PERSON ALIZED Britt W.H. van der Arend towards the role of sex hormones telemedicine and cardiovascular safety MIGRAINE CARE
Towards personalized migraine care: the role of sex hormones, telemedicine, and cardiovascular safety Britt Willemijn Heleen van der Arend
Towards personalized migraine care: the role of sex hormones, telemedicine, and cardiovascular safety PhD thesis, Leiden University, Leiden, The Netherlands, 2025 © Britt Willemijn Heleen van der Arend, 2025 ISBN: 978-94-6473-783-7 Cover design: Patrick Kooijman – Studio Paardenkracht – studiopaardenkracht.nl Layout: Douwe Oppewal Printing: Ipskamp Printing The research presented in this thesis was supported by grants of the Dutch Research Council (849200007) and the Dutch Brain Foundation (HA2017.01.05). The funding agencies had no role in the design or conduct of the studies. Funding for publication of this thesis has been provided by the Nederlandse Hoofdpijn Vereniging (NHV) and Teva Nederland.
Towards personalized migraine care: the role of sex hormones, telemedicine, and cardiovascular safety Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Leiden, op gezag van rector magnificus prof.dr.ir. H. Bijl, volgens besluit van het college voor promoties te verdedigen op dinsdag 14 oktober 2025 klokke 16:00 uur door Britt Willemijn Heleen van der Arend Geboren te Tubbergen in 1994
Promotiecommissie Promotores Prof. dr. G.M. Terwindt Prof. dr. A. Maassen van den Brink Prof. dr. A.M.J.M. van den Maagdenberg Promotiecommissie Prof. dr. S.C. Cannegieter Prof. dr. E.A. MacGregor, Queen Mary, University of London Prof. dr. A.H.J. Danser, Erasmus Medical Center Rotterdam Prof. dr. J.J.G.M. Verschuuren
6 CONTENTS Chapter 1 General introduction and outline of the thesis 9 Part I The use of telemedicine in the monitoring and treatment of migraine Chapter 2 Practical experience with the use of electronic headache diaries 37 and video consultations in migraine care Telemedicine and e-Health 2024;30:2696-2703. Chapter 3 Defining migraine days, based on longitudinal E-diary data 59 Cephalalgia 2023;43:3331024231166625. Chapter 4 Effect of COVID vaccination on monthly migraine days: 79 a longitudinal cohort study Cephalalgia 2023;43:3331024231198792. Part II Clinical aspects and treatment of menstrual migraine Chapter 5 Migraine with and without aura in relation to the menstrual cycle 101 and other hormonal milestones: A prospective cohort study Cephalalgia 2023;43:3331024231164322. Chapter 6 Continuous combined oral contraceptive use versus vitamin E in 123 the treatment of menstrual migraine: rationale and protocol of a randomized controlled trial (WHAT!) Trials 2024;25:123. Chapter 7 Migraine attack incidence in relation to ovulation: 143 a prospective cohort study Submitted. Chapter 8 Estradiol and other sex-hormones dynamics in menstrual migraine: 165 pathway analysis of hormonal fluctuations in a case-control study Submitted.
7 Part III Safety of treament with anti-CGRP (receptor) antibodies Chapter 9 Safety considerations in the treatment with anti-CGRP (receptor) 191 antibodies in patients with migraine Frontiers in Neurology 2024;15:1387044. Chapter 10 Impact of CGRP monoclonal antibody treatment on blood pressure 215 in patients with migraine: a systematic review and potential clinical implications Cephalalgia. 2025;45:3331024241297673. Chapter 11 General discussion and future perspectives 245 Addendum Summary 272 Nederlandse samenvatting 276 List of publications 280 Curriculum vitae 283 Dankwoord 284
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9 General introduction B.W.H. van der Arend Adapted from: van der Arend BWH, van Casteren DS, Maassen van den Brink A, Terwindt GM. Migraine. Sekse- en Gendersensitieve Geneeskunde. Prelum 2023:176-194. van der Arend BWH, Verhagen IE, van Casteren DS, Maassen van den Brink A, Terwindt GM. Medicamenteuze behandeling van (menstruele) migraine bij vrouwen. PiL 2022;1:6-15. van der Arend BWH, van Casteren DS, de Vries Lentsch S, Terwindt GM. Migrainemanagement: preventieve behandelmogelijkheden en het gebruik van ‘telemedicine’. TNN 2024;3:104-111. van der Arend BWH, van Casteren DS, Verhagen IE, Maassen van den Brink A, Terwindt GM. Migraine en vrouwspecifieke factoren. Nervus 2024;2:4-12.
