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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.

Background and purpose: The patterns of long-term risk of SARS-CoV-2 infection, hospitalization for COVID-19, and related death are uncertain in people with Parkinson disease (PD) or parkinsonism (PS). The aim of the study was to quantify these risks compared to a control population cohort, during the period March 2020–May 2021, in Bologna, Northern Italy. Methods: ParkLink Bologna cohort (759 PD, 192 PS) and controls (9226) anonymously matched (ratio=1:10) for sex, age, district, and comorbidity were included. Data were analysed in the whole period and in the two different pandemic waves (March–May 2020 and October 2020–May 2021). Results: Adjusted hazard ratio of SARS-CoV-2 infection was 1.3 (95% confidence interval [CI] = 1.04–1.7) in PD and 1.9 (95% CI=1.3–2.8) in PS compared to the controls. The trend was detected in both the pandemic waves. Adjusted hazard ratio of hospitalization for COVID-19 was 1.1 (95% CI=0.8–1.7) in PD and 1.8 (95% CI=0.97–3.1) in PS. A higher risk of hospital admission was detected in PS only in the first wave. The 30-day mortality risk after hospitalization was higher (p= 0.048) in PS (58%) than in PD (19%) and controls (26%). Conclusions: Compared with controls, after adjustment for key covariates, people with PD and PS showed a higher risk of SARS-CoV-2 infection throughout the first 15 months of the pandemic. COVID-19 hospitalization risk was increased only in people with PS and only during the first wave. This group of patients was burdened by a very high risk of death after infection and hospitalization.

Objective: This article reviews current headache disability measures and clinical need, as well as presenting the rationale for a new measure addressing work-related disability in migraine patients and the steps devoted to this aim. Background: Episodic and chronic migraine (EM and CM) constitute an enormous economic burden to societies, and the vast majority of this burden is attributable to indirect costs, ie those associated with productivity loss. A measure of work-related disability is therefore needed to quantify the impact of EM and CM on patients' ability to carry out work tasks. Methods: We briefly present the advantages and disadvantages of the disability measures that have been most commonly used for this purpose and the rationale for developing a new measure. Results: The entire process of development of HEADWORK, a questionnaire designed to assess work-related disability, is presented together with short-term sensitivity to change. Conclusions: Current headache disability measures need improvement. HEADWORK is a valid, reliable, and sensitive questionnaire to address the amount and severity of work-related difficulties and of the factors contributing to such difficulties. HEADWORK is suitable for daily clinical practice, epidemiological research and for clinical trials, and potentially to define work-related disability weights for the calculation of migraine indirect costs.

Background In idiopathic normal pressure hydrocephalus (iNPH), gait and balance impairment is the most frequent symptom, and it is often associated with a higher fall risk. In a prior study, the anterior callosal angle (ACA) was validated as a reliable marker to discriminate iNPH from Alzheimer's disease and healthy controls. However, the potential correlation between the ACA with clinical symptoms and functional outcomes has not been assessed. The objective of this study is to determine the utility of the ACA in predicting gait improvement after ventriculoperitoneal (VP) shunting.Methods Patients with probable iNPH who underwent shunt placement at a single institution were prospectively enrolled from May 2015 to May 2019. Patients were assessed preoperatively and at 6 months postoperatively following a standard clinical and MRI protocol. Callosal angle (CA) and ACA were calculated from 3 T MRI preoperatively and at 6 months postoperatively. CA and ACA were tested for correlation with clinical scores.Results Forty-seven patients with probable INPH who completed 6-month postoperative follow-up were enrolled in the study. Baseline ACA was significantly correlated with preoperative fall risk, gait, and balance impairment assessed with Tinetti POMA scale. Additionally, baseline ACA differentiated patients who experienced improvement at Tinetti POMA scale after surgery.Conclusions The baseline ACA is a useful neuroradiological marker to differentiate patients by fall risk and has significant correlation with the improvement in gait and balance impairment following surgery. This study demonstrated that the ACA may be a complementary tool to the CA in predicting shunt responsiveness in iNPH.

Background The PRESTO study of non-invasive vagus nerve stimulation (nVNS; gammaCore®) featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication. Methods Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation. Results A significantly higher percentage of patients who used acute nVNS treatment (n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min (nVNS, 32.2%; sham, 18.5%; P = 0.020), 60 min (nVNS, 38.8%; sham, 24.0%; P = 0.017), and 120 min (nVNS, 46.8%; sham, 26.2%; P = 0.002) after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack (nVNS, 59.3%; sham, 41.9%; P = 0.013) and all attacks (nVNS, 52.3%; sham, 37.3%; P = 0.008). When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min (all attacks: nVNS, 37.0%; sham, 21.2%; P = 0.025) and 120 min (first attack: nVNS, 50.0%; sham, 25.0%; P = 0.018; all attacks: nVNS, 46.7%; sham, 30.1%; P = 0.037). Conclusions This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events. Trial registration ClinicalTrials.gov identifier: NCT02686034.

