Migraine

Migraine  is a genetically influenced complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea and light and sound sensitivity. Other characterizing symptoms may include vomiting, cognitive dysfunction, allodynia, and dizziness. Exacerbation of headache symptoms during physical activity is another distinguishing feature. Up to one-third of migraine sufferers experience aura, a premonitory period of sensory disturbance widely accepted to be caused by cortical spreading depression at the onset of a migraine attack. 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. Disease burden can range from episodic discrete attacks to chronic disease.

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. An older "vascular hypothesis" postulated that the aura of migraine is produced by vasoconstriction and the headache of migraine is produced by vasodilation, but the vasoconstrictive mechanism has been disproven, and the role of vasodilation in migraine pathophysiology is uncertain. 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.

Initial recommended treatment for acute attacks is with over-the-counter analgesics (pain medication) such as ibuprofen and paracetamol (acetaminophen) for headache, antiemetics (anti-nausea medication) for nausea, and the avoidance of triggers. Specific medications such as triptans, ergotamines, or CGRP inhibitors may be used in those experiencing headaches that are refractory to simple pain medications. For individuals who experience four or more attacks per month, or could otherwise benefit from prevention, prophylactic medication is recommended. Commonly prescribed prophylactic medications include beta blockers like propranolol, anticonvulsants like sodium valproate, antidepressants like amitriptyline, and other off-label classes of medications. 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. Nonpharmacological preventative therapies include nutritional supplementation, dietary interventions, sleep improvement, and aerobic exercise.

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

Signs and symptoms
Migraine typically presents with self-limited, recurrent severe headache associated with autonomic symptoms. About 15–30% of people living with migraine experience episodes with aura, and they also frequently experience episodes without aura. The severity of the pain, duration of the headache, and frequency of attacks are variable. A migraine attack lasting longer than 72 hours is termed status migrainosus. There are four possible phases to a migraine attack, although not all the phases are necessarily experienced:
 * The prodrome, which occurs hours or days before the headache
 * The aura, which immediately precedes the headache
 * The pain phase, also known as 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.

Prodrome phase
Prodromal or premonitory symptoms occur in about 60% of those with migraines, with an onset that can range from two hours to two days before the start of pain or the aura. These symptoms may include a wide variety of phenomena, 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. This may occur in those with either migraine with aura or migraine without aura. Neuroimaging indicates the limbic system and hypothalamus as the origin of prodromal symptoms in migraine.

Aura phase
Aura is a transient focal neurological phenomenon that occurs before or during the headache. Aura appears gradually over a number of minutes (usually occurring over 5–60 minutes) and generally lasts less than 60 minutes. Symptoms can be visual, sensory or motoric in nature, and many people experience more than one. 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. If any symptom remains after 60 minutes, the state is known as persistent aura.

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). 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. Usually the lines are in black and white but some people also see colored lines. Some people lose part of their field of vision known as hemianopsia while others experience blurring.

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

Pain phase
Classically the headache is unilateral, throbbing, and moderate to severe in intensity. It usually comes on gradually and is aggravated by physical activity during a migraine attack. 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. The feeling of pulsating pain is not in phase with the pulse. 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. Bilateral pain is particularly common in those who have migraine without aura. Less commonly pain may occur primarily in the back or top of the head. The pain usually lasts 4 to 72 hours in adults; however, in young children frequently lasts less than 1 hour. The frequency of attacks is variable, from a few in a lifetime to several a week, with the average being about one a month.

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

Silent migraine
Sometimes, aura occurs without a subsequent headache. This is known in modern classification as a typical aura without headache, or acephalgic migraine in previous classification, or commonly as a silent migraine. 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. It can last from 15 to 30 minutes, usually no longer than 60 minutes, and it can recur or appear as an isolated event.

Postdrome
The migraine postdrome could be defined as that constellation of symptoms occurring once the acute headache has settled. 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. According to one summary, "Some people feel unusually refreshed or euphoric after an attack, whereas others note depression and malaise."

Cause
The underlying causes of migraines are unknown. However, they are believed to be related to a mix of environmental and genetic factors. They run in families in about two-thirds of cases and rarely occur due to a single gene defect. While migraines were once believed to be more common in those of high intelligence, this does not appear to be true. A number of psychological conditions are associated, including depression, anxiety, and bipolar disorder.

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

Genetics
Studies of twins indicate a 34% to 51% genetic influence of likelihood to develop migraine. This genetic relationship is stronger for migraine with aura than for migraines without aura. It is clear from family and populations studies, that migraine is a complex disorders, where numerous of genetic risk variants exist, and where each variant increase the risk of migraine marginally. It is also known that having several of these risk variants increase the risk by a small to moderate amount.

