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.

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.

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.

Rapid response to galcanezumab and predictive factors in chronic migraine patients: A 3-month observational, longitudinal, cohort, multicenter, Italian real-life study.

BACKGROUND AND PURPOSE: A rapid response to preventive therapy is of pivotal importance in severely disabled patients with chronic migraine (CM) and diverse preventive treatment failures. This prospective, observational, multicenter real-life study aimed at investigating the effectiveness of galcanezumab in the first 3 months of treatment of CM patients at 14 Italian headache centers. METHODS: All consecutive adult patients with CM diagnosis with the clinical indication for galcanezumab were considered. We collected patients' baseline characteristics, monthly headache days, monthly painkiller intake, migraine clinical characteristics, and disability scale scores during a 1-month run-in period (baseline) and the first 3 months of therapy. Possible predictive factors of treatment were considered. RESULTS: A total of 156 patients (82.4% female, aged 47.3 ± 12.3 years) were enrolled. The 65 (41.7%) patients with a consecutive ≥50% response rate (RR) in the 3 months of therapy presented a lower body mass index (p = 0.004) and more frequently presented unilateral migraine pain (p = 0.002) and good response to triptans (p = 0.003). Persistent conversion from CM to episodic migraine was observed in 55.8% (87/156) of patients. They more frequently presented a good response to triptans (p = 0.003) and unilateral pain (p = 0.046). At baseline, 131 of 156 (83.9%) patients presented medication overuse (MO). Of these, 61.8% (81/131) no longer displayed MO consistently during the 3 months. These patients were more frequently responders to triptans (p = 0.002) and less frequently suffered from gastrointestinal comorbidity (p = 0.007). CONCLUSIONS: Unilateral pain, good response to triptans, and normal weight may be associated with a persistent positive response in the first 3 months of therapy with galcanezumab in CM patients.

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.

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.

Task-switching abilities in episodic and chronic migraine.

Migraineurs show impaired cognitive functions interictally, mainly involving information processing speed, basic attention, and executive functions. We aimed to assess executive impairment in migraine patients with different attack frequencies through a task-switching protocol designed to assess different sub-processes of executive functioning. We enrolled 42 migraine patients and divided them into three groups based on the attack frequency: 13 subjects had episodic migraine with a low frequency (LFEM, 4-7 migraine days per month), 14 subjects had high-frequency episodic migraine (HFEM, 8-14 days) and, finally, 15 subjects presented chronic migraine (≥ 15 headache days/month, CM); we compared them to 20 healthy control (HC), matched to both gender and education. Patients with high headache frequencies (CM and HFEM) showed worse performance than LFEM and HC controls, as indicated by poor accuracy, increased switch cost, and reaction times. Our study demonstrated a difference in task-switching abilities in patients with high frequency or chronic migraine compared with low-frequency episodic migraine and healthy controls. These difficulties in executive control processes could be related to altered functioning of the frontal cortex and its cortical and subcortical connections.

Erenumab does not alter cerebral hemodynamics and endothelial function in migraine without aura.

OBJECTIVE: To assess whether erenumab influences cerebral vasomotor reactivity and flow-mediated dilation in migraine patients. METHODS: Consecutive migraineurs prescribed erenumab at our Headache Centre and age and sex-matching controls were invited to participate in this observational longitudinal study. Patients were evaluated for cerebral vasomotor reactivity to hypercapnia (breath-holding index) in middle and posterior cerebral arteries and for brachial corrected flow mediated dilation at baseline (T0), after 2 weeks from the first erenumab injection (T2) and after 2 weeks from the fourth Erenumab injection (T18). Patients displaying a reduction of at least 50% in monthly migraine days after completing the fourth month of therapy were classified as responders. RESULTS: Sixty patients and 25 controls agreed to participate. Middle and posterior cerebral artery mean flow velocities, breath-holding index and flow-mediated dilation did not differ at T0 and from T0 to T2 in patients and controls. In patients, we neither observed a variation of the explored variables from T0 to T18 nor an interaction between evaluation times (T0-T2 or T0-T18) and chronic condition at T0, responder state or erenumab fourth dose. CONCLUSIONS: Our findings demonstrate that erenumab preserves cerebral vasomotor reactivity and flow-mediated dilation in migraineurs without aura.

Discontinuing monoclonal antibodies targeting CGRP pathway after one-year treatment: an observational longitudinal cohort study.