10 Chapter 1 CHARACTERISTICS AND DIAGNOSIS OF MIGRAINE Migraine is a multifactorial episodic brain disorder characterised by recurring headache attacks. Diagnosis is based solely on clinical characteristics. Typically, the headache presents with a throbbing quality, moderate to severe pain intensity, unilateral localization, and worsening with routine physical activity, lasting up to 72 hours.1 In addition to the headache, attacks are accompanied by photophobia and phonophobia or nausea or vomiting. These diagnostic criteria are outlined in the International Classification of Headache Disorders, third edition (ICHD-3), and summarized in Table 1.1 About one third of patients experience an aura prior to or during the headache phase (migraine with aura). The aura may include visual, sensory, speech/language and (rarely) motor symptoms. It nearly always begins with visual symptoms, in which patients see scotomas, glitter, lightning, spots or other figures. These symptoms gradually expand in minutes, and two or more aura symptoms may also occur consecutively. Each individual aura symptom lasts from 5 to 60 minutes. At least one aura symptom is often present unilaterally. The phase between aura symptoms and headache usually lasts up to 60 minutes, but an aura can also occur without a headache (migraine with aura without headache). Thus, migraine is a heterogeneous disorder with multiple subtypes. In the ICHD-3, a distinction is also made between episodic and chronic migraine. Chronic migraine is defined as headache on ≥15 days per month for ≥3 months. Among them, headaches on ≥8 days per month must fulfill the criteria for a migraine day.1 Migraine is better understood as a cyclical brain disorder that involves at least four distinct phases: interictal, preictal, ictal, and postictal.2 In the preictal phase, a large proportion of patients with migraine experience prodromal symptoms before the headache or aura occurs, such as fatigue, yawning, cravings for certain foods or a stiff feeling in the neck. These can occur as early as 48 hours before the headache or aura phase occurs and are most likely the result of hypothalamic activation.3 Since many women report fatigue and cravings for certain foods, such as chocolate, during this prodromal phase, it often resembles the premenstrual phase in terms of symptomatology.4 The ictal phase is the most well defined and follows the definition of a migraine attack, lasting from 30 minutes up to several days. The postictal or the postdromal phase is the period after the headache, characterized by symptoms
11 General introduction 1 Table 1. Diagnostic criteria for several migraine subtypes according to the ICHD-3. Pure menstrual migraine and menstrually-related migraine are now still part of the ICHD-3 appendix as they had not been sufficiently validated. Migraine without aura (MO) A. At least five attacks fulfilling criteria B-D B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics: 1. unilateral location 3. moderate or severe pain intensity 2. pulsating quality 4. aggravation by or causing avoidance of routine physical activity 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. Migraine with aura (MA) A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. visual 4. motor 2. speech and/or language 5. brainstem 3. sensory 6. retinal C. At least three of the following six characteristics: 1. at least one aura symptom spreads gradually over ≥5 minutes 2. two or more aura symptoms occur in succession 3. each individual aura symptom lasts 5-60 minutes 4. at least one aura symptom is unilateral 5. at least one aura symptom is positive 6. the aura is accompanied, or followed within 60 minutes, by headache D. Not better accounted for by another ICHD-3 diagnosis. Chronic migraine (CM) A. Headache (migraine-like or tension-type-like) on ≥15 days/month for >3 months, and fulfilling criteria B and C B. Occurring in a patient who has had at least five attacks fulfilling criteria B-D for Migraine without aura and/or criteria B and C for Migraine with aura C. On ≥8 days/month for >3 months, fulfilling any of the following: 1. criteria C and D for Migraine without aura 2. criteria B and C for Migraine with aura 3. believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative D. Not better accounted for by another ICHD-3 diagnosis. Pure menstrual migraine (ICHD-3 appendix) A. Attacks, in a menstruating woman, fulfilling criteria for Migraine without aura or Migraine with aura and criterion B B. Occurring exclusively on day 1 ± 2 (i.e., days −2 to +3) of menstruation in at least two out of three menstrual cycles and at no other times of the cycle. Menstrually-related migraine (ICHD-3 appendix) A. Attacks, in a menstruating woman, fulfilling criteria for Migraine without aura or Migraine with aura and criterion B B. Occurring on day 1 ± 2 (i.e., days −2 to +3) of menstruation in at least two out of three menstrual cycles, and additionally at other times of the cycle.
