Pathophysiology, clinical manifestations, and diagnosis of migraine in adults

INTRODUCTION — Migraine is an episodic disorder, the centerpiece of which is a severe headache generally associated with nausea and/or light and sound sensitivity. It is one of the most common complaints encountered by neurologists in day-to-day practice.

The pathophysiology, clinical manifestations, diagnosis, and complications of migraine will be reviewed here. Other aspects of migraine are discussed separately. (See "Acute treatment of migraine in adults" and "Preventive treatment of episodic migraine in adults" and "Chronic migraine" and "Migraine with brainstem aura" and "Hemiplegic migraine" and "Vestibular migraine" and "Migraine-associated stroke: risk factors, diagnosis, and prevention".)

PATHOPHYSIOLOGY — The current state of knowledge suggests that a primary neuronal dysfunction leads to a sequence of changes intracranially and extracranially that account for migraine [1,2], including the four phases of premonitory symptoms, aura, headache, and postdrome.

The once-popular vascular theory of migraine, which suggested that migraine headache was caused by the dilatation of blood vessels while the aura of migraine resulted from vasoconstriction, is no longer considered viable [3-5]. Vasodilatation, if it occurs at all during spontaneous migraine attacks [5], is probably an epiphenomenon resulting from instability in the central neurovascular control mechanism [6].

Cortical spreading depression — A causal association between migraine aura and headache is supported by evidence that both are linked to the phenomenon known as cortical spreading depression of Leão [3,7,8]. Cortical spreading depression is a self-propagating wave of neuronal and glial depolarization that spreads across the cerebral cortex. Cortical spreading depression is hypothesized to:

●Cause the aura of migraine [9]

●Activate trigeminal nerve afferents [10,11]

●Alter blood-brain barrier permeability by matrix metalloproteinase activation and upregulation [12]

The activation of trigeminal afferents by cortical spreading depression in turn causes inflammatory changes in the pain-sensitive meninges that generate the headache of migraine through central and peripheral reflex mechanisms [13]. The likely molecular cascade of events by which pain-sensitive trigeminal afferent neurons are activated by cortical spreading depression involves the opening of neuronal pannexin-1 megachannels and subsequent activation of caspase-1, followed by the release of the proinflammatory mediators, activation of nuclear factor kappa-B in astrocytes, and transduction of the inflammatory signal to trigeminal nerve fibers around pial vessels [11]. Thus, this pathway links cortical spreading depression, the phenomenon thought to underlie the migraine aura, to prolonged activation of trigeminal nociception, which generates the pain of the migraine headache.

It has been suggested that migraine without aura may be caused by the occurrence of cortical spreading depression in areas of the brain (eg, cerebellum) where depolarization is not consciously perceived [14].

Trigeminovascular system — The pathophysiology of migraine involves activation of the trigeminovascular system, which consists of small caliber pseudounipolar sensory neurons that originate from the trigeminal ganglion and upper cervical dorsal roots [15]. These sensory neurons project to innervate large cerebral vessels, pial vessels, dura mater, and large venous sinuses. Most of the innervation of the anterior structures is via the ophthalmic division of the trigeminal nerve with a greater contribution of upper cervical roots to posterior structures.

There is convergence of the projections from the upper cervical nerve roots and the trigeminal nerve at the trigeminal nucleus caudalis [16,17]. This convergence can explain the distribution of migraine pain, which often includes anterior and posterior regions of the head and the upper neck. Once transmitted to the trigeminal nucleus caudalis by trigeminal axons, central signals can be modulated by projections from the rostral trigeminal nuclei [18], the periaqueductal gray, and the nucleus raphe magnus [19], as well as by descending cortical inhibitory systems [19,20].

From the trigeminal nucleus caudalis, fibers that are involved in the localization of pain ascend to the thalamus (mostly to the ventroposterior medial nucleus of the thalamus) and to the sensory cortex [21]. Other second-order neurons from the trigeminal nucleus caudalis project to numerous subcortical sites including the more rostral segments of the trigeminal complex [22], the reticular formation of the brain stem [23], the cerebellum [24,25], the midbrain and pontine parabrachial nuclei [26,27], the ventrobasal thalamus [22,25,28,29], the posterior thalamus [30,31], and the medial thalamus [32]. From more rostral brain stem nuclei, nociceptive information is transmitted to other brain areas (eg, limbic regions) involved in the emotional and vegetative responses to pain [26].

Stimulation of the trigeminal ganglion results in release of vasoactive neuropeptides, including substance P, calcitonin gene-related peptide (CGRP), and neurokinin A [33]. Release of these neuropeptides is associated with the process of neurogenic inflammation. The two main components of this sterile inflammatory response are vasodilation (CGRP is a potent vasodilator) and plasma protein extravasation.