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

The common forms migraine are Polygenetic, where common variants of numerous genes contributes to the predisposition for migraine. These genes can be placed in three categories increaseing the risk of migraine in general, specifically migraine with aura, or migraine without aura. 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 migriane 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.

Triggers
Migraine may be induced by triggers, with some reporting it as an influence in a minority of cases and others the majority. 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. Most people with migraines report experiencing triggers. Symptoms may start up to 24 hours after a trigger.

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

Dietary aspects
Between 12% and 60% of people report foods as triggers.

There are many reports    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, 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".

Environmental aspects
A 2009 review on potential triggers in the indoor and outdoor environment concluded that while there were insufficient studies to confirm environmental factors as causing migraine, "migraineurs worldwide consistently report similar environmental triggers".

Pathophysiology
Migraine is believed to be primarily a neurological disorder, while others believe it to be a neurovascular disorder with blood vessels playing the key role, although evidence does not support this completely. Others believe both are likely important. One theory is related to increased excitability of the cerebral cortex and abnormal control of pain neurons in the trigeminal nucleus of the brainstem.

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

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 migraines with aura. There are a number of explanations for its occurrence, including activation of NMDA receptors leading to calcium entering the cell. After the burst of activity, the blood flow to the cerebral cortex in the area affected is decreased for two to six hours. It is believed that when depolarization travels down the underside of the brain, nerves that sense pain in the head and neck are triggered.

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

Neuromodulators
Adenosine, a neuromodulator, may be involved. 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 have been found to be high during migraine attacks. Caffeine's role as an inhibitor of adenosine may explain its effect in reducing migraine. Low levels of the neurotransmitter serotonin, also known as 5-hydroxytryptamine (5-HT), are also believed to be involved.

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.

Diagnosis
The diagnosis of a migraine is based on signs and symptoms. 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. It is believed that a substantial number of people with the condition remain undiagnosed.

The diagnosis of migraine without aura, according to the International Headache Society, can be made according the "5, 4, 3, 2, 1 criteria," which is as follows:
 * 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. 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%. In those with fewer than three of these symptoms, the probability is 17%.

Classification
Migraine was first comprehensively classified in 1988.

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

Migraine is divided into six subclasses (some of which include further subdivisions):
 * 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 a number of 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. 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 migraines, but where there is not enough evidence to diagnose it as a migraine with certainty (in the presence of concurrent medication overuse).
 * Chronic migraine is a complication of migraines, and is a headache that fulfills diagnostic criteria for migraine headache and occurs for a greater time interval. Specifically, greater or equal to 15 days/month for longer than 3 months.

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

Differential diagnosis
Other conditions that can cause similar symptoms to a migraine headache include temporal arteritis, cluster headaches, acute glaucoma, meningitis and subarachnoid hemorrhage. 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. Tension headaches typically occur on both sides, are not pounding, and are less disabling.

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

Management
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.

Prognosis
"Migraine exists on a continuum of different attack frequencies and associated levels of disability." 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. But fewer than half of people with migraine seek medical care and more than half go undiagnosed and undertreated. "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." Repeated migraine results in "reorganization of brain circuitry," causing "profound functional as well as structural changes in the brain." "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." 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.

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

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

Worldwide, migraine affects nearly 15% or approximately one billion people. 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. In Europe, migraines affect 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 yearly. Rates of migraine are slightly lower in Asia and Africa than in Western countries. Chronic migraine occurs in approximately 1.4 to 2.2% of the population.

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

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

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

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.

A second-century description by Aretaeus of Cappadocia divided headaches into three types: cephalalgia, cephalea, and heterocrania. Galen of Pergamon used the term hemicrania (half-head), from which the word migraine was eventually derived. He also proposed that the pain arose from the meninges and blood vessels of the head. 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. The mystical visions of Hildegard von Bingen, which she described as "reflections of the living light", are consistent with the visual aura experienced during migraines.

Trepanation, the deliberate drilling of holes into a skull, was practiced as early as 7,000 BCE. While sometimes people survived, many would have died from the procedure due to infection. It was believed to work via "letting evil spirits escape". William Harvey recommended trepanation as a treatment for migraines in the 17th century. 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."

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

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 €27 billion per year. In the United States, direct costs have been estimated at $17 billion, while indirect costs – such as missed or decreased ability to work – is estimated at $15 billion. Nearly a tenth of the direct cost is due to the cost of triptans. In those who do attend work during a migraine attack, effectiveness is decreased by around a third. Negative impacts also frequently occur for a person's family.

Prevention mechanisms
Transcranial magnetic stimulation shows promise, as does transcutaneous supraorbital nerve stimulation. There is preliminary evidence that a ketogenic diet may help prevent episodic and long-term migraine.

Sex dependency
Statistical data indicates that women may be more prone to having migraine, showing migraine incidence three times higher among women than men. 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 still ongoing, and conclusions have yet to be achieved.