BACKGROUND: Monoclonal antibodies anti-calcitonin gene-related peptide (mAbs anti-CGRP) pathway are effective and safe on migraine prevention. However, some drug agencies limited these treatments to one year due to their high costs. This study aimed at evaluating the effect of discontinuing mAbs anti-CGRP on monthly migraine days (MMDs) and disability in high-frequency episodic (HFEM) and chronic migraine (CM) patients. METHODS: This observational longitudinal cohort study was conducted at 10 Italian headache centres. Consecutive adult patients were followed-up for three months (F-UP1-3) after discontinuation of a one-year erenumab/galcanezumab treatment. The primary endpoint was the change in F-UP MMDs. Secondary endpoints included variation in pain intensity (Numerical Rating Scale, NRS), monthly acute medication intake (MAMI), and HIT-6 scores. We also assessed from F-UP1 to 3 the ≥50% response rate, relapse rate to CM, and recurrence of Medication Overuse (MO). RESULTS: We enrolled 154 patients (72.1% female, 48.2 ± 11.1 years, 107 CM, 47 HFEM); 91 were treated with erenumab, 63 with galcanezumab. From F-UP1 to F-UP3, MMDs, MAMI, NRS, and HIT-6 progressively increased but were still lower at F-UP3 than baseline (Friedman's analysis of rank, p < .001). In the F-UP1-3 visits, ≥50% response rate frequency did not differ significantly between CM and HFEM patients. However, the median reduction in response rate at F-UP3 was higher in HFEM (- 47.7% [25th, - 79.5; 75th,-17.0]) than in CM patients (- 25.5% [25th, - 47.1; 75th, - 3.3]; Mann-Whitney U test; p = .032). Of the 84 baseline CM patients who had reverted to episodic migraine, 28 (33.3%) relapsed to CM at F-UP1, 35 (41.7%) at F-UP2, 39 (46.4%) at F-UP3. Of the 64 baseline patients suffering of medication overuse headache ceasing MO, 15 (18.3%) relapsed to MO at F-UP1, 26 (31.6%) at F-UP2, and 30 (42.3%, 11 missing data) at F-UP3. Lower MMDs, MAMI, NRS, and HIT-6 and higher response rate in the last month of therapy characterized patients with ≥50% response rate at F-UP1 and F-UP3 (Mann-Whitney U test; consistently p < .01). CONCLUSION: Migraine frequency and disability gradually increased after mAbs anti-CGRP interruption. Most patients did not relapse to MO or CM despite the increase in MMDs. Our data suggest to reconsider mAbs anti-CGRP discontinuation.

Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study).

BACKGROUND: The clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting. METHODS: This multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation. RESULTS: One hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both p < .001). NRS, MPI, HIT-6 and MIDAS scores significantly decreased (p < .001). Ten patients (6.1%) dropped out for inefficacy and classified as non-responders. Patients with ≥50%RRs, i.e. responders, were 76.5% in the HFEM and 63.5% in the CM group at V6. Among CM patients, the V6 responders presented a lower body mass index (p = .018) and had failed a lower number of preventive treatments (p = .013) than non-responders. At V6, 77.2% of CM patients converted to EM, and 82.0% ceased MO. Adverse events, none serious, were reported in up to 10.3% of patients during evaluation times. CONCLUSIONS: Galcanezumab in real life was safe, well tolerated and seemed more effective than in RCTs. Normal weight and a low number of failed preventives were positively associated with galcanezumab effectiveness in CM patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04803513 .

Locking down the CGRP pathway during the COVID-19 pandemic lockdown: the PandeMig study.

OBJECTIVES: The COVID-19 pandemic and the consequent lockdown came as a storm disrupting people's everyday life. This study aimed at observing whether the COVID-19 related lockdown influenced migraine frequency and disability in migraine patients on therapy with monoclonal antibodies inhibiting the CGRP pathway. METHODS: In this longitudinal observational cohort study, 147 consecutive patients receiving monthly administration of erenumab or galcanezumab were enrolled in four Italian headache centers. All patients filled a questionnaire concerning working and household settings, recent flu symptoms or COVID-19 diagnosis, and family loss due to COVID-19 infection. Monthly migraine days (MMDs), monthly painkiller intake (MPI), and HIT-6 disability relative to the first month of lockdown imposition (T-lock) and the month before (T-free) were also collected. RESULTS: From T-free to T-lock, the cohort displayed a reduction in MMDs (from 10.5 ± 7.6 to 9.8 ± 7.6, p = .024) and HIT-6 scores (from 59.3 ± 8.3 men reduced MPI more frequently than women (p = .005). CONCLUSIONS: Our study observed that the lockdown impact to 57.8 ± 8.8, p = .009), while MPI resulted unchanged (from 11.6 ± 11.5 to 11.1 ± 11.7; p = .114). MMDs, MPI, and HIT-6 variations from T-free to T-lock did not differ according to work settings or household. Patients beyond the first 3 months of therapy presented less often a reduction in MMDs (p = .006) and on everyday life did not affect the migraine load in patients receiving monoclonal antibodies inhibiting the CGRP pathway. Patients in the first months of therapy experienced a greater improvement according to drug pharmacokinetics, while women more frequently needed rescue medications, possibly indicating presenteeism or cephalalgophobia.

Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence.

