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.

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.

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.

Epidemiology, work and economic impact of migraine in a large hospital cohort: time to raise awareness and promote sustainability.

BACKGROUND: Migraine is not routinely assessed at work, making impossible to realize its impact and the potential benefit of migraine-related health strategies. We aimed to assess epidemiology, work and economic impact of migraine in a workplace cohort of a tertiary hospital. METHODS: Cross-sectional analysis of a cohort of employees working in a Spanish tertiary hospital. Through a web questionnaire, we screened participants for migraine, collecting demographic data, work characteristics, work impairment due to headache (WPAI), treatments and healthcare resource utilization. We calculated direct and indirect costs for the hospital. RESULTS: Six hundred sixty-seven employees participated (8.8%). 71.2% (475/667) fulfilled criteria for migraine, being 76.8% (365/475) low-frequency episodic migraine (LFEM), 12.6% (60/475) high-frequency episodic migraine (HFEM) and 10.5% (50/475) chronic migraine (CM). Only 56.2% (267/475) were aware of suffering from migraine. Only 43.3% (26/60) of HFEM and 56.0% (28/50) of CM have been on preventive treatment in the last year. Migraine caused an overall economic loss for the hospital of 439,848.90 €/month, as a result of utilization of healthcare resources at the workplace (136,028.0 €/month) and indirect costs (absenteeism + presenteeism: 303,820.90 €/month). Specifically, only 110 participants (HFEM + CM) were responsible for half of indirect costs (165,017.2€/month). CONCLUSIONS: Although healthcare professionals have greater knowledge on health issues, migraine is underdiagnosed and undertreated, leading to a significant economic loss for the hospital. These results urge companies to assess migraine and promote stronger and migraine-specific health strategies at the workplace as a way to improve their own economic sustainability and the burden of migraine in their workforce.

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.

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.

Headache: A striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution.

OBJECTIVE: To define headache characteristics and evolution in relation to COVID-19 and its inflammatory response. METHODS: This is a prospective study, comparing clinical data and inflammatory biomarkers of COVID-19 patients with and without headache, recruited at the Emergency Room. We compared baseline with 6-week follow-up to evaluate disease evolution. RESULTS: Of 130 patients, 74.6% (97/130) had headache. In all, 24.7% (24/97) of patients had severe pain with migraine-like features. Patients with headache had more anosmia/ageusia (54.6% vs. 18.2%; p < 0.0001). Clinical duration of COVID-19 was shorter in the headache group (23.9 ± 11.6 vs. 31.2 ± 12.0 days; p = 0.028). In the headache group, IL-6 levels were lower at the ER (22.9 (57.5) vs. 57.0 (78.6) pg/mL; p = 0.036) and more stable during hospitalisation. After 6 weeks, of 74 followed-up patients with headache, 37.8% (28/74) had ongoing headache. Of these, 50% (14/28) had no previous headache history. Headache was the prodromal symptom of COVID-19 in 21.4% (6/28) of patients with persistent headache (p = 0.010). CONCLUSIONS: Headache associated with COVID-19 is a frequent symptom, predictive of a shorter COVID-19 clinical course. Disabling headache can persist after COVID-19 resolution. Pathophysiologically, its migraine-like features may reflect an activation of the trigeminovascular system by inflammation or direct involvement of SARS-CoV-2, a hypothesis supported by concomitant anosmia.

Impact of Puberty in Pediatric Migraine: A Pilot Prospective Study.

BACKGROUND AND PURPOSE: The short-term evolution of pediatric migraine remains unclear. We aimed to describe the evolution of migraine before and after puberty and its relationship with lifestyle habits. METHODS: We prospectively selected prepuberal patients from a neuropediatric unit who had a migraine diagnosis. Their medical history, migraine characteristics and impact, and lifestyle habits were recorded at the baseline visit. After 2 years we performed a telephone follow-up assessment. RESULTS: Nineteen patients were recruited (age 10.2±2.9 years, mean±SD; 57.9% female), of whom 27.5% had migraine with aura. The accompanying symptoms had changed at the follow-up, with significantly higher prevalence rates of dizziness (44.4% vs. 88.9%), vertigo (11.1% vs. 66.7%), mood changes (38.9% vs 83.3%), confusion (5.6% vs. 77.8%), and allodynia (27.8% vs. 61.1%). Sleep disturbances (5.6% vs. 38.9%) and schedule changes (0% vs. 38.9%) increased significantly as triggers. Prodromal symptoms became more prevalent (16.7% vs. 50%), with a higher proportion of sleep disturbances reported (50.0% vs. 87.5%). CONCLUSIONS: Prodromal symptoms increase in pediatric migraine after 2 years, and some trigger factors for migraine become more prevalent, including sleep disturbances. New accompanying symptoms are also identified. These changes provide information about how migraine changes during puberty along with physical and lifestyle changes, and represent a dynamic physiopathological process that deserves more research.

