Profiling migraine patients according to clinical and psychophysical characteristics: clinical validity of distinct migraine clusters.

AIMS: Investigate if different clinical and psychophysical bedside tools can differentiate between district migraine phenotypes in ictal/perictal (cohort 1) and interictal (cohort 2) phases. METHOD: This observational study included two independent samples in which patients were subgrouped into distinct clusters using standardized bedside assessment tools (headache frequency, disability, cervical active range of motion, pressure pain threshold in different areas): (A) cohort 1-ictal/perictal migraine patients were subgrouped, based on previous studies, into two clusters, i.e., Cluster-1.1 No Psychophysical Impairments (NPI) and Cluster-1.2 Increased Pain Sensitivity and Cervical Musculoskeletal Dysfunction (IPS-CMD); (B) cohort 2-interictal migraine patients were subgrouped into three clusters, i.e., Cluster-2.1 NPI, Cluster-2.2 IPS, and Cluster-2.3 IPS-CMD. Clinical characteristics (multiple questionnaires), somatosensory function (comprehensive quantitative sensory testing (QST)), and cervical musculoskeletal impairments (cervical musculoskeletal assessment) were assessed and compared across headache clusters and a group of 56 healthy controls matched for sex and age. RESULTS: Cohort 1: A total of 156 subjects were included. Cluster-1.2 (IPS-CMD) had higher headache intensity (p = 0.048), worse headache-related (p = 0.003) and neck-related disability (p = 0.005), worse quality of life (p = 0.003), and higher symptoms related to sensitization (p = 0.001) and psychological burden (p = 0.005) vs. Cluster-1.1(NPI). Furthermore, Cluster-1.2 (IPS-CMD) had (1) reduced cervical active and passive range of motion (p < 0.023), reduced functionality of deep cervical flexors (p < 0.001), and reduced values in all QST(p < 0.001) vs. controls, and (2) reduced active mobility in flexion, left/right lateral flexion (p < 0.045), and reduced values in QST (p < 0.001) vs. Cluster-1.1 (NPI). Cohort 2: A total of 154 subjects were included. Cluster-2.3 (IPS-CMD) had (1) longer disease duration (p = 0.006), higher headache frequency (p = 0.006), disability (p < 0.001), and psychological burden (p = 0.027) vs. Cluster-2.2 (IPS) and (2) higher headache-related disability (p = 0.010), neck-related disability (p = 0.009), and higher symptoms of sensitization (p = 0.018) vs. Cluster-2.1 (NPI). Cluster-2.3(IPS-CMD) had reduced cervical active and passive range of motion (p < 0.034), and reduced functionality of deep cervical flexors (p < 0.001), vs. controls, Custer-2.1 (NPI), and Cluster-2.2 (IPS). Cluster-2.2 (IPS) and 2.3 (IPS-CMD) had reduced QST values vs. controls (p < 0.001) and Cluster-2.1 (p < 0.039). CONCLUSION: A battery of patient-related outcome measures (PROMs) and quantitative bedside tools can separate migraine clusters with different clinical characteristics, somatosensory functions, and cervical musculoskeletal impairments. This confirms the existence of distinct migraine phenotypes and emphasizes the importance of migraine phases of which the characteristics are assessed. This may have implications for responders and non-responders to anti-migraine medications.

The first interim analysis of Italian patients enrolled in the real-world, Pan-European, prospective, observational, phase 4 PEARL study of fremanezumab effectiveness.

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.

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.

Profiling migraine patients according to clinical and psychophysical characteristics: a cluster analysis approach.

