Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.

Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world.

BACKGROUND: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. METHODS: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. RESULTS: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. CONCLUSIONS: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.

Improvement of migraine depressive symptoms is not related to headache frequency: exploring the impact of anti-CGRP therapies.

BACKGROUND: The present study aimed to describe the prevalence and evolution of depressive symptoms in a cohort of migraine patients treated with anti-CGRP monoclonal antibodies. METHODS: This is an exploratory, prospective, unicentric, one-year longitudinal study. We included migraine patients who started treatment with anti-CGRP monoclonal antibodies. Baseline demographic data, medical history, concomitant medication and migraine characteristics were collected. The presence of depressive symptoms was evaluated using the Beck Depression Inventory-II quarterly and treatment response was categorized according to the reduction in monthly headache days. A generalized mixed-effect regression model was used to model depression score over a one-year treatment taking into account frequency response rates. RESULTS: We included 577 patients: 84.2% females; median (range) age 47.0 (39.0-53.0) years, 46.1% (266/577) of them presented depressive symptoms at baseline (16.1% mild, 13.3% moderate and 16.6% severe). After six-month treatment, 47.4% (126/266) reduced headache frequency ≥50% after one year and 63.5% (169/266) achieved a clinically significant improvement in depression symptoms. We observed a 30.8% (-50.0%, -3.2%) main reduction in depression score during the first quarter. The improvement in depression symptoms was independently associated with headache frequency response: non-responders, -25.0% (-43.9%, -1.1%); partial responders, -30.2% (-51.3%, -7.6%); and good responders, -33.3% (-54.6%, -7.5%). CONCLUSIONS: Anti-CGRP monoclonal antibodies targeting CGRP are effective in reducing depressive symptoms in patients with migraine. The main change of depression score happens during the first three months of treatment. The reduction in depressive symptoms is independent of migraine frequency improvement.

Quantifying sensory thresholds along the migraine cycle: An exploratory longitudinal study.

BACKGROUND: To date, a number of studies on migraine have cross-sectionally evaluated sensory sensitivity with aversion thresholds/scores along the migraine cycle, reporting a decreased tolerance to sensory stimuli in different sensory modalities. Our hypothesis was that patients with migraine would exhibit heightened sensitivity to sound, light, touch and smell on days where they reported greater headache intensity. METHODS: This is an exploratory, longitudinal study, carried out over the course of 27 days. Aversion thresholds or scores to sound, light, touch and smell were quantified in six patients with migraine (11.33 ± 6.53 headache days/month). RESULTS: Patients reported an increased sensitivity to light (padj = 0.0297), touch (padj = 0.0077), and smell (padj = 0.0201) on days with higher headache intensity. However, a greater sensitivity to sound on days with higher headache intensity was only reported when anxiety levels were high (padj = 1.4e-06). Interestingly, variable levels of tolerance to bothersome light over time can also influence the correlation between light sensitivity and headache intensity (padj = 1.4e-06). CONCLUSIONS: Based on the present findings, future longitudinal studies evaluating sensory threshold changes along the migraine cycle in patients with migraine should account for the increased tolerance to bothersome light over time as well as the effect of anxiety on auditory sensitivity.

Dynamic fluctuations of salivary CGRP levels during migraine attacks: association with clinical variables and phenotypic characterization.