Influence of headache pain intensity and frequency on migraine-related disability in chronic migraine patients treated with OnabotulinumtoxinA.

BACKGROUND: There is a need to establish which are the more relevant headache-related outcomes that have an impact on our patient's lives to accurately evaluate treatment response in daily clinical practice. OBJECTIVE: The aim of this study was to evaluate the relevance of clinical trial endpoints in clinical real-life disability improvement in response to migraine preventive treatment with OnabotulinumtoxinA. METHODS: This is an observational prospective study. We included patients with chronic migraine fulfilling ICHD-3beta/3 criteria. We prospectively collected data of 8 headache-related and acute medication use endpoints recommended by the Guidelines of the International Headache Society for controlled trials of preventive treatment of chronic migraine. We evaluated their impact on disability improvement after 6 months of treatment with OnabotulinumtoxinA. We defined as a responder in disability, patients with ≥50% MIDAS score reduction after 2 cycles of treatment following PREEMPT protocol. We performed an analysis to measure the impact of improvement in the evaluated outcome measures according to perceived disability in clinical practice. RESULTS: We included 395 patients (85.1% women, mean age 46.7 ± 12.6 years). Mean headache frequency at baseline was 26.5 ± 5.2 headache days/month. After 6 months, 49.1% of patients were headache-related disability responders. From all outcome measures collected, variables independently associated to disability improvement were headache days reduction (p = 0.02) and ≥ 50% pain intensity reduction (p = 0.04). A ≥ 50% reduction in headache frequency or pain intensity showed similar influence on disability improvement after treatment. CONCLUSIONS: Headache pain intensity is as important as frequency when evaluating the clinical response and impact on patient headache-related disability after migraine preventive treatment with OnabotulinumtoxinA.

Short and Mid-Term Predictors of Response to OnabotulinumtoxinA: Real-Life Experience Observational Study.

OBJECTIVE: To identify clinical predictors of excellent response to OnabotulinumtoxinA in patients with chronic migraine (CM) at 6 and 12 months of follow-up. BACKGROUND: Clinical predictors of response to OnabotulinumtoxinA are scarce and have not been clearly reproduced and analyzed in detail. So far, predictors of response to OnabotulinumtoxinA assess response in general or good response, but not an excellent response. METHODS: Cohort study of patients attended in a specialized Headache Clinic in treatment with OnabotulinumtoxinA were classified according to their improvement in frequency: no-response (<25%) and excellent response (≥75%). A comparative analysis was carried out at 6 and 12 months identifying clinical predictors of excellent response to OnabotulinumtoxinA at each timepoint. RESULTS: Data were collected from 221 patients. After 6 and also 12 months, we observed a statistically significant mean reduction in frequency and analgesic intake. At month 6, independent variables associated with excellent response (OR[95%CI]) were daily headache frequency (0.32[0.14-0.74]; P = .005), medication overuse (MO) (2.28[1.19-4.37]; P = .013), and a higher ratio of migraine days/month (MDM) (1.20[1.10-1.45]; P = .018) at baseline. At month 12, independent predictors of excellent response were patients with less than 30 years of migraine evolution (0.43[0.23-0.82]; P = .011), presence of anxiety (0.44[0.23-0.85]; P = .018), and aura (0.48[0.25-0.92]; P = .037). Excellent responders showed a higher improvement rate in pain intensity at 6 and 12 months. CONCLUSIONS: Patients with daily frequency and MO show a clinical improvement in short-term. Patients with comorbidities who start treatment earlier in the course of the disease need a longer duration of treatment. The profile of response to treatment with OnabotulinumtoxinA determines its minimum treatment duration and the timepoint of a meaningful response.

How Does Migraine Change After 10 Years? A Clinical Cohort Follow-Up Analysis.

