Common Idiopathic Intracranial Hypertension Drugs Show Modest Intracranial Pressure Reduction, With Noted Adverse Effects

Alexandra J. Sinclair, MD, PhD, FRCP

(Credit: LinkedIn)

A recently published randomized, cross-over extension trial in Headache reported that 4 drugs frequently used in idiopathic intracranial hypertension (IIH)—acetazolamide, furosemide, spironolactone, and topiramate—significantly reduced intracranial pressure (ICP) after 2 weeks of treatment, whereas amiloride did not show a significant effect.¹

The analysis involved 14 women with active IIH who were treated in randomized order with the 5 different drugs over a 2-week period, separated by at least a 1-week washout. At 2 weeks, all treatments except amiloride resulted in a significant reduction in ICP: acetazolamide (−3.3 mmHg, P = .001), furosemide (−3.0 mmHg, P = .001), spironolactone (−2.7 mmHg, P = .003), and topiramate (−2.3 mmHg, P = .010). Amiloride showed a nonsignificant change of −0.5 mmHg (P = .559). Notably, no drug showed superiority over another when directly compared, but greater ICP reduction was observed in participants with higher baseline ICP.

Conducted by senior author Alexandra J. Sinclair, MD, PhD, FRCP, neurology consultant and professor of neurology at the University of Birmingham, and colleagues, the study utilized telemetric, intraparenchymal ICP monitors and also included an exploratory assessment of cognition using the NIH Toolbox Cognitive Battery. At baseline, cognitive performance was impaired across all fluid cognitive domains, with the most notable deficits seen in the fluid composite, flanker task, and dimension change task.

Following treatment, researchers reported that performance on the dimension change task significantly worsened among participants treatment with acetazolamide (−10.3, P = .002), spironolactone (−6.2, P = .030), and topiramate (−7.0, P = .012). Authors also noted that topiramate impaired performance on the pattern comparison task (−6.3, P = .037). Although reductions in the overall fluid composite score were observed with acetazolamide and topiramate, authors noted that they did not reach statistical significance.

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All told, no drug affected crystallized cognition scores and that headache symptoms remained unchanged across all treatments. Adverse event (AE) profiles varied across the medications, with acetazolamide and topiramate associated with the highest number of reported AEs, including paresthesia, nausea, and cognitive disturbance. Paresthesia was reported by all participants taking acetazolamide, and 71% of participants reported cognitive disturbances after taking topiramate. Authors noted that amiloride was associated with the fewest AEs.

Authors reported that tolerability issues led some of the participants to reduce doses or discontinue certain medications. Not all participants completed all treatment arms, with 11 who received acetazolamide, 13 on amiloride, 13 on furosemide, 13 on spironolactone, and 14 on topiramate. This short-term exploratory study suggested that several unlicensed drugs commonly used in IIH can lower ICP but may negatively affect cognition, especially in those with pre-existing impairment. Balancing potential benefits with adverse effects could remain critical, and a well-tolerated, licensed treatment for IIH may remain a significant unmet need.

Building on growing evidence of the effects of common IIH treatments, another recently published study revealed that both acetazolamide and topiramate demonstrated efficacy in improving long-term outcomes, including visual function and cerebrospinal fluid pressure.² Following 6 months of treatment, patients showed a 67% increased likelihood of clinical improvement from baseline and a 3.6-fold reduction in visual obscuration, reinforcing the clinical utility of both medications.

Conducted according to PRISMA guidelines and registered with PROSPERO, the analysis included a broad mix of randomized clinical trials and both retrospective and prospective cohort studies in IIH. Risk of bias was assessed using the Critical Appraisal Skills Program, and data were extracted with the Rayyan application. Among the findings, topiramate showed an additional benefit over acetazolamide because of its effect on weight reduction. Despite this, acetazolamide remains the standard treatment owing to its strong effect on cerebrospinal fluid pressure and improvement of visual symptoms.

REFERENCES
1. Mitchell JL, Lyons HS, Walker JK, et al. A randomized sequential cross-over trial evaluating five purportedly ICP-lowering drugs in idiopathic intracranial hypertension. Headache. 2025;65(2):258-268. doi:10.1111/head.14897
2. Almaqhawi A, Alokley A, Alamri R, et al. Effectiveness of Topiramate Versus Acetazolamide in the Management of Idiopathic Intracranial Hypertension: A Systematic Review and Meta-Analysis. Medicina (Kaunas). 2025;61(3):450. Published 2025 Mar 4. doi:10.3390/medicina61030450