BACKGROUND: Migraine is a complex neurological disorder with significant heterogeneity in its clinical presentation and molecular mechanisms. Calcitonin gene-related peptide (CGRP) has emerged as a key player in migraine pathophysiology, but challenges remain in its utilization as a biomarker. This study aimed to investigate salivary CGRP levels during migraine attacks across the frequency spectrum and explore associations with clinical variables. METHODS: A prospective longitudinal pilot study was conducted, recruiting migraine patients from an outpatient headache clinic. Salivary CGRP levels were measured at interictal, onset, post-2 h of onset and end-of-attack. Using generalized linear mixed models, we explored the effect of CGRP changes over the attack in presence of depressive symptoms (DS), acute attack treatment, and after three-months of erenumab treatment. Finally, patients were classified and compared according to their CGRP phenotype. RESULTS: A total of 44 migraine patients were included (90.9% women), with 80 migraine attacks analyzed. Salivary CGRP levels increased at the onset of migraine attacks. We observed statistically significant interactions between DS and both the linear (Est. [SE]: 19.4 [5.8], p = 0.001) and quadratic terms of time (-19.1 [6.0], p = 0.002). Additionally, a significant three-way interaction within the use of acute treated attack (linear-term: -18.5 [6.2], p = 0.005; quadratic-term: 19.2 [6.8], p = 0.005) was also found. Molecular phenotyping revealed that 72.7% (32/44) of patients presented only CGRP-dependent attacks, while 27.3% (12/44) presented non-CGRP-dependent migraine attacks. Patients with only CGRP-dependent attacks were associated with younger age, shorter disease evolution time, a higher proportion of aura, and fewer monthly headache days (p < 0.05). Exploratory analysis of erenumab treatment effects did not result in changes in CGRP levels during migraine attacks. CONCLUSIONS: Our study underscores the dynamic nature of migraine at a molecular level and emphasizes the importance of integrating clinical variables, such as depressive symptoms, in understanding its pathophysiology. The identification of distinct migraine subtypes based on CGRP dependence suggests potential opportunities for personalized treatment approaches.

Early and annual projected savings from anti-CGRP monoclonal antibodies in migraine prevention: a cost-benefit analysis in the working-age population.

BACKGROUND: Migraine is one of the main causes of disability worldwide. Anti-CGRP monoclonal antibodies (MAbs) have proven to be safe and efficacious as preventive migraine treatments. However, their use is restricted in many countries due to their apparently high cost. Cost-benefit studies are needed. OBJECTIVE: To study the cost-benefit of anti-CGRP MAbs in working-age patients with migraine. METHODS: This is a prospective cohort study of consecutive migraine patients treated with anti-CGRP MAbs (erenumab, fremanezumab and galcanezumab) following National reimbursement policy in a specialized headache clinic. Migraine characteristics and the work impact scale (WPAI) were compared between baseline (M0) and after 3 (M3) and 6 months (M6) of treatment. Using WPAI and the municipal average hourly wage, we calculated indirect costs (absenteeism and presenteeism) at each time point. Direct costs (emergency visits, acute medication use) were also analysed. A cost-benefit study was performed considering the different costs and savings of treating with MAbs. Based on these data an annual projection was conducted. RESULTS: From 256 treated working-age patients, 148 were employed (89.2% women; mean age 48.0 ± 8.5 years), of which 41.2% (61/148) were responders (> 50% reduction in monthly headache days (MHD)). Statistically significant reductions between M0 and M3/M6 were found in absenteeism (p < 0.001) and presenteeism (p < 0.001). Average savings in indirect costs per patient at M3 were absenteeism 105.4 euros/month and presenteeism 394.3 euros/month, similar for M6. Considering the monthly cost of anti-CGRP MAbs, the cost-benefit analysis showed savings of 159.8 euros per patient at M3, with an annual projected savings of 639.2 euros/patient. Both responders and partial responders (30-50% reduction in MHD) presented a positive cost-benefit balance. The overall savings of the cohort at M3/M6 compensated the negative cost-benefit balance for non-responders (< 30% reduction in MHD). CONCLUSION: Anti-CGRP MAbs have a positive impact in the workforce significantly reducing absenteeism and presenteeism. In Spain, this benefit overcomes the expenses derived from their use already at 3 months and is potentially sustainable at longer term; also in patients who are only partial responders, prompting reconsideration of current reimbursement criteria and motivating the extension of similar cost-benefit studies in other countries.

Salivary CGRP and Erenumab Treatment Response: Towards Precision Medicine in Migraine.

