ISSN doi: /head VC 2018 American Headache Society Published by Wiley Periodicals, Inc.

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1 ISSN Headache doi: /head VC 2018 American Headache Society Published by Wiley Periodicals, Inc. Supplement Article Migraine Burden of Disease: From the Patient s Experience to a Socio-Economic View Reto Agosti, MD Migraine is one of the most common diseases worldwide and, importantly, a major cause of disability. This translates into a huge clinical and economic burden to individuals and society. Despite existing data on how migraine affects populations, the disease continues to be underdiagnosed and therefore undertreated, so the scale of the public health problem may be underestimated. The impact on the daily lives of patients and their families has also been underappreciated. Clinical and regulatory guidelines are encouraging the use of patient-reported outcome tools (PROs), as these may help in disease management and facilitate physician patient interactions. In clinical trials in migraine, PRO data are key to evaluating the effects of new therapies on patients, such as disability assessment, productivity, quality of life, and emotional and physical functioning. Digital technologies have enabled the development of epro tools, which may play a growing role in the collection of PRO data in the future. Here, we will consider the current view of the burden imposed by migraine on patients and society, illustrate this with two patient case studies, and examine the initiatives underway to use our knowledge to improve our management approaches for the disease. Key words: migraine, epidemiology, quality of life, patient-reported outcomes, disability, disease burden Abbreviations: GBD Global Burden of Disease, HIT Headache Impact Test, HRQoL health-related quality of life, MIDAS Migraine Disability Assessment, MPFID Migraine Physical Function Impact Diary, MSQ Migraine-Specific Qol Questionnaire, PRO patient-reported outcome, QoL quality of life, YLDs years lived with disability (Headache 2018;58:17-32) INTRODUCTION Migraine has long been known by patients and their families to have a heavy impact on their daily life; but healthcare systems in many countries are still lagging in terms of recognizing the humanitarian burden and socioeconomic cost of this condition. 1,2 In 2004, the World Headache Alliance, the International Headache Society, the European From the Headache Center Zurich Hirslanden, Zurich, Switzerland. Address all correspondence to R. Agosti, Headache Center Zurich Hirslanden, Forchstrasse 424, 8702 Zollikon, Zurich, Switzerland, reto.agosti@kopfwww.ch Accepted for publication March 28, Headache Federation, and the World Health Organization collaborated on an initiative called Lifting The Burden to ensure that migraine gained greater attention. 1,2 Objectives were set for assessing the scale and scope of migraine, using this knowledge to raise awareness, and eventually influencing a change in behavior of healthcare providers. Better therapies for migraine are still needed, but progress in managing the condition also depends on a thorough understanding of disease burden and Financial Support: Financial support for medical editorial assistance with this manuscript was provided by Novartis Pharma AG. Conflict of Interest: Reto Agosti has served as a consultant and a speaker for Novartis. 17

2 18 May 2018 incorporating patient perspectives on how migraine affects their lives. 1,2 EPIDEMIOLOGY Prevalence and Demographics. Migraine is the third most common disease worldwide, with a global prevalence (1 year prevalence) estimated at 14.7% in both genders in the Global Burden of Disease (GBD) Survey. 3-5 Migraine is believed to affect over 20% of people at some point in their lives, but continues to be underdiagnosed. 6 There appear to be no clear geographical relationships nor underlying trends for its occurrence over long periods of time. 7,8 A notable difficulty in making firm conclusions about migraine prevalence trend data is that increased awareness, improved diagnosis of the condition and better access to care can influence the numbers reported rather than there being a fundamental change in actual migraine prevalence. 9 Therefore, this must always be considered when reviewing epidemiological data. High-quality epidemiological data regarding migraine continue to be sparse for some regions of the world, but a clearer picture of the disease is emerging. 5,8 A meta-analysis of 302 communitybased studies (covering the period January 1, 1920 until August 31, 2015) determined a weighted average global migraine prevalence. 8 Geographically, prevalence was 10.4% in Africa, 10.1% in Asia, 11.4% in Europe, 9.7% in North America, and 16.4% in Central and South America. 8 This study estimated that 1 in 10 people worldwide were affected by migraine. 8 U.S. government statistics from 2015 suggest that migraine affects approximately 1 out of every 7 Americans annually. 10 Current data show migraine to be a condition that varies greatly with age, gender, and sociodemographic variables, and that it often remains underdiagnosed. 4,5,8 Influence of age on the prevalence of migraine is well documented, although limited data exist across the lifespan. 11 U.S. population data analysis of 162,576 individuals aged 12 years or older revealed migraine prevalence to be at its highest for people aged 30 to 39 years old. 9 Additional insight regarding migraine in the general population is available from a Swiss cohort study, where 591 people aged were interviewed seven times across 30 years of follow-up. 12 The investigators reported that around 20% of people with migraine developed a chronic course. 12 On average, the people with migraine surveyed reported headaches for 1 month a year for 24 years of the 30 year period. This long-term study clearly showed the tremendous impact that migraine had on patients daily lives. 12 Migraine disproportionately affects women, with population studies showing it is two to three times more common in females than in males. 13 Puberty is the time when women begin to demonstrate an increase in migraine prevalence as compared with men. 14 Several hypotheses have been put forward to explain this difference, such as the influence of hormones, genetic factors, and exposure to environmental stressors. 