1 Migraine History, definitions and diagnosis - PowerPoint Presentation

1. 1MigraineHistory, definitions and diagnosis

2. MigraineMigraine through historyMigraine comes from the Greek word ‘hemicrania’, which referred to pain occurring on one side of the head (‘half skull’)1The earliest descriptions of migraine are said to be from 3,000 BC2Hippocrates provided an account of a severe headache that was associated with a visual disturbance, describing the experience as “something shining before him”2Migraine has been described by physicians through the last two millennia, with some paying greater attention to symptoms other than headache2Historically, ‘surgical’ techniques have included scalp incisions, application of heated irons, and blood letting2,3In the less-distant past, treatments have included several chemicals, including trinitrine (nitroglycerin), which is now known to be a vasoactive substance21. Pearce. Eur Neurol 2005;53(2):109–110;2. Pearce. J Neurol Neurosurg Psychiatry 1986;49(10):1097–1103;3. Koehler & Boes. Brain 2010;133:2489–25002

3. MigraineTimeline of migraine researchCALCRL=calcitonin receptor-like receptor; CGRP=calcitonin gene-related peptide; CSD=cortical spreading depression (or depolarisation); IHS=International Headache Society; PET=positron emission tomography; RAMP1=receptor activity-modifying protein 1; RCP=receptor coupling proteinAdapted from: Edvinsson et al. Nat Rev Neurol 2018;14(6):338–350; Tfelt-Hansen & Koehler. Headache 2011;51(5):752–7783First measurement of CGRP released by trigeminal stimulation in humans19811982Oligaemia in the wake of CSD in ratsNeurogenic inflammation theory of migraine19841986Discovery of the trigeminovascular reflex: a physiological role for CGRPPresence of CGRP confirmed in human cerebral vasculature19871990First demonstration in people with migraine that CGRP is released during an acute migraine attack1988Demonstration that CGRP release by trigeminal activation is inhibited by triptansCharacterisation of the multicomponent CGRP receptor that consists of CALCRL, RAMP1 and RCPCharacterisation of the gepants2002Infusion of CGRP shown to trigger migraine attack in people prone to migraine19181940Isolation and clinical testing of an ergot alkaloidIdentification of pain-sensitive structures in the brain1941Lashley’s description of spreading scotoma1944Leão’s experiments into CSD1984Discovery of CGRPCGRP antibodies made to measure and localise CGRP in the trigeminal–cerebrovascular system, where CGRP was found to be a potent vasodilator1988Discovery of proto-typical triptan1988New headache classification from IHS1996Gene for familial hemiplegicmigraine identified1996Meningeal sensitisation, central sensitisation and allodynia1938Vasodilation in migraine, and ergot therapies1959Serotonin – serum(‘sero’) vasoconstrictor (‘tonin’) factorSpreading oligaemia in migraine with auraPET studies highlight the importance of the brainstemTriptan shown to normalise CGRP levels during acute migraine attack199319941995CGRP first proposed to play a role in migraine1982199819852000

4. MigraineMigraine epidemiologyAn estimated 1.3 billion individuals were affected by migraine across the globe in 20171In the WHO global burden of disease study, headache disorder has consistently been the 2nd most prevalent disease in the world1Women are approximately 3 times more likely than men to have migraine2 Among people aged less than 50 years old, migraine is the most common cause of disability3Migraine is associated with high levels of disability and comorbidity, including an increased risk of insomnia, depression, and anxiety4WHO=World Health Organization1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet 2018;392(10159):1789–1858; 2. Gasparini et al. Curr Genomics 2013;14(5):300–315; 3. Steiner et al. J Headache Pain 2018;19(1):17; 4. Buse et al. J Headache Pain 2020;21(1):234Migraine is a highly prevalent condition

