Insights from triggers and prodromal symptoms on how migraine attacks start: The threshold hypothesis.

BACKGROUND: The prodrome or premonitory phase is the initial phase of a migraine attack, and it is considered as a symptomatic phase in which prodromal symptoms may occur. There is evidence that attacks start 24-48 hours before the headache phase. Individuals with migraine also report several potential triggers for their attacks, which may be mistaken for premonitory symptoms and hinder migraine research. METHODS: This review aims to summarize published studies that describe contributions to understanding the fine difference between prodromal/premonitory symptoms and triggers, give insights for research, and propose a way forward to study these phenomena. We finally aim to formulate a theory to unify migraine triggers and prodromal symptoms. For this purpose, a comprehensive narrative review of the published literature on clinical, neurophysiological and imaging evidence on migraine prodromal symptoms and triggers was conducted using the PubMed database. RESULTS: Brain activity and network connectivity changes occur during the prodromal phase. These changes give rise to prodromal/premonitory symptoms in some individuals, which may be falsely interpreted as triggers at the same time as representing the early manifestation of the beginning of the attack. By contrast, certain migraine triggers, such as stress, hormone changes or sleep deprivation, acting as a catalyst in reducing the migraine threshold, might facilitate these changes and increase the chances of a migraine attack. Migraine triggers and prodromal/premonitory symptoms can be confused and have an intertwined relationship with the hypothalamus as the central hub for integrating external and internal body signals. CONCLUSIONS: Differentiating migraine triggers and prodromal symptoms is crucial for shedding light on migraine pathophysiology and improve migraine management.

Effectiveness and safety of monthly versus quarterly fremanezumab for migraine prevention: An Italian, multicenter, real-life study.

BACKGROUND AND PURPOSE: Fremanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide for migraine prevention, is available in monthly (225 mg) and quarterly (675 mg) doses. Previous studies showed efficacy and safety for both regimens, but a real-life comparison is lacking. This study aimed to compare the effectiveness and safety of monthly and quarterly fremanezumab in a real-life setting. METHODS: This Italian, prospective, multicenter study enrolled 95 migraine patients. During a 3-month treatment period, patients received either monthly or quarterly fremanezumab (49 monthly, 46 quarterly). A 6-month treatment period involved 79 patients (43 monthly, 36 quarterly). Monthly headache (MHD) and migraine days (MMD), number of days (AMD) and pills (AMP) of acute medication intake, and Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS) test, and Numeric Rating Scale (NRS) scores were recorded at baseline and after 3 and 6 months of treatment. Adverse events (AEs), responder rates, and medication overuse were also investigated. RESULTS: Both monthly and quarterly treatments led to significant reductions in MMD, MHD, AMP, AMD, HIT-6, MIDAS, and NRS scores after 3 and 6 months. The monthly regimen exhibited a slightly greater reduction in MMD and MHD after the first quarter, with no significant difference observed after 6 months. The most common AE was transient injection-site reaction, without between-group differences. Responder rates and resolution of medication overuse did not significantly differ between the groups. CONCLUSIONS: Both monthly and quarterly regimens were effective and safe, with a tendency for an advantage of the monthly regimen only in the first quarter of treatment.

The impact of primary headaches on disability outcomes: a literature review and meta-analysis to inform future iterations of the Global Burden of Disease study.

BACKGROUND: The burden and disability associated with headaches are conceptualized and measured differently at patients' and populations' levels. At the patients' level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0-1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients' disability which might inform future GBD definitions of DW for headache disorders. METHODS: We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females' percentage in the sample, and age). We developed a 0-1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium. RESULTS: A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake. CONCLUSIONS: Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels.

Ultra-late response (> 24 weeks) to anti-CGRP monoclonal antibodies in migraine: a multicenter, prospective, observational study.