14 As migraine is less common in men, it is often under-recognized; as a result, men with migraine are less likely than women to consult health services or receive appropriate care. 15 Prevalence data (meta-analysis of 302 community-based studies) also show higher migraine rates among the urban population compared with rural settings. 8 Migraine Is a Leading Cause of Disability. Although not a fatal disease, migraine ranks as the sixth highest cause of disability as measured by years lived with disability (YLDs) worldwide. 3,5 Among women, neurological disorders, mostly migraine, represent the second leading cause of YLDs. 4 In women, migraine attacks duration tend to be longer, with a pattern of increased risk of headache recurrence, greater disability, and a longer period of time needed to recover. 13 In each of the 195 countries and territories included in the GBD database, migraine was in the top 10 of YLDs, dispelling the myth that it primarily affects those in more industrialized nations. 3,4 Across sociodemographic index (SDI) quintiles, migraine was in the top five causes of YLDs in high-income, high-middle, and middle-income SDI quintile countries. 4 Although migraine is increasingly recognized as a global cause of disability, more work remains to be done to understand the scale of the public

3 Headache 19 health problem. 3 For example, GBD currently considers only the disability burden associated with the ictal state of headache disorders, despite evidence of interictal burden in a considerable proportion of people with migraine. 3 Whereas the ictal burden is typically present during only a few days in every month, interictal burden can make itself felt on all of the other days, thereby considerably affecting patients daily activities. 16 A study in a European population found that time in the interictal state, when symptoms might be present continuously, was, on average, 317 days/year for sufferers of migraine. 16 A significant problem that can interfere with medical care, is the fear that patients experience of the next migraine attack during a pain-free period. 17,18 This anticipatory anxiety can prompt them to overuse medications such as analgesics in the hope of being able to ward off a headache attack. 17,18 Structured interviews with patients have shown that the higher the migraine attack frequency, the greater the fear of the patient regarding such an attack and the more likely the potential for medication overuse. 18 Addressing these patient fears should also be an important part of medical care for migraine. 18 Types of Headache Disorders and Migraine. Migraine is the second of the primary headache disorders after tension-type headache in terms of prevalence, but ranks first in terms of disability. 3,4 Two main subtypes have been characterized, migraine without aura (approximately 70% of attacks) and migraine with aura (approximately 30% of attacks) (Table 1]). 19,20 Migraines with and without aura are believed to have different, though somewhat overlapping, etiologies 21 Studies with twins indicate that genetics plays a greater role in migraine with aura than without. 21 Recently, a genetic risk score that combined multiple genetic risk variants confirmed that these the two main forms of migraine have a different genetic susceptibility background. 22 Episodic migraine and chronic migraine are distinguished by monthly headache days, but this classification may not apply to all situations as there can be natural within-person variability in headache day frequency. 23 A longitudinal survey of U.S. adults with migraine revealed that transitions from episodic migraine to chronic migraine were more common (7.6%) than had been anticipated. 23 In addition, based on follow-up data over a 12 month period, nearly 75% of patients with chronic migraine shifted to episodic migraine. 23 The dynamic nature of migraine, with shifts between episodic migraine and chronic migraine, needs to be further studied as such findings could have implications for how the condition is managed. 23 Episodic migraine is defined as 1-14 headache days per month, while chronic migraine is characterized by 15 or more headache days per month for more than 3 months, with features of migraine headache on at least 8 days per month. 20,24,25 This distinction, derived from observational studies, reflects groups that differ in epidemiology, disability, symptomatic and functional profiles, rates of comorbidities, and response to treatments; and therefore, possibly, in the pathophysiology. 24,26-28 Chronic migraine is associated with a greater degree of headache-associated disability than episodic migraine. 25 A large Internet-based migraine study that assessed 5915 respondents over the course of a year reported that the rate of disability days per month was 3.63 times greater for patients with chronic migraine than for patients with episodic migraine. 25 Secondary headaches are an important category to recognize as they can be serious and life-threatening. 20,29 Medication overuse headache, linked to overuse of attack aborting medication, is an important consideration with patients presenting to the specialist headache clinic. Its prevalence in the general adult population of different countries ranges from 0.5% to 7.6% In patients with chronic daily headache, its prevalence may be as high as 11-70%. 33,34 Suggested risk factors of medication overuse headache include female gender, psychiatric comorbidities, pre-existing pain and various lifestyle-related factors. 33 Secondary headaches also cover various other headaches attributed to factors such as trauma or injury, infections and distinct clinical disorders. 20,29 Risk Factors for Migraine. The etiology of migraine is complex and still poorly understood,

