Abstract
A diagnosis of traumatic brain injury (TBI) is typically based on patient medical history, a clinical examination, and imaging tests. Elevated plasma levels of glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NFL) have been observed in numerous studies of TBI patients. It is reasonable to view traumatic optic neuropathy (TON) as a focal form of TBI. The purpose of this study was to assess if circulating GFAP, UCH-L1, and NFL are also elevated in a porcine model of TON. Serum levels of GFAP, UCH-L1, and NFL were measured immediately before optic nerve crush and 1 h post-injury in 10 Yucatan minipigs. Severity of optic nerve crush was confirmed by visual inspection of the optic nerve at time of injury, loss of visual function as measured by flash visual evoked potential (fVEP) at 7 and 14 days, and histological analysis of axonal transport of cholera toxin-β (CT-β) within the optic nerve. Post-crush concentrations of GFAP, UCH-L1, and NFL were all significantly elevated compared with pre-crush concentrations (p < 0.01, p = 0.01, and p < 0.01, respectively). The largest increase was observed for GFAP with the post-injury median concentration increasing nearly sevenfold. The use of these TBI biomarkers for diagnosing and managing TON may be helpful for non-ophthalmologists in particular in diagnosing this condition. In addition, the potential utility of these biomarkers for diagnosing other optic nerve and/or retinal pathologies should be evaluated.
Highlights
Adiagnosis of traumatic brain injury (TBI) is based on patient medical history, a clinical examination, and imaging tests.[1,2,3,4,5] The ability to diagnose and classify TBI as well as to decide when imaging is indicated has advanced with the identification of circulating biomarkers often elevated in TBI patients
The combined measurement of glial fibrillary acidic protein (GFAP, an abundant intermediate filament contained within astrocytes) and ubiquitin c-terminal hydrolase L1 (UCH-L1, a neuronal cystosolic enzyme) was recently approved by the United States Food and Drug Administration (FDA) as part of the Banyan Trauma Indicator (BTI) to aid in the evaluation of patients ‡18 years of age with a suspected TBI (Glasgow Coma Scale [GCS] score 13–15) when collected within 12 h of the injury
In efforts to elucidate the conditions conducive to the regeneration of retinal ganglion cells (RGCs) and their axons, a well-established murine optic nerve crush model of traumatic optic neuropathy (TON) has been developed, characterized, and extensively used.[42,43,44]. Using this model as a paradigm, we developed a porcine optic nerve crush model of TON to research neuroprotective and neuro-regenerative optic nerve treatments that have had some success in the murine model.[45]
Summary
Adiagnosis of traumatic brain injury (TBI) is based on patient medical history, a clinical examination, and imaging tests.[1,2,3,4,5] The ability to diagnose and classify TBI as well as to decide when imaging is indicated has advanced with the identification of circulating biomarkers often elevated in TBI patients. ALERTTBI, the landmark multi-center observational study, key in obtaining FDA approval for these biomarkers, collected data from 1959 patients with suspected non-penetrating TBI and a Glasgow Coma Scale score of 9–15. The authors found that the combined use of GFAP and UCH-L1 had a sensitivity of 97.6% and negative predictive value (NPV) of 99.6% for the detection of acute intracranial lesions on computed tomography (CT).[6] Other biomarkers, including neurofilament light chain (NFL, a neuron specific intermediate filament) are elevated in TBI but are not FDA approved for use in TBI evaluation.[6,7,8,9,10,11,12,13,14,15,16,17,18,19,20]
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