Pathophysiology of the Post-Traumatic Confusional State and Post-Traumatic Amnesia: A Scoping Review

The post-traumatic confusional state (PTCS) is a period of recovery that follows traumatic brain injury (TBI), characterized by post-traumatic amnesia (PTA), impairments in attention, and behavioral dysregulation, among other clinical symptoms. The pathophysiology of PTCS is unknown, contributing to the absence of neurobiologically based diagnostic criteria, prognostic models, and treatments. The workgroup conducted a scoping review of the literature in MEDLINE/PubMed database and manual searches of references to synthesize the existing knowledge on structural, functional, electroencephalographic (EEG), molecular, and genetic biomarkers underlying PTCS diagnosis and prognosis through five Population, Intervention, Comparison, and Outcome (PICO) questions. The search yielded 3,333 abstracts of which 69 were retained and included. Teams of two workgroup members independently reviewed abstracts and articles. Most articles addressed whether biomarkers differentiated patients with PTCS/PTA from those not in PTCS/PTA, and whether biomarkers were associated with severity or duration of PTCS/PTA. Our findings suggest that transition through PTCS/PTA from lower to higher states of consciousness involves increased thalamic function, restoration of default mode network dynamics, and normalizing of excessive slow wave activity on quantitative EEG. For patients with mild TBI, PTCS/PTA was associated with greater TBI lesion burden on structural imaging. PTCS/PTA severity and duration were associated with lesion burden, reduced white matter integrity, and electrophysiological signatures. Results across studies were variable with many finding no relationship between PTCS/PTA and biomarkers. In summary, while it is premature to include biomarkers in the definition of PTCS/PTA, our findings provide avenues for future research that is designed specifically to address the pathophysiology of this condition.