In the field of so-called chronic daily headache, it is not easy for migraine that worsens progressively until it becomes daily or almost daily to find a precise and universally recognized place within the current international headache classification systems. In line with the 2006 revision of the second edition of the International Classification of Headache Disorders (ICHD-2R), the current prevailing opinion is that this headache type should be named chronic migraine (CM) and be characterized by the presence of at least 15 days of headache per month for at least 3 consecutive months, with headache having the same clinical features of migraine without aura for at least 8 of those 15 days. Based on much evidence, though, a CM with the above characteristics appears to be a heterogeneous entity and the obvious risk is that its definition may be extended to include a variety of different clinical entities. A proposal is advanced to consider CM a subtype of migraine without aura that is characterized by a high frequency of attacks (10–20 days of headache per month for at least 3 months) and is distinct from transformed migraine (TM), which in turn should be included in the classification as a complication of migraine. Therefore, CM should be removed from its current coding position in the ICHD-2 and be replaced by TM, which has more restrictive diagnostic criteria (at least 20 days of headache per month for at least 1 year, with no more than 5 consecutive days free of symptoms; same clinical features of migraine without aura for at least 10 of those 20 days).

ObjectiveTo evaluate the efficacy, safety, and tolerability of noninvasive vagus nerve stimulation (nVNS; gammaCore; electroCore, LLC, Basking Ridge, NJ) for the acute treatment of migraine in a multicenter, double-blind, randomized, sham-controlled trial.MethodsA total of 248 participants with episodic migraine with/without aura were randomized to receive nVNS or sham within 20 minutes from pain onset. Participants were to repeat treatment if pain had not improved in 15 minutes.ResultsnVNS (n = 120) was superior to sham (n = 123) for pain freedom at 30 minutes (12.7% vs 4.2%; p = 0.012) and 60 minutes (21.0% vs 10.0%; p = 0.023) but not at 120 minutes (30.4% vs 19.7%; p = 0.067; primary endpoint; logistic regression) after the first treated attack. A post hoc repeated-measures test provided further insight into the therapeutic benefit of nVNS through 30, 60, and 120 minutes (odds ratio 2.3; 95% confidence interval 1.2, 4.4; p = 0.012). nVNS demonstrated benefits across other endpoints including pain relief at 120 minutes and was safe and well-tolerated.ConclusionThis randomized sham-controlled trial supports the abortive efficacy of nVNS as early as 30 minutes and up to 60 minutes after an attack. Findings also suggest effective pain relief, tolerability, and practicality of nVNS for the acute treatment of episodic migraine.ClinicalTrials.gov identifierNCT02686034.Classification of evidenceThis study provides Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 hours poststimulation (absolute difference 13.2%).

Metabolites and migraine

Headache, anxiety and depressive disorders: the HADAS study J Headache Pain (2010) 11:141–150 Ettore Beghi • Gennaro Bussone • Domenico D’Amico • Pietro Cortelli • Sabina Cevoli • Gian Camillo Manzoni • Paola Torelli • Maria Clara Tonini • Giovanni Allais • Roberto De Simone • Florindo D’Onofrio • Sergio Genco • Franca Moschiano • Massimiliano Beghi • Sara Salvi Abstract The objective of this paper was to assess prevalence and characteristics of anxiety and depression in migraine without aura and tension-type headache, either isolated or in combination. Although the association between headache and psychiatric disorders is undisputed, patients with migraine and/or tension-type headache have been frequently investigated in different settings and using different tests, which prevents meaningful comparisons. Psychiatric comorbidity was tested through structured interview and the MINI inventory in 158 adults with migraine without aura and in 216 persons with tension-type headache or migraine plus tension-type headache. 49 patients reported psychiatric disorders: migraine 10.9%, tension-type headache 12.8%, and migraine plus tensiontype headache 21.4%. The MINI detected a depressive episode in 59.9, 67.0, and 69.6% of cases. Values were 18.4, 19.3, and 18.4% for anxiety, 12.7, 5.5, and 14.2%, for panic disorder and 2.3, 1.1 and 9.4% (p = 0.009) for obsessive–compulsive disorder. Multivariate analysis showed panic disorder prevailing in migraine compared with the other groups (OR 2.9; 95% CI 1.2–7.0). The association was higher (OR 6.3; 95% CI 1.4–28.5) when migraine (with or without tension-type headache) was compared to pure tension-type headache. This also applied to obsessive–compulsive disorder (OR 4.8; 95% CI 1.1– 20.9) in migraine plus tension-type headache. Psychopathology of primary headache can reflect shared risk factors, pathophysiologic mechanisms, and disease burden.

To determine the diagnostic accuracy of an algorithm structured in four clinical scenarios to discriminate benign primary headaches from serious secondary non-traumatic headaches (NTH) in the emergency department (ED).NTH is usually a benign symptom but can occasionally result in serious outcome making the disposition of patients with NTH difficult in the ED.Consecutive adults patients referring to 8 EDs of the Emilia-Romagna region in Italy for NTH as the chief complaint were recruited in the study for a 30-day period. ED physicians attributed to each patient one of the four clinical scenarios (1, 2 and 3 identifying serious secondary headaches and scenario 4 identifying benign primary headaches) or an undetermined scenario when none of the four scenarios applied. Reference standards of the study were the head CT scan and a follow-up telephone interview after three months by the ED admission.The test was administered to 256 out of 302 (85%) eligible patients. The analysis (scenario 1,2,3 vs scenario 4) was based on 180 patients who completed the follow-up showing a sensitivity of 100% (95% confidence interval, 81% to 100%) and a specificity of 64% (56% to 71%). The likelihood ratio for a positive test was 2.67 (2.15 to 3.31) and the likelihood ratio for a negative test was 0.04 (0.003 to 0.64).An algorithm based on four clinical scenarios can be administered to the majority of patients presenting to the ED with the chief complaint of NTH. The algorithm showed a good accuracy in identifying patients with non-life threatening causes of headache and could be used as a risk stratification tool to improve clinical decision- making. Further studies are required to validate this diagnostic algorithm.