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Background: The patterns and outcomes of deterioration during prehospital transport and the first phase of ED care are important for planning for diversion of acute cerebral ischemia (ACI) patients to designated stroke centers and design of prehospital treatment trials.Methods: We analyzed patients enrolled in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) trial within 2h of last known well (LKW). Deterioration was defined as worsening by ≥2 on the Glasgow Coma Scale (GCS), performed serially by paramedics in the field, upon ED arrival, and after the early ED course.Results: Among 713 acute cerebral ischemia patients, age was 65.4 (±13.4), 45% female. Times from LKW to GCS assessments were: paramedic, 25 mins (IQR 15-46); ED arrival, 60 mins (IQR 48-82); and after early ED course, 83 mins (IQR 60-106). Overall, 16.3% experienced neurological deterioration, including 9.0% in prehospital phase only, 7.3% in early ED phase only, and none in both phases. Granular patterns of deficit progression were: Prehospital Sustained - prehospital deterioration, then stable early ED phase, 2.2% (16); Dippers - prehospital deterioration, then early ED improvement, 6.7% (48); Delayed - stable prehospital, then ED deterioration, 3.0% (22); and Peakers - prehospital improvement, then early ED deterioration, 4.2% (30) (Figure). Ischemic stroke patients who experienced any U-END had higher age, 73.2 vs 69.8, p<0.01; lower prehospital GCS scores, 14 (IQR 11-15) vs 15 (IQR 14-15), p<0.001; and greater prehospital focal weakness, LAMS 4.2 vs 3.6, p<0.001. U-END was associated with higher rates of disability or death (mRS 2-6) at 90 days, 77.8% vs 53.8%, p<0.001.Conclusions: Ultra-early neurological deterioration occurs in one-sixth of EMS-transported acute cerebral ischemia patients, and is associated with less favorable outcome. Early identification and effective management strategies are needed to reduce its occurrence.