Publications

    Dalca AV, Sridharan R, Cloonan L, Fitzpatrick KM, Kanakis A, Furie KL, Rosand J, Wu O, Sabuncu M, Rost NS, Golland P. Segmentation of cerebrovascular pathologies in stroke patients with spatial and shape priors. Med Image Comput Comput Assist Interv 2014;17(Pt 2):773-80.Abstract
    We propose and demonstrate an inference algorithm for the automatic segmentation of cerebrovascular pathologies in clinical MR images of the brain. Identifying and differentiating pathologies is important for understanding the underlying mechanisms and clinical outcomes of cerebral ischemia. Manual delineation of separate pathologies is infeasible in large studies of stroke that include thousands of patients. Unlike normal brain tissues and structures, the location and shape of the lesions vary across patients, presenting serious challenges for prior-driven segmentation. Our generative model captures spatial patterns and intensity properties associated with different cerebrovascular pathologies in stroke patients. We demonstrate the resulting segmentation algorithm on clinical images of a stroke patient cohort.
    Battey TWK, Karki M, Singhal AB, Wu O, Sadaghiani S, Campbell BCV, Davis SM, Donnan GA, Sheth KN, Kimberly TW. Brain edema predicts outcome after nonlacunar ischemic stroke. Stroke 2014;45(12):3643-8.Abstract
    BACKGROUND AND PURPOSE: In malignant infarction, brain edema leads to secondary neurological deterioration and poor outcome. We sought to determine whether swelling is associated with outcome in smaller volume strokes. METHODS: Two research cohorts of acute stroke subjects with serial brain MRI were analyzed. The categorical presence of swelling and infarct growth was assessed on diffusion-weighted imaging (DWI) by comparing baseline and follow-up scans. The increase in stroke volume (ΔDWI) was then subdivided into swelling and infarct growth volumes using region-of-interest analysis. The relationship of these imaging markers with outcome was evaluated in univariable and multivariable regression. RESULTS: The presence of swelling independently predicted worse outcome after adjustment for age, National Institutes of Health Stroke Scale, admission glucose, and baseline DWI volume (odds ratio, 4.55; 95% confidence interval, 1.21-18.9; P<0.02). Volumetric analysis confirmed that ΔDWI was associated with outcome (odds ratio, 4.29; 95% confidence interval, 2.00-11.5; P<0.001). After partitioning ΔDWI into swelling and infarct growth volumetrically, swelling remained an independent predictor of poor outcome (odds ratio, 1.09; 95% confidence interval, 1.03-1.17; P<0.005). Larger infarct growth was also associated with poor outcome (odds ratio, 7.05; 95% confidence interval, 1.04-143; P<0.045), although small infarct growth was not. The severity of cytotoxic injury measured on apparent diffusion coefficient maps was associated with swelling, whereas the perfusion deficit volume was associated with infarct growth. CONCLUSIONS: Swelling and infarct growth each contribute to total stroke lesion growth in the days after stroke. Swelling is an independent predictor of poor outcome, with a brain swelling volume of ≥11 mL identified as the threshold with greatest sensitivity and specificity for predicting poor outcome.
    Greer DM, Rosenthal ES, Wu O. Neuroprognostication of hypoxic-ischaemic coma in the therapeutic hypothermia era. Nat Rev Neurol 2014;10(4):190-203.Abstract
    Neurological prognostication after cardiac arrest has always been challenging, and has become even more so since the advent of therapeutic hypothermia (TH) in the early 2000s. Studies in this field are prone to substantial biases--most importantly, the self-fulfilling prophecy of early withdrawal of life-sustaining therapies--and physicians must be aware of these limitations when evaluating individual patients. TH mandates sedation and prolongs drug metabolism, and delayed neuronal recovery is possible after cardiac arrest with or without hypothermia treatment; thus, the clinician must allow an adequate observation period to assess for delayed recovery. Exciting advances have been made in clinical evaluation, electrophysiology, chemical biomarkers and neuroimaging, providing insights into the underlying pathophysiological mechanisms of injury, as well as prognosis. Some clinical features, such as pupillary reactivity, continue to provide robust information about prognosis, and EEG patterns, such as reactivity and continuity, seem promising as prognostic indicators. Evoked potential information is likely to remain a reliable prognostic tool in TH-treated patients, whereas traditional serum biomarkers, such as neuron-specific enolase, may be less reliable. Advanced neuroimaging techniques, particularly those utilizing MRI, hold great promise for the future. Clinicians should continue to use all the available tools to provide accurate prognostic advice to patients after cardiac arrest.
