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INTRODUCTION: In 2020, the Italian Medicines Agency (AIFA) approved the reimbursement of calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies (mAbs), including fremanezumab, in patients with a Migraine Disability Assessment Scale (MIDAS) score ≥ 11, with prescription renewals for up to 12 months in patients with ≥ 50% reduction in MIDAS score at Months 3 and 6. In this sub-analysis of the Pan-European Real Life (PEARL) study, we provide real-world data on fremanezumab use in Italian routine clinical practice (EUPAS35111). METHODS: This first interim analysis for Italy was conducted when 300 enrolled adult patients with episodic or chronic migraine (EM, CM) completed 6 months of treatment with fremanezumab. The primary endpoint is the proportion of patients achieving ≥ 50% reduction in monthly migraine days (MMD) across the 6 months post-fremanezumab initiation. Secondary endpoints include: proportion of patients achieving ≥ 50% reduction in MIDAS score at Months 3 and 6, and mean change from baseline across Months 1-6 in MMD and headache-related disability. Safety was assessed through adverse events (AEs) reported. RESULTS: Of 354 patients enrolled at Italian centers, 318 (EM, 35.5%, CM, 64.5%) were included in the effectiveness analysis. Of patients with available data, 109 (61.2%) achieved the primary endpoint. 61.0% and 65.1% achieved ≥ 50% reduction in MMDs at Months 3 and 6, respectively; 79.9% and 81.0% experienced ≥ 50% reduction in MIDAS at the same timepoints. CONCLUSION: Fremanezumab was effective and well-tolerated over the first 6 months of treatment, with approximately 80% of patients meeting Italian criteria for treatment continuation at Months 3 and 6.
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Anticorpos Monoclonais , Transtornos de Enxaqueca , Adulto , Humanos , Anticorpos Monoclonais/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Migraine is the second world's cause of disability. Among non-pharmacological treatments, nutritional intervention, particularly ketogenic diet, represents one of the most promising approaches. METHODS: This a prospective, single center, randomized, controlled study aimed at evaluating the efficacy of a very low-calorie ketogenic diet (VLCKD) compared to a hypocaloric balanced diet (HBD) in migraine prophylaxis in patients affected by high-frequency episodic migraine (HFEM) with a Body Mass Index (BMI) > 27 kg/m2. Fifty-seven patients were randomly assigned to a VLCKD (group 1) or HBD (group 2). Group 1 patients followed a VLCKD for 8 weeks, followed by a low calorie diet (LCD, weeks 9-12), and a HBD (weeks 13-24), whereas group 2 patients followed a HBD from week 0 to 24. Anthropometric indexes, urine and blood chemistry were assessed at enrollment, baseline, weeks 4, 8, 12, and 24. Migraine characteristics were evaluated at baseline, weeks 8, 12 and 24. Change in monthly migraine days (MMDs) at weeks 5-8 compared to baseline was the primary endpoint. Secondary endpoints encompassed changes in visual analogue scale (VAS), Headache Impact Test-6 (HIT-6) and Short Form Health Survey-36 (SF-36) scores. We also studied effects on circulating lymphocytes and markers of inflammation, changes in plasma aldosterone and renin levels before and after VLCKD or HBD treatment. RESULTS: Reduction from baseline in MMDs was greater in VLCKD compared to HBD group at week 8 (p = 0.008), at week 12 (p = 0.007), when ketosis had been interrupted by carbohydrates reintroduction, and at week 24 (p = 0.042), when all patients were following the same dietary regimen. Quality of life scores (SF-36) were improved in VLCKD group at week 8 and 12, and were also improved in HBD group, but only at week 12. Weight-loss was significantly higher in VLCKD group at week 8 (p = 0.002) and week 12 (p = 0.020). At the end of the study weight loss was maintained in VLCKD group whereas a slight weight regain was observed in HBD group. Inflammatory indexes, namely C reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and total white blood cell count (WBC) were significantly reduced (p < 0.05) in VLCKD group at week 12. Aldosterone plasma level were significantly increased in both groups at week 8, particularly in VLCKD group. However, electrolytes and renin plasma levels were never altered throughout the study in both groups. CONCLUSIONS: VLCKD is more effective than HBD in reducing MMD in patients with HFEM and represents an effective prophylaxis in patients with overweight/obesity. Trial registration ClinicalTrials.gov identifier: NCT04360148.