Neurogenic inflammation is thought to be important in the prolongation and intensification of the pain of migraine. Elevated levels of vasoactive neuropeptides have been found in the cerebrospinal fluid of patients with chronic migraine, suggesting chronic activation of the trigeminovascular system in these patients [34]. Neurogenic inflammation may lead to the process of sensitization.

Sensitization — Sensitization refers to the process in which neurons become increasingly responsive to nociceptive and non-nociceptive stimulation: response thresholds decrease, response magnitude increases, receptive fields expand, and spontaneous neuronal activity develops [35-37]. Peripheral sensitization in the primary afferent neurons and central sensitization within second-order neurons in the trigeminal nucleus caudalis and higher-order neurons in the central nervous system are thought to play a role within individual migraine attacks and, perhaps, even in the transformation of episodic migraine to chronic migraine.

Sensitization is likely responsible for many of the clinical symptoms of migraine, including the throbbing quality of the pain, the worsening of pain with coughing, bending, or sudden head movements (as is often observed during the postdrome), hyperalgesia (increased sensitivity to painful stimuli), and allodynia (pain produced by normally non-noxious stimulation).

Functional brain imaging has identified abnormalities in the ascending and descending pain pathways of patients with migraine during and in between attacks. Alterations in blood flow to the dorsal pons, anterior cingulate cortex, visual cortex, and auditory association cortex have been seen [38,39]. Patients with chronic migraine are found to have altered blood flow to the dorsal pons, anterior cingulate cortex, and cuneus [40].

Structural changes in the brain have also been found. Studies suggest that patients with migraine have increased cortical thickness in motion-processing visual areas, increased density of the periaqueductal gray and dorsolateral pons, and decreased gray matter in the anterior cingulate cortex and insula [41,42]. Increased iron levels have been identified in the periaqueductal gray of episodic and chronic migraineurs [43].

Role of serotonin — Although activation at serotonin receptors is of known importance in the acute treatment of migraine, its role in the generation of migraine is unclear [44]. Some authors have suggested that serotonin (released from brainstem serotonergic nuclei) plays a role in the pathogenesis of migraine, perhaps mediated by its direct action upon the cranial vasculature, by its role in central pain control pathways, or by cerebral cortical projections of brainstem serotonergic nuclei [45,46]. Such a role for serotonin is supported by the fact that tricyclic antidepressants, which block serotonin reuptake, are effective antimigraine prophylactic agents. In contrast, however, more selective serotonin reuptake inhibitors are not very effective in migraine prevention. There is other evidence that a low serotonin state may result in a deficit in the serotonin descending pain inhibitory system, facilitating activation of the trigeminovascular nociceptive pathways in conjunction with cortical spreading depression [45,46].

Role of calcitonin gene-related peptide — The calcitonin gene-related peptide has a key role in migraine pathophysiology [47]. CGRP is a 37 amino acid neuropeptide that is expressed in trigeminal ganglia nerves and is a potent vasodilator of cerebral and dural vessels [48]. CGRP appears to mediate trigeminovascular pain transmission from intracranial vessels to the central nervous system, as well as the vasodilatory component of neurogenic inflammation [47]. Stimulation of the trigeminal ganglion induces the release of CGRP [33], and CGRP infusion can trigger a migraine attack in patients with migraine [49]. One study found elevation of CGRP levels in external jugular venous blood during migraine attacks [50]. Another found that elevated CGRP levels were normalized in patients with migraine following administration of the serotonin 1b/1d receptor agonist sumatriptan [51], suggesting that triptans may act to control migraine at least in part by blocking the release of CGRP. These and other data have established that CGRP release plays an important modulatory role in migraine headache [47].

The use of CGRP antagonists for migraine treatment is discussed separately. (See "Acute treatment of migraine in adults", section on 'CGRP antagonists' and "Preventive treatment of episodic migraine in adults", section on 'CGRP antagonists'.)

Right-to-left cardiac shunt — Migraine with aura has been linked to right-to-left cardiac shunts, usually in the setting of a patent foramen ovale (PFO) or, much less often, an atrial septal defect (ASD) [52-54] or pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) [55]. (See "Clinical manifestations and diagnosis of atrial septal defects in adults" and "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

Evidence regarding the association of migraine with PFO is conflicting.

●In a population-based study of 1101 stroke-free subjects (mean age 69 years) from the NOMAS cohort who were evaluated for PFO using transthoracic echocardiography with saline contrast and provocative maneuvers, there was no significant difference in the prevalence of PFO among subjects who had migraine compared with those who did not have migraine (14.6 versus 15.0 percent) [56]. The presence of PFO was not associated with an increased prevalence of migraine (odds ratio [OR] 1.01, 95% CI 0.63-1.61) or an increased prevalence of migraine with aura (OR 1.01, 95% CI 0.71-1.69) compared with no migraine.

