- Email: [email protected]
Migraine
Med Clin (Barc). 2016;146(1):35–39
www.elsevier.es/medicinaclinica
Diagnosis and treatment
Migraine夽 ˜ Migrana Nuria Riesco a , Carmen García-Cabo a , Julio Pascual b,∗ a b
Área de Neurociencias, Hospital Universitario Central de Asturias, Oviedo, Spain Hospital Universitario Marqués de Valdecilla e IDIVAL, Santander, Spain
a r t i c l e
i n f o
Article history: Received 16 June 2015 Accepted 3 July 2015 Available online 7 May 2016
Introduction Most headaches are primary headaches. By primary headaches it is understood headaches with no demonstrable cause and whose diagnosis lies in clinical criteria related to anamnesis and a normal examination. More than 90% of primary headaches are migraine or a tension headache.1 Approximately 15% of the population meets the diagnostic criteria for migraine.2 Migraine is 2–3 times more common in females. The prevalence of active migraine decreases from the age of 50. In our area, the prevalence of chronic migraine is 2.4% of the population,3 and the prevalence of chronic migraine with analgesic overuse criteria, 0.9%.4 These data show that migraine, an entity to which medical professionals often do not pay enough attention due to not being life threatening, is a disease that should be recognized and treated. Aetiology and pathophysiology Migraine has a strong inherited component. 3 genes have been identified for an extremely rare, migraine autosomal-dominant variant: the familial hemiplegic migraine.5 The three genes involved are actually neuronal membrane channels involved in ion exchange processes. In summary, these mutations result in increased intracellular calcium and extracellular potassium and glutamate, which determines a state of cell hyperexcitability capable of generating the cortical spreading depression phenomenon, responsible for the aura. The wide genetic association studies or GWAS (genome-wide association studies) have identified up to 42 loci potentially associated with common forms of migraine.6 At
夽 Please cite this article as: Riesco N, García-Cabo C, Pascual J. Migrana. ˜ Med Clin (Barc). 2016;146:35–39. ∗ Corresponding author. E-mail address: [email protected] (J. Pascual). ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,
the moment, none of these loci has identified a gene that explains consistently and jointly migraine pathogenesis. In light of these findings, migraine might not be a single entity, but the common phenotypic expression of heterogeneous genetic changes, or a polygenic condition in which genetic changes interact with various environmental factors. The pathophysiology of migraine is known in considerable detail. The brainstem is the generator of migraine, specifically the area that corresponds to the locus coeruleus and raphe nuclei, innervation cerebral sources for catecholamines and serotonin.7 The aura is due to a phenomenon of cortical spreading depression, which is a cortical depolarization wave which advances forward at a rate of 3 mm/min from the occipital lobe.8 Trunk activation results in activation of the so-called trigeminal vascular system, formed by the trigeminal nerve and the parasympathetic nerve portion of the facial nerve.9 When activated, this system’s terminations dilate the cranial vessels sensitive to pain, mostly leptomeningeal, and release algogenic neuropeptides mainly by the trigeminal, the calcitonin gene-related peptide (CGRP), and by the parasympathetic autonomic system, the vasoactive intestinal peptide, which induce dilation and sterile inflammation. Both vascular phenomena, dilation and leptomeningeal inflammation, are responsible for migraine pain and are negatively controlled by two serotonin receptors, the 5-HT1B receptor, located postsynaptically on the vascular wall and responsible for vasodilation, and 5-HT1D, located in the presynaptic terminals and trigeminal nerve responsible for peptide release.9 It has been shown that frequent release of these algogenic peptides may induce a phenomenon of sensitization of the central lines of pain control, which would be the pathophysiological substrate of migraine chronicity. Diagnosis The diagnosis of migraine is clinical. The most common form of migraine is called “migraine without aura”. Diagnostic criteria
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N. Riesco et al. / Med Clin (Barc). 2016;146(1):35–39
Table 1 Diagnostic criteria for migraine without aura according to the International Classification of Headache Disorders.10 A. At least five attacks that meet the B–D criteria B. 4–72 h long headache episodes (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics: 1. Unilateral location 2. Pulsatile character 3. Moderate to severe intensity pain 4. Routine physical activity is made worse by it or causes its abandonment (e.g., walking or climbing stairs D. At least has one of the following during the headache: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. No better explanation by another diagnosis
are shown in Table 1.10 As we will next review, migraine is a chameleonic disease, and sometimes more complex than these simple criteria indicate. Migraine is an entity both chronic and episodic, often precipitated by various triggers. It manifests itself in the form of crisis or attacks, and between these, the patient is fine. The attacks begin very characteristically in the first 2 decades of life, never above 50 years of age. The frequency of episodes is variable, ranging between one a year and several a week, although a typical migraine patient has between one crisis every two months and one every week. Migraine attacks are composed of 3 major and distinct phases: prodrome, aura and headache and associated symptoms. The prodrome precedes the rest of migraine symptoms between a few hours and a maximum of 2 days. Approximately one third of patients with migraine refer prodromal symptoms, either inhibitory, such as mental sluggishness, fatigue or anorexia, or excitatory, such as irritability, euphoria, yawning or craving for certain foods.11 Up to a third of patients occasionally experience “aura” that is, transient focal symptoms of pain immediately before or coinciding with its appearance. We must be familiar with the semiotics of migraine aura, not only for its significant frequency, but because the migraine aura itself is one of the reasons that most often lead the patient to the doctor. Migraine aura symptoms must be reversible in 60 min, maximum, they develop gradually, and typically include positive phenomena, photopsias type, coloured zigzag images or paresthesias. More than 90% of the auras have a visual component and nearly two thirds of patients with migraine have auras with isolated visual symptoms. The characteristic visual aura begins as a scotoma, which appears on the point of vision and grows larger in a visual hemifield. Typically, the edges of the scotoma are bright and colourful in nature, a phenomenon known by the name of “fortification spectra”. The sensory symptoms are second in frequency, between 30–40% of auras occur with cheiro-oral paresthesias established progressively in minutes. In less than 20% of auras, the symptoms include aphasia, and except in the hemiplegic migraine variant, motor symptoms are exceptional, which, along with positive visual symptoms, help regarding differential diagnosis with transient stroke. There is migraine variant, with basilar aura, in the form of bilateral visual blur, dizziness, diplopia, ataxia, paresthesias or bilateral weakness and decreased level of consciousness.10 Many migraine patients only experience the headache phase (and associated symptoms). The duration of pain ranging from 4 (without treatment) to 72 h (median 12–24 h) except in children, in which the duration may be less than 4 h. Pain is only hemicranial in 50% of cases. Most patients with bilateral pain, however, report that this rests primarily in the anterior region (temple or periocular) of one of the hemicrania. A small percentage of patients, those with basilar migraine, experience occipital pain. The migraine attack begins as hemicranial discomfort, which, between 30 and 120 min,
