Migraine

Migraine (Template:IPA-cen, Template:IPA-cen)<ref>Template:Cite LPD</ref><ref>Template:Cite EPD</ref> is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, light sensitivity and sound sensitivity.<ref name="Pescador_Ruschel_2024">Template:Cite book</ref><ref name="Cephalalgia_2018">Template:Cite journal</ref> Other characteristic symptoms include vomiting, cognitive dysfunction, allodynia, dizziness,<ref name="Pescador_Ruschel_2024" /> and/or exacerbation of symptoms by routine physical activity.<ref>Template:Cite journal</ref> Some 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.<ref name="Cephalalgia_2018" />

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.<ref name="Katsarava_2012">Template:Cite journal</ref> Disease burden can range from episodic discrete attacks to chronic disease.<ref name="Katsarava_2012" /><ref>Template:Cite web</ref> Incidence of migraines may increase over time, evolving from episodic migraine to chronic migraine. Overuse of acute pain medications may hasten this process of chronification, and is a risk factor in developing medication overuse headache.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Migraine is believed to be caused by a combination of genetic, environmental, and neurological factors that influence the behavior of nerve cells, chemical signals and blood vessels within the brain. 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.<ref name="Bentivegna">Template:Cite journal</ref><ref name="Levy"/><ref>Template:Cite journal</ref>

A migraine management plan often includes lifestyle modifications to cope with migraine triggers and reduce the impact of comorbidities.<ref name=":0" /><ref name="Elmazny">Template:Cite journal</ref><ref>Template:Cite journal</ref> Non-pharmacological preventive therapies include stress management,<ref name="Stubberud">Template:Cite journal</ref> sleep improvement,<ref name=":2">Template:Cite journal</ref><ref name=":4">Template:Cite journal</ref><ref name=":5">Template:Cite journal</ref> dietary interventions,<ref name="Gazerani">Template:Cite journal</ref> and aerobic exercise.<ref name="Barber">Template:Cite journal</ref><ref name=":0">Template:Cite journal</ref><ref name="Elmazny" /> Initial recommended treatment for acute attacks is with over-the-counter (OTC) pain medications (such as ibuprofen and paracetamol) and anti-nausea medications.<ref name=Gilmore2011>Template:Cite journal</ref> The approval of CGRP inhibitors is seen as a major advance in migraine treatment:<ref name="Zobdeh" /> According to the American Headache Society, CGRP targeting therapies are a first-line option for migraine prevention.<ref>Template:Cite journal</ref><ref name=":3">Template:Cite web</ref> Specific medications such as triptans or ergotamines may be used by those experiencing headaches that do not respond to over-the-counter pain medications.<ref>Template:Cite journal</ref>

Commonly prescribed prophylactic medications include beta blockers, anticonvulsants, tricyclic antidepressants, calcium channel blockers, various other off-label classes of medications, and CGRP inhibitors.<ref name="Zobdeh">Template:Cite journal</ref><ref name="Aguilar-Shea">Template:Cite journal</ref><ref name="NBK507873">Template:Cite web</ref> Medications inhibit migraine pathophysiology through various mechanisms, such as blocking calcium and sodium channels, activation of serotonin by 5-HT receptor agonists, and blocking of CGRP transmission in the trigeminovascular system.<ref name="Zobdeh"/>

Globally, approximately 15% of people are affected by migraine,<ref name=LancetEpi2012>Template:Cite journal</ref> making it the third-most prevalent disorder in the world<ref>Template:Cite web</ref> and one of the most common causes of disability.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> Beginning at puberty, women experience higher rates than men of incidence, severity of symptoms, and disability related to migraines.<ref name="Allais"/><ref name="Kuruvilla"/><ref name="Denney"/> From age 30 to 50, up to 4 times as many women experience migraine attacks as men.<ref name=Ferrari2022/> Estrogen levels may impact migraine mechanisms of action through neurotransmitters, ion levels, and blood flow.<ref name="Allais">Template:Cite journal</ref><ref name="Kuruvilla">Template:Cite journal</ref><ref name="Denney">Template:Cite journal</ref>

Signs and symptoms

Migraine typically presents with self-limited, recurrent severe headaches associated with autonomic symptoms.<ref name="Bart10">Template:Cite journal</ref><ref name="Prognosis2008">Template:Cite journal</ref> About 15–30% of people living with migraine experience episodes with aura,<ref name=Gilmore2011/><ref>Template:Cite book</ref> and they also frequently experience episodes without aura.<ref name = "Olesen_2006" /> The severity of the pain, duration of the headache, and frequency of attacks are variable.<ref name=Bart10/> A migraine attack lasting longer than 72 hours is termed status migrainosus.<ref>Template:Cite book</ref> There are four possible phases to a migraine attack, although not all the phases are necessarily experienced:<ref name="ICHD2004">Template:Cite journal</ref>

