Publications by authors named "Dimos Mitsikostas"

71 Publications

Structured Q1 headache services as the solution to the ill-health burden of headache: 1. Rationale and description.

J Headache Pain 2021 Jul 21;22(1):78. Epub 2021 Jul 21.

Department of Neurology, Ghent University Hospital, Ghent, Belgium.

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles.High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary.The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded.It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses.
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http://dx.doi.org/10.1186/s10194-021-01265-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293530PMC
July 2021

Diagnosis and management of migraine in ten steps.

Nat Rev Neurol 2021 Jun 18. Epub 2021 Jun 18.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up.
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http://dx.doi.org/10.1038/s41582-021-00509-5DOI Listing
June 2021

Safety and tolerability evaluation of erenumab for the preventive treatment of migraine.

Expert Opin Drug Saf 2021 Jul 16:1-10. Epub 2021 Jul 16.

Danish Headache Center, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark.

: Erenumab, a monoclonal antibody targeting the receptor of calcitonin gene related peptide (CGRP), is the first disease-specific and mechanism-based treatment approved for the prevention of migraine. Although the safety and tolerability data from randomized trials are clear, the physiological effects of CGRP rise reasonable concerns. We aimed to evaluate the current evidence for safety and tolerability related to erenumab use in migraine. : This review outlines the severe adverse events (AEs), common AEs, AEs leading to treatment discontinuation and AEs of special interest, reported in all phase 2, phase 3, open label, and observational studies with erenumab in migraine. Individual safety reports were also included in the systematic review of evidence. : No safety and tolerability flags were detected in this review. The most common AE are local skin reactions and constipation. No severe AEs, or frequent AEs leading to treatment discontinuation were detected. Treatment is well tolerated. The only AE of interest that may play a role in decision making and treatment monitoring is constipation. These findings are in line with previous safety reports, further highlighting the substantial tolerability and safety profile of the modern anti-CGRP monoclonal antibodies for the prevention of migraine.
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http://dx.doi.org/10.1080/14740338.2021.1933941DOI Listing
July 2021

Current advances in the management of cluster headaches.

Expert Opin Pharmacother 2021 May 14:1-13. Epub 2021 May 14.

1 Neurology Department, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

: Cluster headache (CH) is probably the most severe idiopathic pain condition, yet its current medical management remains poor.: Only repurpose medicines are currently in use for the prevention of CH, partially because the pathophysiology of the condition is still elusive. In this article we performed a systematic review to evaluate the evidence for efficacy of the currently available or emerging treatments for CH.: We found several ongoing randomized clinical trials testing prophylactic treatments for CH and only few for the standard ones. Recent data from randomized trials with monoclonal antibodies targeting the calcitonin gene related peptide pathway (anti-CGRP mAbs) are controversial, although its role in the pathogenesis of the condition is well documented. This inconsistency may depict inadequacies in clinical trial designing. Anti-CGRP mAbs and antagonists of pituitary adenylate cyclase-activating polypeptide (PACAP) along with neuromodulation techniques, are curing the necessary valuable evidence that could illuminate the therapeutical future for cluster headache. Orexin pathway is another attractive target for CH treatment. To improve the evidence for efficacy, we further propose that the design of the clinical trials for CH needs to be radically reviewed to allow more patients to participate.
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http://dx.doi.org/10.1080/14656566.2021.1924148DOI Listing
May 2021

The Role of Galcanezumab in Migraine Prevention: Existing Data and Future Directions.

Pharmaceuticals (Basel) 2021 Mar 9;14(3). Epub 2021 Mar 9.

1st Neurology Department, Aeginition Hospital, National and Kapodistrian University of Athens, 11521 Athens, Greece.

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.
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http://dx.doi.org/10.3390/ph14030245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998387PMC
March 2021

Migraine: integrated approaches to clinical management and emerging treatments.

Lancet 2021 04 25;397(10283):1505-1518. Epub 2021 Mar 25.

Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.

