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Patients who present to the Emergency Department with altered mental status may suffer from serious, time-sensitive conditions where appropriate initial management improves prognosis. The differential diagnoses of altered mental status is broad and the assessment is complicated by the patient's inability to provide a detailed history. This article presents a systematic approach to patients with altered mental status in the Emergency Department. Data from a structured physical examination and bedside tests are interpreted in light of the medical background and available history. A checklist is recommended to consider key time-sensitive conditions. The article covers the emergency treatment of selected time-sensitive conditions and provides guidance for when head CT-scan is warranted.