Benjamin Hotter

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

BackgroundThe 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 design1000Plus 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.DiscussionsThe 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 Registrationclinicaltrials.gov NCT00715533

GABAB receptor antibodies in paraneoplastic cerebellar ataxia.

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.

FLAIR vascular hyperintensities in acute ICA and MCA infarction: a marker for mismatch and stroke severity?.

Background: Vascular hyperintensities of brain-supplying arteries on stroke FLAIR MRI are common and represent slow flow or stasis. FLAIR vascular hyperintensities (FVH) are discussed as an independent marker for cerebral hypoperfusion, but the impact on infarct size and clinical outcome in acute stroke patients is controversial. This study evaluates the association of FVH with infarct morphology, clinical stroke severity and infarct growth in patients with symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion. Methods: MR images of 84 patients [median age 73 years (IQR 65–80), 56.0% male, median NIHSS 7 (IQR 3–13)] with acute stroke due to symptomatic ICA or MCA occlusion or stenosis were reviewed. Vessel occlusions were identified by MRA time of flight and graded with the TIMI score. Diffusion and perfusion deficit volumes on admission and FLAIR lesion volumes on discharge were assessed. The presence and number of FVH were evaluated according to MCA-ASPECT areas, and associations with MR volumes, morphology of infarction, recanalization status, presence of 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 >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.

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

ObjectivesThe 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.MethodsIt 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.ResultsOf 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.ConclusionHARM 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.

Fully Automated Postprocessing Carries a Risk of Substantial Overestimation of Perfusion Deficits in Acute Stroke Magnetic Resonance Imaging

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 Tmax 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.

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

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 Tmax 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 Tmax 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.

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

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.

The Potential of Microvessel Density in Prediction of Infarct Growth: A Two-Month Experimental Study in Vessel Size Imaging

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.

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

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

Impact of Selection Criteria on Recruitment in an Interventional Stroke Trial

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.