Ranked eighth in 2010 Global Burden of Disease study as leading cause of years lived with disability.

One of only 8 chronic medical issues that affect more than 10% of the population worldwide.

It is the second leading cause of disability worldwide, with very high burden in women between the ages of 15 and 49 years.
Migraine imposes the longest duration of disability during a patient’s lifetime, and exacts substantial and long-term healthcare costs.
After tension headache migraine is the second most prevalent neurological disorder, with a female to male ratio of 3:1 and an estimated 1 year prevalence of approximately 15% in the general population.
Less than 10% of migraine patients ever see a physician and less than 10% receive effective therapy.
Prevalence peaks during the ages of 18-44 years.
About 75% of affected people report onset of migraine before the age of 35 years.
In children  of school age there is about a one year prevalence of about 7%.
Occurs nearly 1 in seven individuals between 15 and 49 years of age and is three times more frequent in women than men.

The disorder tends to remit with all the rage, and the onset of migraine after age 50 arouses suspicion of a secondary headache disorder.

Associated with a high rate of disability and the WHO finds migraine to be the third most common disease, ranking sixth as a cause of major disability.

More frequent in adult women than men.

Worldwide approximately 1 billion individuals are estimated to have migraine.

Approximately 40, 000,000 Americans have migraine.

14 million Americans suffer with chronic daily headaches.

One in four households has someone with a migraine.

Approximately 18% of women 6% of men suffer from migraines.

Results in extremely high cost of healthcare systems as well as patients because of loss productive time.

Overall increase in the prevalence worldwide, which correlates with rising average life expectancy in developing countries and growth of urban living, a risk factor for migraine.

27% more likely to occur in overweight individuals.

The incidence of migraine is elevated in patients with a patent foramen ovale, with the incidence of migraine particularly high in patients with auras occurring before the headache developed.

Research suggests  that a proportion of cases of migraine may be caused by PFO, and closure of a PFO can reduce symptoms in certain cases.

This remains controversial; 20% of the general population has a PFO, which for the most part, is asymptomatic. 

About 20% of the female population has migraines, and the placebo effect in migraine typically averages around 40%.

The high frequency of these facts make finding statistically significant relationships between PFO and migraine difficult.

In a large randomized controlled trial, migraine headache cessation was not more prevalent in the group of migraine patients who underwent closure of their PFOs.

Individuals with migraines have diminished involvement in family activities, misgivings about parenting ability, and persistent feelings of financial insecurity.

Most commonly occurs between 25 and 55 years and is three times more common in females.

By the end of their reproductive life cycle, approximately 40% of women have experienced a migraine headache.

Commonly misdiagnosed.

Occurs three times more commonly in women than in men, and worldwide roughly 1/4 of reproductive age women have migraine.

Affects 14.2% of US population.

Highest of 23 1/2% in women aged 18 to 44 years.

Migraines ranked in the top 20 of the world’s most disabling medical illnesses.

The third most prevalent disorder and seventh highest cause of disability worldwide.

Associated with high rates of comorbidities and reduced health-related quality-of-life.

Every 10 seconds someone in the United States goes to the ER with a headache or migraine.

Migraines are the seventh leading cause of global disability.

Most frequent type of headache for which patients seek evaluation.

91% of patients with a migraine attack cannot function during the process.

Chronic neurovascular disorder with recurrent episodes of headache and autonomic nervous system dysfunction.

Family history is coming, with heritability estimated to be approximately 42%

Presumably a genetically induced hypersensitivity of the brain to both internal and external changes that can act as a headache trigger.

Triggers influence the trigeminovascular system, which contains both peripheral and central nervous system components.

It involves the trigeminal nerve and its aconal projections to the intracranial vasculature.

Nociceptive signals from the trigeminal vascular system are related to areas in the brain that yield the perception of migraine pain.

Stimulation of the trigeminovascular system results in the release of neuropeptides and other agents which causes local inflammation and distant amplification of neural circuitry in the brainstem, trigeminal nucleus caudalis, thalamus, and cortex leading to entail sensitization and symptoms worsening along with reduced activity in central of descending inhibitory systems and reduced ability to control or extinguish a headache attack.

Defined as having occurred at least 5 times, with headaches lasting 4-72 hours and pain localized to one side of the head, of moderate to severe intensity, and worsened by physical activity.

Is usually a unilateral, pulsating, occurrence in the frontal temporal or ocular areas.
Migraine headache may be associated with transient paralysis or sensory changes.
It is aggravated by physical activity.

Chronic migraine defined as at least 15 days of headache per month with majority having moderate to severe intensity, pulsating quality, nausea, vomiting, photophonia, and photophobia.

