Haemorrhage after thrombectomy with adjuvant thrombolysis in unknown onset stroke depends on high early lesion water uptake.

BACKGROUND AND PURPOSE: In wake-up stroke, CT-based quantitative net water uptake (NWU) might serve as an alternative tool to MRI to guide intravenous thrombolysis with alteplase (IVT). An important complication after IVT is symptomatic intracerebral haemorrhage (sICH). As NWU directly implies ischaemic lesion progression, reflecting blood-brain barrier injury, we hypothesised that NWU predicts sICH in patients who had a ischaemic stroke undergoing thrombectomy with unknown onset. METHODS: Consecutive analysis of all patients who had unknown onset anterior circulation ischaemic stroke who underwent CT at baseline and endovascular treatment between December 2016 and October 2020. Quantitative NWU was assessed on baseline CT. The primary endpoint was sICH. The association of NWU and other baseline parameters to sICH was investigated using inverse-probability weighting (IPW) analysis. RESULTS: A total of 88 patients were included, of which 46 patients (52.3%) received IVT. The median NWU was 10.7% (IQR: 5.1-17.7). The proportion of patients with any haemorrhage and sICH were 35.2% and 13.6%. NWU at baseline was significantly higher in patients with sICH (19.1% vs 9.6%, p<0.0001) and the median Alberta Stroke Program Early CT Score (ASPECTS) was lower (5 vs 8, p<0.0001). Following IPW, there was no association between IVT and sICH in unadjusted analysis. However, after adjusting for ASPECTS and NWU, there was a significant association between IVT administration and sICH (14.6%, 95% CI: 3.3% to 25.6%, p<0.01). CONCLUSION: In patients with ischaemic stroke with unknown onset, the combination of high NWU with IVT is directly linked to higher rates of sICH. Besides ASPECTS for evaluating the extent of the early infarct lesion, quantitative NWU could be used as an imaging biomarker to assess the degree of blood-brain barrier damage in order to predict the risk of sICH in patients with wake up stroke.

Association Between Net Water Uptake and Functional Outcome in Patients With Low ASPECTS Brain Lesions: Results From the I-LAST Study.

BACKGROUND AND OBJECTIVES: The effect of mechanical thrombectomy (MT) on functional outcome in patients with ischemic stroke with low ASPECTS is still uncertain. ASPECTS rating is based on the presence of ischemic hypoattenuation relative to normal; however, the degree of hypoattenuation, which directly reflects net uptake of water, is currently not considered an imaging biomarker in stroke triage. We hypothesized that the effect of thrombectomy on functional outcome in low ASPECTS patients depends on early lesion water uptake. METHODS: For this multicenter observational study, patients with anterior circulation stroke with ASPECTS ≤5 were consecutively analyzed. Net water uptake (NWU) was assessed as a quantitative imaging biomarker in admission CT. The primary end point was the rate of favorable functional outcome defined as modified Rankin Scale score 0-3 at day 90. The effect of recanalization on functional outcome was analyzed according to the degree of NWU within the early infarct lesion. RESULTS: A total of 254 patients were included, of which 148 (58%) underwent MT. The median ASPECTS was 4 (interquartile range [IQR] 3-5), and the median NWU was 11.4% (IQR 8.9%-15.1%). The rate of favorable outcome was 27.6% in patients with low NWU (<11.4%) vs 6.3% in patients with high NWU (≥11.4%; p < 0.0001). In multivariable logistic regression analysis, NWU was an independent predictor of outcome, whereas vessel recanalization (modified thrombolysis in cerebral infarction ≥2b) was only significantly associated with better outcomes if NWU was lower than 12.6%. In inverse-probability weighting analysis, recanalization was associated with 20.7% (p = 0.01) increase in favorable outcome in patients with low NWU compared with 9.1% (p = 0.06) in patients with high NWU. DISCUSSION: Early NWU was independently associated with clinical outcome and might serve as an indicator of futile MT in low ASPECTS patients. NWU could be tested as a tool to select low ASPECTS patients for MT. TRIAL REGISTRATION INFORMATION: The study is registered within the ClinicalTrials.gov Protocol Registration and Results System (NCT04862507).

Favourable arterial, tissue-level and venous collaterals correlate with early neurological improvement after successful thrombectomy treatment of acute ischaemic stroke.

