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.

The state of art on the use of patient reported outcomes in migraine.

PURPOSE OF REVIEW: This review aims to explore the use of patient-reported outcome measures (PROMs) in migraine. Traditionally assessed through specific features, recent adoption of PROMs allows for a more objective and quantifiable evaluation. PROMs, which are standardized questionnaires collecting health information directly from a patients' perspective, cover various aspects, including migraine specific aspects. The review focuses on delineating the applications and interpretation of commonly used PROMs in migraine research, with an emphasis on their integration in clinical care. RECENT FINDINGS: Generic and migraine-specific PROMs play a crucial role in clinical research, particularly in assessing health-related quality of life, disability, impact, and associated comorbidities. Some of these measures are strongly recommended to be used by the International Guidelines and are, in fact, mandated by the FDA for product labeling. Recently, there has been an expansion in the use of PROMs to assess migraine in diverse populations, in particular pediatric patients. However, the application of these measures in clinical care shows considerable heterogeneity, and some have not been validated specifically for migraine. The existing multitude of PROMs, coupled with ongoing development of new ones to better capture patient concerns, creates complexity in their research and clinical application. To address these challenges, it becomes imperative to streamline their use, focusing on those that are more validated and better aligned with the patients' perspective including different populations' needs. SUMMARY: The utilization of PROMs in evaluating migraine enables a more holistic assessment, helps quantify the impact of the disease facilitating change measurement, improves communication between healthcare providers and patients and, guides treatment decisions for improved outcomes. However, the increasing number of PROMs questionnaires, underscores the importance of validating these tools for migraine and, the dynamic nature of the disease makes it relevant to decide with whom, why and when these should be used.

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.

CGRP monoclonal antibodies and CGRP receptor antagonists (Gepants) in migraine prevention.

Migraine is a prevalent and disabling neurological disease. Its preventive treatment for decades has been rather limited due to the absence of disease-specific therapies with limited efficacy and tolerability. The advances made in migraine research have led to the discovery of the calcitonin gene-related peptide (CGRP) and its role in migraine pathophysiology. CGRP is a neuropeptide that acts as potent vasodilator and is involved in pain processing. Increased levels of plasma CGRP have been observed during migraine attacks as well as interictally when comparing patients with migraine and healthy controls. In the last years, two classes of drugs antagonizing CGRP have therefore been developed as the first migraine-specific preventive treatments: anti-CGRP monoclonal antibodies (mAbs) and gepants. Four mAbs have been approved: erenumab, galcanezumab, fremanezumab, and eptinezumab. Gepants are small molecules that antagonize the CGRP receptor; currently only rimegepant and atogepant have been approved for migraine prevention. These new drugs have demonstrated efficacy and safety in clinical trials for both episodic and chronic migraine, and results from their real-world experience are being increasingly reported in literature. In this review, we provide an overview of anti-CGRP drugs and their placement in migraine prevention.

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.

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.

Headaches and facial pain attributed to SARS-CoV-2 infection and vaccination: a systematic review.

BACKGROUND AND PURPOSE: The aim was to provide insights to the characteristics of headache in the context of COVID-19 on behalf of the Headache Scientific Panel and the Neuro-COVID-19 Task Force of the European Academy of Neurology (EAN) and the European Headache Federation (EHF). METHODS: Following the Delphi method the Task Force identified six relevant questions and then conducted a systematic literature review to provide evidence-based answers and suggest specific diagnostic criteria. RESULTS: No data for facial pain were identified in the literature search. (1) Headache incidence during acute COVID-19 varies considerably, with higher prevalence rates in prospective compared to retrospective studies (28.9%-74.6% vs. 6.5%-34.0%). (2) Acute COVID-19 headache is usually bilateral or holocranial and often moderate to severe with throbbing pain quality lasting 2-14 days after first signs of COVID-19; photo-phonophobia, nausea, anosmia and ageusia are common associated features; persistent headache shares similar clinical characteristics. (3) Acute COVID-19 headache is presumably caused by immune-mediated mechanisms that activate the trigeminovascular system. (4) Headache occurs in 13.3%-76.9% following SARS-CoV-2 vaccination and occurs more often amongst women with a pre-existing primary headache; the risk of developing headache is higher with the adenoviral-vector-type vaccines than with other preparations. (5) Headache related to SARS-CoV-2 vaccination is mostly bilateral, and throbbing, pressing, jolting or stabbing. (6) No studies have been conducted investigating the underlying mechanism of headache attributed to SARS-CoV-2 vaccines. CONCLUSION: The results of this joint EAN/EHF initiative provide a framework for a better understanding of headache in the context of SARS-CoV-2 infection and vaccination.

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.

Headache in COVID-19 and Long COVID: to Know Facts for Clinical Practice.

