Response to the Letter to the Editor: “Reaffirming Caution—The Unacceptable Vasoconstrictive Risk of CGRP-Related Therapies in Moyamoya Angiopathy” - Letter to the Editor

Sep 30, 2026

Response letter to the editor discussing headache management in Moyamoya angiopathy (MMA) and the concern over calcitonin gene–related peptide (CGRP)–targeted therapies. The authors agree that management should follow prudence, individualized assessment, and recognition of MMA’s hemodynamic fragility. They clarify their review did not encourage CGRP-targeted treatment in MMA, cite experimental data suggesting potentially worse infarction outcomes under CGRP receptor antagonism, and note that clinical trials typically excluded cerebrovascular disease with limited safety evidence for high-risk populations. Pending further data, anti-CGRP therapy is not recommended and decisions should rely on individualized multidisciplinary risk-benefit assessment.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages2

Reading Time5 min

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Letter to the Editor

Response and clarification on CGRP-targeted therapies in MMA

Evidence from experimental studies and clinical trial exclusions

Erenumab effects on cerebral hemodynamics

Conclusions and recommendation status

European Journal of Neurology LETTER TO THE EDITOR OPEN ACCESS Response to the Letter to the Editor: “Reaffirming Caution—The Unacceptable Vasoconstrictive Risk of CGRP-Related Therapies in Moyamoya Angiopathy” Nicola Rifino1 | Anne Hege Aamodt2 | Markus Wiedmann3 | Markus Kramer4 | Jana Becker4 | Stéphanie Guey5 | Francesco Acerbi6 | Dominique Herve5 | Anna Bersano1 1Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy | 2Department of Neurology, Oslo University Hospital, Oslo, Norway | 3Department of Neurosurgery, Oslo University Hospital, Oslo, Norway | 4Department of Neurology, Alfried Krupp Hospital, Essen, Germany | 5CNVT-CERVCO et département de Neurologie, Hôpital Lariboisière, APHP Nord, Paris, France | 6Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Correspondence: Nicola Rifino (nicola.rifino@istituto-besta.it) Received: 12 November 2025 | Revised: 12 November 2025 | Accepted: 4 December 2025 Dear Editor, We thank Drs. Gaul and Naegel for their thoughtful comments on our recent consensus review addressing the spectrum of headaches in Moyamoya angiopathy (MMA) . We fully agree that the management of headache in this rare and complex cerebrovascular disorder should be guided by prudence, individualized assessment, and a deep understanding of the disease's unique hemodynamic fragility. As the authors rightly emphasize, MMA represents a condition in which cerebral perfusion critically depends on compensatory vasodilatory mechanisms that may be highly sensitive topharmacological modulation [1] . From this perspective, any therapeutic approach acting on vascular tone requires careful consideration, especially when its vascular effects are incompletely understood in such a context. We would like to clarify that our review did not suggest or encourage the use of calcitonin gene–related peptide (CGRP)–targeted therapies in patients with MMA. Our intention was indeed to acknowledge their relevance in the broader landscape of migraine management, while underscoring that, in the specific setting of MMA, the absence of clinical data and the theoretical implications on cerebrovascular autoregulation call for particular caution. In fact, as also mentioned by Drs. Gaul and Naegel, the study by Mulder and colleagues [2] provides relevant experimental evidence in this regard. In their murine model of middle cerebral artery occlusion, the authors demonstrated that exposure to small-molecule CGRP receptor antagonists led to higher rates of cerebral infarction compared with placebo and resulted in larger infarct volumes with longer durations of occlusion. These findings suggest that while CGRP receptor blockade may not independently induce ischemic events, it could potentially exacerbate outcomes when cerebral perfusion is already compromised. For this reason, pivotal clinical trials of anti-CGRP therapies systematically excluded patients with cerebrovascular disease, and post-marketing surveillance has identified occasional cardiovascular adverse events [3, 4] . On the other hand, to thoroughly examine the effect of erenumab on cerebral hemodynamics, one study evaluated cerebral vasomotor reactivity and endothelial function in 60 patients with migraine without aura [5] . The findings revealed no significant alterations following treatment, indicating that in certain contexts, anti-CGRP antibodies preserve cerebral vasomotor reactivity in migraineurs without aura. Moreover, current evidence from large randomized controlled trials does not indicate an increased risk of stroke associated with CGRP-targeted therapies, but data regarding their safety in individuals with preexisting cerebrovascular or cardiovascular disease remain very limited [6] . This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original w

FAQs

What position do the authors take regarding CGRP-targeted therapies in patients with Moyamoya angiopathy (MMA)?

The authors clarify that their review did not suggest or encourage CGRP-targeted therapies in MMA. Until stronger evidence is available, anti-CGRP therapies cannot be recommended for this population.

What experimental findings are cited to support caution with CGRP receptor blockade in MMA-related contexts?

In a murine model of middle cerebral artery occlusion, small-molecule CGRP receptor antagonists were associated with higher cerebral infarction rates and larger infarct volumes with longer occlusion duration compared with placebo.

How do the authors describe evidence on anti-CGRP therapies and stroke risk?

The letter states that large randomized trials do not indicate an increased stroke risk overall, but safety data for individuals with preexisting cerebrovascular or cardiovascular disease remain very limited.

Sep 30, 2026

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