BACKGROUND AND PURPOSE: Early neurological improvement (ENI) after thrombectomy is associated with better long-term outcomes in patients with acute ischaemic stroke due to large vessel occlusion (AIS-LVO). Whether cerebral collaterals influence the likelihood of ENI is poorly described. We hypothesised that favourable collateral perfusion at the arterial, tissue-level and venous outflow (VO) levels is associated with ENI after thrombectomy. MATERIALS AND METHODS: Multicentre retrospective study of patients with AIS-LVO treated by thrombectomy. Tissue-level collaterals (TLC) were measured on cerebral perfusion studies by the hypoperfusion intensity ratio. VO and pial arterial collaterals (PAC) were determined by the Cortical Vein Opacification Score and the modified Tan scale on CT angiography, respectively. ENI was defined as improvement of ≥8 points or a National Institutes of Health Stroke Scale score of 0 hour or 1 24 hours after treatment. Multivariable regression analyses were used to determine the association of collateral biomarkers with ENI and good functional outcomes (modified Rankin Scale 0-2). RESULTS: 646 patients met inclusion criteria. Favourable PAC (OR: 1.9, CI 1.2 to 3.1; p=0.01), favourable VO (OR: 3.3, CI 2.1 to 5.1; p<0.001) and successful reperfusion (OR: 3.1, CI 1.7 to 5.8; p<0.001) were associated with ENI, but favourable TLC were not (p=0.431). Good functional outcomes at 90-days were associated with favourable TLC (OR: 2.2, CI 1.4 to 3.6; p=0.001), VO (OR: 5.7, CI 3.5 to 9.3; p<0.001) and ENI (OR: 5.7, CI 3.3 to 9.8; p<0.001), but not PAC status (p=0.647). CONCLUSION: Favourable PAC and VO were associated with ENI after thrombectomy. Favourable TLC predicted longer term functional recovery after thrombectomy, but the impact of TLC on ENI is strongly dependent on vessel reperfusion.

The Cerebral Collateral Cascade: Comprehensive Blood Flow in Ischemic Stroke.

BACKGROUND AND PURPOSE: Robust cerebral collaterals are associated with favorable outcomes in patients with acute ischemic stroke due to large vessel occlusion treated by thrombectomy. However, collateral status assessment mostly relies on single imaging biomarkers and a more comprehensive holistic approach may provide deeper insights into the biology of collateral perfusion on medical imaging. Comprehensive collateralization is defined as blood flow of cerebral arteries through the brain tissue and into draining veins. We hypothesized that a comprehensive analysis of the cerebral collateral cascade (CCC) on an arterial, tissue and venous level would predict clinical and radiological outcomes. MATERIALS AND METHODS: Multicenter retrospective cohort study of acute stroke patients undergoing thrombectomy triage. CCC was determined by quantifying pial arterial collaterals, tissue-level collaterals, and venous outflow. Pial arterial collaterals were determined by CT angiography, tissue-level collaterals were assessed on CT perfusion. Venous outflow was assessed on CT angiography using the cortical vein opacification score. 3 groups were defined: CCC+ (good pial collaterals, tissue-level collaterals, and venous outflow), CCC- (poor pial collaterals, tissue-level collaterals, and venous outflow) and CCCmixed (remainder of patients). Primary outcome was functional independence (modified Rankin Scale: 0-2) at 90-days. Secondary outcome was final infarct volume. RESULTS: 647 patients met inclusion criteria: 176 CCC+, 345 CCC mixed and 126 CCC-. Multivariable ordinal logistic regression showed that CCC+ predicted good functional outcomes (OR=18.9 [95% CI 8-44.5]; p<0.001) compared to CCC- and CCCmixed patients. CCCmixed patients likely had better functional outcomes compared to CCC- patients (OR=2.5 [95% CI 1.2-5.4]; p=0.014). Quantile regression analysis (50th percentile) showed that CCC+ (ß: -78.5, 95% CI -96.0- -61.1; p<0.001) and CCCmixed (ß: -64.0, 95% CI -82.4- -45.6; p<0.001) profiles were associated with considerably lower final infarct volumes compared to CCC- profiles. CONCLUSION: Comprehensive assessment of the collateral blood flow cascade in acute stroke patients is a strong predictor of clinical and radiological outcomes in patients treated by thrombectomy.

