Migraine is a recurrent condition marked by moderate to severe episodic headaches. They are often pulsatile, unilateral, last for 4-72 hours, and are associated with nausea, vomiting, photophobia, phonophobia, and osmophobia. While once thought to be due to dysfunction of cerebral blood vessel dilation, migraines are now understood to be related to a phenomenon known as cortical spreading depression. Cortical spreading depression is a self-disseminating wave of glial cell depolarization that extends across the cerebral cortex. This event may lead to activation of the trigeminovascular system, symptoms of aura, and alterations in the blood-brain barrier.

The pain associated with migraines is thought to be related to trigeminovascular activation and subsequent inflammatory cascade that impacts pain-sensitive meninges and meningeal vessels. Additionally, the release of vasoactive polypeptides such as substance P and possible alteration in serotonin metabolism contributes to further inflammation.[1],[2],[3]

Migraine attacks evolve through a pattern of events that occur over hours to days. A typical migraine has four phases: prodrome, aura, headache, and postdrome.

The prodrome occurs 1-2 days prior to the headache and is seen in about 60% of migraine sufferers.[4] Common symptoms of prodrome include fatigue, irritability, and gastrointestinal dysfunction.

The aura, a focal neurologic symptom, occurs in 25% of patients either prior to or during the headache. The most common manifestations are visual phenomena (flashing lights, jagged lines, and scotomata, usually still visible with the eyes closed), sensory symptoms (e.g., tingling or numbness in the hand and mouth, altered taste or smell, or dizziness) or verbal symptoms.[5] Auras typically last 5-60 minutes and are completely reversible. Aura without headache (acephalgic migraine or “atypical” migraine) may also occur. Migraines with motor symptoms are classified as familial or sporadic hemiplegic migraine.

Most often, but not always, the headache is experienced unilaterally and tends to have a pulsating or throbbing quality. Pain escalation is usually gradual, progressing from dull to severe, and can be exacerbated by light, sound, and activity. Nausea is common, and vomiting may result. The headache may last anywhere from a few hours to multiple days. Explosive onsets of headaches should be investigated for alternative causes, although this pattern, too, may represent migraine.

The postdrome is characterized by exhaustion or, paradoxically, elation, as well as possible focal areas of pain in the distribution of the preceding headache.

Migraines typically begin in the teenage years or early adulthood. Migraine without aura (“common” migraine) makes up the majority of cases. Migraine with aura (“classic” migraine) is the second most common type. There are various subtypes of migraine which include: migraine with brainstem aura, hemiplegic migraine, ocular migraine, vestibular migraine, menstrual migraine, and chronic migraine.

Tension headaches may be confused with migraine headaches.

The symptoms that suggest a headache may be migraine include:

Multiple headaches of moderate-to-severe intensity, lasting from 4-72 hours.

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).[6]

Pain sensation with normal stimuli (cutaneous allodynia).

Triggers may include menses, fasting, bright lights, overexertion, sleep deprivation, head trauma, changes in weather, changes in eating or sleeping schedules, stress, alcohol, and chemicals such as nitrites, glutamate, aspartate, and tyramine. These chemicals can be found in such foods and beverages as chocolate, red wine, nuts, and strong cheese. Other identified triggers are excessive vitamin A intake, histamine, corticosteroid withdrawal, caffeine or analgesic withdrawal, and strong odors.[7] Chemical triggers may promote migraines by affecting the cortex, trigeminal nerve, brainstem trigeminal nuclei, thalamus, and brainstem or limbic pathways via modulation of neurotransmitter release or stimulation of neuroreceptors or the trigeminovascular pathway. Triggers are rarely part of an immunological response (food allergy).[8]

Risk Factors

Migraine is a syndrome that, in most cases, has an inheritable predisposition. Up to 50% of migraine cases are familial, with specific gene abnormalities in some cases.[9],[10] Women are affected about 3 times more often than men. Persons with right-to-left cardiac shunts (usually due to patent foramen ovale) have increased prevalence of migraine with aura.[11],[12],[13]

Several studies have linked obesity to the frequency and severity of migraine attacks, although not all studies are in agreement.[14],[15]

Estrogen withdrawal may precipitate migraine. This may occur with normal menstrual cycles, menopause, or variation in oral exogenous doses (e.g., missed oral contraceptive pills or drug interactions that affect estrogen concentrations).[16]

Diagnosis

Migraine is a clinical diagnosis. Neuroimaging is only necessary if another etiology is suspected due to the presence of neurologic abnormalities, an atypical pattern of headache, or progression of symptoms despite appropriate treatment. Providers may consider a CT scan and lumbar puncture for patients with rapid or explosive onset of severe headache (to rule out subarachnoid hemorrhage). MRI scanning is more effective in patients with focal neurologic signs, gait instability, or other findings inconsistent with migraine.