12 Chapter 1 such as cognitive deficits and fatigue.2, 5 The extent of inter-personal and inter-attack variations in the preictal/postictal phases remains unknown. Therefore, a single, clear-cut definition (48 hours) may not apply to all patients or attacks. MONITORING WITH ELECTRONIC E-DIARIES Electronic headache diaries (E-diaries), which are based on AI algorithms that analyse headache characteristics rather than relying on patient-reported migraine days (as seen in commercial apps), are highly useful in the monitoring and treatment of migraine.6 For effective implementation in clinical practice, an e-tool must meet several key requirements.6 The e-tool must be validated to ensure accuracy and reliability in measuring, diagnosing, or monitoring the intended condition or health issue. Consistency in performance is important, providing the same results across repeated measurements. Clinical relevance is essential, ensured by providing information that aids in decision-making and treatment. Privacy and security standards must be upheld to protect patient data. E-tools should be user-friendly to promote acceptance among both healthcare providers and patients. Seamless integration with existing clinical systems and electronic medical records is necessary, alongside compliance with regulatory guidelines and obtaining the required approvals. Finally, adequate support, including training and technical assistance, should be available for healthcare providers. Using unvalidated E-tools demonstrates a lack of understanding and recognition of the complexity of migraine as a condition. The combination of validated questionnaires and an E-diary has high sensitivity and specificity for diagnosing migraine.7 However, clinical assessment remains essential for diagnosing aura.7 E-diaries are useful for monitoring sex-specific aspects of migraine8-10 and for tracking the effectiveness of new therapeutic options for migraine, such as anti-CGRP(-R)-mAbs.11, 12 With an estimated average cost of CGRP monoclonal antibodies of €6,000 per patient per year, these treatments are expensive and require careful monitoring.13 In fact, the Dutch Healthcare Institute (Zorginstituut Nederland, ZIN) has specifically recommended that patients receiving treatment with anti-CGRP(-R) monoclonal antibodies be closely monitored.13 Without adequate monitoring of the number of migraine days, it is impossible to assess whether the criteria for continuing CGRP-mAbs treatment (≥30% reduction in migraine days) are met, which could result in unexpectedly high unwanted costs. By using an E-diary, both patients and healthcare providers can obtain reliable insights into the effectiveness of this treatment. This helps to avoid continuing ineffective medication and contributes to cost savings. Additionally,
13 General introduction 1 the E-diary supports shared decision-making by providing patients with real-time insights into their headache patterns. However, implementation in clinical practice is sometimes hindered by various barriers faced by physicians, such as unfamiliarity, costs, and technical issues. Despite these challenges, integrating an E-diary into any electronic health record system is relatively straightforward. Moreover, if specific requirements are met, there are reimbursement options for remote care using these validated tools. DIAGNOSIS OF MENSTRUAL MIGRAINE USING AN E-DIARY The risk of having a migraine attack is highest in women during the period from two days before the first day of menstruation to the first three days of menstruation (days -2 to +3 of the menstrual cycle).10 A migraine attack occurring during this period is referred to as a perimenstrual migraine attack (Figure 1). According to the ICHD-3 criteria, if a perimenstrual migraine attack occurs in two out of three consecutive menstrual cycles, the patient is considered to have menstrual migraine.1, 9 Sometimes, a distinction is made for those with pure menstrual migraine, where the attacks occur exclusively during menstruation. However, when adequately monitored with an E-diary, the occurrence of pure menstrual migraine seems rare (< 1%).9 Figure 1. Example of a headache diary with a perimenstrual attack. The perimenstrual period is indicated in the red-bordered box (day -2 to +3 of the menstrual cycle).
