Calcitonin Gene-Related Peptide (CGRP) Antibodies in Neuro Ophthalmology
Migraine can be a debilitating form of headache that can present with numerous neuro-ophthalmological symptoms, including photophobia, visual aura, visual hallucinations, illusions, distortions, and persistent positive visual phenomena. Migraine medications vary in side effect profile, cost, safety and efficacy. Current understanding of migraine pathophysiology continues to evolve and expand and with that new knowledge has come new therapies including the calcitonin gene-related peptide (CGRP) antagonists. This EyeWiki chapter summarizes the mechanism of action, indications, and side effect profile for CGRP antagonists in relation to neuro-ophthalmology.
Mechanism of Action
CGRP is a neuropeptide with an N-terminal disulfide bond and an amidated C-terminus that allows it to bind to its corresponding receptor. The CGRP receptor is a G-protein coupled receptor and consists of a calcitonin-like receptor, receptor activity-modifying protein 1, and receptor component protein.
The trigeminovascular system (TVS) is a key player in regulating cerebral vascular tone and controlling the transmission of sensory information. The TVS consists of the trigeminal nerve, spinal trigeminal nucleus, and cranial vessels. The corresponding neurons of the TVS express CGRP, while the intracranial vascular tissues express the CGRP receptors. The CGRP acts to vasodilate the cranial arterioles but not the venous sinuses. Thus, CGRP and TVS are important in maintaining cerebrovascular resting tone. Studies have shown that during migraines, there are increased levels of CGRP in the cranial but not peripheral circulation. Alternatively, trigeminal stimulation and the TVS increase CGRP levels. Several migraine treatments reduce CGRP levels and thus blocking or modulating CGRP may be a potential therapeutic target in migraine. Lassen et al. showed that injection of CGRP produced migraine symptoms in participating subjects.
CGRP helps produce migraines through cerebral vessel vasodilation, neurogenic inflammation, and nervous system sensitization. The adenylate cyclase pathway mediates CGRP’s vasodilatory action. CGRP contributes to neurogenic inflammation by activating the release of neurokinin A and substance P, which leads to plasma extravasation, and by interacting with glial and mast cells to release inflammatory agents. Lastly, CGRP produces central nervous system sensitization via cAMP cascade-dependent receptor phosphorylation, which increases postsynaptic neuron excitability. It produces peripheral nervous system sensitization by increasing gene expression of P2X3 and brain-derived neurotrophic factor, which increases nociceptive sensory transmission in trigeminal afferent nerves, resulting in greater pain sensation.
Recent advancements in migraine treatment development consist of antibodies against CGRP and CGRP receptors, which aim to block trigeminal nociceptive signaling and might treat both acute migraine symptoms and provide prophylactic protection. Erenumab is a humanized monoclonal antibody that acts as a competitive, reversible inhibitor by binding directly to the CGRP receptor. Eptinezumab, fremanezumab, and galcanezumab are similar antibodies for migraines that instead bind to the CGRP molecules. Collectively, these drugs are too large to cross the blood brain barrier, and thus they act peripherally. Administration of these antibodies is done parenterally because of poor bioavailability of these CGRP antagonists. These drugs also have half-lives ranging from weeks to months, which improves efficacy of migraine prevention and aids in patient compliance.
The American Academy of Neurology and the American Headache Society guidelines from 2012 for episodic migraine prevention in adults recommends several possible options (e.g., metoprolol, propranolol, timolol, divalproex sodium, sodium valproate, topiramate, and triptans). Side effects of these conventional migraine medications include increased rates of paresthesias, weight gain, cognitive impairment, fatigue, and gastrointestinal upset. In general, these medications are efficacious (defined by a 50% reduction of mean monthly attack frequency) in about 45% of patients.
When compared to some of these medications used for migraines, research suggests CGRP antibodies can be just as or even more effective. Deen et al. describes a few studies comparing these antibodies and placebos that have shown a 1 to 2.8 reduction in migraine days per month and 22.7 to 30.4 reduction in migraine hours per month in the CGRP antibody group. Wang et al. presents a meta-analysis showing similar and significant reduction in migraine days between the 4 drugs compared to placebo, with a similar side effect profile as the placebo.
Though CGRP is widely expressed throughout the peripheral and enteric nervous systems, the prevalence of adverse events is low, with those events only being mild to moderate in severity. CGRP antibodies are metabolized into peptides and single amino acids, thus reducing the risk of drug-to-drug interactions and hepatotoxicity. Due to CGRP’s vasodilatory mechanism, there is also the possible risk of complications in cardiovascular and cerebrovascular compromised patients. There is no data reporting this however, perhaps because of the drug’s relative infancy. Risk in pregnancy is unknown.
In summary, clinicians should be aware of the visual symptoms (e.g., migraine aura) and other neuro-ophthalmic presentations of migraine. Newer anti-migraine therapies including CGRP antibodies hold promise for novel and more effective treatments for this potentially debilitating condition. Although the precise mechanism of migraine remains incompletely understood, recent breakthrough work on CGRP has enhanced our understanding of migraine pathophysiologic pathways including the TVS. This work has led to the development of a promising new class of CGRP antibodies that may provide increased efficacy and safety over conventional pharmacotherapy for migraine. The European headache federation formulated a guideline on the use of CGRP antibodies for migraine prevention based on available evidence from a meta-analysis with the inclination that these medications can be recommended for patients with migraine but further studies are recommended, and some recommendations were based on expert opinion due to lacking data. There is much yet to be studied to formulate a robust start and stop criteria guideline for use of CGRP antibodies. Ophthalmologists should be aware of these newer agents for their patients with migraine.
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- Urits, I., Jones, M. R., Gress, K., Charipova, K., Fiocchi, J., Kaye, A. D., & Viswanath, O. (2019). CGRP Antagonists for the Treatment of Chronic Migraines: a Comprehensive Review. Current pain and headache reports, 23(5), 29. https://doi.org/10.1007/s11916-019-0768-y
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- Deen, M., Correnti, E., Kamm, K. et al. Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain 18, 96 (2017). https://doi.org/10.1186/s10194-017-0807-1
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- Wang, X., Chen, Y., Song, J., & You, C. (2021). Efficacy and Safety of Monoclonal Antibody Against Calcitonin Gene-Related Peptide or Its Receptor for Migraine: A Systematic Review and Network Meta-analysis. Frontiers in pharmacology, 12, 649143. https://doi.org/10.3389/fphar.2021.649143
- Simona Sacco, Lars Bendtsen, Messoud Ashina, Uwe Reuter, Gisela Terwindt, Dimos-Dimitrios Mitsikostas, and Paolo Martelletti. European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. J Headache Pain. 2019; 20(1): 6.doi: 10.1186/s10194-018-0955-y. PMID: 30651064. PMCID: PMC6734227
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