Overview and Risk Factors

Migraine is a recurrent condition marked by severe episodic headaches, other neurologic manifestations, or both. Migraine may be caused by dysfunction of the trigeminovascular system and is attended by a wave of hyperpolarization of cells and hypoperfusion across the cerebral cortex. These events can cause the patient to experience an "aura," a state characterized by unusual visual or other sensory phenomena. The headache is believed to result from multiple factors, including sensitization of trigeminal sensory neurons and activation of the trigeminovascular system, altered serotonin metabolism, the release of vasoactive polypeptides such as substance P, causing inflammation of the meninges.^1-3

In approximately 60% of cases, the headache is unilateral, but it can occur globally and bifrontally, as well as (rarely) in other patterns. Pain escalation is gradual, progressing from dull to throbbing in most cases, and can be exacerbated by light, sound, and activity. Explosive onsets of headaches should be investigated for alternative causes, although this pattern, too, may represent migraine.

Migraines typically begin in the teenage years or early adulthood; they rarely commence after age 40. There are uncommon variants of migraine including retinal, ophthalmoplegic, and familial hemiplegic. Migraine without aura ("common" migraine) makes up about 80% of all cases. Migraine with aura ("classic"migraine) is the second most common type.

Aura is caused by neuronal dysfunction. The most common manifestations are visual phenomena (flashing lights, jagged lines, and scotomata, usually still visible with the eyes closed), with other sensory symptoms (altered taste or smell, tingling or numbness, dizziness). Migraines with motor symptoms are classified as familial or sporadic hemiplegic migraine. Auras typically last no more than an hour, except in cases of motor dysfunction. In complicated migraines, neurologic symptoms may last weeks or may be permanent (usually with evidence of a stroke). Aura without headache (acephalgic migraine or "atypical migraine") may also occur.

Symptoms that suggest that a headache may be migraine include:

• Multiple headaches of moderate-to-severe intensity, lasting from hours to days
• Unilateral, throbbing quality
• Photophobia, phonophobia
• Nausea/vomiting
• Aggravation of headache by activity
• Autonomic features such as rhinorrhea or congestion, tearing, changes in pupil size, and others (these occur occasionally, not routinely)⁴
• Pain sensation with normal stimuli (cutaneous allodynia)

Triggers include stress, menses, oral contraception, overexertion, sleep deprivation, fasting, head trauma, bright lights, changes in weather, changes in eating or sleeping schedules, and substances in food or beverages, such as nitrites, glutamate, aspartate, and tyramine. Other identified triggers are excessive vitamin A intake, histamine, corticosteroid withdrawal, caffeine or analgesic withdrawal, and strong odors.⁵ Triggers may act as vasodilators^2,6 or through allergic reactions.^7,8

Risk Factors

Up to 60% of migraine cases are familial, with specific gene abnormalities in some cases. Women are affected about 3 times more often than men.⁹ Persons with right-to-left cardiac shunts (patent foramen ovale, and atrial septal defect to a lesser degree) have increased migraine prevalence,^10-12 for unknown reason.

Diagnosis and Treatment

Diagnosis

Migraine is a clinical diagnosis. Neuroimaging is only necessary if another possible etiology is suspected. Providers may consider a CT scan and lumbar puncture for patients with rapid onset of severe headache (to rule out subarachnoid hemorrhage), focal neurologic signs, gait instability, or other migraine-inconsistent findings.

Migraine without aura

A clinical diagnosis of migraine is indicated for patients who experience 5 or more episodes fulfilling the following criteria:

• Duration of 4 to 72 hours.
• Two or more of the following: unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity.
• One or more of the following: nausea/vomiting, photo/phonophobia.
• Headache not attributed to another disorder.

Migraine with aura   

The following criteria establish the clinical diagnosis of migraine with aura:

• Aura consisting of one or more of the following, and without motor weakness: fully reversible visual symptoms, fully reversible sensory symptoms, or fully reversible speech disturbance.
• Two or more of the following: homonymous (same field defect in both eyes) visual symptoms or unilateral sensory symptoms, at least one aura developing gradually over 5 minutes or different auras developing in succession over at least 5 minutes, or each aura lasting between 5 to 60 minutes
• Two episodes fulfilling above criteria with migraine headaches beginning within 1 hour of the aura(s)
• Headache not attributed to any other disorder

Treatment

Prevention is the mainstay of migraine therapy. The patient will benefit from avoiding situations that trigger or exacerbate migraines-for example, by maintaining appropriate sleep patterns, avoiding fasting and trigger foods, and participating in stress management. It should be kept in mind that absorption of oral medicines may be decreased due to migraine-induced gastric stasis.

Abortive therapy

Abortive therapies are more effective when given early, and in larger appropriate doses, although frequent use (more than 10 times per month) can lead to medication-overuse headaches. All short-acting analgesic medications can result in these headaches (also called analgesic rebound headaches or transformed migraine). Non-oral drugs-suppository, intramuscular, or intravenous-may work better for the many patients who suffer from nausea and vomiting during episodes. The following agents are commonly used:

Analgesics. Aspirin, other NSAIDs including indomethacin, and acetaminophen. Chronic use can lead to overuse headaches.