14 Chapter 1 Accurate diagnosis necessitates the use of (electronic) headache diaries. Patients with migraine often struggle to retrospectively estimate the number of migraine days per month accurately. When there are fewer than eight migraine days per month, the frequency is often underestimated, while with more than eight monthly migraine days, there is an overestimation.6 This distinction is particularly important for distinguishing episodic from chronic migraine.6 For the diagnosis of menstrual migraine, keeping a headache diary that also tracks the menstrual cycle is essential. When asked, around 80% of women believe they have menstrual migraine.9 However, when these women maintain a headache diary for at least three months, only two-thirds are confirmed to have menstrual migraine. Conversely, among women who think they do not have menstrual migraine, about two-thirds also meet the criteria for menstrual migraine when keeping a headache diary.9 This underscores the unreliability of self-diagnosing menstrual migraine and demonstrates the utility of an (electronic) diary for accurate diagnosis. PREVALENCE AND BURDEN OF MIGRAINE In the Netherlands, the prevalence of migraine is around 10%, but this varies depending on age and sex.14 Migraine is three times more common in women than in men. Approximately 1 in 3 women will experience migraine at some point in their lives. Among children, the prevalence is equal between boys and girls, but around menarche, the prevalence among women increases. The peak age for migraine is between 30 and 40 years, and after the age of 50, the prevalence gradually decreases, although women remain more frequently affected than men (Figure 2). Notably, before menopause, about two-thirds of women with migraine experience menstrual migraine. Migraine ranks among the top 10 most disabling diseases, as identified by the World Health Organization (WHO).15 For young women, it even occupies the second position. These are often the years when building a career, starting a family, and/or engaging in other social activities play a major role. The burden that patients experience in daily life occurs both during an attack (ictal) and between attacks (interictal). The ictal burden is related to the experience of migraine headaches and accompanying symptoms. During a migraine attack, a patient’s ability to function in daily life is limited. The interictal burden of migraine is particularly evident in planning activities due to the potential onset of a migraine attack and the fear of having another attack (anticipatory anxiety). Compared to men, women more frequently report reduced
15 General introduction 1 Figure 2. Prevalence of migraine by sex and age categories. The dashed line was derived from the Global Burden of Disease study, whereas the solid line was derived from a Dutch population based study.14, 15 productivity at work or in the household and are more likely to miss social activities. Migraine has a negative impact on health-related quality of life.16 Pregnancy and perimenopause The majority of women with migraine without aura report a decrease in migraine frequency during pregnancy and breastfeeding (Figure 3). During the first trimester of pregnancy, 47% report an improvement in migraine frequency, followed by 83% and 87% during the second and third trimester, respectively. Some women even become completely attack free during pregnancy. A small proportion of women, however, experience a worsening of migraine frequency (8%) or develop new-onset migraine (3-6%) during pregnancy, but these are mostly migraine with aura attacks.17 A woman can be assigned as postmenopausal 12 months after her last menstruation. The period before menopause is called the perimenopause. This perimenopausal phase is an important risk factor for worsening of pre-existing migraine, particularly in women with menstrual migraine (Figure 3).18 Migraine with aura appears to be less influenced by the perimenopause and menopause. From the onset of natural menopause, migraine improves in about two-thirds of women with migraine without aura. The frequency of attacks decreases and the severity of attacks lessens.19
16 Chapter 1 CHARACTERISTICS OF PERIMENSTRUAL MIGRAINE ATTACKS The duration of perimenstrual migraine attacks is ≈20% longer compared to non-perimenstrual attacks.10 Additionally, perimenstrual migraine attacks have higher pain intensity and are associated with reduced pain coping mechanisms. Moreover, there is a higher frequency of recurrences (return or worsening of headache within Figure 3. Attack incidence (migraine with aura versus migraine without aura) during the menstrual cycle, pregnancy and perimenopause.
17 General introduction 1 24 hours after taking attack medication despite an initial response). 10, 20 As a result, repetitive use of acute medication is necessary during a single attack, increasing the risk of medication overuse in women with menstrual migraine. Interestingly, while acute migraine treatments are not less effective for perimenstrual attacks, as indicated by a similar 2-hour response rate after triptan use, recurrence rates are higher.20 Additionally, differences in attack duration also exist between migraine attacks in women and those in men, with perimenstrual attacks lasting the longest.8 Although smaller, there are also differences in duration between non-perimenstrual migraine attacks in women and attacks in men, despite women being more likely to use long-acting triptans.8 Clinicians should be aware of the longer attack duration in women, particularly the increased risk of recurrence during the perimenstrual window. Women also more often experience accompanying symptoms during a migraine attack compared to men, increasing the severity of an attack.8 Further research is needed to determine the extent to which the differences between men and women are attributable to biological factors.21 PATHOPHYSIOLOGY OF MIGRAINE The headache that occurs during a migraine attack is caused by the activation of the trigeminovascular system. This system consists of nociceptive trigeminal afferents and the cranial blood vessels that they surround. The exact mechanism of how this system is activated remains largely unknown, but changes in the brainstem and hypothalamus likely play an important role.22 The trigeminovascular system can be activated by CSD, considered the electrophysiological substrate for migraine aura. Upon activation of the trigeminovascular system, the trigeminal afferents, trigeminal ganglion, and trigeminal nucleus caudalis (TNC) in the brainstem are stimulated (Figure 4). Calcitonin gene-related peptide (CGRP) is a key neurotransmitter in this signal transmission. Sensory information is then transmitted from the TNC to the thalamus, where all sensory information converges. The processing of this information is influenced by pain-modulating systems that can either facilitate or inhibit nociception. CGRP is a potent vasodilator and a modulator of cerebrovascular nociception. Moreover, an infusion of CGRP in patients with migraine may trigger migrainous headache.23 For these reasons, CGRP is believed to play a crucial role in the pathophysiology of migraine.