AIM: This study aims to profile migraine patients according clinical and psychophysical characteristics. METHOD: In this observational study, two cohorts of migraine patients(episodic/chronic) were included. Cohort-1: ictal/perictal phase; Cohort-2: interictal phase.The following variables were assessed: headache frequency; disability; cervical active range of motion(AROM) in flexion, extension, right/left lateral flexion, right/left rotation; pressure-pain threshold(PPT) over: temporalis, two cervical areas(C1/C4 vertebral segments), and two distal pain-free areas(hand/leg). Cluster analysis was performed using the K-means algorithm. Differences across clusters were investigated. RESULTS: Cohort-1: 100 patients were included, and two clusters were identified. Cluster-1.1 (19%), Cluster-1.2 (81%). Cluster 1.1 had a higher percentage of men (P = .037) and higher disability (P = .003) compared to Clusters 1.2. Cluster 1.2 had reduced AROM in flexion, extension, and left/right lateral flexion (P < .037), and lower PPT value in all areas (P < .001) compared to Cluster 1.1. Cohort-2: 98 patients were included and three clusters were identified. Cluster-2.1(18%), Cluster-2.2(45%), and Cluster-2.3(37%). Cluster-2.1 had a higher percentage of men compared to clusters-2.2 and 2.3 (P = .009). Cluster-2.3 had higher headache frequency, and disability compared to Cluster-2.2 (P < .006), and higher disability compared to Cluster-2.1 (P = .010). Cluster-2.3 had reduced AROM in all directions compared to Clusters-2.1 and 2.2 (P < .029). Clusters-2.2 and 2.3 have lower PPT values in all areas compared to Cluster-1.1 (P < .001). CONCLUSION: In the Ictal/perictal phase, two clusters were identified according to clinical and psychophysical characteristics, with one group showing no psychophysical impairment and one with increased pain-sensitivity and cervical musculoskeletal-dysfunctions.In the interictal phase, three clusters could be identified, with one group showing no psychophysical impairment, one increased pain-sensitivity, and one increased pain sensitivity and cervical musculoskeletal-dysfunctions.

Trigeminocervical pain sensitivity during the migraine cycle depends on headache frequency.

OBJECTIVE: This experimental study aimed to assess pain sensitivity in low-frequency episodic migraine (LFEM), high-frequency episodic migraine (HFEM), and chronic migraine (CM) patients across the different phases of the migraine cycle. METHOD: In this observational, experimental study, clinical characteristics (diary and time from the last/next headache attack), and quantitative sensory testing (QST) (wind-up pain ratio (WUR) and pressure pain threshold (PPT) from the trigeminal area and PPT from the cervical spine) was performed. LFEM, HFEM, and CM were assessed in each of the 4 migraine phases (HFEM and LFEM: interictal, preictal, ictal, and postictal; CM: interictal and ictal) and compared vs. each other's (matched for the phase) and controls. RESULTS: A total of 56 controls, 105 LFEM, 74 HFEM, and 32 CM were included. No differences in QST parameters were observed between LFEM, HFEM, and CM in any of the phases. During the interictal phase and when comparing with controls the following were found: 1) LFEM had lower trigeminal PPT (p = 0.001) and 2) lower cervical PPT (p = 0.001). No differences were observed between HFEM or CM and healthy controls. During the ictal phase and when comparing with controls the following were found: HFEM and CM had 1) lower trigeminal PPTs (HFEM p = 0.001; CM = p < 0.001), 2) lower cervical PPT s (HFEM p = 0.007; CM p < 0.001), and 3) higher trigeminal WUR (HFEM p = 0.001, CM p = 0.006). No differences were observed between LFEM and healthy controls. During the preictal phase and when comparing with controls the following were found: 1) LFEM had lower cervical PPT (p = 0.007), 2) HFEM had lower trigeminal (p = 0.013) and 3) HFEM had lower cervical (p = .006) PPTs. During the postictal phase and when comparing with controls the following were found: 1) LFEM had lower cervical PPT (p = 0.003), 2) HFEM had lower trigeminal PPT (p = 0.005), and 3) and HFEM had lower cervical (p = 0.007) PPTs. CONCLUSION: This study suggested that HFEM patients have a sensory profile matching CM better than LFEM. When assessing pain sensitivity in migraine populations, the phase with respects to headache attacks is of utmost importance and can explain the inconsistency in pain sensitivity data reported in the literature.

The PRESTO study: awareness of stroke symptoms and time from onset to intervention.

