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Migraine is a leading cause of disability worldwide, yet it remains underrecognized and undertreated, especially in the pediatric and adolescent population. Chronic migraine occurs approximately in 1% of children and adolescents requiring preventive treatment. Topiramate is the only FDA-approved preventative treatment for children older than 12 years of age, but there is conflicting evidence regarding its efficacy. OnabotulinumtoxinA is a known and approved treatment for the management of chronic migraine in people older than 18 years. Several studies examine its role in the pediatric population with positive results; however, the clear-cut benefit is still unclear. OnabotulinumtoxinA seems not only to improve disability scores (PedMIDAS) but also to improve the quality, characteristics, and frequency of migraines in the said population. This systematic review aims to summarize the evidence on the efficacy, dosing, administration, long-term outcomes, and safety of onabotulinumtoxinA in pediatric and adolescent migraine. Eighteen studies met the eligibility criteria and were included in this review. The mean monthly migraine days (MMDs), decreased from of 21.2 days per month to 10.7 after treatment. The reported treatment-related adverse effects were mild and primarily injection site related and ranged from 0% to 47.0%. Thus, this review provides compelling evidence suggesting that OnabotulinumtoxinA may represent a safe and effective preventive treatment option for pediatric migraine. [ABSTRACT FROM AUTHOR]

Background: Headache disorders have been associated with anxiety and depressive disorders. The aim of this study was to assess symptoms of anxiety and depression in a large sample of individuals with different headache disorders (HDs) in order to determine whether their frequency differs by headache type. Methods: Consecutive individuals with headache attending a headache outpatient clinic were interviewed with the HAM-D and HAM-A, along with age, sex, and education matched non-headache individuals. Results: Individuals numbering 2673 with headache (females 71.2%) and 464 non-headache individuals (females 70.9%) were interviewed (with participation rates of 98.3% and 91.0%, respectively). Migraine was diagnosed in 49.7%, tension-type headache in 38%, cluster headache 5.2%, and medication overuse (MO) in 21.8%. Participants with HD scored more in HAM-A (OR = 4.741, CI95%: 3.855–5.831, p < 0.001) and HAM-D scales (OR = 2.319, CI95%: 1.892–2.842, p < 0.001) than non-headache individuals. Participants with chronic HDs (≥15 days with headache for ≥3 consecutive months; 52.5%) scored higher for both HAM-A (OR = 1.944, CI95%: 1.640–2.303, p < 0.001) and HAM-D (OR = 1.625, CI95%: 1.359–1.944, p < 0.001) than those with episodic HDs (33.1%), as did participants with MO vs. participants without MO (OR = 3.418, CI95%: 2.655–4.399, p < 0.001 for HAM-A, OR = 3.043, CI95%: 2.322–3.986, p < 0.001 for HAM-D). Female and low-educated participants scored higher on both scales. Conclusion: Because symptoms of anxiety and depression are substantial in people with HD, the treating physicians should look out for such symptoms and manage them appropriately. [ABSTRACT FROM AUTHOR]

Background and purpose: Eptinezumab reduced monthly migraine days more than placebo in the DELIVER study, a clinical trial with patients with difficult‐to‐treat migraine and prior preventive treatment failures. This post hoc analysis assesses the sustained response to eptinezumab at the population and patient level and evaluates the potential for response in initial non‐responders. Methods: Adults with chronic or episodic migraine and two to four prior preventive treatment failures were randomized to eptinezumab 100 mg, 300 mg or placebo every 12 weeks. Primary outcomes in this post hoc analysis are the proportion of patients with ≥30%, ≥50% or ≥75% reduction in monthly migraine days (i.e., migraine responder rates [MRRs]) during weeks 1–12 and weeks 13–24 and across 4‐week intervals. Secondary outcomes are maintenance and shifts in MRRs from weeks 1–12 to weeks 13–24. Results: Between weeks 1–12 and 13–24, ≥30% MRRs increased from 65.9% to 70.4% (100 mg) and from 71.0% to 74.5% (300 mg), versus 36.9% to 43.1% (placebo). The ≥50% and ≥75% MRRs were sustained or increased over the 24‐week period. The largest increase in ≥30% MRRs occurred after the second infusion with eptinezumab. The percentage of initial non‐responders (<30% MRRs during weeks 1–12) who experienced response (≥30% MRRs during weeks 13–24) to the second dose was 34.7% (100 mg) and 30.4% (300 mg) with eptinezumab versus 21.1% with placebo. Conclusion: Across MRR thresholds, most patients who responded to eptinezumab during weeks 1–12 maintained or improved response during weeks 13–24. More than one‐third of initial non‐responders became responders after their second infusion. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine the number needed to treat (NNT), number needed to harm (NNH), and likelihood of being helped or harmed (LHH) in a post hoc analysis of the phase 3b FOCUS trial. Background: Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene–related peptide (CGRP), has demonstrated efficacy, tolerability, and safety in adults with episodic migraine (EM) or chronic migraine (CM), with documented previous inadequate response to two to four classes of migraine preventive medications. Methods: In the 12‐week double‐blind period of the FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. NNT was based on responder analysis, defined as ≥50% reduction in monthly average number of migraine days at 12 weeks. NNH was based on discontinuations due to adverse events (AEs). Results: Among patients with CM (n = 509), response rates and discontinuation rates were 27% (45/169) and 0 for quarterly fremanezumab, 29% (50/173) and 2% (3/173) for monthly fremanezumab, and 8% (13/167) and <1% (1/167) for placebo, respectively. These results translated to NNTs of 5.3 and 4.7, NNHs of 1000 and 88, and LHHs of 188 and 19 for quarterly and monthly fremanezumab, respectively. Among patients with EM (n = 328), response rates were 47% (50/107) for quarterly fremanezumab, 43% (47/110) for monthly fremanezumab, and 10% (11/111) for placebo. Discontinuation rates were <1% (n = 1) in all three groups. These results translated to NNTs of 2.7 and 3.0, NNHs of 1000 and 1000, and LHHs of 368 and 328 for quarterly and monthly fremanezumab, respectively. Conclusions: The NNT, NNH, and LHH for quarterly and monthly fremanezumab compare favorably with those for traditional oral preventive medications, including topiramate, valproate, and propranolol. [ABSTRACT FROM AUTHOR]

Reversible cerebral vasoconstriction syndrome (RCVS) is a condition with variable outcomes presenting a new onset thunderclap headache accompanied by focal neurological symptoms or seizures. It can be idiopathic or arise secondarily to a variety of trigger factors. The condition is increasingly recognized in clinical practice, but many facets remain poorly understood. This article aims to clarify the headache characteristics in RCVS, the temporal association of angiographic findings, the potential association of the condition with SARS-CoV-2 infection, and the clinical presentation of RCVS in children and is based on a systematic PRISMA search for published analytical or large descriptive observational studies. Data from 60 studies that fulfilled specific criteria were reviewed. Most people with RCVS exhibit a typical thunderclap, explosive, or pulsatile/throbbing headache, or a similar acute and severe headache that takes longer than 1 min to peak. Atypical presentations or absence of headaches are also reported and may be an underrecognized phenotype. In many cases, headaches may persist after resolution of RCVS. Focal deficits or seizures are attributed to associated complications including transient ischemic attacks, posterior reversible encephalopathy syndrome, ischemic stroke, cerebral edema, and intracranial hemorrhage. The peak of vasoconstriction occurs usually within two weeks after clinical onset, possibly following a pattern of centripetal propagation, and tends to resolve completely within 3 months, well after symptoms have subsided. There are a few reports of RCVS occurring in relation to SARS-CoV-2 infection, but potential underlying pathophysiologic mechanisms and etiological associations have not been confirmed. RCVS occurs in children most often in the context of an underlying disease. Overall, the available data in the literature are scattered, and large-scale prospective studies and international collaborations are needed to further characterize the clinical presentation of RCVS. [ABSTRACT FROM AUTHOR]

