Reducing the Impact of Headache and Allodynia Score in Chronic Migraine: An Exploratory Analysis from the Real-World Effectiveness of Anti-CGRP Monoclonal Antibodies Compared to Onabotulinum Toxin A (RAMO) Study.

BACKGROUND: Chronic migraine (CM) is a disabling and hard-to-treat condition, associated with high disability and high cost. Among the preventive treatments, botulinum toxin A (BoNT-a) and monoclonal antibodies against the calcitonin gene-related protein (anti-CGRP mAbs) are the only disease-specific ones. The assessment of the disease burden is complex, and among others, tools such as the allodynia symptoms checklist (ASC-12) and headache impact test (HIT-6) are very useful. This exploratory study analysed the impact of these two therapies on migraine burden. METHODS: The RAMO study was a multicentre, observational, retrospective investigation conducted in two headache centres: the Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan) and the Fondazione Policlinico Campus Bio-Medico (Rome). This study involved patients with chronic migraine treated with mAbs or BoNT-A. We conducted a subgroup exploratory analysis on HIT-6 and ASC-12 scores in the two groups. The Wilcoxon rank-sum test, Fisher's exact test, and ANOVA were performed. RESULTS: Of 126 patients, 36 on mAbs and 90 on BoNT-A had at least one available follow-up. mAbs resulted in a mean reduction of -11.1 and -11.4 points, respectively, in the HIT-6 at 6 and 12 months, while BoNT-A was reduced -3.2 and -3.6 points, respectively; the mAbs arm resulted in mean reductions in ASC-12 at 6 and 12 months of follow-up of -5.2 and -6.0 points, respectively, while BoNT-A showed lesser mean changes of -0.5 and -0.9 points, respectively. The adjusted analysis confirmed our results. CONCLUSIONS: In this exploratory analysis, anti-CGRP mAbs showed superior effectiveness for HIT-6 and ASC12 compared to BoNT-A. Reductions in terms of month headache days (MHD), migraine disability assessment test (MIDAS), and migraine acute medications (MAM) were clinically relevant for both treatments.

Effects of prophylactic drug therapies and anti-calcitonin peptide-related monoclonal antibodies on subjective sleep quality: An Italian multicenter study.

OBJECTIVE/BACKGROUND: sleep alterations strongly influence migraine severity. Prophylactic therapies have a major impact on migraine frequency and associated symptoms. The study purpose was to compare the impact of oral drug therapies or gene-related anti-calcitonin monoclonal antibodies (anti-CGRP mAbs) on sleep alterations. We also evaluated which drug therapies are more effective on sleep quality and the different impact on migraine frequency and life quality. PATIENTS/METHODS: this is a multicenter, prospective study conducted in three specialized headache centers (Marche Polytechnic University, Ancona; University of Palermo, Palermo; Fondazione Policlinico Campus Bio-Medico, Rome). At baseline, we assigned migraine patients to preventive therapy with first-line drugs or anti-CGRP mAbs. The Pittsburgh Sleep Quality Index (PSQI) and Migraine Disability Assessment (MIDAS) scales were administered. After three months, we re-evaluated the patients with the same scales. RESULTS: 214 patients were enrolled. Any prophylaxis was significantly associated with a reduction in PSQI score (mean difference 1.841; 95%CI:1.413-2.269; p < 0.0001), most significantly in the anti-CGRP mAb group (mean difference 1.49; 95%CI:2.617-0.366; p = 0.010). Anti-CGRP mAbs resulted in significant improvement in migraine severity and MIDAS scores. Among oral therapies, calcium antagonists and antidepressants were the most effective in reducing PSQI score between T0 and T1 (p = 0.042; p = 0.049; p < 0.0001, respectively). CONCLUSIONS: anti-CGRP mAbs revitalized the management of migraine with stable and well-documented efficacy. Our data also suggest that anti-CGRP mAbs result in a positive effect on sleep quality, with a significant improvement in PSQI scores. Knowing the relevant impact of sleep disruption on migraine severity, these data could help for the management of migraine patients.