Timely access to medical assistance is the first crucial step to improving clinical outcomes of stroke patients. Many educational campaigns have been organized with the purpose of making people aware of what a stroke is and what is necessary to do after its clinical onset. The PRESTO campaign was organized in Genoa (Italy) to spread easy messages regarding the management of the acute phase of stroke. Educational material was disseminated to educate people to call the emergency medical services as soon as symptoms appear. Data collected were analyzed in three different phases of the campaign: before the beginning, during, and after the end. We enrolled 1,132 patients with ischemic stroke admitted to hospital within 24 hours of symptoms onset. Our data showed a mild reduction in onset-to-door time (24 minutes) during the months following the end of the campaign and a slight increase in number of patients who arrived at hospitals, in particular with milder symptoms and transient ischemic attack, as opposed to the same period before the campaign. Interestingly, in the months after the end of the campaign, we observed a slight reduction of the percentage of patients who accessed hospitals after 4.5 hours from symptoms onset. In conclusion, our results may suggest that an informative campaign can be successful in making people rapidly aware of stroke onset, with the consequent rapid access to hospitals. Considering the changing of way of access to information, we think that an extensive multimedia campaign should be evaluated in the next future.

Early and sustained efficacy of fremanezumab over 24-weeks in migraine patients with multiple preventive treatment failures: the multicenter, prospective, real-life FRIEND2 study.

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.

Cervical musculoskeletal impairments in the 4 phases of the migraine cycle in episodic migraine patients.

OBJECTIVE: To assess cervical musculoskeletal impairments during the 4 phases of a migraine cycle in episodic migraine patients, controlling for the presence of concomitant neck pain. METHODS: Differences in cervical musculoskeletal impairments were assessed during the 4 migraine phases in episodic migraine patients and compared with healthy controls controlling for concomitant neck pain. Cervical musculoskeletal impairments were assessed as follow: cervical active range of motion; flexion rotation test; craniocervical flexion test and calculation of activation pressure score; the total number of myofascial trigger points in head/neck muscles; the number of positivevertebral segments (headache's reproduction) during passive accessory intervertebral movement; pressure pain thresholds over C1, C2, C4, C6 vertebral segments bilaterally, trigeminal area, hand, and leg. Signs of pain sensitization were assessed by evaluating mechanical pain threshold over trigeminal area and hand, pressure pain thresholds, and the wind-up ratio. The Bonferroni-corrected p-value (05/4 = 0.013) was adopted to assess the difference between groups, while a p-value of 0.05 was considered significant for the correlation analysis. RESULTS: A total of 159 patients and 52 controls were included. Flexion rotation test and craniocervical flexion test were reduced in all 4 phases of the migraine cycle versus healthy controls (p < 0.001). The number of myofascial trigger points and positive vertebral segments was increased in all 4 phases of the migraine cycle versus healthy controls (p < 0.001). Flexion, extension, and total cervical active range of motion and cervical pressure pain thresholds were reduced in episodic migraine in the ictal phase versus controls (p < 0.007) with no other significant differences. Outside the ictal phase, the total cervical active range of motion was positively correlated with trigeminal and leg pressure pain threshold (p < 0.026), the number of active myofascial trigger points and positive positive vertebral segments were positively correlated with higher headache frequency (p=0.045), longer headache duration (p < 0.008), and with headache-related disability (p = 0.031). Cervical pressure pain thresholds were positively correlated with trigeminal, hand, and leg pressure pain threshold (p < 0.001), and trigeminal and leg mechanical pain thresholds (p < 0.005), and negatively correlated with the wind-up ratio (p < 0.004). CONCLUSION: In all phases of the migraine cycle, independent of the presence of concomitant neck pain, episodic migraine patients showed reduced flexion rotation test and craniocervical flexion test and an increased number of myofascial trigger points and passive accessory vertebral segments. These impairments are correlated with enhanced headache duration, headache-related disability, and signs of widespread pain sensitization. Reduction in active cervical movement and increased mechanical hyperalgesia of the cervical was consistent in ictal episodic migraine patients and the subgroups of episodic migraine patients with more pronounced widespread sensitization.

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.

Trigeminal and cervical sensitization during the four phases of the migraine cycle in patients with episodic migraine.

