Background Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for dot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage.Methods MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0.3 mg or 1.0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770.Findings Between Feb 2,2006, and April 8,2013,96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9.5%, 95% CI 2.7-22.6] vs eight [14.8%, 6.6-27.1], p=0.542), 7 day mortality (zero [0%, 0-8.4] vs one [1.9%, 0-1-9.9], p=0.562), symptomatic bleeding (one [2.4%, 0.1-12.6] vs five [9.3%, 3.1-20.3], p=0.226), and brain bacterial infections (one [2.4%, 0.1-12.6] vs zero [0%, 0-6.6], p=0.438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22.2%; 95% CI 12.0-35.6] vs three [7.1%; 1.5-19.5]; p=0.051).Interpretation MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage.

Background and Purpose— The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography–based planimetry (CTP). Methods— In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. Results— In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC ( r 2 =0.93) than with site-ABC ( r 2 =0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm 3 ; CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P <0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. Conclusions— ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

Background and Purpose-The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography-based planimetry (CTP).Methods-In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression.Results-In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r(2)=0.93) than with site-ABC (r(2)=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm(3); CTP, 12.7 cm(3)), agreement was reasonable when categorized into mild, moderate, and severe ICH (kappa=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting >= 5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots.Conclusions-ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots.

Purpose An automatic, accurate and fast segmentation of hemorrhage in brain Computed Tomography (CT) images is necessary for quantification and treatment planning when assessing a large number of data sets. Though manual segmentation is accurate, it is time consuming and tedious. Semi-automatic methods need user interactions and might introduce variability in results. Our study proposes a modified distance regularized level set evolution (MDRLSE) algorithm for hemorrhage segmentation. Methods Study data set (from the ongoing CLEAR-IVH phase III clinical trial) is comprised of 200 sequential CT scans of 40 patients collected at 10 different hospitals using different machines/vendors. Data set contained both constant and variable slice thickness scans. Our study included pre-processing (filtering and skull removal), segmentation (MDRLSE which is a two-stage method with shrinking and expansion) with modified parameters for faster convergence and higher accuracy and post-processing (reduction in false positives and false negatives). Results Results are validated against the gold standard marked manually by a trained CT reader and neurologist. Data sets are grouped as small, medium and large based on the volume of blood. Statistical analysis is performed for both training and test data sets in each group. The median Dice statistical indices (DSI) for the 3 groups are 0.8971, 0.8580 and 0.9173 respectively. Pre- and post-processing enhanced the DSI by 8 and 4% respectively. Conclusions The MDRLSE improved the accuracy and speed for segmentation and calculation of the hemorrhage volume compared to the original DRLSE method. The method generates quantitative information, which is useful for specific decision making and reduces the time needed for the clinicians to localize and segment the hemorrhagic regions.

Brain hemorrhage is the most frequent fatal form of stroke and has the highest level of morbidity of any stroke subtype. For patients with both intracerebral hemorrhage and intraventricular hemorrhage (IVH), expected mortality is 50-80%. No validated, efficacious treatment exists for humans, but animal models demonstrate substantial physiologic and functional benefits associated with rapid, near-complete removal of blood from either the ventricle or intracerebral location (i.e., ~80% removal over 48 h). The purpose of the CLEAR-IVH trial (Parts A and B) is to evaluate safety and efficacy of using multiple injections of low-dose rt-PA to accelerate lysis and evacuation of IVH.

IntroductionCompared to ischemic stroke, intracerebral hemorrhage (ICH) is easily and rapidly identified, occurs in younger patients, and produces relatively small initial injury to cerebral tissues - all factors suggesting that interventional amelioration is possible. Investigations from the last decade established that extent of ICH-mediated brain injury relates directly to blood clot volume and duration of blood exposure to brain tissue. Using minimally-invasive surgery plus recombinant tissue plasminogen activator (rtPA), MISTIE investigators explored aggressive avenues to treat ICH.MethodsWe investigated the difference between surgical intervention plus rtPA and standard medical management for ICH. Subjects in both groups were medically managed according to standard ICU protocols. Subjects randomized to surgery underwent ste-reotactic catheter placement and clot aspiration. Injections of rtPA were then given through hematoma catheter every 8 h, up to 9 doses, or until a clot-reduction endpoint. After each injection the system was flushed with sterile saline and closed for 60 min before opening to spontaneous drainage.ResultsAverage aspiration of clots for all patients randomized to surgery plus rtPA was 20% of mean initial clot size. After acute treatment phase (aspiration plus rtPA), clot was reduced an average of 46%. Recorded adverse events were within safety limits, including 30-day mortality, 8%; symptomatic re-bleeding, 8%; and bacterial ventriculitis, 0%. Patients randomized to medical management showed 4% clot resolution in a similar time window. Preliminary analysis indicates that clot resolution rates are greatly dependent on catheter placement. Location of ICH also affects efficacy of aggressive treatment of ICH.ConclusionThere is tentative indication that minimally-invasive surgery plus rtPA shows greater clot resolution than traditional medical management.