Migraine

Migraines typically present as recurrent, mostly one-sided, pulsating headaches, along with heightened sensitivity to light, sound, and other sensory stimuli. The severity of pain, duration of the headache, and frequency of attacks vary. Symptoms may last for hours or days, seriously affecting quality of life. Migraine attacks can be described in terms of four stages or phases, which may not all be experienced. In addition, the period between migraine attacks is sometimes called the interictal phase. • The premonitory phase or prodrome, generally defined as the 48 hours preceding the pain phase. These are reported by about 30% of migraineurs. Migraine is associated with neuropsychiatric disorders including major depression, bipolar disorder, anxiety disorders, obsessive–compulsive disorder, and sleep disorders. Shared neurobiological mechanisms may underlie multiple conditions. Co-occurrence with specific psychiatric disorders differs for those experiencing migraine with and without aura. Prodrome phase The prodrome phase of migraine is generally defined as the 48 hours preceding the pain or aura phases of an attack. Symptoms may vary widely, and can include 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. Premonitory symptoms may occur with both migraine without aura and migraine with aura. Aura phase Aura is a short-term neurological event that can occur over 5–60 minutes, generally just prior to the onset of headache pain. Symptoms can be visual, sensory or motor in nature, but visual effects occur most frequently, in as many as 99% of cases of migraine with aura. In rare cases known as persistent aura, aura symptoms may remain after 60 minutes. Visual disturbances often consist of a scintillating scotoma or flickering in someone's field of vision that may interfere with their ability to read or drive. This typically starts near the center of vision and then spreads out to the sides with jagged or zigzagging lines. Lines are usually black and white, but may also appear colored. Some people lose part of their field of vision, while others experience blurring. Sensory auras are the second most common type; they occur in 30–40% of people with auras. A feeling of pins-and-needles may begin on one side in the hand and arm and spread to the nose and 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 a hemiplegic migraine, and weakness often lasts longer than one hour unlike other auras. Pain phase Classically, a migraine headache occurs on one side, throbbing, with moderate to severe intensity. In around 40% of cases, the pain may affect both sides of the head. The pain phase usually lasts 4 to 72 hours in adults. Pain is frequently accompanied by nausea, vomiting, sensitivity to light, sensitivity to sound, sensitivity to smells, fatigue, and irritability. Many prefer a dark and quiet environment and seek to avoid stimuli to which they are sensitive. Nausea occurs in almost 90% of people, and vomiting occurs in about one-third. diarrhea, neck pain, and swelling or tenderness of the scalp. In rare cases called migraine with brainstem aura, neurological symptoms such as a sense of the world spinning, light-headedness, and confusion may affect both sides of the body. During the pain phase, motion and physical activity may increase pain. Migraineurs are likely to decrease physical activity during this time. However, the effects of physical activity on migraine are complex. Regular exercise may reduce the frequency of migraine attacks. Silent migraine Aura may occur without a subsequent headache, which is called a typical aura without headache. It may also be referred to as a "silent migraine", though this term is discouraged by some agencies due to its lack of specificity or association with symptoms from a different condition. Symptoms such as visual disturbance, vision loss, alterations in color perception, and sensitivity to light, sound, and odors may still interfere with normal activity in the absence of pain. Other symptoms reported include dizziness and euphoria. == Causes ==