Rethinking the Collateral Vasculature Assessment in Acute Ischemic Stroke: The Comprehensive Collateral Cascade.

ABSTRACT: Occlusion of a cervical or cerebral artery results in disruption of blood flow to the brain and may result in irreversible infarction. Intracranial pial collaterals are a network of arteries that may preserve blood flow to otherwise critically hypoperfused brain areas until vessel recanalization is achieved. The robustness of these arterial collaterals is pivotal for the survivability of ischemic brain tissue and is associated with treatment success and long-term clinical outcome. More recently, the importance of venous outflow from ischemic brain tissue has been appreciated. Arterial collaterals and venous outflow are evaluated by neuroimaging parameters, and recent imaging advances have enabled a more comprehensive assessment of the entire collateral cascade in patients with acute ischemic stroke. Here we review novel imaging biomarkers for the assessment of arterial collaterals, tissue-level collateral blood flow, and venous outflow. We also summarize how a more comprehensive assessment of the cerebral blood flow leads to a better prediction of treatment efficacy and improved clinical outcomes.

Association of Venous Outflow Profiles and Successful Vessel Reperfusion After Thrombectomy.

OBJECTIVE: Robust arterial collaterals are associated with successful reperfusion after thrombectomy treatment of acute ischemic stroke due to large vessel occlusion (AIS-LVO). Excellent venous outflow (VO) reflects excellent tissue perfusion and collateral status in AIS-LVO patients. To determine whether favorable VO profiles assessed on pre-treatment CT angiography (CTA) images correlate with successful vessel reperfusion after thrombectomy in AIS-LVO patients. METHODS: Multicenter retrospective cohort study of consecutive AIS-LVO patients treated by thrombectomy. Baseline CTA was used to assess collateral status (Tan scale) and VO using the cortical vein opacification score (COVES). Favorable VO was defined as COVES ≥3. Primary outcome was excellent vessel reperfusion status (modified Thrombolysis In Cerebral Infarction [TICI] 2c-3). Secondary outcome was good functional outcome defined as 0-2 on the Modified Ranking Scale (mRS) after 90 days. RESULTS: 565 patients met inclusion criteria. Multivariable logistic regression analysis showed that favorable VO (OR= 2.10 [95% CI 1.39-3.16]; p<0.001) was associated with excellent vessel reperfusion during thrombectomy, regardless of good CTA collateral status (OR= 0.87 [95%CI 0.58-1.34]; p=0.48). A favorable VO profile (OR= 8.9 [95%CI 5.3-14.9]; p<0.001) and excellent vessel reperfusion status (OR = 2.7 [95%CI 1.7-4.4]; p<0.001) were independently associated with good functional outcome adjusted for age, sex, glucose, tPA administration, good CTA collateral status and presentation NIHSS. CONCLUSION: A favorable VO profile is associated with reperfusion success and good functional outcomes in patients with AIS-LVO treated by endovascular thrombectomy.

Factors Associated with Failure of Reperfusion in Endovascular Therapy for Acute Ischemic Stroke : A Multicenter Analysis.

AIM: In acute large vessel occlusions, endovascular therapy (EVT) achieves flow restoration in the majority of cases; however, EVT fails to achieve sufficient reperfusion in a substantial minority of patients. This study aimed to identify predictors of failed reperfusion. METHODS: In this study 2211 patients from the German Stroke Registry who received EVT for anterior circulation stroke were retrospectively analyzed. Failure of reperfusion was defined as thrombolysis in cerebral infarction (TICI) grades 0/1/2a, and sufficient reperfusion as TICI 2b/3. In 1629 patients with complete datasets, associations between failure of reperfusion and baseline clinical data, comorbidities, location of occlusion, and procedural data were assessed with multiple logistic regression. RESULTS: Failure of reperfusion occurred in 371 patients (16.8%) and was associated with the following locations of occlusion: cervical internal carotid artery (ICA, adjusted odds ratio, OR 2.01, 95% confidence interval, CI 1.08-3.69), intracranial ICA without carotid T occlusion (adjusted OR 1.79, 95% CI 1.05-2.98), and M2 segment (adjusted OR 1.86, 95% CI 1.21-2.84). Failed reperfusion was also associated with cervical ICA stenosis (>70% stenosis, adjusted OR 2.90, 95% CI 1.69-4.97), stroke of other determined etiology by TOAST (Trial of ORG 10172 in acute stroke treatment) criteria (e.g. nonatherosclerotic vasculopathies, adjusted OR 2.73, 95% CI 1.36-5.39), and treatment given outside the usual working hours (adjusted OR 1.41, 95% CI 1.07-1.86). Successful reperfusion was associated with higher Alberta stroke program early CT score (ASPECTS) on initial imaging (adjusted OR 0.85, 95% CI 0.79-0.92), treatment with the patient under general anesthesia (adjusted OR 0.72, 95% CI 0.54-0.96), and concomitant ICA stenting in patients with ICA stenosis (adjusted OR 0.20, 95% CI 0.11-0.38). CONCLUSION: Several factors are associated with failure of reperfusion, most notably occlusions of the proximal ICA and low ASPECTS on admission. Conversely, stent placement in the proximal ICA was associated with reperfusion success.

