Understanding Migraine: Pathophysiology and Presentation

Undiagnosed, self-medicated, and poorly controlled—as it very often is, according to surveys—migraine can transform from episodic to chronic and can lead to a downward socioeconomic spiral. In this first article of a series, headache specialists explore the nature of this inherited disorder and how to recognize the patient who needs help with migraine management.

By Jeff Unger, MD, Roger K. Cady, MD, and Kathleen Farmer-Cady, PsyD

Even though some 28 million Americans suffer from migraine headaches, most migraineurs have not actually had their condition diagnosed by a physician, and they self-medicate with over-the-counter analgesics. In 1989, the American Migraine Study I reported that of those individuals interviewed by telephone who had headache symptoms meeting the accepted diagnostic criteria for migraine, only 39% had been diagnosed by a physician. The American Migraine Study II published in 1999 found that half of all migraineurs interviewed continued to be undiagnosed. Today, 39% of migraineurs do not seek medical attention for their disabling headaches, and 21% of diagnosed headache patients discontinue medical care because of frustrations over inadequate treatment.

Over 1 million headache consultations are performed annually, the vast majority (70%) by primary care physicians. About 20% of patients report headache as one of their major concerns on their initial physician visit.

Unfortunately, many patients are reluctant to discuss headaches with their physicians. They may feel that little can be done for their headaches or that the headaches are simply a fact of life that they must tolerate. On average, a migraineur has tried 4.6 different medications unsuccessfully before finding an effective symptomatic treatment for the headaches. In addition, some patients believe that headaches are a psychological problem that is not appropriate for medical evaluation. Physicians, therefore, must be willing to validate the biological nature of headache disorders and assure patients that seeking treatment is a wise decision. Once a headache diagnosis is established, a treatment plan can be developed with specific goals that give the patient a rationale for ongoing management.

In this article, the first of a three-part series, we will review the definition and causes of migraine, its biological mechanisms, and key diagnostic considerations. We will also discuss the five phases of the migraine process.
 

INHERITED DISORDER

Migraine is an inherited neurologic disorder. Nearly 90% of migraine sufferers have a primary relative with similar headaches. Patients with migraine inherit a uniquely sensitive nervous system, which can be disrupted by numerous life events, such as sleep deprivation, strong odors, traveling, skipping meals, stress, and changes in hormone levels.

Migraine headaches affect women two to three times as often as men. Although attacks can begin at any age, they typically start early in life, during childhood or adolescence. With children, boys and girls are affected equally. By early adolescence, however, the prevalence is decidedly biased toward women. In theory, the cyclic fluctuations in estrogen levels explain this disparity. After age 60, migraine becomes less prevalent but does not necessarily resolve. In postmenopausal women, estrogen levels decline and stabilize significantly, resulting in decreased migraine frequency with aging. Women who are placed on estrogen replacement therapy, especially if cycled with progesterone, can have persistent migraines into later life.

Also, some migraineurs can develop headaches when they first start taking drugs such as nitrates, sildenafil, antihypertensive agents, oral contraceptives, or hormone replacement therapy. Often, these precipitating factors are considered triggering events for migraine. However, migraine usually occurs when several precipitating factors occur in proximity to each other. Thus, for many migraineurs, these events should be perceived as risk factors rather than triggering events. Explaining this concept can help patients avoid trying to identify a single trigger that causes their headaches.

The frequency of migraine headaches varies. Approximately 59% of migraineurs experience one to four attacks per month, while 22% have 10 or more attacks per month. The headache phase associated with migraine typically lasts about 24 to 72 hours. During this period, patients often experience significant disability. Frequent and inadequately controlled migraine may disrupt families, social interactions, and even limit the ability of patients to find or maintain gainful employment. As a consequence, patients often do not have access to health insurance and medical care. For a sizable minority of patients, poorly controlled migraine eventually results in a downward socioeconomic spiral.
 

MIGRAINE TRANSFORMATION

Chronic daily headache afflicts an estimated 4% of the American population. For most of these individuals, the evolution of their headaches from episodic to chronic occurs gradually over many years. Susceptible individuals with intermittent migraine begin to have a gradual increase in headache frequency, intensity, and duration. Eventually, the headache pattern transforms from episodic and well controlled to daily and poorly controlled. Typically, in this patient population, there is a baseline persistent headache with superimposed episodes of more disabling migraine-like pain. This transformational process can develop from either an initial migraine or tension-type headache pattern.