Migraine is a highly disabling neurological disorder that directly affects more than 1 billion individuals worldwide. Available treatment options differ between countries and include acute, preventive, and non-pharmacological therapies. Because of major progress in the understanding of migraine pathogenesis, novel mechanism-based medications have emerged and expanded the armamentarium of treatments. We provide a comprehensive overview of the current standard of care that will enable informed clinical management. First, we discuss the efficacy, tolerability, and safety profile of various pharmacological therapies for acute and preventive treatment of migraine. Second, we review the current knowledge on non-pharmacological therapies, such as neuromodulation and biobehavioural approaches, which can be used for a multidisciplinary approach to clinical management. Third, we emphasise that any effective treatment strategy starts with building a therapeutic plan tailored to individual clinical characteristics, preferences, and needs. Finally, we explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management of migraine.
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http://dx.doi.org/10.1016/S0140-6736(20)32342-4DOI Listing
April 2021

Tension-type headache.

Nat Rev Dis Primers 2021 03 25;7(1):24. Epub 2021 Mar 25.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.

Tension-type headache (TTH) is the most prevalent neurological disorder worldwide and is characterized by recurrent headaches of mild to moderate intensity, bilateral location, pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based on headache history and the exclusion of alternative diagnoses, with clinical criteria provided by the International Classification of Headache Disorders, third edition. Although the biological underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for the genesis of pain in TTH, whereas central sensitization may be involved in transformation from episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and can be divided into acute and preventive treatments. Simple analgesics have evidence-based effectiveness and are widely regarded as first-line medications for the acute treatment of TTH. Preventive treatment should be considered in individuals with frequent episodic and chronic TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some selected non-pharmacological therapies. Despite the widespread prevalence and associated disability of TTH, little progress has been made since the early 2000s owing to a lack of attention and resource allocation by scientists, funding bodies and the pharmaceutical industry.
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http://dx.doi.org/10.1038/s41572-021-00257-2DOI Listing
March 2021

Anti-CGRP monoclonal antibodies for migraine prevention: A systematic review and likelihood to help or harm analysis.

Cephalalgia 2021 Jun 10;41(7):851-864. Epub 2021 Feb 10.

1st Neurology Department, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

Introduction And Objective: Monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) have shown promising efficacy in randomised clinical trials for the prevention of episodic and chronic migraine, but no head-to-head comparisons with established treatments are available. We aimed to examine absolute differences in benefit-risk ratios between anti-CGRP mAbs, topiramate and propranolol for the prevention of episodic migraine and between anti-CGRP mAbs, topiramate and onabotulinumtoxinA for the prevention of chronic migraine using a likelihood to help versus harm analysis.

Methods: The number of patients needed to be treated for a patient to achieve ≥ 50% reduction in migraine days (NNTB) was used as an effect size metric of efficacy. The number of patients needed to be treated for a patient to experience an adverse event that led to treatment discontinuation (NNTH) was used as a measure of risk. Likelihood to help versus harm values - which are the ratios of NNTH:NNTB - were calculated using data from phase 3 randomised clinical trials.

Results: All agents tested were more likely to be beneficial than harmful (likelihood to help versus harm > 1) with the exception of topiramate at 200 mg per day for the prevention of episodic migraine. Anti-CGRP mAbs in all tested doses had higher LHH values than propranolol or topiramate for episodic migraine and onabotulinumtoxinA or topiramate for chronic migraine prevention. Fremanezumab had the highest LHH ratio in episodic migraine and galcanezumab in chronic migraine.

Conclusion: This analysis showed that anti-CGRP mAbs exhibit a more favourable benefit-risk ratio than established treatments for episodic and chronic migraine. Head-to-head studies are needed to confirm these results.
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http://dx.doi.org/10.1177/0333102421989601DOI Listing
June 2021

Monoclonal Antibodies as Neurological Therapeutics.

Pharmaceuticals (Basel) 2021 Jan 26;14(2). Epub 2021 Jan 26.

Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 129 Vasilissis Sophias Avenue, 11521 Athens, Greece.