4 20 May 2018 Table 1. International Headache Society (IHS) Criteria for the Two Main Subtypes of Migraine 20 Subtype Description IHS Diagnostic Criteria Migraine without aura Migraine with aura Recurrent headache disorder manifesting in attacks lasting 4-72 hours Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity and association with nausea and/or photophobia and phonophobia Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other central nervous system symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms A. At least 5 attacks 1 fulfilling criteria B D B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following 4 characteristics: 1. unilateral location 2. pulsating quality 3. moderate or severe pain intensity 4. aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. During headache at least one of the following: 1. nausea and/or vomiting 2. photophobia and phonophobia E. Not better accounted for by another ICHD-3 diagnosis. A. At least 2 attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. visual 2. sensory 3. speech and/or language 4. motor 5. brainstem 6. retinal C. At least 2 of the following four characteristics: 1. at least 1 aura symptom spreads gradually over 5 minutes, and/or two or more symptoms occur in succession 2. each individual aura symptom lasts 5-60 minutes 3. at least 1 aura symptom is unilateral 4. the aura is accompanied, or followed within 60 minutes, by headache D. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded particularly as there can be substantial interindividual variation. Genetic factors are thought to be responsible for around 60% of the clinical features, with the remainder being due to nongenetic factors. 35 Environmental factors identified as potentially triggering or worsening an attack include hormonal fluctuations, comorbid diseases, strong sensor stimuli (eg, light, smells, or noises), fatigue, food, changes in the environment or habits (eg, weather, sleeping, or eating patterns). 35 Notable comorbid conditions modulating migraine risk or severity include allergies, respiratory illnesses (sinusitis, asthma, chronic bronchitis), cardiovascular disorders (eg, high cholesterol, angina, stroke, vascular disorders), psychiatric disorders (eg, anxiety, depression, stress), arthritis, obesity, noncephalic pain, and ulcers. 26,36 Comorbidities are more prevalent in patients with chronic migraine than those with episodic migraine. 26 In patients with episodic migraine, comorbidities constitute risk factors

5 Headache 21 for the onset or persistence of chronic migraine, eg, psychiatric disorders, 28 asthma, 37 and noncephalic pain. 38 It has been proposed that higher blood pressure may be inversely correlated with the development of migraine, but these findings need to be further investigated. 39 BURDEN OF DISEASE Impact of Episodic and Chronic Migraine Symptoms and Comorbidities on Patients Daily Living Activities, Productivity and Quality of Life. Migraine has a substantial impact on patients activities of daily living such as work or school, housework, and social or leisure activities. 40,41 A large European study revealed the very high personal impact of migraine, with 17.7% of males and 28.0% of females losing over 10 days of activities during a 3 month period. 41 The mean loss was approximately 1 work day per month for both genders, 1 housework day per month in men and 2 days per month in women, and 1 day per month of social time per month in men and 1.5 days per month in women. 41 U.S. data show that people with migraine missed significantly more time at work or school because of headaches, and that over the previous 3 months these factors led to a reduction in work or school productivity by >50%. 42 Similar findings emerged from a self-reported headache cross-sectional observational study among the employees of a Swiss university hospital. 43 Participants were asked in a self-administered questionnaire about their migraine and tension-type headache, and data from 1192 respondents who completed the survey were analyzed. 43 Although 14% of the overall responders had suffered from migraine and tension-type headache, most (73%) of these headache sufferers had not consulted a physician about it. 43 Furthermore, around one-third of these sufferers had not used any medication. Of the occupational groups included, healthcare staff suffered the most from headaches, and a strong association with age and sex was observed. 43 Individuals with headaches lost 10.2 workday equivalents per year (estimated from absenteeism and days with productivity reduction 50%, typically without including days with productivity reduction <50%). 43 The study is a reminder that as prevalence of migraine peaks during the most productive years of life, it represents an important cause of lost work time. 43 The extent to which migraine affects patients psychologically may not be fully appreciated. One study found a drastic deterioration in psychological status of patients during an acute migraine attack as compared with the interval between migraines, with almost all aspects of psychological status being impaired. 44 An analysis of clinical trials and observational studies catalogued 34 psychosocial variations in patients with migraine (with and without aura). 45 The most frequent of these were reduced vitality and fatigue, emotional problems, pain, difficulties at work, general physical and mental health, social functioning, and global disability. 45 Although productivity studies give some insight into the impact of migraine, they may provide little information on patient perspectives of their disease. 46 For example, it has been shown that, while patients with migraine are strongly affected by the pain associated with the headache phase, their health-related quality of life (HRQoL) is considerably impacted by the difficulties with daily social and family activities that characterize the postheadache phase. 46 Comorbid conditions, especially if untreated or left uncontrolled may affect a patient s QoL. 26,47 Comorbid psychiatric conditions for example, have been shown to increase migraine-related disability, reduce QoL, and also negatively impact treatment outcomes. 47 Despite the high prevalence of headaches in youth, comparatively less is known about the relationship between migraine and QoL than in adults. 48 A survey of young patients (age range: 2-18 years) who attended a children s headache center reported that migraine affects QoL at levels equivalent to or greater than other chronic illnesses of childhood, particularly with respect to school performance and emotional functioning. 48 A separate study found that children with migraine were absent from school activities, did not perform household tasks, and did not participate in leisure activities for 23.9 days, on average, during the last 3 months because of migraine. 49 Notably, children

