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Background A novel formulation of diclofenac, complexed with hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer, in a prefilled syringe for self-administered subcutaneous injection may overcome the limitations of acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes. Methods This multicentre, phase 2, double-blind, randomized, placebo-controlled, dose-finding pilot study evaluated the efficacy, safety and tolerability of three different doses (25/50/75 mg/1 mL) of subcutaneous diclofenac sodium in the treatment of an acute migraine attack in 122 subjects. The primary efficacy endpoint was the percentage of patients pain-free at 2 hours after the study drug injection. Results A significantly higher percentage of patients in the 50 mg diclofenac group 14 (46.7%) were pain-free at 2 hours when compared with placebo: 9 (29.0%) ( p = 0.01). The 50 mg dose proved superior to placebo also in the majority of the secondary endpoints. The overall global impression favoured diclofenac vs placebo. There were no adverse events leading to study withdrawal. The majority of treatment-emergent adverse events were mild. Conclusions The 50 mg dose of this novel formulation of diclofenac represents a valuable self-administered option for the acute treatment of migraine attacks. Trial registration: EudraCT Registration No. 2017-004828-29.

Background Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM. Methods This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9-12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥50%, ≥75% and 100% responder rates at the same time intervals. Results 67 migraine patients had received ≥1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p

In this study, the performance of 63 existing pedotransfer functions (PTFs) is evaluated to estimate oven-dry soil bulk density (BD) by using a dataset of 3316 soil cores taken in the farmlands of Campania (southern Italy). As expected, the lack of direct calibration yields prediction accuracy from unsatisfactory to rather weak. Therefore, we advance the working hypothesis that the use of hierarchical soil mapping information can make the application of existing PTFs more reliable. We show that grouping data according to land-systems classes or soil groups considerably improves the prediction ability quantified through the root mean squared error (RMSE) and the coefficient of determination (R2). An independent data set of 105 soil cores taken from two hillslopes in the Upper Alento River Catchment in southern Campania was used to verify our assumption. The validation step shows that the knowledge of a soil-landscape map is an efficient tool for improving the prediction of BD. This approach will be employed in a subsequent study to develop site-specific PTFs for the study region.

Background and aims: Erenumab proved to be safe and well tolerated in a 5-year continuation of a 1-year double-blind, placebo-controlled study. Aim: to assess >48-week erenumab tolerability and safety in a real-world setting. Methods: In this long term (>48-week), multicenter (n = 15), longitudinal cohort real life study, we monitored all the adverse events emerged in consecutive adult patients with high-frequency episodic migraine (HFEM) or chronic migraine (CM) treated with monthly erenumab 70 mg or 140 mg from 20 December 2018 to 15 December 2020. Results: 442 patients (HFEM: 115;CM: 327) were treated with erenumab for >48 weeks: 209 (47.3%) patients were treated for 49–60 weeks, 132 (29.9%) for 61–72 weeks;73 (16.5%) for 73–84 weeks;21 (4.7%) for 85–100 weeks. Overall, >1 treatment emergent adverse event (TEAE) was reported by 136 (30.8%) [HFEM: 43 (37.4%);CM: 93 (28.4%)]. Most common TEAE were constipation (n = 66;14.9%), injection site erythema (n = 15;3.4%), and influenza (n = 7;1.6%). Serious adverse events (SAE) were reported by 8 patients (1.8%) and led to treatment discontinuation: severe constipation (n = 3), abdominal pain (n = 1), NSTEMI (n = 3), Covid-19 infection (n = 1). Only severe constipation was considered treatment-related SAE (0.45%). Conclusions: Conclusion: Erenumab is safe and well tolerated also in long-term treatment (>48 weeks) in real life.

Since chronic migraine is difficult to treat and often associated with medication overuse, non-invasive neurostimulation approaches are worth investigating. Transcutaneous supraorbital neurostimulation using the Cefaly® device is promising as a non-invasive preventive treatment for episodic migraine, but no data are available for chronic migraine. Our aim was to perform a preliminary evaluation of the efficacy of the Cefaly® device for the prophylaxis of chronic migraine with or without medication overuse. Primary endpoints were 50% reduction in monthly migraine days and 50% reduction in monthly medication use over 4 months. In an open-label study, twenty-three consecutive headache center patients with chronic migraine, diagnosed according to International Headache Society criteria, were recruited prospectively. After informed consent, patients were trained to use Cefaly® and instructed to use it for 20 min daily over 4 months. All patients received active neurostimulation. Thirty-five percent of the patients enrolled in the study achieved the study endpoints. Over half the patients had a greater than 50% reduction in acute medication consumption.

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Several studies report the presence of white matter lesions on brain magnetic resonance imaging in patients with migraine. The aim of our study was to detect the entity of white matter T2-hyperintensities in 90 high selected patients affected by migraine with aura, compared to a group of 90 healthy controls. We found no significant difference of incidence of white matter alterations comparing these two groups.

Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache.