5. MigraineThe burden of migraineMigraine is a burdensome condition, and has a substantial impact on activities of daily living, such as work, school, and social activities1-3A systematic literature review of the burden of migraine identified several psychosocial difficulties:2Energy and drive – fatigue, reduced vitality, difficulties with sleepEmotional functioning – depressive symptoms, anxiety, stress, angerPain – general pain, and the sensation of painEmployment – reduced efficiency at work, restriction in time given to work, partial absenceGeneral physical and mental health – general mobility, carrying out daily routineSocial functioning – relationships with others, family relationships, leisure activities Global disability – global functioning, quality of life, self-efficacyMany of the psychosocial difficulties identified in the review (e.g., emotional functioning, and employment) appeared to respond well to migraine therapy, particularly to preventive treatment21. Agosti. Headache 2018;58(Suppl 1):17–32; 2. Raggi et al. J Headache Pain 2012;13(8):595–606; 3. Smitherman et al. Headache 2013;53(3):427–4365Migraine is a highly burdensome condition

6. MigraineMigraine-related impairment in the AMPP studyThe AMPP survey of 77,879 households in the USA asked respondents in what way they are “usually affected by severe headaches”:1 No impairment: able to function normallySome impairment: able to function, but with reduced performanceSevere impairment: unable to function or requiring bed restThe results showed migraine-related impairment was common among respondents:147.7% did no household work29.1% missed family or social activity25.3% missed at least 1 day of work/school AMPP=American Migraine Prevalence and Prevention; USA=United States of America1. Lipton et al. Neurology 2007;68(5):343–34963. Severe impairment(53.7%)2. Some impairment(39.1%)1. No impairment(7.2%)Headache-related impairment during severe headache in the AMPP study1Migraine is commonly associated with severe impairment or need for bed rest1

7. MigraineDepression among people with migraine in the AMPP studyLow-frequency EM: 0–3 headache days per month; moderate-frequency EM: 4–7 headache days per month; high-frequency EM: 8–14 headache days per month; chronic migraine: ≥15 headache days per month;none or minimum depression: PHQ-9 score 0–4; mild depression: PHQ-9 score 5–9; moderate depression: PHQ-9 score 10–14; moderately severe depression: PHQ-9 score 15–19; severe depression: PHQ-9 score 20–27AMPP=American Migraine Prevalence and Prevention; EM=episodic migraine; PHQ-9=9-item Patient Health Questionnaire 1. Buse et al. Headache 2020;60:2340–23567None or minimum depressionMild depressionModerate depressionModerately severe depressionSevere depressionComorbidity of depression and migraine in AMPP study (n=11,603)1Rates of comorbidity, including depression, generally increased with headache frequency1

8. MigraineMigraine stigma and social isolation (from the Eurolite project)Adapted from: Lampl et al. J Headache Pain 2016;17:98MaleFemaleAvoid telling othersMigraineTension-type headacheFamily, friends don’t understandMigraineTension-type headacheEmployer, colleagues don’t understandMigraineTension-type headacheDifficulties in love life were reported by 17.6% of respondents, and ~1% of respondents reported having fewer children, or had avoided having children altogether, because of migraine

9. MigraineThe economic burden of migraineDirect costs of migraineExamples of direct costs include prescription medication, and hospitalisation1A study of 215,209 people with migraine found that migraine was associated with $2,571 greater costs per person per year:1People with migraine: $7,007Control individuals: $4,436Estimates of direct migraine costs across the whole of the USA were:1Outpatient care: $5.21 billionPrescriptions: $4.61 billionInpatient care: $0.73 billionEmergency department care: $0.52 billionIndirect costs of migraineExamples of indirect costs include lost productivity at work, and workplace absence2An analysis of 6,516 people with migraine found that migraine was associated with $2,834 greater indirect workplace costs per person per year:2People with migraine: $4,453 Control individuals: $1,619The indirect cost of migraine across the whole of the USA was estimated to be $12 billion2USA=United States of America1. Hawkins et al. Headache 2008;48(4):553–563; 2. Hawkins et al. J Occup Environ Med 2007;49(4):368–3749Increased knowledge, and access to appropriate migraine management, are likely to help in reducing the economic burden of migraine2

