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1.  Difficulty of MRI Based Identification of Lesion Age by Acute Infra-Tentorial Ischemic Stroke 
PLoS ONE  2014;9(3):e92868.
Background
Systemic thrombolysis in acute ischemic stroke is restricted to the 4.5 h time window. Many patients are excluded from this treatment because symptom onset is unknown. Magnetic resonance imaging (MRI) studies have shown that stroke patients presenting with acute supra-tentorial diffusion-weighted imaging (DWI) lesions that do not have matching lesions on fluid attenuated inversion recovery (FLAIR) are likely to be within a 4.5 hour time window. This study examines the DWI-FLAIR mismatch in infra-tentorial stroke.
Methods
This was a retrospectively conducted substudy of the “1000+” study; a prospective, single-center observational study (http://clinicaltrials.gov; NCT00715533). Fifty-six patients with infra-tentorial stroke confirmed by MRI and known symptom onset who underwent the scan within 24 h after symptom onset were analysed. Two neurologists blinded to clinical information separately rated the DWI lesion visibility on FLAIR. Lesion volume, relative signal intensities of DWI and relative apparent diffusion coefficient values were determined.
Results
Regarding baseline characteristics our study population had a median age of 66 years, a median time from symptom onset to MRI of 616.5 minutes, a median NIHSS of 3 and a median DWI lesion volume of 0.26 ml. A negative FLAIR allocated patients to a time window under 4.5 h correctly with a sensitivity of 55% and a specificity of 61%, a positive predictive value of 44% and a negative predictive value of 71%. FLAIR positivity decreased with age (p = 0.018), and showed no significant correlation to lesion volume (p = 0.145).
Conclusions
In our study the DWI-FLAIR-Mismatch does not help to reliably identify patients within 4.5 h of symptom onset in acute ischemic infra-tentorial stroke. Thus therapeutical decisions based on the DWI-FLAIR mismatch estimation of time from onset cannot be recommended in patients with infra-tentorial stroke.
doi:10.1371/journal.pone.0092868
PMCID: PMC3961416  PMID: 24651570
2.  IV t-PA Influences Infarct Volume in Minor Stroke: A Pilot Study 
PLoS ONE  2014;9(10):e110477.
Background
There is an ongoing debate whether stroke patients presenting with minor or moderate symptoms benefit from thrombolysis. Up until now, stroke severity on admission is typically measured with the NIHSS, and subsequently used for treatment decision.
Hypothesis
Acute MRI lesion volume assessment can aid in therapy decision for iv-tPA in minor stroke.
Methods
We analysed 164 patients with NIHSS 0–7 from a prospective stroke MRI registry, the 1000+ study (clinicaltrials.org NCT00715533). Patients were examined in a 3 T MRI scanner and either received (n = 62) or did not receive thrombolysis (n = 102). DWI (diffusion weighted imaging) and PI (perfusion imaging) at admission were evaluated for diffusion - perfusion mismatch. Our primary outcome parameter was final lesion volume, defined by lesion volume on day 6 FLAIR images.
Results
The association between t-PA and FLAIR lesion volume on day 6 was significantly different for patients with smaller DWI volume compared to patients with larger DWI volume (interaction between DWI and t-PA: p = 0.021). Baseline DWI lesion volume was dichotomized at the median (0.7 ml): final lesion volume at day 6 was larger in patients with large baseline DWI volumes without t-PA treatment (median difference 3, IQR −0.4–9.3 ml). Conversely, in patients with larger baseline DWI volumes final lesion volumes were smaller after t-PA treatment (median difference 0, IQR −4.1–5 ml). However, this did not translate into a significant difference in the mRS at day 90 (p = 0.577).
Conclusion
Though this study is only hypothesis generating considering the number of cases, we believe that the size of DWI lesion volume may support therapy decision in patients with minor stroke.
