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Authors : Peter J. Goadsby, M.D., D.Sc., Richard B. Lipton, M.D., and Michel D. Ferrari, M.D., Ph.D.


Migraine is a common, chronic, incapacitating neurovascular disorder, characterized by attacks of severe headache, autonomic nervous system dysfunction, and in some patients, an aura involving neurologic symptoms.Recent advances in basic and applied clinical neuroscience have led to the development of a new class of selective serotonin (5-hydroxytryptamine [5-HT]) receptor agonists that activate 5-HT1B and 5-HT1D (5-HT1B/1D) receptors and are known as the triptans; these agents have changed the lives of countless patients with migraine. Despite such progress, migraine remains underdiagnosed and the available therapies underused.In this article, we review the current understanding of the epidemiology, pathophysiology, and treatment of migraine.

Clinical Manifestations

Migraine is characterized by episodes of head pain that is often throbbing and frequently unilateral and may be severe. In migraine without aura (previously known as common migraine), attacks are usually associated with nausea, vomiting, or sensitivity to light, sound, or movement.When untreated, these attacks typically last 4 to 72 hours.A combination of features is required for the diagnosis, but not all features are present in every attack or in every patient
These symptoms distinguish migraine from tension-type headache, the most common form of primary headache, which is characterized by the lack of associated features. Any severe and recurrent headache is most likely to be a form of migraine and to be responsive to antimigraine therapy. In 15 percent of patients, migraine attacks are usually preceded or accompanied by transient focal neurologic symptoms, which are usually visual; such patients have migraine with aura (previously known as classic migraine). In a recent large, population-based study, 64 percent of patients with migraine had only migraine without aura, 18 percent had only migraine with aura, and 13 percent had both types of migraine (the remaining 5 percent had aura without headache). Thus, up to 31 percent of patients with migraine have aura on some occasions,but clinicians who rely on the presence of aura for the diagnosis of migraine will miss many cases.

We find it useful to assess the severity and effects of migraine by asking about time lost because of migraine at work or school, in performing household work or chores, or in family, social, and leisure activities. One can ask patients directly about temporary disability, have them keep a diary, or get a quick but accurate estimate with the use of the Migraine Disability Assessment Scale (MIDAS), a well-validated five-item questionnaire that is easy to use in practice.

Although attacks of migraine may start at any age, the incidence peaks in early to mid-adolescence. In the United States and Western Europe, the one-year prevalence of migraine is 11 percent overall: 6 percent among men and 15 to 18 percent among women. The median frequency of attacks is 1.5 per month, and the median duration of an attack is 24 hours; at least 10 percent of patients have weekly attacks, and 20 percent have attacks lasting two to three days.12 Thus, 5 percent of the general population have at least 18 days of migraine per year, and at least 1 percent — that is, more than 2.5 million persons in North America — have at least 1 day of migraine per week. The lifetime prevalence of migraine is at least 18 percent,13 although among older subjects the figures are deflated by recall bias. In the United States, most patients with migraine have not seen a physician for headache during the previous year, have never received a medical diagnosis of migraine, and use over-the-counter medications to the exclusion of prescription drugs. A recent survey by the World Health Organization (WHO) rates severe migraine, along with quadriplegia, psychosis, and dementia, as one of the most disabling chronic disorders.This ranking suggests that in the judgment of the WHO, a day with severe migraine is as disabling as a day with quadriplegia.

Pathophysiology

Migraine is best understood as a primary disorder of the brain.It is a form of neurovascular headache: a disorder in which neural events result in the dilation of blood vessels, which, in turn, results in pain and further nerve activation.Migraine is not caused by a primary vascular event. Migraine attacks are episodic and vary within and among patients. We may best explain this variability by considering the basic biologic problem in migraine to be the dysfunction of an ion channel in the aminergic brain-stem nuclei that normally modulates sensory input and exerts neural influences on cranial vessels.

In patients with familial hemiplegic migraine, missense mutations in the 1 subunit of the voltage-gated P/Q-type calcium channel have been identified. It is possible that other ion-channel mutations contribute to migraine without aura, since it is primarily cases of migraine with aura that have been linked to the familial-hemiplegic-migraine locus. It thus seems possible that the aura of migraine is separate from the headache, with aura susceptibility genes as its determinant; the pain and associated features of migraine itself may be determined by another gene or genes.