Triptans (sumatriptan, rizatriptan, almotriptan, zolmitriptan). These serotonin receptor agonists are for moderate-to-severe migraine when vascular disease and uncontrolled hypertension are absent. Triptans inhibit vasoactive peptide release, cause vasoconstriction, and block pain pathways in the brainstem.¹³ Sensitization may decrease effect. They should be avoided in pregnancy and in hemiplegic migraine.

Dihydroergotamine (intranasal or injectable). This medicine is effective for moderate-to-severe attacks when vascular disease and hypertension are absent. Administration may require anti-emetic premedication. The medicine should not be used within 24 hours of triptans due to risk of myocardial infarction, and should be avoided during pregnancy.

Aspirin or acetaminophen with caffeine. Note: Caffeine withdrawal is a very common migraine trigger.

Isometheptene (a vasoconstrictor) and dichloralphenazone (a mild sedative), both components of the drug Midrin).

Intranasal lidocaine solution (4%).

Anti-emetics, prochlorperazine and metoclopramide. These can be administered intravenously, as monotherapy, or as an adjunct to above therapies.

Benzodiazepines, narcotics, and barbiturates should be used sparingly, due to their habit-forming qualities.

Prophylactic therapy

Daily prophylaxis is indicated if headaches are more frequent than 4 per month, or have associated severe disability or complications. It may be several weeks before benefits are evident. The following agents are commonly used:

Beta-Adrenergic blockers, such as propranolol or atenolol. Propranolol  increases rizatriptan levels, so doses of rizatriptan being used to abort migraine should be halved.

Anticonvulsants, such as topiramate, gabapentin, or valproic acid.

Calcium channel blockers, such as verapamil.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen,¹⁴ which are most useful when there is a short period of migraine susceptibility each month.

Tricyclic antidepressants, such as amitriptyline or nortriptyline.

Riboflavin (high dose, 200 mg twice daily).

Cognitive and behavioral therapy.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). The evidence supporting the use of these drugs for migraine is weak.

Two medicinal botanicals, feverfew¹⁵ and petasites,¹⁶ are under study for their efficacy in migraine treatment.

Butterbur (Petasites hybridusroot ). In double-blind, randomized clinical trials, butterbur reduced migraine frequency by roughly half, compared with placebo. Although this effect was achieved with 25 mg BID in one study,¹⁷ a second trial with a larger number of patients found that only a higher dose (75 mg BID) resulted in a statistically significant reduction in migraine frequency (~ 50% fewer attacks over a 4-month period), when compared with 50 mg BID.16 Similar results were obtained in a multicenter prospective open-label study with children and adolescents.¹⁸

The mechanisms by which this botanical may reduce migraine attacks have not been established, but may include spasmolytic and anti-leukotriene effects and an effect on calcium channels.¹⁷ So far, Petasites has a good safety record; belching is its most common side effect.¹⁹ Efficacy comparisons with commonly-prescribed medications for migraine have not yet been performed.

Feverfew is an herb with anti-inflammatory properties. Research studies have yielded mixed verdicts as to its efficacy for migraines. Some clinical trials have suggested efficacy of the native herb or its extracts in preventing or aborting migraines, while others have yielded inconclusive results, perhaps due to variations in preparations tested.²⁰ However, a recent randomized, double-blind, multicenter, parallel-group study found that a fever few extract (6.25 mg TID) decreased migraine attacks by 40%, compared with a 27% reduction for placebo (P = .05).²¹

Nutritional Considerations

Nutritional approaches to migraine can be particularly attractive when treating pregnant women, where pharmacologic interventions are generally contraindicated.

Foods containing tyramine and other biogenic amines have long been suspected of triggering migraine. Although a review of randomized, double-blind, placebo-controlled studies failed to establish these as a cause of either headache or migraine,²² other studies (see below) indicate that dietary treatment may still be helpful for preventing migraine in certain individuals. Additional controlled clinical trials are required to firmly establish a role for diet in the causation or prevention of migraine; nevertheless, dietary treatment may be considered first as a low-cost, low-risk treatment before medication is used or in patients who either do not respond to or tolerate medication well.

Avoidance of foods found to trigger migraine can reduce or eliminate headache in approximately 20% to 50% of patients.^23,24 Foods commonly identified as migraine triggers include (in order of importance): dairy products (eg, cheese), chocolate, eggs, citrus fruits, meat, wheat, nuts and peanuts, tomatoes, onions, corn, apples, and bananas.²⁵ Tyramine- and phenylalanine-containing foods, such as aged cheese, beer, and red wine, have also been implicated in migraine.^24,25 Although evidence is limited, dietary treatment of pediatric migraine with an allergen-free diet was effective in over 90% of subjects.²⁶ Elimination of certain food additives, including MSG, aspartame, and sodium nitrate, may also be helpful.^27,28

To identify trigger foods, an elimination diet may be conducted on an outpatient basis if the patient can control his or her diet for several weeks.