• The premonitory phase or 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.<ref name=Baskin06>Template:Cite journal</ref>

Prodrome phase

Prodromal or premonitory symptoms occur in about 60% of those with migraine,<ref name="Amin2009">Template:Cite book</ref><ref name=Five2004>Template:Cite book</ref> with an onset that can range from two hours to two days before the start of pain or the aura.<ref name=Buzzi2005>Template:Cite journal</ref> These symptoms may include a wide variety of phenomena,<ref>Template:Cite journal</ref> including altered mood, irritability, depression or euphoria, fatigue, craving for certain food(s), difficulty speaking or reading, yawning, stiff muscles (especially in the neck), constipation or diarrhea, and sensitivity to smells or noise.<ref name=Five2004/><ref>Template:Cite web</ref> This may occur in those with either migraine with aura or migraine without aura.<ref name=Sam2009>Template:Cite book</ref> Neuroimaging indicates the limbic system and hypothalamus as the origin of prodromal symptoms in migraine.<ref>Template:Cite journal</ref>

Aura phase

Aura is a transient focal neurological phenomenon that occurs before or during the headache.<ref name=Amin2009/> Aura appears gradually over a number of minutes (usually occurring over 5–60 minutes) and generally lasts less than 60 minutes.<ref name=Tint2010/><ref name="Ashina">Template:Cite journal</ref> Symptoms can be visual, sensory or motoric in nature, and many people experience more than one.<ref name = "Cutrer_2006" /> 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.<ref name = "Cutrer_2006" /> If any symptom remains after 60 minutes, the state is known as persistent aura.<ref>Template:Cite journal</ref>

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).<ref name=Amin2009/> 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.<ref name = "Cutrer_2006" /> Usually, the lines are in black and white, but some people also see colored lines.<ref name = "Cutrer_2006" /> Some people lose part of their field of vision known as hemianopsia while others experience blurring.<ref name = "Cutrer_2006" />

Sensory auras are the second most common type; they occur in 30–40% of people with auras.<ref name = "Cutrer_2006" /> 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.<ref name = "Cutrer_2006" /> Numbness usually occurs after the tingling has passed with a loss of position sense.<ref name = "Cutrer_2006" /> Other symptoms of the aura phase can include speech or language disturbances, world spinning, and, less commonly, motor problems.<ref name = "Cutrer_2006" /> Motor symptoms indicate that this is a hemiplegic migraine, and weakness often lasts longer than one hour unlike other auras.<ref name = "Cutrer_2006" /> Auditory hallucinations or delusions have also been described.<ref>Template:Cite book</ref>

Pain phase

Classically the headache is unilateral, throbbing, and moderate to severe in intensity.<ref name=Tint2010>Template:Cite book</ref> It usually comes on gradually<ref name=Tint2010/> and is aggravated by physical activity during a migraine attack.<ref name=ICHD2004/> 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.<ref name="Barber"/><ref name="The association between migraine an">Template:Cite journal</ref> The feeling of pulsating pain is not in phase with the pulse.<ref name="pathos">Template:Cite journal</ref> 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.<ref>Template:Cite book</ref> Bilateral pain is particularly common in those who have migraine without aura.<ref name=Amin2009/> Less commonly pain may occur primarily in the back or top of the head.<ref name=Amin2009/> The pain usually lasts 4 to 72 hours in adults;<ref name=Tint2010/> however, in young children frequently lasts less than 1 hour.<ref name=Bigal2010>Template:Cite journal</ref> The frequency of attacks is variable, from a few in a lifetime to several a week, with the average being about one a month.<ref name = "Rasmussen_2006">Template:Cite book</ref><ref>Template:Cite book</ref>

The pain is frequently accompanied by nausea, vomiting, sensitivity to light, sensitivity to sound, sensitivity to smells, fatigue, and irritability.<ref name=Amin2009/> Many thus seek a dark and quiet room.<ref name=Walton2009/> In a basilar migraine, a migraine with neurological symptoms related to the brain stem or with neurological symptoms on both sides of the body,<ref name=Basil2009>Template:Cite journal</ref> common effects include a sense of the world spinning, light-headedness, and confusion.<ref name=Amin2009/> Nausea occurs in almost 90% of people, and vomiting occurs in about one-third.<ref name=Walton2009>Template:Cite book</ref> Other symptoms may include blurred vision, nasal stuffiness, diarrhea, frequent urination, pallor, or sweating.<ref name=Joel1999>Template:Cite book</ref> Swelling or tenderness of the scalp may occur as can neck stiffness.<ref name=Joel1999/> Associated symptoms are less common in the elderly.<ref name=ElderlyBook2008/>

