In the absence of direct evidence that IV alteplase provides no benefit or produces harm in eligible patients with CMBs, withholding treatment on the basis of the presence of CMBs could lead to the exclusion of patients who would benefit from treatment. See Table XXI in online Data Supplement 1. Powers et al 2019 Guidelines for Management of AIS e357 In patients eligible for IV alteplase, because benefit of therapy is time dependent, treatment should be initiated as quickly as possible and not delayed for additional multimodal neuroimaging, such as CT and MRI perfusion imaging. I B-NR New recommendation. NCCT was the only neuroimaging modality used in the NINDS rt-PA trial and in ECASS III and is therefore sufficient neuroimaging for decisions about IV alteplase in most patients.48,49 Multimodal CT and MRI, including diffusion and perfusion imaging, are not necessary when the diagnosis of ischemic stroke is very likely, and their performance may delay time-sensitive administration of IV alteplase. In some cases, particularly when there is substantial diagnostic uncertainty, advanced imaging may be beneficial. See Table XX in online Data Supplement 1. In patients with AIS who awake with stroke symptoms or have unclear time of onset > 4.5 hours from last known well or at baseline state, MRI to identify diffusion-positive FLAIR-negative lesions can be useful for selecting those who can benefit from IV alteplase administration within 4.5 hours of stroke symptom recognition. IIa B-R New recommendation. The WAKE-UP trial (Efficacy and Safety of MRI-based Thrombolysis in Wake-Up Stroke) randomized 503 patients with AIS who awoke with stroke or had unclear time of onset >4.5 hours from last known well and could be treated with IV alteplase within 4.5 hours of stroke symptom recognition. 