Advanced imaging in acute ischemic stroke of unknown onset

Stroke of unknown onset accounts for up to 20% of all acute ischemic stroke. Prior to the successful completion of the Efficacy and Safety of MRI-Based Thrombolysis in WAKE UP Stroke (WAKE UP) trial, these patients were typically excluded from treatment with IV tPA as this therapy was only approved for cases within 4.5 hours of known symptom onset. WAKE UP utilized a novel imaging biomarker of lesion age, the DWI-FLAIR mismatch (acute stroke visible on DWI but not yet visible on FLAIR), to allocate patients into the early time window for which thrombolysis has been proven safe and efficient; a concept which became known as “tissue clocking”. As a multicenter and imaging-heavy trial, WAKE UP relied upon a homogeneous understanding and interpretation of its imaging criteria by all of its many investigators, a process that was safeguarded by dedicated training developed especially for the study’s purposes. The study was successful and, upon its completion in 2017, together with two smaller and similar trials that were completed at comparable time points, WAKE UP generated enough high quality evidence to influence a change in official guidelines, now recommending thrombolysis for patients with stroke of unknown onset who satisfy WAKE UP criteria. Various sub-analyses conducted since on the WAKE UP cohort further cemented the credibility of tissue clocking as a patient selection paradigm. But it is not the only such model. In addition to tissue clocking another concept, dubbed penumbral imaging and used as a biomarker of tissue at risk of infarction, has also been investigated in large clinical trials such as EXTEND and ECASS-4, as a way to offer treatment to patients with unknown symptom onset. Both of these methods fall under the umbrella of advanced imaging because they necessitate hardware and/or software as well as expertise in image interpretation that is not routinely available in the majority of the world’s hospitals. Tissue clocking (using magnetic resonance imaging and the DWI-FLAIR mismatch) as well as penumbral imaging (using MR or CT based perfusion imaging) offer a lot of additional information, and through it, assurance to the treating physician that potential risks have been minimized and possible benefits of therapy enhanced. In this sense, advanced brain imaging should definitely be considered as part of state of the art, evidence based stroke treatment. Especially in the unknown time window, and due to its ability to perform both tissue clocking and penumbral imaging, MRI as a modality has been proposed as the most inclusive approach to screening ischemic stroke patients in hopes of identifying those still eligible for thrombolytic treatment. However, this approach clearly suffers the drawback of limited availability in everyday clinical practice. Further, well-designed and well-conducted prospective, randomized, controlled trials should be performed to evaluate the exact scope of (advanced) imaging needed for an as-inclusive-as-possible and successful patient selection in the unknown time window

The ratio between cerebral blood flow and Tmax predicts the quality of collaterals in acute ischemic stroke

Background In acute ischemic stroke the status of collateral circulation is a critical factor in determining outcome. We propose a less invasive alternative to digital subtraction angiography for evaluating collaterals based on dynamic-susceptibility contrast magnetic resonance imaging. Methods Perfusion maps of Tmax and cerebral blood flow (CBF) were created for 35 patients with baseline occlusion of a major cerebral artery. Volumes of hypoperfusion were defined as having a Tmax delay of > 4 seconds (Tmax4s) and > 6 seconds (Tmax6s) and a CBF drop below 80% of healthy, contralateral tissue. For each patient a ratio between the volume of the CBF and the Tmax based perfusion deficit was calculated. Associations with collateral status and radiological outcome were assessed with the Mann-Whitney-U test, uni- and multivariable logistic regression analyses as well as area under the receiver-operator- characteristic (ROC) curve. Results The CBF/Tmax volume ratios were significantly associated with bad collateral status in crude logistic regression analysis as well as with adjustment for NIHSS at admission and baseline infarct volume (OR = 2.5 95% CI[1.2–5.4] p = 0.020 for CBF/Tmax 4s volume ratio and OR = 1.6 95% CI[1.0–2.6] p = 0.031 for CBF/Tmax6s volume ratio). Moreover, the ratios were significantly correlated to final infarct size (Spearman’s rho = 0.711 and 0.619, respectively for the CBF/Tmax4s volume ratio and CBF/Tmax6s volume ration, all p<0.001). The ratios also had a high area under the ROC curve of 0.93 95%CI[0.86–1.00]) and 0.90 95%CI[0.80–1.00]respectively for predicting poor radiological outcome. Conclusions In the setting of acute ischemic stroke the CBF/Tmax volume ratio can be used to differentiate between good and insufficient collateral circulation without the need for invasive procedures like conventional angiography