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Dieta Cetogênica , Transtornos de Enxaqueca , Humanos , Qualidade de Vida , Aldosterona , Estudos Prospectivos , Renina , Redução de Peso , Transtornos de Enxaqueca/prevenção & controleRESUMO
BACKGROUND AND PURPOSE: In the phase 3b, randomized, double-blind, placebo-controlled DELIVER clinical trial, eptinezumab reduced migraine frequency and headache in adults with two to four prior preventive treatment failures. Here, the effect of eptinezumab on coinciding patient-reported outcomes is reported. METHODS: Adults were randomized to receive eptinezumab 100, 300 mg or placebo intravenously at weeks 12 and 24. The EQ-5D-5L, measuring overall patient health, and the six-item Headache Impact Test were completed every 4 weeks. The Patient Global Impression of Change was completed at weeks 4, 12 and 24. Patient-identified most bothersome symptom and the Migraine-Specific Quality of Life Questionnaire were administered at weeks 12 and 24. RESULTS: Eptinezumab improved patient-reported outcomes more than placebo, starting at week 4 and at all subsequent time points. By week 12, patients' overall health (EQ-5D-5L visual analog scale score) improved with eptinezumab treatment (difference from placebo in change from baseline: 100 mg, 5.1, 95% confidence interval [CI] 2.2, 8.1, p < 0.001; 300 mg, 7.5, 95% CI 4.5, 10.4, p < 0.0001). At week 12, eptinezumab improved headache-related quality of life (difference from placebo in change from baseline in Headache Impact Test total score: 100 mg, -3.8, 95% CI -5.0, -2.5, p < 0.0001; 300 mg, -5.4, 95% CI -6.7, -4.2, p < 0.0001), including each Migraine-Specific Quality of Life Questionnaire domain (p ≤ 0.0001, all comparisons). Over twice as many patients receiving eptinezumab than placebo reported much or very much improvement on the Patient Global Impression of Change and patient-identified most bothersome symptom. CONCLUSION: Patients with two to four prior preventive treatment failures receiving eptinezumab versus placebo reported greater improvements in well-being, quality of life and most bothersome symptoms compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04418765; EudraCT identifier: 2019-004497-25.
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Transtornos de Enxaqueca , Qualidade de Vida , Adulto , Humanos , Resultado do Tratamento , Transtornos de Enxaqueca/tratamento farmacológico , Falha de Tratamento , Cefaleia , Método Duplo-Cego , Medidas de Resultados Relatados pelo PacienteRESUMO
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.
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Transtornos de Enxaqueca , Humanos , Estudos Prospectivos , Resultado do Tratamento , Método Duplo-Cego , Transtornos de Enxaqueca/tratamento farmacológico , Triptaminas/uso terapêuticoRESUMO
BACKGROUND: To verify the long-term (24-week) efficacy, safety, and tolerability of fremanezumab in real-life patients with high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM: ≥ 15 days/month), and multiple preventive treatment failures. METHODS: This is a prospective, cohort, real-life study at 28 headache centers on consecutive patients affected by HFEM or CM with multiple preventive treatment failures who were prescribed subcutaneous fremanezumab (225 mg monthly/675 mg quarterly) for ≥ 24 weeks. Primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM at weeks 21-24 compared to baseline. Secondary endpoints encompassed changes in monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS, HIT-6 and MIDAS scores at the same time interval. Changes in MMDs/MHDs, monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS and HIT-6 scores at week 4 were also monitored. RESULTS: Four hundred ten patients who had received ≥ 1 dose of fremanezumab were considered for safety analysis while 148 patients treated for ≥ 24 weeks were included in the efficacy analysis. At weeks 21-24, fremanezumab significantly (p < 0.001) reduced MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM compared to baseline. The proportions of ≥ 50%, ≥ 75% and 100% responders at weeks 21-24were 75.0%, 30.8%, 9.6% (HFEM), and 72.9, 44.8 and 1% (CM). A significant (p < 0.001) decrease in MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM was already present at week 4. The proportions of ≥ 50%, ≥ 75%, and 100% responders at week 4 were 67.6%, 32.4%, 11.8% (HFEM) and 67.3%, 40%, 1.8% (CM). CM remitted to episodic migraine and medication overuse to no-medication overuse in 83.3 and 75% of patients at week 24, and in 80 and 72.4% at week 4. Adverse events were rare (2.4%), mild and transient. No patient discontinued treatment for any reason. CONCLUSIONS: Fremanezumab is characterized by an early and sustained efficacy in HFEM and CM patients with multiple preventive treatment failures in real-life, revealing an optimal safety and tolerability profile.