PURPOSE OF REVIEW: Headache is one of the most frequent symptoms of the acute and post-acute phase of COVID-19. Specific epidemiology, clinical features, risk factors, pathophysiology, and treatment have been reported in these two scenarios. With this narrative review of the literature, we aim to provide updated knowledge on headache in the COVID-19 setting and give clinicians a practical approach on this topic to guide them in their clinical practice. RECENT FINDINGS: Headache mechanisms in COVID-19 are still poorly understood. Strong evidence is also lacking on how to best treat and manage these patients, especially those with persistent and disabling headache after COVID-19. Data are also scarce on the characteristics of headache in COVID-19 caused by the new SARS-CoV-2 (Omicron) variants and how these may influence the acute and persistent symptoms of COVID-19. Patients with pre-existing primary headache disorders remain a particularly concerning population due to their biological predisposition in suffering from headaches and the potential risk of worsening in the setting of SARS-CoV-2 infection. Although there is an exponential growth of scientific evidence, studies are often controversial and focused on the first wave of the pandemic, making COVID-19 headache still a challenging matter for clinicians. New research is therefore needed.

Mode and site of action of therapies targeting CGRP signaling.

Targeting CGRP has proved to be efficacious, tolerable, and safe to treat migraine; however, many patients with migraine do not benefit from drugs that antagonize the CGRPergic system. Therefore, this review focuses on summarizing the general pharmacology of the different types of treatments currently available, which target directly or indirectly the CGRP receptor or its ligand. Moreover, the latest evidence regarding the selectivity and site of action of CGRP small molecule antagonists (gepants) and monoclonal antibodies is critically discussed. Finally, the reasons behind non-responders to anti-CGRP drugs and rationale for combining and/or switching between these therapies are addressed.

Impact of anti-CGRP monoclonal antibodies on migraine attack accompanying symptoms: A real-world evidence study.

BACKGROUND: Clinical trials on anti-calcitonin gene-related peptide monoclonal antibodies poorly investigated their impact on migraine accompanying symptoms. OBJECTIVE: To evaluate the impact of basal accompanying symptoms on anti-CGRP monoclonal antibodies treatment response and their evolution after six months of treatment in migraine patients. METHODS: Patients with migraine diagnosis seen in the Headache Clinic and treated with erenumab, galcanezumab or fremanezumab were prospectively recruited. They completed a daily eDiary which provided data on headache frequency and the following accompanying symptoms of each day: photophobia, phonophobia, nausea, dizziness, and aura. Patients were classified as responders or non-responders based on 50% or greater reduction in headache days per month at month 6 (≥50% response rate). Accompanying symptoms ratios based on headache days per month were assessed per patient at baseline and after three and six months. Comparisons for basal characteristics, basal accompanying symptoms ratios and their evolution after six months between responders and non-responders were performed. RESULTS: One hundred and fifty-eight patients were included, 44% (69/158) showed ≥50% response rate after six months. A significant reduction in headache days per month in both groups was found at month 6 (-9.4 days/month in ≥50% response rate group; p < 0.001, -2.2 days/month in <50% response rate group; p = 0.004). Additionally, significant decreases in photophobia (-19.5%, p < 0.001), phonophobia (-12.1%, p = 0.010) and aura ratios (-25.1%, p = 0.008) were found in ≥50% response rate group. No statistically significant reductions were found in nausea and dizziness in any group since their reduction was correlated with the decrease in headache days per month. Higher photophobia ratios at baseline were predictive of an increased response between months 3 and 6 (Incidence Risk Ratio = 0.928, p = 0.040). CONCLUSIONS: The days per month with photophobia, phonophobia and aura decreased at a higher rate than headache days per month after six months in the ≥50% response group. Higher photophobia ratios were associated with higher response rates between three and six months. It could indicate an involvement of peripheral CGRP in photophobia as well as a central modulation of migraine through these treatments which mainly act on the periphery.

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.

Effectiveness and safety of anti-CGRP monoclonal antibodies in patients over 65 years: a real-life multicentre analysis of 162 patients.

BACKGROUND: Anti-CGRP monoclonal antibodies have shown notable effectiveness and tolerability in migraine patients; however, data on their use in elderly patients is still lacking, as clinical trials have implicit age restrictions and real-world evidence is scarce. In this study, we aimed to describe the safety and effectiveness of erenumab, galcanezumab and fremanezumab in migraine patients over 65 years old in real-life. METHODS: In this observational real-life study, a retrospective analysis of prospectively collected data from 18 different headache units in Spain was performed. Migraine patients who started treatment with any anti-CGRP monoclonal antibody after the age of 65 years were included. Primary endpoints were reduction in monthly migraine days after 6 months of treatment and the presence of adverse effects. Secondary endpoints were reductions in headache and medication intake frequencies by months 3 and 6, response rates, changes in patient-reported outcomes and reasons for discontinuation. As a subanalysis, reduction in monthly migraine days and proportion of adverse effects were also compared among the three monoclonal antibodies. RESULTS: A total of 162 patients were included, median age 68 years (range 65-87), 74.1% women. 42% had dyslipidaemia, 40.3% hypertension, 8% diabetes, and 6.2% previous cardiovascular ischaemic disease. The reduction in monthly migraine days at month 6 was 10.1 ± 7.3 days. A total of 25.3% of patients presented adverse effects, all of them mild, with only two cases of blood pressure increase. Headache and medication intake frequencies were significantly reduced, and patient-reported outcomes were improved. The proportions of responders were 68%, 57%, 33% and 9% for reductions in monthly migraine days ≥ 30%, ≥ 50%, ≥ 75% and 100%, respectively. A total of 72.8% of patients continued with the treatment after 6 months. The reduction in migraine days was similar for the different anti-CGRP treatments, but fewer adverse effects were detected with fremanezumab (7.7%). CONCLUSIONS: Anti-CGRP mAbs are safe and effective treatments in migraine patients over 65 years old in real-life clinical practice.