Introduction: Fingolimod is the first approved oral therapy for relapsing–remitting multiple sclerosis (RRMS). The present study aimed to further characterize fingolimod's safety profile, and to assess the patient-reported treatment satisfaction and impact of fingolimod on the quality of life (QoL) of patients with multiple sclerosis (MS) treated in routine care in Greece. Methods: This was a multicenter, prospective, observational, 24-month study conducted in Greece by hospital-based and private practice neurologists who specialize in MS. Eligible patients had initiated fingolimod within 15 days in accordance with the locally approved label. Safety outcomes included any adverse event (AE) observed during the study period and efficacy outcomes included both objective (disability progression and 2-year annualized relapse rate) and patient-reported assessments (Treatment Satisfaction Questionnaire for Medication (TSQM) v1.4 and the EuroQol (EQ)-5-dimension (5D) 3-level instruments). Results: A total of 489 eligible patients (age 41.2 ± 9.8 years; 63.7% female; 4.2% treatment-naive) were exposed to fingolimod for a median of 23.7 months. During the observation period, 20.5% of the participants experienced 233 AEs. Lymphopenia (8.8%), leukopenia (4.2%), hepatic enzyme increased (3.4%), and infections (3.0%) were the most common. Most patients (89.3%) did not experience disability progression; the 2-year annualized relapse rate decreased by 94.7% compared to baseline. The median EQ-visual analogue scale (VAS) was 74.5 at month 24 vs. 65.0 at enrollment (p < 0.001) and the EQ-5D index score was 0.80 vs. 0.78, respectively. Significant improvements were noted in the TSQM global satisfaction and effectiveness domain scores between 6 and 24 months post enrollment (median scores at month 24, 71.4 and 66.7, respectively) (p < 0.001). Significant increases from enrollment to the 24th month were also noted in the patients' global satisfaction and effectiveness domain scores [mean change of 7.4 ± 17.7 (p = 0.005) and mean increase of 5.4 ± 16.2) (p = 0.043), respectively]. Conclusion: In the real-world setting of Greece, fingolimod demonstrates a clinical benefit and a predictable and manageable safety profile, which contribute towards high patient-reported treatment satisfaction and improvements in the QoL of patients with MS. [ABSTRACT FROM AUTHOR]

Summary: Dropout from placebo arms in randomized-controlled trials is a surrogate for nocebo responses, resulting from patients' negative expectations to treatment. Among 16,460 placebo-treated patients in oral anti-osteoporotic drug trials, nocebo dropouts were 8% on average, being higher in older patients. This implies that nocebo may contribute to the osteoporosis treatment gap in clinical practice. Purpose: Osteoporosis is a common disease requiring long-term treatment. Despite the availability of effective anti-osteoporotic drugs, adherence to treatment is low. Nocebo, a behavior mostly related to the negative expectations to a certain treatment, decreases adherence and negatively affects treatment outcomes and health-related care costs in chronic diseases. Since in double-blind placebo-controlled randomized trials any unfavorable outcome leading to discontinuation in placebo arms is considered as nocebo, we aimed to investigate the size of nocebo response in patients participating in osteoporosis trials. Methods: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for dropouts due to reported adverse events in the placebo arms (nocebo dropouts) in all double-blind trials investigating anti-osteoporotic drugs published between January 1993 and March 2022. Only data on bisphosphonates and selective estrogen receptor modulators (SERMs) were analyzed (Prospero registration number CRD42020212843). Results: Data from 44 trials were extracted. In 16,460 placebo-treated patients, the pooled nocebo-dropout was 8% both for bisphosphonates (average: 0.08; range 0.01–0.27; 95%CI 0.06–0.10) and SERMs (average: 0.08; range 0.03–0.15; 95%CI 0.05–0.13). Nocebo-dropouts were higher in bisphosphonate trials enrolling individuals ≥ 65 years (11%) (n = 18) compared to trials enrolling younger individuals (6%) (n = 18) (average: 0.11; 95%CI 0.08–0.13 vs. average: 0.06; 95%CI 0.05–0.08, respectively, p = 0.001). Participants' sex, dosing-intervals, publication year, or severity of osteoporosis had no impact on the nocebo-dropouts. Conclusion: Almost 1 in 10 osteoporosis patients receiving placebo in trials of bisphosphonates and SERMs experiences AEs leading to dropout, implying that nocebo contributes to treatment-discontinuation in clinical practice. Efforts to identify and minimize nocebo, especially in older patients, are warranted. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic had remarkable effects on psychological distress. The main stressors were prolonged quarantine and social isolation, fear of infection and death, stigmatization, infodemic, financial difficulties, and job loss. These negative stressors, which affect mental and physical health, make people more vulnerable to nocebo-related risk behaviors. We aimed to summarize data on nocebo behaviors, such as the negative psychological consequences of the COVID-19 pandemic in terms of how people perceive and interpret medical services and treatments. Limited data were found from randomized controlled trials with SARS-CoV-2 vaccines and from surveys on healthy people, healthcare workers, and patients with chronic pain disorders. Studies have shown nocebo effects among participants in SARS-CoV-2 vaccines trials, among patients with chronic pain, and among healthcare workers. These effects were widely amplified during the pandemic era, prefiguring a 'nocebodemic effect' to describe the massive negative interpretation of health services and medical treatments. Greater awareness of these findings could reduce the impact of the 'nocebodemic effect' and increase public trust in science. [ABSTRACT FROM AUTHOR]

Headaches occur when cerebrospinal fluid (CSF) pressure drops following dural puncture or trauma or spontaneously. As the features of these headaches and their accompanying symptoms might not be typical, low CSF pressure headache syndromes, and spontaneous intracranial hypotension in particular, are often misdiagnosed and underdiagnosed. The aim of this narrative review is to summarize the most recent evidence regarding the clinical presentation and the diagnosis of low CSF pressure headache syndromes. The clinical spectrum low CSF pressure headache syndromes varies significantly and key signs might be missing. Low CSF pressure headache syndromes should be included in the differential diagnosis of any case of refractory headache, even when the headache is not orthostatic, or there are normal neuroimaging findings, and/or lumbar puncture opening pressure is within normal limits. Future research should focus on controlled interventional studies on the treatment of low CSF pressure headache syndromes, which are currently lacking. [ABSTRACT FROM AUTHOR]

Background: Multiple Sclerosis treatment with B-cell targeted therapies may be associated with an increased incidence of headache. We aimed to find and compare the association of B-cell targeted therapies with the incidence of headache in patients with Multiple Sclerosis. Methods: In a systematic based approach, the following databases were searched from inception until the 6th of June 2020: Pubmed/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. Only randomized clinical trials (RCTs) enrolling patients with Multiple Sclerosis comparing B-cell targeted therapies (Rituximab, Ocrelizumab, Ofatumumab, Ublituximab or Cladribine) with placebo were selected for the systematic review and further meta-analysis. PRISMA guidelines were followed at all stages of the systematic review. The primary outcome was an all-cause headache of B-cell targeting therapy in patients with Multiple Sclerosis. Results: Nine RCTs were included. Compared with placebo, treatment with B-cell targeting therapies revealed a trend in headache risk, but it was not statistically significant (Relative Risk 1.12 [95% Confidence Interval 0.96–1.30]; p = 0.15; I2 = 9.32%). Surprisingly, in a sub-group analysis, Cladribine was statistically significant for an increase in headache risk (RR 1.20 [95% CI 1.006–1.42]; p = 0.042; I2 = 0%; 3 studies with 2107 participants). Conclusions: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Sub-analyses revealed a significant association between Cladribine alone and an increased incidence of headache. Whereas a purinergic signaling cascade is proposed as a mechanism of action, further research is needed to unravel the underlying pathogenetic mechanism of headache induction and establish headache prevention strategies. [ABSTRACT FROM AUTHOR]