Silent migraine

Sometimes, aura occurs without a subsequent headache.<ref name = "Cutrer_2006">Template:Cite book</ref> This is known in modern classification as a typical aura without headache, or acephalgic migraine in previous classification, or commonly as a silent migraine.<ref name="americanmigrainefoundation.org-Robblee-2019-Silent-Guide">Template:Cite web</ref><ref name="jmedicalcaserep-Yusheng-2015-aura-w/o-headache">Template:Cite journal</ref> 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.<ref name="medicalnewstoday-Leonard-2018-Silent-migraine">Template:Cite web</ref>

Postdrome

The migraine postdrome is the constellation of symptoms occurring once the acute headache has ceased.<ref>Template:Cite journal</ref> A study found reports of a sore feeling in the same area as the migraine;<ref name="pmid16426278" /> reports of impaired thinking for a few days after the headache passed;<ref name="pmid16426278" /> reports of tiredness, feeling "hungover", head pain, cognitive difficulties, gastrointestinal symptoms, weakness,<ref name="pmid16426278">Template:Cite journal</ref> body aches, and nausea.<ref name="Cleveland">Template:Cite web</ref><ref>Template:Cite web</ref>

Cause

Migraine is believed to result from a mix of genetic, environmental, and neurological factors.<ref name="Bentivegna"/> Migraine runs in families in about two-thirds of cases<ref name=Bart10/> but this rarely reflects a single gene defect.<ref name="Schurk2012"/> Rather, a variety of genetic factors may relate to neuronal, vascular and other systems, and create genetic susceptibility. Migraine has high comorbidity with depression, anxiety, and bipolar disorder, which often have a bidirectional relationship (either one can worsen the other). It is likely that shared genetic and neurobiological mechanisms contribute to risk factors that underlie multiple conditions.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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<ref>Template:Cite journal</ref> suggests that some people with migraine may have an anatomical predisposition for neurovascular compression<ref>Template:Cite journal</ref> that may be caused by both intracranial and extracranial vasodilation due to migraine triggers.<ref>Template:Cite journal</ref> This, along with the existence of numerous cranial neural interconnections,<ref>Template:Cite journal</ref> may explain the multiple cranial nerve involvement and consequent diversity of migraine symptoms.<ref name=":7">Template:Cite journal</ref>

Genetics

Studies of twins indicate a 34–51% genetic influence on the likelihood of developing migraine.<ref name=Lulli2007>Template:Cite journal</ref> This genetic relationship is stronger for migraine with aura than for migraine without aura.<ref name="Olesen_2006" /> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> It is also known that having several of these risk variants increases the risk by a small to moderate amount.<ref name="Schurk2012" />

Single gene disorders that result in migraine are rare.<ref name=Schurk2012>Template:Cite journal</ref> One of these is known as familial hemiplegic migraine, a type of migraine with aura, which is inherited in an autosomal dominant fashion.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Four genes have been shown to be involved in familial hemiplegic migraine.<ref name=Ducros2013>Template:Cite journal</ref> Three of these genes are involved in ion transport.<ref name=Ducros2013/> The fourth is the axonal protein PRRT2, associated with the exocytosis complex.<ref name=Ducros2013/> Another genetic disorder associated with migraine is CADASIL syndrome or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.<ref name=Amin2009/> One meta-analysis found a protective effect from angiotensin converting enzyme polymorphisms on migraine.<ref>Template:Cite journal</ref> The TRPM8 gene, which codes for a cation channel, has been linked to migraine.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Triggers

Categories of hypothesized migraine triggers include emotion, nutrition, sleep disturbance, hormones, weather, sensory overstimulation and strenuous exercise.<ref>Template:Cite web</ref> A migraine trigger reduces the threshold at which a migraine attack occurs in someone who is predisposed to migraine. Migraine triggers may be classified as internal, modifying the body's homeostasis (e.g. hormonal variability, stress, sleep disturbance, fasting) or external, originating outside the body and influencing the perception of sensory signals (e.g. temperature fluctuations, noises, and odors). In some cases, factors reported as triggers (e.g. sensory sensitivities, food cravings and mood change) may be more appropriately considered as premonitory symptoms resulting from changes in brain activity during the prodromal phase of migraine.<ref name="Sebastianelli">Template:Cite journal</ref><ref name="Zobdeh" /><ref name=":6">Template:Cite journal</ref><ref>Template:Cite journal</ref> Determining whether and when something acts as a true causal trigger, and when it is a symptom of already-occurring changes, is an ongoing area of study.<ref name="Sebastianelli" />

