Corticosteroids, Intracranial Pressure and the Pathogenesis of Idiopathic Intracranial Hypertension.

Lead Research Organisation: University of Birmingham
Department Name: Sch of Biosciences

Abstract

Idiopathic intracranial hypertension, (IIH), is a common blinding condition in overweight women. Affected patients suffer with severe headaches and significant visual loss resulting from increased brain pressure, called intracranial pressure. The cause of raised brain pressure in IIH is not known, but it is likely to relate to abnormalities in the balance between production and drainage of brain fluid, known as cerebrospinal fluid (CSF). As greater than 90% of IIH patients are female and obese we expect that the disordered CSF balance may relate to hormones and obesity, our study will investigate this further. Initially, we will identify where and how these hormones act in the areas of the brain that are known to produce and drain CSF. We will then study the urine, serum and CSF of patients with IIH to determine which hormones and chemicals are unique to the disease. Finally, weight loss has previously been suggested as a treatment for IIH, but to date this has not been proven. A clinical study will be carried out to identify whether weight loss is truly effective in treating IIH, and if so whether this works by altering disease specific hormone levels.

Technical Summary

Idiopathic intracranial hypertension, (IIH), is a common blinding condition of unknown aetiology amongst the young obese female population (20 per 100,000). It is likely the incidence will rise further with the global obesity epidemic. IIH is characterised by elevated intracranial pressure (ICP) which manifests as disabling headaches and severe visual loss secondary to optic nerve compression. Based on our work in the related ocular ciliary epithelium, and also the link between IIH and obesity, I propose a role for corticosteroids and their pre-receptor regulator, the enzyme 11?-Hydroxysteroid dehydrogenase, in the pathogenesis of the raised ICP. Importantly, treatment protocols for IIH are not established. In fact, a recent Cochrane Review concluded that there was inadequate information regarding causation and which treatments were considered beneficial and which were potentially harmful. I aim to develop a novel therapeutic target for patients with IIH, and provide an evidence base for the use of weight loss regimens in affected cases.

The objectives of my proposal are to:

1. Perform in vitro studies to characterise the role of corticosteroids and their metabolic pathways in CSF production by the choroid plexus and drainage through the arachnoid granulation tissue.

2. Conduct in vivo studies in patients with IIH to define the function of the hypothalamo-pituitary-adrenal axis, cortisol metabolism and CSF steroid levels.

3. Undertake a detailed clinical interventional study that will evaluate whether a carefully monitored and previously validated weight loss program is effective in reducing ICP and treating IIH. If so, address why weight loss may be beneficial by monitoring for changes in the levels of corticosteroids and related metabolites.

Unravelling the role of corticosteroids and particularly their metabolism by enzymes such as 11?-hydroxysteroid dehydrogenase (11?-HSD), may have major ramifications for patients with IIH. In addition to weight loss, selective inhibitors of 11?-HSD that may reduce local CSF steroid hormone production are under development. The translational component of this work offers potentially exciting therapies for the treatment of IIH.

Publications

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Hornby C (2017) What Do Transgender Patients Teach Us About Idiopathic Intracranial Hypertension? in Neuro-ophthalmology (Aeolus Press)

 
Description Impacted on how IIH is treated internationally (following IIH weight trial) - data presented in presenttions and numerous review papers
 
Description Clinician Scientist Fellowship
Amount £866,454 (GBP)
Funding ID 011-028 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 06/2012 
End 06/2019
 
Description Drummond Foundation
Amount £30,000 (GBP)
Organisation Drummond Foundation 
Start 01/2017 
End 12/2020
 
Description Funding for registers and databases
Amount £20,000 (GBP)
Organisation The Health Quality Improvement Partnership (HQIP) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2013 
End 06/2016
 
Description Midland Neuroscience Teaching & Research Fund consumables funds
Amount £38,320 (GBP)
Organisation Midland Neuroscience Teaching and Research Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2017 
End 12/2020
 
Description The Midlands Neuroscience Teaching and Research Fund
Amount £5,000 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 01/2006 
End 01/2010
 
Title NMR Metabolomic biomarkers 
Description Cerebrospinal fluid and serum Metaboloite biomarkers to diagnose neurological diseases Basic metholdology explored using proton NMR spectroscopy and analysis with partial least squares discriminant analysis. 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact Metabolomics needs furthur evalualting but has significant potential. The method now needs optimising. 
 
Description Adviser for Idiopathic Intracranial Hypertension UK Charity 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Medical advise for the newly established National charity IIH UK. Facilitating set up and anual conference.

Website information on IIH for patients
Year(s) Of Engagement Activity 2012
 
Description IIH presentation at Keel Headache education course 2014 
Form Of Engagement Activity
Part Of Official Scheme? No
Primary Audience
Year(s) Of Engagement Activity
 
Description Patron of IIH UK patient charity 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Being patron of the main IIH patient charity in the UK has led to closer collaboration with the charity. This has led to their involvement in Patient and Public Involvement aspects of my trials, and to their help with publicising the trials.

I have been able to work with the charity trustees to suggest direction for research, and have received their help in patient surveys to preview/inform research questions, for example.

We have had patients contact the trials team to then take part in the trials that we would not have otherwise reached. The trials website receive more traffic when the charity's promotion of them/the trials is more active.
Year(s) Of Engagement Activity 2014,2015
URL http://www.iih.org.uk