6 22 May 2018 self-reported a worse emotional QoL but not HRQoL, whereas the parents perceived their general, emotional, and HRQoL to be worse. 49 Few studies have assessed the impact of migraine on the families of patients, their partners and children, and all report detrimental effects on QoL and social/leisure time. 40,43,50 For adolescents, the impact of migraine on social functioning is particularly important in the family and the wider social context. 51 A qualitative interview-based study of adolescents with migraine, their caregivers, and the treating clinicians showed social functioning impairment of the adolescents because of the recurrent pain, and that this also had a negative impact on the family, parents, and siblings. 51 A longitudinal, U.S. internet-based study investigated the impact of migraine on the family from the perspective of patients and their spouses. 52 The survey employed a questionnaire that was specifically designed to provide quantifiable data on the impact of migraine on family. 53 Usable data came from 58,418 (72.3%) of those who responded to the survey. 52 Reduced involvement in family activities was reported 1 or more times per month among 48.2% 57.4% of those suffering from migraine and was related to their headache frequency. 52 A third of the patients expressed their concerns about the long-term financial security for themselves and their family because of their headaches. 52 Viewing migraine from a patient s perspective can give greater insight into the pertinent aspects relating to its impact on HRQoL. 54 A systematic review identified three overlapping, overarching effects of chronic headache on patients lives, namely, as a driver of their behavior, as a specter hanging over their lives, and as a cause of strain on their relationships. 54 It showed that uncertainty regarding when a migraine attack might occur and the frequency of attacks has a strong bearing on their ability to function and interact with others. 54 Chronic migraine imposes a heavier burden than episodic migraine on multiple aspects of a patient s life. 54 Stigma is an under-recognized feature of migraine. It has important consequences for patients in hampering social interactions, decreasing quality of life and disrupting work. 55,56 Due to the emotional burden it adds, stigma also influences a patient s willingness to seek treatment. 56 The largest study of stigma in migraine, conducted in a U.S. clinical setting, used validated questionnaires to demonstrate the disease s stigma severity. 55 Stigma was worse for patients with chronic migraine than episodic migraine, and was related to the degree of job-related disability experienced. Based on learnings from other neurological conditions, such as epilepsy, stigma is known to have important public health consequences and so needs to be further investigated in migraine. 55,56 Economic Burden. Migraine imposes a heavy economic burden in terms of direct and indirect costs. 57 A better understanding of the economic impact can help stakeholders with management approaches to lessen migraine s burden on individuals and society. 58 Direct costs include cost of pharmaceutical treatments, primary care visits, diagnostic tests, blood tests, specialist visits, emergency department visits, and hospitalizations. 42,59 Importantly, cost categories vary greatly across countries, reflecting different healthcare systems and management strategies of migraine In the United States, the total annual direct costs have been estimated at $9.2 billion and have not changed significantly between the years 2004 and Indirect costs, which include aspects such as work loss and reduced productivity, greatly exceed direct costs (medical care). 57,60,64 In Europe, of the annual per-person cost of e1177 for migraine, 93% was attributed to indirect costs. 60 Migraine s economic impact is particularly evident in stressful work environments. For example, productivity losses among employees in a large university hospital in Switzerland, where 3 month migraine prevalence was 20% (women 24%, men 13%), amounted to CHF14 million (e9.5 million), which represented 3.2% of the overall annual hospital personnel expenditure. 43 While absenteeism and disability are significant components of employee productivity, the associated costs represent only a part of the total cost associated with lost productivity. 65 In this regard,

7 Headache 23 Fig. The economic impact (direct medical costs) across 5 European countries for chronic and episodic migraine. 60 the concept of presenteeism (ie, attending work while ill) is important, as it promotes awareness of how a person s effectiveness at work is affected by the condition they suffer from. 65 In a study where productivity losses were estimated for 10 health conditions that commonly affect employees, presenteeism-related costs were most pronounced among sufferers of migraine, representing 89% of the total costs associated with the condition (compared to 61% across all the conditions studied). 66 A U.S. study found that of the total $13 billion economic burden of migraine $5 billion was accounted for by impaired work function and that direct medical costs only amounted to $1 billion. 67 International data consistently show chronic migraine to be more disabling than episodic migraine and this difference is also reflected in terms of the economic impact (Fig.). 28,60 Healthcare costs incurred for patients with chronic migraine are two to four times higher than for patients with episodic migraine in the United States, and five countries in Europe (France, Germany, Italy, Spain, United Kingdom). 28,59,68 A U.S. population-based study found that when lost productivity time was expressed in monetary terms, costs were higher for chronic migraine than for episodic migraine at every age and for both men and women. 58 These observed cost differences appear to reflect both the increased disease severity and the increased rates of comorbidities in chronic migraine compared with episodic migraine. 58 For example, depression increased the likelihood of all-cause emergency department visits, and was associated with higher total and migraine-related health expenses. 69 PATIENT-REPORTED OUTCOMES The accuracy of a migraine diagnosis and informed therapy decisions are reliant on a good understanding of patient reported symptoms and potential outcomes. Clinical and regulatory guidelines encourage the use of Patient Reported Outcome (PRO) tools, as they can capture valuable information that can be used broadly in disease management. 70 These encompass diagnosis and screening, QoL and functional disability assessment, and finally treatment initiation, monitoring, and

