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Introduction Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data. Methods This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6–8 hours apart). Results Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) ( p = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53; p = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common. Conclusions Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The “sham” device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. Study identification and registration: PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844

Background: Spontaneous intracranial hypotension (SIH) is a rare syndrome characterized by heterogeneity of presentation and prognosis, which can occasionally result in serious complications, such as the formation of subdural hematoma (SDH). This case series aims to emphasize that SIH remains a diagnostic and therapeutic challenge; it can present with a far broad clinical spectrum of symptoms, can lead to SDH and if conservative treatment fails, an epidural blood patch (EBP) is a viable treatment option. Although the exact aetiology of SIH is not known, it is believed to be due to cerebrospinal fluid (CBF) leak or a low CBF pressure. Case report: Three patients (two males and one female) with age ranging between 38-53 years old who presented with complaints not only of an orthostatic headache, but with a variety of symptoms of SIH, including the formation of two SDHs in one of them, were included in this series. These patients did not respond to conservative management and subsequently, given the clinical and radiological evidence of SIH, were referred to the Anaesthesia Department for an EBP. The exact site of the CSF leak was identified with imaging modalities, including magnetic resonance imaging (MRI) of the brain and spinal cord, prior to the EBP. All three patients were subjected to an EBP with an 18-gauge epidural needle placed into the middle epidural compartment at the T12–L3 level. A total of between 30–43 mL of autologous blood was collected from the patients’ left basilic vein and was injected into the epidural space under strict aseptic conditions. Two lumbar (L1–L2, L2–L3) and one thoracic (T11–T12) EBPs were performed on the three patients. All patients reported complete resolution of symptoms following the EBPs, while MRI imaging improved substantially. Discussion: This report describes three cases of SIH with CSF leak originating from the cervical, the thoracic and the lumbar level. The EBP restored CSF volume and relieved the patients' persistent symptoms. MRI helps in showing indirect signs of low volume of CSF, though it may not be possible to find the actual site of leak. In conclusion, EBP is a well-accepted and beneficial treatment modality for SIH when conventional measures fail. © 2021, Pharmamed Mado Ltd. All rights reserved.

