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Migraine
Woman during a migraine attack
SpecialtyNeurology
SymptomsHeadaches coupled with sensory disturbances such as nausea, sensitivity to light, sound, and smell
Usual onsetAround puberty
DurationRecurrent, long term
CausesEnvironmental and genetic
Risk factorsFamily history, female sex
Differential diagnosisSubarachnoid hemorrhage, venous thrombosis, idiopathic intracranial hypertension, brain tumor, tension headache, sinusitis, cluster headache
PreventionPropranolol, amitriptyline, topiramate, calcitonin gene-related peptide receptor antagonists (CGRPs)
MedicationIbuprofen, paracetamol (acetaminophen), triptans, ergotamines
Prevalence~15%

Migraine (UK: /ˈmiːɡreɪn/, US: /ˈmaɪ-/)[1][2] is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity.[3][4] Other characterizing symptoms may include vomiting, cognitive dysfunction, allodynia, and dizziness.[3] Exacerbation or worsening of headache symptoms during physical activity is another distinguishing feature.[5]

Up to one-third of people with migraine experience aura, a premonitory period of sensory disturbance widely accepted to be caused by cortical spreading depression at the onset of a migraine attack.[4] Although primarily considered to be a headache disorder, migraine is highly heterogenous in its clinical presentation and is better thought of as a spectrum disease rather than a distinct clinical entity.[6] Disease burden can range from episodic discrete attacks to chronic disease.[6][7]

Migraine is believed to be caused by a mixture of environmental and genetic factors that influence the excitation and inhibition of nerve cells in the brain.[8] The accepted hypothesis suggests that multiple primary neuronal impairments lead to a series of intracranial and extracranial changes, triggering a physiological cascade that leads to migraine symptomatology.[9]

Initial recommended treatment for acute attacks is with over-the-counter (OTC) analgesics (pain medication) such as ibuprofen and paracetamol (acetaminophen) for headache, antiemetics (anti-nausea medication) for nausea, and the avoidance of migraine triggers.[10] Specific medications such as triptans, ergotamines, or calcitonin gene-related peptide receptor (CGRP) antagonists may be used in those experiencing headaches that do not respond to the OTC pain medications.[11] For people who experience four or more attacks per month, or could otherwise benefit from prevention, prophylactic medication is recommended.[12] Commonly prescribed prophylactic medications include beta blockers like propranolol, anticonvulsants like sodium valproate, antidepressants like amitriptyline, and other off-label classes of medications.[13] Preventive medications inhibit migraine pathophysiology through various mechanisms, such as blocking calcium and sodium channels, blocking gap junctions, and inhibiting matrix metalloproteinases, among other mechanisms.[14][15] Non-pharmacological preventive therapies include nutritional supplementation, dietary interventions, sleep improvement, and aerobic exercise.[16] In 2018, the first medication (Erenumab) of a new class of drugs specifically designed for migraine prevention called CGRPs was approved by the United States Food and Drug Administration (FDA).[17] As of July 2023, the FDA has approved eight drugs that act on the CGRP system for use in the treatment of migraine.[18]

Globally, approximately 15% of people are affected by migraine.[19] In the Global Burden of Disease Study, conducted in 2010, migraine ranked as the third-most prevalent disorder in the world.[20] It most often starts at puberty and is worst during middle age.[21] As of 2016, it is one of the most common causes of disability.[22]

Signs and symptoms

[edit]

Migraine typically presents with self-limited, recurrent severe headaches associated with autonomic symptoms.[23][24] About 15–30% of people living with migraine experience episodes with aura,[10][25] and they also frequently experience episodes without aura.[26] The severity of the pain, duration of the headache, and frequency of attacks are variable.[23] A migraine attack lasting longer than 72 hours is termed status migrainosus.[27] There are four possible phases to a migraine attack, although not all the phases are necessarily experienced:[28]

  • The prodrome, which occurs hours or days before the headache
  • The aura, which immediately precedes the headache
  • The pain phase, also known as the headache phase
  • The postdrome, the effects experienced following the end of a migraine attack

Migraine is associated with major depression, bipolar disorder, anxiety disorders, and obsessive–compulsive disorder. These psychiatric disorders are approximately 2–5 times more common in people without aura, and 3–10 times more common in people with aura.[29]

Prodrome phase

[edit]

Prodromal or premonitory symptoms occur in about 60% of those with migraine,[30][31] with an onset that can range from two hours to two days before the start of pain or the aura.[32] These symptoms may include a wide variety of phenomena,[33] including altered mood, irritability, depression or euphoria, fatigue, craving for certain food(s), stiff muscles (especially in the neck), constipation or diarrhea, and sensitivity to smells or noise.[31] This may occur in those with either migraine with aura or migraine without aura.[34] Neuroimaging indicates the limbic system and hypothalamus as the origin of prodromal symptoms in migraine.[35]

Aura phase

[edit]
Enhancements reminiscent of a zigzag fort structure Negative scotoma, loss of awareness of local structures
Positive scotoma, local perception of additional structures Mostly one-sided loss of perception

Aura is a transient focal neurological phenomenon that occurs before or during the headache.[30] Aura appears gradually over a number of minutes (usually occurring over 5–60 minutes) and generally lasts less than 60 minutes.[36][37] Symptoms can be visual, sensory or motoric in nature, and many people experience more than one.[38] Visual effects occur most frequently: they occur in up to 99% of cases, and in more than 50% of cases are not accompanied by sensory or motor effects.[38] If any symptom remains after 60 minutes, the state is known as persistent aura.[39]

Visual disturbances often consist of a scintillating scotoma (an area of partial alteration in the field of vision, which flickers and may interfere with a person's ability to read or drive).[30] These typically start near the center of vision and then spread out to the sides with zigzagging lines, which have been described as looking like fortifications or walls of a castle.[38] Usually, the lines are in black and white, but some people also see colored lines.[38] Some people lose part of their field of vision known as hemianopsia while others experience blurring.[38]

Sensory auras are the second most common type; they occur in 30–40% of people with auras.[38] Often, a feeling of pins-and-needles begins on one side in the hand and arm and spreads to the nose–mouth area on the same side.[38] Numbness usually occurs after the tingling has passed with a loss of position sense.[38] Other symptoms of the aura phase can include speech or language disturbances, world spinning, and, less commonly, motor problems.[38] Motor symptoms indicate that this is a hemiplegic migraine, and weakness often lasts longer than one hour unlike other auras.[38] Auditory hallucinations or delusions have also been described.[40]

Pain phase

[edit]

Classically the headache is unilateral, throbbing, and moderate to severe in intensity.[36] It usually comes on gradually[36] and is aggravated by physical activity during a migraine attack.[28] However, the effects of physical activity on migraine are complex, and some researchers have concluded that, while exercise can trigger migraine attacks, regular exercise may have a prophylactic effect and decrease frequency of attacks.[41] The feeling of pulsating pain is not in phase with the pulse.[42] In more than 40% of cases, however, the pain may be bilateral (both sides of the head), and neck pain is commonly associated with it.[43] Bilateral pain is particularly common in those who have migraine without aura.[30] Less commonly pain may occur primarily in the back or top of the head.[30] The pain usually lasts 4 to 72 hours in adults;[36] however, in young children frequently lasts less than 1 hour.[44] The frequency of attacks is variable, from a few in a lifetime to several a week, with the average being about one a month.[45][46]

The pain is frequently accompanied by nausea, vomiting, sensitivity to light, sensitivity to sound, sensitivity to smells, fatigue, and irritability.[30] Many thus seek a dark and quiet room.[47] In a basilar migraine, a migraine with neurological symptoms related to the brain stem or with neurological symptoms on both sides of the body,[48] common effects include a sense of the world spinning, light-headedness, and confusion.[30] Nausea occurs in almost 90% of people, and vomiting occurs in about one-third.[47] Other symptoms may include blurred vision, nasal stuffiness, diarrhea, frequent urination, pallor, or sweating.[49] Swelling or tenderness of the scalp may occur as can neck stiffness.[49] Associated symptoms are less common in the elderly.[50]

Silent migraine

[edit]

Sometimes, aura occurs without a subsequent headache.[38] This is known in modern classification as a typical aura without headache, or acephalgic migraine in previous classification, or commonly as a silent migraine.[51][52] However, silent migraine can still produce debilitating symptoms, with visual disturbance, vision loss in half of both eyes, alterations in color perception, and other sensory problems, like sensitivity to light, sound, and odors.[53] It can last from 15 to 30 minutes, usually no longer than 60 minutes, and it can recur or appear as an isolated event.[54] Many report a sore feeling in the area where the migraine was, and some report impaired thinking for a few days after the headache has passed. The person may feel tired or "hung over" and have head pain, cognitive difficulties, gastrointestinal symptoms, mood changes, and weakness.[55] According to one summary, "Some people feel unusually refreshed or euphoric after an attack, whereas others note depression and malaise."[56][unreliable medical source?]

Cause

[edit]

The underlying cause of migraine is unknown.[57] However, it is believed to be related to a mix of environmental and genetic factors.[8] Migraine runs in families in about two-thirds of cases[23] and rarely occur due to a single gene defect.[58] While migraine attacks were once believed to be more common in those of high intelligence, this does not appear to be true.[45] A number of psychological conditions are associated, including depression, anxiety, and bipolar disorder.[59]

Intracranial cavernous sinus: a potential site where dilation of cerebral vessels can compress multiple cranial nerves.

Success of the surgical migraine treatment by decompression of extracranial sensory nerves adjacent to vessels[60] suggests that people with migraine may have anatomical predisposition for neurovascular compression[61] that may be caused by both intracranial and extracranial vasodilation due to migraine triggers.[62] This, along with the existence of numerous cranial neural interconnections,[63] may explain the multiple cranial nerve involvement and consequent diversity of migraine symptoms.[64]

Genetics

[edit]
Main article: Genetics of migraine

Studies of twins indicate a 34–51% genetic influence on the likelihood of developing migraine.[8] This genetic relationship is stronger for migraine with aura than for migraine without aura.[26] It is clear from family and populations studies that migraine is a complex disorder, where numerous genetic risk variants exist, and where each variant increases the risk of migraine marginally.[65][66] It is also known that having several of these risk variants increases the risk by a small to moderate amount.[58]

Single gene disorders that result in migraine are rare.[58] One of these is known as familial hemiplegic migraine, a type of migraine with aura, which is inherited in an autosomal dominant fashion.[67][68] Four genes have been shown to be involved in familial hemiplegic migraine.[69] Three of these genes are involved in ion transport.[69] The fourth is the axonal protein PRRT2, associated with the exocytosis complex.[69] Another genetic disorder associated with migraine is CADASIL syndrome or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.[30] One meta-analysis found a protective effect from angiotensin converting enzyme polymorphisms on migraine.[70] The TRPM8 gene, which codes for a cation channel, has been linked to migraine.[71]

The common forms of migraine are polygenetic, where common variants of numerous genes contribute to the predisposition for migraine. These genes can be placed in three categories, increasing the risk of migraine in general, specifically migraine with aura, or migraine without aura.[72][73] Three of these genes, CALCA, CALCB, and HTR1F are already target for migraine specific treatments. Five genes are specific risk to migraine with aura, PALMD, ABO, LRRK2, CACNA1A and PRRT2, and 13 genes are specific to migraine without aura. Using the accumulated genetic risk of the common variations, into a so-called polygenetic risk, it is possible to assess e.g. the treatment response to triptans.[74][75]

Triggers

[edit]

Migraine may be induced by triggers, with some reporting it as an influence in a minority of cases[23] and others, the majority.[76] Many things, such as fatigue, certain foods, alcohol, and weather, have been labeled as triggers; however, the strength and significance of these relationships are uncertain.[76][77] Most people with migraine report experiencing triggers.[78] Symptoms may start up to 24 hours after a trigger.[23]

