John Muschelli

Minimally Invasive Surgery Plus Recombinant Tissue-type Plasminogen Activator for Intracerebral Hemorrhage Evacuation Decreases Perihematomal Edema

Background and Purpose— Perihematomal edema (PHE) can worsen outcomes after intracerebral hemorrhage (ICH). Reports suggest that blood degradation products lead to PHE. We hypothesized that hematoma evacuation will reduce PHE volume and that treatment with recombinant tissue-type plasminogen activator (rt-PA) will not exacerbate it. Methods— Minimally invasive surgery and rt-PA in ICH evacuation (MISTIE) phase II tested safety and efficacy of hematoma evacuation after ICH. We conducted a semiautomated, computerized volumetric analysis on computed tomography to assess impact of hematoma removal on PHE and effects of rt-PA on PHE. Volumetric analyses were performed on baseline stability and end of treatment scans. Results— Seventy-nine surgical and 39 medical patients from minimally invasive surgery and rt-PA in ICH evacuation phase II (MISTIE II) were analyzed. Mean hematoma volume at end of treatment was 19.6±14.5 cm3 for the surgical cohort and 40.7±13.9 cm3 for the medical cohort (P<0.001). Edema volume at end of treatment was lower for the surgical cohort: 27.7±13.3 cm3 than medical cohort: 41.7±14.6 cm3 (P<0.001). Graded effect of clot removal on PHE was observed when patients with >65%, 20% to 65%, and <20% ICH removed were analyzed (P<0.001). Positive correlation between PHE reduction and percent of ICH removed was identified (&rgr;=0.658; P<0.001). In the surgical cohort, 69 patients underwent surgical aspiration and rt-PA, whereas 10 underwent surgical aspiration only. Both cohorts achieved similar clot reduction: surgical aspiration and rt-PA, 18.9±14.5 cm3; and surgical aspiration only, 24.5±14.0 cm3 (P=0.26). Edema at end of treatment in surgical aspiration and rt-PA was 28.1±13.8 cm3 and 24.4±8.6 cm3 in surgical aspiration only (P=0.41). Conclusions— Hematoma evacuation is associated with significant reduction in PHE. Furthermore, PHE does not seem to be exacerbated by rt-PA, making such neurotoxic effects unlikely when the drug is delivered to intracranial clot.

Disruption of functional organization within the primary motor cortex in children with autism

Accumulating evidence suggests that motor impairments are prevalent in autism spectrum disorder (ASD), relate to the social and communicative deficits at the core of the diagnosis and may reflect abnormal connectivity within brain networks underlying motor control and learning. Parcellation of resting‐state functional connectivity data using spectral clustering approaches has been shown to be an effective means of visualizing functional organization within the brain but has most commonly been applied to explorations of normal brain function. This article presents a parcellation of a key area of the motor network, the primary motor cortex (M1), a key area of the motor control network, in adults, typically developing (TD) children and children with ASD and introduces methods for selecting the number of parcels, matching parcels across groups and testing group differences. The parcellation is based solely on patterns of connectivity between individual M1 voxels and all voxels outside of M1, and within all groups, a gross dorsomedial to ventrolateral organization emerged within M1 which was left–right symmetric. Although this gross organizational scheme was present in both groups of children, statistically significant group differences in the size and segregation of M1 parcels within regions of the motor homunculus corresponding to the upper and lower limbs were observed. Qualitative comparison of the M1 parcellation for children with ASD with that of younger and older TD children suggests that these organizational differences, with a lack of differentiation between lower limb/trunk regions and upper limb/hand regions, may be due, at least in part, to a delay in functional specialization within the motor cortex. Hum Brain Mapp 35:567–580, 2014.