The Association Between Recanalization, Collateral Flow, and Reperfusion in Acute Stroke Patients: A Dynamic Susceptibility Contrast MRI Study

Background: Collateral circulation in ischemic stroke patients plays an important role in infarct evolution und assessing patients' eligibility for endovascular treatment. By means of dynamic susceptibility contrast MRI, we aimed to investigate the effects of reperfusion, recanalization, and collateral flow on clinical and imaging outcomes after stroke. Methods: Retrospective analysis of 184 patients enrolled into the prospective observational 1000Plus study (clinicaltrials.org NCT00715533). Inclusion criteria were vessel occlusion on baseline MR-angiography, imaging within 24 h after stroke onset and follow-up perfusion imaging. Baseline Higashida score using subtracted dynamic MR perfusion source images was used to quantify collateral flow. The influence of these variables, and their interaction with vessel recanalization, on clinical and imaging outcomes was assessed using robust linear regression. Results: Ninety-eight patients (53.3%) showed vessel recanalization. Higashida score (p = 0.002), and recanalization (p = 0.0004) were independently associated with reperfusion. However, we found no evidence that the association between Higashida score and reperfusion relied on recanalization status (p = 0.2). NIHSS on admission (p < 0.0001) and recanalization (p = 0.001) were independently associated with long-term outcome at 3 months, however, Higashida score (p = 0.228) was not. Conclusion: Higashida score and recanalization were independently associated with reperfusion, but the association between recanalization and reperfusion was similar regardless of collateral flow quality. Recanalization was associated with long-term outcome. DSC-based measures of collateral flow were not associated with long-term outcome, possibly due to the complex dynamic nature of collateral recruitment, timing of imaging and the employed post-processing

Clinical characteristics of unknown symptom onset stroke patients with and without diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch

Background: Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) mismatch was suggested to identify stroke patients with unknown time of symptom onset likely to be within the time window for thrombolysis. Aims: We aimed to study clinical characteristics associated with DWI-FLAIR mismatch in patients with unknown onset stroke. Methods: We analyzed baseline MRI and clinical data from patients with acute ischemic stroke proven by DWI from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. Clinical characteristics were compared between patients with and without DWI-FLAIR mismatch. Results: Of 699 patients included, 418 (59.8%) presented with DWI-FLAIR mismatch. A shorter delay between last seen well and symptom recognition (p = 0.0063), a shorter delay between symptom recognition and arrival at hospital (p = 0.0025), and history of atrial fibrillation (p = 0.19) were predictors of DWI-FLAIR mismatch in multivariate analysis. All other characteristics were comparable between groups. Conclusions: There are only minor differences in measured clinical characteristics between unknown symptom onset stroke patients with and without DWI-FLAIR mismatch. DWI-FLAIR mismatch as an indicator of stroke onset within 4.5 h shows no relevant association with commonly collected clinical characteristics of stroke patients

Stroke with unknown time of symptom onset: baseline clinical and magnetic resonance imaging data of the first thousand patients in WAKE-UP (efficacy and safety of mri-based thrombolysis in wake-up stroke: a randomized, doubleblind, placebo-controlled trial)