Also, evidence shows a strong association between migraine and the quality of sleep, particularly poor subjective quality of sleep. The relationship seems to be bidirectional, as migraine frequency increases with low quality of sleep, yet the underlying mechanism of this correlation remains poorly understood.[79]

Physiological aspects

[edit]

Common triggers quoted are stress, hunger, and fatigue (these equally contribute to tension headaches).[76] Psychological stress has been reported as a factor by 50–80% of people.[80] Migraine has also been associated with post-traumatic stress disorder and abuse.[81] Migraine episodes are more likely to occur around menstruation.[80] Other hormonal influences, such as menarche, oral contraceptive use, pregnancy, perimenopause, and menopause, also play a role.[82] These hormonal influences seem to play a greater role in migraine without aura.[45] Migraine episodes typically do not occur during the second and third trimesters of pregnancy, or following menopause.[30]

Dietary aspects

[edit]

Between 12% and 60% of people report foods as triggers.[83][84]

There are many reports[85][86][87][88][89] that tyramine – which is naturally present in chocolate, alcoholic beverages, most cheeses, processed meats, and other foods – can trigger migraine symptoms in some individuals. Monosodium glutamate (MSG) has been reported as a trigger for migraine,[90] but a systematic review concluded that "a causal relationship between MSG and headache has not been proven... It would seem premature to conclude that the MSG present in food causes headache".[91]

Environmental aspects

[edit]

Migraines may be triggered by weather changes, including changes in temperature and barometric pressure.[92][93]

A 2009 review on potential triggers in the indoor and outdoor environment previously concluded that while there were insufficient studies to confirm environmental factors as causing migraine, "migraineurs worldwide consistently report similar environmental triggers ... such as barometric pressure change, bright sunlight, flickering lights, air quality and odors".[94]

Pathophysiology

[edit]
Animation of cortical spreading depression

Migraine is believed to be primarily a neurological disorder,[95][96] while others believe it to be a neurovascular disorder with blood vessels playing the key role, although evidence does not support this completely.[97][98][99][100] Others believe both are likely important.[101][102][103][104] One theory is related to increased excitability of the cerebral cortex and abnormal control of pain neurons in the trigeminal nucleus of the brainstem.[105]

Sensitization of trigeminal pathways is a key pathophysiological phenomenon in migraine. It is debatable whether sensitization starts in the periphery or in the brain.[106][107]

Aura

[edit]

Cortical spreading depression, or spreading depression according to Leão, is a burst of neuronal activity followed by a period of inactivity, which is seen in those with migraine with aura.[108] There are several explanations for its occurrence, including activation of NMDA receptors leading to calcium entering the cell.[108] After the burst of activity, the blood flow to the cerebral cortex in the affected area is decreased for two to six hours.[108] It is believed that when depolarization travels down the underside of the brain, nerves that sense pain in the head and neck are triggered.[108]

Pain

[edit]

The exact mechanism of the head pain that occurs during a migraine episode is unknown.[109] Some evidence supports a primary role for central nervous system structures (such as the brainstem and diencephalon),[110] while other data support the role of peripheral activation (such as via the sensory nerves that surround blood vessels of the head and neck).[109] The potential candidate vessels include dural arteries, pial arteries and extracranial arteries such as those of the scalp.[109] The role of vasodilatation of the extracranial arteries, in particular, is believed to be significant.[111]

Neuromodulators

[edit]

Adenosine, a neuromodulator, may be involved.[112] Released after the progressive cleavage of adenosine triphosphate (ATP), adenosine acts on adenosine receptors to put the body and brain in a low activity state by dilating blood vessels and slowing the heart rate, such as before and during the early stages of sleep. Adenosine levels are high during migraine attacks.[112][113] Caffeine's role as an inhibitor of adenosine may explain its effect in reducing migraine.[114] Low levels of the neurotransmitter serotonin, also known as 5-hydroxytryptamine (5-HT), are also believed to be involved.[115]

Calcitonin gene-related peptides (CGRPs) have been found to play a role in the pathogenesis of the pain associated with migraine, as levels of it become elevated during an attack.[10][42]

Diagnosis

[edit]

The diagnosis of a migraine is based on signs and symptoms.[23] Neuroimaging tests are not necessary to diagnose migraine, but may be used to find other causes of headaches in those whose examination and history do not confirm a migraine diagnosis.[116] It is believed that a substantial number of people with the condition remain undiagnosed.[23]

The diagnosis of migraine without aura, according to the International Headache Society, can be made according to the "5, 4, 3, 2, 1 criteria", which is as follows:[28]

  • Five or more attacks – for migraine with aura, two attacks are sufficient for diagnosis.
  • Four hours to three days in duration
  • Two or more of the following:
    • Unilateral (affecting one side of the head)
    • Pulsating
    • Moderate or severe pain intensity
    • Worsened by or causing avoidance of routine physical activity
  • One or more of the following:

If someone experiences two of the following: photophobia, nausea, or inability to work or study for a day, the diagnosis is more likely.[117] In those with four out of five of the following: pulsating headache, duration of 4–72 hours, pain on one side of the head, nausea, or symptoms that interfere with the person's life, the probability that this is a migraine attack is 92%.[10] In those with fewer than three of these symptoms, the probability is 17%.[10]

Classification

[edit]
Main article: ICHD classification and diagnosis of migraine

Migraine was first comprehensively classified in 1988.[26]

The International Headache Society updated its classification of headaches in 2004.[28] A third version was published in 2018.[118] According to this classification, migraine is a primary headache disorder along with tension-type headaches and cluster headaches, among others.[119]

Migraine is divided into six subclasses (some of which include further subdivisions):[120]

  • Migraine without aura, or "common migraine", involves migraine headaches that are not accompanied by aura.
  • Migraine with aura, or "classic migraine", usually involves migraine headaches accompanied by aura. Less commonly, aura can occur without a headache or with a nonmigraine headache. Two other varieties are familial hemiplegic migraine and sporadic hemiplegic migraine, in which a person has migraine with aura and with accompanying motor weakness. If a close relative has had the same condition, it is called "familial"; otherwise, it is called "sporadic". Another variety is basilar-type migraine, where a headache and aura are accompanied by difficulty speaking, world spinning, ringing in ears, or several other brainstem-related symptoms, but not motor weakness. This type was initially believed to be due to spasms of the basilar artery, the artery that supplies the brainstem. Now that this mechanism is not believed to be primary, the symptomatic term migraine with brainstem aura (MBA) is preferred.[48] Retinal migraine (which is distinct from visual or optical migraine) involves migraine headaches accompanied by visual disturbances or even temporary blindness in one eye.
  • Childhood periodic syndromes that are commonly precursors of migraine include cyclical vomiting (occasional intense periods of vomiting), abdominal migraine (abdominal pain, usually accompanied by nausea), and benign paroxysmal vertigo of childhood (occasional attacks of vertigo).
  • Complications of migraine describe migraine headaches and/or auras that are unusually long or unusually frequent, or associated with a seizure or brain lesion.
  • Probable migraine describes conditions that have some characteristics of migraine, but where there is not enough evidence to diagnose it as migraine with certainty (in the presence of concurrent medication overuse).
  • Chronic migraine is a complication of migraine, and is a headache that fulfills diagnostic criteria for migraine headache and occurs for a greater time interval. Specifically, greater than or equal to 15 days/month for longer than 3 months.[121]

Abdominal migraine

[edit]

The diagnosis of abdominal migraine is controversial.[122] Some evidence indicates that recurrent episodes of abdominal pain in the absence of a headache may be a type of migraine[122][123] or are at least a precursor to migraine attacks.[26] These episodes of pain may or may not follow a migraine-like prodrome and typically last minutes to hours.[122] They often occur in those with either a personal or family history of typical migraine.[122] Other syndromes that are believed to be precursors include cyclical vomiting syndrome and benign paroxysmal vertigo of childhood.[26]

Differential diagnosis

[edit]

Other conditions that can cause similar symptoms to a migraine headache include temporal arteritis, cluster headaches, acute glaucoma, meningitis and subarachnoid hemorrhage.[10] Temporal arteritis typically occurs in people over 50 years old and presents with tenderness over the temple, cluster headache presents with one-sided nose stuffiness, tears and severe pain around the orbits, acute glaucoma is associated with vision problems, meningitis with fevers, and subarachnoid hemorrhage with a very fast onset.[10] Tension headaches typically occur on both sides, are not pounding, and are less disabling.[10]

Those with stable headaches that meet criteria for migraine should not receive neuroimaging to look for other intracranial disease.[124][125][126] This requires that other concerning findings such as papilledema (swelling of the optic disc) are not present. People with migraine are not at an increased risk of having another cause for severe headaches.[citation needed]

Management

[edit]
Main article: Management of migraine

Management of migraine includes prevention of migraine attacks and rescue treatment. There are three main aspects of treatment: trigger avoidance, acute (abortive), and preventive (prophylactic) control.[127]

Modern approaches to migraine management emphasize personalized care that considers individual patient needs. Lifestyle modifications, such as managing triggers and addressing comorbidities, form the foundation of treatment. Behavioral techniques and supplements like magnesium and riboflavin can serve as supportive options for some individuals.[128] Behavioral techniques that have been utilized in the treatment of migraines include Cognitive Behavioral Therapy (CBT), relaxation training, biofeedback, Acceptance and Commitment Therapy (ACT), as well as mindfulness-based therapies.[129] A 2024 systematic literature review and meta analysis found evidence that treatments such as CBT, relaxation training, ACT, and mindfulness-based therapies can reduce migraine frequency both on their own and in combination with other treatment options.[129] In addition, it was found that relaxation therapy aided in the lessening of migraine frequency when compared to education by itself.[129] Similarly, for children and adolescents, CBT and biofeedback strategies are effective in decreasing of frequency and intensity of migraines. These techniques often include relaxation methods and promotion of long-term management without medication side effects, which is emphasized for younger individuals.[129] Acute treatments, including NSAIDs and triptans, are most effective when administered early in an attack, while preventive medications are recommended for those experiencing frequent or severe migraines. Proven preventive options include beta blockers, topiramate, and calcitonin gene related peptides (CGRP) inhibitors like erenumab and galcanezumab, which have demonstrated significant efficacy in clinical studies.[130] The European Consensus Statement provides a framework for diagnosis and management, emphasizing the importance of accurate assessment, patient education, and consistent adherence to prescribed treatments. Innovative therapies of oral medications used to treat migraine symptoms, such as gepants and ditans, are emerging as alternatives for patients who cannot use traditional options.[131]

A 2024 systematic review and network meta analysis compared the effectiveness of medications for acute migraine attacks in adults. It found that triptans were the most effective class of drugs, followed by non-steroidal anti-inflammatories. Gepants were less effective than non-steroidal anti-inflammatory drugs.[132][133]

[edit]

Calcitonin gene-related peptide is a neuropeptide implicated in the pathophysiology of migraines. It is predominantly found in the trigeminal ganglion and central nervous system pathways associated with migraine mechanisms.[134] During migraine attacks, elevated levels of CGRP are detected, leading to vasodilation of cerebral and dural blood vessels and the release of inflammatory mediators from mast cells. These actions contribute to the transmission of nociceptive signals, culminating in migraine pain. Targeting CGRP has emerged as a promising therapeutic strategy for migraine management.[135][136]

Prognosis

[edit]