Trial Registration
Clinicaltrials.org NCT00715533
doi:10.1371/journal.pone.0110477
PMCID: PMC4211677  PMID: 25350762
3.  Acute Stroke Imaging Research Roadmap II 
doi:10.1161/STROKEAHA.113.002015
PMCID: PMC4040226  PMID: 23860298
4.  Thyroid-Stimulating Hormone, White Matter Hyperintensities, and Functional Outcome in Acute Ischemic Stroke Patients 
Background
Thyroid-stimulating hormone (TSH) concentrations are frequently altered in acute ischemic stroke patients. It is becoming increasingly apparent that various hormones in the hypothalamus-pituitary-thyroid axis may be associated with functional stroke outcome. We have previously shown that white matter hyperintensities (WMH) of presumed vascular origin are strong indicators of functional outcome. It is unclear whether an association exists between WMH and TSH. We therefore sought to determine whether TSH levels, measured in acute ischemic stroke patients, are associated with WMH and functional outcome.
Methods
We analyzed all first ischemic stroke patients who participated in the Berlin ‘Cream & Sugar’ Study (NCT 01378468) and completed a 1-year follow-up assessment from January 2009 to March 2013. Patients were stratified into 3 groups: (1) low TSH (0.1-0.44 μU/ml); (2) normal TSH (0.44-2.5 μU/ml), and (3) high TSH (2.5-20 μU/ml). WMH were assessed using the Fazekas and Wahlund visual rating scales. Functional outcome was assessed using the modified Rankin Scale and was performed via telephone at 1 year by a certified rater.
Results
183 patients were included [median age 66, interquartile range (IQR) 54-75; 33% females; median National Institute of Health Stroke Scale 3, IQR 1-4, range 0-24]. Venous samples were collected a median of 4 days (IQR 3-5) following initial symptom onset between 8 and 9 a.m. following a 10-hour fast. Patients with normal TSH levels (n = 132; 72%) had significantly higher rates of prestroke diabetes than patients with high TSH levels (normal TSH 17%; high TSH 1%; p = 0.03). Additionally, patients with normal TSH levels tended to have higher estimated glomerular filtration rates than patients with high and low TSH concentrations (normal TSH median estimated glomerular filtration rates: 83 ml/min/1.73 m2; high TSH median estimated glomerular filtration rates: 76 ml/min/1.73 m2; low TSH median: 78 ml/min/1.73 m2; p = 0.068). Logistical regression analysis force-adjusted for age (quartiles), NIHSS (quartiles), prestroke diabetes status, and stroke subtype revealed significant associations between WMH and TSH [Wahlund scores: odds ratio 2.547, 95% confidence interval (CI) 1.159-5.598, p = 0.020; Fazekas scores: odds ratio 2.530, 95% CI 1.115-5.741, p = 0.003]. Functional outcome was not significantly associated with TSH levels in univariate or multivariate models.
Conclusion
TSH levels are independently associated with WMH in acute ischemic stroke patients. Based on our findings, we cannot recommend assessing TSH to estimate the 1-year functional outcome following ischemic stroke.
doi:10.1159/000360217
PMCID: PMC3995386  PMID: 24803914
Stroke; Ischemia; Hyperthyroidism; Hypothyroidism; Thyrotropin; White matter hyperintensities; Leukoaraiosis

5.  DWI Intensity Values Predict FLAIR Lesions in Acute Ischemic Stroke 
PLoS ONE  2014;9(3):e92295.
Background and Purpose
In acute stroke, the DWI-FLAIR mismatch allows for the allocation of patients to the thrombolysis window (<4.5 hours). FLAIR-lesions, however, may be challenging to assess. In comparison, DWI may be a useful bio-marker owing to high lesion contrast. We investigated the performance of a relative DWI signal intensity (rSI) threshold to predict the presence of FLAIR-lesions in acute stroke and analyzed its association with time-from-stroke-onset.
Methods
In a retrospective, dual-center MR-imaging study we included patients with acute stroke and time-from-stroke-onset ≤12 hours (group A: n = 49, 1.5T; group B: n = 48, 3T). DW- and FLAIR-images were coregistered. The largest lesion extent in DWI defined the slice for further analysis. FLAIR-lesions were identified by 3 raters, delineated as regions-of-interest (ROIs) and copied on the DW-images. Circular ROIs were placed within the DWI-lesion and labeled according to the FLAIR-pattern (FLAIR+ or FLAIR−). ROI-values were normalized to the unaffected hemisphere. Adjusted and nonadjusted receiver-operating-characteristics (ROC) curve analysis on patient level was performed to analyze the ability of a DWI- and ADC-rSI threshold to predict the presence of FLAIR-lesions. Spearman correlation and adjusted linear regression analysis was performed to assess the relationship between DWI-intensity and time-from-stroke-onset.
