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Migraine is a complex disorder characterized by recurrent episodes of headache, most often unilateral and in some cases associated with

visual or sensory symptoms collectively known as an aurathat arise most often before the head pain but that may occur during or afterward. Migraine is most common in women and has a strong genetic component.

Essential update: New transdermal triptan patch for migraine approved


A transdermal patch for migraine, sumatriptan iontophoretic transdermal system (Zecuity, NuPathe Inc), was approved by the FDA in January 2013 for the acute treatment of migraine with or without aura in adults. The single-use patch also treats migraine-related nausea. In phase 3 trials involving 800 patients, the patches safely and effectively relieved migraine pain, migraine-related nausea, sonophobia, and photophobia within 2 hours of activation.[1]

Signs and symptoms


Typical symptoms of migraine include the following: Throbbing or pulsatile headache, with moderate to severe pain that intensifies with movement or physical activity Unilateral and localized pain in the frontotemporal and ocular area, but the pain may be felt anywhere around the head or neck Pain builds up over a period of 1-2 hours, progressing posteriorly and becoming diffuse Headache lasts 4-72 hours Nausea (80%) and vomiting (50%), including anorexia and food intolerance, and light-headedness Sensitivity to light and sound Features of migraine aura are as follows: May precede or accompany the headache phase or may occur in isolation Usually develops over 5-20 minutes and lasts less than 60 minutes Most commonly visual but can be sensory, motor, or any combination of these Visual symptoms may be positive or negative The most common positive visual phenomenon is the scintillating scotoma, an arc or band of absent vision with a shimmering or glittering zigzag border Physical findings during a migraine headache may include the following: Cranial/cervical muscle tenderness Horner syndrome (ie, relative miosis with 1-2 mm of ptosis on the same side as the headache) Conjunctival injection Tachycardia or bradycardia Hypertension or hypotension Hemisensory or hemiparetic neurologic deficits (ie, complicated migraine) Adie-type pupil (ie, poor light reactivity, with near dissociation from light) See Clinical Presentation for more detail.

Diagnosis
The diagnosis of migraine is based on patient history. International Headache Society diagnostic criteria are that patients must have had at least 5 headache attacks that lasted 4-72 hours (untreated or unsuccessfully treated) and that the headache must have had at least 2 of the following characteristics [2] : Unilateral location Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) In addition, during the headache the patient must have had at least 1 of the following: Nausea and/or vomiting

Photophobia and phonophobia Finally, these features must not have been attributable to another disorder. Classification of migraine is as follows: Migraine without aura (formerly, common migraine) Probable migraine without aura Migraine with aura (formerly, classic migraine) Probable migraine with aura Chronic migraine Chronic migraine associated with analgesic overuse Childhood periodic syndromes that may not be precursors to or associated with migraine Complications of migraine Migrainous disorder not fulfilling above criteria Migraine variants include the following: Childhood periodic syndromes Late-life migrainous accompaniments Basilar-type migraine Hemiplegic migraine Status migrainosus Ophthalmoplegic migraine Retinal migraine A migraine variant may be suggested by focal neurologic findings, such as the following, that occur with the headache and persist temporarily after the pain resolves: Unilateral paralysis or weakness - Hemiplegic migraine Aphasia, syncope, and balance problems - Basilar-type migraine Third nerve palsy with ocular muscle paralysis and ptosis, including or sparing the pupillary response Ophthalmoplegic migraine Testing and imaging studies Selection of laboratory and/or imaging studies to rule out conditions other than migraine headache is determined by the individual presentation (eg, erythrocyte sedimentation rate and C-reactive protein levels may be appropriate to exclude temporal/giant cell arteritis). Neuroimaging is not necessary in patients with a history of recurrent migraine headaches and a normal neurologic examination. See Workup for more detail.

Management
Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie, for alleviating the acute phase) or prophylactic (ie, preventive). Acute/abortive medications Acute treatment aims to reverse, or at least stop the progression of, a headache. It is most effective when given within 15 minutes of pain onset and when pain is mild.[3] Abortive medications include the following: Selective serotonin receptor (5-hydroxytryptamine1, or 5-HT1) agonists (triptans) Ergot alkaloids (eg, ergotamine, dihydroergotamine [DHE]) Analgesics Nonsteroidal anti-inflammatory drugs (NSAIDs) Combination products Antiemetics Preventive/prophylactic medications

The following may be considered indications for prophylactic migraine therapy: Frequency of migraine attacks is greater than 2 per month Duration of individual attacks is longer than 24 hours The headaches cause major disruptions in the patient's lifestyle, with significant disability that lasts 3 or more days Abortive therapy fails or is overused Symptomatic medications are contraindicated or ineffective Use of abortive medications more than twice a week Migraine variants such as hemiplegic migraine or rare headache attacks producing profound disruption or risk of permanent neurologic injury[4] Prophylactic medications include the following: Antiepileptic drugs Beta blockers Tricyclic antidepressants Calcium channel blockers Selective serotonin reuptake inhibitors (SSRIs) NSAIDs Serotonin antagonists Botulinum toxin Other measures Treatment of migraine may also include the following: Reduction of migraine triggers (eg, lack of sleep, fatigue, stress, certain foods) Nonpharmacologic therapy (eg, biofeedback, cognitive-behavioral therapy) Integrative medicine (eg, butterbur, riboflavin, magnesium, feverfew, coenzyme Q10) See Treatment and Medication for more detail.

Image library

Migraine headache. Example of a visual migraine aura as described by a person who experiences migraines. This patient reported that these visual auras preceded her headache by 20-30 minutes.

BACKGROUND

Migraine headache is a complex, recurrent headache disorder that is one of the most common complaints in medicine. In the United States, more than 30 million people have 1 or more migraine headaches per year. Approximately 75% of all persons who experience migraines are women (see Epidemiology). The term migraine is derived from the Greek word hemikrania. This term was corrupted into low Latin as hemigranea, the French translation of which was migraine.

Causes of migraine
Migraine was previously considered to be a vascular phenomenon that resulted from intracranial vasoconstriction followed by rebound vasodilation. Currently, however, the neurovascular theory describes migraine as primarily a neurogenic process with secondary changes in cerebral perfusion associated with a sterile neurogenic inflammation (see Pathophysiology). A genetic component to migraine is indicated by the fact that approximately 70% of patients have a firstdegree relative with a history of migraine. In addition, a variety of environmental and behavioral factors may precipitate migraine attacks in persons with a predisposition to migraine (see Etiology).