8 24 May 2018 optimization. 71 Although generic PROs can be of some use in measuring migraine burden compared with normal populations, disease-specific PRO instruments may be of greater value. 70 An added benefit of PROs is that they may improve communication between patients and their physicians. 72 Measuring the Burden of Disease and Impact of Therapy in Patients with Migraine. Numerous PRO tools have been developed and used in the clinic and clinical trials, but most do not assess physical functioning. This is a highly desirable aspect of a PRO, as physical function may be important to evaluate the immediate benefits of interventions that prevent migraines. 73 Another limitation of current PROs is that they do not discriminate between a person who is working and one who is on medical disability. In theory, a person working full-time and a person on medical leave could obtain the same scores. All PRO tools come with their own individual strengths and limitations with respect to data generation in the clinic and clinical trials. 70,73 Some of these aspects are highlighted in the patient case studies covered in the Patient Cases section. The Migraine Disability Assessment questionnaire (MIDAS) covers three activity domains for disability assessment: work/school work, housework, family/social/leisure activities. 74 MIDAS has been reported as being reliable, accurate, and easy to use, all of which would favor its use in clinical practice. 74 It also appears to show sensitivity to change, making it useful to monitor therapy outcomes. 72 However, it does not assess the full spectrum of headache, covering only about 35% of the range between moderate and severe intensity. 72 Furthermore, some physicians believe MIDAS to be too heavily weighted toward the measurement of headache frequency rather than disability. 72 Some practical limitations are explored in the Patient Cases section. The Headache Impact Test (HIT-6) assesses lost time (work, school work, housework, social activities), pain severity, fatigue, and mood. 75,76 In comparison to MIDAS, HIT-6 is accurate at all severity levels and offers a wider range of questions. 72 Additionally, as it features only six questions, this makes the patient s task for completion easier. 72 The 1 month recall of the HIT-6 may offer a more accurate evaluation of impact than the 3 month recall used in MIDAS. 77 HIT-6 is not specific to migraine, but appears to discriminate well between chronic migraine, episodic migraine, and nonmigraine patients. 73,77 Practical experience with HIT-6 is explored in the Patient Cases section. The Migraine-Specific QoL Questionnaire (MSQ) provides an assessment of the degree to which activities are prevented or restricted by migraine, and emotional functioning. 75,76 MSQ assesses a broad impact on QoL and features a 4 week memory recall period, similar to HIT-6, 72 although it may be too complex for use in every day clinical practice. 65 A weakness of these three PRO tools is that they did not benefit from patient input during their conceptualization. 73 Also, none were designed to capture the impact of migraine on physical functioning and the day-to-day variability of the experience, as reported by patients. 73 Therefore, a new tool called the Migraine Physical Function Impact Diary (MPFID) was developed to better assess daily impacts of migraine on physical function over the previous 24 hours. 70,78 MPFID was designed to be compliant with the Food and Drug Administration s (FDA) guidelines for PROs to support label claims (the development of MIDAS, HIT-6, and MSQ preceded this guideline s release). 70,79 MPFID has 13 questions that focus on the daily impact of migraine on everyday activities and on physical impairment (ie, time with difficulty moving head, body, getting out of bed, bending over, or other physical efforts). 70 The FDA has shown a strong preference for short recall periods as a guard against recall bias, and so the 24 hour periodicity in MPFID could be advantageous compared with other PROs. 70,80 MPFID appears able to discriminate among groups of subjects known to be clinically different based on headache variables and other PRO scores, but its ability to offer a complete picture of migraine is unclear. 78 Views on its usefulness are likely to depend on the publication of data from ongoing trials. 78

9 Headache 25 Overview of Current PRO Approaches from Migraine Prevention Clinical Trials. Clinical trials are currently being conducted for monoclonal antibodies against calcitonin gene-related peptide (CGRP) and the CGRP receptor. 81 Based on a variety of PROs, QoL data are beginning to emerge for these promising new therapies in both episodic and chronic migraine. 82 The HIT-6 score has been most widely used, with MSQ, MIDAS, and MPFID being employed to a lesser degree In one trial, improvements were also shown for another PRO measure, the Short-Form Health Survey (SF-36) questionnaire, for the QoL domains considered to be most impacted by migraine. 50 Impact on work productivity and activity impairment has also been assessed based on the Work Productivity and Activity Impairment (WPAI) questionnaire. 88 The WPAI includes questions regarding the impact of health on the extent of work loss and productivity impairment during work and other activities, with higher scores indicating greater impairment. 88 One study also used the Migraine Functional Impact Questionnaire, a new 31 item PRO to assess the impact of migraine on functional outcomes over the previous 7 days. 89,90 The Future of PRO Collection. As the adoption of mobile technologies has grown among patients (ie, smartphones, electronic tablets, connected watches, and wearables), this has enabled the opportunity to collect PRO data remotely through the development of epro tools. 91,92 Some of these are proving to be useful in clinical trials. 91 One such system, ASyMS, has been tested in oncology trials for self-assessment of pain PROs by patients. 93,94 No statistically significant differences were found between collecting PRO data traditionally via paper/pencil or using an alternative approach via electronic tablet. In addition, patients were content to use a tablet in the clinic to complete their PROs. 93,94 Beyond clinical trials, if appropriate and practical, such epros could help patients in routine management of their disease, and possibly facilitate the development of personalized care. 93,94 For patients with migraine, avoiding attacks would be the ultimate target. Examples of such approaches are arising in other disease areas. In asthma, a study was conducted which assessed self-reported physical activity and sleep quality via a patient smart wearable (wrist-worn device). 