Introduction: Scarce data exist about clinical/radiological differences between acute ischemic strokes diagnosed in the emergency room (AISER) and stroke chameleons (SCs). We aimed at describing the differences observed in a comprehensive stroke center in Chile. Methods: Prospective observational study of patients with ischemic stroke syndromes admitted to the emergency room (ER) of Clínica Alemana between December 2014 and October 2023. Results: 1,197 patients were included; of these 63 (5.2%, 95% CI: 4.1–6.6) were SC; these were younger (p < 0.001), less frequently hypertensive (p = 0.03), and they also had lower systolic (SBP) (p < 0.001), diastolic blood pressures (DBP) (p = 0.011), and NIHSS (p < 0.001). Clinically, they presented less frequently gaze (p = 0.008) and campimetry alterations (p = 0.03), facial (p < 0.001) and limb weakness (left arm [p = 0.004], right arm (p = 0.041), left leg (p = 0.001), right leg p = 0.0029), sensory abnormalities (p < 0.001), and dysarthria (p < 0.001). Neuroradiological evaluations included less frequently large vessel occlusions (p = 0.01) and other stroke locations (p = 0.005); they also differed in their etiologies (p < 0.001). Brainstem strokes (p < 0.001) and extinction/inattention symptoms (p < 0.001) were only seen in AISER. In multivariate analysis, younger age (OR: 0.945; 95% CI: 0.93–0.96), DBP (OR: 0.97; 95% CI, 0.95–0.99), facial weakness (OR: 0.39; 95% CI: 0.19–0.78), sensory abnormities (OR: 0.16.18; 95% CI, 0.05–0.4), infratentorial location (OR: 0.36; 95% CI, 0.15–0.78), posterior circulation involvement (OR: 3.02; 95% CI, 1.45–6.3), cardioembolic (OR: 3.5; 95% CI, 1.56–7.99), and undetermined (OR: 2.42; 95% CI, 1.22–4.7; 95%) etiologies, remained statistically significant. A stepwise analysis including only clinical elements present on the patient’s arrival to the ER, demonstrates that age (OR: 0.95; 95% CI: 0.94–0.97), DBP (OR: 0.97; 95% CI, 0.95–0.99), the presence of atrial fibrillation (OR: 2.22; 95% CI, 1.04–4.75, NIHSS (OR: 0.88; 95% CI, 0.71–0.89) and the presence in NIHSS of 1a level of consciousness (OR: 5.66; CI: 95% 1.8–16.9), 1b level of consciousness questions (OR: 3.023; 95% CI, 1.35–6.8), facial weakness (OR: 0.3; CI: 95% 0.17–0.8), and sensory abnormalities (OR: 0.27; 95% CI, 0.1–0.72) remained statistically significant. Conclusion: SC had clinical and radiological differences compared to AISER. An additional relevant finding is that neurological symptoms in a patient with atrial fibrillation, even with a negative diffusion-weighted imaging, should be carefully evaluated as a potential stroke until other causes are satisfactorily ruled out.

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