"Migraine exists on a continuum of different attack frequencies and associated levels of disability."[137] For those with occasional, episodic migraine, a "proper combination of drugs for prevention and treatment of migraine attacks" can limit the disease's impact on patients' personal and professional lives.[138] But fewer than half of people with migraine seek medical care and more than half go undiagnosed and undertreated.[139] "Responsive prevention and treatment of migraine is incredibly important" because evidence shows "an increased sensitivity after each successive attack, eventually leading to chronic daily migraine in some individuals."[138] Repeated migraine results in "reorganization of brain circuitry", causing "profound functional as well as structural changes in the brain."[140] "One of the most important problems in clinical migraine is the progression from an intermittent, self-limited inconvenience to a life-changing disorder of chronic pain, sensory amplification, and autonomic and affective disruption. This progression, sometimes termed chronification in the migraine literature, is common, affecting 3% of migraineurs in a given year, such that 8% of migraineurs have chronic migraine in any given year." Brain imagery reveals that the electrophysiological changes seen during an attack become permanent in people with chronic migraine; "thus, from an electrophysiological point of view, chronic migraine indeed resembles a never-ending migraine attack."[140] Severe migraine ranks in the highest category of disability, according to the World Health Organization, which uses objective metrics to determine disability burden for the authoritative annual Global Burden of Disease report. The report classifies severe migraine alongside severe depression, active psychosis, quadriplegia, and terminal-stage cancer.[141]

Migraine with aura appears to be a risk factor for ischemic stroke[142] doubling the risk.[143] Being a young adult, being female, using hormonal birth control, and smoking further increases this risk.[142] There also appears to be an association with cervical artery dissection.[144] Migraine without aura does not appear to be a factor.[145] The relationship with heart problems is inconclusive with a single study supporting an association.[142] Migraine does not appear to increase the risk of death from stroke or heart disease.[146] Preventative therapy of migraine in those with migraine with aura may prevent associated strokes.[147] People with migraine, particularly women, may develop higher than average numbers of white matter brain lesions of unclear significance.[148]

Epidemiology

[edit]
Percent of women and men who have experienced migraine with or without aura within the last 3 months

Migraine is common, with around 33% of women and 18% of men affected at some point in their lifetime.[149] Onset can be at any age, but prevalence rises sharply around puberty, and remains high until declining after age 50.[149] Before puberty, boys and girls are equally impacted, with around 5% of children experiencing migraine attacks. From puberty onwards, women experience migraine attacks at greater rates than men. From age 30 to 50, up to 4 times as many women experience migraine attacks as men;[149] this is most pronounced in migraine without aura.[150]

Worldwide, migraine affects nearly 15% or approximately one billion people.[19] In the United States, about 6% of men and 18% of women experience a migraine attack in a given year, with a lifetime risk of about 18% and 43%, respectively.[23] In Europe, migraine affects 12–28% of people at some point in their lives, with about 6–15% of adult men and 14–35% of adult women getting at least one attack yearly.[151] Rates of migraine are slightly lower in Asia and Africa than in Western countries.[45][152] Chronic migraine occurs in approximately 1.4–2.2% of the population.[153]

During perimenopause symptoms often get worse before decreasing in severity.[154] While symptoms resolve in about two-thirds of the elderly, in 3–10% they persist.[50]

History

[edit]
The Head Ache, George Cruikshank (1819)

An early description consistent with migraine is contained in the Ebers Papyrus, written around 1500 BCE in ancient Egypt.[155]

The word migraine is from the Greek ἡμικρᾱνίᾱ (hēmikrāníā), 'pain in half of the head',[156] from ἡμι- (hēmi-), 'half' and κρᾱνίον (krāníon), 'skull'.[157]

In 200 BCE, writings from the Hippocratic school of medicine described the visual aura that can precede the headache and a partial relief occurring through vomiting.[158]

A second-century description by Aretaeus of Cappadocia divided headaches into three types: cephalalgia, cephalea, and heterocrania.[159] Galen of Pergamon used the term hemicrania (half-head), from which the word migraine was eventually derived.[159] Galen also proposed that the pain arose from the meninges and blood vessels of the head.[158] Migraine was first divided into the two now used types – migraine with aura (migraine ophthalmique) and migraine without aura (migraine vulgaire) in 1887 by Louis Hyacinthe Thomas, a French librarian.[158] The mystical visions of Hildegard von Bingen, which she described as "reflections of the living light", are consistent with the visual aura experienced during migraine attacks.[160]

A trepanated skull, from the Neolithic. The perimeter of the hole in the skull is rounded off by ingrowth of new bony tissue, indicating that the person survived the operation.

Trepanation, the deliberate drilling of holes into a skull, was practiced as early as 7,000 BCE.[155] While sometimes people survived, many would have died from the procedure due to infection.[161] It was believed to work via "letting evil spirits escape".[162] William Harvey recommended trepanation as a treatment for migraine in the 17th century.[163] The association between trepanation and headaches in ancient history may simply be a myth or unfounded speculation that originated several centuries later. In 1913, the world-famous American physician William Osler misinterpreted the French anthropologist and physician Paul Broca's words about a set of children's skulls from the Neolithic age that he found during the 1870s. These skulls presented no evident signs of fractures that could justify this complex surgery for mere medical reasons. Trepanation was probably born of superstitions, to remove "confined demons" inside the head, or to create healing or fortune talismans with the bone fragments removed from the skulls of the patients. However, Osler wanted to make Broca's theory more palatable to his modern audiences, and explained that trepanation procedures were used for mild conditions such as "infantile convulsions headache and various cerebral diseases believed to be caused by confined demons."[164]

While many treatments for migraine have been attempted, it was not until 1868 that use of a substance that eventually turned out to be effective began.[158] This substance was the fungus ergot from which ergotamine was isolated in 1918[165] and first used to treat migraine in 1925.[166] Methysergide was developed in 1959 and the first triptan, sumatriptan, was developed in 1988.[165] During the 20th century, with better study design, effective preventive measures were found and confirmed.[158]

Society and culture

[edit]

Migraine is a significant source of both medical costs and lost productivity. It has been estimated that migraine is the most costly neurological disorder in the European Community, costing more than €27 billion per year.[167] In the United States, direct costs have been estimated at US$17 billion, while indirect costs – such as missed or decreased ability to work – is estimated at US$15 billion.[168] Nearly a tenth of the direct cost is due to the cost of triptans.[168] In those who do attend work during a migraine attack, effectiveness is decreased by around a third.[167] Negative impacts also frequently occur for a person's family.[167]

Research

[edit]

Prevention mechanisms

[edit]

Transcranial magnetic stimulation shows promise,[10][169] as does transcutaneous supraorbital nerve stimulation.[170] There is preliminary evidence that a ketogenic diet may help prevent episodic and long-term migraine.[171][172]

Sex dependency

[edit]

Statistical data indicates that women may be more prone to having migraine, showing migraine incidence three times higher among women than men.[173][174] The Society for Women's Health Research has also mentioned hormonal influences, mainly estrogen, as having a considerable role in provoking migraine pain. Studies and research related to the sex dependencies of migraine are ongoing, and conclusions have yet to be achieved.[175]

See also

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References

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Further reading

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A migraine is a chronic characterized by recurrent attacks of moderate to severe throbbing or pulsating pain, typically unilateral and lasting from 4 to 72 hours if untreated, often accompanied by , , and heightened sensitivity to light (), sound (), and sometimes smells or touch. These episodes can significantly impair daily functioning, with attacks frequently preceded by a phase of subtle changes like mood shifts or food cravings and followed by a postdrome phase of exhaustion or . Migraines affect approximately 1 in 5 women and 1 in 16 men worldwide, with a higher among females due to hormonal influences, and often begin in or early adulthood, peaking in the 30s. Globally, migraines contribute to the third-highest burden of neurological , measured by disability-adjusted life years (DALYs), impacting through personal suffering, economic costs, and associations with conditions like anxiety and depression. There are several types, including migraine without (the most common, comprising about 70-90% of cases), migraine with (affecting around 25-30% of sufferers, involving temporary sensory disturbances like visual flashes or numbness), chronic migraine (15 or more headache days per month for over three months), and rarer variants such as hemiplegic or . The exact causes of migraine remain incompletely understood but involve a combination of — with a 50% heritability risk if one is affected— and environmental triggers that activate abnormal brain activity, including changes in the , imbalances in neurotransmitters like serotonin, and release of inflammatory peptides such as (CGRP). Common triggers include hormonal fluctuations (e.g., during ), stress, irregular , certain foods or beverages (like alcohol, , or aged cheeses), sensory stimuli, and weather changes, though these vary by individual. Risk factors extend beyond to include , low , and certain ethnic backgrounds, such as higher rates among Native Americans. Diagnosis typically relies on a detailed , symptom patterns, and exclusion of secondary causes through physical and neurological exams, with imaging like MRI or CT scans used only if red flags suggest other conditions. Treatment strategies encompass acute relief with over-the-counter analgesics (such as NSAIDs), triptans (which, according to a 2024 network meta-analysis, generally achieve higher rates of pain freedom at 2 hours compared to NSAIDs alone), or CGRP antagonists to abort attacks, and preventive measures for frequent sufferers, including beta-blockers, anticonvulsants, Botox injections, or newer monoclonal antibodies targeting CGRP, alongside lifestyle modifications like trigger avoidance, regular , hydration, and . Complications can include medication-overuse headaches from frequent painkiller use, persistent without , or status migrainosus—a debilitating migraine attack lasting more than 72 hours that requires prompt medical attention . A migraine duration of 4 days or longer exceeds this 72-hour threshold and warrants seeing a doctor or visiting the emergency room promptly, especially if symptoms are severe, unresponsive to usual treatments, or complicated by dehydration, intense nausea, vomiting, or other issues , underscoring the need for tailored, multidisciplinary management.

Clinical Presentation

Prodromal and Aura Phases

The prodromal phase, also referred to as the premonitory phase, precedes the aura or headache in a significant proportion of migraine episodes, occurring in up to 66% of clinic-based cases. This phase typically begins up to 48 hours before headache onset, with symptoms often emerging 6 to 11 hours prior on average. Common manifestations include (reported in 49% of cases), mood changes such as or depression (37%), (46%), yawning (22%), food cravings (11%), and . These nonspecific symptoms arise from hypothalamic and dysregulation, providing early indicators of an impending attack without causing permanent neurological changes. The aura phase, experienced in approximately 25–30% of migraine cases, follows the and lasts 5 to 60 minutes. It represents a focal neurological disturbance that is fully reversible and does not result in lasting damage. The underlying mechanism involves , a wave of neuronal and glial that propagates across the at 2 to 5 mm per minute. Visual auras are the most prevalent, occurring in over 90% of aura cases and featuring phenomena such as blurred or decreased eyesight, (a shimmering blind spot), zigzag lines, or temporary blind spots. A representative example is the fortification spectrum, a dynamic pattern of flickering, crenellated lines that begins centrally in the and expands outward, mimicking the battlements of a fortified wall. Sensory auras, affecting about 30–35% of those with aura, manifest as unilateral numbness or tingling that typically starts in the fingers or hand, migrates gradually over 5 to 20 minutes, and lasts 5 to 60 minutes before resolving. Speech disturbances, including transient dysphasia or difficulty finding words, occur in roughly 10–30% of aura episodes. In rarer instances, auras include motor symptoms, as seen in , where temporary unilateral weakness or paralysis develops over 20–30 minutes, often spreading from the hand to the arm and face before fully resolving. These phases commonly transition into the headache stage, where pain intensifies.