OBJECTIVE: Assessing mechanical pain thresholds from trigeminal, cervical, and distal pain-free areas during the four phases of a migraine cycle in patients with episodic migraine (EM). METHODS: This multicenter, cross-sectional, observational study conducted in Parma and Genoa's Headache Centers assessed quantitative sensory tests during the four migraine phases in patients with EM compared to controls. Temporal summation of pain (TSP), static pressure pain threshold (sPPT), and mechanical pinprick pain threshold (MPT) were assessed from the trigeminal area, sPPT and dynamic PPT (dPPT) from the cervical area, sPPT and MPT over the hand, and sPPT from the tibialis anterior. RESULTS: A total of 135 patients and 46 controls were included. TSP was facilitated in ictal EM (EM vs. controls: mean [standard deviation] 2.7 [2.0] vs. 1.4 [1.8]; p = 0.004); trigeminal sPPT and MPT were reduced in interictal (sPPT: 198.5 [79.3] kPa; p = 0.021; MPT: 12.6 [15.7] g; p = 0.001), preictal (sPPT: 200.6 [71.6] kPa; p = 0.033; MPT: 10.7 [12.4] g; p < 0.001), ictal (sPPT: 171.4 [95.9] kPa; p < 0.001; MPT: 7.3 [12.0] g; p < 0.001), and postictal EM (sPPT: 182.2 [76.3] kPa; p = 0.006; MPT: 10.1 [14.9] g; p = 0.001), compared to controls (sPPT: 238.3 [73.8] kPa; MPT: 21.9 [17.3] g). Cervical sPPTs and dPPT were reduced in interictal (sPPT upper cervical spine: 420.5 [176.7] kPa; p = 0.031; sPPT lower cervical spine: 458.6 [207.3] kPa; p = 0.002; dPPT: 4826.5 [2698.0] g; p < 0.001), preictal (sPPT upper cervical spine: 389.3 [133.4] kPa; p = 0.006; sPPT lower cervical spine: 450.8 [174.3] kPa; p = 0.005; dPPT: 4184.2 [2628.3] g; p < 0.001), ictal (sPPT upper cervical spine: 379.9 [205.6] kPa p = 0.003; sPPT lower cervical spine: 436.3 [271.1] kPa; p = 0.001; dPPT: 3838.3 [2638.7] g; p < 0.001), and postictal EM (sPPT upper cervical spine: 385.5 [131.6] kPa; p = 0.020; sPPT lower cervical spine: 413.0 [150.3] kPa; p = 0.002; dPPT: 4679.6 [2894.9] g; p = 0.001), compared to controls (sPPT upper cervical spine: 494.9 [171.5] kPa; sPPT lower cervical spine: 586.9 [210.8] kPa; dPPT: 7693.9 [2896.8] g). Preictal EM had reduced hand sPPT and MPT (sPPT: 248.8 [96.6] kPa vs. 319.8 [112.3] kPa; p = 0.006; MPT: 23.6 [12.2] g vs. 32.5 [14.4] g; p = 0.035), while EM in the other phases showed reduction in hand MPT (interictal: 22.3 [15.6] g vs. 32.5 [14.4] g; p = 0.002; ictal: 22.4 [17.0] g vs. 32.5 [14.4] g; p = 0.004; postictal: 24.2 [18.8] g vs. 32.5 [14.4] g; p = 0.003) without significant reduction in hand sPPT. No difference in sPPT over the tibialis anterior was found. Hand MPT was negatively correlated with longer disease duration (r = -0.25; p = 0.011) and hand sPPT was negatively correlated with higher drug usage (r = -0.31; p = 0.002). TSP during the ictal phase was positively correlated with the physical (r = 0.38; p = 0.040) and emotional headache-related disability (r = 0.53; p = 0.003). CONCLUSION: In all phases of the migraine cycle, patients with EM show signs of sensitization in the trigeminocervical area, with patients with the most prominent sensitization in the ictal phase. Signs of widespread sensitization were consistent in the preictal phase in patients with EM and in the subgroups of patients with EM with the longest disease duration and more usage of symptomatic drugs.