OBJECTIVE: We aimed (1) to analyze salivary calcitonin gene-related peptide (CGRP) levels in patients with migraine, (2) to predict erenumab response from baseline CGRP levels, and (3) to evaluate CGRP change post-treatment. METHODS: This is a prospective observational study that measured salivary CGRP levels in healthy controls (HCs), patients with episodic migraine (EM) and patients with chronic migraine (CM). Participants collected saliva samples at baseline and, the patients who were candidates to receive erenumab, also collected saliva after 3 doses of treatment. We quantified CGRP-like immunoreactivity (CGRP-LI) by enzyme-linked immunosorbent assay (ELISA) and we performed an analysis at baseline and post-treatment through generalized linear mixed models. RESULTS: At baseline, a higher headache frequency was associated with higher CGRP levels, those being even higher in the presence of depressive symptoms. A cutoff point (mean, 95% confidence interval [CI]) of 103.93 (95% CI = 103.35-104.51) pg/ml was estimated to differentiate migraine from controls with an area under the receiver operating characteristic (ROC) curve (AUC, 95% CI) of 0.801 (95% CI = 0.798-0.804). We also found that higher pretreatment salivary CGRP levels were statistically significantly associated to a higher probability of having 50% or greater reduction in headache frequency in patients with EM, but not in patients with CM. After 12 weeks of treatment with erenumab, salivary CGRP levels from patients within all spectrum of migraine frequency converged to similar CGRP values. In contrast, in patients with concomitant depressive symptoms, this convergence did not happen. INTERPRETATION: Patients with migraine not only have higher CGRP levels compared with HCs, but also the presence of depressive symptoms seems to increase salivary CGRP levels and we have evidence, for the first time, that baseline salivary CGRP concentration is associated with treatment response to erenumab. ANN NEUROL 2022;92:846-859.

The impact of epigenetic mechanisms in migraine: Current knowledge and future directions.

BACKGROUND: Epigenetic mechanisms, including DNA methylation, microRNAs and histone modifications, may modulate the genetic expression in migraine and its interaction with internal and external factors, such as lifestyle and environmental changes. OBJECTIVE: To summarize, contextualize and critically analyze the published literature on the current state of epigenetic mechanisms in migraine in a narrative review. FINDINGS: The studies published to date have used different approaches and methodologies to determine the role of epigenetic mechanisms in migraine. Epigenetic changes seem to be involved in migraine and are increasing our knowledge of the disease. CONCLUSIONS: Changes in DNA methylation, microRNA expression and histone modifications could be utilized as biomarkers that would be highly valuable for patient stratification, molecular diagnosis, and precision medicine in migraine.

Patterns of response to anti-calcitonin gene-related peptide monoclonal antibodies during first 6 months of treatment in resistant migraine patients: Impact on outcome.

BACKGROUND AND PURPOSE: The response pattern to monoclonal antibodies against calcitonin gene-related peptide (anti-CGRP MAbs) shown in migraine prevention clinical trials is not always reproducible at an individual level. This study was undertaken to describe patterns of start and consistency of the response to anti-CGRP MAbs during the first 6 months of treatment and the association with baseline clinical characteristics. METHODS: This is a prospective clinical cohort observational study. We included migraine patients treated with erenumab or galcanezumab evaluated at baseline and after 3 and 6 months (M3, M6) of treatment. The response was categorized according to reduction in monthly headache days (MHD): Sustained-response (SustainedR, ≥50% at M3 and M6), Short-Response (ShortR, M3 ≥50% and M6 <50%), Late-Response (LateR, M3 <50% and M6 ≥50%), Limited-Response (LimitedR, 25%-50% at M3 and M6), and No-Response (NoR, <25% at M3 and M6). Response patterns were compared at baseline and with outcome variables at M3 and M6. RESULTS: We included 357 patients with a headache frequency of 21.0 (interquartile range = 16.0-28.0) MHD, and 84.0% (300/357) were chronic migraine. The distribution according to response pattern was 37.0% (110/297) SustainedR, 16.8% (50/297) LateR, 10.4% (31/297) ShortR, 22.6% (67/297) LimitedR, and 13.1% NoR (39/297). The SustainedR and LateR groups showed statistically significant anxiety and depression score reduction at M3 and M6 compared to the other groups. CONCLUSIONS: Initial response to anti-CGRP MAbs is not consistent in all patients. Persistence of anxiety and depression might be associated with lower response rates at M6.

Migraine worsening after COVID-19 and COVID-19 vaccination: Are we facing a nocebo effect?

