IIH Provoke
(2026)Objective
To characterise plasma cytokine alterations during the ictal phase of CGRP-provoked idiopathic intracranial hypertension (IIH) headache attacks vs placebo, in a randomised, double-blind, two-way crossover provocation study.
Study Summary
• During the ictal phase after CGRP, 8 cytokines were significantly elevated vs baseline: IL-6 (P=0.014), CCL4 (P=0.038), CCL8 (P=0.049), HGF (P=0.007), IL-17C (P=0.044), IL-27 (P<0.001), OSM (P=0.011) and TGF-α (P=0.042); FLT3LG decreased (P=0.022)
• Cytokine changes were absent after placebo and in CGRP recipients who did not develop headache, supporting a CGRP-headache-specific neuroimmune signature
• No serious adverse events reported; findings are exploratory and hypothesis-generating
Intervention
Intravenous CGRP infusion 1.5 µg/min for 20 minutes (placebo arm: matched isotonic saline)
Inclusion Criteria
Women 18–60 yr with confirmed IIH (papilloedema, LP opening pressure ≥25 cm H₂O, normal neuroimaging and CSF) and headache attributed to IIH per ICHD-3
Study Design
Arms: IV CGRP 1.5 µg/min x 20 min vs IV isotonic saline placebo; two-way crossover, ≥6 days washout, double-blind
Patients per Arm: 16 women (each received both interventions; 7 developed CGRP-provoked headache and were sampled at peak, 9 remained headache-free and sampled at ~4 h)
Outcome
• FLT3LG decreased after both CGRP (P=0.022) and placebo (P=0.038), suggesting a non-specific procedural/temporal effect
• Placebo: no significant cytokine elevations; CCL8 decreased (P=0.04)
• No significant changes in CGRP recipients who did not develop headache
• No baseline cytokine differences between H+ and H- participants and no carryover/period effects
Clinical Question
In women with idiopathic intracranial hypertension (IIH), are CGRP-provoked typical IIH headache attacks accompanied by measurable changes in circulating plasma cytokines (a neuroimmune signature) during the ictal phase?
Bottom Line
In a small (n=16) double-blind, placebo-controlled, two-way crossover provocation study, IV CGRP triggered typical IIH headache in 44% of women and was accompanied by elevations in 8 pro-nociceptive and immunoregulatory cytokines (CCL4, CCL8, IL-6, IL-17C, IL-27, OSM, HGF, TGF-α) that were not seen after placebo or in CGRP recipients without headache, supporting a neuroimmune component of CGRP-induced IIH headache.
Major Points
- Double-blind, placebo-controlled, two-way crossover provocation study (parent trial IIH Provoke, ISRCTN13251508) in 16 women with IIH; 4 enrolled but did not complete both visits.
- IV CGRP (1.5 µg/min x 20 min) provoked a typical IIH headache attack in 7/16 (44%); no participant developed headache during the placebo visit.
- Eight cytokines were significantly elevated during the ictal phase vs baseline after CGRP: CCL4 (P=0.038), CCL8 (P=0.049), IL-6 (P=0.014), IL-17C (P=0.044), IL-27 (P<0.001), OSM (P=0.011), HGF (P=0.007) and TGF-α (P=0.042).
- These cytokine changes were absent after placebo and in CGRP recipients who did not develop headache (H-), supporting specificity to the CGRP-provoked ictal phase rather than a direct CGRP pharmacologic effect.
- FLT3LG decreased after both CGRP (P=0.022) and placebo (P=0.038) and CCL8 decreased after placebo (P=0.04), highlighting non-specific procedural/temporal effects.
- Mechanistic interpretation: glial-immune activation, BBB modulation, vascular/tissue remodelling and trigeminal sensitisation in a primed neuroimmune state in IIH; exploratory and hypothesis-generating only.
Study Design
- Study Type
- Randomised, double-blind, placebo-controlled, two-way crossover mechanistic provocation RCT
- Randomization
- Yes
- Blinding
- Double-blind (participants and investigators masked; drug prepared/administered by independent staff)
- Sample Size
- 16
- Follow-up
- Two inpatient visits ≥6 days apart; sampling baseline and peak headache or ~4 h post-infusion
- Centers
- 1
- Countries
- United Kingdom
Primary Outcome
Definition: Change in plasma cytokine levels (Olink Target 48 PEA panel, 45 proteins; 38 passing QC) from baseline (BL) to peak headache (H+) during the ictal phase after CGRP infusion in participants who developed a typical IIH headache (n=7)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - (Not reported (means and SDs presented per cytokine; FDR-adjusted P-values provided post-hoc in Supplementary Table)) | Multiple; see description |
Limitations & Criticisms
- Very small sample size (n=16 overall, n=7 in the primary ictal analysis) limits statistical power and precludes correction-robust inferences
- Single-centre (UK) and all-female, predominantly White British population — limits generalisability across sex, ethnicity, and healthcare setting
- Provoked rather than spontaneous IIH headache attacks; experimental ictal pathophysiology may differ from naturally occurring attacks
- Peripheral plasma cytokines may not reflect central CSF/meningeal neuroimmune events
- Exploratory analysis without prespecified correction for multiple comparisons; FDR adjustments provided only as post-hoc sensitivity analysis
- 7 of 45 cytokines below the limit of quantification (including IL-17A, IL-1β, IL-33, TSLP) restricted the breadth of the inflammatory profile
- Study design cannot establish whether cytokine elevations cause headache or are downstream consequences of CGRP-induced trigeminovascular activation
Citation
Yiangou A et al. J Headache Pain. 2026;27(1). DOI: 10.1186/s10194-026-02385-0