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Current Opportunities for Clinical Monitoring of Axonal Pathology in Traumatic Brain Injury

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Review

Current Opportunities for Clinical Monitoring of Axonal Pathology in Traumatic Brain Injury

Parmenion P Tsitsopoulos et al. Front Neurol.

Abstract

Traumatic brain injury (TBI) is a multidimensional and highly complex disease commonly resulting in widespread injury to axons, due to rapid inertial acceleration/deceleration forces transmitted to the brain during impact. Axonal injury leads to brain network dysfunction, significantly contributing to cognitive and functional impairments frequently observed in TBI survivors. Diffuse axonal injury (DAI) is a clinical entity suggested by impaired level of consciousness and coma on clinical examination and characterized by widespread injury to the hemispheric white matter tracts, the corpus callosum and the brain stem. The clinical course of DAI is commonly unpredictable and it remains a challenging entity with limited therapeutic options, to date. Although axonal integrity may be disrupted at impact, the majority of axonal pathology evolves over time, resulting from delayed activation of complex intracellular biochemical cascades. Activation of these secondary biochemical pathways may lead to axonal transection, named secondary axotomy, and be responsible for the clinical decline of DAI patients. Advances in the neurocritical care of TBI patients have been achieved by refinements in multimodality monitoring for prevention and early detection of secondary injury factors, which can be applied also to DAI. There is an emerging role for biomarkers in blood, cerebrospinal fluid, and interstitial fluid using microdialysis in the evaluation of axonal injury in TBI. These biomarker studies have assessed various axonal and neuroglial markers as well as inflammatory mediators, such as cytokines and chemokines. Moreover, modern neuroimaging can detect subtle or overt DAI/white matter changes in diffuse TBI patients across all injury severities using magnetic resonance spectroscopy, diffusion tensor imaging, and positron emission tomography. Importantly, serial neuroimaging studies provide evidence for evolving axonal injury. Since axonal injury may be a key risk factor for neurodegeneration and dementias at long-term following TBI, the secondary injury processes may require prolonged monitoring. The aim of the present review is to summarize the clinical short- and long-term monitoring possibilities of axonal injury in TBI. Increased knowledge of the underlying pathophysiology achieved by advanced clinical monitoring raises hope for the development of novel treatment strategies for axonal injury in TBI.

Keywords: biomarkers; diffuse axonal injury; microdialysis; monitoring; neurocritical care; neuroimaging; traumatic brain injury.

Figures

Figure 1
Figure 1
Schematic illustration of monitoring options for axonal injury. Biomechanically, traumatic axonal injury results from head impact with rotational acceleration-deceleration forces. Detection and monitoring of axonal injury is possible with numerous advanced neuroimaging techniques such as magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and magnetic resonance spectrometry (MRS), as well as neuromolecular imaging by single-photon emission computed tomography (SPECT) and/or positron emission tomography (PET). Axonal injury also results in the secretion of various biomarkers into the interstitial fluid (ISF), cerebrospinal fluid (CSF) and the bloodstream which can be detected in ISF using microdialysis, in CSF by sampling through an external ventricular drainage or through lumbar puncture, and in serum by blood sampling. These biomarkers provide clues of temporal patterns of axonal injury and ongoing secondary injury processes and may be associated with outcome. Monitoring of axonal injury progression may also be achieved by placement of an intracranial pressure (ICP) monitoring device for continuous surveillance of ICP, neurophysiological methods such as electroencephalography (EEG) and periodic assessments of neurological status including level of consciousness. Furthermore, the genetic profile may add additional information of risk for secondary injury cascades and neurodegenerative development.
Figure 2
Figure 2
Detection of axonal injury with conventional magnetic resonance imaging (MRI) using different MRI sequences. (A) Fluid-attenuated inversion recovery (FLAIR) image depicting non-hemorrhagic diffuse axonal injury (DAI)-associated lesions in the subcortical white matter of the right cerebral hemisphere (arrow). (B) Diffusion-weighted image (DWI) depicting non-hemorrhagic DAI-associated lesions in the body and splenium of the corpus callosum. (C) T2*-weighted gradient echo (T2*GRE) image depicting hemorrhagic DAI-associated lesions in the right thalamus and putamen (arrow). (D) Susceptibility-weighted image (SWI) depicting hemorrhagic DAI-associated lesions in the right mesencephalon (arrow) and in the white matter of right temporal lobe.

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