BACKGROUND AND PURPOSE: In clinical practice patients may report migraine worsening as a consequence of COVID-19 (either infection or vaccines), however, data in this area are lacking. We aimed to investigate the link between COVID-19 and COVID-19 vaccination with migraine worsening and its associated factors. METHODS: An online survey was sent to migraine patients followed up in a Spanish Headache Clinic, collecting demographic data, and information regarding SARS-CoV-2 infection and vaccination. We asked patients if they had noticed worsening of their migraine after these events and assessed concerns about infection, vaccination and migraine worsening. We also extracted data from participants' own electronic diaries (e-diaries), including 1-month data before and after their reported infection and/or vaccination. We compared participants who self-reported migraine worsening since infection or vaccination with those who did not. RESULTS: Of 550 participants, 44.9% (247/550) reported having had COVID-19 at least once and 83.3% (458/550) had been vaccinated. Sixty-one patients reported migraine worsening since COVID-19 and 52 since the vaccination. Among the risk factors for perceived migraine worsening in the two settings (infection and vaccination) was concern about migraine worsening itself (infection: odds ratio [OR] 2.498 [95% CI: 1.02-6.273], p = 0.046; vaccination: OR 17.3 [95% CI: confidence interval 5.3-68], p < 0.001). e-diary information was available for 136 of the 550 patients, 38.2% (52/136) for COVID-19 and 39.7% (54/136) for vaccination. We observed no significant difference in headache frequency 1 month before and after infection or vaccination, even when comparing patients with and without self-reported migraine worsening. CONCLUSIONS: Our preliminary data point to a negligible role of the infection and vaccination on migraine worsening and to the possible presence of a nocebo effect in these settings, as a remarkable proportion of patients had a clear perception of migraine worsening.

The Role of Glial Cells in Different Phases of Migraine: Lessons from Preclinical Studies.

Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the neuropeptide calcitonin gene-related peptide to migraine pathophysiology, but the mechanisms underlying its pathogenesis and chronification remain unknown. Glial cells are essential for the correct development and functioning of the nervous system and, due to its implication in neurological diseases, have been hypothesised to have a role in migraine. Here we provide a narrative review of the role of glia in different phases of migraine through the analysis of preclinical studies. Current evidence shows that astrocytes and microglia are involved in the initiation and propagation of cortical spreading depolarization, the neurophysiological correlate of migraine aura. Furthermore, satellite glial cells within the trigeminal ganglia are implicated in the initiation and maintenance of orofacial pain, suggesting a role in the headache phase of migraine. Moreover, microglia in the trigeminocervical complex are involved in central sensitization, suggesting a role in chronic migraine. Taken altogether, glial cells have emerged as key players in migraine pathogenesis and chronification and future therapeutic strategies could be focused on targeting them to reduce the burden of migraine.

Exploring sensory sensitivity, cortical excitability, and habituation in episodic migraine, as a function of age and disease severity, using the pattern-reversal task.

BACKGROUND: Migraine is a cyclic, neurosensory disorder characterized by recurrent headaches and altered sensory processing. The latter is manifested in hypersensitivity to visual stimuli, measured with questionnaires and sensory thresholds, as well as in abnormal cortical excitability and a lack of habituation, assessed with visual evoked potentials elicited by pattern-reversal stimulation. Here, the goal was to determine whether factors such as age and/or disease severity may exert a modulatory influence on sensory sensitivity, cortical excitability, and habituation. METHODS: Two similar experiments were carried out, the first comparing 24 young, episodic migraine patients and 28 healthy age- and gender-matched controls and the second 36 middle-aged, episodic migraine patients and 30 healthy age- and gender-matched controls. A neurologist confirmed the diagnoses. Migraine phases were obtained using eDiaries. Sensory sensitivity was assessed with the Sensory Perception Quotient and group comparisons were carried out. We obtained pattern-reversal visual evoked potentials and calculated the N1-P1 Peak-to-Peak amplitude. Two linear mixed-effects models were fitted to these data. The first model had Block (first block, last block) and Group (patients, controls) as fixed factors, whereas the second model had Trial (all trials) and Group as fixed factors. Participant was included as a random factor in both. N1-P1 first block amplitude was used to assess cortical excitability and habituation was defined as a decrease of N1-P1 amplitude across Blocks/Trials. Both experiments were performed interictally. RESULTS: The final samples consisted of 18 patients with episodic migraine and 27 headache-free controls (first experiment) and 19 patients and 29 controls (second experiment). In both experiments, patients reported increased visual hypersensitivity on the Sensory Perception Quotient as compared to controls. Regarding N1-P1 peak-to-peak data, there was no main effect of Group, indicating no differences in cortical excitability between groups. Finally, significant main effects of both Block and Trial were found indicating habituation in both groups, regardless of age and headache frequency. CONCLUSIONS: The results of this study yielded evidence for significant hypersensitivity in patients but no significant differences in either habituation or cortical excitability, as compared to headache-free controls. Although the alterations in patients may be less pronounced than originally anticipated they demonstrate the need for the definition and standardization of optimal methodological parameters.

