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Systemic Metabolomic Changes in Idiopathic Intracranial Hypertension: A Substudy of the IIH Treatment Trial
Journal article   Open access   Peer reviewed

Systemic Metabolomic Changes in Idiopathic Intracranial Hypertension: A Substudy of the IIH Treatment Trial

Yin Allison Liu, Anastasia Krajnovic, Christopher Brydges, Oliver Fiehn, Shana Mccormack, Kristin Wade, Mark J. Kupersmith, Michael Wall and Grant T. Liu
Neurology Open Access, Vol.2(3), e000119
09/2026
DOI: 10.1212/WN9.0000000000000119
url
https://doi.org/10.1212/WN9.0000000000000119View
Published (Version of record) Open Access

Abstract

Background and Objectives Obesity is a well-established risk factor for idiopathic intracranial hypertension (IIH), yet the metabolic mechanisms linking obesity to IIH remain poorly understood. Previous metabolomic studies in obesity have identified characteristic alterations in lipid and amino acid pathways, but it is unclear whether individuals with IIH exhibit distinct metabolic profiles beyond those attributable to obesity alone. The objective of this study was to identify metabolomic differences between patients with newly diagnosed IIH and age-, sex-, race/ethnicity-, and body mass index (BMI)-matched controls. Methods We conducted a cross-sectional metabolomic analysis using peripheral blood samples obtained from participants enrolled in the Idiopathic Intracranial Hypertension Treatment Trial. Untargeted metabolomic profiling was performed to compare circulating metabolites between IIH and matched controls. Differential metabolites and enriched metabolic pathways were identified using independent-sample testing with batch correction and false discovery rate adjustment. Results The study included 321 participants, comprising 178 individuals with newly diagnosed, untreated IIH and 143 matched controls. The mean age was 29.0 ± 7.4 years, and 98% of participants were female. Compared with controls, IIH was associated with differential abundance of 221 metabolites, including 90 increased and 131 decreased metabolites. Increased metabolites were predominantly lipid species, whereas decreased metabolites were largely lipid-related as well. Notable increases in IIH included allantoin (1.6-fold), linoleic acid (1.2-fold), and ribose (1.2-fold). Decreased metabolites included ornithine (0.7-fold), tyrosine (0.8-fold), and isoleucine (0.8-fold). Altered pathways involved branched-chain amino acid metabolism, cysteine and methionine metabolism, tyrosine metabolism, fatty acid biosynthesis, and linoleic acid metabolism. Discussion Patients with newly diagnosed IIH demonstrate a distinct circulating metabolomic profile compared with BMI-matched controls, characterized by alterations in lipid and amino acid metabolic pathways that differ from patterns previously reported in obesity alone. These findings suggest metabolic heterogeneity among individuals with obesity and identify potential pathways relevant to IIH pathophysiology. Limitations include the cross-sectional design, which precludes causal inference, and reliance on peripheral blood metabolites, which may not fully reflect central nervous system metabolic processes.

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