The International Classification of Headache Disorders, 3rd edition (ICHD-3) lists the following criteria for migraine diagnosis:[17]

Migraine without aura

At least 5 attacks that have all of the following:

1. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated).
2. Headache has at least 2 of the following characteristics: unilateral, pulsating, moderate-to-severe pain, aggravation by routine physical activity.
3. Headache is accompanied by at least 1 of the following: nausea and/or vomiting or photophobia and phonophobia.
4. Not better accounted for by another ICHD-3 diagnosis.

Migraine with aura

At least 2 attacks that have the following:

1. One or more of the following fully reversible aura symptoms: visual, sensory, speech and/or language, motor, brainstem, retinal.
2. At least 2 of the following 4 characteristics:
   1. At least 1 aura symptom spreads gradually over ≥ 5 minutes, and/or 2 or more symptoms occur in succession
   2. Each individual aura symptom lasts 5-60 minutes.
   3. At least 1 aura symptom is unilateral.
   4. The aura is accompanied, or followed within 60 minutes, by headache
3. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been ruled out.

Migraine with typical aura

All the criteria for migraine with aura are fulfilled with the exception that the aura consists of visual, sensory and/or speech/language symptoms, each fully reversible, but with no motor, brainstem, or retinal symptoms.

Treatment

Lifestyle modification can be highly effective for migraine prevention. The patient may benefit from avoiding situations that trigger or exacerbate migraines, for example, by maintaining appropriate sleep patterns, avoiding fasting and trigger foods, and participating in aerobic exercise and stress management. Conversely, there is also evidence that exposure to triggers may aid with desensitization and better migraine control.[18]

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 (suppository, intranasal, intramuscular, or intravenous) drugs may work better for patients who suffer from nausea and vomiting during episodes. The following agents are commonly used:

Analgesics (aspirin, other NSAIDs including indomethacin, and acetaminophen). NSAIDs may be combined with acetaminophen. A combined naproxen-sumatriptan formulation is available. Medication overuse headache can result from frequent use of all acute medications but risk is lowest with NSAIDs, and this class of medications may even prevent the development of chronic migraine in individuals who have less than 10 headache days per month.[19]

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.[20] Sensitization may decrease effect. They should be avoided in pregnancy and in hemiplegic or basilar migraine. Serotonin syndrome is possible, especially when used with selective serotonin reuptake inhibitors.

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

Aspirin and/or acetaminophen with caffeine. Note: Caffeine withdrawal can be a migraine trigger.

Isometheptene (a vasoconstrictor) and dichloralphenazone (a mild sedative). Both are components of the drug Midrin.

Antiemetics, 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 and the high potential for analgesic-overuse (analgesic-rebound) headache.[21],[22] This can result from the frequent use of any short-acting analgesic but is more common and severe with narcotics, barbiturates, and benzodiazepines.

Prophylactic therapy. Daily prophylaxis is indicated if headaches occur at least 2 times per month, last longer than 24 hours or when they are particularly prolonged, or have associated severe disability or complications. It may be several weeks before benefits are evident. Many prophylactic agents are pharmaceuticals, although there is also good evidence for effectiveness of some botanicals, vitamins, and minerals.[23] The following agents are commonly used:

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

Anticonvulsants, such as topiramate or valproic acid.

Calcium channel blockers, such as verapamil.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen.[24] These agents are most useful when there is a short period of migraine susceptibility each month.

Antidepressants. Tricyclic antidepressants, such as amitriptyline, and serotonin antagonists, such as venlafaxine, are effective.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) have some evidence for effectiveness, but further studies are needed.

Riboflavin (see Nutritional Considerations below).

Cognitive and behavioral therapy.

Botulinum toxin is effective for chronic migraine.

Two medicinal botanicals, petasites and feverfew, are under study for their efficacy in migraine treatment.[25],[26]

Butterbur (Petasites hybridus root). In double-blind, randomized clinical trials, butterbur reduced migraine frequency by roughly half compared with placebo. Although this effect was achieved with 25 mg twice daily in one study, a second trial with a larger number of patients found that only a higher dose (75 mg twice daily) resulted in a statistically significant reduction in migraine frequency (~ 50% fewer attacks over a 4-month period) when compared with 50 mg twice daily.[25],[27] The American Academy of Neurology and the American Headache Society have suggested butterbur be classified as “Level A” in the hierarchy of evidence and have further described it as established as effective for migraine prevention.[28]

Feverfew is an herb with anti-inflammatory properties. Previous studies 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.[29] However, a recent review concluded that the evidence for the efficacy of feverfew is mixed and inconclusive and is derived from low quality evidence, which needs to be confirmed in larger rigorous trials.[30]

Nutritional Considerations

Nutritional approaches to migraine are often effective and are appealing to patients. They can be particularly attractive when treating pregnant women, for whom 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, other studies (see below) indicate that dietary treatment may still be helpful for preventing migraine in certain individuals.[31] Additional controlled clinical trials are required to firmly establish the 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.