Migraine and the Brain

As noted above, migraine probably results from a dysfunction of brain-stem or diencephalic nuclei that are involved in the sensory — particularly nociceptive — modulation of craniovascular afferents. Activation in the brain stem during attacks of migraine has been detected with the use of positron-emission tomography. Moreover, the aura of migraine is likely to be the human counterpart of the animal phenomenon of Leão's spreading depression.Aura is characterized by a wave of oligemia that passes across the cortex at the characteristically slow rate of 2 to 6 mm per minute. A short phase of hyperemia precedes this oligemia and is likely to be a correlate of such symptoms as flashing, jagged lights. Oligemia is a response to depressed neuronal function and is still clearly present when the headache starts.These findings, together with direct evidence that the local oxygen supply is more than adequate, make the notion that migraine is simply a vascular headache untenable

Pain Mechanisms

We do not completely understand the pathogenesis of pain in migraine, but three key factors merit consideration: the cranial blood vessels, the trigeminal innervation of the vessels, and the reflex connections of the trigeminal system with the cranial parasympathetic outflow. The substance of the brain is largely insensate; pain can be generated by large cranial vessels,35 proximal intracranial vessels,or by the dura mater.These vessels are innervated by branches of the ophthalmic division of the trigeminal nerve,whereas the structures of the posterior fossa are innervated by branches of the C2 nerve roots.

In nonhuman primates, stimulation of vascular afferents leads to the activation of neurons in the superficial layers of the trigeminal nucleus caudalis in the region of the cervicomedullary junction and the superficial layers of the dorsal horns of the C1 and C2 levels of the spinal cord — the trigeminocervical complex. Similarly, stimulation of branches of C2 activates neurons in the same regions of the brain.The involvement of the ophthalmic division of the trigeminal nerve and the overlap with structures innervated by C2 explain the common distribution of migraine pain over the frontal and temporal regions, as well as the involvement of parietal, occipital, and high cervical regions by what is, in essence, referred pain.

Peripheral trigeminal activation in migraine is evidenced by the release of calcitonin-gene–related peptide, a vasodilator,but the mechanism of the generation of pain is not clear. Studies in animals suggest that the pain may be caused by a sterile neurogenic inflammatory process in the dura mater,but this mechanism has no clearly demonstrated correlate in humans.The pain may be a combination of an altered perception — as a result of peripheral or central sensitization — of craniovascular input that is not usually painful34 and the activation of a feed-forward neurovascular dilator mechanism that is functionally specific for the first (ophthalmic) division of the trigeminal nerve.

Drug Therapy

Approaches to treating migraine can be divided into nonpharmacologic therapies and pharmacologic therapies. Nonpharmacologic therapies include education of the patient about the disorder, its mechanisms, approaches to treatment, and changes in lifestyle involved in the avoidance of triggers of migraine. In patients with migraine, the brain does not seem to tolerate the peaks and troughs of life well. Thus, regular sleep, regular meals, exercise, avoidance of peaks of stress and troughs of relaxation, and avoidance of dietary triggers can be helpful. The crucial message is that the patient should aim for a certain regularity of habits, rather than adhere to a long list of prohibitions of foods and activities. What cannot be known is the sensitivity of the brain to such triggers at any given time. This uncertainty leaves many patients frustrated by the fact that the same manipulations intended to avoid triggering migraine will lead to different outcomes on different days. It can be helpful to explain the nature of this variability to patients. An evidence-based review of nonpharmacologic approaches to treatment of migraine was recently published.

Drugs for the treatment of migraine can be divided into drugs that are taken daily whether or not headache is present to reduce the frequency and severity of attacks and drugs that are taken to treat attacks as they arise. Treatments for attacks can be further divided into nonspecific and migraine-specific treatments. Nonspecific treatments, such as aspirin, acetaminophen, nonsteroidal antiinflammatory drugs, opiates, and combination analgesics, are used to treat a wide range of pain disorders. Specific treatments,7 including ergotamine, dihydroergotamine, and the triptans, are effective for treating neurovascular headaches, such as migraine and cluster headache, but not for treating other types of pain, such as pure tension-type headache or atypical facial pain.Given that there are responses to placebo in patients with migraine,that there is a significant rate of nonresponse to oral drugs, and that triptans have not been studied systematically in patients with such problems as subarachnoid hemorrhage or meningitis, triptans should not be used as diagnostic testing agents in patients with headache.

Preventive Therapy

The decision to start a preventive therapy in a patient with migraine is best made collaboratively. On the basis of a combination of the frequency, duration, severity, and tractability of acute attacks, as well as the preference of the patient, a sensible selection can be made. Patients who have attacks that are unresponsive to acute-attack medications and that cause substantial disability are candidates for preventive therapy. If attacks occur at least twice a month, if the patient may be at risk for rebound headache, or if the migraine diary kept by the patient reveals a clear trend toward an increasing frequency of attacks, it is probably better to consider prevention than to wait for the problem to become more troublesome. It is not clear how preventive therapy works, although it seems likely that it modifies the sensitivity of the brain that underlies migraine.

In general, if headaches occur one to two days per month, there is usually no need for preventive therapy; if they occur three to four days per month, preventive therapy should be considered; if the patient has five or more attacks per month, preventive therapy should be considered seriously.And the evidence regarding their use has been extensively reviewed.Often, the doses required to reduce the frequency of headache cause marked and intolerable side effects. Each drug should be started at a low dose, and the dose should be gradually increased to a reasonable maximum; patients should be reminded that this approach often entails some delay in achieving efficacy.