Computed tomography-based triage of extensive baseline infarction: ASPECTS and collaterals versus perfusion imaging for outcome prediction.

BACKGROUND: Patients presenting with large baseline infarctions are often excluded from mechanical thrombectomy (MT) due to uncertainty surrounding its effect on outcome. We hypothesized that computed tomography perfusion (CTP)-based selection may be predictive of functional outcome in low Alberta Stroke Program Early CT Score (ASPECTS) patients. METHODS: This was a double-center, retrospective analysis of patients presenting with ASPECTS≤5 who received multimodal admission CT imaging between May 2015 and June 2020. The predicted ischemic core (pCore) was defined as a reduction in cerebral blood flow (rCBF), while mismatch volume was defined using time to maximum (Tmax). The pCore perfusion mismatch ratio (CPMR) was also calculated. These parameters (pCore, mismatch volume, and CPMR), as well as a combined radiological score consisting of ASPECTS and collateral status (ASCO score), were tested in logistic regression and receiver operating characteristic (ROC) analyses. The primary outcome was favorable modified Rankin Scale (mRS) at discharge (≤3). RESULTS: A total of 113 patients met the inclusion criteria. The median ischemic core volume was 74.1 mL (IQR 43.8-121.8). The ASCO score was associated with favorable outcome at discharge (aOR 3.7, 95% CI 1.8 to 10.7, P=0.002), while no association was observed for the CTP parameters. A model including the ASCO score also had significantly higher area under the curve (AUC) values compared with the CTP-based model (0.88 vs 0.64, P=0.018). CONCLUSIONS: The ASCO score was superior to the CTP-based model for the prediction of good functional outcome and could represent a quick, practical, and easily implemented method for the selection of low ASPECTS patients most likely benefit from MT.

Computed tomography findings in patients with primarily unknown causes of severe or recurrent epistaxis.

OBJECTIVE: In addition to rhinoscopy, computed tomography of paranasal sinuses (CT) may be performed on patients with primary unknown cause of severe epistaxis (SE) or recurrent epistaxis (RE) to further assess the potential cause of bleeding. The aim of this study was to evaluate CT findings during the work-up of intractable epistaxis patients. METHODS: 6937 patients were treated in our emergency department with acute epistaxis between 2009-2018. 304/6937 patients underwent CT and rhinoscopy due to intractable SE or RE. 33 patients presented with head trauma prior to epistaxis and were excluded from the final analysis. In 271 cases the primary causes of SE (n = 252) or RE (n = 19) remained unknown. Two observers retrospectively evaluated CT scans for potential sources of epistaxis. Disagreement was settled by consensus. CT and rhinoscopy findings were compared. RESULTS: In 247/271 (91.1%) SE patients no related pathology was found on CT. A possible cause for epistaxis was found in all RE patients, but only in 5/252 (1.9%) patients with SE. Most tumours (10/11) and inflammatory conditions (9/10) were found in patients with RE. In three SE cases, a tumour was suspected on CT, from which two suspicions were refuted during rhinoscopy. CT revealed 10 cases of inflammatory conditions of the sinus and anatomical variant as potential cause of bleeding. CONCLUSION: For patients with unknown causes of epistaxis, supplementary CT imaging may be a useful diagnostic add-on to rhinoscopy in the event of RE, tumour suspicion or inflammation of the paranasal sinuses. However, in most cases of first-time SE, CT does not necessarily add to the diagnosis. In these cases, the marginal benefit of CT needs to be weighed carefully against its risks.

