Hirsch KG, Mlynash M, Eyngorn I, Pirsaheli R, Okada A, Komshian S, Chen C, Mayer SA, Meschia JF, Bernstein RA, Wu O, Greer DM, Wijman CA, Albers GW. Multi-Center Study of Diffusion-Weighted Imaging in Coma After Cardiac Arrest. Neurocrit Care 2016;24(1):82-9.Abstract
    BACKGROUND: The ability to predict outcomes in acutely comatose cardiac arrest survivors is limited. Brain diffusion-weighted magnetic resonance imaging (DWI MRI) has been shown in initial studies to be a simple and effective prognostic tool. This study aimed to determine the predictive value of previously defined DWI MRI thresholds in a multi-center cohort. METHODS: DWI MRIs of comatose post-cardiac arrest patients were analyzed in this multi-center retrospective observational study. Poor outcome was defined as failure to regain consciousness within 14 days and/or death during the hospitalization. The apparent diffusion coefficient (ADC) value of each brain voxel was determined. ADC thresholds and brain volumes below each threshold were analyzed for their correlation with outcome. RESULTS: 125 patients were included in the analysis. 33 patients (26%) had a good outcome. An ADC value of less than 650 × 10(-6) mm(2)/s in ≥10% of brain volume was highly specific [91% (95% CI 75-98)] and had a good sensitivity [72% (95% CI 61-80)] for predicting poor outcome. This threshold remained an independent predictor of poor outcome in multivariable analysis (p = 0.002). An ADC value of less than 650 × 10(-6) mm(2)/s in >22% of brain volume was needed to achieve 100% specificity for poor outcome. CONCLUSIONS: In patients who remain comatose after cardiac arrest, quantitative DWI MRI findings correlate with early recovery of consciousness. A DWI MRI threshold of 650 × 10(-6) mm(2)/s in ≥10% of brain volume can differentiate patients with good versus poor outcome, though in this patient population the threshold was not 100% specific for 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.
    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.
    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.
    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.
    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.
    Greer DM, Yang J, Scripko PD, Sims JR, Cash S, Kilbride R, Wu O, Hafler JP, Schoenfeld DA, Furie KL. Clinical examination for outcome prediction in nontraumatic coma. Crit Care Med 2012;40(4):1150-6.Abstract
    OBJECTIVES: Determine the utility of the neurologic examination in comatose patients from nontraumatic causes in the modern era. DESIGN: Prospective observational study. SETTING: Single academic medical center. PATIENTS: Data from 500 patients in nontraumatic coma collected sequentially from 2000 to 2007 in the emergency department and neuroscience, medical, and cardiac intensive care units. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data were collected on days 0, 1, 3, and 7. Outcome was assessed at 6 months; good outcome was determined at two levels by modified Rankin Scale, ≤3 as independence and ≤4 as moderate but not severe disability. A classification and regression tree analysis was performed to determine prognostic variables, creating predictive algorithms of good vs. poor outcome for each day. Patients with coma attributable to subarachnoid hemorrhage (4/80; 5%) or global hypoxic-ischemic injury (20/202, 10%) were more likely to achieve good outcomes. The pupillary reflex was an important determinant, regardless of day or modified Rankin Scale cut point (mean odds ratio 12.51, range [6.01, 22.56] for modified Rankin Scale ≤3; mean odds ratio 19.26, range [5.38, 42.26] for modified Rankin Scale ≤4). A less robust effect was seen for oculocephalic reflexes (mean odds ratio 62.61, range [2.24, 177] for modified Rankin Scale ≤3; mean odds ratio 34.13, range [4.95, 89.93] for modified Rankin Scale ≤4). The motor response was selected as a predictor of outcome only on day 0 (odds ratio 2.35, 95% confidence interval 0.64-5.74 for modified Rankin Scale ≤3; odds ratio 2.1, 95% confidence interval 0.81-4.24 for modified Rankin Scale score ≤4). Age was not associated with outcome. CONCLUSIONS: The clinical neurologic examination remains central to determining prognosis in nontraumatic coma. Additional clinical and diagnostic variables may also aid in outcome prediction for specific disease states.