Migraine characteristics and treatment


Migraine is characterized most often by unilateral head pain that is moderate to severe, throbbing, and aggravated by activity. It may also be associated with various visual or sensory symptoms, which occur most often before the headache component but which may occur during or after the headache; these are collectively known as an aura. Most commonly, the aura consists of visual manifestations, such as scotomas, photophobia, or visual scintillations (eg, bright zigzag lines) (see Presentation). The head pain may also be associated with weakness. This form of migraine is termed hemiplegic migraine. In practice, however, migraine headaches may be unilateral or bilateral and may occur with or without an aura. In the current International Headache Society categorization, the headache previously described as classic migraine is now known as migraine with aura, and the headache that was described as common migraine is now termed migraine without aura. Migraines without aura are the most common, accounting for more than 80% of all migraines. The diagnosis of migraine is clinical in nature, based on criteria established by the International Headache Society. A full neurologic examination should be performed during the first visit, to exclude other disorders; the findings are usually normal in patients with migraine. Neuroimaging is not necessary in a typical case, but other diagnostic investigations may be indicated to guide management (see Workup). Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable. Acute treatment aims to eliminate, or at least prevent the progression of, a headache. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of migraine attacks, to make acute attacks more responsive to abortive therapy, and perhaps also to improve the patient's quality of life (see Treatment). See Migraine in Children for a pediatric perspective on migraine. Also see Migraine Variants and Childhood Migraine Variants.

Migraine classification
The second edition of the International Classification of Headache Disorders (ICHD)[5] lists the following types of migraine: Migraine without aura (formerly, common migraine) Probable migraine without aura Migraine with aura (formerly, classic migraine) Probable migraine with aura Chronic migraine Chronic migraine associated with analgesic overuse Childhood periodic syndromes that may not be precursors to or associated with migraine

Complications of migraine Migrainous disorder not fulfilling above criteria

Diagnostic criteria
According to the International Headache Society, the diagnosis of migraine requires that the patient has experienced at least 5 attacks that fulfill the following 3 criteria and that are not attributable to another disorder.[2] First, the headache attacks must have lasted 4-72 hours (untreated or unsuccessfully treated). Second, the headache must have had at least 2 of the following characteristics: Unilateral location Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) Third, during the headache the patient experiences at least 1 of the following: Nausea and/or vomiting Photophobia and phonophobia

Migraine guidelines
In April 2000, the US Headache Consortium, a multispecialty group that includes the American College of Emergency Physicians, released evidence-based guidelines for the diagnosis, treatment, and prevention of migraine headaches. Guidelines are also available from the American Academy of Neurology, the National Headache Foundation, and the Canadian Association of Emergency Physicians. [3, 6, 7]

PATHOPHYSIOLOGY
The mechanisms of migraine remain incompletely understood. However, new technologies have allowed formulation of current concepts that may explain parts of the migraine syndrome.

Vascular theory
In the 1940s and 1950s, the vascular theory was proposed to explain the pathophysiology of migraine headache. Wolff et al believed that ischemia induced by intracranial vasoconstriction is responsible for the aura of migraine and that the subsequent rebound vasodilation and activation of perivascular nociceptive nerves resulted in headache. This theory was based on the following 3 observations: Extracranial vessels become distended and pulsatile during a migraine attack Stimulation of intracranial vessels in an awake person induces headache Vasoconstrictors (eg, ergots) improve the headache, whereas vasodilators (eg, nitroglycerin) provoke an attack However, this theory did not explain the prodrome and associated features. Nor did it explain the efficacy of some drugs used to treat migraines that have no effect on blood vessels and the fact that most patients do not have an aura. Moreover, with the advent of newer imaging technologies, researchers found that intracranial blood flow patterns were inconsistent with the vascular theory. No consistent flow changes have been identified in patients suffering from migraine headache without aura. Regional cerebral blood flow (rCBF) remains normal in the majority of patients. However, bilateral decrease in rCBF, beginning at the occipital cortex and spreading anteriorly, has been reported. More recently, Perciaccante has shown that migraine is characterized by a cardiac autonomic dysfunction. [8] As a result of these anomalous findings, the vascular theory was supplanted by the neurovascular theory.

Neurovascular theory

The neurovascular theory holds that a complex series of neural and vascular events initiates migraine.[9] According to this theory, migraine is primarily a neurogenic process with secondary changes in cerebral perfusion.[10] At baseline, a migraineur who is not having any headache has a state of neuronal hyperexcitability in the cerebral cortex, especially in the occipital cortex.[11] This finding has been demonstrated in studies of transcranial magnetic stimulation and with functional magnetic resonance imaging (MRI). This observation explains the special susceptibility of the migrainous brain to headaches. [12] One can draw a parallel with the patient with epilepsy who similarly has interictal neuronal irritability.

Cortical spreading depression


In 1944, Leao proposed the theory of cortical spreading depression (CSD) to explain the mechanism of migraine with aura. CSD is a well-defined wave of neuronal excitation in the cortical gray matter that spreads from its site of origin at the rate of 2-6 mm/min. This cellular depolarization causes the primary cortical phenomenon or aura phase; in turn, it activates trigeminal fibers, causing the headache phase. The neurochemical basis of the CSD is the release of potassium or the excitatory amino acid glutamate from neural tissue. This release depolarizes the adjacent tissue, which, in turn, releases more neurotransmitters, propagating the spreading depression. Oligemia Positron emission tomography (PET) scanning demonstrates that blood flow is moderately reduced during a migrainous aura, but the spreading oligemia does not correspond to vascular territories. The oligemia itself is insufficient to impair function. Instead, the flow is reduced because the spreading depression reduces metabolism. Although CSD is the disturbance that presumably results in the clinical manifestation of migraine aura, this spreading oligemia can be clinically silent (ie, migraine without aura). Perhaps a certain threshold is required to produce symptoms in patients having aura but not in those without aura. A study of the novel agent tonabersat, which inhibits CSD, found that the agent helped to prevent migraine attacks with aura only, suggesting that CSD may but not be involved in attacks without aura.[13] Trigeminovascular system Activation of the trigeminovascular system by CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and pain-generating substances such as calcitonin gene-related peptide, substance P, vasoactive intestinal peptide, and neurokinin A. The resultant state of sterile inflammation is accompanied by further vasodilation, producing pain. The initial cortical hyperperfusion in CSD is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. According to Moulton et al, altered descending modulation in the brainstem has been postulated to contribute to the headache phase of migraine; this leads to loss of inhibition or enhanced facilitation, resulting in trigeminovascular neuron hyperexcitability.[14] Metalloproteinases In addition, through a variety of molecular mechanisms, CSD upregulates genes, such as those encoding for cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, galanin, and metalloproteinases. The activation of metalloproteinases leads to leakage of the blood-brain barrier, allowing potassium, nitric oxide, adenosine, and other products released by CSD to reach and sensitize the dural perivascular trigeminal afferent endings.[15] Increased net activity of matrix metalloproteinase2 (MMP-2) has been demonstrated in migraineurs. Patients who have migraine without aura seem to have an increased ratio of matrix metalloproteinase 9