18 Chapter 1 Influence of sex hormones Despite the well-recognized epidemiological relationship between sex hormones and migraine in women, the specific mechanisms by which hormonal factors influence migraine susceptibility are still insufficiently understood. It is hypothesized that the sudden drop in estradiol prior to menses lowers the threshold for an upcoming migraine attack,24-26 but there is still poor understanding of the exact underlying pathophysiological mechanism of menstrual migraine. Fluctuations in estradiol are Figure 4. Influence of CGRP and the different oestrogen receptors: oestrogen receptor-alpha (ERα), oestrogen receptor-beta (ERβ), and the G-protein-coupled oestrogen receptor (GPER). PAG = periaqueductal grey; LC = locus coeruleus; TNC = trigeminal nucleus caudalis; TG = trigeminal ganglion.
19 General introduction 1 also observed during the perimenopausal period, which may explain the increased incidence of attacks during this time (Figure 3).18 A study suggested that women with migraine exhibit a faster decline in urinary conjugated oestrogens (E1c) after the luteal peak compared to women without migraine.27 Another study found a lower serum estradiol on days 19-21 of the menstrual cycle (luteal phase) in women with menstrual migraine, but no differences at the day of menstruation onset.28 Both studies found no differences in progesterone concentrations. Since results were inconsistent and migraine attacks were not defined, further research is needed to determine whether women with migraine truly have different hormonal levels compared to controls, or if similar hormonal fluctuations make (genetically) predisposed women susceptible for attacks at certain time points. Sex hormone receptors are present in various migraine-related brain areas, including several of the trigeminovascular system (Figure 4).29, 30 Oestrogens classically bind to nuclear receptors, mediating gene expression, but membrane-associated forms of oestrogen receptors, such as the G-protein coupled oestrogen receptor (GPER), have also been identified.31 Therefore, oestrogen can have both immediate and delayed effects. After a rapid drop in estradiol levels different effects of estradiol may occur. The effects mediated through membrane receptors quickly dissipate, while those mediated through nuclear receptors may persist, possibly predisposing for migraine attacks.32 A similar decrease in circulating estradiol occurs at ovulation, but ovulation has not been clearly linked to an increased incidence of migraine attacks. One explanation might be that estradiol levels do not remain elevated for a sufficiently long enough time before declining in the early luteal phase.33 If the period of elevation is too short, the subsequent drop might not have as significant an impact as the longer period of elevation observed in the late luteal phase. Alternatively, rising levels of progesterone, or its metabolite allopregnanolone, may counteract the effects of drop of estradiol, as these hormones have an inhibitory effect on neuronal excitability, unlike estrogens.34 However, accurately pinpointing the exact timing of ovulation without measuring the preceding luteinizing hormone (LH) surge poses challenges, thus limiting the availability of conclusive evidence. Although it is assumed that sex hormones also influence CGRP levels in the trigeminovascular system, the limited studies are inconsistent. Sex hormone receptors, such as oestrogen receptors, show co-expression with CGRP receptors in the trigeminovascular system (Figure 4).29 Plasma CGRP levels are higher in women than in men, and the use of the combined contraceptive pill is associated with
20 Chapter 1 even higher plasma CGRP levels.35 A recent study on menstrual migraine suggested that CGRP concentrations (in serum and tear fluid) in women with migraine during menstruation are higher compared to those in women without migraine.36 However, it is important to note that there are both peripheral and cranial levels of CGRP, which presents some challenges in measuring CGRP. Interestingly, migraine with aura seems to be differentially affected by sex hormones compared to migraine without aura (Figure 3). In contrast to migraine without aura, it is hypothesized that increased estradiol levels during pregnancy and breastfeeding may increase the susceptibility to CSD, thereby initiating or exacerbating migraine attacks with aura.37-39 Studies in CACNA1A knock-in migraine mouse models have shown that female mice exhibit higher susceptibility to CSD compared to males.37, 40 This sex difference was eliminated after ovariectomy in female mice and partially reappeared following treatment with 17β-estradiol.37 Similar findings have been observed in other studies with rodents.39, 41, 42 APPROACHES TO TREATING (MENSTRUAL) MIGRAINE Acute treatment Paracetamol or an Non Steroid Anti Inflammatory Drug (NSAID) in combination with an antiemetic (metoclopramide or domperidone) is the first step. There is no clear benefit of opioids.43 If non-migraine-specific attack medication is