Objective: Our study aimed to estimate the incidence of neoplasms in clinical trials of DMTs for MS and to test the hypothesis that DMTs increase the risk of neoplasms in the duration of MS randomized controlled trials (RCTs). Methods: Data were extracted from 42 RCTs of DMTs published between 1991 and 2020. The incidence rate (IR) of neoplasms was estimated by pooling the neoplasms in the active and placebo-treatment arm per patient-year. The neoplasm incidence rate ratio (IRR) of active over placebo-treatment arms was used as measure of the effect of DMTs on the risk of developing neoplasms. Results: The meta-analysis included 10,638 placebo and 16,360 active-treatment arm patients. A non-significant pooled neoplasm incidence rate ratio (IRR: 1.0797; 95% CI: 0.8281 to 1.4077; P = 0.5711) with no heterogeneity (I2 = 0%) was observed in active over placebo-treatment groups from 1991 to 2020. We found a significant association between the incidence of neoplasms and the year of publication in both active and placebo arms of RCTs. Trials of sequestrating and depletive DMTs were associated with significantly higher incidence of neoplasms in both active and placebo-treated arms compared to immunomodulatory treatment trials. Conclusions: Our study indicates that treatment with DMTs has not modified the risk of neoplasms in MS clinical trials from 1991 to 2020, which may reflect a low carcinogenic potential of DMTs and/or that the neoplasia latencies far exceed the typical MS trial observation periods. [ABSTRACT FROM AUTHOR]

Aims: Drug tolerability refers to the degree to which drugs' overt adverse effects can be tolerated by patients. The tolerability profile is of comparative importance to its efficacy and safety, as it largely determines adherence to treatment and ultimately treatment success or failure. However, the term is frequently used imprecisely, and it is unclear if tolerability is limited to subjective patient‐reported symptoms or also covers certain objective signs and findings. The aim of this systematic review was to assess how clinical studies define, evaluate and present drug tolerability. Methods: The study consisted of a systematic review of clinical studies in PubMed® reporting the term "tolerability". Results: Eighty clinical studies were screened and 56 studies reporting drug tolerability were retained. None of the retained studies defined events encompassed by the term tolerability by making a distinction between safety and tolerability. Twenty‐five studies claimed to evaluate tolerability, but none of them described how to evaluate tolerability from the patient perspective. Most studies (54 out of 56) concluded that the treatment was well tolerated, apparently implying favourable safety. However, none of them actually presented tolerability in terms of a contrast between safety and tolerability. Conclusions: Tolerability is used frequently, albeit incorrectly, to refer to a drug's favourable safety profile. Focused evaluation of drug tolerability (i.e., the patient perspective of adverse drug reactions) should become routine. Presentation in regulatory documents, such as risk management plan summaries, product information and patient leaflets should be a continuation of the process of patient‐centred healthcare. [ABSTRACT FROM AUTHOR]

Objective: To describe the rate and type of adverse effects (AEs) and the frequency of disease flares after COVID-19 vaccination and to assess the reasons for vaccination hesitancy (non-vaccination) in SRD patients. Methods: Telephone interviews were conducted of SRD patients consecutively enrolled (15/06/2021–1/7/2021). Participants were asked about the type of AEs and disease flare after vaccination. Reasons for vaccination hesitancy were recorded. Univariate and mutivariable analyses examined associations of demographic, clinical and other features, with occurrence of AEs, disease flare and non-vaccination. For the latter, association with negative vaccination behaviour (not influenza vaccinated for the last 2 years) and nocebo-prone behaviour (denoting AEs attributed to negative expectations [Q-No questionnaire]) was also tested. Results: 561 out of 580 contacted patients were included in the study. 441/561 (78.6%) patients were vaccinated [90% (Pfizer, Moderna), 10% (Astra-Zeneca)]. AEs were reported by 148/441 (33.6%), with rates being comparable between the three vaccines. AEs were more common in females and those with chronic obstructive pulmonary disease [OR, 95% CI; females: 2.23 (1.30–3.83); COPD: 3.31 (1.24–8.83)]. Disease flare was reported in 9/441 (2%) patients. For those unvaccinated, fear that the vaccine would be harmful (53.3%), could cause disease flare (24.2%) and/or could cause thrombosis (21.7%) were the main reasons to do so. Multivariable analysis identified as independent variables for non-vaccination: nocebo-prone behaviour (OR; 95% CI, 3.88; 1.76–8.55), negative vaccination behaviour (6.56; 3.21–13.42) and previous COVID-19 infection (2.83; 1.13–7.05). Higher educational status was protective (0.49; 0.26–0.92). Conclusion: No new safety signals for COVID-19 vaccination were observed. Vaccination campaign should target SRD patients with nocebo-prone and negative influenza vaccination behaviour. [ABSTRACT FROM AUTHOR]

Blepharospasm is a focal dystonia whereby excessive eyelid muscle contractions cause involuntary eye closure. Botulinum neurotoxin type A (BoNT-A) injections are an approved treatment. This randomized placebo-controlled trial (NCT01896895; EudraCT number 2012-004821-26) assessed the efficacy, safety, and treatment effect duration of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH), a BoNT-A formulation without complexing proteins, in BoNT-A-naïve adults with blepharospasm. Subjects received incobotulinumtoxinA 50 U, 25 U (total dose) or placebo during a main study period (MP; 6–20 weeks). Patients needing a second injection received incobotulinumtoxinA ≤70 U in an open-label extension period (EP; 6–20 weeks). Treatment effect durations were time from first injection to EP injection or final MP visit and from EP injection to end-of-study visit. Times to effect onset and to waning of effect (MP) were time from injection to first subject-assessed onset effect and time from injection to subject-reported waning of effect, respectively. Of 61 subjects, 39 entered the EP. During the MP, median duration of treatment effect was longer with incobotulinumtoxinA 50 U (20 weeks) versus incobotulinumtoxinA 25 U (11 weeks) or placebo (6 weeks). Median duration of treatment effect was 20 weeks during the EP. Median time to effect onset was 5, 7, and 14 days with 50 U, 25 U, and placebo, respectively (p =.022 for 50 U versus placebo). Median time to waning of treatment effect was comparable between groups. Subjects reported an effect onset from 5 days after injection lasting up to 20 weeks (maximum observation period). Data indicate that incobotulinumtoxinA re-treatment of blepharospasm may not be required at fixed 12-week intervals and provide evidence for a patient-tailored approach. Blepharospasm is a condition in which involuntary contractions of the eyelid muscles cause the eye to close. The condition can be treated with botulinum neurotoxin type A (BoNT-A) injections. This study assessed the duration of effect and time to onset of effect for the BoNT-A formulation incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) in adults with blepharospasm. Subjects received a single injection of one of two doses of incobotulinumtoxinA (total dose 25 or 50 U) or placebo and received a second injection of incobotulinumtoxinA only (total dose ≤70 U; the second injection was not compared with placebo) if needed 6–20 weeks after the first injection. After the first injection, the median (mid-point of values from all subjects) duration of treatment effect was longer with the higher incobotulinumtoxinA dose (20 weeks) than with the lower dose (11 weeks) and was longer with both incobotulinumtoxinA doses than with placebo (6 weeks). After the second incobotulinumtoxinA injection, the median duration of treatment effect was 20 weeks. The time to onset of effect was quicker with both incobotulinumtoxinA doses (5 and 7 days for the higher and lower doses, respectively) than with placebo (14 days) and the difference was statistically significant for the higher incobotulinumtoxinA dose compared with placebo. The time to waning of treatment effect was similar for the two incobotulinumtoxinA doses and placebo. This study shows that incobotulinumtoxinA is an effective treatment for blepharospasm, with a fast onset of action. In addition, the effects of one injection can last for up to 20 weeks. [ABSTRACT FROM AUTHOR]

