pathophysiology clinical manif

Official reprint from UpToDate www.uptodate.com 2014 UpToDate

Authors F Michael Cutrer, MD Zahid H Bajwa, MD Ashraf Sabahat, MD

Section Editor Jerry W Swanson, MD

Deputy Editor John F Dashe, MD, PhD

Pathophysiology, clinical manifestations, and diagnosis of migraine in adults

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2014. | This topic last updated: Apr 21, 2014.

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 migraine in adults" and "Chronic migraine" and "Migraine with brainstem aura (basilar-type migraine)" and "Hemiplegic migraine" and "Vestibular migraine" and "Headache, migraine, and stroke".)

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], 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 [2-4]. Vasodilatation, if it occurs at all during spontaneous migraine attacks [4], is probably an epiphenomenon resulting from instability in the central neurovascular control mechanism [5].

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 Leo [2,6,7]. 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:

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 [12]. 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 pro-inflammatory mediators, activation of nuclear factor kappa-B in astrocytes, and transduction of the inflammatory signal to trigeminal nerve fibers around pial vessels [10]. 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 [13].

Trigeminovascular system The pathophysiology of migraine involves activation of the trigeminovascular system, which consists of small caliber pseudounipolar sensory neurons that

Cause the aura of migraine [8]Activate trigeminal nerve afferents [9,10]Alter blood-brain barrier permeability by matrix metalloproteinase activation and upregulation [11]

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originate from the trigeminal ganglion and upper cervical dorsal roots [14]. 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 [15,16]. 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 [17], the periaqueductal gray, and the nucleus raphe magnus [18] as well as by descending cortical inhibitory systems [18,19].

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 [20]. Other second-order neurons from the trigeminal nucleus caudalis project to numerous subcortical sites including the more rostral segments of the trigeminal complex [21], the reticular formation of the brain stem [22], the cerebellum [23,24], the midbrain and pontine parabrachial nuclei [25,26], the ventrobasal thalamus [21,24,27,28], the posterior thalamus [29,30], and the medial thalamus [31]. 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 [25].

Stimulation of the trigeminal ganglion results in release of vasoactive neuropeptides, including substance P, calcitonin gene-related peptide, and neurokinin A [32]. Release of these neuropeptides is associated with the process of neurogenic inflammation. The two main components of this sterile inflammatory response are vasodilation (calcitonin gene-related peptide 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 [33]. 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 [34-36]. 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 [37,38]. Patients with chronic migraine are found to have altered blood flow to the dorsal pons, anterior cingulate cortex, and cuneus [39].

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 [40,41]. Increased iron levels have been identified in the periaqueductal gray of episodic and chronic migraineurs [42].



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. 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 [43,44]. 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 [43,44].

Role of calcitonin gene-related peptide The calcitonin gene-related peptide (CGRP) may also play a role in migraine pathophysiology. CGRP is a 37 amino acid neuropeptide that is expressed in trigeminal ganglia nerves and is a potent vasodilator of cerebral and dural vessels [45].

CGRP may mediate trigeminovascular pain transmission from intracranial vessels to the central nervous system, as well as the vasodilatory component of neurogenic inflammation. However, the evidence is conflicting. Stimulation of the trigeminal ganglion induces the release of CGRP [32], and CGRP infusion can trigger a migraine attack in migraineurs [46]. In healthy subjects without migraine, a placebo-controlled crossover trial found that exogenous CGRP infusion causes vasodilation of the middle meningeal artery (extracranial) but not the middle cerebral artery (intracranial), whereas sumatriptan infusion causes vasoconstriction of the middle meningeal artery [47]. The lack of vasodilatory response of the intracranial artery to CGRP infusion in this trial may be explained by the inability of exogenous CGRP to cross the blood-brain-barrier. Although one study found elevation of CGRP levels in external jugular venous blood during migraine attack [48], this result was not reproduced in a subsequent study [49]. Furthermore, CGRP did not activate or sensitize meningeal nociceptors in an animal model [50].