(MMP-9) to tissue inhibitors of metalloproteinase1 (TIMP-1), in contrast to a lower MMP-9/TIMP-1 ratio in patients who have migraine with aura.[16] Measured levels of MMP-9 alone are the same for migraine patients with or without aura.[17] . Hypoxia In an experimental study, acute hypoxia was induced by a single episode of CSD. This was accompanied by dramatic failure of brain ion homeostasis and prolonged impairment of neurovascular and neurometabolic coupling.[18]

Vasoactive substances and neurotransmitters


Perivascular nerve activity also results in release of substances such as substance P, neurokinin A, calcitonin gene-related peptide, and nitric oxide, which interact with the blood vessel wall to produce dilation, protein extravasation, and sterile inflammation. This stimulates the trigeminocervical complex, as shown by induction of c-fos antigen by PET scan. Information then is relayed to the thalamus and cortex for registering of pain. Involvement of other centers may explain the associated autonomic symptoms and affective aspects of this pain. Neurogenically induced plasma extravasation may play a role in the expression of pain in migraine, but it may not be sufficient by itself to cause pain. The presence of other stimulators may be required. Although some drugs that are effective for migraine inhibit neurogenic plasma extravasation, substance P antagonists and the endothelin antagonist bosentan inhibit neurogenic plasma extravasation but are ineffective as antimigraine drugs. Also, the pain process requires not only the activation of nociceptors of pain-producing intracranial structures but also reduction in the normal functioning of endogenous paincontrol pathways that gate the pain.

Migraine center
A potential "migraine center" in the brainstem has been proposed, based on PET-scan results showing persistently elevated rCBF in the brainstem (ie, periaqueductal gray, midbrain reticular formation, locus ceruleus) even after sumatriptan-produced resolution of headache and related symptoms. These were the findings in 9 patients who had experienced spontaneous attack of migraine without aura. The increased rCBF was not observed outside of the attack, suggesting that this activation was not due to pain perception or increased activity of the endogenous antinociceptive system. The fact that sumatriptan reversed the concomitant increased rCBF in the cerebral cortex but not the brainstem centers suggests dysfunction in the regulation involved in antinociception and vascular control of these centers. Thalamic processing of pain is known to be gated by ascending serotonergic fibers from the dorsal raphe nucleus and from aminergic nuclei in the pontine tegmentum and locus ceruleus; the latter can alter brain flow and blood-brain barrier permeability. Because of the set periodicity of migraine, linkage to the suprachiasmatic nucleus of the hypothalamus that governs circadian rhythm has been proposed. Discovering the central trigger for migraine would help to identify better prophylactic agents.

Brainstem activation
PET scanning in patients having an acute migraine headache demonstrates activation of the contralateral pons, even after medications abort the pain. Weiler et al proposed that brainstem activation may be the initiating factor of migraine. Once the CSD occurs on the surface of the brain, H+ and K+ ions diffuse to the pia mater and activate Cfiber meningeal nociceptors, releasing a proinflammatory soup of neurochemicals (eg, calcitonin gene related peptide) and causing plasma extravasation to occur. Therefore, a sterile, neurogenic inflammation of the trigeminovascular complex is present.

Once the trigeminal system is activated, it stimulates the cranial vessels to dilate. The final common pathway to the throbbing headache is the dilatation of blood vessels.

Cutaneous allodynia
Burstein et al described the phenomenon of cutaneous allodynia, in which secondary pain pathways of the trigeminothalamic system become sensitized during a migrainous episode.[19] This observation demonstrates that, along with the previously described neurovascular events, sensitization of central pathways in the brain mediates the pain of migraine.

Dopamine pathway
Some authors have proposed a dopaminergic basis for migraine.[20] In 1977, Sicuteri postulated that a state of dopaminergic hypersensitivity is present in patients with migraine. Interest in this theory has recently been renewed. Some of the symptoms associated with migraine headaches, such as nausea, vomiting, yawning, irritability, hypotension, and hyperactivity, can be attributed to relative dopaminergic stimulation. Dopamine receptor hypersensitivity has been shown experimentally with dopamine agonists (eg, apomorphine). Dopamine antagonists (eg, prochlorperazine) completely relieve almost 75% of acute migraine attacks.

Magnesium deficiency
Another theory proposes that deficiency of magnesium in the brain triggers a chain of events, starting with platelet aggregation and glutamate release and finally resulting in the release of 5-hydroxytryptamine, which is a vasoconstrictor. In clinical studies, oral magnesium has shown benefit for preventive treatment and intravenous magnesium may be effective for acute treatment, particularly in certain subsets of migraine patients.[21]

Endothelial dysfunction
Vascular smooth muscle cell dysfunction may involve impaired cyclic guanosine monophosphate and hemodynamic response to nitric oxide.[22] Nitric oxide released by microglia is a potentially cytotoxic proinflammatory mediator, initiating and maintaining brain inflammation through activation of the trigeminal neuron system. Nitric oxide levels continue to be increased even in the headache-free period in migraineurs.[23] In premenopausal women with migraine, particularly in those with migraine aura, increased endothelial activation, which is a component of endothelial dysfunction, is evident. [24]

Serotonin and migraine


The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important receptor in the headache pathway. Immunohistochemical studies have detected 5-hydroxytryptamine1D (5-HT1D) receptors in trigeminal sensory neurons, including peripheral projections to the dura and within the trigeminal nucleus caudalis (TNC) and solitary tract, while 5-HT1B receptors are present on smooth muscle cells in meningeal vessels; however, both can be found in both tissues to some extent and even in coronary vessels. All the currently available triptans (see Medication) are selective 5-HT1B/D full agonists. These agents may decrease headache by abolishing neuropeptide release in the periphery and blocking neurotransmission by acting on second-order neurons in the trigeminocervical complex.

Migraine risk factors


Predisposing vascular risk factors for migraine include the following[25] : Increased levels of C-reactive protein

Increased levels of interleukins Increased levels of TNF-alpha and adhesion molecules (systemic inflammation markers) Oxidative stress and thrombosis Increased body weight High blood pressure Hypercholesterolemia Impaired insulin sensitivity High homocysteine levels Stroke Coronary heart disease

Transformed migraine/medication overuse headache


In some patients, migraine progresses to chronic migraine. Acute overuse of symptomatic medication is considered one of the most important risk factors for migraine progression. Medication overuse headache can occur with any analgesic, including acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin. In addition, Bigal and Lipton identified the following associations of medication with progression to chronic migraine[26] : Opiates - Critical dose of exposure is around 8 days per month; the effect is more pronounced in men Barbiturates - Critical dose of exposure is around 5 days per month; the effect is more pronounced in women Triptans - Migraine progression is seen only in patients with high frequency of migraine at baseline (1014 days/mo) In the study, the effect of anti-inflammatory medications varied with headache frequency. These agents were protective in patients with fewer than 10 days of headache at baseline but induced migraine progression in patients with a high frequency of headaches at baseline. [26]

ETIOLOGY

Migraine has a strong genetic component. Approximately 70% of migraine patients have a first-degree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of people who have migraine with aura.[27] Nonsyndromic migraine headache with or without aura generally shows a multifactorial inheritance pattern, but the specific nature of the genetic influence is not yet completely understood. Certain rarer syndromes with migraine as a clinical feature generally show an autosomal dominant inheritance pattern.[28] However, recent genome-wide association studies have suggested 4 regions in which single-nucleotide polymorphisms influence the risk of developing migraine headache.[29, 30, 31] Other associations have been found in individual studies but could not be replicated in other populations.

