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Background and aimsTo investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).MethodsWe conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU)admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.ResultsWe identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with ahigher likelihood of ICU admission, need ofMV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need ofMV and ICU admission, respectively.ConclusionsBlood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

Objective The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis. Methods We report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach. Results Our search yielded 10.826 unique records, of which three trials (n=622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo. We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo. Conclusions Our meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention.

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

BackgroundLiterature suggests an association between patent foramen ovale (PFO) and migraine, mostly migraine with aura (MA). Previous data suggest that air microembolism through PFO can lead to bioelectrical abnormalities detectable at electroencephalogram (EEG) in patients with MA, thus suggesting a pathophysiological mechanism for the MA-PFO association. However, those data lack replication.MethodsPatients with MA or migraine without aura (MO) and large PFO underwent a 19-channel EEG recording before and after injection of air microbubbles. We compared EEG power before and after microbubble injection for each electrode location, for each frequency band (theta: 5–7 Hz; alpha: 8–12 Hz; beta: 13–30 Hz; lower gamma: 31–45 Hz), and for total global power (the average of EEG power at each location and frequency band).ResultsWe included 10 patients, four with MA and six with MO; six patients had medium-to-high migraine frequency (four or more monthly migraine days), while four had low frequency (one monthly migraine day). EEG power changes after air microembolism varied across patients. Considering the overall group, total global EEG power did not change; however, EEG power in the higher frequency ranges (beta and lower gamma) increased in patients with MA.ConclusionsWe did not replicate the effects of air microembolism previously reported in patients with migraine. Aura status, migraine frequency, and medications might influence patients' response to microembolism. More refined EEG measurements are needed to clarify the dynamic role of PFO on migraine occurrence.

Migraine is a complex condition in which genetic predisposition interacts with other biological and environmental factors determining its course. A hyperresponsive brain cortex, peripheral and central alterations in pain processing, and comorbidities play a role from an individual biological standpoint. Besides, dysfunctional psychological mechanisms, social and lifestyle factors may intervene and impact on the clinical phenotype of the disease, promote its transformation from episodic into chronic migraine and may increase migraine-related disability.Thus, given the multifactorial origin of the condition, the application of a biopsychosocial approach in the management of migraine could favor therapeutic success. While in chronic pain conditions the biopsychosocial approach is already a mainstay of treatment, in migraine the biomedical approach is still dominant. It is instead advisable to carefully consider the individual with migraine as a whole, in order to plan a tailored treatment. In this review, we first reported an analytical and critical discussion of the biological, psychological, and social factors involved in migraine. Then, we addressed the management implications of the application of a biopsychosocial model discussing how the integration between non-pharmacological management and conventional biomedical treatment may provide advantages to migraine care.

Background and Purpose: Clinical trials on stroke prevention in patients with atrial fibrillation have consistently shown clinical benefit from either warfarin or non–vitamin K antagonist oral anticoagulants (NOACs). NOAC-treated patients have consistently reported to be at lower risk for intracerebral hemorrhage (ICH) than warfarin-treated patients. The aims of this prospective, multicenter, multinational, unmatched, case-control study were (1) to investigate for risk factors that could predict ICH occurring in patients with atrial fibrillation during NOAC treatment and (2) to evaluate the role of CHA 2 DS 2 -VASc and HAS-BLED scores in the same setting. Methods: Cases were consecutive patients with atrial fibrillation who had ICH during NOAC treatment. Controls were consecutive patients with atrial fibrillation who did not have ICH during NOAC treatment. As within the CHA 2 DS 2 -VASc and HAS-BLED scores there are some risk factors in common, several multivariable logistic regression models were performed to identify independent prespecified predictors for ICH events. Results: Four hundred nineteen cases (mean age, 78.8±8.1 years) and 1526 controls (mean age, 76.0±10.3 years) were included in the study. From the different models performed, independent predictors of ICH were increasing age, concomitant use of antiplatelet agents, active malignancy, high risk of fall, hyperlipidemia, low clearance of creatinine, peripheral artery disease, and white matter changes. Low doses of NOACs (given according to label or not) and congestive heart failure were inversely associated with the risk of ICH. HAS-BLED and CHA 2 DS 2 -VASc scores performed poorly in predicting ICH with areas under the curves of 0.496 (95% CI, 0.468–0.525) and 0.530 (95% CI, 0.500–0.560), respectively. Conclusions: Several risk factors were associated to ICH in patients treated with NOACs for stroke prevention but not HAS-BLED and CHA 2 DS 2 -VASc scores.

Subarachnoid hemorrhage (SAH) carries high mortality and disability rates, which are substantially driven by complications. Early brain injury and vasospasm can happen after SAH and are crucial events to prevent and treat to improve prognosis. In recent decades, immunological mechanisms have been implicated in SAH complications, with both innate and adaptive immunity involved in mechanisms of damage after SAH. The purpose of this review is to summarize the immunological profile of vasospasm, highlighting the potential implementation of biomarkers for its prediction and management. Overall, the kinetics of central nervous system (CNS) immune invasion and soluble factors’ production critically differs between patients developing vasospasm compared to those not experiencing this complication. In particular, in people developing vasospasm, a neutrophil increase develops in the first minutes to days and pairs with a mild depletion of CD45+ lymphocytes. Cytokine production is boosted early on after SAH, and a steep increase in interleukin-6, metalloproteinase-9 and vascular endothelial growth factor (VEGF) anticipates the development of vasospasm after SAH. We also highlight the role of microglia and the potential influence of genetic polymorphism in the development of vasospasm and SAH-related complications.