ineffective, the next step is acute migraine-specific medication. Triptans are agonists of 5-hydroxytryptamine (5-HT; serotonin) receptors, binding to 5-HT1B and 5-HT1D receptors and some also to the 5-HT1F receptor. The 5-HT1B receptors are responsible for vasoconstriction. In addition, triptans induce central and peripheral inhibition of the trigemino-vascular system, where 5-HT1D and 5-HT1F receptors appear to play an important role. Lasmiditan is a selective 5-HT1F receptor agonist (ditan), and therefore has no vasoconstrictive effects. This is seen as an advantage over triptans, which have a (relative) contraindication in patients with a (severe) CVD risk profile. Lasmiditan demonstrates similar efficacy to triptans; however, its side-effect profile, including dizziness and drowsiness, keeps triptans the preferred choice.44 Among triptans, sumatriptan is also available as a subcutaneous injection, with higher bioavailability.45 It is recommended for a patient to treat at least three attacks with a medication before evaluating its effectiveness. If there is no response during an attack, repeated dosing of a triptan or ditan is not useful, as central sensitization occurs, with activation of second- and third-order neurons in the brainstem and thalamus.46 The timing of
21 General introduction 1 intake is thus important. Also, a triptan or ditan should be taken at the beginning of the headache phase (Figure 5a), as they have no effect on CSD. Women more often experience side effects from triptans than men.20 This can be explained by a higher maximum plasma concentration compared to men. The initial response is similar in men and women, yet despite higher plasma concentrations women have an increased risk of recurrences.20 In cases of side effects, lowering the dosage for women should therefore be avoided, as it may further increase the likelihood of recurrences. Instead, opting to switch to another triptan or other migraine specific acute treatment is advisable. Regrettably, in practice, it remains common for clinicians to prescribe triptans in too low doses. However, this practice exacerbates recurrences, increases medication usage, and consequently, increases the risk of chronification. A novel class of acute medication are the gepants, which are small molecular CGRP receptor antagonists. In clinical trials, the efficacy of gepants is comparable to that of triptans.47 Rimegepant can be used as both acute and preventive treatment, challenging the traditional view of the division between acute and preventive treatments.47 Medication overuse headache Women are more prone to develop medication overuse headache (MOH) due to their longer attack duration and thereby increased triptan or ditan intake.8, 10, 20 MOH is defined as the use of triptans, ditans, opioids, or in combinations with analgesics, on ten or more days per month, or the use of simple analgesics on 15 or more days per month, for at least three months.1 The pathophysiological mechanisms of MOH include changes in descending pain modulation, central sensitization with increased responsiveness and excitability of neurons, and biobehavioural factors.46 Both triptans and lasmiditan can induce hypersensitivity and increase the risk of progression to MOH in patients with an underlying headache condition when used excessively.48 For lasmiditan, this has so far only been demonstrated in preclinical models.49 Importantly, gepants do not seem to induce MOH-like phenotypes in mice.48, 50 Therefore, they have the potential for longer treatment during the perimenstrual window without the risk of MOH and chronification of attacks. Treatment of recurrences of (perimenstrual) attacks Recurrences often occur during perimenstrual attacks and treatment should be adjusted (Figure 5b). The first step would be to treat (perimenstrual) attacks with adequate dose of medication. If a woman is using sumatriptan 50 mg or lasmiditan
22 Chapter 1 Figure 5a. Timing of triptan or ditan intake should occur at the onset of headache symptoms. Figure 5b. Treatment of recurrences in perimenstrual attacks – taking a second triptan. 50 mg, the dosage should be increased. In addition to treatment with a triptan or ditan, a long-acting NSAID, such as etoricoxib (90 mg), can be added before the night (Figure 5c). An alternative treatment can be eletriptan 40 or 80 mg, which has a slightly longer half-life (Figure 5d). Frovatriptan has the longest half-life and theoretically should work best to prevent recurrences. However, in practice, this drug is less potent
23 General introduction 1 Figure 5c. Treatment of recurrences in perimenstrual attacks – adding a longacting NSAID Figure 5d. Treatment of recurrences in perimenstrual attacks – switching to a longer-acting triptan and moderately effective, and the initial response is often insufficient. If triptans or lasmiditan fail, gepants are now a viable substitute. Their relatively long half-life may contribute to sustained effects lasting up to 48 hours post-dose.51 However, there is limited data on the incidence of recurrence with gepants.