10. Migraine criteria, diagnosis and subtypesMigraine10

11. MigraineWhat is migraine? What are migraine attacks?Migraine is a chronic neurological disease with episodic attacks of head pain1If caused by another medical condition, the headache is said to be a secondary headache2Migraine is characterised, including by International Classification of Headache Disorders, 3rd edition (ICHD-3), from the IHS, by attacks of moderate-to-severe headache and reversible neurological and systemic symptoms:1,2Photophobia – extreme sensitivity to lightPhonophobia – extreme sensitivity to soundAllodynia – pain resulting from a stimulus that would not normally provoke pain (e.g., a light touch of the skin)Nausea and vomitingOther symptoms – including vertigo, dizziness, and cognitive impairmentResearch into the genetic and biological mechanisms underlying migraine has led to a better understanding of the condition, and to the development of novel therapies and treatments1IHS=International Headache Society1. Dodick. Lancet 2018;391(10127):1315–1330; 2. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–21111

12. MigraineICHD-3 criteria for migraine and migraine attacksaPeople who do not fulfil criteria for chronic migraineICHD-3=International Classification of Headache Disorders, 3rd edition; MHD=monthly headache day; MMD=monthly migraine day1. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;2. Buse et al. Headache 2012;52(10):1456–147012Chronicmigraine1≥15 MHDs and ≥8 MMDs>3 months7.7% ofpeople withmigraine2Episodicmigraine1During a lifetime, ≥5 migraine attacks lasting 4–72 hoursaMajority ofpeople withmigraine2Monthly migraine day (MMD)1≥2 migraine characteristics, such as:If no aura, ≥1 of the following migraine symptoms:UnilateralPulsatingModerate/severeAggravation by, or causing avoidance of, routine physical activityNausea/vomitingPhotophobia/phonophobiaMonthly headache day (MHD)1A day with migraine-type or tension-type headache

13. MigraineMigraine symptoms and neurobiologyCSD, a phenomenon observed in early migraine research, describes a propagated slow wave of depolarisation of neurons and glia, followed by suppression of neural activity and eventual return to baseline1,2 Based on early experiments, and later MRI observations in humans, CSD is hypothesised to be the pathology underlying aura – however, not all people with migraine experience aura3The vascular theory of migraine proposes that pain results from vasodilation of cranial blood vessels – however, not all data fit the hypothesis that vasodilation can cause migraine pain4,5The pain in migraine is typically a throbbing, pulsating pain.4 This pulsating pain sensation has been linked to arterial pulsation in some studies, but not in others4CGRP, a 37-amino acid peptide localised to C- and Aδ-fibres, is a potent vasodilator, and several lines of evidence point towards CGRP playing a crucial role in migraine symptoms6,7CGRP=calcitonin gene-related peptide; CSD=cortical spreading depression; MRI=magnetic resonance imaging1. Charles & Brennan. Cephalalgia 2009;29(10):1115–1124; 2. Leão. J Neurophysiol 1944;7(6):359–390; 3. Tolner et al. Cephalalgia 2019;39(13):1683–1699; 4. Mason & Russo. Front Cell Neurosci 2018;12:233; 5. Charles & Brennan. Handb Clin Neurol 2010;97:99–108; 6. Russell et al. Physiol Rev 2014;94(4):1099–1142; 7. CGRP Forum website. https://www.cgrpforum.org. Accessed Jan 2020; 8. Burstein et al. J Neurosci 2015;35(17):6619–6629; 9. Goadsby et al. Physiol Rev 2017;97(2):553–62213Migraine is a complex neurological disease with multiple processes, which lead to the varied symptoms that people with migraine may experience (e.g., cognitive, sensory [aura], autonomic, and affective symptoms)8,9