Familial hemiplegic migraine


Familial hemiplegic migraine (FHM) is a rare type of migraine with aura that is preceded or followed by hemiplegia, which typically resolves. FHM may be associated with cerebellar ataxia, which is also linked to the 19p locus. Evidence suggests that the 19p locus for FHM may also be involved in patients with other forms of migraine. Three genes have thus far been identified as being causative for FHM. FHM type 1 is characterized clinically by episodes that commonly include nystagmus and cerebellar signs. This disorder is caused by mutations in theCACNA1A gene located on 19p13, which codes for a brain-specific calcium channel. Mutations in CACNA1A were previously thought to account for 50% of

cases of FHM,[32] but a Danish study showed that only 7% of patients with a clinical diagnosis of FHM had a mutation in that gene.[33] FHM type 2 occurs in patients who also have a seizure disorder. This condition has been attributed to mutations in the ATP1A2 gene, located on 1q21q23, which encodes a sodium/potassium pump. [34, 35] However, the Danish study found mutations in ATP1A2 in only 7% of patients with a clinical diagnosis of FHM.[33] FHM type 3 is caused by mutations in the SCN1A gene, located on 2q24. Mutations in SCN1A are also known to cause familial febrile seizure disorders and infantile epileptic encephalopathy.[36] Although SCN1A mutation has been reported in several unrelated families, it is felt to be a rare cause of FHM.[37]

Migraine in other inherited disorders


Migraine occurs with increased frequency in patients with mitochondrial disorders, such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a genetic disorder that causes migraine with aura, strokes before the age of 60, progressive cognitive dysfunction, and behavioral changes. CADASIL is inherited in an autosomal dominant fashion, and most patients with the disorder have an affected parent. Approximately 90% of cases result from mutations of the <inotch3< i="">gene, located on chromosome 19. Patients with CADASIL have significant morbidity from their ailment, and life expectancy is approximately 68 years.[38]</inotch3<> Migraine is also a common symptom in other genetic vasculopathies, including 2 autosomal dominant disorders: (1) RVCL (retinal vasculopathy with cerebral leukodystrophy), which is caused by mutations in the TREX1 gene,[39] and (2) HIHRATL (hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy), which is suggested to be caused by mutations in the COL4A1 gene.[40] The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear. [41]

Migraine precipitants
Various precipitants of migraine events have been identified, as follows: Hormonal changes, such as those accompanying menstruation (common), [42] pregnancy, and ovulation Stress Excessive or insufficient sleep Medications (eg, vasodilators, oral contraceptives [43] ) Smoking Exposure to bright or fluorescent lighting Strong odors (eg, perfumes, colognes, petroleum distillates) Head trauma Weather changes Motion sickness Cold stimulus (eg, ice cream headaches) Lack of exercise Fasting or skipping meals Red wine Certain foods and food additives have been suggested as potential precipitants of migraine, including the following: Caffeine Artificial sweeteners (eg, aspartame, saccharin) Monosodium glutamate (MSG) Citrus fruits

Foods containing tyramine (eg, aged cheese) Meats with nitrites However, large epidemiologic studies have failed to substantiate most of these as triggers, [44] and no diets have been shown to help migraine. Nevertheless, patients who identify particular foods as triggers should avoid these foods. Although chocolate has been considered a migraine trigger, data from the PAMINA study do not support this contention.[44] Instead, it has been hypothesized that ingestion of chocolate may be in response to a craving brought on at the start of a migraine, as a result of hypothalamic activation.

Migraine and other vascular disease


People who suffer from migraine headaches are more likely to also have cardiovascular or cerebrovascular disease (ie, stroke, myocardial infarction).[45]Reliable evidence comes from the Women's Health Study, which found that migraine with aura raised the risk of myocardial infarction by 91% and ischemic stroke by 108% and that migraine without aura raised both risks by approximately 25%.[46] Migraines during pregnancy are also linked to stroke and vascular diseases. [47] Migraine with aura for women in midlife has a statistically significant association with late-life vascular disease (infarcts) in the cerebellum. This association is not seen in migraine without aura. [48]

Migraine and iron


In a population-based MRI study by Kruit et al, migraineurs had increased local iron deposits in the putamen, globus pallidus, and red nucleus, compared with controls. [49] This increase in iron deposits may be explained as a physiologic response induced by repeated activation of nuclei involved in central pain processing or by damage to these structures secondary to the formation of free radicals in oxidative stress (possibly the cause of the disease becoming chronic). [50]

Migraine and sensory perception


In a study by Nguyen et al, quantitative sensory testing found significant differences in the perception of vibrotactile stimulation in patients with migraine compared with controls, including stimulus amplitude discrimination, temporal order judgment, and duration discrimination.[51] In the United States, more than 30 million people have 1 or more migraine headaches per year. This corresponds to approximately 18% of females and 6% of males.[52] Migraine accounts for 64% of severe headaches in females and 43% of severe headaches in males. Approximately 75% of all persons who experience migraines are women. Currently, 1 in 6 American women has migraine headaches. (The reported incidence of migraine in females of reproductive age has increased over the last 20 years, but this change probably reflects greater awareness of the condition.) The incidence of migraine with aura peaks in boys at around age 5 years and in girls at around age 12-13 years. The incidence of migraine without aura peaks in boys at age 10-11 years and in girls at age 14-17 years.[53] Before puberty, the prevalence and incidence of migraine are higher in boys than in girls. After age 12 years, the prevalence increases in males and females, reaching a peak at age 30-40 years. The femaleto-male ratio increases from 2.5:1 at puberty to 3.5:1 at age 40 years. Attacks usually decrease in severity and frequency after age 40 years, except for women in perimenopause. A study by Hsu et al suggests that women aged 40-50 years are also more susceptible to migrainous vertigo.[54] Onset of migraine after age 50 years is rare.

Race-related differences in prevalence


The prevalence of migraine appears to be lower among African Americans and Asian Americans than among whites. One study showed that among women, 20.4% of whites, 16.2% of African Americans, and 9.2% of Asian Americans met International Classification of Headache Disorders (ICHD) criteria for

migraine. Similarly, in males, 8.6% of whites, 7.2% of African Americans, and 4.8% of Asian Americans were considered to have migraine.

