Abstract
Dear Editor-in-Chief,
We read with great interest the recent publication by Favrelière et al. on drug use in the context of reversible cerebral vasoconstriction syndrome (RCVS) (1). However, no comprehensive analysis of drug-induced RCVS has been conducted, with existing studies relying primarily on retrospective data (2). The study provides valuable insights by analyzing drug-induced RCVS cases from VigiBase, an international pharmacovigilance database. It focused on drugs already linked to RCVS and explored potential new associations, including 560 cases, primarily involving females (72.5%) aged 18 to 64. Notably, up to half of the drugs reported are recognized as predisposing factors for RCVS, including antidepressants, immunosuppressants, and vasoactive agents like triptans and nasal decongestants. Interestingly, most of reported drugs in this article (23 out of 24, 95.8%) were not flagged by the Food and Drug Administration (FDA) in post-marketing pharmacovigilance, contributing to under-recognition of the risk. Moreover, the European Medicines Agency (EMA) recently raised awareness of potential risks linked to nasal decongestants (3).
The spectrum of drug classes, patient characteristics, time to onset, and outcomes varied widely, underscoring the polymorphic nature of drug-induced RCVS and its diverse mechanisms. Selective serotonin reuptake inhibitor (SSRI) and triptans elevate serotonin levels, a key regulator of vascular tone. Nasal decongestants like pseudoephedrine and phenylephrine stimulate alpha-adrenergic receptors, leading to sympathetic hyperactivity and abnormal vascular response. Immunosuppressants such as tacrolimus and ciclosporin impair endothelial function through various mechanisms, further contributing to RCVS.
This study confirmed well-known associations between drug categories like vasoconstrictors and antidepressants with RCVS, but also identified signals in 14 other drugs through disproportionality analysis. While this method uncovers potential drug–adverse reaction associations, it does not establish causality, as noted by the authors, and further analysis is needed to confirm these findings. On the one hand, hormonal therapies such as anastrozole and leuprorelin may be linked to RCVS, aligning with previous reports associating hormonal imbalance with RCVS (4). On the other hand, drugs like erenumab—a Calcitonin Gene-Related Peptide (CGRP) antagonist—show findings inconsistent with current literature. Previous studies found increased miRNA expression related to CGRP levels in RCVS (5), which correlates with the higher prevalence of migraine sufferers in the RCVS population (2). Targeting the CGRP pathway may offer a novel therapeutic approach for RCVS.
This study highlights the wide variability in drug exposure timelines for drug-induced RCVS, raising questions about precipitating versus predisposing factors. While triptans and nasal decongestants are well-established iatrogenic causes of RCVS, retrospective cohorts strongly suggest that antidepressants and immunosuppressants may predispose individuals to RCVS development rather than directly cause it (2).
Most pharmacovigilance systems rely on spontaneous reporting, which generates a large volume of data and facilitates the early detection of common adverse drugs events. These systems are designed to capture detailed information on adverse drug reactions through focused data collection on treatment modalities. However, many healthcare professionals and patients may not report adverse events due to lack of awareness, time constraints, or uncertainty about drug-event relationships. RCVS exemplifies these limitations, as major pharmacovigilance systems failed to detect significant signals, despite several neurologists independently reporting similar clinical cases, eventually identifying a new disorder (2). Their publications, based on diverse patient populations, identified vasoconstrictive agents and antidepressants as the primary drug classes predisposing individuals to RCVS. This underscores the critical role of clinicians in detecting novel, previously unknown drug-related complications and raising alerts, even outside of formal pharmacovigilance systems, to expedite the dissemination of warning signals.
One critical issue not addressed in this article is the management of drug rechallenge in drug-induced RCVS. While most cases require discontinuation of the offending agent, there is currently no data on the safety of re-exposing patients to these drugs. Some agents, like nasal decongestants, have limited therapeutic value, whereas others, such as antidepressants, are essential treatments for the 3.8% of the population suffering from mood disorders. In such cases, the potential harm from re-exposure must be carefully weighed against therapeutic benefits, particularly in patients with other underlying conditions, such as migraine or depression. In absence of advice and given the unpredictable effects of rechallenge, some patients may be tempted to reintroduce these medications for practical reasons, such as lack of alternative therapies or rebound of their primary disease.