Studies of the brain's structure and function indicate that brain activity changes during the 48 (or even 72) hours before the pain phase of migraine. During this initial phase of a migraine attack, people may report prodromal/premonitory symptoms (PSs) such as fatigue, yawning, difficulty concentrating, mood changes, dizziness, neck pain, light sensitivity, food cravings, and nausea. Such symptoms may continue into the pain phase and postdrome.<ref name="Sebastianelli" /> Some studies suggest that PSs may be linked to activity in particular neuroanatomical pathways and areas of the brain. Yawning, food cravings, homeostatic regulation, and sleep disturbance may be linked to activation in the hypothalamus. Other PSs, such as neck pain and nausea, may be related to activity in the brainstem.<ref name="Sebastianelli" /> The stimuli that are found disturbing vary from person to person.<ref name="Smith"/> Those experiencing PSs can sometimes correctly predict an oncoming attack.<ref name="Sebastianelli" />

The extent to which a possible trigger has an actual causal connection with headache onset is uncertain in most cases, and some relationships may be bidirectional.<ref name="Trigger09">Template:Cite journal</ref><ref>Template:Cite journal</ref> However, there are strong associations between migraine and hormonal changes, stress, quality of sleep, and fasting. It has been theorized that these "catalyst triggers" may act by increasing activity in the hypothalamus or trigeminal system and exceeding the brain's migraine threshold.<ref name="Sebastianelli" /> Lifestyle changes that help to maintain bodily homeostasis, such as regular sleep, managing of stress, and eating regularly, can be helpful interventions.<ref name=":1" /> Regardless of whether a possible trigger is a cause or an early symptom, it may help to manage exposure to sensory stimuli such as smells, lights, sound or touch.<ref name="Smith">Template:Cite web</ref>

Hormonal changes

From puberty onwards, women experience migraine attacks at greater rates than men. Incidence of attacks is related to hormonal changes in estrogen, which varies monthly and across a woman's lifespan.<ref>Template:Cite journal</ref> Migraine episodes are more likely to occur around menstruation, possibly due to the drop in estrogen levels before the menstrual period.<ref name="Rad2013">Template:Cite journal</ref> Hormonal changes may also affect incidence and occurrence of migraines in relation to menarche, oral contraceptive use, pregnancy, perimenopause, and menopause.<ref name=Chai2014>Template:Cite journal</ref> Attacks may worsen during perimenopause due to fluctuating estrogen levels.<ref name="Ferrari2022" /> Migraine episodes typically do not occur during the second and third trimesters of pregnancy, and may rapidly decline following menopause.<ref name=Amin2009/> Women are more likely to have migraine without aura.<ref name="Rasmussen_2006" />

Stress

The headache trigger that people are most aware of is stress, ranking first in reports for men, and second to hormonal factors for women.<ref name=":6" /><ref name="Stubberud" /> Best practices for psychologically addressing stress as a possible migraine trigger include relaxation therapy, biofeedback, and cognitive behavioral therapy (CBT). Activities such as relaxation therapy are more likely to be effective when used as a routine part of daily life or to address incidents of stress as a risk factor, rather than during the pain phase of a migraine attack.<ref name="Sturgeon">Template:Cite journal</ref>

Sleep

Migraineurs report a variety of sleep-related issues as possible triggers. These include undersleeping, irregular sleep, frequent night-time waking, and oversleeping. Those who experience chronic migraine may be less likely to maintain consistent sleep habits than those who experience episodic migraines.<ref name="Elmazny"/> Jet-lag, shift work, and other disruptions of circadian rhythms may increase migraines.<ref name="Woldeamanuel">Template:Cite journal</ref><ref name="Stanyer">Template:Cite journal</ref><ref name="Leso">Template:Cite journal</ref> Sleep hygiene improvements and maintaining a consistent sleep schedule are among the most frequently recommended migraine management techniques.<ref name="Robblee">Template:Cite journal</ref> <ref name=":2" /><ref name=":4" /><ref name=":5" />

Diet

Fasting or missed meals are a commonly perceived trigger for migraines, and dietary modifications are a frequent management technique.<ref name="Elmazny"/> Missing meals like breakfast can reduce brain glucose levels, leading to hypoglycemia and triggering the release of stress hormones like cortisol and adrenaline, which can affect migraines. Irregular meals are particularly strong predictors of attacks for those experiencing chronic migraines. Eating balanced meals at consistent times and hydrating well can help to prevent migraines and lessen migraine symptoms.<ref name="Legesse">Template:Cite journal</ref>

