Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label phase 3 trial with blinded endpoint

SUMMARY Background Craniotomy, when evaluated in trials, does not improve outcome after intracerebral haemorrhage (ICH). Whether minimally invasive catheter evacuation followed by thrombolysis is safe and can achieve a good functional outcome by removing clot is unknown. We investigated safety and efficacy of alteplase with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage. Methods MISTIE was an international, randomized, open-label study and was done in 26 hospitals in the USA, Canada, the UK, and Germany. Patients (aged 18–80 years), with non-traumatic (spontaneous) ICH ≥20 mL were randomly allocated, centrally, to medical care or image-guided MIS plus rt-PA (0.3 mg or 1.0 mg every 8 hours for up to 9 doses) to remove clot using surgical aspiration followed with alteplase clot irrigation. The primary efficacy outcome was the adjusted dichotomized modified Rankin Scale (mRS) 0–3 vs 4–6 assessed at day 180 after symptom onset. Analysis was by intention to treat. (ClinicalTrials.gov number NCT00224770). Findings Between February 2, 2006 and April 8, 2013, 96 subjects were randomized and completed follow-up: 54 received treatment and 42 medical care. Primary safety outcomes: mortality, symptomatic bleeding, brain infections, as well as withdrawal of care, did not differ between groups. Asymptomatic hemorrhages were more common in the surgical group (3 (7%) vs. 12 (22%) p= 0.05) producing a difference of 15.1% (95% CI: 1.5% to 28.6%). The estimated absolute benefit, i.e., the unadjusted difference in observed proportions of all subjects with mRS 0–3 (33% vs 21%) at 180 days comparing MISPA vs. medical control, is 0.109 [95%CI: −0.088, 0.294; p=0.26], and is 0.162 [95%CI: 0.003, 0.323; p=0.05] after adjustment for potential imbalances in baseline severity between study arms (primary efficacy outcome). Interpretation MIS+rt-PA appears safe with an apparent advantage of better functional outcome at 180 days. Increased asymptomatic bleeding is a major cautionary finding. The MISTIE trial results, if replicable, could produce a meaningful functional benefit adding surgical management as a therapeutic strategy for ICH. Funding National Institute of Neurologic Disorders and Stroke, Genentech, and Codman.

Summary Background Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. Methods In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. Findings Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88–1·28; p=0–554]). A difference of 3·5% (RR 1·08 [95% CI 0·90–1·29], p=0–420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41–0·86], p=0–006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22–3·26], p=0–007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31–0·97], p=0–048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64–0·90], p=0–002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37–3·91], p=0–771) was similar. Interpretation In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status.

Background and Purpose Perihematomal edema (PHE) can worsen outcomes following ICH. Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with rt-PA will not exacerbate it. Methods MISTIE II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semi-automated, computerized volumetric analysis on CT to assess impact of hematoma removal on PHE and 2) effects of rt-PA on PHE. Volumetric analyses were performed on Baseline Stability (BLS) and End of Treatment (EOT) scans. Results Seventy-nine surgical and 39 medical patients from MISTIE II were analyzed. Mean hematoma volume at EOT was 19.6±14.5 cc for the surgical cohort and 40.7±13.9 cc for the medical cohort (p<0.001). Edema volume at EOT was lower for the surgical cohort: 27.7±13.3 cc than medical cohort: 41.7±14.6 cc (p<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20-65%, and <20% ICH removed were analyzed (p<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (ρ=0.658; p<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA (S+rt-PA) while 10 underwent surgical aspiration only (SO). Both cohorts achieved similar clot reduction: S+rt-PA, 18.9±14.5 cc; and SO, 24.5±14.0 cc (p=0.26). Edema at EOT in S+rt-PA was 28.1±13.8 cc and 24.4±8.6 cc in SO (p=0.41). Conclusions Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not appear to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot. Clinical Trial Registration Information URL: http://clinicaltrials.gov/ct2/show/NCT00224770?term=MISTIE&rank=1 Clinicaltrials.gov ID: NCT00224770

IntroductionIntracerebral hemorrhage (ICH), where a blood vessel ruptures into areas of the brain, accounts for approximately 10–15% of all strokes. X-ray computed tomography (CT) scanning is largely used to assess the location and volume of these hemorrhages. Manual segmentation of the CT scan using planimetry by an expert reader is the gold standard for volume estimation, but is time-consuming and has within- and across-reader variability. We propose a fully automated segmentation approach using a random forest algorithm with features extracted from X-ray computed tomography (CT) scans.MethodsThe Minimally Invasive Surgery plus rt-PA in ICH Evacuation (MISTIE) trial was a multi-site Phase II clinical trial that tested the safety of hemorrhage removal using recombinant-tissue plasminogen activator (rt-PA). For this analysis, we use 112 baseline CT scans from patients enrolled in the MISTE trial, one CT scan per patient. ICH was manually segmented on these CT scans by expert readers. We derived a set of imaging predictors from each scan. Using 10 randomly-selected scans, we used a first-pass voxel selection procedure based on quantiles of a set of predictors and then built 4 models estimating the voxel-level probability of ICH. The models used were: 1) logistic regression, 2) logistic regression with a penalty on the model parameters using LASSO, 3) a generalized additive model (GAM) and 4) a random forest classifier. The remaining 102 scans were used for model validation.For each validation scan, the model predicted the probability of ICH at each voxel. These voxel-level probabilities were then thresholded to produce binary segmentations of the hemorrhage. These masks were compared to the manual segmentations using the Dice Similarity Index (DSI) and the correlation of hemorrhage volume of between the two segmentations. We tested equality of median DSI using the Kruskal-Wallis test across the 4 models. We tested equality of the median DSI from sets of 2 models using a Wilcoxon signed-rank test.ResultsAll results presented are for the 102 scans in the validation set. The median DSI for each model was: 0.89 (logistic), 0.885 (LASSO), 0.88 (GAM), and 0.899 (random forest). Using the random forest results in a slightly higher median DSI compared to the other models. After Bonferroni correction, the hypothesis of equality of median DSI was rejected only when comparing the random forest DSI to the DSI from the logistic (p < 0.001), LASSO (p < 0.001), or GAM (p < 0.001) models. In practical terms the difference between the random forest and the logistic regression is quite small. The correlation (95% CI) between the volume from manual segmentation and the predicted volume was 0.93 (0.9,0.95) for the random forest model. These results indicate that random forest approach can achieve accurate segmentation of ICH in a population of patients from a variety of imaging centers. We provide an R package (https://github.com/muschellij2/ichseg) and a Shiny R application online (http://johnmuschelli.com/ich_segment_all.html) for ...

