Causes of migraine

Migraine was previously considered to be a vascular phenomenon that resulted from intracranial vasoconstriction followed by rebound vasodilation. Currently, however, the neurovascular theory describes migraine as primarily a neurogenic process with secondary changes in cerebral perfusion associated with a sterile neurogenic inflammation (see Pathophysiology).

A genetic component to migraine is indicated by the fact that approximately 70% of patients have a first-degree relative with a history of migraine. In addition, a variety of environmental and behavioral factors may precipitate migraine attacks in persons with a predisposition to migraine (see Etiology).

Migraine characteristics and treatment

Migraine is characterized most often by unilateral head pain that is moderate to severe, throbbing, and aggravated by activity. It may also be associated with various visual or sensory symptoms, which occur most often before the headache component but which may occur during or after the headache; these are collectively known as an aura. Most commonly, the aura consists of visual manifestations, such as scotomas, photophobia, or visual scintillations (eg, bright zigzag lines) (see Presentation).

The head pain may also be associated with weakness. This form of migraine is termed hemiplegic migraine.

In practice, however, migraine headaches may be unilateral or bilateral and may occur with or without an aura. In the current International Headache Society categorization, the headache previously described as classic migraine is now known as migraine with aura, and the headache that was described as common migraine is now termed migraine without aura. Migraines without aura are the most common, accounting for more than 80% of all migraines.

The diagnosis of migraine is clinical in nature, based on criteria established by the International Headache Society. A full neurologic examination should be performed during the first visit, to exclude other disorders; the findings are usually normal in patients with migraine. Neuroimaging is not necessary in a typical case, but other diagnostic investigations may be indicated to guide management.

A screening tool called the ID-CM may be useful in diagnosis. The ID-CM is a 12-item screening tool for chronic migraine that has a sensitivity of 82% and a specificity of 87% compared with semi-structured clinical interviews.[6]

Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable.

Acute treatment aims to eliminate, or at least prevent the progression of, a headache. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of migraine attacks, to make acute attacks more responsive to abortive therapy, and perhaps also to improve the patient's quality of life (see Treatment).

See Migraine in Children for a pediatric perspective on migraine. Also see Migraine Variants and Childhood Migraine Variants.

Migraine classification

The second edition of the International Classification of Headache Disorders (ICHD)[7] lists the following types of migraine:

Migraine without aura (formerly, common migraine) Probable migraine without aura Migraine with aura (formerly, classic migraine) Probable migraine with aura Chronic migraine Chronic migraine associated with analgesic overuse Childhood periodic syndromes that may not be

precursors to or associated with migraine Complications of migraine Migrainous disorder not fulfilling above criteria

Diagnostic criteria

According to the International Headache Society, the diagnosis of migraine requires that the patient has experienced at least 5 attacks that fulfill the following 3 criteria and that are not attributable to another disorder.[1] First, the headache attacks must have lasted 4-72 hours (untreated or unsuccessfully treated). Second, the headache must have had at least 2 of the following characteristics:

Unilateral location

Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical

activity (eg, walking or climbing stairs) Third, during the headache the patient experiences at least 1 of the following:

Nausea and/or vomiting Photophobia and phonophobia

In June 2013, the International Classification of Headache Disorders, Third Edition(ICHD-III, beta version) was published and is available for field testing, which will take place for several years before the final version is published.

Changes from the previous edition include the following[8] :

The addition of chronic migraines: Those that occur on at least 15 days of the month for more than 3 months

For a diagnosis of migraine with aura, the following criteria must be met: One or more visual, sensory, speech, motor, brainstem, or retinal symptoms, as well as at least 2 of the following 4 criteria: (1) at least 1 aura symptom spreading gradually over 5 or more minutes and/or 2 or more symptoms occurring in succession; (2) each aura symptom lasting 5-60 minutes; (3) at least 1 aura symptom being unilateral; and (4) the aura being accompanied by or followed shortly by headache

Under headaches associated with sexual activity, the subtypes of preorgasmic and orgasmic headache have been eliminated

For thunderclap headaches, the headache must last at least 5 minutes, but the criterion of not recurring regularly during subsequent weeks or months has been discarded

Hypnic headaches no longer have to first occur after age 50 years

A number of pain characteristics under the new daily persistent headaches section have been eliminated

For secondary headaches, it is not required that the causative agent be removed before a diagnosis

The mechanisms of migraine remain incompletely understood. However, new technologies have allowed formulation of current concepts that may explain parts of the migraine syndrome.