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.

Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review.

OBJECTIVE: The objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders. METHODS: This is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords "COVID 19" or "vaccine" and "headache" to assess the appropriateness of all published articles for their inclusion in the review. RESULTS: Headache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced. CONCLUSIONS: The ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care.

Incidence of Status Migrainosus in Olmsted County, Minnesota, United States: Characterization and Predictors of Recurrence.

BACKGROUND AND OBJECTIVES: SM is recognized as a complication of migraine in which pain and/or associated symptoms are unremitting and debilitating for more than 72 hours. The epidemiology of SM in the general population is not known. The aim of this study is to determine the incidence, recurrence rate, and clinical associations of status migrainosus (SM) in care-seeking residents of Olmsted County, Minnesota. METHODS: The Rochester Epidemiology Project was used to identify the incident cases of SM according to the International Classification of Headache Disorders, Third Edition criteria and based on the first physician-encountered case in the record. The clinical characteristics of the incident cases were abstracted from the medical record. One-year recurrence-free survival was evaluated and compared between clinically relevant groups, including baseline demographics, migraine characteristics, and treatment exposures. RESULTS: Between January 1, 2012, and December 31, 2017, 237 incident cases of SM were identified. The median age was 35 (IQR 26-47) years, and 210 (88.6%) were female. A history of chronic migraine was recorded in 82/226 (36.3%) and a history of aura in 76/213 (35.7%). At the time of the incident case, medication reconciliation included a triptan or ergotamine in 127/233 (53.6%) and/or an opioid-containing analgesic in 43/233 (18.5%). The overall age- and sex-adjusted incidence rate was 26.60 per 100,000 [95% CI, 23.21-29.97], with a peak incidence between ages 40 and 49 years. The median (95% CI) attack duration was 5 (4.48-5.42) days. The most frequent triggers were stress (40/237, 16.9%) and too much or too little sleep (27/237, 11.4%). Recurrence occurred in 35/237 (14.8%) at a median of 58 (IQR 23-130) days following the initial attack. In our age- and sex-adjusted multivariable model, too much or too little sleep as a trigger was associated with 12-month risk of recurrence (adjusted OR 3.59 [95% CI 1.58-8.14], p = 0.0022). DISCUSSION: Our study provides a population-based estimate of SM incidence. We identified aberrant sleep patterns as a potentially modifiable risk factor for 1-year SM recurrence.

Efficacy and safety of galcanezumab as a treatment of refractory episodic and chronic cluster headache: Case series and narrative review.

BACKGROUND: Galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), has demonstrated clinical benefit as a preventive treatment of episodic cluster headache (ECH) but not in chronic cluster headache (CCH) to this date. Our objective was to analyze our clinical experience of the compassionate use of galcanezumab in cluster headache and to conduct a narrative review of the published literature. METHODS: We present a case series of patients with refractory ECH and CCH treated with 240 mg galcanezumab monthly in an outpatient headache clinic. We recorded epidemiologic and clinical data and analyzed the disease evolution after 3 and 6 months. The review was performed following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: We included three patients with ECH who were treated during a refractory cluster bout (mean duration of 83.7 days since the first attack, range 46.0-105.0 days) and six patients with CCH who had a high frequency of attacks (mean 35.8 attacks/week, range 7-56) and refractory to a mean of 5.2 preventive treatments (range, 3-9). In the CCH group, >50% frequency reduction was seen in 83% (5/6 patients) and the number of attacks per week showed a mean reduction of -24.2 at month 3 (range, -6 to -49) and -27.6 at month 6 (range, -7 to -49). In the ECH group, the bout ended a mean 17.3 days (range, 10-28) after galcanezumab administration. One third of patients reported mild adverse events, none of them leading to discontinuation. CONCLUSION: In conclusion, our clinical experience supports the use of galcanezumab in patients with refractory cluster headache. These results might encourage the possibility of continuing clinical development with randomized controlled trials of anti-CGRP treatments in patients with cluster headache.

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.