OBJECTIVE: Nearly 60% of migraine patients treated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway experience a ≥ 50% reduction in monthly migraine days (MMD) at 12 weeks compared to baseline (responders). However, approximately half of the patients not responding to anti-CGRP mAbs ≤ 12 weeks do respond ≤ 24 weeks (late responders). We assessed frequency and characteristics of patients responding to anti-CGRP mAbs only > 24 weeks (ultra-late responders). METHODS: In this multicenter (n = 16), prospective, observational, real-life study, we enrolled all consecutive adults affected by high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM), with ≥ 3 prior therapeutic failures, treated with any anti-CGRP mAbs for ≥ 48 weeks. We defined responders patients with a ≥ 50% response rate ≤ 12 weeks, late responders those with a ≥ 50% response rate ≤ 24 weeks, and ultra-late responders those achieving a ≥ 50% response only > 24 weeks. RESULTS: A total of 572 migraine patients completed ≥ 48 weeks of anti-CGRP mAbs treatment. Responders accounted for 60.5% (346/572), late responders for 15% (86/572), and ultra-late responders for 15.7% (90/572). Among ultra-late responders, 7.3% (42/572) maintained the ≥ 50% response rate across all subsequent time intervals (weeks 28, 32, 36, 40, 44, and 48) and were considered persistent ultra-late responders, while 8.4% (48/572) missed the ≥ 50% response rate at ≥ 1 subsequent time interval and were classified as fluctuating ultra-late responders. Fifty patients (8.7%) did not respond at any time interval ≤ 48 weeks. Ultra-late responders differed from responders for higher BMI (p = 0.033), longer duration of medication overuse (p < 0.001), lower NRS (p = 0.017) and HIT-6 scores (p = 0.002), higher frequency of dopaminergic symptoms (p = 0.002), less common unilateral pain-either alone (p = 0.010) or in combination with UAS (p = 0.023), allodynia (p = 0.043), or UAS and allodynia (p = 0.012)-a higher number of comorbidities (p = 0.012), psychiatric comorbidities (p = 0.010) and a higher proportion of patients with ≥ 1 comorbidity (p = 0.020). CONCLUSION: Two-thirds of patients not responding to anti-CGRP mAbs ≤ 24 weeks do respond later, while non-responders ≤ 48 weeks are quite rare (8.7%). These findings suggest to rethink the duration of migraine prophylaxis and the definition of resistant and refractory migraine, currently based on the response after 2-3 months of treatment.

The effect of erenumab on brain network function in episodic migraine patients: a randomized, placebo-controlled clinical trial (RESET BRAIN).

BACKGROUND: We aimed to explore whether erenumab, a monoclonal antibody targeting the calcitonin gene-related peptide receptor, could exert a central effect on brain network function in migraine, and investigate the persistence of such an effect following treatment discontinuation. METHODS: This was a randomized, double-blind, placebo-controlled, multicenter trial with a crossover design performed in adult episodic migraine patients with previous treatment failure. Patients were randomized (1:1) to 12 weeks of erenumab 140 mg or placebo, followed by a 12-week crossover. Resting state (RS) functional connectivity (FC) changes of brain networks involved in migraine were investigated using a seed-based correlation approach. RESULTS: Sixty-one patients were randomized to treatment. In each treatment sequence, 27 patients completed the visit at week 12. Forty-four enrolled patients, 22 in each treatment sequence, completed the study procedures with no major protocol violations. We observed a carry-over effect of erenumab during the placebo treatment and therefore data analysis was performed as a parallel comparison of erenumab vs placebo of the first 12 weeks of treatment. From baseline to week 12, compared to placebo, patients receiving erenumab showed RS FC changes within the cerebellar, thalamic and periaqueductal gray matter networks, significantly associated with clinical improvement. Compared to non-responders, patients achieving a 50% reduction in migraine days had distinct patterns of thalamic and visual network RS FC. Brain RS FC changes reversed when erenumab was stopped. A lower baseline RS FC of the pontine network identified patients responding to erenumab. CONCLUSION: Erenumab modulates RS FC of networks involved in migraine pathophysiology. In line with clinical response, erenumab-induced brain RS FC changes tend to reverse when treatment is stopped.