Automated diagnoses of attention deficit hyperactive disorder using magnetic resonance imaging

Successful automated diagnoses of attention deficit hyperactive disorder (ADHD) using imaging and functional biomarkers would have fundamental consequences on the public health impact of the disease. In this work, we show results on the predictability of ADHD using imaging biomarkers and discuss the scientific and diagnostic impacts of the research. We created a prediction model using the landmark ADHD 200 data set focusing on resting state functional connectivity (rs-fc) and structural brain imaging. We predicted ADHD status and subtype, obtained by behavioral examination, using imaging data, intelligence quotients and other covariates. The novel contributions of this manuscript include a thorough exploration of prediction and image feature extraction methodology on this form of data, including the use of singular value decompositions (SVDs), CUR decompositions, random forest, gradient boosting, bagging, voxel-based morphometry, and support vector machines as well as important insights into the value, and potentially lack thereof, of imaging biomarkers of disease. The key results include the CUR-based decomposition of the rs-fc-fMRI along with gradient boosting and the prediction algorithm based on a motor network parcellation and random forest algorithm. We conjecture that the CUR decomposition is largely diagnosing common population directions of head motion. Of note, a byproduct of this research is a potential automated method for detecting subtle in-scanner motion. The final prediction algorithm, a weighted combination of several algorithms, had an external test set specificity of 94% with sensitivity of 21%. The most promising imaging biomarker was a correlation graph from a motor network parcellation. In summary, we have undertaken a large-scale statistical exploratory prediction exercise on the unique ADHD 200 data set. The exercise produced several potential leads for future scientific exploration of the neurological basis of ADHD.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

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. FUNDING National Institute of Neurological Disorders and Stroke.

Minimally invasive evacuation of spontaneous intracerebral hemorrhage using sonothrombolysis

OBJECT Catheter-based evacuation is a novel surgical approach for the treatment of brain hemorrhage. The object of this study was to evaluate the safety and efficacy of ultrasound in combination with recombinant tissue plasminogen activator (rt-PA) delivered through a microcatheter directly into spontaneous intraventricular (IVH) or intracerebral (ICH) hemorrhage in humans. METHODS Thirty-three patients presenting to the Swedish Medical Center in Seattle, Washington, with ICH and IVH were screened between November 21, 2008, and July 13, 2009, for entry into this study. Entry criteria included the spontaneous onset of intracranial hemorrhage ≥ 25 ml and/or IVH producing ventricular obstruction. Nine patients (6 males and 3 females, with an average age of 63 years [range 38-83 years]) who met the entry criteria consented to participate and were entered into the trial. A ventricular drainage catheter and an ultrasound microcatheter were stereotactically delivered together, directly into the IVH or ICH. Recombinant tissue plasminogen activator and 24 hours of continuous ultrasound were delivered to the clot. Gravity drainage was performed. In patients with IVHs, 3 mg of rt-PA was injected; in patients with intraparenchymal hemorrhages, 0.9 mg of rt-PA was injected. The rt-PA was delivered in 3 doses over 24 hours. RESULTS All patients had significant volume reductions in the treated hemorrhage. The mean percentage volume reduction after 24 hours of therapy, as determined on CT and compared with pretreatment stability scans, was 59 ± 5% (mean ± SEM) for ICH and 45.1 ± 13% for IVH (1 patient with ICH was excluded from analysis because of catheter breakage). There were no intracranial infections and no significant episodes of rebleeding according to clinical or CT assessment. One death occurred by 30 days after admission. Clinical improvements as determined by a decrease in the National Institutes of Health Stroke Scale score were demonstrated at 30 days after treatment in 7 of 9 patients. The rate of hemorrhage lysis was compared between 8 patients who completed treatment, and patient cohorts treated for IVH and ICH using identical doses of rt-PA and catheter drainage but without the ultrasound (courtesy of the MISTIE [Minimally Invasive Surgery plus T-PA for Intracerebral Hemorrhage Evacuation] and CLEAR II [Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage II] studies). Compared with the MISTIE and CLEAR data, the authors observed a faster rate of lysis during treatment for IVH and ICH in the patients treated with sonolysis plus rt-PA versus rt-PA alone. CONCLUSIONS Lysis and drainage of spontaneous ICH and IVH with a reduction in mass effect can be accomplished rapidly and safely through sonothrombolysis using stereotactically delivered drainage and ultrasound catheters via a bur hole. A larger clinical trial with catheters specifically designed for brain blood clot removal is warranted.