Clinical benefit of thrombectomy in stroke patients with low ASPECTS is mediated by oedema reduction.

The impact of endovascular vessel recanalization on patients with a low initial Alberta Stroke Program Early Computer Tomography Score (ASPECTS) is still uncertain. We hypothesized that vessel recanalization leads to an improvement in mortality and degree of disability by reducing brain oedema and malignant mass effect. In this multicentre observational study, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and an ASPECTS of ≤ 5 were analysed. Patients were assembled into two groups: successful vessel recanalization (thrombolysis in cerebral infarctions, TICI scale 2b/3) or persistent vessel occlusion (no endovascular procedure or TICI scale 0-2a). Observers were blinded to clinical data. Net water uptake within brain infarct, a quantitative biomarker based on CT densitometry, was used to quantify oedema in admission and follow-up CT and Δ-water uptake was calculated as difference between water uptake at both time points. Occurrence of malignant infarctions and secondary parenchymal haemorrhage was documented. Furthermore, modified Rankin scale score at 90 days was used for functional outcome. We included 117 patients admitted between March 2015 and August 2017 in three German stroke centres: 71 with persistent vessel occlusion and 46 with successful recanalization. The mean water uptake in the admission imaging was not different between both groups: 10.0% (±4.8) in patients with persistent vessel occlusion and 9.0% (±4.8) in patients with vessel recanalization (P = 0.4). After follow-up CT, the mean Δ-water uptake was 16.0% (±7.5) in patients with persistent vessel occlusion and 8.0% (±5.7) in patients with vessel recanalization (P < 0.001). Successful reperfusion was independently associated with a lowered Δ-water uptake of 8.0% (95% confidence interval, CI: -10.5 to -5.3%; P < 0.001) and lowered modifed Rankin scale score after 90 days of 1.5 (95% CI: -2.2 to -0.8; P < 0.001). The prevalence of malignant infarctions was 44.3% in patients with persistent vessel occlusion and 26.1% in patients with vessel recanalization. There was no significant difference for secondary haemorrhage in both groups (P = 0.7). In conclusion, successful recanalization in patients with low initial ASPECTS resulted in a significant reduction of oedema formation and was associated with a decreased prevalence of malignant infarctions and an improvement of clinical outcome.

Reasons for failed endovascular recanalization attempts in stroke patients.

PURPOSE: Mechanical thrombectomy (MT) is a highly effective therapy in patients with acute ischemic stroke due to large vessel occlusion (LVO). However, complete recanalization of the occluded vessel cannot be achieved in all patients, leading to poor clinical outcome. We analyzed the reasons for failed recanalization to help direct future improvements in therapy. METHODS: 648 consecutive stroke patients with LVO and an MT attempt were retrospectively analyzed for none or minimal recanalization, assessed according to the Thrombolysis in Cerebral Infarction (TICI) score (0/1). Procedural parameters were evaluated in a standardized approach. Among other variables, number of retrieval attempts, devices, duration of the intervention, and rescue methods were analyzed. RESULTS: TICI 0/1 was observed in 72/648 patients (11%). In these patients, the thrombus could not be reached in 21% (n=15/72), was reached but not passed in 21% (n=15/72), and was reached and passed in 58% (n=42/72). Only a minor degree of initial recanalization was achieved in 19% (n=8/42) of patients with a reached occlusion during the course of the intervention. Furthermore, a higher number of passes with a single retriever device led to significant prolongation of the intervention. Therefore, major reasons for failed endovascular recanalization were difficult anatomical access and hard or resistant occlusions that might reflect hard thrombi or pre-existing atherosclerotic stenosis. Procedural complications such as dissection or perforation played a minor role. CONCLUSION: In stroke patients with failed MT attempts, approximately 60% of occlusions can be passed. In such cases, rescue therapy might be considered to improve recanalization and clinical outcome. Further development of access devices might help in the remaining cases where the microcatheter could not be manipulated to or through the occlusion.

Highest Lesion Growth Rates in Patients With Hyperacute Stroke: When Time Is Brain Particularly Matters.