14. MigraineMigraine with aura, and migraine without auraA person may experience migraine both with and without aura, and the aura experience varies between and within individuals1Compared with migraine without aura, migraine with aura appears to have:2,3Greater association with certain comorbid conditions Different alterations of brain structure and function as revealed by imaging studiesDifferences in heritability4,5Aura occurs in a minority of people with migraine: ~25%6Most studies of migraine therapies include mixed populations of migraine with and without aura2,3This is problematic, because there is evidence that migraine with and without aura respond differently to treatment2Some have argued that the two conditions – migraine with aura and migraine without aura – should be separated in clinical studies of migraine therapies3ICHD-3=International Classification of Headache Disorders, 3rd edition1. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;2. Hansen & Charles. J Headache Pain 2019;20(1):96; 3. Hauge et al. Cephalalgia 2010;30(9):1041–1048;4. Gervil et al. Ann Neurol 1999;46(4):606–611; 5. Ulrich et al. Ann Neurol 1999;45(2):242–246; 6. Shankar Kikkeri & Nagalli. Migraine with Aura. 202014Migraine with aura is characterised, according to ICHD-3 criteria, by at least 2 migraine attacks with the presence of the following categories of fully reversible aura symptoms:1…and at least 3 of the following 6 characteristics:1At least 1 aura symptom spreads gradually over ≥5 minutes2 or more aura symptoms occur in successionEach individual aura symptom lasts 5–60 minutesAt least 1 aura symptom is unilateralAt least 1 aura symptom is positiveThe aura is accompanied, or followed within 60 minutes, by headacheVisualSensorySpeech and/or languageMotorBrainstemRetinal

15. MigraineICHD-3 diagnostic criteria – episodic migraine with/without auraAt least 5 attacks fulfilling criteria B–DHeadache attacks lasting 4–72 hours (when untreated or unsuccessfully treated)Headache has at least 2 of the following 4 characteristics:Unilateral locationPulsating qualityModerate or severe pain intensityAggravation by or causing avoidance of routing physical activity (e.g., walking or climbing stairs)During headache at least 1 of the following:Nausea and/or vomitingPhotophobia and phonophobiaNot better accounted for by another ICHD-3 diagnosisAt least 2 attacks fulfilling criteria B and CAt least 1 of the following fully reversible aura symptoms:VisualSensorySpeech and/or languageMotorBrainstemRetinalAt least 3 of the following 6 characteristics:At least 1 aura symptom spreads gradually over ≥5 minutes2 or more aura symptoms occur in successionEach individual aura symptom lasts 5–60 minutesAt least 1 aura symptom is unilateralAt least 1 aura symptom is positiveThe aura is accompanied, or followed within 60 minutes, by headacheNot better accounted for by another ICHD-3 diagnosisSee slide notes for further information on diagnostic criteriaICHD-3=International Classification of Headache Disorders, 3rd editionHeadache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211151.1 Migraine without aura1.2 Migraine with aura

16. MigraineICHD-3 diagnostic criteria – chronic migraineSee slide notes for further information on diagnostic criteriaICHD-3=International Classification of Headache Disorders, 3rd editionHeadache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–21116Headache (migraine-like or tension-type-like) on 15 days/month for >3 months, and fulfilling criteria B and COccurring in a patient who has had at least 5 attacks fulfilling criteria B–D for ‘1.1 Migraine without aura’ and/or criteria B and C for ‘1.2 Migraine with aura’On 8 days/month for >3 months, fulfilling any of the following:Criteria C and D for ‘1.1 Migraine without aura’Criteria B and C for ‘1.2 Migraine with aura’Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivativeNot better accounted for by another ICHD-3 diagnosis1.3 Chronic migraineThe clinical criteria for episodic migraine with and without aura apply to the chronic diagnosis, with the only differentiator being frequency and duration of symptoms