    Schröder J, Cheng B, Ebinger M, Köhrmann M, Wu O, Kang D-W, Liebeskind DS, Tourdias T, Singer OC, Christensen S, Campbell B, Luby M, Warach S, Fiehler J, Fiebach JB, Gerloff C, Thomalla G. Validity of acute stroke lesion volume estimation by diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomographic Score depends on lesion location in 496 patients with middle cerebral artery stroke. Stroke 2014;45(12):3583-8.Abstract
    BACKGROUND AND PURPOSE: Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) has been used to estimate diffusion-weighted imaging (DWI) lesion volume in acute stroke. We aimed to assess correlations of DWI-ASPECTS with lesion volume in different middle cerebral artery (MCA) subregions and reproduce existing ASPECTS thresholds of a malignant profile defined by lesion volume ≥100 mL. METHODS: We analyzed data of patients with MCA stroke from a prospective observational study of DWI and fluid-attenuated inversion recovery in acute stroke. DWI-ASPECTS and lesion volume were calculated. The population was divided into subgroups based on lesion localization (superficial MCA territory, deep MCA territory, or both). Correlation of ASPECTS and infarct volume was calculated, and receiver-operating characteristics curve analysis was performed to identify the optimal ASPECTS threshold for ≥100-mL lesion volume. RESULTS: A total of 496 patients were included. There was a significant negative correlation between ASPECTS and DWI lesion volume (r=-0.78; P<0.0001). With regards to lesion localization, correlation was weaker in deep MCA region (r=-0.19; P=0.038) when compared with superficial (r=-0.72; P<0.001) or combined superficial and deep MCA lesions (r=-0.72; P<0.001). Receiver-operating characteristics analysis revealed ASPECTS≤6 as best cutoff to identify ≥100-mL DWI lesion volume; however, positive predictive value was low (0.35). CONCLUSIONS: ASPECTS has limitations when lesion location is not considered. Identification of patients with malignant profile by DWI-ASPECTS may be unreliable. ASPECTS may be a useful tool for the evaluation of noncontrast computed tomography. However, if MRI is used, ASPECTS seems dispensable because lesion volume can easily be quantified on DWI maps.
    Auriel E, Edlow BL, Reijmer YD, Fotiadis P, Ramirez-Martinez S, Ni J, Reed AK, Vashkevich A, Schwab K, Rosand J, Viswanathan A, Wu O, Gurol EM, Greenberg SM. Microinfarct disruption of white matter structure: a longitudinal diffusion tensor analysis. Neurology 2014;83(2):182-8.Abstract
    OBJECTIVE: To evaluate the local effect of small asymptomatic infarctions detected by diffusion-weighted imaging (DWI) on white matter microstructure using longitudinal structural and diffusion tensor imaging (DTI). METHODS: Nine acute to subacute DWI lesions were identified in 6 subjects with probable cerebral amyloid angiopathy who had undergone high-resolution MRI both before and after DWI lesion detection. Regions of interest (ROIs) corresponding to the site of the DWI lesion (lesion ROI) and corresponding site in the nonlesioned contralateral hemisphere (control ROI) were coregistered to the pre- and postlesional scans. DTI tractography was additionally performed to reconstruct the white matter tracts containing the ROIs. DTI parameters (fractional anisotropy [FA], mean diffusivity [MD]) were quantified within each ROI, the 6-mm lesion-containing tract segments, and the entire lesion-containing tract bundle. Lesion/control FA and MD ratios were compared across time points. RESULTS: The postlesional scans (performed a mean 7.1 ± 4.7 months after DWI lesion detection) demonstrated a decrease in median FA lesion/control ROI ratio (1.08 to 0.93, p = 0.038) and increase in median MD lesion/control ROI ratio (0.97 to 1.17, p = 0.015) relative to the prelesional scans. There were no visible changes on postlesional high-resolution T1-weighted and fluid-attenuated inversion recovery images in 4 of 9 lesion ROIs and small (2-5 mm) T1 hypointensities in the remaining 5. No postlesional changes in FA or MD ratios were detected in the 6-mm lesion-containing tract segments or full tract bundles. CONCLUSIONS: Asymptomatic DWI lesions produce chronic local microstructural injury. The cumulative effects of these widely distributed lesions may directly contribute to small-vessel-related vascular cognitive impairment.
