Hartmut Göbel

Background/Objectives: Nitric oxide (NO) donors reliably provoke cluster headache attacks in susceptible individuals, supporting an important role of NO signalling in cluster headache pathophysiology. Headache following accidental nitric acid inhalation has previously been reported; however, de novo chronic cluster headache following inhalational exposure to nitric acid and nitrogen oxides has not been described. We report a case in which the close temporal relationship and clinical circumstances raise the possibility of secondary headache attribution according to the principles of the International Classification of Headache Disorders, 3rd edition (ICHD-3). Methods: We describe the clinical course of a 54-year-old man without a previous history of cluster headache or comparable recurrent headache attacks who developed a novel headache immediately following occupational inhalational exposure involving nitric acid and nitrogen oxides. Clinical characteristics, temporal evolution, diagnostic findings and treatment response were evaluated according to ICHD-3 criteria and interpreted in the context of published evidence concerning nitric acid-induced headache and NO-provoked cluster headache. Results: Following the inhalational event in September 2024, a novel headache occurred immediately and subsequently evolved into a characteristic trigeminal autonomic cephalalgia. From December 2024 onward, the patient experienced 5–8 daily attacks of severe to very severe, strictly left-sided periorbital–temporal pain lasting 15–20 min, accompanied by ipsilateral lacrimation and marked restlessness. The disorder persisted without sustained remission for more than one year, fulfilling the phenotypic criteria of chronic cluster headache. Cranial magnetic resonance imaging revealed no structural cause. According to ICHD-3 attribution principles, the de novo onset in close temporal relation to an exposure capable of causing headache supports classification as secondary headache. This attribution is further supported biologically by the established ability of NO donors to provoke cluster headache attacks and activate trigeminovascular mechanisms. Conclusions: This case describes a de novo chronic cluster headache phenotype temporally associated with occupational inhalational exposure to nitric acid and nitrogen oxides. The temporal relationship and experimental evidence concerning TRPA1-mediated chemosensory activation, NO–cGMP signalling, CGRP release and trigeminovascular activation provide biological plausibility for a possible exposure-related association. However, neither a toxicological causal relationship nor the proposed transition to persistent trigeminal–autonomic sensitization can be established from this single case.

Background: CGRP contributes to cerebrovascular regulation, mainly based on experimental and translational data; human evidence remains limited. Gepants, including atogepant, are effective migraine preventives and achieve partial penetration across the blood–brain barrier. However, their neurologic and cerebrovascular safety in heterogeneous patient populations remains incompletely characterized. Objective: To describe acute neurologic events observed during atogepant therapy, provide contextual information regarding their baseline occurrence, and explore potential mechanisms by which CGRP receptor blockade may influence neurovascular resilience. Methods: We report five adults treated with atogepant (30–60 mg/day) who developed acute neurologic symptoms prompting emergency hospital admission. All patients underwent comprehensive diagnostic assessment including neuroimaging, vascular studies, cardiac evaluation, and laboratory testing. To provide context, a retrospective comparison cohort of migraine patients not treated with gepants during a similar period was analyzed. Baseline characteristics were summarized, and event occurrence was compared using Fisher’s exact test. Results: Among 575 individuals treated with atogepant, five experienced acute neurologic events, including one cerebellar infarction and several transient focal syndromes without structural correlates. No cerebrovascular events requiring hospitalization were identified in the non-gepant cohort (n = 610). In an unadjusted analysis, this difference was statistically significant (p = 0.027). The events were clinically heterogeneous, and several lacked radiologic confirmation of ischemia. Conventional vascular risk factors were present in some patients. Conclusions: These findings do not imply causality but raise the possibility that CGRP receptor blockade may reduce cerebrovascular adaptability in susceptible individuals. Clinicians should remain vigilant for ischemia or microvascular dysfunction when patients receiving atogepant present with acute vertigo, diplopia, ptosis, or hemisensory symptoms—even when CT and CTA are normal—and obtain timely MRI and vascular assessment. The absence of comparable events in a retrospective non-gepant cohort provides contextual information but does not permit inference regarding increased risk due to potential confounding and unmeasured factors. The findings are exploratory and hypothesis-generating, underscoring the need for prospective controlled studies to clarify the cerebrovascular safety of CGRP receptor antagonists in routine clinical practice.