Background X-ray Computed Tomography (CT) imaging of the brain is commonly used in diagnostic settings. Although CT scans are primarily used in clinical practice, they are increasingly used in research. A fundamental processing step in brain imaging research is brain extraction – the process of separating the brain tissue from all other tissues. Methods for brain extraction have either been 1) validated but not fully automated, or 2) fully automated and informally proposed, but never formally validated. Aim To systematically analyze and validate the performance of FSL's brain extraction tool (BET) on head CT images of patients with intracranial hemorrhage. This was done by comparing the manual gold standard with the results of several versions of automatic brain extraction and by estimating the reliability of automated segmentation of longitudinal scans. The effects of the choice of BET parameters and data smoothing is studied and reported. Methods All images were thresholded using a 0 – 100 Hounsfield units (HU) range. In one variant of the pipeline, data were smoothed using a 3-dimensional Gaussian kernel (σ = 1mm3) and re-thresholded to 0 – 100 HU; in the other, data were not smoothed. BET was applied using 1 of 3 fractional intensity (FI) thresholds: 0.01, 0.1, or 0.35 and any holes in the brain mask were filled. For validation against a manual segmentation, 36 images from patients with intracranial hemorrhage were selected from 19 different centers from the MISTIE (Minimally Invasive Surgery plus recombinant-tissue plasminogen activator for Intracerebral Evacuation) stroke trial. Intracranial masks of the brain were manually created by one expert CT reader. The resulting brain tissue masks were quantitatively compared to the manual segmentations using sensitivity, specificity, accuracy, and the Dice Similarity Index (DSI). Brain extraction performance across smoothing and FI thresholds was compared using the Wilcoxon signed-rank test. The intracranial volume (ICV) of each scan was estimated by multiplying the number of voxels in the brain mask by the dimensions of each voxel for that scan. From this, we calculated the ICV ratio comparing manual and automated segmentation: 1ICVautomatedICVmanual. To estimate the performance in a large number of scans, brain masks were generated from the 6 BET pipelines for 1095 longitudinal scans from 129 patients. Failure rates were estimated from visual inspection. ICV of each scan was estimated and and an intraclass correlation (ICC) was estimated using a one-way ANOVA. Results Smoothing images improves brain extraction results using BET for all measures except specificity (all p < 0.01, uncorrected), irrespective of the FI threshold. Using an FI of 0.01 or 0.1 performed better than 0.35. Thus, all reported results refer only to smoothed data using an FI of 0.01 or 0.1. Using an FI of 0.01 had a higher median sensitivity (0.9901) than an FI of 0.1 (0.9884, median difference: 0.0014, p < 0.001), accuracy (0.9971 vs. 0.9971; median difference: 0.0001, p < 0.001), and...

BACKGROUND:Minimally invasive surgery procedures, including stereotactic catheter aspiration and clearance of intracerebral hemorrhage (ICH) with recombinant tissue plasminogen activator hold a promise to improve outcome of supratentorial brain hemorrhage, a morbid and disabling type of stroke. A recently completed Phase III randomized trial showed improved mortality but was neutral on the primary outcome (modified Rankin scale score 0 to 3 at 1 yr). OBJECTIVE: To assess surgical performance and its impact on the extent of ICH evacuation and functional outcomes. METHODS: Univariate and multivariate models were used to assess the extent of hematoma evacuation efficacy in relation to mRS 0 to 3 outcome and postulated factors related to patient, disease, and protocol adherence in the surgical arm (n = 242) of the MISTIE trial. RESULTS: Greater ICH reduction has a higher likelihood of achieving mRS of 0 to 3 with a minimum evacuation threshold of ≤15 mL end of treatment ICH volume or ≥70% volume reduction when controlling for disease severity factors. Mortality benefit was achieved at ≤30 mL end of treatment ICH volume, or >53% volume reduction. Initial hematoma volume, history of hypertension, irregular-shaped hematoma, number of alteplase doses given, surgical protocol deviations, and catheter manipulation problems were significant factors in failing to achieve ≤15 mL goal evacuation. Greater surgeon/site experiences were associated with avoiding poor hematoma evacuation. CONCLUSION: This is the first surgical trial reporting thresholds for reduction of ICH volume correlating with improved mortality and functional outcomes. To realize the benefit of surgery, protocol objectives, surgeon education, technical enhancements, and case selection should be focused on this goal.

Patients with lower GCS, higher IVH severity, and lower ICH volume are more likely to have an EVD placed. EVD placement is associated with reduced mortality and improved short-term outcomes in patients with IVH after adjusting for known severity factors. EVD use should be protocolized in clinical trials of ICH management where IVH is included.