Background: Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure occurring predominantly in women with obesity. The pathogenesis is not understood. We have applied untargeted metabolomic analysis using ultrahigh-performance liquid chromatography-mass spectrometry to characterize the cerebrospinal fluid (CSF) and serum in IIH compared to control subjects. Methods and findings: Samples were collected from IIH patients (n = 66) with active disease at baseline and again at 12 months following therapeutic weight loss. Control samples were collected from gender- and weight-matched healthy controls (n = 20). We identified annotated metabolites in CSF, formylpyruvate and maleylpyruvate/fumarylpyruvate, which were present at lower concentrations in IIH compared to control subjects and returned to values observed in controls following weight loss. These metabolites showed the opposite trend in serum at baseline. Multiple amino acid metabolic pathways and lipid classes were perturbed in serum and CSF in IIH alone. Serum lipid metabolite pathways were significantly increased in IIH. Conclusions: We observed a number of differential metabolic pathways related to amino acid, lipid, and acylpyruvate metabolism, in IIH compared to controls. These pathways were associated with clinical measures and normalized with disease remission. Perturbation of these metabolic pathways provides initial understanding of disease dysregulation in IIH.

Birmingham Neuro Ophthalmology Queen Elizabeth Hospital University Hospitals Birmingham Birmingham B15 2WB U K

Centre for Endocrinology Diabetes and Metabolism Birmingham Health Partners Birmingham B15 2TT U K

Department of Biochemistry and Systems Biology Institute of Systems Molecular and Integrative Biology University of Liverpool Liverpool L69 7ZB U K

Department of Neurology Queen Elizabeth Hospital University Hospitals Birmingham NHS Foundation Trust Birmingham B15 2WB U K

Institute of Metabolism and Systems Research College of Medical and Dental Sciences University of Birmingham Birmingham B15 2TT U K

Institute of Molecular and Translational Medicine Palacký University Olomouc Hněvotínská 5 Olomouc 77900 Czech Republic

Phenome Centre Birmingham University of Birmingham Birmingham B15 2TT U K

School of Biosciences University of Birmingham Birmingham B15 2TT U K

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