transforms gradually into moderate pain (interferes with common tasks) or severe pain (prevents them). The pain is referred to as pulsatile and is aggravated by light (photophobia), noises (phonophobia) and physical exercise, and is accompanied by symptoms, generally digestive in nature, especially nausea and, to a lesser extent, diarrhoea or vomiting.10 We know there are certain syndromes in childhood that are precursors of migraine in adulthood. These include cyclic vomiting, abdominal migraine and benign paroxysmal vertigo.10 Chronic migraine In short, it is understood that chronic migraine is a clinical situation in which a patient with a history of migraine has headaches during 15 or more days a month, who retains migraine characteristics during at least 8 days a month.10 More than a third of patients who consult meet criteria for painkiller abuse; that is, they take simple analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) more than 15 days a month, or ergotics, triptans or opiates more than 10 days a month. Chronic migraine justifies one in 25 standard Neurology consultations in our country and is difficult to treat entity.12,13 Because many cases are associated with analgesic and drug abuse, with vasoconstrictor effects, it is not uncommon to find that these patients have a history of hypertension or gastric problems (gastritis, peptic ulcer, hiatal hernia, etc.). The list of comorbidities and predisposing factors does not end here. It is well known that these patients have a higher than expected overweight, depression, anxiety, personality disorder or fibromyalgia incidence. Complications of migraine The migraine attacks that go over 72 h are renamed as status migrainosus, which requires specific hospital treatment.10 Many of these patients with status migrainosus have chronic migraine and meet the painkiller abuse criteria. In a minority of patients, the aura lasts for over a week with no evidence of ischaemia in neuroimaging. This clinical condition is known as persistent aura without infarction and it is usually visual, bilateral and lasts for months or years.10 In a minority of patients, an epileptic seizure occurs within a migraine aura. This clinical condition is known as migralepsy and must be differentiated from the headache that occurs after an epileptic seizure.10 Any symptoms of migraine aura that are associated with cerebral ischaemic injury confirmed by neuroimaging, clinically consistent with the aura are considered as a migrainous infarction. The real migrainous infarction occurs mainly in the posterior circulation and affects young women, and its diagnosis also requires the lack of any other cause. Several population studies have shown that patients, mainly women younger than 45, suffering migraine with aura, double the risk of ischaemic stroke. However, it should be noted that many of these strokes are not true migrainous infarctions and we do not know the relationship between the frequency and the pathophysiology of the aural symptoms denoting increased risk. Most studies have shown a lack of association between migraine without aura and ischaemic stroke.10 Complementary studies and differential diagnosis Simply applying the criteria, differential diagnosis of migraine with other primary headaches, such as tension headache, cluster headache or hemicrania continua, is simple. There are no findings in laboratory parameters or neurophysiological and neuroimaging studies that allow diagnosis confirmation. In the future, the serum levels of CGRP and vasoactive intestinal peptide may be able to help in the diagnosis of migraine.14,15 The diagnosis of migraine does not require any additional study in a patient with a normal
N. Riesco et al. / Med Clin (Barc). 2016;146(1):35–39
physical examination that presents with painful episodic attacks of migrainous characteristics. This implies that in more than 90% of patients with migraine, diagnosis is made solely with a formal medical history and a standard physical examination.16,17 When should we request additional studies in patients with migraine and what kind of studies? The neuroimaging (CT or cranial MRI) are only indicated in patients with atypical migraine attacks, in patients with non-visual migraine aura, if the pain is always located on the same side of the head and in patients with a recent increase in the frequency of their attacks. It is important to insist that the only evidence able to rule out headache secondary to a structural process are neuroimaging techniques; that is, tests such as electroencephalogram are not indicated in the routine differential diagnosis of headaches, unless we think it might be a case of migralepsy. In patients with atypical auras (e.g., those including hemiparesis or lasting more than 60 min), apart from neuroimaging studies, antiphospholipid antibodies or thrombophilia studies can be requested. There are some entities, including CADASIL, reversible cerebral vasoconstriction syndrome, pseudomigraine with pleocytosis, SMART or MELAS, which may mimic a migraine headache with atypical aura, but a regulated medical history should enable us to get close to a diagnosis and then request the appropriate complementary studies in each case.16,17 Treatment General measures After the diagnosis of migraine, an understandable explanation of the process needs to be given to the patient. It is important to explain that migraine is a recurrent and episodic disease for which there is no cure, but in general, it can be controlled. Clarify the differences between the treatment of acute attacks and the preventive treatment. The next step is to identify possible triggers. These are varied and complex, since they are particular to each patient. In addition, many of these potential factors are impossible to avoid in patients with migraine. For the vast majority of patients, treatment solely based on preventing the triggers may achieve a marginal therapeutic effect, at the most, and, today, drug treatment is necessary. In any case, we must recommend the patient to have a healthy lifestyle, being as orderly as possible regarding daily schedules, doing regular exercise and trying to avoid overweight.16,17 Symptomatic or attack treatment Symptomatic treatment is mandatory in all migraineurs. Medications for the treatment of migraine may be divided into nonspecific, specific and adjuvants. Nonspecific medications include analgesics and NSAIDs. Specific drugs include ergotics and 5HT 1B/D receptors agonists, commonly known as “triptans”. The adjuvants are fundamentally antiemetic/prokinetics medications (domperidone, metoclopramide), required in patients with nausea and vomiting. Analgesics have a very limited use in the treatment of migraine, so their indication is very limited (migraine in childhood and adolescence). It is advisable to avoid combinations of analgesics with barbiturates, codeine and/or caffeine because of the risk of developing chronic headache due to abuse of these drugs. Because of their side effects and because, in our country, commercial presentations include other analgesics, caffeine and/or barbiturates, ergotics are not recommended.16,17 Symptomatic treatment of migraine resides therefore in the judicious use of triptans and NSAIDs. Patients with mild to moderate migraine attacks may be treated initially with oral NSAIDs, preferably in combination with metoclopramide or domperidone.