Elevated CGRP levels are 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.

Pharmacologic modulation of CGRP activity offers the promise of future treatment options for acute migraine attacks. This is discussed separately. (See "Acute treatment of migraine in adults", section on 'CGRP receptor antagonists'.)

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 [52]. One early general population based study found that the risk of migraine in relatives of migraineurs was three times greater than that of relatives of non-migraine control subjects [53]. However segregation analysis does not identify any single Mendelian pattern of inheritance in the common forms of migraine [54]. 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 [55].



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, but some noteworthy clues have emerged:

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 to 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 mutations in the CACNA1A gene, FHM2 by mutations in the ATP1A2 gene, and FHM3 by mutations in the SCN1A gene. Mutations in 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 up to 12 percent of the general population [61]. It is more frequent in women than in men, with attacks occurring in up to 17 percent of women and 6 percent of men each year [62,63]. Migraine is most common in those aged 30 to 39, an age span in which prevalence in men and women reaches 7 and 24 percent, respectively (figure 1) [63]. Migraine also tends to run in families.

The KCNK18 gene that encodes for TRESK, a two-pore domain potassium channel (K2P), has been implicated as a probable cause of migraine with aura in a candidate gene study [56]. The report identified KCNK18 variants by sequencing the gene in cohorts of unrelated subjects with and without migraine. One particular frameshift mutation (F139WfsX24) in the KCNK18 gene, first identified in migraineurs, was then found to segregate only with individuals affected by migraine with aura in a large multigenerational kindred; it was not found in unaffected individuals. Functional analysis revealed that the mutant TRESK channels are nonfunctional and cause a dominant-negative downregulation of wild-type TRESK activity. In addition, the investigators demonstrated that TRESK is expressed in trigeminal ganglia. The results suggest that the KCNK18 mutation causes suppression of TRESK channel activity and thereby alters neuronal excitability, consistent with a possible pathogenic role in migraine.

A distinct missense mutation in the CSNK1D gene, which encodes casein kinase I isoform delta, was shown to cosegregate with both the presence of migraine and advanced sleep phase disorder in two unrelated families [57]. In addition, mice carrying the CSNK1D-T44A mutation showed a decreased threshold for cortical spreading depression and increased arterial dilation during cortical spreading depression. These findings suggest that diminished casein kinase I isoform delta activity may play a role in the mechanism of migraine.

In a meta-analysis of 29 genome-wide association studies (GWAS) with over 23,000 migraine cases and 95,000 population-matched controls, there were 12 loci associated with migraine susceptibility [58]. Of these, the strongest association in the primary analysis was observed for the rs11172113 locus at 12q13.3 (LRP1 gene). In subgroup analysis, however, only six loci were associated with migraine without aura, and none was associated with migraine with aura. Case control studies have shown modest associations with migraine for several other candidate genes, but the findings of these studies have often not been replicated [59,60]. Thus, it is still uncertain which candidate loci and genes are truly implicated in the pathogenesis of migraine.



Migraine without aura is the most common type, accounting for approximately 75 percent of cases.

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) [64-66] or pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) [67]. (See "Clinical manifestations and diagnosis of atrial septal defects in adults" and "Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

Evidence regarding the association of migraine with PFO is conflicting.

While definitive conclusions are not yet possible, the population-based NOMAS study provides high-quality observational evidence that PFO is not associated with migraine [70]. In contrast, the association of PFO with migraine in the systematic review is supported by low or low to moderate quality evidence [69].

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 [71]. 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 [72]. 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".)

Closure of the defect has been reported to prevent or reduce the frequency of subsequent migraines. However, the data are conflicting, and it is premature to recommend closure of a PFO or ASD solely as a treatment for migraine. (See "Preventive treatment of migraine in adults", section on 'Closure of right-to-left cardiac shunt'.)

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 [73].