Impact of carotid stenosis on the outcome of stroke patients submitted to reperfusion treatments: a narrative review.

Intravenous thrombolysis (IT) and mechanical thrombectomy (MD) are the two interventional approaches that have changed the outcome of patients with acute ischemic stroke (AIS). Ipsilateral and contralateral carotid stenosis (ICS, CCS) play an important role in regulating cerebral hemodynamics, both in chronic and acute situations such as AIS. Several studies have explored their role in the incidence and severity of stroke, but very few have investigated the possible impact of ICS and CCS on the efficacy of interventional procedures. The purpose of this review was to I) highlight the incidence and prevalence of carotid stenosis (CS); II) assess the impact of ICS and CCS on cerebral hemodynamics; III) evaluate the effect of carotid stenosis on the efficacy of interventional therapies (IT and MT) for AIS; and IV) report therapeutic complications related to CS. We searched PubMed/Medline for case reports, reviews, and original research articles on English-language review topics during the period from January 1, 2000 to October 1, 2023. CS is associated with 15-20 % of the total number of AIS. ICS and CCS had a negative influence on both cerebral hemodynamics before AIS and outcome after interventional procedures (IT, MT alone or in bridging). Available data on cerebral hemodynamics and efficacy of interventional therapies for AIS suggest a negative role of CS. Therefore, early diagnosis of CS may be considered relevant to preventive and post-stroke treatment strategies.

The evolving concept of multimorbidity and migraine.

Migraine presents with high prevalence and similar clinical course with different disorders such as neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metabolic-endocrine, and immunological conditions, which can often cooccur themselves. Multifaceted mechanisms subtend these comorbidities with a bidirectional link. First, a shared genetic load can explain the cooccurrence. Second, comorbid pathologies can promote disproportionate energetic needs, thalamocortical network dysexcitability, and systemic transient or persistent proinflammatory state, which may trigger the activation of a broad self-protective network that includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This response results in maintenance of brain homeostasis by modulating subcortical-cortical excitability, energetic balance, osmoregulation, and emotional response. In this process, the CGRP is released in the trigeminovascular system. However, the calcitonin gene-related peptide (CGRP) plays several actions also outside the brain to maintain the homeostatic needs and is involved in the physiological functions of different systems, whose disorders are associated with migraine. This aspect further increases the complexity of migraine treatment, where standard therapies often have systemic adverse effects. On the other hand, some preventives can improve comorbid conditions. In summary, we propose that migraine management should involve a multidisciplinary approach to identify and mitigate potential risk factors and comorbidity and tailor therapies individually.

Real-world effectiveness of Anti-CGRP monoclonal antibodies compared to OnabotulinumtoxinA (RAMO) in chronic migraine: a retrospective, observational, multicenter, cohort study.