Results
DWI-rSI performed well in predicting lesions in FLAIR-imaging (mean area under the curve (AUC): group A: 0.84; group B: 0.85). An optimal mean DWI-rSI threshold was identified (A: 162%; B: 161%). ADC-maps performed worse (mean AUC: A: 0.58; B: 0.77). Adjusted regression models confirmed the superior performance of DWI-rSI. Correlation coefficents and linear regression showed a good association with time-from-stroke-onset for DWI-rSI, but not for ADC-rSI.
Conclusion
An easily assessable DWI-rSI threshold identifies the presence of lesions in FLAIR-imaging with good accuracy and is associated with time-from-stroke-onset in acute stroke. This finding underlines the potential of a DWI-rSI threshold as a marker of lesion age.
doi:10.1371/journal.pone.0092295
PMCID: PMC3962388  PMID: 24658092
6.  Quantitative measurements of relative fluid-attenuated inversion recovery (FLAIR) signal intensities in acute stroke for the prediction of time from symptom onset 
In acute stroke magnetic resonance imaging, a ‘mismatch' between visibility of an ischemic lesion on diffusion-weighted imaging (DWI) and missing corresponding parenchymal hyperintensities on fluid-attenuated inversion recovery (FLAIR) data sets was shown to identify patients with time from symptom onset ≤4.5 hours with high specificity. However, moderate sensitivity and suboptimal interpreter agreement are limitations of a visual rating of FLAIR lesion visibility. We tested refined image analysis methods in patients included in the previously published PREFLAIR study using refined visual analysis and quantitative measurements of relative FLAIR signal intensity (rSI) from a three-dimensional, segmented stroke lesion volume. A total of 399 patients were included. The rSI of FLAIR lesions showed a moderate correlation with time from symptom onset (r=0.382, P<0.001). A FLAIR rSI threshold of <1.0721 predicted symptom onset ≤4.5 hours with slightly increased specificity (0.85 versus 0.78) but also slightly decreased sensitivity (0.47 versus 0.58) as compared with visual analysis. Refined visual analysis differentiating between ‘subtle' and ‘obvious' FLAIR hyperintensities and classification and regression tree algorithms combining information from visual and quantitative analysis also did not improve diagnostic accuracy. Our results raise doubts whether the prediction of stroke onset time by visual image judgment can be improved by quantitative rSI measurements.
doi:10.1038/jcbfm.2012.129
PMCID: PMC3965287  PMID: 23047272
acute stroke; diffusion-weighted imaging; fluid-attenuated inversion recovery; magnetic resonance imaging
7.  Biomarkers and perfusion – training-induced changes after stroke (BAPTISe): protocol of an observational study accompanying a randomized controlled trial 
BMC Neurology  2013;13:197.
Background
Physical activity is believed to exert a beneficial effect on functional and cognitive rehabilitation of patients with stroke. Although studies have addressed the impact of physical exercise in cerebrovascular prevention and rehabilitation, the underlying mechanisms leading to improvement are poorly understood. Training-induced increase of cerebral perfusion is a possible mediating mechanism. Our exploratory study aims to investigate training-induced changes in blood biomarker levels and magnetic resonance imaging in patients with subacute ischemic stroke.