Vascular theory

In the 1940s and 1950s, the vascular theory was proposed to explain the pathophysiology of migraine headache. Wolff et al believed that ischemia induced by intracranial vasoconstriction is responsible for the aura of migraine and that the subsequent rebound vasodilation and activation of perivascular nociceptive nerves resulted in headache.

This theory was based on the following 3 observations:

Extracranial vessels become distended and pulsatile during a migraine attack

Stimulation of intracranial vessels in an awake person induces headache

Vasoconstrictors (eg, ergots) improve the headache, whereas vasodilators (eg, nitroglycerin) provoke an attack

However, this theory did not explain the prodrome and associated features. Nor did it explain the efficacy of some drugs used to treat migraines that have no effect on blood vessels and the fact that most patients do not have an aura. Moreover, with the advent of newer imaging technologies, researchers found that intracranial blood flow patterns were inconsistent with the vascular theory.

No consistent flow changes have been identified in patients suffering from migraine headache without aura. Regional cerebral blood flow (rCBF) remains normal in the majority of patients. However, bilateral decrease in rCBF, beginning at the occipital cortex and spreading anteriorly, has been reported. More recently, Perciaccante has shown that migraine is characterized by a cardiac autonomic dysfunction.[11]

As a result of these anomalous findings, the vascular theory was supplanted by the neurovascular theory.

Neurovascular theory

The neurovascular theory holds that a complex series of neural and vascular events initiates migraine.[12] According to this theory, migraine is primarily a neurogenic process with secondary changes in cerebral perfusion.[13]

At baseline, a migraineur who is not having any headache has a state of neuronal hyperexcitability in the cerebral cortex, especially in the occipital cortex.[14] This finding has been demonstrated in studies of transcranial magnetic

stimulation and with functional magnetic resonance imaging (MRI).

This observation explains the special susceptibility of the migrainous brain to headaches.[15] One can draw a parallel with the patient with epilepsy who similarly has interictal neuronal irritability.

Cortical spreading depression

In 1944, Leao proposed the theory of cortical spreading depression (CSD) to explain the mechanism of migraine with aura. CSD is a well-defined wave of neuronal excitation in the cortical gray matter that spreads from its site of origin at the rate of 2-6 mm/min.

This cellular depolarization causes the primary cortical phenomenon or aura phase; in turn, it activates trigeminal fibers, causing the headache phase. The neurochemical basis of the CSD is the release of potassium or the excitatory amino acid glutamate from neural tissue. This release depolarizes the adjacent tissue, which, in turn, releases more neurotransmitters, propagating the spreading depression.

Oligemia

Positron emission tomography (PET) scanning demonstrates that blood flow is moderately reduced during a migrainous aura, but the spreading oligemia does not correspond to vascular territories. The oligemia itself is insufficient to impair function. Instead, the flow is reduced because the spreading depression reduces metabolism.

Although CSD is the disturbance that presumably results in the clinical manifestation of migraine aura, this spreading oligemia can be clinically silent (ie, migraine without aura). Perhaps a certain threshold is required to produce symptoms in patients having aura but not in those without aura. A study of the novel agent tonabersat, which inhibits CSD, found that the agent helped to prevent migraine attacks with aura only, suggesting that CSD may but not be involved in attacks without aura.[16]

Trigeminovascular system

Activation of the trigeminovascular system by CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and pain-generating substances

such as calcitonin gene-related peptide, substance P, vasoactive intestinal peptide, and neurokinin A. The resultant state of sterile inflammation is accompanied by further vasodilation, producing pain.