BACKGROUND: Chronic migraine (CM) is a disabling condition with high prevalence in the general population. Until the recent approval of monoclonal antibodies targeting the calcitonin gene-related peptide (Anti-CGRP mAbs), OnabotulinumtoxinA (BoNT-A) was the only treatment specifically approved for CM prophylaxis. Direct comparisons between the two treatments are not available so far. METHODS: We performed an observational, retrospective, multicenter study in Italy to compare the real-world effectiveness of Anti-CGRP mAbs and BoNT-A. Patients with CM who had received either treatment according to Italian prescribing regulations were extracted from available clinical databases. Efficacy outcomes included the change from baseline in monthly headache days (MHD), MIgraine Disability ASsessment test (MIDAS), and monthly acute medications (MAM) evaluated at 6 and 12 months of follow-up. The primary outcome was MHD change from baseline at 12 months. Safety outcomes included serious adverse events (SAE) and treatment discontinuation. Unadjusted and adjusted models were used for the analyses. RESULTS: Two hundred sixteen potentially eligible patients were screened; 183 (86 Anti-CGRP mAbs; 97 BoNT-A) were included. One hundred seventy-one (80 Anti-CGRP mAbs; 91 BoNT-A) and 154 (69 Anti-CGRP mAbs; 85 BoNT-A) patients were included in the efficacy analysis at 6 and 12 months of follow-up, respectively. Anti-CGRP mAbs and BoNT-A both resulted in a mean MHD reduction at 6 (-11.5 and -7.2 days, respectively; unadjusted mean difference -4.3; 95%CI -6.6 to -2.0; p = 0.0003) and 12 months (-11.9 and -7.6, respectively; unadjusted mean difference -4.4; 95%CI -6.8 to -2.0; p = 0.0002) of follow-up. Similar results were observed after adjusting for baseline confounders. Anti-CGRP mAbs showed a significant MIDAS (-31.7 and -19.2 points, p = 0.0001 and p = 0.0296, respectively) and MAM reduction (-5.1 and -3.1 administrations, p = 0.0023 and p = 0.0574, respectively) compared to BoNT-A at 6 and 12 months. No SAEs were reported. One patient receiving fremanezumab discontinued treatment due to arthralgia. Treatment discontinuations, mainly for inefficacy, were comparable. CONCLUSION: Both Anti-CGRP mAbs and BoNT-A were effective in CM patients with Anti-CGRP mAbs presenting higher effect magnitude, with comparable safety. Still, BoNT-A remains a valuable option for CM patients with contraindications to Anti-CGRP mAbs or for frail categories who are candidates to local therapy with limited risk of systemic administration.

Long-Term Effectiveness of Galcanezumab in the Prevention of Migraine: An Italian Retrospective Analysis (REALITY).

BACKGROUND: Galcanezumab is approved in the European Union (EU) as migraine prophylaxis in adults with at least four migraine days per month. The aim of this retrospective observational study was to evaluate the long-term effectiveness of galcanezumab on migraine-related burdens and its impact on the use of healthcare resources for migraine prophylaxis in an Italian setting. METHODS: This retrospective study was conducted in patients with migraine who initiated treatment with galcanezumab for migraine prevention between September 2019 and December 2020. Patient data for monthly migraine days (MMDs) and MMDs with acute medication intake were obtained by medical chart reviews. Information on patient-reported outcomes (using the Migraine Disability Assessment [MIDAS] questionnaire and Headache Impact Test 6 [HIT-6] questionnaire) and on the use of healthcare resources were also collected. The time points of interest were 1, 3, 6, 9, 12 months after the initiation of galcanezumab, and the most recent time point available during follow-up. RESULTS: A total of 207 patients were enrolled in the study. Starting from month 3 after treatment initiation, more than half of the patients presented at least a 50% reduction in MMDs, and approximately one-third of non-responders at month 3 became responders at month 6. From month 3 to month 12, MMDs decreased on average by 10 days. Headache impact and disability, as well as migraine-associated health resource utilization decreased significantly during the treatment period. A positive significant association among the three dimensions of clinical burden (MMDs, MIDAS and days of acute medication intake) was also observed. CONCLUSION: The results of this Italian real-world study confirmed that galcanezumab has a rapid onset of effect and provides a long-term response among patients over different migraine-related burdens. The use of healthcare resources was also remarkably reduced.

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.

Galcanezumab in the Treatment of Migraine: A Narrative Review of Real-World Studies.