24 Chapter 1 Preventive treatment In accordance with (inter)national guidelines, preventive treatment is indicated for patients with at least two attacks or at least four migraine days per month. Candesartan and beta-blockers are often used as first choice although the latter might be less effective in women.52 Other preventive medications include topiramate, valproic acid, amitriptyline, flunarizine. For migraine with aura, there is a preference for antiepileptic drugs (lamotrigine, valproic acid, topiramate).53 For women of childbearing age using antiepileptic drugs may be difficult and highly effective contraception is needed due to the risk of teratogenicity. There is no information on the potential differences in effectiveness of these treatments between perimenstrual and non-perimenstrual attacks. In recent years, monoclonal antibodies targeting CGRP (fremanezumab, galcanezumab, eptinezumab) or the CGRP receptor (erenumab) have become available as preventive treatments for migraine. These anti-CGRP monoclonal antibodies are equally effective in reducing perimenstrual attacks as they are for non-perimenstrual attacks.11 Unfortunately, no data has emerged from the clinical trials that distinguishes between men and women, but data from the Food and Drug Administration indicate that anti-CGRP monoclonal antibodies and gepants are effective in both male and female patients with episodic migraine, though potential sex differences in efficacy remain unclear.54 In patients with chronic migraine, anti-CGRP monoclonal antibodies have been found to be similarly effective in both men and women.54 Anti-CGRP agents, besides their beneficial effect on migraine, may potentially alleviate vasomotor symptoms (VMS) as CGRP is implicated in neural regulation affecting vasodilation and cholinergic sweating during hot flushes, and elevated CGRP concentrations have been observed during VMS.55 While mouse studies suggest that blocking CGRP could alleviate VMS, clinical studies are required to validate these findings.56 Short-term prophylaxis for perimenstrual attacks For women with menstrual migraine short-term prophylaxis with acute medication such as NSAIDs or the long acting frovatriptan is often prescribed. This is started 1-2 days before the expected menstruation for a total of 5-7 days. However, the menstrual cycle must be regular or predictable for this to be effective. Besides, with this approach, women often report postponed attacks.57 Additionally, the risk of medication overuse increases with prolonged use of triptans or ditans, especially if migraine attacks also occur outside of menstruation.9 Gepants might offer a revolutionary change in the prevention of these perimenstrual attacks, as they do not seem to have a risk of medication overuse. Given the effectiveness of anti-CGRP monoclonal antibodies in preventing perimenstrual attacks, gepants are likely to be similarly effective.11
25 General introduction 1 Hormonal treatment specific for menstrual migraine Considering the oestrogen withdrawal theory, some small studies suggest that continuous estradiol supplementation might benefit women with migraine.58-60 For instance, a small double-blind placebo-controlled crossover study reported a 22% reduction in migraine frequency with daily estradiol (1·5 mg) administration.61 However, there was a 40% increase in migraine frequency observed five days after stopping the intervention, indicating that while migraine attacks can be delayed by preventing the oestrogen drop before menstruation, they may not be entirely prevented. Combined oral contraceptive pills are frequently prescribed as preventive treatment for migraine in women, even though there is no evidence of its effectiveness to date. These pills typically contain an oestrogen (typically ethinylestradiol) and a progestogen (typically progestin) to prevent pregnancy. Combined oral contraceptives come in various hormone doses and regimes, with the 21/7 regimen – 21 days of pill administration followed by a seven-day hormone-free interval – being the most common. However, evidence supporting their efficacy for migraine prevention is lacking, and their usage may be associated with side effects.62, 63 Hence, there is a strong need for clarity on the potential role of combined oral contraceptives in the prevention of migraine. Studies have investigated strategies such as shortening or eliminating the hormonalfree-interval or adding oestrogen supplementation during this period to prevent perimenstrual migraine attacks.26, 64 Shortening the hormonal-free-interval has shown promise in reducing migraine intensity and frequency in some studies, but exacerbation of symptoms has also been reported in others.59, 65 Extended regimens (without a hormone-free interval) are suggested to be more effective than traditional 21/7 regimen in terms of reducing migraine days and medication intake.57, 66 It is advised not to prescribe combined oral contraceptive pills to women with migraine with aura or women with migraine without aura with additional cardiovascular risk factors because this further increases the risk of cardiovascular diseases. Administration of progesterone alone, such as with the mini-pill or a hormonal intrauterine device, is considered safer from a cardiovascular perspective. However, the fact remains that the effect on migraine has not been sufficiently studied.64 A pragmatic trial is being conducted in the Netherlands (the WHAT study). This is the first large randomized trial studying the effect of continuous combined oral contraceptive pill as a preventive treatment for menstrual migraine.
