Migraine

Abstract

Key points•Migraine is a neurological disorder with genetic predisposition.•Diagnosis is essentially clinical, which is based upon compatible history and normal neurological examination.•Current literature supports that primary headache disorders are principally neurally mediated.•If treated early in the course of attacks, abortive strategies may be more effective if given as a large single dose.•Prophylaxis should be considered in patients who have ≥4–5 headache days per month to avoid medication overuse headache, which is reported for ≥8 treated days per month. •Migraine is a neurological disorder with genetic predisposition.•Diagnosis is essentially clinical, which is based upon compatible history and normal neurological examination.•Current literature supports that primary headache disorders are principally neurally mediated.•If treated early in the course of attacks, abortive strategies may be more effective if given as a large single dose.•Prophylaxis should be considered in patients who have ≥4–5 headache days per month to avoid medication overuse headache, which is reported for ≥8 treated days per month. Migraine is considered to be a common disabling primary headache disorder. It has a high prevalence with epidemiological studies documenting high socio-economic and personal impact. It is one of the most common clinical presentations to neurologists in routine practice. In a systematic analysis of Global Burden of Disease Study 2010,1Vos T Flaxman AD Naghavi M et al.Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2163-2196Abstract Full Text Full Text PDF PubMed Scopus (5591) Google Scholar it was found that migraine is the seventh most common cause globally of years lived with disability with a global prevalence of 14.7% and nearly 3% worldwide disability attributable to any specific disease. Migraine is about twice as common in women (12–14%) than men (6–8%). If untreated, the median duration of a migraine attack is 18 h with the median attack frequency 1 per month. In Europe, 12–28% of people get affected by migraine at some stage in their lives, which includes about 6–15% of adult men and 14–35% of adult women.2Stovner LJ Zwart JA Hagen K Terwindt GM Pascual J Epidemiology of headache in Europe.Eur J Neurol. 2006; 13: 333-345Crossref PubMed Scopus (322) Google Scholar A typical migraine attack is a spectrum that may consist of: premonitory symptoms, headache, and the postdrome. Nearly 20–30% of people experience one or more focal reversible neurological symptoms, called the migraine aura. Although the majority of individuals have episodic migraine, about 2–3% of the population has chronic migraine currently defined as migraine headache on at least 15 days per month for at least 3 months. Prevalence varies from 7% to 88% and symptoms may commence 24–72 h before the onset of headache. Commonly reported premonitory symptoms include feeling tired and weary (72%), difficulty in concentration (51%), neck stiffness (50%), irritability, depression, craving for specific foods, constipation, and increased yawning. A recent study3Giffin NJ Ruggiero L Lipton RB et al.Premonitory symptoms in migraine: an electronic diary study.Neurology. 2003; 60: 935-940Crossref PubMed Scopus (489) Google Scholar demonstrated 72% patients correctly predicted migraine headache through their premonitory symptoms. Although not always, but commonly, the headache is unilateral in presentation. The headache presents with a throbbing or pulsatile characteristic, increasing in proportion with the intensity of the headache. During an attack, patients commonly experience nausea, whereas vomiting, photophobia, and phonophobia are less frequent. Additionally, osmophobia and cutaneous allodynia may occur. A headache episode may last from few hours to several days if left untreated. Some attacks resolve while sleeping. A postdromal phase may follow the headache episode. Postdrome may be characterized by the symptoms of exhaustion although could alternate between mild elation or euphoria. Migraine aura, consisting of focal neurological symptoms, has an incidence of 20–30%. Although these symptoms usually precede the headache, they may occur concurrently with the pain, after or independent to headache. Aura is not specifically associated with migraine, it can occur in all primary headaches.4Bahra A May A Goadsby PJ Cluster headache: a prospective clinical study with diagnostic implications.Neurology. 2002; 58: 354-361Crossref PubMed Scopus (432) Google Scholar Auras are most commonly visual (90%), although may also be sensory or associated with language or motor abnormalities. Typical aura evolves gradually, usually no longer than an hour, has a mix of positive and negative features and complete reversibility.5Headache Classification Committee of the International Headache Society (IHS)The International Classification of Headache Disorders, 3rd edition (beta version).Cephalalgia. 