LAUSR

Migraine is a complex neurological disorder whose biologic underpinnings have not been completely unravelled [1]. The trigeminovascular system (TVS) is the main mediator of pain generation in migraine and its activation usually follows a cortical spreading depression (CSD) in migraine with aura patients [1]. Calcitonin gene-related peptide (CGRP) is pivotal in TVS response and likely plays a role in the sensitisation process that leads to chronification of migraine [2]. Anti-CGRP molecules have recently proven their efficacy in both episodic and chronic migraine [3], while their action in migraine aura and CSD has been poorly investigated so far. We report a 42-year-old man with a history of chronic migraine with visual aura who presented at our Headache Centre for a second opinion. Notably, preceding each headache attack, the patient invariably experienced a visual aura consisting of “flashing lights” that spread throughout one visual field over ~ 15 min and resolved completely within 60 min. Since migraine frequency had been increasing over time, several prophylactic agents were tried, including verapamil, propranolol, flunarizine, topiramate, valproate acid, lamotrigine, amitriptyline, and botulinum toxin. Most of the aforementioned therapies were either ineffective or poorly tolerated. Lamotrigine successfully decreased aura frequency, without affecting headache recurrence; it was eventually withdrawn because the patient preferred to be forewarned by aura, to promptly take the analgesics and, therefore, experience a milder pain. At the time of consultation, the patient reported on average 15–20 attacks of migraine with aura per month that he used to treat with a combination of non-steroidal anti-inflammatory drugs and triptans. He reported no significant comorbidities. Patent foramen ovale had been excluded. A brain MRI comprehensive of vessel study and the neurological examination were unrevealing. Since the patient was refractory to multiple pharmacological preventive therapies, we started an antiCGRP receptor monoclonal antibody therapy with erenumab (70 mg subcutaneously monthly). After the first dose, both migraine and aura frequency dramatically dropped to maximum one attack per month, with persistent efficacy after one year, when erenumab was stopped. Migraine with aura attacks relapsed one month after the last injection, returning to the pre-treatment frequency. Our patient suffered from chronic migraine with aura which was refractory to various pharmacological treatments. Migraine aura and migraine pain represent different phases of a migraine attack and they have different pathophysiological mechanisms. Indeed, treatments with evidence of benefit in migraine with aura, such as lamotrigine [4], are utterly different from classic pain-relief and prophylactic interventions indicated for migraine without aura [5]. Response limited to aura symptoms was observed in our patient during lamotrigine. This may be related to its specific action on ion channels that might have lowered CSD intensity enough to make it clinically silent without preventing activation of TVS, resulting in headache persistence. Differently, we observed an immediate and persistent response to erenumab, both on aura and migraine pain. While the latter was predictable given erenumab’s mechanism of action, the former may suggest an extension of CGRP sensitisation beyond the pain-related structures in the brainstem, involving the CSD generator that is postulated to be in the brainstem itself. An alternative explanation is that CGRP may be involved directly in CSD generation, since it has been demonstrated that acting on the trigeminal ganglion, which is rich in CGRP-expressing neurons, is effective in reducing aura frequency [6], and that CGRP antagonism is able to modulate CSD in vitro and in vivo animal experiments [7]. Eleonora Matteo and Umberto Pensato contributed equally to this work.