Aim Restlessness/agitation is a formal diagnostic feature of cluster headache (CH), but whether it is identified may depend on which attack-related behaviors are specifically asked about. We aimed to compare the proportions of participants meeting different behavior-based definitions of restlessness/agitation. We also examined whether participants reporting rolling/rocking on bed or floor without an urge to move, pacing/walking, or sitting restlessness had longer delay to first CH awareness. Methods We conducted a cross-sectional online survey with an embedded telephone validation substudy within the Chinese Online Registry for Cluster Headache, a patient-community registry in China. Adults with self-reported definite or suspected cluster headache were recruited from two long-standing WeChat patient-support communities in late 2025. After prespecified screening, quality-control procedures, and International Classification of Headache Disorders, 3rd edition (ICHD-3)-based case ascertainment, the final analytic cohort comprised 366 participants. Recognition delay was defined as the interval from first CH symptom onset to first CH awareness. Readily recognized restlessness/agitation comprised an urge to move, pacing/walking, or sitting restlessness; hidden supine-dominant restlessness/agitation comprised rolling/rocking on bed or floor in the absence of an urge to move, pacing/walking, or sitting restlessness. Together, these categories formed the primary behaviorally-anchored restlessness/agitation definition. Extreme self-directed attack-related behaviors were additionally included in a broader exploratory category. Among participants meeting the primary definition, multivariable median regression estimated the adjusted median difference in recognition delay between hidden supine-dominant and readily recognized restlessness/agitation. Results The proportion meeting the readily recognized definition was 202/366 (55.2%), compared with 279/366 (76.2%) under the primary behaviorally-anchored definition; the broader exploratory category included 305/366 participants (83.3%). Among participants meeting the primary behaviorally-anchored definition, hidden supine-dominant restlessness/agitation ( n = 77) was associated with longer recognition delay than readily recognized restlessness/agitation ( n = 202) before adjustment (median 9.0 vs 7.0 years; P = 0.006) and after adjustment (+3.40 years, 95% CI 1.86 to 4.94; P < 0.001). Among 56 interviewed participants eligible under the final cohort criteria, the positive predictive value for definite CH was 98.2% (55/56; 95% CI, 90.4–100.0). Conclusion In this online patient-community registry, asking specifically about rolling/rocking on bed or floor identified additional participants who did not report readily recognized components of restlessness/agitation. This response pattern was associated with longer recognition delay. For patients who lie down during an attack, clinicians should ask: “When you lie down during an attack, can you actually remain still?” The clinical value of this question should be evaluated prospectively in clinician-assessed cohorts.
Aim To report on the three-year safety, tolerability, clinical efficacy, and functional outcomes of atogepant for the preventive treatment of migraine from the phase 3, 156-week, open-label safety extension study in participants with chronic migraine (CM) or episodic migraine (EM) who had a prior inadequate response to two to four classes of conventional oral, non-migraine-specific preventive migraine treatments. Methods This was a 156-week, long-term, open-label extension (OLE) safety study in adult participants with either CM or EM who completed the lead-in PROGRESS or ELEVATE trials, respectively. The primary outcome was safety and tolerability of atogepant. Clinical efficacy and functional outcomes were prespecified exploratory analyses. Clinical efficacy endpoints were change from baseline (CFB) in mean monthly migraine days (MMDs), mean monthly headache days (MHDs), mean monthly acute medication use days, and responder rates (CFB ≥ 50%, ≥ 75% or 100% reduction in MMDs). Functional outcomes included CFB in Activity Impairment in Migraine-Diary domain score and Migraine-Specific Quality of Life Questionnaire version 2.1 for 156 weeks. All participants received atogepant 60 mg once daily. Results Of 596 participants, 595 (PROGRESS, N = 325; ELEVATE, N = 270) were treated and included in the safety population, and 529 (PROGRESS, N = 285; ELEVATE, N = 244) were included in the modified intention-to-treat population. The mean duration of atogepant exposure was 808.1 days. Overall, 63.2% (376/595) of participants completed the 3-year open-label treatment period. Treatment-emergent adverse events (TEAEs) occurred in 83.2% (495/595) of participants. Common TEAEs (≥ 10%) were COVID-19 (33.6%, 200/595) and nasopharyngitis (15.5%, 92/595). Serious TEAEs occurred in 8.7% (52/595) of participants, including one death attributed to asphyxia from a house fire, and none were related to atogepant. TEAEs leading to study treatment discontinuation occurred in 6.7% (40/595) of participants. Alanine aminotransferase/aspartate aminotransferase ≥ 3× the upper limit of normal occurred in three participants; none met Hy's Law. Improvements in clinical efficacy and functional outcomes observed during the lead-in studies were maintained through 156 weeks. Post-baseline potentially clinically significant (PCS) weight loss of ≥ 7% from lead-in study baseline at any visit was reported in 37.2% (220/592) of participants, whereas 16.7% (99/592) reported PCS weight gain of ≥ 7%. Conclusions In this 3-year OLE study, atogepant was safe and well tolerated over three years for the preventive treatment of migraine in participants with CM and EM who had prior inadequate response to two to four classes of conventional oral, non-migraine-specific preventive migraine treatments. Overall safety results were consistent with the known safety profile of atogepant. No new safety signals were identified. Improvements in clinical efficacy and functional outcomes were maintained through 156 weeks. Trial Registration ClinicalTrials.gov NCT04686136; EudraCT Identifier 2020-002470-27.
Background Traditionally, migraine has been characterized by its paroxysmal attacks, with the interictal phase considered to be a symptom-free interval. However, emerging evidence suggests that the “migraine brain” remains in a state of altered neuro-excitability and impaired habituation between attacks, manifesting as debilitating interictal symptoms. This narrative review aims to describe the spectrum of interictal symptoms, their underlying mechanisms, and their impact on the cumulative disease burden, at the same time as exploring the implications for clinical management. Methods An extensive literature search of the PubMed database was performed using terms related to the migraine cycle, interictal phase, and disease burden. Original articles published within the last 10 years were prioritized, focusing on clinical trials, real-world evidence, and neurophysiological studies. Results Interictal symptoms, including sensory hypersensitivity (photophobia, phonophobia, osmophobia, allodynia), cognitive dysfunction (“brain fog”), vestibular symptoms, and affective dysregulation, affect between 26% and 76% of patients. These symptoms significantly contribute to the socioeconomic burden of migraine, leading to substantial productivity losses (absenteeism and presenteeism) and reduced quality of life. While non-specific preventives often fail to alleviate interictal symptoms, calcitonin gene-related peptide-pathway targeted therapies and onabotulinumtoxinA have demonstrated promising results in reducing the interictal burden, as measured by standardized tools such as the Migraine Interictal Burden Scale (MIBS-4). Conclusions Migraine management requires a paradigm shift from focusing solely on attack frequency to a more holistic approach that includes the interictal period. Standardizing interictal symptoms definitions and implementing specific outcome measures in clinical practice are essential to restore full functional capacity and provide comprehensive care for patients.