Background and Purpose- The early growth of ischemic lesions has been described as being nonlinear, with lesion growth rates at their highest during the earliest period after stroke onset. We hypothesized that the time gap from imaging to revascularization results in higher lesion growth in patients with hyperacute presentation. Methods- Fifty-one patients with ischemic stroke with initial multimodal computed tomography (CT), follow-up CT after 24 hours, and successful endovascular recanalization were included and separated into 2 groups according to their median time from symptom onset to imaging (eg, hyperacute versus acute). The difference in Alberta Stroke Program Early CT Score (ASPECTS) between initial CT and follow-up CT was assessed, as well as volumetric lesion growth from early ischemic core in admission perfusion CT and total lesion volume in follow-up CT. Results- The median time from onset to imaging was 1.85 hours. There was no significant difference in admission ASPECTS (mean, 8.5 versus 8.2) or time from imaging to recanalization in both groups (median, 2.7 versus 2.4 hours; P=0.4). The mean (SD) lesion growth assessed by ASPECTS difference was 2.7 (2.3) in the hyperacute group and 1.6 (1.3) in the acute group (P=0.03). The mean (SD) volumetric difference in the hyperacute group was 26.6 mL (43.2 mL) and 17.2 mL (26.3 mL; P=0.36) in the acute group, respectively. For every passing hour after onset, ASPECTS lesion growth was reduced by 0.4. Conclusions- Patients in the hyperacute phase showed increased ASPECTS lesion growth from imaging to recanalization suggesting a particular benefit of faster recanalization times in this group of patients with stroke.

Recanalization Rate per Retrieval Attempt in Mechanical Thrombectomy for Acute Ischemic Stroke.

Background and Purpose- In acute ischemic stroke, mechanical thrombectomy allows flow restoration in the majority of cases. In case of an unsuccessful retrieval, little is known about how many retrieval attempts should be performed before stopping the procedure. This study assessed the recanalization rate and clinical outcome per retrieval maneuver. Methods- In this analysis, 330 patients with acute large vessel occlusion treated exclusively with stentrieval devices were included. Successful recanalization was defined as Thrombolysis in Cerebral Infarction 2b-3, a good clinical outcome was defined as modified Rankin Scale at 90 days of ≤2. Results- The median number of retrieval attempts was 1 (interquartile range, 1-2, maximum 8). Recanalization rates per retrieval attempt were highest for the first retrieval (46.8%) and lowest for the fifth retrieval (22.7%). After 3 retrieval attempts, 67.9% of patients were successfully recanalized. Patients with 1 to 3 retrieval attempts had higher rates of good clinical outcome (28.9% versus 7.4%; P=0.018). The number of passes was an independent negative predictor of good clinical outcome (adjusted odds ratio, 0.65; 95% CI, 0.435-0.970; P=0.035). Conclusions- Two-thirds of occlusions were successfully recanalized with up to 3 retrieval attempts. Further attempts had good recanalization rates, but the rate of favorable clinical outcome did not improve.

Subacute Infarct Volume With Edema Correction in Computed Tomography Is Equivalent to Final Infarct Volume After Ischemic Stroke: Improving the Comparability of Infarct Imaging Endpoints in Clinical Trials.

OBJECTIVES: Final infarct volume is regularly used as an end point of tissue outcome in stroke trials; however, the reported volumes are most commonly derived from early follow-up imaging. Those volumes are significantly impaired by ischemic edema, which causes an overestimation of the true final lesion volume. As net water uptake within ischemic brain can be quantified densitometrically in computed tomography (CT) as recently described, we hypothesized that the final lesion volume can be better estimated by correcting the lesion volume in early follow-up for the corresponding proportion of edema. MATERIALS AND METHODS: After retrospective consecutive screening of the local registry, 20 patients with acute middle cerebral artery large vessel occlusion met the inclusion criteria with early and late follow-up CT; the latter acquired at least 4 weeks after admission. In early follow-up imaging 24 hours after onset, the proportion of edema contributing to the infarct lesion was calculated by quantifying the total volume of ischemic net water uptake. Edema volume was then subtracted from the total lesion volume to obtain edema-corrected lesion volumes. Finally, these corrected lesion volumes were compared with the final lesion volume on late follow-up serving as ground truth. RESULTS: The median lesion volume in the early follow-up was 115.1 mL (range, 21.9-539.9 mL) and significantly exceeded the median final lesion volume in the late follow-up CT, which was 86.6 mL (range, 11.2-399.0 mL; p < 0.001). The calculated mean proportion of edema within the early lesion volume was 25.8% (±5.9%; range, 11.1%-35.9%. The median edema-corrected lesion volume measured after 24 hours was 87.1 mL (range, 18.2-376.3 mL). The estimation of final lesion volume in the early follow-up CT was therefore improved by a mean of 31.4% (±2.1%) when correcting for the proportion of edema and did not differ significantly from the true final infarct volume (p = 0.2). CONCLUSIONS: Edema-corrected volumes of early follow-up infarct lesion in CT were in close agreement with the actual final infarct volumes. Computed tomography-based edema correction of subacute infarct lesions improves the estimation of final tissue outcome. This could especially improve the comparability of imaging end points and facilitate patient recruitment in clinical trials.

