Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache

Background and Objective We evaluated the metabolomic profile in the CSF, serum, and urine of participants with idiopathic intracranial hypertension (IIH) compared with that in controls and measured changes in metabolism associated with clinical markers of disease activity and treatment. Methods A case-control study compared women aged 18-55 years with active IIH (Friedman diagnostic criteria) with a sex-matched, age-matched, and body mass index-matched control group. IIH participants were identified from neurology and ophthalmology clinics from National Health Service hospitals and underwent a prospective intervention to induce disease remission through weight loss with reevaluation at 12 months. Clinical assessments included lumbar puncture, headache, papilledema, and visual measurements. Spectra of the CSF, serum, and urine metabolites were acquired using proton nuclear magnetic resonance spectroscopy. Results Urea was lower in IIH participants (CSF, controls median +/- IQR 0.196 +/- 0.008, IIH 0.058 +/- 0.059, p < 0.001; urine, controls 5971.370 +/- 3021.831, IIH 4691.363 +/- 1955.774, p = 0.009), correlated with ICP (urine p = 0.019) and headache severity (CSF p = 0.031), and increased by 12 months (CSF 12 months; 0.175 +/- 0.043, p = 0.004, urine; 5210.874 +/- 1825.302, p = 0.043). The lactate:pyruvate ratio was increased in IIH participants compared with that in controls (CSF, controls 49.739 +/- 19.523, IIH 113.114 +/- 117.298, p = 0.023; serum, controls 38.187 +/- 13.392, IIH 54.547 +/- 18.471, p = 0.004) and decreased at 12 months (CSF, 113.114 +/- 117.298, p < 0.001). Baseline acetate was higher in IIH participants (CSF, controls 0.128 +/- 0.041, IIH 0.192 +/- 0.151, p = 0.008), correlated with headache severity (p = 0.030) and headache disability (p = 0.003), and was reduced at 12 months (0.160 +/- 0.060, p = 0.007). Ketones, 3-hydroxybutyrate and acetoacetate, were altered in the CSF at baseline in IIH participants (3-hydroxybutyrate, controls 0.074 +/- 0.063, IIH 0.049 +/- 0.055, p = 0.019; acetoacetate, controls 0.013 +/- 0.007, IIH 0.017 +/- 0.010, p = 0.013) and normalized at 12 months (0.112 +/- 0.114, p = 0.019, 0.029 +/- 0.017, p = 0.015, respectively). Discussion We observed metabolic disturbances that are evident in the CSF, serum, and urine of IIH participants, suggesting global metabolic dysregulation. Altered ketone body metabolites normalized after therapeutic weight loss. CSF:serum urea ratio was altered, which may influence ICP dynamics and headache. Elevated CSF acetate, known to stimulate trigeminal sensitization, was associated with headache morbidity. These alterations of metabolic pathways specific to IIH provide biological insight and warrant mechanistic evaluation.