Headache disorders in multiple sclerosis: Is there an association? A systematic review and meta-analysis.

OBJECTIVE: To look for any potential association of headache disorders with multiple sclerosis (MS). BACKGROUND: The prevalence of headache disorders has been found to be increased in people with MS (pwMS), however, an association has not been established. Existing studies have provided conflicting results mostly because of methodological differences. METHODS: PubMed, Embase and Scopus were searched to identify eligible studies. Studies were included if they were cross-sectional, case-control or cohort. Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias of the included studies. Case-control, cross sectional or cohort studies that used the International Classification of Headache Disorders (ICHD)-2 or-3 criteria for headache diagnosis and Mc Donald or Poser criteria for MS diagnosis were included. Data were extracted using standardized data collection form. Meta-analysis was conducted by calculating the overall prevalence of headache disorders in pwMS as well as the association of headache disorders with MS. The Newcastle-Ottawa Scale (NOS), a tool for assessing the quality of non-randomized studies, was used to assess the quality of the included studies. RESULTS: Twenty-three studies were included yielding a total of 5,440 MS patients and 28,0958 controls. The majority of them scored a NOS score between 5 and 6 (max 9), which indicates that they did not rank high in terms of quality, because most studies were cross-sectional and uncontrolled, and only one was prospective, controlled, and longitudinal, but with small population size. Pooled prevalence for all headache disorders, migraine and tension-type headache (TTH) in pwMS was 58 % (95 % CI 0.54-0.61), 30 % (95 % CI 0.25-0.34) and 19 % (95 % CI 0.15-0.23) respectively. A significant association between migraine and MS was found (OR = 2.02, 95 % CI = 1.14-3.57). CONCLUSION: PwMS are twice as likely to experience migraine as controls, but the results need to be translated with caution since most of the studies included in the meta-analysis were of low or moderate quality. Larger prospective cohort, controlled, longitudinal studies are needed to confirm whether there is indeed an association between MS and migraine.

The World Health Organization Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders and the headache revolution: from headache burden to a global action plan for headache disorders.

The World Health Organization (WHO) Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders was developed by WHO to address the worldwide challenges and gaps in provision of care and services for people with epilepsy and other neurological disorders and to ensure a comprehensive, coordinated response across sectors to the burden of neurologic diseases and to promote brain health across life-course. Headache disorders constitute the second most burdensome of all neurological diseases after stroke, but the first if young and midlife adults are taken into account. Despite the availability of a range of treatments, disability associated with headache disorders, and with migraine, remains very high. In addition, there are inequalities between high-income and low and middle income countries in access to medical care. In line with several brain health initiatives following the WHOiGAP resolution, herein we tailor the main pillars of the action plan to headache disorders: (1) raising policy prioritization and strengthen governance; (2) providing effective, timely and responsive diagnosis, treatment and care; (3) implementing strategies for promotion and prevention; (4) fostering research and innovation and strengthen information systems. Specific targets for future policy actions are proposed. The Global Action Plan triggered a revolution in neurology, not only by increasing public awareness of brain disorders and brain health but also by boosting the number of neurologists in training, raising research funding and making neurology a public health priority for policy makers. Reducing the burden of headache disorders will not only improve the quality of life and wellbeing of people with headache but also reduce the burden of neurological disorders increasing global brain health and, thus, global population health.

Rethinking headache as a global public health case model for reaching the SDG 3 HEALTH by 2030.