Migraine prodrome The prodrome occurs in up to 60 percent of people and consists of affective or vegetative symptoms that appear 24 to 48 hours prior to the onset of headache. Frequently reported prodromal symptoms include euphoria, depression, irritability, food cravings, constipation, neck stiffness, and increased yawning [74].

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 [75].

In a population-based study of 1101 stroke-free subjects (mean age 69) 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) [68]. The presence of PFO was not associated with an increased prevalence of migraine (odds ratio [OR] 1.01, 95% CI 0.63 to 1.61) or an increased prevalence of migraine with aura (OR 1.01, 95% CI 0.71 to 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 [69].



Typical migraine auras are characterized by gradual development, duration no longer than one hour, a mix of positive and negative features, and complete reversibility [76]. 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.

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 [77].

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 [77].

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. 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") [76]. The aura symptoms may occur either singly or in sequence but they do not generally occur simultaneously.

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 TIA or stroke more likely. In one case series, four patients (2 percent) had exclusively acute onset visual aura [78].

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. Auras without headache may be confused with transient ischemic attacks, especially in older patients [79]. 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 [78].

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 migraine sufferers 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 [73,80-82].



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.

Precipitating and exacerbating factors 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 [83]. 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 [84]. In order of descending frequency these included:

Obesity has been associated with an increased frequency and severity of migraine [85-87]. Migraine headaches are often worsened by rapid head motion, sneezing, straining, constant movement, or physical exertion.

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 [88]. (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 soreness, 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 [89]. 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 [90]. 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.

Emotional stress (80 percent)Hormones in women (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)



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 [88]. 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) [76].

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 (basilar-type migraine)"), 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 to 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 (basilar-type migraine)" 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 [76], but ocular migraine has been suggested as a more precise term, since both retinal and ciliary circulations may be involved [91]. Occasionally the onset may be abrupt and difficult to distinguish from amaurosis fugax [79]. (See "Amaurosis fugax (transient monocular or binocular visual loss)".)



GADELIHighlight

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) [92]. 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 [92]. (See "Headache, migraine, and stroke", section on 'Migrainous infarction definition' and "Preventive treatment of migraine in adults".)

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 8 days a month [76]. 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.

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.

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 [76]. Women with menstrual migraine may also have migraine at other times during the month. (See "Estrogen-associated migraine", section on 'Menstrual migraine'.)

The treatment of menstrual migraine is discussed separately. (See "Estrogen-associated migraine", section on 'Menstrual migraine' and "Estrogen-associated migraine", section on 'Preventive therapies'.)

Status migrainosus is a debilitating migraine attack lasting for more than 72 hours

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 "Headache, migraine, and stroke", section on 'Migrainous stroke')

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



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 [93]. Food triggers are also more common with migraine than tension-type headache. (See "Tension-type headache in adults: Pathophysiology, clinical features, and diagnosis".)

Diagnostic criteria The International Classification of Headache Disorders, 3rd edition (ICHD-3) specifies diagnostic criteria for migraine (table 3) [76].

The ICHD-3 criteria for migraine without aura are the following [76]:

The ICHD-3 criteria for migraine with aura are as follows [76]:

The ICHD-3 criteria for migraine with typical aura require the following [76]:

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 locationPulsating qualityModerate or severe pain intensityAggravation 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 bothPhotophobia and phonophobia

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

A) At least two attacks fulfilling criterion B and C

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

VisualSensorySpeech and/or languageMotorBrainstemRetinal

C) At least two of the following four characteristics:

At least one aura symptom spreads gradually over 5 minutes, and/or two or more symptoms occur in succession

Each individual aura symptom lasts 5 to 60 minutesAt least one aura symptom is unilateralThe aura is accompanied, or followed within 60 minutes, by headache

D) Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded

Page 10 of 26Pathophysiology, clinical manifestations, and diagnosis of migraine i...


When the aura includes motor weakness, the disorder is diagnosed as hemiplegic migraine [76]. 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 [94]:

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 studies'.)

