Causes of migraine A screening tool called the ID-CM may be useful in

diagnosis. The ID-CM is a 12-item screening tool for

Migraine was previously considered to be a vascular
chronic migraine that has a sensitivity of 82% and a
phenomenon that resulted from intracranial
specificity of 87% compared with semi-structured clinical
vasoconstriction followed by rebound vasodilation.
interviews.[6]
Currently, however, the neurovascular theory describes
migraine as primarily a neurogenic process with Migraine treatment involves acute (abortive) and
secondary changes in cerebral perfusion associated with a preventive (prophylactic) therapy. Patients with frequent
sterile neurogenic inflammation (see Pathophysiology). attacks usually require both. Measures directed toward
reducing migraine triggers are also generally advisable.
A genetic component to migraine is indicated by the fact
that approximately 70% of patients have a first-degree Acute treatment aims to eliminate, or at least prevent the
relative with a history of migraine. In addition, a variety of progression of, a headache. Preventive treatment, which
environmental and behavioral factors may precipitate is given even in the absence of a headache, aims to
migraine attacks in persons with a predisposition to reduce the frequency and severity of migraine attacks, to
migraine (see Etiology). make acute attacks more responsive to abortive therapy,
and perhaps also to improve the patient's quality of life
Migraine characteristics and treatment
(see Treatment).
Migraine is characterized most often by unilateral head
pain that is moderate to severe, throbbing, and See Migraine in Children for a pediatric perspective on
aggravated by activity. It may also be associated with migraine. Also see Migraine Variants and Childhood
various visual or sensory symptoms, which occur most Migraine Variants.
often before the headache component but which may Migraine classification
occur during or after the headache; these are collectively
known as an aura. Most commonly, the aura consists of The second edition of the International Classification of
[7]
visual manifestations, such as scotomas, photophobia, or Headache Disorders (ICHD) lists the following types of
visual scintillations (eg, bright zigzag lines) (see migraine:
Presentation).
Migraine without aura (formerly, common migraine)
The head pain may also be associated with weakness. This Probable migraine without aura
form of migraine is termed hemiplegic migraine. Migraine with aura (formerly, classic migraine)
Probable migraine with aura
In practice, however, migraine headaches may be Chronic migraine
unilateral or bilateral and may occur with or without an Chronic migraine associated with analgesic overuse
aura. In the current International Headache Society Childhood periodic syndromes that may not be
categorization, the headache previously described as precursors to or associated with migraine
classic migraine is now known as migraine with aura, and Complications of migraine
the headache that was described as common migraine is Migrainous disorder not fulfilling above criteria
now termed migraine without aura. Migraines without Diagnostic criteria
aura are the most common, accounting for more than
80% of all migraines. According to the International Headache Society, the
diagnosis of migraine requires that the patient has
The diagnosis of migraine is clinical in nature, based on experienced at least 5 attacks that fulfill the following 3
criteria established by the International Headache Society. criteria and that are not attributable to another
A full neurologic examination should be performed during disorder.[1] First, the headache attacks must have lasted 4-
the first visit, to exclude other disorders; the findings are 72 hours (untreated or unsuccessfully treated). Second,
usually normal in patients with migraine. Neuroimaging is the headache must have had at least 2 of the following
not necessary in a typical case, but other diagnostic characteristics:
investigations may be indicated to guide management.
Unilateral location
 Pulsating quality Vascular theory
Moderate or severe pain intensity
In the 1940s and 1950s, the vascular theory was proposed
Aggravation by or causing avoidance of routine physical
to explain the pathophysiology of migraine headache.
activity (eg, walking or climbing stairs)
Wolff et al believed that ischemia induced by intracranial
Third, during the headache the patient experiences at
vasoconstriction is responsible for the aura of migraine
least 1 of the following:
and that the subsequent rebound vasodilation and
Nausea and/or vomiting activation of perivascular nociceptive nerves resulted in
Photophobia and phonophobia headache.
In June 2013, the International Classification of Headache
This theory was based on the following 3 observations:
Disorders, Third Edition(ICHD-III, beta version) was
published and is available for field testing, which will take Extracranial vessels become distended and pulsatile
place for several years before the final version is during a migraine attack
published. Stimulation of intracranial vessels in an awake person
induces headache
Changes from the previous edition include the
[8] Vasoconstrictors (eg, ergots) improve the headache,
following :
whereas vasodilators (eg, nitroglycerin) provoke an
The addition of chronic migraines: Those that occur on attack
at least 15 days of the month for more than 3 months However, this theory did not explain the prodrome and
For a diagnosis of migraine with aura, the following associated features. Nor did it explain the efficacy of
criteria must be met: One or more visual, sensory, some drugs used to treat migraines that have no effect on
speech, motor, brainstem, or retinal symptoms, as well blood vessels and the fact that most patients do not have