As headache frequency increases, patients seek relief by increasing their dependency on analgesics, both prescribed and over-the-counter. Overuse of these medications has been implicated in expediting the transformational process, which leads to the potential withdrawal headache known as analgesic rebound. Not only does this compound the disability of transformed migraine, but it also complicates the medical management of these patients. Headache sufferers in the United States spend over $2 billion annually on over-the-counter medications for headache, none of which carries a warning about the consequences of overuse. Thus, physicians must define clear limits on the use of symptomatic medications and educate headache patients as to the mechanism and chronicity of analgesic rebound headaches.
 

TRIPTANS: CORNERSTONE OF THERAPY

The modern approach to treating migraine headaches can be traced back to the 1970s and the theory that serotonin could relieve headache, which led to the development of the first serotonin agonist (sumatriptan). Today in the United States, there are seven triptans that are considered to be the clinical cornerstone of migraine therapy.

During the 1990s, clinical trials demonstrated that triptans were efficacious in the treatment of migraine. Nearly 80% of migraineurs reported relief of migraine symptoms within two hours of dosing and rapid restoration to normal function. Triptans are well tolerated and their side effects are generally mild and short-lived. When these drugs are used in appropriate patients, they are extremely safe. Patients who use triptans like being able to treat their headaches and feeling in control of their disease.

Thus, triptans have significantly improved patient outcomes. Unfortunately, despite abundant evidence-based clinical data, many patients and some physicians continue to believe that migraine-specific treatments are ineffective, have too many side effects, are not consistent in eliminating pain, and are overpriced.
 

BIOLOGICAL MECHANISMS IN MIGRAINE

The migraine process begins in the nervous system. Thus, migraine is a neurologic condition rather than a vascular or muscular disorder, as has been proposed in the past. Migraine presumably begins when a biologically sensitive nervous system is confronted with an environment that can provoke migraine. In this environment, the neurochemical balance of the nervous system changes and symptoms recognized as premonitory or prodromal may occur. This change can progress until the migraine threshold is crossed and an area in the brainstem called the migraine generator is activated. This may initiate a wave of neuronal depression to move across the cortex and activate trigeminal afferents and the vascular structures they innervate.

As branches of the first division of the trigeminal nerve are activated, neuropeptides (substance P, CGRP) are released at the neurovascular junction. The neuropeptides produce a sterile inflammation of the meningeal arteries associated with platelet aggregation and release of serotonin, which can potentiate the migraine process. Via bidirectional conduction, nerve impulses are transmitted back into the trigeminal nucleus caudalis, located in the brainstem, where they are routed to various third-order neurons in the thalamus and cerebral cortex. Input from the upper cervical dermatomes is also processed in the trigeminal nucleus caudalis, which may explain the high prevalence (80%) of neck pain associated with a migraine attack.

As the migraine process unfolds, brainstem reflexes are activated that produce the migraine-associated symptoms, including nausea, vomiting, photophobia, and phonophobia. Autonomic activation occurs via the facial nerve and results in nasal congestion, rhinorrhea, and lacrimation in 47% of migraineurs. Pain in the face over the sinus cavities is common in migraine and likely results from activation of the second branch of the trigeminal nerve or as referred pain from the first division.

Recent functional imaging studies have supported the concept of a migraine generator in the midbrain, possibly in the periaqueductal gray (PAG). Chronic migraine has been associated with iron deposition in the PAG in the midbrain, which may be a biological marker for transformed chronic daily headache.

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DIAGNOSING MIGRAINE

Migraine is defined as a stable pattern of recurrent disabling headaches without evidence of an underlying cause. Disabling primary headaches should be considered as being migraine. According to the International Headache Society (IHS) criteria, migraine headache should be moderate to severe and should last 4 to 72 hours. It should also be throbbing, associated with nausea or vomiting and sensitivity to light, sound, or both, and aggravated by activity.

The Landmark Study evaluated headache diaries of patients seen in the primary care setting and determined that 94% of these patients could be diagnosed as having migraine based on their diary entries. Four questions can assist in making a rapid diagnosis of migraine while ruling out both secondary headaches and chronic daily headaches (see box below).