Economic impact of migraine


The economic cost resulting from migraine-related loss of productive time in the US workforce is more than $13 billion per year, most of which is in the form of reduced work productivity. In the American Migraine Study, more than 85% of women and 82% of men with severe migraine had some headacherelated disability. Migraineur men required 3.8 bed-rest days per year, whereas women required 5.6 bedrest days per year.[55]

International statistics
The World Health Organization (WHO) estimates the worldwide prevalence of current migraine to be 10% and the lifetime prevalence to be 14%. The adjusted prevalence of migraine is highest in North America, followed by South and Central America, Europe, Asia, and Africa.[21] Approximately 3000 migraine attacks per million persons worldwide occur every day. According to the WHO, migraine is 19th among all causes of years lived with disability. In the United States, migraine prevalence is inversely correlated with household income and level of education. Internationally, however, a relationship between migraine and socioeconomic status is not present.

Prognosis
Migraine is a chronic condition, but prolonged remissions are common. One study showed that among persons who had migraine during childhood, 62% were migraine free for more than 2 years during puberty and as young adults but that only 40% were still migraine free at age 30 years. [56] The severity and frequency of migraine attacks tend to diminish with increasing age. After 15 years of suffering migraines, approximately 30% of men and 40% of women no longer have migraine attacks.

Migraine and vascular disorders


Migraine and ischemic strokes reportedly occur in 1.4-3.3 per 100,000 population and account for 0.8% of total strokes. Milhaud et al showed that in young patients (< 45 y) with active migraine who had suffered ischemic stroke, risk factors such as patent foramen ovale, female gender, and oral contraceptive use were much more likely to be present; posterior circulation stroke was characteristic. Surprisingly, older patients characteristically lacked vascular risk factors (ie, previous hypertension, ischemic heart disease, cigarette smoking).[57] Even in patients older than 45 years, women with migraine are more likely to suffer from ischemic stroke. Migraineurs, male and female, have a 2.5-fold increased risk of subclinical cerebellar stroke and those with migraines with aura and increased headache frequency are at the highest risk.[58] Migraineurs also have a higher incidence of adverse cardiovascular profiles (including diabetes and hypertension), and they are more likely to be smokers, have a family history of early heart attacks, and have an unfavorable cholesterol profile. The odds of an elevated Framingham risk score of coronary artery disease are doubled with migraine with aura, and women who have migraine with aura are more likely to be using oral contraceptives.[59, 60] The Women's Health Study, which included professional women older than 45 years, showed that any history of migraine is associated with a higher incidence of major cardiovascular disease and that the highest risk is associated with migraine with aura, with a 2.3-fold risk of cardiovascular death and a 1.3fold risk of coronary vascularization.[61] However, those who have migraine without aura have the same risks as the general population.

These findings have been confirmed in a population-based study by Bigal et al.[62]Similarly, a study by Gudmundsson et al found that men and women who have migraine with aura are at a higher risk for cardiovascular and all-cause mortality than are those without headache.[63]

Patient Education
Patient education is key to successful long-term management. Migraine is a chronic neurologic disorder that requires a lifestyle change at some level. For patient education information, see the Headache and Migraine Center, as well as the following: Causes and Treatments of Migraine and Related Headaches Migraine Headache Alternative and Complementary Approaches to Migraine and Cluster Headaches Migraine Headache FAQs Migraine and Cluster Headache Medications

Migraine attacks commonly occur when the migraineur is awake, although an attack may have already started by the time the individual wakes. Less commonly, it may awaken the patient at night. The typical migraine headache is throbbing or pulsatile. However, more than 50% of people who suffer from migraines report nonthrobbing pain at some time during the attack. The headache is initially unilateral and localized in the frontotemporal and ocular area, but pain can be felt anywhere around the head or neck. The pain typically builds up over a period of 1-2 hours, progressing posteriorly and becoming diffuse. The headache typically lasts from 4-72 hours. Among females, more than two thirds of patients report attacks lasting longer than 24 hours. Pain intensity is moderate to severe and intensifies with movement or physical activity. Many patients prefer to lie quietly in a dark room. The pain usually subsides gradually within a day and after a period of sleep. Most patients report feeling tired and weak after the attack.

Other symptoms
Nausea and vomiting usually occur later in the attack in about 80% and 50% of patients, respectively, along with anorexia and food intolerance. Some patients have been noted to be pale and clammy, especially if nausea develops. Photophobia and/or phonophobia also commonly are associated with the headache. Lightheadedness is frequent. See Migraine-Associated Vertigo for more information on migraine-related vestibulopathy. Other neurologic symptoms that may be observed include the following: Hemiparesis (this symptom defines hemiplegic migraine) Aphasia Confusion Paresthesias or numbness

Prodrome
About 60% of people who experience migraines report premonitory symptoms that occur hours to days before headache onset. Although the prodromal features vary, they tend to be consistent for a given individual and may include the following: Heightened sensitivity to light, sound, and odors

Lethargy or uncontrollable yawning Food cravings Mental and mood changes (eg, depression, anger, euphoria) Excessive thirst and polyuria Fluid retention Anorexia Constipation or diarrhea These symptoms may be difficult to diagnose as part of the migraine complex if they occur in isolation from the headache or if they are mild. The prodrome of migraine has yet to receive significant investigational attention.

Aura
The migraine aura is a complex of neurologic symptoms that may precede or accompany the headache phase or may occur in isolation. It usually develops over 5-20 minutes and lasts less than 60 minutes. The aura can be visual, sensory, or motor or any combination of these. Visual symptoms Auras most commonly consist of visual symptoms, which may be negative or positive. Negative symptoms (see the images below) include negative scotomata or negative visual phenomena, such as the following: Homonymous hemianopic or quadrantic field defects Central scotomas Tunnel vision Altitudinal visual defects

Complete blindness

Migraine headache. Frank visual field loss can also occur associated with migraine. This example shows loss of the entire right visual field as described by a person who

experiences migraines. Migraine headache. Example of a central scotoma as described by a person who experiences migraines. Note the visual loss in the center of vision.

Migraine headache. Example of a central scotoma as described by a person who experiences migraine headaches. Again note the visual loss in the center of vision.

The most common positive visual phenomenon is the scintillating scotoma. This consists of an arc or band of absent vision with a shimmering or glittering zigzag border. The disturbance begins in the paracentral area, and gradually enlarges and moves across the hemifield, eventually breaking up and resolving. It is often combined with photopsias (uniform flashes of light) or visual hallucinations, which may take various shapes (see the images below).

Migraine headache. Example of a visual migraine aura as described by a person who experiences migraines. This patient reported that these visual auras preceded her headache by 20-30 minutes.

Migraine headache. Example of visual changes during migraine. Multiple spotty scotomata are described by a person who experiences migraines.