Introduction: The efficacy of prolonged-release fampridine (PR-FAM) may extend in multiple sclerosis (MS) beyond walking ability. The objective of this study was to evaluate the effect of PR-FAM treatment on cognition, fatigue, depression, and quality of life (QoL) in adult patients with MS in a real-world setting. Methods: FAMILY was a multi-center, prospective, observational, real-world cohort study of MS patients receiving PR-FAM in the outpatient setting. Patients were treated as per PR-FAM's local prescribing information for 6 months. Standardized protocols and questionnaires were used to evaluate changes in cognition (PASAT; Paced Auditory Serial Addition Test), fatigue (MFIS; Modified Fatigue Impact Scale), depression (BDI-II; Beck Depression Inventory-II) and QoL (MusiQoL; MS International Quality-of-Life questionnaire, MSIS-29; Multiple Sclerosis Impact Scale: PHYS and PSYCH subscales) at 3 and 6 months compared to baseline. Results: In total, 102 eligible patients from 8 sites in Greece were analysed, of whom 92 completed the study and 10 discontinued. At 6 months, PR-FAM treatment resulted in improvements from baseline in PASAT-3′′ (p = 0.044), MFIS (p < 0.001), BDI-II (p < 0.001), MusiQoL (p < 0.001) and MSIS-29-PHYS (p = 0.012) and MSIS-PSYCH (p < 0.001). A positive effect was evident already at 3 months in PASAT-3′′ (ns), MFIS (p = 0.020), BDI-II (p = 0.034), MusiQoL (p = 0.001), MSIS-29-PHYS (ns) and MSIS-29-PSYCH (p < 0.001). Conclusions: This observational study provides new data to the current literature in support of PR-FAM's positive effects in cognition, fatigue, depression, and QoL in a large, heterogeneous group of Greek MS patients in the real-world setting. Trial Registration: ClinicalTrials.gov identifier, NCT03164018. [ABSTRACT FROM AUTHOR]

Introduction: In clinical trials of alemtuzumab, autoimmune thyroid adverse events (AEs) were frequent. Here, we assess the impact of thyroid AEs on health-related quality of life (HRQL) in alemtuzumab-treated patients with relapsing-remitting multiple sclerosis (RRMS). Methods: In phase 3 CARE-MS I (NCT00530348) and II (NCT00548405) trials, patients with RRMS were administered alemtuzumab 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Patients could participate in an extension study (NCT00930553) through year 6. HRQL was assessed at baseline and annually using the Functional Assessment of Multiple Sclerosis (FAMS), EuroQoL-5 Dimension Visual Analog Scale (EQ-5D VAS), and 36-Item Short-Form Survey (SF-36) questionnaires. Outcomes were analyzed in patients with or without thyroid AEs (nonserious or serious). A subset of patients with thyroid AEs was analyzed to assess HRQL before and during the onset of thyroid AEs. Results: A total of 811 CARE-MS patients were treated with alemtuzumab. Of these, 342 (42%) patients experienced thyroid AEs over 6 years; serious thyroid AEs occurred in 44 (5%) patients. At year 6, HRQL outcomes generally remained slightly improved or similar to core study baseline in alemtuzumab-treated patients with or without thyroid AEs: FAMS (least-squares mean change from baseline without thyroid AEs, 0.7; with nonserious thyroid AEs, 5.1; with serious thyroid AEs, − 5.3), EQ-5D VAS (2.0; 3.0; − 6.8), SF-36 mental component summary (MCS [0.6; 1.6; − 2.8]), SF-36 physical component summary (PCS [0.8; 1.0; 1.1]). Over 6 years, 63–82% of patients in each group had improved/stable SF-36 MCS and PCS scores. Among patients with thyroid AE onset in year 3 (peak incidence), there were minimal differences between HRQL outcomes before onset (year 2) and after onset (year 3). Conclusion: Autoimmune thyroid AEs (serious and nonserious) had minimal impact on HRQL in alemtuzumab-treated patients. These data may aid therapeutic decisions in patients with relapsing MS. Plain Language Summary: This study looked at alemtuzumab, an approved treatment for multiple sclerosis (MS). People who receive alemtuzumab may develop thyroid problems. The researchers wanted to know whether people who developed thyroid problems with alemtuzumab had a worse quality of life compared with those who did not. The researchers measured quality of life using a questionnaire. The questionnaire looked at people's physical, social, and psychological well-being over 6 years. A total of 811 people with MS treated with alemtuzumab took part in this study. Of these, 469 people (58%) did not develop thyroid problems and 342 people (42%) developed thyroid problems. The thyroid problems were serious in 44 people. The researchers observed that thyroid problems during alemtuzumab treatment did not make quality of life worse in most people. Some people with serious thyroid problems had worsened quality of life; this was mostly among people who required certain treatments for their thyroid problems. Quality of life did not change much in people while the thyroid problems were ongoing. This study shows that thyroid problems after alemtuzumab treatment for MS have little negative impact on quality of life for most people. These findings may help healthcare providers make decisions about MS treatment. [ABSTRACT FROM AUTHOR]

Background: In the phase 2 CAMMS223 trial (NCT00050778), alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over 3 years in treatment-naive patients with relapsing–remitting MS. Here, we assess efficacy and safety of alemtuzumab over 12 years in CAMMS223 patients who enrolled in the CAMMS03409 extension (NCT00930553), with available follow-up through the subsequent TOPAZ extension (NCT02255656). Methods: In CAMMS223, patients received 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days); 22% received a third course. In the open-label, nonrandomized extensions, patients could receive as-needed additional alemtuzumab or other disease-modifying therapies. Results: Of 108 alemtuzumab-treated patients in CAMMS223, 60 entered the CAMMS03409 extension; 33% received a total of 2 alemtuzumab courses, and 73% received no more than 3 courses through Year 12. Over 12 years, annualized relapse rate was 0.09, 71% of patients had stable or improved Expanded Disability Status Scale scores, and 69% were free of 6-month confirmed disability worsening. In Year 12, 73% of patients were free of MRI disease activity. Cumulatively throughout the extensions (Years 7–12), 34% of patients had no evidence of disease activity. Adverse event (AE) incidence declined through Year 12. Infusion-associated reactions peaked at first course and declined thereafter. Cumulative thyroid AE incidence was 50%; one immune thrombocytopenia event occurred, and there were no autoimmune nephropathy cases. Conclusions: Alemtuzumab efficacy was maintained over 12 years in CAMMS223 patients, with 73% receiving no more than three courses. The safety profile in this cohort was consistent with other alemtuzumab clinical trials. [ABSTRACT FROM AUTHOR]