●A systematic review of case-control studies published in 2008 concluded that migraine with aura (but not without aura) is more common in patients with PFO than in the general population and that PFO is more prevalent in patients who have migraine with aura than in the general population [57].

While definitive conclusions are not yet possible, the population-based NOMAS study provides high-quality observational evidence that PFO is not associated with migraine [58]. In contrast, the association of PFO with migraine in the systematic review is supported by low or low to moderate quality evidence [57].

The mechanism of any possible association between right-to-left cardiac shunt and migraine is not known. One theory is that a genetic influence might predispose some patients to a higher risk of developing both atrial septal abnormalities and migraine [59]. Other theories focus on the shunt pathway. As examples, one hypothesis is that the venous circulation contains vasoactive substances capable of triggering migraine; these are normally inactivated in the lungs but gain access to the cranial circulation in the presence of a right-to-left shunt [60]. Another hypothesis is that the existence of the shunt provides a pathway for paradoxical embolism and subsequent cerebral ischemia, which in turn triggers migraine. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults".)

GENETIC BASIS — Migraine is a syndromic disorder of the brain that is in most instances inherited. As with most common diseases, the genetic basis of migraine is likely to be complex and in some individuals may be based on the additive effect of more than one genetic source. Individuals prone to migraine have a genetic threshold that renders them susceptible to an acute migraine attack depending upon the balance between excitation and inhibition at various levels of the nervous system. Subtle abnormalities, involving membrane channels, receptor families, and enzyme systems have been linked to migraine in certain groups and individuals.

The importance of inheritance in migraine has long been recognized [61]. One early general population-based study found that the risk of migraine in relatives of patients with migraine was three times greater than that of relatives of non-migraine control subjects [62]. However segregation analysis does not identify any single Mendelian pattern of inheritance in the common forms of migraine [63]. Large national registry-based twin studies have confirmed a consistently higher concordance of migraine in monozygotic twins versus dizygotic twins. In one such study, using a polygenic multifactorial model, researchers estimated that inheritance accounts for 40 to 50 percent of an individual's susceptibility to migraine [64].

Genetics of the common forms of migraine — The genetic basis of the common forms of migraine (migraine with aura and migraine without aura) has not been clarified despite increasing research. A number of candidate genes have been linked with migraine, a list that includes the KCNK18 gene that encodes for TRESK, a two-pore domain potassium channel [65], and the CSNK1D gene, which encodes casein kinase I isoform delta [66]. However, the findings of gene studies in migraine generally have not been replicated in subsequent reports. As an example, a systematic reevaluation of 27 promising candidate migraine genes in a large dataset compiled from genome-wide association studies (GWAS), with over 5175 patients with migraine and 13,972 control subjects, found that none of the candidate genes reached the threshold for statistical significance [67]. Thus, it is still uncertain which candidate loci and genes are truly implicated in the pathogenesis of migraine.

The common forms of migraine are likely to be complex genetic disorders, meaning that multiple genes at different genomic sites act in tandem with environmental factors to confer both the susceptibility to and the characteristics of the disease in affected individuals. One possible explanation for the lack of replication in genetic studies of migraine is that a few gene polymorphisms are frequently tested for association in relatively small populations in which only a portion of the subjects have migraine that arises from the studied variant, while the migraine in other case subjects has a different basis. This would tend to lower the power of many of these studies to detect a significant difference in the case subjects compared with the non-migraine control subjects. The eventual identification of the genes that underlie migraine in an individual patient is extremely important, as it may be predictive of the type of prophylactic treatment to which the patient will respond.

Familial hemiplegic migraine — Hemiplegic migraine may occur either in families or only in one individual (sporadic). The first three types of familial hemiplegic migraine (FHM) are channelopathies. FHM1 is caused by variants of the CACNA1A gene, FHM2 by variants of the ATP1A2 gene, and FHM3 by variants of the SCN1A gene. Variants of the PRRT2 gene also cause some cases of familial hemiplegic migraine. The known types of familial hemiplegic migraine account for only a small proportion of cases. (See "Hemiplegic migraine", section on 'Familial hemiplegic migraine'.)

EPIDEMIOLOGY — Migraine is a common disorder that affects 12 to 15 percent of the general population [68,69]. It is more frequent in females than in males, with attacks occurring in up to 17 percent of females and 6 percent of males each year [70,71]. Migraine without aura is the most common type, accounting for approximately 75 percent of cases.

Migraine is most common in those aged 30 to 39, an age span in which prevalence in males and females reaches 7 and 24 percent, respectively (figure 1) [71]. Migraine also tends to run in families. (See 'Genetic basis' above.)

Migraine is a major cause of disability and ranked second after low back pain worldwide among all diseases with respect to years of life lived with disability [69,72].