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Table 2 Potential indications of each of the different triptans according to their pharmacological profile and clinical experience data. Compound
Formulation
Indication
Sumatriptan
Subcutaneous 6 mg
Severe attacks resistant to oral and nasal route Attacks resistant to oral route Patients with vomiting Children and adolescents Standard migraine patient Patient likely to get pregnant Standard migraine patient Attacks resistant to oral route Patients with vomiting Mild to moderate long-term attacks Adverse effects with other triptans Severe, fast and short attacks Standard migraine patient Side effects with other triptans Severe attacks, long duration Mild to moderate attacks Long duration attacks Adverse effects with other triptans
Nasal 20 mg Nasal 10 mg Oral 50 mg Zolmitriptan
Oral 2.5–5 mg Nasal 5 mg
Naratriptan
Oral 2.5 mg
Rizatriptan Almotriptan
Oral 10 mg Oral 12.5 mg
Eletriptan Frovatriptan
Oral 20 and 40 mg Oral 2.5 mg
Not all NSAIDs are useful in migraine. NSAIDs with well proven efficacy available in our area are: acetylsalicylic acid, naproxen sodium, ibuprofen and dexketoprofen. Patients with mild-moderate attacks and lack of response or intolerance to NSAIDs have to be treated with triptans. Triptans are drugs with proven efficacy in the symptomatic treatment of migraine attacks, being of choice in moderate-severe type. Its contraindication is ischaemic heart disease. Triptans marketed and their specific indications are collected in Table 2. There are currently seven triptans marketed, which do not differ in their mechanism of action, but have relevant pharmacokinetic differences that make certain triptans more suitable than others depending on the type of attack. In patients with nausea or vomiting, liotab or nasal formulations may be used. If the patient does not respond to these options, we can use the subcutaneous formulation of sumatriptan and/or dexketoprofen trometamol or parenteral diclofenac with parenteral metoclopramide (Fig. 1).16,17 Preventive treatment It is estimated that at least 25% of patients who consult need preventive treatment. Preventive treatment has as main objective to reduce the frequency of attacks and make these milder and therefore easier to deal with. This treatment is our unfinished business in this field: it is estimated that less than 10% of patients who consult receive it. It is indicated for those who have 3 or more migraine attacks per month. It has to be maintained for a recommended period of 6–12 months, with a minimum of 3 months. Preventive treatment should be kept at least for 6 weeks before considering that the drug that is being used does not have therapeutic utility.16,17 Drugs with proven efficacy in the preventive treatment of standard migraine (without aura or with typical aura) are: some beta-blockers, candesartan, flunarizine, amitriptyline and some antiepileptic drugs. Indications, recommended dose and adverse effects of these drugs are variable and are listed in Table 3. Beta blockers are of choice in patients with migraine without aura and have no use contraindications (asthma and diabetes, mainly). The most commonly used in our area are propranolol and nadolol at doses of between 40 and 80 mg/day.16,17 One option of recently demonstrated efficacy in patients with contraindications to betablockers is candesartan at doses of 8–32 mg/day.18 Traditionally, in our area, flunarizine (2.5–10 mg/dinner) was the drug of choice
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N. Riesco et al. / Med Clin (Barc). 2016;146(1):35–39
Symptomatic treatment of migraine
Oral NSAIDs No response
Oral triptans No response
Triptans + oral NSAIDs No response
Intranasal zolmitriptan No response
Intranasal zolmitriptan + diclofenac suppository No response
Parenteral dexketoprofen No response
Subcutaneous sumatriptan No response
Metoclopramide IV + Dexketoprofen IV + Subcutaneous sumatriptan No response
Consider methylprednisolone and initiate preventive treatment Fig. 1. Options for the symptomatic treatment of migraine. NSAIDs: nonsteroidal anti-inflammatory drugs; IV: intravenous.
for patients without efficacy or intolerance/contraindication to the use of beta-blockers. AEDs are the most recommended drugs for most of the people who have not responded to beta-blockers or candesartan, except children and very thin women without a history of depression, as their side effects are mainly overweight and depression. 2 antiepileptic drugs with well proven efficacy
in migraine are topiramate (ideal dose 100 mg/day) and valproic acid (usual dose 500–1000 mg/day). Valproic acid needs lab tests to control the possibility of inducing fulminant hepatitis or disorders in the blood count. Topiramate advantages relate to its quick efficacy, which does not require lab tests control and being the only drug which does not induce overweight. Therefore, topiramate should be the antiepileptic drug of choice. However, 20% of patients cannot tolerate it due to adverse effects, including distal paresthesias, difficulty in mental concentration, abdominal pain, weight loss, depression, acute glaucoma, and renal calculi. Data from open series of patients indicate that zonisamide (100–300 mg/day), a drug profile very similar to topiramate is also useful in preventing migraine. Amitriptyline, at low doses of between 10 and 50 mg (evening dinner/supper) is the only antidepressant with proven efficacy in preventing migraine, especially when associated with tension headache. Fluoxetine and other serotonin reuptake inhibitors have not proven effective in preventing migraine, regardless of their antidepressant effect, which can be useful in these patients.16,17 In refractory patients with chronic migraine, clinical practice has proven that combinations of these drugs, in general, a beta blocker or candesartan with topiramate, are useful as they induce a synergistic effect.19,20 If there is no response or an antiepileptic (preferably topiramate) and/or a beta blocker or candesartan are not tolerated in patients with chronic migraine, quarterly pericranial injections of botulinum toxin type A are indicated, which, at doses of between 155 and 195 units at least 31 points, have shown efficacy over placebo controlled trials.21 It has been shown that the toxin does not act due to its muscle relaxant effect, but appears to decrease the pericranial release of algogenic peptides mainly CGRP.22 In clinical practice botulinum toxin type A achieves a significant reduction of migraine attacks as regards number of episodes, but mainly in relation to severity, in 70% of patients with chronic migraine, with excellent tolerability.23 Other advantages are that