The 2030 Agenda for Sustainable Development sets out, through 17 Sustainable Development Goals (SDGs), a path for the prosperity of people and the planet. SDG 3 in particular aims to ensure healthy lives and promote well-being for all at all ages and includes several targets to enhance health. This review presents a "headache-tailored" perspective on how to achieve SDG 3 by focusing on six specific actions: targeting chronic headaches; reducing the overuse of acute pain-relieving medications; promoting the education of healthcare professionals; granting access to medication in low- and middle-income countries (LMIC); implementing training and educational opportunities for healthcare professionals in low and middle income countries; building a global alliance against headache disorders. Addressing the burden of headache disorders directly impacts on populations' health, as well as on the possibility to improve the productivity of people aged below 50, women in particular. Our analysis pointed out several elements, and included: moving forward from frequency-based parameters to define headache severity; recognizing and managing comorbid diseases and risk factors; implementing a disease management multi-modal management model that incorporates pharmacological and non-pharmacological treatments; early recognizing and managing the overuse of acute pain-relieving medications; promoting undergraduate, postgraduate, and continuing medical education of healthcare professionals with specific training on headache; and promoting a culture that favors the recognition of headaches as diseases with a neurobiological basis, where this is not yet recognized. Making headache care more sustainable is an achievable objective, which will require multi-stakeholder collaborations across all sectors of society, both health-related and not health-related. Robust investments will be needed; however, considering the high prevalence of headache disorders and the associated disability, these investments will surely improve multiple health outcomes and lift development and well-being globally.

Migraine in multiple sclerosis patients: potential links and treatment approach.

INTRODUCTION: Migraine has been reported to be twice as prevalent in patients with multiple sclerosis (MS) compared to the non-MS population. However, prospective, controlled studies that could lead to robust conclusions are still lacking. AREAS COVERED: Treatment of migraine in patients with MS can be challenging. Comorbidities need to be assessed and managed early, and preventive treatment should be initiated when indicated. Caution is warranted regarding the selection of the preventive medication since certain agents can magnify MS symptoms and particularly cognitive symptoms. This paper aims to discuss the association of MS and migraine, shed light on distinguishing points and red flags, as well as offer practical advice on the selection of treatment according to patients' characteristics. EXPERT OPINION: A holistic approach including pharmacological and non-pharmacological modifications is required to treat migraine in patients with MS effectively. Anti-CGRP monoclonal antibodies are a promising option due to limited drug-to-drug interactions; however, larger prospective studies are required to draw robust conclusions on the concomitant use of anti-CGRPs with MS disease modifying treatments. Early migraine preventive treatment might be needed to reduce the burden of disease in patients with MS.

Treating Spontaneous Intracranial Hypotension with an Anesthetic Modality: The Role of the Epidural Blood Patch.

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 hematomas (SDHs). This case series aims to emphasize that SIH remains a diagnostic and therapeutic challenge; it can present with a 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 etiology of SIH is not known, it is believed to be due to cerebrospinal fluid (CSF) leak or a low CSF pressure. Case Series: Three patients (two males and one female) with ages ranging between 38 and 53 years old who presented with complaints of not only an orthostatic headache, but also 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 Anesthesiology Department for an EBP. Diagnostic workup was facilitated by 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. A total of between 30 and 43 mL of autologous blood was collected from the patients and was injected into the epidural space under strict aseptic conditions. Two lumbar (L1-L2, L2-L3) EBPs and one thoracic (T11-T12) EBP were performed on the three patients, respectively. All patients reported complete resolution of symptoms following the EBPs, while MRI improved substantially. Conclusions: This report describes three cases of SIH with CSF leak originating from the cervical, the thoracic and the lumbar level. The EBP restored CSF pressure and relieved the patients' persistent symptoms. MRI helps in revealing indirect signs of a low volume of CSF, though it may not be possible to locate the actual site of the leak. In conclusion, EBP is a well-accepted and beneficial treatment modality for SIH when conventional measures fail.

Real-World Assessment of Quality of Life in Patients with Relapsing Remitting Multiple Sclerosis Treated with Teriflunomide for Two Years: Patient-Reported Outcomes from the AURELIO Study in Greece.