Migranya crònica; Estudi multicèntric; Evidència de la vida real Migraña crónica; Estudio multicéntrico; Evidencia de la vida real Chronic migraine; Multicenter study; Real-life evidence Introduction OnabotulinumtoxinA (BT-A) quarterly was the first treatment approved specifically for chronic migraine (CM). It is unclear whether three cycles are better than two to assess early BT-A response. Methods We performed a retrospective analysis on real-life prospectively collected data in 16 European headache centers. All the centers provided data on patients treated with BT-A for CM over the first three cycles of treatment. For each treatment cycle we defined patients as “good responders” if reporting a ≥ 50% reduction in monthly headache days compared with the three months before starting BT-A, “partial responders” if reporting a 30–49% reduction in monthly headache days, and “non-responders” if reporting a

ObjectiveCranial autonomic symptoms (CAS), including conjunctival injection, tearing, nasal congestion or rhinorrhea, eyelid edema, miosis or ptosis, and forehead or facial sweating ipsilateral to headache, are often reported by patients with migraine during headache attacks. CAS is a consequence of the activation of the trigeminovascular system, which is the target of monoclonal antibodies acting on the CGRP pathway. Therefore, we hypothesized that patients with CAS might have higher trigeminovascular activation than those without CAS leading to a better response to anti-CGRP treatments.MethodsWe performed a prospective analysis including patients with episodic or chronic migraine treated with anti-CGRP monoclonal antibodies (i.e., erenumab, fremanezumab, and galcanezumab) between 2019 and 2021. The observation period included a 12-week baseline before treatment with anti-CGRP antibodies and a 12-week treatment follow-up. We evaluated the prevalence of CAS in our cohort and compared disease characteristics and treatment response (i.e., 12-week monthly headache days and 0–29, 30–49, 50–74, 75–99, and 100% monthly headache days reduction from baseline) among patients with and without CAS using the χ2 test, Kruskal–Wallis test, and Mann–Whitney U-test.ResultsOut of 136 patients, 88 (65%) had CAS. Both patients with and without CAS reported a significant decrease in monthly headache days from baseline. During the 12-week follow-up, the median difference in monthly headache days from baseline was higher in patients with CAS (-10, IQR−15 to−6) than in those without CAS (6, IQR 12 to 3; P = 0.009). However, the proportions of patients with 0 to 29, 30 to 49, 50 to 74, 75 to 99, and 100% response rates did not differ between the two groups.ConclusionsIn our cohort, the presence of CAS was associated with a greater response to monoclonal antibodies targeting the CGRP pathway. CAS could be a clinical marker of trigeminovascular activation and thus be related to a better response to CGRP treatments.

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA 2 DS 2 -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

International audience; Introduction: Migraine and combined hormonal contraceptives (CHCs) increase the risk of ischemic stroke in young women; however, the contribution of low-dose (

BackgroundMigraine is a recurrent headache disorder that has a still unclear pathophysiology, involving several circuits of both the central and peripheral nervous system. Monoclonal antibodies acting on the calcitonin gene-related (CGRP) pathway (CGRP-MAbs) are the first drugs specifically designed for migraine; those drugs act peripherally on the trigeminal ganglion without entering the blood-brain barrier. Conversely, neuromodulation techniques such as transcranial direct current stimulation (tDCS) act centrally by increasing or decreasing the neuronal firing rate of brain cortical areas. The aim of the study will be to evaluate whether tDCS, in addition to CGRP-MAbs, is an effective add-on treatment in reducing headache frequency, intensity and acute medication use in patients with migraine. To demonstrate the biological effects of tDCS, the electroencephalographic (EEG) power changes after tDCS will be assessed.MethodsWe will include patients with migraine on treatment with CGRP-MAbs and reporting ≥8 monthly migraine days. During a prospective 28-day baseline period, patients will fill in a headache diary and questionnaires to evaluate migraine-related disability, anxiety and depressive symptoms, sleep quality, and health-related quality of life. Subjects will be randomly assigned in a 1:1 ratio to active or sham tDCS. The stimulation protocol will consist in five daily sessions, the cathodes will be applied bilaterally above the occipital areas, with the reference anode electrodes positioned above the primary motor areas. Before the first, and immediately after the last stimulation session, patients will perform a 10-min resting EEG recording. During a 28-day follow-up period following tDCS, patients will have to fill in a headache diary and questionnaires identical to those of the baseline period.DiscussionThis trial will evaluate the efficacy of an add-on treatment acting on the brain in patients with migraine, who are already treated with peripherally acting drugs, showing how tDCS acts in restoring the dysfunctional brain networks typical of the migraine patient.Clinical Trial RegistrationNCT05161871.

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.

OnabotulinumtoxinA (BT-A) is one of the few drugs approved for the preventive treatment of chronic migraine (CM). Despite this, some aspects of its mechanism of action are still a matter of debate, and the precise magnitude of BT-A effects needs to be completely elucidated. BT-A acts primarily upon trigeminal and cervical nerve endings, by inhibiting the release of inflammatory mediators such as calcitonin gene-related peptide, as well as reducing the insertion of ionotropic and metabotropic receptors into the neuronal membrane. These actions increase the depolarization threshold of trigeminal and cervical nerve fibers, thus reducing their activation. The central actions of BT-A are still a matter of debate: a retrograde axonal transport has been postulated, but not clearly assessed in humans. Clinically, the efficacy of BT-A in CM has been assessed by large, randomized placebo-controlled trials, such as the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials. Those results were also confirmed in a wide range of open-label studies, even for long-term periods. Recently, novel findings have led to a better understanding of its pharmacological actions and clinical usefulness in migraine prevention. This narrative review summarizes, updates and critically revises the available data on BT-A and its possible implementation in chronic migraine. Moreover, the current role of BT-A in CM treatment has been discussed.