Methods/design
This biomarker-driven study uses an observational design to examine a subgroup of patients in the randomized, controlled PHYS-STROKE trial. In PHYS-STROKE, 215 patients with subacute stroke (hemorrhagic and ischemic) receive either 4 weeks of physical training (aerobic training, 5 times a week, for 50 minutes) or 4 weeks of relaxation sessions (5 times a week, for 50 minutes). A convenience sample of 100 of these patients with ischemic stroke will be included in BAPTISe and will receive magnetic resonance imaging (MRI) scans and an additional blood draw before and after the PHYS-STROKE intervention. Imaging scans will address parameters of cerebral perfusion, vessel size imaging, and microvessel density (the Q factor) to estimate the degree of neovascularization in the brain. Blood tests will determine several parameters of immunity, inflammation, endothelial function, and lipometabolism. Primary objective of this study is to evaluate differential changes in MRI and blood-derived biomarkers between groups. Other endpoints are next cerebrovascular events and functional status of the patient after the intervention and after 3 months assessed by functional scores, in particular walking speed and Barthel index (co-primary endpoints of PHYS-STROKE). Additionally, we will assess the association between functional outcomes and biomarkers including imaging results. For all endpoints we will compare changes between patients who received physical fitness training and patients who had relaxation sessions.
Discussion
This exploratory study will be the first to investigate the effects of physical fitness training in patients with ischemic stroke on MRI-based cerebral perfusion, pertinent blood biomarker levels, and functional outcome. The study may have an impact on current patient rehabilitation strategies and reveal important information about the roles of MRI and blood-derived biomarkers in ischemic stroke.
Trial registration
NCT01954797.
doi:10.1186/1471-2377-13-197
PMCID: PMC3870989  PMID: 24330706
Physical training; Exercise; Subacute stroke; Ischemic stroke; Cerebral perfusion; Biomarkers; Vessel size imaging; Neovascularization; MRI; Rehabilitation
8.  Hyperintense vessels on acute stroke Fluid-attenuated Inversion Recovery imaging: Associations with clinical and other MRI findings 
Background and Purpose
Hyperintense vessels (HV) have been observed in Fluid-Attenuated Inversion Recovery (FLAIR) imaging of patients with acute ischemic stroke and been linked to slow flow in collateral arterial circulation. Given the potential importance of HV, we used a large, multicentre dataset of stroke patients to clarify which clinical and imaging factors play a role in HV.
Methods
We analyzed data of 516 patients from the previously published PRE-FLAIR study. Patients were studied by MRI within 12 hours of symptom onset. HV were defined as hyperintensities in FLAIR corresponding to the typical course of a blood vessel that was not considered the proximal, occluded main artery ipsilateral to the diffusion restriction. Presence of HV was rated by two observers and related to clinical and imaging findings.
Results
Presence of HV was identified in 240 of all 516 patients (47%). Patients with HV showed larger initial ischemic lesion volumes (median 12.3 vs. 4.9 ml; p<0.001) and a more severe clinical impairment (median NIHSS 10.5 vs. 6; p<0.001). In 198 patients with MR-angiography, HV were found in 80% of patients with vessel occlusion and in 17% without vessel occlusion. In a multivariable logistic regression model, vessel occlusion was associated with HV (OR 21.7%; 95% CI 9.6–49.9, p < 0.001). HV detected vessel occlusion with a specificity of 0.86 (95% CI 0.80–0.90) and sensitivity of 0.76 (95% CI 0.69–0.83).
Conclusions
HV are a common finding associated with proximal arterial occlusions and more severe strokes. HV predict arterial occlusion with high diagnostic accuracy.
doi:10.1161/STROKEAHA.112.658906
PMCID: PMC3495102  PMID: 22933582
magnetic resonance imaging; diffusion-weighted fluid-attenuated inversion recovery stroke; acute
9.  Adapting the Computed Tomography Criteria of Hemorrhagic Transformation to Stroke Magnetic Resonance Imaging 
Cerebrovascular Diseases Extra  2013;3(1):103-110.
Background
The main safety aspect in the use of stroke thrombolysis and in clinical trials of new pharmaceutical or interventional stroke therapies is the incidence of hemorrhagic transformation (HT) after treatment. The computed tomography (CT)-based classification of the European Cooperative Acute Stroke Study (ECASS) distinguishes four categories of HTs. An HT can range from a harmless spot of blood accumulation to a symptomatic space-occupying parenchymal bleeding associated with a massive deterioration of symptoms and clinical prognosis. In magnetic resonance imaging (MRI) HTs are often categorized using the ECASS criteria although this classification has not been validated in MRI. We developed MRI-specific criteria for the categorization of HT and sought to assess its diagnostic reliability in a retrospective study.