Table 3 Indications and major adverse effects of drugs effective in the preventive treatment of migraine. Compound
Beta-blockers
Migraine without aura Migraine and hypertension Migraine and shaking
Candesartan
Migraine with/without aura Migraine and hypertension Migraine and depression Migraine with/without aura Chronic migraine Migraine and overweight
Topiramate/zonisamide
Adverse effects
Indications
Valproic acid
Refractory migraine with/without aura Chronic migraine
Flunarizina
Migraine with and without aura in children/adolescents or thin adults without tendency to depression
Amitriptyline
Migraine and tension headache Migraine and depression Migraine and insomnia
Botulinum toxin type A
Chronic migraine
Common
Rare
Fatigue Dizziness Nausea Orthostatic hypotension Impotence Distal coldness Fatigue Hypotension Teratogenicity Distal paresthesias Cognitive symptoms Intestinal disorders Weightloss Nausea/vomiting Drowsiness Overweight Shaking Alopecia Teratogenicity Depression
Depression Bradycardia Heart failure Bronchoconstriction Insomnia/nightmares
Drowsiness Overweight Drowsiness Constipation Overweight Skin/mucous dryness Palpitations Ptosis Cervicalgia
Galactorrhoea
Kidney failure Hyperkalaemia Glaucoma Nephrolithiasis Depression Hepatotoxicity Ovarian cysts Thrombocytopenia
Parkinsonism
Cognitive symptoms Urinary retention Glaucoma
Diplopia Dysphagia
N. Riesco et al. / Med Clin (Barc). 2016;146(1):35–39
this drug produces no systemic or central nervous system effects, and can be combined with oral preventive drugs. Special situations In children, adjusting doses to the weight, the recommendations of symptomatic and preventive treatment are similar to those of adults for most drugs. Among triptans, sumatriptan nasal 10 mg and almotriptan have studies in children/adolescents with positive results. As to preventive treatment, a drug that is not recommended in adults, but it can be effective in children, is cyproheptadine.16,17 Migraine is the main neurological disease during pregnancy, regarding frequency. Some migraine patients go through an ordeal during pregnancy, as all kinds of medication are denied to them, except paracetamol. Clinical practice and prospective pregnancy registries have shown that sumatriptan and propranolol are safe during pregnancy as symptomatic and preventive treatment, respectively. Not only can we prescribe these drugs in pregnant women with incapacitating migraine attacks, after the appropriate patient explanation of the risk/benefit ratio, but we should consider prescribing these drugs also to women likely to get pregnant.24 The aura will have to be treated in a minority of patients due to their frequency or because of their incapacitating symptoms (e.g., basilar migraine). In these cases, lamotrigine is indicated at doses between 100 and 200 mg/day.25 Conflict of interests Dr. Julio Pascual has been a scientific advisor to Allergan. The other authors declare no conflicts of interest. References 1. Pascual J, Combarros O, Leno C, Polo JM, Rebollo M, Berciano J. Distribución por diagnósticos del dolor de cabeza como motivo de consulta neurológica. Med Clin (Barc). 1995;104:161–4. 2. Matías-Guiu J, Porta-Etessam J, Mateos V, Díaz-Insa S, López-Gil A, Fernández C, Scientific Committee of the PALM Program. One-year prevalence of migraine in Spain: a nationwide population-based survey. Cephalalgia. 2011;31: 463–70. ˜ P, Guitera V, Pascual J. Epidemiology of chronic daily headache 3. Castillo J, Munoz in the general population. Headache. 1999;39:190–6. ˜ 4. Colás R, Munoz P, Temprano R, Gómez C, Pascual J. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62:1338–42.
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5. Schürks M. Genetics of migraine in the age of genome-wide association studies. J Headache Pain. 2012;13:1–9. 6. Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:656–60. 7. Hadjikhani N, Sánchez del Río M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98:4687–92. 8. Noseda R, Burstein R. Migraine pathophysiology: anatomy of trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013;154 Suppl. 1:S44–53. ˜ Neurologia. 1998;13:29–32. 9. Castro ME, Pascual J. Fisiopatología de la migrana. 10. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl. 1:9–160. ˜ 11. Quintela E, Castillo J, Munoz P, Pascual J. Premonitory and resolution symptoms in migraine: a prospective study in 100 unselected patients. Cephalalgia. 2006;26:1051–60. 12. Pascual J, Sánchez del Río M, Jiménez MD, Láinez-Andrés JM, Mateos V, Leira ˜ crónica vista por el neurólogo y el paciente: resultados del R, et al. La migrana proyecto CIEN-mig (III). Rev Neurol. 2010;50:705–10. ˜ crónica: tratamiento. Rev Neurol. 2012;54 Suppl. 29:S31–8. 13. Pascual J. Migrana 14. Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81:1191–6. 15. Cernuda-Morollón E, Martínez-Camblor P, Alvarez R, Larrosa D, Ramón C, Pascual J. Increased VIP levels in peripheral blood outside migraine attacks as a potential biomarker of cranial parasympathetic activation in chronic migraine. Cephalalgia. 2015;35:310–6. 16. Díaz-Insa S, editor. Guía oficial para el diagnóstico y tratamiento de las cefaleas ˜ de Neurología. Barcelona: Thomson Reuters; 2011. de la Sociedad Espanola 17. Mateos V, Pareja J, Pascual J. Tratado de cefaleas. Madrid: Ergón; 2009. 18. Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T, et al. A comparative study of candesartan versus propranolol for migraine prophylaxis: a randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia. 2013;34:523–32. 19. Pascual J, Leira R, Láinez JM. Combined therapy for migraine prevention? Clinical experience with a beta-blocker plus sodium valproate in 52 resistant migraine patients. Cephalalgia. 2003;23:961–2. 20. Pascual J, Rivas MT, Leira R. Testing the combination beta-blocker plus topiramate in refractory migraine. Acta Neurol Scand. 2007;115:81. 21. Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50:921–36. 22. Cernuda-Morollón E, Ramón C, Martínez-Camblor P, Serrano-Pertierra E, Larrosa D, Pascual J. OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine. Pain. 2015;156:820–4. 23. Cernuda-Morollón E, Ramón C, Larrosa D, Alvarez R, Riesco N, Pascual J. Long-term experience with onabotulinumtoxinA in the treatment of chronic migraine: what happens after one year? Cephalalgia. 2015;35:864–8. ˜ y gestación: una relación compleja. Rev Neurol. 24. Pascual-Gómez J. Migrana 2010;50:321–4. 25. Pascual J, Caminero AB, Mateos V, Roig C, Leira R, García-Moncó JC, et al. Preventing disturbing migraine aura with lamotrigine: an open study. Headache. 2004;44:1024–8.