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

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

Age-dependent effect of susceptibility factors on the risk of intracerebral haemorrhage: Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

OBJECTIVE: To investigate the age-dependent impact of traditional stroke risk factors on the occurrence of intracerebral haemorrhage (ICH). METHODS: We performed a case-control analysis, comparing consecutive patients with ICH with age-matched and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) between 2002 and 2014 by multivariable logistic regression model within subgroups stratified by age quartiles (Q1-Q4). RESULTS: We analysed 3492 patients and 3492 controls. The impact of untreated hypertension on the risk of ICH was higher in the lower than in the upper age quartile (OR 11.64, 95% CI 7.68 to 17.63 in Q1 vs OR 6.05, 95% CI 3.09 to 11.85 in Q4 with intermediate ORs in Q2 and Q3), while the opposite trend was observed for untreated hypercholesterolaemia (OR 0.63, 95% CI 0.45 to 0.97 in Q1 vs OR 0.36, 95% CI 0.26 to 0.56 in Q4 with intermediate ORs in Q2 and Q3). The effect of untreated diabetes and excessive alcohol intake was detected only in the older age group (OR 3.63, 95% CI 1.22 to 10.73, and OR 1.69, 95% CI 1.13 to 2.51, respectively). CONCLUSIONS: Our findings provide evidence of age-dependent differences in the effects of susceptibility factors on the risk of ICH.

Clinical features, disease progression, and use of healthcare resources in a large sample of 866 patients from 24 headache centers: A real-life perspective from the Italian chROnic migraiNe (IRON) project.

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.

An eleven-year history of Vanishing White Matter Disease in an adult patient with no cognitive decline and EIF2B5 mutations. A case report.

Vanishing White Matter Disease (VWMD) is a rare autosomal recessive leukoencephalopathy . The classical presentation is characterized by a severe cerebellar ataxia, spasticity, neurological deterioration with a chronic progressive course and episodes of acute neurological deterioration after stress conditions.We report a 52-year-old man with VWMD and atypical features who manifested two major events of transient aphasia eleven years apart with complete recovery in 48 hours. No cognitive decline was present. Brain MRI revealed typical aspects of VWMD including diffuse leukoencephalopathy with relative sparing of U-fibers. We identified the presence of c.592G>A (p.Glu198Lys) and c.1360 C>T (p.Pro454Ser) mutations in EIF2B5.

Mechanical thrombectomy in acute ischemic stroke with tandem occlusions: impact of extracranial carotid lesion etiology on endovascular management and outcome.

OBJECTIVE: Different etiologies of extracranial internal carotid artery steno-occlusive lesions (ECLs) in patients with acute ischemic stroke (AIS) and tandem occlusion (TO) have been pooled together in randomized trials. However, carotid atherosclerosis (CA) and carotid dissection (CD), the two most common ECL etiologies, are distinct nosological entities. The authors aimed to determine if ECL etiology has impacts on the endovascular management and outcome of patients with TO. METHODS: A multicenter, retrospective study of prospectively collected data was conducted. AIS patients were included who had TO due to internal CA or CD and ipsilateral M1 middle cerebral artery occlusion and underwent endovascular treatment (EVT). Comparative analyses including demographic data, safety, successful recanalization rates, and clinical outcome were performed according to EVT and ECL etiology. RESULTS: In total, 214 AIS patients with TOs were included (77.6% CA related, 22.4% CD related). Patients treated with a retrograde approach were more often functionally independent at 3 months than patients treated with an antegrade approach (OR 0.6, 95% CI 0.4-0.9). Patients with CD-related TOs achieved 90-day clinical independence more often than patients with CA-related TOs (OR 1.4, 95% CI 1.1-2.0). Emergency stenting use was associated with good 3-month clinical outcome only in patients with CA-related TOs (OR 1.4, 95% CI 1.1-2.1). Symptomatic intracranial hemorrhage (sICH) occurred in 10.7% of patients, without differences associated with ECL etiology. CONCLUSIONS: ECL etiology impacts both EVT approach and clinical outcome in patients with TOs. Patients with CD-related TO achieved higher 3-month functional independence rates than patients with CA-related TOs. A retrograde approach can be desirable for both CA- and CD-related TOs, and emergency stenting is likely better justified in CA-related TOs.