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Transtornos de Enxaqueca , Humanos , Estudos Prospectivos , Resultado do Tratamento , Método Duplo-Cego , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Cefaleia , Falha de TratamentoRESUMO
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.
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Transtornos de Enxaqueca , Adulto , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Estudos Prospectivos , Resultado do TratamentoRESUMO
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.
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Cuidadores , Transtornos de Enxaqueca , Humanos , Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina , Cefaleia/tratamento farmacológico , Ligantes , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/diagnóstico , Percepção , Estudos Prospectivos , Resultado do TratamentoRESUMO
Italian Migraine Registry (I-GRAINE) is a multicenter (n = 38), prospective, observational, non-interventional study aimed at providing big data on migraine to ensure proper clinical disease management, according to scientific, and sustainability criteria. We enrolled consecutive patients affected by episodic or chronic migraine according to the systematic random method. Information on sociodemographic characteristics, lifestyle, migraine features, patient's journey, and healthcare resource use were gathered using face-to-face interviews.On the date of 31 December 2021, we enrolled 231 patients at 12 headache centers. Most of them were women (84.4%), with high migraine frequency (9.6 ± 6.9 days/month) and severe disability (MIDAS score: 43.0 ± 40.8; HIT-6 score: 60.4 ± 10.6). Only a minority of patients (38.1%) had previously visited a headache center.A clear-cut difference emerged in the proportion of responders to nonspecific acute treatments (43.5-66.7%) compared to triptans (76.3%) and in responders to unspecific prophylaxis (5.4-35%) compared to anti-CGRP monoclonal antibodies (69.2-78.6%). Most patients underwent ≥ 1 specialist visit (66.9%) or diagnostic investigation (77.4%) over the last 3 years-mostly subsidized by our national health system-inappropriate in 64.9% and 25% of the cases, respectively.The I-GRAINE registry is expected to provide a large and exponentially increasing collection of clinical, biological, and epidemiologic information and will contribute to moving migraine out of the shadow cone of marginalization, which has been often relegated up to now.
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Transtornos de Enxaqueca , Feminino , Cefaleia , Humanos , Masculino , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/epidemiologia , Estudos Prospectivos , Sistema de Registros , Triptaminas/uso terapêuticoRESUMO
White matter hyperintensities (WMHs) in migraine could be related to inflammatory and antioxidant events. The aim of this study is to verify whether migraine patients with WMHs carry a genetic pro-inflammatory/pro-oxidative status. To test this hypothesis, we analyzed lymphotoxin alpha (LTA; rs2071590T and rs2844482G) and superoxide dismutase 1 (SOD1; rs2234694C) and 2 (SOD2; rs4880T) gene polymorphisms (SNPs) in 370 consecutive patients affected by episodic (EM; n = 251) and chronic (CM; n = 119) migraine and in unrelated healthy controls (n = 100). Brain magnetic resonance was available in 183/370 patients. The results obtained show that genotypes and allele frequencies for all tested SNPs did not differ between patients and controls. No association was found between single SNPs or haplotypes and sex, migraine type, cardiovascular risk factors or disorders. Conversely, the LTA rs2071590T (OR = 2.2) and the SOD1 rs2234694C (OR = 4.9) alleles were both associated with WMHs. A four-loci haplotype (TGCT haplotype: rs2071590T/rs2844482G/rs2234694C/rs4880T) was significantly more frequent in migraineurs with WMHs (7 of 38) compared to those without WMHs (4 of 134; OR = 8.7). We may, therefore, conclude by suggesting that that an imbalance between pro-inflammatory/pro-oxidative and antioxidant events in genetically predisposed individuals may influence the development of WMHs.