Headache and Associated Symptoms

The headache phase of a migraine attack is characterized by unilateral throbbing or pulsating pain that is moderate to severe in intensity, may localize to various regions including the occipital area at the back of the head, and is typically aggravated by routine , such as walking or stairs. This pain often begins unilaterally but may become bilateral in approximately one-third of attacks and is frequently accompanied by autonomic symptoms. Common associated symptoms include , , (sensitivity to light), (sensitivity to sound), and osmophobia (aversion to smells), with at least one of these sensory sensitivities present during most attacks. Cutaneous , a heightened sensitivity to touch where non-painful stimuli like brushing or wearing cause discomfort, develops in up to 70% of patients during this phase and reflects central sensitization. Untreated or unsuccessfully treated, the headache typically lasts 4 to 72 hours, with pain building over 1 to 2 hours, often progressing from the frontal region posteriorly to become more diffuse, and peaking early in the course before gradually subsiding. Cutaneous may intensify as the attack progresses, contributing to overall debilitation. Acephalgic migraine, also known as , is characterized by typical symptoms without subsequent . In this form, reversible neurological disturbances like visual scintillations or sensory changes last 5 to 60 minutes without evolving into head pain.

Postdromal Phase

The postdrome, often referred to as the "migraine hangover," represents the recovery phase following the resolution of the and associated symptoms in a migraine attack. This phase typically lasts from a few hours to up to 48 hours, with most individuals experiencing symptoms that persist for 24 hours or less. Common manifestations include profound exhaustion or weakness, affecting up to 88% of those in postdrome, alongside cognitive impairments such as difficulty concentrating or mental fog in about 56% of cases. Mood alterations, ranging from or depression to occasional elation, are also reported, as are residual sensitivities to light () and sound (), along with mild or head discomfort. These symptoms contribute to significant functional impairment during the postdrome, disrupting daily activities and . Individuals often describe a reduced , with scores averaging 57 out of 100 compared to 81 between attacks, due to challenges in focusing on tasks, physical weakness, and overall that can extend work or social engagements for hours to days. In some instances, a sense of relief or mild emerges as the acute phase subsides, though this is less common and varies by individual. Such impairments highlight the postdrome's role in prolonging the overall burden of a migraine episode beyond the itself. Physiologically, the postdrome involves the gradual normalization of excitability following the heightened neuronal activity of the earlier phases, with suggesting persistent alterations in diencephalic and function that contribute to lingering symptoms. Recovery also encompasses restoration of hydration status, as from , , or reduced intake during the attack can exacerbate and cognitive issues, necessitating rehydration for full resolution. These processes typically complete within 24 to 48 hours, returning most individuals to baseline functioning, independent of acute treatment use or attack severity.

Migraine Variants

Migraine variants encompass less common subtypes that diverge from the typical episodic pattern, often involving atypical symptoms or chronicity, and primarily affect a of individuals with migraine disorders. is characterized by recurrent episodes of moderate to severe, midline lasting 1–72 hours, accompanied by , , , or anorexia, and it predominantly affects children aged 4–15 years without prominent during attacks. These episodes interfere with daily activities and are interspersed with asymptomatic periods, often serving as a precursor to classic migraine in adulthood, with up to 70% of affected children developing migraine headaches later in life. is more prevalent in pediatric populations, occurring in about 1–4% of children experiencing recurrent . Hemiplegic migraine features migraine accompanied by reversible motor weakness, typically unilateral and affecting the face, arm, or leg, which may last from minutes to days and can mimic symptoms. It includes other elements such as visual disturbances, sensory changes, or speech difficulties, and is linked to genetic , notably in the CACNA1A gene encoding a subunit, which heightens neuronal excitability. This variant occurs in familial (autosomal dominant inheritance with affected relatives) and sporadic forms (no family history, often due to de novo ), with the latter comprising a significant portion of cases. Chronic migraine represents a progression from episodic migraine, defined by the , third edition (ICHD-3) as headaches occurring on ≥15 days per month for >3 months, with at least 8 of those days fulfilling criteria for migraine (such as unilateral throbbing pain with or ). It evolves gradually from lower-frequency attacks, influenced by factors like medication overuse, and affects daily functioning more severely than episodic forms. Retinal migraine involves transient monocular visual disturbances, including partial vision loss or scotomas in one eye due to involvement of the retinal vasculature, typically lasting 5–60 minutes and often preceding or accompanying a headache. These episodes are fully reversible but require differentiation from more serious ocular or vascular conditions. Vestibular migraine is defined by episodes of vertigo or lasting 5 minutes to 72 hours, with features of migraine such as , , or , and a history of migraine. It affects approximately 10% of migraine patients in clinical settings and is more common among those with a personal or family history of migraine.

Etiology and Risk Factors

Genetic Influences

Migraine is a polygenic disorder with heritability estimates ranging from 40% to 60%, indicating a substantial genetic contribution to susceptibility. Genome-wide association studies (GWAS) have identified over 120 genetic loci associated with migraine risk, highlighting its complex genetic architecture. Notable examples include variants in PRDM16 and TRPM8, which influence neuronal excitability and pain pathways. These GWAS findings reveal shared genetic influences with vascular traits such as blood pressure, though the primary mechanisms appear neuronal, involving ion channels and synaptic function. In contrast to the common polygenic forms, rare monogenic subtypes exist, most prominently (FHM), which follows an autosomal dominant inheritance pattern. FHM type 1 (FHM1) results from mutations in CACNA1A, encoding a subunit that regulates neuronal signaling. FHM type 2 (FHM2) is caused by mutations in ATP1A2, which encodes a sodium-potassium involved in homeostasis across neuronal membranes. FHM type 3 (FHM3) arises from mutations in SCN1A, affecting a voltage-gated critical for generation. These mutations disrupt cortical excitability, leading to hemiplegic aura symptoms. Family-based studies underscore the hereditary component, showing that first-degree relatives of individuals with migraine face a 1.5- to 3-fold increased risk compared to the general . This aggregation is influenced by sex-specific patterns, with GWAS identifying loci that differentially affect migraine susceptibility in males and females, such as those linked to hormonal interactions.

Physiological Triggers

Hormonal fluctuations, particularly involving , play a significant role in triggering migraine attacks, especially in women. Drops in levels during the are associated with menstrual migraine, where attacks occur in relation to menstruation due to the withdrawal of this . Approximately 60% of women with migraine experience attacks linked to their menstrual period, highlighting the influence of these cyclical changes. In contrast, often leads to a reduction in migraine frequency, with 50% to 80% of affected women reporting fewer or less severe attacks, attributed to the sustained high levels of during this period. Sleep disturbances are common physiological triggers for migraine, disrupting the body's internal rhythms and exacerbating susceptibility to attacks. Conditions such as , oversleeping, and can precipitate migraines by altering quality and duration, with poor sleep patterns identified as a for increased attack frequency and intensity. Severe sleep deprivation, in particular, disrupts brain excitability and lowers the threshold for cortical spreading depression, the neural phenomenon implicated in migraine aura (see Pathophysiology). These disruptions are linked to dysregulation of the , including abnormal secretion, which normally modulates pain pathways and sleep-wake cycles; in migraineurs, melatonin levels may fail to peak appropriately, contributing to vulnerability. Stress and subsequent relaxation phases also act as internal triggers through their effects on the body's regulatory systems. Acute stress activates the , leading to physiological changes that can initiate a migraine attack in susceptible individuals. Paradoxically, the "letdown" effect following a period of high stress—such as during weekends or vacations—can trigger attacks the next day, as a reduction in perceived stress from one day to the next is associated with onset, possibly due to shifts in neuroendocrine and autonomic balance. Physical exertion represents another endogenous trigger, where intense bodily activity strains physiological systems and provokes attacks. Overexertion during exercise is reported as a lifetime trigger in approximately 38% of migraineurs, regardless of migraine type or , due to increased and vascular changes. Similarly, sexual activity can precipitate migraines in a subset of patients, with about 15% of exercise-related headaches manifesting as migrainous, often involving autonomic responses similar to those in primary headaches. Genetic susceptibility may amplify the impact of these physiological triggers, making certain individuals more prone to attacks under such conditions. Emerging evidence indicates that alterations in the gut microbiome contribute to migraine risk, with patients showing reduced abundance of butyrate-producing bacteria and lower levels of butyrate, a short-chain fatty acid with anti-inflammatory effects that may modulate neuroinflammation.

Dietary and Environmental Triggers

Dietary factors are among the most commonly reported precipitants of migraine attacks, with certain foods and beverages implicated due to their vasoactive compounds or effects on cerebral blood flow. Alcohol, particularly , is frequently cited as a trigger, potentially owing to its , , and content. Aged cheeses, , and processed meats containing nitrites or nitrates can also provoke episodes by influencing release and vascular tone. (MSG), found in many processed foods, has been associated with onset in susceptible individuals through excitotoxic mechanisms. Additionally, caffeine withdrawal can induce migraines by causing and altered signaling in the . Environmental changes play a significant role in triggering migraines for many patients. Drops in barometric pressure, often linked to weather fronts, are reported to initiate attacks, possibly via effects on cerebral vasculature and oxygenation. Bright lights, strong odors such as perfumes or chemicals, and high altitude exposure—associated with hypoxia—further contribute by sensitizing pathways. At elevations above 8,500 feet, reduced oxygen levels may exacerbate susceptibility, leading to increased migraine frequency. Sensory stimuli often act as precipitants through overload of neural processing centers. Loud noises and flickering screens, including those from fluorescent lights or digital devices, can trigger attacks by heightening cortical excitability. Studies indicate that 50–70% of patients identify such personal triggers, with prevalence varying by type; for instance, weather changes affect about 53% and odors around 44%. and skipping meals are common modifiable triggers, primarily through inducing and reduced cerebral glucose availability. Low blood sugar from irregular eating patterns, such as or missing , has been linked to migraine onset in over 57% of cases in some cohorts. These factors may interact with physiological states like stress to lower the threshold for attacks.

Pathophysiology

Cortical Spreading Depression

(CSD) is a slowly propagating wave of neuronal and glial that sweeps across the , characterized by a speed of 2–5 mm/min, followed by a prolonged period of suppressed activity. This phenomenon, first described in , involves a massive influx of ions and neurotransmitters that disrupt normal cortical function temporarily. The phase leads to a breakdown in ionic , while the subsequent depression phase reflects recovery and inhibition of electrical activity. Imaging studies provide direct evidence linking CSD to migraine . (fMRI) has captured blood oxygenation level-dependent (BOLD) signals consistent with CSD propagation in the during aura episodes, showing a slow march of hyperactivity followed by oligemia. (EEG), including intracranial recordings, reveals characteristic negative shifts in potential and slowed rhythms during aura, aligning with CSD's electrophysiological signature. These events typically endure for 20–60 minutes, mirroring the temporal profile of aura symptoms. At the ionic level, CSD is driven by extracellular efflux, which depolarizes adjacent cells and triggers further propagation. This is accompanied by glutamate release from neurons, amplifying the wave through excitotoxic mechanisms, while both neuronal and glial cells contribute via gap junctions and ion pumps. Glial involvement, particularly , facilitates spatial buffering of ions and modulates the wave's intensity. The spatial and temporal dynamics of CSD closely match the perceptual disturbances of migraine , such as the gradual expansion of defects from central to peripheral regions. CSD is primarily associated with the perceptual disturbances of migraine , though evidence suggests it may occur subclinically in migraine without . Severe sleep deprivation disrupts brain excitability, reducing GABAergic inhibition and lowering the threshold for CSD initiation, thereby increasing susceptibility to migraine attacks. CSD may also indirectly contribute to trigeminovascular activation, bridging to subsequent .

