Characterising severe traumatic brain injury from fresh cerebral biopsy in living patients

Abstract

AbstractTraumatic brain injury (TBI) is one of the most complex disorder in the most complex organ in the body and current classifications of mild, moderate and severe often fail to capture this complexity. Although the mainstay of prognosis involves several clinical classification systems, these systems are confined to macroscopic analysis. Therefore, we aim to use immunohistochemical examination of fresh brain biopsy samples to study the cellular and molecular changes caused by severe TBI.Twenty-five adult patients suffering severe TBI were recruited into the Severe Head Injury Brain Analysis (SHIBA) study. Fresh brain biopsies obtained prior intracranial pressure (ICP) monitor insertion or during craniotomy underwent immunohistochemical analysis using the neuronal marker (NeuN), dendritic marker (MAP2), vascular markers (claudin-5 and vWF), and neuroinflammation markers (Iba1 and P2Y12) to investigate the injury severity at microscopic level.Obtaining brain biopsy from the twenty-five patients in the study did not cause any additional burden to patient’s standard care and there were no adverse effects. The mean (± SD) Glasgow Outcome Scale-Extended (GOS-E) 3-months after injury was 4.0 (± 2.7), consisting of 64% unfavourable outcomes and 36% favourable outcomes. Immunostaining of brain tissue revealed various qualitative changes resulting in neuronal injury, dendritic injury, neurovascular injury, and neuroinflammation, which we classified into 4 subgroups for each injury type using the newly devised Yip, Hasan and Uff (YHU) grading system. Using this grading scale, patients with a total YHU grade of ≥ 11, 100% (n=11) had a GOS-E of ≤ 4, including death (54.5%), vegetative state (18.2%) and severe disability (27.3%) 3-months post injury. In contrast, those with a YHU grade of ≤ 8, 100% (n=8) had a GOS-E of 5 or higher, indicating a favourable outcome. Linear regression showed a significant negative correlation between the GOS-E and neuronal injury (R2 =0.240, p= 0.0129), dendritic injury (R2 =0.430, p= 0.0004), neurovascular injury (R2 =0.538, p<0.0001), and neuroinflammation (R2 =0.361, p= 0.0015).Brain biopsy in severe TBI is a simple and safe procedure. Furthermore, immunofluorescence staining enables classification of this heterogeneous patient population into various categories of injury severity based on the cellular and molecular pathophysiology according to the YHU grading system. This new grading scale should facilitate a more precise diagnosis, similar to what is currently standard in oncology, allowing earlier and more accurate prognosis than current grading systems, thereby adding to the arsenal of resources available to guide clinical decision making in treating patients with severe TBI.