    Kimberly TW, Battey TWK, Pham L, Wu O, Yoo AJ, Furie KL, Singhal AB, Elm JJ, Stern BJ, Sheth KN. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit Care 2014;20(2):193-201.Abstract
    BACKGROUND: Brain edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death. Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4. However, the relevance of this pathway to the development of cerebral edema in stroke patients is not known. METHODS: Using a case-control design, we retrospectively assessed neuroimaging and blood markers of cytotoxic and vasogenic edema in subjects who were enrolled in the glyburide advantage in malignant edema and stroke-pilot (GAMES-Pilot) trial. We compared serial brain magnetic resonance images (MRIs) to a cohort with similar large volume infarctions. We also compared matrix metalloproteinase-9 (MMP-9) plasma level in large hemispheric stroke. RESULTS: We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level. CONCLUSIONS: Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke. Verification of these potential imaging and blood biomarkers is warranted in the context of a randomized, placebo-controlled trial.
    Greer DM, Yang J, Scripko PD, Sims JR, Cash S, Wu O, Hafler JP, Schoenfeld DA, Furie KL. Clinical examination for prognostication in comatose cardiac arrest patients. Resuscitation 2013;84(11):1546-51.Abstract
    OBJECTIVE: To build new algorithms for prognostication of comatose cardiac arrest patients using clinical examination, and investigate whether therapeutic hypothermia influences the value of the clinical examination. METHODS: From 2000 to 2007, 500 consecutive patients in non-traumatic coma were prospectively enrolled, 200 of whom were post-cardiac arrest. Outcome was determined by modified Rankin Scale (mRS) score at 6 months, with mRS≤3 indicating good outcome. The clinical examination was performed on days 0, 1, 3 and 7 post-arrest, and clinical variables analyzed for importance in prognostication of outcome. A classification and regression tree analysis (CART) was used to develop a predictive algorithm. RESULTS: Good outcome was achieved in 9.9% of patients. In CART analysis, motor response was often chosen as a root node, and spontaneous eye movements, pupillary reflexes, eye opening and corneal reflexes were often chosen as splitting nodes. Over 8% of patients with absent or extensor motor response on day 3 achieved a good outcome, as did 2 patients with myoclonic status epilepticus. The odds of achieving a good outcome were lower in patients who suffered asystole (OR 0.187, 95% CI: 0.039-0.875, p=0.033) compared with ventricular fibrillation or non-perfusing ventricular tachycardia, but some still achieved good outcome. The absence of pupillary and corneal reflexes on day 3 remained highly reliable for predicting poor outcome, regardless of therapeutic hypothermia utilization. CONCLUSION: The clinical examination remains central to prognostication in comatose cardiac arrest patients in the modern area. Future studies should incorporate the clinical examination along with modern technology for accurate prognostication.
    Kamps MJA, Horn J, Oddo M, Fugate JE, Storm C, Cronberg T, Wijman CA, Wu O, Binnekade JM, Hoedemaekers CWE. Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature. Intensive Care Med 2013;39(10):1671-82.Abstract
    PURPOSE: To assess the sensitivity and false positive rate (FPR) of neurological examination and somatosensory evoked potentials (SSEPs) to predict poor outcome in adult patients treated with therapeutic hypothermia after cardiopulmonary resuscitation (CPR). METHODS: MEDLINE and EMBASE were searched for cohort studies describing the association of clinical neurological examination or SSEPs after return of spontaneous circulation with neurological outcome. Poor outcome was defined as severe disability, vegetative state and death. Sensitivity and FPR were determined. RESULTS: A total of 1,153 patients from ten studies were included. The FPR of a bilaterally absent cortical N20 response of the SSEP could be calculated from nine studies including 492 patients. The SSEP had an FPR of 0.007 (confidence interval, CI, 0.001-0.047) to predict poor outcome. The Glasgow coma score (GCS) motor response was assessed in 811 patients from nine studies. A GCS motor score of 1-2 at 72 h had a high FPR of 0.21 (CI 0.08-0.43). Corneal reflex and pupillary reactivity at 72 h after the arrest were available in 429 and 566 patients, respectively. Bilaterally absent corneal reflexes had an FPR of 0.02 (CI 0.002-0.13). Bilaterally absent pupillary reflexes had an FPR of 0.004 (CI 0.001-0.03). CONCLUSIONS: At 72 h after the arrest the motor response to painful stimuli and the corneal reflexes are not a reliable tool for the early prediction of poor outcome in patients treated with hypothermia. The reliability of the pupillary response to light and the SSEP is comparable to that in patients not treated with hypothermia.