Erenumab is a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor suitable for episodic and chronic migraine prevention. Randomized clinical trials proved the superiority of erenumab to placebo in a strictly selected population, while real-world studies confirmed treatment efficacy in more severe forms of disease - most patients suffered from chronic migraine with medication overuse headache, had prior treatment failures, and long disease duration. According to guidelines, anti-CGRP pathway monoclonal antibodies should be reserved to patients who failed or have contraindication to several classes of preventive treatments. However, their ease of use, tolerability and efficacy make these monoclonal antibodies ideally suitable for most patients with migraine; cost-effectiveness needs to be considered when looking at expanding current prescription criteria. Also, data from open label extensions of randomized control trials confirmed sustained benefits of prolonged treatment up to 5 consecutive years without significant risk of adverse events. Further studies will provide insights on optimal treatment duration to achieve migraine remission and predictors of treatment response. In the present work, we aimed at reviewing design and results of the main studies on erenumab and discussing treatment use in the current migraine prevention scenario; we also summarized the main ongoing research projects and provided clinical perspectives for the future.

Background Transcranial direct current stimulation (tDCS) could counteract the pathophysiological triggers of migraine attacks by modulating cortical excitability. Several pilot randomized controlled trials (RCTs) assessed the efficacy of tDCS for migraine prevention. We reviewed and summarized the state of the art of tDCS protocols for migraine prevention, discussing study results according to the stimulations parameters and patients’ populations. Main body We combined the keywords ‘migraine’, ‘headache’, ‘transcranial direct current stimulation’, and ‘tDCS’ and searched Pubmed, Scopus, and Web of Science, from the beginning of indexing to June 22, 2021. We only included RCTs comparing the efficacy of active tDCS with sham tDCS to decrease migraine frequency, intensity, and/or acute drug utilization. The risk of bias of each RCT was assessed by using the RoB-2 tool (Cochrane Collaboration). Thirteen RCTs (from 2011 to 2021) were included in the review. The included patients ranged from 13 to 135. RCTs included patients with any migraine (n=3), chronic migraine (n=6), episodic migraine (n=3) or menstrual migraine (n=1). Six RCTs used cathodal and five anodal tDCS, while two RCTs compared the efficacy of both cathodal and anodal tDCS with that of sham. In most of the cathodal stimulation trials, the target areas were the occipital regions, with reference on central or supraorbital areas. In anodal RCTs, the anode was usually placed above the motor cortical areas and the cathode on supraorbital areas. All RCTs adopted repeated sessions (from 5 to 28) at variable intervals, while the follow-up length spanned from 1 day up to 12 months. Efficacy results were variable but overall positive. According to the RoB-2 tool, only four of the 13 RCTs had a low risk of bias, while the others presented some concerns. Conclusions Both anodal and cathodal tDCS are promising for migraine prevention. However, there is a need for larger and rigorous RCTs and standardized procedures. Additionally, the potential benefits and targeted neurostimulation protocols should be assessed for specific subgroups of patients.

Background: Patients who are in a coma, a vegetative state or a minimally conscious state present a clinical challenge for neurological assessment, which is a prerequisite for establishing a prognosis and planning management. Several scales have been developed to evaluate these patients. The Wessex Head Injury Matrix is a comprehensive tool but is currently available only in the French and English languages. The aim of this study was to translate and evaluate the reliability of the Italian version of the scale. Methods: The original scale was translated according to a standard protocol: three separate translations were made, and a selected version was back-translated to check for any errors in order to obtain the most accurate Italian translation. A final back translation of the agreed version was made as a further check. The final version was then administered blind to a consecutive series of patients with severe acquired brain injury by two examiners. Inter-rater and test-retest reliability were assessed using a weighted Cohen’s kappa (Kw). Concurrent validity of the WHIM was evaluated by ρ Spearman’s correlation coefficient using the Glasgow Coma Scale (GCS) and the Coma Recovery Scale Revised (CRS-R) as the available gold standard. Results: Twenty-four patients (12 males and 12 females; mean age 59.9 ± 20.1; mean duration from index event 17.7 ± 20.0 days) with stroke (n = 15), traumatic brain injury (n = 7) and anoxic encephalopathy (n = 2) were included. Inter-rater [Kw 0.80 (95% CI 0.75–0.84)] and test-retest reliability [Kw 0.77 (95% CI 0.72–0.81)] showed good values. WHIM total scores correlated significantly with total scores on the GCS (ρ = 0.776; p < 0.001) and the CRS-R (ρ = 0.881; p < 0.001) demonstrating concurrent validity; Conclusion: The Italian version of the scale is now available for clinical practice and research.