Methods
Consecutive acute ischemic stroke patients, who had received a 3-tesla MRI before and 12-36 h after thrombolysis, were screened retrospectively for an HT of any kind in post-treatment MRI. Intravenous tissue plasminogen activator was given to all patients within 4.5 h. HT categorization was based on a simultaneous read of 3 different MRI sequences (fluid-attenuated inversion recovery, diffusion-weighted imaging and T2* gradient-recalled echo). Categorization of HT in MRI accounted for the various aspects of the imaging pattern as the shape of the bleeding area and signal intensity on each sequence. All data sets were independently categorized in a blinded fashion by 3 expert and 3 resident observers. Interobserver reliability of this classification was determined for all observers together and for each group separately by calculating Kendall's coefficient of concordance (W).
Results
Of the 186 patients screened, 39 patients (21%) had an HT in post-treatment MRI and were included for the categorization of HT by experts and residents. The overall agreement of HT categorization according to the modified classification was substantial for all observers (W = 0.79). The degrees of agreement between experts (W = 0.81) and between residents (W = 0.87) were almost perfect. For the distinction between parenchymal hematoma and hemorrhagic infarction, the interobserver agreement was almost perfect for all observers taken together (W = 0.82) as well as when experts (W = 0.82) and residents (W = 0.91) were analyzed separately.
Conclusion
The ECASS CT classification of HT was successfully adapted for usage in MRI. It leads to a substantial to almost perfect interobserver agreement and can be used for safety assessment in clinical trials.
doi:10.1159/000354371
PMCID: PMC3776466  PMID: 24052796
Acute ischemic stroke; Hemorrhagic transformation; Magnetic resonance imaging; Computed tomography; Thrombolysis; Imaging in stroke
10.  Fasting Versus Post-Challenge Triglycerides and Pre-Existing Cavitating Lacunes: A Berlin “Cream & Sugar” Substudy 
Background and Purpose: Although the presence of cavitating lacunes on brain imaging may have prognostic implications, the modifiable risk factors underlying these frequently observed lesions are not completely understood. We sought to determine if fasting and post-challenge triglycerides associate with cavitating lacunes.
Methods: All first ischemic stroke patients who completed a novel combined oral triglyceride and glucose tolerance test and MRI between January 2009 and June 2012 were included. Fluid-attenuated inversion recovery or T2 MRI sequences were used to visualize cavitating lacunes and white matter hyperintensities, which were graded using the Wahlund visual scale.
Results: One hundred and ninety patients were included (median age 66, IQR 52–73; 33% female; median National Institute of Health Stroke Scale 2, IQR 1–4). A forward stepwise binary logistical regression analysis applying the Hosmer–Lemeshow goodness of fit test adjusted for parameters significant in univariate analyses (at the p < 0.10 level) revealed that Wahlund scores (Wahlund 0–4: reference; Wahlund 5–10: adjusted odds ratio, 5.1; 95% confidence interval, 1.3–20.0, p = 0.019; Wahlund>10: adjusted odds ratio 9.6; 95% CI, 1.55–59.35; p = 0.015) and the highest quartile of post-challenge triglycerides (>295 mg/dL; adjusted odds ratio, 7.36; 95% confidence interval 1.24–43.70; p = 0.028) independently associated with the presence of cavitating lacunes.
Conclusion: Post-challenge serum triglycerides are independently associated with the presence of cavitating lacunes.
doi:10.3389/fneur.2013.00092
PMCID: PMC3706746  PMID: 23847590
ischemia; cerebral lacunes; leukoaraiosis; white matter disease; triglycerides; glucose
11.  Intensified secondary prevention intending a reduction of recurrent events in TIA and minor stroke patients (INSPiRE-TMS): a protocol for a randomised controlled trial 
BMC Neurology  2013;13:11.
