Many patients initially diagnosed with ADEM develop clinically definite MS upon long-term follow-up. The authors found no useful diagnostic criteria for the differentiation of a first episode of MS from monophasic ADEM. The term ADEM may still be employed as a description of a clinical syndrome, but should not be used as a distinct entity until reliable diagnostic criteria have been developed.

Background and Purpose-Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. Methods-This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. Results-Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (Pϭ0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (nϭ42 of 256) in the EPO and 9.0% (nϭ24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; Pϭ0.01) without any particular mechanism of death unexpected after stroke. Conclusions-Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis. (Stroke. 2009;40:e647-e656.)

Background and Purpose-We aimed to determine the diagnostic value of perfusion computed tomography (PCT) and CT angiography (CTA) including CTA source images (CTA-SI) in comparison with perfusion-weighted magnetic resonance imaging (MRI) (PWI) and diffusion-weighted MRI (DWI) in acute stroke Ͻ6 hours. Methods-Noncontrast-enhanced CT, PCT, CTA, stroke MRI, including PWI and DWI, and MR angiography (MRA), were performed in patients with symptoms of acute stroke lasting Ͻ6 hours. We analyzed ischemic lesion volumes on patients' arrival as shown on NECT, PCT, CTA-SI, DWI, and PWI (Wilcoxon, Spearman, Bland-Altman) and compared them to the infarct extent as shown on day 5 NECT. Results-Twenty-two stroke patients underwent CT and MRI scanning within 6 hours. PCT time to peak (PCT-TTP) volumes did not differ from PWI-TTP (Pϭ0.686 for patients who did not undergo thrombolysis/Pϭ0.328 for patients who underwent thrombolysis), nor did PCT cerebral blood volume (PCT-CBV) differ from PWI-CBV (Pϭ0. Pϭ0.0047, rϭ1.0/Pϭ0.0046, rϭ0.819). Conclusions-In hyperacute stroke, the combination of PCT and CTA can render important diagnostic information regarding the infarct extent and the perfusion deficit. Lesions on PCT-TTP and PCT-CBV do not differ from lesions on PWI-TTP and PWI-CBV; lesions on CTA source images do not differ from lesions on DWI. The combination of noncontrast-enhanced CT (NECT), perfusion CT (PCT), and CT angiography (CTA) can render additional information within Ͻ15 minutes and may help in therapeutic decision-making if PWI and DWI are not available or cannot be performed on specific patients.

Background and Purpose-Thrombectomy, primarily with stent retrievers with or without adjunctive aspiration, provided clinical benefit across multiple prospective randomized trials. Whether this benefit is exclusive to stent retrievers is unclear. Methods-THERAPY (The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke; NCT01429350) was an international, multicenter, prospective, randomized (1:1), open label, blinded end point evaluation, concurrent controlled clinical trial of aspiration thrombectomy after intravenous alteplase (IAT) administration compared with intravenous-alteplase alone in patients with large vessel ischemic stroke because of a thrombus length of ≥8 mm. The primary efficacy end point was the percent of patients achieving independence at 90 days (modified Rankin Scale score, 0-2; intention-to-treat analysis). The primary safety end point was the rate of severe adverse events (SAEs) by 90 days (as treated analysis). Patients were randomized 1:1 across 36 centers in 2 countries (United States and Germany). Results-Enrollment was halted after 108 (55 IAT and 53 intravenous) patients (of 692 planned) because of external evidence of the added benefit of endovascular therapy to intravenous-alteplase alone. Functional independence was achieved in 38% IAT and 30% intravenous intention-to-treat groups (P=0.52). Intention-to-treat ordinal modified Rankin Scale odds ratio was 1.76 (95% confidence interval, 0.86-3.59; P=0.12) in favor of IAT. Secondary efficacy analyses all demonstrated a consistent direction of effect toward benefit of IAT. No differences in symptomatic intracranial hemorrhage rates (9.3% IAT versus 9.7% intravenous, P=1.0) or 90-day mortality (IAT: 12% versus intravenous: 23.9%, P=0.18) were observed. Conclusions-THERAPY did not achieve its primary end point in this underpowered sample. Directions of effect for all prespecified outcomes were both internally and externally consistent toward benefit. It is possible that an alternate method of thrombectomy, primary aspiration, will benefit selected patients harboring large vessel occlusions. Further study on this topic is indicated. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01429350.