Introduction Migraine prevalence is higher in fertile than in postmenopausal women. However, few literature data are available on the prevalence and characteristics of migraine after the menopause and on the effect of hormones in postmenopausal women with migraine. Methods We performed a systematic literature review of studies available on Scopus and Web of Science from the beginning off indexing until October 18th, 2020. We included both randomized trials and observational studies. Results We included 12 papers, six of which assessed the prevalence and characteristics of migraine in postmenopausal women, while the other six assessed the effect of hormones on migraine after the menopause. One of the studies was a randomized trial, while the remaining 11 were observational studies. Ten studies were clinic-based, while the remaining two were population-based. Studies assessing the prevalence and characteristics of migraine after the menopause reported inconsistent findings; in studies performed in headache clinics, likely affected by selection bias towards the most severe cases, a relevant proportion of women reported migraine worsening after the menopause. Studies assessing the effect of hormones on migraine after the menopause showed that postmenopausal hormone replacement therapy was invariably associated with migraine worsening, if containing estrogen. Conclusion Our systematic review showed that migraine could be a relevant health problem in postmenopausal women, mostly in headache clinics. However, the available studies allow a limited assessment of the prevalence and characteristics of postmenopausal migraine. Further large studies are needed to better determine the burden of migraine after the menopause according to migraine characteristics and the impact of hormonal treatments.

Background Triptans and erenumab are both migraine-specific agents acting on the calcitonin gene-related peptide pathway. Therefore, response to triptans might be associated with response to erenumab. Main body In our study, consecutive patients referring to the Headache Centers of the Abruzzo region from January 2019 to March 2020 and treated with erenumab were interviewed about past use and efficacy of triptans. Triptan users were classified as ‘triptan responders’ if they were headache-free 2 h after treating ≥3 migraine attacks with ≥1 triptan. We considered patients as ‘erenumab responders’, if they had a ≥ 50% mean reduction in monthly migraine days between the 4th and the 6th month from treatment start compared with baseline. Of 91 triptan users, 73 (80.2%) were triptan responders and 58 (63.7%) were erenumab responders. The odds ratio of being erenumab responder was 3.64 (95% CI, 1.25–10.64) for triptan users as compared to non-users. (P = 0.014). Besides, starting erenumab improved triptan response in both erenumab responders and non-responders. Conclusions Our data of an association between response to triptans and response to erenumab can be useful for patient advice and to improve the understanding of migraine pathophysiology and treatment.

Real-life data on the efficacy of anti-calcitonin gene–related peptide (GCRP) monoclonal antibodies (mAbs) have significantly enriched the knowledge on these innovative treatments indicated for migraine prevention. As of August 2020, ten observational studies on the efficacy and safety of erenumab have been published and a preliminary study on galcanezumab is available. Conversely, there are no real-life data on the two other mAbs.

During the last decade, the evidence-based treatment of headaches has gained important advances. Several guidelines to perform research in this field have been published. The specificity, innovative mode of administration, and excellent safety profile of monoclonal antibodies acting on the CGRP or its receptor has several implications for present and future clinical trials. In this Chapter, we will discuss the aspects of patient selection, operating procedures, and outcome assessment that are mostly relevant for trials of monoclonal antibodies acting on the CGRP pathway.

Background: Previous studies during SARS and Ebola pandemics have shown that quarantine is associated with several negative psychological effects, such as post-traumatic stress symptoms, confusion, and anger. These conditions may affect the course of many diseases, including migraine. Although it is possible that the quarantine measures for the current COVID-19 pandemic affect migraine burden, no information is currently available on this issue. Aim: In this study, we aimed to: (1) explore the possible changes in migraine frequency, severity, and days with acute medication intake during quarantine period; (2) evaluate possible differences in migraine outcomes in consideration of lifestyle changes, emotions, pandemic diffusion, and COVID-19 infection. Methods: We interviewed patients who were included in the observational Italian Headache Registry (Registro Italiano Cefalee, RICE), retrospectively collecting information on main headache features, lifestyle factors, emotions, individual infection status, and perception of COVID-19 for 2 months before (pre-quarantine) and after the beginning of the quarantine (quarantine). Inclusion criteria were: age > 18, diagnosis of migraine without aura, migraine with aura and chronic migraine, last in-person visit more than 3 months preceding the beginning of quarantine. Results: A total of 433 migraine subjects agreed to be interviewed. We found an overall reduction in headache frequency (9.42 ± 0.43 days with headache vs. 8.28 ± 0.41) and intensity (6.57 ± 0.19 vs. 6.59 ± 0.21) during the quarantine, compared to pre-quarantine. There was a correlation between improvement and number of days of stay-at-home. When results were stratified for geographic area, we found a tendency toward worsening of headache frequency in northern Italy. Disgust regarding viral infection corresponded to a minor improvement in migraine. Conclusions: Migraine patients showed a mild improvement of migraine features, probably attributable to resilient behavior toward pandemic distress. Disgust regarding the contagion whereas potentially favoring defensive behavior, could potentially worsen migraine. The spontaneous limitation of migraine burden during quarantine could favor patient follow-up via the use of telemedicine visits, reliable diaries, and frequent remote contacts.

BACKGROUND: Previous studies during SARS and Ebola pandemics have shown that quarantine is associated with several negative psychological effects, such as post-traumatic stress symptoms, confusion and anger. These conditions may affect the course of many diseases, including migraine. Although it is possible that the quarantine measures for the current COVID-19 pandemic affect migraine burden, no information is currently available on this issue. AIM: In this study, we aimed to: 1) explore the possible changes in migraine frequency, severity, and days with acute medication intake during quarantine period; 2) evaluate possible differences in migraine outcomes in consideration of lifestyle changes, emotions, pandemic diffusion, and COVID-19 infection. METHODS : We interviewed patients who were included in the observational Italian Headache Registry (Registro Italiano Cefalee, RICE), retrospectively collecting information on main headache features, lifestyles factors, emotions, individual infection status, and perception of COVID-19 for two months before (pre-quarantine) and after the beginning of the quarantine (quarantine). Inclusion criteria were: age > 18, diagnosis of migraine without aura, migraine with aura and chronic migraine, last in-person visit more than 3 months preceding the beginning of quarantine. RESULTS: A total of 433 migraine subjects agreed to be interviewed. We found an overall reduction in headache frequency and intensity during the quarantine, compared to pre-quarantine. There was a correlation between improvement and number of days of stay-at-home. When results were stratified for geographic area, we found a tendency towards worsening of headache frequency in northern Italy. Disgust regarding viral infection corresponded to a minor improvement in migraine.CONCLUSIONSMigraine patients showed resilient behavior toward pandemic distress. Disgust regarding the contagion whereas potentially favoring defensive behavior, could potentially worsen migraine.

