Longitudinal Assessment of Ocular Biomarkers in Individuals With Gulf War Illness Symptoms
Authors: Lai James , Kalahasty Karthik , Cabrera Kimberly , Pakravan Parastou , Klimas Nancy , Goldhardt Raquel , Galor Anat 
Published: October 2024

ABSTRACT

Introduction
Gulf War illness (GWI) is characterized by a constellation of symptoms, including, but not limited to, diarrhea, fatigue, and memory problems that affect Gulf War veterans. Currently, there are no objective biomarkers for GWI. Previous studies have identified differences in optical coherence tomography (OCT) metrics between individuals with GWI symptoms and those without. However, there are limited data on how these metrics change over time. Therefore, in this current study, we conducted a prospective case–control investigation to determine if OCT metrics show longitudinal changes in those affected by GWI.

Material and Methods
We conducted a prospective study with 100 Gulf War-era veterans at the Miami Veterans Affairs Hospital from November 2018 to February 2022. Inclusion criteria required service during 1990–1991, with both deployed and nondeployed veterans included. Exclusions were based on factors like active infection, unmanaged psychotic disorders, significant head injuries, severe neurological disorders, and eye pathologies affecting OCT imaging. All participants provided informed consent, and the study was institutional review board-approved and conducted per the Declaration of Helsinki and Health Insurance Portability and Accountability Act guidelines. GWI symptoms were assessed using the modified Kansas questionnaire, categorizing veterans into groups based on GWI symptoms presence and deployment status. Data on demographics, comorbidities, medications, and medical and ocular diagnoses were collected. Participants underwent OCT imaging at 2 time points, 1 year apart, with macular, retinal nerve fiber layer, and ganglion cell layer–inner plexiform layer (GCL–IPL) thicknesses measured. Additionally, blood samples were collected and cytokine levels measured at baseline. Data analysis involved descriptive statistics, t-tests, and multivariable regression models. Statistical analyses were performed using SPSS 28.0.

Results
Logistic regression demonstrated that post-traumatic stress disorder (odds ratio [OR]: 8.18, 95% confidence interval [CI]: 2.327–28.851, P = .001) and a lower baseline macular thickness in the outer nasal segment (OR: 0.959, 95% CI: 0.924–0.994, P = .023) remained significantly associated with GWI symptoms. The model also found that individuals with GWI symptoms were more likely to have an increase in inner temporal GCL–IPL layer thickness over a 1-year period (OR: 1.187, 95% CI: 0.974–1.447, P = .089). When analysis was conducted only among those deployed, only baseline interleukin (IL) 1a (OR = 1.24, CI = 1.019–1.52, P = .03) and interleukin-10 (OR = 0.95, CI = 0.91–0.99, P = .02) levels remained significantly associated with GWI symptoms.

Conclusions
Baseline OCT measures, especially a thinner outer nasal macula, were associated with GWI symptoms. Longitudinally, individuals with GWI symptoms had greater thickening of their inferotemporal GCL compared to those without symptoms. When the model was re-examined in deployed veterans, OCT measures (at baseline and longitudinally) no longer remained significantly related with GWI symptoms and instead baseline levels of plasma inflammatory cytokine markers, IL1a and IL10, were most closely related to symptoms. Our longitudinal study builds on our previous retrospective and cross-sectional work on identifying ocular biomarkers in GWI. Across the studies, macular thinning at baseline and inferotemporal GCL-IPL thickening have been noted between cases and controls. Some of these findings share correlates with OCT biomarkers identified in conditions such as Alzheimer’s, Parkinson’s and Multiple Sclerosis. This is significant as it may help contextualize future research and help us develop better models of GWI.