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Transtornos de Enxaqueca , Substância Branca , Humanos , Linfotoxina-alfa , Superóxido Dismutase-1/genética , Antioxidantes , Substância Branca/diagnóstico por imagem , Transtornos de Enxaqueca/genética , Polimorfismo de Nucleotídeo Único , Superóxido Dismutase/genéticaRESUMO
BACKGROUND: The multinational phase 3b DELIVER trial was designed to evaluate the efficacy and safety of eptinezumab for migraine prevention in patients with prior preventive treatment failures across 17 countries. In the placebo-controlled portion, eptinezumab relative to placebo demonstrated greater reductions in migraine and headache frequency, migraine and headache severity, and acute medication use. The objective of this report is to describe the effects of eptinezumab on self-reported work productivity in the placebo-controlled portion of DELIVER. METHODS: Adults 18-75 years of age with migraine and documented evidence of 2 to 4 prior preventive treatment failures in the past 10 years were randomized to receive eptinezumab 100 mg, 300 mg, or placebo intravenously (IV) every 12 weeks. The Work Productivity and Activity Impairment questionnaire specific to migraine (WPAI:M), which comprises 6 items (4 of which are completed by currently employed patients only), was administered every 4 weeks. Changes from baseline in subscores (absenteeism, presenteeism, work productivity loss, and activity impairment) were calculated based on item responses. A mixed model for repeated measures was used to analyze changes from baseline in WPAI:M subscores. RESULTS: A total of 890 adults (mean age, 43.8 years) were included in the full analysis set (eptinezumab 100 mg, n = 299; eptinezumab 300 mg, n = 293; placebo, n = 298). Mean WPAI:M subscores at baseline indicated a negative impact of migraine attacks on work productivity and ability to complete normal daily activities. Eptinezumab improved WPAI:M subscores more than placebo at all assessment points throughout the study. Mean changes from baseline in self-reported work productivity loss were -19.5, -24.0, and -9.7 at Week 12; and -22.6, -20.2, and -7.2 at Week 24 (all P < 0.001 vs placebo) for eptinezumab 100 mg, eptinezumab 300 mg, and placebo, respectively. Mean changes from baseline in activity impairment were -21.3, -23.8, and -11.2 at Week 12; and -24.7, -22.6, and -10.1 at Week 24 (all P < 0.0001 vs placebo). Similarly, mean improvements in absenteeism and presenteeism were greater in the eptinezumab groups than in the groups receiving placebo at all timepoints (P < 0.05). CONCLUSION: In adults with migraine and prior preventive treatment failure, eptinezumab 100 mg and 300 mg IV every 12 weeks improved absenteeism, presenteeism, work productivity loss, and activity impairment more than placebo. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765 ); EudraCT (Identifier: 2019-004497-25) ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004497-25/PL ). Eptinezumab improves self-reported work productivity in patients with migraine and prior preventive treatment failures.
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Transtornos de Enxaqueca , Adulto , Humanos , Método Duplo-Cego , Cefaleia , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Autorrelato , Falha de Tratamento , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , IdosoRESUMO
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.
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Transtornos de Enxaqueca , Anticorpos Monoclonais , Estudos de Coortes , Método Duplo-Cego , Cefaleia/prevenção & controle , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Resultado do TratamentoRESUMO
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.
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Hiperalgesia , Transtornos de Enxaqueca , Adulto , Humanos , Estudos Prospectivos , Hiperalgesia/tratamento farmacológico , Método Duplo-Cego , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/diagnóstico , Anticorpos Monoclonais/uso terapêutico , Cefaleia/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. METHODS: ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. RESULTS: Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. CONCLUSIONS: The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.