The following clinical situations may warrant neuroimaging [95,96]:

A head CT scan (without and with contrast) is sufficient in many patients when neuroimaging is deemed necessary [97]. An 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.

A) At least two attacks fulfilling criteria B through D

B) Aura consisting of visual, sensory and/or speech/language symptoms, each fully reversible, but no motor, brainstem or retinal symptoms

C) At least two of the following four characteristics:


Each individual aura symptom lasts 5 to 60 minutesAt least one aura symptom is unilateralThe aura is accompanied, or followed within 60 minutes, by headache

D) Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded

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)

The first or worst headacheRecent significant change in the pattern, frequency or severity of headachesNew or unexplained neurologic symptoms or signsHeadache always on the same sideHeadaches not responding to treatmentNew-onset headaches after age 50 yearsNew-onset headaches in patients with cancer or HIV infectionAssociated symptoms and signs such as fever, stiff neck, papilledema, cognitive impairment, or personality change



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 (table 6). 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 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 "Spontaneous cerebral and cervical artery dissection: Clinical features and diagnosis".)

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 to 6 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 to 12 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 e-mail 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.)

SUMMARY AND RECOMMENDATIONS

th th

th th

Basics topics (see "Patient information: Headache (The Basics)")

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

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 and in some individuals may be based on the additive effect of more than one genetic source. The KCNK18 and CSNK1D genes have been implicated in the pathogenesis of migraine with aura. Familial hemiplegic migraine is associated with mutations in four genes, three of which encode for transmembrane ion channels. (See 'Genetic basis' above.)

Migraine is a common condition that affects up to 12 percent of the general population. It is more frequent in women than in men. (See 'Epidemiology' above.)



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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.)

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Topic 3348 Version 19.0



GRAPHICS

Migraine prevalence

Data from: Lipton, RB, Bigal, ME, Diamond, M, et al. Migrane prevalence, disease burden, and the need for preventative therapy. Neurology 2007; 68:343.

Graphic 57550 Version 1.0



Clinical characteristics of migraine with brainstem aura (basilar-type migraine)

Always present:

Two or more brainstem-related aura symptoms (ie, dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia, decreased level of consciousness)

May be present:

Visual aura characterized by positive features (ie, zigzag lines, flickering light) or negative features (ie, scotoma)

Sensory aura characterized by positive features (ie, pins and needles) or negative features (ie, numbness)

Aphasic aura

Temporal characteristics of aura

Aura symptoms almost always develop gradually over 5 minutes and/or aura symptoms occur in succession over 5 minutes

Duration of individual aura symptom is 5 to 60 minutes

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

Patient characteristics

Onset occurs before age 50 years

Most patients with migraine with brainstem aura also have attacks of migraine with typical aura (ie, without brainstem-related symptoms)

Adapted from: 1. Kirchmann M, Thomsen LL, Olesen J. Basilar-type migraine: clinical, epidemiologic, and genetic features. Neurology 2006; 66:880. 2. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33:629.




Criteria for vestibular migraine

A. At least five episodes fulfilling criteria C and D

B. A current or past history of migraine without aura or migraine with aura

C. Vestibular symptoms of moderate or severe intensity, lasting between 5 minutes and 72 hours

D. At least 50 percent of episodes are associated with at least one of the following three migrainous features:

1. Headache with at least two of the following four characteristics:

a) Unilateral location

b) Pulsating quality

c) Moderate or severe intensity

d) Aggravation by routine physical activity

2. Photophobia and phonophobia

3. Visual aura

E. Not better accounted for by another ICHD-3 diagnosis or by another vestibular disorder

ICHD-3: the International Classification of Headache Disorders, 3rd edition.

Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33:629.