Retreating migraine patients in the second year with monoclonal antibodies anti-CGRP pathway: the multicenter prospective cohort RE-DO study.

BACKGROUND: The outcome of migraine patients retreated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (anti-CGRP) or its receptor (anti-CGRPr) is not completely known. METHODS: This multicentric prospective observational cohort study assessed monthly migraine days (MMDs), migraine acute medication intake (MAMI), and HIT-6 at baseline, after 90-112 days (Rev-1), after 84-90 days since Rev-1 (Rev-2) and 30 days after the last injection of anti-CGRP/CGRPr mAbs (Year-end), in the first and the second year after a discontinuation period. RESULTS: We enrolled 226 patients (79.6% with chronic migraine; 55.3% on erenumab and 44.7% on galcanezumab or fremanezumab). MMDs, MAMI, and HIT-6-did not differ at the respective first and second-year evaluations in the entire cohort, and comparing anti-CGRP with anti-CGRPr Abs. MMDs (18.1 ± 7.8 vs. 3.4 ± 7.8), MAMI (26.7 ± 28.3 vs.17.7 ± 17.2), and HIT-6 scores (63.1 ± 5.9 vs. 67.1 ± 10.3) were lower in the second year than in the pre-treatment baseline (consistently, p < 0.0001). Second-year baseline MMDs were lower in patients on anti-CGRP mAbs (p = 0.001) and with lower pre-treatment baseline MMDs (p ≤ 0.001). CONCLUSION: Anti-CGRP/CGRPr mAbs are effective in the second as in the first year. The use of anti-CGRP or CGRPr mAbs influenced the second-year baseline MMDs, but their effectiveness did not differ during the two treatment years.

Ocrelizumab extended-interval dosing in multiple sclerosis during SARS-CoV-2 pandemic: a real-world experience.

BACKGROUND AND PURPOSE: During the COVID-19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed. METHODS: Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended-interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B-cell counts were also retrospectively collected and analysed. RESULTS: A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow-up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%, p = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%, p = 0.374) or disability progression (11.3% vs. 18.4%, p = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19-positive relative (r = 0.530, p < 0.001) and absolute (r = 0.491, p < 0.001) cell counts, without implications on disease activity. CONCLUSIONS: Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended-interval regimens.

Tracking the evolution of non-headache symptoms through the migraine attack.

BACKGROUND: The migraine attack is classically divided into the prodromal, aura, headache and postdromal phase. Previous studies have highlighted non-headache symptoms associated with migraine occurring during the prodromal or postdromal phase. This study aimed to track the evolution of non-headache symptoms throughout all phases of the migraine attack. We also wished to delineate the phenotype of patients with more symptomatic migraine episodes and explore the association between non-painful symptoms and migraine disease activity and patients' disability. METHODS: Two-hundred and twenty-five migraine patients were enrolled and were asked to recall retrospectively whether non-headache symptoms occurred during the prodromal, headache and postdromal phase of their attacks. The occurrence of symptoms during the different migraine phases was tested using the Cochran's Q tests, Cohen's and Fleiss' kappa. Differences between groups according to the presence of non-headache symptoms through the entire migraine attack and correlations between the frequency of non-headache symptoms experienced during all phases and patients' disease activity and disability were also assessed. RESULTS: Ninety-nine percent of patients reported having at least one non-headache symptom in one phase of the migraine attack and 54% of patients had at least one non-headache symptom occurring during all phases of migraine. The occurrence of non-headache symptoms was different throughout the three phases of migraine, being higher during the headache phase than during the prodromal and postdromal phases. Symptoms with the highest co-occurrence throughout all migraine phases were neck stiffness, thirst and abdominal pain. Patients who experienced non-headache symptoms during all three phases of migraine were more frequently females, had a higher disability, were suffering from chronic migraine and had more frequently medication overuse headache. CONCLUSION: Migraine is a complex neurological disorder with a wide constellation of non-headache symptoms that can affect the burden of the disease. A better characterization of the evolution of non-headache symptoms through the different phases of migraine can enrich our knowledge on migraine pathophysiology and improve the management of the disease.