Background
Patients with recent stroke or TIA are at high risk for new vascular events. Several evidence based strategies in secondary prevention of stroke are available but frequently underused. Support programs with multifactorial risk factor modifications after stroke or TIA have not been investigated in large-scale prospective controlled trials so far. INSPiRE-TMS is a prospective, multi-center, randomized open intervention trial for intensified secondary prevention after minor stroke and TIA.
Methods/design
Patients with acute TIA or minor stroke admitted to the participating stroke centers are screened and recruited during in-hospital stay. Patients are randomised in a 1:1 ratio to intervention (support program) and control (usual care) arms. Inclusion of 2.082 patients is planned. The support program includes cardiovascular risk factor measurement and feedback, monitoring of medication adherence, coaching in lifestyle modifications, and active involvement of relatives. Standardized motivational interviewing is used to assess and enhance patients’ motivation. Primary objective is a reduction of new major vascular events defined as nonfatal stroke and myocardial infarction or vascular death. Recruitment time is planned for 3.5 years, follow up time is at least 2 years for every patient resulting in a total study time of 5 years (first patient in to last patient out).
Discussion
Given the high risk for vascular re-events in acute stroke and the available effective strategies in secondary prevention, the INSPIRE-TMS support program has the potential to lead to a relevant reduction of recurrent events and a prolongation of the event-free survival time. The trial will provide the basis for the decision whether an intensified secondary prevention program after stroke should be implemented into regular care. A cost-effectiveness evaluation will be performed.
Trial registration
clinicaltrials.gov: 01586702
doi:10.1186/1471-2377-13-11
PMCID: PMC3563480  PMID: 23347503
TIA; Stroke; Secondary prevention; Intervention trial
12.  Rate of cardiac arrhythmias and silent brain lesions in experienced marathon runners: rationale, design and baseline data of the Berlin Beat of Running study 
Background
Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing.
Methods/ Design
In the prospective observational “Berlin Beat of Running” study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38th BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year.
Results
Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 ± 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 ± 6.6 marathon races within the last 5 years and a mean of 16 ± 36 marathon races in total. Their weekly running distance prior to the 38th BMW BERLIN-MARATHON was 65 ± 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38th BMW BERLIN-MARATHON 2011.
Discussion
Findings from the “Berlin Beats of Running” study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage.
Trial registration
clinicaltrials.gov NCT01428778
doi:10.1186/1471-2261-12-69
PMCID: PMC3458995  PMID: 22938148
Marathon running; ECG-recording; Magnetic resonance imaging; Blood sampling; Cardiac arrhythmia
13.  Vessel size imaging reveals pathological changes of microvessel density and size in acute ischemia 
The aim of this study was to test the feasibility of vessel size imaging with precise evaluation of apparent diffusion coefficient and cerebral blood volume and to apply this novel technique in acute stroke patients within a pilot group to observe the microvascular responses in acute ischemic tissue. Microvessel density-related quantity Q and mean vessel size index (VSI) were assessed in 9 healthy volunteers and 13 acute stroke patients with vessel occlusion within 6 hours after symptom onset. Our results in healthy volunteers matched with general anatomical observations. Given the limitation of a small patient cohort, the median VSI in the ischemic area was higher than that in the mirrored region in the contralateral hemisphere (P<0.05). Decreased Q was observed in the ischemic region in 2 patients, whereas no obvious changes of Q were found in the remaining 11 patients. In a patient without recanalization, the VSI hyperintensity in the subcortical area matched well with the final infarct. These data reveal that different observations of microvascular response in the acute ischemic tissue seem to emerge and vessel size imaging may provide useful information for the definition of ischemic penumbra and have an impact on future therapeutic approaches.
doi:10.1038/jcbfm.2011.38
PMCID: PMC3170945  PMID: 21468091
acute stroke; brain imaging; brain ischemia; MRI; perfusion-weighted MRI
14.  Automated vs manual delineations of regions of interest- a comparison in commercially available perfusion MRI software 
BMC Medical Imaging  2012;12:16.
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.
doi:10.1186/1471-2342-12-16
PMCID: PMC3423015  PMID: 22809148
Magnetic resonance imaging; Perfusion MRI; Acute ischemic stroke
15.  Stroke risk associated with balloon based catheter ablation for atrial fibrillation: Rationale and design of the MACPAF Study 
BMC Neurology  2010;10:63.