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 .

Transcranial Doppler sonography for detecting stenosis or occlusion of intracranial arteries in people with acute ischaemic stroke.

BACKGROUND: An occlusion or stenosis of intracranial large arteries can be detected in the acute phase of ischaemic stroke in about 42% of patients. The approved therapies for acute ischaemic stroke are thrombolysis with intravenous recombinant tissue plasminogen activator (rt-PA), and mechanical thrombectomy; both aim to recanalise an occluded intracranial artery. The reference standard for the diagnosis of intracranial stenosis and occlusion is intra-arterial angiography (IA) and, recently, computed tomography angiography (CTA) and magnetic resonance angiography (MRA), or contrast-enhanced MRA. Transcranial Doppler (TCD) and transcranial colour Doppler (TCCD) are useful, rapid, noninvasive tools for the assessment of intracranial large arteries pathology. Due to the current lack of consensus regarding the use of TCD and TCCD in clinical practice, we systematically reviewed the literature for studies assessing the diagnostic accuracy of these techniques compared with intra-arterial IA, CTA, and MRA for the detection of intracranial stenosis and occlusion in people presenting with symptoms of ischaemic stroke. OBJECTIVES: To assess the diagnostic accuracy of TCD and TCCD for detecting stenosis and occlusion of intracranial large arteries in people with acute ischaemic stroke. SEARCH METHODS: We limited our searches from January 1982 onwards as the transcranial Doppler technique was only introduced into clinical practice in the 1980s. We searched MEDLINE (Ovid) (from 1982 to 2018); Embase (Ovid) (from 1982 to 2018); Database of Abstracts of Reviews of Effects (DARE); and Health Technology Assessment Database (HTA) (from 1982 to 2018). Moreover, we perused the reference lists of all retrieved articles and of previously published relevant review articles, handsearched relevant conference proceedings, searched relevant websites, and contacted experts in the field. SELECTION CRITERIA: We included all studies comparing TCD or TCCD (index tests) with IA, CTA, MRA, or contrast-enhanced MRA (reference standards) in people with acute ischaemic stroke, where all participants underwent both the index test and the reference standard within 24 hours of symptom onset. We included prospective cohort studies and randomised studies of test comparisons. We also considered retrospective studies eligible for inclusion where the original population sample was recruited prospectively but the results were analysed retrospectively. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened the titles and abstracts identified by the search strategies, applied the inclusion criteria, extracted data, assessed methodological quality (using QUADAS-2), and investigated heterogeneity. We contacted study authors for missing data. MAIN RESULTS: A comprehensive search of major relevant electronic databases (MEDLINE and Embase) from 1982 to 13 March 2018 yielded 13,534 articles, of which nine were deemed eligible for inclusion. The studies included a total of 493 participants. The mean age of included participants was 64.2 years (range 55.8 to 69.9 years). The proportion of men and women was similar across studies. Six studies recruited participants in Europe, one in south America, one in China, and one in Egypt. Risk of bias was high for participant selection but low for flow, timing, index and reference standard. The summary sensitivity and specificity estimates for TCD and TCCD were 95% (95% CI = 0.83 to 0.99) and 95% (95% CI = 0.90 to 0.98), respectively. Considering a prevalence of stenosis or occlusion of 42% (as reported in the literature), for every 1000 people who receive a TCD or TCCD test, stenosis or occlusion will be missed in 21 people (95% CI = 4 to 71) and 29 (95% CI = 12 to 58) will be wrongly diagnosed as harbouring an intracranial occlusion. However, there was substantial heterogeneity between studies, which was no longer evident when only occlusion of the MCA was considered, or when the analysis was limited to participants investigated within six hours. The performance of either TCD or TCCD in ruling in and ruling out a MCA occlusion was good. Limitations of this review were the small number of identified studies and the lack of data on the use of ultrasound contrast medium. AUTHORS' CONCLUSIONS: This review provides evidence that TCD or TCCD, administered by professionals with adequate experience and skills, can provide useful diagnostic information for detecting stenosis or occlusion of intracranial vessels in people with acute ischaemic stroke, or guide the request for more invasive vascular neuroimaging, especially where CT or MR-based vascular imaging are not immediately available. More studies are needed to confirm or refute the results of this review in a larger sample of stroke patients, to verify the role of contrast medium and to evaluate the clinical advantage of the use of ultrasound.