A wide variety of specific foods and drinks have been reported as possible triggers, including alcohol, coffee, chocolate, cheese, nuts, citrus fruits, fatty foods, processed meats, monosodium glutamate, and aspartame.<ref name="Legesse"/> Mechanisms of action have been proposed for some of the commonly reported foods and drinks, such as red and white wine, hot dogs, and chocolate.<ref name=":6"/> Tyramine, which is naturally present in alcoholic beverages, most cheeses, processed meats, and other foods may trigger migraine symptoms in some individuals.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Tyramine is also present at low levels in chocolate.<ref>Template:Cite journal</ref> Monosodium glutamate (MSG) has been reported as a trigger for migraine in some individuals, but whether or not there is a causative relationship continues to be debated.<ref name="Ahdoot">Template:Cite journal</ref>

People may experience food cravings as a result of changes in brain activity during the prodromal phase of migraine. Reports that foods such as chocolate are triggers may actually reflect a increased desire for such foods as an early symptom of migraine attacks.<ref name="Lisicki">Template:Cite journal</ref><ref name="Sebastianelli" />

Sensory sensitivity

Sensitivity to light (photophobia), sensitivity to sound (phonophobia), and sensitivity to smells (osmophobia) are often reported as migraine triggers. Some migraineurs may also report sensitivity to touch (allodynia).<ref name="Aguilar-Shea" /><ref name=":7" /> Neuroimaging and neurophysiological studies show changes in sensory thresholds relating to sensitivity to light, sound and smell and to pain perception.<ref name="Sebastianelli"/> Patient reports of sensitivity triggers may be early symptoms in the premonitory phase of a migraine attack.<ref name="Imai"/> People often deal with migraine attacks by avoiding sensory stimulation including movement, light, sounds, touch or smells.<ref name=":7" />

Light

Sensitivity to light is a common symptom in migraine. Discomfort is associated with four categories of stimulation: bright light, flickering light, pattern, and color. While retinal mechanisms also may be involved, cortical mechanisms are increasingly seen as explaining discomfort from all four types of visual stimulation.<ref name="Wilkins" />

People have been shown to have different thresholds for discomfort from stimuli. During migraine, stimulation can provoke a hyper-excitable cortical response involving specific subsets of neurons. Thresholds at which a response occurs and the size of the response that occurs may both be involved. For example, those with a more sensitive discomfort glare threshold have been shown to display greater activity in the cunei, lingual gyri and superior parietal lobules in response to peripheral lights. Photophobia may reflect individual differences in homeostatic response to stimuli, in which cortical hyper-excitability is further aggravated by visual stimulation.<ref name="Wilkins" /> Those who are less sensitive to light may better reduce discomfort and avoid over-stimulation.<ref>Template:Cite journal</ref><ref name="Wilkins">Template:Cite journal</ref> It has been suggested that migraineurs may experience dysfunction in inhibitory mechanisms, have difficulty habituating to ongoing stimuli, and even become sensitized to such stimuli.<ref>Template:Cite journal</ref>

Sound

Migraineurs frequently report hypersensitivity to auditory stimuli. Research indicates that they may have lower hearing thresholds<ref name="Kalita"/> and lower thresholds of discomfort for sounds than non-migraineurs generally, not just during migraine attacks.<ref>Template:Cite journal</ref> Migraineurs also have lower hearing thresholds than usual while they are experiencing headaches. Lower hearing threshold correlates with headache frequency, and with frequency of auditory, visual, and tactile triggers. Phonophobia in migraineurs correlates with higher brainstem neuronal excitability.<ref name="Kalita">Template:Cite journal</ref><ref>Template:Cite journal</ref> Therer is some evidence suggesting that migraineurs experience an increase or potentiation in response to blocks of sound, rather than habituation.<ref name=":7" />

Smell

Osmophobia is a possible diagnostic marker of migraine, distinguishing it from other types of headaches.<ref>Template:Cite journal</ref> Migraineurs may report increased aversion to a smell that would not be unpleasant normally, heightened awareness of a smell, or other olfaction-related symptoms.<ref>Template:Cite journal</ref><ref name="Smith" /> Osmophobia is more often observed in people with a longer history of migraines and greater migraine-related impairment. This may suggest that sensitivity to stimuli increases over time.<ref>Template:Cite journal</ref> Migraineurs who experience scent-related symptoms are more likely to experience insomnia, depression, fatigue and neuropathic pain, and to report lower quality of life than those without osmophobia.<ref>Template:Cite journal</ref>