Migraines are believed to result from a mix of genetic, environmental, and neurological factors. Genetics Studies of twin adults indicate a 0.36 to 0.48 genetic influence on the likelihood of developing migraine. However, few studies examine non-European populations or distinguish between migraine with aura and migraine without aura. It is clear from family and population studies that migraine is a complex disorder, where numerous genetic risk variants exist, and where each variant increases the risk of migraine marginally. It is also known that having several of these risk variants increases the risk by a small to moderate amount. The TRPM8 gene, which codes for a cation channel, has been linked to migraine. One meta-analysis found a protective effect from angiotensin converting enzyme polymorphisms on migraine. 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. 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 common variations to calculate a so-called polygenetic risk score, it is possible to assess, e.g., the treatment response to triptans. Triggers 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, affecting the body's ability to maintain a stable state (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 thought of as premonitory symptoms during the prodromal phase of migraine. 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. Hormonal changes From puberty onwards, women experience migraine attacks more frequently and with greater severity than men. Migraine episodes are more likely to occur immediately before and during menstruation, possibly due to the drop in estrogen levels before the menstrual period. The occurrence of migraine without aura displays an age-related pattern. Migraine episodes tend to diminish during the 2nd and 3rd trimesters of pregnancy, when elevated estrogen levels are stable. They are likely to return following the abrupt drop in estrogen levels after childbirth. 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, rather than during the pain phase of a migraine attack. 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. Jet-lag, shift work, and other disruptions of circadian rhythms may increase migraines. Changes in migraine frequency have been reported in relation to changes between daylight saving time and standard time. Sleep habits are negatively affected by factors such as air quality and exposure to ambient and indoor pollutants. A nationwide study of household fuel use in China found that those using solid fuel rather than cleaner fuel were more likely to develop migraines; those who switched from solid fuels to cleaner fuels showed a lower risk of migraines. However, those who used solid fuel but reported good sleep duration were not at a significantly higher risk for migraines, suggesting that sleep played a protective role. Sleep hygiene improvements and maintaining a consistent sleep schedule are among the most frequently recommended migraine management techniques. Diet Fasting or missing meals are commonly perceived triggers for migraines, and dietary modifications are a frequent management technique. 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. Tyramine is also present at low levels in chocolate. 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. 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 an increased desire for such foods as an early symptom of migraine attacks. Neuroimaging and neurophysiological studies show changes in sensory thresholds related to sensitivity to light, sound and smell and to pain perception. Patient reports of sensitivity triggers may be early symptoms in the premonitory phase of a migraine attack. 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. Strategies for reducing discomfort may include staying in a darkened room, wearing sunglasses or hats to avoid direct sunlight and minimize glare, using fluorescent light filters to soften and diffuse light and reduce flicker, and using anti-glare filters with computers. Evaluating workspace ergonomics and using suitable chairs and proper posture while working may also be helpful. Migraineurs also experience lower hearing thresholds than usual during 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. There is some evidence suggesting that migraineurs may react equally or more strongly to repeated stimuli (potentiation), rather than becoming accustomed to it (habituation). It 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. 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. The brain processes smells 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 product categories: oil derivatives and others; fetid odors; cooking smells; shampoos and conditioners; cleaning products; and perfumes, insecticides, and rose scent. Those with chronic migraines appear more likely than those with episodic migraines to be sensitive to floral scents. Strategies for reducing scent exposure include using fragrance-free products, improving ventilation and air quality, wearing masks, and using air cleaners. == Mechanism ==

Migraine is a complex pain disorder involving both blood vessels and neurons within the meninges, the brain's protective layers. The system involved is sometimes referred to as the trigeminovascular system. The trigeminal nerve, located within the dura mater, carries sensory information about pain, touch, heat, and cold from the face to the brain. The hypothalamus receives input from the trigeminal nerve and can modulate its activity. Initiation of a migraine attack may begin with disruption in the hypothalamus and limbic system. Disruption of the connection between the hypothalamus and limbic system may increase activity in the pain pathway from the trigeminal nerve to the brain, resulting in a migraine attack. The activity of calcitonin gene-related peptide (CGRP) in the meninges is linked to migraine. CGRP is released from both the trigeminal ganglion (TG) and the trigeminal nucleus caudalis (TNC) in response to trigeminal nerve activation. CGRP activates receptors on meningeal blood vessels, causing dilation and changes in blood flow. CGRP also activates specialized nerve endings in the dura mater (nociceptors) that transmit pain signals to the central nervous system. Increased neuronal activity in the trigeminal pain pathway reaches higher cortical pain regions via the brainstem, midbrain, and thalamus. Cerebrospinal fluid may play a role in migraine by conveying signals from the brain to overlying pain-sensitive meningeal tissues, including the dura mater. Incidence of migraines may increase over time, evolving from episodic migraine to chronic migraine. Overuse of acute pain medications may hasten this, and is a risk factor in developing medication overuse headache. == 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. 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: 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%. The IHS updated its classification of headaches in 2004, According to this classification, migraine is a primary headache disorder along with tension headaches and cluster headaches. The classification of migraine includes six broad categories: • Migraine without aura involves migraine headaches that are not accompanied by aura. • Migraine with aura 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: migraine with brainstem aura (MBA), 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. Retinal migraine (which is distinct from visual or optical migraine) involves migraine headaches accompanied by visual disturbances or even temporary blindness in one eye. • Episodic syndromes that may be associated with migraine are often noted in childhood. These 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. • Chronic migraine is defined as headaches occurring on at least 15 days per month for more than three months, with at least eight days per month fulfilling criteria for migraine. Abdominal migraine Abdominal migraine is most frequently diagnosed in children, but occasionally in adults. Diagnostic criteria for abdominal migraine are outlined by both the Rome IV and ICHD III classification systems. Criteria include repeated, acute, paroxysmal attacks of abdominal pain that may be associated with nausea and vomiting. Attacks last for at least 1 hour and interfere with normal life. Average attack duration has been reported as 17 hours. Abdominal migraine often occurs in people with either a personal or family history of typical migraine, and children may develop typical migraine later in life. Abdominal migraine, migraine, and cyclical vomiting syndrome share common symptoms. Differential diagnosis Other conditions that can cause similar symptoms to a migraine headache include temporal arteritis, cluster headaches, acute glaucoma, meningitis and subarachnoid hemorrhage. == Management ==

