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®) 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 <1 hour and <3 hour prehospital samples, and <3 hour 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 <3 hour prehospital sampling (ACI n = 178, HS n = 59), a combined rule (prehospital GFAP >410 pg/mL, or prehospital GFAP 90-410 pg/mL together with GFAP release >0.6 pg/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.