The brain processes odorous stimuli through the olfactory, trigeminal, and pheromone systems. There is evidence that different odors may activate different brain regions. Reported trigger smells have been grouped into six general categories of products: oil derivatives and others; fetid odor; cooking products; shampoos and conditioners; cleaning products; and perfumes, insecticides, and rose.<ref name="Imai"/> Perfumes were the smells most frequently reported in connection with migraine attacks.<ref name="Imai"/><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> There is evidence that those with chronic migraines are more likely than those with episodic migraines to be sensitive to floral scents in various types of products. Strategies for reducing scent exposure include using fragrance-free products, improving ventilation and air quality, wearing masks, and using air cleaners.<ref name="Imai">Template:Cite journal</ref><ref name="Smith" />

Weather

Migraines have been reported to be triggered by changes in weather conditions such as temperature, ambient pressure, and humidity, but studies have shown mixed results.<ref name="Li">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name=":6"/>

Pathophysiology

Animation of cortical spreading depression

Migraine is believed to be primarily a neurological disorder,<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> while othersTemplate:Who? believe it to be a neurovascular disorder with blood vessels playing the key role, although evidence does not support this completely.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> OthersTemplate:Who? believe both are likely important.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Neurovascular contributions to migr">Template:Cite journal</ref><ref>Template:Cite journal</ref> One theory is related to increased excitability of the cerebral cortex and abnormal control of pain neurons in the trigeminal nucleus of the brainstem.<ref>Template:Cite journal</ref>

Sensitization of trigeminal pathways is a key pathophysiological phenomenon in migraine. It is debatable whether sensitization starts in the periphery or in the brain.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Aura

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.<ref name=HA28>The Headaches, Chp. 28, pp. 269–72</ref> There are several explanations for its occurrence, including activation of NMDA receptors leading to calcium entering the cell.<ref name=HA28/> After the burst of activity, the blood flow to the cerebral cortex in the affected area is decreased for two to six hours.<ref name=HA28/> It is believed that when depolarization travels down the underside of the brain, nerves that sense pain in the head and neck are triggered.<ref name=HA28/>

Pain

The exact mechanism of the head pain that occurs during a migraine episode is unknown.<ref name=Olesen2009>Template:Cite journal</ref> Some evidence supports a primary role for central nervous system structures (such as the brainstem and diencephalon),<ref>Template:Cite journal</ref> while other data support the role of peripheral activation (such as via the sensory nerves that surround blood vessels of the head and neck).<ref name=Olesen2009/> The potential candidate vessels include dural arteries, pial arteries and extracranial arteries such as those of the scalp.<ref name=Olesen2009/> The role of vasodilatation of the extracranial arteries, in particular, is believed to be significant.<ref>Template:Cite journal</ref>

Neuromodulators

Adenosine, a neuromodulator, may be involved.<ref name=Burn2015/> 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.<ref name=Burn2015>Template:Cite book</ref><ref>Template:Cite book</ref> Caffeine's role as an inhibitor of adenosine may explain its effect in reducing migraine.<ref>Template:Cite journal</ref> Low levels of the neurotransmitter serotonin, also known as 5-hydroxytryptamine (5-HT), are also believed to be involved.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> During migraine attacks, elevated levels of CGRP are detected.<ref name=Gilmore2011/><ref name=pathos/> These elevated levels lead 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.<ref>Template:Cite journal</ref><ref name="Gawde">Template:Cite journal</ref><ref name="Levy">Template:Cite journal</ref>

Diagnosis

The diagnosis of a migraine is based on signs and symptoms.<ref name=Bart10/> A headache calendar is a useful diagnostic tool for tracking the date, duration, and symptoms of headaches. Migraine can be classified according to whether the patient experiences an aura (MA) or not (MO) and frequency of headaches (episodic or chronic).<ref name="Aguilar-Shea" /> 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.<ref name="AHSfive">

• Template:Cite journal
• Template:Cite journal
• Template:Cite journal</ref> It is believed that a substantial number of people with the condition remain undiagnosed.<ref name=Bart10/>

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:<ref name=ICHD2004/>

• 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:
  • Nausea and/or vomiting
  • Sensitivity to both light (photophobia) and sound (phonophobia)

If someone experiences two of the following: photophobia, nausea, or inability to work or study for a day, the diagnosis is more likely.<ref>Template:Cite journal</ref> 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%.<ref name=Gilmore2011/> In those with fewer than three of these symptoms, the probability is 17%.<ref name=Gilmore2011/>

Classification

Migraine was first comprehensively classified in 1988.<ref name="Olesen_2006">Template:Cite book</ref>

The International Headache Society updated its classification of headaches in 2004.<ref name=ICHD2004/> A third version was published in 2018.<ref>Template:Cite journal</ref> According to this classification, migraine is a primary headache disorder along with tension-type headaches and cluster headaches, among others.<ref>Template:Cite journal</ref>

