The brain has a higher demand for cardiac output than any other organ, and it strictly relies on oxygen and glucose metabolism. Consequently, the brain is exquisitely sensitive to homeostatic disturbances and extraneural organ dysfunction leading to cardiac, pulmonary, renal, hepatobiliary, and hematologic diseases. The primary neurologic manifestation of extraneural organic dysfunction is diffuse bihemispheric dysfunction or encephalopathy, which often lacks lateralizing or localizing signs. Common clinical findings are lethargy, difficulty with attention and orientation, sleep-wake disturbance, and psychomotor slowing. As organic dysfunction progresses, a moderate encephalopathy ensues, with worsening cognitive function, gross disorientation, hypoactive or hyperactive psychomotor state, frontal release signs, asterixis, and myoclonus. If organ failure (eg, hepatic or renal) progresses further, stupor and coma may result unless organ function improves. Patients with underlying organic brain disease from degenerative dementia can decompensate out of proportion to neurologically normal counterparts, resulting in encephalopathy even from minor organ dysfunction or infection.