26 Chapter 1 CARDIOVASCULAR RISK IN WOMEN WITH MIGRAINE Migraine is associated with an increased risk of myocardial infarction (OR 2.2, 95% CI 1.7-2.8) and stroke (OR 1.5, 95% CI 1.2-2.1).67-69 Especially women with migraine with aura exhibit a higher incidence of cardio- or cerebrovascular diseases (CVD), and the relative risk of stroke increases to a 35-fold elevated risk when a young woman with migraine with aura also smokes and uses the oral contraceptive pill.62, 63, 70-72 Migraine poses a greater risk factor than an unfavourable cholesterol profile, overweight, or familial predisposition to CVD.67, 69 Therefore, it is important to monitor the CVD risk in patients, especially in young women. The hypothesis is that this increased risk is the result of a shared pathophysiological mechanism, where both the cardiovascular risk and migraine are manifestations of the same predisposition to vascular dysfunction of small blood vessels, in which endothelial dysfunction may play a role.73 Genetic factors likely play an important role, since genome-wide association studies have identified vascular risk factors and observed associations between migraine and vascular diseases.74 This association is stronger for migraine with aura compared to migraine without aura, suggesting that the underlying mechanisms may differ between the two migraine subtypes, with migraine with aura potentially involving more pronounced vascular abnormalities or endothelial dysfunction. Important to note is that after an ischemic event, elevated levels of CGRP are observed, which likely play a protective role in regulating vascular tone after an infarct.75 Since CGRP is elevated during a migraine attack and thus treatment is now focused on inhibiting CGRP, clinicians should carefully evaluate the safety of CGRP inhibitors for women with migraine, particularly concerning potential ischemic events.76, 77 OUTLINE OF THE THESIS The aim of this thesis is to provide a deeper understanding of the clinical aspects of migraine, particularly in women, and to explore the impact of emerging anti-CGRP treatments, including potential cerebro- and cardiovascular risks. Various clinical and pathophysiological factors that influence the threshold for upcoming migraine attacks will be studied.
27 General introduction 1 This thesis can be roughly divided into three parts. Part I focusses on the use of E-diaries for clinical and research purposes. Part II focusses on migraine in women in relation to the menstrual cycle. Part III highlights the pros and cons of treating migraine with anti-CGRP (ligand or receptor) antibodies. Part I. The use of telemedicine in the monitoring and treatment of migraine Chapter 2 introduces an electronic E-diary developed and validated by the Leiden Headache Center. This chapter offers insights into the practical experiences with this E-diary, including patient and clinician satisfaction and its user-friendliness. In chapter 3, the definitions of a migraine day and a headache day are reevaluated in light of the emerge of E-diaries, which have established new standards. It emphasizes the importance of adhering to consistent outcome measurements. Chapter 4 demonstrates the broad potential of headache E-diaries for ad hoc research, particularly during the COVID-19 pandemic. Data is collected prospectively with a 48-hour time-lock, minimizing recall bias and creating a unique dataset to assess the impact of COVID-19 vaccinations and infections. Part II. Migraine in women in relation to the menstrual cycle In chapter 5, differences between migraine with aura and migraine without aura are examined concerning their association with menstruation and other hormonal milestones like pregnancy and breastfeeding. It also provides a cross-sectional analysis of the effects of the oral contraceptive pill, but chapter 6 details the rationale and protocol for the ongoing WHAT! Trial, which is the first large randomized trial studying the effect of continuous combined oral contraceptive pill as a preventive treatment for menstrual migraine. Chapter 7 is evaluating the course of migraine during the menstrual cycle, particularly in regards to ovulation, as there is still limited evidence whether the ovulation period is also associated with an increase in migraine. In chapter 8, serum hormone levels are collected throughout the menstrual cycle and compared between women with migraine and healthy controls, in order to study the underlying pathophysiology of menstrual migraine. Part III. Safety of treatment with anti-CGRP (receptor) antibodies Chapter 9 discusses cardiovascular safety outcomes during at least 12 months of treatment with these medications and assesses related safety considerations. Chapter 10 presents the results of a systematic review on the impact of anti-CGRP monoclonal antibody treatments on blood pressure in patients with migraine.
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