Cerebral Vasomotor Reactivity in the acute phase and after 6 months in non-disabling stroke/TIA: a prospective cohort study.

BACKGROUND AND AIM: Cerebral Vasomotor Reactivity (VMR) is a property of cerebral hemodynamics that protects from cerebrovascular disease. We aimed to explore the VMR longitudinal changes in patients with acute non-disabling stroke/Transient Ischemic Attack (TIA) to understand its implication in stroke ethiopatogenesis. METHODS: VMR by Transcranial Doppler Breath Holding test was performed at 48-72 h from stroke onset (T1) and after 6 months (T2) on MCA of the non-affected hemisphere and PCA of the affected hemisphere. RESULTS: We consecutively enrolled 124 patients with a median age of 66.0 (IQR 54.75-74.25) years with a median NIHSS 2 (IQR 1-3). Both MCA (1.38 %/s SD 0.58) and PCA (1.35 %/s SD 0.75) BHI at T1 did not differ among different stroke subtypes (p=0.067 and p=0.350; N=124). MCA and PCA BHI decreased from T1 to T2 (respectively 1.39 %/s SD 0.56 vs 1.18%/s SD 0.44 and 1.30 %/s SD 0.69 vs 1.20 %/s SD 0.51; N=109) regardless of ethiopatogenesis (respectively p<0.0001 and p=0.111). CONCLUSION: the VMR is higher in acute phase than at 6 months in patients with non-disabling stroke/TIA, regardless of etiopathogenesis. The higher VMR in acute phase could be sustained by an increased Cerebral Blood Flow due to collateral circulation activation supporting the ischemic zone.

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.

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.

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.

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.

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.

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.

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.

Gepants - a long way to cure: a narrative review.

Calcitonin gene-related peptide (CGRP) is probably the most potent vasodilator in cerebral circulation. Forty years after its discovery, the new CGRP-targeted therapy monoclonal antibodies, and the small molecule gepants, are now available for clinical practice. While randomized controlled trials and real-world experience consistently demonstrated the high efficacy and tolerability of monoclonal antibodies, limited evidence is available to characterize gepants fully. Depending on pharmacokinetics, these CGRP receptor antagonists can be used for acute (ubrogepant, rimegepant, and the not yet approved zavegepant) or preventive (atogepant and rimegepant) migraine treatment. Randomized placebo-controlled trials demonstrated gepants efficacy in treating acute attacks to obtain 2 h pain freedom in about 20% of patients and pain relief in about 60%, while up to 60% of treated patients with episodic migraine may experience a 50% reduction in monthly migraine days. The most common treatment-related emergent adverse events were gastrointestinal (nausea, constipation) for the acute or preventive use. No vascular or hepatic concerns have emerged so far. More studies are ongoing to investigate gepant tolerability and safety also if associated with monoclonal antibodies targeting CGRP and other therapeutic classes. Gepants are also under investigation to treat other painful and non-painful conditions. Real-life studies are necessary to confirm the trials' findings and investigate more practical clinical aspects.

Conversion from chronic to episodic migraine in patients treated with galcanezumab in real life in Italy: the 12-month observational, longitudinal, cohort multicenter GARLIT experience.

OBJECTIVE: To investigate in real-life the conversion from chronic migraine (CM) to episodic migraine (EM), specifically to EM with High-Frequency (HFEM: 8-14 monthly migraine days, MMDs), Medium-Frequency (MFEM, 4-7 MMDs), and Low-Frequency EM (LFEM, 0-3 MMDs), and its persistence during 1 year of treatment with galcanezumab. METHODS: Consecutive CM patients treated with galcanezumab completing 1 year of observation were enrolled. We collected data on MMDs, pain intensity (Numeric Rating Scale, NRS score), and monthly acute medication intake (MAMI) from baseline (V1) to the 12-month visit (V12). RESULTS: Of the 155 enrolled patients, 116 (around 75%) reverted to EM at every visit and 81 (52.3%) for the entire 1-year treatment. Patients with older onset age (p = 0.010) and fewer baseline MMDs (p = 0.005) reverted more frequently to EM. At V12, 83 participants (53.5%) presented MFEM or LFEM. Patients reverted to MFEM or LFEM for 7 months (25th 1, 75th 11). The medication overuse discontinuation rate at V12 was 82.8% and occurred for 11 months (25th 8, 75th 12). From baseline to V12, the MAMI decreased by 17 symptomatic drugs (p < 0.000001) while the NRS score reduced by almost 2 points (p < 0.000001). A consistent transition to EM for the entire treatment year was observed in 81 (52.3%) patients. DISCUSSION: The 1-year GARLIT experience suggests that more than half of CM patients treated with galcanezumab persistently reverted to EM in real life. TRIAL REGISTRATION: ClinicalTrials.gov NCT04803513.

Carotid Artery Plaque Progression: Proposal of a New Predictive Score and Role of Carotid Intima-Media Thickness.

BACKGROUND: We aimed to investigate if the carotid intima-media thickness (IMT) at baseline and the HAD2S score, composed of the sum of single risk factors (hypertension, age ≥ 75 years, diabetes, dyslipidemia, smoking), were predictive of plaque progression. METHODS: We performed a retrospective analysis on real-life prospectively collected data from patients with any detectable carotid plaque at follow up. The plaque score, calculated at baseline (T0) and at a median follow up of 36.6 months (IQR 39.6-34.3) (T3), was defined as 0: no plaque or stenosis < 30%; 1: stenosis in the range 30-49%; 2: in the range 50-69%; 3: in the range 70-99% and 4: occlusion. Carotid IMT was measured at T0 and T3; HAD2S score was calculated at baseline. RESULTS: We included 340 patients with a mean age of 69.9 (9.1) years and 25.3% subjects had plaque progression. Individuals with progression had a median HAD2S score of 3 (1) while those without progression had 2 (1). Patients with progression had a mean baseline IMT of 0.86 (0.17) while those without progression had 0.77 (0.18) (p < 0.0001). A correlation between progression and baseline IMT was found (p = 0.002). CONCLUSION: Baseline IMT could be considered a predictor of progression. Patients with progression had an HAD2S score higher than those without evolution.