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Anticorpos Monoclonais Humanizados , Transtornos de Enxaqueca , Anticorpos Monoclonais Humanizados/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Feminino , Humanos , Masculino , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controleRESUMO
OBJECTIVE: To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. BACKGROUND: Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. METHODS: A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15 headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18-65 years. Each patient was treated with erenumab 70 mg, administered monthly. The dose was switched to 140 mg in nonresponders and in responders who had become nonresponders for at least 4 weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45-48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. RESULTS: A total of 242 patients with migraine received at least one dose of erenumab 70 mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48 weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3 migraine-preventive medication classes. From baseline to Weeks 45-48, erenumab treatment reduced MMD by 4.3 ± 5.3 (mean ± SD) in patients with HFEM, and MHD by 12.8 ± 8.9 (mean ± SD) in subjects with CM. VAS and HIT-6 scores were decreased by 1.8 ± 1.9 (mean ± SD) and 12.3 ± 11 (mean ± SD) in HFEM, and by 3.0 ± 2.2 (mean ± SD) and 13.1 ± 11.2 (mean ± SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0-13.0) to 5 (IQR 2.0-8.0) in HFEM and from 20.0 (IQR 15.0-30.0) to 6.0 (IQR 3.8-10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52-19.41; p = 0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03-8.7; p = 0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05-1.20; p = 0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15-0.87; p = 0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64-0.92; p = 0.004). CONCLUSIONS: Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140 mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Hiperalgesia/fisiopatologia , Transtornos de Enxaqueca/prevenção & controle , Transtornos de Enxaqueca/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Doença Crônica , Feminino , Humanos , Itália , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
OBJECTIVE: To develop a dedicated Italian chronic migraine (CM) database (IRON project) to overcome disease misconceptions, improve clinical administration, reduce patients' burden, and rationalize economic resource allotment. BACKGROUND: Proper CM management requires a comprehensive appraisal of its full clinical, social, and economic complexity. METHODS: In this cross-sectional study, CM patients were screened in 24 certified headache centers with face-to-face interviews. Information on sociodemographic factors, medical history, characteristics of CM, and of prior episodic migraine (EM), and healthcare resource use was gathered using a semistructured web-based questionnaire. RESULTS: A total of 866 CM patients were enrolled. CM started ~20 years after EM onset (age at EM onset 17.4 ± 9.1 vs. age at CM onset 35.3 ± 12.5 [mean ± SD]). CM prophylaxis, used by 430/866 (49.6%) of the patients, was often ineffective, not tolerated, and prematurely discontinued. Medications and diagnostic workup, frequently inappropriate, were mostly subsidized by the Italian national health service. CM patients with ≥25 headache days/month revealed substantial clinical differences and heavier disability and economic burden compared with those with <25 headache days/month. CONCLUSIONS: CM is a heterogeneous headache disorder deserving more in-depth clinical characterization, sharper diagnostic criteria, and tailored treatments. CM registries are expected to improve clinical management, resulting in increased disease awareness, better healthcare resource allocation, and reduced economic burden.
Assuntos
Progressão da Doença , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/terapia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adulto , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Itália , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Transtornos de Enxaqueca/patologia , Clínicas de Dor , Fatores Socioeconômicos , Medicina Estatal , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. BACKGROUND: Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. METHODS: This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18-65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70 mg, administered subcutaneously every 4 weeks. Treatment duration was planned to last from 6 to 12 months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9-12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). RESULTS: In total, 372 migraine patients were treated with at least one dose of erenumab 70 mg. At weeks 9-12, erenumab decreased MMDs by 4.5 ± 4.1 days (mean ± SD) in patients with HFEM and by 9.3 ± 9.1 (mean ± SD) days in those with CM compared to baseline. At weeks 9-12 VAS score was reduced by 1.9 ± 1.9 (mean ± SD), HIT score by 10.7 ± 8.8 (mean ± SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0-14.0) to 5.0 (IQR 3.0-7.0) in HFEM. In CM patients, VAS was reduced by 1.7 ± 2.0 (mean ± SD), HIT by 9.7 ± 10.4 (mean ± SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0-30.0) to 8.0 (IQR 5.0-15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24-7.40; p = 0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02-1.11; p = 0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14-3.52; p = 0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20-0.93; p = 0.003). CONCLUSIONS: Erenumab 70 mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Transtornos de Enxaqueca/prevenção & controle , Avaliação de Resultados em Cuidados de Saúde , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Efeitos Psicossociais da Doença , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos ProspectivosRESUMO
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.
