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Diagnostic Accuracy of Glial Fibrillary Acidic Protein and Ubiquitin Carboxy-Terminal Hydrolase-L1 Serum Concentrations for Differentiating Acute Intracerebral Hemorrhage from Ischemic Stroke

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An Invited Editorial Commentary to this article was published on 05 March 2020

Abstract

Background

Biomarkers indicative of intracerebral hemorrhage (ICH) may help triage acute stroke patients in the pre-hospital phase. We hypothesized that serum concentration of glial fibrillary acidic protein (GFAP) in combination with ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), measured by a rapid bio-assay, could be used to distinguish ICH from ischemic stroke.

Methods

This prospective two-center study recruited patients with a clinical diagnosis of acute stroke both in the pre-hospital phase and at hospital admission (within 4 and 6 h after symptom onset, respectively). Blood samples were analyzed for concentrations of GFAP and UCH-L1 using ELISA techniques. The reference standard was the diagnosis of ICH, ischemic stroke, or stroke mimicking condition achieved after clinical workup including brain imaging.

Results

A total of 251 patients were included (mean age [± SD] 72 ± 15 years; 5 ICH, 23 ischemic strokes and 14 stroke mimics in the pre-hospital part; and 59 ICH, 148 ischemic strokes and 2 stroke mimics in the in-hospital part). Mean delay (± SD) from symptom onset to blood withdrawal was 130 ± 79 min for the pre-hospital patients and 136 ± 86 min for the in-hospital patients. Both GFAP and UCH-L1 serum concentrations were higher in patients having ICH as compared to other diagnoses (GFAP: median 330 ng/L [interquartile range 64–7060, range 8–56,100] vs. 27.5 ng/L [14–57.25, 0–781], p < 0.001; UCH-L1: 401 ng/L [265–764, 133–1812] vs. 338 ng/L [213–549.5, 0–2950], p = 0.025). Area-under-the-curve values were 0.866 (95% CI 0.809–0.924, p < 0.001) for GFAP, and 0.590 (0.511–0.670, p = 0.033) for UCH-L1. Regarding overall diagnostic accuracy, UCH-L1 did not add significantly to the performance of GFAP.

Conclusions

GFAP may differentiate ICH from ischemic stroke and stroke mimics. A point-of-care test to distinguish between ischemic and hemorrhagic strokes might facilitate triage to different treatment pathways or locations, or be used to select patients for trials of ultra-early interventions.

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Abbreviations

GFAP:

Glial fibrillary acidic protein

UCH-L1:

Ubiquitin carboxy-terminal hydrolase-L1

ICH:

Intracerebral hemorrhage

NIHSS:

National Institute of Health Stroke Scale

AUC:

Area under the curve

IQR:

Interquartile range

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Funding

The Norwegian Air Ambulance Foundation (non-profit organization) sponsored the prehospital part of the study. For the inhospital part of the study there was no special funding. Banyan Biomarkers provided the GFAP and UCH-L1 measurements free of charge.

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Author notes

  1. Sebastian Luger and Henriette S. Jæger have contributed equally to this paper.

Authors and Affiliations

  1. Department of Neurology, Goethe-University Hospital Frankfurt, Schleusenweg 2-16, 60528, Frankfurt am Main, Germany

    Sebastian Luger, Joanna Dixon, Ferdinand O. Bohmann, JanHendrik Schaefer & Christian Foerch

  2. The Norwegian Air Ambulance Foundation, Oslo, Norway

    Henriette S. Jæger, Karianne Larsen, Maren R. Hov & Kristi G. Bache

  3. Banyan Biomarkers, Inc., San Diego, CA, USA

    Steven P. Richieri

  4. Department of Neurology, Oslo University Hospital, Oslo, Norway

    Maren R. Hov

  5. Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

    Henriette S. Jæger, Karianne Larsen & Kristi G. Bache

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for the BE FAST III Study Group

Contributions

All authors confirmed they have contributed to the intellectual content of this paper and have met the following three requirements: (a) substantial contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article critically for important intellectual content; and (c) final approval of the published article.

Corresponding author

Correspondence to Sebastian Luger.

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Conflict of interest

FOB reports personal fees from Medtronic, non-financial support from Boehringer Ingelheim, grants from Stryker, outside the submitted work. JHS reports non-financial support from Boehringer Ingelheim and from Biogen (travel expenses), outside the submitted work. SPR is an employee of Banyan Biomarkers, and Banyan Biomarkers has submitted patents relative to the use of GFAP and UCH-L1. CF reports non-financial support from Banyan Biomarkers during the conduct of the study (Banyan Biomarkers provided the GFAP and UCH-L1 measurements free of charge), personal fees from Boehringer Ingelheim (advisory board honoraria), personal fees from Bristol Myers Squibb (speaker honoraria), personal fees from Boehringer Ingelheim (lecturer—stroke school), outside the submitted work. CF has a patent GFAP for the identification of intracerebral hemorrhage (EP1519194A1). All other authors report no conflicts of interest.

Ethical Approval

The study protocol was approved by the institutional review board of both the Goethe-University Frankfurt am Main and the regional committees for medical and health research ethics in Norway. The study has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

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Informed consent was obtained from patients and legal representatives, respectively.

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Luger, S., Jæger, H.S., Dixon, J. et al. Diagnostic Accuracy of Glial Fibrillary Acidic Protein and Ubiquitin Carboxy-Terminal Hydrolase-L1 Serum Concentrations for Differentiating Acute Intracerebral Hemorrhage from Ischemic Stroke. Neurocrit Care 33, 39–48 (2020). https://doi.org/10.1007/s12028-020-00931-5

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