BACKGROUND: According to the International Classification of Headache Disorders 3, post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache reported to have developed within 7 days from head injury, regaining consciousness following the head injury, or discontinuation of medication(s) impairing the ability to sense or report headache following the head injury. It is one of the most common secondary headache disorders, and it is defined as persistent when it lasts more than 3 months. MAIN BODY: Currently, due to the high prevalence of this disorder, several preclinical studies have been conducted using different animal models of mild TBI to reproduce conditions that engender PTH. Despite representing a simplification of a complex disorder and displaying different limitations concerning the human condition, animal models are still a mainstay to study in vivo the mechanisms of PTH and have provided valuable insight into the pathophysiology and possible treatment strategies. Different models reproduce different types of trauma and have been ideated in order to ensure maximal proximity to the human condition and optimal experimental reproducibility. CONCLUSION: At present, despite its high prevalence, PTH is not entirely understood, and the differential contribution of pathophysiological mechanisms, also observed in other conditions like migraine, has to be clarified. Although facing limitations, animal models are needed to improve understanding of PTH. The knowledge of currently available models is necessary to all researchers who want to investigate PTH and contribute to unravel its mechanisms.

Right-to-Left Shunt and the Clinical Features of Migraine with Aura: Earlier but Not More.

BACKGROUND: The causal relationship between patent foramen ovale (PFO) and migraine with aura (MA) is controversial. We aimed at exploring whether attack clinical features relate to the presence of right-to-left shunt (RLS) in MA patients. METHODS: We retrospectively examined a cohort of consecutive patients diagnosed with MA in our headache center and undergoing transcranial doppler (TCD) for RLS detection. We collected from our clinical electronic dossiers, clinical features of MA attacks (type, frequency, duration of aura phenomenon, trigger factors, onset age), family history for MA, thrombophilia genotypes, and the response to preventive treatments. RLS was stratified for severity according to the results of the TCD examination. RESULTS: We found 111 patients. Binary logistic regression analysis showed that among features of MA attacks, only onset age was associated with the presence of RLS (p < 0.0001). Patients with RLS presented the first MA attack at a younger age (p < 0.0001). The greater RLS severity, the younger was onset age (p < 0.00001) and the presence of atrial septal aneurysms (ASA) was associated with a further decrease in onset age (ρ = -539, p < 0.00001). Family history for MA was associated with the presence of RLS (chi-square p = 0.022). Response to preventive treatments was not influenced by the type of treatment (antiplatelet compared with no antiplatelet drugs), comorbidity with migraine without aura, RLS presence, or by their double interactions (Logistic regression, consistently p > 0.05). CONCLUSION: Our findings support the hypothesis that although PFO does not influence MA attack frequency, it is not merely a bystander in MA physiopathology, as RLS, its severity, and the presence of ASA possibly make a difference in the disease history.

Influence of chronotype on migraine characteristics.

BACKGROUND: The aim of this study was to investigate chronotype in migraine patients and possible influences on the clinical expression of the disease. METHODS: During a one-year period, all consecutive patients admitted to two third-level headache centres with a new diagnosis of migraine were enrolled in a cross-sectional study. All subjects were submitted to the Morningness-Eveningness Questionnaire (MEQ-SA) and then classified in five different categories, from late to early-rising chronotype. Differences and trends among MEQ-SA categories and years from migraine onset, attacks' intensity and frequency were analysed first with analysis of variance, then with a multivariate/generalized linear model. RESULTS: One hundred seventy one migraine patients were included. Early-rising patients showed a lower migraine attacks frequency and longer disease duration with respect to late-rising patients. The categorical variable containing the five circadian types was able to identify a significantly different trend both for the monthly attacks frequency and for the disease duration (p < 0.0001 and p < 0.0001, respectively, analysis of variance). The results were also confirmed after correction for main influencing variables (multivariate/generalized linear model). The intensity of migraine attacks was not influenced by chronotype. CONCLUSIONS: According to the results of the present study, chronotype seems to influence number and duration of migraine attacks. Although sleep-wake cycle is a well-recognized factor able to influence thalamic-cortical synchronization, it usually does not receive appropriate consideration during migraine patients' assessment.

Methylprednisolone plus diazepam i.v. as bridge therapy for medication overuse headache.

Management of medication overuse headache (MOH) requires abrupt suspension of overused drugs either alone or in association with a detoxification protocol to prevent withdrawal. However, there is no consensus about which suspension strategy is the most effective. Moreover, reliable data about the possible mid-term effect of detoxification are not available. The objective of this study was to evaluate whether a bridge therapy consisting of a 5-day i.v. infusion of methylprednisolone and diazepam determines a significant reduction in headache frequency and drug assumption during the detoxification protocol (day 5) and in the first 3 months in patients with MOH. We conducted a retrospective non-randomized before-and-after study comparing patients with MOH undergoing a bridge therapy protocol (5-day infusion of methylprednisolone, diazepam) with those who refused the treatment and were only recommended to suspend overused painkillers. Both groups started a prophylactic treatment and were followed-up for 3 months. At day 5, 82% of our patients were headache-free; moreover, 48% of the patients did not take any painkiller during the 5-day treatment. Three months after, the intervention group showed a greater reduction of monthly headache days (9.4 vs 3.0) and drugs (19.7 vs 6.5), a greater rate of patients with a ≥ 50% reduction of monthly headaches (p = 0.019) and symptomatic drug consumption (p = 0.000), than the control group. The methylprednisolone and diazepam detoxification protocol reduced headache attacks and drug assumption immediately and in the first 3 months after the intervention, concurring to improve the effect of a new prophylactic therapy.