    Sridharan R, Dalca AV, Fitzpatrick KM, Cloonan L, Kanakis A, Wu O, Furie KL, Rosand J, Rost NS, Golland P. Quantification and Analysis of Large Multimodal Clinical Image Studies: Application to Stroke. Multimodal Brain Image Anal (2013) 2013;8159:18-30.Abstract
    We present an analysis framework for large studies of multimodal clinical quality brain image collections. Processing and analysis of such datasets is challenging due to low resolution, poor contrast, mis-aligned images, and restricted field of view. We adapt existing registration and segmentation methods and build a computational pipeline for spatial normalization and feature extraction. The resulting aligned dataset enables clinically meaningful analysis of spatial distributions of relevant anatomical features and of their evolution with age and disease progression. We demonstrate the approach on a neuroimaging study of stroke with more than 800 patients. We show that by combining data from several modalities, we can automatically segment important biomarkers such as white matter hyperintensity and characterize pathology evolution in this heterogeneous cohort. Specifically, we examine two sub-populations with different dynamics of white matter hyperintensity changes as a function of patients' age. Pipeline and analysis code is available at http://groups.csail.mit.edu/vision/medical-vision/stroke/.
    Cheng B, Brinkmann M, Forkert ND, Treszl A, Ebinger M, Köhrmann M, Wu O, Kang D-W, Liebeskind DS, Tourdias T, Singer OC, Christensen S, Luby M, Warach S, Fiehler J, Fiebach JB, Gerloff C, Thomalla G. Quantitative measurements of relative fluid-attenuated inversion recovery (FLAIR) signal intensities in acute stroke for the prediction of time from symptom onset. J Cereb Blood Flow Metab 2013;33(1):76-84.Abstract
    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.
    Greer DM, Scripko PD, Wu O, Edlow BL, Bartscher J, Sims JR, Camargo EEC, Singhal AB, Furie KL. Hippocampal magnetic resonance imaging abnormalities in cardiac arrest are associated with poor outcome. J Stroke Cerebrovasc Dis 2013;22(7):899-905.Abstract
    BACKGROUND: The role of neuroimaging in assessing prognosis in comatose cardiac survivors appears promising, but little is known regarding the import of particular spatial patterns. We report a specific spatial imaging abnormality on magnetic resonance imaging (MRI) that portends a poor prognosis: bilateral hippocampal hyperintensities on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences. METHODS: Eighty sequential comatose cardiac arrest patients underwent MRI scans. Qualitative and quantitative regional analyses were performed. Patients were categorized as HIPPO(+) (n = 18) or HIPPO(-) (n = 62) based on whether they had bilateral hippocampal hyperintensities. Poor outcome was defined by a modified Rankin Scale (mRS) score ≥4 at 6 months. RESULTS: Patients with bilateral hippocampal abnormalities had a higher frequency of poor outcome (P = .032). HIPPO(+) patients suffered more severe cerebral injury, with lower whole brain apparent diffusion coefficient values (P = .043) and a greater number of affected regions on DWI (P = .001) and FLAIR (P = .001) than HIPPO(-) patients. The hippocampal approach was 100% specific for a poor prognosis; only 1 patient survived and remained in a vegetative state. CONCLUSIONS: Bilateral hippocampal hyperintensities on MRI may be a specific imaging finding that is indicative of poor prognosis in patients who suffer global hypoxic-ischemic injury. More research on the prognostic significance of this and similar neuroimaging patterns is indicated.