A healthy weight. While being underweight confers an approximately 20% greater risk for migraine, a greater risk exists with carrying excess weight. Obese individuals had a 75% greater risk for chronic migraine, while overweight individuals had a roughly 40% higher risk, when compared with normal weight persons.[32] Weight loss has been found to reduce migraine frequency, intensity, and duration.[33],[34]

Diets that are low in fat, higher in omega-3 fatty acids, or plant-based. Several types of diet interventions have been shown to be effective for reducing migraine pain, and additional clinical trials are needed to further document their efficacy. One central feature of these diets is that they would be expected to reduce oxidative stress, which is known to impact migraine through the TRPA1 ion channel that triggers nociception.[35] These studies are described below:

Some evidence suggests that reducing total and omega-6 fat and increasing the ratio of omega-3 to omega-6 fatty acids in the diet may reduce migraine occurrence in some patients.[36],[37],[38] A low-fat, vegan diet was found to be helpful in reducing migraine pain.[39] One suggested mechanism for this effect relates to arachidonic acid metabolism. This omega-6 fatty acid, found in animal products, is a precursor for both prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), levels of which are elevated during migraine attacks.[40],[41] Although inhibition of the production of these eicosanoids by NSAIDs (see above Treatment section) and by antileukotriene drugs has been found effective for migraine prevention, changes in diet that limit the intake of omega-6 fats may have a similar benefit.[42]

Elimination diets. Two randomized, controlled clinical trials found significant reductions in migraine in individuals who removed foods from their diets for which they had IgG antibodies. One of these found a 29% reduction in migraine days, while the other revealed a 19% reduction.[43],[44] Previous research studies have established that avoidance of foods found to trigger migraine can reduce or eliminate headache in approximately 20-50% of patients.[45],[46] Foods and beverages commonly identified as migraine triggers include alcohol, dairy products (e.g., cheese), chocolate, citrus fruits, caffeinated drinks and coffee, and aspartame-containing foods.[40] Elimination of certain additives, including MSG, aspartame, and nitrites in cured meats, may also be helpful.[47]

Elimination of suspected trigger foods may be done with the help of an allergist. However, patients can also pursue an elimination diet on their own.

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

• Brown rice.
• Cooked or dried fruits, such as cherries, cranberries, pears, or prunes (avoid citrus fruits).
• Cooked green, yellow, and orange vegetables (artichokes, asparagus, broccoli, chard, collards, lettuce, spinach, string beans, squash, sweet potatoes, tapioca, and taro).
• Plain or carbonated water.
• Condiments flavorings (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 1-2 weeks and then reintroduced to see if the same reaction occurs. If no symptoms are experienced, that food can remain in the diet.

Caffeine. A study that analyzed data from more than 50,000 individuals over 2 decades found a 10% higher risk for migraine in persons consuming more than 540 mg of caffeine per day, when compared to those consuming between 0 and 240 mg/day (about two cups of coffee). Conversely, caffeine has been found useful for the treatment of headaches caused by post-dural puncture and hypnic (“alarm clock”) headaches, possibly because plasma adenosine increases during migraines and caffeine is a well-known adenosine antagonist.[44]

Heart health-promoting diets. Metabolic syndrome, obesity, stroke, subclinical vascular brain lesions, coronary artery disease, and hypertension often coexist with migraines.[48] In the Women’s Health Study, those with a history of migraine had more than twice the risk for myocardial infarction (MI) compared with women who had no migraine history.[49] Similarly, the Physicians Health Study of more than 20,000 individuals found that those with a history of migraine had a more than 40% greater risk for MI compared with other people.[50] (See also Coronary Heart Disease chapter.)

Supplements. Several supplements have shown promise for migraine prevention or treatment. Their utility is based on evidence indicating that a defect in mitochondrial energy production and increase in oxidative stress exists in migraine sufferers. Coenzyme Q10 (CoQ10), magnesium, and riboflavin (vitamin B2) have all been tested in migraineurs with varying degrees of success, as described below:[35],[48]

In a randomized, placebo-controlled, double-blind multicenter trial that enrolled 130 patients, a combination of 150 mg CoQ10, 400 mg B2, and 600 mg magnesium, combined with a multivitamin-mineral formula containing 200 mg vitamin C, 134 mg vitamin E, and amounts close to Recommended Daily Intakes (RDI) of other micronutrients was taken daily for 3 months. The number of monthly days with migraine fell from 6.2 at baseline to 4.4 during active treatment (-1.8 days), compared with a reduction of 1 day in the control group, while the intensity of migraine pain was significantly reduced in the active treatment group. The HIT-6 summary score was significantly reduced by roughly 5 points (compared to 2 points in the placebo group).[35]

A meta-analysis of trials involving the use of intravenous (I.V.) or oral forms of magnesium in migraine patients concluded that I.V. magnesium provided significant relief in acute migraine within 15-45 minutes and lasting up to 24 hours after infusion, while oral magnesium significantly reduced both the frequency and intensity of migraines.[51]

In addition, the American Academy of Neurology and the American Headache Society have classified the evidence of the efficacy of riboflavin for migraine as Level B (probably effective and should be considered for migraine prevention).[28]

Orders

Nutrition consultation to identify food triggers, prescribe elimination diet as described above, formulate meal plans, and help with the attainment of a healthy body weight. (See also Coronary Heart Disease chapter.)

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.

References