BackgroundMost patients treated with erenumab in clinical practice have chronic migraine (CM). We assessed the rate and possible predictors of conversion from CM to episodic migraine (EM) in a real-life study.Main bodyWe performed a subgroup analysis of patients treated with erenumab from January 2019 to February 2020 in the Abruzzo region, central Italy. Treatment was provided according to current clinical practice. For the purpose of the present study, we included patients fulfilling the definition of CM for the three months preceding erenumab treatment and with at least 6 months of follow-up after treatment. We assessed the rate of conversion to EM from baseline to Months 4–6 of treatment and during each month of treatment. To test the clinical validity of conversion to EM, we also assessed the decrease in monthly headache days (MHDs), acute medication days, and median headache intensity on a Numerical Rating Scale (NRS). We included in our study 91 patients with CM. At Months 4–6, 62 patients (68.1%) converted from CM to EM; the proportion of converters increased from Month 1 to Month 5. In the overall group of patients, median MHDs decreased from 26.5 (IQR 20–30) to 7.5 (IQR 5–16;P P P ConclusionsIn our study, two thirds of patients with CM converted to EM during 6 months of treatment with erenumab. MHDs, acute medication use, and headache intensity decreased regardless of conversion from CM to EM.

Background Identifying the cause of intracerebral hemorrhage (ICH) is relevant to optimize its management. We aimed to assess the applicability and utility of the Edinburgh CT criteria for cerebral amyloid angiopathy (CAA) in an unselected cohort of hospitalized patients. Patients and Methods We retrospectively applied the Edinburgh criteria to the first available brain CTs of patients hospitalized for a first-ever lobar ICH in the district of L’Aquila from 2011 to 2017. ICH characteristics and outcomes were compared according to the presence of the Edinburgh CT criteria, including associated subarachnoid hemorrhage (aSAH) and finger-like projections (FLPs). The outcome of ICH in-hospital mortality was assessed with multivariate logistic regression analysis. We adopted the Edinburgh criteria, age, NIHSS and Glasgow Coma Scale scores, systolic blood pressure, antiplatelet treatment, ICH volume, and intraventricular extension on admission as covariates. Results Of 178 patients with lobar ICH, 52 (29.2%) had aSAH+FLPs, 60 (33.7%) aSAH only, 1 (0.6%) FLPs, and 65 (36.5%) none. Patients with aSAH+FLPs were older (79.0 ± 9.2 years) than those with only one criterion or none (74.0 ± 15.3 and 72.2 ± 13.8 years, respectively; P = 0.020). Patients with aSAH+FLPs also had more severe ICH at onset, higher in-hospital case-fatality (log rank test P = 0.003) and higher mRS scores at discharge (P Discussion Our data suggest the applicability of the Edinburgh CT criteria in a hospital setting. The presence of those criteria reflects ICH clinical severity. Conclusions Applying the Edinburgh CT criteria might help refining the diagnosis and improving the management of patients with lobar ICH.

BACKGROUND Previous studies during the SARS and Ebola pandemics have shown that quarantine is associated with several negative psychological effects. Although it is possible that quarantine for the current COVID-19 pandemic affects migraine burden, no information is currently available on this i AIM: In this study, we aimed: a) to explore the effect of quarantine on migraine frequency, severity and days with acute medication intake, and b) to evaluate whether migraine, changes in lifestyle, and emotions. were affected in a different manner in three geographic Italian areas with diverse COVID-19 diffusion, METHODS We interviewed patients included in the observational Italian registry of headache (Registro Italiano Cefalee, RICe), retrospectively collecting information on main headache features, lifestyles factors, emotions, individual infection status, and perception for COVID-19 for the two months before quarantine and during quarantine. Inclusion criteria were: age > 18; diagnosis of migraine without aura, migraine with aura, and chronic migraine; last in-person visit in the 3 months before the beginning of the quarantine. RESULTS A total of 433 migraine subjects agreed to be interviewed. We found an overall reduction in headache frequency and days with acute medication intake during the quarantine as compared to pre-quarantine. Reduction in headache frequency prevailed in patients reported more days of effective staying at home. Improvement was not evident in northern Italy. Disgust against viral infection corresponded to a reduced improvement in migraine parameters. CONCLUSIONS. Migraine patients showed a resilient behavior toward the pandemic distress. Disgust against the contagious disease, could increase migraine frequency. ssue.

