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Randomized Controlled Trial
. 2025 Feb;65(2):258-268.
doi: 10.1111/head.14897. Epub 2025 Jan 24.

A randomized sequential cross-over trial evaluating five purportedly ICP-lowering drugs in idiopathic intracranial hypertension

James L Mitchell  1   2   3   4 , Hannah S Lyons  1   2   3 , Jessica K Walker  1   2 , Andreas Yiangou  1   2   3 , Mark Thaller  1   2   3 , Olivia Grech  1   2 , Zerin Alimajstorovic  1   2 , Georgios Tsermoulas  1   2   5 , Kristian Brock  6 , Susan P Mollan  1   2   7 , Alexandra J Sinclair  1   2   3
Affiliations
Randomized Controlled Trial

A randomized sequential cross-over trial evaluating five purportedly ICP-lowering drugs in idiopathic intracranial hypertension

James L Mitchell et al. Headache. 2025 Feb.

Abstract

Objective: To gain initial insight into the efficacy to lower intracranial pressure (ICP), side effects, and effects on cognition of five drugs commonly used to treat idiopathic intracranial hypertension (IIH).

Background: Limited clinical data exist for the treatment for IIH. Impaired cognition is recognized in IIH and can be exacerbated by medications.

Methods: This human experimental medicine study was a secondary analysis that focused on an unblinded randomized, sequential, cross-over extension of a previously completed randomized controlled trial. This study evaluated females with active IIH, recruited from University Hospital Birmingham, UK. Participants were treated, in randomized order, for 2 weeks with acetazolamide, amiloride, furosemide, spironolactone, and topiramate; assessment was at baseline and 2 weeks with a minimum 1-week drug washout between drugs. The primary outcome was change in ICP at 2 weeks post-drug administration. The cognitive evaluation was an exploratory study of the trial. ICP was recorded with telemetric, intraparenchymal ICP monitors (Raumedic, Hembrechts, Germany). Adverse events were recorded, and cognition was assessed utilizing the National Institutes of Health Toolbox Cognitive Battery.

Results: Fourteen participants were recruited and evaluated by intention-to-treat analysis. Mean (standard deviation) body mass index was 37.3 (7.0) kg/m2 and ICP was 33.2 (7.1) cm cerebrospinal fluid (CSF) at baseline. ICP fell with four drugs (mean [standard error (SE)]), acetazolamide -3.3 (1.0) mmHg, p = 0.001, furosemide -3.0 (0.9) mmHg, p = 0.001, spironolactone -2.7 (0.9) mmHg, p = 0.003, and topiramate -2.3 (0.9) mmHg, p = 0.010. There was no significant difference between drugs. Side effects were common with acetazolamide (100%, 11/11) and topiramate (93%, 13/14). Baseline cognitive performance was impaired, T-score (mean [SE]) 37.2 (2.6). After treatment, there was a further significant reduction in the fluid cognition domain (ability to process and integrate) with acetazolamide (mean T-score [SE]), -5.0 (2.6), p = 0.057 and topiramate -4.1 (2.0), p = 0.061.

Conclusions: Acetazolamide, furosemide, spironolactone, and topiramate marginally reduced ICP. While their effects were not significant, this study was not powered to detect a difference between drugs. Participants reported significant side effects with acetazolamide and topiramate including cognitive decline. Cognitive measures were impaired by acetazolamide and topiramate. Therapeutics with greater efficacy and a favorable side effect profile are an unmet need in the treatment of IIH.

Keywords: adverse events; cerebrospinal fluid; cognition; idiopathic intracranial hypertension; intracranial pressure; therapeutics.

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Conflict of interest statement

James L. Mitchell was funded by the UK Ministry of Defense for the duration of the trial. Olivia Grech reports scientific consultancy fees from Invex Therapeutics (2020). Andreas Yiangou reports receiving speaker fees from Teva, UK, outside the submitted work. Kristian Brock works for AstraZeneca; and owns shares in GSK. Susan P. Mollan reports consultancy fees (Invex Therapeutics), advisory board fees (Invex therapeutics; Gensight), speaker fees (Heidelberg engineering; Chugai‐Roche Ltd.; Allergan; Santen; Chiesi; and Santhera), and travel (Abbie Vie). Alexandra J. Sinclair reports personal fees from Invex Therapeutics in her role as director with stock holdings, during the conduct of the trial (since 28.06.2019); others from Allergan, Novartis, Cheisi, and Amgen outside the submitted work. Hannah S. Lyons, Jessica K. Walker, Andreas Yiangou, Mark Thaller Zerin Alimajstorovic, and Georgios Tsermoulas declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Consort diagram. Consort diagram describing the numbers and disposition of study participants. IIH, idiopathic intracranial hypertension. [Colour figure can be viewed at wileyonlinelibrary.com]
FIGURE 2
FIGURE 2
ICP change. (A–E) Mean ICP (mean [SEM]) at baseline and 2 weeks; (A) acetazolamide, (B) amiloride, (C) furosemide, (D) spironolactone, (E) topiramate. (F) Percentage change in ICP between baseline and week 2. **p < 0.01, ***p < 0.001 (significance level set at p < 0.05). Statistical values represent result from hierarchical linear regression model at the 2 week time point. ICP, intracranial pressure; SEM, standard error of the mean. [Colour figure can be viewed at wileyonlinelibrary.com]
FIGURE 3
FIGURE 3
Baseline cognition. Baseline cognitive scores, mean (standard error of the mean), t‐scores fully corrected for age, sex, ethnicity, and educational attainment. [Colour figure can be viewed at wileyonlinelibrary.com]
FIGURE 4
FIGURE 4
Cognitive change. (A–C) Change in fully corrected t‐score, mean (standard error of the mean), following 2 weeks of treatment: (A) fluid composite score, (B) pattern comparison task, (C) dimensional change task. *p < 0.05, **p < 0.01 (significance level set at p < 0.05). [Colour figure can be viewed at wileyonlinelibrary.com]
FIGURE 5
FIGURE 5
Adverse event reports. Number of adverse events reported for each drug. [Colour figure can be viewed at wileyonlinelibrary.com]
See this image and copyright information in PMC

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