17. MigraineICHD-3 diagnostic criteria – status migrainosus If a migraine attack lasts >72 hours, it is diagnosed as ‘status migrainosus’1Status migrainosus often requires immediate medical attention, because of the length, severity, and persistence of symptoms2The longer a migraine persists, the greater the risk of dehydration, stroke, aneurysm, permanent vision loss, serious dental problems, coma, and even death2Treatment approaches for people with status migrainosus include pharmacotherapy and surgery, however, these approaches have only limited success3More research and specific treatment guidelines are needed to better serve this difficult-to-treat population3See slide notes for further information on diagnostic criteriaaRemissions of up to 12 hours due to medication or sleep are accepted; bmilder cases, not meeting criterion C2, are coded 1.5.1 ‘Probable migraine without aura’ICHD-3=International Classification of Headache Disorders, 3rd edition1. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;2. The Migraine Institute website. https://www.themigraineinstitute.com/status-migrainosus-migraines/. Accessed May 2020;3. Iljazi et al. Cephalalgia 2020;40(8):818–82717A headache attack fulfilling criteria B and COccurring in a patient with 1.1 ‘Migraine without aura’ and/or 1.2 ‘Migraine with aura’, and typical of previous attacks except for its duration and severityBoth of the following characteristics:Unremitting for >72 hoursaPain and/or associated symptoms are debilitatingbNot better accounted for by another ICHD-3 diagnosis1.4.1 Status migrainosus1

18. MigraineICHD-3 definitions for episodic and chronic migraineChronic migraine is defined as having a headache ≥15 days per month for >3 months, of which ≥8 days meet criteria for migraine1,2For most people with migraine, migraine is episodic – estimates suggest up to 7.7% of people with migraine have chronic migraine2,3It is estimated that episodic migraine progresses to chronic migraine in approximately 3% of people with migraine annually4Compared with people with episodic migraine, those with chronic migraine show:2Higher percentage with severe pain – 92.4% versus 78.1% Greater percentage of occupational disability – 20.0% versus 11.1%Greater healthcare resource use, including visits to primary care providers and headache specialistsHigher levels of comorbidities, including depression, anxiety, and obesity1. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;2. Katsarava et al. Curr Pain Headache Rep 2012;16(1):86–92; 3. Buse et al. Headache 2012;52(10):1456–1470; 4. Bigal & Lipton. Curr Neurol Neurosci Rep 2011;11:139–14818030815Monthly migraine daysMonthly headache daysChronic migraine: Lasting >3 months300Episodic migraine:People who have had ≥5 attacks of migraine lasting 4–72 hours during lifetime and do not fulfil the criteria for chronic migraine

19. MigraineICHD-3 differential diagnosis – tension-type headacheAt least 10 episodes occurring 1–14 days/month for >3 months fulfilling criteria B–DLasting from 30 minutes to 7 daysHeadache has at least 2 of the following 4 characteristics:Bilateral locationPressing or tightening (non-pulsating) qualityMild to moderate intensityNot aggravated by routine physical activity such as walking or climbing stairsBoth of the following:No nausea or vomitingNo more than 1 of photophobia and phonophobiaNot better accounted for by another ICHD-3 diagnosisHeadache occurring on >15 days/month for 3 months fulfilling criteria B–DLasting hours to days, or unremittingAt least 2 of the following 4 characteristics:Bilateral locationPressing or tightening (non-pulsating) qualityMild to moderate intensityNot aggravated by routine physical activity such as walking or climbing stairsBoth of the followingNo more than 1 of photophobia, phonophobia or mild nauseaNeither moderate or severe nausea of vomiting Not better accounted for by another ICHD-3 diagnosisSee slide notes for further information on diagnostic criteriaICHD-3=International Classification of Headache Disorders, 3rd editionHeadache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211192.2 Frequent episodic tension-type headache2.3 Chronic tension-type headache

20. Attacks fulfilling criteria for ‘3.1 Cluster headache’, and criterion B belowOccurring without a remission period, or with remissions lasting <3 months, for at least 1 yearMigraineICHD-3 differential diagnosis – cluster headacheAt least 5 attacks fulfilling criteria B–DSevere or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15–180 minutes (when untreated)Either or both of the following:At least 1 of the following symptoms or signs, ipsilateral to the headache:Conjunctival injection and/or lacrimationNasal congestion and/or rhinorrhoeaEyelid oedemaForehead and facial sweatingMiosis and/or ptosisA sense of restlessness or agitationOccurring with a frequency between 1 every other day and 8 per dayNot better accounted for by another ICHD-3 diagnosisAttacks fulfilling criteria for ‘3.1 Cluster headache’ and occurring in bouts (cluster periods)At least 2 cluster periods lasting from 7 days to 1 year (when untreated) and separated by pain-free remission periods of ≥3 monthsSee slide notes for further information on diagnostic criteriaICHD-3=International Classification of Headache Disorders, 3rd editionHeadache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211203.1 Cluster headache3.1.1 Episodic cluster headache3.1.2 Chronic cluster headache