Patients usually have nausea, vomiting, with the headache and have increased light or sound sensitivity.

In young adults about 6% in men and 15-17% in women.

Headaches are commonly made worse by activity, and patients usually desire to be left alone, and lie motionless in a darkened room.

Half of patients have their first attack before age 12.

Increases in women during the years of menstruation, peaks before the average age at menopause, and then declines.

About 20% of women worldwide have migraine.

As many as 14% of women have menstrual migraine.

Patients with menstrual related migraine account for about half of all migraine patients.

Many women find that their migraines change as their hormone levels fluctuate during menstrual cycles, pregnancy, and menopause.

Decreases in estrogen are hypothesized to trigger some migraines, which, in women often begin with menarche and increase through midlife.

Their frequency and severity can worsen during menstrual cycles, can intensify during the transition to menopause, and then abate once the menopausal transition is complete.

By the end of their reproductive years 40.9% of women have had migraine headaches and menstrual attacks are up to four times were likely to be severe, to be associated with nausea and vomiting, or to be resistant to abortive treatments.

Hormonal prophylaxis helpful for migraines that do not respond to usual treatments.

Attacks correlated with declining plasma estradiol levels and particularly seen after prolonged elevated levels as is seen prior to menses.

Women, with migraine, have higher CGRP concentrations in tear fluid, but not plasma, than women without mega migraine.

It is thought, female sex hormones are involved in the stimulation of the trigeminal vascular system, and the release of CGRP.

Small, preliminary Dutch study found elevated estrogen levels in nonobese men with migraine compared to nonobese men without migraine.

Men with migraine also showed evidence of lower levels of testosterone

Menstrual migraine is common, affecting at least 50% of female migraine sufferers.

Up to 70% of female patients with migraine report a menstrual association with their attacks and changes in headaches related to hormonal contraception, pregnancy, and menopause.

Migraine typically improves during pregnancy.

There is no diagnostic test for migraine.

The headache is typically unilateral, in approximately 60% of cases, and moderate to severe intensity.

Headaches may be followed by impaired concentration and feelings of fatigue or feeling washed out.

Imaging studies are overwhelmingly likely to be unremarkable.

Treatments for menstrual migraine are largely similar to the treatment of migraine in general, but a subset of patients can potentially benefit from therapies that are more directly targeted to hormonally-influenced migraine headaches.

The main goals of acute treatment include: rapid treatment of attacks with minimal recurrence, reducing the use of additional rescue medications, restoring function, minimizing resource use, cost effectiveness, and minimizing the occurrence of adverse effects.
Headaches have been related to imbalances in neurotransmitters, especially serotonin, in the brain stem.

Such neurotransmitter imbalances are thought to lead to changes in brain blood vessel function with resulting edema that activates pain fibers outside the brain.

Serotonin receptor agonists, triptans, are the most widely prescribed acute migraine treatments.

Triptans may not be efficacious in about 34% of patients and patients may have recurrent attacks at about 30-40%, and up to 52% have adverse affects from triptans.

Preventative medications for migraine include antidepressants, propranolol, and anticonvulsants.

Hormonal treatments, either in the form of contraceptive pills or other hormonal combinations, are used in menstrual migraine with a degree of success.

Some non-pharmacological therapies for the prevention of menstrual migraine headaches include magnesium and/or Vitamin E.

Some studies show that there may be a diminished magnesium level in association with migraine headaches.

Vitamin E is a progesterone antagonist, and therefore has been proposed as a potential treatment for menstrual migraines because of the progesterone fluctuations that occur during the menstrual cycle.

Associated with elevated levels of calcitonin gene-related peptide (CGRP).

Calcitonin gene-related peptide (CGRP) plays a role in the pathogenesis of migraine.

Pre- and postmenopausal women with a history of migraine headache 26% reduced risk for breast cancer: the Woman’s Contraceptive and Reproductive Experiences study interviewed 4568 women with breast cancer and 4000 678 matched controls.

Associated symptoms include photophobia (80%), phonophobia (76%), nausea (73%) and aura (36%).

Prodrome occurs in 40-60% of migraineurs.

The prodromal phase can occur several hours to days before a headache and maybe modulated by the hypothalamus.

Up to 80% of migraines occur without aura.

The aura phase is caused by cortical spreading depression, a slow wave of neural depolarization, that involves changes in brain glial activity and alteration of cerebral blood.

Migraine aura typically involves visual scintillations and scotoma and less often spreading semi sensory symptoms or speech dysfunction
Aura’s reversible neurologic symptoms develop gradually over a period of 5-60 minutes.