Data from several retrospective nationwide cohort studies in Taiwan, all from the same group of investigators, suggest that migraine is a potential risk factor for Bell's palsy, sensorineural hearing loss, and oculomotor cranial nerve palsies [73-75]; independent reports are needed to confirm these associations.

PRECIPITATING AND EXACERBATING FACTORS — Several environmental and dietary stimuli have been reported to trigger migraine attacks. An evidence-based review concluded that stress, menstruation, visual stimuli, weather changes, nitrates, fasting, and wine were probable migraine trigger factors, while sleep disturbances and aspartame were possible migraine triggers [76]. All of the probable and possible migraine triggers except aspartame were also general headache triggers. There was evidence that monosodium glutamate was a general headache trigger but unproven as a migraine trigger. Smoking, odors, chocolate, and tyramine were unproven as triggers of migraine or general headache.

In a retrospective study of 1750 patients with migraine, approximately 75 percent reported at least one trigger of acute migraine attacks [77]. In order of descending frequency these included:

●Emotional stress (80 percent)

●Hormones in females (65 percent)

●Not eating (57 percent)

●Weather (53 percent)

●Sleep disturbances (50 percent)

●Odors (44 percent)

●Neck pain (38 percent)

●Lights (38 percent)

●Alcohol (38 percent)

●Smoke (36 percent)

●Sleeping late (32 percent)

●Heat (30 percent)

●Food (27 percent)

●Exercise (22 percent)

●Sexual activity (5 percent)

Many alcoholic beverages can trigger migraine, but red wine appears to be the most common trigger in cross-sectional studies [78,79]. Flavonoid phenols, sulfites, or other compounds have been posited to account for "red wine headache" amongst patients reporting this trigger [80,81]. Additional factors may be implicated, as white wine, spirits, and other alcoholic beverages are triggers for other patients.

Sleep disturbances and migraine are often comorbid, but both disorders are fairly common in the general population and their co-occurrence could be coincidental [82-85]. Nevertheless, the study cited above suggests that sleep disorders can exacerbate migraine [77]. In addition, poor sleep quality has been associated with increased migraine headache frequency and disability [86,87]. Obesity also has been associated with an increased frequency and severity of migraine [88-90]. Migraine headaches are often worsened by rapid head motion, sneezing, straining at stool, constant movement, or physical exertion.

CLINICAL FEATURES — Migraine is a disorder of recurrent attacks. The attacks unfold through a cascade of events that occur over the course of several hours to days. A typical migraine attack progresses through four phases: the prodrome, the aura, the headache, and the postdrome [91].

Migraine prodrome — The prodrome occurs in up to 77 percent of patients with migraine and consists of affective or vegetative symptoms that appear 24 to 48 hours prior to the onset of headache [92,93]. Frequently reported prodromal symptoms include increased yawning, euphoria, depression, irritability, food cravings, constipation, and neck stiffness.

Migraine aura — About 25 percent of people with migraines experience one or more focal neurologic symptoms in the second phase, called the migraine aura. Traditional teaching is that migraine aura usually precedes the headache. However, prospective data suggest that most patients with migraine experience headache during the aura phase [94].

Typical migraine auras are characterized by gradual development, duration no longer than one hour, a mix of positive and negative features, and complete reversibility [95]. Positive symptoms indicate active discharge from central nervous system neurons. Typical positive symptoms can be visual (eg, bright lines, shapes, objects), auditory (eg, tinnitus, noises, music), somatosensory (eg, burning, pain, paresthesia), or motor (eg, jerking or repetitive rhythmic movements). Negative symptoms indicate an absence or loss of function, such as loss of vision, hearing, feeling, or ability to move a part of the body. Auras are most often visual but can also be sensory, verbal, or motor disturbances.

The aura of migraine usually develops gradually over more than five minutes. Less often, the aura develops more acutely (ie, in less than five minutes). The acute onset of aura makes confusion with a transient ischemic attack (TIA) or stroke more likely. In one case series, four patients (2 percent) had exclusively acute-onset visual aura [96].

Visual aura — A visual aura classically begins as a small area of visual loss often just lateral to the point of visual fixation. It may either appear as a bright spot or as an area of visual loss. Over the following five minutes to one hour, the visual disturbance expands to involve a quadrant or hemifield of vision. Along the expanding margin, geometric shapes or zigzagging lines often appear. The shapes account for one of the common names for aura, the "fortification spectrum," because of the resemblance of the aura to the walls of a medieval fortress. The positive visual phenomena may assume a sickle or C-shape, expanding over time toward the peripheral visual field, leaving a scotoma or area of complete visual loss in their wake. As the aura moves off into the peripheral visual field, it often assumes a shimmering or scintillating quality. As the aura resolves, vision usually returns first to the areas of central vision initially affected by the aura [97]. (See "Approach to the patient with visual hallucinations", section on 'Migraine aura'.)