Migraine is divided into six subclasses (some of which include further subdivisions):<ref>Template:Cite journal</ref>

• 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.
  • Subtype of migraine with aura: 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".
  • Subtype of migraine with aura: 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.<ref name=Basil2009/> 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.<ref>Template:Cite journal</ref>

Abdominal migraine

The diagnosis of abdominal migraine is controversial.<ref name=Abdo2002>Template:Cite book</ref> Some evidence indicates that recurrent episodes of abdominal pain in the absence of a headache may be a type of migraine<ref name=Abdo2002/><ref>Template:Cite journal</ref> or are at least a precursor to migraine attacks.<ref name = "Olesen_2006" /> These episodes of pain may or may not follow a migraine-like prodrome and typically last minutes to hours.<ref name=Abdo2002/> They often occur in those with either a personal or family history of typical migraine.<ref name=Abdo2002/> Other syndromes that are believed to be precursors include cyclical vomiting syndrome and benign paroxysmal vertigo of childhood.<ref name = "Olesen_2006" />

Differential diagnosis

Other conditions that can cause similar symptoms to a migraine headache include temporal arteritis, cluster headaches, acute glaucoma, meningitis and subarachnoid hemorrhage.<ref name=Gilmore2011/> 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 associated with fever. Subarachnoid hemorrhage is associated with a very fast onset.<ref name=Gilmore2011/> Tension headaches typically occur on both sides, are not pounding, and are less disabling.<ref name=Gilmore2011/>

Those with stable headaches that meet criteria for migraine should not receive neuroimaging to look for other intracranial disease.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Management

Management of migraine includes both prevention of migraine attacks and rescue treatment. There are three main aspects of treatment: preventive (prophylactic) control, trigger avoidance, and acute (abortive).<ref>Template:Cite journal</ref>

Managing possible triggers and addressing comorbidities are the first step of treatment. Recommended lifestyle modifications promote maintaining a consistent lifestyle, through regular sleep patterns, regular eating, staying hydrated, managing stress, engaging in moderate exercise, and maintaining a healthy body weight. Avoiding dietary triggers and caffeine overuse may also be recommended lifestyle modifications.<ref name=":1">Jenkins, B. Migraine management. Australian Prescriber. 2020; 43(5):148–151. https://doi.org/10.18773/austprescr.2020.047</ref> Data suggests that sleep modification may be particularly helpful in reducing migraine frequency for adults with chronic migraines.<ref name="Treadwell_2024" />

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.<ref name="Treadwell_2024" /> 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.<ref name="Treadwell_2024">Template:Cite report</ref> In addition, it was found that relaxation therapy aided in the lessening of migraine frequency when compared to education by itself.<ref name="Treadwell_2024" /> 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.<ref name="Treadwell_2024" />

A variety of possible diets have been proposed, including ketogenic diet,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Mediterranean diet, DASH diet, and high intakes of fruits, vegetables, legumes, and oil seeds<ref>Template:Cite journal</ref>. Further research is needed to examine whether and when dietary interventions are beneficial to migraineurs.<ref name="Gazerani"/> Transcranial magnetic stimulation shows promise as a prevention mechanism,<ref name="Gilmore2011" /><ref>Template:Cite journal</ref> as does transcutaneous supraorbital nerve stimulation.<ref>Template:Cite journal</ref>

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.<ref name="pmid32802591">Template:Cite journal</ref> Other medications, such as gepants and ditans, are used as third-line treatment options. Prokinetic antiemetics are used as adjunctives for patients with nausea and/or vomiting.<ref name="pmid34145431">Template:Cite journal</ref> Corticosteroids are also used to treat migraine, and most benefited patients with status migrainosus, severe baseline disability, or refractory or recurrent headaches.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Prognosis

"Migraine exists on a continuum of different attack frequencies and associated levels of disability."<ref>Template:Cite journal</ref> 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.<ref name="NINDS">Template:Cite web</ref> Fewer than half of people with migraine seek medical care.<ref>Template:Cite web</ref> Severe migraine ranks in the highest category of disability, according to the World Health Organization, which uses metrics to determine disability burden,<ref>Template:Cite web</ref> and the bulk of disability burden is due to chronic (as opposed to episodic) migraine.<ref name="Brennan_2018" />

Repeated experiences of pain, including migraine pain, cause functional and structural changes in the brain<ref name="Brennan_2018">Template:Cite journal</ref> It is possible for migraine to progress from an occasional inconvenience to a life-changing, chronic disorder. This "chronification" affects 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."<ref name="Brennan_2018" />

