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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 15headache 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 18–65years. Each patient was treated with erenumab 70mg, administered monthly. The dose was switched to 140mg in nonresponders and in responders who had become nonresponders for at least 4weeks. 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 70mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3migraine-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-6scores 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 140mg 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.

White matter lesions (WMLs) are commonly found on brain MRI of migraine patients. Migraine with aura (MA+) is associated with an increased frequency of right-to-left shunt (RLS) mostly due to patent foramen ovale. The relationship between WML load and RLS in MA+ is currently unknown.MA+ patients were consecutively enrolled as part of the Shunt Associated Migraine (SAM) study. Patients underwent a standardized headache and vascular risk factors questionnaire, contrast-enhanced transcranial Doppler, blood coagulation tests, and brain MRI. RLS was categorized into four grades: no shunt,10 microbubbles (mb),10 mb single spikes pattern, and10 mb shower/curtain pattern. Standard and fluid-attenuated inversion recovery T2-weighted MRI sequences were inspected for WMLs by three independent raters blinded to RLS grade. WML load was scored in the periventricular areas (PV-WMLs) with the Fazekas scale and in the deep white matter (D-WMLs) with the Scheltens scale. Interobserver agreement was good to excellent (kappa = 0.64 to 0.96, p0.0001). WML load was then correlated between patients with and without RLS.One hundred eighty-five patients (77% women) were included. PV-WML load was similar between patients with and without RLS. D-WML load decreased in patients with RLS (p = 0.045). On logistic regression analysis, only age was associated with WMLs (p0.001).The presence of right-to-left shunt does not increase white matter lesion load in patients who have migraine with aura.

Background and purpose: Perfusion imaging with dynamic susceptibility contrast MR imaging (DSC-MRI) has been used to evaluate hemodynamic status in patients with symptomatic occlusive cerebrovascular disease. The aim of the present study was to determine the hemodynamic changes occurring in asymptomatic patients with unilateral internal carotid artery (ICA) occlusion by use of DSC-MRI with transcranial Doppler (TCD) measurement of the breath-holding index (BHI). Methods: Nine patients with asymptomatic unilateral ICA occlusion underwent DSC-MRI and TCD examination. One patient was excluded from final analysis because of severe movement artifacts. On a separate workstation, regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and regional mean time to peak (rMTT) were calculated on the basis of signal decay rate during the passage of gadolinium bolus through the sampled volume in the territory of the middle cerebral artery. TCD-BHI was calculated in all patients. Six healthy subjects underwent the same MR protocol as the patients. Results: Compared with control subjects, patients with unilateral ICA occlusions had hemodynamic changes in the ipsilateral hemisphere: rCBF was significantly lower than in controls (P

BACKGROUND AND PURPOSE: Perfusion imaging with dynamic susceptibility contrast MR imaging (DSC-MRI) has been used to evaluate hemodynamic status in patients with symptomatic occlusive cerebrovascular disease. The aim of the present study was to determine the hemodynamic changes occurring in asymptomatic patients with unilateral internal carotid artery (ICA) occlusion by use of DSC-MRI with transcranial Doppler (TCD) measurement of the breath-holding index (BHI). METHODS: Nine patients with asymptomatic unilateral ICA occlusion underwent DSC-MRI and TCD examination. One patient was excluded from final analysis because of severe movement artifacts. On a separate workstation, regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and regional mean time to peak (rMTT) were calculated on the basis of signal decay rate during the passage of gadolinium bolus through the sampled volume in the territory of the middle cerebral artery. TCD-BHI was calculated in all patients. Six healthy subjects underwent the same MR protocol as the patients. RESULTS: Compared with control subjects, patients with unilateral ICA occlusions had hemodynamic changes in the ipsilateral hemisphere: rCBF was significantly lower than in controls (P < .01), and r MTT was significantly increased in both white (WM) and gray matter (GM) in the affected side (WM: P < .01; GM: P < .05). No statistically significant difference in rCBV was found in the group of patients (occluded versus contralateral, P < .1) or between the patient and control groups (occluded side versus controls, P < .1). The correlation of rCBV and BHI showed a strong relation of the two variables, showing a decrease of the latter when the former increased. CONCLUSION: DSC-MRI is a valuable tool for measuring hemodynamic changes in the presence of carotid disease with hemodynamic impairment. In our opinion, hemodynamic changes and efficiency of collateral pathways can be evaluated in occlusive carotid disease by using paired measurement of BHI and DSC-MRI. In the patient group, MR-determined rCBV and TCD-determined BHI showed a significant inverse correlation, suggesting similar significance of the two indices.