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.
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http://dx.doi.org/10.3390/ph14020092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912592PMC
January 2021

A Prospective, Observational, Cohort Study to Assess the Efficacy and Safety of Prolonged-Release Fampridine in Cognition, Fatigue, Depression, and Quality of Life in Multiple Sclerosis Patients: The FAMILY Study.

Adv Ther 2021 03 2;38(3):1536-1551. Epub 2021 Feb 2.

Neurology Department, University General Hospital of Heraklion, Heraklion Crete, Greece.

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.
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http://dx.doi.org/10.1007/s12325-020-01606-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932964PMC
March 2021

A population-based survey for disabling headaches in Greece: Prevalence, burden and treatment preferences.

Cephalalgia 2021 Jun 1;41(7):810-820. Epub 2021 Feb 1.

First Neurology Department, Aeginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Objective: To estimate the prevalence, burden and current treatment of disabling primary headaches in a large sample of the Greek population aged 18-70 years old.

Methods: This is an observational descriptive study, with cross-sectional design performed by quantitative computer-assisted telephone interviews, using a validated 37-item questionnaire for headaches. The prevalence, burden, and current treatment of primary headaches (ICHD-3) were recorded along with participants' treatment preferences.

Results: Out of 10,008 interviewed participants, 1197 (12.0%) reported headaches affecting performance. The annual prevalence of migraine was 8.1% (95% confidence interval, 7.6-8.7, corresponding to 0.6 million Greeks), of chronic migraine 1.0% (95% confidence interval, 0.8-1.2, corresponding to 0.1 million), and of tension-type headache 3.8% (95% confidence interval, 3.4-4.2, corresponding to 0.3 million). The participants with headaches reported 0.5 headache-induced lost workdays per month (corresponding to 5.8 million lost workdays annually) and reductions in performance on 2.8 workdays per month (corresponding to 30.9 million workdays annually). In all, 43.4% of headache participants felt bad/ashamed because of headaches and 21.9% sought professional treatment, most often from a private neurologist. 83.8% of headache participants had never taken pharmacological prophylaxis, and only 5.5% were currently under preventative treatment. For both prophylactic and acute treatment, headache participants prefer oral medication to injection or stimulation devices.

Conclusion: More than 10% of the Greek adult population up to 70 years old experience disabling headaches, causing a dramatic work loss. More than 80% of these have never taken pharmacological prophylaxis. Thus, enriching the quality of life of people with headaches relies crucially on expanding awareness about headaches and their treatment.
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http://dx.doi.org/10.1177/0333102421989630DOI Listing
June 2021

Diarrhoea in systemic sclerosis patients as a nocebo effect of nintedanib.

Eur Respir J 2021 04 22;57(4). Epub 2021 Apr 22.

Joint Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.1183/13993003.03021-2020DOI Listing
April 2021

Making headway - a role for CGRP in post-traumatic headache.

Nat Rev Neurol 2021 Mar;17(3):133-134

Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.

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http://dx.doi.org/10.1038/s41582-020-00431-2DOI Listing
March 2021

Nocebo-Prone Behaviour in Patients with Autoimmune Rheumatic Diseases during the COVID-19 Pandemic.

Mediterr J Rheumatol 2020 Sep 21;31(Suppl 2):288-294. Epub 2020 Sep 21.

First Department of Propaedeutic Internal Medicine, Joint Rheumatology Program, National and Kapodistrian University of Athens Medical School, "Laiko" General Hospital, Athens, Greece.

Background: The COVID-19 pandemic is associated with emotional distress and significant disruptions in health-care services. These are key players in the development of nocebo phenomena. We aimed to investigate nocebo-prone behaviour in patients with autoimmune rheumatic diseases (ARD) amid the COVID-19 pandemic-associated lockdown.

Methods: Consecutive patients were telephone-interviewed during the COVID-19 pandemic in Greece. Clinical and socioeconomic characteristics (eg, level of education) were recorded. For nocebo behaviour, a four-item validated questionnaire (Q-No, cut-off score>15), was used. Results were compared with pre-COVID-19 Q-No scores collected from patients followed-up in our department.