Sensory aura — The sensory aura is also common and typically follows the visual aura within minutes, although it may also occur without the visual aura. A sensory aura usually begins as a tingling in one limb or on one side of the face. As the tingling sensation migrates across one side of the face or down the limb, numbness is left in its wake that may last up to an hour. The sensory aura may also move inside the mouth, affecting the buccal mucosa and half the tongue. The slow spread of positive symptoms (scintillations or tingling) followed by negative symptoms (scotoma or numbness) is quite characteristic of migraine aura and is not typical for an ischemic event [97].

Language aura — Less common than the visual and sensory auras is the language or dysphasic aura. Language auras cause transient problems that may run the gamut from mild wording difficulties to frank dysphasia with paraphasic errors.

Motor aura — In the rarest of auras, motor aura, the limbs and possibly the face on one side of the body become weak. Because of information related to the genetic basis of the motor aura, it has been separated from the other forms of aura and classified as hemiplegic migraine (see "Hemiplegic migraine"). The aura symptoms may occur either singly or in sequence, but they do not generally occur simultaneously.

Aura without headache — Some patients may experience aura without an associated headache. Migraine aura without headache (also known as migraine equivalent and acephalgic migraine) manifests as isolated aura unaccompanied by headache. In a Danish case study, 38 percent of patients reported having both attacks of migraine aura without headache as well as migraine aura with headache, and 4 percent had exclusively migraine aura without headache [96]. Auras without headache may be confused with transient ischemic attacks, especially when they first present in older patients as late-life migraine accompaniments, which are described in the next section.

Late-life migraine accompaniments — Late-life migraine accompaniments are symptoms related to the onset after the age of 50 years of migraine aura without headache [98,99]. The most common symptoms are visual auras, followed by sensory auras (paresthesia), speech disturbances, and motor auras (weakness or paralysis). The most common presentation is gradual evolution of aura symptoms with spread of transient neurologic deficits over several minutes and serial progression from one symptom to another.

Migraine headache — The headache of migraine is often but not always unilateral and tends to have a throbbing or pulsatile quality, especially as the intensity increases. As the attack severity increases over the course of one to several hours, patients frequently experience nausea and sometimes vomiting. Many individuals report photophobia or phonophobia during attacks, leading such patients with migraine to seek relief by lying down in a darkened, quiet room. Additional migrainous features such as osmophobia and cutaneous allodynia (see 'Cutaneous allodynia' below) may occur during attacks [91,100-102].

In adults, an untreated headache can last as little as four hours and as long as several days. Many attacks resolve in sleep.

Migraine postdrome — Once the spontaneous throbbing of the headache resolves, the patient may experience a postdromal phase, during which sudden head movement transiently causes pain in the location of the antecedent headache. During the postdrome, patients often feel drained or exhausted, although some report a feeling of mild elation or euphoria [103-105].

Cutaneous allodynia — Cutaneous allodynia is the perception of pain produced by innocuous stimulation of normal skin and may result from sensitization of central pain pathways in migraine [106]. (See 'Sensitization' above.)

As examples, brushing hair, touching the scalp, shaving, or wearing contact lenses may trigger allodynic symptoms of pain during migraine. Additional symptoms include tenderness or difficulty resting on the allodynic side.

Cutaneous allodynia occurs frequently with migraine, and it may occur even in the absence of headache. In one study, allodynia was reported by 62 percent of 11,094 patients with migraine who completed a questionnaire [107]. In an earlier survey of 157 patients with migraine and allodynia, the most common locations of allodynia were pure cephalic and cephalic plus extracephalic, occurring in 85 and 34 percent, respectively [108]. Pure extracephalic allodynia occurred in 15 percent. Scalp allodynia was ipsilateral to the predominant headache side in the majority of cases and occurred at the height of headache. Trunk allodynia occurred in a few patients.

The true frequency of allodynia appears to be even higher when assessed by measurement of mechanical and thermal pain thresholds of skin. In a case series of 42 subjects with migraine, 79 percent reported cutaneous allodynia on the head ipsilateral to the migraine pain by quantitative sensitivity testing, and 67 percent experienced cutaneous allodynia in additional regions such as the contralateral head or extracephalic sites [106]. The actual percentage of people with migraine spontaneously reporting cutaneous allodynia is lower.

Severe or persistent cutaneous allodynia may respond to abortive and prophylactic therapy. However, existing data suggest that abortive therapy with triptans is less effective once cutaneous allodynia develops. (See "Acute treatment of migraine in adults", section on 'Triptans'.)