Migraine with aura appears to be a risk factor for ischemic stroke<ref name=Stroke2009>Template:Cite journal</ref> doubling the risk.<ref>Template:Cite journal</ref> Being a young adult, being female, using hormonal birth control, and smoking further increases this risk.<ref name=Stroke2009/> There also appears to be an association with cervical artery dissection.<ref>Template:Cite journal</ref> Migraine without aura does not appear to be a factor.<ref name=Kurth2010>Template:Cite journal</ref> The relationship with heart problems is inconclusive with a single study supporting an association.<ref name=Stroke2009/> Migraine does not appear to increase the risk of death from stroke or heart disease.<ref name="Death2011">Template:Cite journal</ref> Preventative therapy of migraine in those with migraine with aura may prevent associated strokes.<ref>Template:Cite journal</ref> People with migraine, particularly women, may develop higher than average numbers of white matter brain lesions of unclear significance.<ref>Template:Cite journal</ref>

Epidemiology

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.<ref name=Ferrari2022>Template:Cite journal</ref> Onset can be at any age, but prevalence rises sharply around puberty, and remains high until declining after age 50.<ref name=Ferrari2022/> 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;<ref name=Ferrari2022/> this is most pronounced in migraine without aura.<ref>Template:Cite journal</ref>

Worldwide, migraine affects nearly 15% or approximately one billion people.<ref name=LancetEpi2012/> 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.<ref name=Bart10/> 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.<ref name="Stovner2007">Template:Cite journal</ref> Rates of migraine are slightly lower in Asia and Africa than in Western countries.<ref name = "Rasmussen_2006" /><ref name=AsiaEpi2003>Template:Cite journal</ref> Chronic migraine occurs in approximately 1.4–2.2% of the population.<ref>Template:Cite journal</ref>

During perimenopause symptoms often get worse before decreasing in severity.<ref name="Pol2009">Template:Cite journal</ref> While symptoms resolve in about two-thirds of the elderly, in 3–10% they persist.<ref name="ElderlyBook2008">Template:Cite book</ref>

History

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.<ref name=Miller2005>Template:Cite book</ref>

The word migraine is from the Greek ἡμικρᾱνίᾱ (hēmikrāníā), 'pain in half of the head',<ref>Template:Cite web on Perseus</ref> from ἡμι- (hēmi-), 'half' and κρᾱνίον (krāníon), 'skull'.<ref>Template:Cite book</ref> Template:TOC limit

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.<ref name=Borsook2012>Template:Cite book</ref>

A second-century description by Aretaeus of Cappadocia divided headaches into three types: cephalalgia, cephalea, and heterocrania.<ref name=Waldman2011>Template:Cite book</ref> Galen of Pergamon used the term hemicrania (half-head), from which the word migraine was eventually derived.<ref name=Waldman2011/> Galen also proposed that the pain arose from the meninges and blood vessels of the head.<ref name=Borsook2012/> 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.<ref name=Borsook2012/> 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.<ref name="Distillations">Template:Cite web</ref>

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.<ref name=Miller2005/> While sometimes people survived, many would have died from the procedure due to infection.<ref>Template:Cite book</ref> It was believed to work via "letting evil spirits escape".<ref>Template:Cite book</ref> William Harvey recommended trepanation as a treatment for migraine in the 17th century.<ref>Template:Cite book</ref> 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."<ref>Template:Cite book</ref>

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.<ref name=Borsook2012/> This substance was the fungus ergot from which ergotamine was isolated in 1918<ref name=Hanson2011>Template:Cite journal</ref> and first used to treat migraine in 1925.<ref>Template:Cite journal</ref> Methysergide was developed in 1959 and the first triptan, sumatriptan, was developed in 1988.<ref name=Hanson2011/> During the 20th century, with better study design, effective preventive measures were found and confirmed.<ref name=Borsook2012/>

Society and culture

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 Template:Currency per year.<ref name=EU2008>Template:Cite journal</ref> In the United States, direct costs have been estimated at Template:Currency, while indirect costs – such as missed or decreased ability to work – is estimated at Template:Currency.<ref name=EcoUSA2008>Template:Cite journal</ref> Nearly a tenth of the direct cost is due to the cost of triptans.<ref name=EcoUSA2008/> In those who do attend work during a migraine attack, effectiveness is decreased by around a third.<ref name=EU2008/> Negative effects also frequently occur for a person's family.<ref name=EU2008/>

Demographics

Statistical data indicates that women are more prone to having migraine, showing migraine incidence three times higher among women than men.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite web</ref> Template:Clear

See also

• List of investigational headache and migraine drugs

Further reading

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