    Wintermark M, Albers GW, Broderick JP, Demchuk AM, Fiebach JB, Fiehler J, Grotta JC, Houser G, Jovin TG, Lees KR, Lev MH, Liebeskind DS, Luby M, Muir KW, Parsons MW, von Kummer R, Wardlaw JM, Wu O, Yoo AJ, Alexandrov AV, Alger JR, Aviv RI, Bammer R, Baron J-C, Calamante F, Campbell BCV, Carpenter TC, Christensen S, Copen WA, Derdeyn CP, Haley CE, Khatri P, Kudo K, Lansberg MG, Latour LL, Lee T-Y, Leigh R, Lin W, Lyden P, Mair G, Menon BK, Michel P, Mikulik R, Nogueira RG, Ostergaard L, Pedraza S, Riedel CH, Rowley HA, Sanelli PC, Sasaki M, Saver JL, Schaefer PW, Schellinger PD, Tsivgoulis G, Wechsler LR, White PM, Zaharchuk G, Zaidat OO, Davis SM, Donnan GA, Furlan AJ, Hacke W, Kang D-W, Kidwell C, Thijs VN, Thomalla G, Warach SJ. Acute Stroke Imaging Research Roadmap II. Stroke 2013;44(9):2628-39.
    Meschia JF, Arnett DK, Ay H, Brown RD, Benavente OR, Cole JW, de Bakker PIW, Dichgans M, Doheny KF, Fornage M, Grewal RP, Gwinn K, Jern C, Conde JJ, Johnson JA, Jood K, Laurie CC, Lee J-M, Lindgren A, Markus HS, McArdle PF, McClure LA, Mitchell BD, Schmidt R, Rexrode KM, Rich SS, Rosand J, Rothwell PM, Rundek T, Sacco RL, Sharma P, Shuldiner AR, Slowik A, Wassertheil-Smoller S, Sudlow C, Thijs VNS, Woo D, Worrall BB, Wu O, Kittner SJ. Stroke Genetics Network (SiGN) study: design and rationale for a genome-wide association study of ischemic stroke subtypes. Stroke 2013;44(10):2694-702.Abstract
    BACKGROUND AND PURPOSE: Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. METHODS: The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. CONCLUSIONS: The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
    Edlow BL, Giacino JT, Wu O. Functional MRI and outcome in traumatic coma. Curr Neurol Neurosci Rep 2013;13(9):375.Abstract
    Advances in task-based functional MRI (fMRI), resting-state fMRI (rs-fMRI), and arterial spin labeling (ASL) perfusion MRI have occurred at a rapid pace in recent years. These techniques for measuring brain function have great potential to improve the accuracy of prognostication for civilian and military patients with traumatic coma. In addition, fMRI, rs-fMRI, and ASL perfusion MRI have provided novel insights into the pathophysiology of traumatic disorders of consciousness, as well as the mechanisms of recovery from coma. However, functional neuroimaging techniques have yet to achieve widespread clinical use as prognostic tests for patients with traumatic coma. Rather, a broad spectrum of methodological hurdles currently limits the feasibility of clinical implementation. In this review, we discuss the basic principles of fMRI, rs-fMRI, and ASL perfusion MRI and their potential applications as prognostic tools for patients with traumatic coma. We also discuss future strategies for overcoming the current barriers to clinical implementation.
    Edlow BL, Haynes RL, Takahashi E, Klein JP, Cummings P, Benner T, Greer DM, Greenberg SM, Wu O, Kinney HC, Folkerth RD. Disconnection of the ascending arousal system in traumatic coma. J Neuropathol Exp Neurol 2013;72(6):505-23.Abstract
    Traumatic coma is associated with disruption of axonal pathways throughout the brain, but the specific pathways involved in humans are incompletely understood. In this study, we used high angular resolution diffusion imaging to map the connectivity of axonal pathways that mediate the 2 critical components of consciousness-arousal and awareness-in the postmortem brain of a 62-year-old woman with acute traumatic coma and in 2 control brains. High angular resolution diffusion imaging tractography guided tissue sampling in the neuropathologic analysis. High angular resolution diffusion imaging tractography demonstrated complete disruption of white matter pathways connecting brainstem arousal nuclei to the basal forebrain and thalamic intralaminar and reticular nuclei. In contrast, hemispheric arousal pathways connecting the thalamus and basal forebrain to the cerebral cortex were only partially disrupted, as were the cortical "awareness pathways." Neuropathologic examination, which used β-amyloid precursor protein and fractin immunomarkers, revealed axonal injury in the white matter of the brainstem and cerebral hemispheres that corresponded to sites of high angular resolution diffusion imaging tract disruption. Axonal injury was also present within the gray matter of the hypothalamus, thalamus, basal forebrain, and cerebral cortex. We propose that traumatic coma may be a subcortical disconnection syndrome related to the disconnection of specific brainstem arousal nuclei from the thalamus and basal forebrain.