Background and Purpose—We describe clinical and magnetic resonance imaging (MRI) characteristics of stroke patients with unknown time of symptom onset potentially eligible for thrombolysis from a large prospective cohort. Methods—We analyzed baseline data from WAKE-UP (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke: A Randomized, Doubleblind, Placebo-Controlled Trial), an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset. MRI judgment included assessment of the mismatch between visibility of the acute ischemic lesion on diffusion-weighted imaging and fluid-attenuated inversion recovery. Results—Of 1005 patients included, diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was present in 479 patients (48.0%). Patients with daytime-unwitnessed stroke (n=138, 13.7%) had a shorter delay between symptom recognition and hospital arrival (1.5 versus 1.8 hours; P=0.002), a higher National Institutes of Stroke Scale score on admission (8 versus 6; P&lt;0.001), and more often aphasia (72.5% versus 34.0%; P&lt;0.001) when compared with stroke patients waking up from nighttime sleep. Frequency of diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch was comparable between both groups (43.7% versus 48.7%; P=0.30). Conclusions—Almost half of the patients with unknown time of symptom onset stroke otherwise eligible for thrombolysis had MRI findings making them likely to be within a time window for safe and effective thrombolysis. Patients with daytime onset unwitnessed stroke differ from wake-up stroke patients with regards to clinical characteristics but are comparable in terms of MRI characteristics of lesion age. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01525290. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2011-005906-32

Total perfusion-diffusion mismatch detected using resting-state functional MRI

Total perfusion-diffusion mismatch is a well-recognised phenomenon in patients with acute ischaemic stroke. We describe a case of total perfusion-diffusion mismatch detected using an emerging contrast-agent-free perfusion imaging technique in a young patient with acute cerebellar stroke

The biennial cycle of respiratory syncytial virus outbreaks in Croatia

The paper analyses the epidemic pattern of respiratory syncytial virus (RSV) outbreaks in children in Croatia. Over a period of 11 consecutive winter seasons (1994–2005) 3,435 inpatients from Zagreb County aged from infancy to 10 years who were hospitalised with acute respiratory tract infections were tested for RSV-infection. RSV was identified in nasopharyngeal secretions of patients by virus isolation in cell culture and by detection of viral antigen with monoclonal antibodies

Automated acute ischemic stroke lesion delineation based on apparent diffusion coefficient thresholds

Purpose: Automated lesion segmentation is increasingly used in acute ischemic stroke magnetic resonance imaging (MRI). We explored in detail the performance of apparent diffusion coefficient (ADC) thresholding for delineating baseline diffusion-weighted imaging (DWI) lesions. Methods: Retrospective, exploratory analysis of the prospective observational single-center 1000Plus study from September 2008 to June 2013 (clinicaltrials.org; NCT00715533). We built a fully automated lesion segmentation algorithm using a fixed ADC threshold (≤620 × 10–6 mm2/s) to delineate the baseline DWI lesion and analyzed its performance compared to manual assessments. Diagnostic capabilities of best possible ADC thresholds were investigated using receiver operating characteristic curves. Influential patient factors on ADC thresholding techniques’ performance were studied by conducting multiple linear regression. Results: 108 acute ischemic stroke patients were selected for analysis. The median Dice coefficient for the algorithm was 0.43 (IQR 0.20–0.64). Mean ADC values in the DWI lesion (β = −0.68, p < 0.001) and DWI lesion volumes (β = 0.29, p < 0.001) predicted performance. Optimal individual ADC thresholds differed between subjects with a median of ≤691 × 10−6 mm2/s (IQR ≤660–750 × 10−6 mm2/s). Mean ADC values in the DWI lesion (β = −0.96, p < 0.001) and mean ADC values in the brain parenchyma (β = 0.24, p < 0.001) were associated with the performance of individual thresholds. Conclusion: The performance of ADC thresholds for delineating acute stroke lesions varies substantially between patients. It is influenced by factors such as lesion size as well as lesion and parenchymal ADC values. Considering the inherent noisiness of ADC maps, ADC threshold-based automated delineation of very small lesions is not reliable