2013; 33: 629Crossref PubMed Scopus (5791) Google Scholar The positive features may include visual symptoms (bright lines, shapes, visual loss), auditory symptoms (tinnitus), and somatosensory features (paresthesia). Negative features may include a loss of function, such as visual or hearing loss and inability to feel or move a part of the body. The majority of aura symptoms last <60 min. A differential diagnosis of transient ischaemic attack (TIA) should be considered if neurological symptoms have a very rapid onset with a simultaneous rather than sequential pattern. In TIA, the characteristic visual phenomenon is a descending curtain deficit (amaurosis fugax) contrary to scintillating visual disturbance of migraine aura. In a study of migraine performed retrospectively,6Kelman L The triggers or precipitants of the acute migraine attack.Cephalalgia. 2007; 7: 394Crossref Scopus (526) Google Scholar at least one trigger was associated with acute attacks by 75% of the patients. These trigger factors include: emotional stress (80%), hormones (65%), weather (53%), sleep disturbances (50%), odours (44%), neck pain (38%), light (38%), alcohol (38%), smoke (36%), sleeping late (32%), heat (30%), food (27%), exercise (22%), and sexual activity (5%). Migranous neck pain/stiffness can be misdiagnosed as pain originating from the neck. As initially stated, migraine is essentially a clinical diagnosis which is based upon a compatible history and normal neurological examination. The International Classification of Headache Disorders (ICHD), 3rd edition,5Headache Classification Committee of the International Headache Society (IHS)The International Classification of Headache Disorders, 3rd edition (beta version).Cephalalgia. 2013; 33: 629Crossref PubMed Scopus (5791) Google Scholar has classified migraine without aura (MwoA) and migraine with aura (MwA) (Table 1).Table 1Migraine classification based on the International Classification of Headache Disorders, 3rd edition (beta version)1.1Migraine without aura1.2Migraine with aura1.2.1Migraine with typical aura1.2.1.1Typical aura with headache1.2.1.2Typical aura without headache1.2.2Migraine with brainstem aura1.2.3Hemiplegic migraine1.3Chronic migraine Open table in a new tab (A)At least five headache attacks fulfilling criteria B–D(B)Headache attacks lasting 4–72 h (untreated or unsuccessfully treated)(C)Headache has at least two of the following four characteristics: (i)Unilateral location(ii)Pulsating quality(iii)Moderate or severe pain intensity(iv)Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)(D)During headache at least one of the following: (i)Nausea and/or vomiting(ii)Photophobia and phonophobia (A)At least two attacks fulfilling criteria B and C(B)One or more of the following fully reversible aura symptoms: (i)Visual(ii)Sensory(iii)Speech and/or language(C)At least two of the following four characteristics: (i)At least one aura symptom spreads gradually over 5 min, and/or two or more symptoms occur in succession(ii)Each individual aura symptom lasts 5–60 min(ii)At least one aura symptom is unilateral(iii)The aura is accompanied, or followed within 60 min, by headache Although not essential in diagnosis, imaging (CT/MRI) should be considered in the following patients:7Bahra A Secondary headache.Adv Clin Neurosci Rehabil. 2013; 13Google Scholar (i)Patients with sudden severe headache (thunderclap onset). The pain escalates from no pain to maximum intensity within 5 min. The most common presentation of subarachnoid haemorrhage is with thunderclap headache. The diagnosis of subarachnoid haemorrhage is based upon CT within 24 h of ictus and if normal, CSF examination for xanthochromia detected with spectrophotometry within 12 h to 2 weeks after ictus.(ii)Patients presenting with headache and focal neurology (including seizures).(iii)Patients presenting with headache and systemic ill-health.(iv)There should be a lower threshold for investigating headache in individuals >50 yr, particularly with new onset or change in character/pattern. Migraine was originally thought to be of vascular origin and was supposedly attributed to the dilatation of blood vessels, while the vasoconstriction was thought to cause aura.8Amin FM Asghar MS Hougaard A et al.Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study.Lancet Neurol. 