The aura phase is usually fall by headache within 60 minutes, although it may occur during or in the absence of subsequent headache.

Migraine affects up to 15% of the population.

Headaches described frequently as localized, throbbing and incapacitating.

Up to one third of patients associated neurological aura.

If an aura contains multiple features, symptoms usually occur in succession of at least five or so minutes each, with the total symptom complex of 5 – 60 minutes.

Auras can be followed by headache that can last from several hours to several days.

Aura symptoms include: visual, sensory, speech, motor, brain stem, or retinal changes that precede the headache, spread gradually, and last 5-60 minutes.

Visual symptoms, both positive, such as scintillations, and negative, such as scotoma, are typically noted at the onset followed by the development of sensory complaints, then a mixed dysarthric / aphasic language disorder, followed by gradual clearing.

Headache usually begins within 60 minutes after resolution of neurologic symptoms.

Some patients experience aura, usually visual, without an accompanying headache and that is referred to as typical auhhra without headache.

Patients have a higher and greater volume of magnetic resonance imaging measured deep white matter hyperintensity, infratentorial hyperintensity and posterior circulation infarction like lesions.

The above changes are thought to be ischemic in origin.

White matter hyperintensity is associated with atherosclerotic disease risk factors, increasing risk of ischemic stroke and cognitive impairment.

The association of migraine with MRI measured lesions and clinical site are consistent with the hypothesis that recurrent migraine headaches may be associated with cerebral ischemia.

Migraines are theoretically the result of changes in the activity of the locus ceruleus, which can cause neuronal excitation in the trigeminal nucleus.
The trigeminal nucleus releases vasoactive substances, especially calcitonin gene-related peptide, nitric oxide, and substance P.
Calcitonin gene-related peptide (CGRP) effects include arterial dilatation, inflammation, and pain.
CGRP causes inflammation making the brain hyperexcitable and a postsynaptic neuron firing is increased resulting in exaggerated pain signals sent to the brain.
During a migraine attack calcitonin gene-related peptide binds to receptors on the smooth muscles within arterial walls and causes dilatation of intracranial arteries.

Locking CGRP can reduce migraine manifestations.

In the Cerebral Abnormalities in Migraine, and Epidemiological Risk Analysis study: follow up after 9 years, women with migraine had a higher incidence of deep white matter hyperintensities, but they did not have significantly higher progression of other MRI measured brain changes.

The main subtypes are migraine with and without aura.

Clinically migraine may be divided into four phases: prodrome, aura, headache phase, and postdrome.

The migraine prodrome is present in up to 60% of patients and may precede development of headache by hours to days and can consist of a multitude of symptoms, including depression, hyperactivity, cognitive changes, frequent urination, irritability, Euphoria, neck stiffness and pain, and fatigue.

Aura is fully reversible set of nervous system symptoms, most often visual or sensory, they typically develop gradually, recede, and is then followed by headache accompanied by nausea, vomiting, photophobia and phonophobia.

Less common symptomatology of aura include: speech and language symptoms, motor or brainstem symptoms, or retinal symptoms.

When aura present it must be associated with reversible neurological changes involving visual, sensory, or language symptoms.

Visual aura travels at 3 mm per minute and this slow speed is referred to as spreading depression.

The aura of migraine originates from spreading depression.

Spreading depression associated with transient loss of brain electrical activity, a potential shift to negativity on the outside of brain cells and movement to areas of the brain at three mm per minute.

Patients with this disorder have more excitable brains than those who do not suffer from this disorder.

Spreading depression causes release of nitric oxide, potassium, and arachidonic acid that diffuses to the blood vessels of the meninges and activates the trigeminal nucleus in the brain stem.

Migraineurs can precipitate events with stimuli from sounds, smells or visual experiences triggering a spreading depression.

Spreading depression is initiated secondary to loss of inhibition at neuronal cell bodies.

Neurologic symptoms may include flickering spots altering vision, pins and needles on one side of the body and aphasia.

Precipitating factors include: alcohol, tyramine, aspartame, cured meats, chocolate, hypoglycemia, stress, relaxation periods and menses.

Obese persons are 81% more likely to have episodic migraine of any frequency compared with persons of normal weight.

The link between episodic migraine and obesity is stronger in persons younger than 50 years.

Pain unilateral in 59%.

Evaluation includes testing to rule out other disease processes.

No diagnostic test is specific or necessary.

Patients should avoid triggering agents.

Skipped meals can precipitate migraine.

Sleep deprivation can precipitate events as can sleeping excessively.

Triptans equally effective in menstrual and nonmenstrual migraine.