OBJECTIVES: Randomized controlled trials (RCTs) have established the efficacy of galcanezumab, an antibody binding calcitonin gene-related peptide (CGRP) ligand, in the preventive treatment of migraine. The objective was to summarize real-world data evaluating galcanezumab in the preventive treatment of migraine, to complement RCT results with evidence observed in clinical practice. METHODS: A literature search was conducted to identify real-world studies evaluating galcanezumab in the treatment for patients with migraine. RESULTS: Twenty-five studies were identified; some only evaluated galcanezumab, and others used pooled data from multiple anti-CGRP antibodies. The studies recruited diverse patient populations, including patients who had failed multiple prior preventive therapies. Treatment was associated with significant reductions from baseline in monthly migraine days and monthly headache days by 4.3 to 12.9 and 3.1 to 13.9, respectively. These values were numerically greater than those reported in most galcanezumab RCTs. Significant decreases from baseline were evident within the first month of treatment, and efficacy was maintained throughout the follow-up periods, ranging from 3 to 12 months. Galcanezumab was also associated with improvements in other efficacy end points, including decreased headache pain intensity, reduction in analgesic use, and improvements in daily functioning and quality of life. Functionality scores, as assessed by the Migraine Disability Assessment Scale questionnaire, decreased by 27 to 75 points from baseline at 3 to 12 months. Galcanezumab was associated with a low discontinuation rate and higher rates of persistence compared with standard migraine preventive treatments. CONCLUSIONS: The results provide complementary data that galcanezumab is effective across the diverse patient populations observed in routine clinical practice.

Eptinezumab for the Prevention of Migraine: Clinical Utility, Patient Preferences and Selection - A Narrative Review.

The new Calcitonin Gene-Related Peptide (CGRP)-targeted therapies have proven high efficacy and tolerability in episodic and chronic migraine. Eptinezumab is a humanized monoclonal antibody that selectively binds CGRP with high affinity. Eptinezumab was approved by the Food and Drug Administration on February 21st, 2020, for the preventive treatment of migraine in adults. It is administered intravenously over 30 minutes with a standard dose of 100 mg and has a T-max of 30 minutes-1 hour and a half-life of 27 days. These pharmacological properties allow for a very rapid onset of effect and a quarterly administration. It is the first time that a preventive treatment for migraine can be offered as an intravenous administration. As the range of therapeutic possibilities in migraine is expanding, the treatment process must include common decision-making, where physicians should explain in detail to patients the different characteristics of treatment options beyond efficacy and side effects. Patients can now express a preference on a range of opportunities: pharmacological versus non-pharmacological approaches, route of administration, frequency of administration, efficacy, rapidity, side effects, costs, the possibility of titration or dosing, and durability of effectiveness at suspension. Also, patient preferences can be influenced by age, country, migraine severity, and earlier experience with CGRP-targeted therapies. Besides, adherence may be influenced by several factors, including route and the schedule of administration. This narrative review describes a new perspective from the patient's point of view. Clinicians should ally with patients to select treatments that meet each patient's needs and thus apply a tailored approach, addressing not only headaches. In this way, physicians would care for the patients globally and stand out their preferences on different aspects of treatment. Besides, healthcare professionals shall be aware that patients' beliefs about therapies are subject to change with increasing experience with new therapeutic approaches.

Calcitonin Gene-Related Peptide Systemic Effects: Embracing the Complexity of Its Biological Roles-A Narrative Review.

The calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed throughout the human body. While primarily recognized as a nociceptive mediator, CGRP antagonists are currently utilized for migraine treatment. However, its role extends far beyond this, acting as a regulator of numerous biological processes. Indeed, CGRP plays a crucial role in vasodilation, inflammation, intestinal motility, and apoptosis. In this review, we explore the non-nociceptive effects of CGRP in various body systems, revealing actions that can be contradictory at times. In the cardiovascular system, it functions as a potent vasodilator, yet its antagonists do not induce arterial hypertension, suggesting concurrent modulation by other molecules. As an immunomodulator, CGRP exhibits intriguing complexity, displaying both anti-inflammatory and pro-inflammatory effects. Furthermore, CGRP appears to be involved in obesity development while paradoxically reducing appetite. A thorough investigation of CGRP's biological effects is crucial for anticipating potential side effects associated with its antagonists' use and for developing novel therapies in other medical fields. In summary, CGRP represents a neuropeptide with a complex systemic impact, extending well beyond nociception, thus offering new perspectives in medical research and therapeutics.