INTRODUCTION: Multiple sclerosis (MS) is a highly heterogeneous inflammatory disease of the central nervous system. Patient-reported outcomes (PROs) in a real-world clinical setting can provide detailed information about MS from the patient's perspective. PROs were used here to assess quality of life (QoL), treatment satisfaction, clinical efficacy, and safety outcomes in a Greek cohort of relapsing remitting MS (RRMS) patients treated with oral teriflunomide (14 mg/day). METHODS: AURELIO was a 2-year, prospective, observational study whose QoL primary endpoint was assessed with the Multiple Sclerosis Impact Scale (MSIS-29). Secondary endpoints included analyses of Patient Determined Disease Steps (PDDS), Treatment Satisfaction Questionnaire for Medication (TSQM), Expanded Disability Status Scale (EDSS), annualized relapse rate (ARR), adherence, and safety outcomes. RESULTS: AURELIO enrolled 282 patients (62.8% female; mean age 44.8 [SD ± 11] years; EDSS 2.0 [SD ± 1.6]; 44.6% treatment-naïve), with 212 patients (75%) remaining on treatment at study end. MSIS-29 total scores remained stable, while the MSIS-29 psychological scale showed significant improvement (p = 0.0015) at 2 years vs. baseline. TSQM scores at 2 years showed significant improvements in effectiveness (+ 6.6, p = 0.0001), convenience (+ 1.9, p = 0.0256), and global satisfaction (+ 8.1, p = 0.0001) vs. baseline. Disease progression was stable as indicated by non-significant changes in PDDS and EDSS vs. baseline. The ARR was low at 0.065, with a slightly higher ARR in previously treated (0.070) vs. naïve patients (0.058). Adherence was high at > 90%. Overall, 91 patients (32.3%) in the study reported a total of 215 safety events (32 serious, of which 21 were classified as mild-moderate). No new safety signals were observed. CONCLUSIONS: These data highlight the importance of PROs to facilitate personalized treatment strategies in MS. In line with other teriflunomide studies, AURELIO showed stable QoL, efficacy and safety outcomes, and good treatment satisfaction both in treatment-naïve and previously treated patients in this Greek cohort of patients with RRMS.

A systematic review with expert opinion on the role of gepants for the preventive and abortive treatment of migraine.

INTRODUCTION: Gepants are small molecules targeting the calcitonin gene-related peptide (CGRP) that have been recently introduced and are under additional clinical development as preventive and abortive treatment options for migraine. AREAS COVERED: After providing a narrative overview of current preventive and acute treatment options for migraine and summarizing the pathophysiology of migraine attack and the role of CGRP, we performed a systematic review, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on trials on gepants in preventive and acute treatment of migraine. Studies and results were reviewed and discussed, and expert opinion was presented. We also collected data on relevant ongoing trials. EXPERT OPINION: Whether direct targeting CGRP pathways within the central nervous system or indirectly modulating them from the peripheral nervous system is more effective and safer in migraine remains still unclear. The available data on the efficacy and safety of gepants suggest they may represent an abortive, and to some extent, preventive treatment option for migraine, in patients who do not respond or have adverse effects to first/second line treatments or at high risk for medication overuse headache; thus opening new therapeutic horizons.

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention - 2022 update.

BACKGROUND: A previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments. METHODS: The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. RESULTS: We found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts' opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives. CONCLUSION: Monoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.

Neuropathic Pain in Neurologic Disorders: A Narrative Review.

Neuropathic pain is defined as a painful condition caused by neurological lesions or diseases. Sometimes, neurological disorders may also be associated with neuropathic pain, which can be challenging to manage. For example, multiple sclerosis (MS) may cause chronic centralized painful symptoms due to nerve damage. Other chronic neuropathic pain syndromes may occur in the form of post-stroke pain, spinal cord injury pain, and other central pain syndromes. Chronic neuropathic pain is associated with dysfunction, disability, depression, disturbed sleep, and reduced quality of life. Early diagnosis may help improve outcomes, and pain control can be an important factor in restoring function. There are more than 100 different types of peripheral neuropathy and those involving sensory neurons can provoke painful symptoms. Accurate diagnosis of peripheral neuropathy is essential for pain control. Further examples are represented by gluten neuropathy, which is an extraintestinal manifestation of gluten sensitivity and presents as a form of peripheral neuropathy; in these unusual cases, neuropathy may be managed with diet. Neuropathic pain has been linked to CoronaVirus Disease (COVID) infection both during acute infection and as a post-viral syndrome known as long COVID. In this last case, neuropathic pain relates to the host's response to the virus. However, neuropathic pain may occur after any critical illness and has been observed as part of a syndrome following intensive care unit hospitalization.

