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Background: Neuroprotective agents have the potential to reduce ischemia to penumbra of the cortex, but are time-sensitive. To quickly determine whether a cortical stroke is present without imaging, we created a scoring system based on the NIH stroke scale (NIHSS) that can accurately predict cortical damage in an acute ischemic stroke (AIS)., Methods: Patients treated with tPA for AIS were retrospectively assessed through prospectively acquired databases at two stroke centers. Stroke was classified as cortical vs. non-cortical stroke. The total NIHSS score, cortical components (gaze, visual fields, language, and neglect) and cortical score (sum of cortical components) were analyzed for site 1 and then validated for site 2 for sensitivity and positive predictive value (PPV) for a cortical stroke., Results: An acute infarct was detected in 194/239 (81%) patients at site 1 and 122/174 (70%) at site 2 on diffusion-weighted MRI. Cortical involvement was found in 71% (site 1) and 75% (site 2). The median cortical score was 25% of the total NIHSS score at both sites. NIHSS ≥ 4 had the highest sensitivity; PPV was 90% for any cortical sign with ≥ 2 points. The best combination of sensitivity and PPV was cortical score/NIHSS score ≥10%., Discussion: If a trial targeting cortical stroke required that the cortical score represent at least 10% of the total NIHSS score with no imaging, less than 10% of patients with cortical stroke would be missed and less than 18% of patients would be misclassified as having a cortical stroke.