Topographical cortical organization of sensorimotor area has been shown to be highly plastic, altering his configuration in response to training in different tasks in healthy controls and neurological patients. The term ''brain plasticity'' encompasses all possible mechanisms of neuronal reorganization: recruitment of pathways that are functionally homologous to, but anatomically distinct from, the damaged ones (eg, non-pyramidal corticospinal pathways), synaptogenesis, dendritic arborisation and reinforcement of existing but functionally silent synaptic connections (particularly at the periphery of core lesion). The study of neuroplasticity has clearly shown the ability of the developing brain--and of the adult and ageing brain--to be shaped by environmental inputs both under normal conditions (ie, learning) and after a lesion. Neuronal aggregates adjacent, or distant to a lesion in the sensorimotor area can progressively adopt the function of the injured area. Imaging studies indicate that recovery of motor function after a lesion (i.e. stroke) is associated with a progressive change of activation patterns in specific brain structures. Transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) can detect reshaping of sensorimotor areas; they have a high temporal resolution but have several limitations. TMS can only provide bidimensional scalp maps and MEG depicts three-dimensional spatial characteristics of virtual neural generators obtained by use of a mathematical model of the head and brain. However, the use of objective methods that assess brain reactivity to a physical stimulus (i.e., TMS) or to a sensory input (ie, electrical stimulation to hand and fingers) can integrate information from self-paced motor tasks, because the resolution of abnormal activation over time could be secondary to recovery. Functional MRI (fMRI) and positron emission tomography (PET), on their own, have insufficient time resolution to follow the hierarchical activation of relays within a neural network; however, because of their excellent spatial resolution, they can integrate the findings of TMS and MEG. An integrated approach constitutes, at present, the best way to assess the brain plasticity both under normal conditions and after a lesion.

Migranya crònica; Diferència de gènere; OnabotulinumtoxinA Migraña crónica; Diferencia de género, OnabotulinumtoxinA Chronic migraine; Gender difference; OnabotulinumtoxinA Introduction Migraine is mostly a female disorder because of its lower prevalence in men. Less than 20% of patients included in the available studies on migraine treatments are men; hence, the evidence on migraine treatments might not apply to men. The aims of the present study were to provide reliable information on the effectiveness of onabotulinumtoxinA (BT-A) for chronic migraine in men and to compare clinical benefits between men and women. Methods We performed a pooled patient-level gender-specific analysis of real-life data on BT-A for chronic migraine of patients followed-up to 9 months. We reported the 50% responder rates during each BT-A cycle, defined as percentage of reduction in monthly headache days (MHDs) compared to baseline, along with 75% and 30% responder rates. We also reported the mean decrease in MHDs and in days of acute medication use (DAMs) during each BT-A cycle as compared to baseline. We also evaluated the reasons for stopping the treatment within the third cycle. Results We included an overall cohort of 2879 patients, 522 of whom (18.1%) were men. In men, 50% responder rates were 27.7% during the first BT-A cycle, 29.2% during the second, and 35.6% during the third cycle; in women, the corresponding rates were 26.6%, 33.5%, and 41.0%. In the overall cohort, responder rates did not differ between men and women during the first two cycles; during the third cycle, the distribution was different (P

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 70mg, administered subcutaneously every 4weeks. Treatment duration was planned to last from 6 to 12months, 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 70mg. At weeks 9–12, erenumab decreased MMDs by 4.5±4.1days (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 70mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

OBJECTIVE To clarify whether the clinical response after the first 2 cycles with Onabotulinumtoxin A can accurately predict the long-term response. BACKGROUND Onabotulinumtoxin-A (OBT-A) is an approved preventive treatment option for chronic migraine (CM). Nowadays, it remains to be clarified if the treatment has to be prolonged for at least an entire year (4 injections every 3 months - ie, quarterly, as proposed in the PREEMPT trials) or it can be halted after the second or third injection if not clinically effective. DESIGN AND METHODS We conducted a multicenter observational cohort study based on real-life data on the usage of OBT-A in CM patients from 2 Italian headache centers, Roma Campus Bio-Medico and Milano Besta, adopting the whole 4-injections protocol. We performed a retrospective analysis of medical records of consecutive patients treated in the 2 centers. The main statistical analysis aimed to evaluate longitudinal measures related to headache (monthly headache frequency, monthly number of analgesic drugs, MIDAS). We hypothesized from our clinical practice with OBT-A that only 2 cycles of treatment were not enough to actually define the non-responder status to botulinum toxin A and that probably a longer time of treatment is needed to get the condition of long-term (delayed) responder. RESULTS We considered 115 patients from the 2 centers: 53 in Roma and 62 in Milano. Regarding the main analysis, a clear improvement in each measure was obtained at the 6 months assessment and maintained up to 12 months. Comparing patients with

Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with mild cognitive impairment (MCI). Here, we tested the hypothesis that these sources in amnesic MCI subjects further deteriorate over 1 year. To this aim, the resting state eyes-closed EEG data were recorded in 54 MCI subjects at baseline (Mini Mental State Examination I = 26.9; standard error [SE], 0.2) and at approximately 1-year follow-up (13.8 months; SE, 0.5; Mini Mental State Examination II = 25.8; SE, 0.2). As a control, EEG recordings were also performed in 45 normal elderly and in 50 mild Alzheimer's disease subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), and beta2 (20-30 Hz). Cortical EEG sources were estimated using low-resolution brain electromagnetic tomography. Compared with the normal elderly and mild Alzheimer's disease subjects, the MCI subjects were characterized by an intermediate power of posterior alpha1 sources. In the MCI subjects, the follow-up EEG recordings showed a decreased power of posterior alpha1 and alpha2 sources. These results suggest that the resting state EEG alpha sources were sensitive-at least at the group level-to the cognitive decline occurring in the amnesic MCI group over 1 year, and might represent cost-effective, noninvasive and widely available markers to follow amnesic MCI populations in large clinical trials.

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Background: The North American Alzheimer's Disease Neuroimaging Initiative (NA-ADNI) was the first program to develop standardized procedures for Alzheimer's disease (AD) imaging biomarker collection. Objective: We describe the validation of acquisition and processing of structural magnetic resonance imaging (MRI) in different Italian academic AD clinics following NA-ADNI procedures. Methods: 373 patients with subjective memory impairment (n = 12), mild cognitive impairment (n = 92), Alzheimer's dementia (n = 253), and frontotemporal dementia (n = 16) were enrolled in 9 Italian centers. Also included were 22 cognitively healthy elderly controls. MRI site qualification and MP-RAGE quality assessment was applied following the NA-ADNI procedures. Indices of validity were: (i) AN-ADNI phantom's signal-to-noise and contrast-to-noise ratio, (ii) proportion of images passing quality control, (iii) comparability of automated intracranial volume (ICV) estimates across scanners, and (iv) known-group validity of manual hippocampal volumetry. Results: Results on Phantom and Volunteers scans showed that I-ADNI acquisition parameters were comparable with those one of the ranked-A ADNI scans. Eighty-seven percent of I-ADNI MPRAGE images were ranked of high quality in comparison of 69% of NA-ADNI. ICV showed homogeneous variances across scanners except for Siemens scanners at 3.0 Tesla (p = 0.039). A significant difference in hippocampal volume was found between AD and controls on 1.5 Tesla scans (p < 0.001), confirming known group validity test. Conclusion: This study has provided standardization of MRI acquisition and imaging marker collection across different Italian clinical units and equipment. This is a mandatory step to the implementation of imaging biomarkers in clinical routine for early and differential diagnosis.

Resting state electroencephalographic (EEG) rhythms do not deteriorate with the increase of white matter vascular lesion in amnesic mild cognitive impairment (MCI) subjects [1], although white matter is impaired along Alzheimer's disease (AD). Here we tested whether this is true even in AD subjects. Closed-eye resting state EEG data were recorded in 40 healthy elderly (Nold), 96 amnesic MCI, and 83 AD subjects. White matter vascular lesions were indexed by magnetic resonance imaging recorded in the MCI and AD subjects (about 42% of cases following ADNI standards). The MCI subjects were divided into two sub-groups based on the median of the white matter lesion, namely MCI+ (people with highest vascular load; n = 48) and MCI- (people with lowest vascular load; n = 48). The same was true for the AD subjects (AD+, n = 42; AD-, n = 41). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). LORETA software estimated cortical EEG sources. When compared to Nold group, MCI and AD groups showed well known abnormalities of delta and alpha sources. Furthermore, amplitude of occipital, temporal, and limbic alpha 1 sources were higher in MCI+ than MCI- group. As a novelty, amplitude of occipital delta sources was lower in AD+ than AD- group. Furthermore, central, parietal, occipital, temporal, and limbic alpha sources were higher in amplitude in AD+ than AD- group. Amplitude of these sources was correlated to global cognitive status (i.e., Mini Mental State Evaluation score). These results suggest that in amnesic MCI and AD subjects, resting state posterior delta and alpha EEG rhythms do not deteriorate with the increase of white-matter vascular lesion. These rhythms might be more sensitive to AD neurodegenerative processes and cognitive status rather than to concomitant lesions to white matter.