Annually, an estimated 4 million Americans are treated for recurrent sinus infections and countless others take over-the-counter analgesics for self-described "sinusitis." Yet new evidence suggests that these headaches often meet migraine diagnostic criteria. In 2001, Schrieber and Cady evaluated 30 patients with the self-diagnosis of sinus headache and determined that 96% met IHS diagnostic criteria for migraine. Patients were asked to treat two "sinus headaches" with sumatriptan 50 mg and record the outcomes in a headache diary. Two hours after using sumatriptan, 74% of patients noted improvement in their headache intensity and 36% were pain-free. When asked to express their satisfaction regarding the use of sumatriptan versus their previous sinus medication, 62% favored the use of the triptan to treat their headaches versus only 33% who preferred their over-the-counter drugs.

Patients who believe they have sinus headaches commonly experience a watery nasal discharge and facial pressure with the headaches. In addition, they notice that changes in the weather often trigger headaches. These observations have recently been confirmed in a large multicenter clinical study of subjects with sinus headaches (as diagnosed by either the subject or a physician). As in the pilot study, 90% of these research subjects met diagnostic criteria for IHS migraine and responded to interventions with sumatriptan similarly to patients diagnosed with migraine. It seems highly probable that most so-called sinus headaches are actually migraine.

Many patients will diagnose themselves as having a sinus infection because of the presence of facial pain. This perception often results in the prescribing of antibiotics for headaches by physicians. However, the diagnosis of sinusitis is symptom-based and focused on a potential infection rather than a migraine headache process. Criteria for the diagnosis of acute rhinosinusitis are listed in the box below. Acute sinusitis requires the presence of at least two major criteria or one major and two minor criteria.

The current gold standard for headache therapy is to achieve freedom from pain and associated migraine symptoms two hours after receiving treatment. For those patients with migraine as the underlying cause of headache, treating the process of migraine rather than a nonexistent infectious condition may significantly improve the outcome for headache management.

Not every headache patient requires an extensive or expensive workup to establish a diagnosis. Migraine sufferers often have comfort signs that may lead the physician to believe that the headaches are primary in nature and therefore benign (see box, below left). Headache danger signs should alert the physician to order additional testing to determine if the patient has a secondary or life-threatening headache disorder (see box, below right).

IMAGING STUDIES

In 2000, the U.S. Headache Consortium published guidelines for performing magnetic resonance imaging (MRI) and computed tomography (CT) scans. Patients who should receive an imaging study include those with a nonacute headache and an abnormal neurologic examination and those who have atypical headaches that may not represent a primary headache disorder. Magnetic resonance imaging is preferred to evaluate the possibility of a structural lesion in the brain. A CT scan should be used when considering the diagnosis of subarachnoid hemorrhage.

One in 250,000 headaches is due to a life-threatening disorder, whereas 1 in 11 people in the United States have migraine. The chance of a migraineur having the symptoms of typical migraine headaches, a normal neurologic exam, and an abnormal MRI scan is less than 0.2%.

Migraine patients should have laboratory tests done for thyroid disorders and anemia; correcting these problems can significantly reduce the frequency of migraine. Patients who have migraine with aura should have an anticardiolipin antibody blood test performed. A positive test would indicate an increased risk for future stroke. Migraine-with-aura patients who smoke, are on birth control pills, and have a positive anticardiolipin antibody test should be placed on prophylactic aspirin because of the increased risk of stroke. They should also stop smoking immediately. Oral contraceptives should be used with informed consent.

Several medical disorders are observed more frequently in migraine patients than in nonmigraineurs. Depression is three times more common in migraineurs; anxiety and panic disorder, six to eight times more common; irritable bowel syndrome, eight times more common; and stroke, four times more common. Migraine patients frequently suffer from dysmenorrhea, epilepsy, fibromyalgia, seasonal allergies, and toxemia. These coexisting disorders are thought to be linked by serotonin abnormalities in the brain. Therefore, patients with depression should be evaluated for migraine headaches. Likewise, migraineurs should be monitored for symptoms of depression and panic disorder. Often, a discussion of disabling headaches can be initiated by the astute physician who recognizes the presence of a coexisting disorder in the patient.

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FIVE PHASES OF THE MIGRAINE PROCESS

Migraineurs may experience five different phases during a typical attack: premonitory or prodrome, aura, headache, resolution, and postdrome (see illustration, below). A variety of different clinical presentations may develop during each attack. Migraine phase recognition is helpful in diagnosing migraine and in formulating a proactive treatment strategy. Some patients awaken from sleep with a severe migraine headache associated with nausea and vomiting. Others may be able to predict that they will experience a headache within 24 hours and take measures to abort the headache before they become symptomatic. The complete process of migraine may interfere with a person's ability to function at home, school, or work for five to seven days.