Scintillating scotoma occurs prior to the headache phase of an attack and is pathognomonic of a classic migraine. It is sometimes called a "fortification spectrum," because the serrated edges of the hallucinated "C" resemble a "fortified town with bastions around it." Heat waves, fractured vision, macropsia, micropsia, and achromatopsia are other visual symptoms that may occur. Sensory symptoms Paresthesias, occurring in 40% of cases, constitute the next most common aura; they are often cheirooral, with numbness starting in the hand, migrating to the arm, and then jumping to involve the face, lips, and tongue. As with visual auras, positive symptoms typically are followed by negative symptoms; paresthesias may be followed by numbness. Sensory aura rarely occurs in isolation and usually follows visual aura. The rate of spread of sensory aura is helpful in distinguishing it from transient ischemic attack (TIA) or a sensory seizure. Just as a visual aura spreads across the visual field slowly, paresthesias may take 10-20 minutes to spread, which is slower than the spread of sensory symptoms of TIA.

Motor symptoms Motor symptoms may occur in 18% of patients and usually are associated with sensory symptoms. Motor symptoms often are described as a sense of heaviness of the limbs before a headache but without any true weakness. Speech and language disturbances have been reported in 17-20% of patients. These disturbances are commonly associated with upper extremity heaviness or weakness. Course and diagnostic significance The migrainous aura generally resolves within a few minutes and then is followed by a latent period before the onset of headache. However, some patients report merging of the aura with the headache. Whether migraine with and without aura (prevalences, 36% and 55%, respectively) represent 2 distinct processes remains debatable; however, the similarities of the prodrome, headache, and resolution phases of the attacks, as well as the similarity in therapeutic response and the fact that 9% of patients experience both, suggest that they are the same entity. When an aura is not followed by a headache, it is called a migraine equivalent or acephalic migraine. This is reported most commonly in patients older than 40 years who have a history of recurrent headache. Scintillating scotoma has been considered to be diagnostic of migraine even in the absence of a headache; however, paresthesias, weakness, and other transient neurologic symptoms are not. In the absence of a prior history of recurrent headache and first occurrence after age 45 years, TIA should be considered and investigated fully.

Postdromal symptoms
Postdromal symptoms may persist for 24 hours after the headache and can include the following: Tired, washed out, or irritable feeling Unusually refreshed or euphoric feeling Muscle weakness or myalgias Anorexia or food cravings

Migraine triggers
A history of migraine triggers may be elicited. Common triggers include the following: Hormonal changes (eg, those resulting from menstruation, ovulation, oral contraceptives, or hormone replacement) Head trauma Lack of exercise[44] Sleep changes Medications (eg, nitroglycerin, histamine, reserpine, hydralazine, ranitidine, estrogen) Stress

Family history
Approximately 70% of patients have a first-degree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of people who have migraine with aura.[27] Migraine headache generally shows a multifactorial inheritance pattern, but the specific nature of the genetic influence is not yet completely understood.

Disability assessment
Simple questionnaires, such as the Migraine Disability Assessment Scale(MIDAS), can be used to quantify the extent of disability on the first visit. These questionnaires can also be used for follow-up evaluations.

Physical Examination
Although a thorough screening neurologic examination is essential, the results will be normal in most patients with headache. Evidence of autonomic nervous system involvement can be helpful, although most patients with migraine exhibit few or no findings. Serial neurologic examinations are recommended. Possible findings during a migraine include the following: Cranial/cervical muscle tenderness Horner syndrome (ie, relative miosis with 1-2 mm of ptosis on the same side as the headache) Conjunctival injection Tachycardia/bradycardia Hypertension/hypotension Hemisensory or hemiparetic neurologic deficits (ie, complicated migraine) Adie-type pupil (ie, poor light reactivity, with near dissociation to light) Pertinent physical examination findings that suggest a headache diagnosis other than migraine include the following: Dim scotoma lasting a few seconds to several minutes (ie, amaurosis) Temporal artery tenderness in the elderly Meningismus Increased lethargy (unrelated to medication use) Mental status changes Physical examination findings suggesting a more serious cause of headache include systemic symptoms (eg, myalgia, fever, malaise, weight loss, scalp tenderness, jaw claudication) and focal neurologic abnormalities or confusion, seizures, or any impairment of level of consciousness. On the other hand, focal neurologic findings that occur with the headache and persist temporarily after the pain resolves suggest a migraine variant, as follows: Unilateral paralysis or weakness - Hemiplegic migraine Aphasia, syncope, and balance problems - Basilar-type migraines Third nerve palsy, with ocular muscle paralysis and ptosis, including or sparing the pupillary response Ophthalmoplegic migraine Ophthalmic migraines cause a visual disturbance (usually lateral field deficit). This variant is more common in children, with the abnormal motor findings lasting hours to days after the headache.

Diagnostic Criteria
The diagnosis of migraine is based on the history. According to diagnostic criteria established by the International Headache Society, patients must have had at least 5 headache attacks that lasted 4-72 hours (untreated or unsuccessfully treated) and the headache must have had at least 2 of the following characteristics[2] : Unilateral location Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (eg, walking, climbing stairs) In addition, during the headache the patient must have had at least 1 of the following: Nausea and/or vomiting Photophobia and phonophobia Finally, these features must not be attributable to another disorder. (See the chart below.)

International Headache Society criteria for migraine without aura.

The International Headache Society defines aura as reversible focal neurologic symptoms that usually develop gradually over 5-20 minutes and last for less than 60 minutes. Headache with the features of migraine without aura usually follows the aura symptoms. Less commonly, the headache lacks migrainous features or is completely absent.

Migraine Variants
Migraine variants include the following: Childhood periodic syndromes Late-life migrainous accompaniments Basilar-type migraine Hemiplegic migraine Status migrainosus Ophthalmoplegic migraine Retinal migraine See the Medscape Reference article Childhood Migraine Variants for more information on these topics.

Childhood periodic syndromes


Childhood periodic syndromes evolve into migraine in adulthood. These syndromes include cyclic vomiting, abdominal migraine, and benign paroxysmal vertigo of childhood. In cyclic vomiting, the child has at least 5 attacks of intense nausea and vomiting ranging from 1 hour to 5 days. Abdominal migraine consists of episodic midline abdominal pain lasting 1-72 hours with at least 2 of 4 other symptoms (ie, nausea, vomiting, anorexia, and/or pallor). Benign paroxysmal vertigo of childhood involves recurrent attacks of vertigo, often associated with vomiting or nystagmus. See Migraine in Children for more information on these topics.

Late-life migrainous accompaniments


In elderly persons, a stereotypical series of prodromelike symptoms may entirely replace the migrainous episode; this is termed late-life migrainous accompaniments. If the headache is always on one side, a structural lesion needs to be excluded using imaging studies. Eliciting a history of recurrent typical attacks and determining the provoking agent are important because a secondary headache can mimic migraine. A new headache, even if it appears typical on the basis of its history, should always suggest a broad differential diagnosis and the possibility of a secondary headache.