    Edlow BL, Takahashi E, Wu O, Benner T, Dai G, Bu L, Grant PE, Greer DM, Greenberg SM, Kinney HC, Folkerth RD. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol 2012;71(6):531-46.Abstract
    The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.
    Wu O, Batista LM, Lima FO, Vangel MG, Furie KL, Greer DM. Predicting clinical outcome in comatose cardiac arrest patients using early noncontrast computed tomography. Stroke 2011;42(4):985-92.Abstract
    BACKGROUND AND PURPOSE: Early assessment of the likelihood of neurological recovery in comatose cardiac arrest survivors remains challenging. We hypothesize that quantitative noncontrast computed tomography (NCCT) combined with neurological assessments, are predictive of outcome. METHODS: We analyzed data sets acquired from comatose cardiac arrest patients who underwent CT within 72 hours of arrest. Images were semiautomatically segmented into anatomic regions. Median Hounsfield units (HU) were measured regionally and in the whole brain (WB). Outcome was based on the 6-month modified Rankin Scale (mRS) score. Logistic regression was used to combine Glasgow Coma Scale (GCS) score measured on Day 3 post arrest (GCS_Day3) with imaging to predict poor outcome (mRS>4). RESULTS: WB HU (P=0.02) and the ratio of HU in the putamen to the posterior limb of the internal capsule (PLIC) (P=0.004) from 175 datasets from 151 patients were univariate predictors of poor outcome. Thirty-three patients underwent hypothermia treatment. Multivariate analysis showed that combining median HU in the putamen (P=0.0006) and PLIC (P=0.007) was predictive of poor outcome. Combining WB HU and GCS_Day3 resulted in 72% [61% to 80%] sensitivity and 100% [73% to 100%] specificity for predicting poor outcome in 86 patients with measurable GCS_Day3. This was an improvement over prognostic performance based on GCS_Day3≤8 (98% sensitive but 71% specific). DISCUSSION: Combining density changes on CT with GCS_Day3 may be useful for predicting poor outcome in comatose cardiac arrest patients who are neither rapidly improving nor deteriorating. Improved prognostication with CT compared with neurological assessments can be achieved in patients treated with hypothermia.
    Wu O, Sorensen GA, Benner T, Singhal AB, Furie KL, Greer DM. Comatose patients with cardiac arrest: predicting clinical outcome with diffusion-weighted MR imaging. Radiology 2009;252(1):173-81.Abstract
    PURPOSE: To examine whether the severity and spatial distribution of reductions in apparent diffusion coefficient (ADC) are associated with clinical outcomes in patients who become comatose after cardiac arrest. MATERIALS AND METHODS: This was an institutional review board-approved, HIPAA-compliant retrospective study of 80 comatose patients with cardiac arrest who underwent diffusion-weighted magnetic resonance imaging. The need to obtain informed consent was waived except when follow-up phone calls were required; in those cases, informed consent was obtained from the families. Mean patient age was 57 years +/- 16 (standard deviation); 31 (39%) patients were women. ADC maps were semiautomatically segmented into the following regions: subcortical white matter; cerebellum; insula; frontal, occipital, parietal, and temporal lobes; caudate nucleus; putamen; and thalamus. Median ADCs were measured in these regions and in the whole brain and were compared (with a two-tailed Wilcoxon test) as a function of clinical outcome. Outcome was defined by both early eye opening in the 1st week after arrest (either spontaneously or in response to external stimuli) and 6-month modified Rankin scale score. RESULTS: Whole-brain median ADC was a significant predictor of poor outcome as measured by no eye opening (specificity, 100% [95% confidence interval {CI}: 86%, 100%]; sensitivity, 30% [95% CI: 18%, 45%]) or 6-month modified Rankin scale score greater than 3 (specificity, 100% [95% CI: 73%, 100%]; sensitivity, 41% [95% CI: 29%, 54%]), with patients with poor outcomes having significantly lower ADCs for both outcome measures (P