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Official reprint from UpToDate


www.uptodate.com 2014 UpToDate
Pathophysiology, clinical manifestations, and diagnosis of migraine in adults
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

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

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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].

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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].

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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 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.
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.

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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.
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].
While definitive conclusions are not yet possible, the population-based NOMAS study provides highquality 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].

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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].

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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:
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)
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.

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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)".)

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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.
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
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'.)

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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]:
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 [76]:
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:
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 minutes
At least one aura symptom is unilateral
The 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
The ICHD-3 criteria for migraine with typical aura require the following [76]:

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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:
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 minutes
At least one aura symptom is unilateral
The 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
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 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 studies'.)
The following clinical situations may warrant neuroimaging [95,96]:
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
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.

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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 5th to 6th 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 10th to 12th 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 information: Headache (The Basics)")
Beyond the Basics topics (see "Patient information: Headache causes and diagnosis in adults
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
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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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 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.)
Subtypes of migraine include 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 auratriggered seizure). Ophthalmoplegic migraine is now considered a cranial neuralgia called
recurrent painful ophthalmoplegic neuropathy. (See 'Migraine subtypes' above.)
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.)
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 3348 Version 19.0

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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

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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.
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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.
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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:


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 minutes
At least one aura symptom is unilateral
The 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

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:
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 minutes

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At least one aura symptom is unilateral


The 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

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.
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Characteristics of migraine, tension-type, and cluster


headache syndromes
Symptom

Migraine

Tensiontype

Cluster

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

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Differential diagnosis of transient neurologic symptoms


Transient
Seizure

ischemic

Migraine

Syncope

attack
Demography

Any age, often


younger

Older patients

Younger age

Stroke risk
factors present

Women>men

Any age, often


younger
Women>men

Men>women
Central
nervous
system
symptoms

Timing

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

Negative
symptoms:
numbness,
visual loss,
paralysis,
ataxia

Negative
symptoms may
develop,
remain
postictally, and
persist

Multiple deficits
(eg, language
and sensation)
occur
simultaneously

20 to 80
seconds

Usually
minutes,
mostly <1 hour

Absence,
atonic seizures
and myoclonic
jerks are
shorter
Postictal
depression

Recurrent
spells over
days, weeks,
or months; not
usually years

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

Light-headed,
dim vision,
noises distant,
decreased
alertness
Transient loss
of
consciousness

One aura type


may be
clearing as
next aura
develops

Usually 20 to
30 minutes

Usually a few
seconds

Sporadic
attacks during
years

Sporadic
attacks during
years

Headache after
attack, nausea,
vomiting,
photophobia,
phonophobia

Sweating,
pallor, nausea

Spells occur
during years
Associated
symptoms

Tongue biting,
incontinence,
sore muscles,
headache after
attack

Headaches
may occur
during time
period of TIAs

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Focal or nonfocal symptoms of transient neurologic attacks


Focal symptoms

Nonfocal symptoms

+++

++

Transient ischemic
attack

++++

Migraine aura

++++

++++

++

++

+++

"Tumor attacks"

+++

Multiple sclerosis

++++

++

++

Nerve and nerve root

++++

Transient global amnesia

++++

Common disorders
Seizure

Syncope
Less common disorders
Vestibulopathy
Metabolic

Psychiatric

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Disclosures
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

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