Introduction: Post-traumatic headache (PTH), a common type of headache secondary to traumatic brain injury (TBI) or whiplash, carries a relevant burden on patients. PTH is still an undertreated condition because of limited pharmacological treatment options. Therefore, multimodal non-pharmacologic approaches, which account for comorbidities and biopsychosocial factors, are often used in PTH patients. Areas covered: After providing a brief overview of PTH, a systematic review was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations on recently published (2015–2020) papers on non-pharmacological interventions for PTH. We also collected data on ongoing trials on this topic. Studies and results are reviewed and discussed. Expert opinion: PTH is one of the most common complications of TBI and accounts for almost 4% of symptomatic headache disorders. The most common clinical presentations of PTH are migraine-like or tension type (TTH)-like headache, neck pain, cognitive complaints, and psychological/psychiatric symptoms. Growing evidence suggests that combined pharmacological and non-pharmacological interventions, encompassing noninvasive neuromodulation, physical therapy, cognitive-behavioral treatment, and education, may be the best approaches for PTH and related comorbidities. Acute/preemptive pharmacological treatments for PTH include drugs used for migraine and TTH. When PTH management is multidisciplinary, the patient benefits most. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Introduction: Botulinum neurotoxin type-A (BoNTA) is licensed for the treatment of chronic migraine (CM), but it has been tested off-label as a therapeutic choice in other primary headaches (PHs). We aimed to provide a systematic review and expert opinion on BoNTA use in PHs, beyond CM. Areas covered: After providing an overview on PHs and mechanism of BoNTA action, we report the results of a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, of BoNTA therapeutic trials in PHs beyond CM. Studies and results were reviewed and discussed, and levels of evidence were graded. We also collected data on relevant ongoing trials. Expert opinion: Although there are contradictory findings on PHs other than CM, BoNTA may represent a therapeutic option for patients who do not respond to conventional prophylactic treatments. Based on limited available evidence, BoNTA may be considered in refractory tension-type headache, trigeminal autonomic cephalalgias, primary stabbing headache, nummular headache, hypnic headache, and new daily persistent headache, after the primary nature of cephalalgia has been documented and other drugs have failed. Experienced physicians in BoNTA treatment are required to guide the therapeutic protocol for each patient to optimize good and safe outcomes. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Background and objectives: There is no data regarding validity and reliability of the Greek version of Neurogenic Bladder Symptom Score (NBSS) questionnaire. In this study we investigated these parameters using a sample of Greek patients with multiple sclerosis (MS). Materials and methods: Patients with different types and severity of multiple sclerosis were recruited from a single center in Greece prospectively. All patients completed the MusiQoL and NBSS questionnaires at baseline and 20 days later, without receiving any new treatment. Construct validity, internal consistency and test–retest reliability were tested. Internal consistency was investigated using Cronbach’s alpha coefficient, while test–retest reliability using Intraclass Correlation Coefficient (ICC). Construct validity was assessed by comparing NBSS quality of life question 24 with MusiQoL questionnaire. Results: A total of 91 patients were evaluated. The dimensions of NBSS exhibited high internal consistency, both for overall questionnaire score (Cronbach’s alpha coefficient of 0.91) and for every subdomain separately (Cronbach’s alpha coefficient of 0.95 for incontinence, 0.88 for storage symptoms and 0.74 for consequences). Test–retest reliability was satisfactory both for overall score [ICC of 0.85, (0.35–0.94), p < 0.001] and for every subdomain separately (ICC of 0.90 for incontinence, 0.83 for storage symptoms and 0.90 for consequences). Pearson’s correlation coefficient of question number 24 of the NBSS questionnaire regarding quality of life with the MusiQoL questionnaire revealed a moderate correlation [r = 0.64, (0.48–0.80), p < 0.0001]. Conclusions: The Greek version of NBSS appears to be a valid and reliable instrument for assessing neurogenic bladder symptoms in Greek population suffering from multiple sclerosis. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Purpose of Review: To present the interaction between brain/heart and emphasize the role of combined brain/heart magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA) and other seronegative spondyloarthropathies (SNA). Recent Findings: Both traditional cardiovascular disease (CVD) risk factors and intrinsic RA/SNA features contribute to the increased CVD-related morbidity/mortality. CVD in RA usually occurs a decade earlier than age- and sex-matched controls, and RA patients are twice more likely to develop myocardial infarction irrespective of age, history of prior CVD, and traditional CVD risk factors. RA also increases risk of non-ischemic heart failure (HF), valvular disease, and myo-pericarditis. CVD in SNA affects more commonly patients with long-standing disease. Ascending aortitis, aortic/mitral insufficiency, conduction defects, and diastolic dysfunction are the commonest findings in ankylosing spondylitis (AS). CVD is also the leading cause of death in psoriatic arthritis (PsA), due to myopericarditis, diastolic dysfunction, and valvular disease. Brain damage, due to either ischemic or hemorrhagic stroke and silent vascular damage, such as white matter hyperenhancement (WMH), is increased in both RA/SNA and may lead to cognitive dysfunction, depression, and brain atrophy. Magnetic resonance imaging (MRI) is ideal for serial brain/heart evaluation of patients with systemic diseases. Summary: RA/SNA patients are at high risk for brain/heart damage at early age, irrespectively of classic risk factors. Until more data will be obtained, a combined brain/heart MRI evaluation can be proposed in RA/SNA with new onset of arrhythmia and/or HF, cognitive dysfunction and/or depression. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Studies point to an increased hereditary risk of cluster headache. HCRTR2 gene rs2653349 and ADH4 gene rs1800759 polymorphisms have been associated with cluster headache susceptibility. Also, GNB3 rs5443 polymorphism, associated with increased signal transduction via GPCRs, seems to influence triptan treatment response. DNA from 114 cluster headache patients and 570 non-related controls, representing a general Southeastern European Caucasian (SEC) population, was extracted from buccal swabs and genotyped using real-time PCR. Gene distribution for the rs2653349 was GG = 79.8%, GA = 18.4%, and AA = 1.8% for patients and GG = 79.1%, GA = 19.1%, and AA = 1.8% for controls. The frequency of the mutated A allele was 11.0% for patients and 11.3% for controls. The frequencies for rs5443 were CC = 44.7%, CT = 44.7%, and TT = 10.5% for patients and CC = 43.9%, CT = 42.6%, and TT = 13.5% for controls. The frequency of the mutated T allele was 32.9% for patients and 34.8% for controls. A 2.7-fold more frequent appearance of the mutated T allele was observed in patients with better triptan treatment response, although not statistically significant. For rs1800759, the frequencies were CC = 36.0%, CA = 43.0%, and AA = 21.0% for patients and CC = 34.0%, CA = 50.2%, and AA = 15.8% for controls. The frequency of the mutated A allele was 42.5% and 40.9% for patients and controls, respectively. The mutated T allele of GNB3 rs5443 polymorphism was more prevalent in patients with better triptan treatment response, indicating a possible trend of association between this polymorphism and triptan treatment response in SEC population. According to our observation, no association of HCRTR2 rs2653349 and ADH4 rs1800759 polymorphisms and cluster headache in SEC population could be documented. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Background: The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta-analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied. Methods: After a systematic Medline search for TMS randomized controlled trials (RCTs), we assessed the number of patients reporting at least one AE and the number of discontinuations because of AE in active and sham TMS groups. Results: Data were extracted from 93 RCTs. The overall pooled estimate of active TMS and placebo treated patients who discontinued treatment because of AEs was 2.5% (95% CI 1.9%-3.2%) and 2.7% (95% CI 2.0%-3.5%), respectively. The pooled estimate of active TMS and placebo treated patients experiencing at least one AE was 29.3% (95% CI 19.0%-22.6%) and 13.6% (95% CI 11.6%-15.8%), respectively, suggesting that the odds of experiencing an AE is 2.60 times higher (95% CI 1.75-3.86) in the active treatment group compared to placebo (p < 0.00001). The most common AE was headache, followed by dizziness. Secondary meta-analyses in depression and psychotic disorders showed that the odds of experiencing an AE is 3.98 times higher (95% CI 2.14-7.40) and 2.93 times higher (95% CI 1.41-6.07), respectively, in the active treatment groups compared to placebo. Conclusions: TMS is a safe and well-tolerated intervention. Nocebo phenomena do occur during TMS treatment and should be acknowledged during clinical trial design and daily clinical practice. © 2019 International Neuromodulation Society