The initial cortical hyperperfusion in CSD is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. According to Moulton et al, altered descending modulation in the brainstem has been postulated to contribute to the headache phase of migraine; this leads to loss of inhibition or enhanced facilitation, resulting in trigeminovascular neuron hyperexcitability.[17]

Metalloproteinases

In addition, through a variety of molecular mechanisms, CSD upregulates genes, such as those encoding for cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, galanin, and metalloproteinases. The activation of metalloproteinases leads to leakage of the blood-brain barrier, allowing potassium, nitric oxide, adenosine, and other products released by CSD to reach and sensitize the dural perivascular trigeminal afferent endings.[18]

Increased net activity of matrix metalloproteinase–2 (MMP-2) has been demonstrated in migraineurs. Patients who have migraine without aura seem to have an increased ratio of matrix metalloproteinase–9 (MMP-9) to tissue inhibitors of metalloproteinase–1 (TIMP-1), in contrast to a lower MMP-9/TIMP-1 ratio in patients who have migraine with aura.[19] Measured levels of MMP-9 alone are the same for migraine patients with or without aura.[20]

Hypoxia

In an experimental study, acute hypoxia was induced by a single episode of CSD. This was accompanied by dramatic failure of brain ion homeostasis and prolonged impairment of neurovascular and neurometabolic coupling.[21]

Vasoactive substances and neurotransmitters

Perivascular nerve activity also results in release of substances such as substance P, neurokinin A, calcitonin

gene-related peptide, and nitric oxide, which interact with the blood vessel wall to produce dilation, protein extravasation, and sterile inflammation. This stimulates the trigeminocervical complex, as shown by induction of c-fos antigen by PET scan. Information then is relayed to the thalamus and cortex for registering of pain. Involvement of other centers may explain the associated autonomic symptoms and affective aspects of this pain.

Neurogenically induced plasma extravasation may play a role in the expression of pain in migraine, but it may not be sufficient by itself to cause pain. The presence of other stimulators may be required.

Although some drugs that are effective for migraine inhibit neurogenic plasma extravasation, substance P antagonists and the endothelin antagonist bosentan inhibit neurogenic plasma extravasation but are ineffective as antimigraine drugs. Also, the pain process requires not only the activation of nociceptors of pain-producing intracranial structures but also reduction in the normal functioning of endogenous pain-control pathways that gate the pain.

Migraine center

A potential "migraine center" in the brainstem has been proposed, based on PET-scan results showing persistently elevated rCBF in the brainstem (ie, periaqueductal gray, midbrain reticular formation, locus ceruleus) even after sumatriptan-produced resolution of headache and related symptoms. These were the findings in 9 patients who had experienced spontaneous attack of migraine without aura. The increased rCBF was not observed outside of the attack, suggesting that this activation was not due to pain perception or increased activity of the endogenous antinociceptive system.

The fact that sumatriptan reversed the concomitant increased rCBF in the cerebral cortex but not the brainstem centers suggests dysfunction in the regulation involved in antinociception and vascular control of these centers. Thalamic processing of pain is known to be gated by ascending serotonergic fibers from the dorsal raphe nucleus and from aminergic nuclei in the pontine tegmentum and locus ceruleus; the latter can alter brain flow and blood-brain barrier permeability.

Because of the set periodicity of migraine, linkage to the suprachiasmatic nucleus of the hypothalamus that

governs circadian rhythm has been proposed. Discovering the central trigger for migraine would help to identify better prophylactic agents.

Brainstem activation

PET scanning in patients having an acute migraine headache demonstrates activation of the contralateral pons, even after medications abort the pain. Weiler et al proposed that brainstem activation may be the initiating factor of migraine.

Once the CSD occurs on the surface of the brain, H+ and K+ ions diffuse to the pia mater and activate C-fiber meningeal nociceptors, releasing a proinflammatory soup of neurochemicals (eg, calcitonin gene–related peptide) and causing plasma extravasation to occur. Therefore, a sterile, neurogenic inflammation of the trigeminovascular complex is present.

Once the trigeminal system is activated, it stimulates the cranial vessels to dilate. The final common pathway to the throbbing headache is the dilatation of blood vessels.

Cutaneous allodynia

Burstein et al described the phenomenon of cutaneous allodynia, in which secondary pain pathways of the trigeminothalamic system become sensitized during a migrainous episode.[22] This observation demonstrates that, along with the previously described neurovascular events, sensitization of central pathways in the brain mediates the pain of migraine.

Dopamine pathway

Some authors have proposed a dopaminergic basis for migraine.[23] In 1977, Sicuteri postulated that a state of dopaminergic hypersensitivity is present in patients with migraine. Interest in this theory has recently been renewed.