Salivary CGRP can monitor the different migraine phases: CGRP (in)dependent attacks.

BACKGROUND: CGRP plays a key role in the transmission and modulation of nociceptive signals and is a critical component in the pathogenesis of migraine. OBJECTIVE: To assess saliva as a substrate to measure CGRP by comparing interictal levels in patients with episodic migraine and controls; and to evaluate CGRP's temporal profile during migraine attacks. METHODS: This prospective observational pilot study included young women with episodic migraine and healthy controls. We monitored salivary CGRP-like immunoreactivity (CGRP-LI) during 30 consecutive days and during migraine attacks. We considered six timepoints for the analysis: interictal (72h headache free), preictal (PRE-24h before the attack), ictal (headache onset, after 2h, after 8h), postictal (POST-24h after the attack). CGRP levels were quantified by ELISA. RESULTS: 44 women (22 with episodic migraine, 22 healthy controls) were recruited. Differences in interictal salivary levels of CGRP between patients and controls (Me [IQR]: 98.0 [80.3] (95% CI 56.6, 124.0) vs. 54.3 [44.0] (95% CI 42.2, 70.1) pg/mL, p = 0.034) were found. An increase in CGRP levels during migraine attacks was detected (pre:169.0 [95% CI 104.2-234.0]; headache onset: 247.0 [181.9-312.0]; after 2h: 143.0 [77.6-208.0]; after 8h: 169.0 [103.5-234.0], post: 173.0 [107.8-238.0]). Patients were classified as having CGRP-dependent (79.6%) and non-CGRP dependent migraine attacks (20.4%) according to the magnitude of change between preictal and ictal phase. Accompanying symptoms such as photophobia and phonophobia were significantly associated to the first group. CONCLUSIONS: Salivary CGRP-LI levels, which interictally are elevated in episodic migraine patients, usually increase during a migraine attack in the majority of patients. However, not every attack is CGRP-dependent, which in turn, might explain different underlying pathophysiology and response to treatment.

Avoidance behaviour modulates but does not condition phonophobia in migraine.

BACKGROUND: Past studies do not account for avoidance behaviour in migraine as a potential confounder of phonophobia. OBJECTIVE: To analyse whether phonophobia is partially driven by avoidance behaviour when using the classic methodology (method of limits). METHODS: This is a case-control study where we tested phonophobia in a cohort of high-frequency/chronic migraine patients (15.5 ± 0.74 headache days/month) and non-headache controls. Auditory stimuli, delivered in both ears, were presented using three different paradigms: the method of limits, the method of constant stimuli, and the adaptive method. Participants were asked to report how bothersome each tone was until a sound aversion threshold was estimated for each method. RESULTS: In this study, we successfully replicate previously reported reduction in sound aversion threshold using three different methods in a group of 35 patients and 25 controls (p < 0.0001). Avoidance behaviour in migraine reduced sound aversion threshold in the method of limits (p = 0.0002) and the adaptive method (p < 0.0001) when compared to the method of constant stimuli. While thresholds in controls remained the same across methods (method of limits, p = 0.9877 and adaptive method, p = 1). CONCLUSION: Avoidance behaviour can exacerbate phonophobia. The current methodology to measure phonophobia needs to be revised.

Post-COVID-19 persistent headache: A multicentric 9-months follow-up study of 905 patients.

BACKGROUND: Headache is a frequent symptoms of coronavirus disease 2019 (COVID-19). Its long-term evolution remains unknown. We aim to evaluate the long-term duration of headache in patients that presented headache during the acute phase of COVID-19. METHODS: This is a post-hoc multicenter ambisective study including patients from six different third-level hospitals between 1 March and 27 April 2020. Patients completed 9 months of neurological follow-up. RESULTS: We included 905 patients. Their median age was 51 (IQR 45-65), 66.5% were female, and 52.7% had a prior history of primary headache. The median duration of headache was 14 (6-39) days; however, the headache persisted after 3 months in 19.0% (95% CI: 16.5-21.8%) and after 9 months in 16.0% (95% confidence interval: 13.7-18.7%). Headache intensity during the acute phase was associated with a more prolonged duration of headache (Hazard ratio 0.655; 95% confidence interval: 0.582-0.737). CONCLUSION: The median duration of headache was 2 weeks, but in approximately a fifth of patients it became persistent and followed a chronic daily pattern.