    Saver JL, Jovin TG, Smith WS, Albers GW, Baron J-C, Boltze J, Broderick JP, Davis LA, Demchuk AM, DeSena S, Fiehler J, Gorelick PB, Hacke W, Holt B, Jahan R, Jing H, Khatri P, Kidwell CS, Lees KR, Lev MH, Liebeskind DS, Luby M, Lyden P, Megerian TJ, Mocco J, Muir KW, Rowley HA, Ruedy RM, Savitz SI, Sipelis VJ, Shimp SK, Wechsler LR, Wintermark M, Wu O, Yavagal DR, Yoo AJ. Stroke treatment academic industry roundtable: research priorities in the assessment of neurothrombectomy devices. Stroke 2013;44(12):3596-601.Abstract
    BACKGROUND AND PURPOSE: The goal of the Stroke Treatment Academic Industry Roundtable (STAIR) meetings is to advance the development of stroke therapies. At STAIR VIII, consensus recommendations were developed for clinical trial strategies to demonstrate the benefit of endovascular reperfusion therapies for acute ischemic stroke. SUMMARY OF REVIEW: Prospects for success with forthcoming endovascular trials are robust, because new neurothrombectomy devices have superior reperfusion efficacy compared with earlier-generation interventions. Specific recommendations are provided for trial designs in 3 populations: (1) patients undergoing intravenous fibrinolysis, (2) early patients ineligible for or having failed intravenous fibrinolysis, and (3) wake-up and other late-presenting patients. Among intravenous fibrinolysis-eligible patients, key principles are that CT or MRI confirmation of target arterial occlusions should precede randomization; endovascular intervention should be pursued with the greatest rapidity possible; and combined intravenous and neurothrombectomy therapy is more promising than neurothrombectomy alone. Among patients ineligible for or having failed intravenous fibrinolysis, scientific equipoise was affirmed and the need to randomize all eligible patients emphasized. Vessel imaging to confirm occlusion is mandatory, and infarct core and penumbral imaging is desirable in later time windows. Additional STAIR VIII recommendations include approaches to test multiple devices in a single trial, utility weighting of disability end points, and adaptive designs to delineate time and tissue injury thresholds at which benefits from intervention no longer accrue. CONCLUSIONS: Endovascular research priorities in acute ischemic stroke are to perform trials testing new, highly effective neuro thrombectomy devices rapidly deployed in patients confirmed to have target vessel occlusions.
    Edlow BL, Giacino JT, Hirschberg RE, Gerrard J, Wu O, Hochberg LR. Unexpected recovery of function after severe traumatic brain injury: the limits of early neuroimaging-based outcome prediction. Neurocrit Care 2013;19(3):364-75.Abstract
    BACKGROUND: Prognostication in the early stage of traumatic coma is a common challenge in the neuro-intensive care unit. We report the unexpected recovery of functional milestones (i.e., consciousness, communication, and community reintegration) in a 19-year-old man who sustained a severe traumatic brain injury. The early magnetic resonance imaging (MRI) findings, at the time, suggested a poor prognosis. METHODS: During the first year of the patient's recovery, MRI with diffusion tensor imaging and T2*-weighted imaging was performed on day 8 (coma), day 44 (minimally conscious state), day 198 (post-traumatic confusional state), and day 366 (community reintegration). Mean apparent diffusion coefficient (ADC) and fractional anisotropy values in the corpus callosum, cerebral hemispheric white matter, and thalamus were compared with clinical assessments using the Disability Rating Scale (DRS). RESULTS: Extensive diffusion restriction in the corpus callosum and bihemispheric white matter was observed on day 8, with ADC values in a range typically associated with neurotoxic injury (230-400 × 10(-6 )mm(2)/s). T2*-weighted MRI revealed widespread hemorrhagic axonal injury in the cerebral hemispheres, corpus callosum, and brainstem. Despite the presence of severe axonal injury on early MRI, the patient regained the ability to communicate and perform activities of daily living independently at 1 year post-injury (DRS = 8). CONCLUSIONS: MRI data should be interpreted with caution when prognosticating for patients in traumatic coma. Recovery of consciousness and community reintegration are possible even when extensive traumatic axonal injury is demonstrated by early MRI.