MIGRAINE SUBTYPES — Although there are numerous references in the medical literature to unexplained neurologic symptoms that are called migraine variant or migraine equivalent, most of these are probably not related to migraine. Nevertheless, there are several well-characterized subtypes of migraine, including migraine with brainstem aura, hemiplegic migraine, retinal migraine, vestibular migraine, menstrual migraine, and chronic migraine. Complications of migraine are characterized by prolonged symptoms or, rarely, with infarction or seizures (ie, status migrainosus, persistent aura without infarction, migrainous infarction, and migraine aura-triggered seizure) [95].

Recurrent painful ophthalmoplegic neuropathy, previously termed ophthalmoplegic migraine, is discussed elsewhere. (See "Overview of craniofacial pain", section on 'Recurrent painful ophthalmoplegic neuropathy'.)

Migraine with brainstem aura — Migraine with brainstem aura, reviewed here briefly and discussed in detail elsewhere (see "Migraine with brainstem aura"), is an uncommon form of migraine with aura wherein the primary signs and symptoms are referable to the brainstem without weakness. Migraine with brainstem aura was previously called basilar-type migraine. It occurs more often in females than in males. Onset is usually between ages 7 and 20. The auras consist of some combination of vertigo, dysarthria, tinnitus, diplopia, ataxia, decreased level of consciousness, and hypacusis. Attacks nearly always include two or more brainstem-related aura symptoms (table 1). Attacks may evolve to more typical common forms of migraine with age.

The occurrence of decreased level of consciousness followed by headache sometimes results in diagnostic difficulty. It is important to remember that migraine with brainstem aura is rare and that there must be another brainstem symptom in addition to decreased consciousness to make the diagnosis. In the absence of a second brainstem-localizing symptom, other causes of unexplained loss of consciousness such as seizure and cardiogenic syncope must be considered and appropriately investigated. Migraine with brainstem aura should be diagnosed only when weakness is absent, since a number of patients with familial hemiplegic migraine have brainstem symptoms. (See "Migraine with brainstem aura" and "Hemiplegic migraine".)

Hemiplegic migraine — The primary feature that separates hemiplegic migraine from other types of migraine with aura is the presence of motor weakness as a manifestation of aura in at least some attacks. In addition to motor weakness during the aura phase, which is typically unilateral, the manifestations of hemiplegic migraine attacks may variously include severe headache, scintillating scotoma, visual field defect, numbness, paresthesia, aphasia, fever, lethargy, coma, and seizures. Hemiplegic migraine may occur either in families or only in one individual (sporadic). (See "Hemiplegic migraine".)

Retinal migraine — Retinal migraine is a rare condition that is characterized by repeated attacks of monocular scotomata or blindness lasting less than one hour, associated with or followed by headache. The International Headache Society prefers the term retinal migraine [95], but ocular migraine has been suggested as a more precise term, since both retinal and ciliary circulations may be involved [109]. Occasionally, the onset may be abrupt and difficult to distinguish from amaurosis fugax [98]. (See "Amaurosis fugax (transient monocular or binocular visual loss)".)

Irreversible visual loss may be a complication of retinal migraine, although the incidence is uncertain. In one of the largest studies to date that reported 6 new cases and reviewed 40 from the literature, permanent visual loss was eventually present in 20 patients (43 percent) [110]. No predictors of irreversible visual loss could be identified, and no consistent pattern of visual loss was observed among these patients. However, permanent visual loss may be less frequent than suggested by these data, since it is likely that cases with such a major complication are more apt to be identified and to be reported (ie, reporting bias).

The authors speculated that permanent visual loss resulting from retinal migraine may be a type of migrainous infarction, leading them to suggest the use of prophylactic migraine therapy with antiepileptic or tricyclic medications for patients with this condition [110]. (See "Preventive treatment of episodic migraine in adults" and "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Diagnostic criteria'.)

Chronic migraine — Chronic migraine is defined as headache occurring 15 or more days a month for more than three months, which has the features of migraine headache on at least eight days a month [95]. The current classification scheme recognizes chronic migraine as a separate subform because it may be impossible to distinguish the individual episodes of headache in patients with such frequent or continuous headaches. Furthermore, the characteristics of the headache may change from day to day or even within the same day. (See "Chronic migraine".)

Complications of migraine — Complications of migraine are characterized by attacks associated with prolonged symptoms or, rarely, with infarction or seizures. Prolonged symptoms may last for the entire headache, for several days or weeks, or in some cases leave a permanent neurologic deficit.

●Status migrainosus is a debilitating migraine attack lasting for more than 72 hours. The median attack duration is approximately five days. The incidence rate of status migrainosus is 27 per 100,000 with a peak incidence in the fifth decade [111]. It is more common among females than males and may occur in patients with migraine either with or without aura.

●Persistent aura without infarction is defined by aura symptoms persisting for one week or more with no evidence of infarction on neuroimaging.