Trigeminovascular System Activation

The trigeminovascular system plays a central role in the generation of by transmitting nociceptive signals from the to the . During a migraine attack, activation of this pathway begins with peripheral sensitization of meningeal nociceptors, leading to the throbbing pain typically felt in the and temples. This system involves the and its connections to vascular structures, where inflammatory and neural processes amplify pain signals, contributing to the characteristic unilateral or bilateral phase. The , particularly its ophthalmic division (V1), provides dense innervation to the , pial vessels, and large via thinly myelinated Aδ fibers and unmyelinated C-fibers originating from the and upper (C1-C3). These meningeal nociceptors, which are pseudounipolar neurons, become activated by mechanical distortion, inflammatory mediators, or osmotic changes in the dura, resulting in to the craniofacial region due to convergence of trigeminal and cervical afferents onto second-order neurons in the . This activation is thought to underlie the localized distribution in migraine, with developing rapidly during attacks. Upon activation, trigeminal afferents release such as and (CGRP) from their peripheral terminals in the and from the trigeminal ganglia, initiating neurogenic inflammation. This process causes plasma protein extravasation, mast cell degranulation, and in meningeal vessels, further sensitizing nociceptors and perpetuating the pain cycle. The release of these peptides can be triggered by peripheral stimuli and is a key mechanism linking vascular changes to nociceptive signaling, though it is modulated by antimigraine therapies like that inhibit neuropeptide release. Central occurs as prolonged input from activated meningeal nociceptors leads to enhanced excitability of second-order neurons in the trigeminocervical complex, located in the caudal portion of the (medullary dorsal horn) and upper cervical . This amplification results in cutaneous , where innocuous stimuli like touch or hair brushing become painful, often in the periorbital and temporal regions, reflecting widespread central hyperexcitability during the phase. Such can persist and contribute to treatment resistance if the attack progresses. Vasoactive changes in the trigeminovascular system involve dilation of meningeal and extracranial arteries, primarily mediated by CGRP, which promotes sustained vasodilation without being the direct cause of pain. While intracranial vessels show modest dilation, extracranial arteries like the temporal artery exhibit more pronounced changes, correlating with the pulsating quality of migraine pain; however, pain persists even after vessel constriction, indicating that neural activation is paramount. These vascular shifts are secondary to the primary nociceptive drive but exacerbate the sensory experience.

Neurotransmitter and Inflammatory Roles

(CGRP) serves as a pivotal in migraine , functioning as both a potent vasodilator and a key transmitter. Released from trigeminal sensory neurons, CGRP promotes neurogenic inflammation by dilating cranial blood vessels and sensitizing nociceptors in the trigeminovascular system. During migraine attacks, CGRP concentrations are markedly elevated in jugular , , and tear fluid, correlating with intensity and returning to baseline after effective treatment. These elevations persist interictally in some chronic migraine patients, suggesting a role in attack predisposition and central sensitization. Serotonin (5-hydroxytryptamine, 5-HT) modulates vascular tone and nociceptive signaling in migraine, with fluctuations contributing to the disorder's vascular and sensory components. Interictal 5-HT synthesis is reduced in migraineurs, particularly in the dorsal brainstem, while levels increase during attacks, potentially reflecting compensatory release to counteract pain. These changes induce via 5-HT1B receptors on and inhibit trigeminovascular through 5-HT1D receptors on sensory neurons. Peripheral 5-HT reactivity is heightened in migraine patients, with reduced to stimuli, exacerbating vascular instability during episodes. Glutamate, the primary excitatory , drives central in migraine via activation of N-methyl-D-aspartate (NMDA) receptors on trigeminal and thalamic neurons. Elevated glutamate levels during attacks promote , , and enhanced pain transmission, amplifying hypersensitivity to sensory stimuli. This process intersects with , as glutamate release from neurons stimulates satellite glial cells to produce proinflammatory cytokines, including interleukin-6 (IL-6). IL-6, which rises rapidly within hours of attack onset, sustains neurogenic and nociceptor , particularly in chronic cases where it correlates with attack frequency and severity. Recent investigations as of 2025 highlight the neuromodulatory roles of pituitary adenylate cyclase-activating polypeptide (PACAP) and orexins in migraine. PACAP, a vasodilatory structurally related to VIP, induces migraine-like attacks upon and contributes to trigeminovascular , with ongoing trials of anti-PACAP antibodies showing partial reductions in monthly migraine days. Orexins, hypothalamic regulating and , exhibit dysregulated levels in migraineurs—elevated in cerebrospinal fluid of chronic patients and reduced in episodic cases—modulating pain via OX1 receptors to inhibit trigeminal firing, though with sex-specific effects observed in preclinical models. These mediators integrate with the trigeminovascular system to influence attack initiation and chronification.

Diagnosis and Classification

Diagnostic Criteria

The diagnosis of migraine relies on standardized clinical criteria outlined in the , third edition (ICHD-3), developed by the International Headache Society, which provides an algorithmic framework for classifying primary disorders based on patient-reported symptoms. These criteria emphasize the recurrent nature of attacks and specific associated features, enabling clinicians to distinguish migraine from other types without relying on laboratory tests in typical cases. For the most prevalent subtype, migraine without aura, ICHD-3 requires at least five attacks meeting the following specifications:
  • Headache attacks lasting 4–72 hours when untreated or unsuccessfully treated.
  • Headache exhibiting at least two of these characteristics: unilateral , pulsating , moderate or severe intensity, or aggravation by (or avoidance of) routine .
  • Accompanying at least one of: and/or , or and .
  • Not better accounted for by another ICHD-3 diagnosis.
Criteria for migraine with aura build on these by adding requirements for at least two attacks involving one or more reversible aura symptoms (such as visual, sensory, or speech disturbances) that develop gradually over at least 5 minutes, last 5–60 minutes, are accompanied or followed by , and are not better explained by another diagnosis. These thresholds ensure high specificity, with studies validating ICHD-3's diagnostic accuracy at 96–98% for migraine subtypes when applied rigorously. A comprehensive patient history is essential for applying these criteria, involving detailed questioning about attack frequency, duration, triggers (e.g., stress, hormonal changes), and prodromal or postdromal symptoms, often supplemented by a headache diary to prospectively track patterns and verify fulfillment of ICHD-3 thresholds. Clinicians must systematically exclude red flags indicative of secondary headaches, such as sudden thunderclap onset, progressive neurological deficits (e.g., focal weakness), new headaches in individuals over 50, or associated systemic signs like fever or weight loss, using tools like the SNOOP4 mnemonic (Systemic symptoms, Neurologic deficits, Onset sudden, Older age, Pattern change, Positional). Physical and neurological examinations further support the diagnosis by confirming the absence of abnormalities in typical presentations. Neuroimaging, such as MRI, is not routinely indicated for straightforward migraine diagnoses meeting ICHD-3 criteria, as it rarely alters management and exposes patients to unnecessary risks; however, it is advised for atypical features (e.g., progressively worsening headaches), abnormal neurological exams, or first-time onset in adults over 50 to rule out structural causes like tumors or vascular issues. As of 2025, updated guidelines from organizations like the and International Headache Society increasingly incorporate app-based tracking tools for enhanced diagnostic precision, allowing real-time logging of symptoms, triggers, and attack characteristics to better align with ICHD-3 requirements and facilitate remote monitoring in clinical practice.

Migraine Subtypes

Migraine is classified into subtypes primarily based on the presence or absence of , frequency of attacks, and specific modifiers such as hormonal or vestibular associations, according to the , 3rd edition (ICHD-3). These classifications aid in diagnosis and management by delineating distinct clinical presentations within the broader migraine spectrum. The most common subtype is migraine without , also known as common migraine, which accounts for approximately 70-75% of cases. It is characterized as a recurrent disorder with attacks lasting 4-72 hours when untreated or unsuccessfully treated. Diagnostic criteria require at least five attacks fulfilling specific features: with at least two of unilateral location, pulsating quality, moderate or severe intensity, and aggravation by routine ; during the , at least one of / or /; and not better accounted for by another ICHD-3 diagnosis. This subtype lacks preceding neurological symptoms, distinguishing it from aura-associated forms. Migraine with aura represents 25-30% of cases and involves transient focal neurological symptoms that typically precede or accompany the headache phase. The aura consists of fully reversible visual, sensory, speech/language, or other symptoms that develop gradually over at least 5 minutes and last 5-60 minutes. Typical aura, the most frequent variant, includes visual disturbances such as or zigzag lines, or sensory symptoms like unilateral tingling, without motor weakness. At least two attacks are required, with aura symptoms meeting at least three characteristics: spreading gradually, occurring in succession with two or more symptoms, each lasting 5-60 minutes, at least one being unilateral, at least one being positive (e.g., ), and headache following within 60 minutes. This subtype highlights the neurological component of migraine, often resolving before the headache intensifies. Migraines are further categorized by frequency into episodic and chronic forms. Episodic migraine involves fewer than 15 headache days per month, aligning with the acute attack patterns of subtypes like those with or without aura. In contrast, chronic migraine is defined as headache occurring on 15 or more days per month for more than 3 months, with at least 8 days per month featuring migraine characteristics (e.g., fulfilling criteria for migraine without aura or responding to migraine-specific treatments). This distinction underscores the progression potential of the disorder, with chronic forms often requiring preventive strategies. Other recognized subtypes include those influenced by hormonal cycles, vestibular symptoms, or incomplete diagnostic fulfillment. Pure menstrual migraine without aura occurs exclusively on days -2 to +3 of menstruation (day 1 being the first day of menstruation) in at least two out of three cycles, with no attacks at other times, fulfilling criteria for migraine without aura. Menstrually related migraine without aura extends this pattern, with attacks during menstruation in at least two out of three cycles but also occurring at other times. Vestibular migraine, classified in the ICHD-3 appendix, features at least five episodes of moderate or severe vestibular symptoms (e.g., vertigo or ) lasting 5 minutes to 72 hours, accompanied by a current or past history of migraine, and at least one migrainous feature (such as or ) in at least 50% of episodes; it is not better explained by another diagnosis. Probable migraine applies to attacks that meet all but one criterion for migraine without aura or with aura, without fulfilling criteria for another headache disorder. These subtypes accommodate variations in presentation while maintaining alignment with core ICHD-3 standards.