Some of the symptoms associated with migraine headaches, such as nausea, vomiting, yawning, irritability, hypotension, and hyperactivity, can be attributed to relative dopaminergic stimulation. Dopamine receptor hypersensitivity has been shown experimentally with dopamine agonists (eg, apomorphine). Dopamine antagonists (eg, prochlorperazine) completely relieve almost 75% of acute migraine attacks.

Magnesium deficiency

Another theory proposes that deficiency of magnesium in the brain triggers a chain of events, starting with platelet aggregation and glutamate release and finally resulting in the release of 5-hydroxytryptamine, which is a vasoconstrictor. In clinical studies, oral magnesium has shown benefit for preventive treatment and intravenous magnesium may be effective for acute treatment, particularly in certain subsets of migraine patients.[24]

Endothelial dysfunction

Vascular smooth muscle cell dysfunction may involve impaired cyclic guanosine monophosphate and hemodynamic response to nitric oxide.[25] Nitric oxide released by microglia is a potentially cytotoxic proinflammatory mediator, initiating and maintaining brain inflammation through activation of the trigeminal neuron system.

Nitric oxide levels continue to be increased even in the headache-free period in migraineurs.[26] In premenopausal women with migraine, particularly in those with migraine aura, increased endothelial activation, which is a component of endothelial dysfunction, is evident.[27]

Serotonin and migraine

The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important receptor in the headache pathway. Immunohistochemical studies have detected 5-hydroxytryptamine–1D (5-HT1D) receptors in trigeminal sensory neurons, including peripheral projections to the dura and within the trigeminal nucleus caudalis (TNC) and solitary tract, while 5-HT1B receptors are present on smooth muscle cells in meningeal vessels; however, both can be found in both tissues to some extent and even in coronary vessels.

All the currently available triptans (see Medication) are selective 5-HT1B/D full agonists. These agents may decrease headache by abolishing neuropeptide release in the periphery and blocking neurotransmission by acting on second-order neurons in the trigeminocervical complex.

Migraine risk factors

Predisposing vascular risk factors for migraine include the following[28] :

Increased levels of C-reactive protein Increased levels of interleukins Increased levels of TNF-alpha and adhesion molecules

(systemic inflammation markers) Oxidative stress and thrombosis Increased body weight High blood pressure Hypercholesterolemia Impaired insulin sensitivity High homocysteine levels Stroke Coronary heart disease

Transformed migraine/medication overuse headache

In some patients, migraine progresses to chronic migraine. Acute overuse of symptomatic medication is considered one of the most important risk factors for migraine progression. Medication overuse headache can occur with any analgesic, including acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin. In addition, Bigal and Lipton identified the following associations of medication with progression to chronic migraine[29] :

Opiates - Critical dose of exposure is around 8 days per month; the effect is more pronounced in men

Barbiturates - Critical dose of exposure is around 5 days per month; the effect is more pronounced in women

Triptans - Migraine progression is seen only in patients with high frequency of migraine at baseline (10-14 days/mo)

In the study, the effect of anti-inflammatory medications varied with headache frequency. These agents were protective in patients with fewer than 10 days of headache at baseline but induced migraine progression in patients with a high frequency of headaches at baseline.[29]

Etiology

Migraine has a strong genetic component. Approximately 70% of migraine patients have a first-degree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of people who have migraine with aura.[30]

Nonsyndromic migraine headache with or without aura generally shows a multifactorial inheritance pattern, but the specific nature of the genetic influence is not yet

completely understood. Certain rarer syndromes with migraine as a clinical feature generally show an autosomal dominant inheritance pattern.[31]

However, recent genome-wide association studies have suggested 4 regions in which single-nucleotide polymorphisms influence the risk of developing migraine headache.[32, 33, 34] Other associations have been found in individual studies but could not be replicated in other populations.

Familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare type of migraine with aura that is preceded or followed by hemiplegia, which typically resolves. FHM may be associated with cerebellar ataxia, which is also linked to the 19p locus. Evidence suggests that the 19p locus for FHM may also be involved in patients with other forms of migraine. Three genes have thus far been identified as being causative for FHM.

