Background Cognitive dysfunction adversely effects multiple functional outcomes and social roles after TBI. We hypothesize that chronic systemic inflammation exacerbates cognitive deficits post-injury and diminishes functional cognition and quality of life (QOL). Yet few studies have examined relationships between inflammation and cognition after TBI. Associations between early chronic serum inflammatory biomarker levels, cognitive outcomes, and QOL 6-months and 12-months after moderate-to-severe TBI were identified using unweighted (uILS) and weighted (wILS) inflammatory load score (ILS) formation. Methods Adults with moderate-to-severe TBI (n ​= ​157) completed neuropsychological testing, the Functional Impairment Measure Cognitive Subscale (FIM-Cog) and self-reported Percent Back to Normal scale 6 months (n ​= ​139) and 12 months (n ​= ​136) post-injury. Serial serum samples were collected 1–3 months post-TBI. Cognitive composite scores were created as equally weighted means of T-scores derived from a multidimensional neuropsychological test battery. Median inflammatory marker levels associated with 6-month and 12-month cognitive composite T-scores (p ​< ​0.10) were selected for ILS formation. Markers were quartiled, and quartile ranks were summed to generate an uILS. Marker-specific β-weights were derived using penalized ridge regression, multiplied by standardized marker levels, and summed to generate a wILS. ILS associations with cognitive composite scores were assessed using multivariable linear regression. Structural equation models assessed ILS influences on functional cognition and QOL using 12-month FIM-Cog and Percent Back to Normal scales. Results ILS component markers included: IL-1β, TNF-α, sIL-4R, sIL-6R, RANTES, and MIP-1β. Increased sIL-4R levels were positively associated with overall cognitive composite T-scores in bivariate analyses, while remaining ILS markers were negatively associated with cognition. Multivariable receiver operator curves (ROC) showed uILS added 14.98% and 31.93% relative improvement in variance captured compared to the covariates only base model (age, sex, education, Glasgow Coma Scale score) when predicting cognitive composite scores at 6 and 12 months, respectively; wILS added 33.99% and 36.87% relative improvement in variance captured. Cognitive composite mediated wILS associations with FIM-Cog scores at 12 months, and both cognitive composite and FIM-Cog scores mediated wILS associations with QOL. Conclusions Early chronic inflammatory burden is associated with cognitive performance post-TBI. wILS explains greater variance in cognitive composite T-scores than uILS. Linking inflammatory burden associated with cognitive deficits to functional outcome post-TBI demonstrates the potential impact of immunotherapy interventions aimed at improving cognitive recovery post-TBI.

A previously independent 75-yr-old man developed postoperative intracranial hypotension–associated venous congestion after an elective T10-pelvis fusion, which was complicated by durotomy. Postoperative day 0 magnetic resonance imaging noted symmetric edema of the basal ganglia, thalami, and cerebellar cortex as well as smooth diffuse pachymeningeal enhancement and dural thickening, consistent with postoperative intracranial hypotension–associated venous congestion. On postoperative day 0, patient developed tonic clonic seizures, and on postoperative day 2, patient was unable to follow commands or blink to visual threat, able to track eyes to sound only, and spontaneously moved all limbs. Patient was started on zolpidem 2.5 mg on postoperative day 2, and 12 hrs later, he had significantly improved motor function, arousal, verbalization, and followed simple commands. After three doses, patient was fully alert and oriented with improved mobility and comprehension. Six zolpidem doses were administered in total, and repeat magnetic resonance imaging on postoperative day 16 showed markedly improved regional edema. The patient was admitted to a brain injury inpatient rehabilitation unit and was discharged to home 9 days later with Functional Independence Measure gain of 17. Intracranial hypotension can adversely affect primary mesocircuit structures supporting arousal. Zolpidem, a selective α-1-subunit GABA-A agonist, supports GABAergic tone in these regions. This patient’s clinical presentation and recovery paralleled selective basal ganglial-thalamic edema development and resolution.