Assuntos
Anticorpos Monoclonais , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos da Cefaleia Secundários , Transtornos de Enxaqueca , Adulto , Anticorpos Monoclonais/uso terapêutico , Feminino , Transtornos da Cefaleia Secundários/tratamento farmacológico , Humanos , Itália , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológicoRESUMO
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 .
Assuntos
Anticorpos Monoclonais , Transtornos de Enxaqueca , Adulto , Anticorpos Monoclonais Humanizados , Estudos de Coortes , Método Duplo-Cego , Feminino , Humanos , Itália , Masculino , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Resultado do TratamentoRESUMO
BACKGROUND: Dopaminergic symptoms may be extremely pronounced in some migraine patients during the attack, representing a major source of disability. OBJECTIVES: We aimed to carefully characterize the clinical picture of migraine patients with dopaminergic symptoms in a large patients' population as a putative migraine endophenotype, allowing more precise disease management, treatment and outcome prediction. METHODS: We screened 1148 consecutive tertiary care episodic and chronic migraine patients with face-to-face interviews collecting thorough data on lifestyle, socio-demographic factors, and clinical migraine features. RESULTS: We identified 374 patients with migraine with dopaminergic symptoms (32.6%). The most frequent dopaminergic symptom was yawning followed by somnolence, nausea, vomiting, fatigue, mood changes and diuresis. Migraine patients with dopaminergic symptoms had longer attack duration (OR: 1.82; 95% CI: 1.41-2.36, p < 0.0001), more frequent osmophobia (OR: 2.01; 95% CI: 1.50-2.69, p < 0.0001), allodynia (OR: 1.43; 95% CI: 1.10-1.85, p = 0.0071) and unilateral cranial autonomic symptoms (OR: 1.31; 95% CI: 1.01-1.68, p = 0.045), but used less preventative treatments (OR: 0.74; 95% CI: 0.57-0.98, p = 0.033) than patients without dopaminergic symptoms. CONCLUSIONS: Migraine patients with dopaminergic symptoms are characterized by a full-blown, more disabling migraine. Dopaminergic system modulation should be carefully considered in individuals with migraine with dopaminergic symptoms for both acute and preventative treatments in future ad hoc designed studies.
Assuntos
Transtornos de Enxaqueca/complicações , Adulto , Idoso , Estudos Transversais , Diurese , Dopamina/metabolismo , Fadiga/epidemiologia , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/metabolismo , Transtornos do Humor/epidemiologia , Transtornos do Humor/etiologia , Náusea/epidemiologia , Náusea/etiologia , Sonolência , Vômito/epidemiologia , Vômito/etiologia , BocejoRESUMO
PURPOSE: Migraine is an exclusively human chronic disorder with ictal manifestations characterized by a multifaceted clinical complexity pointing to a cerebral cortical involvement. The present review is aimed to cover the clinical, neuroimaging, and neurophysiological literature on the role of the cerebral cortex in migraine pathophysiology. OVERVIEW: Converging clinical scenarios, advanced neuroimaging data, and experimental neurophysiological findings, indicate that fluctuating excitability, plasticity, and metabolism of cortical neurons represent the pathophysiological substrate of the migraine cycle. Abnormal cortical responsivity and sensory processing coupled to a mismatch between the brain's energy reserve and workload may ignite the trigeminovascular system, leading to the migraine attack through the activation of subcortical brain trigeminal and extra-trigeminal structures, and driving its propagation and maintenance. DISCUSSION: The brain cortex emerges as the crucial player in migraine, a disorder lying at the intersection between neuroscience and daily life. Migraine disorder stems from an imbalance in inhibitory/excitatory cortical circuits, responsible for functional changes in the activity of different cortical brain regions encompassing the neurolimbic-pain network, and secondarily allowing a demodulation of subcortical areas, such as hypothalamus, amygdala, and brainstem nuclei, in a continuous mutual crosstalk.