A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial).

OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial. CLINICAL TRIAL REGISTRATION: NCT01450124; Results.

Computed Tomography-Based Imaging of Voxel-Wise Lesion Water Uptake in Ischemic Brain: Relationship Between Density and Direct Volumetry.

OBJECTIVES: Net water uptake per volume of brain tissue may be calculated by computed tomography (CT) density, and this imaging biomarker has recently been investigated as a predictor of lesion age in acute stroke. However, the hypothesis that measurements of CT density may be used to quantify net water uptake per volume of infarct lesion has not been validated by direct volumetric measurements so far. The purpose of this study was to (1) develop a theoretical relationship between CT density reduction and net water uptake per volume of ischemic lesions and (2) confirm this relationship by quantitative in vitro and in vivo CT image analysis using direct volumetric measurements. MATERIALS AND METHODS: We developed a theoretical rationale for a linear relationship between net water uptake per volume of ischemic lesions and CT attenuation. The derived relationship between water uptake and CT density was tested in vitro in a set of increasingly diluted iodine solutions with successive CT measurements. Furthermore, the consistency of this relationship was evaluated using human in vivo CT images in a retrospective multicentric cohort. In 50 edematous infarct lesions, net water uptake was determined by direct measurement of the volumetric difference between the ischemic and normal hemisphere and was correlated with net water uptake calculated by ischemic density measurements. RESULTS: With regard to in vitro data, water uptake by density measurement was equivalent to direct volumetric measurement (r = 0.99, P < 0.0001; mean ± SD difference, -0.29% ± 0.39%, not different from 0, P < 0.0001). In the study cohort, the mean ± SD uptake of water within infarct measured by volumetry was 44.7 ± 26.8 mL and the mean percent water uptake per lesion volume was 22.7% ± 7.4%. This was equivalent to percent water uptake obtained from density measurements: 21.4% ± 6.4%. The mean difference between percent water uptake by direct volumetry and percent water uptake by CT density was -1.79% ± 3.40%, which was not significantly different from 0 (P < 0.0001). CONCLUSIONS: Volume of water uptake in infarct lesions can be calculated quantitatively by relative CT density measurements. Voxel-wise imaging of water uptake depicts lesion pathophysiology and could serve as a quantitative imaging biomarker of acute infarct lesions.

CT-perfusion stroke imaging: a threshold free probabilistic approach to predict infarct volume compared to traditional ischemic thresholds.

The aim was to evaluate a novel method of threshold-free prediction of brain infarct from computed tomography perfusion (CTP) imaging in comparison to conventional ischemic thresholds. In a multicenter cohort of 161 patients with acute large vessel occlusion who received endovascular therapy, brain infarction was predicted by CTP using (1) optimized parameter cut-off values determined by ROC curve analysis and (2) probabilistic logistic regression threshold-free analysis. Predicted infarct volumes and prediction errors based on four perfusion parameter maps were compared against observed infarcts. In 93 patients with successful recanalization, the mean observed infarct volume was 35.7 ± 61.9 ml (the reference for core infarct not savable by reperfusion). Optimal parameter thresholds predicted mean infarct volumes between 53.2 ± 44.4 and 125.0 ± 95.4 ml whereas threshold-free analysis predicted mean volumes between 35.9 ± 28.5 and 36.1 ± 29.0 ml. In 68 patients with persistent occlusion, the mean observed infarct volume was 113.4 ± 138.3 ml (the reference to define penumbral infarct savable by reperfusion). Predicted mean infarct volumes by parameter thresholds ranged from 91.4 ± 81.5 to 163.8 ± 135.7 ml, by threshold-free analysis from 113.2 ± 89.9 to 113.5 ± 89.0 ml. Threshold-free prediction of infarct volumes had a higher precision and lower patient-specific prediction error than conventional thresholding. Penumbra to core lesion mismatch estimate may therefore benefit from threshold-free CTP analysis.