Premonitory or prodrome. Up to 80% of migraineurs note the presence of a prodrome beginning 24 hours or so in advance of their headache. Premonitory symptoms include fatigue, yawning, change in appetite, excitement, frequent urination, difficulty with memory, weakness, cold hands, irritability, and loss of concentration. During the prodrome, alterations in neurologic function are frequently noted. Exposure to environmental triggers such as light, sound, hormonal changes, certain foods, stress, and exercise may reach a critical threshold in the central nervous system (CNS), resulting in disinhibition of the migraine generator. This in turn initiates the headache phase of migraine.

Patients who can recognize their prodromes and treat themselves at that time with a triptan are able to consistently abort or minimize their subsequent headache. In addition, patients who recognize their prodrome may practice relaxation exercises or biofeedback to prevent the advancement of the migraine process.

Aura. Approximately 10% to 15% of migraineurs experience an aura prior to the headache. Auras last 5 to 60 minutes and usually stop when the headache begins. They represent focal neurologic symptoms that develop as a result of a spreading wave of cortical depression moving from the back of the brain forward at the rate of 2 mm/sec. Occasionally, patients may experience an aura without headache.

The most common auras are visual, such as scotomata (absent spots in the visual field) and teichopsia (zigzag lines). Sensory auras also occur and can be worrisome to the patient. Digital lingual paresthesia (DLP) results in a progressive numbness on one side of the face and in one arm. Unlike a transient ischemic attack, the symptoms of DLP become more widespread over time and then quickly disappear.

Dysarthria may also occur as an aura. Patients may experience syncope, dizziness, confusion, dysarthria, diplopia, and vomiting prior to the onset of basilar migraine. Retinal migraine occurs primarily in women older than age 45 and is associated with extensive scotomata and loss of vision. This aura may not be followed by a headache, but it can make driving a motor vehicle hazardous. An aura that lasts more than 60 minutes, results in paralysis or syncope, or occurs for the first time in a patient over age 50 or after initiation of oral contraceptives warrants a comprehensive neurologic evaluation.

Headache. As noted earlier, the headache phase of migraine lasts 4 to 72 hours in adults. The pain is usually unilateral, throbbing, and moderate to severe in intensity, and it worsens with activity. Migraine-associated symptoms include nausea, vomiting, light and/or sound sensitivity, dizziness, and loss of concentration. Migraine commonly occurs in the early morning hours and awakens the patient from sleep, but paradoxically it can be relieved by sleep induction. Exertion typically worsens the headache, so most migraineurs prefer to remain in a quiet, dark environment as their headache slowly resolves.

The headache phase of migraine usually progresses from mild to moderate and finally to severe pain. During the early headache phase, pain may be diffuse and nondescript. Migraineurs may feel discomfort in their neck or face, which signals the disinhibition of the trigeminal system. Associated symptoms have not yet fully developed during the mild headache phase. Ideally, acute therapy should be initiated when the headache is mild, rather than waiting until neurovascular inflammation is full-blown and the pain is moderate to severe. Therefore, appropriate patients should be informed that use of symptomatic medication early in the course of their headache makes the medication more efficacious and headache recurrence less likely.

As the headache phase reaches its full potential and the pain becomes severe, patients may develop cutaneous allodynia, a painful response to a nonpainful stimulus. Just rubbing one's head or combing one's hair can be painful. The chest, extremities, and back may become tender. The presence of cutaneous allodynia is suggestive of central sensitization, in which central neurons are recruited to produce and transmit more pain sensations. Treating the migraine attack within 30 to 60 minutes of headache onset generally will limit the severity of the allodynia.

Patients may experience more sustained pain, vertigo, and increased sensitivity to common migraine triggers. The goal of acute therapy should be to prevent this stage of migraine because the triptans are considerably less effective when administered after the CNS is sensitized. Acute management of migraine at this phase may require the use of rescue medications and result in headache recurrence.

Resolution. The body returns to normal homeostasis through medications, sleep, or, rarely, vomiting. The exact mechanism of terminating the headache phase remains unknown. Restoration of normal serotonin metabolism probably plays a pivotal role in ending the migraine process.

Postdrome. After the headache pain has resolved, many patients experience a postdrome. Although pain-free, patients may experience a "migraine hangover," characterized by cognitive difficulty, dizziness, and concern that the headache may recur. Patients feel that they are "walking on eggshells" during their postdrome, which may last 24 to 48 hours.

Next month: Treatment of migraine headaches.
 

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