This study aimed to assess the efficacy/safety of incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH) in botulinum neurotoxin-naïve subjects with blepharospasm. Botulinum neurotoxin-naïve subjects (≥ 12 months without botulinum neurotoxin treatment for blepharospasm) received single-dose incobotulinumtoxinA 50 U, 25 U, or placebo. Subjects were followed for 6–20 weeks (main period). Qualified subjects entered an open-label extension period and received another incobotulinumtoxinA injection (≤ 70 U). The primary efficacy variable was change from baseline in the Jankovic Rating Scale (JRS) severity subscore at the main period of week 6. Other efficacy variables included changes in the Blepharospasm Disability Index score and JRS frequency subscore and sumscore. Adverse events were monitored. Sixty-one subjects were randomized (main period: incobotulinumtoxinA 50 U, n = 19; incobotulinumtoxinA 25 U, n = 22; placebo, n = 20); 39 entered the open-label extension period (9, 14, and 16 subjects from the incobotulinumtoxinA 50 U, incobotulinumtoxinA 25 U, and placebo groups [main period], respectively, changed to open-label extension period dosing). A statistically significantly greater reduction in JRS severity subscore was reported for subjects receiving incobotulinumtoxinA 50 U versus placebo (ANCOVA, least square mean difference: − 1.2, p = 0.0004). Subjects receiving incobotulinumtoxinA experienced improvements in other efficacy variables versus baseline and/or placebo. Sustained clinical improvements and low adverse event rates (22.2–42.1%) were observed. This is the second placebo-controlled, double-blind study that demonstrates favorable efficacy/safety of incobotulinumtoxinA in subjects with blepharospasm. IncobotulinumtoxinA is the first botulinum neurotoxin that could fulfill the American Academy of Neurology criteria for a Level A recommendation for blepharospasm. Trial registration ClinicalTrials.gov identifier, NCT01896895. [ABSTRACT FROM AUTHOR]

Aging is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying aging. Several stressors associated with aging and MS pathology, such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of cellular senescence. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with aging and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression. [ABSTRACT FROM AUTHOR]

Background: Galcanezumab, along with three other monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, represents the latest disease-specific and mechanism-based treatment for the prophylaxis of migraine. Galcanezumab shares data also for the prophylaxis of cluster headache. Objective: To provide a pooled safety and efficacy analysis of all phase III randomized controlled trials of galcanezumab in the preventive therapy of migraine. Methods: A computer-based literature search was conducted on MEDLINE and the US National Institutes of Health Clinical Trials Registry for phase III randomized controlled trials of galcanezumab in migraine prevention. The primary outcome was the mean change in monthly migraine days (MMDs). The proportions of patients who reported at least one adverse event (AE), at least one serious adverse event (SAE) or withdrew from the study were used as safety outcomes. Results: Two trials were included in the efficacy meta-analysis and three in the safety meta-analysis. Migraine preventive treatment with subcutaneous galcanezumab, at both 120 mg and 240 mg dosages, was associated with a significantly greater reduction in the mean number of MMDs versus placebo (120 mg, MD = –1.98, 95% CI = –2.33 to –1.63; p < 0.0001) or (240 mg, MD = –1.86, 95% CI = –2.20 to –1.53; p < 0.0001). Galcanezumab was found to be more efficacious in all key secondary outcomes as well. Regarding safety, most of the adverse events were mild to moderate, while drop-out rates and serious adverse events were low. Conclusions: Galcanezumab is an efficacious and well-tolerated preventive treatment for migraine. Larger clinical trials with longer follow-up periods need to be conducted in order to provide more safety data of the above-mentioned drug. [ABSTRACT FROM AUTHOR]

High placebo and low nocebo phenomena mirror high positive expectations for a novel treatment, among other reasons. In a meta-analysis aimed to identify placebo and nocebo phenomena in the placebo-controlled randomized trials (RCTs) with the monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) all the placebo-treated patients were pooled and compared with the placebo-treated patients in RCTs with topiramate and onabotulinum toxin A (OBTA). In episodic migraine (EM), the proportion of placebo-treated patients who achieved the 50% responder rate (placebo) was 32.7% (95% CI 28.6%–37.0%) in anti-CGRP mAbs vs. 24.4% (95% CI 20.5%–28.5%) in topiramate trials. The proportion of dropouts due to adverse events in placebo-treated patients (nocebo) was 1.9% (95% CI 1.4%–2.6%) in anti-CGRP mAbs vs. 9.9% (95% CI 7.7%–12.3%) in topiramate RCTs. In chronic migraine (CM), the placebo 50% responder rate was 23.6% (95% CI 11.2%–38.8%) in anti-CGRP mAbs RCTs vs. 36.4% (95% CI 32.6%–39.3%) in RCTs with OBTA. The nocebo dropout in anti-CGRP mAbs and OBTA RCTs was 1.4% (95% CI 0.8%–2.1%) and 0.9 (95% CI 0.3%–1.7%), respectively. The stronger placebo and weaker nocebo phenomena in RCTs with anti-CGRP mAbs vs. those with topiramate in the prophylaxis of EM, may decisively determine anti-CGRP mAbs treatment success. No differences were detected between the anti-CGRP mAbs and OBTA in the treatment of CM. [ABSTRACT FROM AUTHOR]

Background: Galcanezumab, along with three other monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, represents the latest disease-specific and mechanism-based treatment for the prophylaxis of migraine. Galcanezumab shares data also for the prophylaxis of cluster headache. Objective: To provide a pooled safety and efficacy analysis of all phase III randomized controlled trials of galcanezumab in the preventive therapy of migraine. Methods: A computer-based literature search was conducted on MEDLINE and the US National Institutes of Health Clinical Trials Registry for phase III randomized controlled trials of galcanezumab in migraine prevention. The primary outcome was the mean change in monthly migraine days (MMDs). The proportions of patients who reported at least one adverse event (AE), at least one serious adverse event (SAE) or withdrew from the study were used as safety outcomes. Results: Two trials were included in the efficacy meta-analysis and three in the safety metaanalysis. Migraine preventive treatment with subcutaneous galcanezumab, at both 120 mg and 240 mg dosages, was associated with a significantly greater reduction in the mean number of MMDs versus placebo (120 mg, MD = –1.98, 95% CI = –2.33 to –1.63; p < 0.0001) or (240 mg, MD = –1.86, 95% CI = –2.20 to –1.53; p < 0.0001). Galcanezumab was found to be more efficacious in all key secondary outcomes as well. Regarding safety, most of the adverse events were mild to moderate, while drop-out rates and serious adverse events were low. Conclusions: Galcanezumab is an efficacious and well-tolerated preventive treatment for migraine. Larger clinical trials with longer follow-up periods need to be conducted in order to provide more safety data of the above-mentioned drug. [ABSTRACT FROM AUTHOR]