as at least 2 of the following 4 criteria: (1) at least 1 aura an aura. Moreover, with the advent of newer imaging
symptom spreading gradually over 5 or more minutes technologies, researchers found that intracranial blood
and/or 2 or more symptoms occurring in succession; (2) flow patterns were inconsistent with the vascular theory.
each aura symptom lasting 5-60 minutes; (3) at least 1
No consistent flow changes have been identified in
aura symptom being unilateral; and (4) the aura being
patients suffering from migraine headache without aura.
accompanied by or followed shortly by headache
Regional cerebral blood flow (rCBF) remains normal in the
Under headaches associated with sexual activity, the
majority of patients. However, bilateral decrease in rCBF,
subtypes of preorgasmic and orgasmic headache have
beginning at the occipital cortex and spreading anteriorly,
been eliminated
has been reported. More recently, Perciaccante has
For thunderclap headaches, the headache must last at
shown that migraine is characterized by a cardiac
least 5 minutes, but the criterion of not recurring
autonomic dysfunction.[11]
regularly during subsequent weeks or months has been
discarded As a result of these anomalous findings, the vascular
Hypnic headaches no longer have to first occur after age theory was supplanted by the neurovascular theory.
50 years
A number of pain characteristics under the new daily Neurovascular theory
persistent headaches section have been eliminated The neurovascular theory holds that a complex series of
For secondary headaches, it is not required that the neural and vascular events initiates migraine.[12] According
causative agent be removed before a diagnosis to this theory, migraine is primarily a neurogenic process
with secondary changes in cerebral perfusion.[13]
The mechanisms of migraine remain incompletely At baseline, a migraineur who is not having any headache
understood. However, new technologies have allowed has a state of neuronal hyperexcitability in the cerebral
formulation of current concepts that may explain parts of cortex, especially in the occipital cortex.[14] This finding has
the migraine syndrome. been demonstrated in studies of transcranial magnetic
stimulation and with functional magnetic resonance such as calcitonin gene-related peptide, substance P,
imaging (MRI). vasoactive intestinal peptide, and neurokinin A. The
resultant state of sterile inflammation is accompanied by
This observation explains the special susceptibility of thefurther vasodilation, producing pain.
migrainous brain to headaches.[15] One can draw a parallel
with the patient with epilepsy who similarly has interictal The initial cortical hyperperfusion in CSD is partly
neuronal irritability. mediated by the release of trigeminal and
parasympathetic neurotransmitters from perivascular
Cortical spreading depression nerve fibers, whereas delayed meningeal blood flow
In 1944, Leao proposed the theory of cortical spreading increase is mediated by a trigeminal-parasympathetic
depression (CSD) to explain the mechanism of migraine brainstem connection. According to Moulton et al, altered
with aura. CSD is a well-defined wave of neuronal descending modulation in the brainstem has been
excitation in the cortical gray matter that spreads from its postulated to contribute to the headache phase of
site of origin at the rate of 2-6 mm/min. migraine; this leads to loss of inhibition or enhanced
facilitation, resulting in trigeminovascular neuron
This cellular depolarization causes the primary cortical hyperexcitability.[17]
phenomenon or aura phase; in turn, it activates
trigeminal fibers, causing the headache phase. The Metalloproteinases
neurochemical basis of the CSD is the release of
In addition, through a variety of molecular mechanisms,
potassium or the excitatory amino acid glutamate from
CSD upregulates genes, such as those encoding for cyclo-
neural tissue. This release depolarizes the adjacent tissue,
oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-
which, in turn, releases more neurotransmitters,
alpha), interleukin-1beta, galanin, and
propagating the spreading depression.
metalloproteinases. The activation of metalloproteinases
Oligemia leads to leakage of the blood-brain barrier, allowing
potassium, nitric oxide, adenosine, and other products
Positron emission tomography (PET) scanning released by CSD to reach and sensitize the dural
demonstrates that blood flow is moderately reduced perivascular trigeminal afferent endings.[18]
during a migrainous aura, but the spreading oligemia does
not correspond to vascular territories. The oligemia itself Increased net activity of matrix metalloproteinase2
is insufficient to impair function. Instead, the flow is (MMP-2) has been demonstrated in migraineurs. Patients
reduced because the spreading depression reduces who have migraine without aura seem to have an
metabolism. increased ratio of matrix metalloproteinase9 (MMP-9) to
tissue inhibitors of metalloproteinase1 (TIMP-1), in
Although CSD is the disturbance that presumably results contrast to a lower MMP-9/TIMP-1 ratio in patients who
in the clinical manifestation of migraine aura, this have migraine with aura.[19] Measured levels of MMP-9
spreading oligemia can be clinically silent (ie, migraine alone are the same for migraine patients with or without
without aura). Perhaps a certain threshold is required to aura.[20]
produce symptoms in patients having aura but not in
those without aura. A study of the novel agent Hypoxia
tonabersat, which inhibits CSD, found that the agent
In an experimental study, acute hypoxia was induced by a
helped to prevent migraine attacks with aura only,
single episode of CSD. This was accompanied by dramatic
suggesting that CSD may but not be involved in attacks
failure of brain ion homeostasis and prolonged
without aura.[16]
impairment of neurovascular and neurometabolic
Trigeminovascular system coupling.[21]