The present study applied T2- and diffusion-weighted magnetic resonance imaging to examine if mild cerebral edema and subsequent brain swelling are implicated in the pathophysiology of acute mountain sickness (AMS). Twenty-two subjects were examined in normoxia (21% O2), after 16 hours passive exposure to normobaric hypoxia (12% O2) corresponding to a simulated altitude of 4,500 m and after 6 hours recovery in normoxia. Clinical AMS was diagnosed in 50% of subjects during hypoxia and corresponding headache scores were markedly elevated (P<0.05 versus non-AMS). Hypoxia was associated with a mild increase in brain volume (+7.0+/-4.8 ml, P<0.05 versus pre-exposure baseline) that resolved during normoxic recovery. Hypoxia was also associated with an increased T2 relaxation time (T2rt) and a general trend toward an increased apparent diffusion coefficient (ADC). During the normoxic recovery, brain volume and T2rt recovered to pre-exposure baseline values, whereas a more marked reduction in ADC in the splenium of the corpus callosum (SCC) was observed (P<0.05). While changes in brain volume and T2rt were not selectively different in AMS, ADC values were consistently lower (P<0.05 versus non-AMS) and associated with the severity of neurologic symptoms. Acute mountain sickness was also characterized by an increased brain to intracranial volume ratio (P<0.05 versus non-AMS). These findings indicate that mild extracellular vasogenic edema contributes to the generalized brain swelling observed at high altitude, independent of AMS. In contrast, intracellular cytotoxic edema combined with an anatomic predisposition to a 'tight-fit' brain may prove of pathophysiologic significance, although the increase in brain volume in hypoxia was only about 0.5% of total brain volume.

The combination of non-contrast-enhanced CT (exclusion of intracranial hemorrhage), CTA (vessel status), and early contrast-enhanced CTA-SI (demarcation of irreversible infarct) allows diagnostic assessment of acute stroke with a quality comparable to that of stroke MRI. Furthermore, it is possible to distinguish patients at risk of infarct growth from those who are not according to the collateral status, in analogy with the stroke MRI mismatch concept.

Background and Purpose-Diffusion-weighted MRI (DWI) has become a commonly used imaging modality in stroke centers. The value of this method as a routine procedure is still being discussed. In previous studies, CT was always performed before DWI. Therefore, infarct progression could be a reason for the better result in DWI. Methods-All hyperacute (Ͻ6 hours) stroke patients admitted to our emergency department with a National Institutes of Health Stroke Scale (NIHSS) score Ͼ3 were prospectively randomized for the order in which CT and MRI were performed. Five stroke experts and 4 residents blinded to clinical data judged stroke signs and lesion size on the images. To determine the interrater variability, we calculated values for both rating groups. Results-A total of 50 patients with ischemic stroke and 4 patients with transient symptoms of acute stroke (median NIHSS score, 11; range, 3 to 27) were analyzed. Of the 50 patients, 55% were examined with DWI first. The mean delay from symptom onset until CT was 180 minutes; that from symptom onset until DWI was 189 minutes. The mean delay between DWI and CT was 30 minutes. The sensitivity of infarct detection by the experts was significantly better when based on DWI (CT/DWI, 61/91%). Accuracy was 91% when based on DWI (CT, 61%). Interrater variability of lesion detection was also significantly better for DWI (CT/DWI, ϭ0.51/0.84). The assessment of lesion extent was less homogeneous on CT (CT/DWI, ϭ0.38/0.62). The differences between the 2 modalities were stronger in the residents' ratings (CT/DWI: sensitivity, 46/81%; ϭ0.38/0.76). Conclusions-CT and DWI performed with the same delay after onset of ischemic stroke resulted in significant differences in diagnostic accuracy. DWI gives good interrater homogeneity and has a substantially better sensitivity and accuracy than CT even if the raters have limited experience.

Quantification of brain water uptake identifies stroke patients with symptom onset within 4.5 hours with high accuracy and may guide the decision to use thrombolysis in patients with unknown time of stroke onset. Ann Neurol 2016;80:924-934.