Large-scale Radiomic Profiling of Recurrent Glioblastoma Identifies an Imaging Predictor for Stratifying Anti-Angiogenic Treatment Response.

Purpose: Antiangiogenic treatment with bevacizumab, a mAb to the VEGF, is the single most widely used therapeutic agent for patients with recurrent glioblastoma. A major challenge is that there are currently no validated biomarkers that can predict treatment outcome. Here we analyze the potential of radiomics, an emerging field of research that aims to utilize the full potential of medical imaging. Experimental Design: A total of 4,842 quantitative MRI features were automatically extracted and analyzed from the multiparametric tumor of 172 patients (allocated to a discovery and validation set with a 2:1 ratio) with recurrent glioblastoma prior to bevacizumab treatment. Leveraging a high-throughput approach, radiomic features of patients in the discovery set were subjected to a supervised principal component (superpc) analysis to generate a prediction model for stratifying treatment outcome to antiangiogenic therapy by means of both progression-free and overall survival (PFS and OS). Results: The superpc predictor stratified patients in the discovery set into a low or high risk group for PFS (HR = 1.60; P = 0.017) and OS (HR = 2.14; P < 0.001) and was successfully validated for patients in the validation set (HR = 1.85, P = 0.030 for PFS; HR = 2.60, P = 0.001 for OS). Conclusions: Our radiomic-based superpc signature emerges as a putative imaging biomarker for the identification of patients who may derive the most benefit from antiangiogenic therapy, advances the knowledge in the noninvasive characterization of brain tumors, and stresses the role of radiomics as a novel tool for improving decision support in cancer treatment at low cost. Clin Cancer Res; 22(23); 5765–71. ©2016 AACR.

Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial

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 clot 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. FUNDING National Institute of Neurological Disorders and Stroke, Genentech, and Codman.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.

Resolution of Intraventricular Hemorrhage Varies by Ventricular Region and Dose of Intraventricular Thrombolytic The Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) Program

Background and Purpose— The Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) program is assessing the efficacy of intraventricular recombinant tissue-type plasminogen activator (rtPA) for spontaneous intraventricular hemorrhage (IVH). This subanalysis assesses the effect of dose of rtPA by region on clearance of IVH. Methods— Sixty-four patients within 12 to 24 hours of spontaneous IVH were randomized to placebo or 0.3 mg, 1 mg, or 3 mg of rtPA twice daily through an extraventricular drain. Twelve subregions of the ventricles were scored from 0 to 4. Effect of dose on IVH clearance to 50% of baseline score was compared by survival analysis for all regions combined and by subregion. Models including ventricular region, dose, and baseline score were compared by Cox proportional hazards. Results— IVH score reduced faster across all regions with increasing rtPA dose (clearance to 50%: log-rank P<0.0001; placebo—11.43 days, 95% CI, 5.68–17.18; 0.3 mg—3.19 days, 1.00–5.38; 1 mg—3.54 days, 0.45–6.64; 3 mg—2.59 days, 1.72–3.46). In the combined models, dose and baseline score were independently associated with reduction in IVH score, which was quickest in the midline ventricles, then the anterior half of the lateral ventricles and slowest in the posterior half of the lateral ventricles (clearance to 50%: P<0.0001; rtPA dose: hazard ratio, 1.47, 1.30–1.67; midline versus anterolateral hazard ratio, 1.71, 1.08–2.71; midline versus posterolateral hazard ratio, 4.05, 2.46–6.65; baseline score hazard ratio, 0.96, 0.91–1.01) with a significant interaction between dose and ventricular region (P=0.005). Conclusions— rtPA accelerates resolution of IVH. This effect is dose-dependent, is greatest in the midline ventricles, and least in the posterolateral ventricles. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00650858.