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.

Quantitative and Qualitative Pain Evaluation in Response to OnabotulinumtoxinA for Chronic Migraine: An Observational Real-Life Study.

(1) Background: Randomized controlled trials and real-life studies demonstrated the efficacy of OnabotulinumtoxinA (OBT-A) for CM prevention. However, no studies specifically addressed its effect on pain's quantitative intensity and qualitative characteristics. (2) Methods: This is an ambispective study: a post-hoc retrospective analysis of real-life prospectively collected data from two Italian headache centers on CM patients treated with OBT-A over one year (i.e., Cy1-4). The primary endpoint was the changes in pain intensity (Numeric Rating Scale, NRS; the Present Pain Intensity (PPI) scale, the 6-point Behavioral Rating Scale (BRS-6)) and quality scale (the short-form McGill Pain Questionnaire (SF-MPQ)) scores. We also assessed the relationship between changes in intensity and quality of pain and disability scale (MIDAS; HIT-6) scores, monthly headache days (MHDs), and monthly acute medication intake (MAMI) (3) Results: We retrieved 152 cases (51.5 years SD 11.3, 80.3% females). From baseline to Cy-4, MHDs, MAMI, NRS, PPI, and BRS-6 scores decreased (consistently p < 0.001). Only the throbbing (p = 0.004), splitting (p = 0.018), and sickening (p = 0.017) qualities of pain collected in the SF-MPQ were reduced. Score variations in MIDAS related to those in PPI scales (p = 0.035), in the BRS-6 (p = 0.001), and in the NRS (p = 0.003). Similarly, HIT-6 score changes related to PPI score modifications (p = 0.027), in BRS-6 (p = 0.001) and NRS (p = 0.006). Conversely, MAMI variation was not associated with qualitative or quantitative pain score modifications except BRS-6 (p = 0.018). (4) Conclusions: Our study shows that OBT-A alleviates migraine by reducing its impact on multiple aspects, such as frequency, disability, and pain intensity. The beneficial effect on pain intensity seems specific to pain characteristics related to C-fiber transmission and is associated with a reduction in migraine-related disability.

Stroke territory and atherosclerosis in ischemic stroke patients with a history of migraine with aura.

Introduction: The mechanisms subtending the increased stroke risk in migraine with aura (MA) are not fully understood. Our study aims to evaluate if the clinical profile in stroke patients with MA differentiates from those without MA. Methods: We retrieved the prospective registered electronic clinical dossiers of adult patients younger than 60 years with acute ischemic stroke admitted in four hospitals between January 2016 and June 2022. Patients were classified by the history of MA (MA+ and MA-). Results: We identified 851 stroke patients (59 MA+, 6.9%). Compared to MA-, MA+ patients were characterized by younger age (44.0 ± 10.6 vs 50.1 ± 8.2 years), female sex (59.3% vs 29.0%), and affected by cryptogenic (OR 2.594 95% CI 1.483-4.537), and cerebellar stroke (OR 3.218 95% CI 1.657-6.250; p ≤ 0.001 for all comparisons). After adjusting for age and sex, MA+ patients presented less frequently hypertension (OR 0.349 95% CI 0.167-0.470; p=0.005) and dyslipidemia (OR 0.523 95% CI 0.280-0.974; p = 0.041). After adjusting also for risk factors, the MA+ group had less frequently symptomatic large vessel stenosis (OR 0.126 95% CI 0.017-0,924; p = 0.042) and clinical atherosclerosis (OR 0.103 95% CI 0.014-0.761; p = 0.026), while intima-media thickness did not differ (p = 0.395). Discussion: Cryptogenic and cerebellar stroke and fewer vascular risk factors and clinical atherosclerosis seem to characterize stroke patients with MA.

Effective Intracerebral Connectivity in Acute Stroke: A TMS-EEG Study.