Background
Catheter ablation of the pulmonary veins has become accepted as a standard therapeutic approach for symptomatic paroxysmal atrial fibrillation (AF). However, there is some evidence for an ablation associated (silent) stroke risk, lowering the hope to limit the stroke risk by restoration of rhythm over rate control in AF. The purpose of the prospective randomized single-center study "Mesh Ablator versus Cryoballoon Pulmonary Vein Ablation of Symptomatic Paroxysmal Atrial Fibrillation" (MACPAF) is to compare the efficacy and safety of two balloon based pulmonary vein ablation systems in patients with symptomatic paroxysmal AF.
Methods/Design
Patients are randomized 1:1 for the Arctic Front® or the HD Mesh Ablator® catheter for left atrial catheter ablation (LACA). The predefined endpoints will be assessed by brain magnetic resonance imaging (MRI), neuro(psycho)logical tests and a subcutaneously implanted reveal recorder for AF detection. According to statistics 108 patients will be enrolled.
Discussion
Findings from the MACPAF trial will help to balance the benefits and risks of LACA for symptomatic paroxysmal AF. Using serial brain MRIs might help to identify patients at risk for LACA-associated cerebral thromboembolism. Potential limitations of the study are the single-center design, the existence of a variety of LACA-catheters, the missing placebo-group and the impossibility to assess the primary endpoint in a blinded fashion.
Trial registration
clinicaltrials.gov NCT01061931
doi:10.1186/1471-2377-10-63
PMCID: PMC2919504  PMID: 20663131
16.  Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion–diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study 
Lancet neurology  2008;8(2):141-150.
Summary
Background
Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3–9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI).
Methods
In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 µg/kg desmoteplase, 125 µg/kg desmoteplase, or placebo within 3–9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0–2 points, and a Barthel index of 75–100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study registered with ClinicalTrials.gov, NCT00111852.
Findings
Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 µg/kg desmoteplase; 66 received 125 µg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6–14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10·6 cm3 and 52·5 cm3, respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 µg/kg desmoteplase, 36% (24 of 66) for 125 µg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 µg/kg desmoteplase 14·0% (0·5 cm3); 125 µg/kg desmoteplase 10·8% (0·3 cm3 placebo −10·0% (−0·9 cm3). The rates of symptomatic intracranial haemorrhage were 3·5% (2 of 57) for 90 µg/kg desmoteplase, 4·5% (3 of 66) for 125 µg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 µg/kg desmoteplase; 21% [14 of 66] for 125 µg/kg desmoteplase; and 6% [4 of 63] for placebo).
Interpretation
The DIAS-2 study did not show a benefit of desmoteplase given 3–9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase.
doi:10.1016/S1474-4422(08)70267-9
PMCID: PMC2730486  PMID: 19097942
17.  Prospective study on the mismatch concept in acute stroke patients within the first 24 h after symptom onset - 1000Plus study 
BMC Neurology  2009;9:60.
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
doi:10.1186/1471-2377-9-60
PMCID: PMC3224745  PMID: 19995432
18.  Acute Stroke Imaging Research Roadmap 
The recent “Advanced Neuroimaging for Acute Stroke Treatment” meeting on September 7 and 8, 2007 in Washington DC, brought together stroke neurologists, neuroradiologists, emergency physicians, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), industry representatives, and members of the US Food and Drug Administration (FDA) to discuss the role of advanced neuroimaging in acute stroke treatment. The goals of the meeting were to assess state-of-the-art practice in terms of acute stroke imaging research and to propose specific recommendations regarding: (1) the standardization of perfusion and penumbral imaging techniques, (2) the validation of the accuracy and clinical utility of imaging markers of the ischemic penumbra, (3) the validation of imaging biomarkers relevant to clinical outcomes, and (4) the creation of a central repository to achieve these goals. The present article summarizes these recommendations and examines practical steps to achieve them.
doi:10.1161/STROKEAHA.107.512319
PMCID: PMC2716734  PMID: 18477656

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