2013; 12: 454Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar Migraine is now considered to be a disorder of the brain in individuals with an inherited predisposition. It has been estimated that genetic inheritance may account for 40–50% of an individual's susceptibility to migraine. Three genes have been identified to cause one of the more uncommon forms of migraine'familial hemiplegic migraine (FHM). FHM has been linked to CACNA1A, ATP1A2, and SCN1A gene mutation-related channelopathies. The more common forms of migraine with and without typical aura may have a more complex pattern of inheritance. The pathophysiology of migraine involves activation of the trigeminovascular system, consisting of sensory neurones supplying large cerebral and pia vessels, the duramater, and large venous sinuses. These sensory, small caliber pseudo-unipolar neurones originate from the trigeminal ganglion and upper cervical dorsal roots. The anterior structures of the cranial fossa are innervated via the ophthalmic division of the trigeminal nerve, whereas the posterior structures receive a greater contribution from upper cervical roots. Central projections from the upper cervical nerve roots and the trigeminal nerve converge at the trigeminal nucleus caudalis and extend to the C2–3 segment in the dorsal horn forming the trigemino-cervico complex (TCC).9Goadsby PJ Hoskin KL The distribution of trigeminovascular afferents in the non-human primate brain Macaca nemestrina: a c-fos immunocytochemical study.J Anat. 1997; 190: 367-375Crossref PubMed Google Scholar This may explain frontal, occipital, and cervical distribution of the symptoms. Activation of this network releases various neurotransmitters including serotonin, substance P, calcitonin gene-related peptide, glutamate, and neurokinin A, which may in turn lead to the process of sensitization. This phase is characterized by an increased responsiveness to nociceptive and non-nociceptive stimulation.10Burstein R Deconstructing migraine headache into peripheral and central sensitization.Pain. 2001; 89: 107Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar From the TCC, second-order neurones project to the thalamus and hypothalamus via the trigeminothalamic and trigeminohypothalamic tracts en route to cortical structures. In addition numerous subcortical connections including projections to periaqueductal grey, nucleus raphe magnus, brain stem, cerebellum, and midbrain play important role in central modulation of pain. The hypothalamus has been associated with migraine premonitory symptoms through its projections to TCC and the sensitization of thalamic neurones has been implicated in the spread of cutaneous allodynia. Although not shown in humans, animal work has demonstrated that the phenomenon of cortical spreading depression (CSD) may cause aura symptoms:11Smith JM Bradley DP James MF Huang CL Physiological studies of cortical spreading depression.Biol Rev. 2006; 81: 457-481Crossref PubMed Scopus (97) Google Scholar CSD is a slowly propagating wave (2–6 mm min−1) of neuronal and glial depolarization which is followed by inhibition of cortical activity (15–30 min). How aura is linked to headache remains largely speculative. Migraine management is targeted as acute and preventive treatment. This should be tailored to an individual's requirements depending upon the severity and frequency of attacks, co-existing symptoms, comorbidities, and the patient choice. A step-wise ladder approach may be used, initiating with an analgesic and anti-emetic and escalating to 5HT1 receptor agonist (triptan) as needed. However, a stratified approach in which attacks are treated according to the severity at the time of treatment has been demonstrated to be more cost-effective. During the acute phase, options include a non-steroidal anti-inflammatory drug (NSAID), such as aspirin (1000 mg) or ibuprofen (400–800 mg), paracetamol (1 g), or triptan. Acute treatments can also be taken in combination and with an anti-emetic, which has been shown to improve gastric absorption and efficacy. A single adequate dose of acute treatment (or combination of acute treatments) is more effective than suboptimal doses taken throughout the day. A meta-analysis12Ferrari MD Roon KI Lipton RB Goadsby PJ Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials.Lancet. 2001; 358: 1668Abstract Full Text Full Text PDF PubMed Scopus (870) Google Scholar has shown that in comparison with sumatriptan 100 mg: rizatriptan 10 mg demonstrates better efficacy, consistency, and equal tolerability; eletriptan 80 mg a lower tolerability; almotriptan 12.5 mg an equal efficacy but better consistency and tolerability; naratriptan l2.5 mg lower efficacy but better tolerability. Zolmitriptan 5 mg/10 mg, eletriptan 40 mg, and rizatriptan 5 mg were comparable with each other. In the UK, sumatriptan is also available as a subcutaneous and intranasal preparation, rizatriptan has a melt, and zolmitriptan both intranasal and melt formulations. In the absence of enough good quality evidence, ergot alkaloids are not recommended routinely and are no longer available in many parts of the Europe. During the aura phase, acute attack treatment is not effective at preventing the migraine headache, hence should be taken when the headache evolves.13Bates D Ashford E Dawson R et al.Subcutaneous sumatriptan during migraine aura.Neurology. 