95 In the field of migraine, one might leverage existing digital resources such as migraine-tracking apps or online programs (eg, Migraine Buddy, iheadache, Migraine Coach, imigraine, Migraine idiary, Curelator Headache) and adapting these digital resources to include PRO measurements. 96,97 In adolescents with migraine, Kroon van Dienst and colleagues assessed the adherence to preventive medication intake and to lifestyle recommendations (regular exercise, eating, and fluid intake) using daily self-reports on personal electronic devices and the imigraine program. 98 Adherence was improved for all factors, although to varying degrees. The study also identified additional behavior to monitor, such as sleeping patterns. 98 Although a range of options are being investigated, the success of such e-strategies requires the appropriate PRO tool to be selected and its practicality to be assessed. For the prevention of migraine, relevant measures would be physical functioning, frequency of migraine days, and frequency of medication use. Another requirement of the epro tools would be to further facilitate patient physician interactions, meaning that the tool needs to be user friendly for the patient but also allow the physician easy access to the data or patient feedback, without adding layers of complexity. 99 Ideally, the epro tool would generate data that the physician and the healthcare community could use to improve understanding of the disease and optimize migraine prevention strategies. 99 PATIENT CASES Case Study 1. Background. A 22-year-old female student of business administration was unable to continue her education due to increasingly frequent and severe migraine attacks. Her migraine attacks started in her late teens and were characterized by moderate headaches, photo- and phonophobia. Many of the attacks initiated with a typical scintillation scotome. However, the vomiting she experienced was more disabling than the headaches and associated migraine symptoms. Once it

10 26 May 2018 started, the vomiting could not be controlled, despite use of various antiemetic drugs. As a result, she experienced exhaustion from vomiting that lasted up to 3 days just until the next attack would start. Due to this situation, continuation of her education was no longer possible. Treatment Experience. Several standard attack treatments were applied but these had only minimal success. Only zolmitriptan nasal spray was efficacious, ie, able to halt the attack and especially the severe vomiting. Nevertheless, the frequency of the attacks remained high and her education continued to be disrupted. After several prophylactic regimens were tried without success, pericranial treatment with botulinum toxin 100 IU* was administered, and as a result the attacks began to diminish gradually to a point where the patient was motivated to look for a part-time job (approximately 20-30% on an irregular basis). From a practical standpoint, finding a job on this basis is nearly impossible. Only due to the physician s personal efforts was the patient able to start on an administrative job with a monthly goal. Gradually this young woman managed to maintain a constant job commitment up to 40%, was able to get married, and has since had two children. Botox is now applied on an irregular schedule in a reduced dosage and zolmitriptan nasal spray is still a standard treatment. Burden of Disease and Impact on the Patient. Migraine, especially with the very severe vomiting, disrupted the higher administrative education of this patient, necessitated high medication use and physician costs during the youthful period of this patient s life. Finding an individually-adjusted treatment was essential to bring this patient literally back in to her life. Obtaining an individual job with irregular *In Switzerland, patients must pay for Botox treatment; 100 IU Botox was more affordable for the patient. Furthermore, the patient was of slim build and so this lower dose was appropriate. It is a common approach to start with a lower dose of Botox and then, if needed, to titrate up. In this case 100 IU was sufficient for the patient. work hours that still provides a long-term goal is also essential but extremely difficult since most companies and public offices prefer full time occupation. A work environment (eg, in big companies) that enables the patient still to pursue education could help many migraine sufferers lead fulfilling, productive, and satisfying lives. PRO data for the patient. MIDAS during maximum suffering of chronic migraine: 72 days (last 3 months) MIDAS during years of stabilization: 3 days 711 (last 3 months) HIT-6 during maximum chronic migraine: 70 points (mainly in the last 4 weeks) HIT-6 during years of stable life: 36 points Commentary on the PRO Information for the Patient. In this case, subjective assessment was done through the patient; the maximum personal suffering in terms of the highest suffering from migraine was set to 100%. Recently, this patient suffered 15% of the original 100% during occasional application of zolmitriptan nasal spray 5 mg and botulinum toxin 100 IU several times per year, as needed. This is reflected by the MIDAS PRO tool (72 days to 3 days) but not in the HIT-6 questionnaire. With respect to HIT-6, the patient s severest suffering was not the pain, but the excessive vomiting leading to disability for 2 to 3 days. This aspect is not assessed with HIT-6. There are certain limitations of MIDAS that are evident from this patient case study: The maximum of 21 points is reached very easily and does not allow for a realistic comparison. MIDAS is useful in the lower frequency range of disability, ie, in episodic migraine The 3-months recall is subjective and only moderately reliable If a patient is capable of doing any household chores then MIDAS will calculate this as 90 days (per three months). If a patient has no social life then a 0 will be reported, although the patient would not be able to be involved in social activities for 90 days Case Study 2. Background. A community police officer born in 1970 started to suffer from