Psoriatic arthritis (PsA) patients are at a higher risk of systemic inflammatory sequelae, leading to microalbuminuria, cardiovascular (CVD) and neuropsychiatric (NPD) disease. Our aim is to present the existing literature about the relationship between CVD, kidney and NPD in PsA. The literature evaluation of PsA revealed that chronic T-cell activation and increased levels of circulating immune complexes can cause glomerular injury leading to microalbuminuria, which predicts CVD and all-cause mortality in both diabetic and non-diabetic patients. Furthermore, it is a marker of preclinical brain damage and identifies patients at higher risk of NPD/CVD events. Among the currently used imaging modalities in PsA, magnetic resonance imaging (MRI) maintains a crucial role, because it is ideal for concurrent evaluation of brain/heart involvement and serial follow up assessment. There is increasing evidence regarding the relationship between kidneys, heart and brain in PsA. Although currently there are no official recommendations about a combined brain/heart MRI in PsA, it could be considered in PsA with microalbuminuria, arrhythmia, HF, cognitive dysfunction and/or depression. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

NEDA was evaluated as the proportion of patients free of relapses, 3-month confirmed disability progression, and free of new or newly enlarging T2 lesion and Gadolinium enhancing lesions. © 2018, Springer Nature Switzerland AG.

Background: Migraine is a common, chronic neurovascular brain disorder with non-negligible multifaceted economic costs. Existing preventive treatments involve the selective use of onabotulinumtoxinA, which aims at migraine morbidity reduction for patients who have failed initial preventive treatment with oral agents. Erenumab is a new preventive treatment for migraines. Objective: To evaluate the differences in costs and outcomes of the preventive treatment with erenumab versus onabotulinumtoxinA in patients with chronic migraines (CM) in Greece to assess the economic value of this treatment. Methods: We conducted a cost-effectiveness analysis from both the payer and the societal perspective using a decision-tree analytic model. Outcomes were expressed in migraines avoided and in quality-adjusted life-years (QALYs). We obtained model inputs from the existing literature. The decision path adjusted for variation in the probability of adherence and the resulting differential effectiveness between the two treatments. Direct costs included the cost of the two drugs and administration costs, the costs of acute drugs used under usual care, and the costs of hospitalization, physician, and emergency department visits. Indirect costs for the societal perspective analyses included wages lost on workdays. The time-horizon of the analysis was 1 year and all costs were calculated in 2019 euros (€). Sensitivity analyses were conducted to control for parameter uncertainty and to evaluate the robustness of the findings. Results: Our results indicate that treatment of CM with erenumab compared to onabotulinumtoxinA resulted in incremental cost-effectiveness ratios (ICERs) of €218,870 and €231,554 per QALY gained and €620 and €656 per migraine avoided, from the societal and the payer’s perspective, respectively. Using a common cost-effectiveness threshold equal to three times the local gross domestic product (GDP) per capita (€49,000), for the erenumab ICERs to fall below this threshold, the erenumab price would have to be no more than €192 (societal perspective) or €173 (payer perspective). Conclusion: The prophylactic treatment of CM with erenumab in Greece might be cost effective compared to the existing alternative of onabotulinumtoxinA from both the payer and the societal perspective, but only at a highly discounted price. Nevertheless, erenumab could be considered a therapeutic option for patients who fail treatment with onabotulinumtoxinA. © 2019, Springer Nature Switzerland AG.

Following publication of the original article [1], the authors notified us of some misreported data due to the publication of the EVOLVE-2 trial (Cephalalgia. 2018;38:1442-1454), which substantially changed the level of evidence of galcanezumab for the prevention of episodic migraine. All changes are marked in bold and with red in Figure 1 and Figure 2. Please note that the final recommendations remain unchanged. Reference #51 was added: Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim B-K, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38:1442-1454. Please find below the updated text, tables, and figures. Results We identified 29 studies eligible to be considered in the present guidelines (Fig. 1) [23-51]. Fifteen of the selected studies (Tables 1 and 2) were phase II or III randomized clinical trials (RCTs) reporting data on safety or efficacy of the CGRP mAbs [26,27,31-36,41-45,50,51]; 14 additional studies were post-hoc or pooled analyses from the RCTs, open label-extension of the RCTs, or open label studies [23-25,28-30,37-40,46-49]. Risk of bias summary for the selected studies is reported in Fig. 2. Certainty assessment of outcomes for studies in EM and CM is reported in Tables 3 and 4. Recommendations related to the use of CGRP mAbs for prevention of EM and CM are reported in Table 5. PICO question 1: In patients with EM, is preventive treatment with CGRP mAbs as compared to placebo, effective and safe? Population: patients with EM Intervention: any preventive CGRP mAb Comparison: placebo Outcome: reduction in days of migraine or headache, reduction in the use of acute attack medication, improvement in function, responder ratio (patients with > 50% reduction in migraine or headache days), serious adverse events (SAEs), mortality (grade of importance: critical) Analysis of evidence We found 15 eligible studies which evaluated whether treatment with CGRP mAbs as compared to placebo is effective and safe [26,27,31-36,41-45,50,51]. Among the eligible studies one was on eptinezumab [32], five studies on erenumab [35,36,44,45,50], four studies on fremanezumab [26,27,34,41], and five studies on galcanezumab [31,33,42,43]. One phase IIIb study on erenumab was not included in the PICO question 1 because it included only patients with previous drug failure [50]. Eptinezumab Summary of findings for treatment with eptinezumab quarterly injection compared with placebo for prevention of EM is provided in Table 6. (Figure presented). © 2019 The Author(s).