www.elsevier.es/medicinaclinica
Diagnosis and treatment
Migraine夽 ˜ Migrana Nuria Riesco a , Carmen García-Cabo a , Julio Pascual b,∗ a b
Área de Neurociencias, Hospital Universitario Central de Asturias, Oviedo, Spain Hospital Universitario Marqués de Valdecilla e IDIVAL, Santander, Spain
a r t i c l e
i n f o
Article history: Received 16 June 2015 Accepted 3 July 2015 Available online 7 May 2016
Introduction Most headaches are primary headaches. By primary headaches it is understood headaches with no demonstrable cause and whose diagnosis lies in clinical criteria related to anamnesis and a normal examination. More than 90% of primary headaches are migraine or a tension headache.1 Approximately 15% of the population meets the diagnostic criteria for migraine.2 Migraine is 2–3 times more common in females. The prevalence of active migraine decreases from the age of 50. In our area, the prevalence of chronic migraine is 2.4% of the population,3 and the prevalence of chronic migraine with analgesic overuse criteria, 0.9%.4 These data show that migraine, an entity to which medical professionals often do not pay enough attention due to not being life threatening, is a disease that should be recognized and treated. Aetiology and pathophysiology Migraine has a strong inherited component. 3 genes have been identified for an extremely rare, migraine autosomal-dominant variant: the familial hemiplegic migraine.5 The three genes involved are actually neuronal membrane channels involved in ion exchange processes. In summary, these mutations result in increased intracellular calcium and extracellular potassium and glutamate, which determines a state of cell hyperexcitability capable of generating the cortical spreading depression phenomenon, responsible for the aura. The wide genetic association studies or GWAS (genome-wide association studies) have identified up to 42 loci potentially associated with common forms of migraine.6 At
夽 Please cite this article as: Riesco N, García-Cabo C, Pascual J. Migrana. ˜ Med Clin (Barc). 2016;146:35–39. ∗ Corresponding author. E-mail address: [email protected] (J. Pascual). ˜ S.L.U. All rights reserved. 2387-0206/© 2015 Elsevier Espana,
the moment, none of these loci has identified a gene that explains consistently and jointly migraine pathogenesis. In light of these findings, migraine might not be a single entity, but the common phenotypic expression of heterogeneous genetic changes, or a polygenic condition in which genetic changes interact with various environmental factors. The pathophysiology of migraine is known in considerable detail. The brainstem is the generator of migraine, specifically the area that corresponds to the locus coeruleus and raphe nuclei, innervation cerebral sources for catecholamines and serotonin.7 The aura is due to a phenomenon of cortical spreading depression, which is a cortical depolarization wave which advances forward at a rate of 3 mm/min from the occipital lobe.8 Trunk activation results in activation of the so-called trigeminal vascular system, formed by the trigeminal nerve and the parasympathetic nerve portion of the facial nerve.9 When activated, this system’s terminations dilate the cranial vessels sensitive to pain, mostly leptomeningeal, and release algogenic neuropeptides mainly by the trigeminal, the calcitonin gene-related peptide (CGRP), and by the parasympathetic autonomic system, the vasoactive intestinal peptide, which induce dilation and sterile inflammation. Both vascular phenomena, dilation and leptomeningeal inflammation, are responsible for migraine pain and are negatively controlled by two serotonin receptors, the 5-HT1B receptor, located postsynaptically on the vascular wall and responsible for vasodilation, and 5-HT1D, located in the presynaptic terminals and trigeminal nerve responsible for peptide release.9 It has been shown that frequent release of these algogenic peptides may induce a phenomenon of sensitization of the central lines of pain control, which would be the pathophysiological substrate of migraine chronicity. Diagnosis The diagnosis of migraine is clinical. The most common form of migraine is called “migraine without aura”. Diagnostic criteria
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Table 1 Diagnostic criteria for migraine without aura according to the International Classification of Headache Disorders.10 A. At least five attacks that meet the B–D criteria B. 4–72 h long headache episodes (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics: 1. Unilateral location 2. Pulsatile character 3. Moderate to severe intensity pain 4. Routine physical activity is made worse by it or causes its abandonment (e.g., walking or climbing stairs D. At least has one of the following during the headache: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. No better explanation by another diagnosis
are shown in Table 1.10 As we will next review, migraine is a chameleonic disease, and sometimes more complex than these simple criteria indicate. Migraine is an entity both chronic and episodic, often precipitated by various triggers. It manifests itself in the form of crisis or attacks, and between these, the patient is fine. The attacks begin very characteristically in the first 2 decades of life, never above 50 years of age. The frequency of episodes is variable, ranging between one a year and several a week, although a typical migraine patient has between one crisis every two months and one every week. Migraine attacks are composed of 3 major and distinct phases: prodrome, aura and headache and associated symptoms. The prodrome precedes the rest of migraine symptoms between a few hours and a maximum of 2 days. Approximately one third of patients with migraine refer prodromal symptoms, either inhibitory, such as mental sluggishness, fatigue or anorexia, or excitatory, such as irritability, euphoria, yawning or craving for certain foods.11 Up to a third of patients occasionally experience “aura” that is, transient focal symptoms of pain immediately before or coinciding with its appearance. We must be familiar with the semiotics of migraine aura, not only for its significant frequency, but because the migraine aura itself is one of the reasons that most often lead the patient to the doctor. Migraine aura symptoms must be reversible in 60 min, maximum, they develop gradually, and typically include positive phenomena, photopsias type, coloured zigzag images or paresthesias. More than 90% of the auras have a visual component and nearly two thirds of patients with migraine have auras with isolated visual symptoms. The characteristic visual aura begins as a scotoma, which appears on the point of vision and grows larger in a visual hemifield. Typically, the edges of the scotoma are bright and colourful in nature, a phenomenon known by the name of “fortification spectra”. The sensory symptoms are second in frequency, between 30–40% of auras occur with cheiro-oral paresthesias established progressively in minutes. In less than 20% of auras, the symptoms include aphasia, and except in the hemiplegic migraine variant, motor symptoms are exceptional, which, along with positive visual symptoms, help regarding differential diagnosis with transient stroke. There is migraine variant, with basilar aura, in the form of bilateral visual blur, dizziness, diplopia, ataxia, paresthesias or bilateral weakness and decreased level of consciousness.10 Many migraine patients only experience the headache phase (and associated symptoms). The duration of pain ranging from 4 (without treatment) to 72 h (median 12–24 h) except in children, in which the duration may be less than 4 h. Pain is only hemicranial in 50% of cases. Most patients with bilateral pain, however, report that this rests primarily in the anterior region (temple or periocular) of one of the hemicrania. A small percentage of patients, those with basilar migraine, experience occipital pain. The migraine attack begins as hemicranial discomfort, which, between 30 and 120 min,