Beyond chronic migraine: a systematic review and expert opinion on the off-label use of botulinum neurotoxin type-A in other primary headache disorders.

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.

PEARL study protocol: a real-world study of fremanezumab effectiveness in patients with chronic or episodic migraine.

Fremanezumab is a humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide and is approved in Europe for migraine prevention in adults with ≥4 migraine days/month. The Pan-European Real Life (PEARL) study is a 24-month, prospective, observational study of fremanezumab in chronic or episodic migraine. End points include proportion of patients with ≥50% reduction in monthly migraine days during 6 months of treatment (primary); changes in monthly migraine days, disability scores and acute headache medication use; adherence and persistence; and effectiveness in patients switching from another calcitonin gene-related peptide pathway-targeting monoclonal antibody. PEARL is being conducted in approximately 100 centers in 11 European countries (estimated n = 1100). PEARL will generate important real-world data on effectiveness of fremanezumab and treatment patterns in patients with chronic migraine or episodic migraine.

Lay abstract Fremanezumab is an injectable biologic medication that targets calcitonin gene-related peptide, a substance released in the nerves and blood vessels during a migraine attack that plays a role in migraine pain. Fremanezumab is approved in Europe for preventing migraine in adults who experience ≥4 migraine days/month. The Pan-European Real Life (PEARL) study is a 24-month long study that will observe patients with migraine who are starting treatment with fremanezumab in a clinical practice setting under the care of their treating physician. The major goals of the study are to evaluate the effectiveness of fremanezumab for reducing days with migraine attacks in a month, disability associated with migraine and use of acute headache medications to treat migraine, including in patients switching from other biologic migraine therapies in the same drug class. The extent to which patients follow their recommended treatment schedule per their providers' instructions and whether patients discontinue treatment will also be evaluated. The PEARL study will include >1000 patients in 100 centers across 11 European countries. The study will provide important information on effectiveness for patients with migraine receiving fremanezumab in the normal course of their treatment, as well as on patients' use of fremanezumab according to their prescribing physicians' recommendations. Trial registration number: EUPAS35111 (European Network of Centres for Pharmacoepidemiology and Pharmacovigilance).

An updated brief overview on post-traumatic headache and a systematic review of the non-pharmacological interventions for its management.

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.

Validity and reliability of the Greek version of the neurogenic bladder symptom score (NBSS) questionnaire in a sample of Greek patients with multiple sclerosis.

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.

Safety, Tolerability, and Nocebo Phenomena During Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Placebo-Controlled Clinical Trials.

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.

Analysis of HCRTR2, GNB3, and ADH4 Gene Polymorphisms in a Southeastern European Caucasian Cluster Headache Population.

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.

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

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.

Cost-Effectiveness Analysis of Erenumab Versus OnabotulinumtoxinA for Patients with Chronic Migraine Attacks in Greece.

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.

Correction to: European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention.

AbstractFollowing 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.

European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention.

BACKGROUND AND AIM: Monoclonal antibodies acting on the calcitonin gene-related peptide or on its receptor are new drugs to prevent migraine. Four monoclonal antibodies have been developed: one targeting the calcitonin gene-related peptide receptor (erenumab) and three targeting the calcitonin gene-related peptide (eptinezumab, fremanezumab, and galcanezumab). The aim of this document by the European Headache Federation (EHF) is to provide an evidence-based and expert-based guideline on the use of the monoclonal antibodies acting on the calcitonin gene-related peptide for migraine prevention. METHODS: The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed systematic review and analysis of the literature, assessed the quality of available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. RESULTS: We found low to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in patients with episodic migraine and medium to high quality of evidence to recommend erenumab, fremanezumab, and galcanezumab in patients with chronic migraine. For several clinical questions, there was not enough evidence to provide recommendations using the GRADE approach and recommendations relied on experts' opinion. CONCLUSION: Monoclonal antibodies acting on the calcitonin gene-related peptide are new drugs which can be recommended for migraine prevention. Real life data will be useful to improve the use of those drugs in clinical practice.