Basilar-type and hemiplegic migraine


Patients with basilar-type migraine can present without headaches but with basilar-type symptoms, such as the following: Vertigo Dizziness Confusion Dysarthria Tingling of extremities Incoordination

Hemiplegic migraine is a very rare migraine variant in which headaches are associated with temporary, unilateral hemiparesis or hemiplegia, at times accompanied by ipsilateral numbness or tingling, with or without a speech disturbance. The focal neurologic deficit may precede or accompany the headache, which is usually less dramatic than the motor deficit. Other migraine symptoms may variably be present. Patients may also experience disturbance of consciousness, and (rarely) coma

Ophthalmoplegic and retinal migraine


Ophthalmoplegic migraine Ophthalmoplegic migraine is characterized by transient palsies of the extraocular muscle with dilated pupils and eye pain. This migraine variant has been reclassified by the International Headache Society as a neuralgia and is thought to be caused by idiopathic inflammatory neuritis. In the acute phase, enhancement of the cisternal segment of the third cranial nerve occurs. Retinal migraine Rarely, patients develop retinal and optic nerve involvement during or before a migraine headache and present with visual disturbance, papilledema, and retinal hemorrhages affecting 1 eye. This variant is called retinal migraine or ocular migraine. The International Headache Society criteria for retinal migraine[64] are at least 2 attacks of fully reversible, monocular visual phenomena, positive and/or negative (eg, scintillations, scotomata, or blindness). These are to be confirmed by examination during an attack or (after proper instruction) by the patient's drawing of a monocular field defect during an attack. In addition, migraine without aura must begin during the visual symptoms or follow them within 60 minutes. The patient must have a normal ophthalmologic examination between attacks. Other causes of transient, monocular blindness must be excluded with appropriate investigations.

Status migrainosus and chronic migraine


Status migrainosus occurs when the migraine attack persists for more than 72 hours. It may result in complications such as dehydration. Chronic migraine is defined as migraine headache that occurs for more than 15 days a month for greater than 3 months. Most patients with chronic migraine have a history of migraine headaches that started at a young age. Associated symptoms of nausea, vomiting, photophobia, and phonophobia may be less frequent.

Comorbidities of Migraine
Migraine is associated with the following: Epilepsy (eg, benign rolandic epilepsy, benign childhood epilepsy) Familial dyslipoproteinemias Hereditary hemorrhagic telangiectasia Tourette syndrome Hereditary essential tremor Hereditary cerebral amyloid angiopathy Ischemic stroke (migraine with aura is a risk factor, with an odds ratio of 6) Depression and anxiety Asthma Patent foramen ovale Obesity Posttraumatic stress disorder

Epilepsy increases the relative risk of migraine by 2.4. A Danish study found that migraine occurs in 2030% of patients with several medical conditions, including kidney stone, psoriasis, rheumatoid arthritis, and fibromyalgia.[65] Migraine with aura had more comorbidities than migraine without aura.

Complications of Migraine
Complications of migraine include the following: Chronic migraine Migraine-triggered seizures Migrainous infarction (stroke with migraine) Persistent aura (eg, 30-60 minutes) without infarction Ischemic stroke may occur as a rare, but serious, complication of migraine.[66] In migraines with aura, hemorrhagic stroke is also a possible, but rare, complication.[67] Risk factors for stroke include the following: Migraine with aura Female sex Cigarette smoking Estrogen use

DIAGNOSTIC CONSIDERATION
When headache is episodic and recurrent and follows a well-established pattern, the patient likely has a primary headache disorder (ie, headaches with no organic or structural etiology). Differentiating migraine from other primary headaches (eg, muscle contraction tension headache, cluster headache) is important, as optimal treatment may differ. Migraine may also may simulate or be simulated by secondary headache disorders or coexist with a secondary headache disorder. Any of the following features suggest a secondary headache disorder and warrant further investigation: The first or worst headache of the patient's life, especially if rapid in onset A change in frequency, severity, or clinical features of the attack New progressive headache that persists for days Precipitation of headache with Valsalva maneuvers (ie, coughing, sneezing, bearing down) The presence of associated neurologic signs or symptoms (eg, diplopia, loss of sensation, weakness, ataxia) Onset of headaches after the age of 55 years Headache developing after head injury or major trauma Persistent, 1-sided throbbing headaches Headache accompanied by stiff neck or fever Atypical history or unusual character that does not fulfill the criteria for migraine Inadequate response to optimal therapy Crash migraine Severe headache of sudden onset is a concern despite its occurrence in primary headache disorders. Migraine headaches may have an abrupt onset; these are termed "crash" migraine headaches and are similar to a "thunderclap" headache. Cluster headache also may be sudden and excruciating, but it lasts only 15-180 minutes and is recognized easily if the patient has had previous attacks. Exertional headache Exertional headaches are precipitated by strenuous activity (eg, running, coughing, sneezing, Valsalva maneuver) and build in intensity over minutes. They are particularly common in patients who have an

inherited susceptibility to migraine. Coital headache is a type of exertional headache that can develop at the height of orgasm or it may build up through intercourse. Intracranial aneurysm Despite the possibility of a benign cause, a ruptured intracranial aneurysm is the primary consideration if the headache is severe and of sudden onset and reaches maximum intensity in minutes. The classic presentation of an aneurysmal subarachnoid hemorrhage (SAH) is as follows: Severe headache with sudden, explosive onset Stiff neck Photophobia Nausea and vomiting Possibly, alteration of consciousness An extensive evaluation is indicated in such cases, including an initial computed tomography (CT) scan of the head without contrast. Lumbar puncture (LP) should be considered if the scan is negative, as 25% of cases are missed by CT scanning. Questions remain over whether an angiogram should be performed if the patient has normal findings on neurologic and cerebrospinal fluid (CSF) examination, as well as on CT scan or MRI. In one study, acute, severe thunderclap headache comparable to that of SAH without the nuchal rigidity occurred in 6.3% of patients with unruptured aneurysm. Other studies have revealed that in patients with severe thunderclap headache with normal CT-scan and CSF findings, none developed SAH.[68] In selected cases, angiography should probably be performed if an experienced angiographer is available. Patients at risk include those whose CT scan and LP are performed late after symptom onset, so that negative results are unreliable, and patients with suggestive clinical features, such as family history or past medical history of SAH, classic SAH-like symptoms, or the presence of neurologic signs (in particular a third cranial nerve palsy affecting the pupil) In patients with unrevealing studies in whom the diagnosis of aneurysmal SAH is possible but very unlikely, MRI and magnetic resonance angiography (MRA) are screening tests. Close follow-up is appropriate if the findings of these tests are negative. Space-occupying lesion Another concern is the possibility of a space-occupying lesion mimicking migraine. In a series of 111 patients with primary (34%) or metastatic (66%) brain tumor, headache was reported in 48%; the headache had characteristics similar to migraine in 9% and to tension-type headache in 77%, while the so-called classic early morning brain tumor headache occurred in only 17%. Headache was intermittent in 62%, usually lasting a few hours.[69] All patients with headaches similar to migraine had other neurologic symptoms or abnormal signs. Of note is that 32% of the patients had a history of headache; in 36% of those patients, the headache was of identical character to prior headaches but was more severe or frequent and was associated with other symptoms, such as seizures, confusion, prolonged nausea, and hemiparesis. [69] These data indicate that patients with a history of headache should have further diagnostic workup if the headache is accompanied by new symptoms or abnormal signs or differs in any way from their usual headache. With new-onset headache, imaging should be obtained if headache is severe or occurs with nausea, vomiting, or abnormal signs. Other space-occupying lesions must be considered in the appropriate clinical setting. Large intraparenchymal hemorrhage presents dramatically with headache and neurologic symptoms or signs shortly after onset. Of patients with chronic, subacute, or acute subdural hematoma, 81%, 53%, and 11%, respectively, have headaches. In brain abscesses, a progressive, severe, intractable headache is common, and headache is reported in 70-90% of patients.