Calcitonin Gene-Related Peptide (CGRP) has gradually emerged as a suitable therapeutic target to treat migraine. Considering the social and economic burden of migraine, it is fundamental to optimize the disease management with efficacious and safe treatments. In this scenario, drugs targeting GCRP, monoclonal antibodies (MoAbs) and gepants, represent new therapeutic strategies.In the present work, the authors aim at appraising the main insights and implications of treatments targeting CGRP by reviewing pathophysiology and clinical information.Anti-CGRP MoAbs are the first migraine-specific preventive treatments representing a suitable option especially for difficult-to-treat patients. They can be safely administered for long periods even in association with preventatives acting on different targets. Gepants are a safe alternative to triptans for the acute management of migraine and are currently being tested for prevention, thus representing the first transitional molecules for disease therapy. In the future, it might be possible to adapt the treatment according to patients' characteristics and disease phenotype even combining the two treatments targeting the CGRP pathway.

Migraine, and especially migraine with aura, is associated with an increased risk of stroke and vascular events; however, the reasons for this association are unclear. Several studies evaluated cerebral autoregulation and vasomotor reactivity in patients with migraine compared with non-migraineurs, with conflicting results. Our narrative review aimed at summarizing their results to find the most reliable evidence in the field. Studies which used visual stimuli to evoke vascular responses consistently showed an increased vascular reactivity in migraineurs compared with non-migraineurs, while studies which used systemic stimuli such as hyper- or hypocapnia showed inconsistent results. Therefore, central neural mechanisms might be more important than peripheral vascular mechanisms in determining the cerebral vascular responses of patients with migraine. However, a large body of evidence supports the existence of peripheral vascular dysfunction in patients with migraine. Further studies are needed to explain the complex interactions between central neural and peripheral vascular mechanisms in determining migraine and its vascular risk. Migraine preventive treatments, and especially the most recent ones with a peripheral action, might provide important insights in this field.

OBJECTIVE To quantify wear-off of the response to OnabotulinumtoxinA (OnabotA) treatment over the treatment cycle in chronic migraine at group and individual level. BACKGROUND OnabotA administered quarterly is an effective treatment for chronic migraine. However, some patients report that headache recurs before the scheduled follow-up injection. METHODS In this retrospective chart review performed in 6 university outpatient centers or private practices specialized in headache treatment, 112 patients with a ≥30% response to OnabotA who completed headache diaries over 13 weeks after OnabotA treatment were included (age [mean ± SD] 45 ± 12 years, 82% female, headache days/month at baseline 24 ± 6). RESULTS Compared to weeks 5 to 8 after injection, headache days/week increased significantly in weeks 12 (+0.52 ± 1.96, 95% CI [0.15, 0.88], P

Background We aimed to assess the efficacy and safety of erenumab, a fully human monoclonal antibody inhibiting the calcitonin gene-related peptide receptor (CGRPr), for the prevention of migraine in a real-life setting. Main body We included in our observational study all patients with episodic or chronic migraine treated with erenumab during the year 2019 in the Abruzzo region, central Italy, and with a 6-month follow-up. We included 89 patients; 76 (85.4%) received 6 doses of erenumab, 11 (12.4%) autonomously withdrew the drug due to perceived inefficacy, and 2 (2.2%) due to adverse events. Seventy-eight patients (87.6%) were female, with a mean age of 46.8 ± 11.2 years; 84 (94.4%) had chronic migraine, and 64 (71.9%) medication overuse. All patients had ≥2 prior preventive treatment failures. Fifty-three patients (69.7%) had a 50% decrease in monthly migraine days (MMDs) within the first three doses; 46 (71.9%) of 64 patients withdrew medication overuse. In the 76 patients who completed a 6-dose treatment, erenumab decreased median MMDs from 19 (interquartile range [IQR] 12–27.5) to 4 (IQR 2–9.5; P Conclusions Our real-life data confirm the efficacy and tolerability of erenumab for the prevention of migraine in a difficult-to-treat population of patients with a high prevalence of chronic migraine and medication overuse.

Background Rare primary headaches are mainly included in Chapters 3, Trigeminal autonomic cephalalgias, and 4, Other primary headache disorders, Part One of the International Classification of Headache Disorders 3rd edition. Epidemiological data are scarce, mostly emerging from case series or small studies, with the exception of cluster headache. In order to overcome the knowledge gap about rare primary headaches, the RegistRare Network was launched in 2017 to promote research in the field. Methods A retrospective cohort study including patients who, from April 30, 2014 to May 1, 2017, visited seven Italian tertiary Headache Centres, was undertaken to estimate in that clinical setting prevalence and incidence of headaches included in Chapters 3 and 4, Part One of the International Classification of Headache Disorders 3rd edition. Prevalent headache is defined as a headache recorded within the study timeframe, regardless of when the diagnosis was made. Incident headache is defined as a headache diagnosed for the first time in the patient during the study period. Results Twenty thousand and eighty-three patients visited the participating centres, and 822 (4.1%) prevalent cases, of which 461 (2.3%) were incident cases, were registered. Headaches listed in Chapter 3 affected 668 patients, representing 81.3% of the total number of prevalent cases. Headaches listed in Chapter 4 affected 154 patients and represent 18.7% of the total number of prevalent cases. Cluster headaches represent the most frequently diagnosed rare headaches (70.4%). For 13 entities out of 20, no cases were registered in more than 50% (n ≥ 4) of the centres, and for 14 entities more than 50% of diagnoses were incident. Conclusions This large, multicentre study gives the first wide-ranging snapshot of the burden in clinical practice of rare headaches and confirms that cooperative networks are necessary to study rare headaches, as their prevalence is often very low. The launch of a disease registry by the RegistRare Network will favour research in this neglected population of headache patients. Trial registration NCT03416114.