More than 0.6 million people suffer from disabling migraines in Greece causing a dramatic work loss, but only a small proportion of migraineurs attend headache centres, most of them being treated by non-experts. On behalf of the Hellenic Headache Society, we report here a consensus on the diagnosis and treatment of adult migraine that is based on the recent guidelines of the European Headache Federation, on the principles of Good Clinical Practice and on the Greek regulatory affairs. The purposes are three-fold: (1) to increase awareness for migraine in Greece; (2) to support Greek practitioners who are treating migraineurs; and (3) to help Greek migraineurs to get the most appropriate treatment. For mild migraine, symptomatic treatment with high dose simple analgesics is suggested, while for moderate to severe migraines triptans or non-steroidal anti-inflammatory drugs, or both, should be administered following an individually tailored therapeutic strategy. A rescue acute treatment option should always be advised. For episodic migraine prevention, metoprolol (50–200 mg/d), propranolol (40–240 mg/d), flunarizine (5–10 mg/d), valproate (500–1800 mg/d), topiramate (25–100 mg/d) and candesartan (16–32 mg/d) are the drugs of first choice. For chronic migraine prevention topiramate (100-200 mg/d), valproate (500–1800 mg/d), flunarizine (5–10 mg/d) and venlafaxine (150 mg/d) may be used, but the evidence is very limited. Botulinum toxin type A and monoclonal antibodies targeting the CGRP pathway (anti-CGRP mAbs) are recommended for patients suffering from chronic migraine (with or without medication overuse) who failed or did not tolerate two previous treatments. Anti-CGRP mAbs are also suggested for patients suffering from high frequency episodic migraine (≥8 migraine days per month and less than 14) who failed or did not tolerate two previous treatments. [ABSTRACT FROM AUTHOR]

Background: Nocebo refers to adverse events related to patients' negative expectations and previous experiences, mediated by several neurobiological pathways within the brain. It is common among neurological patients and affects adherence and treatment outcomes, representing a real clinical challenge. Methods: We conducted a systematic search based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in MEDLINE database, using several keywords for studies that can be processed to investigate the magnitude of nocebo in generics and biosimilars used in the most common neurological diseases. The aim was to estimate its size and suggest strategies to minimize its prevalence in clinical trials and practice. Results: Of a total of 2,606 identified articles, after criteria-based selection, 35 studies were included for analysis. Overall, there was vast heterogeneity across the studies concerning population, study design, and outcomes. Nocebo response could be estimated only in one double-blind randomized trial of generic glatiramer acetate in relapsing remitting multiple sclerosis that included a placebo arm. In this trial, no significant differences observed between the three arms (innovator, bioequivalent, and placebo) in favorable and unfavorable outcomes. In the open-label phase of the trial, an increased withdrawal rate was recorded in patients switched from placebo to bioequivalent (8.4%) that may be related to nocebo. In other open-label and real-world studies evaluating biosimilars or generics for brain disorders, a similar indirect nocebo effect is assuming by several investigators. Also, knowledge gaps between health-care providers and patients exist towards generics and biosimilars. Conclusions: Despite its presence, the true burden of the nocebo response and effect cannot be accurately estimated in existing studies with generics and biosimilars in neurological diseases. Targeted strategies for clinical trials' design are needed in order to measure the exact nocebo's size. [ABSTRACT FROM AUTHOR]

Nocebo Effects in RCTs of Placebo Groups in Patients With Neurological Disorders and Psychiat... Spanou et al. described nocebo effects in RCTs of placebo groups, considering studies and trials regarding neurological diseases in adults. Palermo et al. described nocebo effects in RCTs of placebo groups in patients with schizophrenia spectrum disorders. [Extracted from the article]

Background: Burning Mouth Syndrome (BMS) is a chronic pain condition characterized by persistent intraoral burning without related objective findings and unknown etiology that affects elderly females mostly. There is no satisfactory treatment for BMS. We aimed to observe the long-term efficacy of high velanfaxine doses combined with systemic and topical administered clonazepam in a particular subgroup of BMS patients who do not respond to current clinical management. Results: Eight (66.1 ± 6.2 years old females) out of 14 BMS patients fulfilled the inclusion criteria and were treated with venlafaxine (300 mg/d) and clonazepam (5 mg/d) for 35.4 ± 12.1 (mean ± SD) months. The average duration of the symptoms at baseline was 4.3 ± 1.4 years and the overall mean daily pain intensity score was 8.6 ± 1.3 (VAS); pain was in tongue and within the oral mucosa, accompanying by oral and facial dysesthesia. In five patients tasting was abnormal. All patients had positive history of concomitant primary headache. The average score of Hamilton Rating scale for Anxiety and Depression was 21 ± 4.2, and 26.1 ± 2.9, respectively. Previous ineffective treatments include anticonvulsants and anti-depressants. All patients responded (more than 50% decrease in VAS) after three months treatment (mean VAS 3.2 ± 2.2) with no remarkable adverse events. Conclusion: BMS deserves bottomless psychiatric evaluation and management when current available treatments fail. Treatment with venlafaxine combined with topical and systemic clonazepam may be effective in refractory BMS cases but further investigation in a large-scale controlled study is needed to confirm these results. [ABSTRACT FROM AUTHOR]

Trigeminal‐targeted treatments (TTTs), the most specific and selective therapeutic migraine approach to date, are effective in approximately 60% of patients regardless of treatment type or mechanism, at least if used alone. Sixty percent is also the proportion of migraineurs who develop migraine‐like episodes following experimental intravenous administration of trigeminal neuropeptides and roughly 60% is the percentage of patients with a unilateral migraine tracing the area of cutaneous distribution of the trigeminal ophthalmic branch. Hence, mechanisms other than the trigeminovascular activation are probably involved in the 40% of migraineurs who do not respond to TTTs. A closer cooperation between clinical and basic neuroscientists is needed to explore migraine models because only a careful appraisal of migraine endophenotypes may help to unravel their underlying multifaceted pathophysiological machinery. [ABSTRACT FROM AUTHOR]

Migraine is a common, chronic disorder of the brain causing much disability, as well as personal, familial and societal impact. Several oral preventive agents are available in different countries for the prevention of migraine, but none have performed better than 50% improvement in 50% of patients in a clinical trial. Additionally, each has various possible adverse events making their tolerability less than optimal. Recently, three monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) ligand (LY2951742, ALD403 and TEV-48125) and one targeting the CGRP receptor (AMG 334) have completed phase 2 trials, and the results have been reported. These early results show them all to be somewhat more effective than placebo, with no serious adverse events. Three have been studied for episodic migraine, and only TEV-48125 has been studied for both high frequency episodic and chronic migraine. Moreover, preliminary data suggests that neurostimulation is effective in migraine treatment, including stimulation of the sphenopalatine ganglion, transcutaneous supraorbital and supratrochlear nerve, and transcutaneous vagus nerve. In this article, these innovative therapies will be reviewed. [ABSTRACT FROM AUTHOR]

Chronic cluster headache (CCH) often resists to prophylactic pharmaceutical treatments resulting in patients’ life damage. In this rare but pragmatic situation escalation to invasive management is needed but framing criteria are lacking. We aimed to reach a consensus for refractory CCH definition for clinical and research use. The preparation of the final consensus followed three stages. Internal between authors, a larger between all European Headache Federation members and finally an international one among all investigators that have published clinical studies on cluster headache the last five years. Eighty-five investigators reached by email. Proposed criteria were in the format of the International Classification of Headache Disorders III-beta (description, criteria, notes, comments and references). Following this evaluation eight drafts were prepared before the final. Twenty-four (28.2%) international investigators commented during two rounds. Refractory CCH is described in the present consensus as a situation that fulfills the criteria of ICHD-3 beta for CCH with at least three severe attacks per week despite at least three consecutive trials of adequate preventive treatments. The condition is rare, but difficult to manage and invasive treatments may be needed. The consensus addresses five specific clinical and paraclinical diagnostic criteria followed by three notes and specific comments. Although refractory CCH may be not a separate identity these specific diagnostic criteria should help clinicians and investigators to improve patient’s quality of life. [ABSTRACT FROM AUTHOR]