Results: Nocebo behaviour was detected in 51/500 (10.2%) individuals. In patients with nocebo behaviour, use of anti-hypertensives was less common (17.6% vs 31.8%, p=0.04), but a higher level of education was more common (58.8% vs 35.9%, p=0.002), compared with patients with Q-No score ≤15; the latter retained statistical significance in multivariate regression analysis (p=0.009, OR [95%CI]: 2.29, [1.23-4.25]). Total Q-No scores were higher in the COVID-19-period compared to the pre-COVID-19 era [median (range); 12 (4-20) vs 11 (4-20), p=0.02]. Among 78 patients with available Q-No questionnaires in the pre-COVID-19 era, 11 (14.1%) displayed nocebo behaviour, which increased to 16 (20.5%) amid the COVID-19 pandemic. Interim development of nocebo behaviour was also associated with higher educational level (p=0.049, OR: 3.65, 95%CI: 1.005-13.268).

Conclusion: A considerable proportion of ARD patients manifested nocebo-prone behaviour during the COVID-19 pandemic, which was more common among those with high educational level.
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http://dx.doi.org/10.31138/mjr.31.3.288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656135PMC
September 2020

European Headache Federation recommendations for placebo and nocebo terminology.

J Headache Pain 2020 Sep 25;21(1):117. Epub 2020 Sep 25.

Physiology and Neuroscience, University of Turin Medical School, Turin, Italy.

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).
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http://dx.doi.org/10.1186/s10194-020-01178-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519524PMC
September 2020

IncobotulinumtoxinA for the Treatment of Blepharospasm in Toxin-Naïve Subjects: A Multi-Center, Double-Blind, Randomized, Placebo-Controlled Trial.

Adv Ther 2020 10 10;37(10):4249-4265. Epub 2020 Aug 10.

Department of Neurology, Georgetown University Hospital Pasquerilla Healthcare Center, Washington, DC, USA.

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.
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http://dx.doi.org/10.1007/s12325-020-01427-6DOI Listing
October 2020

Aging, Cellular Senescence, and Progressive Multiple Sclerosis.

Front Cell Neurosci 2020 30;14:178. Epub 2020 Jun 30.

Department of Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, London, United Kingdom.

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.
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http://dx.doi.org/10.3389/fncel.2020.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338849PMC
June 2020

Current understanding and future perspectives of brain-heart-kidney axis in psoriatic arthritis.

Rheumatol Int 2020 Sep 27;40(9):1361-1368. Epub 2020 Jun 27.

Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61 P. Faliro, Athens, Greece.

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.
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http://dx.doi.org/10.1007/s00296-020-04633-1DOI Listing
September 2020

Long-term efficacy and safety of alemtuzumab in patients with RRMS: 12-year follow-up of CAMMS223.

J Neurol 2020 Nov 24;267(11):3343-3353. Epub 2020 Jun 24.

University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1007/s00415-020-09983-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578137PMC
November 2020

Is There a Brain/Heart Interaction in Rheumatoid Arthritis and Seronegative Spondyloartropathies? A Combined Brain/Heart Magnetic Resonance Imaging Reveals the Answer.

Curr Rheumatol Rep 2020 06 19;22(8):39. Epub 2020 Jun 19.

Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61 P.Faliro, Athens, Greece.

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. 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.
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http://dx.doi.org/10.1007/s11926-020-00922-7DOI Listing
June 2020

Galcanezumab in migraine prevention: a systematic review and meta-analysis of randomized controlled trials.

Ther Adv Neurol Disord 2020 28;13:1756286420918088. Epub 2020 Apr 28.

First Neurology Department, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, 74 V. Sofia's Avenue, Athens 11528, Greece.