    Rowley J, Fonov V, Wu O, Eskildsen SF, Schoemaker D, Wu L, Mohades S, Shin M, Sziklas V, Cheewakriengkrai L, Shmuel A, Dagher A, Gauthier S, Rosa-Neto P. White matter abnormalities and structural hippocampal disconnections in amnestic mild cognitive impairment and Alzheimer's disease. PLoS One 2013;8(9):e74776.Abstract
    The purpose of this project was to evaluate white matter degeneration and its impact on hippocampal structural connectivity in patients with amnestic mild cognitive impairment, non-amnestic mild cognitive impairment and Alzheimer's disease. We estimated white matter fractional anisotropy, mean diffusivity and hippocampal structural connectivity in two independent cohorts. The ADNI cohort included 108 subjects [25 cognitively normal, 21 amnestic mild cognitive impairment, 47 non-amnestic mild cognitive impairment and 15 Alzheimer's disease]. A second cohort included 34 subjects [15 cognitively normal and 19 amnestic mild cognitive impairment] recruited in Montreal. All subjects underwent clinical and neuropsychological assessment in addition to diffusion and T1 MRI. Individual fractional anisotropy and mean diffusivity maps were generated using FSL-DTIfit. In addition, hippocampal structural connectivity maps expressing the probability of connectivity between the hippocampus and cortex were generated using a pipeline based on FSL-probtrackX. Voxel-based group comparison statistics of fractional anisotropy, mean diffusivity and hippocampal structural connectivity were estimated using Tract-Based Spatial Statistics. The proportion of abnormal to total white matter volume was estimated using the total volume of the white matter skeleton. We found that in both cohorts, amnestic mild cognitive impairment patients had 27-29% white matter volume showing higher mean diffusivity but no significant fractional anisotropy abnormalities. No fractional anisotropy or mean diffusivity differences were observed between non-amnestic mild cognitive impairment patients and cognitively normal subjects. Alzheimer's disease patients had 66.3% of normalized white matter volume with increased mean diffusivity and 54.3% of the white matter had reduced fractional anisotropy. Reduced structural connectivity was found in the hippocampal connections to temporal, inferior parietal, posterior cingulate and frontal regions only in the Alzheimer's group. The severity of white matter degeneration appears to be higher in advanced clinical stages, supporting the construct that these abnormalities are part of the pathophysiological processes of Alzheimer's disease.
    Bouts MJRJ, Tiebosch IA, van der Toorn A, Viergever MA, Wu O, Dijkhuizen RM. Early identification of potentially salvageable tissue with MRI-based predictive algorithms after experimental ischemic stroke. J Cereb Blood Flow Metab 2013;33(7):1075-82.Abstract
    Individualized stroke treatment decisions can be improved by accurate identification of the extent of salvageable tissue. Magnetic resonance imaging (MRI)-based approaches, including measurement of a 'perfusion-diffusion mismatch' and calculation of infarction probability, allow assessment of tissue-at-risk; however, the ability to explicitly depict potentially salvageable tissue remains uncertain. In this study, five predictive algorithms (generalized linear model (GLM), generalized additive model, support vector machine, adaptive boosting, and random forest) were tested in their potency to depict acute cerebral ischemic tissue that can recover after reperfusion. Acute T2-, diffusion-, and perfusion-weighted MRI, and follow-up T2 maps were collected from rats subjected to right-sided middle cerebral artery occlusion without subsequent reperfusion, for training of algorithms (Group I), and with spontaneous (Group II) or thrombolysis-induced reperfusion (Group III), to determine infarction probability-based viability thresholds and prediction accuracies. The infarction probability difference between irreversible-i.e., infarcted after reperfusion-and salvageable tissue injury-i.e., noninfarcted after reperfusion-was largest for GLM (20±7%) with highest accuracy of risk-based identification of acutely ischemic tissue that could recover on subsequent reperfusion (Dice's similarity index=0.79±0.14). Our study shows that assessment of the heterogeneity of infarction probability with MRI-based algorithms enables estimation of the extent of potentially salvageable tissue after acute ischemic stroke.

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