21. MigraineICHD-3 differential diagnosis – medication-associated headacheSee slide notes for further information on diagnostic criteriaICHD-3=International Classification of Headache Disorders, 3rd edition1. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;2. Kristoffersen & Lundqvist. Ther Adv Drug Saf 2014;5(2):87–9921a. Patients should be coded for one or more subtypes of ‘8.2 Medication-overuse headache’ according to the specific medication(s) overused and the criteria for each below. For example, a patient who fulfils the criteria for ‘8.2.2 Triptan-overuse headache’ and the criteria for one of the sub-forms of ‘8.2.3 Non-opioid analgesic-overuse headache’ should receive both these codes. The exception occurs when patients overuse combination-analgesic medications, who are coded ‘8.2.5 Combination analgesic-overuse headache’ and not according to each constituent of the combination analgesic medicationb. Patients who use multiple drugs for acute or symptomatic treatment of headache may do so in a manner that constitutes overuse even though no individual drug or class of drug is overused; such patients should be coded ‘8.2.6 Medication-overuse headache attributed to multiple drug classes not individually overused’c. Patients who are clearly overusing multiple drugs for acute or symptomatic treatment of headache but cannot give an adequate account of their names and/or quantities are coded ‘8.2.7 Medication-overuse headache attributed to unspecified or unverified overuse of multiple drug classes’ until better information is available. In almost all cases, this necessitates diary follow-upThe prevalence of medication-overuse headache is 1–2% in the general population, higher among women than men, and is highest among those aged in their forties2Headache occurring on ≥15 days/month in a patient with a pre-existing headache disorderRegular overuse for >3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headachea-cNot better accounted for by another ICHD-3 diagnosis8.2 Medication-overuse headache1

22. Short-term pain reliefRebound headacheHigher medication doseMigraineMedication overuseICHD-3 thresholds for overuse: regular intake of ≥1 opioid or triptan on ≥10 days/month for >3 months, or regular intake of acetaminophen or ≥1 NSAID on ≥15 days/month for >3 months2ICHD-3=International Classification of Headache Disorders, 3rd edition; NSAID=non-steroidal anti-inflammatory drugAdapted from: 1. Da Silva & Lake. Headache 2014;54(1):211–217; 2. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–21122MedicationHeadachePain reliefSuccessful acute treatment of migraine involves treatment and resolution of the migraine attack and symptomsMedication-overuse headache can occur with several classes of migraine therapy, including acetaminophen, caffeine combinations, opioids, barbiturates, NSAIDs, and triptansThe vicious cycle of medication overuse1

23. Phases of a migraine attackMigraine23

24. MigraineProposed phases of a migraine attackSymptoms in bold denote criteria in the ICHD-3 classificationICHD-3=International Classification of Headache Disorders, 3rd editionAdapted from: Dodick. Lancet 2018;391(10127):1315–1330; Cady et al. Headache 2002;42(3):204–216; Goadsby et al. Physiol Rev 2017;97(2):553–622;Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;The American Migraine Foundation. https://americanmigrainefoundation.org/resource-library/timeline-migraine-attack/. Accessed May 2020;Migraine Buddy website. Available at: https://migrainebuddy.com/migraine/2018/11/22/the-stages-of-a-migraine-postdrome-phase. Accessed May 202024PremonitoryAuraHeadachePostdromeFatigueCognitive difficultiesMood changesFood cravingsNeck painYawningVisual aura (scotoma, fortification spectrum)Sensory disturbanceSpeech disturbanceMotor symptomsHeadacheNausea with or without vomitingPhotophobiaPhonophobiaOsmophobiaFeeling tired or wearyDifficulty with concentration Neck stiffnessHeadache4–72 hrs<12–24 hrs5–60 minutesA few hoursto days