11 Headache 27 severe migraine attacks, characterized by very intense bifrontal and bitemporal disabling headaches and accompanied by rather mild photo and phono phobia, but no nausea or auras. At age 40, migraine attacks increased quickly to a near daily frequency of severe headaches. One day he received a tablet of eletriptan from his mother who also suffers from migraine. Eletriptan immediately relieved the pain but needed to be taken daily. Due to his condition the patient was no longer able to fulfill the typical routine of police duties, which included demanding night shifts with a variety of responsibilities. From a work teamperspective this affected his reliability and so he was forced to quit front-line duties and instead conduct administrative work. Treatment Experience. After trials with several prophylactic medical and complementary treatments, that were not efficacious and/or not tolerable, an in-patient pain rehabilitation approach was applied for several weeks. The patient s migraine became somewhat milder and could be tolerated better. Also, eletriptan intake was reduced to once per week. However, his job as a police officer was still at risk. After informative talks with the chief of the local police office, the patient was kept on the job featuring a 40% employment base for administrative work and parking fines. Gradually the job involvement has increased to a 60% level now for several years (and 40% disability has been administered). Burden of Disease and Impact on the Patient. Familial pattern of migraines led to medication-overuse headache with a very high and costly eletriptan intake, led to in-house treatment and a reduced working capacity over a period of years. The search for further disease modifications continues and there is hope for a more effective migraine treatment with erenumab or other anti- CGRP-antibody therapies. PRO Data for the Patient. MIDAS during maximum chronic migraine: 90 days (last 3 months) MIDAS during years of stabilization: 119 days (last 3 months) HIT-6 during maximum chronic migraine: 64 points (in the last 4 weeks) HIT-6 during years of stable life: 70 points (in the last 4 weeks) Commentary on the PRO information for the patient. In this case, subjective assessment was done through the patient; the maximum personal suffering in terms of the highest suffering from migraine was set to 100%. Recently, this patient still suffered 50% 60% of the original 100% subjective suffering during regular application of eletriptan and flexibly and markedly reduced working hours. The MIDAS score has been maxed out (>21, ie, 90 vs 119) days. HIT-6 increased despite a subjective improvement by approximately 50%. CONCLUSIONS Migraine is a highly disabling, costly, underdiagnosed, undertreated disorder which has been shown to have a similarly high prevalence in all countries studied. In most countries, studies show it to be ranked among the 10 diseases with the highest burden of disease. Despite these facts, public and political awareness of migraine lag behind that of many other conditions (which exhibit a lower disease burden). At present, we still lack a biologic marker to estimate the grade of disability of patients with migraine before and during treatment. PRO tools are the only tools being used to measure burden and success of patient management approaches. There remains a need for higherquality data and the development of better PROs in order to improve the outlook for patients. STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Reto Agosti (b) Acquisition of Data Reto Agosti (c) Analysis and Interpretation of Data Reto Agosti Category 2 (a) Drafting the Manuscript Reto Agosti

12 28 May 2018 (b) Revising It for Intellectual Content Reto Agosti Category 3 (a) Final Approval of the Completed Manuscript Reto Agosti Acknowledgments: The author thanks Faiz Kermani (Health Interactions) for medical editorial assistance with this manuscript. REFERENCES 1. Steiner TJ. Lifting the burden: The global campaign to reduce the burden of headache worldwide. J Headache Pain. 2005;6: Lifting the Burden. Lifting the Burden (in Official Relations with the World Health Organization). The Global Campaign against Headache. Available at: Accessed February 12, Steiner TJ, Stovner LJ, Vos T. GBD 2015: Migraine is the third cause of disability in under 50s. J Headache Pain. 2016;17: GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, : a systematic analysis for the Global Burden of Disease Study Lancet. 2017;390: GBD Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during : a systematic analysis for the Global Burden of Disease Study Lancet Neurol. 2015;16: Weatherall MW. The diagnosis and treatment of chronic migraine. Ther Adv Chronic Dis. 2015;6: World Health Organization WorldHealthOrganization Available at: qa/25/en/ 8. Woldeamanuel YW, Cowan RP. Migraine affects 1 in 10 people worldwide featuring recent rise: A systematic review and meta-analysis of community-based studies involving 6 million participants. J Neurol Sci. 2017;372: Lipton RB, Bigal ME, Diamond M. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68: Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: Updated statistics from government health surveillance studies. Headache. 2015;55: Bigal ME, Lipton RB. Migraine at all ages. Curr Pain Headache Rep. 2006;10: Merikangas KR, Cui L, Richardson AK, et al. Magnitude, impact, and stability of primary headache subtypes: 30 year prospective Swiss cohort study. BMJ. 2011;343:d Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol. 2017;16: Peterlin BL, Gupta S, Ward TN, MacGregor A. Sex matters: evaluating sex and gender in migraine and headache research. Headache. 2011; 51: Rossi P, Nappi G. Migraine in men: fact sheet. A publication to mark European Migraine Day of Action Funct Neurol. 2014;29: Lampl C, Thomas H, Stovner LJ, et al. Interictal burden attributable to episodic headache: Findings from the Eurolight project. J Headache Pain. 2016; 17: Peres MF, Mercante JP, Guendler VZ, et al. Cephalalgiaphobia: A possible specific phobia of illness. J Headache Pain. 2007;8: Giannini G, Zanigni S, Grimaldi D, et al. Cephalalgiaphobia as a feature of high-frequency migraine: A pilot study. J Headache Pain. 2013;14: MacGregor EA. Diagnosing migraine. J Fam Plann Reprod Health Care. 2016;42: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33: Hansen RD, Christensen AF, Olesen J. Family studies to find rare high risk variants in migraine. J Headache Pain. 2017;18: Pisanu C, Preisig M, Castelao E, et al. A genetic risk score is differentially associated with migraine with and without aura. Hum Genet. 2017;136: Serrano D, Lipton RB, Scher AI, et al. Fluctuations in episodic and chronic migraine status over the course of 1 year: implications for diagnosis, treatment and clinical trial design. J Headache Pain. 2017;18:101.