OBJECTIVE: To describe the 10-year evolution of a cohort of migraine patients, focusing on prognostic factors of improvement. BACKGROUND: Migraine is one of the most prevalent and disabling diseases and migraineurs often want to know about the evolutionary timeline of their condition. Yet, data from longitudinal studies with a long-term follow-up is scarce. METHODS: This is a 10-year longitudinal study. In 2008, we recruited 1109 consecutive migraine patients who answered an initial survey. In 2018, we did a follow-up. We compared initial and final (after 10 years) data. A reduction ≥50% in Headache days/month was considered as improvement. A comparative study was carried out to identify predictors of improvement or no improvement. RESULTS: After 10 years, 380 patients completed the survey (34.3% of the initial cohort), 77.1% (293/380) were women; mean age 41.0 ± 10.6 years and 73.7% (280/380) had an initial diagnosis of episodic migraine (EM). After 10 years, 48.2% (183/380) of patients did not have a medical follow-up of their migraine; 47.4% (180/380) decreased ≥50% in frequency, which increased the proportion of EM (73.7% vs 87.4%) (P < .001) as compared to the initial results. Factors independently associated with improvement were: a baseline frequency >10 days/month (OR[95%]: 3.04 [1.89, 4.89]; P < .001), nonsmoking (2.13 [1.23, 3.67]; P = .006) and a medical follow-up for migraine (2.45 [1.54, 3.90]; P < .001). Additionally, after 10 years, we observed a reduction in the use of preventive treatment (48.7% vs 23.5%) and an increase in monotherapy (42.2% vs 72.7%) (P < .001). CONCLUSION: After 10 years, in almost half of the patients who answered the survey, migraine improved. Other than the natural pathophysiology of migraine, having a medical follow-up and healthy habits such as nonsmoking were independent factors associated with improvement.

Headache, comorbidities and lifestyle in an adolescent population (The TEENs Study).

OBJECTIVE: To evaluate the prevalence and characteristics of headache and its relationship with comorbidities and lifestyle in a teenage population. METHODS: This is a cross-sectional study. Data was collected from students aged 12-18 years from six different schools in Catalonia, Spain. They completed an anonymous questionnaire with demographic, lifestyle, medical data, presence of recurrent headaches and its features, and completed the Strengths and Difficulties Questionnaire. We defined probable migraine if headache presented ≥ 3 ICHD-3 beta criteria for migraine. An analysis was performed to evaluate headache characteristics and compare lifestyles between those with or without headache. RESULTS: 1619 out of 1873 students completed the survey (response rate 86.4%). From these, 30.5% suffered from recurrent headache and 11.3% had migraine features; 32.9% of adolescents with headache had at least one episode per week and 44.1% showed some degree of headache-related disability measured by the PedMIDAS scale. In a univariate analysis, headache was significantly more frequent in girls (35.1% vs. 25.5%, p < 0.001), teenagers with poor sleeping habits (36.6% vs. 27.6%, p < 0.001), lower physical activity ( p = 0.002), those who did not have breakfast (37.3 vs. 28.4%, p = 0.001), smokers (10.5% vs. 4.9%, p < 0.001) and caffeine overusers (30.9% vs. 24.7%, p = 0.009). Comorbidities significantly associated with headache were: allergies (38.8% vs. 29.3%, p = 0.007), other chronic pain disorders (44.7% vs. 27.6% p < 0.001), mental health problems (53.2% vs. 29.0%, p < 0.001) and worse SDQ scores ( p < 0.001). CONCLUSIONS: Headache is a common health problem among adolescents which impacts their quality of life. Headache is associated with presence of "unhealthy lifestyle" and other medical comorbidities. Educational initiatives should be started.

OnabotulinumtoxinA: An Effective Tool in the Therapeutic Arsenal for Chronic Migraine With Medication Overuse.

Objective: To evaluate the early response of onabotulinumtoxinA as a treatment tool in patients with chronic migraine (CM) and medication overuse (MO). Patients and Methods: This is a retrospective study in patients with CM and MO who received two cycles of onabotulinumtoxinA infiltrations following PREEMPT protocol. We evaluated the efficacy of onabotulinumtoxinA in MO resolution, defined as less than 10 days/month of acute medication intake (triptans, opioids, and combinations) or 15 days/month (non-steroidal anti-inflammatory drugs - and simple analgesics). In addition, we analyzed changes in headache frequency, pain intensity, and headache-related disability (MIDAS scale). A multivariate analysis was carried out to identify factors independently related to MO resolution. Results: We included 139 consecutive patients with CM and MO. After 2 cycles of onabotulinumtoxinA, 73.4% had ≥50% reduction in acute medication intake and 57.6% achieved MO resolution. 7.9% of patients did not use any acute medication after treatment. Even though both MO-ongoing group and MO-resolution group improve in headache frequency, the reduction was significantly higher for the group which discontinued the use of acute medication after onabotulinumtoxinA treatment (p < 0.001). In this group, 73.0% reduced headache frequency ≥50%. Daily headache changed from 71.2 to 23.2% (p < 0.001). Both groups showed an improvement in pain intensity and in MIDAS score (p < 0.05). In the multivariate analysis we observed that MO resolution had an inverse association with medication intake at baseline (OR:0.294, p < 0.05) and a direct association with frequency (OR:20.455, p < 0.001) and MIDAS score (OR: 6.465, p < 0.05) improvements. Conclusion: OnabotulinumtoxinA has an early beneficial effect on the discontinuation of acute medication in a substantial proportion of patients with CM and MO. Therefore, onabotulinumtoxinA might be considered a therapeutic tool in CM with MO.