Abstract text (incl. figure legends and references)
Idiopathic intracranial hypertension (IIH) is a disease characterised by raised intracranial pressure (ICP) and occurs predominantly in women with obesity; however the underlying molecular pathogenesis is not fully understood. We have applied untargeted metabolomic analysis using ultra high performance liquid chromatography-mass spectrometry to characterise the cerebrospinal fluid (CSF) and serum metabolite profiles in IIH compared to control subjects and to probe underlying disease mechanisms.
CSF and serum were collected from IIH patients (n=66) with active disease (lumbar puncture pressure >25 cmCSF and Frisén papilloedema grade ≥1) at baseline and again at 12 months following therapeutic weight loss. Analogous samples were collected at baseline from gender and body mass index matched healthy controls with obesity (n=20). We identified two annotated metabolite features in CSF; (1) formylpyruvate and (2) maleylpyruvate and/or fumarylpyruvate isomers, which were present at lower concentrations in IIH compared to control subjects and returned to relative values of control subjects following weight loss. These metabolites showed the opposite trend in serum. Several amino acid and fatty acid metabolic pathways were repeatedly perturbed in serum. Arginine metabolism and arginine biosynthesis pathways were also altered in CSF and serum in relation to IIH symptoms and remission. Lipid classes related to obesity were observed as biologically important in serum supporting the link between obesity and lipid metabolism in IIH.
These results support IIH being a systemic metabolic disease, not merely a pathology of the central nervous system and optic nerve. The perturbed pathways were also associated with disease clinical features and normalised over 12 months in line with disease remission. Perturbation of these metabolic pathways provides initial understanding of disease dysregulation in IIH and require further mechanistic evaluation.