The procedure is as follows: Start with a baseline diet including only those foods not implicated in migraine:

1. Brown rice.
2. Cooked or dried fruits, other than citrus fruits (cherries, cranberries, pears, prunes).
3. Cooked green, yellow, and orange vegetables (artichokes, asparagus, broccoli, chard, collards, lettuce, spinach, string beans, squash, sweet potatoes, tapioca, and taro).
4. Plain or carbonated water.
5. Condiments (modest amounts of salt, maple syrup, and vanilla extract).

Wean from caffeine-containing beverages gradually, or avoid caffeine if not habitually consumed.

When migraines have stopped or diminished (usually within a week or so), the patient should keep a food diary and add in foods one at a time in generous amounts every other day to observe which cause migraine recurrence.

Foods listed above that are the most common triggers of migraine attacks should be added last. If the food is associated with a migraine attack, it should be removed from the diet for 1 to 2 weeks and then reintroduced to see if the same reaction occurs. If no symptoms are experienced, that food can remain in the diet.

Some evidence suggests that reducing total and omega-6 fat in the diet may reduce migraine occurrence in some patients. In an open trial including 54 migraine patients, reducing total fat intake from 66 grams to 28 grams per day resulted in a significant decrease in headache frequency, intensity, duration, and medication intake.²⁹ It is not clear if the effect was due to reduced fat intake or to the exclusion of specific high-fat foods.

One suggested mechanism relates to arachidonic acid. This omega-6 fatty acid, found in animal products and derived to a lesser degree from the intake of the polyunsaturated fat linoleic acid, is a precursor for both prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), levels of which are elevated during migraine attacks.^30,31 Although inhibition of the production of these eicosanoids by NSAID's (see Migraine Treatment section) and by antileukotriene drugs³² has been found effective for migraine prevention, changes in diet that limit the intake of omega-6 fats may have a similar biological action.

Studies with supplemental fatty acids that are known to reduce the production of PGE2 and LTB4 (eg, EPA, DHA, and GLA) have also been found to reduce the frequency, duration, and severity of migraine attacks in a limited number of clinical trials.^33,34 As with diets that eliminate biogenic amines or allergens, further study of the potential for low-fat diets and fatty acid supplements is required to establish a role in migraine prevention.

Supplements

A particular complication of research into therapy of migraine is the very strong placebo effect that requires sound experimental design. The following nutriceuticals have some experimental evidence although some have been investigated with greater rigor than others.

Vitamin B₂. Studies have found significant reductions in headache frequency and headache days with pharmacologic doses (400 mg) of riboflavin per day.^35,36

Magnesium. Magnesium deficiency is a common finding in patients with menstrual migraine.³⁷ Migraine patients retain more magnesium after an oral load than control patients, also suggesting systemic magnesium deficiency .38 Magnesium therapy has been found to improve migraine symptoms when given intravenously³⁹ and to reduce the number of headache days in children given oral magnesium.⁴⁰ Magnesium has also been used intravenously to abort severe migraine attacks in the emergency room. Whether this is by a different mechanism than its prophylactic effect is not known.

Omega-3 fatty acids. Evidence of efficacy of omega-3 fatty acids for migraine prophylaxis has been mixed. The rationale for their use was based on anti-inflammatory effects as well as platelet stabilizing effects. However, two earlier promising reports^41,42 were followed by a later negative report.⁴³ The latter report suggested the presence of a strong placebo effect that may influence research findings, as noted above.

Coenzyme Q10. Coenzyme Q10 is being investigated for the treatment of several neurologic disorders. There is some evidence from randomized clinical trials that this is effective in migraine prophylaxis, although most studies have been small and some have been unblinded. ⁴⁴

5-Hydroxytryptophan. Small studies have suggested a benefit for supplementation with 5-hydroxytryptophan.⁴⁵ Its role as an intermediary in the metabolic pathway of serotonin production has provided some theoretical underpinning for these studies. However, evidence of efficacy at this point is weak.

Caffeine. Some patients report anecdotally that 1 to 2 cups of strong black coffee may stop an evolving migraine. Caffeine withdrawal appears to trigger headache46 that is abated by coffee drinking.⁴⁷ However, daily use may contribute to development of frequent and resistant headaches.⁴⁸

Orders

Nutrition consultation to help identify food triggers, prescribe elimination diet as described above, and formulate meal plans.

Consider allergist referral on an outpatient basis.

What to Tell the Family

The patient's family should be taught about the possible role of dietary and environmental triggers and how family members can assist the patient in avoiding them. Among individuals with identified triggers, even minor exposures can cause migraines. The family can assist and encourage the patient to keep a headache and diet diary to better identify headache-provoking foods and substances. The whole family can use the elimination diet short-term. This will help the patient comply with the diet. Riboflavin and magnesium supplements may also be considered.

References

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