transforms gradually into moderate pain (interferes with common tasks) or severe pain (prevents them). The pain is referred to as pulsatile and is aggravated by light (photophobia), noises (phonophobia) and physical exercise, and is accompanied by symptoms, generally digestive in nature, especially nausea and, to a lesser extent, diarrhoea or vomiting.10 We know there are certain syndromes in childhood that are precursors of migraine in adulthood. These include cyclic vomiting, abdominal migraine and benign paroxysmal vertigo.10 Chronic migraine In short, it is understood that chronic migraine is a clinical situation in which a patient with a history of migraine has headaches during 15 or more days a month, who retains migraine characteristics during at least 8 days a month.10 More than a third of patients who consult meet criteria for painkiller abuse; that is, they take simple analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) more than 15 days a month, or ergotics, triptans or opiates more than 10 days a month. Chronic migraine justifies one in 25 standard Neurology consultations in our country and is difficult to treat entity.12,13 Because many cases are associated with analgesic and drug abuse, with vasoconstrictor effects, it is not uncommon to find that these patients have a history of hypertension or gastric problems (gastritis, peptic ulcer, hiatal hernia, etc.). The list of comorbidities and predisposing factors does not end here. It is well known that these patients have a higher than expected overweight, depression, anxiety, personality disorder or fibromyalgia incidence. Complications of migraine The migraine attacks that go over 72 h are renamed as status migrainosus, which requires specific hospital treatment.10 Many of these patients with status migrainosus have chronic migraine and meet the painkiller abuse criteria. In a minority of patients, the aura lasts for over a week with no evidence of ischaemia in neuroimaging. This clinical condition is known as persistent aura without infarction and it is usually visual, bilateral and lasts for months or years.10 In a minority of patients, an epileptic seizure occurs within a migraine aura. This clinical condition is known as migralepsy and must be differentiated from the headache that occurs after an epileptic seizure.10 Any symptoms of migraine aura that are associated with cerebral ischaemic injury confirmed by neuroimaging, clinically consistent with the aura are considered as a migrainous infarction. The real migrainous infarction occurs mainly in the posterior circulation and affects young women, and its diagnosis also requires the lack of any other cause. Several population studies have shown that patients, mainly women younger than 45, suffering migraine with aura, double the risk of ischaemic stroke. However, it should be noted that many of these strokes are not true migrainous infarctions and we do not know the relationship between the frequency and the pathophysiology of the aural symptoms denoting increased risk. Most studies have shown a lack of association between migraine without aura and ischaemic stroke.10 Complementary studies and differential diagnosis Simply applying the criteria, differential diagnosis of migraine with other primary headaches, such as tension headache, cluster headache or hemicrania continua, is simple. There are no findings in laboratory parameters or neurophysiological and neuroimaging studies that allow diagnosis confirmation. In the future, the serum levels of CGRP and vasoactive intestinal peptide may be able to help in the diagnosis of migraine.14,15 The diagnosis of migraine does not require any additional study in a patient with a normal
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physical examination that presents with painful episodic attacks of migrainous characteristics. This implies that in more than 90% of patients with migraine, diagnosis is made solely with a formal medical history and a standard physical examination.16,17 When should we request additional studies in patients with migraine and what kind of studies? The neuroimaging (CT or cranial MRI) are only indicated in patients with atypical migraine attacks, in patients with non-visual migraine aura, if the pain is always located on the same side of the head and in patients with a recent increase in the frequency of their attacks. It is important to insist that the only evidence able to rule out headache secondary to a structural process are neuroimaging techniques; that is, tests such as electroencephalogram are not indicated in the routine differential diagnosis of headaches, unless we think it might be a case of migralepsy. In patients with atypical auras (e.g., those including hemiparesis or lasting more than 60 min), apart from neuroimaging studies, antiphospholipid antibodies or thrombophilia studies can be requested. There are some entities, including CADASIL, reversible cerebral vasoconstriction syndrome, pseudomigraine with pleocytosis, SMART or MELAS, which may mimic a migraine headache with atypical aura, but a regulated medical history should enable us to get close to a diagnosis and then request the appropriate complementary studies in each case.16,17 Treatment General measures After the diagnosis of migraine, an understandable explanation of the process needs to be given to the patient. It is important to explain that migraine is a recurrent and episodic disease for which there is no cure, but in general, it can be controlled. Clarify the differences between the treatment of acute attacks and the preventive treatment. The next step is to identify possible triggers. These are varied and complex, since they are particular to each patient. In addition, many of these potential factors are impossible to avoid in patients with migraine. For the vast majority of patients, treatment solely based on preventing the triggers may achieve a marginal therapeutic effect, at the most, and, today, drug treatment is necessary. In any case, we must recommend the patient to have a healthy lifestyle, being as orderly as possible regarding daily schedules, doing regular exercise and trying to avoid overweight.16,17 Symptomatic or attack treatment Symptomatic treatment is mandatory in all migraineurs. Medications for the treatment of migraine may be divided into nonspecific, specific and adjuvants. Nonspecific medications include analgesics and NSAIDs. Specific drugs include ergotics and 5HT 1B/D receptors agonists, commonly known as “triptans”. The adjuvants are fundamentally antiemetic/prokinetics medications (domperidone, metoclopramide), required in patients with nausea and vomiting. Analgesics have a very limited use in the treatment of migraine, so their indication is very limited (migraine in childhood and adolescence). It is advisable to avoid combinations of analgesics with barbiturates, codeine and/or caffeine because of the risk of developing chronic headache due to abuse of these drugs. Because of their side effects and because, in our country, commercial presentations include other analgesics, caffeine and/or barbiturates, ergotics are not recommended.16,17 Symptomatic treatment of migraine resides therefore in the judicious use of triptans and NSAIDs. Patients with mild to moderate migraine attacks may be treated initially with oral NSAIDs, preferably in combination with metoclopramide or domperidone.