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 placebo (120 mg, MD = -1.98, 95% CI = -2.33 to -1.63;  < 0.0001) or (240 mg, MD = -1.86, 95% CI = -2.20 to -1.53;  < 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.
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http://dx.doi.org/10.1177/1756286420918088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222235PMC
April 2020

Quality of Life Improves with Alemtuzumab Over 6 Years in Relapsing-Remitting Multiple Sclerosis Patients with or without Autoimmune Thyroid Adverse Events: Post Hoc Analysis of the CARE-MS Studies.

Neurol Ther 2020 Dec 14;9(2):443-457. Epub 2020 May 14.

University of Alberta, Edmonton, AB, Canada.

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.
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http://dx.doi.org/10.1007/s40120-020-00191-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606412PMC
December 2020

Editorial: Nocebo Effects and Their Influence on Clinical Trials and Practice: Modulating Factors in Healthy and Pathological Conditions.

Front Pharmacol 2020 19;11:100. Epub 2020 Feb 19.

First Department of Neurology, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.3389/fphar.2020.00100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042386PMC
February 2020

Combined Brain-Heart Magnetic Resonance Imaging in Autoimmune Rheumatic Disease Patients with Cardiac Symptoms: Hypothesis Generating Insights from a Cross-sectional Study.

J Clin Med 2020 Feb 6;9(2). Epub 2020 Feb 6.

Onassis Cardiac Surgery Center, 17674 Athens, Greece.

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 ( < 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 ( < 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), = 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.
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http://dx.doi.org/10.3390/jcm9020447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074384PMC
February 2020

Placebo and nocebo phenomena in anti- CGRP monoclonal antibody trials for migraine prevention: a meta-analysis.

J Neurol 2020 Apr 9;267(4):1158-1170. Epub 2020 Jan 9.

1st Neurology Department, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, 72-74 V. Sofia's Avenue, 11528, Athens, Greece.

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.
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http://dx.doi.org/10.1007/s00415-019-09673-7DOI Listing
April 2020

Consensus of the Hellenic Headache Society on the diagnosis and treatment of migraine.

J Headache Pain 2019 Dec 13;20(1):113. Epub 2019 Dec 13.

First Neurology Department, School of Medicine, National & Kapodistrian University of Athens, Aeginition Hospital, 72-74 Vl Sofia's Avenue, 11528, Athens, Greece.

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.
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http://dx.doi.org/10.1186/s10194-019-1060-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911284PMC
December 2019

Lateralization of Insular Ischemic Stroke is Not Associated With Any Stroke Clinical Outcomes: The Athens Stroke Registry.

J Stroke Cerebrovasc Dis 2020 Feb 3;29(2):104529. Epub 2019 Dec 3.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Greece; Hellenic Cardiovascular Research Society, Athens, Greece.

Background: Controversial evidence suggests that right insular stroke may be associated with worse outcomes compared to the left insular ischemic lesion.

Objectives: We investigated whether lateralization of insular stroke is associated with early and late outcome in terms of in-hospital complications, stroke recurrence, cardiovascular events, and death.

Methods: Data were prospectively collected from the Athens Stroke Registry. Insular cortex involvement was identified based on brain CT scans or MRI images. Patients were followed up prospectively at 1, 3, 6 months after hospital discharge and yearly thereafter up to 5-years or until death. The assessed outcomes were in-hospital complications, functional outcome assessed by the modified Rankin Scale, stroke recurrence, cardiovascular events, and death. Cox-regression analysis was performed to estimate the cumulative probability of each outcome according to the lateralization of insular strokes.

Results: Among the 1212 patients, 650 had left insular stroke involvement and 562 had right. New onset of in-hospital atrial fibrillation was similar between right and left insular strokes (11.6% versus 12.9%, P = .484). During the 5-year follow-up sudden death occurred in 21 (3.7%) patients with right insular compared to 30 (4.6%) with left insular stroke (P = .476). There was no difference between left and right insular strokes regarding mortality (adjusted odds ratio [OR]: .92, 95% confidence interval [CI]: .80-1.06), stroke recurrence (4.3% versus 4.9%; adjusted OR: .81 95% CI: .58-1.13), cardiovascular events, and sudden death (adjusted OR: .99, 95% CI: .76-1.29) and on death and dependency (adjusted OR: .88, 95% CI: .75-1.02) during a 5-year follow up.