Higher incidence of brain infarction than general population.

Fewer than 50% of patients with this process are appropriately diagnosed and only one third of affected patients are prescribed specific medications for migraine.

Most individuals who believe that they have sinus headaches probably have migraine.

Women’s Health Study revealed that women with active migraine with aura have an associated risk of increased major cardiovascular disease, increased cardiovascular deaths, myocardial infarction, ischemic stroke, coronary artery revascularization and angina, while there was no association if aura was absent.

Women with migraine headache have an 83% increase risk of cardiovascular events on long term follow-up (Rambarat C).

A study of female health professionals aged at least 45 years with migraines with aura had a higher adjusted incidence of cardiovascular disease compared with women with migraine without aura or no migraines (Kurth T).

Women with migraine headaches have a greater than 2 fold increase in the risk of stroke compared to women without such a history.

57% of males, and 68% of females experiencing migraine never consult a physician for the disorder.

The treatment of migraine and other primary headache proportional to the severity of the symptoms and disability.

Treatment goals are to prevent or reverse the process.

Mild and infrequent symptoms may be treated with lifestyle modification initially, along with stress management techniques and over the counter medications.

Hemiplegic migraine is a rare subtype with aura that is characterized by unilateral weakness and maybe familial or sporadic.

Aura is likely linked to a spreading cortical depression, starting posteriorly and moving slowly across the brain surface, producing an orderly progression of neurologic symptoms.

Prescription medications may be added as warranted to prevent disability and to maintain function.

Medications are divided into abortive and preventative

Abortive medicines are prescribed to treat an individual attack.

Abortive medication is include nonsteroidal anti-inflammatory drugs, anti-emetic medications, and corticosteroids.

Opioid medications are generally discouraged because of the risk of overuse and potential for rebound.

Anti-migraine agents include 5-HT1B/D serotonin agonists, the triptans, and ergotamine containing preparations, such as intravenous/intranasal dihydrergotamine.

Early treatment in the course of the migraine attack produces best results.

Many patients with migraine report dissatisfaction with treatments, with a high number of discontinuation of medications, switching treatments, and adding additional medications to improve effectiveness and tolerance.
Many patients end up on narcotics, some with disastrous results.

Migraine patients are commonly seen in the ED departments and or a major cause of distress and disability.

Preventative medications are used to reduce frequency and severity of individual attacks, attempting to reduce disability.

Triptanshave high strength of evidence for use in acute migraine.

NSAIDS evidence of benefit for acute treatment of migraine is moderate.

Small molecule oral calcitonin gene related peptide (CGRP) antagonists have moderate to high strength of evidence for their use:rimegipant, ubrogepant.

Lasmiditan. a 5-HT1f receptor agonist has efficacy but increased risk of toxicity.

Remote electrical neuromodulation and external Vegas nerve stimulation have moderate strength of evidence of benefit.

External trigeminal nerve stimulation is slightly less robust.

Ergot alkaloids or affective but have a higher risk of adverse events.

Antiemetics have a lower strength of evidence for effectiveness.

Triptans mainstay of treatment.

Triptans reduce the activation of the trigeminal sensory nerve fibers carrying pain sensations from the meninges to the brainstem, and trigger constriction of vascular smooth muscle in blood vessels.

Non-steroidal anti-inflammatory drugs can be effective by reducing inflammation in the meninges and reduce pain.

The use of anticonvulsants reduce the likelihood for spreading depression to occur.

A common cause of primary headaches in children.

Humanized monoclonal antibodies target CGRP either bind to the CGRP receptor or to its ligand: erenumab, fremanezumab, and galcanezumab.
Humanized monoclonal antibodies are indicated for preventative treatment of episodic chronic migraine in adults and they are administered subcutaneously from once monthly or every three months.

Rimegepant an oral calcitonin gene-related peptide receptor antagonist results in a higher percentage of patients free of pain and free from most of the bothersome symptoms than placebo.

Ubrogepant in migraine results in a higher percentage of patients with freedom from pain and absence of the most bothersome symptoms at two hours after the dose compared to placebo (Dodick DW).

Oral atogepant once daily is effective in reducing the number of migraine days and headaches over a 12 week period.
High-dose aspirin in the range of 900-1300 mg, equivalent to 3-4 325 mg aspirin tablets,  is effective in many patients with migraines when compared with alternative therapies (Biglione B).
Zavegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist nasal spray used to treat acute migraine in adults.
Lidocaine infusions can provide relief.
Eptiezumab an intravenous administered monoclonal antibody significantly reduces the number of average monthly migraine days compared with placebo.

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