Migraine is a chronic, painful, and often disabling primary headache disorder, typically presenting with recurrent attacks that may be accompanied by a variety of neurological, gastrointestinal, and autonomic symptoms. Gastrointestinal symptoms in association with migraine including, nausea, vomiting, and gastroparesis, affect a large proportion of migraine sufferers. These symptoms may result in delays or inconsistencies in the absorption of oral treatments. Hence, the necessity for an innovative, non-invasive, parenteral delivery formulation for quick and effective treatment of migraine attacks is evident. Iontophoresis utilizes minimal amounts of electrical potential to support the fast transfer of ionized medication transdermally and into the general circulation. Two pharmacokinetic clinical trials have shown that iontophoretic delivery of sumatriptan through the skin produces quick and reproducible therapeutic plasma concentrations. A randomized, double-blind, multicenter, phase III study demonstrated superior efficacy versus placebo and excellent tolerability, with no triptan-related adverse events. The proportion of patients that were pain-free at 2 h post-treatment was 18% for the sumatriptan patch vs 9% for placebo (P = 0.0092; number needed to treat = 11.1). Upon approval from the Food and Drug Administration and other regulatory authorities, the iontophoretic transdermal delivery of sumatriptan will be a good choice for patients experiencing poor absorption of oral medication often associated with migraine and/or for those with intolerable triptan-related adverse events. [ABSTRACT FROM AUTHOR]

Objective.- To clarify whether headache, and particularly migraine, belongs to the spectrum of neurologic manifestations of systemic lupus erythematosus (SLE), the archetypal autoimmune disease. Methods.- Consecutive SLE patients were matched 1:1 for age, gender, and level of education with healthy control subjects. A representative subgroup of SLE patients were also matched with patients suffering from multiple sclerosis (MS), a nervous system-specific autoimmune disease. All study participants were assessed for headache present in the previous year. Anxiety, depression, and quality of life were also estimated at baseline. During the following year, all participants were assessed every 3 months using specific headache diaries. Results.- Seventy-two SLE/control pairs and 48 MS patients completed 12 months of follow-up. Prevalence of migraine, with or without aura, was similar between SLE patients (21%), MS patients (23%), and controls (22%), as was the prevalence of frequent tension-type headache. Duration and severity of migraine attacks were milder in SLE patients than controls. Only chronic tension-type headache was significantly more prevalent in SLE patients (12.5%) compared to controls (1.4%). MS patients also presented increased frequency of chronic tension-type headache (8.3%). No associations of any headache type with particular clinical manifestations, autoantibody, or disease activity, either in SLE or MS patient groups, were found. Irrespective of the presence of headache, anxiety symptoms and impaired quality of life were more frequent among SLE than MS patients or controls. Conclusion.- Migraine should be no longer considered a neurologic manifestation of systemic or organ-specific autoimmunity. Increased migraine prevalence in these patients found in previous studies could be due to methodological weaknesses. [ABSTRACT FROM AUTHOR]

Objective.— To explore the efficacy and tolerability of levetiracetam in medical treatment of trigeminal neuralgia. Background.— Antiepileptic drugs (AEDs) are considered as first-line treatment for trigeminal neuralgia, although their use is often limited due to incomplete efficacy and tolerability. Newer AEDs with improved safety profile may be useful in this disorder. Methods.— Patients suffering from trigeminal neuralgia (either primary or secondary) refractory to previous treatments were recruited to be treated with levetiracetam (3-4 g/day) for 16 weeks as add-on therapy, after a 2-week baseline period. Rescue medication was allowed in both the baseline and treatment phases. The primary efficacy measure was the number of attacks per day. The patients' efficacy evaluation, the patients' global evaluation for both safety and efficacy, changes in the Hamilton Depression Scale, the Hamilton Anxiety Scale, and the Quality of Life Measure Short Form-36 were secondary parameters. Results.— Twenty-three patients were included in the analysis. After treatment and compared to the baseline phase, the number of daily attacks decreased by 62.4%. All secondary parameters changed significantly with the exception of the Quality of Life Measure Short Form-36 score. Seven patients withdrew from the study. Five patients (21.7%) reported side effects and 2 withdrew. Conclusions.— Levetiracetam may be effective and safe in trigeminal neuralgia treatment. Confirmation in a randomized controlled study is needed. ( Headache 2010;50:1371-1377) [ABSTRACT FROM AUTHOR]

The article presents a review of studies on the link between sleep disorders and headaches. A U.S. study indicated that the adult participants aged 18 years or older who reported severe headaches were significantly more likely to have insomnia, excessive sleepiness, recurrent pain and depression or anxiety symptoms during the preceding 12 months. Another study showed a 2-to-3-fold increase in migraine prevalence in narcoleptic patients, and narcolepsy preceded migraine onset in the study participants.

In order to promote education on headache disorders, European Headache Federation (EHF) in conjunction with National Headache Societies organizes educational courses meeting uniform standards according to previous published guidelines. Based on six headache summer schools’ experience, an EHF subcommittee has reviewed these guidelines, and here the revised version is presented. The goals remain the same: quality courses that will attract physicians and neurologists seeking to increase their knowledge, skills, and understanding in the area of primary and secondary headache. Detailed guidelines, a day-to-day program, and a multiple-choice test battery have now been outlined. It is recommended to include practical sessions with patient interviews and hands-on demonstrations of non-pharmacological treatment strategies. For countries that want a ‘low cost’ education program, a Video School program of a similar scientific standard has been developed. To be certified for CME credits, patronage, and financial support from EHF, it is highly recommended to adhere to the suggested teaching strategies. We hereby aim to promote and professionalize the education in headache disorders and endorse the educational courses meeting uniform standards of excellence. [ABSTRACT FROM AUTHOR]

Among healthcare workers (HCWs), SARS-CoV-2 vaccine hesitancy may be linked to a higher susceptibility to nocebo effects, i.e., adverse events (AEs) experienced after medical treatments due to negative expectations. To investigate this hypothesis a cross-sectional survey was performed with a self-completed questionnaire that included a tool (Q-No) for the identification of nocebo-prone individuals. A total of 1309 HCWs (67.2% women; 43.4% physicians; 28.4% nurses; 11.5% administrative staff; 16.6% other personnel) completed the questionnaires, among whom 237 (18.1%) had declined vaccination. Q-No scores were ≥15 in 325 participants (24.8%) suggesting nocebo-prone behavior. In a multivariate logistic regression model with Q-No score, age, gender, and occupation as independent variables, estimated odds ratios (ORs) of vaccination were 0.43 (i.e., less likely, p < 0.001) in participants with Q-No score ≥ 15 vs. Q-No score < 15, 0.58 in females vs. males (p = 0.013), and 4.7 (i.e., more likely) in physicians vs. other HCWs (p < 0.001), independent of age, which was not significantly associated with OR of vaccination. At least one adverse effect (AE) was reported by 67.5% of vaccinees, mostly local pain and flu-like symptoms. In a multivariate logistic regression model, with Q-No score, age, gender, and occupation as independent variables, estimated ORs of AE reporting were 2.0 in females vs. males (p < 0.001) and 1.47 in physicians vs. other HCWs (p = 0.017) independently of age and Q-No score, which were not significantly associated with OR of AE. These findings suggest that nocebo-prone behavior in HCWs is associated with SARS-CoV-2 vaccination hesitancy indicating a potential benefit of a campaign focused on nocebo-prone people. [ABSTRACT FROM AUTHOR]