Stroke is a major cause of disability because of its motor and cognitive sequelae even when the acute phase of stabilization of vital parameters is overcome. The most important improvements occur in the first 8-12 weeks after stroke, indicating that it is crucial to improve our understanding of the dynamics of phenomena occurring in this time window to prospectively target rehabilitation procedures from the earliest stages after the event. Here, we studied the intracortical excitability properties of delivering transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) of left and right hemispheres in 17 stroke patients who suffered a mono-lateral left hemispheric stroke, excluding pure cortical damage. All patients were studied within 10 days of symptom onset. TMS-evoked potentials (TEPs) were collected via a TMS-compatible electroencephalogram system (TMS-EEG) concurrently with motor-evoked responses (MEPs) induced in the contralateral first dorsal interosseous muscle. Comparison with age-matched healthy volunteers was made by collecting the same bilateral-stimulation data in nine healthy volunteers as controls. Excitability in the acute phase revealed relevant changes in the relationship between left lesioned and contralesionally right hemispheric homologous areas both for TEPs and MEPs. While the paretic hand displayed reduced MEPs compared to the non-paretic hand and to healthy volunteers, TEPs revealed an overexcitable lesioned hemisphere with respect to both healthy volunteers and the contra-lesion side. Our quantitative results advance the understanding of the impairment of intracortical inhibitory networks. The neuronal dysfunction most probably changes the excitatory/inhibitory on-center off-surround organization that supports already acquired learning and reorganization phenomena that support recovery from stroke sequelae.

Maintenance of response and predictive factors of 1-year GalcanezumAb treatment in real-life migraine patients in Italy: The multicenter prospective cohort GARLIT study.

BACKGROUND AND PURPOSE: To evaluate the 1-year effectiveness and tolerability of galcanezumab in real life and the prognostic indicators of persistent response. METHODS: High-frequency episodic migraine (HFEM) and chronic migraine (CM) patients treated with galcanezumab who completed a 1-year observation were enrolled. The primary outcomes assessed during the 12 months (V1-V12) were the change in monthly migraine days (MMDs) from baseline and the response rates ≥50% in MMDs (MMD ≥50% RR). The secondary outcomes were changes in pain intensity (numerical rating scale [NRS]) and in monthly acute medication intake (MAMI). RESULTS: We enrolled 191 patients (77.5% CM). Twenty-three patients (12%) dropped out, two for nonserious adverse events. At least 40% of patients took add-on standard preventives from baseline to V12. At V12, MMDs were reduced by 6.0 days in HFEM and by 11.9 days in CM patients (both p < 0.00001); NRS and MAMI were also decreased in both groups (p < 0.00001). One-hundred eight (56.5%) patients presented MMD ≥50% RR for 9 cumulative months (interquartile range=8): we defined this value as the cutoff for a persistent response. Persistent responders were less likely to have a higher body mass index (BMI) (p = 0.007) but more frequently had a good response to triptans (p = 0.005) and MMD ≥50% RR at V1 (p < 0.0000001). Patients without a persistent response were on add-on therapy for longer periods of time (p < 0.001). CONCLUSIONS: Galcanezumab was effective and well-tolerated in the 1-year term, with most patients presenting MMD ≥50% RR for at least 9 months. Triptan response, lower BMI, and MMD ≥50% RR in the first month emerged as predictive factors for a persistent response.

Predictors of response to anti-CGRP monoclonal antibodies: a 24-week, multicenter, prospective study on 864 migraine patients.

BACKGROUND AND OBJECTIVES: The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8-14 days/month) or chronic migraine (CM). METHODS: This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician's choice, or patient's preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. RESULTS: Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57-11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05-2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15-3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04-2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07-0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42-8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14-2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22-3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. CONCLUSIONS: A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.

Improving distress perception and mutuality in migraine caregivers after 6 months of galcanezumab treatment.