13 Headache Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep. 2012;16: Adams AM, Serrano D, Buse DC, et al. The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia. 2015;35: Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry. 2010;81: Katsarava Z, Manack A, Yoon MS, et al. Chronic migraine: Classification and comparisons. Cephalalgia. 2011;31: Blumenfeld AM, Varon SF, Wilcox TK, et al. Disability, HRQoL and resource use among chronic and episodic migraineurs: Results from the International Burden of Migraine Study (IBMS). Cephalalgia. 2011;31: Ahmed F. Headache disorders: differentiating and managing the common subtypes. Br J Pain. 2012;6: Westergaard ML, Hansen EH, Glumer C, Olesen J, Jensen RH. Definitions of medication-overuse headache in population-based studies and their implications on prevalence estimates: A systematic review. Cephalalgia. 2014;34: Alstadhaug KB, Ofte HK, Kristoffersen ES. Preventing and treating medication overuse headache. Pain Rep. 2017;2:e Cha MJ, Moon HS, Sohn JH, et al. Chronic daily headache and medication overuse headache in first-visit headache patients in Korea: A multicenter clinic-based study. J Clin Neurol. 2016;12: Diener HC, Holle D, Solbach K, Gaul C. Medication-overuse headache: risk factors, pathophysiology and management. Nat Rev Neurol. 2016;12: Schmid CW, Maurer K, Schmid DM, et al. Prevalence of medication overuse headache in an interdisciplinary pain clinic. J Headache Pain. 2013;14: Ferrari MD, Klever RR, Terwindt GM, Ayata C, van den Maagdenberg AM. Migraine pathophysiology: Lessons from mouse models and human genetics. Lancet Neurol. 2015;14: Wang SJ, Chen PK, Fuh JL. Comorbidities of migraine. Front Neurol. 2010;1: Martin VT, Fanning KM, Serrano D, Buse DC, Reed ML, Lipton RB. Asthma is a risk factor for new onset chronic migraine: Results from the American migraine prevalence and prevention study. Headache. 2016;56: Scher AI, Buse DC, Fanning KM, et al. Comorbid pain and migraine chronicity: The Chronic Migraine Epidemiology and Outcomes Study. Neurology. 2017;89: Fagernaes CF, Heuch I, Zwart JA, Winsvold BS, Linde M, Hagen K. Blood pressure as a risk factor for headache and migraine: A prospective population-based study. Eur J Neurol. 2015;22:156-62, e MacGregor EA, Brandes J, Eikermann A, Giammarco R. Impact of migraine on patients and their families: The Migraine and Zolmitriptan Evaluation (MAZE) survey Phase III. Curr Med Res Opin. 2004;20: Steiner TJ, Stovner LJ, Katsarava Z, et al. The impact of headache in Europe: Principal results of the Eurolight project. J Headache Pain. 2014;15: Munakata J, Hazard E, Serrano D, et al. Economic burden of transformed migraine: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2009;49: Sokolovic E, Riederer F, Szucs T, Agosti R, Sandor PS. Self-reported headache among the employees of a Swiss university hospital: Prevalence, disability, current treatment, and economic impact. J Headache Pain. 2013;14: G obel H, Krapat S. Psychological status during migraine attack and interval before and after treatment with a selective 5-HT1-agonist. Headache. 1993;33: Raggi A, Giovannetti AM, Quintas R, et al. A systematic review of the psychosocial difficulties relevant to patients with migraine. J Headache Pain. 2012;13: Gonzalez JM, Johnson FR, Runken MC, Poulos CM. Evaluating migraineurs preferences for migraine treatment outcomes using a choice experiment. Headache. 2013;53: Minen MT, Begasse De Dhaem O, Kroon Van Diest A, et al. Migraine and its psychiatric