Objectively Defined Phenotypes in Gulf War Illness (GWI)

Abstract

RATIONALE: Neuroinflammation provides a unifying mechanism for fatigue, exertional exhaustion, cognitive, sleep, migraine, nociceptive and interoceptive dysfunction in GWI. Exposures to acetylcholinestase inhibitors (nerve agents, organophosphates, pesticides), DEET, permethrin, and oil well fire smoke may have induced long-lasting cholinergic and other dysfunction. METHOD(S): Sedentary control (SC) and GWI veterans were diagnosed by history and physical (Steele 2000) before submaximal bicycle exercise testing on 2 days, fMRI before and after exercise, and lumbar puncture. RESULT(S): GWI veterans were readily differentiated from SC by ceiling and floor effects on SF-36, McGill Pain, fatigue, irritability, depression, anxiety, and other questionnaires. Central sensitization caused systemic hyperalgesia (tenderness) with reduced thresholds for painful perception of light (photophobia), sound (phonophobia), hyperventilation (dyspnea), orthostasis (vestibular intolerance), nasal irritation (nonallergic rhinopathy), and visceral distention (irritable bladder and bowel). Brain white matter was dysfunctional with increased axial diffusivity on diffusion tensor imaging. Two GWI phenotypes were defined. START (Stress Test Activated Reversible Tachycardia) developed postural tachycardia after exercise, and had brain stem atrophy on MRI, elevated cerebrospinal fluid microRNA levels, and enhanced brain functional connectivity of the dorsal attention network during a simple attention task. STOPP (Stress Test Originated Phantom Perception) accounted for 2/3rds of GWI and showed increased basal ganglia and anterior insula brain activation, and reduced cerebrospinal fluid microRNA levels. CONCLUSION(S): Objective markers indicate the START and STOPP phenotypes of GWI are as distinctly different from each other as they are from controls. Disordered choroid plexus miRNA production and brain network activation during cognition contribute to GWI symptomatology.