Now more than ever is the time of monoclonal antibody use in neurology. In headaches, disease-specific and mechanism-based treatments existed only for symptomatic management of migraines (i.e., triptans), while the standard prophylactic anti-migraine treatments consist of non-specific and repurposed drugs that share limited safety profiles and high risk for interactions with other medications, resulting in rundown adherence rates. Recent advances in headache science have increased our understanding of the role of calcitonin gene relate peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) pathways in cephalic pain neurotransmission and peripheral or central sensitization, leading to the development of monoclonal antibodies (mAbs) or small molecules targeting these neuropeptides or their receptors. Large scale randomized clinical trials confirmed that inhibition of the CGRP system attenuates migraine, while the PACAP mediated nociception is still under scientific and clinical investigation. In this review, we provide the latest clinical evidence for the use of anti-CGRP in migraine prevention with emphasis on efficacy and safety outcomes from Phase III and real-world studies. [ABSTRACT FROM AUTHOR]

Galcanezumab is a humanized monoclonal antibody blocking the calcitonin gene-related peptide (CGRP) pathway by targeting the CGRP. Data from four phase-3 randomized placebo-controlled clinical trials showed that galcanezumab is superior to placebo in reducing migraine headaches, migraine-specific quality of life, and headache-related disability. Most of the adverse events (AEs) were mild to moderate and did not affect trial completion rates significantly. Along with erenumab, fremanezumab, and eptinezumab, galcanezumab forms a novel class of anti-migraine preventative treatments that is disease-specific and mechanism-based, unlike the standard ones. In addition, galcanezumab has also been shown to be effective in cluster headache, though more clinical trials are required. Overall, galcanezumab is a promising emerging treatment in migraine prophylaxis. However, it needs to be tested in larger clinical trials focused on treatment-resistant migraine. Furthermore, its safety profile, especially its potential association with an increased cardiovascular risk, needs to be established through long-term, real-world data. This review aims to give an overview of its pharmacological properties as well as to report and discuss data from clinical trials and its potential place in headache therapeutics. [ABSTRACT FROM AUTHOR]

Over the last 30 years the role of monoclonal antibodies in therapeutics has increased enormously, revolutionizing treatment in most medical specialties, including neurology. Monoclonal antibodies are key therapeutic agents for several neurological conditions with diverse pathophysiological mechanisms, including multiple sclerosis, migraines and neuromuscular disease. In addition, a great number of monoclonal antibodies against several targets are being investigated for many more neurological diseases, which reflects our advances in understanding the pathogenesis of these diseases. Untangling the molecular mechanisms of disease allows monoclonal antibodies to block disease pathways accurately and efficiently with exceptional target specificity, minimizing non-specific effects. On the other hand, accumulating experience shows that monoclonal antibodies may carry class-specific and target-associated risks. This article provides an overview of different types of monoclonal antibodies and their characteristics and reviews monoclonal antibodies currently in use or under development for neurological disease. [ABSTRACT FROM AUTHOR]

Background and aim: Despite recent publications, practitioners remain unfamiliar with the current terminology related to the placebo and nocebo phenomena observed in clinical trials and practice, nor with the factors that modulate them. To cover the gap, the European Headache Federation appointed a panel of experts to clarify the terms associated with the use of placebo in clinical trials. Methods: The working group identified relevant questions and agreed upon recommendations. Because no data were required to answer the questions, the GRADE approach was not applicable, and thus only expert opinion was provided according to an amended Delphi method. The initial 12 topics for discussion were revised in the opinion of the majority of the panelists, and after a total of 6 rounds of negotiations, the final agreement is presented. Results/recommendations: Two primary and mechanism-based recommendations are provided for the results of clinical trials: [1] to distinguish the placebo or nocebo response from the placebo or nocebo effect; and [2] for any favorable outcome observed after placebo administration, the term "placebo response" should be used, and for any unfavorable outcome recorded after placebo administration, the term "nocebo response" should be used (12 out of 17 panelists agreed, 70.6% agreement). The placebo or nocebo responses are attributed to a set of factors including those that are related to the medical condition (e.g. natural history, random comorbidities, etc.), along with idiosyncratic ones, in which the placebo or nocebo effects are attributed to idiosyncratic, or nonspecific mechanisms, exclusively (e.g. expectation, conditioning, observational learning etc.). To help investigators and practitioners, the panel summarized a list of environmental factors and idiosyncratic dynamics modulating placebo and nocebo effects. Some of them are modifiable, and investigators or physicians need to know about them in order to modify these factors appropriately to improve treatment. One secondary recommendation addresses the use of the terms "placebo" and "nocebo" ("placebos" and "nocebos" in plural), which refer to the triggers of the placebo/nocebo effects or responses, respectively, and which are inert agents or interventions that should not be confused with the placebo/nocebo responses or effects themselves (all panelists agreed, 100% agreement). Conclusion: The working group recommends distinguishing the term response from effect to describe health changes from before to after placebo application and to distinguish the terms placebo(s) or nocebo(s) from the health consequences that they cause (placebo/nocebo responses or effects). [ABSTRACT FROM AUTHOR]

Background: Autoimmune rheumatic diseases (ARDs) may affect both the heart and the brain. However, little is known about the interaction between these organs in ARD patients. We asked whether brain lesions are more frequent in ARD patients with cardiac symptoms compared with non-ARD patients with cardiovascular disease (CVD). Methods: 57 ARD patients with mean age of 48 ± 13 years presenting with shortness of breath, chest pain, and/or palpitations, and 30 age-matched disease-controls with non-autoimmune CVD, were evaluated using combined brain–heart magnetic resonance imaging (MRI) in a 1.5T system. Results: 52 (91%) ARD patients and 16 (53%) controls had white matter hyperintensities (p < 0.001) in at least one brain area (subcortical/deep/periventricular white matter, basal ganglia, pons, brainstem, or mesial temporal lobe). Only the frequency and number of subcortical and deep white matter lesions were significantly greater in ARD patients (p < 0.001 and 0.014, respectively). ARD vs. control status was the only independent predictor of having any brain lesion. Specifically for deep white matter lesions, each increase in ECV independently predicted a higher number of lesions [odds ratio (95% confidence interval): 1.16 (1.01–1.33), p = 0.031] in ordered logistic regression. Penalized logistic regression selected only ARD vs. control status as the most important feature for predicting whether brain lesions were present on brain MRI (odds ratio: 5.46, marginal false discovery rate = 0.011). Conclusions: Subclinical brain involvement was highly prevalent in this cohort of ARD patients and was mostly independent of the severity of cardiac involvement. However, further research is required to determine the clinical relevance of these findings. [ABSTRACT FROM AUTHOR]

Background: The three primary headaches, tension-type headache, migraine and cluster headache, occur in both genders, but all seem to have a sex-specific prevalence. These gender differences suggest that both male and female sex hormones could have an influence on the course of primary headaches. This review aims to summarise the most relevant and recent literature on this topic.Methods: Two independent reviewers searched PUBMED in a systematic manner. Search strings were composed using the terms LH, FSH, progesteron*, estrogen*, DHEA*, prolactin, testosterone, androgen*, headach*, migrain*, "tension type" or cluster. A timeframe was set limiting the search to articles published in the last 20 years, after January 1st 1997.Results: Migraine tends to follow a classic temporal pattern throughout a woman's life corresponding to the fluctuation of estrogen in the different reproductive stages. The estrogen withdrawal hypothesis forms the basis for most of the assumptions made on this behalf. The role of other hormones as well as the importance of sex hormones in other primary headaches is far less studied.Conclusion: The available literature mainly covers the role of sex hormones in migraine in women. Detailed studies especially in the elderly of both sexes and in cluster headache and tension-type headache are warranted to fully elucidate the role of these hormones in all primary headaches. [ABSTRACT FROM AUTHOR]