Comparison of efficacy and safety of erenumab between over and under 65-year-old refractory migraine patients: a pivotal study.

Previous studies reported a positive effect of anti-CGRP monoclonal antibodies (mAbs) in migraine prevention, either in over (O65) and under (U65) 65-year-aged patients. The aim of our study was to evaluate and compare real-life efficacy and safety of mAbs between young and elder migraine patients. Fifteen O65 and fifteen U65 patients, treated with monthly mAbs for 6 months, were enrolled and matched for sex, monthly headache days (MHD), and monthly migraine days (MMD) at baseline. Between-group differences in MHD and MMD, number of pills and days of acute medication intake, HIT-6, MIDAS, Numeric Rating Scale (NRS), and Allodynia Symptom Checklist (ASC-12) were assessed after 3 (M3) and 6 (M6) months of treatment. Adverse events (AEs) were also investigated. In each group, thirteen patients (87%) were women and nine (60%) had chronic migraine. Baseline mean MHD and MMD of both groups were 20 (SD 9.6). Mean age was 70 (65-76) and 45 (19-55) in the O65 and U65 group, respectively. Before starting mAbs, patients have tried an average of 4 preventives in both groups. After 3 and 6 months of treatment, both groups had a reduction of all clinical features under examination, without statistically significant differences between groups. A similar proportion of patients in each group complained of AEs (M3 and M6, p = 1.0). Our real-life data showed that treatment with mAbs is as effective and safe in O65 as U65 migraine patients. Further studies are needed to confirm these findings.

Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study).

BACKGROUND: Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM. METHODS: This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9-12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals. RESULTS: Sixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p < 0.05), MHDs (-9.4, p < 0.001), MAI (-5.7, p < 0.05; -11.1, p < 0.001), NRS (-3.1, p < 0.001; -2.5, p < 0.001), and MIDAS scores (-58.3, p < 0.05; -43.7; p < 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p < 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85-0.98, p = 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason. CONCLUSIONS: Fremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.

Cortical M1 plasticity and metaplasticity in patients with multiple sclerosis.

BACKGROUND: Previous studies on patients with Multiple Sclerosis (MS) have reported contrasting findings on cortical plasticity of the primary motor cortex and no study has yet evaluated the regulatory mechanisms of cortical plasticity (i.e., metaplasticity) in MS patients. The aim of the present study was to investigate primary motor cortex (M1) plasticity and metaplasticity in patients with MS. METHODS: Nineteen patients affected by Relapsing--Remitting MS (RR-MS) and 16 age- and sex-matched healthy controls underwent intermittent Theta Burst Stimulation (iTBS) to evaluate cortical plasticity and iTBS preceded by repetitive index finger movements to evaluate M1 metaplasticity. RESULTS: In healthy subjects MEP size significantly increased after iTBS whereas it significantly decreased when repetitive index finger movements preceded iTBS (metaplasticity) (factor PROTOCOL: p < 0.0001; PROTOCOL x TIME interaction: p = 0.001). Conversely, in MS patients MEP size mildly increased, albeit not significantly in both conditions (p > 0.05). In MS patients, percentage changes in MEP size induced by plasticity and metaplasticity protocol were significantly associated to EDSS (p = 0.001) and kinematics of index finger movements (p = 0.01). CONCLUSION: M1 plasticity and metaplasticity are both altered in MS patients. When TBS is used for therapeutic purposes, TBS protocols should be tailored according to the M1 plasticity functional reserve of each MS patient.