Activation of the trigeminovascular system by CSD Vasoactive substances and neurotransmitters

stimulates nociceptive neurons on dural blood vessels to Perivascular nerve activity also results in release of
release plasma proteins and pain-generating substances substances such as substance P, neurokinin A, calcitonin
gene-related peptide, and nitric oxide, which interact with governs circadian rhythm has been proposed. Discovering
the blood vessel wall to produce dilation, protein the central trigger for migraine would help to identify
extravasation, and sterile inflammation. This stimulates better prophylactic agents.
the trigeminocervical complex, as shown by induction of
c-fos antigen by PET scan. Information then is relayed to Brainstem activation
the thalamus and cortex for registering of pain. PET scanning in patients having an acute migraine
Involvement of other centers may explain the associated headache demonstrates activation of the contralateral
autonomic symptoms and affective aspects of this pain. pons, even after medications abort the pain. Weiler et al
proposed that brainstem activation may be the initiating
Neurogenically induced plasma extravasation may play a
factor of migraine.
role in the expression of pain in migraine, but it may not
be sufficient by itself to cause pain. The presence of other Once the CSD occurs on the surface of the brain, H+ and
stimulators may be required. K+ ions diffuse to the pia mater and activate C-fiber
meningeal nociceptors, releasing a proinflammatory soup
Although some drugs that are effective for migraine
of neurochemicals (eg, calcitonin generelated peptide)
inhibit neurogenic plasma extravasation, substance P
and causing plasma extravasation to occur. Therefore, a
antagonists and the endothelin antagonist bosentan
sterile, neurogenic inflammation of the trigeminovascular
inhibit neurogenic plasma extravasation but are
complex is present.
ineffective as antimigraine drugs. Also, the pain process
requires not only the activation of nociceptors of pain- Once the trigeminal system is activated, it stimulates the
producing intracranial structures but also reduction in the cranial vessels to dilate. The final common pathway to the
normal functioning of endogenous pain-control pathways throbbing headache is the dilatation of blood vessels.
that gate the pain.
Cutaneous allodynia
Migraine center
Burstein et al described the phenomenon of cutaneous
A potential "migraine center" in the brainstem has been allodynia, in which secondary pain pathways of the
proposed, based on PET-scan results showing persistently trigeminothalamic system become sensitized during a
elevated rCBF in the brainstem (ie, periaqueductal gray, migrainous episode.[22] This observation demonstrates
midbrain reticular formation, locus ceruleus) even after that, along with the previously described neurovascular
sumatriptan-produced resolution of headache and related events, sensitization of central pathways in the brain
symptoms. These were the findings in 9 patients who had mediates the pain of migraine.
experienced spontaneous attack of migraine without
aura. The increased rCBF was not observed outside of the Dopamine pathway
attack, suggesting that this activation was not due to pain Some authors have proposed a dopaminergic basis for
perception or increased activity of the endogenous migraine.[23] In 1977, Sicuteri postulated that a state of
antinociceptive system. dopaminergic hypersensitivity is present in patients with
The fact that sumatriptan reversed the concomitant migraine. Interest in this theory has recently been
increased rCBF in the cerebral cortex but not the renewed.
brainstem centers suggests dysfunction in the regulation Some of the symptoms associated with migraine