Objective:To evaluate the association between migraine and body composition status as estimated based on body mass index and WHO physical status categories.Methods:Systematic electronic database searches were conducted for relevant studies. Two independent reviewers performed data extraction and quality appraisal. Odds ratios (OR) and confidence intervals (CI) were pooled using a random effects model. Significant values, weighted effect sizes, and tests of homogeneity of variance were calculated.Results:A total of 12 studies, encompassing data from 288,981 unique participants, were included. The age- and sex-adjusted pooled risk of migraine in those with obesity was increased by 27% compared with those of normal weight (odds ratio [OR] 1.27; 95% confidence interval [CI] 1.16–1.37, p < 0.001) and remained increased after multivariate adjustments. Although the age- and sex-adjusted pooled migraine risk was increased in overweight individuals (OR 1.08; 95% CI 1.04, 1.12, p < 0.001), significance was lost after multivariate adjustments. The age- and sex-adjusted pooled risk of migraine in underweight individuals was marginally increased by 13% compared with those of normal weight (OR 1.13; 95% CI 1.02, 1.24, p < 0.001) and remained increased after multivariate adjustments.Conclusions:The current body of evidence shows that the risk of migraine is increased in obese and underweight individuals. Studies are needed to confirm whether interventions that modify obesity status decrease the risk of migraine.

Background Migraine is a major public health issue associated with significant morbidity, considerable negative impact on quality of life, and significant socioeconomic burden. Preventive treatments are required to reduce the occurrence and the severity of acute attacks and to minimize the use of abortive medications and the associate risk of drug-related adverse events, as well as the onset of medication-overuse headache and chronification of migraine. We performed a review of all available evidence on the safety and efficacy of monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor for the preventive treatment of migraine to provide evidence-based guidance on their use in clinical practice. Abstract main body Monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor are mechanism-specific drugs for the preventive treatment of migraine. Double-blind randomized clinical trials have shown that monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor are effective across all the spectrum of migraine patients who require prevention and have a good safety and tolerability profile. Nevertheless, high costs limit the affordability of those drugs at the moment. Conclusions Specificity, long half-life, efficacy, tolerability, and ease of use make monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor an appealing treatment option for migraine prevention. Optimal strategies to manage treatment over time still need to be clarified with real-life data.

Background Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. Methods The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. Results We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. Conclusions Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Epilepsy management in elderly patients is often complex because of several concomitant comorbidities that may limit the use of some antiepileptic drugs (AEDs). Levetiracetam (LEV) is a second-generation AED widely used in elderly patients with epilepsy while lacosamide (LCM), which has been recently approved in European Union (EU) as monotherapy for the treatment of focal onset seizures, is affected by a scarcity of data in such frail population. This study is aimed at assessing the efficacy and the tolerability of LCM as monotherapy in elderly patients affected by focal onset epilepsy compared with those receiving LEV.A retrospective chart review of patients aged ≥65 years suffering from focal onset seizures, with or without secondary generalization on LCM monotherapy or LEV monotherapy, was performed. Data regarding demographic characteristics, seizure type and etiology, LCM and LEV daily dose, number of lifetime AEDs, seizure frequency at baseline and at 12 months of follow-up, and seizure freedom rates were reported.In this observational retrospective study, 22 patients on LCM (10 males, 12 females, mean age: 76.23 ± 7.5) and 24 patients on LEV (10 males, 14 females, mean age: 73.58 ± 6.39) were enrolled. Mean LCM daily dose was 204.51 ± 88.51 mg and mean LEV daily dose was 1281.25 ± 378.15 mg. All patients had comorbidities on chronic treatment. At 12 months of follow-up, mean monthly seizure frequency reduced from 4.23 ± 8.53 to 0.33 ± 0.9 (p .001) in LCM group and from 2.29 ± 6.11 to 0.2 ± 0.81 (p .001) in LEV group. Furthermore, 16/22 (72.7%) LCM patients were seizure-free at 12 months of follow-up while seizure freedom was achieved by 17/24 (70.8%) patients in LEV group.Epilepsy management in elderly patients is often challenging. In this retrospective real-life study, the efficacy and the tolerability of LCM as monotherapy was favorable even at low doses in older patients and comparable with LEV with a high rate of long-term seizure freedom. Considering the frequent comorbidities and the risk of drug-drug interactions, LCM monotherapy may be a valuable option in elderly patients with focal onset epilepsy because of its favorable pharmacokinetic profile.

Objectives: The study aims to assess the impact of the second COVID-19 pandemic wave on migraine characteristics. Methods: This is an observational cross-sectional study conducted on migraine patients previously interviewed during the first Italian pandemic outbreak. A second structured telephone interview was conducted between 20 November 2020 and 18 January 2021. We compared migraine characteristics among T0 (before pandemic), T1 (during the first pandemic phase), and T2 (during the second pandemic phase). Results: Among the 433 patients interviewed during the first pandemic phase, 304 cases were finally considered. One hundred forty-eight patients had a control visit between March 2020 and December 2020, 120 had an in-person visit, 14 by phone, the remainder used telemedicine software provided by the hospital. Frequency of headache, number of symptomatic drugs and headache intensity worsened during T2, compared to T0 and T1, especially in episodic migraine. Headache intensity increased relating to the negative emotional impact of the pandemic. Migraine management during the pandemic did not influence the clinical outcome. Conclusion: The prolongation of the pandemic seems to have a negative impact on migraine evolution. The arousal and negative psychological behavior toward the COVID-19 outbreak seem to worsen migraine.

