Background: It is uncertain whether deterioration after acute ischemic stroke is neurological and/or systemic (somatic) in origin. Methods: 442 consecutive patients admitted with first-ever ischemic stroke (FIS) were assessed by the Unified Neurological Stroke Scale (UNSS) at admission, on hospitalization days 1, 2 and 3 and before discharge. Results: Among 71/442 (16.1%) patients deteriorated during hospitalization, the worsening from stroke onset was early (≤72 h) in 67 (94.4%) of them. The majority (57/71, 80.3%) had CT-confirmed cerebral causes and 14/71 (19.7%) had systemic causes. The causes of late deterioration were exclusively systemic. In the logistic regression analysis the initial mean UNSS score was the only significant independent predictor of stroke deterioration (p < 0.0001). Conclusions: Early clinical deterioration in FIS patients results from infarct-inherent mechanisms while late stroke deterioration is due primarily to systemic factors. An initially severe neurological deficit might predict further decline.

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