Objective: This study evaluated the benefit-risk profile of erenumab relative to other therapies approved for migraine prophylaxis and available in the majority of European countries. Methods: Trials were identified via a published systematic literature review updated to December 2017 using MEDLINE. Erenumab’s pivotal trials study reports were also included (NCT02066415, NCT02456740). From these sources, ≥ 50% responder rates and discontinuations due to adverse events were extracted to generate numbers needed to treat and harm and likelihood of being helped or harmed, a quantitative benefit-risk measure. Results: Eleven articles (nine randomized clinical trials) met the inclusion/exclusion criteria. Low numbers needed to treat (range: 4–13) were observed for most treatments, while numbers needed to harm showed substantial differences (erenumab’s higher numbers needed to harm indicating better tolerability). In chronic and episodic migraine, likelihoods of being helped or harmed for erenumab 70 mg were 143 and 167, and 42 and 167 for erenumab 140 mg. Likelihoods of being helped or harmed in chronic migraine were 2 and 3 for topiramate (two studies) and 4 for onabotulinumtoxinA. In episodic migraine, likelihoods of being helped or harmed were 2 for topiramate and 2 for propranolol. Conclusions: While all prophylactic treatments were more likely to help than harm (likelihood of being helped or harmed > 1), erenumab showed a likelihood of being helped or harmed of high magnitude, supporting its favorable benefit-risk profile across the entire migraine frequency spectrum, in contrast with other prophylactic treatments. © International Headache Society 2018.

Introduction: Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data. Methods: This multicentre study included a 4-week run-in period, a 12-week double-blind period of randomised treatment with nVNS or sham, and a 24-week open-label period of nVNS. Patients were to administer two 120-second stimulations bilaterally to the neck three times daily (6–8 hours apart). Results: Of 477 enrolled patients, 332 comprised the intent-to-treat (ITT) population. Mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS (n = 165; baseline, 7.9 days) and 1.80 for sham (n = 167; baseline, 8.1 days) (p = 0.15). Results were similar across other outcomes. Upon observation of suboptimal adherence rates, post hoc analysis of patients with ≥ 67% adherence per month demonstrated significant differences between nVNS (n = 138) and sham (n = 140) for outcomes including reduction in migraine days (2.27 vs. 1.53; p = 0.043); therapeutic gains were greater in patients with aura than in those without aura. Most nVNS device-related adverse events were mild and transient, with application site discomfort being the most common. Conclusions: Preventive nVNS treatment in episodic migraine was not superior to sham stimulation in the ITT population. The “sham” device inadvertently provided a level of active vagus nerve stimulation. Post hoc analysis showed significant effects of nVNS in treatment-adherent patients. Study identification and registration: PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844. © International Headache Society 2019.

In joint initiatives, the European Headache Federation and Lifting The Burden have described a model of structured headache services (with their basis in primary care), defined service quality in this context, and developed practical methods for its evaluation. Here, in a continuation of the service quality evaluation programme, we set out ten suggested role- and performance-defining standards for specialized headache centres operating as an integral component of these services. Verifiable criteria for evaluation accompany each standard. The purposes are five-fold: (i) to inspire and promote, or stimulate the establishment of, specialized headache centres as centres of excellence; (ii) to define the role of such centres within optimally structured and organized national headache services; (iii) to set out criteria by which such centres may be recognized as exemplary in their fulfilment of this role; (iv) to provide the basis for, and to initiate and motivate, collaboration and networking between such centres both nationally and internationally; (v) ultimately to improve the delivery and quality of health care for headache. © 2019 The Author(s).

Introduction: Nocebo is very prevalent among neurological disorders, resulting in low adherence and treatment outcome. We sought to examine the adverse events (AE) following placebo administration in placebo-controlled randomized clinical trials (RCTs) for chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: After a systematic literature search for RCTs for CIDP pharmacotherapy treatments, we assessed the number of AE in the placebo groups and the number discontinuations because of placebo intolerance. Results: Our literature search strategy revealed 82 papers. Data were extracted from three RCTs fulfilling our inclusion criteria. Approximately two in five placebo-treated patients (42.0%) reported at least one AE and approximately one in fifty placebo-treated patients discontinued placebo treatment because of AEs (2.1%). All patients participating in the CIDP trials reported similar AEs independently of the study arm they belonged. Conclusion: Compared to other neurological diseases the nocebo effect in CIDP is significantly smaller. © 2018 Elsevier B.V.