Cerebral venous thrombosis Cerebral venous thrombosis involves the sagittal sinus in about 70% of cases; these patients present with signs and symptoms of increased intracranial pressure (ICP), such as headache and papilledema. Should the thrombus extend to the superficial cortical veins, then focal findings may be noted. In the appropriate setting with known risk factors, cerebral venous thrombosis must be considered, with the patient evaluated with MRI, MRA, or magnetic resonance venography (MRV). Spontaneous internal carotid artery dissection Spontaneous internal carotid artery dissection is an uncommon cause of headache and acute neurologic deficit, but it must be considered in younger patients who have unilateral, severe, persistent head pain of sudden onset preceding the development of neurologic signs, most commonly Horner syndrome. This differentiates spontaneous from posttraumatic cases, in which cerebral ischemic symptoms are more common. Other secondary causes Other secondary causes of alarming headaches should be sought, in the proper clinical setting, in the presence of the "red flags" mentioned above. Increased ICP may result from colloid cysts, ventricular tumors (such as ependymomas), or Chiari malformations. Other features needing further diagnostic workup include positional headaches, which may result from low CSF pressure. Headaches after age 50 years must be investigated to consider temporal or giant cell arteritis. Headaches associated with systemic disease require consideration of infectious and noninfectious inflammatory processes. Bear in mind that response to 5-hydroxytryptamine1 (5-HT1) agonists (sumatriptan and related compounds) is not diagnostic of a migraine headache. Because of their ability to block expression of c-fos by their action on 5-HT1 receptors, these agents may be effective in decreasing headache pain associated with meningovascular irritation from a variety of causes, such as viral and bacterial infections and subarachnoid hemorrhage.

Differential Diagnoses
Cerebral Aneurysms Chronic Paroxysmal Hemicrania Cluster Headache Dissection Syndromes Herpes Simplex Encephalitis Intracranial Hemorrhage Muscle Contraction Tension Headache Temporal/Giant Cell Arteritis Tolosa-Hunt Syndrome Viral Meningitis

Approach Considerations
Migraine is a clinical diagnosis. Diagnostic investigations are performed for the following reasons: Exclude structural, metabolic, and other causes of headache that can mimic or coexist with migraine Rule out comorbid diseases that could complicate headache and its treatment Establish a baseline for treatment and exclude contraindications to drug administration Measure drug levels to determine compliance, absorption, or medication overdose The choice of laboratory and/or imaging studies is determined by the individual presentation. For example, in an older person with compatible findings (eg, scalp tenderness), measurement of erythrocyte

sedimentation rate (ESR) and C-reactive protein (CRP) may be appropriate to rule out temporal/giant cell arteritis. Visual field testing should be performed in patients with persistent visual phenomena. The development of an objective, quantitative biologic measurement of headache-pain severity could help to improve the diagnosis of migraine and enable more accurate assessments of treatment efficacy. In a study by Nguyen et al, as previously mentioned, quantitative sensory testing found significant differences in the perception of vibrotactile stimulation in patients with migraine compared with controls, including stimulus amplitude discrimination, temporal order judgment, and duration discrimination.[51]

Insurance status and migraine care


A study by Wilper et al found that insurance status affects migraine care in the United States. After controlling for age, gender, race, and geographic location, the investigators found evidence that patients with migraines with no insurance or with Medicaid are less likely than privately insured patients to receive either abortive or prophylactic migraine therapy. This difference, according to the report, is at least partially due to the fact that persons who are uninsured or on Medicaid receive more medical care in emergency departments and less treatment in physicians offices than do persons with private insurance, resulting in a greater frequency of substandard migraine care.[70]

Indications for Neuroimaging


Neuroimaging is not necessary in patients with a history of recurrent migraine headaches and a normal neurologic examination. Neuroimaging is indicated for any of the following[71] : First or worst severe headache Change in the pattern of previous migraine Abnormal neurologic examination Onset of migraine after age 50 years New onset of headache in an immunocompromised patient (eg, one with cancer or HIV infection) Headache with fever Migraine and epilepsy New daily, persistent headache Escalation of headache frequency/intensity in the absence of medication overuse headache Posteriorly located headaches (especially in children, but also in adults) CT scanning of the head is indicated to rule out intracranial mass or hemorrhage in selected or atypical cases. A negative CT scan may miss some small subarachnoid hemorrhages, tumors, and strokes, particularly those in the posterior fossa. A CT scan without intravenous contrast also may miss some aneurysms. MRI and MRA are more sensitive for the detection of aneurysm or arteriovenous malformation.

Lumbar Puncture Indications


Indications for LP include the following: First or worst headache of a patient's life Severe, rapid-onset, recurrent headache Progressive headache Unresponsive, chronic, intractable headache Neuroimaging (CT or MRI scan) should precede LP to rule out a mass lesion and/or increased intracranial pressure.

Approach Considerations
Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable. Acute treatment aims to reverse, or at least stop, the progression of a headache that has started. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of the migraine attack, make acute attacks more responsive to abortive therapy, and perhaps also improve the patient's quality of life. An overview of migraine treatment is shown in the image below.

Overview of migraine treatment. Five steps.

Migraineurs should be screened for cardiovascular risk factors, which, if present, should be aggressively treated. Migraineurs with aura should also be counseled on the increased risk of stroke with smoking and oral contraceptive use. A neurologist, neuro-ophthalmologist, and/or neurosurgeon should be consulted as deemed clinically appropriate for the treatment of patients with migraine.

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