involved in antinociception and vascular control of these headaches, such as nausea, vomiting, yawning, irritability,
centers. Thalamic processing of pain is known to be gated hypotension, and hyperactivity, can be attributed to
by ascending serotonergic fibers from the dorsal raphe relative dopaminergic stimulation. Dopamine receptor
nucleus and from aminergic nuclei in the pontine hypersensitivity has been shown experimentally with
tegmentum and locus ceruleus; the latter can alter brain dopamine agonists (eg, apomorphine). Dopamine
flow and blood-brain barrier permeability. antagonists (eg, prochlorperazine) completely relieve
Because of the set periodicity of migraine, linkage to the almost 75% of acute migraine attacks.
suprachiasmatic nucleus of the hypothalamus that
Magnesium deficiency Increased levels of C-reactive protein
Increased levels of interleukins
Another theory proposes that deficiency of magnesium in
Increased levels of TNF-alpha and adhesion molecules
the brain triggers a chain of events, starting with platelet
(systemic inflammation markers)
aggregation and glutamate release and finally resulting in
Oxidative stress and thrombosis
the release of 5-hydroxytryptamine, which is a
Increased body weight
vasoconstrictor. In clinical studies, oral magnesium has
High blood pressure
shown benefit for preventive treatment and intravenous
Hypercholesterolemia
magnesium may be effective for acute treatment,
[24] Impaired insulin sensitivity
particularly in certain subsets of migraine patients.
High homocysteine levels
Endothelial dysfunction Stroke
Coronary heart disease
Vascular smooth muscle cell dysfunction may involve Transformed migraine/medication overuse headache
impaired cyclic guanosine monophosphate and
hemodynamic response to nitric oxide.[25] Nitric oxide In some patients, migraine progresses to chronic
released by microglia is a potentially cytotoxic migraine. Acute overuse of symptomatic medication is
proinflammatory mediator, initiating and maintaining considered one of the most important risk factors for
brain inflammation through activation of the trigeminal migraine progression. Medication overuse headache can
neuron system. occur with any analgesic, including acetaminophen or
nonsteroidal anti-inflammatory drugs (NSAIDs), such as
Nitric oxide levels continue to be increased even in the ibuprofen, naproxen, and aspirin. In addition, Bigal and
headache-free period in migraineurs.[26] In premenopausal Lipton identified the following associations of medication
women with migraine, particularly in those with migraine with progression to chronic migraine[29] :
aura, increased endothelial activation, which is a
component of endothelial dysfunction, is evident.[27] Opiates - Critical dose of exposure is around 8 days per
month; the effect is more pronounced in men
Serotonin and migraine Barbiturates - Critical dose of exposure is around 5 days
The serotonin receptor (5-hydroxytryptamine [5-HT]) is per month; the effect is more pronounced in women
believed to be the most important receptor in the Triptans - Migraine progression is seen only in patients
headache pathway. Immunohistochemical studies have with high frequency of migraine at baseline (10-14
detected 5-hydroxytryptamine1D (5-HT1D) receptors in days/mo)
trigeminal sensory neurons, including peripheral In the study, the effect of anti-inflammatory medications
projections to the dura and within the trigeminal nucleus varied with headache frequency. These agents were
caudalis (TNC) and solitary tract, while 5-HT1B receptors protective in patients with fewer than 10 days of
are present on smooth muscle cells in meningeal vessels; headache at baseline but induced migraine progression in
however, both can be found in both tissues to some patients with a high frequency of headaches at
extent and even in coronary vessels. baseline.[29]