1994; 44: 1587-1592Crossref PubMed Google Scholar Successful treatment of migraine attacks in recent randomized controlled trials achieve the following endpoints: no pain after 2 h,headache improves from moderate/severe to mild/none after 2 h,the treatment is consistently effective in two of three attacks,no further recurrence of headache and no need to take the drug within 24 h after successful treatment. Acute treatment for more than 8 days a month has been associated with medication overuse headache (MOH). As it is the frequency of treatment rather than the dosing which has been implicated in MOH, the acute-relief medication use should be restricted to once or twice a week at most. If the frequency starts to increase towards the higher end of the range, preventive strategies should be introduced early to avoid the development of MOH and ensure that any prophylactic benefit remains maximal. All acute-relief medications are associated with MOH. The most protracted withdrawal occurs with opioids followed by simple analgesics; hence, opioids should be avoided in migraine. NSAIDs have been the least implicated in MOH, hence use is advised as first line. If not tolerated, paracetamol can then be considered. Although triptans are associated with the most rapid development of MOH, they are the most effective acute treatments and withdrawal faster than with other acute treatment options. Prophylactic treatment in migraine may be indicated if headache frequency is more than four in a month, or if less but without adequate response to acute treatments. After 6–12 months of effective prophylaxis, gradual reduction or withdrawal of medication can be considered. The aim is to tailor treatment according to the symptoms. Thus, if on withdrawal or reduction in the preventive treatment, symptoms recur, the treatment can be re-established at effective doses. Some patients may need a combination of preventive treatments to minimize disability from their headache disorder. Migraine prophylaxis may be deemed successful if there is a decrease in 50% frequency of migraine attacks per month. Recommendations based on the scientific evidence from clinical trials and the expert consensus by the task force of the European Federation of Neurological Societies (EFNS)14Eversa S Afra J Frese A et al.EFNS guideline on the drug treatment of migraine'report of an EFNS task force.Eur J Neurol. 2009; 16: 968-981Crossref PubMed Scopus (539) Google Scholar on the drug treatment of migraine have been summarized in Tables Table 2, Table 3.Table 2Acute drug treatment of migraine: Based on the European Federation of Neurological Societies (EFNS) guidelines 2009. *Level A: (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies. Level B: (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence. Level C: (possible effective, ineffective, or harmful) rating requires at least two convincing class III studiesNSAIDs, paracetamol, and other analgesics, antiemetics and triptansSubstanceDose (minimum to maximum)Recommendation level*CommentAcetylsalicylic acid (ASA)1000 mg (oral or i.v.)AGastrointestinal side-effects, risk of bleedingIbuprofen200–800 mgASide-effects as for ASANaproxen500–1000 mgASide-effects as for ASADiclofenac50–100 mgAIncluding diclofenacParacetamol1000 mg (oral), 1000 mg (supp.)ACaution in liver and kidney failureASA plus, paracetamol plus, and caffeine50 mg (oral), 200–250, and 50 mg AAs for ASA and paracetamolMetoclopramide10–20 mg (oral) 20 mg (suppository) B 10 mg (i.m., i.v., or s.c.)BSide-effect: dyskinesia; contraindicated in childhood and in pregnancyDomperidone20–30 mg (oral)BSide-effects less severe than in metoclopramide; can be given to childrenSumatriptan25, 50, and 100 mg (oral including rapid-release), 25 mg (suppository), 10 and 20 mg (nasal spray), 6 mg (subcutaneous)AGeneral side-effects for all triptans: chest symptoms, nausea, distal paresthesia, fatigue. General contraindications: arterial hypertension (untreated), coronary heart disease, cerebrovascular disease, Raynaud's disease, pregnancy and lactation, age under 18 (except sumatriptan nasal spray) and age above 65 yr, severe liver or kidney failureZolmitriptan2.5 and 5 mg (oral including disintegrating form), 2.5 and 5 mg (nasal spray)ANaratriptan2.5 mg (oral)ALess side-effects and efficacy than sumatriptanRizatriptan10 mg (oral)A5 mg when taking propranolol Almotriptan12.5 mg (oral)AProbably less side-effects than sumatriptanEletriptan20 and 40 mg (oral)A80 mg allowed if 40 mg not effectiveFrovatriptan2.5 mg (oral)ALess side-effects and efficacy than sumatriptan Open table in a new tab Table 3Prophylactic drug treatment of migraine: Based on the European Federation of Neurological Societies (EFNS) guidelines 2009. Certain other drugs for prophylaxis with probable efficacy are gabapentin, magnesium, riboflavin, coenzyme Q10 (level C evidence).SubstanceDose (minimum to maximum)Recommendation level*Commentβ-Blockers Metoprolol50–200 mgACautious use: asthma, diabetes, bradycardia, peripheral vascular disease, comorbid depression Propranolol40–240 mgAPreferred in: comorbid anxietyAnti-epileptics Valproic acid500–1800 mgACautious use: obesity, liver disease, pregnancyPreferred in: depression Topiramate25–200 mgACautious use: renal stone, angle closure glaucoma, pregnancy, anorexiaPreferred in: comorbid obesityAmitriptyline50–150 mgBCautious use: angle closure glaucomaPreferred in: comorbid depression, sleep disturbanceBisoprolol5–10 mgB Open table in a new tab About 2–3% of the population have chronic migraine, defined as more than 15 headache days a month for at least 3 months. The treatment of chronic migraine should focus on prophylactic drug treatment as a first-line therapy (Table 3). More invasive treatments such as greater occipital nerve block with local anaesthetic and steroid, botulinum toxin type A administration and neuromodulation including occipital nerve stimulation (ONS) are reserved for individuals with refractory migraine. Acute headache medication intake should be limited in order to avoid MOH, but severe superimposed migraine headaches are treated in the same manner as episodic migraine headaches. The pertinence of this is that prophylactic treatments are rendered less efficacious in the presence of acute-relief medication overuse.15Zeeberg P Olesen J Jensen R Discontinuation of medication overuse in headache patients: recovery of therapeutic responsiveness.Cephalalgia. 2006; 26: 1192-1198Crossref PubMed Scopus (155) Google Scholar I.V. dihydroergotamine has been associated with the improvements in headache and disability in chronic refractory migraine patients16Nagy AJ Gandhi S Bhola R Goadsby PJ Intravenous dihydroergotamine for inpatient management of refractory primary headaches.Neurology. 2011; 77: 1827-1832Crossref PubMed Scopus (86) Google Scholar and can be effective in the presence of MOH. However, the effect tends to be self-limiting. Botulinum toxin type A is recommended by NICE for adults with chronic migraine, who have not responded to at least three preventive medications and have been managed appropriately for medication overuse. In recent data from the pooled analyses of the PREEMPT 1 and PREEMPT 2 trials of more than 1300 patients, nearly half of patients (47%) who received Botox reported a 50% or higher decrease in headache days 24 weeks after treatment.17Diener HC Dodick DW Aurora SK et al.OnabotulinumtoxinA for treatment of chronic migraine: results from the double blind, randomized, placebo-controlled phase of the PREEMPT 2 trial.Cephalalgia. 2010; 30: 804Crossref PubMed Scopus (680) Google Scholar Although limited, evidence has shown benefit from the greater occipital nerve block, but the treatment usually requires repeat procedures over time. ONS peripherally stimulates the occipital nerves with a subcutaneous battery-powered implantable pulse generator has proven to be effective in managing some patients with chronic refractory migraine. A 52 week open-label extension study has reported 30% responder rate of 59.5% and 50% responder of 47.8% with headache days being significantly reduced by 6.7 days per month at the end of 52 weeks.18Dodick DW Silberstein SD Reed KL et al.Safety and efficacy of peripheral nerve stimulation of occipital nerves for the management of chronic migraine: long term results from a randomized, multicentre, double blinded, controlled study.Cephalagia. 2015; 35: 344-358Crossref PubMed Scopus (107) Google Scholar NICE is currently reviewing its clinical commissioning policy for ONS (at the time of print). Migraine tends to improve in pregnancy. Nevertheless, if problematic during the pregnancy, paracetamol is safe. Codeine may also be used, although there is a risk of MOH with both treatments. There is post-marketing data for the safety of sumatriptan during the first trimester.19vans EW Lorber KC Use of 5-HT1 agonists in pregnancy.Ann Pharmacother. 2008; 42: 543-549Crossref PubMed Scopus (33) Google Scholar V.M. is an editor of BJA Education. Other authors: none declared. The associated MCQs (to support CME/CPD activity) can be accessed at https://access.oxfordjournals.org by subscribers to BJA Education.