Ultra-Early Differential Diagnosis of Acute Cerebral Ischemia and Hemorrhagic Stroke by Measuring the Prehospital Release Rate of GFAP

BACKGROUND: Plasma glial fibrillary acidic protein (GFAP) and tau are promising markers for differentiating acute cerebral ischemia (ACI) and hemorrhagic stroke (HS), but their prehospital dynamics and usefulness are unknown. METHODS: We performed ultra-sensitivite single-molecule array (Simoa((R))) measurements of plasma GFAP and total tau in a stroke code patient cohort with cardinal stroke symptoms [National Institutes of Health Stroke Scale (NIHSS) >= 3]. Sequential sampling included 2 ultra-early samples, and a follow-up sample on the next morning. RESULTS: We included 272 cases (203 ACI, 60 HS, and 9 stroke mimics). Median (IQR) last-known-well to sampling time was 53 (35-90) minutes for initial prehospital samples, 90 (67-130) minutes for secondary acute samples, and 21 (16-24) hours for next morning samples. Plasma GFAP was significantly higher in patients with HS than ACI (P<0.001 for <1hour and <3hour prehospital samples, and <3hour secondary samples), while total tau showed no intergroup difference. The prehospital GFAP release rate (pg/mL/minute) occurring between the 2 very early samples was significantly higher in patients with HS than ACI [2.4 (0.6-14.1)] versus 0.3 (-0.3-0.9)pg/mL/minute, P<0.001. For cases with <3hour prehospital sampling (ACI n=178, HS n=59), a combined rule (prehospital GFAP >410pg/mL, or prehospital GFAP 90-410pg/mL together with GFAP release >0.6pg/mL/minute) enabled ruling out HS with high certainty (NPV 98.4%) in 68% of patients with ACI (sensitivity for HS 96.6%, specificity 68%, PPV 50%). CONCLUSIONS: In comparison to single-point measurement, monitoring the prehospital GFAP release rate improves ultra-early differentiation of stroke subtypes. With serial measurement GFAP has potential to improve future prehospital stroke diagnostics.

Automated summary

This study demonstrates the potential of plasma GFAP and total tau measurements in aiding the differentiation of acute cerebral ischemia and hemorrhagic stroke in the prehospital setting. Monitoring the GFAP release rate can improve early subtype differentiation in stroke patients, particularly in ruling out hemorrhagic stroke.