The predictive dysphagia score (PreDyScore) in the short- and medium-term post-stroke: a putative tool in PEG indication.

PURPOSE: We performed an evaluation of dysphagia in an unselected series of strokes to identify factors causing persisting dysphagia at 1 month after onset and to formulate a predictive score. METHODS: We evaluated the association between dysphagia and clinical aspects (univariate analysis) at the 7th and 30th days after admission. We performed a multivariate logistic regression at the 30th day on the factors that were significant. We computed a simple score for predicting persistent dysphagia. RESULTS: We recruited 249 patients. At the 7th day, 94 patients were dysphagic (37.75%). Factors associated with dysphagia included TACI (OR 3.85), mRS ≥ 3 (OR 4.45), malnutrition (OR 2.69), and BMI ≥ 20 (OR 0.52). At the 30th day, 217 patients remained in the study, and dysphagia persisted in 75 (36.76%). The factors that were associated with dysphagia were age > 74 years (OR 1.99), TACI (OR 5.82), mRS score ≥ 3 (OR 4.31), malnutrition (OR 3.27), and BMI ≥ 20 (OR 0.45). The multivariate analysis indicated that mRS ≥ 3 (OR 1.80) and BMI ≥ 20 (OR 0.45) remained significantly associated with dysphagia. The best correlation with dysphagia was the sum of mRS and the reciprocal of the BMI multiplied by 100 ((mRS + 1 ∕ BMI) × 100). We named this score PreDyScore that ranged between 3.7 and 10.47. Using < 6 and > 8 as cutoffs, the sensitivity was 67.03%, and the specificity 95.65%. CONCLUSION: BMI < 20 and mRS ≥ 3 are easily measurable bedside predictive factors of persistent dysphagia. PreDyScore showed good sensitivity and very good specificity and enables the prediction of persistent dysphagia with great accuracy in any clinical setting.

Management of acute ischemic stroke, thrombolysis rate, and predictors of clinical outcome.

BACKGROUND AND AIMS: Monitoring the quality of acute ischemic stroke (AIS) management is increasingly important since patient outcome could be improved with better access to evidence-based treatments. In this scenario, the aim of our study was to identify thrombolysis rate, reasons for undertreatment, and factors associated with better outcome. METHODS: From January to December 2016, individuals diagnosed with AIS at the Policlinic San Martino Hospital in Genoa, Italy, were prospectively included. Severity of stroke, site of occlusion, rate and time related in-hospital management of systemic thrombolysis, and mechanical thrombectomy were recorded. Safety and clinical outcomes were compared between different subgroups. RESULTS: Of 459 AIS patients (57.3% females, mean age 78.1), 111 received i.v. thrombolysis (24.4%) and 50 received mechanical thrombectomy (10.9%). Apart from arrival behind the therapeutic window, which was the first limitation to thrombolysis, the main reason of undertreatment was minor stroke or stroke in rapid improvement. Baseline NIHSS ≥ 8 was associated with unfavorable clinical outcome (mRS > 2) (OR 20.1; 95% CI, 1.1-387.4, p = 0.047). Age older than 80 years (OR 5.0; 95% CI, 1.4-64.1, p = 0.01), baseline NIHSS ≥ 7 (OR 20.1; 95% CI, 1.1-387.4, p = 0.047), and symptomatic intracranial hemorrhage (OR 22.9; 95% CI, 2.0-254.2, p = 0.01) proved independently associated with mortality. CONCLUSIONS: i.v. thrombolysis and mechanical thrombectomy rate was higher than that of previous reports. Minor stroke or stroke in rapid improvement was a major reason for exclusion from thrombolysis of eligible patients. Higher NIHSS proved an independent predictor of unfavorable clinical outcome and death. Strategies to avoid in-hospital delays need to be enforced.