All the currently available triptans (see Medication) are

selective 5-HT1B/D full agonists. These agents may
decrease headache by abolishing neuropeptide release in Etiology
the periphery and blocking neurotransmission by acting Migraine has a strong genetic component. Approximately
on second-order neurons in the trigeminocervical 70% of migraine patients have a first-degree relative with
complex. a history of migraine. The risk of migraine is increased 4-
fold in relatives of people who have migraine with aura.[30]
Migraine risk factors
Nonsyndromic migraine headache with or without aura
Predisposing vascular risk factors for migraine include the
[28] generally shows a multifactorial inheritance pattern, but
following :
the specific nature of the genetic influence is not yet
completely understood. Certain rarer syndromes with arteriopathy with subcortical infarcts and
migraine as a clinical feature generally show an autosomal leukoencephalopathy) is a genetic disorder that causes
dominant inheritance pattern.[31] migraine with aura, strokes before the age of 60,
progressive cognitive dysfunction, and behavioral
However, recent genome-wide association studies have changes.
suggested 4 regions in which single-nucleotide
polymorphisms influence the risk of developing migraine CADASIL is inherited in an autosomal dominant fashion,
headache.[32, 33, 34] Other associations have been found in and most patients with the disorder have an affected
individual studies but could not be replicated in other parent. Approximately 90% of cases result from mutations
populations. of the <INOTCH3< I>gene, located on chromosome 19.
Patients with CADASIL have significant morbidity from
Familial hemiplegic migraine their ailment, and life expectancy is approximately 68
Familial hemiplegic migraine (FHM) is a rare type of years.[41]
migraine with aura that is preceded or followed by
Migraine is also a common symptom in other genetic
hemiplegia, which typically resolves. FHM may be
vasculopathies, including 2 autosomal dominant
associated with cerebellar ataxia, which is also linked to
disorders: (1) RVCL (retinal vasculopathy with cerebral
the 19p locus. Evidence suggests that the 19p locus for
leukodystrophy), which is caused by mutations in
FHM may also be involved in patients with other forms of
the TREX1 gene,[42] and (2) HIHRATL (hereditary infantile
migraine. Three genes have thus far been identified as
hemiparesis, retinal arteriolar tortuosity, and
being causative for FHM.
leukoencephalopathy), which is suggested to be caused
FHM type 1 is characterized clinically by episodes that by mutations in theCOL4A1 gene.[43] The mechanisms by
commonly include nystagmus and cerebellar signs. This which these genetic vasculopathies give rise to migraine
disorder is caused by mutations in theCACNA1A gene are still unclear.[44]
located on 19p13, which codes for a brain-specific calcium
Migraine precipitants
channel. Mutations in CACNA1A were previously thought
[35]
to account for 50% of cases of FHM, but a Danish study Various precipitants of migraine events have been
showed that only 7% of patients with a clinical diagnosis identified, as follows:
of FHM had a mutation in that gene.[36]
Hormonal changes, such as those accompanying
FHM type 2 occurs in patients who also have a seizure menstruation (common), [45]pregnancy, and ovulation
disorder. This condition has been attributed to mutations Stress
in the ATP1A2 gene, located on 1q21q23, which encodes Excessive or insufficient sleep
a sodium/potassium pump.[37, 38] However, the Danish Medications (eg, vasodilators, oral contraceptives [46] )
study found mutations in ATP1A2 in only 7% of patients Smoking
with a clinical diagnosis of FHM.[36] Exposure to bright or fluorescent lighting
Strong odors (eg, perfumes, colognes, petroleum
FHM type 3 is caused by mutations in the SCN1A gene, distillates)
located on 2q24. Mutations in SCN1A are also known to Head trauma
cause familial febrile seizure disorders and infantile Weather changes
epileptic encephalopathy.[39] Although SCN1A mutation Motion sickness
has been reported in several unrelated families, it is felt Cold stimulus (eg, ice cream headaches)
to be a rare cause of FHM.[40] Lack of exercise
Migraine in other inherited disorders Fasting or skipping meals
Red wine
Migraine occurs with increased frequency in patients with Certain foods and food additives have been suggested as
mitochondrial disorders, such as MELAS (mitochondrial potential precipitants of migraine, including the following:
myopathy, encephalopathy, lactic acidosis, and strokelike
episodes). CADASIL (cerebral autosomal dominant Caffeine
 Artificial sweeteners (eg, aspartame, saccharin) vibrotactile stimulation in patients with migraine
Monosodium glutamate (MSG) compared with controls, including stimulus amplitude
Citrus fruits discrimination, temporal order judgment, and duration
Foods containing tyramine (eg, aged cheese) discrimination.[54]
Meats with nitrites
However, large epidemiologic studies have failed to
substantiate most of these as triggers,[47] and no diets
have been shown to help migraine. Nevertheless, patients
who identify particular foods as triggers should avoid
these foods.

Although chocolate has been considered a migraine

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

Migraine and other vascular disease

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

Migraine with aura for women in midlife has a statistically

significant association with late-life vascular disease
(infarcts) in the cerebellum. This association is not seen in
migraine without aura.[51]

Migraine and iron

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

Migraine and sensory perception

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