Differential Diagnosis

Differentiating migraine from other headache disorders is essential, as it ensures timely identification of potentially life-threatening secondary causes while avoiding misdiagnosis of primary conditions. Clinicians rely on patient history, symptom patterns, and red-flag assessments to distinguish migraine, which typically features recurrent, unilateral throbbing pain with associated or , from mimics that may share some features like but differ in onset, duration, or accompanying signs. Persistent or chronic headache accompanied by nausea is commonly attributable to migraine, particularly chronic migraine, which is characterized by headaches occurring on 15 or more days per month for more than three months, with at least eight days exhibiting migrainous features such as throbbing pain (often unilateral), nausea, vomiting, and sensitivity to light and sound. However, other causes must be considered and excluded, including medication overuse headache resulting from frequent use of acute pain relievers, chronic tension-type headaches (which less commonly involve nausea), dehydration, infections (such as influenza or meningitis), low blood sugar, hormonal changes, or serious secondary conditions including increased intracranial pressure, brain tumors, or stroke. Persistent symptoms warrant prompt medical evaluation to rule out underlying pathology. Secondary headaches, arising from underlying , require exclusion before confirming a primary like migraine. Subarachnoid hemorrhage often presents as a thunderclap headache with abrupt, maximal-intensity onset within seconds, unlike the gradual build-up in migraine; it may be accompanied by or altered consciousness, necessitating urgent . Temporal arteritis, more common in individuals over 50, manifests as a new or worsening with tenderness, jaw during chewing, and elevated inflammatory markers, distinguishing it from migraine through systemic symptoms and vascular involvement. Sinusitis can mimic sinus-related migraine pain with facial pressure and congestion, but it typically involves purulent nasal discharge, fever, or tenderness over the sinuses, often confirmed by or response to antibiotics. Among primary headache mimics, features excruciating, unilateral pain lasting 15-180 minutes, occurring in bouts with prominent autonomic symptoms such as ipsilateral lacrimation, , or ptosis, contrasting with migraine's longer duration (4-72 hours) and less intense autonomic features; it predominantly affects males and has a circadian pattern. Tension-type headache presents as bilateral, pressing or tightening pain of mild to moderate intensity without significant , , or , differing from migraine's throbbing quality and associated symptoms; it often lacks the disabling impact of migraine attacks. Neurological conditions can closely resemble migraine, particularly those involving aura-like phenomena. Seizure aura may produce transient visual or sensory disturbances similar to migraine aura, but it often evolves into altered awareness, motor convulsions, or postictal confusion, unlike the fully reversible nature of migrainous aura without infarction. Stroke-related headaches, especially in cases of ischemic or hemorrhagic events, may include focal neurological deficits that persist beyond the typical 60-minute migraine aura resolution, with risk factors like sudden onset or vascular history prompting immediate evaluation. To identify red flags suggestive of secondary headaches, the SNNOOP10 criteria are widely used, encompassing systemic symptoms (fever, weight loss), neurologic deficits, new-onset or progressive headache, sudden onset, onset after age 50, pattern change, positional worsening, and other factors like immunosuppression or prior malignancy.
CriterionDescriptionExample Implications
S (Systemic symptoms)Fever, Suggests or
N (Neurologic deficit)Focal weakness, Indicates or mass lesion
N (New headache)First or atypical onsetWarrants
O (Onset sudden)Thunderclap patternRaises concern for
O (Onset after age 50)New headache in elderlyTemporal arteritis risk
P (Pattern change)Worsening or different from priorPossible progression of underlying disease
1 (Positional headache)Worse lying down/standingConsider issues
0 (Other), cancer historyHigher secondary headache likelihood
In 2025, telemedicine plays a growing role in initial screening for migraine differentials by enabling remote history-taking, symptom assessment via video, and application of tools like SNNOOP10, facilitating early referral for urgent cases while improving access in underserved areas.

Treatment and Management

Acute Pharmacological Therapies

Acute pharmacological therapies aim to abort or alleviate migraine attacks during their occurrence, targeting pain, associated symptoms such as and , and restoring function as quickly as possible. These treatments are stratified by attack severity, with nonsteroidal drugs (NSAIDs) recommended as first-line options for mild to moderate episodes, while more specific agents like or calcitonin gene-related peptide (CGRP) antagonists are preferred for moderate to severe attacks unresponsive to initial therapy. Combination strategies, such as pairing an with an , enhance efficacy by addressing multiple migraine facets. Nonsteroidal anti-inflammatory drugs, including ibuprofen and naproxen, serve as initial therapy for mild migraine attacks by inhibiting synthesis to reduce and pain. Ibuprofen at doses of 400–800 mg provides pain relief in approximately 50% of patients within 2 hours, with a number needed to treat (NNT) of 4–5 for sustained relief. Naproxen sodium (550 mg) similarly achieves relief in about 45–60% of cases, often combined with antiemetics like metoclopramide (10 mg) to mitigate and improve gastric , thereby enhancing overall absorption and response rates. These agents are widely accessible over-the-counter and carry a favorable safety profile for short-term use in most adults, though gastrointestinal risks warrant caution in susceptible individuals. In network meta-analyses of oral monotherapies, NSAIDs generally achieve lower pain freedom rates at 2 hours compared to triptans. Triptans, selective agonists of 5-HT1B/1D serotonin receptors, represent the cornerstone for moderate to severe acute migraine treatment by promoting , inhibiting activation, and reducing neurogenic . Examples include and rizatriptan, available in oral, , and subcutaneous injection formulations to accommodate varying levels and onset needs. subcutaneous injection (6 mg) yields the highest efficacy, with an NNT of 2 for pain-free status at 2 hours and relief in 70–80% of patients. Oral rizatriptan (10 mg) achieves pain relief in 60–72% within 2 hours, outperforming sumatriptan oral (50 mg) in direct comparisons for sustained freedom from pain (18–34% vs. lower rates). Overall, provide 2-hour headache relief in 42–76% of attacks, though contraindications include due to vasoconstrictive effects. Combining with NSAIDs boosts sustained pain-free outcomes by 13% over monotherapy, per moderate-certainty evidence. A 2024 network meta-analysis further confirmed that certain triptans, particularly eletriptan (odds ratio 5.19, 95% CI 4.25-6.33 versus placebo), rizatriptan, sumatriptan, and zolmitriptan, were superior to NSAIDs and other agents for achieving pain freedom at 2 hours, with eletriptan demonstrating the highest efficacy among acute oral treatments (certainty of evidence varying, often low to moderate). Gepants, small-molecule CGRP receptor antagonists, offer a targeted alternative for acute migraine, particularly in triptan non-responders or those with contraindications, by blocking CGRP-mediated vasodilation and pain signaling without serotonergic effects. As of February 2026, gepants such as ubrogepant (Ubrelvy), rimegepant (Nurtec ODT), and zavegepant (Zavzpret) are highly effective for acute attacks and often preferred for their targeted mechanism and reduced side effects compared to triptans. Ubrogepant (50–100 mg) and rimegepant (75 mg) are FDA-approved for as-needed use, demonstrating pain freedom at 2 hours in 19–22% of patients versus 12–14% with placebo, comparable to triptans in network meta-analyses. Ubrogepant exhibits rapid onset, with significant relief by 15–30 minutes in some trials, and low adverse event rates (e.g., nausea in <5%). Rimegepant similarly provides 2-hour pain relief in 21% of cases. Zavegepant nasal spray demonstrates significant improvements in pain freedom at 2 hours (odds ratio 1.6 vs placebo) and freedom from most bothersome symptoms, with common side effects including dysgeusia and nasal discomfort. Gepants position as effective options for patients intolerant to triptans, though cost and availability may limit access. More recent approvals as of 2025 include Symbravo (AXS-07, and rizatriptan combination, approved January 2025), which provides rapid and sustained relief for acute migraine in adults, with efficacy shown in phase 3 trials for pain freedom at 2 hours comparable to alone. Atzumi (dihydroergotamine mesylate nasal powder, approved May 2025) offers a needle-free option for acute treatment with or without , targeting severe attacks via and serotonin modulation, with onset within 15 minutes. Brekiya (dihydroergotamine , approved May 2025) delivers subcutaneous DHE for acute migraine, achieving pain relief in up to 70% of patients within 2 hours in trials, suitable for those needing fast absorption without oral intake. Lasmiditan, a selective 5-HT1F receptor agonist (ditan), addresses acute migraine in patients with cardiovascular risks by inducing analgesia without , thus avoiding triptan-related cardiac concerns. Administered orally at 50–200 mg, it achieves 2-hour pain freedom in 32–39% of attacks versus 21% with , with sustained up to 24 hours in real-world data. As of 2025, remains a key option for those with comorbidities, showing comparable or superior relief to in subsets with , though occurs in up to 20% of users. Ditans like complement by expanding treatment options without vascular risks, per recent guidelines emphasizing personalized selection.

Preventive Pharmacological Strategies

Preventive pharmacological strategies aim to reduce the frequency, severity, and duration of migraine attacks over the long term, particularly in patients who experience significant impairment. These treatments are typically recommended for individuals with four or more days per month or those whose migraines cause substantial , such as interference with daily activities or work. A trial of 2 to 3 months at therapeutic doses is standard to evaluate efficacy before adjusting or discontinuing therapy. Selection of agents considers comorbidities, side effect profiles, and patient preferences, with CGRP-targeted therapies now representing the current standard of care for many patients based on recent clinical data and guidelines. Beta-blockers, particularly , represent a cornerstone of preventive due to their proven efficacy in reducing migraine frequency. at doses of 80 to 240 mg per day has been shown to decrease monthly migraine days by an average of 1.3 compared to , with moderate certainty evidence from systematic reviews. It is especially suitable for patients with coexisting or anxiety, though contraindications include and . Anticonvulsants such as topiramate are considered first-line preventive options by some guidelines (e.g., American Headache Society), but third-line by the (2025) for episodic migraine. At doses of 50 to 200 mg per day, topiramate significantly lowers monthly migraine days, with clinical trials demonstrating sustained reductions maintained over several months of treatment. Common side effects include , cognitive slowing, and , necessitating gradual to improve tolerability. Tricyclic antidepressants like amitriptyline provide preventive benefits, particularly in patients with overlapping mood disorders. Dosed at 10 to 150 mg per day at bedtime, amitriptyline reduces migraine frequency through modulation of pain pathways, supported by consensus guidelines as a second-line for prophylaxis. and effects are frequent, limiting its use in some populations. Calcitonin gene-related peptide (CGRP) monoclonal antibodies have transformed preventive care and are considered first-line therapies by organizations like the American Headache Society for both episodic and chronic migraine, though recommended as second-line by the (2025 guidelines) for episodic migraine. Agents such as erenumab (Aimovig; 70 or 140 mg subcutaneous monthly), fremanezumab (Ajovy; 225 mg monthly or 675 mg quarterly), galcanezumab (Emgality; 240 mg loading dose followed by 120 mg subcutaneous monthly), and eptinezumab (Vyepti; 100 or 300 mg intravenous quarterly) target CGRP or its receptor, achieving a 50% reduction in monthly migraine days in approximately 50% of patients, per pivotal trials and real-world data. These biologics offer favorable tolerability with minimal systemic effects, though injection-site reactions occur. As of 2026, oral gepants like represent a key advancement in non-injectable prevention as part of CGRP-targeted therapies. Approved for daily use at 60 mg, reduces monthly migraine days more effectively than topiramate in head-to-head studies, with over 60% of patients achieving at least a 50% response rate. It provides an oral alternative for those averse to injections, with gastrointestinal upset as the primary . OnabotulinumtoxinA (Botox) remains effective and is specifically indicated for chronic migraine, defined as 15 or more headache days per month. Administered as 155 units intramuscularly every 12 weeks across 31 sites, it decreases headache days by about 2 per month compared to , based on phase 3 trials. This neuromodulator is particularly valuable for treatment-resistant cases, with as a common but transient .

