IIH Provoke
(2026)Objective
To determine whether intravenous CGRP provokes typical idiopathic intracranial hypertension (IIH) headache attacks and alters intracranial pressure dynamics in women with IIH and no prior migraine.
Study Summary
• 12-h AUC of headache severity higher after CGRP vs placebo (P=0.016); median peak NRS 6.5 vs 3 (P=0.020)
• Mean ICP unchanged, but ICP pulse amplitude increased significantly after CGRP (P=0.005) — suggests reduced intracranial compliance
• CGRP produced expected cerebrovascular effects: ↑ heart rate (P<0.001), ↑ oxygenated haemoglobin (P<0.001), ↑ tissue oxygenation index (P=0.041), ↓ MAP (P=0.010), ↓ MCA blood velocity (P=0.006)
• All 4 participants with a family history of migraine had CGRP-provoked headache but none after placebo
• Provides mechanistic rationale for testing CGRP-pathway blockade in IIH headache
Intervention
20-min continuous intravenous infusion of CGRP 1.5 μg/min vs placebo (isotonic saline) — two-way crossover, visits ≥6 days apart.
Inclusion Criteria
Women aged 18-60 with previously diagnosed IIH (revised criteria) and ICHD-3B headache attributed to IIH, either active (RNFL ≥109 μm or specialist-confirmed papilloedema) or in ocular remission; no prior migraine history.
Study Design
Arms: CGRP infusion (1.5 μg/min × 20 min) vs Placebo (isotonic saline) — crossover
Patients per Arm: 17 completed both arms (20 randomized)
Outcome
• Median (IQR) onset of provoked attack: CGRP 90 min (35-285) vs placebo 360 min (100-390)
• Nine of 12 participants showed a biphasic headache after CGRP (early peak ≈30 min, delayed peak ≈300 min)
• Photophobia (65% vs 24%, P=0.023), heat sensation (94% vs 6%, P<0.001), flushing (76% vs 6%, P=0.002), palpitations (59% vs 0%, P=0.004) all more common after CGRP
• ICP amplitude AUC−10min-90min significantly higher after CGRP (140.1 vs 60.6 cm H2O·min, P=0.005) with mean ICP unchanged
Clinical Question
Does intravenous CGRP provoke typical migraine-like headache attacks and alter intracranial pressure dynamics in patients with idiopathic intracranial hypertension who have no prior migraine history?
Bottom Line
IV CGRP triggered typical IIH headache attacks in 71% vs 18% with placebo (P=0.004) and increased ICP pulse amplitude without changing mean ICP, supporting a CGRP-mediated mechanism for IIH headache and justifying trials of CGRP-pathway blockade.
Major Points
- First human provocation trial testing CGRP as a trigger for IIH headache — 20-min CGRP infusion (1.5 μg/min) provoked typical IIH headache with migraine-like features in 71% of participants vs 18% with placebo (P=0.004).
- Novel finding: CGRP increased ICP pulse amplitude (measure of intracranial compliance) without changing mean ICP — links vascular signalling to symptom generation in a secondary headache disorder.
- Cerebrovascular signature matched prior migraine provocation studies: ↑ HR, ↑ oxygenated haemoglobin, ↑ tissue oxygenation, ↓ MAP, ↓ MCA velocity — consistent with vasodilation.
- Provides mechanistic rationale for prospective evaluation of CGRP monoclonal antibodies / gepants in IIH-related headache, an area with no approved targeted therapy.
- Small sample (n=17) at a single centre and women-only cohort limits generalisability; findings need replication and translation into a therapeutic trial.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, two-way crossover provocation trial
- Randomization
- Yes
- Blinding
- Double-blind (participant and investigators masked; independent CRF staff prepared/administered drug)
- Sample Size
- 20
- Follow-up
- 12 h post-infusion observation per visit; visits ≥6 days apart
- Centers
- 1
- Countries
- United Kingdom
Primary Outcome
Definition: Difference in proportion of participants developing a provoked IIH headache attack (with migraine-like features) during 12 h after infusion
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - | 0.004 |
Limitations & Criticisms
- Small single-centre sample (n=17 completers) and women-only cohort — replication in men and multi-centre samples needed.
- Selected participants with no prior migraine history to isolate IIH mechanism, which excludes the many IIH patients who have coexisting migraine and may most benefit from CGRP blockade.
- Provocation model demonstrates a causal signal but does not directly show that CGRP-pathway blockade prevents spontaneous IIH headache — therapeutic RCT still required.
- ICP monitoring only available in the 13 participants with in-situ telemetric shunts; ICP amplitude analyses based on n=8 per arm — modest precision.
- 12-hour observation may miss delayed effects, and participants were kept in a semi-recumbent position for the entire recording period, which may attenuate positional headache features.
Citation
Brain 2026;149(8):2629-2642