The relationship of headache as a symptom to COVID-19 survival: A systematic review and meta-analysis of survival of 43,169 inpatients with COVID-19.

OBJECTIVE: To study the relationship between coronavirus disease 2019 (COVID-19) mortality and headache among patients evaluated for COVID-19 in Emergency Departments and hospitals. BACKGROUND: COVID-19 has disparate impacts on those who contract it. Headache, a COVID-19 symptom, has been associated with positive disease prognosis. We sought to determine whether headache is associated with relative risk of COVID-19 survival. METHODS: A systematic search in PubMed was performed independently by three reviewers to identify all COVID-19 clinical inpatient series in accordance with the PRISMA guideline. Studies were included if the study design, COVID-19 confirmation method, disease survival ratio, and presence of headache symptom were accessible. We included 48 cohort studies with a total of 43,169 inpatients with COVID-19: 81.4% survived (35,132/43,169) versus 18.6% non-survived (8037/43,169). A meta-analysis of the included studies was then performed. The study was registered on PROSPERO (ID: CRD42021260151). RESULTS: When considering headache as a symptom of COVID-19, we observed a significantly higher survival rate (risk ratio: 1.90 [1.46, 2.47], p < 0.0001) among COVID-19 inpatients with headache compared to those without headache. CONCLUSION: Headache among patients with COVID-19 presenting to hospitals may be a marker of host processes which enhance COVID-19 survival. Future studies should further confirm these findings, in order to better understand this relation and to try to address possible limitations related to the inclusion of more severe patients who would be unable to report symptoms (e.g., patients who were intubated).

Neurophysiological correlates of abnormal auditory processing in episodic migraine during the interictal period.

BACKGROUND: The characteristics of the hypersensitivity to auditory stimuli during the interictal period in episodic migraine are discussed. The combined use of event-related potentials, time-frequency power and phase-synchronization can provide relevant information about the time-course of sensory-attentional processing in migraine and its underlying mechanisms. OBJECTIVE: The aim of this nested case-control study was to examine these processes in young, female, episodic migraine patients interictally and compare them to controls using an active auditory oddball task. METHOD: We recorded, using 20 channels, the electrophysiological brain activity of 21 women with episodic migraine without aura and 21 healthy matched controls without family history of migraine, during a novelty oddball paradigm. We collected sociodemographic and clinical data as well as scores related to disability, quality of life, anxiety and depression. We calculated behavioural measures including reaction times, hit rates and false alarms. Spectral power and phase-synchronization of oscillatory activity as well as event-related potentials were obtained for standard stimuli. For target and novel stimuli, event-related potentials were acquired. RESULTS: There were no significant differences at the behavioural level. In migraine patients, we found an increased phase-synchronization at the theta frequency range and a higher N1 response to standard trials. No differences were observed in spectral power. No evidence for a lack of habituation in any of the measures was seen between migraine patients and controls. The Reorienting Negativity was reduced in migraine patients as compared to controls on novel but not on target trials. CONCLUSION: Our findings suggest that migraine patients process stimuli as more salient, seem to allocate more of their attentional resources to their surrounding environment, and have less available resources to reorient attention back to the main task.

Partial and nonresponders to onabotulinumtoxinA can benefit from anti-CGRP monoclonal antibodies preventive treatment: A real-world evidence study.