●Migrainous infarction is defined by a migraine attack, occurring in a patient with migraine with aura, in which one or more aura symptoms persist for more than one hour and neuroimaging shows an infarction in a relevant brain area. (See "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Migraine-associated ischemic stroke'.)

●Migraine aura-triggered seizure is a seizure triggered by an attack of migraine with aura.

Vestibular migraine — Vestibular migraine (also called migrainous vertigo) is reviewed briefly here and discussed in detail elsewhere. (See "Vestibular migraine".)

Vestibular migraine is a term used to describe episodic vertigo in patients with a history of migraines or with other clinical features of migraine (photophobia, phonophobia, visual aura, etc). The association of headache with vertigo is variable, even in individual patients. There are no confirmatory tests for vestibular migraine (table 2). Other disorders, specifically Meniere disease and structural and vascular brainstem disease, must be excluded in most patients.

Estrogen-associated (menstrual) migraine — Menstrual migraine (also called menstrually associated migraine or catamenial migraine) is defined as migraine headache that occurs in close temporal relationship to the onset of menstruation; this time period usually encompasses two days before through three days after the onset of menstrual bleeding [95]. Females with menstrual migraine may also have migraine at other times during the month. (See "Estrogen-associated migraine headache, including menstrual migraine".)

The treatment of menstrual migraine is discussed separately. (See "Estrogen-associated migraine headache, including menstrual migraine", section on 'Treatment progression'.)

DIAGNOSIS — The diagnosis of migraine is a clinical task and is based upon a compatible history, physical examination, and fulfillment of the diagnostic criteria listed below. There are no diagnostic tests specific for migraine.

While the features of migraine and tension headache overlap, the clinical features that appear to be most predictive of migraine include nausea, photophobia, phonophobia, and exacerbation by physical activity [112]. Food triggers are also more common with migraine than tension-type headache. (See "Tension-type headache in adults: Etiology, clinical features, and diagnosis".)

Diagnostic criteria — The International Classification of Headache Disorders, 3^rd edition (ICHD-3) specifies diagnostic criteria for migraine (table 3) [95].

The ICHD-3 criteria for migraine without aura are the following [95]:

●(A) At least five attacks fulfilling criteria B through D

●(B) Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated)

●(C) Headache has at least two 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)

●(D) During headache, at least one of the following:

•Nausea, vomiting, or both

•Photophobia and phonophobia

●(E) Not better accounted for by another ICHD-3 diagnosis

The ICHD-3 criteria for migraine with aura are as follows [95]:

●(A) At least two attacks fulfilling criterion B and C

●(B) One or more of the following fully reversible aura symptoms:

•Visual

•Sensory

•Speech and/or language

•Motor

•Brainstem

•Retinal

●(C) At least three of the following six characteristics:

•At least one aura symptom spreads gradually over ≥5 minutes

•Two or more symptoms occur in succession

•Each individual aura symptom lasts 5 to 60 minutes

•At least one aura symptom is unilateral

•At least one aura symptom is positive

•The aura is accompanied, or followed within 60 minutes, by headache

●(D) Not better accounted for by another ICHD-3 diagnosis

The ICHD-3 criteria for migraine with typical aura require attacks fulfilling criteria for migraine with aura and auras consisting of visual, sensory, and/or speech/language symptoms but no motor, brainstem, or retinal symptoms [95]. When the aura includes motor weakness, the disorder is diagnosed as hemiplegic migraine. When the aura symptoms arise from the brainstem, the disorder is diagnosed as migraine with brainstem aura. When the aura involves documented monocular visual phenomena (documented by clinical visual field examination or patient drawing of a monocular field defect), the disorder is diagnosed as retinal migraine.

Diagnostic testing — Neuroimaging is not necessary in most patients with migraine. Evidence-based guidelines issued by the American Academy of Neurology suggest considering neuroimaging in the following patients with non-acute headache [113]:

●Patients with an unexplained abnormal finding on neurologic examination

●Patients with atypical headache features or headaches that do not fulfill the strict definition of migraine or other primary headache disorder (or have some additional risk factor, such as immune deficiency)

Patients with sudden, severe headache also need neuroimaging because of the suspicion of subarachnoid hemorrhage. (See "Evaluation of headache in adults", section on 'Indications for imaging'.)

The following clinical situations may warrant neuroimaging [114,115]:

●The "first or worst" headache

●Recent significant change in the pattern, frequency, or severity of headaches

●New or unexplained neurologic symptoms or signs

●Headache always on the same side

●Headaches not responding to treatment

●New-onset headaches after age 50 years

●New-onset headaches in patients with cancer or HIV infection

●Associated symptoms and signs such as fever, stiff neck, papilledema, cognitive impairment, or personality change

Head computed tomography (CT) scan (without and with contrast) is sufficient in many patients when neuroimaging is deemed necessary [116]. Magnetic resonance imaging (MRI) is indicated when posterior fossa lesions or cerebrospinal fluid (CSF) leak are suspected. Magnetic resonance angiography (MRA) and magnetic resonance venography (MRV) are indicated when arterial or venous lesions, respectively, are considered in the differential diagnosis.