25. MigraineThe premonitory phase of a migraine attackThe headache phase of migraine is preceded by a cluster of symptoms, known as the premonitory symptoms, which can last from a few hours to days1,2Common premonitory symptoms include:1,3FatigueConcentration difficultiesNeck painMood changesOther premonitory symptoms include nausea, food cravings, and yawning1-3Research into the neurobiology underlying the premonitory phase of migraine has pointed to early brainstem involvement, as well as the hypothalamus and limbic networks as key2Frequency of the 5 most common premonitory symptoms in a study of 100 children with migraine31. Dodick. Lancet 2018;391(10127):1315–1330; 2. Karsan & Goadsby. Front Neurol 2020;11:140;3. Karsan et al. J Headache Pain 2016;17(1):9425

26. MigraineThe aura phase of a migraine attack1. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;2. Viana et al. J Headache Pain 2019;20(1):6426Migraine aura is a complex set of fully reversible visual, sensory, speech/language, motor, brainstem, and retinal symptoms that usually begin before the headache phase of an attack, but can occur during the headache1Elementary visual symptoms of migraine aura and their description2Bright light – single area of bright light Foggy/blurred visionZigzag lines – zigzag or jagged lines Scotoma – single blind area Scotomata – several blind/black areas Small bright dots – small bright dots/stars White dots/round forms – medium sized white dots/round formsColoured dots/round forms – medium sized coloured dots/round forms Lines (coloured lines) Geometrical shapes“Like looking through heat waves, water or oil”Visual snow – dynamic, continuous, tiny dots usually black/grey on white background or grey/white on black background ‘Bean-like’ forms – ‘bean-like’ forms like a crescent or C-shape Hemianopsia – blindness in half of the visual field Deformed images – deformed images (alteration of lines/angles) Tunnel vision – blindness in the whole periphery Oscillopsia – movement of stationary objects Mosaic vision – seeing images in a mosaic-like patternFractured objects Corona effect – an extra edge on objects Anopia – total blindness Micropsia – objects appear smaller or more distant than they actually are Macropsia – objects appear larger or closer than they actually are “Like a negative film” Complex hallucinations – visual perception of something not present (e.g., objects, animals, and persons)

27. MigraineThe headache phase of a migraine attackMigraine headache (head pain) is often unilateral (affecting one side of the head)1The headache of a migraine is reported by people with migraine to be:1,2The headache phase of migraine is of moderate-to-severe intensity, and is often accompanied by nausea (with or without vomiting), photophobia, and phonophobia1,21. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;2. Dodick. Lancet 2018;391(10127):1315–133027Unilateral (60%)Aggravated by physical movement (90% of people with migraine)Throbbing (50%)

28. MigraineThe postdrome phase of a migraine attackPostdrome is a symptomatic phase, lasting up to 48 hours following the resolution of pain in migraine attacks with or without aura1Postdrome symptoms overlap with those experienced in the premonitory phase, and include:1,2Feeling tired or wearyConcentration difficulties Neck stiffnessPostdrome symptoms can persist for up to 48 hours after the headache phase of migraine1An electronic diary study followed 120 people with migraine over 3 months3There was no relationship between medication taken for the headache and the duration of the postdrome3The severity of migraine was not associated with the duration of the postdrome phase31. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211;2. Goadsby et al. Physiol Rev 2017;97(2):553–622; 3. Giffin et al. Neurology 2016;87(3):309–31328Postdrome symptoms are common, but poorly studied – more research is needed to understand the link between postdrome and the underlying pathophysiology of migraine1-3In total, 85% of participants reported ≥1 non-headache symptom in the postdrome phase3

29. Migraine is a chronic neurological disease with episodic attacks of head painDodick. Lancet 2018;391(10127):1315–133029