Background Chronic migraine with medication overuse (CM-MO) impairs quality of life (QoL) and causes disability. Psychosocial variables such as depressive symptomatology, self-efficacy, and social support have been sparingly investigated, and their impact on disability and QoL is unknown. Methods Patients with CM-MO under withdrawal were consecutively enrolled. Standardized measures of disability and QoL were used as outcomes; psychosocial (ie, mood state, self-efficacy, social support) and clinical (ie, headache frequency and intensity) variables were considered as associated variables. Associations between these variables, disability, and QoL were tested with Pearson's correlations. Hierarchical multiple regression was used to assess the cumulative contribution of psychosocial variables on disability and QoL variation when added to clinical variables. Results One hundred ninety-four patients were enrolled; 82.5% were females and mean age was 43.9. Disability and QoL were moderately or little correlated to clinical and psychosocial variables. Models based on clinical variables explained 7.5-14.3% of disability and QoL variation, with pain intensity being the only significant predictor; when psychosocial variables were added, the explained variation increased to 21.5-35.2%, with depressive symptomatology always having independent predictive power and perceived social support having independent predictive power in the regression model over role-prevention component of QoL. Conclusions Adding information on psychosocial variables to headache features improved our ability to understand disability and QoL of CM-MO patients. We deem that the inclusion of psychosocial variables in standard evaluation protocols may contribute to the global assessment of CM-MO patients, and eventually to their success in reducing the personal and social impact of this condition. Future longitudinal studies are needed to confirm this hypothesis.

Patients with chronic migraine with medication overuse (CM-MO) have decreased quality of life (QoL) and increased disability: the degree to which these outcomes are connected to disease severity and the pattern of MO towards disease severity are unclear. Patients under withdrawal were administered the Migraine Disability Assessment (MIDAS), the WHO Disability Assessment Schedule (WHODAS), and the Migraine-Specific Quality of Life Questionnaire (MSQ). They overused NSAIDs, triptans, NSAIDs and triptans, and other drugs (ergotamine, caffeine, opioids/barbiturates). We calculated the correlations between MIDAS, WHODAS, and MSQ; compared WHODAS to normative scores; compared MIDAS, WHODAS, and MSQ in patients with different CM-MO severity; and run a logistic regression to predict CM-MO severity based on overused drugs. One hundred ninety-four patients were enrolled: correlations between WHODAS, MSQ, and MIDAS were moderate; wide differences on WHODAS against normative were found; and no trend was found across severity groups. Compared to triptans overusers, patients overusing NSAID and other drugs had higher odds of severe CM-MO. Coupling different disability measures with QoL assessment offered different insights on the lived experience of CM-MO. Future studies are needed to clarify the relationship between overused drugs and CM-MO severity: we added evidence that NSAIDs do not have protective effect in high-frequency CM-MO.

Migraine is a common primary episodic headache disorder. The most common migraine form is migraine without aura, with an estimated prevalence of 10–12 % in most Western societies. It is more frequent in women and usually starts before the age of 20, peaking between 35 and 45. In women, migraine often develops post menarche, worsens during menses, and may vanish during the last two trimesters of pregnancy or after menopause, suggesting an endocrine component to be involved. Two forms of migraine without aura are recognized: episodic (0–14 days per month with headache) and chronic (15 or more days per month with headache; Table 1). Usually, headache is unilateral, in the frontotemporal region, reaches its peak intensity gradually, is moderate to severe, is usually throbbing, and is aggravated by movements. It lasts 4–72 h (untreated or unsuccessfully treated) and can be associated with other symptoms, such as phonophobia, photophobia, nausea, and vomiting. Premonitory symptoms occur in 20–60 % of patients with migraines, hours to days before headache onset. They can include depression, fatigue, irritability, sensory sensitivity, anorexia/hunger, diarrhea/constipation, sensations of heat or cold, and sweating. In migraine with aura, focal neurological symptoms, mainly in the visual field, precede the headache and last about 15–30 min.

We evaluated the association between depressive symptoms and migraine using cross-sectional data from the Zabút Aging Project, a population-based study including subjects agedor =50 years. A total of 1285 nonmigraineurs and 151 migraineurs were included. Diagnosis of migraine was carried out using the criteria of the International Headache Society. The Center for Epidemiologic Studies Depression scale (CES-D) was used to score depressive symptoms. Depressive symptoms were clustered in four groups: depressed and positive affects, somatic activity and intrapersonal feelings. Migraineurs showed higher total and specific depressive symptoms than controls (p from 0.005 to0.0001). Mild-to-moderate depressive symptoms (CES-D score ofor =16) were present in 47.2% of migraineurs compared to 15.8% of controls (p0.0001). After adjustment for demographics, mild-to-moderate depressive symptoms were strongly associated with migraine (OR [95% CI]=4.7 [3.1-7.0]). This association significantly increased in males (OR [95% CI]=6.2 [2.8-14.6]). Depressive features represent highly frequent comorbid symptoms of adult-to-elderly migraineurs.

The peripheral and central origin of pain in cluster headache (CH) and trigeminal autonomic cephalgias (TACs) has been matter of debate. In the last decade, a number of information came from both animal and human studies. This paper briefly highlights main data from these studies. Taken together, there is now sufficient body of evidence indicating that CH and TACs can be regarded as a unique headache spectrum–syndrome, due to involvement of specific brain areas.

Neuropsychiatric symptoms (NPS) are common clinical features of Parkinson's disease (PD). However, NPS profiles in PD subjects with mild cognitive impairment (MCI) have scarcely been investigated. We aimed to describe the NPS profiles of non-demented PD subjects with and without MCI. A total of 410 non-demented PD subjects were included. Of these, 164 were cognitively normal PD subjects (PD-cn), 142 PD had amnestic MCI (PD-aMCI), and 104 had PD with non-amnestic MCI (PD-naMCI). NPS were evaluated in accordance with the Neuropsychiatric Inventory (NPI). PD-aMCI subjects revealed the highest NPS burden, followed by PD-naMCI and then PD-cn. Overall, the most common NPS in PD-MCI were in order: depression, sleep disturbance, anxiety and apathy. Irritability was significantly associated with PD-aMCI and PD-naMCI. Prospective studies are required to evaluate the significance, clinical correlates and prognostic role of NPS in subject with PD-MCI.