Management of migraine includes both prevention of migraine attacks and acute treatment. Preventive (prophylactic) treatment can be given in the absence of a headache to reduce the frequency and severity of future attacks. Acute (abortive) treatment attempts to diminish or reverse the progression of a headache that has already started. Measures for reducing and avoiding triggers may also be beneficial. Headache tracking, using a headache diary or smartphone app, is a standard self-management tool used to monitor frequency of headache occurrence, associated symptoms or triggers, and effects of treatments. Prevention A migraine management plan often includes lifestyle modifications to cope with migraine triggers and reduce the impact of comorbidities. Recommended lifestyle modifications support a consistent lifestyle, through regular sleep patterns, managing stress, Improving sleep patterns may be particularly helpful in reducing migraine frequency for adults with chronic migraines. For children and adolescents, CBT and biofeedback strategies are effective in decreasing the 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. Mediterranean diet, DASH diet, and high intakes of fruits, vegetables, legumes, and oil seeds. Further research is needed to examine whether and when dietary interventions are beneficial. Preventive medications may be recommended for those experiencing frequent or severe migraines. According to the American Headache Society, CGRP targeting therapies are a first-line option for migraine prevention. Botox injections can also help prevent migraine attacks, and are sometimes used for chronic migraines when other medications fail. Recent research also suggests taking oral nutrient supplements that correspond with mitochondrial function and brain energy metabolism, such as riboflavin, omega-3 fatty acids, magnesium, alpha-lipoic acid, and coenzyme Q10, as a way of decreasing the frequency of migraine attacks. Acute treatment Acute treatments are most effective when administered early in an attack. Initial recommended treatment for acute mild to moderate attacks is with over-the-counter (OTC) medications such as ibuprofen (Advil, Motrin) and paracetamol (acetaminophen, Tylenol) for pain. Corticosteroids such as dexamethasone have been used to treat patients with status migrainosus, severe baseline disability, or refractory or recurrent headaches. Systematic review and network meta-analysis have been used to compare the effectiveness of medications for acute migraine attacks in adults. Results suggest that triptans, ditans, and gepants are all associated with reduced pain at 2 hours, with triptans being the most successful. Gepants were the least likely to cause adverse events, with some triptans having a higher risk than gepants, and ditans having the highest risk among all treatments. == Prognosis ==

For those with occasional episodes of 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. It is believed that a substantial number of people with the condition remain undiagnosed. Severe migraine ranks in the highest category of disability, according to the World Health Organization, and the bulk of disability burden is due to chronic (as opposed to episodic) migraine. Migraines can 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." Women who experience migraine with aura and use estrogen-containing oral contraceptives have a higher risk of ischemic stroke. Preventive therapy, particularly for 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. According to the Global Burden of Disease 2021 database approximately 14% (1.16 billion) of people worldwide are affected by migraine. Rates of migraine are slightly lower in Asia and Africa than in Western countries. Chronic migraine occurs in approximately 1.4–2.2% of the population. == Economic impact ==

Migraines are a significant source of both medical costs and lost productivity. It has been estimated that migraine is the most costly headache disorder in the European Community, costing per year in 2012. Most of the costs were due to lost work. As of 2017, in the United States, total costs were estimated at , with the cost per person multiple times bigger for those with chronic migraines. In those who do attend work during a migraine attack, effectiveness is decreased by around a third. Negative effects also frequently occur for a person's family. == Research ==

Compared to the disease burden of migraine, the amount of healthy life years lost, the field is severely underfunded. In the US in 2019, migraine research got just 7.8% of the funding expected based on its burden. In Europe, it was the most underfunded brain disease when compared to its economic impact. == 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 (hēmikrāníā), 'pain in half of the head', from (hēmi-), 'half' and (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. 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. The association between trepanation and headaches in ancient history may be a myth or unfounded speculation that originated several centuries later. It was believed to work via "letting evil spirits escape". William Harvey recommended trepanation as a treatment for migraine in the 17th century. 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 that eventually turned out to be effective began. and first used to treat migraine in 1925. Methysergide was developed in 1959. The first triptan, sumatriptan, was developed in 1988. During the 20th century, with better study design, effective preventive measures were found and confirmed. == See also ==