OBJECTIVE: This prospective cohort, real-life study aimed to evaluate whether galcanezumab, a monoclonal antibody anti-calcitonin gene-related peptide (CGRP) ligand, can reduce caregivers' distress and improve their mutuality with patients. BACKGROUND: Migraine is a highly disabling chronic disease that negatively impacts patients' and often their relatives' lives, occurring during an active phase of life with direct consequences on leisure- and work-related activities. The figure of caregiver is crucial in several neurological conditions but poorly accounted for in migraine care so far. Studies on monoclonal antibodies against the CGRP pathway, recently introduced as migraine-preventive treatments, demonstrated that they significantly reduce migraine frequency and disability in the first weeks of treatment. METHODS: Consecutive patient-caregiver dyads were evaluated at baseline and after 6 months of treatment with galcanezumab (V6) at our headache center from September 2020 to September 2021. Enrolled patients were requested to report their monthly migraine days, monthly intake of acute medications, attack pain intensity (on the Numeric Rating Scale), concomitant preventives, and disability questionnaires (Headache Impact Test, Migraine Disability Assessment). Each dyad filled in the Mutuality Scale to check their reciprocity; moreover, the Relatives' Stress Scale was used to detect caregivers' distress. RESULTS: We enrolled 27 patient-caregiver dyads. At 6 months, migraine burden significantly improved with reductions in monthly migraine days (falling from 14.8 [SD = 4.8] days by 10.3 [SD = 4.8] days; 95% CI: 8.4, 12.2; p < 0.001) and Migraine Disability Assessment scores (lowering from 83.6 [SD = 46.7] by 71.5 points [SD = 49.3]; 95% CI: 51.2, 91.9; p < 0.001). From baseline to month 6, the caregiver Relatives' Stress Scale score significantly decreased (falling from 20.7 [SD = 13.7] by 6.5 [SD = 14.1] points; 95% CI: 0.8, 12.2; p = 0.027), while the Mutuality Scale's caregiver total score increased (from 3.04 [SD = 0.61] by 0.29 [SD = 0.49] points; 95% CI: -0.508, -0.064; p = 0.014). CONCLUSIONS: Our findings preliminarily demonstrated that patients' migraine improvement after 6 months of galcanezumab treatment could be favorably perceived by caregivers, significantly reducing their distress with better reciprocity within the dyad.

Excellent Response to OnabotulinumtoxinA: Different Definitions, Different Predictors.

The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle.

Cerebral Hemodynamics, Right-to-Left Shunt and White Matter Hyperintensities in Patients with Migraine with Aura, Young Stroke Patients and Controls.

Background: Migraine with aura (MA) patients present an increased risk of cerebrovascular events. However, whether these patients present an increased white matter hyperintensities (WMHs) load compared to the general population is still under debate. Our study aimed to evaluate the relationship between cerebral hemodynamics, right-to-left shunt (RLS) and WMHs in MA patients, young patients with cryptogenic stroke or motor transient ischemic attack (TIA) and controls. Methods: We enrolled 30 MA patients, 20 young (<60 years) patients with cryptogenic stroke/motor TIA, and 10 controls. All the subjects underwent a transcranial Doppler bubble test to detect RLS and cerebral hemodynamics assessed by the breath holding index (BHI) for the middle (MCA) and posterior (PCA) cerebral arteries. Vascular risk factors were collected. The WMHs load on FLAIR MRI sequences was quantitatively assessed. Results: The stroke/TIA patients presented a higher prevalence of RLS (100%) compared with the other groups (p < 0.001). The MA patients presented a higher BHI compared with the other groups in the PCA (p = 0.010) and higher RLS prevalence (60%) than controls (30%) (p < 0.001). The WMHs load did not differ across groups. BHI and RLS were not correlated to the WMHs load in the groups. Conclusions: A preserved or more reactive cerebral hemodynamics and the presence of a RLS are likely not involved in the genesis of WMHs in MA patients. A higher BHI may counteract the risk related to their higher prevalence of RLS. These results need to be confirmed by further studies to be able to effectively identify the protective role of cerebral hemodynamics in the increased RLS frequency in MA patients.