ISLES 2015 - A public evaluation benchmark for ischemic stroke lesion segmentation from multispectral MRI

&NA; Ischemic stroke is the most common cerebrovascular disease, and its diagnosis, treatment, and study relies on non‐invasive imaging. Algorithms for stroke lesion segmentation from magnetic resonance imaging (MRI) volumes are intensely researched, but the reported results are largely incomparable due to different datasets and evaluation schemes. We approached this urgent problem of comparability with the Ischemic Stroke Lesion Segmentation (ISLES) challenge organized in conjunction with the MICCAI 2015 conference. In this paper we propose a common evaluation framework, describe the publicly available datasets, and present the results of the two sub‐challenges: Sub‐Acute Stroke Lesion Segmentation (SISS) and Stroke Perfusion Estimation (SPES). A total of 16 research groups participated with a wide range of state‐of‐the‐art automatic segmentation algorithms. A thorough analysis of the obtained data enables a critical evaluation of the current state‐of‐the‐art, recommendations for further developments, and the identification of remaining challenges. The segmentation of acute perfusion lesions addressed in SPES was found to be feasible. However, algorithms applied to sub‐acute lesion segmentation in SISS still lack accuracy. Overall, no algorithmic characteristic of any method was found to perform superior to the others. Instead, the characteristics of stroke lesion appearances, their evolution, and the observed challenges should be studied in detail. The annotated ISLES image datasets continue to be publicly available through an online evaluation system to serve as an ongoing benchmarking resource (www.isles‐challenge.org). HighlightsEvaluation framework for automatic stroke lesion segmentation from MRIPublic multi‐center, multi‐vendor, multi‐protocol databases releasedOngoing fair and automated benchmark with expert created ground truth setsComparison of 14+7 groups who responded to an open challenge in MICCAISegmentation feasible in acute and unsolved in sub‐acute cases Graphical abstract Figure. No caption available.

Epidemiology of central line-associated bloodstream infections in the pediatric intensive care unit

OBJECTIVE Describe central line-associated bloodstream infection (CLA-BSI) epidemiology in pediatric intensive care units (PICUs). DESIGN Descriptive study (29 PICUs); cohort study (18 PICUs). SETTING PICUs in a national improvement collaborative. PATIENTS/PARTICIPANTS Patients admitted October 2006 to December 2007 with 1 or more central lines. METHODS CLA-BSIs were prospectively identified using the National Healthcare Safety Network definition and then readjudicated using the revised 2008 definition. Risk factors for CLA-BSI were examined using age-adjusted, time-varying Cox proportional hazards models. RESULTS In the descriptive study, the CLA-BSI incidence was 3.1/1,000 central line-days; readjudication with the revised definition resulted in a 17% decrease. In the cohort study, the readjudicated incidence was 2.0/1,000 central line-days. Ninety-nine percent of patients were CLA-BSI-free through day 7, after which the daily risk of CLA-BSI doubled to 0.27% per day. Compared with patients with respiratory diagnoses (most prevalent category), CLA-BSI risk was higher in patients with gastrointestinal diagnoses (hazard ratio [HR], 2.7 [95% confidence interval {CI}, 1.43-5.16]; P < .002 ) and oncologic diagnoses (HR, 2.6 [CI, 1.06-6.45]; P = .037). Among all patients, including those with more than 1 central line, CLA-BSI risk was lower among patients with a central line inserted in the jugular vein (HR, 0.43 [CI, 0.30-0.95]; [P < .03). CONCLUSIONS The 2008 CLA-BSI definition change decreased the measured incidence. The daily CLA-BSI risk was very low in patients during the first 7 days of catheterization but doubled thereafter. The risk of CLA-BSI was lower in patients with lines inserted in the jugular vein and higher in patients with gastrointestinal and oncologic diagnoses. These patients are target populations for additional study and intervention.