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Table 2 Potential indications of each of the different triptans according to their pharmacological profile and clinical experience data. Compound
Formulation
Indication
Sumatriptan
Subcutaneous 6 mg
Severe attacks resistant to oral and nasal route Attacks resistant to oral route Patients with vomiting Children and adolescents Standard migraine patient Patient likely to get pregnant Standard migraine patient Attacks resistant to oral route Patients with vomiting Mild to moderate long-term attacks Adverse effects with other triptans Severe, fast and short attacks Standard migraine patient Side effects with other triptans Severe attacks, long duration Mild to moderate attacks Long duration attacks Adverse effects with other triptans
Nasal 20 mg Nasal 10 mg Oral 50 mg Zolmitriptan
Oral 2.5–5 mg Nasal 5 mg
Naratriptan
Oral 2.5 mg
Rizatriptan Almotriptan
Oral 10 mg Oral 12.5 mg
Eletriptan Frovatriptan
Oral 20 and 40 mg Oral 2.5 mg
Not all NSAIDs are useful in migraine. NSAIDs with well proven efficacy available in our area are: acetylsalicylic acid, naproxen sodium, ibuprofen and dexketoprofen. Patients with mild-moderate attacks and lack of response or intolerance to NSAIDs have to be treated with triptans. Triptans are drugs with proven efficacy in the symptomatic treatment of migraine attacks, being of choice in moderate-severe type. Its contraindication is ischaemic heart disease. Triptans marketed and their specific indications are collected in Table 2. There are currently seven triptans marketed, which do not differ in their mechanism of action, but have relevant pharmacokinetic differences that make certain triptans more suitable than others depending on the type of attack. In patients with nausea or vomiting, liotab or nasal formulations may be used. If the patient does not respond to these options, we can use the subcutaneous formulation of sumatriptan and/or dexketoprofen trometamol or parenteral diclofenac with parenteral metoclopramide (Fig. 1).16,17 Preventive treatment It is estimated that at least 25% of patients who consult need preventive treatment. Preventive treatment has as main objective to reduce the frequency of attacks and make these milder and therefore easier to deal with. This treatment is our unfinished business in this field: it is estimated that less than 10% of patients who consult receive it. It is indicated for those who have 3 or more migraine attacks per month. It has to be maintained for a recommended period of 6–12 months, with a minimum of 3 months. Preventive treatment should be kept at least for 6 weeks before considering that the drug that is being used does not have therapeutic utility.16,17 Drugs with proven efficacy in the preventive treatment of standard migraine (without aura or with typical aura) are: some beta-blockers, candesartan, flunarizine, amitriptyline and some antiepileptic drugs. Indications, recommended dose and adverse effects of these drugs are variable and are listed in Table 3. Beta blockers are of choice in patients with migraine without aura and have no use contraindications (asthma and diabetes, mainly). The most commonly used in our area are propranolol and nadolol at doses of between 40 and 80 mg/day.16,17 One option of recently demonstrated efficacy in patients with contraindications to betablockers is candesartan at doses of 8–32 mg/day.18 Traditionally, in our area, flunarizine (2.5–10 mg/dinner) was the drug of choice
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Symptomatic treatment of migraine
Oral NSAIDs No response
Oral triptans No response
Triptans + oral NSAIDs No response
Intranasal zolmitriptan No response
Intranasal zolmitriptan + diclofenac suppository No response
Parenteral dexketoprofen No response
Subcutaneous sumatriptan No response
Metoclopramide IV + Dexketoprofen IV + Subcutaneous sumatriptan No response
Consider methylprednisolone and initiate preventive treatment Fig. 1. Options for the symptomatic treatment of migraine. NSAIDs: nonsteroidal anti-inflammatory drugs; IV: intravenous.
for patients without efficacy or intolerance/contraindication to the use of beta-blockers. AEDs are the most recommended drugs for most of the people who have not responded to beta-blockers or candesartan, except children and very thin women without a history of depression, as their side effects are mainly overweight and depression. 2 antiepileptic drugs with well proven efficacy
in migraine are topiramate (ideal dose 100 mg/day) and valproic acid (usual dose 500–1000 mg/day). Valproic acid needs lab tests to control the possibility of inducing fulminant hepatitis or disorders in the blood count. Topiramate advantages relate to its quick efficacy, which does not require lab tests control and being the only drug which does not induce overweight. Therefore, topiramate should be the antiepileptic drug of choice. However, 20% of patients cannot tolerate it due to adverse effects, including distal paresthesias, difficulty in mental concentration, abdominal pain, weight loss, depression, acute glaucoma, and renal calculi. Data from open series of patients indicate that zonisamide (100–300 mg/day), a drug profile very similar to topiramate is also useful in preventing migraine. Amitriptyline, at low doses of between 10 and 50 mg (evening dinner/supper) is the only antidepressant with proven efficacy in preventing migraine, especially when associated with tension headache. Fluoxetine and other serotonin reuptake inhibitors have not proven effective in preventing migraine, regardless of their antidepressant effect, which can be useful in these patients.16,17 In refractory patients with chronic migraine, clinical practice has proven that combinations of these drugs, in general, a beta blocker or candesartan with topiramate, are useful as they induce a synergistic effect.19,20 If there is no response or an antiepileptic (preferably topiramate) and/or a beta blocker or candesartan are not tolerated in patients with chronic migraine, quarterly pericranial injections of botulinum toxin type A are indicated, which, at doses of between 155 and 195 units at least 31 points, have shown efficacy over placebo controlled trials.21 It has been shown that the toxin does not act due to its muscle relaxant effect, but appears to decrease the pericranial release of algogenic peptides mainly CGRP.22 In clinical practice botulinum toxin type A achieves a significant reduction of migraine attacks as regards number of episodes, but mainly in relation to severity, in 70% of patients with chronic migraine, with excellent tolerability.23 Other advantages are that