Conclusions: Lateralization of insular ischemic stroke involvement is not associated with stroke outcomes.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.104529DOI Listing
February 2020

Headaches in the emergency department -a survey of patients' characteristics, facts and needs.

J Headache Pain 2019 Nov 5;20(1):100. Epub 2019 Nov 5.

Headache Medical Center Linz, Ordensklinikum Barmherzige Schwestern, Seilerstaette 2-4, 4020, Linz, Austria.

Background And Aim: Headache is very often the cause for seeking an emergency department (ED). However, less is known about the different diagnosis of headache disorders in the ED, their management and treatment. The aim of this survey is to analyse the management of headache patients in two different ED in Europe.

Methods: This retrospective survey was performed from September 2018 until January 2019. Patients were collected from the San Luca Hospital, Milan, Italy and the Ordensklinikum Barmherzige Schwestern, Linz, Austria. Only patients with a non-traumatic headache, as the primary reason for medical clarification, were included. Patients were analysed for their complexity and range of examination, their diagnoses, acute treatment and overall efficacy rate.

Results: The survey consists of 415 patients, with a mean age of 43.32 (SD ±17.72); 65% were female. Technical investigation was performed in 57.8% of patients. For acute treatment non-steroidal-anti-inflammatory drugs (NSAIDs) were the most used, whereas triptans were not given. A primary headache disorder was diagnosed in 45.3% of patients, being migraine the most common, but in 32% of cases the diagnosis was not further specified. Life-threatening secondary headaches accounted for less than 2% of cases.

Conclusions: The vast majority of patients attending an ED because of headache are suffering from a primary headache disorder. Life-threatening secondary headaches are rare but seek attention. NSAIDs are by far the most common drugs for treating headaches in the ED, but not triptans.
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http://dx.doi.org/10.1186/s10194-019-1053-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833179PMC
November 2019

Nocebo in multiple sclerosis trials: A meta-analysis on oral and newer injectable disease-modifying treatments.

Mult Scler Relat Disord 2019 Nov 9;36:101389. Epub 2019 Sep 9.

First Neurology Department, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, 74 V. Sofia's Avenue, Athens 11528, Greece. Electronic address:

Background: Nocebo phenomena are linked to decreased adherence to treatments in clinical practice as well as difficulty in assessing the adverse effect profile in clinical trials.

Objective: To estimate the incidence and severity of nocebo responses in clinical trials of oral and newer injectable disease-modifying treatments (DMTs) for relapsing multiple sclerosis (MS).

Methods: Meta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events (AEs) in randomized, placebo-controlled MS trials published between 2005 and 2018. Nocebo severity was estimated as a percentage of placebo-treated patients who discontinued the treatment due to drug-related AEs.

Results: The pooled incidence of nocebo was 89% (95% CI: 88%-90%) in trials for oral DMTs (cladribine, fingolimod, teriflunomide and dimethyl fumarate) and 66% (95% CI: 51%-80%) in trials of newer injectable DMTs (biosimilar glatiramer acetate 20 mg, innovator glatiramer acetate 40 mg and pegylated interferon beta). The pooled nocebo severity was 8% (95% CI: 5%-12%) for oral treatments and 2% (95% CI: 0-2%) for newer injectable DMTs.

Conclusions: Oral DMTs may be associated with a higher incidence and greater nocebo severity than newer injectables.
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http://dx.doi.org/10.1016/j.msard.2019.101389DOI Listing
November 2019

Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: The multicentre, double-blind, randomised, sham-controlled PREMIUM trial.

Cephalalgia 2019 Oct 15;39(12):1475-1487. Epub 2019 Sep 15.

Leiden University Medical Center, Leiden, The Netherlands.

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) ( = 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;  = 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. PREMIUM; NCT02378844; https://clinicaltrials.gov/ct2/show/NCT02378844.
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http://dx.doi.org/10.1177/0333102419876920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791025PMC
October 2019
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