Non-Pharmacological Interventions

Non-pharmacological interventions for migraine management encompass a range of behavioral, device-based, and complementary strategies aimed at reducing attack frequency, severity, and duration by addressing triggers and promoting overall . These approaches empower patients to take an active role in symptom control, often serving as adjuncts to pharmacological treatments for enhanced outcomes. Evidence from systematic reviews indicates that such interventions can achieve clinically meaningful reductions in migraine days, with varying by individual factors like adherence and baseline symptom severity. For acute migraine attacks, several evidence-based home remedies can provide rapid relief. These include resting in a dark, quiet room to minimize light and sound triggers; applying cold or warm compresses to the forehead, temples, or neck (cold compresses constrict blood vessels and may provide a numbing effect, while warm compresses relax tense muscles); staying hydrated by drinking plenty of water, as dehydration can worsen symptoms; consuming a small amount of caffeine (e.g., coffee or tea) if it typically helps the individual; practicing relaxation techniques such as deep breathing or progressive muscle relaxation; gently massaging the temples, scalp, or neck; and trying acupressure on the LI4 point (between the thumb and index finger). Effectiveness varies by individual, and these remedies may provide quick relief for some people but are not guaranteed to stop a migraine. If migraines are severe or frequent, consult a doctor. Over-the-counter pain relievers may be needed if home methods fail. Lifestyle modifications form a foundational element of non-pharmacological management, focusing on trigger avoidance and habit optimization. Consistent , such as maintaining a regular schedule of 7-9 hours per night, has been shown to significantly decrease migraine frequency by stabilizing circadian rhythms disrupted in susceptible individuals. Regular meals to prevent fasting-induced attacks, combined with a balanced diet low in processed foods and high in omega-3 fatty acids, further mitigates triggers like and . , such as 30 minutes of moderate activity three times weekly, reduces attack incidence by 25-50% in some cohorts, likely through endorphin release and improved vascular health, though gradual implementation is advised to avoid exertion as a trigger. techniques, including and journaling via headache diaries, help identify and avert personalized triggers, with studies demonstrating up to a 40% reduction in monthly migraine days among adherent participants. Cognitive behavioral therapy (CBT) targets psychological aspects of migraine, such as pain perception and trigger identification, through structured sessions that teach coping skills and relaxation. A of randomized trials found CBT reduced headache frequency by an average of 1.4 days per month and improved disability scores on the Migraine Disability Assessment Scale () by 20-30 points, with effects persisting up to 12 months post-treatment. Group-based CBT programs show comparable efficacy to relaxation training, emphasizing to reframe pain-related anxiety. These interventions are particularly beneficial for patients with comorbid anxiety or depression, enhancing overall without medication side effects. Device-based neuromodulation offers non-invasive options for acute and preventive relief by modulating neural pathways involved in migraine . The Cefaly device, which delivers transcutaneous electrical stimulation to the supraorbital nerve, has demonstrated pain freedom in 30-50% of acute attacks within two hours and a 50% reduction in monthly migraine days after three months of preventive use in clinical trials. Similarly, the gammaCore stimulator, applied to the neck, achieves pain relief in approximately 65% of users for acute episodes and reduces attack frequency by 20-40% over two months, with mild side effects like skin irritation reported in less than 10% of cases. Both devices are FDA-approved and well-tolerated, providing targeted relief without systemic effects. Complementary therapies, including , , and nutritional supplements, provide additional avenues for symptom control supported by meta-analytic evidence. sessions, typically three per week, reduce migraine frequency by 4-5 attacks per month compared to sham treatments, with benefits lasting up to six months and minimal adverse events. , particularly thermal or electromyographic variants, lowers headache severity and frequency by 30-50%, enabling patients to self-regulate physiological responses like muscle tension or hand temperature. In addition, mind-body practices such as yoga and mindfulness meditation have been investigated for migraine management. Some studies have demonstrated that yoga can significantly reduce migraine frequency, with one randomized trial reporting a 50% reduction in headache frequency and nearly 50% drop in rescue medication use. Mindfulness meditation has been shown in a meta-analysis to significantly reduce headache frequency and pain intensity in primary headache disorders, including migraine. Supplements such as (400 mg daily), magnesium (400-600 mg daily), and (100-300 mg daily) yield 30-50% reductions in attack frequency after 3-6 months, attributed to mitochondrial support and effects, though efficacy is higher in those with deficiencies. A 2025 review confirms these nutraceuticals as safe preventive options, with response rates of 40-60% in adults. Patients should consult a healthcare provider before initiating new interventions or supplements due to potential side effects or interactions.

Prognosis and Complications

Long-Term Disease Course

The long-term course of migraine often involves a progression from episodic to chronic forms, with an estimated 2.5% to 3% of individuals with episodic migraine transitioning to chronic migraine each year. This transformation is influenced by factors such as suboptimal acute treatment and medication overuse, but it is potentially reversible, as approximately 20% of those with chronic migraine revert to episodic patterns annually with appropriate interventions. Migraine prevalence typically peaks in the 30s and 40s, coinciding with midlife hormonal stability in many individuals, before declining in later years. In women, who comprise the majority of cases, symptoms often remit post- in approximately two-thirds of patients due to stabilized levels following the cessation of menstrual cycles. Conversely, perimenopause is frequently associated with worsening of attack frequency and severity, driven by fluctuating . Key prognostic factors for migraine persistence include early onset of the disorder and high baseline attack frequency, which elevate the likelihood of long-term chronification. Without intervention, 20% to 30% of individuals with episodic migraine may progress to chronic forms over extended periods, underscoring the importance of early management. Recent data from 2025 highlight improved long-term outcomes with early initiation of (CGRP) therapies, which have demonstrated efficacy in preventing chronification by reducing monthly migraine days in up to 56% of at-risk patients.

Status Migrainosus

Status migrainosus is a complication of migraine defined by the International Classification of Headache Disorders, third edition (ICHD-3), as a debilitating migraine attack lasting more than 72 hours. The attack occurs in patients with a history of migraine (with or without aura) and is typical of prior attacks except for duration and severity, with unremitting pain and/or associated symptoms that are debilitating. Brief remissions of up to 12 hours due to sleep or medication are permitted in assessing duration. A migraine attack lasting more than 72 hours (about 3 days) is classified as status migrainosus and requires medical attention, as it frequently does not respond to usual acute treatments and may necessitate more intensive management. A duration of 4 days or longer exceeds this threshold and warrants prompt consultation with a doctor or emergency room visit, especially if symptoms are severe, unresponsive to standard treatments, or include dehydration, intense nausea, vomiting, or other complications.

Comorbidities and Risks

Migraine is frequently associated with a range of comorbidities that can exacerbate its impact and influence overall health outcomes. These co-occurring conditions span psychiatric, cardiovascular, and other neurological and systemic disorders, with bidirectional relationships often observed, where migraine may heighten susceptibility to these conditions and vice versa. Psychiatric disorders, particularly depression and anxiety, exhibit strong bidirectional links with migraine. Individuals with migraine are two to five times more likely to develop depression or anxiety disorders, even after accounting for demographic factors. Conversely, those with depression or anxiety face an elevated risk of migraine onset and progression. This can intensify migraine frequency and severity, contributing to a cycle of heightened . Cardiovascular risks are notably elevated in migraine, especially among women with aura. Migraine with aura approximately doubles the risk of ischemic stroke, particularly in younger women under 45 years old. This association is further compounded by factors such as oral contraceptive use. Additionally, patent foramen ovale (PFO), a congenital heart defect allowing right-to-left shunting of blood, is strongly linked to migraine with aura and may amplify stroke risk in affected individuals. Other comorbidities include , sleep disorders, , and , each showing bidirectional associations with migraine. Migraine patients have an approximately 80% higher lifetime prevalence of compared to the general population, independent of seizure type or . Sleep disturbances, such as , are prevalent and mutually reinforcing, with poor sleep quality triggering migraines and migraine attacks disrupting sleep architecture. co-occurs frequently, with shared pain processing mechanisms leading to amplified symptom burden in comorbid cases. acts as a bidirectional , where excess weight increases the likelihood of chronic migraine through inflammatory pathways, while migraine-related limitations may promote weight gain. Recent research as of 2025 has highlighted stronger links between migraine and Raynaud's phenomenon, a vasospastic disorder involving episodic extremity color changes due to cold or stress. Studies indicate that migraine and Raynaud's often coexist, potentially sharing vascular reactivity mechanisms, with prevalence of migraine significantly higher among those with Raynaud's. , characterized by impaired vascular relaxation and , has also emerged as a key pathway in migraine , particularly in those with , contributing to heightened cardiovascular vulnerability. These associations underscore the need for integrated monitoring of vascular health in migraine management.

Epidemiology

Global Prevalence and Incidence

Migraine affects approximately 14-15% of the global population, corresponding to over 1 billion individuals as of 2021. This includes an estimated 1.2 billion prevalent cases worldwide in 2021, with the condition being roughly three times more common in women than in men. Episodic migraine, characterized by fewer than 15 headache days per month, accounts for the majority of cases at around 12-13%, while chronic migraine, defined by 15 or more headache days per month for at least three months, affects 1-2% of the population globally. The lifetime risk of developing migraine is substantially higher, estimated at 43% for women and 18% for men, with most onsets occurring before age 35. Annual incidence rates have shown a gradual increase, with global incident cases rising from about 64 million in 1990 to over 90 million in 2021, reflecting a 23-24% growth in new cases over three decades. Women consistently face higher incidence, with 55.4 million new cases in 2021 compared to 34.8 million in men. According to the , migraine ranks as the second leading cause of years lived with disability (YLDs) worldwide and third in neurological by disability-adjusted life years (DALYs) in , contributing to 45.1 million YLDs globally. Despite advances in treatments, the overall burden has not declined, with prevalent cases increasing by 58% from 1990 to . Underreporting is particularly prevalent in low- and middle-income countries, where limited access to healthcare, low awareness among providers, and unavailability of diagnostic tools and medications lead to underdiagnosis and undertreatment of up to 90% of disorder cases, including migraine, in some regions.

Demographic and Geographic Patterns

Migraine exhibits a pronounced disparity, with a female-to-male of approximately 3:1 following , attributed primarily to hormonal influences such as fluctuations in levels. This emerges during adolescence and persists into adulthood, reflecting the condition's sensitivity to reproductive hormones. In terms of age distribution, migraine typically onset occurs in the teens to early 20s, with peaking between 35 and 45 years of age before gradually declining after 50. The highest incidence rates are observed in adolescents aged 10–14, comprising about 43.7% of global cases in recent analyses. Geographically, migraine prevalence is higher in and , ranging from 13% to 15%, compared to 9% to 10% in and . This variation is linked to and associated lifestyle factors, with elevated rates in more developed regions. As of 2025, migraine incidence is rising among adolescents, potentially driven by increased and related lifestyle changes such as —reported in approximately 75% of cases in certain studies of children and adolescents, including those with migraine with aura, as a major trigger for migraine attacks in adolescents, particularly from school pressures, exams, social factors, or performance anxiety—and disrupted sleep.

Historical Perspectives

Early Historical Accounts

The earliest documented descriptions of migraine-like symptoms appear in ancient Egyptian medical texts, where unilateral head pain was recognized as a distinct condition. The , dating to approximately 1550 BCE, refers to a "disease of one half of the head," with treatments including anointing the head with the skull of a fried in oil and herbal mixtures such as terebinth , , and juniper berries, often applied topically or ingested. This text reflects an early understanding of the condition's localized nature, though treatments were rooted in magical and empirical practices, including incantations to ward off supernatural causes. In ancient Greece, Hippocrates of Kos, around 400 BCE, provided one of the first detailed accounts of migraine aura, describing it as "something shining before him like a light" in the right eye, followed by intense unilateral head pain and sometimes vomiting. He attributed such episodes to imbalances in bodily humors—excess phlegm or bile rising to the head—aligning with the humoral theory that dominated Western medicine for centuries. Cultural interpretations often linked these symptoms to divine punishment or demonic influence, particularly in Mesopotamian and Egyptian traditions, where headaches were seen as assaults by evil spirits requiring exorcism or amulets. During the medieval period, Islamic scholars advanced the classification of headaches, with (Ibn Sina) in his 11th-century distinguishing migraine (shaghighe in Persian) from other types like tension headaches or sinus pain, based on its pulsating, unilateral quality, , and . He proposed humoral imbalances, such as excess black bile, as the cause and recommended dietary adjustments, purgatives, and cupping to restore equilibrium. Surgical interventions like trephination—drilling holes in the to release pressure or evil humors—were occasionally attempted for severe cases, as advocated by figures like Guy de Chauliac in the , though evidence of its efficacy remains anecdotal and risky. These views persisted amid cultural attributions to supernatural forces, with gender biases emerging in descriptions that disproportionately framed migraine as a "hysterical" affliction of women, tied to menstrual cycles or emotional fragility. By the 17th to 19th centuries, European medicine reframed migraine as "sick headache" or "megrim," emphasizing its association with and gastrointestinal upset, often blamed on dietary excesses or vascular disturbances within the humoral framework. Treatments included , laxatives, and avoiding triggers like fatty foods, reflecting ongoing humoral influences. A significant pharmacological milestone occurred in 1918 when Arthur Stoll isolated ergotamine from the rye fungus , marking the first specific alkaloid-based therapy for to abort attacks, derived from ergot's long history as both a poison and folk remedy. Gender biases intensified, with 19th-century texts portraying migraine as a disorder of "delicate" females or "nervous" women, often dismissing it as psychosomatic rather than a neurological event.