Table 3 Indications and major adverse effects of drugs effective in the preventive treatment of migraine. Compound
Beta-blockers
Migraine without aura Migraine and hypertension Migraine and shaking
Candesartan
Migraine with/without aura Migraine and hypertension Migraine and depression Migraine with/without aura Chronic migraine Migraine and overweight
Topiramate/zonisamide
Adverse effects
Indications
Valproic acid
Refractory migraine with/without aura Chronic migraine
Flunarizina
Migraine with and without aura in children/adolescents or thin adults without tendency to depression
Amitriptyline
Migraine and tension headache Migraine and depression Migraine and insomnia
Botulinum toxin type A
Chronic migraine
Common
Rare
Fatigue Dizziness Nausea Orthostatic hypotension Impotence Distal coldness Fatigue Hypotension Teratogenicity Distal paresthesias Cognitive symptoms Intestinal disorders Weightloss Nausea/vomiting Drowsiness Overweight Shaking Alopecia Teratogenicity Depression
Depression Bradycardia Heart failure Bronchoconstriction Insomnia/nightmares
Drowsiness Overweight Drowsiness Constipation Overweight Skin/mucous dryness Palpitations Ptosis Cervicalgia
Galactorrhoea
Kidney failure Hyperkalaemia Glaucoma Nephrolithiasis Depression Hepatotoxicity Ovarian cysts Thrombocytopenia
Parkinsonism
Cognitive symptoms Urinary retention Glaucoma
Diplopia Dysphagia
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this drug produces no systemic or central nervous system effects, and can be combined with oral preventive drugs. Special situations In children, adjusting doses to the weight, the recommendations of symptomatic and preventive treatment are similar to those of adults for most drugs. Among triptans, sumatriptan nasal 10 mg and almotriptan have studies in children/adolescents with positive results. As to preventive treatment, a drug that is not recommended in adults, but it can be effective in children, is cyproheptadine.16,17 Migraine is the main neurological disease during pregnancy, regarding frequency. Some migraine patients go through an ordeal during pregnancy, as all kinds of medication are denied to them, except paracetamol. Clinical practice and prospective pregnancy registries have shown that sumatriptan and propranolol are safe during pregnancy as symptomatic and preventive treatment, respectively. Not only can we prescribe these drugs in pregnant women with incapacitating migraine attacks, after the appropriate patient explanation of the risk/benefit ratio, but we should consider prescribing these drugs also to women likely to get pregnant.24 The aura will have to be treated in a minority of patients due to their frequency or because of their incapacitating symptoms (e.g., basilar migraine). In these cases, lamotrigine is indicated at doses between 100 and 200 mg/day.25 Conflict of interests Dr. Julio Pascual has been a scientific advisor to Allergan. The other authors declare no conflicts of interest. References 1. Pascual J, Combarros O, Leno C, Polo JM, Rebollo M, Berciano J. Distribución por diagnósticos del dolor de cabeza como motivo de consulta neurológica. Med Clin (Barc). 1995;104:161–4. 2. Matías-Guiu J, Porta-Etessam J, Mateos V, Díaz-Insa S, López-Gil A, Fernández C, Scientific Committee of the PALM Program. One-year prevalence of migraine in Spain: a nationwide population-based survey. Cephalalgia. 2011;31: 463–70. ˜ P, Guitera V, Pascual J. Epidemiology of chronic daily headache 3. Castillo J, Munoz in the general population. Headache. 1999;39:190–6. ˜ 4. Colás R, Munoz P, Temprano R, Gómez C, Pascual J. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62:1338–42.
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5. Schürks M. Genetics of migraine in the age of genome-wide association studies. J Headache Pain. 2012;13:1–9. 6. Weiller C, May A, Limmroth V, Juptner M, Kaube H, Schayck RV, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:656–60. 7. Hadjikhani N, Sánchez del Río M, Wu O, Schwartz D, Bakker D, Fischl B, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98:4687–92. 8. Noseda R, Burstein R. Migraine pathophysiology: anatomy of trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Pain. 2013;154 Suppl. 1:S44–53. ˜ Neurologia. 1998;13:29–32. 9. Castro ME, Pascual J. Fisiopatología de la migrana. 10. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24 Suppl. 1:9–160. ˜ 11. Quintela E, Castillo J, Munoz P, Pascual J. Premonitory and resolution symptoms in migraine: a prospective study in 100 unselected patients. Cephalalgia. 2006;26:1051–60. 12. Pascual J, Sánchez del Río M, Jiménez MD, Láinez-Andrés JM, Mateos V, Leira ˜ crónica vista por el neurólogo y el paciente: resultados del R, et al. La migrana proyecto CIEN-mig (III). Rev Neurol. 2010;50:705–10. ˜ crónica: tratamiento. Rev Neurol. 2012;54 Suppl. 29:S31–8. 13. Pascual J. Migrana 14. Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81:1191–6. 15. Cernuda-Morollón E, Martínez-Camblor P, Alvarez R, Larrosa D, Ramón C, Pascual J. Increased VIP levels in peripheral blood outside migraine attacks as a potential biomarker of cranial parasympathetic activation in chronic migraine. Cephalalgia. 2015;35:310–6. 16. Díaz-Insa S, editor. Guía oficial para el diagnóstico y tratamiento de las cefaleas ˜ de Neurología. Barcelona: Thomson Reuters; 2011. de la Sociedad Espanola 17. Mateos V, Pareja J, Pascual J. Tratado de cefaleas. Madrid: Ergón; 2009. 18. Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T, et al. A comparative study of candesartan versus propranolol for migraine prophylaxis: a randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia. 2013;34:523–32. 19. Pascual J, Leira R, Láinez JM. Combined therapy for migraine prevention? Clinical experience with a beta-blocker plus sodium valproate in 52 resistant migraine patients. Cephalalgia. 2003;23:961–2. 20. Pascual J, Rivas MT, Leira R. Testing the combination beta-blocker plus topiramate in refractory migraine. Acta Neurol Scand. 2007;115:81. 21. Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50:921–36. 22. Cernuda-Morollón E, Ramón C, Martínez-Camblor P, Serrano-Pertierra E, Larrosa D, Pascual J. OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine. Pain. 2015;156:820–4. 23. Cernuda-Morollón E, Ramón C, Larrosa D, Alvarez R, Riesco N, Pascual J. Long-term experience with onabotulinumtoxinA in the treatment of chronic migraine: what happens after one year? Cephalalgia. 2015;35:864–8. ˜ y gestación: una relación compleja. Rev Neurol. 24. Pascual-Gómez J. Migrana 2010;50:321–4. 25. Pascual J, Caminero AB, Mateos V, Roig C, Leira R, García-Moncó JC, et al. Preventing disturbing migraine aura with lamotrigine: an open study. Headache. 2004;44:1024–8.