imaging (DWI) lesion and perfusion imaging (PI) deficit v... more 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

Aktuelle Neurologie, 2009