Modern Classification and Advances

In the early , the vascular theory of migraine gained prominence, positing that attacks resulted from initial cerebral followed by extracranial , with adrenaline implicated in modulating vascular tone during episodes. This model, advanced by Harold Wolff in the 1930s and 1940s through studies linking adrenaline infusions to pain relief in some patients, dominated migraine research for decades, emphasizing dilation as the primary pain generator. A pivotal advancement occurred in 1988 when the International Headache Society (IHS) published the first edition of the (ICHD-1), establishing standardized diagnostic criteria for migraine and distinguishing it from other headache types based on clinical features like aura, duration, and associated symptoms. This classification system provided a rigorous, operational framework that facilitated epidemiological studies, clinical trials, and global consistency in , marking a shift toward evidence-based categorization. The advent of in the revolutionized understanding of migraine mechanisms, with functional MRI and demonstrating (CSD)—a wave of neuronal followed by suppression—as the likely substrate for in migraine with . Studies by Jes Olesen and colleagues in the early using regional cerebral blood flow measurements confirmed CSD's slow propagation across the occipital cortex during human , linking it directly to visual disturbances and challenging purely vascular explanations. In the 2000s, genome-wide association studies (GWAS) identified key genetic contributors to migraine susceptibility, with early efforts like the 2010 International Headache Genetics Consortium analysis revealing variants in genes such as MTDH and associated with common migraine forms. Subsequent meta-analyses in the decade expanded this to over a dozen loci, highlighting polygenic influences on neuronal excitability and vascular function, which informed personalized . Treatment milestones in the 1990s included the introduction of , serotonin 5-HT1B/1D receptor agonists that targeted the trigeminovascular system to abort attacks; , the first, was approved in 1991 in and 1992 in the , offering superior efficacy over ergotamines with fewer side effects. By the 2010s, (CGRP) inhibitors emerged as a breakthrough for prevention; monoclonal antibodies like , , and received FDA approvals in 2018, reducing monthly migraine days by 50% or more in clinical trials by blocking CGRP-mediated neurogenic inflammation. From a perspective, migraine has shifted from the vascular model to a neuroinflammatory framework, emphasizing central sensitization, activation, and immune-mediated processes in the as core drivers, supported by recent studies of pro-inflammatory cytokines during attacks. The ICHD-3, finalized in 2018 after beta testing from 2013, refined migraine subtypes—including chronic migraine and probable migraine—incorporating genetic and imaging data for more precise diagnostics, with minor updates emphasizing medication-overuse overlaps.

Societal Impact

Economic and Quality-of-Life Burden

Migraine imposes a substantial economic burden on individuals and societies worldwide, primarily through lost productivity and healthcare expenditures. A meta-analysis of 116 studies estimates the global economic cost of migraine at approximately $9,896 per affected individual per year, equivalent to about 1.9% of gross domestic product in impacted countries, with indirect costs from reduced work efficiency and absenteeism comprising the majority. In the United States, this translates to approximately $19 billion annually in indirect costs alone (as of 2020 estimates), driven largely by missed workdays and impaired performance during attacks. Globally, these costs are exacerbated by the high prevalence of migraine, affecting over 1.2 billion people as of 2021 and leading to widespread productivity losses that strain economies, particularly in working-age populations. As of 2023 Global Burden of Disease data, headache disorders affect 2.9 billion people globally (34.6% age-standardized prevalence), with migraine contributing significantly to the burden. Indirect costs account for 70% to 93% of the total economic impact of migraine, with the bulk stemming from work-related losses such as and . In the , employed individuals with migraine experience an average of approximately 5-6 missed workdays per year due to attacks, equating to substantial lost productive time—estimated at over 100 hours annually per sufferer when including reduced efficiency during episodes (based on recent studies). These figures rise significantly in chronic migraine cases, where indirect costs can exceed direct healthcare expenses by several fold, reaching up to $48,810 per patient yearly in some countries due to heightened and long-term . Such losses not only affect personal finances but also burden employers through decreased output and higher turnover rates. The quality-of-life burden of migraine is profound, often measured using the Migraine Disability Assessment Scale (), a validated tool that quantifies across work, household, and social domains over a three-month period, with scores indicating mild to severe impairment. Individuals with migraine face a 2.5-fold increased risk of developing depression compared to the general population, which further doubles the likelihood of significant functionality loss and reduced daily participation. This amplifies overall , leading to diminished well-being even between attacks and contributing to broader challenges. Recent data from 2023–2025 highlight a post-pandemic escalation in prevalence, with some studies noting an approximately 18% relative increase from 2021 to 2023, potentially including rises in and migraine burden attributed to heightened stress and disrupted routines. Equity issues compound this in low-access regions, such as low- and middle-income countries, where limited healthcare resources result in higher unaddressed and economic strain, with indirect costs approximating up to 2% of GDP in countries like for primary headaches.

Awareness, Stigma, and Advocacy

Migraine is frequently stigmatized as "just a ," a misconception that minimizes its severity as a and contributes to widespread under-treatment. This perception leads patients to avoid seeking care, with only 56.2% of those affected receiving a confirmed in some populations, and just 36% utilizing preventive medications despite eligibility. In workplaces, stigma exacerbates challenges, as 79% of patients report career impacts and 46% experience reduced effectiveness during attacks, often hiding symptoms to avoid judgment. Men face particular barriers, as migraine is often viewed as a "women's condition," resulting in delayed and under-treatment compared to women. Efforts to raise awareness have intensified through dedicated campaigns, such as Migraine Awareness Week organized by The Migraine Trust, which aims to reframe migraine as a serious condition disrupting daily life, relationships, and opportunities rather than a mere headache. The World Health Organization (WHO) reinforces this by recognizing migraine as one of the top three most disabling neurological conditions globally, with headache disorders—a category including migraine—affecting approximately 40% of the population (3.1 billion people in 2021) and ranking third in disability-adjusted life years lost in 2021, as outlined in its October 2025 fact sheet. These initiatives highlight the need for greater public education to combat underestimation and improve access to diagnosis and care. Advocacy organizations play a crucial role in addressing these issues, with the American Migraine Foundation (AMF) leading efforts to secure insurance coverage for advanced treatments like (CGRP) inhibitors. The AMF provides resources for patients to navigate barriers such as prior authorizations and "fail first" policies, emphasizing appeals and clinician involvement to ensure access to these therapies, which have transformed migraine management since their introduction. Such advocacy has contributed to increasing coverage by health plans, though challenges persist in layered treatment approaches combining CGRP drugs with other options. To help reduce stigma and promote better understanding of migraine needs, friends, family, and colleagues can provide supportive communication during attacks. Checking in via text is generally recommended and appreciated, as it demonstrates care without being intrusive. Messages should be kept short, empathetic, and low-pressure (for example: "Thinking of you—hope the migraine eases soon. Here if you need anything"). Avoid frequent messages, calls, or expecting immediate replies, due to common symptoms such as sensitivity to light and sound, as well as difficulty concentrating. Silence should not be taken personally, as the individual may be resting in a dark, quiet space to manage the attack. Gender disparities amplify stigma, particularly for women who experience dismissal of symptoms as psychological or exaggerated, leading to undertreatment. Women are three times more likely than men to suffer migraines post-puberty, with menstrual migraine—a severe form triggered by fluctuations—affecting up to 25% of patients yet remaining underdiagnosed, as only 32% receive formal identification despite 39% exhibiting symptoms. In 2025, heightened focus on urges clinicians to improve history-taking and cycle tracking for better recognition and of menstrual migraine.

Current Research

Emerging Pharmacotherapies

Emerging pharmacotherapies for migraine are building on the successes of calcitonin gene-related peptide (CGRP) inhibitors by targeting novel pathways and improving delivery methods to enhance efficacy and patient tolerability. PACAP inhibitors, particularly monoclonal antibodies targeting pituitary adenylate cyclase-activating polypeptide (PACAP), represent a promising class in late-stage development. These agents aim to block PACAP-mediated vasodilation and neurogenic inflammation implicated in migraine attacks. In a phase 2a clinical trial (HOPE study), the anti-PACAP monoclonal antibody Lu AG09222 reduced monthly migraine days by approximately 2 days compared to placebo, with good tolerability and no significant cardiovascular effects. Phase 2 trials for similar PACAP inhibitors, such as LY3451838, are ongoing as of 2025. New generations of gepants and ditans are advancing with optimized oral formulations that offer dual acute and preventive benefits while minimizing side effects like or seen in older agents. For instance, and have demonstrated sustained efficacy in long-term studies, reducing monthly migraine days by 4-6 days with improved gastrointestinal tolerability over . Atzumi ( nasal powder), approved in 2025, provides rapid onset for acute treatment, achieving pain freedom in approximately 36% of attacks within 2 hours, and is being explored for preventive regimens with lower daily dosing to enhance adherence. Ditans such as are positioned as alternatives for patients intolerant to gepants. Device innovations are expanding non-pharmacological options, particularly for migraine. Non-invasive therapy, utilizing low-level 810 nm lasers, has shown preliminary efficacy in reducing migraine frequency by modulating neurovascular responses without skin penetration. A 2024 reported a reduction of 5.2 monthly migraine days after 8 weeks of twice-weekly sessions, with no adverse events. For chronic cases, implantable neuromodulators like the ShiraTronics Reliev@ system deliver targeted occipital nerve stimulation, achieving a 9.6-day reduction in monthly days over 12 months in pivotal trials, offering sustained relief for patients unresponsive to medications. Gene therapies targeting monogenic forms of migraine, such as (FHM) linked to ATP1A3 mutations, are in early preclinical stages using CRISPR-based . These approaches seek to correct defects responsible for . 2025 preclinical data in mouse models discuss potential for of ATP1A3 variants in related disorders like , restoring neuronal function.

Genetic, Hormonal, and Mechanistic Studies

Recent genome-wide association studies (GWAS) conducted in have built upon prior discoveries, integrating multi-ancestry data to identify additional genetic risk loci for migraine subtypes, with analyses uncovering novel genes involved in neuronal excitability and vascular function. These efforts have expanded the catalog of susceptibility variants, emphasizing polygenic contributions across diverse populations. Polygenic risk scores (PRS) derived from these loci enable improved prediction of migraine onset and progression, capturing cumulative genetic burden to stratify individual risk and inform personalized prevention strategies. Hormonal influences on migraine exhibit pronounced sex differences, particularly through signaling, which modulates trigeminal and cortical excitability in females. Studies in 2025 highlight how fluctuations in levels interact with (CGRP) pathways, exacerbating susceptibility during reproductive transitions. Perimenopausal models demonstrate that declining concentrations correlate with intensified migraine frequency and severity, underscoring the need for hormone-targeted interventions in this phase. Mechanistic investigations into migraine chronification increasingly focus on brainstem nuclei, such as the , where altered norepinephrine signaling contributes to central and persistent pain states. Pilot imaging studies from 2025 reveal hypoperfusion and disrupted functional connectivity in the among patients with chronic migraine, linking these changes to the transition from episodic to refractory forms. Advanced computational modeling of (CSD), the electrophysiological substrate of migraine aura, elucidates wave propagation dynamics and ion imbalances, providing insights into aura-triggered headache mechanisms. The Migraine Science Collaborative's mid-2025 updates emphasize multimodal imaging advancements, including 7 Tesla MRI to resolve fine-scale structures and integrate functional data for better understanding of migraine neurovascular pathways. These collaborative initiatives facilitate cross-disciplinary analysis, potentially guiding novel therapeutic targets.

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