FHM type 1 is characterized clinically by episodes that commonly include nystagmus and cerebellar signs. This disorder is caused by mutations in theCACNA1A gene located on 19p13, which codes for a brain-specific calcium channel. Mutations in CACNA1A were previously thought to account for 50% of cases of FHM,[35] but a Danish study showed that only 7% of patients with a clinical diagnosis of FHM had a mutation in that gene.[36]

FHM type 2 occurs in patients who also have a seizure disorder. This condition has been attributed to mutations in the ATP1A2 gene, located on 1q21q23, which encodes a sodium/potassium pump.[37, 38] However, the Danish study found mutations in ATP1A2 in only 7% of patients with a clinical diagnosis of FHM.[36]

FHM type 3 is caused by mutations in the SCN1A gene, located on 2q24. Mutations in SCN1A are also known to cause familial febrile seizure disorders and infantile epileptic encephalopathy.[39] Although SCN1A mutation has been reported in several unrelated families, it is felt to be a rare cause of FHM.[40]

Migraine in other inherited disorders

Migraine occurs with increased frequency in patients with mitochondrial disorders, such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). CADASIL (cerebral autosomal dominant

arteriopathy with subcortical infarcts and leukoencephalopathy) is a genetic disorder that causes migraine with aura, strokes before the age of 60, progressive cognitive dysfunction, and behavioral changes.

CADASIL is inherited in an autosomal dominant fashion, and most patients with the disorder have an affected parent. Approximately 90% of cases result from mutations of the <INOTCH3< I>gene, located on chromosome 19. Patients with CADASIL have significant morbidity from their ailment, and life expectancy is approximately 68 years.[41]

Migraine is also a common symptom in other genetic vasculopathies, including 2 autosomal dominant disorders: (1) RVCL (retinal vasculopathy with cerebral leukodystrophy), which is caused by mutations in the TREX1 gene,[42] and (2) HIHRATL (hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy), which is suggested to be caused by mutations in theCOL4A1 gene.[43] The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear.[44]

Migraine precipitants

Various precipitants of migraine events have been identified, as follows:

Hormonal changes, such as those accompanying menstruation (common), [45]pregnancy, and ovulation

Stress Excessive or insufficient sleep Medications (eg, vasodilators, oral contraceptives [46] ) Smoking Exposure to bright or fluorescent lighting Strong odors (eg, perfumes, colognes, petroleum

distillates) Head trauma Weather changes Motion sickness Cold stimulus (eg, ice cream headaches) Lack of exercise Fasting or skipping meals Red wine

Certain foods and food additives have been suggested as potential precipitants of migraine, including the following:

Caffeine

Artificial sweeteners (eg, aspartame, saccharin) Monosodium glutamate (MSG) Citrus fruits Foods containing tyramine (eg, aged cheese) Meats with nitrites

However, large epidemiologic studies have failed to substantiate most of these as triggers,[47] and no diets have been shown to help migraine. Nevertheless, patients who identify particular foods as triggers should avoid these foods.

Although chocolate has been considered a migraine trigger, data from the PAMINA study do not support this contention.[47] Instead, it has been hypothesized that ingestion of chocolate may be in response to a craving brought on at the start of a migraine, as a result of hypothalamic activation.

Migraine and other vascular disease

People who suffer from migraine headaches are more likely to also have cardiovascular or cerebrovascular disease (ie, stroke, myocardial infarction).[48]Reliable evidence comes from the Women's Health Study, which found that migraine with aura raised the risk of myocardial infarction by 91% and ischemic stroke by 108% and that migraine without aura raised both risks by approximately 25%.[49] Migraines during pregnancy are also linked to stroke and vascular diseases.[50]

Migraine with aura for women in midlife has a statistically significant association with late-life vascular disease (infarcts) in the cerebellum. This association is not seen in migraine without aura.[51]

Migraine and iron

In a population-based MRI study by Kruit et al, migraineurs had increased local iron deposits in the putamen, globus pallidus, and red nucleus, compared with controls.[52] This increase in iron deposits may be explained as a physiologic response induced by repeated activation of nuclei involved in central pain processing or by damage to these structures secondary to the formation of free radicals in oxidative stress (possibly the cause of the disease becoming chronic).[53]

Migraine and sensory perception

In a study by Nguyen et al, quantitative sensory testing found significant differences in the perception of

vibrotactile stimulation in patients with migraine compared with controls, including stimulus amplitude discrimination, temporal order judgment, and duration discrimination.[54]