No other diagnostic tests are typically necessary in patients with suspected migraine.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of migraine headache is broad and includes other types of primary headaches, such as tension-type headache and trigeminal autonomic cephalalgias such as cluster headache (table 4), and secondary headaches (ie, headache caused by another disorder such as head or neck trauma, cerebrovascular disorders, intracranial lesions, disorders of face, skull, or adjacent structures, or infection).

The differential diagnosis for migraine aura includes transient ischemic attack (TIA), seizure, syncope, and vestibular disorders. Useful features for distinguishing these various types of transient neurologic attacks include the nature of the symptoms, their progression, duration and timing, associated symptoms during and after the attacks (table 5), and presence of focal or nonfocal symptoms. The symptoms of TIA and migraine are fully reversible, and neuroimaging is often unrevealing in both conditions. However, both a TIA and an ischemic stroke typically have a sudden onset of symptoms rather than a gradual progressive spread of one aura symptom after another. Ischemic events are also less likely to have positive symptoms such as visual scintillations or paresthesia and are less likely to have migrainous symptoms such as nausea, vomiting, photophobia, and phonophobia. (See "Differential diagnosis of transient ischemic attack and acute stroke".)

An exception might be brain ischemia caused by cervical artery dissection, which can have both a progressive spread of symptoms and some migrainous features. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Migraine in adults (The Basics)" and "Patient education: Headaches in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Migraine in adults (Beyond the Basics)" and "Patient education: Headache causes and diagnosis in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Cortical spreading depression is hypothesized to cause the aura of migraine, activate trigeminal nerve afferents, and alter blood-brain barrier permeability. Activation of the trigeminovascular system plays a central role in the pathophysiology of migraine, including the onset of neurogenic inflammation, which is linked to the pain of migraine. Sensitization, a process in which neurons become increasingly responsive to nociceptive and non-nociceptive stimulation, is likely responsible for many of the clinical symptoms of migraine. (See 'Pathophysiology' above.)

The genetic basis of the common forms of migraine is likely complex. The KCNK18 and CSNK1D genes have been implicated in the pathogenesis of migraine with aura. Familial hemiplegic migraine is associated with pathologic variants in four genes, three of which encode for transmembrane ion channels. (See 'Genetic basis' above.)

●Epidemiology – Migraine is a common condition that affects up to 12 percent of the general population. Migraine is most common in those aged 30 to 39, an age span in which prevalence in males and females reaches 7 and 24 percent, respectively (figure 1). (See 'Epidemiology' above.)

●Precipitating factors – Migraine trigger factors may include stress, menstruation, visual stimuli, weather changes, nitrates, fasting, wine, sleep disturbances, and aspartame, among others. (See 'Precipitating and exacerbating factors' above.)

●Clinical features – Migraine is a disorder of recurrent attacks. The attacks unfold through a cascade of events that occur over the course of several hours to days. A typical migraine attack progresses through four phases: the prodrome, the aura, the headache, and the postdrome. (See 'Clinical features' above.)

•The prodrome consists of affective or vegetative symptoms that appear 24 to 48 hours prior to the onset of headache. (See 'Migraine prodrome' above.)

•About 25 percent of people with migraines experience one or more focal neurologic symptoms in the second phase, called the migraine aura. Auras are most often visual but can also be sensory, verbal, or motor disturbances. (See 'Migraine aura' above.)

•The headache of migraine is often but not always unilateral and tends to have a throbbing or pulsatile quality. Accompanying features may include nausea, vomiting, photophobia, or phonophobia during attacks. (See 'Migraine headache' above.)

●Migraine subtypes – Subtypes of migraine include migraine with brainstem aura, hemiplegic migraine, retinal migraine, vestibular migraine, menstrual migraine, and chronic migraine. (See 'Migraine subtypes' above.)

●Diagnosis and evaluation – The diagnosis of migraine is a clinical task and is based upon a compatible history, physical examination, and fulfillment of the diagnostic criteria (table 3). Neuroimaging is not necessary in most patients. However, we recommend neuroimaging for patients with suspected migraine or nonacute headache who have either an unexplained abnormal finding on neurologic examination, atypical headache features, headaches that do not fulfill the strict definition of migraine or other primary headache disorder, or some additional risk factor for secondary headache, such as immune deficiency. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of migraine headache is broad and includes other types of primary headaches (table 4) and secondary headaches as well as transient neurologic attacks (table 5). (See 'Differential diagnosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ashraf Sabahat, MD and Zahid H Bajwa, MD, who contributed to earlier versions of this topic review.