Diagnostic criteria for migraine

Migraine without aura

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

Migraine with aura

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 two of the following four characteristics:


Each individual aura symptom lasts 5 to 60 minutes

At least one aura symptom is unilateral


D. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded

Migraine with typical aura

A. At least two attacks fulfilling criteria B through D

B. Aura consisting of visual, sensory and/or speech/language symptoms, each fully reversible, but no motor, brainstem or retinal symptoms

C. At least two of the following four characteristics:


Each individual aura symptom lasts 5 to 60 minutes



At least one aura symptom is unilateral


D. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded

Features of migraine in children

Attacks may last 2 to 72 hours

Headache is more often bilateral than in adults; an adult pattern of unilateral pain usually emerges in late adolescence or early adulthood

Occipital headache is rare and raises diagnostic caution for structural lesions

Photophobia and phonophobia may be inferred by behavior in young children

ICHD-3: International Classification of Headache Disorders, 3rd edition.

Adapted from: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33:629.




Characteristics of migraine, tension-type, and cluster headache syndromes

Symptom MigraineTension-

typeCluster

Location Unilateral in 60 to 70 percent; bifrontal or global in 30 percent

Bilateral Always unilateral, usually begins around the eye or temple

Characteristics Gradual in onset, crescendo pattern; pulsating; moderate or severe intensity; aggravated by routine physical activity

Pressure or tightness which waxes and wanes

Pain begins quickly, reaches a crescendo within minutes; pain is deep, continuous, excruciating, and explosive in quality

Patient appearance

Patient prefers to rest in a dark, quiet room

Patient may remain active or may need to rest

Patient remains active

Duration 4 to 72 hours Variable 30 minutes to 3 hours

Associated symptoms

Nausea, vomiting, photophobia, phonophobia; may have aura (usually visual, but can involve other senses or cause speech or motor deficits)

None Ipsilateral lacrimation and redness of the eye; stuffy nose; rhinorrhea; pallor; sweating; Horner's syndrome; focal neurologic symptoms rare; sensitivity to alcohol




Differential diagnosis of transient neurologic symptoms

SeizureTransient ischemic

attackMigraine Syncope

Demography Any age, often younger

Older patients

Stroke risk factors present

Men>women

Younger age

Women>men

Any age, often younger

Women>men

Central nervous system symptoms

Positive symptoms: limb jerking, head turning, loss of consciousness

Negative symptoms may develop, remain postictally, and persist

Negative symptoms: numbness, visual loss, paralysis, ataxia

Multiple deficits (eg, language and sensation) occur simultaneously

First positive symptoms, then negative in same modality: scintillating scotoma and paresthesia most common

One aura type may be clearing as next aura develops

Light-headed, dim vision, noises distant, decreased alertness

Transient loss of consciousness

Timing 20 to 80 seconds

Absence, atonic seizures and myoclonic jerks are shorter

Postictal depression

Spells occur during years

Usually minutes, mostly

Focal or nonfocal symptoms of transient neurologic attacks

Focal symptoms Nonfocal symptoms

Common disorders

Seizure +++ ++

Transient ischemic attack

++++ +

Migraine aura ++++ +

Syncope 0 ++++

Less common disorders

Vestibulopathy ++ ++

Metabolic + +++

"Tumor attacks" +++ +

Multiple sclerosis ++++ +

Psychiatric ++ ++

Nerve and nerve root ++++ 0

Transient global amnesia ++++ 0




Disclosures: F Michael Cutrer, MD Nothing to disclose. Zahid H Bajwa, MD Consultant/Advisory Boards: Allergan (migraine [onabotulinumtoxinA]); Concert Pharma (early development program); Depomed (neuropathic pain, migraine [gabapentin]); Merz (cervical dystonia [botulinum toxin type A]); Monsol (migraine [new technology applied to old drugs]); Boston Scientific (new paradigm for SCS for chronic pain). Ashraf Sabahat, MD Nothing to disclose. Jerry W Swanson, MD Nothing to disclose. John F Dashe, MD, PhD Employee of UpToDate, Inc. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

Disclosures