Reliability of cortical lesion detection on double inversion recovery MRI applying the MAGNIMS-Criteria in multiple sclerosis patients within a 16-months period.

PURPOSE: In patients with multiple sclerosis (MS), Double Inversion Recovery (DIR) magnetic resonance imaging (MRI) can be used to identify cortical lesions (CL). We sought to evaluate the reliability of CL detection on DIR longitudinally at multiple subsequent time-points applying the MAGNIMs scoring criteria for CLs. METHODS: 26 MS patients received a 3T-MRI (Siemens, Skyra) with DIR at 12 time-points (TP) within a 16 months period. Scans were assessed in random order by two different raters. Both raters separately marked all CLs on each scan and total lesion numbers were obtained for each scan-TP and patient. After a retrospective re-evaluation, the number of consensus CLs (conL) was defined as the total number of CLs, which both raters finally agreed on. CLs volumes, relative signal intensities and CLs localizations were determined. Both ratings (conL vs. non-consensus scoring) were compared for further analysis. RESULTS: A total number of n = 334 CLs were identified by both raters in 26 MS patients with a first agreement of both raters on 160 out of 334 of the CLs found (κ = 0.48). After the retrospective re-evaluation, consensus agreement increased to 233 out of 334 CL (κ = 0.69). 93.8% of conL were visible in at least 2 consecutive TP. 74.7% of the conL were visible in all 12 consecutive TP. ConL had greater mean lesion volumes and higher mean signal intensities compared to lesions that were only detected by one of the raters (p<0.05). A higher number of CLs in the frontal, parietal, temporal and occipital lobe were identified by both raters than the number of those only identified by one of the raters (p<0.05). CONCLUSIONS: After a first assessment, slightly less than a half of the CL were considered as reliably detectable on longitudinal DIR images. A retrospective re-evaluation notably increased the consensus agreement. However, this finding is narrowed, considering the fact that retrospective evaluation steps might not be practicable in clinical routine. Lesions that were not reliably identifiable by both raters seem to be characterized by lower signal intensity and smaller size, or located in distinct anatomical brain regions.

Heterogeneity of Multiple Sclerosis Lesions in Multislice Myelin Water Imaging.

PURPOSE: To assess neuroprotection and remyelination in Multiple Sclerosis (MS), we applied a more robust myelin water imaging (MWI) processing technique, including spatial priors into image reconstruction, which allows for lower SNR, less averages and shorter acquisition times. We sought to evaluate this technique in MS-patients and healthy controls (HC). MATERIALS AND METHODS: Seventeen MS-patients and 14 age-matched HCs received a 3T Magnetic Resonance Imaging (MRI) examination including MWI (8 slices, 12 minutes acquisition time), T2w and T1mprage pre and post gadolinium (GD) administration. Black holes (BH), contrast enhancing lesions (CEL) and T2 lesions were marked and registered to MWI. Additionally, regions of interest (ROI) were defined in the frontal, parietal and occipital normal appearing white matter (NAWM)/white matter (WM), the corticospinal tract (CST), the splenium (SCC) and genu (GCC) of the corpus callosum in patients and HCs. Mean values of myelin water fraction (MWF) were determined for each ROI. RESULTS: Significant differences (p≤0.05) of the MWF were found in all three different MS-lesion types (BH, CEL, T2 lesions), compared to the WM of HCs. The mean MWF values among the different lesion types were significantly differing from each other. Comparing MS-patients vs. HCs, we found a significant (p≤0.05) difference of the MWF in all measured ROIs except of GCC and SCC. The mean reduction of MWF in the NAWM of MS-patients compared to HCs was 37%. No age, sex, disability score and disease duration dependency was found for the NAWM MWF. CONCLUSION: MWF measures were in line with previous studies and lesions were clearly visible in MWI. MWI allows for quantitative assessment of NAWM and lesions in MS, which could be used as an additional sensitive imaging endpoint for larger MS studies. Measurements of the MWF also differ between patients and healthy controls.