Metabolomic Analysis Reveals Remodelling of central and systemic metabolite pathways in Idiopathic Intracranial Hypertension linked to disease activity and headache generation

Abstract text (incl. figure legends and references)

Question

The pathogenesis of Idiopathic Intracranial Hypertension (IIH) remains poorly understood and this lack of knowledge hinders advances in IIH. Mounting evidence indicates that IIH is no longer considered exclusively a disease of the central nervous system, but instead involves systemic metabolic perturbation. We sought to determine if metabolic disturbances are evident in IIH and if they are ameliorated by disease remission.

Methods

A case control study utilised proton nuclear magnetic resonance spectroscopy for metabolomic profiling of CSF, serum and urine in IIH patients (n=84) compared to age, gender and body mass index matched controls (n=20). Assessments included intracranial pressure (ICP), headache and papilledema measurements, and were repeated following a 12-months weight loss intervention n IIH patients (n=50).

Results

We identified a distinct metabolic profile in IIH featuring 4 predominant metabolites. Urea was lower in IIH (CSF p<0.001, urine p=0.009) correlated with ICP (p=0.019) and headache severity (p=0.031) and increased by 12 months (CSF p=0.004, urine p=0.043). The lactate:pyruvate ratio was increased in IIH (CSF p=0.023, serum p=0.004) and decreased at 12 months (p<0.001). Acetate was higher in IIH (p=0.008), correlated with headache severity and disability (p = 0.030, p= 0.003) and decreased at 12 months (p = 0.007). Ketones 3-hydroxybutyrate and acetoacetate were altered in IIH CSF and normalized at 12 months (p = 0.019, p = 0.015).

Conclusion

This IIH metabolomics study demonstrates systemic metabolic disturbances evident in CSF, serum and urine. Urea, an osmolar metabolite, was reduced in IIH and normalised as ICP improved. Perturbed lactate:pyruvate ratio, a marker of respiratory chain function, suggests dysregulation of systemic and central metabolic flux. Elevated acetate was associated with headache morbidity. These alterations of metabolic pathways provides biological insight and warrants mechanistic evaluation.