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  • Review Article
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Idiopathic intracranial hypertension: a step change in understanding the disease mechanisms

Nature Reviews Neurology volume 19, pages 769–785 (2023)Cite this article

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Abstract

The understanding of idiopathic intracranial hypertension (IIH) has evolved over the past few years. Previously, IIH was considered a disease exclusively affecting the neuro-ophthalmic axis, characterized by raised intracranial pressure, headache and papilloedema, and resulting in the risk of severe and permanent visual loss and life-changing disabling headaches. Recent advances have begun to redefine IIH as a probable metabolic disease involving a range of systemic manifestations. More than 95% of individuals affected by the disease are women of reproductive age with obesity. The incidence is rapidly rising and parallels the escalating worldwide obesity rates. Contemporary insights identify associations with insulin resistance, type 2 diabetes and a twofold increased risk of cardiovascular disease in excess of that driven by obesity alone. Adipose distribution in people with IIH, like that in other metabolic diseases, is preferentially centripetal and is associated with changes in intracranial pressure. Evidence now demonstrates adipose tissue dysfunction in people with IIH, involving transcriptional and metabolic priming for lipogenesis and weight gain. Hormonal perturbations are also observed, including a unique phenotype of androgen excess that promotes cerebrospinal fluid secretion. Knowledge of these additional disease features is driving research into novel therapeutic targets and altering the approach to multidisciplinary care.

Key points

  • Idiopathic intracranial hypertension (IIH) is emerging as a probable metabolic disease encompassing a range of systemic manifestations.

  • Key disease features of IIH are broadening to include impaired fertility, gestational diabetes, pre-eclampsia, increased risk of cardiometabolic complications and reversible cognitive dysfunction.

  • Comorbid associated conditions include polycystic ovarian syndrome, obstructive sleep apnoea, anxiety and depression.

  • A positive relationship between headache and intracranial pressure has been observed, and specific signalling pathways have been speculated to be mechanistic drivers of IIH headaches.

  • Weight loss is established as the only disease-modifying therapy, with bariatric surgery delivering sustained control of intracranial pressure.

  • New therapeutic avenues are emerging to target metabolic pathways. The glucagon-like peptide 1 receptor agonist exenatide has been demonstrated to significantly reduce intracranial pressure in a randomized placebo-controlled trial.

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Fig. 1: Optical coherence tomography showing global RNFL progression.
Fig. 2: Optical coherence tomography disc volume assessment.
Fig. 3: OCT infrared and cross-sectional image.

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Authors and Affiliations

  1. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

    Andreas Yiangou, Susan P. Mollan & Alexandra J. Sinclair

  2. Department of Neurology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    Andreas Yiangou & Alexandra J. Sinclair

  3. Birmingham Neuro-Ophthalmology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    Susan P. Mollan

  4. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK

    Alexandra J. Sinclair

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  1. Andreas Yiangou
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  2. Susan P. Mollan
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  3. Alexandra J. Sinclair
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The authors contributed equally to all aspects of the article.

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Correspondence to Alexandra J. Sinclair.

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Competing interests

A.Y. declares speaker fees from TEVA UK, 2020; grants/funding for a fellowship from the Association of British Neurologists and Guarantors of the Brain. S.P.M. is a member of the advisory boards for Invex Therapeutics (2020/2021/2022) and Gensight (2022) and declares consultant fees from Invex Therapeutics (Trial Steering Group and Independent Adjudication Committee Fees 2022) and the Velux Foundation (2021), speaker fees from Heidelberg Engineering (2020/2021/2022), Chugai (2021/2022), and Chiesi (2020/2021), royalties/licenses from Springer Publishing: Neuro-Ophthalmology — Global Trends in Diagnosis, Treatment and Management. S.P.M. also declares membership of the following organizational arms, without re-imbursement: North American Neuro-Ophthalmology Society (Abstract Committee, Membership Committee, International Relations Committee), UK Neuro-Ophthalmology Society (Secretary), British Isles Neuro-Ophthalmology Club (Treasurer), and United Kingdom Cerebrospinal Fluid Annual Meeting (Convener), and is a member of the editorial boards for Eye (Nature Portfolio) and Journal of Neuro-Ophthalmology (Springer). A.J.S. declares personal fees, share options and shareholding from Invex therapeutics, speaker fees from Allergan-AbbVie, Novartis and Teva UK, other fees from Amgen, Chiesi and Lundbeck, and grants/funding for research studies from the National Institute for Health Research, Medical Research Council, Sir Jules Thorn Trust, and the UK Space Agency.

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Yiangou, A., Mollan, S.P. & Sinclair, A.J. Idiopathic intracranial hypertension: a step change in understanding the disease mechanisms. Nat Rev Neurol 19, 769–785 (2023). https://doi.org/10.1038/s41582-023-00893-0

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