Background: We aimed to assess the differences between menstrual and non-menstrual headache in women with chronic migraine treated with erenumab. Methods: We included fertile women from a single center. Patients were defined as responders to erenumab if reporting a ≥50% decrease in monthly headache days, as compared to pre-treatment for more than half of the treatment period. Premenstrual days were defined as the two days preceding menstruation, while menstrual days were defined as the first three days of menstruation. Results: We included 18 women (11 erenumab responders and 7 erenumab non-responders) contributing to a total of 103 menstrual cycles and 2926 days. The proportion of headache days was higher in menstrual than in premenstrual and non-menstrual days in erenumab responders (34.4% vs. 14.8% vs. 16.3%, respectively, p &lt, 0.001) and in erenumab non-responders (71.4% vs. 53.6% vs. 48.3%, respectively, 0.001). Headache days with ≥2 acute medications were higher in menstrual than in premenstrual or non-menstrual headache days in erenumab non-responders (p = 0.002) but not in erenumab responders (p = 0.620). Conclusions: Our data suggest that migraine is more frequent during than outside menstrual days even in women treated with erenumab.

Background and purpose The incidence and case-fatality rate (CFR) of primary intracerebral hemorrhage (PICH) over two decades were assessed in a prospective population-based study. Methods Cases of incident first-ever PICH were recorded over a 2-year period (2011–2012) from multiple sources in the district of L'Aquila, central Italy. Included patients were followed up to 1 year after the event to ascertain CFRs. Current data were compared with those previously collected from 1994 through 1998. Results In all, 115 patients (52 men; 45.2%) with a first-ever PICH were included. Mean age ± SD was 77.4 ± 11.8 years. The hemorrhage was lobar in 43 (37.4%) patients, deep in 56 (48.7%), in the posterior fossa in 11 (9.6%) and intraventricular or multiple localized in five (4.3%). Crude annual incidence rate was 19.3 per 100 000 and 14.8 per 100 000 when standardized to the 2011 European population, indicating a 48% reduction comparing data of 2011–2012 to those of 1994–1998 (incidence rate ratio 0.52; 95% confidence interval 0.43–0.64; P < 0.001). In 2011–2012, the 7-day CFR was 27.8%, the 30-day CFR was 42.6% and the 1-year CFR was 52.2%; the 1-year standardized mortality ratio was 0.81 (95% confidence interval 0.63–1.04) compared with 1994–1998. Conclusions The annual incidence rate of PICH was lower than that found two decades before and close to the rates recently found in other western countries. Data also indicated a non-significant trend towards a decrease in mortality, which nonetheless remained high, pointing to the need for more appropriate treatments in order to reduce PICH severity and mortality.

We thank Dr. Gupta for the interest in our article,1 in which we evaluated the relationship between body composition and migraine. The commentary raised an interesting point about biological plausibility and how observed association between low body mass index (BMI) and migraine might be attributable to underlying illness such as thyrotoxicosis. Biologically, it is well-known that there are several potential mechanisms for the BMI–migraine association.2 Adipose tissue is a neuroendocrine organ. Like the thyroid gland, too much or too little can both be associated with medical symptoms or disorders. Adipose tissue is centrally regulated by the hypothalamus and its connections, and peripherally participates in modulation of hormones, immune cells, and inflammatory-related proteins (e.g., adipocytokines).2,3 With adipose tissue expansion, or reduction, changes in macrophage recruitment, receptor expression, and the secretion of cytokines and adipokines occur.2,4 As such, it is not surprising that low BMI is associated with migraine. Is it possible that undetected illness could lead to low BMI? Yes, it is possible. However, as noted in our article, most of the studies included for meta-analysis are population-based studies.1 It is highly unlikely these rare complications can introduce bias in population-based studies. Finally, we would like to clarify that our meta-analysis was not a data-driven exercise. Rather, it was guided by a fundamental biological question with priori set procedures and consistent operational definitions of exposure and outcome variables. The details are summarized in the Methods of our article.1

Background and purpose Several studies have assessed the risk of ischaemic heart diseases in migraineurs, drawing different conclusions. To define and update the issue, a systematic review and meta-analysis of the available observational studies was performed. Methods PubMed and EMBASE were systematically searched up to April 2014 for observational studies dealing with the risk of any form of ischaemic heart disease in migraineurs. Studies assessing migraine as exposure and several types of ischaemic heart disease as outcomes were included in the analysis. A random effects model was used to pool the effect sizes. Results Out of 3348 records, 15 studies (one case−control, one cross-sectional and 13 cohort studies) were identified and were included in the meta-analysis. The pooled analysis indicated an increased risk of myocardial infarction (pooled adjusted effect estimate 1.33, 95% confidence interval 1.08–1.64; P = 0.007) and of angina (pooled adjusted effect estimate 1.29, 95% confidence interval 1.17–1.43; P

In young adults, acute motor axonal neuropathy and transverse myelitis rarely occur as associated conditions. Clinical reasoning, symptoms, laboratory and ancillary investigations (electroneurographic and radiological findings), should properly address the physician to the correct diagnosis.

Background Many studies have investigated the association between chronic daily headache (CDH) and normal weight, preobesity, and obesity, with controversial results. A metaanalysis of observational studies was conducted in order to clarify the association between CDH and body mass index (BMI) categories. Methods Studies published up to April 2015 about the association between CDH and BMI were systematically searched from multiple electronic databases. We included in the analysis observational studies in the English language with CDH as outcome variables, and pre-obesity or obesity as compared with normal weight as exposure variables. Only the studies which defined BMI categories according to the World Health Organization criteria for the Western population were included (underweight