BACKGROUND AND PURPOSE: Monoclonal antibodies targeting CGRP or its receptor, anti-CGRP mAbs, are proven to be effective treatments in migraine prevention. Real-world evidence studies assessing their efficacy are scarce. METHODS: Our objective was to assess the efficacy of anti-CGRP mAbs in our clinical cohort resistant to onabotulinumtoxinA. We prospectively analyzed ≥50% response rate in patients who initiated treatment with anti-CGRP mAbs and who were partial or nonresponders to onabotulinumtoxinA. RESULTS: One hundred fifty-five patients completed treatment with anti-CGRP mAbs at 3 months of follow-up. No statistically significant differences were found in ≥50% response in headache frequency in patients with prior onabotulinumtoxinA treatment partial or complete failure. Regarding dual therapy with onabotulinumtoxinA and anti-CGRP mAbs, no statistically significant differences were found in ≥50% response in headache frequency between monotherapy or dual therapy. CONCLUSIONS: Patients with prior treatment failure or partial efficacy to onabotulinumtoxinA respond to anti-CGRP mAbs. After 3 months, in our cohort, dual therapy does not seem to add more benefit than anti-CGRP mAbs in monotherapy.

The impact of a digital platform on migraine patient-centered outcome research. Evaluation of midolordecabeza.org, a headache website in Spanish.

OBJECTIVE: This internet survey aimed to analyze the activity of midolordecabeza.org, a specialized website for headache stakeholders. BACKGROUND: eHealth tools, such as websites, can be educational for stakeholders of a specific disease, such as patients. This is particularly helpful in chronic disorders such as migraine. eHealth also enhances patient-centered outcome research. The website midolordecabeza.org has the stated aim of organizing key information on headache making it accessible and useful for all stakeholders, and, eventually promoting patient participation. METHODS: We analyzed Google Analytics (GA) data to study the web's activity, traffic source, geographical distribution of access, registered-user behavior, electronic device performance, and temporary references with greater web activity. RESULTS: From January 2015 until December 2020, the website registered 1,121,585 visitors, 1,775,953 sessions, and a total of 3,833,144 views with an average time per session of nearly 2 min. Higher data traffic has been registered in Spanish-speaking countries such as Spain (33.3%; 591,256/1,775,953), where Spain's regions with higher views were statistically significantly correlated with the nationwide migraine prevalence (ρ = 0.505; p = 0.039). In regard to social behavior, returning users were statistically significantly associated with being a woman (84.0%; 5696/6781), and they predominantly acceded from organic searches (50.6%; 3434/6781). When answering available open surveys, 72.5% (1827/2520) described their migraine as a disabling disease with high impact on their daily tasks and 64.4% (14,016/21,764) were unaware of what their headache diagnosis is. CONCLUSIONS: Spanish-speaking patients with migraine around the world increasingly visited the headache-specialized website midolordecabeza.org using different electronic devices, showing great interest in their disease. This website allowed them to get updated information on their disease, share clinical data with physicians, and finally express their concerns.

Anti-CGRP monoclonal antibodies in chronic migraine with medication overuse: real-life effectiveness and predictors of response at 6 months.

BACKGROUND: In daily practice, anti-CGRP monoclonal antibodies (MAbs) may be useful in chronic migraine (CM) with medication overuse (MO), but data is limited. We evaluated their effectiveness in a real-life clinical cohort. METHODS: This is a prospective study conducted in CM patients with and without medication overuse treated with monthly MAbs during 6 months (erenumab/galcanezumab). We collected headache characteristics, including acute medication intake, through an electronic diary. We compared patients (1) with and without MO at baseline, (2) with and without ongoing MO after treatment, defining MO resolution as < 10 or 15 days/month of acute medication intake, according to analgesic type, during the 6-month treatment. RESULTS: Of 139 CM patients completing 6-month treatment with anti-CGRP MAbs, 71.2% (99/139) had MO at baseline. After 6 months, patients with and without MO at baseline had significant and similar proportions of ≥50% reduction in migraine days/month (MO: 63.6% vs. non-MO: 57.5%, p = 0.500). 60.6% (60/99) no longer satisfied MO definition. Reduction in headache frequency compared to baseline occurred in both MO-ongoing and MO-resolution group, although those who stopped overusing had a greater improvement (headache days/month: - 13.4 ± 7.6 vs. -7.8 ± 7.2, p < 0.0001). No differences in MO resolution were observed according to the MAbs used. Baseline lower pain severity was associated with MO resolution (OR [95%]:0.236[0.054-0.975]; p = 0.049). CONCLUSIONS: In real-life anti-CGRP MAbs are as effective in CM patients with MO as in patients without it and facilitate MO cessation. Reduction in headache frequency and acute medication days/month occurs regardless of whether patients stop overusing or not.